Issuu

Volume 12.1 August 2026 emjreviews.com

Reproductive Health

Review of

ESHRE 2026

Interviews:

Editor’s Pick:

ESHRE Chair-Elect, Feki Anis, and ESHRE Immediate Past Chair, Karen Sermon, discuss the latest in reproductive medicine

Endometrial immune profile in primary infertility

Contents Editorial Board 04

Foreword 09

Justin Chu Medical Director, Oxford Fertility, UK; Honorary Consultant Obstetrician and Gynaecologist Sub-specialist in Reproductive Medicine and Surgery, Birmingham, UK

Congress Review

Welcome 07

Congress Review of the European Society of Human 10 Review Reproduction and Embryology (ESHRE) Annual Meeting 2026, 5th–9th July

Congress Features Pregnancy Loss: Beyond 23 Recurrent Euploid Embryo Transfer and Towards Equitable Early Pregnancy Care Sofieva A

in a Name? 29 What’s Why PCOS is Becoming PMOS Fouarge N

in Embryology: Expanding 33 AI Beyond Embryo Selection Nicholson J

Abstract Reviews to Early Fertility 38 Barriers Consultation in Women with PMOS: A Questionnaire-Based Survey Agrawal R

Dissolved Oxygen Profiling 40 Intrauterine During the Luteal Phase: A Feasibility Study in Healthy Women

Troyano AT et al.

Desire: The Rise of AI Relationships 43 Digital and Techno-Intimacy – Impact on Fertility Intentions, Future Reproduction, Family Building, and Mental Health Grace B et al.

a Machine Learning Model to 45 Validating Predict Live Birth After Vitrified Donor Oocyte IVF

Pataia V et al.

Administration Before Frozen 47 Atosiban Embryo Transfer is Associated with Higher Clinical Pregnancy Rates: A Randomised Controlled Trial Nayar KD et al.

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Find out more about our Reproductive Health content

Perinatal Outcomes of Piezo-ICSI Versus IVF Following Vitrified-Warmed Single Blastocyst Transfer: A Retrospective Cohort Study

98 Spotlight from Europe

Hiraoka K and Kawai K

From Evidence to Impact: Translating Research on Quality of Life, Wellbeing, and Spirituality into Person-Centred Fertility Care Bernet M et al.

Articles Endometrial Immune Environment 111 The in Women with Primary Infertility: Prospective Cohort Study

Role of the Exposome and Lifestyle 53 The in Live Birth Outcomes Among Lebanese Patients Undergoing IVF Mrad M et al.

Burac M

Epitranscriptomic Landscape 120 The in Early Mammalian Embryonic Development: A Narrative Review

Embryological and Implantation 56 Preliminary Outcomes of Progesterone Versus GnRH

Antagonist for LH Suppression in IVF Cycles Aslanova R et al.

Bresson SE et al.

Assisted Reproductive Technologies 134 The Conceived Pregnancy: Pathophysiology, Risks, and Evolving Concepts Karakaya H and Akarsu GD

Congress Interviews

Preterm Birth Associated with 141 Early a Different Inflammatory Pattern

58 Anis Feki 62 Karen Sermon 64 Georg Griesinger 68 Maribel Acién 70 Borut Kovačič

than Late Preterm Birth Juárez-Reyes AG et al.

Little Fighter: Overcoming Severe 150 The Fetal Anaemia through 10 Intrauterine Blood Transfusions – A Case Report Asfaw TG et al.

and Fetal Outcome of COVID157 Maternal 19-Positive Antenatal Women Treated

with Monoclonal Antibody (Casirivimab and Imdevimab) in a Tertiary Care Centre: An Observational Cohort Study

Interviews 73 Joyce Harper

Vinodh SL et al.

in an Unscarred Uterus: A Rare 166 Rupture but Catastrophic Obstetric Emergency

78 Andrew Horne 85 Itunu Johnson-Sogbetun

Mitra P et al.

Cytology in Women 172 Cervical with Chronic Kidney Disease

89 Karen Joash

Kirui W et al.

92 Vikram Talaulikar 95 Ertan Saridogan

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Editorial Board Editor-in-Chief Dr Justin Chu University of Birmingham, UK Medical Director, Oxford Fertility, UK; Honorary Consultant Obstetrician and Gynaecologist Sub-specialist in Reproductive Medicine and Surgery, Birmingham Women’s and Children’s NHS Foundation Trust, UK; Honorary Senior Lecturer, Institute of Metabolism and Systems Research, University of Birmingham, UK

Prof Petya Andreeva

Dr Kristo Ausmees

Shterev Hospital, Bulgaria

Medita Clinic, Estonia

Dr Mátyás Benyó University of Debrecen, Hungary

Dr Melihan Bechir

Dr Antonio Simone Laganà

Columna Medical Center, Romania

University of Palermo, Italy

Dr Ioana Rugescu Safety and Quality Specialist, Romania

Dr Arianna D'Angelo

Prof Eduard Ruiz-Castañé

Wales Fertility Institute, Cardiff, UK

Fundació Puigvert, Spain

Dr Georgios-Sprirodon (George) Anifandis University of Thessaly, Greece

Dr Monica Muratori

Prof Felice Petraglia

University of Florence, Italy

Careggi University Hospital, Florence, Italy

Prof Joyce Harper University College London, UK

Dr Galia Oron

Prof Peter Chedruai

University of Santiago de Guayaquil, Ecuadar

Ruth & Bruce Faculty of Medicine, Haifa, Israel

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Aims and Scope EMJ Reproductive Health is an open-access, peer-reviewed eJournal committed to helping elevate the quality of practices in reproductive health globally by informing healthcare professionals on the latest research in the field. EMJ Reproductive Health endeavours to increase knowledge, stimulate discussion, and contribute to a better understanding of current issues around reproductive health. The journal is published annually, six weeks after the European Society of Human Reproduction and Embryology (ESHRE) Annual Meeting, and features highlights from this congress, alongside interviews with experts in the field, reviews of abstracts presented at the congress, as well as in-depth features on congress sessions. Additionally, the journal covers advances within the clinical and pharmaceutical arenas by publishing sponsored content from congress symposia, which is of high educational value for healthcare professionals. This undergoes rigorous quality control checks by independent experts and the in-house editorial team. EMJ Reproductive Health also publishes peer-reviewed research papers, review articles, and case reports relevant to the field. In addition, the journal welcomes the submission of features and opinion pieces intended to create a discussion around key topics in the field and broaden readers’ professional interests. The journal is managed by a dedicated editorial team that adheres to a rigorous double-blind peer-review process, maintains high standards of copy editing, and ensures timely publication. EMJ Reproductive Health focuses on topics that are relevant to healthcare professionals in the field. We do not publish veterinary science papers or laboratory studies that are not linked to patient outcomes. We have a particular interest in topical studies that advance knowledge and inform of coming trends affecting clinical practice in the field. Further details on coverage can be found here: www.emjreviews.com Editorial Expertise EMJ is supported by various levels of expertise: • • • •

Guidance from an Editorial Board consisting of leading authorities from a wide variety of disciplines. Invited contributors who are recognised authorities in their respective fields. Peer review, which is conducted by expert reviewers who are invited by the Editorial team and appointed based on their knowledge of a specific topic. An experienced team of editors and technical editors.

Peer Review On submission, all articles are assessed by the editorial team to determine their suitability for the journal and appropriateness for peer review. Editorial staff, following consultation with either a member of the Editorial Board or the author(s) if necessary, identify three appropriate reviewers, who are selected based on their specialist knowledge in the relevant area. All peer review is double blind. Following review, papers are either accepted without modification, returned to the author(s) to incorporate required changes, or rejected.

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Editorial staff have final discretion over any proposed amendments. Submissions We welcome contributions from professionals, consultants, academics, and industry leaders on relevant and topical subjects. We seek papers with the most current, interesting, and relevant information in each therapeutic area and accept original research, review articles, case reports, and features. We are always keen to hear from healthcare professionals wishing to discuss potential submissions, please email: editorial.assistant@emjreviews.com To submit a paper, use our online submission site: https://emj.kriyadocs.com/submissions/submit/emj/emj/login Submission details can be found through our website: www.emjreviews.com/contributors/authors Reprints All articles included in EMJ are available as reprints (minimum order 1,000). Please contact hello@emjreviews.com if you would like to order reprints. Distribution and Readership EMJ is distributed through controlled circulation to healthcare professionals in the relevant fields across Europe. Indexing and Availability EMJ is indexed on DOAJ, the Royal Society of Medicine, and Google Scholar®; selected articles are indexed in PubMed Central®. EMJ is available through the websites of our leading partners and collaborating societies. EMJ journals are all available via our website: www.emjreviews.com Open Access This is an open-access journal in accordance with the Creative Commons Attribution-Non Commercial 4.0 (CC BY-NC 4.0) license. Congress Notice Staff members attend medical congresses as reporters when required. This Publication Launch Date: 2015 Frequency: Yearly Online ISSN: 2059-450X All information obtained by EMJ and each of the contributions from various sources is as current and accurate as possible. However, due to human or mechanical errors, EMJ and the contributors cannot guarantee the accuracy, adequacy, or completeness of any information, and cannot be held responsible for any errors or omissions. EMJ is completely independent of the review event (ESHRE 2026) and the use of the organisations does not constitute endorsement or media partnership in any form whatsoever. The cover photo is of London, UK, the location of ESHRE 2026. Front cover and contents photograph: Digitally enhanced image © Iakov Kalinin / stock.adobe.com

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Stay at the Forefront of Modern Medicine High-level perspectives. Global experts. Essential updates. Join us for conversations with the minds shaping healthcare's future. Gain the distilled insights you need to lead in your field and make maximum impact.

Jonathan Sackier:

Non Executive Director & CMO, AiM Medical Robotics, Florida, USA

Saranya Ravindran:

Paediatric Emergency Medicine Registrar, Imperial College Healthcare NHS Trust

Catherine Glass: Associate NHS GP and Senior Appraiser, NHS England

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Welcome Editorial Director Andrea Charles Editor Sean Boyle Managing Editor Darcy Richards Associate Editor Helena Bradbury Senior Copy Editor Noémie Fouarge Copy Editors Meghan Garcka, Lizzie Green, Sarah Jahncke Editorial Leads Katrina Thornber, Aleksandra Zurowska Senior Editorial Co-ordinator Bertie Pearcey Editorial Co-ordinators Jess Nicholson, Alena Sofieva Editorial Assistants Niamh Holmes, Josh Lister, Nonyelum Okonkwo, Roli Omamuli Creative Director Tim Uden Design Manager Stacey White Senior Designers Tamara Kondolomo, Owen Silcox Designers Shanjok Gurung, Fabio van Paris Junior Designers Fraser Hoey, Cameron Levett, Helena Spicer, Caleb Wylie Marketing Director Stephanie Corbett Business Unit Lead Kelly Byrne Chief Executive Officer Justin Levett

Dear Readers, I am delighted to welcome you to the 2026 issue of EMJ Reproductive Health, which features coverage of the latest advances presented at this year's European Society of Human Reproduction and Embryology (ESHRE) Congress, held in London, UK. Marking 150 years since the discovery of fertilisation, this year's meeting brought together experts from around the world to discuss developments across assisted reproduction, reproductive genetics, embryology, fertility preservation, and reproductive surgery. Throughout the Congress, speakers emphasised the importance of ensuring that innovation is supported by robust clinical evidence, quality assurance, and patient-centred care. Alongside our congress review, you will find features exploring the evolution of IVF, the future of women's reproductive health, and the changing landscape of fertility care. This issue also includes several abstract reviews, highlighting research on recurrent pregnancy loss, embryo culture media, reproductive genetics, ovarian ageing, endometriosis, and AI in reproductive medicine. Be sure not to miss our exclusive interviews with ESHRE leaders, as well as internationally recognised experts in reproductive genetics, fertility education, endometriosis, and assisted reproduction. Our peer-reviewed content includes original research spanning fertility, embryology, reproductive immunology, obstetrics, and maternal medicine, reflecting the breadth and multidisciplinary nature of modern reproductive healthcare. I would like to take this opportunity to thank our Editorial Board, the authors, peer reviewers, and interviewees for their support and key contributions to this issue. I hope that you find this issue engaging and informative, and that you enjoy reading! Alena Sofieva Editorial Co-ordinator

Contact us Editorial enquiries: editor@emjreviews.com Sales opportunities: salesadmin@emjreviews.com Permissions and copyright: accountsreceivable@emjreviews.com Reprints: info@emjreviews.com Media enquiries: marketing@emjreviews.com

Chief Commercial Officer Dan Healy Founder and Chairman Spencer Gore CC BY-NC 4.0 Licence

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Foreword It is my great pleasure to welcome you to EMJ Reproductive Health 12.1, an edition highlighting the latest advances across reproductive medicine and women's health. This issue brings together high-quality peer-reviewed research, exclusive interviews with internationally renowned experts, and comprehensive coverage of the European Society of Human Reproduction and Embryology (ESHRE) Congress 2026, held in London, UK. This year's ESHRE Congress showcased major developments in assisted reproduction, reproductive genetics, embryology, and fertility care. Throughout this issue, we highlight key scientific advances presented at the Congress and their implications for clinical practice. A particular highlight of this edition is our exclusive interview series with 10 internationally recognised key opinion leaders. Among them are Joyce Harper, discussing the future of fertility education; Andrew Horne, sharing the latest advances in endometriosis research; and ESHRE leaders Karen Sermon, Georg Griesinger, and Anis Feki, who provide expert perspectives on reproductive genetics, IVF innovation, and the future direction of reproductive medicine.

A particular highlight of this edition is our exclusive interview series with 10 internationally recognised key opinion leaders

Complementing our Congress coverage are eight original articles spanning obstetrics, fertility, reproductive immunology, embryology, and maternal medicine, reflecting the breadth and multidisciplinary nature of modern reproductive healthcare. Finally, I would like to sincerely thank our authors, peer reviewers, interviewees, and the EMJ Reproductive Health Editorial Board for their continued expertise and support. I hope you find this edition informative and inspiring.

Justin Chu Medical Director, Oxford Fertility; Honorary Consultant Obstetrician and Gynaecologist Sub-specialist in Reproductive Medicine and Surgery, Birmingham Women’s and Children’s NHS Foundation Trust; Honorary Senior Lecturer, Institute of Metabolism and Systems Research, University of Birmingham, UK

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Congress Review

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ESHRE 2026

ESHRE 2026 Our top six highlights include...

pg 20

4 10

Modern IVF with mainly single embryo transfer achieved cumulative live birth rates of up to 68%, while reducing multiple births to 2.9%.

A novel single-sperm assay outperformed conventional semen analysis, improving male infertility diagnosis. pg 16

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Halving out-of-po treatment costs c triple ART births, affordability as a to care. pg 15

Hospital admissio miscarriage and e pregnancy have r England since CO persistent inequa pg 19

ESHRE 2026

ocket fertility could almost , highlighting major barrier

ons for ectopic risen in OVID-19, with alities.

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Scientific progress is driven not only by discovery, but also by ethical leadership, collaboration, and sustained commitment to the field

Donor eggs may not fully overcome uterine ageing, with women aged ≥49 years experiencing lower live birth rates and higher miscarriage rates. pg 14

Rare genetic variants were found in nearly 70% of people with unexplained infertility, supporting genomic testing. pg 21 Insights from ESHRE 2026

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Congress Introduction

Congress Review

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Congress Review Review of the European Society of Human Reproduction and Embryology (ESHRE) Annual Meeting 2026 Location:

London, UK

Date:

5th–9th July 2026

Citation:

EMJ Repro Health. 2026;12[1]:10-22. https://doi.org/10.33590/emjreprohealth/L6D1U5OZ

THE EUROPEAN Society of Human Reproduction and Embryology (ESHRE) returned to London, UK, this year for its 42nd Annual Meeting, bringing together more than 12,800 delegates from 134 countries for 5 days of cutting-edge science, education, and international collaboration. Hosted at ExCeL London, the congress marked ESHRE's fourth meeting in the UK, following previous congresses in Cambridge, Edinburgh, and London, reflecting the region's longstanding contribution to reproductive medicine. Opening the meeting, ESHRE Chair Anis Feki drew inspiration from London's scientific heritage, encouraging delegates to embrace the Royal Society's motto, Nullius in verba (‘take nobody's word for it’) by questioning evidence, challenging assumptions, and engaging in thoughtful scientific debate throughout the congress.

CELEBRATING A LANDMARK YEAR The congress coincided with several important milestones for reproductive medicine. In 2026, ESHRE celebrated 150 years since the discovery of fertilisation, recognising the extraordinary progress made by the field while looking ahead to its future. Delegates also witnessed the renaming of the ESHRE Nurses Award to the Jean Purdy Nurses Award, honouring the pioneering embryologist and research nurse whose work was instrumental to the birth of IVF and acknowledging the essential contribution of nurses and midwives to reproductive healthcare.

ESHRE BY THE NUMBERS The scale of ESHRE 2026 reflected the continued growth of both the society and 12

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the specialty. More than 12,800 delegates attended from 134 countries, while a record 2,750 abstracts were submitted across 40 scientific topics, representing the highest number in the congress's history. Throughout the meeting, ESHRE also showcased the breadth of its activities beyond the annual congress, from international data collection through the European IVF Monitoring Consortium and Preimplantation Genetic Testing Consortium to guideline development, certification and accreditation, research funding, and policy initiatives that continue to shape reproductive medicine across Europe.

HONOURING THE PEOPLE BEHIND THE PROGRESS A highlight of the Opening Ceremony was the recognition of individuals whose work has had a lasting impact on reproductive

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ESHRE 2026

medicine. Honorary membership was awarded to Françoise Shenfield, University College London, UK; and Guido Pennings, Ghent University, Belgium, for their lifelong contributions to reproductive ethics, while Bruno van den Eede was recognised for more than 40 years of service to ESHRE, having helped transform the society from a small scientific network into one of the world's leading organisations in reproductive medicine. Together, these tributes reflected the congress's broader message that scientific progress is driven not only by discovery, but also by ethical leadership, collaboration, and sustained commitment to the field.

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LOOKING AHEAD With an ambitious programme spanning embryo biology, reproductive genetics, fertility preservation, pregnancy loss, endometriosis, AI, ethics, and health policy, ESHRE 2026 set the stage for another year of scientific progress. A recurring message throughout the Opening Ceremony was that innovation alone is not enough; advances in reproductive medicine must continue to be underpinned by robust evidence, highquality data, and patient-centred care. That theme would resonate across the scientific sessions that followed.

Innovation alone is not enough; advances in reproductive medicine must continue to be underpinned by robust evidence, high-quality data, and patient-centred care

Congress highlights

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Donor Eggs Do Not Fully Offset the Effects of Uterine Ageing After 49 Years NEW RESEARCH presented at ESHRE 2026 suggests that age-related changes in the uterus may reduce the chances of a successful pregnancy even when donor eggs are used. The findings indicate that women aged 49 years and older have significantly lower live birth rates and higher miscarriage rates than younger recipients, highlighting the potential role of uterine ageing in reproductive success.1 While donor-oocyte treatment overcomes the age-related decline in egg quality, relatively little is known about how ageing of the uterus itself affects pregnancy outcomes. To investigate this, Crestani et al.1 analysed 2,760 single blastocyst transfers performed in 1,774 women who underwent donor-oocyte treatment between March 2021–December 2024. By using donor eggs, the researchers were able to largely isolate the effects of the uterine environment from those of oocyte ageing. Pregnancy outcomes were compared across four recipient age groups (35–40 years, 41–45 years, 46–49 years, and ≥49 years), with analyses adjusted for maternal, paternal, and embryo-related factors. The researchers assessed clinical pregnancy, live birth, miscarriage, cumulative live birth rates, and endometrial characteristics. The analysis identified 49 years as a clinically meaningful threshold after which reproductive outcomes declined. Clinical pregnancy rates fell from 54.0% in women aged 35–40 years to 42.6% in women aged 49 years and older. Live birth rates similarly decreased from 46.2% to 31.7%, while miscarriage rates increased from 24.2% to 37.6%. Compared with women aged 35–40 years, women aged 49 years and older had significantly lower odds of achieving a live birth and more than double the odds of 14

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miscarriage. Cumulative live birth rates also declined substantially, from 80.0% in the youngest group to 62.5% among women aged 49 years and older who transferred all available embryos. The study also demonstrated age-related changes in endometrial appearance. Although endometrial thickness remained similar across age groups, the proportion of women with a trilaminar endometrial pattern, a feature associated with optimal uterine receptivity, declined from 94.7% in women aged 35–40 years to 81.0% in those aged 49 years and older. These findings suggest that donor eggs cannot completely overcome the effects of reproductive ageing, with uterine factors appearing to play an increasingly important role beyond the age of 49 years. The authors note that women should continue to be counselled that donor-oocyte treatment remains an effective option, but that success rates may still be influenced by age-related changes within the uterus. The study is observational and cannot establish a direct causal relationship between uterine ageing and reproductive outcomes. The researchers also note that further studies are needed to investigate the biological mechanisms underlying uterine ageing, including vascular, immune, hormonal, and molecular changes, and to identify biomarkers that may better predict uterine biological age.

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Donor eggs cannot completely overcome the effects of reproductive ageing, with uterine factors appearing to play an increasingly important role beyond the age of 49

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Reducing Fertility Treatment Costs Could More Than Double ART Births HALVING out-of-pocket fertility treatment costs could increase births achieved through assisted reproductive technology (ART) by almost three-fold, according to an international study presented at ESHRE 2026.2 Cost remains one of the greatest barriers to accessing fertility treatment worldwide, yet the extent to which affordability influences ART use has not been comprehensively quantified. To address this, researchers analysed ART registry, economic, and demographic data from 22 countries and regions between 2021–2023, representing more than 95% of global ART activity. The team developed a novel ‘cost-to-baby’ metric, which estimates the total cost required to achieve one live birth through ART. The analysis incorporated treatment costs, medications, embryo transfer procedures, and financial support measures such as public reimbursement, subsidies, and tax benefits. Costs were expressed as a proportion of each country’s median aftertax household income. Affordability varied markedly across the world. Gross treatment costs ranged from 66% of median household income in Israel to 833% across much of Africa, while patients’ net out-of-pocket costs ranged from just 13% in Israel to 825% in African countries without substantial funding programmes.

large increases in treatment uptake, particularly in regions where financial barriers were greatest. Modelling suggested that halving patient costs could increase ART births by 2.67-fold.

Gross treatment costs ranged from

Lead author Stephanie Kuku, World Health Organization, said the findings demonstrate that affordability is a measurable determinant of access to fertility care and highlighted the importance of funding multiple treatment cycles rather than a single attempt. The authors also identified tax incentives, expanded public funding, workforce reforms, and improvements in clinical efficiency as potential strategies to reduce treatment costs.

of median household income in Israel to 833% across much of Africa

The findings suggest that improving affordability could substantially increase access to fertility treatment worldwide, providing policymakers with a practical benchmark for expanding equitable access to ART.

66%

Countries where out-of-pocket costs were below 50% of annual household income consistently recorded the highest ART utilisation. South Korea and Spain each reported that more than 11% of all births resulted from ART, while Japan reported 9.3%. In contrast, ART accounted for only 0.2–0.4% of births in regions including Brazil, India, and Southeast Asia, where treatment costs were substantially higher relative to household income. The researchers found that affordability explained between 77% and 84% of the variation in ART use across countries. Importantly, the relationship was not linear: reducing costs produced disproportionately CC BY-NC 4.0 Licence

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Multiplex Sperm Assay Improves Male Infertility Diagnosis MALE INFERTILITY diagnosis continues to rely heavily on conventional semen analysis, despite growing evidence that measures such as sperm concentration, motility, and morphology provide only limited information about sperm functional competence and reproductive potential.3 Emerging research suggests that mitochondrial dysfunction plays a central role in male infertility, yet clinically relevant functional biomarkers remain absent from routine diagnostic testing. A study presented at ESHRE 2026 investigated whether a multiplexed single-sperm functional assay integrating intracellular pH, senescence-associated β-galactosidase (β-gal) activity, and mitochondrial DNA G-quadruplex structures could improve infertility diagnosis and support targeted therapeutic discovery. The findings demonstrated significantly improved diagnostic accuracy compared with conventional semen analysis alone and identified two compounds with the potential to rescue sperm dysfunction. Researchers conducted a diagnostic test study using two independent clinical cohorts comprising 130 participants recruited between 2022–2026. The training cohort included 56 participants from one hospital, while the validation cohort included 74 participants from a second institution. Washed spermatozoa were simultaneously stained using three fluorescent probes targeting intracellular pH, β-gal activity, and mitochondrial G-quadruplex structures, allowing functional assessment at the single-cell level. Biomarker measurements were integrated with standard semen parameters to construct multivariate logistic regression models for infertility prediction. In parallel, sperm samples from infertile patients were exposed to a library of natural compounds in a high-throughput 96-well format to assess their effects on the identified biomarkers. 16

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The multiplexed assay quantified all three sperm functional biomarkers with high specificity and significantly improved diagnostic model performance. In the training cohort, the area under the receiver operating characteristic curve increased from 0.87 (95% CI: 0.79–0.96) using conventional semen parameters alone to 0.93 (95% CI: 0.87–0.99) when functional biomarkers were incorporated (p<0.001). This improvement was replicated in the external validation cohort, where the area under the curve increased from 0.82 (95% CI: 0.68–0.96) to 0.89 (95% CI: 0.79–0.98; p<0.01). Decision curve and calibration analyses further supported the enhanced clinical utility of the integrated model. High-throughput drug screening identified hydroxycamptothecin as a compound capable of significantly increasing sperm intracellular pH, while luteolin reduced both mitochondrial DNA G-quadruplex accumulation and β-gal activity. Functional validation studies in sperm samples from patients with asthenozoospermia demonstrated improvements in mitochondrial membrane potential following treatment with both compounds. In mouse models of sperm dysfunction, luteolin restored early embryonic metabolic profiles, while both compounds improved fertilisation and blastocyst formation rates using cryopreserved sperm.

Researchers conducted a diagnostic test study using two independent clinical cohorts comprising 130 participants recruited between 2022–2026

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These findings suggest that functional sperm biomarkers may provide clinically meaningful information beyond conventional semen analysis and could facilitate more personalised approaches to male infertility management. By combining diagnosis with therapeutic screening, the platform offers a translational pathway linking functional assessment to targeted intervention. Limitations include the moderate sample size, the inclusion of exclusively Chinese populations, and the ex vivo nature of the drug screening experiments. Further validation in larger, ethnically diverse populations and in vivo studies of therapeutic efficacy will be required before clinical implementation.

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Congress Review

Air Pollution Linked to Changes in Sperm Gene Regulation EXPOSURE to common outdoor air pollutants during sperm development has been linked to altered DNA methylation in a new secondary data analysis presented at ESHRE 2026.4 The findings add to growing evidence that environmental exposures may influence male reproductive health and highlight areas for further research into fertility, pregnancy outcomes, and offspring health. Air pollution has previously been associated with reduced semen quality and a range of cardiovascular, respiratory, and reproductive health effects. However, less is known about how exposure may affect sperm at the molecular level. DNA methylation is a chemical modification that regulates gene activity without changing the underlying DNA sequence, and alterations in this process may affect the function of genes involved in reproduction and early development. In this analysis, researchers examined samples from more than 2,000 men who participated in a study conducted in Salt Lake City, Utah, USA, between 2013–2017. Sperm DNA methylation was analysed in 1,220 men who provided samples after a 6-month follow-up. The investigators estimated participants’ exposure to outdoor ozone, nitrogen dioxide, sulphur dioxide, and fine particulate matter during spermatogenesis, the approximately 3-month period of sperm production. 39 DNA methylation changes associated with exposure to mixtures of air pollutants were identified, with ozone and nitrogen dioxide contributing most strongly. One notable finding involved altered methylation of the GNAS gene, an imprinted gene that has previously been associated with poorer semen quality and implicated in embryonic and fetal development. Because imprinted genes can remain active during early embryonic development, the researchers suggested that these findings raise questions about whether paternal environmental exposures could have implications beyond fertility, potentially influencing pregnancy and offspring health.

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It was noted that air pollution is a complex mixture that varies according to season and geographical location, with nitrogen dioxide and ozone commonly elevated in urban environments because of traffic emissions and natural gas combustion. As a result, the findings should be interpreted within the context of varying environmental exposures.

39 DNA methylation changes associated with exposure to mixtures of air pollutants were identified, with ozone and nitrogen dioxide contributing most strongly

The researchers emphasised that the study identified associations rather than cause-and-effect relationships and that replication in other populations will be important. Future studies will also need to determine whether air pollution-related changes in sperm DNA methylation have measurable downstream effects on male fertility, pregnancy outcomes, or child health, while also examining the potential contribution of indoor and personal air pollution exposure.

These findings raise questions about whether paternal environmental exposures could have implications beyond fertility, potentially influencing pregnancy and offspring health

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Geographical location and abstinence duration remained independently associated with semen parameters

Study Reveals Regional Differences in Sperm Quality Despite Similar Lifestyles NEW RESEARCH presented at ESHRE 2026 has found that men in Spain’s best-performing region had almost double the motile sperm count of those in the worst, despite similar lifestyles.5 Sperm quality has long been tied to habits like smoking, diet, and exercise, yet growing evidence points to geography too. This study set out to test whether marked regional differences in male fertility could be pinned on lifestyle and social factors, or whether something in the environment might be at play. The prospective multicentre study analysed semen quality and lifestyle data from 386 men undergoing fertility assessment at seven assisted reproduction centres across Spain between June 2024– December 2025. Participants completed a standardised questionnaire covering residence, BMI, medical history, physical activity, chemical exposure, medication, smoking, alcohol, drug, and coffee use. Researchers compared semen parameters across four regions (north, south, southeast, and central) to see whether geographical gaps in sperm quality reflected lifestyle or sociodemographic differences. 18

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Significant regional differences emerged in semen volume, sperm concentration, motility, morphology, and total motile sperm count. Men in northern Spain had the strongest results, averaging a total motile sperm count of 94.35 million against 50.11 million in central Spain. The north also led on sperm concentration (80.96 million/mL) and motility (44.79%). Reduced motility affected 23.9% of northern men, compared with 55.4% in the south and 53.4% in central Spain. Lifestyle patterns, however, were broadly similar across regions. After adjustment for all measured lifestyle and socio-demographic factors, only geographical location and abstinence duration remained independently associated with semen parameters. The findings suggest that environmental exposures such as pollution or contaminants may drive the differences, warranting larger studies and stronger policies to limit pollutants.

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Men in northern Spain had the strongest results, averaging a total motile sperm count of 94.35 million

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Miscarriage and Ectopic Pregnancy Admissions Rise as Inequalities Persist HOSPITAL admissions for miscarriage and ectopic pregnancy have increased in England in recent years, according to research presented at ESHRE 2026. The nationwide study also found persistent socioeconomic inequalities in early pregnancy complications that remained largely unchanged over the past two decades.6 Researchers analysed national hospital data from England between 2004–2024, including 786,984 miscarriage admissions, 211,727 ectopic pregnancy admissions, and more than 12.4 million deliveries. Miscarriage and ectopic pregnancy are among the most common early pregnancy complications, yet long-term national trends and changes in associated health inequalities have been poorly understood. Miscarriage admissions declined between 2010– 2018, falling from 45,232 to 37,398 annually (annual percent change [APC]: −2.06%), before declining more sharply between 2018–2021 (APC: −4.26%). However, admissions rose again after the COVID-19 pandemic, with 133,400 miscarriage admissions recorded between 2021–2024. A similar pattern was observed for ectopic pregnancy. Admissions increased significantly between 2005– 2012 (APC: +2.81%), remained relatively stable for several years, and then increased again from 2021–2024, during which 44,577 admissions were recorded (APC: +4.28%).

The analysis also highlighted marked socioeconomic disparities. During the most recent decade, miscarriage admissions were approximately 2.7-times higher among women living in the most deprived areas than among those in the least deprived (71,104 versus 26,414 admissions). Ectopic pregnancy admissions showed a similar pattern, with around 2.4-times more admissions in the most deprived compared with the least deprived areas (17,845 versus 7,580 admissions). The researchers suggest that the recent increase in admissions may reflect multiple factors, including changes in healthcare delivery during and after the COVID-19 pandemic, altered healthcare-seeking behaviour, increasing maternal age, rising obesity rates, and other reproductive health risk factors. They conclude that improving equitable access to high-quality early pregnancy care, strengthening Early Pregnancy Assessment Units, investing in preventive strategies, and prioritising research into pregnancy loss will be important for reducing inequalities and improving reproductive health outcomes.

The recent increase in admissions may reflect multiple factors, including changes in healthcare delivery during and after the COVID-19 pandemic

During the same period, the number of deliveries declined substantially, decreasing from 636,401 in 2017 to 545,149 in 2024 (APC: −2.26%).

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Single Embryo Transfer Associated with Improved IVF Outcomes in Modern Practice MODERN IVF treatment using predominantly single embryo transfer was associated with improved cumulative live birth rates while substantially reducing multiple births, according to a new study presented at the ESHRE Congress 2026.7 Historically, in studies carried out before the adoption of modern IVF techniques, three-cycle cumulative live birth rates were between 53–59%, while multiple pregnancy rates exceeded 20%. This study suggests that modern IVF techniques have substantially improved these outcomes.

The authors stated that these outcomes were likely a result of the widespread adoption and advancement of modern IVF techniques such as blastocyst culture, 20

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The highest cumulative live birth rate was 84.5%, observed in women younger than 35. In the remaining age brackets, outcomes were 74.4%, 57.7%, and 30.1% for women aged 35–37 years, 38–40 years, and 41–42 years respectively. Researchers also compared outcomes before and after modern IVF advancements introduced from 2016. These included single-step culture medium and time-lapse embryo culture. There were increases in fertilised eggs developing into usable blastocysts between 2012–2015 and 2017–2021 (48.3% to 57.6%) along with an increase in single embryo transfer (92.8% to 97%). Notably, multiple birth rate fell from 3.2% to 2.7% over the same period.

Researchers examined the outcomes from 18,396 women who underwent their first IVF cycle between January 2012– December 2021 across seven Australian fertility clinics, with follow-up through December 2023. Women underwent treatment using contemporary IVF protocols including extended blastocyst culture, embryo vitrification, and elective freeze-all strategies where appropriate. Cumulative live birth rate over three treatment cycles was 68.2% using optimal per-protocol analysis and 58.7% using intention-to-treat analysis. This was achieved while using a single embryo transfer in 95.3% of embryo transfers and maintaining a multiple birth rate of 2.9%.

embryo vitrification, freeze-all strategies, and optimised frozen embryo transfer protocols. However, success rates varied considerably by maternal age.

Results also suggested that strong outcomes could still be achieved when preimplantation genetic testing for aneuploidy was not performed. There were increases in fertilised eggs developing into usable blastocysts between 2012– 2015 and 2017– 2021 (48.3% to 57.6%) along with an increase in single embryo transfer (92.8% to 97%)

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Overall, the findings suggest that contemporary IVF protocols incorporating single embryo transfer can achieve higher cumulative live birth rates, while substantially reducing multiple births. These findings suggest that modern IVF approaches can achieve high cumulative live birth rates without routinely transferring multiple embryos and may support a safer and more cost-effective route to parenthood.

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Unexplained Infertility Linked to Rare Gene Variants Unexplained infertility may have a substantial genetic basis, according to research presented at ESHRE 2026.8 Unexplained infertility is typically diagnosed once standard clinical investigations have excluded ovulatory, anatomical, endocrine, and male factor causes. Researchers sought to determine whether people with unexplained infertility carry rare variants in genes previously implicated in oocyte dysfunction or early embryonic developmental defects. The study combined a systematic literature review and validated gene-disease assessment, with whole exome sequencing, in a multicentre cohort recruited between July 2021–March 2023. The researchers identified 84 candidate genes associated with oocyte and early embryo competency, among 979 participants with unexplained infertility. Of these, 36 were classified as having strong evidence and 17 as having moderate evidence supporting a gene-disease relationship.

Analysis of clinical outcomes demonstrated that participants carrying any loss of function variant had lower oocyte maturity rates (74.6%) compared with non-carriers (80.6%). However, no differences were observed in fertilisation, blastocyst development, clinical pregnancy, or live birth rates between variant carriers and non-carriers.

No differences were observed in fertilisation, blastocyst development, clinical pregnancy, or live birth rates between variant carriers and non-carriers

Genes with strong or moderate evidence were clustered within biologically relevant pathways, such as DNA damage response pathways involving BRCA1, BRCA2, MLH3, and CHEK1. Among the 979 participants studied, researchers detected 747 rare variants with a minor allele frequency below 1% across 52 of 53 genes with strong or moderate evidence. Overall, 678 participants (69.3%) carried at least one variant and 329 (33.6%) carried multiple variants. CC BY-NC 4.0 Licence

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The authors noted several limitations, including uncertainty surrounding the pathogenicity of many missense variants, the predominance of monoallelic findings, unavailable male partner genotypes, and the possibility of unrecognised endometriosis.

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Despite these limitations, the findings provide a systematically curated genomic framework for unexplained infertility and suggest that a condition traditionally regarded as a diagnosis of exclusion may, in many cases, have an underlying genetic contribution. The study’s findings may be used to inform future diagnostic panels, genetic counselling, mechanistic studies, and precision, individualised fertility care.

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References 1.

Crestani B et al. Advanced maternal age independently affects live birth and increases miscarriage risk in donor oocyte cycles. Abstract deag083.021. ESHRE Annual Meeting, 5-8 July, 2026. Kuku S et al. Cost-to-baby as a percentage of median household income predicts population-level access to assisted reproductive technology (ART): a global health economics analysis of affordability. Abstract deag083.216. ESHRE Annual Meeting, 5-8 July, 2026.

Nobles C. Air pollution may alter how sperm genes function, major fertility study finds. Presentation. ESHRE Annual Meeting, 5-8 July, 2026.

Núñez-Calonge R et al. Does male lifestyle influence geographical differences in sperm parameters? Abstract deag083.204. ESHRE Annual Meeting, 5-8 July, 2026.

Wu S et al. A multiplexed single-sperm functional assay improves diagnostic accuracy and enables targeted compound screening in male infertility. Abstract deag083.318. ESHRE Annual Meeting, 5-8 July, 2026.

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Sekar S et al. Changing trends but persistent inequalities: a 20-year joinpoint analysis of miscarriage and ectopic pregnancy admissions in England. Abstract deag083.274. ESHRE Annual Meeting, 5-8 July, 2026.

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Morbeck D et al. 2026. Modern IVF clinical practices achieve superior cumulative live birth rates with nearuniversal single embryo transfer: a multi-cycle cohort study. Abstract deag083.327. ESHRE Annual Meeting, 5-8 July, 2026.

Applebaum J et al. Systematic gene–disease assessment and whole exome sequencing in women with unexplained infertility. Abstract deag083.279. ESHRE Annual Meeting, 5-8 July, 2026.

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Recurrent Pregnancy Loss: Beyond Euploid Embryo Transfer and Towards Equitable Early Pregnancy Care Author:

Alena Sofieva, EMJ, London, UK

Citation:

EMJ Repro Health. 2026;12[1]:23-28. https://doi.org/10.33590/emjreprohealth/DO9QZP94

AT THE European Society of Human Reproduction and Embryology (ESHRE) Annual Meeting 2026, held in London, UK, Session 81, ‘Unravelling Pregnancy Loss: Maternal Age, Inflammation, Uterine Environment, and Therapeutic Innovations’, brought together experts to explore the complex biological, clinical, and healthcare factors contributing to pregnancy loss. The session examined recurrent pregnancy loss (RPL) from complementary perspectives, ranging from the role of embryo selection and reproductive technologies to national trends in pregnancy loss and inequalities in access to early pregnancy care. Barbara Lawrenz, ART Fertility Clinics, Abu Dhabi and Al Ain, United Arab Emirates, presented evidence evaluating whether preimplantation genetic testing for aneuploidy (PGT-A) improves reproductive outcomes in women with unexplained RPL. Sindhu Sekar, University of Liverpool and Liverpool Women's NHS Foundation Trust, UK, subsequently presented a 20-year joinpoint analysis of miscarriage and ectopic pregnancy admissions in England, highlighting evolving patterns of hospital admissions alongside persistent socioeconomic inequalities that continue to shape women's access to specialist early pregnancy services.

RECURRENT PREGNANCY LOSS AND THE ROLE OF PGT-A RPL remains a challenging condition, affecting approximately 1–2% of couples attempting to conceive. Although embryonic aneuploidy is recognised as a major cause of sporadic miscarriage, whether selecting euploid embryos through PGT-A improves outcomes in women with RPL remains uncertain.1 Current ESHRE and American Society for Reproductive Medicine (ASRM) guidance does not recommend routine PGT-A for unexplained RPL, citing insufficient evidence that it improves live birth rates while acknowledging the associated financial costs and treatment burden.2,3

practice, evidence supporting its benefit specifically in women with unexplained RPL remains limited.

Study Design

The investigators performed a retrospective cohort study including women with unexplained RPL who achieved pregnancy either following euploid embryo transfer after PGT-A or through spontaneous conception. Patients with uterine abnormalities, endocrine disorders, antiphospholipid syndrome, thrombophilia, parental chromosomal abnormalities, or other

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RPL remains a challenging condition,

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recognised causes of miscarriage were excluded. The analysis compared pregnancy outcomes between women undergoing IVF with PGT-A and frozen transfer of a euploid embryo and women who conceived spontaneously.

Similarly, miscarriage rates following confirmation of pregnancy were not significantly different between groups.

The primary outcome was the live birth rate. Secondary outcomes included miscarriage rate and cumulative live birth.

Baseline Characteristics

Women undergoing PGT-A were generally older than those conceiving spontaneously, with a median maternal age of 37 years compared with 33 years in the spontaneous conception group. The PGT-A cohort also demonstrated higher ovarian reserve markers, including anti-Müllerian hormone concentrations, and lower baseline folliclestimulating hormone levels. The median number of previous pregnancy losses was similar between groups.

Live Birth Rates Were Comparable

No statistically significant difference in live birth rates was observed between the two groups. Women who underwent euploid embryo transfer achieved live birth rates comparable to those who conceived naturally.

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When cumulative live birth rates were assessed, no advantage of the PGT-A strategy was demonstrated.

Maternal Age Remained the Strongest Predictor

Consistent with previous evidence, maternal age remained an important determinant of reproductive outcome. Increasing age was associated with declining live birth rates, irrespective of whether pregnancy occurred following euploid embryo transfer or spontaneous conception.

Maternal age remained an important determinant of reproductive outcome The findings suggest that while embryo aneuploidy contributes substantially to miscarriage risk, selecting euploid embryos alone does not overcome the multifactorial mechanisms underlying RPL.

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Clinical Implications

Lawrenz concluded that current evidence does not support routine use of PGT-A solely for the indication of unexplained RPL. The findings are consistent with existing systematic review data demonstrating no improvement in live births despite euploid embryo selection.1 The presentation highlighted that RPL is likely driven by multiple biological mechanisms beyond embryonic chromosomal status. Consequently, transferring a chromosomally normal embryo does not necessarily translate into improved reproductive outcomes. The speaker emphasised that careful patient counselling remains essential, particularly given the emotional, physical, and financial burden associated with IVF and PGT-A treatment.

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delivery, and population demographics have shaped patterns of pregnancy loss over the past 2 decades. Sekar opened the presentation by highlighting that miscarriage and ectopic pregnancy remain major public health challenges despite declining fetal and infant mortality rates. Around 23 million miscarriages occur worldwide each year, affecting approximately one in four pregnancies, while the impact extends far beyond the initial loss. Increasing evidence suggests that RPL is associated with long-term adverse maternal health outcomes, including venous thromboembolism and cardiovascular disease, yet pregnancy loss remains underrecognised and underfunded. Moreover, because many miscarriages occur before women access maternity services, the true burden remains underestimated in routine healthcare datasets.4

Twenty Years of National Data

Careful patient counselling remains essential, particularly given the emotional, physical, and financial burden associated with IVF and PGT-A treatment Conclusion

The study adds to growing evidence suggesting that routine euploid frozen embryo transfer does not improve live birth rates in women with unexplained RPL. These findings support current ESHRE and ASRM recommendations, which advise against routine PGT-A for unexplained RPL outside carefully selected clinical scenarios.2,3 Further prospective studies are needed to identify whether specific patient subgroups may benefit from embryo selection strategies.

CHANGING TRENDS IN PREGNANCY LOSS: PERSISTENT INEQUALITIES ACROSS ENGLAND Sekar presented findings from a 20-year joinpoint analysis of miscarriage and ectopic pregnancy admissions in England, exploring how changes in clinical practice, healthcare CC BY-NC 4.0 Licence

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To better understand long-term trends, the investigators analysed publicly available data from Hospital Episode Statistics (HES) and the Maternity Services Data Set (MSDS), examining hospital admissions for miscarriage and ectopic pregnancy in England between 2004–2024. The researchers employed joinpoint regression analysis, a statistical method widely used in epidemiological surveillance to identify points at which significant changes in trends occur over time. Originally developed for cancer surveillance, the approach is now frequently used to inform healthcare policy and monitor changes in disease incidence and outcomes.5,6 The analysis also examined admission patterns according to maternal age and socioeconomic deprivation.

Changing Patterns of Miscarriage Admissions

Joinpoint analysis demonstrated a significant decline in miscarriage admissions between 2010–2018 (annual percentage change [APC]: −2.06%), followed by a non-significant increase between 2021–2024 (APC: +2.70%).

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Sekar suggested that the reduction after 2010 likely reflected changes in service delivery rather than a true reduction in miscarriage incidence. During the early 2000s, Early Pregnancy Assessment Units (EPAU) became increasingly established across the UK, enabling more women to receive outpatient assessment and management. This shift was further supported by the National Institute for Health and Care Excellence (NICE) guidance recommending expectant, medical, and surgical management within specialist early pregnancy services where clinically appropriate.7,8 The more recent increase in admissions appears multifactorial. While COVID-19 has been associated with miscarriage through several immunopathological mechanisms, Sekar cautioned that the resurgence cannot be explained by the pandemic alone. Increasing maternal age, rising obesity prevalence, environmental influences, and other established miscarriage risk factors are also likely to have contributed to the observed trends.9

Ectopic Pregnancy Admissions Followed a Similar Pattern

time, with a marked increase between 2005– 2012 (APC: +2.81%) and a further significant increase between 2021–2024 (APC: +4.28%). The earlier increase coincided with evolving guidance on ectopic pregnancy management. Sekar highlighted that publication of the Royal College of Obstetricians and Gynaecologists Greentop Guideline promoted earlier diagnosis, laparoscopic management where appropriate, and the use of methotrexate in carefully selected women with suitable follow-up protocols.10 The presentation also highlighted the growing clinical challenge posed by pregnancies of unknown location. Improvements in pregnancy testing allow pregnancy to be detected before ultrasound can reliably visualise an intrauterine gestation, resulting in increasing numbers of women requiring serial assessment and follow-up. Alongside this, rising rates of obesity, pelvic inflammatory disease, sexually transmitted infections, endometriosis, assisted reproductive technologies, and previous Caesarean delivery may all be contributing to increasing ectopic pregnancy admissions.

Hospital admissions for ectopic pregnancy also demonstrated significant changes over 26

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Persistent Socioeconomic Inequalities Perhaps the most striking finding was that improvements in clinical care have not translated into reductions in socioeconomic inequalities.

Women living in the most deprived areas experienced approximately 2.7-fold higher hospital admission rates for miscarriage and 2.4-fold higher admission rates for ectopic pregnancy than women living in the least deprived communities. Importantly, these disparities remained largely unchanged throughout the study period. Sekar suggested that multiple interacting factors likely underpin these differences. Women living in deprived areas tend to be younger but also experience higher prevalence of recognised risk factors, including smoking, obesity, and sexually transmitted infections. Reduced access to timely maternity care may further compound these risks. To explore this further, the investigators compared national deprivation maps with the geographical distribution of EPAUs across England. The analysis demonstrated an apparent mismatch between areas with the greatest socioeconomic deprivation and the availability of specialist early pregnancy services, suggesting that women at highest risk may face the greatest barriers to accessing appropriate care.

Implications for Policy and Future Research

The findings highlight several priorities for improving pregnancy loss care. Sekar suggested that expanding EPAU capacity, strengthening workforce training,

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and improving referral pathways could help reduce inequalities in access to specialist care. Targeted prevention strategies addressing modifiable risk factors, including smoking, obesity, and sexually transmitted infections, alongside greater use of digital platforms to deliver evidence-based reproductive health information, may further improve outcomes. The presentation also identified several priorities for future research, including improving understanding of women’s experiences of accessing EPAUs, evaluating long-term reproductive and mental health outcomes following pregnancy loss, integrating preconception care into early pregnancy services, and addressing the longstanding underinvestment in pregnancy loss research.

Conclusion

Concluding the presentation, Sekar emphasised that although pregnancy loss is common, its impact is profoundly personal. Behind every hospital admission is a woman, a family, and often unanswered questions about why the loss occurred and whether it could happen again. While advances in specialist early pregnancy care have transformed management over the past 2 decades, the findings demonstrate that persistent inequalities remain. Reducing the burden of miscarriage and ectopic pregnancy will require not only continued improvements in clinical care, but also equitable access to specialist services, investment in prevention, and research focused on answering the questions that matter most to patients.

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References

Mumusoglu S et al. Preimplantation genetic testing for aneuploidy in unexplained recurrent pregnancy loss: a systematic review and meta-analysis. Fertil Steril. 2025;123(1):121-36.

National Cancer Institute (NCI). Joinpoint trend analysis software. Available at: https://surveillance. cancer.gov/joinpoint/. Last accessed: 17 July 2026.

The ESHRE Guideline Group on RPL; Atik RB et al. ESHRE guideline: recurrent pregnancy loss: an update in 2022. Hum Reprod Open. 2023;DOI:10.1093/hropen/hoad002.

Arnold M et al. Progress in cancer survival, mortality, and incidence in seven high-income countries 1995–2014 (ICBP SURVMARK-2): a population-based study. Lancet Oncol. 2019;20(11):1493-505.

Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012;98(5):1103-11.

Poddar A et al. Standards of care provided by early pregnancy assessment units (EPAU): a UKwide survey. J Obstet Gynaecol. 2011;31(7):640-4.

10. Royal College of Obstetricians and Gynaecologists (RCOG). Diagnosis and management of ectopic pregnancy (Green-top Guideline No. 21). 2016. Available at: https://www.rcog.org. uk/guidance/browse-all-guidance/ green-top-guidelines/diagnosis-andmanagement-of-ectopic-pregnancygreen-top-guideline-no-21/?utm_ source=chatgpt.com. Last accessed: 17 July 2026.

Quenby S et al. Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet. 2021;397(10285):1658-67.

National Institute for Health and Care Excellence (NICE). Ectopic pregnancy and miscarriage: diagnosis and initial management. 2026. Available at: https://www.nice.org.uk/guidance/ ng126. Last accessed: 17 July 2026.

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Cavalcante MB et al. COVID-19 and miscarriage: from immunopathological mechanisms to actual clinical evidence. J Reprod Immunol. 2021;148:103382.

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What’s in a Name? Why PCOS is Becoming PMOS Author:

Noémie Fouarge, EMJ, London, UK

Citation:

EMJ Repro Health. 2026;12[1]:29-32. https://doi.org/10.33590/emjreprohealth/DX25VIZW

IN MAY 2026, polycystic ovary syndrome (PCOS) was renamed polyendocrine metabolic ovarian syndrome (PMOS) following a global consensus led by Monash University, Melbourne, Australia; the Androgen Excess & PCOS (AE-PCOS) Society; and Verity PCOS UK, Surrey, UK. At the European Society of Human Reproduction and Embryology (ESHRE) Congress 2026, a session titled ‘Renaming PCOS: governance, consensus process, outcomes and global implementation’ explored the whys, hows, and impacts of this change for patients worldwide. The session was chaired by Alessandra Alteri, Saint Camillus International University of Health Sciences, Rome, Italy; and Katerina Bambang, The Delphi Clinic, Liverpool, UK, and featured three speakers from the PCOS Name Change Committee.

WHY THE NAME MATTERS Anju Joham, Monash University, explained that PMOS is a condition characterised by endocrine changes, including insulin resistance, which is present in 75–95% of affected women; gonadotropin-releasing hormone pulsatility changes, leading to luteinising hormone and follicle-stimulating hormone imbalance; elevated anti-Müllerian hormone (AMH), which causes follicular arrest; adipokine dysregulation; and insulinlike growth factor signalling issues.1 The name PCOS implies that the pathology lies with the ovaries. However, Joham explained, this terminology could cause harm, as research has shown that the features of the condition are much broader. Piltonen et al.2 studied the ovarian features of the condition, and their findings showed that the condition is associated with polycystic ovary morphology, with increased ovarian volume and increased follicles, which are deceivingly referred to as cysts. However, the study showed that there was no difference in benign or pathological cysts between the two groups, suggesting that there is no increased risk of cysts in patients with PMOS.2

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Further research has shown a clustering of metabolic features in patients with PMOS, with an increased risk of diabetes, dyslipidaemia, insulin resistance, and hypertension.1 Additionally, data have shown an increased risk of cardiovascular events, including major adverse cardiovascular events, myocardial infarction, angina, and need for revascularisation, unrelated to obesity.3 A subsequent study of Nordic women with PMOS confirmed that in women with a BMI lower than 25 kg/m2, cardiovascular risk was increased.4 An international evidence-based guideline, published in 2023, which looked at the assessment and management of the condition, supports the endocrine and metabolic origins of the condition, with a range of features manifesting across the lifespan.5 In adolescence, the most prominent symptoms are an increasing BMI and psychological burden, while reproductive years are marked by subfertility, pregnancy complications, and more significant metabolic features. Post-menopause, the condition does not disappear, and metabolic features start to predominate. The guidelines also feature updated diagnostic criteria for

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PMOS, with the main change being the addition of AMH, which can be used in lieu of polycystic ovary morphology on ultrasound. For adults, two of the following are now required for diagnosis: oligo- or anovulation; clinical and/or biochemical hyperandrogenism; and polycystic ovaries or elevated AMH levels. In adolescents, both oligo-or anovulation and clinical and/ or biochemical hyperandrogenism need to be present. Since ovarian changes are expected as part of normal pubertal development, it is recommended not to use polycystic ovary morphology for diagnosis, or to include AMH levels, as these do not peak until early 20s. Joham concluded that the term PCOS is a misnomer, focusing on a single organ while ignoring the wide range of endocrine, metabolic, psychological, and dermatological effects of the condition. This mislabelling not only impacts health outcomes but also policy, funding, research, education, and care.

PMOS was chosen as an accurate, symptom-based term that frames this condition as multidisciplinary

THE ROAD TO CONSENSUS In 2012, Joham explained, a workshop was held to change the name, but due to the lack of global leadership, patient alignment, agreement on an alternative name, and implementation strategies, the process stalled. The new initiative addressed these barriers, starting with a survey of nearly 8,000 patients and HCPs, confirming that the name was inaccurate and needed to be changed. This was followed by a significant consultation process, which looked at knowledge gaps, and a workshop at the AE-PCOS Society

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Annual Meeting in 2023, which endorsed the name change. Finally, they conducted another survey with 22,000 participants, showing overwhelming support for a name change. Throughout this process, 56 organisations were involved across six continents, covering a range of disciplines, including gynaecology, endocrinology, dermatology, metabolic health, psychology, and nutrition. The next step was to decide on a new name that would reflect the span of the condition, eliminate the misleading term ‘cysts’, reduce reproductive stigma, and recognise the range of metabolic, psychological, and cardiometabolic features, while facilitating implementation. PMOS was chosen as an accurate, symptom-based term that frames this condition as multidisciplinary, allowing for more holistic, patient-centred care.6

FROM CONSENSUS TO CLINICAL PRACTICE Terhi Piltonen, Oulu University Hospital, Finland, explained that this change now needs to be carried out at all levels, including policy, research, education, and care. To ensure this, they have created a 3-year, eight-step implementation strategy, with an embedded evaluation strategy to monitor global uptake. This starts with the public dissemination through publications; the creation of resources on a global scale; content shared through media and social media; updating health information systems; notifying researchers, funders, journals, and databases; international classification through an updated International Classification of Diseases (ICD) code; education, from global conferences to universities; and revising international guidelines.

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Most of these are already underway, with 25 publications so far across a range of journals, millions of people reached across social media, and the National Institute for Health and Care Excellence (NICE) Guidelines having already adopted the new term.

THE PATIENT VOICE Rachel Morman, Patient Advocate and Chair of Verity PCOS UK, the UK’s leading patient charity for PMOS, emphasised that more than 14,000 women with PMOS, from all over the world, contributed to this consensus and were integral to the process by co-designing surveys, co-chairing workshops alongside HCPs, shaping governance, and bringing realworld multicultural perspectives. “The history of women’s health is littered with decisions made about women’s health without women involved, and this was very much different, and it should set the bar for future condition name changes to come,” said Morman. The name change was able to happen because patients, clinicians, and researchers who wanted better, and cared deeply, refused to give up. While they did not create evidence, they created an environment where the evidence could

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no longer be ignored, and this was the foundation of the name change. In the end, 86% of patients and 76% of HCPs supported the change, and 97% of workshop participants agreed on the final name, showing a democratic, globally informed decision. Morman concluded by sharing the story of Victoria, who was diagnosed with PMOS in her 40s thanks to the name change, and who has already experienced an improvement in quality of life since starting treatment, showing the impact that this is already having on patient care.

CONCLUSION PMOS affects 170 million people of reproductive age worldwide, and it is estimated that more than 70% of women with PMOS are undiagnosed. The transition from PCOS to PMOS is not just a change in terminology but reflects a broader change in how the condition is understood and validates patient experiences. While the change will not, on its own, change care, it lays the foundation for more accurate diagnosis and better care worldwide.

The history of women’s health is littered with decisions made about women’s health without women involved

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References 1.

a population study. J Clin Endocrinol Meta. 2021;106(9):e3369-80.

Stener-Victorin E et al. Polycystic ovary syndrome. Nat Rev Dis Primers. 2024;10(1):27.

Piltonen TT et al. Ovarian cysts in polycystic ovary syndrome. JAMA Intern Med. 2026;DOI:10.1001/ jamainternmed.2026.1370. 5.

Berni TR et al. Women with polycystic ovary syndrome have an increased risk of major cardiovascular events:

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Glintborg D et al. Increased prospective cardiovascular disease risk in 127 517 Nordic women with polycystic ovary syndrome: a national cohort study. Eur J Endocrinol. 2026;194(1):58-68. Monash University. International evidence-based guideline for the assessment and management of polyendocrine metabolic ovarian

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syndrome (formerly PCOS) 2023. Available at: https://www. monash.edu/__data/assets/pdf_ file/0009/4360095/Updated-PMOSGuideline-12-June26.pdf. Last accessed: 14 July 2026. 6.

Teede HJ et al. Polyendocrine metabolic ovarian syndrome, the new name for polycystic ovary syndrome: a multistep global consensus process. Lancet. 2026;407(10545):2329-39.

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AI in Embryology: Expanding Beyond Embryo Selection Author:

Jess Nicholson, EMJ, London, UK

Citation:

EMJ Repro Health. 2026;12[1]:33-36. https://doi.org/10.33590/emjreprohealth/662968VX

AI HAS become synonymous with embryo selection in assisted reproduction, but the 'AI in Embryology' session at the European Society of Human Reproduction and Embryology (ESHRE) Congress 2026 demonstrated that its role is rapidly expanding. Presentations explored how AI could support decision-making across the IVF laboratory, from real-time quality control and objective oocyte assessment to donor programme optimisation and the identification of novel biomarkers of embryo competence. Alongside these innovations, speakers also highlighted the importance of clinical validation, emphasising that AI is most effective when designed to complement, rather than replace, embryologist expertise.

REAL-TIME QUALITY CONTROL FOR THE IVF LABORATORY

FROM INDIVIDUAL OOCYTES TO DONOR COHORTS

Although AI has become increasingly established in embryo selection, one presentation shifted the focus to monitoring the performance of the IVF laboratory itself, highlighting an emerging application of the technology. Research from Bori et al.,1 presented by Sandra Marqueño, IVIRMA Global Research Alliance, Spain, designed a stage-aware AI system to forecast IVF key performance indicators in real time using morphokinetic data from more than 70,000 embryos.1 Rather than predicting the fate of individual embryos, the model aggregated developmental information across incubator embryos to estimate blastocyst utilisation and implantation rates throughout culture. Predictive performance improved as embryo development progressed; the model scored an area under the curve of 0.787 for usable blastocyst prediction after incorporating developmental features. The study introduced a novel way of using AI systems beyond embryo ranking through application at the incubator-population level. This positions AI as a potential quality assurance system, enabling laboratories to identify performance issues while cycles are still in progress rather than retrospectively.

The session also highlighted how AI is extending upstream in the IVF workflow, providing objective tools to inform decisions long before embryos reach the selection stage. Kenji Ezoe, Kato Ladies Clinic, Shinjuku, Japan, presented research on assessing developmental competence of immature oocytes following rescue in vitro maturation using the deep learning platform Magenta™, developed by Future Fertility (Toronto, Canada).2 As expected, rescue-matured oocytes showed lower developmental potential than in vivo-matured oocytes. However, Magenta scores successfully identified rescue-matured oocytes with greater developmental potential, showing significant associations with maturation, fertilisation, and blastocyst development. The study demonstrates AI’s potential to be an objective tool supporting decision-making when considering whether rescue-matured oocytes should be used clinically.

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Once oocyte quality can be objectively quantified, those assessments can also be applied at cohort level. Lais Vanzella, Future Fertility, Canada, shared their research on whether the AI-supported ROSE

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workflow, developed by Future Fertility, could improve donor oocyte allocation by reducing the proportion of donor lots unlikely to achieve clinically meaningful blastocyst yields.3 Across more than 18,000 donor-age oocytes from 11 fertility centres, ROSE consistently outperformed simulated random allocation, producing significantly fewer donor lots that failed to meet predefined blastocyst formation targets (all p<0.01). The greatest benefit was observed under the most stringent allocation criteria, where ROSE reduced the relative risk of complete lot failure by 66.1%. Rather than selecting a single ‘best’ egg, the algorithm balanced the quality of donor eggs across treatment batches, reducing the chance that patients would receive a group of eggs unlikely to produce blastocysts. Together, these studies suggest that AI is evolving from a tool for embryo selection into one that can support decision-making throughout the IVF workflow, enabling more objective assessment of oocyte quality while optimising the allocation of valuable clinical resources.

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AI is evolving from a tool for embryo selection into one that can support decision-making throughout the IVF workflow

SEPARATING VALIDATED AI FROM GENERAL-PURPOSE MODELS Several presentations also explored how AI compares with conventional embryologist evaluation and where its limitations begin to emerge. Ella Krasnitsky, Assuta Medical Center, Tel Aviv, Israel, examined concordance between the Gardner and Schoolcraft morphological grading system for blastocyst quality and iDAScore, an AI-powered embryo assessment platform developed by Vitrolife (Gothenburg, Sweden), across more than 10,500 blastocysts.4 Overall agreement between embryologist assessment and AI scoring was high, with 70.7% of embryos classified as both good-quality Gardner and high AI score, while discordant classifications were

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uncommon. Notably, embryos graded as good quality by morphology but assigned low AI scores still achieved a pregnancy rate of 42.8%, comparable with the unit’s overall pregnancy rate of 46% (p=0.9). These findings suggest that although AI largely reinforces conventional morphological assessment, embryos with discordant classifications may still retain clinically meaningful reproductive potential. Rather than replacing embryologist expertise, AI is more valuable when used to complement clinical judgement and support more nuanced embryo selection. In contrast, Arth Ladva, Oasis Fertility, India, examined what happens when embryo assessment is attempted using generalpurpose AI systems rather than models developed specifically for reproductive medicine. The study looked at whether publicly available large language models (ChatGPT [OpenAI, San Francisco, California, USA], Gemini [Google, Mountain View, California, USA], Claude [Anthropic, San Francisco, California, USA], and Grok [xAI, Palo Alto, California, USA]) could accurately predict live birth using blastocyst morphology images alone across 151 single embryo transfer cycles.5 Overall, all four platforms demonstrated limited discriminatory ability, with area under the receiver operating characteristic curve values ranging from 0.52–0.64, and high rates of prognostic discordance; Grok showed the greatest discordance (60.9%), while Gemini achieved the highest concordance (64.9%), but still misclassified more than one-third of outcomes. Misclassification was predominantly driven by false-negative predictions, suggesting a consistent pessimistic bias when clinical information was unavailable. Agreement between AI-generated assessments and embryologist Gardner grading was also poor, indicating that general-purpose AI does not replicate expert morphological reasoning.

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purpose AI lacks the domain-specific knowledge required for reliable embryo assessment.

NOVEL BIOMARKERS FOR EMBRYO SELECTION Looking ahead, researchers explored how AI could move beyond assisting embryo selection to identifying entirely new markers of developmental competence. Juanjo Fraire-Zamora, Eugin Clinic, Spain, investigated whether dynamic blastocyst behaviour could provide independent information about embryo ploidy beyond conventional morphokinetic milestones.6 Using AI-generated annotations from approximately 1,800 blastocysts, the study showed that euploid embryos achieved significantly larger maximum blastocyst diameters than aneuploid embryos (161.2 μm versus 154.2 μm; p<0.001). Each 10 μm increase in maximum diameter was associated with a 14% increase in the odds of euploidy, independent of developmental timing. In contrast, contraction frequency, amplitude, and timing were not independently associated with chromosomal status. Larger blastocytes at their point of maximum expansion were more likely to be chromosomally normal, regardless of how quickly they had developed. Importantly, this association was independent of developmental timing, indicating that maximum blastocyst expansion may provide biological information beyond conventional morphokinetic markers.

Using AI-generated annotations from approximately 1,800 blastocysts, the study showed that euploid embryos achieved significantly larger maximum blastocyst diameters than aneuploid embryos (161.2 μm versus 154.2 μm; p<0.001)

When considered together, these studies highlight that the value of AI in embryology lies not simply in the technology itself, but in rigorous clinical validation and contextspecific application. While specialist AI models can provide meaningful decision support alongside embryologists, generalCC BY-NC 4.0 Licence

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KEY TAKEAWAYS Taken together, the studies presented during the ‘AI in Embryology’ session reflected a clear evolution in how AI is being applied within reproductive medicine. Rather than focusing solely on embryo ranking, researchers demonstrated how AI could support quality assurance, optimise laboratory workflows, improve objective assessment of oocytes and embryos,

References 1.

Bori L et al. A real-time predictive alert system for monitoring IVF laboratory performance using time-lapse– derived embryo features. Abstract L26-O-135. ESHRE Annual Meeting, 5-8 July, 2026.

Ezoe K et al. Artificial intelligencebased prediction of developmental competence in rescued metaphase II oocytes derived from germinal vesicle and metaphase I stages. Abstract L26-O-132. ESHRE Annual Meeting, 5-8 July, 2026.

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and uncover novel biological markers of developmental competence. Equally, the session reinforced that successful clinical implementation depends on robust validation and thoughtful integration into existing practice. As AI technologies continue to mature, future research will determine how these complementary tools can be incorporated into routine IVF care while maintaining the central role of embryologist expertise.

Vanzella L et al. ROSE, an artificial intelligence (AI) supported workflow system for optimizing donor oocyte management, reduces chances of complete blastulation failure compared with random lot assignment. Abstract L26-O-134. ESHRE Annual Meeting, 5-8 July, 2026.

Ladva DA et al. Can free-access general-purpose AI platforms reliably predict IVF outcomes? A benchmarking study of imagebased embryo interpretation against live-birth results. Abstract L26-O-131. ESHRE Annual Meeting, 5-8 July, 2026.

Krasnitsky E et al. Conventional morphological grading and AI blastocyst assessment: prevalence of grading discordance and analysis of pregnancy rates. Abstract L26-O-136. ESHRE Annual Meeting, 5-8 July, 2026.

Fraire-Zamora J et al. Beyond developmental milestones: maximum expansion and contraction dynamics as euploidy markers in 1,770 PGT-A blastocysts. Abstract L26-O-133. ESHRE Annual Meeting, 5-8 July, 2026.

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Abstract Reviews Drawing on research presented at the European Society of Human Reproduction and Embryology (ESHRE) Annual Meeting 2026, these abstract reviews showcase emerging advances across reproductive medicine. Covering topics from IVF optimisation and embryo transfer to fertility care, lifestyle, digital health, and AI, the authors discuss the clinical significance of their findings, their potential impact on patient care, and the future direction of reproductive research.

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Barriers to Early Fertility Consultation in Women with PMOS: A Questionnaire-Based Survey Author: *Rudri Agrawal1

MATERIALS AND METHODS

1. OASIS Fertility, Reproductive Medicine, Indore, India *Correspondence to rudri28@gmail.com

Women who are infertile with PMOS according to current international evidence-based diagnostic guidelines were enrolled following at least one fertility consultation. A structured, pilot-tested questionnaire assessed the interval from pregnancy intention to initial fertility consultation, patient-perceived barriers to early care, sources of fertility-related information, and prior exposure to fertility counselling. Counselling was categorised as structured (evidencebased and timeline-oriented) or nonstructured. Delayed consultation (>12 months from pregnancy intent) was the primary outcome. Secondary outcomes included anxiety and treatment readiness. Independent predictors were identified using multivariable logistic regression.

Disclosure: The author has declared no conflicts of interest. Keywords: Care-seeking behaviour, delayed fertility consultation, fertility counselling, infertility, polyendocrine metabolic ovarian syndrome (PMOS). Citation: EMJ Repro Health. 2026;12[1]:38-39. https://doi.org/10.33590emjreprohealth/528406W1

BACKGROUND AND AIMS Polyendocrine metabolic ovarian syndrome (PMOS) represents one of the most prevalent causes of anovulatory infertility worldwide; however, a substantial proportion of affected women initiate fertility evaluation only after prolonged delays.1 Such delays may adversely influence cumulative reproductive potential, prolong exposure to anovulatory cycles, and exacerbate psychological distress.2,3 Although fertility counselling is a central component of PMOS management, its timing, content, and effectiveness in facilitating appropriate care-seeking behaviour remain poorly defined. In particular, patient-perceived barriers, including misinformation, reassurancerelated postponement, and lifestyle-driven delays, have not been systematically quantified, limiting the development of targeted interventions to promote timely fertility assessment. This study aimed to identify patientreported barriers contributing to delayed fertility consultation in women with PMOS and to evaluate the association between prior fertility counselling and help-seeking behaviour, psychological burden, and treatment readiness.4

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RESULTS A total of 548 women with PMOS were included in the final analysis. Delayed fertility consultation, defined as presentation more than 12 months after pregnancy intent, was reported by 56.8% of participants (n=311). The most frequently cited patient-perceived barriers to early consultation included reassurance of spontaneous conception despite persistent ovulatory dysfunction (44.9%), prolonged emphasis on weight loss prior to specialist referral (41.6%), misinformation regarding fertility timelines in PMOS (37.8%), and reliance on non-medical information sources such as social media or peer advice (34.1%). Women exposed to structured fertility counselling prior to specialist consultation demonstrated significantly lower odds of delayed care-seeking compared with those receiving non-structured or no counselling (adjusted odds ratio [OR]: 0.52; 95% CI: 0.38–0.71; p<0.001). After adjustment for age, BMI, education level, and duration of infertility, delayed consultation remained

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independently associated with higher anxiety scores (adjusted OR: 1.89; 95% CI: 1.36–2.62) and reduced treatment readiness (adjusted OR: 1.67; 95% CI: 1.21–2.29). These associations persisted across sensitivity analyses, suggesting a low probability that the observed findings were attributable to chance alone.

LIMITATIONS Barriers and counselling exposure were self-reported and subject to recall bias. The cross-sectional design precludes causal inference. Although the large sample size enhances statistical robustness, findings may not be fully generalisable across different healthcare settings.

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improve timely care-seeking, alleviate psychological burden, and optimise patient-centred fertility management, with potential implications for guideline implementation and service delivery.

References 1.

Agrawal R. Barriers to early fertility consultation in women with PCOS: a questionnaire-based survey. Hum Reprod. 2026;41(Suppl 1):deag083.916.

Teede HJ et al. Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. Fertil Steril. 2023;120(4):767-93.

Forslund M et al. International evidence-based guideline on assessment and management of PCOS- a Nordic perspective. Acta Obstet Gynecol Scand. 2024;103(1):7-12.

Sourouni M et al. Unmet clinical needs in women with polycystic ovary syndrome in regard to mental health: a cross-sectional study. Arch Gynecol Obstet. 2024;309(5):2115-26.

These findings highlight delayed fertility consultation in PMOS as a modifiable healthsystem issue. Early, structured fertility counselling may reduce misinformation,

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Intrauterine Dissolved Oxygen Profiling During the Luteal Phase: A Feasibility Study in Healthy Women Authors: *Anna Teixido Troyano,1 Melchor Carbonell Socias,1 Carmen Cabeza Oliver,1 Elisabeth Sanfeliu de España,1 Luis Manuel Artiles Martinez,2 Monica Rodriguez de la Vega Otazo,2 J. Herrero García2 1. Unit of Assisted Reproduction and Gynaecological Endocrinology, Department of Obstetrics and Gynaecology, Vall d’Hebron University Hospital, Barcelona, Spain 2. Manina MedTech S.L., Research and Development, Barcelona, Spain *Correspondence to anna.teixido@vallhebron.cat Disclosure: de la Vega Otazo and Artiles Martinez are founders of Manina MedTech S.L. García and Socias hold equity interests in Manina MedTech S.L. The other authors have declared no conflicts of interest. Disclaimer: This study was promoted by Manina MedTech S.L. and conducted in collaboration with the Vall d’Hebron Research Institute (VHIR). The study was approved by the Vall d’Hebron University Hospital Ethics Committee (PR(AMI)336/2021) and conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent. The clinical trial registration number is ISRCTN85528745 (retrospectively registered). Acknowledgements: The authors would like to thank all the study participants and the staff of the Reproductive Medicine Unit at Vall d’Hebron University Hospital, Barcelona, Spain, for their contribution to this study. Keywords: Angiogenesis, assisted reproduction, embryo–endometrium synchrony, endometrial receptivity, intrauterine oxygen, luteal phase. Citation: EMJ Repro Health. 2026;12[1]:40-42. https://doi.org/10.33590/emjreprohealth/AR8LR9L1

BACKGROUND AND AIMS Assessment of endometrial receptivity remains one of the major challenges in reproductive medicine despite significant advances in embryo selection and assisted reproductive technologies. At the 2026 European Society of Human Reproduction and Embryology (ESHRE) Annual Meeting, the authors presented a feasibility study evaluating serial intrauterine dissolved 40

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oxygen measurements throughout the luteal phase in healthy women.¹ The rationale for the study stems from experimental evidence suggesting that uterine oxygen tension varies dynamically during the peri-implantation period and may reflect underlying endometrial vascular remodelling.2-4 While previous human studies have reported isolated intrauterine oxygen measurements, longitudinal profiling across the entire luteal phase had not previously been described. Furthermore, embryonic metabolic requirements support a physiological role for dynamic intrauterine oxygen regulation. Early embryos rely predominantly on anaerobic metabolism during cleavage stages, whereas oxygendependent metabolism increases substantially at the blastocyst stage. Consequently, changes in intrauterine oxygen availability during the luteal phase may align with the changing metabolic demands of the developing embryo.⁵

MATERIALS AND METHODS In this prospective observational pilot study, eight healthy women aged 18–35 years with regular menstrual cycles underwent serial intrauterine dissolved oxygen (pO₂) measurements during a natural menstrual cycle. Measurements were performed from luteinising hormone (LH) surge LH+1 to LH+13/14 using a fibre-optic microsensor positioned approximately 1 cm from the uterine fundus under ultrasound guidance. The primary objective was to evaluate the feasibility of repeated intrauterine oxygen assessment and to characterise temporal oxygenation patterns across the luteal phase.

RESULTS The investigators successfully obtained serial measurements in all participants and identified two distinct oxygenation profiles. Four participants demonstrated

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a characteristic ‘peak’ pattern, with low oxygen tension during the early luteal phase followed by a marked increase between LH+4 and LH+6, reaching values of approximately 40–45 Torr before declining after LH+8. One of these participants exhibited a similar but temporally advanced peak. In contrast, four participants maintained relatively low oxygen levels throughout the luteal phase without a discernible mid-luteal rise, constituting a ‘no-peak’ pattern. The two distinct oxygenation patterns observed across the luteal phase are illustrated in Figure 1. Post-hoc review identified potential physiological, pharmacological, or lifestylerelated factors among participants exhibiting the no-peak profile. Although causal relationships cannot be established from this small pilot cohort, these observations raise the possibility that intrauterine oxygen dynamics may be

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sensitive to factors influencing endometrial maturation and function. Importantly, the procedure was well tolerated, with reported pain scores ranging from 0–2 on a visual analogue scale and no procedure-related adverse events. These findings support the technical feasibility and acceptability of serial intrauterine oxygen monitoring.

CONCLUSION The study introduces a novel concept: the use of real-time intrauterine oxygen profiling as a functional biomarker of endometrial status. Unlike molecular or histological approaches, oxygen assessment provides an immediate physiological measurement obtained within the same menstrual cycle. If validated in larger studies and infertility populations, this approach could offer a

Figure 1: Representative intrauterine dissolved oxygen profiles during the human luteal phase.

Temporal profiles of intrauterine dissolved oxygen concentration (pO₂, Torr) across the luteal phase. The x-axis represents days relative to the luteinising hormone surge (LH+ days), ranging from LH+0 to LH+14, and the y-axis shows intrauterine oxygen levels (0–50 Torr). Each coloured line represents an individual participant, with mean pO₂ values and error bars indicating standard deviations at each time point. pO₂ values represent averages obtained from a 5-minute continuous recording period at each time point. Participants are categorised into two distinct response patterns: A) Peak pattern: characterised by a mid-luteal rise in O₂ concentration (participants P002, P003, P004, and P008). B) No-peak pattern: characterised by consistently low or stable pO₂ levels throughout the luteal phase (participants P001, P005, P006, and P007). LH: luteinising hormone.

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minimally invasive method for evaluating embryo–endometrium synchrony and potentially refining embryo transfer timing. Although limited by its small sample size and exploratory design, this work represents the first in vivo characterisation of dynamic intrauterine oxygen changes across the luteal phase in women and provides a foundation for future studies evaluating intrauterine oxygen profiling as a potential same-cycle functional biomarker of embryo–endometrium synchrony and endometrial receptivity.

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References 1.

Teixidó Troyano A et al. Intrauterine dissolved oxygen profiling during the luteal phase: a feasibility study in healthy women. Abstract L26/P-554. ESHRE Annual Meeting, 5-8 July, 2026.

Mitchell JA, Yochim JM. Intrauterine oxygen tension during the estrous cycle in the rat: its relation to uterine respiration and vascular activity. Endocrinology. 1968;83:701-5.

Garris DR, Mitchell JA. Intrauterine oxygen tension during the estrous cycle in the guinea pig: its relation to uterine blood volume and plasma estrogen and progesterone levels. Biol Reprod. 1979;21:149-59.

Ottosen LDM et al. Observations on intrauterine oxygen tension measured by fibre-optic microsensors. Reprod Biomed Online. 2006;13:380-5.

Gardner DK, Harvey AJ. Blastocyst metabolism. Reprod Fertil Dev. 2015;27:638-54.

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Digital Desire: The Rise of AI Relationships and Techno-Intimacy – Impact on Fertility Intentions, Future Reproduction, Family Building, and Mental Health Authors: *Bola Grace,1,2 Kehui Li,2 Favour Ajao-Rotimi3 1. UCL EGA Institute for Women’s Health, Faculty of Population Health Sciences, University College London, UK 2. UCL Global Business School for Health, Faculty of Population Health Sciences, University College London, UK 3. Research Department, Cambridge Matrix, UK *Correspondence to bola.grace@ucl.ac.uk Disclosure: The authors have declared no conflicts of interest. Keywords: AI companionship, AI romance, artificial intimacy, digital companions, digital intimacy, fertility intention, mental health, psychosocial, reproductive intention, technorelationship. Citation: EMJ Repro Health. 2026;12[1]:43-44. https://doi.org/10.33590/emjreprohealth/W0MB5N49

BACKGROUND AND AIMS The last 2 decades saw an increase in dating platforms as individuals turned to digital platforms for relationships and to fulfil family-building intentions.1-3 Recently, advances in AI have extended beyond productivity and automation into the deeply personal domain of human relationships. Artificial intimacy is a form of human–AI interaction in which individuals form social connections, emotional bonds, or intimate relationships with various forms of AI, including chatbots, virtual assistants, and other artificial entities. Increasingly, individuals are turning to AIpowered chatbots and virtual companions for emotional support, companionship, and romantic or intimate connection as the lines between psychological support and relationships blur.4 This trend is on the rise, particularly among younger generations already navigating economic uncertainty and changing social norms. While these technologies may offer comfort and CC BY-NC 4.0 Licence

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accessibility, growing reliance may have significant implications for reproductive decision-making.5,6 This research aimed to synthesise current evidence on the emerging trend of AI relationships.

MATERIALS AND METHODS A systematic literature review was conducted following Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) 2020 guidelines. Databases searched included Embase, MEDLINE, Web of Science, and Google Scholar for studies investigating human and AI relationships. Due to the novelty of the topic as a rapidly emerging use of technology, with limited but gradually increasing peer-reviewed published work, grey literature and preprint articles were included. Only studies published in English were included. Content was analysed and categorised thematically.

RESULTS After screening and full-text assessment, 32 studies were included. Most participants were in their peak reproductive age (20s and 30s). Methods included surveys and interviews ranging from 8–1,131 for specific user samples, and qualitative content analysis of user-generated content of international app users from mixed online platforms like Replika (Luka, Inc., San Francisco, California, USA) and Character. AI (Character Technologies Inc., Menlo Park, California, USA) including up to 30,000 conversations. Motivation and positive impact include greater emotional comfort, increased feelings of support, stress relief, and support for socially anxious users. AI tools are reported to be very popular because of the sycophancy and validation provided to users. Negative consequences included

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overdependence and emotional addiction, isolation and social withdrawal, stigma and shame, data privacy and manipulation fears, and emotional distress when AI identity changes or fails. Mental health effects associated with intensive AI companionship were mixed, suggesting both potential emotional support and increased loneliness depending on user vulnerability and usage patterns. Studies also report altered intimacy patterns, reduced motivation for human romantic relationships, and changes in sexual behaviour. In terms of impact on future reproduction, these factors may plausibly influence reproductive timing, likelihood of conception, delayed partner formation, reduced partnered sexual activity, and reduced engagement with reproductive healthcare. Evidence suggests heavy porn users were more open to AI romantic partners. Many want to have children with their AI partner, with reports of an AI partner being ‘pregnant’.

STUDY LIMITATIONS Only studies published in English were eligible for inclusion, limiting the generalisability of study findings. As this is a novel research area involving emerging technologies, longitudinal studies are needed to confirm implications on future reproduction, especially at the population level.

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CONCLUSION As the trend to substitute AI for human partners continues to rise, these behavioural shifts can have direct implications for fertility rates and family formation. Stakeholders, including psychologists, reproductive health educators, healthcare professionals, policy makers, and others, should consider artificial relationships within the wider contexts of fertility trends and reproductive wellbeing.

References 1.

Grace B et al. Digital desire: the rise of artificial intelligence relationships and techno-intimacy; impact on fertility intentions, future reproduction, family building and mental health. Hum Reprod. 2026;41(Suppl 1):deag083.908.

Grace B, Harper J. HealthTech for reproduction: promises, perils and the evidence gap. Reprod Biomed Online. 2026;53(3):105819.

Grace B et al. The ABC of reproductive intentions: a mixed-methods study exploring the spectrum of attitudes towards family building. Hum Reprod. 2022;37(5):988-96.

Grace B et al. Digital health technologies to transform women’s health innovation and inclusive research. BMJ. 2025;391:e085682.

Grace B, Wise LA. Wearables and women’s healthtech: advancing measurement, monitoring and action via digital medicine. Nat Rev Dis Primers. 2026;12(1):31.

Grace B et al. Ctrl + Alt + Conceive: fertility awareness in the age of artificial intelligence, how do large language models compare? Hum Fertil (Camb). 2025;28(1):2584673.

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Validating a Machine Learning Model to Predict Live Birth After Vitrified Donor Oocyte IVF Authors: Vanessa Pataia,1 Mylene W.M. Yao,2 Elizabeth T. Nguyen,2 Marta Wolska,1 Trina Shah,1,3 Hemlata Thackare,1 Shailaja Nair,1 Nick Macklon,1,3 *Kamal Ahuja1,3

predict the likelihood of live birth per embryo transfer (ET) more accurately than age-based counselling.

1. London Egg Bank, UK 2. Univfy, Los Altos, California, USA 3. London Women’s Clinic, UK *Correspondence to kamal.ahuja@londonwomensclinic.com

MATERIALS AND METHODS

Disclosure: Pataia was employed by the London Egg Bank at the time of the study. Yao has declared pending patent families with issued US patents and foreign counterparts (US 10,482,556; US 9,934,361; US 9,348,972; US 9,458,495; and US 10,438,686), as well as additional intellectual property pending. The other authors have declared no conflicts of interest. Multiple copyrights and registered trademarks are owned by Univfy Inc. Commercial licence fees and royalties are waived for Univfy's clients in exchange for product and service fees under the Univfy Services Agreement. Acknowledgements: The authors extend their sincere gratitude to their dedicated team of donor recruiters, patient care coordinators, matching coordinators, clinicians, nurses, scientists, and counsellors. Their invaluable contributions were essential to the successful operation of the vitrified oocyte donation programme and the completion of this study. Keywords: Donor oocytes, egg donation, live birth prediction, machine learning (ML), vitrified oocytes. Citation: EMJ Repro Health. 2026;12[1]:45-46. https://doi.org/10.33590/emjreprohealth/17896371

BACKGROUND AND AIMS Age-based counselling remains standard practice for prospective recipients of donor oocyte IVF, despite substantial variability in outcomes that age alone cannot capture.1 While machine learning (ML) methods have improved outcome prediction in autologous IVF,2-4 their application to donor oocyte cycles has not been explored. A team from London Egg Bank, UK; and Univfy, Los Altos, California, USA, set out to determine whether an ML model built from donor and recipient clinical characteristics could CC BY-NC 4.0 Licence

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The retrospective cohort study analysed 3,036 ETs performed for 1,958 recipients using vitrified oocytes from 1,135 donors between 2017–2022, drawn from a UKregulated vitrified donor oocyte programme. Gradient boosted machine models were developed and validated using five-fold cross-validation to predict live birth per ET. Two prediction models were built: a pre-treatment model, using variables available before treatment began, and a pre-ET model, incorporating variables known immediately before transfer. Both were compared against three age-based control models: recipient age alone, donor age alone, and combined recipient and donor age (RDA).

RESULTS The best prediction model, the pre-ET model, outperformed RDA, the bestperforming age control, achieving a 14.9% improvement in receiver operating characteristic area under the curve (0.50 versus 0.45) and a 12.3% improvement in precision-recall area under the curve (0.50 versus 0.45), reflecting stronger discrimination and prediction of live birth events. Across higher live birth probability thresholds (from 51% upwards), both the pre-treatment and pre-ET models achieved higher F1 scores than any agebased control, indicating a superior overall ability to minimise false positives and false negatives. At a threshold of 58% or above, for example, the pre-treatment and pre-ET models scored 0.26 and 0.45 respectively, compared with 0, 0, and 0.07 for the recipient-age, donor-age, and RDA models. Predictor relative importance analysis of the pre-ET model identified the total number

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of usable embryos as the most influential variable, accounting for 45% relative importance, ahead of recipient ET number (16%), recipient age (11%), donor age (11%), and donor anti-Müllerian hormone (9%). This ranking challenges the assumption that age is the primary determinant of outcome in donor oocyte cycles, suggesting embryo yield and treatment history carry greater predictive weight. Observed live birth rates were 43% after a first ET, decreasing to 34–36% in subsequent transfers. Cumulative analysis of the 1,336 recipients (68% of the cohort) who underwent up to three ETs found a cumulative live birth rate of 87.7%, underscoring the value of encouraging treatment continuation where clinically appropriate.

The authors acknowledge limitations. The cohort was drawn from a limited number of UK centres, which may reflect centrespecific practice and selection criteria, and the outcome modelled was live birth per ET rather than cumulative live birth, since recipients could receive oocytes from more than one donor and varying oocyte numbers.

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These findings support a shift away from age-based counselling alone toward individualised, ML-informed prognostic tools for donor oocyte IVF. Incorporating variables such as embryo yield, treatment history, and donor AMH into patient counselling could help calibrate expectations more precisely and support shared decisionmaking between clinicians and recipients. The authors suggest that further work should explore additional biological markers to refine prediction accuracy, and that prospective validation across a broader range of centres would strengthen the case for clinical implementation of ML-based prognostic counselling in this setting.

References

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Pataia V et al. Validating a machine learning model to predict live birth after vitrified donor oocyte IVF. Abstract L26/P-179. ESHRE Annual Meeting, 5-8 July, 2026.

Barnett-Itzhaki Z et al. Machine learning vs. classic statistics for the prediction of IVF outcomes. J Assist Reprod Genet. 2020;37(10):2405-12.

Banerjee P et al. Deep phenotyping to predict live birth outcomes in in vitro fertilization. Proc Natl Acad Sci U S A. 2010;107(31):13570-5.

Lannon BM et al. Predicting personalized multiple birth risks after in vitro fertilization-double embryo transfer. Fertil Steril. 2012;98(1):69-76.

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Atosiban Administration Before Frozen Embryo Transfer is Associated with Higher Clinical Pregnancy Rates: A Randomised Controlled Trial Authors: *Kanad Dev Nayar,1 Sabina Singh,1 Manika Sachdeva,1 Aashna Arora,1 Gaurav Kant,1 Kapil Dev Nayar1

intravenous atosiban before embryo transfer (Group A; n=50) or standard FET care without atosiban (Group B; n=50).

1. Akanksha IVF Centre – Mata Chanan Devi Hospital, New Delhi, India *Correspondence to kdnayar@usa.net

Eligible participants were 23–35 years of age, had a BMI <30 kg/m², a normal uterine cavity, endometrial thickness ≥7 mm, and underwent transfer of two Grade A blastocysts. Women in the intervention group received a 6.75 mg intravenous bolus of atosiban 30 minutes before embryo transfer. Baseline demographic, hormonal, and ovarian reserve parameters were assessed to ensure comparability between groups. The primary outcome was clinical pregnancy rate confirmed by ultrasonography after a positive serum β-human chorionic gonadotropin test. Secondary outcomes included implantation rate, biochemical pregnancy rate, and firsttrimester miscarriage rate.

Disclosure: The authors have declared no conflicts of interest. Keywords: Atosiban, clinical pregnancy rate, frozen embryo transfer (FET). Citation: EMJ Repro Health. 2026;12[1]:47-48. https://doi.org/10.33590/emjreprohealth/1992EY8R

BACKGROUND AND AIMS Frozen embryo transfer (FET) has become an integral component of assisted reproductive technology, offering outcomes comparable to or better than fresh embryo transfer while reducing the risk of ovarian hyperstimulation syndrome. Despite advances in embryo culture and endometrial preparation, implantation failure remains a significant challenge. Excessive uterine contractility at the time of embryo transfer has been implicated as a potential cause of implantation failure. Atosiban, a competitive oxytocin receptor antagonist, reduces uterine contractions and may improve implantation outcomes. However, evidence supporting its use has largely been derived from fresh embryo transfer cycles, with limited and inconsistent data available for FET. This RCT aimed to determine whether administration of atosiban prior to FET improves clinical pregnancy rates compared with standard FET protocols alone.1,2

RESULTS Baseline demographic and clinical characteristics, including age, duration of infertility, anti-Müllerian hormone levels, antral follicle count, and hormonal parameters, were comparable between the two groups. This similarity strengthens the internal validity of the trial and reduces the likelihood that observed differences were attributable to confounding variables.

MATERIALS AND METHODS

Clinical pregnancy rates were significantly higher in the atosiban group compared with controls (58% versus 38%), representing an absolute increase of 20% (p<0.05). These findings suggest that suppression of uterine activity at the time of embryo transfer may enhance reproductive outcomes in FET cycles.

This prospective RCT was conducted at a tertiary IVF centre in New Delhi, India, between February–September 2025. One hundred women undergoing FET were randomised equally to receive either

Secondary outcomes also favoured atosiban. Implantation rates were higher in the intervention group (33.3% versus 23.8%), although the difference did not reach statistical significance. Biochemical

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Table 1: Outcome of IVF embryo transfers in the Atosiban treatment group (n=50) and control group (n=50).

Clinical outcome (%)

Group A (cases) n=50

Group B (controls) n=50

p value

Clinical pregnancy rate

29/50 (58.00%)

19/50 (38.00%)

0.04 (S)

Implantation rate

30/90 (33.33%)

20/84 (23.81%)

0.12 (NS)

Biochemical pregnancy rate

10/50 (20.00%)

7/50 (14.00%)

0.42 (NS)

Clinical miscarriage rate

5/50 (10.00%)

4/50 (8.00%)

1.00 (NS)

Implantation rate = number of gestational sacs/number of embryos transferred. NS: not significant; S: significant.

pregnancy rates were numerically greater among women receiving atosiban (20% versus 14%), while firsttrimester miscarriage rates were lower (17.2% versus 21.1%; Table 1). Although these differences were not statistically significant, all secondary outcomes demonstrated a consistent trend favouring treatment. The absence of significance for secondary endpoints likely reflects the relatively modest sample size rather than a lack of biological effect, as all outcome measures moved in a favourable direction.

of uterine contractility suppression in enhancing implantation success. Although limited by its single-centre design and relatively small sample size, the trial addresses an important gap in the literature. Larger multicentre studies are needed to confirm these findings, assess live birth outcomes, and clarify the role of atosiban in routine FET practice.

References 1.

Nayar KD et al. Atosiban administration before frozen embryo transfer is associated with higher clinical pregnancy rates: a randomized controlled trial. Abstract L26-1295. ESHRE Annual Meeting, 5-8 July, 2026.

Cai H et al. Effectiveness of atosiban in women with previous single implantation failure undergoing frozen-thawed blastocyst transfer: study protocol for a randomised controlled trial. BMJ Open. 2023;13(10):e076390.

CONCLUSION This study provides evidence that pretransfer administration of atosiban may improve clinical pregnancy rates in women undergoing FET. The increase in clinical pregnancies, together with favourable trends in implantation and miscarriage outcomes, supports the potential role

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Abstract Review

Perinatal Outcomes of Piezo-ICSI Versus IVF Following Vitrified-Warmed Single Blastocyst Transfer: A Retrospective Cohort Study Authors: *Kenichiro Hiraoka,1 Kiyotaka Kawai1 1. Kameda IVF Clinic Makuhari, Chiba City, Japan *Correspondence to ken.msn.hiraoka@gmail.com Disclosure: The authors have declared no conflicts of interest. Acknowledgements: The authors would like to thank the clinical and laboratory staff for their support. Keywords: IVF, perinatal outcomes, Piezo-assisted intracytoplasmic sperm injection (Piezo-ICSI), sex ratio. Citation: EMJ Repro Health. 2026;12[1]:49-50 https://doi.org/10.33590/emjreprohealth/549786Y6

BACKGROUND AND AIMS Piezo-assisted intracytoplasmic sperm injection (Piezo-ICSI) has gained increasing attention as an alternative fertilisation method designed to minimise mechanical trauma to the oolemma and improve oocyte survival. While its laboratory advantages are becoming well recognised, evidence regarding its perinatal safety remains limited. Conventional IVF, which allows natural sperm–oocyte interaction, continues to serve as the benchmark for evaluating the safety of emerging fertilisation techniques. This review summarises findings from a large retrospective cohort study comparing perinatal outcomes following vitrified-warmed single blastocyst transfer after Piezo-ICSI versus IVF, providing important clinical insights into the safety profile of Piezo-ICSI in contemporary assisted reproductive technology (ART) practice.1

MATERIALS AND METHODS The study analysed 3,605 single-blastocyst transfer cycles performed between 2016– 2023 across two centers, including 1,732 IVF cycles and 1,873 Piezo-ICSI cycles. Women under 40 years of age were CC BY-NC 4.0 Licence

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included. Multivariable logistic regression adjusted for maternal age, male partner age, BMI, ovarian reserve, reproductive history, and previous ART cycles. Perinatal outcomes assessed included pregnancy and miscarriage rates, delivery rates, obstetric complications, monozygotic twinning, gestational age, birth weight, congenital anomalies, and neonatal sex ratio.

RESULTS Clinical outcomes were comparable between the two groups. Pregnancy rates (48.4% versus 49.4%), miscarriage rates (18.7% versus 19.8%), and delivery rates (38.0% versus 38.6%) showed no significant differences between IVF and Piezo-ICSI, respectively. Obstetric complication rates were also similar (21.1% versus 21.6%). Among infants born (668 in IVF; 733 in Piezo-ICSI), no significant differences were observed in monozygotic twinning (1.3% versus 1.4%), mean birth weight (3,024.6 g versus 3,008.5 g), gestational age at delivery (39.04 versus 39.00 weeks), or congenital anomaly rates (2.4% versus 1.5%). These findings collectively support the perinatal safety of Piezo-ICSI, aligning with emerging evidence from smaller studies. A notable finding was a significantly higher proportion of female infants in the PiezoICSI group compared with IVF (52.5% versus 43.1%). The biological basis for this difference remains unclear. Possible explanations include subtle variations in sperm selection or oocyte activation mechanisms inherent to Piezo-assisted injection. However, the possibility of a chance finding cannot be excluded, particularly given the large number of comparisons performed. Further mechanistic and multicentre studies are warranted to determine whether this sex ratio shift reflects a reproducible biological phenomenon or statistical variation.

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LIMITATIONS

CONCLUSION

The study’s retrospective design and the absence of a conventional ICSI comparison group represent limitations. Nonetheless, the large sample size, standardised single-blastocyst transfer approach, and comprehensive perinatal assessment strengthen the reliability of the findings. Importantly, the results provide reassurance for clinicians considering Piezo-ICSI as a primary fertilisation method, particularly in settings aiming to optimise oocyte survival while maintaining perinatal safety.

In conclusion, Piezo-ICSI demonstrates perinatal outcomes comparable to IVF in a large real-world cohort. While the increased proportion of female births merits further investigation, the overall findings support the clinical safety of Piezo-ICSI in modern ART practice.

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References 1.

Hiraoka K et al. Perinatal outcomes of Piezo-ICSI versus IVF following vitrified-warmed single blastocyst transfer: a retrospective cohort study. Abstract L26/P 132. ESHRE Annual Meeting, 5-8 July, 2026.

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Abstract Review

From Evidence to Impact: Translating Research on Quality of Life, Wellbeing, and Spirituality into Person-Centred Fertility Care Authors: *Madeleine Bernet,1,2 Alexander M. Quaas,3 Michael von Wolff,4 Eva Soom Ammann,1 Arndt Büssing2 1. Division of Nursing, Department of Health Professions, Bern University of Applied Sciences, Switzerland 2. Faculty of Health, Witten/Herdecke University, Germany 3. Shady Grove Fertility, San Diego, California, USA 4. University Women's Hospital, Division of Gynaecological Endocrinology and Reproductive Medicine, Inselspital, University Hospital, Berne, Switzerland *Correspondence madeleine.bernet@bfh.ch Disclosure: Bernet has received funding and/ or grants for the present work from the Zonta Club Bern and the Bern University of Applied Sciences, with payments made to the individual. Quaas has served as an advisor for Ferring Pharmaceuticals. The other authors have declared no conflicts of interest. Acknowledgements: The authors gratefully acknowledge the contributions of the HoPE study’s participants and professionals. There are no conflicts of interest. The study received ethical approval from the Cantonal Ethics Committee of Bern (BASEC-No: Req2021–00532) and the Ethics Committee of the University of Witten/Herdecke (Nr. S-114/2022). Keywords: Infertility, nursing science, patientcentred care, quality of life, reproductive medicine, spiritual needs. Citation: EMJ Repro Health. 2026;12[1]:51-52. https://doi.org/10.33590/emjreprohealth/6243VT04

BACKGROUND AND AIMS Infertility affects approximately one in six individuals worldwide and extends far beyond its biological dimensions, affecting emotional wellbeing, quality of life, and psychosocial health.1,2 While reproductive medicine has achieved remarkable technological advances, fertility care continues to focus primarily on medical treatment and pregnancy outcomes. Emotional, psychosocial, and spiritual dimensions of infertility remain insufficiently CC BY-NC 4.0 Licence

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addressed despite their profound impact on affected individuals.2-5 The HoPE study (Health care users’ and Professionals’ Perspectives and Experiences in Fertility Treatment in Switzerland) was designed to generate evidence for more holistic, patient-centred fertility care in Switzerland.6,7

MATERIALS AND METHODS Using an explanatory sequential mixedmethods design, the study combined a nationwide multilingual online survey (German, French, and Italian) of individuals with an unfulfilled desire for children (n=326) with semi-structured interviews (n=26) and three focus group discussions with healthcare professionals in reproductive medicine (n=20). Validated instruments assessed fertility-related quality of life (Fertility Quality of Life [FertiQoL]),8 psychological wellbeing (World Health Organization-Five Well-Being Index [WHO-5]),9 and spiritual needs (Spiritual Needs Questionnaire-20 [SpNQ-20]),10 while qualitative data explored lived experiences and opportunities to improve fertility care.

RESULTS The findings confirmed the multidimensional impact of infertility, revealing substantial emotional, psychosocial, and existential burden. Emotional quality of life was the lowest of all FertiQoL domains (mean score [M]=46.35), and participants reported reduced psychological wellbeing (WHO5: M=13.89) together with substantial needs for inner peace, meaning, and support. Spiritual needs were particularly pronounced among individuals without children (SpNQ-20 inner peace: M=1.82), who also experienced significantly greater emotional and existential burden than participants who already had children.

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Qualitative findings revealed infertility as a prolonged experience of uncertainty, repeated disappointment, decision-making pressure, social isolation, and insufficient societal recognition. Participants frequently perceived a lack of understanding not only within their social environment but also within healthcare services. Healthcare professionals confirmed the considerable psychosocial burden experienced by people undergoing fertility treatment, while identifying structural barriers, including limited consultation time, fragmented care pathways, and insufficient integration of psychosocial support into routine fertility services. They advocated for stronger interprofessional collaboration and coordinated care models that address the emotional, psychosocial, and existential dimensions of infertility alongside medical treatment.6,7 A key strength of the HoPE project is its successful translation of research into education, clinical practice, and health policy. The findings informed the development of innovative continuing education programmes (Certificate of Advanced Studies and Short Advanced Studies) at Bern University of Applied Sciences, Switzerland, designed to strengthen competencies in person-centred, interprofessional, and psychosocially informed reproductive healthcare among physicians, nurses, midwives, counsellors, medical practice assistants, and other healthcare professionals. Based on the results, an evidence-based patient information brochure was codeveloped to support individuals during the emotionally challenging waiting period between embryo transfer and pregnancy testing, translating research findings into practical guidance. The project has also contributed to national policy discussions by informing the Swiss Parliamentary Group for Family Policy on issues related to infertility, fertility care, reimbursement, and service organisation. The findings have fostered collaborations and contributed to the growing integration of psychosocial care into reproductive medicine.

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CONCLUSION The HoPE study demonstrates that infertility should be understood not only as a medical condition, but also as an emotional, psychosocial, and existential experience. Its impact illustrates how interprofessional research can drive evidence-based improvements in reproductive healthcare through interdisciplinary collaboration, person-centred care, and effective knowledge translation across education, clinical practice, patient resources, and health policy.

References 1.

Bernet M et al. Beyond medical treatment: addressing the emotional and spiritual dimensions of infertility – a mixed-methods approach. Abstract L26/O-111. ESHRE Annual Meeting, 5-8 July, 2026.

WHO. Infertility prevalence estimates, 1990–2021. 2023. Available at: https://www.who. int/publications/i/item/978920068315. Last accessed: 10 July 2026.

European Society of Human Reproduction and Embryology (ESHRE). Routine psychosocial care in infertility and medically assisted reproduction: a guide for fertility staff. 2023. Available at: https:// www.eshre.eu/-/media/sitecore-files/Guidelines/ Psychology/ESHRE-psychology-guideline_2015_ final_version-1_2.pdf. Last accessed: 10 July 2026.

Lienhard M et al. Bedürfnisse von betroffenen personen während einer kinderwunschbehandlung und deren erwartungen an die pflegerische betreuung. Medical Update Marketing & Media. 2024;DOI:10.24451/dspace/11368.

Sutter L et al. Psychische gesundheit im übergang zum elternsein: herausforderungen und chancen nach kinderwunschbehandlungen. Sozialpsychiatrische Informationen. 2025;55(3):46-50.

Bernet M et al. Quality of life, spiritual needs, and well-being of people affected by infertility and its treatment: quantitative results of a mixed-methods study. J Assist Reprod Genet. 2025;42:1853-62.

Bernet M et al. "It's like having a second job": qualitative insights into the emotional burden of infertility and the need for coordinated care. J Psychosom Obstet Gynaecol. 2025;46(1):2505589.

Boivin J et al. The Fertility Quality of Life (FertiQoL) tool: development and general psychometric properties. Fertil Steril. 2011;96(2):409-15.e3.

WHO Regional Office for Europe. Wellbeing measures in primary health care: the DEPCARE project. 1998. Available at: https://iris.who.int/ items/07a5e1ac-9832-4088-a25d-0338088bdb05. Last accessed: 10 July 2026.

10. Büssing A. The Spiritual Needs Questionnaire in research and clinical application: a summary of findings. J Relig Health. 2021;60(5):3732-48.

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Abstract Review

The Role of the Exposome and Lifestyle in Live Birth Outcomes Among Lebanese Patients Undergoing IVF Authors: *Myriam Mrad,1 Kassandra Fares,2 Emile Whaibeh,1 Jowy Abi Hanna,1 Lina Jaalouk,1 Georges Abi Tayeh3 1. Public Health Department, University of Balamand, Beirut, Lebanon 2. Institut de Santé Publique, University of Saint Joseph, Beirut, Lebanon 3. Obstetrics and Reproduction, Hôtel Dieu de France, University of Saint Joseph, Beirut, Lebanon *Correspondence to myriam.mrad@balamand.edu.lb Disclosure: The authors have declared no conflicts of interest. This research was supported by the National Institutes of Health (NIH) Fogarty Program through project funding awarded to the principal investigators. The study was executed by doctoral students within the University of Saint Joseph Beirut research framework. The funders had no role in the study design, data collection, or decision to publish these findings. Keywords: Assisted reproductive technology, environmental exposures, exposome, in vitro fertilisation (IVF), live birth. Citation: EMJ Repro Health. 2026;12[1]:53-55. https://doi.org/10.33590/emjreprohealth/KY8K1075

BACKGROUND AND AIMS Clinical predictors such as maternal age and ovarian reserve are well-established determinants of IVF success.1 Increasing evidence suggests that environmental and lifestyle exposures also influence reproductive outcomes; however, these factors remain insufficiently investigated in low- and middle-income countries.2,3 In Lebanon, reproductive research has historically focused on maternal and child health, with limited attention paid to the role of environmental exposures in assisted reproductive technologies.4,5 This study aimed to investigate the specific contribution of environmental, chemical, and lifestyle exposures to live birth outcomes among Lebanese patients who have undergone IVF, while integrating complementary biomonitoring evidence CC BY-NC 4.0 Licence

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from the Environmental Exposures in Lebanese Infants (EELI) mother–child cohort to provide a broader, evidence-based understanding of reproductive and early-life environmental health.4-7

MATERIALS AND METHODS This prospective cohort study was conducted within the Fertility in Light of Environmental Exposures and Lifestyle (FEEL) study and included infertile patients undergoing IVF treatment.6 Participants were prospectively followed throughout their treatment cycles to accurately assess cumulative live birth outcomes. Demographic, clinical, lifestyle, dietary, and environmental exposure data were collected using standardised questionnaires and clinical assessments. Principal component analysis was performed to derive robust composite environmental exposure measures, while multivariable logistic regression was used to identify independent predictors of live birth after adjustment for relevant clinical and sociodemographic confounders. To complement these findings, biomonitoring evidence from the EELI cohort, including analyses of heavy metals and legacypesticides in cord blood, was incorporated to contextualise environmental exposure pathways during pregnancy and early life.4,5,7

RESULTS Higher anti-Müllerian hormone (AMH) was independently associated with greater odds of live birth (odds ratio [OR]: 1.94; 95% CI: 1.28–2.94). A principal component representing lower cumulative chemical exposure was also positively associated with live birth (OR: 1.72; 95% CI: 1.12–2.64). Conversely, household pesticide exposure was associated with significantly lower odds of live birth (OR: 0.54; 95% CI: 0.31–0.93), while higher environmental noise exposure demonstrated a negative

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association with reproductive success, including perceived noise affecting sleep (moderate disagreement: OR: 0.020; 95% CI: 0.0007–0.55; strong disagreement: OR: 0.051; 95% CI: 0.003–0.80). Higher maternal education and greater dietary energy intake were positively associated with IVF

outcomes. Complementary evidence from the EELI cohort demonstrated widespread prenatal environmental exposure, with heavy metals detected in nearly all cord blood samples (n=74), a median cord blood lead concentration of 5.45 μg/L, and detectable levels of legacy pesticides,

Figure 1: Environmental, lifestyle, and biomonitoring determinants of live birth outcomes in Lebanese patients undergoing IVF.

Lower odds of live birth

Higher odds of live birth

OR Key finding: Lower cumulative chemical exposure and higher AMH significantly increase the odds of achieving a live birth.

Created using ChatGPT (OpenAI, San Francisco, California, USA). AMH: anti-Müllerian hormone; DDE: dichlorodiphenyldichloroethylene; DDT: dichlorodiphenyltrichloroethane; IQR: interquartile range; OR: odds ratio.

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confirming fetal exposure to environmental contaminants before birth. An overview of the principal findings from the FEEL and EELI cohorts, together with the integrated reproductive exposome framework, is presented in Figure 1.

CONCLUSION Clinical factors remain important determinants of IVF success, but modifiable environmental and lifestyle exposures also contribute to reproductive outcomes. Lower chemical exposure and reduced household pesticide exposure were associated with improved live birth outcomes, while biomonitoring evidence confirmed that environmental contaminants are transferred to the fetus during pregnancy. These findings support the integration of exposome assessment into routine fertility care as a feasible, preventive strategy that complements conventional clinical management. Incorporating environmental health perspectives into reproductive medicine may improve IVF success rates, promote healthier pregnancies, and contribute to better long-term health outcomes across the life course.

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References 1.

Whaibeh E al. Correlates of prenatal heavy metal contamination in Lebanese infants using cord blood analysis. Sci Rep. 2026; DOI:10.1038/s41598-026-46981-1.

Whaibeh E et al. Cord blood lead screening in Lebanon: findings from the environmental exposures in Lebanese infants (EELI) study. Environ Pollut Bioavailab. 2025;37(1):2524084.

Whaibeh E et al. The Environmental Exposures in Lebanese Infants (EELI) birth cohort: an investigation into the Developmental Origins of Health and Diseases (DOHaD). Int J Environ Health Res. 2024;34(3):1675-86.

Whaibeh E et al. Air pollution and perinatal health in the Eastern Mediterranean region: challenges, limitations, and the potential of epigenetics. Curr Environ Health Rep. 2022;9(1):1-10.

Fares KS et al. Exploring determinants of cumulative live birth rates in IVF: insights from the EELI study in Lebanon. Reprod Health. 2026;23(1):35.

Fares KS et al. The role of diet and food supplements in infertility management in the Eastern Mediterranean region: a narrative review. Int J Reprod Biomed. 2025;23(1):1-16.

Fares KS et al. The influence of environmental and chemical exposures on fertility in the Eastern Mediterranean region: a narrative review. Int J Reprod Biomed. 2025;23(10):787-802.

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Preliminary Embryological and Implantation Outcomes of Progesterone Versus GnRH Antagonist for LH Suppression in IVF Cycles Authors: Rahshanda Aslanova,¹ *Khumar Mammadli,1 Kamal Niftiyev1 1. Medilux Eko, Baku Medical Plaza, Azerbaijan *Correspondence to khumarsh@gmail.com Disclosure: The authors have declared no conflicts of interest. Keywords: Embryo quality, gonadotropinreleasing hormone (GnRH) antagonist, implantation, IVF, progesterone-primed ovarian stimulation (PPOS). Citation: EMJ Repro Health. 2026;12[1]:56-57. https://doi.org/10.33590/emjreprohealth/9R918SKG

BACKGROUND AND AIMS Preventing premature luteinising hormone (LH) surge is a fundamental component of controlled ovarian stimulation during IVF. Gonadotropin-releasing hormone (GnRH) antagonist protocols have become the standard approach because of their effectiveness in suppressing premature ovulation while maintaining favourable reproductive outcomes. Progesteroneprimed ovarian stimulation (PPOS) has emerged as an alternative strategy, particularly in freeze-all IVF cycles, owing to its simplicity, lower treatment burden, and reduced cost. Nevertheless, concerns remain regarding the potential effects of progesterone exposure during ovarian stimulation on embryo development and implantation. Comparative clinical data evaluating embryological outcomes between these protocols remain limited.1-4

MATERIALS AND METHODS This retrospective observational study5 compared embryological and implantation outcomes between PPOS and GnRH antagonist protocols in women undergoing IVF/intracytoplasmic sperm injection treatment at a single tertiary IVF centre. A total of 256 treatment cycles were included, 56

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comprising 125 PPOS cycles and 131 GnRH antagonist cycles. Baseline demographic characteristics and ovarian stimulation parameters were comparable between the two groups. The primary outcomes included the number of retrieved oocytes, mature metaphase II oocytes, fertilisation rate, blastocyst quality, and implantation rate.

RESULTS Ovarian response and fertilisation outcomes were comparable between groups. Median retrieved oocytes were 14.0 in the PPOS group versus 13.5 in the GnRH antagonist group, and median mature metaphase II oocytes were 12.0 versus 10.0, respectively. Fertilisation rates were 84.0% and 85.9%. The GnRH antagonist group had a significantly greater proportion of topquality blastocysts (AA, AB, and BA Grades; p=0.024), whereas the PPOS group had a higher proportion of BB-Grade blastocysts (p=0.033). Implantation rate was significantly higher with the GnRH antagonist protocol (14.4% versus 9.4%; p=0.017). These findings are summarised in Table 1. Despite similar ovarian and fertilisation outcomes, significant differences were identified in embryo quality. The GnRH antagonist protocol produced a significantly greater proportion of top-quality blastocysts (AA, AB, and BA Grades; p=0.024), whereas the PPOS group generated a higher proportion of BBgrade blastocysts (p=0.033). Furthermore, implantation rates differed significantly between treatment strategies, with the GnRH antagonist group demonstrating a higher implantation rate than the PPOS group (14.4% versus 9.4%; p=0.017).

CONCLUSION Progesterone-based LH suppression provides ovarian response and fertilisation

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Table 1: Embryological and implantation outcomes by LH suppression protocol.

Outcome

PPOS (n=125)

GnRH antagonist (n=131)

p value

Retrieved oocytes, median (P25–P75)

14.0 (10.0–20.0)

13.5 (11.0–18.0)

MII oocytes, median (P25–P75)

12.0 (7.0–15.5)

10.0 (7.5–14.0)

2PN embryos, median (P25–P75)

10.0 (7.0–13.0)

9.0 (6.0–11.0)

Fertilisation rate (%)

84.0

85.9

A-grade blastocysts

2.14

2.78

0.024

B-grade blastocysts

3.56

3.01

0.033

Implantation rate (%)

9.4

14.4

0.017

2PN: two-pronuclear; GnRH: gonadotropin-releasing hormone; LH: luteinising hormone; MII: mature metaphase II; NS: not statistically significant; P25–P75: 25th–75th percentile; PPOS: progesterone-primed ovarian stimulation.

outcomes comparable to those achieved with GnRH antagonist protocols, but differences in blastocyst quality distribution may translate into lower implantation potential. The observed reduction in implantation rate among women treated with PPOS warrants careful consideration when selecting ovarian stimulation protocols, particularly in patients in whom embryo competence and implantation potential are major clinical priorities. However, the retrospective design and single-centre nature of the present study limit the generalisability of these findings and do not allow causal conclusions to be drawn. Larger multicentre, prospective, randomised studies are required to determine whether these observed differences represent a true biological effect of progesterone-based suppression or reflect patient selection and other confounding factors.

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References 1.

Kuang Y et al. Medroxyprogesterone acetate is an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. Fertil Steril. 2015;104(1):62-70.e3.

Ata B et al. Progestins for pituitary suppression during ovarian stimulation for ART: a comprehensive and systematic review including meta-analyses. Hum Reprod Update. 2021;27(1):48-66.

Al-Inany HG et al. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev. 2016;4(4):CD001750.

Massin N. New stimulation regimens: endogenous and exogenous progesterone use to block the LH surge during ovarian stimulation for IVF. Hum Reprod Update. 2017;23(2):211-20.

Aslanova R et al. Preliminary embryological and implantation outcomes of progesterone versus GnRH antagonist for LH suppression in IVF cycles. Abstract L26/P-138. ESHRE Annual Meeting, 5-8 July, 2026.

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Congress Interviews EMJ had the pleasure of interviewing five leading members of the European Society of Human Reproduction and Embryology (ESHRE) Executive Committee and senior faculty. Chair-Elect Anis Feki discusses the Society's vision for equitable, evidence-based fertility care, while Immediate Past Chair Karen Sermon explores the future of reproductive genetics and the responsible integration of genomic technologies. Chair-Elect Borut Kovačič shares his perspective on innovation in embryology, AI, and quality assurance; Georg Griesinger examines the future of IVF, treatment add-ons, and emerging reproductive technologies; and Maribel Acién reflects on the evolving role of reproductive surgery, multidisciplinary care, and surgical education. Featuring: Anis Feki, Karen Sermon, Borut Kovačič, Georg Griesinger, and Maribel Acién

Citation:

EMJ Repro Health. 2026;12[1]:58-61. https://doi.org/10.33590/emjreprohealth/1N1T76AG

Author:

Alena Sofieva, EMJ, London, UK

Access to fertility care and clinical practice still varies considerably across Europe. In your view, what are the biggest challenges facing reproductive medicine today, and how is European Society of Human Reproduction and Embryology (ESHRE) helping to address them?

Anis Feki Professor and Head of the Department of Obstetrics and Gynaecology, Hôpital Fribourgeois, University of Fribourg, Switzerland; ChairElect, European Society of Human Reproduction and Embryology (ESHRE)

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ESHRE cannot determine national reimbursement policies or legislation, but it can provide a common scientific and ethical reference point. We do this through evidence-based guidelines, education and certification, centre accreditation, European IVF Monitoring, and advocacy for equitable, safe, and effective care.

The central challenge is inequity. Across Europe, access to fertility care still depends too heavily on where people live, on funding arrangements, legislation, geography, and, at times, whether they fit historical definitions of family. There are also important differences in workforce capacity, laboratory standards, data collection, and access to specialised care. At

Policy and clinical standards are strongest when patients are part of the conversation

the same time, patients face an expanding market of tests and treatments, not all supported by robust evidence.

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We work closely with Fertility Europe (Evere, Belgium) because policy and clinical standards are strongest when patients are part of the conversation. We also support clear public information, including through

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the International Human Rights Commission (IHREC), so that people can make informed decisions before they reach the clinic. This is particularly important where regulation does not prevent clinics from offering unproven add-ons. In many countries, clinics remain free to provide these interventions, so patients need clear, evidencebased information to distinguish established treatments from innovations that have not been shown to improve live birth rates. The objective should not simply be access to a procedure. It should be timely access to an evidence-based pathway,

Fertility is not a singleorgan problem, and reproductive medicine cannot be delivered well by isolated specialists

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delivered safely by a trained multidisciplinary team, and measured by outcomes that matter to patients.

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outcomes, multiple-pregnancy rates, ovarian hyperstimulation, laboratory performance, treatment cancellations, complications, and patientreported experience. Results must be interpreted in the context of the patients treated, not used as marketing material.

Quality assurance has been a major focus throughout your career. What practical steps can fertility centres take to improve the quality, safety, and consistency of patient care?

The same principles apply to communication. Informed consent must be a process, not a signature. Patients should understand benefits, limitations, risks, costs, and alternatives.

Quality is not a document on a shelf; it is a daily clinical culture. Every centre should have a functioning quality-management system with clear standard operating procedures, robust patient identification and traceability, documented staff training and competency assessment, incident reporting without blame, regular internal audits, and a tested emergency plan, particularly for cryostorage and critical laboratory equipment.

Specialist nurses, embryologists, and reproductive biologists are indispensable in delivering this continuity and clarity. ESHRE’s laboratory guidance, performance indicators, accreditation programmes, and professional certification support precisely this kind of transparent, team-based quality system.

Centres should monitor meaningful indicators rather than relying on headline pregnancy rates alone: cumulative live-birth

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You have led both academic and clinical departments. How can fertility specialists balance the rapid adoption of new technologies with the need for robust clinical evidence?

already well established in areas such as laboratory diagnostics and cervical cytology screening, where its performance has been extensively validated. Reproductive medicine should follow the same principles.

Innovation is essential in reproductive medicine; many of today’s standard treatments began as bold ideas. But innovation must not outrun evidence.

In embryology, AI may support embryo assessment and clinical decision-making, but these systems require prospective validation, transparent algorithms, and independent evaluation before they can be adopted routinely. AI should support clinicians, not replace clinical judgement, and the final responsibility for patient care must always remain with healthcare professionals.

A plausible biological mechanism, an attractive technology, or an early observational study is not enough to justify routine use. I encourage centres to distinguish clearly between established care, promising innovation, and experimental practice.

Transparency is equally important. If the underlying algorithm cannot be independently assessed or validated, clinicians should be cautious about adopting it into routine practice. Innovation is welcome, but without transparency and external validation, it cannot become evidence-based care.

New technologies should be evaluated for efficacy, safety, cost, equity, and their impact on the whole treatment pathway, not merely on an intermediate laboratory outcome. Whenever possible, this requires welldesigned prospective studies, randomised trials, and meaningful long-term follow-up. Registries also have an important role when trials are not feasible.

The most responsible message to patients is not: “We have the newest technology.” It is: “We will offer what is justified for you and explain honestly what remains uncertain.”

This is particularly relevant for AI, genetic technologies, and IVF add-ons. AI may improve workflow and decision support, but algorithms must be validated, transparent, and monitored in real clinical populations. AI is

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Reproductive medicine is becoming increasingly multidisciplinary. How important is collaboration between reproductive endocrinologists, surgeons, embryologists, geneticists, and other specialists in delivering the best outcomes for patients? It is fundamental. Fertility is not a single-organ problem, and reproductive medicine cannot be delivered well by isolated specialists. The best outcomes come when reproductive endocrinologists, reproductive surgeons, embryologists, andrologists, geneticists, nurses, counsellors, psychologists and, when needed, oncologists or maternal– fetal medicine specialists work as one team. This matters most in complex cases: severe endometriosis, adenomyosis, recurrent implantation failure, severe male infertility, fertility preservation, and genetic disease. The question should never be, “Which discipline owns this patient?” It should be, “What is the best pathway for this patient?” Multidisciplinary boards can avoid unnecessary sequential referrals, reduce delays, and ensure that surgery, laboratory treatment, genetics, and counselling are coordinated from the beginning.

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ESHRE 2026

I would welcome a joint statement from the major scientific societies encouraging this model, particularly for complex fertility care. A patient should not have a different chance of pregnancy merely because she first saw a reproductive surgeon rather than a reproductive endocrinologist or vice versa.

the highest possible number of embryos transferred. It gives practical support for safer decision-making and shared discussions with patients.

ESHRE has played a leading role in education and guideline development. Which recent initiatives do you believe will have the greatest impact on everyday clinical practice?

First, the 2025 update of the ovarian stimulation guideline brings the entire stimulation pathway together, from pre-treatment assessment to prevention of ovarian hyperstimulation syndrome. It helps clinicians personalise care without losing sight of safety.

The greatest advance may also be organisational: better registries, harmonised outcome reporting, multidisciplinary care pathways, and earlier fertility education. We need to move from measuring isolated cycle results to understanding cumulative outcomes, safety, wellbeing, and the health of children born after treatment. ESHRE’s role is to be both a catalyst and a safeguard. We should bring clinicians, scientists, embryologists, nurses, patient organisations, regulators, and policy makers together; support high-quality research; translate evidence into guidelines; strengthen education; and make reliable information understandable to the public.

We are also preparing to update the international guideline on polyendocrine metabolic ovarian syndrome in collaboration with partner societies. As with previous guideline projects, the aim is to ensure that evolving scientific understanding is translated into practical, evidence-based recommendations for clinicians.

I would highlight four areas.

Our ambition must remain clear: a healthy child, safe treatment, informed patients, and fair access. Hope is essential in reproductive medicine, but it has to be shaped by science, honesty, and compassion.

Second, the good-practice recommendations on add-ons are particularly important because they address a real pressure point in daily practice: how to discuss optional interventions honestly when evidence is limited. Their value is not only in recommending or discouraging individual tests or treatments, but in setting a standard for transparent counselling. Third, the embryo-transfer guideline reinforces the central objective of treatment: a healthy pregnancy and birth, rather than

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Looking ahead, what do you hope will be the defining advances in reproductive medicine over the next decade, and what role do you see ESHRE playing in shaping that future?

Our ambition must remain clear: a healthy child, safe treatment, informed patients, and fair access

I hope the next decade will be defined less by technology alone than by precision, responsibility, and equity. We will see progress in AIsupported laboratory and clinical decision-making, fertility preservation, reproductive genetics, the management of endometriosis and adenomyosis, and possibly new approaches to ovarian function and gamete biology. But each advance must be assessed not only for what it

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can do, but for whom it helps, at what cost, and with what longterm consequences.

Finally, education must reach every member of the team. ESHRE certification for clinical embryologists, nurses and midwives, reproductive medicine specialists, and reproductive surgeons, together with centre accreditation, helps turn guidance into practice. Guidelines improve standards of care, but they translate into better outcomes only when implemented by trained professionals within well-organised teams.

This model also recognises the central contribution of embryologists, reproductive biologists, and nurses. Their expertise is not ancillary; it is part of the clinical decision-making process.

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Citation:

EMJ Repro Health. 2026;12[1]:62-63. https://doi.org/10.33590/emjreprohealth/1N1T76AG

Author:

Alena Sofieva, EMJ, London, UK

Genetic technologies are advancing at an extraordinary pace. Which developments do you believe will have the greatest impact on reproductive medicine?

Karen Sermon Professor of Genetics and Embryology, Vrije Universiteit Brussel; Member, Research Department Reproduction and Genetics (REGE), Vrije Universiteit Brussel, Belgium; Immediate Past Chair, European Society of Human Reproduction and Embryology (ESHRE)

Expanded carrier screening is gaining momentum. Do you see this becoming routine before fertility treatment?

I think whole genome sequencing is probably the next major step. Once you're analysing an embryo, it becomes technically possible to look far beyond chromosome number and identify much smaller genetic changes. As sequencing becomes cheaper, that level of information will become increasingly available.

Until stronger evidence becomes available, PGT-A should continue to be evaluated in research settings

The challenge, however, isn't generating more data. It's deciding what that information actually means. We're going to learn an enormous amount, but we'll also have to distinguish between findings that are genuinely important and those that are unlikely to have much impact on the future individual. We've been able to have perfectly healthy children without all this information, so we need to be careful about how we use it. At the same time, genetics is moving upstream. Rather than focusing only on embryos, we're increasingly investigating the genetic causes of infertility itself. Expanded carrier screening before treatment is another important development because it allows us to identify couples at risk of passing on recessive disorders before they begin IVF.

I think that's where we're heading. If both partners carry the same recessive condition, identifying that risk before IVF allows them to make informed reproductive choices, including whether preimplantation genetic testing (PGT) for monogenic disease is appropriate. Of course, accessibility remains a major issue. Reproductive medicine is expensive, and genetic testing adds another layer of cost. But I see this as part of preventive medicine. In Belgium, we've gradually expanded reimbursement for several forms of genetic testing, including non-invasive prenatal testing (NIPT). I hope carrier screening will eventually follow the same path, because preventing severe genetic disease benefits both families and healthcare systems.

PGT for aneuploidy (PGT-A) remains one of the most debated areas in reproductive medicine. Why? I don't think the debate is about whether PGT-A can ever be useful. The real question is which patients benefit and what outcome we're actually trying to improve. It's often presented as something that improves success rates, but

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ESHRE 2026

if you look at the RCTs, it hasn't been shown to improve live birth rates per patient. That doesn't necessarily mean it has no value. It may reduce miscarriage or shorten the time to pregnancy for certain patient groups, but we still don't know which patients those are. I think we need a much more measured approach. Until stronger evidence becomes available, PGT-A should continue to be evaluated in research settings so that we can identify who, if anyone, benefits most and what outcomes it genuinely improves.

Why do you think PGT-A has become so widely adopted despite the remaining uncertainty?

time evaluating the evidence. That doesn't automatically mean one group is right and the other is wrong, but it does remind us that we need robust data before introducing new technologies into routine clinical practice.

Looking ahead, what do you think will define the next decade of reproductive genetics?

One thing I've noticed is that many of the strongest advocates tend to work in commercial settings, whereas many of the people calling for greater caution are academics who spend their

Congress Interview

Alongside education, I think advocacy has become equally important. Infertility is still underfunded, and reproductive research remains underfunded. Many policymakers still don't fully recognise infertility as a disease, so we have an important role in influencing policy while continuing to provide education, publish evidence-based guidelines, and promote high-quality science.

Evidence-based medicine means resisting the temptation to assume that a technically impressive test automatically leads to better patient outcomes. We still need to establish which patients benefit and exactly how they benefit.

I think enthusiasm for new technologies can sometimes outpace the evidence. The technology itself isn't the problem. The question is whether we're introducing it because we know it benefits patients or simply because it's available.

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As Immediate Past Chair of the European Society of Human Reproduction and Embryology (ESHRE), where do you think the Society should focus over the coming years?

I think we'll continue to see more sequencing, more technology, and much more genetic information. The challenge will be making sure we're using that information to improve patient care rather than simply collecting more data. For me, the future of reproductive genetics isn't about knowing everything we possibly can about the genome. It's about understanding which information genuinely matters, using it responsibly, and making sure innovation is always guided by robust evidence.

I think certification and accreditation will become increasingly important. ESHRE is working not only to certify individual embryologists and reproductive medicine specialists, but also to accredit training centres, helping to ensure that practical skills are taught consistently across Europe. It's not enough to assess theoretical knowledge. We also need to make sure people receive high-quality practical training.

The challenge will be making sure we're using that information to improve patient care rather than simply collecting more data

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Citation:

EMJ Repro Health. 2026;12[1]:64-67. https://doi.org/10.33590/emjreprohealth/1N1T76AG

Author:

Alena Sofieva, EMJ, London, UK

With IVF success rates continuing to improve, where do you see the greatest remaining opportunities to optimise treatment outcomes for patients?

Georg Griesinger

I'm not sure if IVF success rates have really improved, but what we can do is have a more targeted approach. We should do IVF in people who have a good chance of achieving success with it, then identify those who are highly unlikely to achieve success and try to channel them towards more appropriate treatment pathways. Typically, this goes towards donation or moving on in your procreation journey, so to speak.

University of Lübeck, Germany; Universitäres Kinderwunschzentrum Lübeck and Manhagen, Germany

You can observe an embryo through the microscope or through the means of AI, but the embryo does not get better because of that

I think, with that, you can make IVF more successful, but you will not treat as many patients who will not benefit from it. This requires that you have access to the full spectrum of methods, including all kinds of donations.

When we work with oocytes and sperm, we do not really interfere in any causal way with the setup of these germ cells. We have come to a plateau, or a limit, of what can be achieved.

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You can biopsy an embryo or perform tests on it; it will never get better from that. The embryo can only get worse from the biopsy, the freezing thereafter, even if only slightly, and because of false positive diagnoses on genetic findings. The end result of all of this is that we do not increase the number of women having a child through IVF, though success rates per treatment attempt can be inflated.

I would also argue that the sentiment in the field is more that IVF success rates have, in a way, levelled off. It's coming to a plateau. Germ cells are germ cells. Our patients get older and older. They are getting less reproductively fit in terms of BMI, concurrent disorders, potential accumulation of environmental toxins, negative health or lifestyle factors, and so on.

A lot of effort has gone into the selection of gametes and embryos. You can spend as much time selecting an embryo as you wish. You can observe an embryo through the microscope or through the means of AI, but the embryo does not get better because of that. I think we can all agree on this.

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What emerging technologies or research directions do you think have the greatest potential to move reproductive medicine beyond the current limits of IVF? So, if the question is what might move us beyond that plateau, then there are some new frontiers being explored. One is the uterus. Many people are sceptical that much can be achieved on that frontier because the uterus is considered a rather simple organ. Decidualisation of the endometrium is a very ancient and reliable mechanism in humans, and there may not be much that we can theoretically improve.

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ESHRE 2026

The observation supporting that is that, in the oocyte donation setting, we see relatively stable success rates independent of uterine age. There was a presentation during the European Society of Human Reproduction and Embryology (ESHRE) Congress where they reported some decrease in live birth rate above 50 years of age in the recipient, independent of paternal age and other factors, so there is some uterine factor there. But many people argue that changing a uterine factor, such as endometrial receptivity, is not going to be the big game changer. On another frontier, a technique that is often discussed is maternal spindle transfer. It brings together oocyte donation and a patient's own genetic material. The patient's nuclear genetic material is transferred into an enucleated donor oocyte at the right moment in meiosis. The oocyte is then reconstituted, and you essentially have a young oocyte with your own nucleus and human genetic material. Then the sperm is added. The promise is that this could improve success rates in older CC BY-NC 4.0 Licence

women in a relevant way. There are, however, many safety concerns. You create ‘threeparent children’ because you're combining mitochondrial DNA from the donor oocyte with nuclear DNA from the mother and father. In essence, you create new genetic combinations.

The oocyte remains the decisive contributor to fertility because it provides the machinery. I often show patients that the sperm is tiny compared with the oocyte. The sperm contributes mostly information and some small tools, but the oocyte provides the large machinery on top of information. When that machinery ages, fertility declines.

There has been a growing debate around treatment add-ons in reproductive medicine, with the current ESHRE Chair, Karen Sermon, describing preimplantation genetic testing for aneuploidy (PGT-A) as a “massively abused method.” What is your view on the evidence supporting PGT-A and other addons, and when, if ever, do you offer these interventions to patients?

Many things are not yet fully understood about this technology, but, to me, this is an example of moving beyond conventional IVF. Conventional IVF, as we see it today, has largely levelled off. We may still optimise culture media or incubator conditions, but those changes are unlikely to dramatically alter outcomes. What may make a difference are approaches that Copyright © 2026 EMJ

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Congress Interview

rejuvenate oocytes, repair agerelated deficiencies, or create artificial gametes.

This is already happening in clinical practice. However, in Germany, for example, it would be forbidden under penal law because it would be considered manipulation of the germline. But there are places where it is not regulated. In Greece, for example, the Institute of Life in Athens has permission to perform this and has published on it, including followup of pregnancies and children.

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An embryo never gets better through testing. The promise that more women can achieve a live birth by applying the technology is likely false from the beginning.

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People argued that it had secondary benefits. Particularly in the USA, they said that if you transfer only one embryo instead of two or three, you could reduce multiple pregnancies. The argument was that genetic testing would identify the best embryo and therefore support elective single embryo transfer. However, an RCT testing explicit single embryo transfer with or without PGT-A failed1 to identify a real benefit, especially when factoring in the size of the embryo cohort available for transfer with or without genetic testing.2

being added (PGT-A, freeze-all strategies, and so on), fewer fresh embryo transfers are occurring, and fewer babies are being born relative to the number of cycles started. This is why I am critical of being overly enthusiastic about some of these innovations. Imagine a healthy 27-yearold woman with blocked tubes. She simply needs IVF. Instead, she may undergo excessive stimulation, freeze-all treatment pathways, additional interventions, and substantial expense that do not improve her chances of having a healthy baby sooner. If this continues for long enough, patients will increasingly question these practices. If there is no self-regulation, other forms of regulation are likely to follow.

The next argument was that the method is nearly 100% negative predictive when a uniform numeric aneuploidy is detected in an embryo biopsy, and I would agree with that. A woman who produces many supernumerary embryos could thus potentially avoid freezing and transferring embryos that will never result in a live birth. However, few women are in a situation to choose from a larger number of optimal blastocysts per one treatment cycle, so on a population level, the purported benefit will likely be negligible.

To answer your question directly: do we apply PGT-A to our patients? Certainly not as a routine, I work in a centre that has licences to perform genetic testing. I participated in major studies, and my team could run the technology without any problem. Nevertheless, I would clearly discourage my average patient from doing it.

Regarding the overutilisation of technology in the context of IVF, Gleicher N et al.3 have recently shown on the USA data that while more interventions are

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I'm not condemning add-ons in principle. Some interventions have a very low likelihood of harm and may reasonably be discussed with patients. For example, hyaluronic acid is relatively low-cost and unlikely to be harmful. If patients ask about it, I feel there is an obligation to explain that the evidence is limited, but that it is unlikely to cause damage. We occasionally use sperm selection devices such as microfluidic systems, although I cannot say with confidence that they work. We use karyotype testing in selected situations. We also apply CatSper testing (Truion GmbH, Münster, Germany) on sperm in idiopathic infertility cases. If positive, it can change the understanding of a couple's infertility. In my practice, I tend to favour low-cost, low-risk interventions that have at least a theoretical possibility of benefit.

Which add-ons do you think are reasonable to discuss with patients?

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We have just published an RCT at this year's ESHRE on intra-ovarian platelet-rich plasma injections. The conclusion was that it does not appear to work. A similar result was presented by another group based on an RCT.

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ESHRE 2026

In areas such as recurrent pregnancy loss, some interventions, including intravenous Ig, continue to be used despite limited evidence. When, if ever, do you think these treatments are appropriate?

AI and digital technologies are gaining momentum in reproductive medicine, while emerging approaches such as spindle transfer are beginning to move beyond the boundaries of conventional IVF. Which developments do you believe have the greatest potential to shape clinical practice over the coming years?

There was a recent Danish trial looking at intravenous Ig combined with corticosteroids. It is extremely difficult to run strong studies in this area. The signal from that study was somewhat encouraging. At least, corticosteroids were not associated with worse perinatal outcomes, which is the main worry in that context.

Medicine has advanced not only through systematic study but also through serendipity. Sometimes, clinicians try something and unexpectedly discover a useful effect. So, I am not opposed to case-by-case decision-making, provided it is honest and transparent.

We are facing a real fertility crisis that many people do not fully understand. The problem is compounded because fertility decline behaves almost like an exponential process. Smaller generations produce even smaller generations. This is a much larger issue than IVF. IVF helps individuals fulfil personal wishes and family planning, but it sits within a much broader demographic picture. Understanding why reproductive fitness is declining is one of the great research frontiers. I would argue that in 100 years, people may look back and be astonished by how reproduction worked in our era. Prenatal testing, for example, has already become routine. We now know information very early in pregnancy that previous generations could only discover at birth. If that trend continues, reproductive medicine may evolve into assisted procreation on a much larger scale than we can currently imagine. In the shorter term, however, I think germline modification and artificial gametes are among the most important frontiers.

Looking beyond AI, I would point to the increasing discussion, particularly during ESHRE, around germline modification technologies, spindle transfer, artificial gametes, stem cell technology, and interventions aimed at rejuvenating oocytes. Those developments move beyond conventional IVF and represent genuinely new directions.

Looking ahead, what unanswered question in reproductive medicine would you most like to see addressed by future research?

References

There are many. One issue I find particularly interesting is the broader question of human reproductive fitness. I believe it is deteriorating, and I would like to understand the determinants of that decline. There are behavioural and psychological factors involved. Are people having less intercourse? Are there hormonal factors? How CC BY-NC 4.0 Licence

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do these interact with trends in nutrition and lifestyle?

AI can help with better targeting of patients, better utilisation of resources, and better expectation management. I think its greatest value will be helping clinicians and patients understand more quickly which treatment pathway is appropriate. I am less convinced that AI-driven embryo selection will transform success rates because observing an embryo for longer with better technology still does not improve the embryo itself.

When a patient has had three pregnancy losses, all investigations are normal, and we genuinely do not know the cause, then there may be situations where I discuss trying something. This relationship must be built on trust and truth. I would explain that we do not know if it works, we think it is less harmful than previously feared, and, in the worst case, it is simply ineffective.

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Munné S et al.; STAR Study Group. Preimplantation genetic testing for aneuploidy versus morphology as selection criteria for single frozenthawed embryo transfer in goodprognosis patients: a multicenter randomized clinical trial. Fertil Steril. 2019;112(6):1071-9.e7.

Paulson RJ. Hidden in plain sight: the overstated benefits and underestimated losses of potential implantations associated with advertised PGT-A success rates. Hum Reprod. 2020;5(3):490-3.

Gleicher N et al. The declining efficiency of IVF in the USA. Hum Reprod Open. 2026;2026(1):hoag004.

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ESHRE 2026

Citation:

EMJ Repro Health. 2026;12[1]:68-69. https://doi.org/10.33590/emjreprohealth/1N1T76AG

Author:

Alena Sofieva, EMJ, London, UK

Reproductive surgery has evolved considerably alongside assisted reproductive technologies. Where does surgery still have the greatest role in fertility care?

Maribel Acién Full Professor of Obstetrics and Gynaecology, Miguel Hernández University, Elche; Senior Consultant Gynaecologist, San Juan University Hospital, Alicante; Director, PARESAN Reproductive Pathologies Research Group, Alicante, Spain; Past coordinator & Senior Deputy (Reproductive Surgery Special Interest Group), European Society of Human Reproduction and Embryology (ESHRE)

The role of reproductive surgery has certainly changed. Before IVF became widely available, surgery played a much larger role. Today, I don't see surgery and IVF as competing options. In many cases, surgery complements assisted reproduction and helps improve outcomes when used appropriately. The key is individualisation. Every couple is different. You need to consider female factors, male factors, age, symptoms, underlying pathology, and reproductive goals before deciding on the best strategy. Sometimes surgery is primarily performed to relieve symptoms rather than improve fertility, while in other cases it optimises the chances of successful fertility treatment. The decision should always be personalised and patient/coupleshared rather than protocol-driven.

Successful management begins with understanding embryology

Congenital female genital tract anomalies remain one of your main areas of expertise. What has most improved diagnosis and surgical management in recent years? Technically, minimally invasive surgery, particularly robotic surgery, has transformed what we can achieve. However, technology alone is not the most important advance. For me, successful management begins with understanding

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embryology. Without a clear understanding of how these malformations develop, imaging findings can easily be misinterpreted. A structure may be mistaken for a cyst when it actually represents part of a congenital anomaly, leading to incorrect surgery and, unfortunately, worse outcomes. This is why I always begin educational sessions with embryology. Many clinicians have not revisited this subject since medical school, yet it remains fundamental when managing complex congenital anomalies.

What misconceptions about reproductive surgery do you encounter most often among clinicians? One common misconception is that imaging reports alone provide enough information for surgical planning. In complex congenital anomalies, they rarely do. I never rely solely on the radiology report. I review every scan personally alongside the radiologist because interpretation depends on understanding embryological development. We discuss every possible explanation for what we are seeing before reaching a conclusion. Managing these patients is also inherently multidisciplinary. Depending on the anatomy involved, I work closely with radiologists, urologists, and other specialists before proposing surgery. Every patient requires an individualised plan built by the whole team.

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ESHRE 2026

Endometriosis management continues to evolve. How do you decide when surgery is the right approach, particularly for women hoping to preserve fertility?

them as separate pathways.

Our philosophy has always been conservative because surgery does not cure endometriosis and recurrence remains common. We try to preserve ovarian reserve whenever possible and routinely discuss fertility preservation in women at higher risk of future ovarian damage. For women presenting primarily with infertility, surgery may still have an important role, particularly when integrated into a broader fertility treatment plan. The objective is to coordinate surgery and assisted reproduction rather than viewing

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Congress Interview

training can significantly improve competence before surgeons enter the operating theatre.

The decision depends on the patient's overall clinical picture rather than fertility alone. If pain is the dominant symptom, surgery may provide significant symptom relief even if it does not dramatically increase the chance of pregnancy.

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You lead both a specialist surgical service and train future reproductive surgeons. Which skills do today's trainees need most?

Looking ahead, which innovations have the greatest potential to improve outcomes for women with complex reproductive conditions?

Technical ability remains important, but I believe today's biggest challenge is maintaining hands-on surgical training.

The future lies in increasingly personalised care. New technologies should help us understand the individual patient better rather than simply introducing new equipment. AI may become valuable in areas such as imaging interpretation, surgical planning, and identifying disease that might otherwise be missed.

For understandable medicolegal reasons, trainees have fewer opportunities to develop practical skills in the operating theatre. If we reduce those opportunities, we must compensate by investing in high-quality simulation training. Simulation allows trainees to develop fundamental surgical movements and confidence before operating on patients. Once those basic skills are mastered, supervised operating becomes safer for both trainees and patients.

These technologies are exciting, but they remain tools. Their true value will depend on whether they meaningfully improve clinical decision-making and patient outcomes rather than simply adding technological complexity.

Through European Society of Human Reproduction and Embryology (ESHRE) certification programmes, we've seen how structured practical

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Citation:

EMJ Repro Health. 2026;12[1]:70-72. https://doi.org/10.33590/emjreprohealth/1N1T76AG

Author:

Alena Sofieva, EMJ, London, UK

The IVF laboratory has transformed dramatically over the past three decades. Which developments have had the greatest impact on success rates?

Borut Kovačič

I'm a senior embryologist, so I have experience with the evolution of laboratory techniques. We started from scratch, but there have always been new technologies coming into the lab. Looking back in history, for me, the first milestone was the culture media that were produced by commercial companies. This definitely meant the first step to the standardisation of laboratory conditions.

Senior Embryologist and Head of the IVF laboratory at the University Medical Center Maribor, Slovenia; Chair-Elect, European Society of Human Reproduction and Embryology (ESHRE)

The second was intracytoplasmic sperm injection (ICSI), the micromanipulation technique that solved the issue of relatively unsuccessful male infertility treatment before this milestone. In fact, 50% of infertile patients benefit from this technology. The next one was prolonged embryo culture. We know that embryos begin with gene expression and, consequently, develop their own metabolism after the third day of embryo development in vitro, and that is a critical point. With prolonged culture to the blastocyst stage, it is possible to identify embryos with greater implantation and developmental potential and, consequently, this dramatically improved the outcome of treatment with assisted reproductive technology. At that time, however, cryopreservation protocols were not adjusted to blastocyst stage embryos, so there was a lot of scepticism about whether prolonged culture was the right way to go, because of concerns

Cryopreservation is becoming increasingly relevant, not only for oncology patients but also for women who may lose fertility because of other medical conditions

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around epigenetics and what to do with blastocysts that were not transferred to the uterus. With the development of vitrification, this issue was solved not only for blastocysts but also for oocyte cryopreservation. Blastocyst, as a larger preimplantation embryonic stage filled with fluid and oocyte as the biggest cell, was not an optimal stage for standard slow-freezing procedure, and vitrification enabled oocytes and blastocysts to much better survive vitrification and thawing steps. Consequently, clinicians decided to perform single embryo transfers more often. The rate of multiple pregnancies significantly dropped, and, with new protocols using agonist triggering, it became possible to freeze all embryos or oocytes and reduce the risk of ovarian hyperstimulation syndrome to a minimum. There are also some other technologies that proved themselves as safe and effective treatment options for certain sub-populations, such as artificial oocyte activation for patients facing problems with fertilisation failure after ICSI, and preimplantation genetic testing for those with heavy indications for genetic diseases.

You mentioned fertility preservation. How do you see this area developing? Fertility preservation remains an important area of development. Ovarian tissue cryopreservation is becoming increasingly relevant, not only for oncology patients

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ESHRE 2026

but also for women who may lose fertility because of other medical conditions. However, relatively few patients currently return to use their preserved tissue, meaning there is still much to learn about its long-term clinical value.

The same applies to testicular tissue preservation. While preserving tissue is technically possible, particularly challenging questions remain for prepubertal boys. Preservation alone is not enough; we also need safe and effective methods to mature this tissue in vitro, and our current knowledge is still limited. As these technologies develop, appropriate regulation becomes increasingly important. The new European Substances of Human Origin (SoHO) Regulation should help ensure that innovations are introduced responsibly. Because reproductive medicine involves handling human genetic material, any new technique should undergo ethical review, appropriate risk assessment, and transparent patient counselling. Patients need to understand when a treatment remains experimental, and be fully informed about both the potential benefits and the unknown risks before making decisions together with their doctors. Better regulation should support this process

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AI is increasingly being applied to embryo assessment. How close are we to meaningful clinical implementation, and where should the field remain cautious?

However, most of the available evidence remains retrospective. Only a small number of prospective RCTs have been conducted, and so far they have not demonstrated improved clinical outcomes or cost-effectiveness. That does not necessarily mean AI will not become useful. Future systems may be trained using much larger datasets and combined with additional noninvasive diagnostics. For example, analysing spent culture media to determine which metabolites an embryo consumes and produces could provide valuable information about embryo viability. These techniques remain technically challenging for routine clinical practice, but combining metabolic data with AI may represent an important direction for the future.

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Congress Interview

metabolic data with AI may represent an important direction for the future.

Embryo assessment by using time-lapse imaging combined with AI is an amazing technology to see the behaviour of embryo development during the first 5, 6, or 7 days. There are many morpho-kinetic parameters that can be followed by AI. It is much simpler to collect all this information and create a scoring system that can improve embryo selection or ranking.

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Future systems may be trained using much larger datasets and combined with additional non-invasive diagnostics

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Reproductive Health

Congress Interview

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ESHRE 2026

As ESHRE Presidentelect, what do you see as the biggest challenges currently facing reproductive medicine in Europe?

individual professionals and accreditation of fertility centres. Accreditation allows independent assessors to evaluate whether centres genuinely follow ESHRE guidance and maintain high clinical and safety standards.

One of the biggest challenges is implementing the new European SoHO Regulation. When the original EU Tissue and Cells Directives (EUTCD) were introduced, many people viewed them simply as additional bureaucracy. Looking back now, they have clearly improved harmonisation and safety across the laboratory sector of reproductive medicine. I believe the SoHO Regulation will have a similarly positive long-term impact.

The ultimate goal is to spread quality consistently across Europe, and I would like to see many more centres participating in ESHRE's accreditation programmes.

Do you think accreditation could ever become mandatory? I remain somewhat sceptical. Looking at the European MAR Registry (EuMAR), we believed it would become something regulated through the new SoHO Regulation.

The regulation is expected to be implemented next year, followed by the authorisation of SoHO preparations. I strongly believe that ESHRE will play an important role in this process, directly or indirectly. ESHRE guidelines are already widely respected, and regulators frequently rely on them during inspections and quality assessments. They have become something of a reference document for reproductive medicine.

ESHRE was very proud to receive funding from the European Commission to establish a pan-European cycle-by-cycle registry. Once the project was finished, however, we did not get a regulation that would require mandatory participation. The centres and national registries that will provide data will have the opportunity to use dashboards and compare their success rates with European averages, and we see a lot of benefits from EuMAR for all stakeholders.

Laboratory practice has already undergone strict quality control through the implementation of the Tissue and Cells Directives and embryologists themselves have recognised ESHRE certification as a minimum educational standard for working in a clinical embryology laboratory. Clinical practice also requires robust guidance, along with subspecialist training and certification of

Reproductive Health

There are other areas where further harmonisation is needed, particularly donor registries. As the demand for donated reproductive material continues to increase, Europe needs greater transparency and traceability for donations, the usage of donated

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gametes or embryos, and the health of offspring conceived from donated sperm or oocytes. At the same time, excessive regulation could unintentionally reduce access to donor material. The challenge is finding the right balance and communicating this effectively to policymakers. Professional societies increasingly have an important role in supporting evidence-based policy development.

Looking ahead to the next decade, which emerging technology has the greatest potential to change the way IVF laboratories operate? I believe the future lies in truly noninvasive embryo assessment. This may involve metabolomics, novel genomic technologies, and noninvasive genetic testing, although these approaches still require considerable validation. Some geneticists remain unconvinced about the current reliability of noninvasive genetic testing. However, combining multiple non-invasive technologies may ultimately provide a much more complete picture of embryo viability. If metabolic profiling, genomic information, and other biological markers can be integrated and analysed using AI, this combination has the potential to substantially improve embryo selection in IVF laboratories over the coming decade.

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Interview

Interviews EMJ spoke with six leading experts in reproductive health, including the Presidents of the World Endometriosis Society (WES) and the European Society for Gynaecological Endoscopy (ESGE), who shared insights into the latest advances across fertility, endometriosis, menopause, maternal health, and gynaecological surgery, highlighting the importance of evidence-based, personalised, and patient-centred care. Featuring: Joyce Harper, Andrew Horne, Itunu Johnson-Sogbetun, Karen Joash, Vikram Talaulikar, Ertan Saridogan

Citation:

EMJ Repro Health. 2026;12[1]:73-77. https://doi.org/10.33590/emjreprohealth/CVBH6558

Author:

Alena Sofieva, EMJ, London, UK

Q1 Joyce Harper Professor of Reproductive Science, University College London, UK; Head of the Reproductive Science and Society Group; Founder of Global Women Connected and Director of the Embryology and PGD Academy; Co-founder of the International Reproductive Health Education Collaboration; Co-founder and Co-lead of InTune; Co-founder of SwimHer

For more than a decade now, my work has focused on educating the public about reproductive health, from puberty through to menopause

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Could you start by telling us about your professional journey? You began in laboratorybased reproductive science and genetics, yet much of your recent work focuses on education, policy, and public engagement. What prompted that shift, and did you encounter resistance within academia when moving beyond the lab?

Life moved quickly, and before I knew it, it was 2015, and the book was still unfinished. More than a decade earlier, I had set up a website called Global Women Connected, where a small team of us worked to debunk fertility myths and discuss new research in women’s health. That experience reinforced my belief that while online resources are useful, books still matter.

When I finished my PhD in 1987, I started working as a clinical embryologist in one of the busiest fertility clinics in the UK. Although I had always been interested in teaching and learning, I quickly realised how little I understood about my own body.

I returned to the manuscript and eventually published ‘Your Fertile Years’ in 2021, a book that had been in development since 1987. Alongside this, I was deeply involved in lab work and loved embryology. However, when I was 29, my boss asked whether I wanted to step out of the lab and manage the clinic. That question prompted me to reflect on whether I wanted to spend the next 20 years in a fertility clinic. Although I enjoyed managing the lab, my passion for education and research was growing.

Despite having two degrees, I was a 25-year-old woman who did not really understand my menstrual cycle or fertility. I began reading extensively and soon realised there was no clear book explaining reproductive health to young women. So in 1987, I started writing one myself.

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Reproductive Health

Interview

In 1992, I returned to academia and joined the Hammersmith Hospital team in the UK, working on preimplantation genetic testing. I remained in lab-based research for many years and, in 1996, established my first Master’s course at University College London, UK, where I still work today. Over time, the field of pre-implantation genetic diagnosis became increasingly commercialised, with large diagnostic companies taking over much of the work. My team and I preferred to remain focused on smaller-scale, research-driven work, and around 10 years ago we closed our preimplantation genetic testing (PGT) programme, and I stepped away from lab work.

to it around 2015, which meant there was almost a 20-year gap. Finishing the book took years and felt like doing another PhD. I read extensively, going back to the original papers on the menstrual cycle, fertility, and the fertile window to understand where common myths came from and what evidence actually supported them. That process made the book very time-consuming, but it was important. Before that, I had written books on PGT.

For many intelligent, educated women, understanding what is evidence-based and what is not is empowering

That allowed me to return fully to public education in reproductive health. In 2015, we established the British Fertility Education Initiative, and in 2019, I set up an international group. For more than a decade now, my work has focused on educating the public about reproductive health, from puberty through to menopause.

I have now just finished my next book, which took 2.5 years to write, so I have definitely become faster.

Your book was written for the public rather than clinicians. What misconceptions about fertility surprised you most while researching it, and how did translating complex science for a lay audience change how you approach your academic work?

Have you been writing your book throughout all these years, or were there breaks in between?

I have always been passionate about engaging with the public. Even when I worked in a fertility clinic, I loved running patient evenings. Patients would come to learn what was going to happen to them, because simply attending a clinic appointment is

There were breaks. I wrote quite a bit, about half a book, in 1987, and then stopped. At the time, I did not feel qualified enough to write it, and life was very busy. I only returned 74

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not enough. I felt it was important to teach the basics before people even saw a doctor. That drive to educate the public has been there since the 1980s. The book is very much written for a lay audience, although it does include a strong scientific foundation. ‘Your Fertile Years’ is the book I would have liked to read when I was 25. I still stand by it. For many intelligent, educated women, understanding what is evidence-based and what is not is empowering.

Women often struggle to find reliable information about reproductive health. Should education start during school years, and how would you change the school curriculum? We have done extensive research in the UK, Japan, Belgium, and Greece, speaking to young people and conducting surveys. Across all of this work, whether with school children, adult women, or perimenopausal and postmenopausal women, the message is consistent: education needs to start at school.

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Interview

I work closely with teachers, and we have developed a free teaching resource covering reproductive health from puberty to menopause, available on the International Reproductive Health Education Collaboration (IRHEC) website. We are also beginning a project to review school curricula in different countries, to understand what is currently taught, identify gaps, and define what should be included. Schools need to address topics such as PCOS, endometriosis, miscarriage, fertility, and menopause.

about what to expect. This is what I am working on now: developing, testing, and refining educational resources around fertility and menopause at key life stages.

insufficient. We are therefore working to make teaching more comprehensive and to ensure boys are included as well, as they are often excluded from these lessons. The UK has a solid framework, but it can still be improved.

Education also needs to be age appropriate. The basics should be taught at school, but when people are trying to conceive, they need a reliable source of information. We have developed information leaflets on getting pregnant and infertility, and I would like people to have access to structured sessions, online or in person, where they can learn about the fertile window, lifestyle factors, and related issues. The same applies at perimenopause, often around the age of 40, women should be offered age-appropriate education

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As a UK-based publication, we are especially interested in the UK curriculum. Do you think it is sufficient, or should it be broader?

One of the main challenges is how this content is delivered. In many schools, it is taught by form tutors rather than by teachers trained in pastoral education. I do not think it should be outsourced to external speakers. Instead, schools need designated teachers who are comfortable with these topics and who students can approach with questions.

It is getting there, and I do think the UK curriculum is probably one of the best in the world. I cannot say that definitively until our study is complete, but the wording is among the most comprehensive. An updated version was published in 2019 and later expanded to include more on periods, including difficult periods, endometriosis, and PCOS.

When lessons on periods, miscarriage, or menopause are delivered by teachers who do not feel confident discussing them, it can reinforce discomfort and taboo rather than reduce it. In some schools, including my local school, this has been addressed by assigning a group of teachers to cover all pastoral topics. These teachers deliver the content every year, not just once, and become trusted sources of support. Importantly, boys and girls are taught together.

I am working with Wellbeing of Women on educational resources focused specifically on menstruation, which we are testing in schools next year. Menstruation is a good example of where education has historically been lacking. Many women around the world report having had no more than two lessons on menstruation during their entire school education, which is clearly

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Reproductive Health

Interview

Although more research in women’s health is essential, women are currently being overwhelmed by misinformation.

As a professor at UCL and a long-time educator, how have your students’ attitudes towards fertility, menstruation, and menopause changed over the past decades? What gaps do you still see in medical and life science education?

Having seen both the scientific and commercial landscape of fertility treatment, do you think the current research model in reproductive medicine adequately protects patients from premature clinical adoption of new technology?

In menopause care, I describe the situation as the ‘Wild West’. I recently recorded a podcast on this topic, and we have submitted a paper examining supplements. Women are frequently encouraged to try multiple interventions to manage symptoms rather than being advised to seek medical care.

No. I think we have got into a mess, and I think it is getting worse. I worked on PGT for many years, and in IVF, we now have a growing list of what we call IVF add-ons, treatments developed to try to improve the chance of getting pregnant. Unfortunately, almost all of them have no evidence that they improve live birth rates, yet they are being used in many clinics. Nonevidence-based treatments have become normalised.

Hormone testing is another example. It is often presented as empowering, yet most women do not need it. This fuels a narrative that women are inherently unwell, that menstruation and menopause require constant testing, treatment, and intervention. I advocate returning to basics: nutrition, exercise, sleep, mental health, and relationships/ community, the five pillars of health. If something is being sold on social media, it should be approached with caution.

Outside clinics, many people turn to supplements, complementary therapies, and alternative treatments, most of which lack evidence. Social media often markets these as beneficial, leading many to take supplements that can be ineffective or even harmful. We are currently researching this area. 76

Reproductive Health

I have been teaching since 1996, and students have changed significantly. We have evolved with them. There is now far greater emphasis on the societal context of what they are learning. One notable shift is in language. Ten years ago, teaching focused on binary descriptions. Women menstruate and men produce sperm. This is no longer sufficient. Gendered language is now more complex, and we must be careful when discussing people who menstruate, as this does not apply only to women. We have undertaken research on supporting the LGBTQ community in this area, although it remains a challenging landscape. Significant gaps in women’s health persist. For decades, women were underrepresented in research because hormonal variation across the menstrual cycle was seen as a barrier. As a result, when treatments were developed for both men and women, women were often excluded. We now recognise that findings from men do not always translate to women.

I advocate returning to basics: nutrition, exercise, sleep, mental health, and relationships/community, the five pillars of health

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Interview

Hormonal biology has a major influence on health outcomes. This affects how women experience conditions such as heart disease, osteoporosis, and dementia. It is encouraging that women’s health is now firmly on the agenda. While some taboos remain, the next decade is likely to see substantial progress, with a growing body of highquality research. Although major knowledge gaps remain, I feel privileged to educate the next generation who will help address them. It is an exciting

It is an exciting time to be working in reproductive health, both in education and in fundamental research

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time to be working in reproductive health, both in education and in fundamental research.

I am active on various platforms and I believe engagement in this space is now essential.

Finally, what advice would you give to an early-career researcher who wants to combine rigorous reproductive science with public education and advocacy? Is there anything you would do differently in your own career?

I do not regret my career path, but I spent many years in laboratory research and enjoy my current work far more. I gain energy from teaching, public engagement, and working with people, and I feel I have found the right fit.

There are now excellent courses that integrate science and society. In my department, I have just finished teaching a module titled ‘Fertility and Infertility, Science and Society’, which reflects how training in this area has evolved. With rapid developments in women’s health technology, fertility research, reproductive health education, and menopause research, this is a far more exciting field to enter than when I began. Early-career researchers need to understand the role of social media and public communication.

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With hindsight, I would have left lab work earlier. My advice to early-career researchers is to think carefully about what they enjoy day to day and choose a career that suits their personality. Gaining qualifications that help identify your passion and then following it will lead to a fulfilling career.

Reproductive Health

Interview

Citation:

EMJ Repro Health. 2026;12[1]:78-84. https://doi.org/10.33590/emjreprohealth/DHPO8497

Author:

Alena Sofieva, EMJ, London, UK

Could you start by telling us about your professional journey and what has driven your long-standing commitment to improving care for women with endometriosis and pelvic pain?

Andrew Horne Professor of Gynaecology and Reproductive Sciences, The University of Edinburgh; Director, Centre for Reproductive Health, The University of Edinburgh, UK; President, World Endometriosis Society; Honorary Consultant Gynaecologist, NHS Lothian, UK; Specialty Advisor to the Chief Medical Officer for Obstetrics and Gynaecology, Scottish Government, UK; Trustee, Endometriosis UK; Adjunct Professor, University of Vienna, Austria

I was born in Edinburgh, went to school there, and later studied at the University of Edinburgh, UK. After I qualified and began working in obstetrics and gynaecology, I realised that if I didn’t leave then, I’d end up stuck there. So, I moved to Dublin, Ireland, to work at the Rotunda Maternity Hospital, which was a fantastic experience, and then to London, UK, where time in a large IVF unit at the Hammersmith Hospital sparked my interest in research. I went on to complete a PhD on endometrial biology in the context of infertility at Imperial College London.

Our aims are to better understand endometriosisassociated pain, improve diagnosis, develop new nonhormonal treatments, and predict response to existing treatments

When I returned to Edinburgh for a clinical lectureship, my early research focused on ectopic pregnancy and abnormal embryo implantation. But as I finished my training, it became clear to me how poorly we were managing patients with pelvic pain, with or without endometriosis. That realisation led me to set up a multidisciplinary pelvic pain service, and my research evolved alongside it. Around that time, I met Philippa Saunders, an eminent discovery scientist, based at the University of Edinburgh. Together, we established a research group called EXPPECT Edinburgh, which

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is a multidisciplinary team focused on endometriosis. Our aims are to better understand endometriosisassociated pain, improve diagnosis, develop new non-hormonal treatments, and predict response to existing treatments. That’s how my career has evolved towards endometriosis and pelvic pain.

Do you still work as a clinician at the moment?

Yes. In the last couple of years, I’ve become Director of the MRC Centre for Reproductive Health in Edinburgh, UK, which is both a management and strategic role. As a result, I’ve reduced my clinical sessions, and I now do about a day and a half of clinical work per week, purely focused on endometriosis and pelvic pain.

Your primary clinical focus is pelvic pain, but do you also see or work with patients whose main issue is infertility related to endometriosis? We do as a BSGE-accredited endometriosis centre, but we bring in infertility experts for that. We have bi-monthly multidisciplinary meetings where all complex cases are discussed, and fertility specialists are always involved. I do see patients whose concerns include fertility, but my main focus is pain associated with endometriosis rather than infertility. That said, pain and infertility often go hand in hand, so I inevitably address both.

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Interview

Your research spans metabolic therapies, immunomodulation, cannabinoids, diet and lifestyle interventions, biomarker development, and surgical trials. How do you prioritise which strategies to pursue? Or do you see them as complementary parts of a broader strategy? I see them as complementary. If we can diagnose endometriosis better, we still need to manage it better to improve patients’ overall quality of life. Diagnosis and treatment need to move forward together. To help prioritise our research, about 7 or 8 years ago, we set up a UK and Ireland James Lind Alliance (JLA) Research Priority Setting Partnership for Endometriosis. This was an initiative that brought patients and clinicians together to identify research priorities using a structured process. We generated a top 10 list of research priorities, published them, and shared them widely. Since then, we’ve used those priorities to guide our research programme. The main messages from that exercise were the urgent need for better diagnostics and better non-hormonal treatments for endometriosis. That has been the key driver of our work.

If we can diagnose endometriosis better, we still need to manage it better to improve patients’ overall quality of life

At the moment, laparoscopy is still the only way to definitively diagnose endometriosis. Are you aiming to move away from surgical diagnosis entirely?

the context of endometriosis.” Her project evolved in that direction. We began by collecting samples from patients undergoing surgery for endometriosis and comparing them to patients without the disease. We looked at the endometriosis lesions, the peritoneum adjacent to the lesions, and the peritoneal fluid. That’s when we identified changes in the metabolic drivers of aerobic glycolysis and, importantly, that peritoneal mesothelial cells in patients with endometriosis produced more lactate than those in women without the condition.

Exactly. The goal is to move away from surgery for diagnosis towards something much less invasive, ideally advanced imaging and/or biomarkers. Ultimately, I suspect it will be a combination: a blood test plus imaging, allowing us to completely dispense with surgery purely for diagnostic purposes.

You mentioned that your primary research focus is on non-hormonal treatments. One of the major strands of your work is dichloroacetate (DCA). What first convinced you that cellular metabolism might be the ‘Achilles heel’ of endometriosis lesions? And what have you learned so far from the early studies and feasibility trials?

The idea to target lactate came from that observation. We decided to go down a drug repurposing route rather than starting from scratch with a new molecule. We searched the literature for drugs that were already used clinically or in trials to modify lactate levels. Dichloroacetate had been around for 15–20 years as a treatment for rare metabolic disorders in children. It wasn’t widely used, but there were safety data. It had also been trialled in other conditions with elevated lactate, such as cardiomyopathy.

This started with a PhD student of mine, Vicky Young. She was formally working on a different project but always came with new ideas. One day she said: “I think we should look at metabolism in

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Reproductive Health

Interview

These patients need alternative treatment options. Interestingly, there is no correlation between the extent of peritoneal disease and symptom severity; someone can have a tiny lesion and very severe symptoms. That suggests that, in this subtype, the lesions are likely more a manifestation of a systemic condition rather than the sole driver of symptoms.

Our preclinical work focused on women with superficial peritoneal disease

Because of this, we could move more quickly into an exploratory trial than we would have with a completely new drug. We tested DCA in an initial cohort of 30 patients with endometriosis and saw encouraging results. On the strength of that, we are now exploring it in a randomised, twocentre clinical trial of 100 patients with endometriosis.

Beyond the larger trials, what are the key steps required to move DCA from experimental therapy into something that could be offered routinely in clinical practice? If we demonstrate efficacy in around 400 women in a welldesigned trial, that should be sufficient to support incorporation into national guidelines and routine practice.

Do you mainly enrol women with Stage I–II endometriosis, or do you also include more advanced disease?

One challenge is that, because DCA is a repurposed drug, it’s less attractive to pharmaceutical companies: the commercial returns are lower, as they don’t own the original intellectual property. So we’ll need to identify an industry partner willing to support translation into practice.

Our preclinical work focused on women with superficial peritoneal disease for two main reasons. First, it’s the most common form of endometriosis (accounts for 80%). Second, I actually think it’s the most challenging to treat. Many patients who have surgery for superficial peritoneal disease either don’t improve or experience recurrence of symptoms.

Reproductive Health

Q10

What are the main side effects you have seen with DCA?

This fits with the idea of endometriosis as a whole-body, systemic condition that may require medical therapy rather than surgery alone. For ovarian and deep endometriosis, surgery often makes more sense, with excision of the disease and potentially medical treatment alongside to reduce recurrence. But for now, our DCA work is focused on superficial peritoneal disease. If it proves effective there, we would then look at ovarian and deep disease as well.

Are you planning to test DCA in a larger sample after this 100-patient trial? Yes, absolutely. A trial with 100 women will not give a definitive answer. If we continue to see a signal of efficacy in those 100 patients, we will need to move to a multicentre trial across the UK, likely involving around 400 patients, to properly determine whether DCA is effective. So, there is still a long way to go, and it takes time, but that is the trajectory.

effects. That could create new intellectual property and make it more commercially attractive, while potentially improving tolerability. But before that, we need robust data in the oral formulation.

One strategy might be to pair DCA with a novel vaginal delivery system to reduce systemic side

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The main side effect patients reported was tingling in their fingers, a peripheral neuropathytype symptom. We investigated whether this correlated with DCA levels in the blood and found that it does: the higher the DCA level, the more likely patients were to experience this side effect. What’s particularly interesting is that individuals can be ‘slow’ or ‘fast’ metabolisers of DCA, depending on their genotype. This means we can genotype patients and tailor the dose to reduce side effects. In the next trial, led by my colleague, Lucy Whitaker at the University of Edinburgh, all patients will be genotyped and then prescribed either a lower or higher dose accordingly. The hope is that efficacy will be preserved while the side effect burden is reduced. The most striking thing was that, in the first exploratory trial, we, as investigators, were more worried about the tingling than the patients were. They generally described it as a mild nuisance rather than a major problem. It resolved when treatment stopped, and there wasn’t really a way to relieve it otherwise. But when you compare it with the side effects of some current endometriosis treatments, which can induce menopausal symptoms like hot flushes, night sweats, vaginal dryness, and mood changes, the patients felt that mild CC BY-NC 4.0 Licence

Interview

In endometriosis, macrophages take on a phenotype very similar to tumour-associated macrophages, pro-repair rather than pro-inflammatory

tingling was relatively minor. Still, we’d like to minimise it through personalised dosing.

Q11

Alongside DCA, you’re also evaluating macrophage-targeted immunotherapies, cannabinoids, tinctures, and other approaches. When you look across these programmes, what do you see as the most promising future treatment landscape for patients? How realistically can we move towards mechanismbased therapy? Starting with cannabinoids, our interest began with a large international survey of patients with endometriosis. We were asking primarily about diet and supplements, but we discovered that nearly a third of respondents were using cannabinoids in some form to manage their pain, and many reported good effects. We then examined whether cannabinoid receptors are expressed in endometriosis lesions and found expression of both CB1 and CB2 in tissue samples. We have a mouse model of induced endometriosis. Mice don’t spontaneously menstruate or develop endometriosis, so the Edinburgh team first developed a menstruating model and then injected menstrual tissue from these mice into recipient mice. Those recipients developed lesions very similar to human endometriosis.

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Using this model, we tested a CB2 agonist that a pharmaceutical company provided. In mice, it reduced lesion volume and attenuated pain-like behaviours. The drug had originally been developed for rheumatoid arthritis but had not shown sufficient efficacy in late-stage trials. Again, we were exploring repurposing. Unfortunately, the company then withdrew from women’s health altogether, so that route closed. We spent about 18 months looking for alternatives and eventually found a company producing a cannabinoid tincture. Cannabinoids include tetrahydrocannabinol (THC), which causes the ‘high’, and cannabidiol, which has different mechanisms of action and is now licensed for childhood epilepsy. The tincture we’re using contains minimal THC, because we don’t want to impair patients’ ability to drive or function day-to-day. We hope this tincture will help with pain and possibly be diseasemodifying. The clinical trial design is similar to the DCA study: a two-centre, randomised, placebocontrolled trial in 100 patients. We’re aiming to start in February next year and are currently working through regulatory approvals.

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Interview

Q12

Could you walk us through the macrophage-targeted approach you’re now exploring? We know macrophages play a key role in the development of endometriosis and likely in pain generation. In endometriosis, macrophages take on a phenotype very similar to tumour-associated macrophages, pro-repair rather than proinflammatory. In cancer, several therapies are being developed to repolarise macrophages.

earlier stage than the DCA and cannabinoid programmes.

Q13

Which of these, DCA, macrophage therapies, or cannabinoids, do you currently see as the most promising? At the moment, we have the strongest evidence for DCA. Many patients in the initial DCA study reported significant benefits and were very keen to continue the treatment, although, of course, we cannot yet prescribe it outside trials without stronger evidence.

We looked at that field and tested a drug called RRx-001, which can repolarise macrophages and also behaves differently in normoxic versus hypoxic environments, both relevant to endometriosis pathology. Together with my collaborator Erin Greaves at the University of Warwick, UK, we evaluated RRx-001 in a mouse model of endometriosis and found that it reduced disease burden and altered pain-like behaviours. On the back of that, we received funding from the Scottish Government for an early clinical trial.

Cannabinoids are also promising, especially since so many patients are already using them informally and reporting benefits. It may be that, in the future, combinations of therapies, metabolic, immunomodulatory, and neuromodulatory, turn out to be most effective.

Q14

Let’s switch to diagnostics. There’s growing work on biomarkers, wearable sensors, and machine learning approaches to shorten the time to diagnosis. You are recruiting patients into the Endo 1000 project. Can you tell us more about this study and how you think big data can help women receive earlier, better-targeted care?

This will be a small, dosefinding study in 36 patients with endometriosis. It involves weekly intravenous infusions over 6 weeks, each lasting about 2 hours, so it’s a high-burden trial in terms of patient time and logistics. We’ll be looking closely at tolerability and side effects.

Endometriosis has historically suffered from a lack of financial investment, which has limited large-scale research. Many studies have been small and underpowered. We need big data to identify patterns that might improve diagnosis and predict treatment responses.

The reassuring thing is that RRx001 has been tested in head and neck cancer trials, and patients tolerated it well with minimal side effects. We’re hopeful that, apart from the inconvenience of regular infusions, patients with endometriosis will also tolerate it well. But it is at a much 82

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Our financial target is 1 million GBP to fund ENDO1000. We’ve just passed the halfway point, 500,000 GBP, which has allowed us to start. As the name suggests, we aim to recruit 1,000 individuals with endometriosis and follow them closely for 2 years. Participants will use our bespoke ENDO1000 app to record detailed information on their symptoms, including pain, bowel symptoms, menstrual cycles, medications, surgeries, and any changes in health. They’ll also log selfmanagement strategies, such as dietary changes. Alongside this, they’ll wear a smartwatch to track activity and sleep. We’ll send postal kits so they can provide saliva (for genetics), blood (for inflammatory profiling), urine, faeces, and vaginal swabs (to study the microbiome and metabolome). All of this will feed into a large bioresource. Once we’ve collated these data, we’ll use AI and machine learning to identify patterns that could help us speed up diagnosis and, crucially, predict who is likely to respond to different treatments: surgery, medical therapies, or selfmanagement strategies.

Our ENDO1000 project is designed to address that. We approached this project in a slightly different way than a traditional grant-funded study. From the outset, we wanted it

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to be an awareness-raising and fundraising campaign, as well as a research project. ENDO1000 is linked to a social media campaign called ‘Let’s Talk Endo’, and we’ve recruited a number of ENDO1000 ambassadors, including wellknown figures from UK radio, television, and sport. Together, we’ve been raising awareness of endometriosis and the project.

We’ve just enrolled our first participants, essentially piloting the app over the festive period to ensure everything works smoothly before we publicise more widely.

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Interview

The initial response has been overwhelming. When we first announced it, we received over 300 emails from patients wanting to take part.

Q15

You recently copresided over the 15th World Congress on Endometriosis in Edinburgh. Looking back, what themes or shifts in thinking from that meeting excited you most, and which directions do you hope the global community will prioritise over the next decade? It was a very positive, energising meeting. We’d just emerged from the pandemic, and the community hadn’t met in person for some time; the previous Congress had been entirely online. So, there was a real sense of reconnection.

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One of the most striking aspects was how multidisciplinary it was: there were sessions on physiotherapy, psychology, and other disciplines, reflecting more holistic approaches to endometriosis care.

That meeting was followed by another major conference led by the World Endometriosis Society (WES) in Sydney, Australia, in May, and we’re keeping that momentum going. I’ve just become President of WES, and we’ll be hosting the next major conference in Istanbul, Türkiye in June 2027. The aim is to maintain that sense of progress, share new ideas, and keep the global community connected.

The breadth of research was also impressive. There was a lot of emerging work on the microbiome and its potential role in endometriosis, as well as diet. Imaging was another big theme: both novel imaging modalities and more advanced use of transvaginal ultrasound to improve diagnosis. There were also important advances in our understanding of the aetiology and genetics of endometriosis.

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Q16

In your own clinic, what do you currently offer when a patient with suspected endometriosis comes to see you? Is it still mainly hormonal treatments?

Q17

Finally, looking ahead, what are the next big research questions for your group? How do you hope your current and future work will change what you can say to a woman sitting in your clinic in 5 to 10 years’ time?

At the moment, broadly speaking, we offer analgesics and a range of different hormonal options. Some of these are very effective, but patients often have to try several different treatments to find one that works for them and has acceptable side effects. We also offer surgery where appropriate, particularly for deep and ovarian disease, and we incorporate non-pharmacological approaches such as physiotherapy and psychological support.

We’re currently developing a project called ENABLE with the University of Oxford, UK, that will compare seven different hormonal treatments for endometriosis. It’s not funded yet, so we’re in the process of convincing funders. The idea is to run a large, multicentre trial across the UK. Traditionally, hormonal treatments have been tested individually against placebo, but rarely headto-head. Our aim is to compare them directly to determine which are most effective and, just as importantly, which have the fewest side effects. A primary outcome will be Patients’ Global Impression of Change (PGIC), their overall assessment of how the treatment affects them.

Again, this is where a project like ENDO1000 may help us in the future by identifying which treatments are most likely to be effective, and best tolerated, in particular groups of patients, so we can move towards more personalised care.

This would be a very large trial, likely involving over 2,000 patients. The challenge will be both securing funding and delivering such a big study, but we think it’s essential. Looking ahead 5–10 years, my hope is that when a woman sits in front of me with suspected or confirmed endometriosis, I’ll be able to offer her non-hormonal, mechanism-based treatments with good evidence behind them, and that I’ll be able to personalise her treatment using biomarkers and big-data insights to minimise side effects and improve outcomes. Just as importantly, I want us to reach the point where we can diagnose endometriosis earlier and without surgery, so women are no longer waiting years for answers.

The aim is to maintain that sense of progress, share new ideas, and keep the global community connected

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Interview

Citation:

EMJ Repro Health. 2026;12[1]:85-88. https://doi.org/10.33590/emjreprohealth/77O1GSU9

Author:

Alena Sofieva, EMJ, London, UK

Q1 Itunu Johnson-Sogbetun GP with specialist interest in women’s health; Advocate for equitable and culturally responsive care; Educator and speaker on menopause and health inequalities, UK

We urgently need more evidence and more inclusive research so that care can become truly equitable for all women

Could you begin by outlining where you believe menopause care pathways are still failing Black women and women from underserved communities?

and women’s health. Historically, healthcare systems were not designed with ethnic minority communities in mind, and we need to address that if we want to prevent underdiagnosis and undertreatment.

I think all women have historically been underserved when it comes to women’s health. Women were not even routinely included in medical research until the 1990s. Although things have improved, only certain groups of women have truly been represented in research and clinical conversations. Women from racially minoritised communities, immigrant backgrounds, lower socioeconomic groups, and other less represented populations have often been left out of the discussion entirely.

That means investing in more diverse research, culturally responsive care, and clinician training, while also encouraging clinicians to approach patients with openness and curiosity. Ultimately, we need an equitable system where all women can access highquality menopause care regardless of their background.

You spoke previously about ethnic differences in disease mechanisms and menopause timing. Why is this area so important?

As a result, many women are not receiving the best possible menopause care. I have had Black women tell me that they did not realise hormone replacement therapy was ‘for Black women’, simply because of the way it is portrayed in the media. There is still a perception in some Black, South Asian, and other communities that these treatments are unnatural or not intended for them.

One of the major issues is that we simply do not know enough. Current evidence suggests that the average age of menopause differs across ethnic groups. For South Asian women, it appears to occur around the age of 46–47 years, while for Black women, it may be around 48–49. For White women, the average age is closer to 51. Women from East Asian backgrounds may experience menopause even later.

The conversation, therefore, needs to become broader and more inclusive. Research, education, and healthcare delivery all need to reflect the diversity of the populations we serve. We also need to understand the cultural stigma, cultural context, and socioeconomic realities that many women are navigating when discussing menopause CC BY-NC 4.0 Licence

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These are important trends, but we still lack robust research validating and exploring them further. We know that earlier menopause is associated with increased cardiometabolic risks, including diabetes and cardiovascular disease. We also know that Black and South Asian women already experience disproportionately

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higher rates of diabetes and hypertension. What we do not yet fully understand is how earlier menopause may contribute to these patterns of morbidity.

women present with anxiety, brain fog, fatigue, joint pain, palpitations, low libido, urinary symptoms, or recurrent urinary tract infections.

These questions matter because women tend to live longer but often experience higher levels of morbidity later in life. We are also seeing higher morbidity rates in women from lower socioeconomic and ethnic minority backgrounds. Could earlier menopause be contributing to this burden? At the moment, we simply do not know.

A large proportion of the women I see have already been passed between multiple specialties. They may have seen rheumatology, urology, psychiatry, or cardiology, with each symptom viewed in isolation. Often, no one has stepped back to consider whether the overall picture could be related to perimenopause or menopause.

This is why we urgently need more evidence and more inclusive research so that care can become truly equitable for all women.

Of course, it is essential to rule out other causes, because many conditions can coexist with menopause. However, many women feel frustrated because they have sought help repeatedly without anyone identifying the underlying hormonal transition contributing to their symptoms.

In both NHS and private practice, what symptoms or concerns are most commonly overlooked during perimenopause and menopause consultations?

Reflecting on my own earlier training, I remember seeing women presenting with ‘all over body pain’, particularly women from Middle Eastern, South Asian, and African backgrounds. At the time, many were labelled

When people think about menopause, they often think only about hot flushes and night sweats. But around 20% of women do not experience those symptoms at all. Instead, many

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as difficult patients or ‘unable to cope’. Looking back now, I suspect many of those women were actually experiencing perimenopausal or menopausal symptoms that we simply failed to recognise. That experience reinforced for me how important it is that clinicians think more broadly and remain open-minded when women present in ways that may not fit traditional expectations.

Many women still describe feeling dismissed when presenting with hormonal or reproductive health concerns. From a clinician’s perspective, what needs to change? As primary care clinicians, we need to move away from seeing ourselves as gatekeepers and instead become partners in care. One of the key concepts I often discuss is culturally responsive care. This should never be treated as a tick-box exercise; it is a learnable skill.

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For me, the starting point is clinical curiosity. Clinicians should care not only about the symptoms patients present with, but also about who they are, their cultural and psychosocial context, and their own understanding of what they are experiencing. The second principle is clinical humility. Clinicians may be experts in medicine, but patients are experts in their own bodies and lived experiences. Good care therefore requires humility, respect, and genuine listening. Communication also matters enormously. We need to avoid jargon, remain non-judgmental, validate concerns, and ensure patients feel heard rather than dismissed or gaslit. That does not mean abandoning evidencebased medicine, but it does mean practising it with empathy. Medicine is not only biological; it is also deeply biopsychosocial and cultural. Clinicians need to recognise the biases they may bring into consultations and create space for truly patient-centred shared care.

in one consultation and continue it during follow-up appointments. When possible, I request longer appointments for women’s health consultations, although this varies between practices.

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You founded Health for Black People to address health inequities and educational gaps. Have you seen meaningful progress in recent years? I think the answer is both yes and no. There has definitely been progress. Women’s health and menopause are now being discussed far more openly, and there is a greater willingness to engage with conversations around inequality and inclusion.

Ultimately, we need healthcare systems that recognise the value of this kind of care. Cutting corners may save time in the short term, but it negatively affects patient outcomes in the long term. In private practice, I am fortunate to have 45 minutes or even an hour with patients, which allows much deeper exploration. But equitable care means ensuring this level of thoughtful,

For me personally, it has been a privilege to contribute to these discussions and advocate for communities that have often been left out of healthcare conversations. My motivation is also deeply personal. My mother was diagnosed with breast cancer at 37 years old, and my grandmother died from breast cancer in her 50s. I was also diagnosed with hypertension at 27 and have polyendocrine metabolic ovarian syndrome (PMOS), both

One of the strengths of general practice is longitudinal care. Conversations do not always have to happen in a single appointment. Sometimes I begin the discussion

Equitable care means ensuring this level of thoughtful, personalised support is not only available to those who can afford private healthcare

You also highlighted the challenge of limited consultation time in primary care. Is this model of care realistically achievable within the NHS? This is exactly why I continue advocating for more time and more resources in primary care. I do believe culturally responsive care is possible, because it is the type of care I try to practise myself, but it does take time and emotional energy.

personalised support is not only available to those who can afford private healthcare.

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conditions with important links to ethnicity and cardiometabolic risk.

I want women who have previously felt dismissed, unheard, or medically gaslit to know that their experiences are valid

I realised how much access to education, healthcare, and advocacy had shaped my own family’s outcomes. My mother recognised her breast cancer symptoms after reading a magazine article, and that knowledge likely saved her life. It made me reflect on how many women may never receive that information.

Even when practical responsibilities are shared, much of the emotional and organisational burden still falls disproportionately on women. This affects physical and mental health in profound ways.

There are now many organisations working to improve health education and advocacy within Black and minority communities, and there is certainly more awareness than before. However, outcomes are not improving as quickly as we would hope. In some cases, disparities appear to be narrowing only because outcomes for everyone are worsening overall, rather than because marginalised groups are receiving significantly better care.

In my consultations, whether women present with endometriosis, PMOS, premenstrual syndrome, premenstrual dysphoric disorder, perimenopause, or other health concerns, this hidden mental load often forms a major part of the picture. Alongside that, many women are carrying unspoken trauma related to infertility, miscarriage, abusive relationships, divorce, sexual trauma, or years of over- or under-sexualisation.

So, although there is more discussion and visibility, we still urgently need policy change, better resourcing, improved research inclusion, and meaningful action rather than rhetoric alone.

These cumulative stresses contribute to allostatic load and long-term morbidity, particularly in women from ethnic minority and lower socioeconomic backgrounds. While we absolutely need more research into issues such as cardiovascular disease, osteoporosis, dementia, and menopause-related morbidity, we also need to recognise and address the immense psychological burden many women are carrying throughout adulthood.

Across your work in clinical care, education, and advocacy, which area of women’s health currently feels most underprioritised? One issue I think we still fail to adequately address is the disproportionate mental load women carry throughout their lives. Women remain the primary caregivers in society, often balancing full-time work alongside caregiving responsibilities for children, older relatives, or vulnerable family members.

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Looking ahead, where do you hope to see the greatest progress in reducing inequalities in women’s healthcare?

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I want to see genuinely inclusive research that answers important questions about morbidity and long-term outcomes for all women, particularly women from lower socioeconomic backgrounds, Black women, South Asian women, and women with disabilities. These communities should not be treated as an afterthought; they need to be central to research design and healthcare planning. I also want clinical guidelines to reflect diversity more accurately. For example, if menopause timing differs across ethnic groups, then our guidance should acknowledge that, rather than relying on blanket averages that ignore huge sections of society. I want clinicians to receive training that genuinely equips them to deliver culturally responsive care. Most importantly, I want accountability and action rather than discussion alone. We need real changes in clinical practice and healthcare systems. Above all, I want women who have previously felt dismissed, unheard, or medically gaslit to know that their experiences are valid, that their symptoms are real, and that they deserve personalised care that meets them where they are.

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Interview

Citation:

EMJ Repro Health. 2026;12[1]:89-91. https://doi.org/10.33590/emjreprohealth/1I378ENW

Author:

Alena Sofieva, EMJ, London, UK

Q1 Karen Joash Consultant Obstetrician and Gynaecologist, Imperial College Healthcare NHS Trust, London, UK

While healthcare systems tend to focus on recovery within the first 6 weeks, the reality is that recovery extends far beyond that

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You have often highlighted the importance of supporting women beyond pregnancy and birth. In your view, what aspects of postnatal care remain most overlooked?

Pregnancy offers valuable insights into future health risks. Women who experience complications such as hypertensive disorders of pregnancy, fetal growth restriction, or gestational diabetes have an increased risk of cardiovascular disease later in life, yet many are never informed of these risks. Similarly, women who experience mental health difficulties during pregnancy may face increased vulnerability later in life, particularly during periods of hormonal change such as menopause.

The postnatal period remains significantly under-resourced. Women move from receiving intensive support throughout pregnancy to often feeling lost and unsupported after birth. While healthcare systems tend to focus on recovery within the first 6 weeks, the reality is that recovery extends far beyond that.

We also need a more familycentred approach. Supporting maternal recovery means supporting partners and families as well. When partners experience trauma or struggle during the perinatal period, this inevitably affects the support available to mothers.

I believe we should think about maternal recovery in the same way we think about the first 1,000 days of a child’s life. The first few years after birth provide important opportunities to support the longterm health of women.

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Perinatal mental health is increasingly recognised as a critical component of maternal care. Have you seen improvements in awareness and access to support? There has been substantial progress. The development of specialist perinatal mental health services and community-based support networks have transformed care for women with moderate-tosevere mental health conditions during pregnancy and after birth. Women are also more willing to discuss anxiety, depression, and other mental health concerns, which is a positive development. However, access remains challenging for many women with mild-to-moderate symptoms, and services are often stretched.

medication management becomes complex during pregnancy. There also remains a degree of hesitation around the use of psychiatric medications during pregnancy. While concerns about fetal safety are understandable, untreated mental illness carries significant risks for both mother and baby. Decisions should always be based on a careful assessment of risks and benefits, supported by specialist multidisciplinary teams.

As both a clinician and leader within maternity services, what do you consider the greatest patient safety challenge facing maternity care today? For me, the answer is culture. We need to move beyond crisis management and focus on prevention, personalised care, and creating environments where both patients and staff can thrive.

One area receiving increasing attention is neurodiversity and personality disorders during pregnancy. As awareness and diagnosis increase, we are seeing more women who require specialist support, particularly when 90

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itself. It affects maternal wellbeing, parent-infant bonding, family functioning, and long-term outcomes. Every woman deserves personalised care regardless of her ethnicity, socioeconomic background, or ability to access additional support outside the healthcare system. Equally important is staff wellbeing. Safe maternity care depends on psychologically safe teams, adequate rest, and a culture of continuous improvement. Staff who feel supported are better equipped to provide safe, compassionate care. Safety is not only the absence of harm for patients; it is also the absence of harm for healthcare professionals. When staff flourish, patients benefit too.

A positive birth experience has implications far beyond delivery

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Women entering pregnancy today often present with increasingly complex health needs. What trends are shaping maternity care? Women are becoming pregnant at older ages, which brings greater complexity during pregnancy. We are seeing increasing rates of hypertension, gestational diabetes, placental disorders, and other complications associated with advancing maternal age.

increasing complexity, and the need for individualised decisionmaking, rather than a one-sizefits-all approach to birth.

disparities when they are implemented consistently and evaluated properly. Reducing inequalities benefits everyone. Better outcomes improve patient care while also reducing pressure on healthcare systems.

At the same time, advances in medicine mean that women with complex medical conditions are living healthier lives and pursuing pregnancy. Fertility treatments are also enabling more women to conceive successfully. These developments are hugely positive, but they require more specialist input throughout pregnancy. Traditional models of care are under increasing pressure as the complexity of pregnancies continues to rise. We are also seeing increasing caesarean section rates. In the UK, rates are approaching 50%, when emergency and elective procedures are combined. This reflects changing demographics,

Despite advances in care, inequalities in maternal outcomes persist. What interventions have the greatest potential to reduce disparities?

Looking ahead, which innovations are most likely to transform maternity care over the next decade?

I am particularly excited by personalised risk prediction. Advances in genomics, biomarkers, digital health records, wearable technologies, and microbiome research are allowing us to identify women at increased risk earlier and tailor interventions accordingly.

Several areas are particularly exciting. Research into miscarriage prevention, including progesterone use and thyroid health, continues to advance. We are also learning more about the importance of nutrition, iron status, vitamin D, choline, and other nutritional factors in pregnancy outcomes.

We are also becoming more culturally aware as healthcare professionals. Greater engagement with communities and patient groups is helping us understand what different populations need and how we can build trust.

Microbiome research has enormous potential, particularly in relation to preterm birth prevention. There is growing interest in how probiotics and other interventions may support healthier pregnancies. Perinatal mental health is another rapidly evolving area, with new therapies emerging to support women at risk of postnatal depression.

Importantly, we are starting to move beyond simply discussing inequalities and towards implementing practical solutions. Recent work examining maternal haemorrhage demonstrated that relatively simple interventions can meaningfully reduce

Perhaps most importantly, researchers are increasingly recognising pregnancy as a window into future health. Complications during pregnancy can provide valuable information about a woman’s long-term cardiovascular and metabolic health. Using pregnancy history more effectively could help close important gaps in women’s healthcare and improve outcomes far beyond the maternity setting.

Traditional models of care are under increasing pressure as the complexity of pregnancies continues to rise

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Citation:

EMJ Repro Health. 2026;12[1]:92-94. https://doi.org/10.33590/emjreprohealth/7NTG07DV

Author:

Alena Sofieva, EMJ, London, UK

Much of your work has focused on reproductive endocrinology and complex fertility care. Where do you see the most persistent gaps between guideline-based evidence and everyday clinical practice?

Vikram Talaulikar Associate Specialist in Reproductive Medicine, University College London Hospitals NHS Foundation Trust; Honorary Associate Professor, University College London; Specialist in Reproductive Endocrinology, Fertility and Menopause Care, The LUNA Clinic, London, UK

One of the biggest misconceptions is that reproductive endocrinology is simply fertility care. In reality, it spans the entire reproductive lifespan, from menarche through fertility and pregnancy to perimenopause and menopause. It is about a woman’s hormonal journey across her life. There are significant gaps in research across this spectrum. Historically, women’s health research has been underfunded. We still lack robust data in many areas, particularly in ethnically diverse populations. For example, we do not have enough highquality research on women of Southeast Asian origin, women of Black Afro-Caribbean origin, or other minority groups. That makes it harder to provide truly evidencebased, individualised counselling.

We still lack robust data in many areas, particularly in ethnically diverse populations

There are also grey areas at the forefront of fertility treatment, such as sperm DNA fragmentation testing, preimplantation genetic testing for aneuploidy, immunological testing, or IVF add-ons. Guidelines may state that there is insufficient evidence, yet these tests are widely used in clinical practice. The challenge is explaining uncertainty to patients, while still offering clear, honest guidance about potential benefits and risks. Until we have stronger data, these grey areas will remain. 92

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You have been closely involved in fertility preservation and counselling across different patient groups. How has that conversation evolved? This is one area where we have seen real progress. In the past, women undergoing cancer treatment or ovarian surgery often had little discussion about future fertility. Now, many are offered a choice before starting treatment, whether that is egg freezing or ovarian tissue preservation. Across the UK, more centres are offering fertility preservation, which is a positive step forward. However, access is still not uniform. Ovarian tissue preservation, for example, is available only in a limited number of centres. Funding also varies by region. While there is NHS funding for fertility preservation when ovarian damage is anticipated, such as in oncology cases, provision is not always equitable across the country. So, while more women now have options, we are not yet at a stage of fully equal access.

Is fertility preservation covered by the NHS?

Yes. When there is a medical indication, for example, cancer treatment or surgery that may damage the ovaries, egg or tissue preservation is funded by the NHS. Timing can be a limiting factor. If cancer treatment must begin urgently, there may not be CC BY-NC 4.0 Licence

Interview

sufficient time to complete a stimulation cycle. In other cases, a patient’s clinical condition may not allow it, but for the majority of women who can safely undergo treatment, and where time permits, fertility preservation is now funded. Social egg freezing, however, is not covered by the NHS.

If a woman feels well on HRT, when would you consider reducing or stopping it? It is entirely individual and there is no arbitrary limit. Many women take HRT for 5–10 years and then try stopping to see whether symptoms return. If symptoms have resolved, they may not need to continue. If symptoms recur, they may restart and reassess again later. Long-term benefits of hormones for heart, bone, and genitourinary health should also be factored in when making decisions about continuing HRT.

Menopause care has gained renewed attention both clinically and publicly. What misconceptions do you encounter most often? The most persistent misconception is the fear of cancer associated with hormone replacement therapy (HRT). This fear remains common among both the public and healthcare professionals. Many women believe that HRT will inevitably cause breast cancer. That is not true. The increased risk associated with HRT is small, and a woman’s background health factors play a much greater role in determining her overall risk.

Some women feel so well on treatment, and have minimal risk factors, that they choose to continue long-term. The key is informed decision-making. As long as a woman understands the benefits and potential risks, the decision should be hers.

comorbidities, such as diabetes, hypertension, or high BMI, and very different life experiences.

Another misconception is that menopause is brief. For some women, symptoms can last 5, 10, 15 years, or even longer, and they can be debilitating. It is not simply a short transitional phase for everyone. It is also important to recognise that HRT is not the right choice for every woman. Some prefer non-hormonal options or lifestyle approaches, but women who wish to consider HRT should receive balanced, up-to-date information. Unfortunately, not all healthcare professionals are fully aligned with current guidance, and that is an area where continued education is needed.

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Your work often emphasises individualised care rather than purely protocol-driven approaches. How do you balance guidelines with personalised treatment?

My approach is to start with the guideline as a foundation. If it fits the individual, we follow it. If the situation is nuanced and the guideline does not perfectly apply, I explain that openly. I discuss the evidence, the uncertainties, and my clinical judgement. Shared decision-making is essential. Guidelines should not be used rigidly to deny or automatically impose treatment without considering the person.

Guidelines provide a framework based on large population studies. They tell us what is generally safe, what the statistical benefits and risks are, and what the evidence shows at a population level, but no guideline can fully account for the individual sitting in front of you. Women come from different genetic, social, and cultural backgrounds. They have different

Guidelines should not be used rigidly to deny or automatically impose treatment without considering the person

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What aspects of reproductive endocrinology remain underrepresented in training pathways? Traditionally, menopause and reproductive endocrinology have not received sufficient emphasis in undergraduate and postgraduate medical training. My own pathway was slightly different, training in India and then completing the Membership of the Royal College of Obstetricians and Gynaecologists (MRCOG) training in the UK before specialising further.

Shared decision-making has been the biggest transformation in women’s health

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Where do you anticipate the most meaningful advances in reproductive health in the near future? In fertility, we will likely continue refining IVF protocols to better individualise treatment and improve outcomes. We may develop improved options for women with premature ovarian insufficiency or those at risk of early menopause.

Listening to patients. Medicine used to be very unidirectional: doctors told patients what to do. That is changing. Patients now have access to information and come prepared with questions. They participate in decisions about their care.

Historically, both endocrinology and gynaecology training have given relatively limited focus to reproductive endocrinology, particularly menopause. That is changing. There is now far greater awareness of menstrual disorders, polycystic ovary syndrome, endometriosis, and menopause. Colleges and training programmes are increasing exposure in these areas, which is encouraging for the future.

Looking back at your career, what shift in clinical thinking has had the greatest positive impact on patient outcomes?

There can be misinformation, particularly on social media, and sometimes patients may request treatments that are not appropriate, but, overall, increased access to evidencebased information has empowered women. Professional bodies, royal colleges, and NHS resources provide reliable guidance. Shared decision-making has been the biggest transformation in women’s health.

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In menopause research, we still need to understand the basics more thoroughly. Why do women with similar backgrounds experience symptoms so differently? Why does HRT work well for one woman and not for another? We are now studying the effects of menopause on the brain, heart, and bone in far greater depth. In the next 5–10 years, we will have much more detailed data. There is still a great deal of work to do, but there is also much to be optimistic about.

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Interview

Citation:

EMJ Repro Health. 2026;12[1]:95-97. https://doi.org/10.33590/emjreprohealth/550KET1C

Author:

Alena Sofieva, EMJ, London, UK

The management of endometriosis has evolved considerably over recent decades. What have been the Ertan Saridogan most important changes in clinical Professor of Gynaecological practice, and where do significant Surgery, University College London; Consultant in Reproductive unmet needs remain? Medicine and Minimal Access Surgery, University College London The management of endometriosis Hospitals, UK; President, European has been evolving for much longer than the past decade. If we look Society for Gynaecological Endoscopy (ESGE) back 40 or 50 years, treatment options were very limited. Medical therapy largely consisted of progestogens or danazol, which was effective for some women but associated with significant side effects. Surgery was usually reserved for women whose symptoms had become severe enough to require hysterectomy.

Multidisciplinary care has become one of the defining developments in modern benign gynaecology

the therapeutic options available for women whose symptoms are not adequately controlled. Perhaps the biggest change, however, has been recognising the limitations of both surgery and medical treatment. Endometriosis is a chronic condition. Even extensive surgery does not necessarily cure the disease, and recurrence remains common. Today, the focus is increasingly on long-term management, recognising that endometriosis is a chronic condition requiring ongoing care rather than a single definitive solution or quick fix.

How do you decide whether surgery or medical treatment is the most appropriate option for an individual patient?

The first major shift came with the wider adoption of laparoscopic surgery during the 1990s and early 2000s. Initially, ablative techniques such as laser surgery became popular, particularly for superficial disease. However, we later recognised that many women have deep endometriosis, where excisional surgery offers much better outcomes.

The decision should always be individualised and made jointly between the patient and her clinician. In many situations, medical therapy represents an appropriate first-line approach, particularly if symptoms are controlled and side effects remain acceptable.

As surgical techniques advanced, understanding of retroperitoneal pelvic anatomy became an essential part of endometriosis surgery. This has allowed surgeons to remove disease more completely while minimising complications.

However, there are circumstances where surgery becomes essential. These include bowel or ureteric obstruction caused by deep endometriosis, suspicion of malignancy within an ovarian endometrioma, or other situations where anatomical distortion threatens organ function.

Medical treatment has also progressed considerably. Newer progestogens and, more recently, gonadotropin-releasing hormone (GnRH) antagonists have expanded CC BY-NC 4.0 Licence

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Outside these indications, both medical and surgical management may be reasonable options. The patient's symptoms, reproductive plans, previous treatments, and personal preferences all need to be considered when deciding on the most appropriate strategy.

support, and specialist nursing alongside surgical and medical treatment. This approach mirrors the multidisciplinary cancer model, which has clearly improved outcomes over many years. Increasingly, similar models are being adopted for other benign gynaecological conditions such as pelvic floor disorders and, in the future, may become routine for fibroid management as newer minimally invasive therapies continue to emerge.

Women with complex benign gynaecological conditions often require input from multiple specialists. How can multidisciplinary care improve outcomes? Multidisciplinary care has become one of the defining developments in modern benign gynaecology.

Fertility preservation has become an increasingly important consideration in women with endometriosis. Which patients should clinicians be thinking about?

Endometriosis affects far more than the reproductive organs. Disease may involve the bowel, bladder, ureters, diaphragm, or thoracic cavity, meaning that optimal care frequently requires collaboration with colorectal surgeons, urologists, thoracic surgeons, radiologists, and pain specialists.

Not every woman with endometriosis will experience infertility. Although the risk is increased compared with the general population, many women conceive naturally.

Equally important is recognising that many women experience chronic or centralised pain. These patients often benefit from physiotherapy, specialist pain management, psychological 96

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This has prompted increasing discussion around fertility preservation. At present, women with bilateral endometriomas or recurrent ovarian surgery appear to be those most likely to benefit from egg or embryo cryopreservation before surgery, as these groups face the greatest risk of diminished ovarian reserve.

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Surgical innovation continues to advance rapidly, from robotics to AI and novel diagnostic technologies. Which developments have the greatest potential to improve patient care? The most exciting developments may not actually be in surgery itself but in diagnosis.

The greatest concern arises when surgery involves ovarian endometriomas because excision inevitably removes some healthy ovarian tissue and reduces ovarian reserve.

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However, many important questions remain unanswered. We still lack robust prospective data identifying exactly who benefits most from fertility preservation, when it should be offered, and whether current strategies are cost-effective. These are areas where further research is urgently needed.

Imaging has improved enormously. High-quality transvaginal ultrasound and MRI can now

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diagnose many cases of deep endometriosis without the need for diagnostic laparoscopy. The challenge is ensuring these techniques become more widely available and that clinicians receive sufficient training to perform and interpret them accurately.

Another particularly promising area is biomarker research. One of the biggest challenges in endometriosis remains delayed diagnosis. Reliable biomarkers, potentially combined with imaging findings, symptom profiles, and AI, could enable women to receive a diagnosis much earlier than is currently possible. Recent work evaluating novel diagnostic tests is encouraging, although these approaches still require robust prospective evaluation before they become part of routine practice.

Training the next generation of minimally invasive surgeons is becoming increasingly challenging. How should surgical education evolve?

Importantly, modern gynaecological surgery itself has evolved. Today's surgeons require skills that were rarely taught during residency several decades ago, particularly advanced retroperitoneal dissection for deep endometriosis. Training programmes therefore need to evolve alongside surgical practice.

Training is changing because healthcare itself is changing. Previous generations of surgeons spent considerably longer hours in hospitals, allowing greater operative exposure during training. Today's trainees have shorter working hours and fewer opportunities to develop technical skills through clinical experience alone.

As the ESGE President, what are your priorities for the Society over the coming years? Education remains one of our highest priorities.

As a result, simulationbased education has become increasingly important.

AI will almost certainly contribute to future diagnosis and clinical decision-making, although I believe its role in surgical planning remains some way off.

Simulation allows trainees to develop psychomotor skills before operating on patients, while hands-on cadaveric courses, structured educational programmes, webinars, and specialist workshops all help bridge the gap created by reduced clinical exposure.

Robotic surgery, meanwhile, should be viewed primarily as another surgical platform. For experienced laparoscopic surgeons, it does not fundamentally change surgical principles. However, robotics may make advanced minimally invasive surgery easier for younger surgeons to learn, and that could have an important impact on future training.

At the European Society for Gynaecological Endoscopy (ESGE), we recognised this challenge many years ago through the development of the Gynaecological Endoscopic Surgical Education and Assessment (GESEA) programme. This provides structured training and certification before surgeons progress to increasingly complex procedures in the operating theatre.

The ESGE has invested heavily in structured training programmes, hands-on courses, scientific meetings, and educational resources designed to support surgeons throughout their careers. Our aim is not only to improve technical skills but also to create opportunities for clinicians to exchange knowledge and share best practice internationally. We are also committed to supporting research and innovation through our congresses and our open-access journal, which provides an important platform for disseminating new evidence. Although the ESGE began as a European society, it has become increasingly international. Our educational programmes are now expanding well beyond Europe, with growing participation across Asia, Africa, the Americas, and Oceania.

Our goal is to ensure that high-quality minimally invasive gynaecological surgery becomes accessible to women worldwide

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Ultimately, our goal is to ensure that high-quality minimally invasive gynaecological surgery becomes accessible to women worldwide through better education, collaboration, and continuous professional development.

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Society Update

Spotlight from Europe British Menopause Society

The British Menopause Society Calls for a Strengthened Evidence-Based Approach in Menopause Care Amid Changing Clinical Landscape The British Menopause Society (BMS) is reinforcing the importance of evidence-based menopause care in response to notable shifts in clinical practice and increasing concerns about misinformation. The Society reports growing variation in prescribing patterns, including use of higher-than-licensed doses of hormone replacement therapy (HRT) and expanded prescribing of testosterone outside established indications. These developments underline the need for consistent application of national guidance and robust clinical education to ensure safe, effective, and appropriate care for women.

OVERVIEW Over the past year, menopause management has continued to evolve rapidly, with increasing patient demand and heightened public attention influencing clinical decision-making. The BMS has observed that, in some settings, treatment approaches are diverging from established evidence, particularly in relation to HRT

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The BMS notes that misinformation in healthcare has become more prevalent over the past decade. This has contributed to inconsistent patient expectations and, in some cases, the use of treatments without clear evidence of benefit. The Society emphasises that menopause is a natural life stage, and that treatment can be appropriate and beneficial for symptom management but should be guided by individual needs and a careful assessment of benefits and risks, rather than being viewed as universally required. In response, the BMS continues to prioritise the development and dissemination of high-quality education for healthcare professionals. Its board of Trustees and Medical Advisory Council remain focused on producing peer-reviewed guidance and structured educational programmes designed to support clinicians in both primary and secondary care. Recent updates include ongoing refinement of clinical resources and expansion of training initiatives aimed at improving consistency in menopause care delivery across the UK.

dosing strategies and testosterone prescribing. While personalised care remains a cornerstone of menopause management, the Society stresses that clinical decisions should remain 98

anchored in validated evidence and recognised guidelines.

The Society is also engaging with emerging clinical areas highlighted in recent academic discussion, including the role of incretin-

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Treatment approaches are diverging from established evidence, particularly in relation to HRT dosing strategies

based weight loss therapies in women using HRT. These developments reflect the need for further evidence to inform safe prescribing and integrated care pathways in midlife women’s health. Looking ahead, the BMS 35th Annual Scientific Conference, titled 'The menopause landscape: pathways to better care', will convene clinicians, researchers, and stakeholders to examine current evidence and emerging areas of practice. The programme will include sessions on emerging therapies such as NK3R antagonists for vasomotor symptoms and incretin therapy in women using HRT, alongside discussions on testosterone and midlife sexual function. Clinical topics will cover sleep disturbance, unscheduled bleeding on HRT, and bone health using FRAX® (University of Sheffield, UK). Broader themes include renal disease and HRT, clotting risk, recurrent urinary tract infections after menopause, and the relevance of menopause in rheumatology. The programme will also address mental health, psychosocial interventions,

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progestogens and metabolic outcomes, and the interpretation of online information in relation to national guidance. The BMS continues to support clinicians through high-quality, peer-reviewed education and clinical guidance, led by its board of Trustees and Medical Advisory Council, to ensure menopause care remains consistent, evidence-based, and patient-centred.

SOCIETY AIMS AND SCOPE The BMS is the specialist authority for menopause and post reproductive health in the UK. Established in 1989, the BMS educates, informs, and guides healthcare professionals, working in both primary and secondary care, on menopause and all aspects of post reproductive health. Emily Josif Communications Manager, BMS

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Society Update

British Society for Paediatric and Adolescent Gynaecology

BritSPAG: Advancing Paediatric and Adolescent Gynaecology Across the UK The British Society for Paediatric and Adolescent Gynaecology (BritSPAG) was established in 2000 with the aim of promoting the sub-specialty, profile, study, and clinical practice of paediatric and adolescent gynaecology (PAG), complex congenital gynaecology, and differences in sex development. Over the past 25 years, the society has become a leading voice in this specialist field, supporting healthcare professionals through education, training, research, and multidisciplinary collaboration, alongside providing patients and families with information and a platform to share their lived experiences. Today, BritSPAG comprises approximately 200 members from a range of clinical backgrounds, united by a shared commitment to improving gynaecological care for children and adolescents, and young adults living with differences in sex development.

OVERVIEW Language and framing in PAG are fundamental to delivering safe, effective, and trauma-informed care. For example, by avoiding terms like disorder and anomaly, and including terms such as differences or diversity. The society strives to learn from patients and communication experts with a view to delivering holistic care and keeping patients engaged in the medical services. Children and adolescents are particularly vulnerable to the lasting psychological impact of how healthcare encounters are conducted. Topics intersect with identity, puberty, sexuality, and body image, and clinicians must be mindful of shame, embarrassment, or fear when discussing sensitive issues.

PAG is a rapidly evolving specialty, and the past 6–12 months have seen several important developments that are shaping clinical practice. One of the most significant changes has been the move towards renaming polycystic ovary syndrome as polyendocrine metabolic ovarian syndrome (PMOS). This shift reflects growing recognition of the metabolic features that often accompany the condition and aims to improve diagnostic accuracy and long-term health outcomes in young people. Alongside this change in terminology, there has been increasing emphasis on appropriate metabolic screening for adolescents with PMOS. As evidence continues to emerge regarding the broader health implications of the condition, clinicians are adopting a more holistic approach to assessment and management, with greater attention paid to metabolic risk factors and preventative care. Another notable development has been the evolving approach to suspected endometriosis in adolescents. Historically, diagnostic laparoscopy was often considered the gold standard for confirming a diagnosis. However, there is now a growing movement towards less invasive investigation and management strategies. Clinicians are increasingly relying on a combination of clinical assessment and advanced imaging techniques, particularly MRI, to support diagnosis and guide treatment decisions. This approach enables earlier symptom management while

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reducing the potential risks associated with surgery in younger patients. Empirical treatment based on clinical suspicion is also widely accepted, allowing adolescents to access symptom relief without necessarily undergoing invasive procedures. In parallel, several promising non-invasive diagnostic tests for endometriosis are currently under

BritSPAG remains dedicated to advancing knowledge, improving clinical practice, and advocating for the needs of young patients investigation. While these tests are not yet available for use in individuals under 18 years of age, and are not currently accessible through the NHS, ongoing research may help transform diagnostic pathways in the very near future.

a valuable opportunity for healthcare professionals to share knowledge, discuss challenging cases, and learn about the latest advances in PAG. The next Annual BritSPAG Conference will take place in Birmingham, UK, on 8th–9th March 2027.

BritSPAG continues to closely monitor emerging evidence in this area, including the outcomes of the ESPriT2 trial. The aim of this multicentre randomised trial is to determine whether laparoscopic excision/ ablation is of clinical benefit to women with chronic pelvic pain where the only finding is superficial peritoneal endometriosis, the form of endometriosis most commonly identified in adolescents. The results are eagerly anticipated and are expected to contribute significantly to future clinical guidance.

As PAG continues to evolve, BritSPAG remains dedicated to advancing knowledge, improving clinical practice, and advocating for the needs of young patients. The society continues to shape the future of PAG and ensure that children and adolescents receive the highest standards of gynaecological care.

Cara Williams

Chair of the British Society for Paediatric and Adolescent Gynaecology

Guideline development continues to be a key area of activity for the society. One of the current priorities is the update of the BritSPAG guideline on ovarian cysts in PAG. This widely used resource supports clinicians in the assessment and management of ovarian cysts in children and young people, helping to ensure consistent, high-quality care across the UK. Education and professional development remain central to BritSPAG’s mission. The society’s annual conference provides CC BY-NC 4.0 Licence

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Society Update

European Menopause and Andropause Society

EMAS: Advancing Midlife Health Through Education, Research, and Collaboration Founded in 1998, the European Menopause and Andropause Society (EMAS) is a non-profit scientific society dedicated to advancing health and wellbeing in midlife and beyond through research, education, and advocacy. With members and affiliated societies across the globe, EMAS brings together a broad community of clinicians, researchers, and healthcare professionals committed to evidence-based, inclusive, and collaborative care. Its work is shaped by wide-ranging expertise across the many disciplines involved in midlife health, helping ensure that menopause and post-reproductive health are approached in a comprehensive, multidisciplinary way.

OVERVIEW At the core of EMAS is a clear mission: to improve care and support healthier ageing by promoting scientific knowledge, professional education, and collaboration. This commitment is reflected not only in its clinical and educational activities, but also in its emphasis on practical guidance for healthcare professionals and better recognition of midlife health in wider society.

clinical decision-making. Its focus reflects a growing need for deeper, structured training in an area where patient demand is rising but formal education has often not kept pace. EMAS has also played a pioneering role in addressing menopause in the workplace. In 2016, EMAS published the first scientific recommendations on menopause and work, followed by an updated position statement in 2021. Since then, the society has continued to develop guidance and educational resources, and has led awareness efforts, including the launch of Menopause in the Workplace Day on 7th September, helping to place menopausal

Education remains central to EMAS activity. EMAS delivers a regular webinar programme, alongside podcasts, clinical guidance, Menopause Essentials fact sheets, and research resources designed to support both healthcare professionals and the wider public. EMAS also contributes to scientific publishing through its official journals, which provide multidisciplinary perspectives on midlife health and support the dissemination of clinically relevant research. A key addition to this educational portfolio is EMAS Academy 2026, which took place in Rotterdam, the Netherlands, on 3rd–4th July 2026. Framed as "a new way of learning midlife care," the Academy is designed to prepare healthcare professionals to deliver confident, evidence-based midlife care with practical tools for real-world 102

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EMAS believes that improving education for both healthcare professionals and the public, while promoting equitable access to modern reproductive and menopausal healthcare, will be essential to improving outcomes across Europe

health within broader discussions on workforce participation, equality, and healthy ageing. One of the greatest challenges facing reproductive and midlife health in 2026 is the growing mismatch between increasing patient needs and unequal access to evidence-based care across Europe. Women are living longer, expectations regarding quality of life continue to rise, and awareness of reproductive and menopausal health is increasing. At the same time, misinformation on social media, persistent stigma surrounding menopause and fertility, and considerable disparities between healthcare systems continue to influence patient care. EMAS believes that improving education for both healthcare professionals and the public, while promoting equitable access to modern reproductive and menopausal healthcare, will be essential to improving outcomes across Europe. Alongside these challenges, the field is undergoing rapid transformation through digitalisation, personalised medicine, and emerging therapeutic innovations. AI, telemedicine, and digital health technologies are increasingly supporting patient management and education, while advances in hormone therapies and fertility preservation are enabling more individualised approaches to care. EMAS envisions a future centred on multidisciplinary, patient-focused care that combines scientific innovation with a holistic understanding of women's health across the lifespan.

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Looking ahead, EMAS continues to strengthen its international scientific exchange through its congresses, with the next EMAS Congress taking place in Gothenburg, Sweden, from 19th–21st May 2027. The congress will bring together a global, multidisciplinary community to share research, clinical advances, and perspectives shaping the future of midlife health. Beyond education and research, EMAS is increasingly contributing to policy discussions. Its President, Petra Stute, and Secretary General, Ludwig Kiesel, were recently invited to speak at a European Parliament public hearing on menopause care, reflecting growing recognition of midlife health as a public health priority. Through these activities, EMAS continues to support clinicians, advance knowledge, and contribute to improving health outcomes at midlife and beyond. Petra Stute President of EMAS

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Society Update

European Society for Gynaecological Endoscopy

ESGE: Leading The Future of Surgical Education, Innovation, and Collaboration The European Society for Gynaecological Endoscopy (ESGE) is dedicated to advancing excellence in gynaecological endoscopy by promoting education, scientific research, innovation, and international collaboration.

OVERVIEW Founded in 1989, ESGE is one of the world's leading organisations dedicated to advancing minimally invasive gynaecological surgery. Bringing together more than 5,000 members and 25 National Affiliated Societies from over 75 countries, the ESGE promotes excellence through education, scientific collaboration, research, guideline development, and international networking. One of the greatest challenges facing minimally invasive gynaecological surgery is the variation in training and clinical practice across Europe. Surgeons often have access to different educational opportunities, technologies, and operative experience depending on where they train. As surgical techniques continue to evolve rapidly, ensuring that clinicians develop validated technical skills and deliver consistently high standards of care has become increasingly important. To address this challenge, the ESGE has significantly expanded its educational activities and strengthened collaboration between European centres. Under the leadership of President Ertan Saridogan, the Society has broadened participation across its committees and Special Interest Groups (SIG), bringing together experts from different countries to advance key areas, including laparoscopy, hysteroscopy, robotics, imaging, reproductive surgery, and surgical education. These groups develop educational programmes, facilitate collaboration, and enable the sharing of expertise across Europe. Education remains at the heart of the Society's mission. Through the ESGE Academy and the Gynaecological 104

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Endoscopic Surgical Education and Assessment (GESEA) programme, surgeons have access to structured training that combines theoretical learning, simulation, practical assessment, and internationally recognised certification. The Young Endoscopists Platform (YEP) further supports trainees by facilitating international educational exchanges, allowing young surgeons to gain experience at recognised European centres before attending the Annual Congress. Together, these initiatives help harmonise surgical standards while fostering collaboration between institutions and countries. Keeping pace with innovation presents another major challenge for the specialty. Robotic surgery, advanced imaging, simulation, AI, and new surgical technologies continue to transform minimally invasive gynaecology. However, adopting new techniques without appropriate training or robust clinical evidence risks compromising patient safety. The ESGE advocates for responsible innovation, ensuring that new technologies

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are introduced alongside high-quality education, structured skills assessment, and evidence-based clinical guidance. Managing increasingly complex benign gynaecological conditions also requires closer collaboration between specialties. Women with severe endometriosis, deep infiltrating disease, complex pelvic pathology, or congenital anomalies often require coordinated care involving gynaecological surgeons, colorectal surgeons, urologists, radiologists, fertility specialists, and pain teams. Recognising this, the ESGE promotes multidisciplinary education through its SIGs, hands-on cadaveric courses, and scientific meetings that encourage collaboration across disciplines and countries. One example of this commitment is the ESGE Hands-on Laparoscopic Cadaveric Dissection Course introduced in the UK by the SIG for Training and Education chaired by Lina Antoun. The course brought together faculty from across Europe, including Ertan Saridogan, Chair of Fibroids & Adenomyosis; Helder Ferreira, ESGE Academy Faculty; Andreas Hackethal, Consultant Gynaecological Oncologist, Frauenklinik an der Elbe, Hamburg, Germany; and Smruta Shanbhag, Consultant Gynaecological Oncologist, NHS Greater Glasgow and Clyde, UK, and provides advanced practical training in pelvic anatomy and complex laparoscopic surgery while encouraging the exchange of surgical experience between international experts.

Poland, from 4th–7th October 2026, with an extensive programme of pre-Congress workshops offering additional opportunities for practical training. The ESGE also recognises that optimal surgical and non-surgical management in contemporary gynaecology requires the creation and dissemination of evidence, so it has established its own international, scientific, peer-reviewed, open-access journal. As minimally invasive gynaecological surgery continues to evolve, the ESGE remains committed to strengthening education, supporting international collaboration, and promoting evidencebased practice. By harmonising surgical training and encouraging responsible innovation, the society continues to improve standards of care and surgical outcomes for women across Europe and beyond. Lina Antoun Consultant Gynaecologist & Obstetrician, Birmingham Women’s and Children’s NHS Foundation Trust; Chair, British Society for Gynaecological Endoscopy (BSGE), UK; Chair, Training and Education Special Interest Group, The European Society for Gynaecological Endoscopy (ESGE), Leuven, Belgium

The ESGE Annual Congress remains the Society's flagship educational event, bringing together surgeons, researchers, trainees, and industry partners from around the world to discuss emerging evidence, share new techniques, and explore the latest developments in minimally invasive gynaecological surgery. The 35th ESGE Annual Congress will take place in Kraków,

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Society Update

Primary Care Women's Health Society

PCWHS: Advancing Women's Healthcare Through Education and Advocacy The Primary Care Women’s Health Society (PCWHS) is dedicated to advancing women’s health in primary care through high-quality, evidence-based education, professional collaboration, and advocacy. By supporting HCPs, promoting best practice, addressing health inequalities, and contributing to national policy and guideline development, the Society aims to improve the quality and accessibility of women's healthcare across the UK.

OVERVIEW The PCWHS started in 2007 as the Primary Care Women’s Health Forum. The founding members were general practitioners with a special interest in women’s health who had just finished their post-graduate diploma in gynaecology at the University of Bradford, UK. They recognised that there was no provider of women’s health education for those working in primary care and started an organisation that would be similar to primary care societies in other areas such as dermatology. Working with very limited resources, they published a journal and ran educational events for primary care practitioners with an interest in women’s health.

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translating current research into practical resources and sharing best practices in women’s health. Ensure we include underserved populations, particularly ethnic minorities and those in deprived or marginalised areas, to address health inequalities. Provide opportunities for peer support, networking, and the exchange of views between our members. Contribute to national and local discussions, ensuring that the experiences and views of primary care clinicians are considered in shaping women’s health policy and practices.

The Forum has now been renamed as the PCWHS, and the 1,000 member threshold was passed in 2026, with 200 attendees at the most recent conference. Membership includes doctors, nurses, pharmacists, paramedics, physiotherapists, and other HCPs with an interest in women’s health in primary care. The PCWHS contributes to the creation of guidelines by organisations such as the National Institute for Health and Care Excellence (NICE) and works collaboratively with Royal Colleges that have primary care relevance. It has a Facebook group, hosting active discussions about both clinical matters and the commissioning of women’s health services in primary care.

Women’s health is not exempt from the challenges facing the rest of the NHS, with themes of increasing demand and underfunding. The 2026 women’s health strategy outlined significant health inequalities; women spend more years in ill health than men, and the wealthiest 10% of women live almost 10 years longer than the poorest 10%. Maternal mortality is significantly higher in Black women than their White counterparts, and babies born to Black women are more than twice as likely to die in their first year than those born to White women. The diagnosis of conditions such as endometriosis can take years, and there are concerns about undertreatment of cardiovascular risk factors in women and under-recognition of the sometimes atypical presentation of heart attacks in women.

The PCWHS’ aims are as follows: • Provide high-quality, practical, and evidence-based education to healthcare clinicians across the entire primary care team. • Support the development of evidencebased practices in primary care by

The NHS 10-year plan aims to move care into the community, which is welcome news for those in primary care with an interest in women’s health, but resourcing and the ability to make long-term plans are an issue; community services are frequently given contracts lasting only a year or two. As well

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as providing education on clinical topics, the PCWHS is active in the area of healthcare planning for women. They attend All-Party Parliamentary Group meetings where they have given their input in discussions on a variety of topics, including the delivery of sexual and reproductive healthcare and the management of common conditions such as fibroids. The PCWHS carries out surveys to inform the resourcing of longacting contraceptive provision in the community and attempts to ensure that community women’s health services are adequately resourced in the long term. Their Women’s Health Hub toolkit is a practical resource that can be used by clinicians and commissioners looking to set up community women’s health services. This is an exciting time to be involved in women’s health, with multiple new developments. Management of the menopause and perimenopause has been transformed over the last decade, with hormone replacement therapy prescribing having trebled since 2015/2016. Women who have had breast cancer and often can’t have systemic hormone replacement therapy are getting more options, with two neurokinin-3 antagonists having been approved by the Medicines and Healthcare Products Regulatory Agency (MHRA) and one of them having achieved NICE approval. The renaming of polycystic ovarian syndrome as polyendocrine metabolic ovarian syndrome (PMOS) reflects the increasing recognition that PMOS is a complex multi-system condition rather than one just affecting the ovaries. The PCWHS is contributing to the upcoming NICE guidance on this and looks forward to seeing more holistic management of women with PMOS. Two completely new diagnostic tests for endometriosis are being reviewed by NICE, although it remains to be seen how implementation in primary care will actually be managed, and new medication options for fibroids and endometriosis should improve outcomes for women with these complex conditions.

health, which is shortly to be published by the Royal College of General Practitioners (RCGP). They are working with NHS England on their framework for practitioners with an extended role in women’s health, and will have their first study day for this cohort later in 2026. With a growing membership and a larger committee, the PCWHS has the capacity to provide more education and leadership and hopes to have real influence in the provision of primary care women’s health service in the years to come.

Toni Hazell

Director, Primary Care Women’s Health Society (PCWHS), UK

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Society Update

British Society for Gynaecological Endoscopy

BSGE: Advancing Standards in Minimally Invasive Gynaecological Surgery Founded in 1989, the British Society for Gynaecological Endoscopy (BSGE) is the UK's leading professional society dedicated to advancing minimally invasive gynaecological surgery. Bringing together around 2,000 members, including consultants, trainees, specialist nurses, and allied HCPs, the Society promotes excellence in laparoscopic, hysteroscopic, robotic, and endometriosis surgery through education, research, guideline development, and multidisciplinary collaboration.

OVERVIEW Education is central to the BSGE's mission. Through its National Training Hub Programme, members have access to structured laparoscopic and hysteroscopic training, including lectures, simulation, and hands-on practical courses delivered across beginner, intermediate, and advanced levels. The society also offers fellowship opportunities, travel bursaries, and research grants to support specialist training and academic development. Monthly webinars and an extensive online surgical video library provide ongoing educational opportunities, while UK and Ireland members also benefit from complimentary corporate membership of the European Society for Gynaecological Endoscopy (ESGE).

Beyond education, the BSGE contributes to national standards through involvement in clinical guidelines, training curricula, accreditation, and international collaboration. Working closely together with the Royal College of Obstetricians and Gynaecologists (RCOG), ESGE, and other international societies, BSGE is one of the leading organisations in laparoscopy, hysteroscopy, and robotic surgery. The BSGE continues to promote innovation that is underpinned by robust evidence while supporting the highest standards of minimally invasive gynaecological care. As surgical techniques continue to evolve, the Society remains committed to advancing education, fostering research, and improving outcomes for women across the UK.

BSGE contributes to national standards through involvement in clinical guidelines, training curricula, accreditation, and international collaboration

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Two current priorities for the BSGE are optimising the management of endometriosis, a highly prevalent condition causing pain and subfertility, and the conduct of outpatient hysteroscopy, the most common endoscopic procedure in contemporary gynaecological practice.

fertility specialists, specialist nurses, and other HCPs to deliver coordinated, patient-centred care. Alongside supporting specialist services, the BSGE continues to promote research into earlier diagnosis, including the development of non-invasive diagnostic approaches that could help reduce diagnostic delays.

ENDOMETRIOSIS AND EndoUK 2026

Reflecting this commitment, the Society will host its first multidisciplinary endometriosis meeting in Birmingham, UK (EndoUK) in December 2026. Bringing together experts from across specialties, the meeting will explore every stage of the patient pathway, from diagnosis and imaging to medical management, surgery, fertility, and longterm care.

The management of endometriosis represents one of the greatest challenges facing gynaecologists today. Despite affecting around one in 10 women of reproductive age, women in the UK wait an average of 8–10 years for a diagnosis, often experiencing persistent pain, reduced quality of life, and repeated healthcare visits before receiving appropriate treatment. Recognising that surgery alone cannot solve this problem, the BSGE advocates for a multidisciplinary approach to endometriosis care. The Society accredits specialist endometriosis centres across the UK, bringing together gynaecologists, colorectal surgeons, urologists, pain specialists, CC BY-NC 4.0 Licence

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OUTPATIENT HYSTEROSCOPY AND THE AMBULATORY CARE NETWORK Improving hysteroscopic surgery and especially its conduct in an outpatient setting is another important priority. BSGE members have played a leading role in developing national guidance alongside the RCOG, helping to improve patient

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experience through evidence-based recommendations on procedural conduct, optimising feasibility, pain management, and informed choice. Moreover, the BSGE has been integral to developing patient information and standardised informed consent. In addition to setting standards, the BSGE has placed an emphasis on quality assurance and supporting research. To this end, the Society has made an online data collection platform and ‘app’ (the BSGE Surgical Information Collection System), as well as developed and validated a patient-reported outcome measure with benchmarking standards. These innovations are used both in the UK and internationally. The BSGE Ambulatory Care Network (ACN) was established in 2019 to share best practice, debate contentious issues, and keep up to date across all aspects of training, education, service delivery, surgical techniques, clinical case management, audit, and research. This is effected through an annual meeting of clinicians involved in ambulatory care, especially outpatient hysteroscopy and imaging. It has been a huge success, with over 250 delegates attending the last meeting in Birmingham in February 2026. The ACN is, however, much more than a meeting; rather, it is a forum for discussion and support in a collegiate atmosphere, and this collaboration has allowed large, multicentred audit and research projects to be undertaken and published. Finally, the BSGE’s showpiece event is its Annual Scientific Meeting (ASM). The most recent ASM was held in April in central London, UK, with over 1,000 delegates. The Meeting covers all aspects of gynaecological endoscopy as well as medical and radiological interventions to optimise the treatment of gynaecological conditions. The

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ASM runs over 4 days, with pre-congress surgical and related workshops on Day 1 and then 3 days of science and fun. The Meeting includes invited national and top international speakers, a keynote lecture, debates, and live surgery. Several streams ensure there is ‘something for everybody’, and there are plenty of opportunities for members and trainees to present their work as free communications and posters. There is always an inclusive and enjoyable social programme! The BSGE has grown exponentially and is by far the largest UK specialist gynaecological society. This gives the BSGE much influence in helping shape UK gynaecological surgical training and practice. Moreover, the BSGE’s strong links with the ESGE and the American Association of Gynecologic Laparoscopists (AAGL) ensure more global influence. The vitality and relevance of the BSGE in modern gynaecological practice is thanks to the commitment of its members, the work of successive elected councils in developing strategy, industry collaborations, and, above, all the patients its members serve. Lina Antoun Consultant Gynaecologist & Obstetrician, Birmingham Women’s and Children’s NHS Foundation Trust; Chair, British Society for Gynaecological Endoscopy (BSGE), UK; Chair, Training and Education Special Interest Group, The European Society for Gynaecological Endoscopy (ESGE), Leuven, Belgium

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Article

The Endometrial Immune Environment in Women with Primary Infertility: Prospective Cohort Study Editor's Pick

This prospective cohort study investigates the endometrial cytokine profile in women with primary infertility, providing new insights into the role of local immune dysregulation in impaired implantation. The authors demonstrate that elevated levels of the pro-inflammatory cytokines IL-1β and IL-8 are associated with primary infertility, highlighting the potential contribution of a persistent inflammatory endometrial environment and offering valuable implications for future diagnostic and therapeutic approaches in reproductive medicine. Justin Chu Medical Director, Oxford Fertility; Honorary Consultant Obstetrician and Gynaecologist Sub-specialist in Reproductive Medicine and Surgery, Birmingham Women’s and Children’s NHS Foundation Trust; Honorary Senior Lecturer, Institute of Metabolism and Systems Research, University of Birmingham, UK

Author:

Mihaela Burac1 1. The Nicolae Testemițanu State University of Medicine and Pharmacy, Chisinau, Moldova *Correspondence to mihaela.burac@usmf.md

Disclosure:

The author has declared no conflicts of interest. The protocol of this study was approved by the Research Ethics Committee of Nicolae Testemitanu State University of Medicine and Pharmacy, Chisinau, Moldova.

Received:

09.05.26

Accepted:

03.06.26

Keywords:

Cytokines, endometrial immune environment, inflammation, primary infertility.

Citation:

EMJ Repro Health. 2026;12[1]:111-119. https://doi.org/10.33590/emjreprohealth/21SUD5ML

Abstract Background: The endometrium functions as an active immunological organ, where cytokines modulate local inflammatory responses essential for implantation. A subtle equilibrium between pro- and anti-inflammatory mediators, such as interleukins, is required for synchronised embryo–endometrial dialogue. Alterations in this cytokine milieu may compromise endometrial receptivity and contribute to primary infertility, even in the absence of structural or hormonal abnormalities. Aims: To assess the endometrial cytokine profile of the endometrial fluid in women with primary infertility. Methods: A prospective cohort study was conducted at the Department of Obstetrics and Gynecology, Nicolae Testemitanu State University of Medicine and Pharmacy Chisinau, Moldova. The protocol of this study was approved by the Research Ethics Committee of

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this institution (no. 79/62 of 26.04.2017). Patients signed informed consent for participation in the research. The study included 96 patients divided into two groups. The study group (L1) included 48 patients with the established diagnosis of primary infertility and the control group (L0) included 48 fertile patients. Endometrial biopsy samples were collected during the proliferative phase of the menstrual cycle using the suction curette Pipelle de Cornier (CooperSurgical, Trumbull, Connecticut, USA). Results: The level of IL-1β was considerably increased in the L1 group, with a median of 679.3 pg/mL. In the L0 group, the median level was 210.5 pg/mL, with a range between 16.5–3,150.8 pg/mL (p<0.001). The median value of IL-4 in the study group was 201.8 pg/mL, with values ranging from 92.8–415.6 pg/mL. In the control group, the median was of 188.0 pg/mL, with a range between 56.6–420.7 pg/mL (p=0.3). In contrast, IL-8 levels were significantly higher in the L1 group. The median was of 665.6 pg/mL and values ranged from 141.9–3,528.4 pg/ mL. In the L0 group, the median value was 473.3 pg/mL, with a range between 126.5–3,401.6 pg/mL (p=0.014). For IL-10, an anti-inflammatory cytokine, no significant differences were observed between the two groups. In the L1 group, the median was 182.4 pg/mL and values ranged from 122.4–254.3 pg/mL. In the L0 group, the median was 181.0 pg/mL with a range between 136.5–257.5 pg/mL (p=0.9). Conclusions: In this study, the authors concluded that the levels of proinflammatory cytokines in the endometrial fluid, such as IL-1β and IL-8, were higher in patients with primary infertility than in the control group. The levels of anti-inflammatory cytokines (IL-10 and IL-4) did not show any statistically significant differences between the groups.

Key Points 1. Primary infertility remains a major reproductive health challenge, and identifying endometrial inflammatory biomarkers may improve understanding of implantation failure and contribute to more accurate diagnosis and individualised patient management. 2. This cohort study evaluated the concentrations of IL-1β, IL-4, IL-8, and IL-10 in endometrial fluid from women with primary infertility and fertile women to investigate local immune alterations associated with infertility. 3. Women with primary infertility demonstrated significantly higher endometrial IL-1β and IL-8 concentrations, supporting the presence of a pro-inflammatory endometrial environment that may contribute to infertility.

BACKGROUND In the human endometrium, a complex system operates to prevent the risk of infection while, at the same time, enabling blastocyst acceptance when pregnancy occurs.1-5 In this context, the endometrium functions as a tertiary lymphoid organ, playing a central role in uterine immune surveillance.6,7 Remarkably, the endometrium also employs mechanisms of acute inflammation during hormonally regulated physiological processes, including menstruation and embryo implantation. These episodes of acute inflammation are rapidly resolved, thereby preventing 112

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tissue scarring and functional impairment. Although critical active processes involved in the resolution of inflammation have been described in other tissues and are clearly relevant to endometrial physiology and pathology, the mechanisms occurring within the endometrium remain largely insufficiently investigated.5,8-10 The immune component of the female genital tract mucosa varies across different regions of the reproductive tract and is predominantly represented by T lymphocytes, macrophages/dendritic cells, natural killer cells, neutrophils, and mast cells.5,11 Macrophages (CD68+), plasma cells (syndecan-positive), and B lymphocytes

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are present in the endometrium throughout all phases of the menstrual cycle, although in relatively low numbers.12,13 The innate and adaptive immune systems of the endometrium are regulated by steroid hormones. For instance, progesterone induces a local Th2-type cytokine response within the uterus, characterised by increased levels of IL-4, IL-5, and IL15, along with downregulation of the IL13 α2 receptor, which acts as a negative regulator of the anti-inflammatory cytokine IL-13 and as a potent inhibitor of the Th2 response.1,14 The Th2 response is believed to counterbalance proinflammatory processes within the endometrium that could otherwise lead to embryo rejection.15,16 Steroid hormone-driven alterations in endometrial chemokine production influence the migration of leukocytes from the bloodstream into the reproductive tract. Furthermore, the actions of progesterone are essential for establishing the overall immunosuppressive phenotype characteristic of the receptive endometrium.2 During the secretory phase, a marked recruitment of leukocytes into the endometrium occurs, originating from perivascular regions surrounding the spiral arterioles and glandular epithelium.1,17 Progesterone-induced changes in endometrial cytokine and chemokine production contribute significantly to this recruitment process. Cytokines such as IL-1, IL-11, IL-15, leukaemia inhibitory factor (LIF), and transforming growth factor beta (TGF-β) regulate leukocyte migration toward the endometrium.18,19 IL-1β is one of the major mediators of the physiological inflammatory response within the endometrium and plays an important role in embryo implantation. IL1β secretion reaches its maximum during the implantation window. It stimulates the expression of molecules required for blastocyst adhesion, including integrins, LIF, and IL-6; activates intracellular signalling pathways in stromal and epithelial cells to prepare the endometrium for implantation; and contributes to the decidualisation process. During the proliferative phase, IL-1β promotes stromal and epithelial cell proliferation and regulates angiogenesis CC BY-NC 4.0 Licence

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through stimulation of vascular endothelial growth factor expression.19,20 IL-8 (CXCL8) is a CXC chemokine best known for its potent chemoattractant activity toward neutrophils and T lymphocytes. In addition, it possesses mitogenic properties and plays a key role in angiogenesis in vivo. These processes are fundamental for endometrial shedding and repair. IL-8 displays angiogenic properties comparable to those of vascular endothelial growth factor, stimulating endothelial cell proliferation, inducing neovascularisation, and contributing to endometrial regeneration during the proliferative phase. IL-8 expression in endometrial epithelial cells is upregulated under hypoxic conditions and by prostaglandin E2, with a synergistic increase observed when both factors are present simultaneously.2,21 IL-4 is a cytokine predominantly secreted by Th2 cells, uterine natural killer cells, mast cells, and macrophages. It plays a central role in polarising the immune response toward an anti-inflammatory profile, which is particularly important during the periimplantation period and throughout early pregnancy. Within the endometrium, IL-4 contributes to the establishment of a tolerogenic microenvironment favourable for implantation and pregnancy maintenance. IL-4 is one of the principal cytokines responsible for the differentiation of CD4+ lymphocytes into the Th2 subset, while simultaneously inhibiting proinflammatory Th1 activity.3,22 IL-10 is an anti-inflammatory cytokine produced within the endometrium by resident macrophages, dendritic cells, regulatory T cells (Tregs), as well as stromal and epithelial cells under specific conditions. Its main function is to limit excessive inflammation and maintain immune tolerance compatible with endometrial receptivity and pregnancy. IL-10 demonstrates a transient peak during the implantation period, which is necessary for trophoblast invasion.13 Studies indicate that IL-10 promotes a Th2/Th1 profile considered protective for implantation and pregnancy through suppression of the Th1 immune response. In addition, IL-10 limits excessive extracellular matrix

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degradation, supports controlled stromal remodelling, and contributes to appropriate decidualisation and vascular integrity by promoting organised angiogenesis without destructive inflammation.3,23 An increased Th2/Th1 ratio is recognised as physiological for endometrial receptivity and maternal tolerance toward the embryo. IL-4 reduces the expression of proinflammatory cytokines such as IL-1β, TNF-α, and IFN-γ, stimulates IL-10 production, and promotes an anti-inflammatory environment. Moreover, it contributes to the regulation of chemokines involved in the recruitment of immune cells supportive of implantation, including M2 macrophages and Tregs.3,21,23 In a healthy endometrium, these four interleukins function as a dynamic ‘brakeand-accelerator’ system. IL-1β and IL-8 exert predominantly proinflammatory effects, increasing during the periimplantation period and inducing matrix metalloproteinases, prostaglandins, angiogenesis, and recruitment of neutrophils and macrophages. These actions facilitate trophoblast invasion and spiral artery remodelling. In contrast, IL-4 and IL-10 exert anti-inflammatory and regulatory effects, increasing after blastocyst implantation. They inhibit excessive Th1/Th17 activity, promote a Th2/ Treg immune profile, stabilise implantation, and protect the maternal–fetal unit from immune rejection.3,16,24

AIMS The aim of this study was to assess the endometrial cytokine profile of the endometrial fluid in women with primary infertility.

METHODS The authors conducted a prospective study, which included 96 patients divided into two groups. The study group included 48 patients with primary infertility and a control group consisting of 48 fertile patients. The inclusion criteria for the study group were patients suffering from primary 114

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infertility with indications for laparoscopy and hysteroscopy, age 20–40 years, lack of hormonal therapy and antibiotic therapy in the last 6 months, lack of intrauterine manipulations in anamnesis, and research participation agreement. The inclusion criteria for the control group were patients who have had a delivery with a living fetus in the last 2 years and who do not breastfeed, patients without a complicated reproductive gynaecological history (infertility, spontaneous or missed abortion), lack of hormonal treatment and antibiotic therapy over the past 6 months, and research participation agreement. Exclusion criteria from the research were patients with acute genital infection, age <20 years and > 40 years, patients suffering from congenital malformations of the uterus, patients who had prior intrauterine surgical manipulations, atypical endometrial hyperplasia, and patients’ refusal for voluntary participation in research. The study was approved by the Research Ethics Committee of the State University of Medicine and Pharmacy Nicolae Testemitanu, Chisinau, Moldova (No. 79/62 of 26.04.2017). Patients have signed informed consent to participate in the research. In both groups, the authors performed endometrial biopsy in the proliferative phase with endometrial suction curette Pipelle de Cornier (CooperSurgical, Trumbull, Connecticut, USA), and assessed pro- and anti-inflammatory cytokines IL-1β, IL-8, IL-10, and IL-4. Statistical data processing was performed using Microsoft Excel 2016 (Microsoft, Redmond, Washington, USA) and SPSS 20 (IBM, Armonk, New York, USA). Quantitative variables were analysed using the Wilcoxon rank-sum test. P values <0.05 were considered statistically significant.

FINDINGS The patients included in the study were evenly distributed between the two study groups (Table 1). No statistically significant differences in age distribution were identified between the groups (χ²=6.94; p=0.076).

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Table 1: Demographic characteristics according to primary infertility status.

Variable

Overal (N=96)

Age, years

29.1±4.4 Median: 29.5 (IQR: 8.0) Range: 20.0–39.0

95% CI 28–30

L0 (N=48) 29.1±4.3 Median: 30.5 (IQR: 7.0) Range: 20.0–35.0

95% CI

L1 (N=48)

28–30

95% CI

29.0±4 Median: 28.0 (IQR: 7.3) Range: 22.0–39.0

28–30

Age groups, n (%) 20–24 years

15 (15.6%)

8.4–23.0%

9 (18.8%)

7.7–30.0%

6 (12.5%)

3.1–22.0%

25–29 years

33 (34.4%)

25.0–44.0%

13 (27.1%)

15.0–40.0%

20 (41.7%)

28.0–56.0%

30–34 years

39 (40.6%)

31.0–50.0%

24(50.0%)

36.0–64.0%

15 (31.3%)

18.0–44.0%

35–40 years

9 (9.4%)

3.5–15.0%

2 (4.2%)

0.0–9.8%

7 (14.6%)

4.6–25.0%

Partner age, years

31.8±5.4

31–33

31.6±4

30–33

31.9±5.9

30–34

Median: 31.0 (IQR: 7.5) Range: 22.0–47.0

Median: 31.5 (IQR: 7.0) Range: 24.0–47.0

Test statistic

p value

1.223

0.600

6.9

0.076

1.145

>0.900

Median: 30.5 (IQR: 9.0) Range: 22.0–46.0

IQR: interquartile range.

The analysis of endometrial immunological parameters revealed significant differences between patients with primary infertility (L1 group; N=48) and fertile patients (L0 group; N=48) for certain proinflammatory cytokines, suggesting a distinct immunological profile associated with primary infertility. IL-1β levels were significantly higher in the L1 group compared with the L0 group. In the study group (L1), the median value of IL-1β concentration was 679.3 pg/mL (interquartile range [IQR]: 1,022.6) and a range between 170.6–4,375.4 pg/mL. In the control group (L0), the median level was 210.5 pg/mL (IQR: 302.5) and values ranged from 16.5–3,150.8 pg/mL. The difference between the two groups was highly statistically significant (p<0.001; Figure 1A). For IL-10, an anti-inflammatory cytokine, no significant differences were observed between the two groups. In the L1 group, the median of IL-10 concentration was 182.4 pg/ CC BY-NC 4.0 Licence

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mL (IQR: 24.9) and values ranged from 122.4– 254.3 pg/mL. In the L0 group, the median was 181.0 pg/mL (IQR: 53.5) and ranged between 136.5–257.5 pg/mL. The difference was not statistically significant (p=0.9; Figure 1B). IL-4 levels were comparable between the two groups. In the L1 group, the median was 201.8 pg/mL (IQR: 168.3) and values ranged from 92.8–415.6 pg/mL. In the L0 group, the median was 188.0 pg/mL (IQR: 136.1) with a range between 56.6–420.7 pg/mL. The difference between the groups did not reach statistical significance (p=0.3; Figure 1C). In contrast, IL-8, a proinflammatory cytokine involved in neutrophil recruitment and local inflammatory processes, demonstrated significantly higher levels in the study group. In the L1 group, the median IL-8 concentration was 665.6 pg/ mL (IQR: 990.4) and values ranged from 141.9–3,528.4 pg/mL. In the L0 group, the

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Figure 1: Levels of IL-1β, IL-10, IL-4, and IL-8.

WMann-Whitney=318.00, p = 1.01e-09, r̂ rank =-0.72, 95% CI: -0.82–-0.59, nobs=96 biserial 5,000

4,000

β̂

3,000

2,000

1,000

L0 (n=48)

WMann-Whitney=1,132.50, p = 0.89, r̂ rank =-0.02, 95% CI: -0.24–0.21, nobs=96 biserial

-10̂

Primary infertility

L1 (n=48)

L0 0 (n=48)

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L11 (n=48)

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Figure 1: Levels of IL-1β, IL-10, IL-4, and IL-8. (continued)

WMann-Whitney=1,015.00, p=0.32, r̂ rank =-0.12, 95% CI: -0.34–0.11, nobs=96 biserial

-44̂

L0 0 (n=48)

L11 (n=48)

Primary infertility

WMann-Whitney=816.00, p=0.01, r̂ rank = -0.29, 95% CI: -0.49–-0.07, nobs=96 biserial 4,000

-8̂

3,000

2,000

1,000

L00 (n=48)

Primary infertility

L1 1 (n=48)

A) Levels of IL-1β in the endometrium, B) levels of IL-10 in the endometrium, C) levels of IL-4 in the endometrium, D) levels of IL-8 in the endometrium.

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median value was 473.3 pg/mL (IQR: 379.9) and ranged between 126.5–3,401.6 pg/mL. The difference was statistically significant (p=0.014; Figure 1D).

investigate whether cytokine profiling could be integrated into patient stratification models or used to identify subgroups of patients who may benefit from targeted therapeutic interventions.

DISCUSSION

The translational implications of these findings are also relevant for the development of novel therapeutic approaches aimed at modulating endometrial inflammation. Previous studies have explored different strategies to improve endometrial immune balance, including anti-inflammatory therapies, immunomodulatory approaches, correction of microbiome dysbiosis, and personalised interventions targeting implantation failure. However, evidence remains heterogeneous, and no standardised therapeutic protocols currently exist for cytokine-guided treatment selection.25-28 Therefore, larger prospective studies are needed to determine whether normalisation of the endometrial inflammatory profile can improve reproductive outcomes.

A challenge in reproductive immunology and embryo implantation research is the development of more precise approaches to better understand the immunological mechanisms involved in successful implantation and pregnancy establishment. The authors’ study demonstrated that patients with primary infertility exhibit altered endometrial immune parameters compared with fertile controls, particularly significantly increased levels of IL-1β. The results of the authors’ study demonstrate elevated levels of proinflammatory cytokines in women with primary infertility compared with fertile controls. These findings may reflect an altered Th1/Th2 balance at the endometrial level, suggesting the presence of an immune environment characterised by increased inflammatory signalling. Similar patterns of immune dysregulation have also been described in chronic inflammatory disorders, including rheumatoid arthritis and inflammatory bowel disease.25 Predominance of a Th1-oriented immune profile may promote recruitment and activation of endometrial macrophages, accompanied by increased production of inflammatory mediators such as IL-1, TNF-α, and IL-6, thereby contributing to maintenance of chronic inflammatory signalling within the endometrium.25,26 From a clinical perspective, these findings suggest that assessment of the endometrial inflammatory profile may become a useful adjunctive tool in the evaluation of women with primary infertility, particularly in cases where standard diagnostic investigations fail to identify a clear aetiology. The significantly elevated concentrations of IL-1β and IL-8 observed in the authors’ cohort support the hypothesis that a persistent proinflammatory endometrial microenvironment may contribute to impaired implantation and reproductive failure. Future studies should 118

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Taken together, the authors’ findings support the concept that primary infertility may be associated not only with endocrine or anatomical factors, but also with a dysregulated local immune environment. Better characterisation of these inflammatory pathways may contribute to the development of more individualised diagnostic and therapeutic strategies in reproductive medicine.

CONCLUSIONS Overall, patients with primary infertility exhibited an endometrial immunological profile characterised by significantly increased levels of the proinflammatory cytokines IL-1β and IL-8, in the absence of significant differences in the antiinflammatory cytokines IL-10 and IL-4. This proinflammatory imbalance suggests the presence of a persistent inflammatory endometrial microenvironment, potentially involved in impaired endometrial receptivity and in the pathogenic mechanisms underlying primary infertility.

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References 1.

Burac M et al. The interplay between reproductive tract microbiota and immunological system in human reproduction. Front Immunol. 2020;11:378. Burac M et al. Molecular characterization of the endometrium as a fertility-determining factor. Moldovan Med J. 2020;63(1):39-43. Burac M et al. Dysregulation of immune response in the endometrium of primary infertility patients. Medicus. 2026;1(79):6-12. Cauș C et al. Contemporary profile of the patient with acute pelvic inflammatory disease. Curierul Medical. 2016;59(6):21-4. Wong FC et al. The human endometrium: atlases, models, and prospects. Curr Opin Genet Dev. 2025;92:102341. Burac M et al. The cytokine profile of the endometrial fluid in women with primary infertility. EMJ Reprod Health. 2026;12(Suppl 1):56-7. Cauș C, Cauș N. Aspecte Generale Ale Infertilităţii: recomandare metodică (2021). Chișinău: CEP Medicina. Burac M et al. The complex interplay between endometrial microbiome, inflammation and primary infertility. Abstract P188. Perspectives of the Balkan Medicine in the Post COVID-19 Era, 7-9 June, 2023. Gholiof M et al. The female reproductive tract microbiotas, inflammation, and gynecological conditions. Front Reprod Health. 2022;4:963752.

10. Mihalcean L et al. Pathogenetic correlation of severe sepsis and multiple organ dysfunction syndrome

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provoked by multiple infections in perinatal period of women. Rev Științe Sănătății Mold. 2022;30(4):70-5.

19. Pulugulla SH et al. Distinct mechanisms regulate IL1B gene transcription in lymphoid CD4 T cells and monocytes. Cytokine. 2018;111:373-81.

11. Coutifaris C et al. Reprint of: histological dating of timed endometrial biopsy tissue is not related to fertility status. Fertil Steril. 2019;112(4):e116-24.

20. Mohajeri MH et al. The role of the microbiome for human health: from basic science to clinical applications. Eur J Nutr. 2018;57(Suppl 1):1-14.

12. Burac M. Characterization of the human endometrial microbiome and its risks associated in infertility patients: a systematic review. Abstract 86. MedEspera: International Medical Congress for Students and Young Doctors, 3-5 May, 2018.

21. Toson B et al. The endometrial microbiome and its impact on human conception. Int J Mol Sci. 2022;23:485. 22. Elahi Z et al. All properties of infertility microbiome in a review article. J Clin Lab Anal. 2025;39(6):e25158.

13. Fitzgerald HC et al. Idiopathic infertility in women is associated with distinct changes in proliferative phase uterine fluid proteins. Biol Reprod. 2018;98(6):752-64.

23. Fitzgerald HC et al. The proliferative phase underpins endometrial development: altered cytokine profiles in uterine lavage fluid of women with idiopathic infertility. Cytokine. 2016;88:12-9.

14. Burac M et al. Aprecierea plasmocitelor în endometrul femeilor cu infertilitate primară. Sănătate Publică Econ Manag Med. 2024;98(1):60.

24. Mihalcean L et al. Caracteristics of the systemic inflammatory response and adaptative mechanisms in puerperal infectious. Medicus. 2026;3(81):6-10.

15. Moreno I et al. Endometrial microbiota composition is associated with reproductive outcome in infertile patients. Microbiome. 2022;10(1):1.

25. Singh N, Sethi A. Endometritis diagnosis, treatment and its impact on fertility: a scoping review. JBRA Assist Reprod. 2022;26(3):538-46.

16. Sagaidac I, Cerneţchi O. Rolul citokinelor proinflamatorii în decolarea prematură de placentă normal inserată. Bull Acad Sci Moldova Med Sci. 2017;56(4):84-8.

26. Yan X et al. The pathogenesis, diagnosis, and treatment of chronic endometritis: a comprehensive review. Front Endocrinol (Lausanne). 2025;16:1603570.

17. Burac M et al. Microbiomul endometrial în infertilitate: roluri, mecanisme şi implicaţii clinice = the endometrial microbiome in infertility: roles, mechanisms, and clinical implications. Rev Științe Sănătății Mold. 2025;12(3 Suppl 2):518.

27. Gu J et al. The effect of chronic endometritis and treatment on patients with unexplained infertility. BMC Womens Health. 2023;23(1):345. 28. Pirtea P et al. Endometrial causes of recurrent pregnancy losses: endometriosis, adenomyosis, and chronic endometritis. Fertil Steril. 2021;115(3):546-60.

18. Noyes RW et al. Reprint of: dating the endometrial biopsy. Fertil Steril. 2019;112(4):e93-115.

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The Epitranscriptomic Landscape in Early Mammalian Embryonic Development: A Narrative Review Authors:

Sophie Emilie Bresson,1,2 Arne Klungland,1,2 *Yanjiao Li1,2 1. Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway 2. CRESCO, Centre for Embryology and Healthy Development, Institute of Clinical Medicine, University of Oslo, Norway *Correspondence to yanjiao.li@medisin.uio.no

Disclosure:

The authors have declared no conflicts of interest. The authors apologise to colleagues whose studies were not cited due to length and reference constraints. This work was supported in part by the Norwegian Research Council (grants no. 361072 and 332713) and the Norwegian Health Association (grant no. 41778). Norwegian Cancer Society (grant no. 298210). This work was also supported in part by the UiO Growth House and SPARK Norway.

Received:

12.03.26

Accepted:

11.06.26

Keywords:

Activation, epitranscriptomics, maternal-to-zygotic transition, preimplantation development, reproductive medicine, RNA capping, RNA editing, RNA modifications, zygotic genome activation.

Citation:

EMJ Repro Health. 2026;12[1]:120-133. https://doi.org/10.33590/emjreprohealth/9S257318

Abstract Early mammalian embryogenesis is driven by a tightly regulated transition from maternally inherited transcripts to zygotically transcribed RNA, a process that requires precise coordination of RNA stability, translation, and selective clearance of maternal transcripts. Emerging evidence places epitranscriptomic regulation at the centre of these mechanisms. This review summarises current knowledge of key RNA modifications, their regulatory machineries, and their functional roles during early mammalian development. Specifically, emphasis is placed on internal base modifications, including N6-methyladenosine, N4-acetylcytidine, and 5-methylcytidine, as well as RNA editing (A-to-I and C-to-U), RNA capping, and cap-proximal methylations. Many RNA modifications are dynamic and reversible, modulating RNA structure, stability, and translational efficiency in a stage-specific manner. Genetic and functional studies demonstrate that these modifications, deposited, decoded, and removed by dedicated writer, reader, and eraser proteins, are essential for zygotic genome activation, preimplantation development, mitochondrial function, cellular fitness, and early lineage specification. Cap formation and cap-adjacent methylations add an additional regulatory layer by coupling mRNA export and translation to maternal RNA decay and the onset of zygotic gene transcription. Furthermore, dynamic RNA editing expands transcriptomic and proteomic diversity, enabling context-dependent gene regulation without altering the underlying DNA sequence. Collectively, these findings establish RNA modifications and RNA processing as key determinants of developmental competence. In the future, modification-specific targets, context-dependent functions, and the mechanisms of epitranscriptomic crosstalk still need to be elucidated, presenting new avenues for the diagnostic and therapeutic targeting of RNA modifications in reproductive medicine.

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Key Points 1. Early mammalian development depends on accurate maternal RNA clearance and zygotic activation; disrupted RNA modification or decay compromises developmental competence and contributes to infertility and recurrent miscarriage. 2. This narrative review integrates systematically screened publications on key RNA modifications, capping, and RNA editing, outlining their writer–reader–eraser machineries and stage-specific functions in early mammalian embryogenesis. 3. Epitranscriptomic regulation of early embryogenesis is an emerging field, with the potential to improve diagnosis of RNA-driven infertility and pregnancy loss and guide future reproductive therapies.

INTRODUCTION In mammals, early embryonic development begins at fertilisation, when the oocyte and sperm fuse to form the one-cell zygote. The one-cell embryo subsequently undergoes a series of cleavage divisions, during which development is initially driven largely by maternally inherited transcripts and proteins accumulated during oogenesis.1 Later, a minor wave of zygotic genome activation (ZGA) occurs at the late one-cell stage. This minor ZGA is characterised by widespread RNA polymerase II recruitment and pervasive, often intergenic transcription, frequently initiated outside canonical transcription start sites, producing short, frequently unspliced transcripts. Despite the necessity of the minor ZGA for further embryo development, this stage is still characterised by an abundance of maternal transcripts. As development proceeds, control shifts from maternal to embryonic gene products, a process referred to as maternal-to-zygotic transition (MZT). MZT consists of a series of molecular events, beginning with the degradation of subsets of maternally deposited RNAs. This maternal RNA clearance occurs in two waves. The first, M-decay, which represents maternal factor-regulated decay, initiates after germinal vesicle breakdown and is sustained until the metaphase II stage before fertilisation.2 The second wave, Z-decay, depends on the expression of specific early zygotic factors for degrading maternal mRNA. Z-decay is coupled to the major ZGA, which features more canonical transcription initiating at defined transcription start sites and regulated by CC BY-NC 4.0 Licence

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splicing and elongation factors. The major ZGA drives active transcription of hundreds of genes required for Z-decay (Figure 1A).2 The timing of these events varies between species. The major ZGA occurs in the twocell stage in mice, and Z-decay follows, lasting from two-cell to four-cell stage. In humans, ZGA is broader and less sharply defined, occurring around the four-cell to eight-cell stage, and the Z-decay spans approximately from the four-cell to morula stage.2 However, both species alike undergo at least two waves of maternal RNA-clearance.3,4 In mice and humans, germ cells initiate meiosis during embryonic development and arrest at the germinal vesicle stage until puberty. Upon the pre-ovulatory hormone surge, these fully grown oocytes resume meiosis, transitioning from the germinal vesicle stage to metaphase II arrested stage. Maternal RNAs accumulate during oocyte growth and maturation and remain translationally dormant until meiotic resumption.5,6 Upon fertilisation, maternal RNAs can be actively translated or degraded within a few hours to days. Substantial advances have deepened our understanding of how RNA stability is regulated in mammalian oocytes and zygotes. MZT transcript fate is governed by interconnected mechanisms involving sequence elements, RNA-binding proteins, poly(A) tail dynamics, and subcellular localisation. Beyond these established pathways, accumulating evidence highlights covalent RNA modifications as an additional layer of post-transcriptional control.

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Figure 1: Overview of RNA modifications discussed in this paper.

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A) Schematic overview of oocyte and embryo RNA levels in mice, indicating important events such as M- and Z-decay and major and minor ZGA. B) Schematic representation of the function of writer proteins (blue), eraser proteins (red) and reader proteins (green). C) Chemical structure of m6A, along with writers, erasers, readers, and established functions of the modification. D) Schematic representation of m6A modification levels through embryonic development in mice.14 E) Chemical structure of ac4C along with writers, and potential eraser, and established functions of the modification. F) Schematic representation of ac4C modification levels through embryonic development in mice. Dotted line represents levels implied from non-quantified immunofluorescence images.38 G) Chemical structure of m5C, along with writers and established functions of the modification. H) Schematic representation of m5C modification levels through embryonic development in zebrafish.42 I) Schematic representation of editing events through embryonic development in humans.50 J) Chemical reaction of A-to-I editing, writers, and established functions of the modification. K) Chemical reaction of C-to-U editing, writers and established functions of the modification. Created in BioRender. Ac⁴C: N⁴-acetylcytidine; ACF: APOBEC-1 complementation factor; ADAR1-2: adenosine deaminase acting on RNA 1 and 2; AID: activation-induced cytidine deaminase; ALKBH1: AlkB homolog 1; ALKBH5: AlkB homolog 5; ALYREF: Aly/ REF export factor; APOBEC: apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like; DNMT2: DNA methyltransferase 2; FTO: fat mass and obesity-associated protein; IGF2BP1-3: insulin-like growth factor 2 mRNA-binding proteins 1–3; m⁵C: 5-methylcytidine; m⁶A: N⁶-methyladenosine; METTL3: methyltransferase-like 3; METTL16: methyltransferase-like 16; NAT10: N-acetyltransferase 10; NSUN1-7: NOP2/Sun RNA methyltransferases 1–7; RBM47: RNA-binding motif protein 47; SIRT7: sirtuin 7; TET1-2: ten-eleven translocation methylcytosine dioxygenases 1 and 2; WTAP: Wilms tumour 1-associated protein; YBX1: Y-box-binding protein 1; YTHDC1-2: YTH domain-containing proteins 1 and 2; YTHDF1-3: YTH N⁶-methyladenosine RNA-binding proteins 1–3; ZCCHC4: zinc finger CCHC-type containing 4; ZGA: zygotic genome activation.

This expanding field, known as epitranscriptomics, investigates how chemical marks on RNA interact with regulatory networks to fine-tune gene expression. ‘Writer’ enzymes deposit chemical modifications, either cotranscriptionally or post-transcriptionally, whereas ‘eraser’ enzymes remove RNA modifications.7 Epitranscriptomic marks influence RNA processes such as stability, translation, and splicing through interactions with RNA-binding ‘reader’ proteins (Figure 1B). RNA can be modified in several ways, including the addition of chemical groups, editing of RNA sequences, and capping of RNA ends.7 Although RNA modifications have been known since the 1970s, only the recent development of sensitive detection techniques has revealed their widespread occurrence, dynamic potential, and biological significance. More than 170 distinct RNA modifications have been identified, yet the specific role of most of these marks remains unclear. RNA modifications hold considerable promise as diagnostic biomarkers and therapeutic targets, with the potential to improve fertility and outcomes of assisted reproductive technologies. In this context, CC BY-NC 4.0 Licence

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a comprehensive literature review was conducted to evaluate current evidence of the roles of epitranscriptomics in preimplantation development and to advance our understanding of early mammalian embryogenesis.

METHODS During the preparation of this review, the scientific literature was searched using PubMed/Medline between January– March 2026. Initially, a broad search was conducted with the following search term: (“epitranscriptomic*” OR “RNA modification*”) AND (“gametogenesis*” OR “embryo*” OR “embryogenesis*” OR “embryo development*” OR “mammalian development*”). The resulting primary research papers and review articles were screened based on titles and abstracts as presented in Figure 2A. For review articles specifically, a stringent inclusion criterion based on publication date was applied to ensure that only the most recent summary works were included. The selected reviews and primary papers were then skimmed for relevance and used to provide background information and to determine which RNA

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Figure 2: Schematic example of workflow.

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*Asterisks are included in the search terms to find variations of a phrase or word. E.g., “Embryo*” will find “Embryo,” “Embryos,” “Embryonic,” and “Embryology.” A) The workflow used for an initial broad search used for compiling initial background information. B) The simplest example of the workflow used for later specific searches for each RNA modification.

modifications to cover, focusing on those that were the most well established and thoroughly investigated. Figure 2B illustrates the workflow applied to individual searches conducted for each RNA modification, as well as for known reader, writer, and eraser proteins (all search term results are listed in Supplementary Table 1). Identified articles were similarly screened based on titles and abstracts. Inclusion criteria were English language, primary research, and meta-analyses published in peer-reviewed journals. Preprints (e.g., from bioRxiv) were also screened for relevance. Exclusion criteria included review articles and studies that did not address epitranscriptomics or the selected RNA modifications in early mammalian development. Studies conducted in nonmammalian species or in embryonic stem cells were reviewed but excluded unless no relevant studies in mammals were available. Papers passing this initial screening were skimmed and excluded if, on closer reading, they did not address the function of the relevant RNA modifications or associated proteins, or if they otherwise met any of the exclusion criteria. For all studies meeting the inclusion criteria, relevant information was manually extracted. The authors reviewed all papers included in the final manuscript.

RESULTS Chemical RNA Modifications in Embryogenesis

Chemical modifications that decorate RNA are diverse and include, for example, methylation and acetylation. These modifications can influence RNA structure, base pairing, and interactions with other molecules, thereby modulating RNA stability and function.7

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N6-methyladenosine

N6-methyladenosine (m6A) is the most abundant internal modification on mammalian mRNA.7 It is installed by a multicomponent methyltransferase complex composed of two subcomplexes of the catalytic subunit m6A-METTL complex (MAC) and the regulatory subunit m6AMETTL-associated complex (MACOM). The catalytic core, MAC, consists of a METTL3– METTL14 heterodimer that transfers a methyl group from S-adenosyl-Lmethionine to the N6 position of adenosine residues.8 MACOM confers substrate specificity and includes components such as WTAP and KIAA1429.7 Additional m6A methyltransferases include METTL16, which modifies structured RNAs containing hairpin motifs;9 METTL5, which catalyses m6A modification of rRNA;10 and ZCCHC4, which methylates 28S rRNA.11,12 m6A marks are recognised by specific RNA-binding ‘reader’ proteins, including YTH domain-containing proteins (YTHDF1–3 and YTHDC1–2) and insulin-like growth factor 2 mRNA-binding proteins (IGF2BP1–3).7 m6A levels are dynamically regulated by the demethylases fat mass and obesity-associated protein (FTO) and ALKB homolog 5 (ALKBH5), which catalyse oxidative removal of the methyl group (Figure 1C).7,13 The picogram-scale m6A RNA immunoprecipitation and sequencing method (pico-MeRIP-seq) was recently developed, enabling the first systematic characterisation of the human m6A landscape during early embryogenesis.14,15 In human embryos, the number and percentage of m6A modified genes steadily decrease until fertilisation, reaching a low point at the one-cell stage, followed by an increase from the twocell stage and a plateau throughout the eight-cell to blastocyst stage.14 A recent study, using crosslinked-antibody RNA immunoprecipitation and sequencing, has

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suggested that m6A levels increase through the pre-fertilisation stages, peaking at the zygote stage, after which it drops, before increasing again from four-cell to blastocyst stage.16 In mice, the m6A landscape follows a similar pattern: the number of m6A modified genes declines until fertilisation, before increasing again as the embryo progresses through the first cell divisions (Figure 1D).17,18 Single-cell sequencing suggests that m6A levels may rise after meiosis II and remain relatively constant from the zygote stage onward.19 In contrast, mass-spectrometry based quantification indicates that m6A levels drop after the germinal vesicle stage and stay low throughout the first two cell divisions,18 while others have recently reported relatively constant m6A levels throughout embryogenesis.16 However, the percentage of the specific m6A modified genes varies between human and mouse, likely reflecting evolutionary divergence.14 m6A can be either maternally inherited or deposited de novo after fertilisation. Maternally inherited m6A modifications serve dual functions: they promote the decay of a subset of transcripts while stabilising others and licensing them for translation upon fertilisation.20

The Role of m6A Writers

The importance of m6A writers in embryonic development has been demonstrated by depleting core components. In mice, Mettl3 knockout (KO) abolished m6A-signals19 and resulted in developmental arrest at the four-cell stage.21 Pharmacological inhibition of METTL3 with STM2457 or cycloleucine similarly reduced m6A levels and delayed development at the four-cell stage, markedly decreasing blastocyst formation.18,22 Mechanistically, METTL3 preferentially mediates de novo establishment of m6A on ZGA transcripts without influencing m6A on maternal transcripts.18 METTL3 primarily methylates transcripts with transient expression, which are downregulated after the twocell stage,18 and its inhibition upregulates these genes at the four-cell and morula stages due to the lack of m6A promoting 126

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mRNA-decay.18 Prior to fertilisation, m6A stabilises transcripts, and Mettl3 knockdown (KD) reduces m6A levels, resulting in downregulation of numerous genes in germinal vesicles,21 which in turn leads to decreased transcription-engaged RNA polymerase and globally reduced transcription.23 METTL3 and global m6A levels were significantly decreased in placentas from patients with fetal growth restriction.24 Other m6A writers also play crucial roles in embryogenesis. Mettl16 KO mice fail to develop beyond the blastocyst stage, exhibiting thousands of differentially expressed genes, which suggests a role in later stages of early embryonic development.9 In contrast, METTL5 depletion can enhance certain developmental outcomes. siRNA-mediated Mettl5 KD in somatic cell nuclear transfer (SCNT) embryos reduced m6A peaks but increased cell numbers and improved blastocyst formation.25 This effect is proposed to result from METTL5-mediated rRNA methylation, which alters ribosomal translation of histone methyltransferases and thereby modulates two-cell stage gene expression.25 MACOM components likewise influence m6A and embryogenesis. Kiaa1429 KO mice experience lower global m6A-levels, with a pronounced effect on Z-decay genes18 and WTAP KD reduced m6A levels and blastocyst formation rate in porcine embryos, accompanied by decreased pluripotency markers.26

The Role of m6A Readers

m6A readers, which recognise the modification and mediate cellular responses, are also essential for early embryonic development. Female mice lacking Ythdf2 are infertile, as loss of Ythdf2 causes an abnormal two-cell stage, preventing further development.18,27 Consequently, Ythdf2-depleted embryos exhibit impaired RNA degradation,27 resulting in increased expression of transcripts normally targeted during Z-decay.18 Similarly, in goat embryos, siRNAmediated KD of YTHDF2 blocks blastocyst formation, with embryos arresting at the

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four- and eight-cell stages due to defective maternal mRNA clearance and ZGA.28 Heterozygous Ythdc1 mutant mice fail to produce homozygous Ythdc1 KO offspring, with embryos being reabsorbed from embryonic day E8.5.29 Igf2bp1 KD reduces m6A levels in parthenogenetic embryos from mice,30 and is associated with lower blastocyst formation rate in both parthenogenetic mouse embryos and porcine embryos.30,31 Meanwhile, maternal depletion of Igf2bp2 in mice leads to severe defects in blastocyst formation, with embryos arresting at the two-cell stage and exhibiting reduced RNA and protein synthesis.32

The Role of m6A Erasers

The two established m6A erasers are FTO and ALKBH5. Studies on FTO in embryogenesis have yielded conflicting results. Wei et al.33 reported that IVF rates are more than halved when wild-type oocytes are fertilised with Fto mutant sperm compared to controls.33 However, when oocytes were fertilised by intracytoplasmic sperm injection using Fto mutant sperm, the resulting embryos exhibited only slightly impaired progression to the blastocyst stage but failed to implant.33 This effect of FTO has been attributed to FTO-mediated m6A removal on LINE1 RNA, and that in turn shapes the global chromatin landscape.33 Contrarily, Kim et al.34 has found that deletion of the Ft-locus (which contains Fto along with five other genes), did not affect early embryonic development, but did result in a lower primordial germ cell proliferation.34 By contrast, ALKBH5 appears to be essential for fertility. Alkbh5 mutant mice are infertile due to meiotic defects that arrest oocyte development35 and metaphase-stage spermatocytes.13 Additionally, lower expression levels were detected in villous tissue of patients with reoccurring miscarriages compared to healthy controls.36

N4-acetylation of cytosine

A much less studied RNA modification is N4-acetylation of cytosine (ac4C), for which only one writer, N-acetyltransferase10 (NAT10), has been identified, and no CC BY-NC 4.0 Licence

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readers or erasers are known to date. ac4C has been shown to enhance the stability and translation of RNAs, thereby modulating gene expression (Figure 1E).37 ac4C levels in early embryonic development have been determined by immunofluorescent staining, showing stable levels from two-cell to morula stage, with a drastic increase at the blastocyst stage (Figure 1F).38 Since NAT10 is the only known ac4C writer, and its depletion markedly reduces ac4C levels in oocytes,39 most functional studies of this acetylation in early embryos have focused on manipulating NAT10 level. Both siNAT10 and dsNAT10 treatment in mouse embryos has been shown to decrease blastocyst formation, arresting embryos at the morula stage,40,41 and causing a cavity collapse and degeneration.38 Furthermore, Nat10 KD in morula resulted in significantly lower expression of the pluripotency factor Nanog.40

5-methylcytosine

5-methylcytosine (m5C) is generated when cytosine is methylated at the 5th carbon by RNA m5C methyltransferases, primarily the NOL1/NOP2/SUN (NSUN) family and the DNA cytosine-5 methyltransferase 2 (DNMT2). To date, two m5C readers have been identified: Y-box binding protein 1 (YBX1) and Aly/REF export factor (ALYREF; Figure 1G).8 The m5C landscape has been mapped across embryonic stages in several species, revealing a conserved pattern of high m5C levels at the one-cell stage, followed by a sharp decline after the MZT (Figure 1H).42 In mice, Nsun2 KO impairs ovarian development, and siRNA-mediated KD of Nsun2 in oocytes blocks development at the two-cell stage, leading to reduced blastocyst formation.43 NSUN3 has also been shown to be important for embryonic development, albeit at later stages, as Nsun3 KO mice die between embryonic day E10.5 and E12.5.44 NSUN4 is a mitochondrial m5C-methyltransferase that methylates rRNA. Its deletion has been shown to cause embryonic lethality in mice, with embryos showing retarded growth with no clearly discernible anatomical structures at E8.5.45

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Nsun5 KO mice produce fewer offspring, with compromised embryogenesis from the one-cell to blastocyst stages, an effect attributed to loss of NSUN5-mediated m5C targets.46 Consistently, Nsun5 KD in mice reduced morula cell number and blastocyst formation, impaired differentiation and trophectoderm development.47 YBX1 KD reduces developmental rates, with decreased blastocyst formation and cell numbers, and impairs maternal mRNA degradation and ZGA in both goat and porcine embryos.31,48 Another m5C reader, ALYREF, is also important in early development: embryonic KD of Alyref impairs blastocyst formation due to insufficient Nanog expression, likely by destabilising the mRNA.49

RNA Editing in Embryogenesis

RNA editing is a co- or post-transcriptional modification by which cells alter the nucleotide sequence of RNA. During human embryonic development, A-to-I and C-to-U edits are the most common, accounting for approximately 86% of all editing events.50 RNA editing exhibits distinct temporal patterns throughout development, with specific sites differentially edited at different stages: some sites are highly edited only at the zygote stage, others remain highly edited until the four-cell stage, and some are edited predominantly at the eight-cell stage (Figure 1I).50 These patterns suggest that RNA editing is stagespecific and may play a role in regulating RNA splicing and gene expression.

Adenosine to inosine

A-to-I editing, one of the most prominent RNA-editing events, involves the conversion of adenosine to inosine in double-stranded RNA. In oocytes, this editing occurs more frequently in protein-coding sequences at the codon wobble position,51 potentially altering protein sequences because translating ribosomes read inosine as guanosine. A-to-I editing is catalysed by adenosine deaminases acting on RNA (ADAR) 1 and 2 (Figure 1J).7 Recent analyses of RNA-seq datasets 128

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have identified recurrent A-to-I edits throughout human embryogenesis. Two independent studies reported that A-toI-edited transcripts are present at all early embryonic stages, but the levels of inosine-containing transcripts decline after the four-cell stage.52,53 Ding et al.52 further observed that A-to-I-edited transcripts tend to show reduced expression in later embryonic stages, proposing that this reduction is partly mediated by microRNAinduced degradation, as A-to-I-edited mRNAs gain microRNA binding sites.52 Given that ADAR proteins catalyse A-to-I editing, their expression patterns are expected to reflect editing dynamics. Indeed, ADAR1 expression mirrors A-to-I editing: high from the zygote to four-cell stage, followed by a drop at the eight-cell stage.53 Bovine embryos conceived via IVF display a similar ADAR expression profile, with high levels at the two-cell stage and a decline at the blastocyst stage, whereas this dynamic pattern is absent in cloned embryos from SCNT.54 These observations suggest that proper A-to-I editing may be one reason why SCNT cloning has proven challenging. In mice, both Adar1 KO animals and mice carrying an editing-deficient ADAR1 mutation (ADAR1E861A) die during embryonic development.55-57 This lethality has been attributed to a failure of RNA editing, which normally introduces destabilising mismatches that prevent dsRNA accumulation. In its absence, endogenous dsRNA builds up, triggering aberrant dsRNA mediated interferon signalling, defective haematopoiesis, and embryonic death around E13.5.56 Consistent with an essential role of ADAR1 in fertility, granulosa cellspecific deletion of Adar1 results in delayed ovulation, impaired oocyte maturation, and infertility in mice.58 Adar2 KO mice are produced at Mendelian ratios from heterozygote intercrosses, but die between P0 and P20 due to defective A-to-I editing of a glutamate receptor mRNA.59

Cytidine to uridine

C-to-U editing is catalysed by members of the activation-induced cytidine deaminase/ apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (AID/APOBEC) family. Mechanistically, C-to-U editing

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involves the deamination of cytidine to uridine, which can alter the coding sequence of the mRNA (Figure 1K).60 The most well-known example is the editing of APOB mRNA, where a single C-to-U change introduces a premature stop codon, producing the truncated APOB48 protein.60 To date, few studies have investigated the role of C-to-U RNA editing during embryonic development. Those that have, focused primarily on cofactors of APOBEC1, notably apobec-1 complementation factor (ACF) and RNA-binding motif protein 47 (RBM47), which guide editing specificity. RBM47 is required for C-to-U editing, as demonstrated by impaired Apob editing in Rbm47-deficient mice.61 These mice exhibit increased mid-gestation embryonic lethality, and surviving Rbm47-deficient pups are consistently smaller than their wild-type littermates.62 Similarly, ACF is essential for preimplantation development, as Acf-deficient embryos fail to develop past the blastocyst stage.63 Because Apobec1-deficient mice are viable,64 the embryonic lethality observed in Rbm47- and Acf-deficient animals may be independent of APOBEC1-mediated C-to-U editing.

RNA Capping and Cap Proximity Methylations in Embryogenesis

RNA products of RNA polymerase II, including mRNAs, are rapidly capped at the 5′ end to protect them from cellular exonucleases. Capping is a multistep, enzyme-catalysed process initiated by the addition of guanosine to the nascent transcript by RNA-triphosphatase and guanylyltransferase. Subsequently, RNA guanine-7-methyltransferase methylates the cap guanosine at the N7 position, generating the 7-methylguanosine (m7G) cap (Figure 3A-C).7 m7G caps can be removed by decapping enzymes, primarily the mRNA-decapping (DCP)1–DCP2 complex (Figure 3D).65 Cap-proximal methylation refers to methylations occurring near the 5′ cap. Cap methyltransferase (CMTR)1 and CMTR2 catalyse 2′-O-ribose methylation of the first and second nucleotides, respectively (Figure 3E–F). When the first nucleotide is adenosine, the cap-specific adenosine CC BY-NC 4.0 Licence

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methyltransferase Phosphorylated CTD Interacting Factor 1 (PCIF1) can methylate the N6 position of 2′-O-methyladenosine, generating N6-O-dimethyladenosine (m6Am), a modification that can be removed by FTO (Figure 3G–H).7 While most genes involved in m7G capping are expressed throughout early embryonic development,66 not all have been thoroughly investigated in the context of embryogenesis. The m7G cap binding complex mainly responsible for the nuclear export of mRNA, is composed of nuclear cap binding protein (NCBP)1 and NCBP2. In mice, lack of Ncbp1 results in developmental arrest in the morula stage and is associated with RNAretention in the nucleus.67 eIF4F is a cap binding complex facilitating steady translation initiation, and is composed of eIF4G, enabling recognition of the poly-A tail and eIF4E, responsible for m7G cap binding. In mice, maternal eIF4E is carried over from the oocyte, but is rapidly degraded upon fertilisation. By the late two-cell stage, when the embryonic gene expression is assured, eIF4E is crucial for protein synthesis.68 Mechanistic studies have shown that inhibiting maternal eIF4E in the zygote stage prevents the development beyond the two-cell stage.68 eIF4E1B is the germinal cell specific eIF4E isoform.69 Eif4e1b is expressed in oocytes and zygotes, but expression diminishes by the two-cell stage.70 Genetic excision of eif4e1b leads to developmental arrest in the two-cell stage in mice70,71 due to impaired transcription of genes activated during the ZGA.71 Additionally, eIF4E1B binds target mRNA, preventing their degradation in metaphase II-stage oocytes,71 which are then, upon fertilisation, translated with a higher efficiency.70 Since eIF4E1B targeted mRNA include chromatin remodelling factors,70 a loss of eIF4E1B is associated with a failure to reset zygotic chromatin to an open structure, leading to failed activation of zygotic genes.71 In humans, mutations in eIF4E nuclear import factor 1 (eIF4ENIF1), a protein critical for eIF4E nucleocytoplasmic shuttling, are associated with autosomal dominant

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Figure 3: Mechanism of RNA capping, decapping, and cap-proximity methylations.

A H (m6Am, cap2)

B F G (m6Am)

D (m7G-cap)

A) RNA-triphosphatase removes the γ-phosphate from the 5’-ppp-RNA forming 5’-pp-RNA. B) Guanyltransferase couples a GMP, from GTP, to the 5’-pp-RNA molecules. C) RNA guanine-7-methyltransferase transfers a methyl group from SAM to the N7 of the terminal guanine to generate the m7G-cap (cap 0). D) m7G-capped RNA can be decapped by the DCP1–DCP2 complex. The catalytically active DCP2 hydrolyses one of the triphosphate bonds between the RNA-molecule and the m7G-cap. E) Alternatively, the m7G-capped RNA can be methylated near the cap. CMTR1 mediates the 2-O-methylation of the ribose in the most proximal nucleotide to the m7G-cap, forming the cap 1 structure. F) This structure can be further 2-O-methylated by CMTR2, methylating the ribose of the second most proximal nucleotide to the m7G-cap, forming the cap 2 structure. Both RNA with cap 1 G) and cap 2 H) structures can be modified by PCIF1, if the proximal nucleotide is adenosine. PCIF1 methylates the N6 of the adenosine forming m6Am, a reaction that can be reversed by FTO. Created in BioRender. CMTR1: cap methyltransferase 1; CMTR2: cap methyltransferase 2; DCP1: mRNA-decapping enzyme 1; DCP2: mRNA-decapping enzyme 2; FTO: fat mass and obesity-associated protein; GMT: guanine-N7 methyltransferase; m⁶A: N⁶-methyladenosine; m⁶Am: N⁶,2′-O-dimethyladenosine; met: methyl group; PCIF1: phosphorylated CTDinteracting factor 1.

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inherited primary ovarian insufficiency and early menopause.72 DCP1–DCP2 form the catalytic core of the m7G decapping complex. In mice, Dcp1a and Dcp2 mRNA are highly expressed in oocytes and one-cell stage, but expression drops thereafter,73 suggesting these transcripts are maternally expressed and loaded into the oocyte and not expressed during the ZGA. siRNA-mediated KD of both Dcp1a and Dcp2 increases maternal mRNA stability, elevating levels of transcripts usually degraded in the two-cell embryo.73 This, in turn, inhibits the ZGA, as evidenced by lower overall transcription levels and active promoter marks in two-cell embryos.73 Using combined RNA-seq and proteomics analysis, Kong et al.74 confirmed that accumulation of DCP1A coincided with increased degradation of maternal mRNA.74 Increased DCP1A protein is observed in postovulatory aged mouse and human oocytes, and suppressing this rise improves oocyte quality, as evidenced by reduced fragmentation and increased blastocyst formation.75 Cap-modifiers have also been shown to be important in embryonic development. Both CMTR1 and CMTR2 are critical for embryonic development, as KO leads to embryonic lethality in mice.76 Cmtr1 and Cmtr2 KO embryos showed no apparent phenotype until E6.5 but displayed signs of arrested development by E7.5.76 Pcif1 KO mice, displaying a prominent decline in m6Am levels, shows no obvious effect on fertility or early development.77 Recent profiling of the m6Am landscape in both mouse and human embryogenesis has shown that it is a highly dynamic process, with m6Am levels reaching a low point around the time of the ZGA.16 Furthermore, it was proposed that m6Am promotes RNA expression and translational efficiency, potentially to a stronger degree than m6A, and can act synergistically with other modifications.16

CONCLUSION Over the last decade, numerous studies have demonstrated that early embryogenesis is not governed solely by CC BY-NC 4.0 Licence

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transcriptional control; it critically depends on a complex epitranscriptomic layer. Lossof-function studies in animals demonstrate that perturbing individual writers, readers, erasers, or cap/decapping factors often results in preimplantation arrest, abnormal blastocyst formation, or impaired exit from pluripotency. These findings indicate that epitranscriptomic regulation orchestrates maternal mRNA clearance, ZGA, embryonic metabolism, and lineage commitment in a coordinated manner to ensure proper embryogenesis. In terms of the clinical implications of RNA modifications, dysregulation of RNA modification-related enzymes may contribute to or exacerbate infertilityassociated conditions, including premature ovarian insufficiency, polyendocrine metabolic ovarian syndrome, and endometriosis.8 Although clinical investigations remain at an early stage, RNA modifications hold considerable promise as diagnostic biomarkers and therapeutic targets, with the potential to improve fertility management and reproductive health outcomes.78 Progress in this field has closely paralleled methodological advances. The development of sensitive, low-input mapping approaches, improved chemical and enzymatic detection strategies, and high-resolution mass spectrometry has enabled studies in a system historically limited by scarce material. The continued development of quantitative, modification- and sitespecific methods capable of single-cell and allele-level resolution in genuine embryos will be crucial. Despite these advances, fundamental questions remain. For most RNA modifications, the transcript- and sitespecific targets that determine function are incompletely defined. Furthermore, how different RNA modifications interact with each other, as well as with chromatin and signalling pathways, is only beginning to be understood. Ongoing efforts will deepen our understanding of how RNA modifications safeguard normal development and may open new avenues to improve the diagnosis of epitranscriptomic causes of infertility and early pregnancy loss, as well as aid assisted reproduction strategies.

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27. Ivanova I et al. The RNA m6A reader YTHDF2 is essential for the post-transcriptional regulation of the maternal transcriptome and oocyte competence. Mol Cell. 2017;67(6):1059-67.

13. Zheng G et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 2013;49(1):18-29.

28. Deng M et al. YTHDF2 regulates maternal transcriptome degradation and embryo development in goat. Front Cell Dev Biol. 2020;8:580367.

14. Li Y et al. The RNA m6A landscape during human oocyte-to-embryo transition. EMBO J. 2025; 44(14):4150-80.

29. Kasowitz SD et al. Nuclear m6A reader YTHDC1 regulates alternative polyadenylation and splicing during mouse oocyte development. PLoS Genet. 2018;14(5):e1007412.

15. Li Y et al. Single-cell m6A mapping in vivo using picoMeRIP-seq. Nat Biotechnol. 2024;42(4):591-6.

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17. Wang Y et al. The RNA m6A landscape of mouse oocytes and preimplantation embryos. Nat Struct Mol Biol. 2023;30(5):703-9.

22. Yu T et al. Dynamic reprogramming and function of RNA N6-methyladenosine modification during porcine early embryonic development. Zygote. 2021;29(6):417-26.

10. Ignatova VV et al. The rRNA m6A methyltransferase METTL5 is involved in pluripotency and developmental programs. Genes Dev. 2020;34(910):715-29.

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30. Hao J et al. microRNA-670 modulates Igf2bp1 expression to regulate RNA methylation in parthenogenetic mouse embryonic development. Sci Rep. 2020;10(1):4782.

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36. Qin C et al. ALKBH5 modulation of ferroptosis in recurrent miscarriage: implications in cytotrophoblast dysfunction. PeerJ. 2024;12:e18227. 37. Arango D et al. Acetylation of cytidine in mRNA promotes translation efficiency. Cell. 2018;175(7):1872-86. 38. Wang M et al. N4-acetylcytidine of Nop2 mRNA is required for the transition of morula-to-blastocyst. Cell Mol Life Sci. 2023;8(10):307. 39. Xiang Y et al. NAT10-mediated N4acetylcytidine of RNA contributes to post-transcriptional regulation of mouse oocyte maturation in vitro. Front Cell Dev Biol. 2021;9:704341. 40. Cui Z et al. NAT10 regulates zygotic genome activation and the morula-to-blastocyst transition. FASEB J. 2025;39(5):e70444. 41. Jiang X et al. Maternal NAT10 orchestrates oocyte meiotic cell-cycle progression and maturation in mice. Nat Commun. 2023;14(1):3729. 42. Liu J et al. Developmental mRNA m5C landscape and regulatory innovations of massive m5C modification of maternal mRNAs in animals. Nat Commun. 2022;13(1):2484. 43. Xu T et al. NSUN2 is critical for mouse oocyte meiosis and early embryonic development. Reproduction. 2024;168(6):e240235.

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44. Murakami Y et al. NSUN3-mediated mitochondrial tRNA 5-formylcytidine modification is essential for embryonic development and respiratory complexes in mice. Commun Biol. 2023;6(1):307. 45. Metodiev MD et al. NSUN4 is a dual function mitochondrial protein required for both methylation of 12S rRNA and coordination of mitoribosomal assembly. PLoS Genet. 2014;10(2):e1004110. 46. Ding C et al. RNA-methyltransferase Nsun5 controls the maternal-tozygotic transition by regulating maternal mRNA stability. Clin Transl Med. 2022;12(12):e1137. 47. Liu D et al. NSUN5 is essential for proper cell proliferation and differentiation of mouse preimplantation embryos. Reproduction. 2024;168(1):e240079. 48. Deng M et al. YBX1 mediates alternative splicing and maternal mRNA decay during pre-implantation development. Cell Biosci. 2022;12(1):12. 49. Ihashi S et al. Incomplete activation of Alyref and Gabpb1 leads to preimplantation arrest in cloned mouse embryos. Life Sci Alliance. 2023;6(11):e202302296. 50. Qiu J et al. RNA editing regulates lncRNA splicing in human early embryo development. PLoS Comput Biol. 2021;17(12):e1009630. 51. Brachova P et al. Inosine RNA modifications are enriched at the codon wobble position in mouse oocytes and eggs†. Biol Reprod. 2019;101(5):938-49. 52. Ding Y et al. Recurrent RNA edits in human preimplantation potentially enhance maternal mRNA clearance. Commun Biol. 2022;5(1):1400. 53. Qiu S et al. Single-cell RNA sequencing reveals dynamic changes in A-to-I RNA editome during early human embryogenesis. BMC Genomics. 2016;17(1):766. 54. Zhang L et al. RNA sequencing revealed the abnormal transcriptional profile in cloned bovine embryos. Int J Biol Macromol. 2020;150:492-500. 55. Hartner JC et al. Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1. J Biol Chem. 2004;279(6):4894-902. 56. Liddicoat BJ et al. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science. 2015;349(6252):1115-20. 57. Wang Q et al. Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene. J Biol Chem. 2004;279(6):4952-61.

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58. Nelson RN et al. Granulosa cell specific loss of Adar in mice delays ovulation, oocyte maturation and leads to infertility. Int J Mol Sci. 2022;23:14001.

72. Kasippillai T et al. Mutations in eIF4ENIF1 are associated with primary ovarian insufficiency. J Clin Endocrinol Metab. 2013;98(9):E1534-9. 73. Ma J et al. Maternally recruited DCP1A and DCP2 contribute to messenger RNA degradation during oocyte maturation and genome activation in mouse. Biol Reprod. 2013;88(1):11.

59. Higuchi M et al. Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2. Nature. 2000;406(6791):78-81.

74. Kong L et al. Multi-omics revealed that DCP1A and SPDL1 determine embryogenesis defects in postovulatory ageing oocytes. Cell Prolif. 2025;58(3):e13766.

60. Pecori R et al. Functions and consequences of AID/APOBECmediated DNA and RNA deamination. Nat Rev Genet. 2022;23(8):505-18. 61. Fossat N et al. C to U RNA editing mediated by APOBEC1 requires RNAbinding protein RBM47. EMBO Rep. 2014;15(8):903-10.

75. Li C et al. Cordycepin delays postovulatory aging of oocytes through inhibition of maternal mRNAs degradation via DCP1A polyadenylation suppression. Cell Mol Life Sci. 2023;80(12):372.

62. Fossat N et al. Conditional restoration and inactivation of Rbm47 reveal its tissue-context requirement for viability and growth. Genesis. 2016; 54(3):115-22.

76. Dohnalkova M et al. Essential roles of RNA cap-proximal ribose methylation in mammalian embryonic development and fertility. Cell Rep. 2023;42(7):112786.

63. Blanc V et al. Targeted deletion of the murine apobec-1 complementation factor (acf) gene results in embryonic lethality. Mol Cell Biol. 2005;25(16):7260-9.

77. Pandey RR et al. The mammalian capspecific m6Am RNA methyltransferase PCIF1 regulates transcript levels in mouse tissues. Cell Rep. 2020;32(7):108038.

64. Hirano K et al. Targeted disruption of the mouse apobec-1 gene abolishes apolipoprotein B mRNA editing and eliminates apolipoprotein B48. J Biol Chem. 1996;271(17):9887-90.

78. Volsa AM et al. Epitranscriptomic modifications in embryonic development: insights into natural and ART-induced mechanisms and implications. Hum Reprod Update. 2026;32(2):181-205.

65. He F, Jacobson A. Eukaryotic mRNA decapping factors: molecular mechanisms and activity. FEBS J. 2023;290(21):5057-85. 66. Mager J. A catalog of early lethal KOMP phenotypes in the Mager Lab (UMASS). Available at: https:// websites.umass.edu/jmager/. Last accessed: 29 January 2026. 67. Liu Y et al. Ncbp1 deficiency affects morula-to-blastocyst transition through lipid metabolic dysregulation. Reproduction. 2026;171(2):xaaf020. 68. Li Y et al. Regulation of the mammalian maternal-to-embryonic transition by eukaryotic translation initiation factor 4E. Development. 2021;148(12):dev190793. 69. Lorenzo-Orts L et al. eIF4E1b is a non-canonical eIF4E protecting maternal dormant mRNAs. EMBO Rep. 2024;25(1):404-27. 70. Guo J et al. Selective translation of maternal mRNA by eIF4E1B controls oocyte to embryo transition. Adv Sci (Weinh). 2023;10(11):e2205500. 71. Yang G et al. Germ cell-specific eIF4E1b regulates maternal mRNA translation to ensure zygotic genome activation. Genes Dev. 2023; 37(9-10):418-31.

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The Assisted Reproductive Technologies Conceived Pregnancy: Pathophysiology, Risks, and Evolving Concepts Authors:

Hüseyin Karakaya,¹ Gökhan Doğukan Akarsu² 1. Department of Gynecology and Obstetrics, Faculty of Medicine, Yozgat Bozok University, Türkiye 2. Department of Pharmacy Services, Vocational School of Health Services, Yozgat Bozok University, Türkiye *Correspondence to gokhan_dogukan_akarsu@hotmail.com

Disclosure:

The authors declare that there are no competing interests. AI tools were used solely for language editing and grammar improvement during the preparation of the English version of the manuscript. All scientific content, interpretation, and final approval of the manuscript were performed by the authors.

Received:

23.02.26

Accepted:

09.06.26

Keywords:

Assisted reproductive technology (ART), congenital anomalies, donor oocyte pregnancy, frozen embryo transfer, preeclampsia.

Citation:

EMJ Repro Health. 2026;12[1]:134-140. https://doi.org/10.33590/emjreprohealth/E7961AOD

Abstract Assisted reproductive technologies (ART) have transformed infertility treatment from a medical intervention into a global standard of care. As the use of ART continues to expand worldwide, questions have emerged regarding whether pregnancies conceived through ART are biologically equivalent to those conceived naturally. Clinical evidence suggests that ART-conceived pregnancies are associated with increased risks of hypertensive disorders, placental complications, and gestational diabetes. However, it remains unclear whether these risks arise directly from ART procedures themselves or from characteristics commonly observed in the ART population, such as advanced maternal age and underlying metabolic disorders. Specific ART practices, including frozen embryo transfer cycles performed without a corpus luteum and donor oocyte cycles, present unique hormonal and immunological challenges that may influence maternal adaptation to a genetically distinct embryo. Furthermore, laboratory conditions during the early stages of embryonic development have raised concerns regarding epigenetic modifications and their potential long-term health consequences. Although the majority of ART pregnancies result in healthy outcomes, growing evidence suggests that they may follow a distinct biological pathway. This perspective highlights the need for a more integrated, multidisciplinary follow-up approach aimed at optimising the long-term health and wellbeing of both mothers and their offspring.

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Key Points 1. As the global use of assisted reproductive technologies (ART) continues to increase, understanding whether ARTconceived pregnancies represent a distinct obstetric phenotype has become increasingly important for maternal and offspring health. 2. This narrative review synthesises current evidence on the biological mechanisms, obstetric complications, epigenetic considerations, and long-term cardiovascular, metabolic, and psychological outcomes associated with ART pregnancies. 3. ART pregnancies should be managed using an integrated multidisciplinary approach, recognising their potential long-term maternal and offspring health implications while acknowledging that many risks also reflect underlying infertility-related factors.

INTRODUCTION Over the past 40 years, assisted reproductive technologies (ART) have evolved into modern practices, influenced by shifts in experimental methodology. For an increasing number of people, ART is no longer just an alternative but is considered a realistic path to parenthood. In the modern world, the age of first-time mothers continues to rise, and societal pressures on fertility are increasing. Therefore, our reliance on these technologies is expected to increase.1,2 However, the adoption of ART in society has changed the fundamental clinical debate. The goal is no longer simply to achieve a pregnancy. Instead, it is to examine the biological development of these pregnancies and whether they truly reflect the conditions of pregnancy occurring naturally. Large-scale observational studies have shown a higher risk of hypertensive disorders, placental problems, gestational diabetes, and altered fetal growth in ART-assisted pregnancies.3,4 However, interpreting these data clearly is not easy. The ART population is inherently different from the general obstetric population. Advanced maternal age, metabolic dysfunction, endometriosis, and chronic inflammation diseases common in infertility cases influence the risk profile independently. This makes it difficult to separate the effects of ART from pregnancy development. Rather than simple epidemiology, various biological theories are beginning to emerge. Successful implantation is not a solitary and CC BY-NC 4.0 Licence

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independent outcome. It requires a perfectly timed interaction between embryo viability and endometrial receptivity. Potential disruptive factors being investigated include hormones above physiological levels during stimulation, altered corpus luteum (CL) function, changes in immune tolerance, and even epigenetic changes in the earliest stages of embryonic development.5 At the same time, there are rapid advances in embryo selection and non-invasive diagnostic methods that are constantly being updated.6 Despite the breadth of existing literature, prior narrative reviews have largely examined individual risk domains such as preeclampsia, congenital anomalies, or epigenetic effects in isolation, without integrating the full spectrum of obstetric, metabolic, psychological, and long-term cardiovascular implications. This review adopts a broader, synthesising perspective, including the underappreciated but clinically significant issue of multiple gestations following ART, to provide a comprehensive biological appraisal of ART pregnancies as a distinct obstetric phenotype. This raises a fundamental conceptual question: should we view ART pregnancies merely as an application for solving infertility treatment, or do they characterise a unique obstetric phenotype shaped by specific technological and hormonal effects? Answering this question is far from easy, but it is necessary to relate some insights to long-term maternal health. In the following sections, the authors evaluate whether ART pregnancies are a separate

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biological issue, and in particular, their lasting effects on maternal cardiovascular health are assessed.

MATERIALS AND METHODS This paper was conducted as a narrative review. A literature search was performed using PubMed/MEDLINE, Scopus, Web of Science, Cochrane Library, and Google Scholar databases. The search covered publications from 2018–2026. Only articles published in English were included. Search terms included combinations of the following: “assisted reproductive technology,” “ART pregnancy,” “preeclampsia,” “placental dysfunction,” “frozen embryo transfer,” “congenital anomalies,” “gestational diabetes,” “cardiovascular outcomes,” “epigenetics,” and “embryo implantation.” Relevant original research articles, systematic reviews, metaanalyses, and consensus statements were evaluated. Studies were selected based on their relevance to the clinical and biological aspects of ART pregnancies discussed in this review.

Placental Dysfunction and Hypertensive Disorders in ART Pregnancies The most prominent and concerning obstetric complication associated with ART is preeclampsia.7 While meta-analyses describe the overall increased risk as normal, its persistence across different populations keeps clinicians on alert. However, the real debate is not simply about the varying numbers. From this perspective, it concerns whether we are seeing a direct side effect of ART or a preexisting vulnerability in the patients themselves. Preeclampsia is fundamentally based on early placental dysfunction. For a pregnancy to develop, trophoblast invasion and the remodelling of the spiral arteries in the first critical weeks must be perfectly synchronised. Even a small disruption in this early stage can impair later vascular adaptation. This raises the question: do ART pregnancies face a fundamentally different implantation environment from Day 1?

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If we consider the hormonal mechanism, controlled ovarian stimulation fills the endometrium with oestradiol levels far beyond the natural level. Fresh embryo transfers occur in this hyperhormonal environment. Planned frozen embryo transfer cycles often take place without the CL. This is not just a technical detail. The CL produces vital molecules such as relaxin, which initiates early cardiovascular adaptation.8 Without the CL, the body can compensate by endothelial remodelling, especially in women prone to cardiometabolic problems. However, research results show higher rates of hypertension in frozen embryo transfer cycles without the CL,7 but we still need to account for other latent variables. Donor egg pregnancies add another factor. Preeclampsia rates are consistently higher in ART pregnancies than in spontaneous pregnancies.7 This cannot be attributed solely to hormones. It also involves the immune system. In the mother–fetus bond, natural killer cells and regulatory T cells in the uterus carefully balance tolerating the foreign embryo while protecting the mother.9 In donor donations, where the genetic difference between mother and fetus is enormous, this immune tolerance is strained. This is a fascinating, yet flawed and incomplete clinical model for studying how a mother’s body adapts to a genetic stranger. Nevertheless, caution is necessary. Women who enrol in ART are often older and have higher rates of experiencing metabolic comorbidities that independently increase their risk of high blood pressure.10 This makes separating this effect from the patient’s own biology a methodological ambiguity. The links are undeniable, but the definitive evidence is still unclear.

Early Pregnancy Loss, Implantation Biology, and Epigenetic Considerations Despite significant advances in fertilisation and implantation rates, early pregnancy loss remains a persistent problem in ART. In the general population, more than half of early miscarriages are due to chromosomal abnormalities.11 This is striking evidence that embryonic genomic integrity is the guardian of viability. Modern genomic tools

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have reshaped our perspective on this issue. Big data analyses are now even more feasible. Thanks to triple exome sequencing and similar high-resolution techniques, previously invisible monogenic and structural variants are being revealed.11-13 It is becoming clear that both sporadic and recurrent losses involve a complex genetic architecture where immune regulatory pathways and variants of rare and uncertain significance intersect.13 In this sense, many ART related pregnancy losses explain an underlying biological vulnerability rather than a direct harm stemming from the ART stages themselves. Additionally, ART does not occur in a biological environment. The preimplantation environment is a carefully, albeit artificially, modulated space. Controlled hormonal stimulation can desynchronise the timing of embryonic and endometrial development. Even a small deviation during the implantation window can affect early stabilisation.12 Beyond hormones, there is growing interest in the genital microbiome. Changes in microbial composition can alter the strength of local inflammation and potentially shift the balance for or against a successful pregnancy.5 The precise weight of this factor is still debated. This hypothesis is gaining significant importance. Additionally, another layer is added to the epigenetic mystery. Early embryogenesis is a period of major DNA methylation and histone remodelling. It is a delicate stage interfered with by laboratory culture conditions.14 While overt suppression disorders remain rare, there are concerns that subtle regulatory changes may affect placental fertility or long-term metabolic health. Whether these molecular responses lead to meaningful clinical outcomes is one of the biggest unknowns. Environmental factors also further complicate the picture. Endocrine disrupting chemicals have been reported to be linked to lower oocyte quality and altered development.14,15 This situation is also considered to compromise sperm integrity.16-18

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These external pressures make it difficult to distinguish between the innate biology of infertility and the effects of ART. Male factor infertility is also more complex than a standard sperm analysis suggests. Problems such as sperm DNA fragmentation and oxidative stress can silently undermine embryo viability.19 The rise of sperm selection suggests we are moving toward a more nuanced understanding, but whether these high-tech tools truly reduce obstetric risk in the long term has not yet been proven.20

Congenital Anomalies in ART Pregnancies: Signal, Bias, or Biological Effect

The debate about the link between ART and congenital anomalies is far from over. Several systematic reviews point to an increase in malformations in children conceived with ART. Congenital heart defects are frequently the focus.20-22 Interpreting these data is quite difficult. When researchers consider parental age, duration of infertility, and metabolic health status, this statistical correlation becomes intractable and does not yield a significant difference.20,21 The dilemma arises again: does the technology itself create new risks, or does it accelerate their emergence in a population already predisposed to them? From a biological perspective, ART procedures occur during a high-risk period of epigenetic reprogramming. While clinically significant genomic imprinting disorders are rare, scientists continue to study the more subtle epigenetic variations associated with ART procedures. Genomic imprinting refers to the epigenetic process by which certain genes are expressed in a parent-of-origin-specific manner, regulated primarily through DNA methylation. Disruption of this process can lead to well-defined clinical syndromes such as Beckwith–Wiedemann syndrome, Silver–Russell syndrome, Angelman syndrome, and Prader–Willi syndrome, which are characterised by growth abnormalities, neurodevelopmental

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delay, endocrine dysfunction, and cancer predisposition. The frequency of some of these disorders is higher than expected in the general population following ART, and experimental evidence suggests that ART procedures may induce stress in the embryo and influence gene expression and DNA methylation patterns (particularly in imprinted regions) without producing global methylation alterations.14,23 There is also much debate about fresh and frozen embryo transfer protocols. However, so far, no approach has emerged as safer when it comes to the risk of congenital anomalies. In a clinical setting, it is more important to discuss the absolute risk. Even if the relative risk appears statistically significant, the actual increase in the number of affected pregnancies is usually very small. The rise of non-invasive prenatal testing has completely changed the way we screen for these pregnancies.6 ART can provide earlier, more accurate diagnoses and personalised counselling, while also protecting patients from unnecessary invasive procedures.

Multiple Pregnancies Following ART: A Distinct Risk Category

Multiple gestation is one of the most significant and well-characterised complications of ART. The practice of transferring more than one embryo to improve cumulative live birth rates has historically driven a substantial increase in twin and higher-order pregnancies. Although elective single embryo transfer policies have reduced the frequency of multiples in many countries, multiple pregnancies continue to represent a disproportionate share of ART outcomes globally. From a maternal perspective, multiple gestations markedly amplify the risks associated with singleton ART pregnancies. Rates of preeclampsia, gestational diabetes, peripartum haemorrhage, and Caesarean delivery are substantially higher in twin and triplet pregnancies.24,25 The physiological demands of carrying multiple fetuses 138

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place greater strain on cardiovascular and metabolic systems already subject to the effects of infertility-related comorbidities and ART-specific endocrine exposures. Preterm labour is a near-universal concern: more than 50% of twin pregnancies deliver before 37 weeks of gestation, and higherorder multiples face even greater risks of extreme prematurity.26 For offspring, the consequences of multiple gestation extend well beyond the perinatal period. Low birthweight, intrauterine growth restriction, and neonatal intensive care admission are far more common in ARTconceived multiples than in singletons. Neurological and developmental sequelae associated with preterm birth, including cerebral palsy, cognitive impairment, and behavioural difficulties, are also elevated in this population.24 Monochorionic twin complications, such as twin-to-twin transfusion syndrome, represent an additional source of perinatal morbidity specific to spontaneous or ART-related monozygotic twinning. The promotion of elective single embryo transfer in clinical guidelines reflects a growing consensus that the optimal outcome of ART is a single healthy live birth. Wide adoption of this approach, supported by cumulative transfer strategies and improved cryopreservation techniques, has the potential to substantially reduce the burden of multiple pregnancyrelated morbidity. Nonetheless, individual counselling remains essential, as the decision to transfer one or more embryos involves a complex negotiation of patient expectations, clinical circumstances, and evidence-based risk communication.

Metabolic, Psychological, and Long-Term Cardiovascular Implications Studies have shown that gestational diabetes and hypertensive disorders are more common in women who conceive via ART.7,10 Many patients undergoing ART already manage obesity, insulin resistance, or other components of metabolic syndrome. Each of these is a significant risk factor in itself.10 In many cases, ART may not even be a trigger,

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but rather a stage in which a pre-existing vulnerability emerges. Furthermore, hypertensive disorders such as preeclampsia should no longer be dismissed as merely temporary complications of pregnancy. We must now consider them as early warning signs for future cardiovascular health. Studies show that women with a history of preeclampsia are at a much higher risk of chronic hypertension, ischaemic heart disease, and stroke later in life.25 Whether ART accelerates this progression or merely intersects with it is still an open question. However, it is not a question with superficial clinical implications. We must also not ignore the psychological aspect of these pregnancies. Conceiving after years of infertility treatment carries an emotional intensity rarely encountered in spontaneous pregnancies. The highrisk nature of pregnancy, the constant monitoring, and the persistent fear of loss create a unique stress profile.24,26-28 Qualitative studies describe a complex, often exhausting situation in these couples, characterised by overprotective behaviours and medical intervention.29 While quantifying these factors is difficult, they are an integral part of the ART pregnancy phenotype. Consequently, current evidence does not point to a single definitive cause. Instead, ART pregnancies are situated at a crossroads of biological predisposition, technology, endocrine changes, immune adaptation, and psychosocial factors. Rather than viewing References 1.

Münch ML et al. Multidisciplinary assessment of the impact of assisted reproductive techniques on pregnancy and long-term outcomes of mother and child: foundation of the LEREP Center. J Reprod Immunol. 2025;159:104457.

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ART as an isolated medical event, it is more accurate to see it as part of a lifelong reproductive and metabolic continuum. Adopting this broader perspective is the first and most important step towards a multidisciplinary approach that looks far beyond standard obstetric examination.

CONCLUSION ART has fundamentally reshaped reproductive medicine, achieving results that seemed like science fiction 40 years ago. The undeniable evidence of this success lies in the millions of children born to families who had no path to parenthood. However, this clinical success does not mean we will not continue to ask more difficult, nuanced questions about biological adaptation and long-term safety. The data we have today show a consistent increase in risks such as hypertension, placental problems, certain congenital anomalies, and metabolic alterations. Importantly, these conditions are almost certainly not the result of a single factor. They represent a complex dialogue between the biology of infertility, parental health, artificial hormonal environments, immune tolerance, and the embryo’s earliest environmental exposures. In the future, it is necessary to uncover the mechanisms behind these. Studies tracking lifelong cardiovascular, metabolic, and even psychosocial outcomes are needed. From this broader perspective, ART should be understood as more than just a tool used to achieve pregnancy. It will remain a critical stage in a woman’s lifelong health journey.

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Article

Early Preterm Birth Associated with a Different Inflammatory Pattern than Late Preterm Birth Authors:

Arised G. Juárez-Reyes,1,2 *Alberto N. Peón,1,3 Roque D. Licona-Meníndez,1,2 Edrey J. Neri Marín,2 José de Jesús Galindo-Juarez,1 Alfredo Templos Morales,2 Brian Hernández-Gonzalez,1 Elías Licona-Venegas2 1. Sociedad Española de Beneficencia, Pachuca de Soto, Mexico 2. Hospital Español de Pachuca, Pachuca de Soto, Mexico 3. Escuela Superior de Apan, Universidad Autónoma del Estado de Hidalgo, Apan, Mexico *Correspondence to investigacion@benepachuca.com

Disclosure:

All the authors declare receiving all support for the present manuscript from Hospital Español de Pachuca (a not-for-profit hospital; the content of the article does not affect the institution in any way); and have received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events, and support for attending meetings and/or travel from Hospital Español de Pachuca.

Received:

03.06.2026

Accepted:

01.07.2026

Acknowledgements:

Juárez-Reyes contributed to conceptualisation, data analysis, and manuscript drafting. Peón contributed to study design, data analysis, manuscript drafting, and final approval of the manuscript. Meníndez and Licona-Venegas contributed to supervision and critical revision. Marin, Galindo-Juarez, Morales, and Hernández-González contributed to data analysis and manuscript drafting.

Disclaimer:

This study and its publication and diffusion were entirely funded by Sociedad Española de Beneficencia (BEN2025-02) and Hospital Español de Pachuca (HEP2025-02). The original database that was used for this secondary analysis was funded by the March of Dimes association for prematurity research. The data supporting this secondary analysis derive from a previously published cohort study. Source data from the parent study are available with the original publication, and any additional data access is subject to the policies and permissions governing the original March of Dimes cohort. The database titled “Microbial-driven preterm labour involves crosstalk between the innate and adaptive immune response” is available at ImmPort.

Keywords:

Early preterm birth, inflammation, late preterm birth, maternal-fetal interface, predictive markers.

Citation:

EMJ Repro Health. 2026;12[1]:141-149. https://doi.org/10.33590/emjreprohealth/ZA4DGNCC

Key Points 1.

Babies that are born closer to their estimated time of delivery have the least risk for morbidity and mortality, but there is a lack of knowledge that allows prognosis and prevention.

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2. The present cohort study delves into the inflammatory and microbial factors associated with early or late preterm birth. 3. The authors show that different inflammatory patterns are associated with early and late preterm birth, pinpointing different pathophysiological mechanisms that may regulate such entities.

Abstract Background: Preterm birth is the main cause of neonatal morbidity and mortality, and its pathophysiology is only beginning to be understood. While it is considered a complex phenomenon where environmental and biological factors converge, inflammation has been identified as an important mechanism. Moreover, preterm birth has been classified as late preterm or early preterm, according to whether it occurs between Weeks 34–<37 or prior to Week 34, respectively. Early preterm carries significantly more risk for the newborn. Nonetheless, there are no known markers that help to make a differential prognosis, or to target in order to optimise prophylactic therapy with a precision medicine focus. Methods: The authors analysed the cervicovaginal immune secretion patterns of a cohort of 133 pregnant individuals at high risk for preterm birth, and compared those who presented with term birth against a group with early preterm or late preterm births. The samples were taken at 20–24 weeks of pregnancy. Results: The authors found that early preterm births are associated with reduced levels of IL-10 and granulocyte-macrophage colony-stimulating factor (GM-CSF), and enhanced levels of IL-8. On the other hand, late preterm birth was associated with increased IL-8, IL-6, IL-1β, C3b/iC3b, C5, IgE, and IgM. All markers except IL-10 and C5 displayed a good ability to work as predictors of their respective preterm birth category. No marker was found to be associated with vaginal dysbiosis. Conclusion: Both early preterm birth and late preterm birth correlate to distinctive inflammatory patterns, which may show that both entities have different pathophysiological mechanisms.

BACKGROUND Spontaneous preterm birth (PTB) is a major cause of neonatal morbidity and mortality worldwide.1 PTB is defined as birth that occurs before 37 completed weeks of gestation. Approximately 13 million preterm babies are born each year, of whom about one million die before the age of 5 years; 35% of these deaths occur in infants younger than 28 days, since they have a higher risk of respiratory, infectious, and neurological complications, as well as long-term sequelae that significantly affect quality of life and health systems. They may present complications such as thermal instability, respiratory distress, infections, apnoea, hypoglycaemia, seizure episodes, jaundice, necrotising enterocolitis, periventricular leukomalacia, 142

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prolonged hospitalisation, and hospital readmission.2 Several risk factors for PTB have been determined, and the commonly recognised aetiologies include individual-level psychosocial and behavioural factors, neighbourhood characteristics, exposure to the environment, medical conditions and comorbidities, infertility treatments, biological factors, and genetics, but PTB is increasingly recognised as a biologically heterogeneous syndrome, in which inflammatory and host-microbiome interactions appear to play a major role.3-5 In fact, recent research has highlighted the role of certain receptors, chemokines, and inflammatory cytokines in cervical ripening, membrane rupture, and uterine contractility.6

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Moreover, a gradient in the risk for adverse outcomes in the neonate has been observed, where those born closer to their estimated time of delivery have the least risk, while those born earlier have an enhanced risk. In such scenarios, PTB has been classified into early PTB for those births that occur before 34 weeks of gestation, and late PTB for those cases where the baby is born between Weeks 35–36.7-9 Despite early PTB being more prone to complications, little research has been done to understand its pathophysiology, to develop strategies for its timely recognition and prevention, and for its treatment.10 Evidence suggests that host-microbiome interactions and cervicovaginal inflammation, including complement activation as well as Ig production, contribute to the pathophysiology of spontaneous preterm birth.1 Nonetheless, the interactions between the aforementioned variables, and their roles and timing, are fields that are just being developed.11,12 Furthermore, fewer analyses have translated these findings into clinically relevant phenotypes such as early PTB and late PTB.12 Although some advancements in the detection of nearing births have been made,13,14 these tests are sensitive only 7 days after a patient starts to develop signs and symptoms of early labour.6 Thus, we currently lack the understanding to develop a test to accurately predict preterm birth with significant advancement and to discriminate the cases where an early or late PTB may occur. On the other hand, precision medicine has delivered enhanced therapeutics and diagnostics in other fields, as it focuses on stratification of risk factors and pathophysiological mechanisms to ‘personalise’ medicine.15-17 In such a context, understanding the inflammatory mechanisms driving either early or late preterm deliveries may allow for better risk stratification and more precise therapeutic tools.

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AIMS The authors hypothesised that the inflammatory mechanisms regulating early and late preterm birth should be different. Thus, they aimed to describe the fundamental differences in the levels of inflammatory markers between individuals presenting with term births, early PTB, and late PTB. They then aimed to study the ability of each marker to work as a diagnostic/prognostic tool for the identification of preterm birth and studied the correlation of the significant markers with vaginal dysbiosis to understand more about the possible aetiologies of both early and/or late PTB.

METHODS Study Design

A secondary analysis of an existing dataset derived from the March of Dimes (MOD) Database for Preterm Birth Research was performed (data descriptor available from Sirota et al.18). The MOD arose from prospectively recruited patients at five preterm birth prevention clinics in the UK.12

Participants

The cohort included 133 individuals with a high risk of PTB. Inclusion criteria were history of previous spontaneous PTB, midtrimester loss, and recurrent miscarriage, as well as the incidental finding of cervical shortening and/or cervical excisional treatment. Exclusion criteria were individuals under the age of 18 years, HIV or hepatitis C positive status, and vaginal intercourse or bleeding within 72 h of sample collection. Participants with iatrogenic preterm birth were eliminated.

Setting

Longitudinal cervicovaginal sample swabs were collected at timepoint A (12–16 weeks), timepoint B (20–24 weeks), and timepoint C (30–34 weeks). Luminex immunoassays (DiaSorin, Saluggia [Vercelli], Italy) were performed to determine the levels of IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10,

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IL-18, interferon (IFN)-γ, granulocytemacrophage colony-stimulating factor (GM-CSF), and TNF-α for cytokines; IgM, IgG1, IgG2, IgG3, IgG4, IgA, and IgE for Igs; and C3b/iC3b, C5, and C5a for complement proteins. 16S ribosomal RNA sequencing was performed to determine the microbiological profile of each individual, and individuals were classified according to the Valencia criteria for vaginal microbiota. All methods were carried out as described in Chan D et al.12

To evaluate predictive performance, receiving operator characteristics (ROC) curve analyses were performed for selected biomarkers measured at period B, and area under the ROC (AUROC) values were calculated, considering markers as good predictors when p≤0.05.

For this analysis, PTB was defined as delivery before 37+0 weeks, early PTB as delivery before 34+0 weeks, and late PTB as delivery between 34+0 and 36+6 weeks, consistent with CDC and American College of Obstetricians and Gynecologists (ACOG) definitions.4

Ethical Approval

Data Collection

The authors of the original study deposited the data at the ImmPort database and datasharing portal.19 For the current study, these data were downloaded from ImmPort.

Data Analysis

Comparisons of immune mediator levels were performed across term birth, early PTB, and late PTB groups. A Shapiro–Wilk test was performed to assess for normality, and data with p≤0.05 were considered nonparametric. The authors next performed a Mann–Whitney U test to compare the levels of Igs, cytokines, and complement proteins among the individuals reaching term birth, late PTB, or early PTB. A Chi-square test was used to assess the association between vaginal dysbiosis and PTB, and odds ratios with CI were calculated, considering p≤0.05 and CI that did not include the value of 1 as significant. Spearman correlation analysis was used to explore associations between inflammatory mediators and Lactobacillus spp. abundance. Correlation coefficients were classified as strong (r≥0.7), good or moderate (r=0.5–0.7), weak (r=0.3–0.5), or very weak (r≤0.3).20

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All data analysis and plotting were performed using GraphPad Prism X9 (GraphPad Software, San Diego, California, USA).

The parent study received approval from the appropriate Institutional Review Board, and all participants provided written informed consent before enrolment. This secondary analysis was conducted using data derived from that approved cohort. The secondary analysis was approved by the Comité de Ética en Investigación del Instituto de Ciencias de la Salud (CEI-ICSa), with the approval number CEI-ICSa-2025/R007.

FINDINGS No significant difference in maternal age (18–46 years [29.7±6]; p=0.93), BMI (p=0.20), or ethnicity (p=0.09) were found among individuals presenting with term birth or PTB.18 The analysis of the secretion patterns of cytokines (Figure 1), complement proteins (Figure 2), and Igs (Figure 3) revealed distinctive patterns for both early and late PTB. While early PTB was associated with a decreased expression of IL-10 (Figure 1A) and GM-CSF (Figure 1B), and an enhanced expression of IL-8 (Figure 1C), late PTB was found to be associated with enhanced levels of IL-8 (Figure 1C), IL-6 (Figure 1D), IL-1β (Figure 1E), C3b/iC3b (Figure 1F), C5 (Figure 1G), IgE (Figure 1H), and IgM (Figure 1I). The authors did not find significant differences between IL-2, IL-5, TNF-α, IL-18, C5a, IgA, IgG1, IgG2, IgG3, or IgG4 (data not shown). Furthermore, a χ² test showed no correlation between vaginal dysbiosis and preterm birth in the author’s cohort (odds ratio: 1.41; CI: 0.47–4.20; p=0.52), but by

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6,000 4,000 2,000

1,000,000

1,000 100

IgM (pg/mL)

10,000

1,500

1,000

500

1,000,000 800,000

IgE (pg/mL)

100,000

C5 (ng/mL)

C3b/iC3b (ng/mL)

8,000

IL-8 (pg/mL)

IL-10 (pg/mL)

10,000

IL-1β (pg/mL)

B GM-CSF (pg/mL)

IL-6 (pg/mL)

Figure 1: Cervicovaginal inflammatory secretion patterns are different for either early or late PTB.

600,000 400,000 200,000

The levels of cervicovaginal IL-10 (A), GM-CSF (B), IL-8 (C), IL-6 (D), IL-1β (E), C3b/iC3b (F), C5 (G), and cervicovaginal IgE (H) and IgM (I), were measured and compared between individuals who gave birth either at term, early PT, or late PT. GM-CSF: granulocyte-monocyte colony-stimulating factor; NS: not significant; PT: preterm; PTB: preterm birth.

means of a Spearman correlation the authors found a weak but significant negative correlation of IL-1β with Lactobacillus crispatus (r=0.36; p=0.00002; Figure 2). Moreover, when the values of cytokines, Igs, and complement proteins of individuals presenting PTB (both in early or late stages) were compared to those of individuals that presented term birth (Figure 3), the authors found that GMCSF (Figure 3B), IL-1β (Figure 3C), IL-8 (Figure 3D), IL-6 (Figure 3E), C3b/iC3B (Figure 3F), IgE (Figure 3H), and IgM (Figure 3I) had significant prognostic values, as calculated by a ROC curve test. Only IL-10 (Figure 3A) and C5 (Figure 3G) did not exhibit significant AUROC values.

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DISCUSSION The present research shows that different underlying immunological mechanisms associate to either early or late PTB. The mechanism behind early PTBs appears to be dependent on decreased IL-10 and GM-CSF production, as well as enhanced IL-8 production. On the other hand, IL-6, IL-8, IL-1β, C3b/iC3b, C5, IgE, and IgM are significantly enhanced in individuals who delivered at late preterm. Moreover, all these markers, except IL-10 and C5, exhibit significant sensitivity to act as predictors for PTB. Although PTB has been described as primarily being caused by infections, multiple gestations (twins/triplets), placental

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complications, or chronic maternal health conditions, among others, the exact cause of more than 50% of preterm deliveries is never precisely determined.5 In such a setting, inflammation has appeared as an important factor that may explain many cases, and its role in the regulation of birth timing is only beginning to be understood.6,21 For instance, the fetus is a semi-allogeneic product; thus, pregnancy must induce a paradoxical immunological state where immune tolerance to the fetus co-exists with immune surveillance and defence. IL-10 has been linked to the induction of such immunotolerance, while the loss of IL-10-producing cells has been demonstrated to correlate with fetal rejection.22-24 In such a scenario, reduced IL-10 production is expected to induce product rejection and thus early PTB. Nonetheless, GM-CSF is known to accelerate membrane rupture as well as cervical remodelling, thus precipitating

deliveries.25,26 Therefore, its lower levels in individuals with early PTB are a finding that requires further investigation. On the other hand, cytokines like IL-1β and IL6, and chemokines like IL-8, have been shown to play important roles in the preterm induction of birth.27 However, the authors did not find enhanced IL-1β or IL-6 levels in individuals with early PTB, and the only pro-inflammatory marker that was over-expressed in such settings was IL-8. In such circumstances, the authors think that increased inflammation in concordance with a loss of tolerance may induce early fetal rejection. Moreover, the authors found that the local immunological profile of individuals with late PTB consists of high levels of IL-6, IL-8, and IL-1β, as well as C3b/iC3b, C5, IgE, and IgM. Such a profile is consistent with an infection-associated acute Th1 immune response at a mucosal interface, but the authors mostly failed to trace its origin to vaginal dysbiosis, only finding a

IL-8

IL-6

IL-1β

GM-CSF

IL-10

L. gasseri

L. jensenii

L. iners

L. crispatus

Figure 2: Cervicovaginal cytokines negatively correlate to Lactobacillus spp.

L. crispatus L. iners L. jensenii L. gasseri IL-10 GM-CSF IL-1β IL-6 IL-8

A Spearman multi-variable correlation was calculated for IL-1β, IL-6, IL-8, GM-CSF, and IL-10 with Lactobacillus crispatus, L. iners, L. jensenii, and L. gasseri.

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Figure 3: Most inflammatory markers exhibit significant sensitivity to predict preterm birth.

F AUROC=0.64 CI: 0.54–0.74

D AUROC=0.61 CI: 0.51–0.72 p=0.04

AUROC=0.66 CI: 0.56–0.66 p=0.0028

AUROC=0.54 CI: 0.43–0.66

AUROC=0.65 CI: 0.56–0.73

H AUROC=0.57 CI: 0.46–0.68

E AUROC=0.65 CI: 0.56–0.75

CI: 0.54–0.75

CI: 0.49–0.71 p=0.07

The levels at period B of cervicovaginal IL-10 (A), GM-CSF (B), IL-1β (C), IL-8 (D), IL-6 (E), C3b/iC3B (F), C5 (G), IgE (H), and IgM (I) were compared in individuals with preterm birth at both early and late stages to individuals with term birth to calculate the sensitivity of each marker. GM-CSF: granulocyte-monocyte colony-stimulating factor; AUROC: area under the receiver operating characteristic curve.

significant negative correlation of IL-1β with L. crispatus.28,29 Such an experiment was not able to confirm that IL-1β correlates with dysbiosis, because it did not seem to be negatively correlated to the other Lactobacillus species. However, most markers exhibited an enhanced ability to work as markers for prediction of PTBs. Interestingly, a shift from a tolerogenic Th2-type immune response to a Th1-type inflammation has been described as a phenomenon that occurs prior to delivery, and that is thought to induce changes at the maternal– fetal interface to induce labour.30,31 It has been shown that this shift, whenever it occurs during pregnancy, is able to induce labour, thus associating with PTBs and even miscarriage.32-34 Recent and pioneering research by Bezirganoglu-Altuntas et al.35 found that, while neutrophil-to-lymphocyte ratio and systemic immune inflammation CC BY-NC 4.0 Licence

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index are good predictors for PTBs, there is no specific marker to distinguish between early and late PTBs. And, to the authors’ knowledge, no other research efforts have been made in order to discover differences in the pathophysiology of early versus late PTB. In such an instance, this is, to their knowledge, the first report about distinctive traits for early versus late PTBs.

IMPLICATIONS FOR PRACTICE Although the role of inflammation, especially of IL-1β, IL-6, IL-8, TNF-α,36,37 C3b/iC3b, C5, and IgM, in the pathophysiology of PTB has been established,12 we currently lack much detail about the interplay between such markers and the specific timing for delivery. In such a context, the authors are unable to stratify the risk for PTB, and thus cannot calculate the urgency for interventions.

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Precision medicine is considered a powerful strategy to enhance treatment success, as it is derived from the integration of big data, AI, various omics, and the study of environmental and social factors, and its objective is to tailor treatments to subpopulations that present a common trait.38 In such an understanding, the discrimination of the mechanisms that may induce PTB either at early or late stages represents a valuable tool for precision medicine. Such distinction could enhance the efficacy of therapies that depend on the modulation of the aforementioned inflammatory markers, such as IL-6.39 Moreover, efforts to predict intra-amniotic infection and inflammation with non-invasive tests may benefit from the knowledge that not all the inflammatory mechanisms that drive preterm delivery work in the same way, or at the same timepoints during pregnancy.40

LIMITATIONS

Thus, the characterisation of distinctive inflammatory profiles for either early or late preterm deliveries may serve to 1) develop precise prognostic tests to assess and stratify the risk, and 2) develop tailored treatments with an enhanced ability to abrogate the pathophysiological mechanisms behind each type of preterm delivery, and thus be more effective at PTB prevention.

The inflammatory patterns for individuals presenting early PTB are radically different from those presenting late preterm deliveries. The first consists not only of enhanced inflammation, but also has elements suggestive of a loss of tolerance. On the other hand, the latter is characterised only by frank inflammation.

Although the authors measured the correlation between the inflammatory status and the vaginal microbiota, the present study is limited by the lack of information regarding the chorioamnionitis status. This hinders the potential for the interpretation of the findings. Moreover, all the individuals in the cohort were at risk of PTB, so the control group does not represent the baseline characteristics of a normal pregnancy. Finally, even when the sample was sufficient to find significant differences, the authors cannot assure that the sample is of adequate size; thus, the results shown here should be interpreted with care.

CONCLUSION

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12. Chan D et al. Microbial-driven preterm labour involves crosstalk between the innate and adaptive immune response. Nat Commun, 2022;13(1):975. 13. Conde-Agudelo A et al. Birth spacing and risk of adverse perinatal outcomes: a meta-analysis. Jama. 2006;295(15):1809-23. 14. Hendler I et al. The preterm prediction study: association between maternal body mass index and spontaneous and indicated preterm birth. Am J Obstet Gynecol. 2005;192(3): 882-6. 15. Durán-Méndez A et al. Tocilizumab reduces COVID-19 mortality and pathology in a dose and timingdependent fashion: a multi-centric study. Sci Rep. 2021;11(1):19728.

11. Florova V et al. Vaginal host immunemicrobiome interactions in a cohort of primarily African-American women who ultimately

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16. Mali SA et al. Robust multicentre detection and classification of colorectal liver metastases on CT: application of foundation models. NPJ Precis Oncol. 2026;DOI:10.1038/ s41698-026-01482-2. 17. Evans W et al. Precision medicineare we there yet? A narrative review of precision medicine's applicability in primary care. J Pers Med. 2024;14(4):418. 18. Sirota M et al.; March of Dimes Prematurity Research Centers. Enabling precision medicine in neonatology, an integrated repository for preterm birth research. Sci Data. 2018;5:180219. Erratum in: Sci Data. 2018;5(1):3. 19. Banerjee M et al. Microbial-driven preterm labour involves crosstalk between the innate and adaptive immune response. 2018. Available at: https://www.immport.org/ browser/?path=SDY1928&page=1. Last accessed: 7 August 2026. 20. Hazra A, Gogtay N. Biostatistics series module 6: correlation and linear regression. Indian J Dermatol. 2016;61(6):593-601. 21. Mor G, Cardenas I. The immune system in pregnancy: a unique complexity. Am J Reprod Immunol, 2010;63(6):425-33. 22. Mobini M et al. Significant roles played by interleukin-10 in outcome of pregnancy. Iran J Basic Med Sci. 2016;19(2):119-24.

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23. Mureanu N et al. The immunomodulatory role of regulatory T cells in preterm birth and associated pregnancy outcomes. Int J Mol Sci. 2024;25(22):11878.

31. Rackaityte E, Halkias J. Mechanisms of fetal t cell tolerance and immune regulation. Front Immunol. 2020;11:588.

24. La Rocca C et al. The immunology of pregnancy: regulatory T cells control maternal immune tolerance toward the fetus. Immunol Lett. 2014;162(1 Pt A):41-8.

32. Kareus E et al. The maternal-fetal interface as an immunological barrier: structure, regulation, and breakdown. Cell Rep. 2026;45(4):117164. 33. Sykes L et al. The Th1:th2 dichotomy of pregnancy and preterm labour. Mediators Inflamm. 2012;2012:967629.

25. Nold C et al. Granulocyte-macrophage colony-stimulating factor initiates amniotic membrane rupture and preterm birth in a mouse model. Am J Reprod Immunol, 2021;86(2):e13424.

34. Laird SM et al. A review of immune cells and molecules in women with recurrent miscarriage. Hum Reprod Update. 2003;9(2):163-74.

26. Nold C et al. Granulocyte macrophagecolony stimulating factor (GM-CSF) antibody prevents inflammationinduced preterm birth and effects on cervix remodeling using a mouse model. Am J Obstet & Gynecol. 2018;218(1):S404-5.

35. Bezirganoglu A et al. Can inflammatory markers predict the risk of preterm and early preterm birth in women with threatened preterm labor? J Matern Fetal Neonatal Med. 2025;38(1):2566235.

27. Elovitz MA et al. Cervicovaginal microbiota and local immune response modulate the risk of spontaneous preterm delivery. Nat Commun. 2019;10(1):1305.

36. Gilman-Sachs A et al. Inflammation induced preterm labor and birth. J Reprod Immunol. 2018;129:53-8. 37. Georges HM et al. Predictors of inflammation-mediated preterm birth. Physiology (Bethesda). 2025;40(1):0.

28. Jonani B et al. Immune responses to vaginal candidiasis in African women: a scoping review of cytokine profiles, T-cell activation, and gene expression. PLoS One. 2025;20(4):e0322072.

38. Naithani N et al. Precision medicine: concept and tools. Med J Armed Forces India. 2021;77(3):249-57.

29. Cornish EF et al. Innate immune responses to acute viral infection during pregnancy. Front Immunol. 2020;11:572567.

39. Valentine CJ et al. Higher-Dose DHA supplementation modulates immune responses in pregnancy and is associated with decreased preterm birth. Nutrients. 2021;13(12):4248.

30. Christiansen OB. A fresh look at the causes and treatments of recurrent miscarriage, especially its immunological aspects. Hum Reprod Update. 1996;2(4):271-93.

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40. Cobo T et al. Noninvasive prediction models of intra-amniotic infection in women with preterm labor. Am J Obstet & Gynecol. 2023;228(1):78.e1-3.

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The Little Fighter: Overcoming Severe Fetal Anaemia through 10 Intrauterine Blood Transfusions – A Case Report Authors:

*Tewodros Getahun Asfaw,1 Birhanu Kebede Dina,1 Yared Tesfaye Wube,1 Nejad Mohammed Omer,1 Tsegaye Legese Deme,1 Muleta Befkene Wayessa1 1. Department of Obstetrics and Gynecology, Yekatit 12 Hospital Medical College, Addis Ababa, Ethiopia *Correspondence to tedymen77@yahoo.com

Disclosure:

The authors have declared no conflicts of interest. The patient provided informed consent for the publication of this case report.

Acknowledgements

The authors would like to express their sincere gratitude to the management team and healthcare professionals involved in the care of this patient at Abebech Gobena Hospital, Addis Ababa, Ethiopia. Their dedication and teamwork were essential in ensuring optimal maternal and fetal outcomes. The authors also thank the mother for her consent to present this case, her cooperation in providing relevant information, and her commitment to consistent follow-up visits.

Received:

17.10.25

Accepted:

16.04.26

Keywords:

Ethiopia, exchange transfusion, fetal anaemia, intrauterine transfusion, Rh isoimmunisation.

Citation:

EMJ Repro Health. 2026;12[1]:150-156. https://doi.org/10.33590/emjreprohealth/635DG9WI

Abstract Background: Fetal anaemia is a serious obstetric complication associated with high perinatal morbidity and mortality, most commonly resulting from maternal red cell alloimmunisation or parvovirus B19 infection. Intrauterine blood transfusion (IUT), performed using a fine needle under continuous ultrasound guidance to deliver blood directly into the fetal circulation, most commonly through the umbilical vein at its placental insertion or via the intrahepatic portion, has revolutionised the management of fetal anaemia. In Ethiopia, Rh alloimmunisation remains relatively common, affecting 9.8–17.1% of RhD negative pregnant women; however, data on fetal anaemia prevalence are lacking. Case presentation: A 28-year-old G4P2A1 from Addis Ababa, Ethiopia, was referred to Abebech Gobena Mothers and Children's Health Hospital at 19 weeks gestation with Rh isoimmunisation: her blood group was O negative, while her partner’s blood group was O positive. Her history included one live birth, one miscarriage, and one stillbirth. The indirect Coombs test was positive, and weekly fetal surveillance using middle cerebral artery (MCA) Doppler was initiated. The first IUT was performed at 21 weeks when the MCA peak systolic velocity reached 1.577 multiple of the median. Fetal blood group and Rh (3rd IUT) was O positive; Direct Coombs test was not performed due to unavailability. Serial transfusions followed, with a total of 10 IUTs completed, the final one at 37 weeks. The decision to perform each IUT was based on elevated MCA peak systolic velocity multiples of the median values,

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indicating ongoing or recurrent fetal anaemia. At 38 weeks, a male neonate weighing 3,500g was delivered via Caesarean section with Apgar scores of 9 and 10 at 1 and 5 minutes, respectively. Postnatal assessment showed normal haematologic and bilirubin levels and normal echocardiography, with no need for exchange transfusion or phototherapy. Both mother and neonate were discharged in good condition. In this case, the decision to proceed with IUT beyond 34 weeks gestation was based on an individualised assessment of risks and benefits, as delivery at 34 weeks in the setting of a limited NICU facility was assessed to carry a higher risk of neonatal morbidity and mortality than continuation of pregnancy following fetal stabilisation. Accordingly, a deliberate fetal protective approach was adopted to optimise fetal survival and minimise overall risk, including the need for emergency neonatal resuscitation. Conclusion: This case demonstrates that late IUT performed at 37 weeks, followed by delivery at term (38 weeks), can result in a favourable neonatal outcome without the need for postnatal interventions. When conducted in experienced centres, late intrauterine transfusion appears to offer a promising strategy for improving outcomes in severely isoimmunised pregnancies.

Key Points 1. Fetal anaemia from Rh alloimmunisation remains a significant contributor to perinatal morbidity and mortality, particularly in low resource settings like Ethiopia, where prevalence among RhD negative pregnancies remains high. 2. This case report describes a 28-year-old multiparous woman with Rh isoimmunisation managed through 10 intrauterine transfusions, including late intervention at 37 weeks gestation. 3. Carefully selected late intrauterine transfusion beyond 34 weeks, guided by fetal monitoring and contextual resource considerations, may safely optimise neonatal outcomes and reduce the need for preterm delivery and postnatal interventions.

INTRODUCTION Haemolytic disease of the fetus occurs when there is red blood cell (RBC) incompatibility between a pregnant women and their fetus. This condition arises when maternal alloantibodies cross the placental barrier in sufficient quantities and bind to specific antigens on the surface of fetal RBCs, leading to fetal haemolysis and anaemia.1,2 Fetal anaemia is a significant obstetric complication that can lead to considerable perinatal morbidity and mortality. The most frequent aetiologies are maternal alloimmunisation and infection with parvovirus B19.3,4 Intrauterine transfusion (IUT) has revolutionised the management of fetal anaemia, and is performed using a fine needle under continuous ultrasound guidance to deliver blood directly into the

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fetal circulation, most commonly through the umbilical vein at its placental insertion or via the intrahepatic portion.5,6 A study conducted at Wolaita Sodo University, Ethiopia, reported that 12.08% of pregnant women were RhD-negative. Among these women, 9.8% were found to be alloimmunised, indicating that approximately one in 10 RhD-negative pregnant women had developed alloantibodies.7 Similarly, research carried out at Addis Ababa University revealed that the prevalence of RhD negativity and Rh alloimmunisation was 2.1% and 17.1%, respectively. These findings highlight a relatively high rate of alloimmunisation, with nearly one in five RhD-negative pregnant women affected.8

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ETHICAL REVIEW Institutional approval was obtained both for the study of the case and for the publication of this case report, in accordance with institutional guidelines. Approval was granted by the Institutional Review Board (IRB) of Yekatit 12 Hospital Medical College (Y12HMC). Written informed consent for publication of this case report and any accompanying images was obtained from the mother involved in the case.

CASE REPORT A 28-year-old G4P2A1 mother from Addis Ababa, Ethiopia, was referred from a local health centre to Abebech Gobena Hospital with a diagnosis of Rh isoimmunisation at 19 weeks of gestation. Her blood group was O negative, while her partner’s blood group was O positive. Her first pregnancy resulted in a healthy vaginal delivery 4 years ago. The second pregnancy ended in a miscarriage at 8 weeks of gestation,

and the third resulted in a stillbirth at 32 weeks for unknown reasons. Evaluation at the maternal fetal medicine unit showed a positive indirect Coombs test; Coombs titration was not performed due to limited resources. Fetal anatomy was normal on ultrasound, and serial assessments of the middle cerebral artery (MCA) peak systolic velocity (PSV) were conducted. The mother was followed for 2 weeks, and the first intrauterine transfusion was performed at 21 weeks when the MCA Doppler PSV reached 42.11 cm/s (1.577 multiples of the median [MoM]), as shown in Figure 1. The initial transfusion was carried out via the transperitoneal route, followed by a second IUT at 22 weeks and 3 days, and on follow-up 1 week later, the previously transfused peritoneal blood had been completely absorbed. At 25 weeks and 3 days of gestation, new onset minimal fetal ascites was detected and MCA Doppler was 2.0 MoM, as shown in Figure 2. A third IUT was then performed

Figure 1: MCA Doppler ultrasound at 21 weeks of gestation showing a peak systolic velocity of 42.11 cm/s, corresponding to 1.577 MoM.

MCA: middle cerebral artery; MoM: multiples of the median.

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Figure 2: Ultrasound sonogram at 25 weeks and 3 days of gestation showing fetal ascites (red arrow) in both transverse (A) and longitudinal (B) views.

Figure 3: Sonogram illustrates an intrauterine blood transfusion through intravascular access at the placental insertion site of the umbilical cord. The red arrow highlights the transfused blood jet, and the blue arrowhead marks the umbilical vein wall.

intravascularly through the umbilical vein at the placental cord insertion site, as shown in Figure 3. The pretransfusion haemoglobin and haematocrit levels were 5.5 g/dL and 14.5%, respectively. Fetal blood group and Rh were O positive; the Direct Coombs test was not performed due to unavailability. The procedure was continued, with the tenth and final IUT conducted at 37 weeks gestation. The decision to perform each IUT was based on elevated MCA-PSV MoM CC BY-NC 4.0 Licence

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values, indicating ongoing or recurrent fetal anaemia. A male infant weighing 3,500 g was delivered via Caesarean section at 38 weeks, with Apgar scores of 9 and 10 at 1 and 5 minutes, respectively. Postnatal haematocrit was 38.1%, haemoglobin 15.1 g/dL, and bilirubin levels were 1.7 mg/dL (direct) and 0.7 mg/dL (indirect). Echocardiography was normal. The neonate required no exchange transfusion or phototherapy and was supported with 2 L nasal continuous positive airway pressure

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Table 1: Summary of intrauterine transfusion procedures.

Round

Gestational age

MCA –PSV MoM

Route of IUT

Pretransfusion haematocrit

Volume of packed RBC transfused

Posttransfusion haematocrit

1st

21 weeks

1.58

Not done

30 mL

Not done

2nd

22+3 weeks

1.90

Not done

40 mL

Not done

3rd

25+3 weeks

2.00

15.0%

40 mL

22.3%

4th

26 weeks

1.80

13.0%

30 mL

23.0%

5th

26+4 weeks

1.60

20.0%

50 mL

32.0%

6th

28+6 weeks

1.70

23.2%

50 mL

8.0%

7th

30+6 weeks

1.60

27.4%

80 mL

45.7%

8th

32+6 weeks

1.50

There was umbilical vein bleeding, and the IUT was deferred

9th

33+6 weeks

1.80

26.6%

80 mL

38.3%

10th

35+3 weeks

1.50

26.1%

80 mL

39.4%

11th

37 weeks

1.50

23.8%

140 mL

37.5%

The required transfusion volume was determined using the Fetal Medicine Foundation online fetal anaemia calculator. IUT: intrauterine transfusion; IV: intravenous; MCA-PSV: middle cerebral artery peak systolic velocity; MoM: multiples of the median; RBC: red blood cell; TP: transperitoneal.

for oxygen saturations of approximately 86–90%, which improved progressively without further intervention. After 1 week of observation and stable follow-up, he was discharged in good condition. Details of the IUT are summarised in Table 1.

DISCUSSION To the best of the authors’ knowledge, this is the first reported case in Africa and the second worldwide following the case reported in Rio de Janeiro, Brazil, in which a fetus successfully underwent 10 intrauterine transfusion cycles and was delivered alive.9 IUT is commonly the treatment of choice for severe cases of Rh alloimmunisation, effectively preventing intrauterine death and achieving fetal survival rates of 60– 90%.10-12 However, the procedure is not without risk. IUT can promote the passage of fetal blood into the maternal circulation, 154

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potentially exacerbating the maternal immune response. Additional complications include hypercapnia, bradycardia, premature rupture of membranes, and umbilical cord bleeding, which can occasionally result in fetal death.13 In the authors’ case, umbilical cord bleeding occurred during the eighth intrauterine transfusion, necessitating the temporary discontinuation of the procedure; the IUT was repeated 7 days later and was successfully completed. In a single centre study at Leiden University Medical Center, the Netherlands, 254 fetuses underwent 740 intrauterine transfusions for maternal red cell alloimmunisation. The overall survival rate was 89%, with procedure-related complications at 9% (3.1% per procedure) and perinatal loss at 4.7% (1.6% per procedure).14 Similarly, at Kanuni Sultan Suleyman Research and Training Hospital in Istanbul, Türkiye, 110 intrauterine transfusions were performed in 42

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fetuses, with a post-transfusion survival rate of 80.95% and procedure-related complications in 12.7% of cases.15 A 5-year retrospective study conducted at St. Paul’s Hospital Millennium Medical College (SPHMMC), Ethiopia, found that among 21 fetuses who required intrauterine transfusion, the average number of transfusions per fetus was two, with a maximum of six transfusions administered to a single case. Nine cases (42.85%) received one transfusion. The earliest gestational age at the first IUT was 24+4/7 weeks, while the latest was 35 weeks. In most cases (61.9%), the IUT was performed between 29 and 33 weeks of gestation. Among the 20 live born neonates, all received phototherapy, and 15 (75%) required exchange transfusion.16 A case from Rio de Janeiro, Brazil, describes a neonate born to a 29-year-old woman who underwent 10 intrauterine transfusions starting at 21 weeks gestation for perinatal haemolytic disease. The male infant was delivered by Caesarean section at 34 weeks and 2 days, weighing 2,540 g. He developed respiratory distress managed with nasal continuous positive airway pressure, and received phototherapy, exchange transfusion, and immunoglobulin. Supraventricular tachycardia was treated with vagal manoeuvres and amiodarone. The infant was discharged in good condition after 13 days.9 Extending IUT beyond 34 weeks in selected cases appears safe and is associated with improved obstetric and neonatal outcomes. This approach did not result in an increase in procedure related complications and was linked to higher mean gestational age

References 1.

Dias M et al. Hemolytic disease of the fetus and newborn and Rhesus alloimmunization in Latin American countries: a scoping review. BMC Pregnancy Childbirth. 2024;24(1):634. de Winter DP et al. Hemolytic disease of the fetus and newborn: systematic literature re-view of the antenatal landscape. BMC Pregnancy Childbirth. 2023;23(1):12.

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at delivery, increased birth weights, and reduced rates of NICU admission.17-20 In this case, the decision to proceed with IUT beyond 34 weeks gestation was based on an individualised assessment of risks and benefits, as delivery at 34 weeks in the setting of a limited NICU facility was assessed to carry a higher risk of neonatal morbidity and mortality than continuation of pregnancy following fetal stabilisation. Accordingly, a deliberate fetal protective approach was adopted to optimise fetal survival and minimise overall risk, including the need for emergency neonatal resuscitation. Late IUT, particularly when performed close to delivery, gradually corrects fetal anaemia, avoids abrupt haemodynamic shifts, improves immediate postnatal adaptation, and reduces the likelihood of postnatal exchange transfusion, thereby lowering the risks of intraventricular haemorrhage, necrotising enterocolitis, pulmonary hypertension, metabolic acidosis, and infection.

CONCLUSION This single case experience demonstrated that late intrauterine transfusion performed at 37 weeks, followed by delivery at term (38 weeks), resulted in a favourable neonatal outcome, with no need for phototherapy or exchange transfusion. Late intrauterine transfusion, when performed in centres with substantial experience and expertise, appears to have the potential to improve the prognosis of severely isoimmunised fetuses.

Lindenburg ITM, van Kamp IL. Intrauterine blood transfusion: current indications and asso-ciated risks. Fetal Diagn Ther. 2014;36(4):263-71.

Prefumo F et al. Fetal anemia: diagnosis and management. Best Pract Res Clin Obstet Gy-naecol. 2019;58:2-14.

Bang J et al. Ultrasound-guided fetal intravenous transfusion for severe rhesus haemolytic disease. Br Med J (Clin Res Ed). 1982;284(6313):373-4.

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Socol ML et al. Percutaneous umbilical transfusion in severe rhesus isoimmunization: resolution of fetal hydrops. Am J Obstet Gynecol. 1987;157(6):1369-75.

Kebamo TE et al. Magnitude of red blood cell alloimmunization among pregnant women at-tending antenatal care at Wolaita Sodo University Comprehensive Specialized Hospital, Southwest Ethiopia. J Blood Med. 2023;14:663-9.

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Maruta MB et al. Prevalence and determinants of Rh alloimmunization in Rh-negative wom-en in teaching hospitals in Addis Ababa, Ethiopia. Front Glob Womens Health. 2023;4:1225015. Bittar RE et al. A case of hemolytic disease of the fetus with ten intrauterine blood transfu-sions. Abstract 0957. FMF World Congress, 21-25 June, 2015.

10. Plöckinger B et al. Diagnosis and treatment of fetal anemia due to isoimmunization. Arch Gynecol Obstet. 1994;255(4):195-200. 11. Ramírez-Robles LJ et al. [Intrauterine transfusion in Rh alloimmunization in Mexico 1987-2008]. Ginecol Obstet Mex. 2010;78(9):469-77. (In Spanish). 12. Newnham JP et al. Intrauterine intravascular transfusion for fetal

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haemolytic anaemia: the Western Australian experience. Med J Aust. 1992;157(10):660-4.

sectional study at a tertiary care hospital in Ethiopia. Int J Womens Health. 2023;15:571-8.

13. Baptista D et al. Intrauterine transfusion for Rhesus alloimmunization: a historical retrospective cohort from a single reference center in Brazil. J Clin Med. 2024;13(5):1362.

17. Cahen Peretz A et al. Late vs. early intrauterine blood transfusion in fetal anemia: impact on maternal and neonatal outcomes. Front Med (Lausanne). 2024;11:1335017.

14. van Kamp IL et al. Complications of intrauterine intravascular transfusion for fetal anemia due to maternal redcell alloimmunization. Am J Obstet Gynecol. 2005;192(1):171-7.

18. Pasman SA et al. Intrauterine transfusion for fetal anemia due to red blood cell alloimmunization: 14 years experience in Leuven. Facts Views Vis Obgyn. 2015;7(2):129-36.

15. Şavkli AÖ et al. Perinatal outcomes of intrauterine transfusion for foetal anaemia due to red blood cell alloimmunisation. J Obstet Gynaecol. 2019;40(3):330-4.

19. Cahen-Peretz A et al. Late intrauterine blood transfusion for fetal anemia. Ultrasound Obstet Gynecol. 2023;62(Suppl 1):148. 20. Youssefzadeh AC et al. Safety of intrauterine transfusion performed beyond 34 weeks of gestation. Prenat Diagn. 2024;44(13):1614-21.

16. Abdurahman Kureba A et al. Perinatal outcome of pregnant women with RhD sensitization: a five-year cross-

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Maternal and Fetal Outcome of COVID19-Positive Antenatal Women Treated with Monoclonal Antibody (Casirivimab and Imdevimab) in a Tertiary Care Centre: An Observational Cohort Study Authors:

S. Lakshmi Vinodh,1 *Jaimie T. Jacob,1 Aravind R.,1 Sreekumari R.,2 Anamika Francis3 1. Department of Obstetrics and Gynecology, Government Medical College, Thiruvananthapuram, India 2. Department of Obstetrics and Gynecology, Credence Hospital, Thiruvananthapuram, India 3. Department of Obstetrics and Gynecology, Dr Moopen's Medical College, Meppadi, India *Correspondence to jaimie.jacob@gmail.com

Disclosure:

The authors have declared no conflicts of interest.

Received:

23.03.25

Accepted:

04.06.26

Keywords:

Casirivimab (CAS), COVID-19, imdevimab (IMD), monoclonal antibody (mAb), pregnancy.

Citation:

EMJ Repro Health. 2026;12[1]:157-165. https://doi.org/10.33590/emjreprohealth/80BESKG8

Abstract Objective: To assess maternal and fetal outcomes of antenatal women who were COVID-19positive and treated with casirivimab and imdevimab (CAS+IMD) monoclonal antibodies. Methods: This was a prospective observational cohort study at the Government Medical College in Thiruvananthapuram, India, from 1st July 2021–30th September 2021. The exposed group comprised 73 high-risk antenatal women with mild–moderate COVID-19 who received CAS+IMD per Kerala State COVID-19 treatment guidelines. Historical controls comprised 40 high-risk antenatal women with mild–moderate COVID-19 who did not receive CAS+IMD. Disease severity and progression were assessed clinically and biochemically. Adjusted logistic regression accounting for baseline imbalances (diabetes) was performed. Results: Among controls, 17.50% had disease progression versus 5.48% in the exposed group (adjusted odds ratio: 0.24; 95% CI: 0.06–0.91; p=0.035). Oxygen requirement was 20.00% in controls versus 5.47% in the exposed group (adjusted odds ratio: 0.23; 95% CI: 0.06–0.88; p=0.031). Non-invasive ventilation was required for 12.50% of the controls versus 2.74% of the exposed group. Invasive ventilation was required for 5.0% of the controls, whereas it was not required for the exposed group. Newborn COVID-19 positivity occurred in 7.50% of controls versus 5.48% of the exposed group (p=0.670). No hypersensitivity reactions occurred in the exposed group. Conclusion: This study demonstrates the effectiveness and safety of monoclonal antibodies in preventing COVID-19 progression in high-risk antenatal patients. In this observational cohort study, CAS+IMD administration was associated with lower rates of COVID-19

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progression and oxygen requirement after adjusting for diabetes. However, residual confounding (including higher remdesivir use in the exposed group) and modest sample size preclude causal claims. Randomised or larger controlled studies are needed.

Key Points 1. Pregnant women with COVID-19 face heightened risk of severe disease. Monoclonal antibodies can reduce this severity, but previous monoclonal antibody data in pregnancy is limited to small, uncontrolled case series lacking a comparison group. 2. This prospective observational cohort study compared 73 high-risk antenatal women with mild–moderate COVID-19 treated with casirivimab and imdevimab against 40 historical controls who did not receive the drug. 3. Casirivimab and imdevimab administration in COVID-19 was associated with lower rates of disease progression and oxygen requirement, but residual confounding and modest sample size mean larger randomised studies are needed to confirm causality.

INTRODUCTION

potential to be transferred from the mother to the developing fetus, but the benefits or risks to the developing fetus are not known.

COVID-19 is a multisystem infectious disease caused by SARS-CoV-2.1 Multiple studies have shown that pregnant women, due to physiological changes in immunity, are susceptible to acquiring COVID-19 infection, with potential grave consequences.2 Neutralising monoclonal antibodies (mAb) targeting specific epitopes in the SARSCoV-2 spike protein have been shown to reduce hospitalisations in high-risk populations with the risk of progression to severe COVID-19.3 In November 2020, the FDA issued an Emergency Use Authorization (EUA) for the monoclonal antibody cocktail casirivimab and imdevimab (CAS+IMD) for the treatment of mild-to-moderate COVID-19 in patients at high risk of progression to severe disease.4 Due to acquired mutations in specific epitopes in the spike protein domain, Omicron-lineage variants are not neutralised by CAS+IMD. The approved dosage in India by the Central Drugs Standard Control Organization (CDSCO) for adults is 600 mg of CAS and 600 mg of IMD administered together either subcutaneously or as a single intravenous infusion.5 Injection site reactions and infusion-related reactions were the most commonly reported adverse events.6 As human IgG1 antibodies are known to cross the placental barrier, CAS+IMD has the 158

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Prior observational reports on the use of CAS and IMD in pregnancy have been limited to small retrospective case series and individual case reports without comparator groups. Thilagar et al.7 reported 51 pregnant women who received mAb therapy, describing no immediate adverse effects or disease progression, but lacked a control arm. Similarly, Hirshberg et al.8 and Mayer et al.9 provided preliminary safety data from small cohorts. The present study expands upon this prior experience by providing a prospective, comparative cohort analysis with a historical control group, thereby allowing preliminary assessment of effectiveness relative to standard care without mAb therapy. To the authors’ knowledge, this is the largest comparative cohort study of CAS and IMD in high-risk antenatal women with mild-to-moderate COVID-19. The authors’ study aimed to assess maternal and fetal outcomes of antenatal women who are COVID-19-positive with risk factors who were treated with this mAb cocktail.

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MATERIALS AND METHODOLOGY

•

The study was designed and conducted as a prospective observational cohort study with historical controls in the Department of Obstetrics and Gynaecology, SAT Hospital, Government Medical College Thiruvananthapuram (GMCT), India, from 1st July 2021–30th September 2021, after obtaining approval from the Institutional Research Committee and Human Ethics Committee (HEC NO:10/09/2021 MCT). The cohort comprised high-risk antenatal patients with COVID-19 confirmed either by molecular methods or rapid antigen tests. The exposed group comprised high-risk antenatal patients with mild-to-moderate COVID-19, who were administered CAS 600 mg and IMD 600 mg as a single-dose intravenous infusion per Kerala State guidelines. Historical controls (unexposed group) comprised high-risk antenatal patients with mild-to-moderate COVID-19 who had not been administered CAS+IMD.

•

Moderate: Respiratory rate between 24–29 /min, SpO2 91–94% on room air Severe: Respiratory rate ≥30 /min, SpO2 <90% on room air

mAbs (CAS and IMD) were administered early in the disease course to prevent progression in the highest-risk groups. mAbs were not administered to: (1) those requiring oxygen therapy due to COVID-19; (2) those on chronic oxygen therapy or requiring increased oxygen from baseline; or (3) those with >10 days from symptom onset.

Inclusion and Exclusion Criteria Inclusion criteria: •

Exposed group: high-risk antenatal women with mild– moderate COVID-19 who were administered CAS+IMD between 1st July 2021–30th September 2021. Unexposed group (historical controls): high-risk antenatal women with mild– moderate COVID-19 who had not been administered CAS+IMD.

•

Disease Severity Assessments

The clinical parameters for disease severity assessment were: • • • • • •

Hypoxia (SpO2 ≤94% on room air) Tachycardia (pulse rate >110/min) Respiratory distress (respiratory rate >24/min) Hypotension (blood pressure <90/60 mmHg) Altered sensorium PaO2/FiO2 <300 mmHg

The laboratory parameters for disease severity assessment were: • • • • • • •

C-reactive protein (CRP) >5 mg/L Creatinine phosphokinase >twice the upper limit of normal Ferritin >300 mcg/mL Lactate dehydrogenase (LDH) >400 U/L Troponin T elevation Elevated D-dimer >2.5 mg/dL Multi-organ dysfunction

COVID-19 disease severity categories:10 •

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Exclusion criteria: High-risk antenatal patients who did not give consent. Risk factors considered: Diabetes, systemic arterial hypertension, cardiovascular disease, pulmonary disease, chronic kidney disease, chronic liver disease, cancer, HIV, BMI >25 kg/m², and immunosuppressants or biologics.

Historical Controls: Definition and Temporal Context

The historical control group comprised consecutive high-risk antenatal patients with mild-to-moderate COVID-19 who presented to the authors’ institution between 1st April 2021–30th June 2021, immediately preceding the availability of CAS+IMD at their centre. The exposed group (also referred to as cases) were enrolled between 1st July–30th September 2021, after CAS+IMD became available under Kerala State guidelines. Both periods fell within the same delta variant surge in India. Controls were consecutive patients

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meeting the same inclusion/exclusion criteria as cases, except for CAS+IMD administration. No other changes occurred in institutional management protocols between the two periods. COVID-19 vaccination was available to all adults ≥18 years in India from 1st May 2021. So, vaccination was available during both periods. Vaccination status was recorded for all participants. After obtaining informed written consent, data for the exposed group were captured on a validated structured questionnaire. Control data were extracted from case records. Both groups were followed up to 6 weeks postpartum. Privacy and confidentiality were maintained.

Statistical Analysis

Data were coded and analysed using IBM SPSS Statistics for Windows version 25 (IBM, Armonk, New York, USA). Descriptive analysis was performed. Categorical variables were compared using chi-square or Fisher’s exact test, and continuous variables using the t-test or Mann–Whitney U test. To address baseline imbalances between groups, multivariable logistic regression was performed for two primary outcomes: (1) COVID-19 disease progression; and (2) oxygen requirement. Covariates were selected in advance based on clinical relevance and baseline differences (diabetes, symptomatic status, disease severity, and remdesivir use). Due to limited outcome events (11 for progression, 12 for oxygen requirement), final adjusted models included only the most imbalanced covariate (diabetes) to avoid overfitting. Adjusted odds ratios (aOR) with 95% CI are reported. A two-sided p value <0.05 was considered statistically significant. A total of 73 cases and 40 controls were studied.

RESULTS During the study period, CAS+IMD was administered to 73 high-risk antenatal women with mild-to-moderate COVID-19. The historical control group comprised 40 such patients who did not receive mAb. 160

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Most patients were symptomatic at diagnosis (84.93% of cases versus 47.5% of controls). Asymptomatic patients (15.07% of cases, 52.2% of controls) were diagnosed via screening before delivery or due to high-risk exposure. Among cases, 82.20% were aged <30 years and 17.80% were aged ≥30 years; in controls, 75% were <30 years and 25% were ≥30 years. At the time of COVID-19 diagnosis, 84.93% of cases and 95.00% of controls were at a gestational age of >28 weeks, whereas 15.07% of cases and 5.00% of controls were diagnosed at <28 weeks (Table 1). Primigravidas constituted 52.05% of the cases and 55.00% of the controls. Regarding vaccination status, 61.64% of cases and 45.00% of controls were unvaccinated, 28.77% of cases and 40.00% of controls had received one dose, and 9.59% of cases and 15.00% of controls had received two doses. Disease severity at presentation was mild in 72.60% of cases and 87.50% of controls, while moderate disease was observed in 27.40% of cases and 12.50% of controls (p=0.068). Diabetes was more prevalent among cases than controls (72.60% versus 30.00%, p=0.00). mAb was administered within 4 days of symptom onset in 78.08% of cases (57/73) and at ≥4 days in 21.91% (16/73). Remdesivir was given to 73.97% of cases and 30.00% of controls. Steroids were not administered in 50.69% of cases and 67.50% of controls. Cumulative methylprednisolone dose >400 mg was given in 6.84% of cases and 5.00% of controls (Table 1). For laboratory markers, among cases, 16.43% had elevated LDH, 16.43% had elevated CRP, and 35.61% had elevated D-dimer before mAb. Among controls, 7.5% had elevated LDH, 35.0% had elevated CRP, and 35.0% had elevated D-dimer. After mAb administration, D-dimer normalised in 93.15% of cases. Chest X-ray had abnormal findings in 23.29% of cases (before mAb) and in 5.00% of controls (Table 1).

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Table 1: Comparison of maternal characteristics in cases and controls.

Maternal characteristics

Cases (n)

Percentage (%)

Controls (n)

Percentage (%)

Age (years) <30

82.20

75.0

≥30

17.80

25.0

Primigravida

52.05

55.0

Multigravida

47.95

45.0

<28 Weeks

15.07

5.0

≥28 Weeks

84.93

95.0

Vaccinated

38.36

55.0

Unvaccinated

61.64

45.0

Symptomatic

84.93

47.5

Asymptomatic

15.07

52.5

Mild

72.60

87.5

Moderate

27.40

12.5

<30

80.82

85.0

≥30

19.18

15.0

Yes

72.60

30.0

27.40

70.0

Yes

21.91

37.5

78.09

62.5

<2.5 mg/dL

64.39

65.0

≥2.5 mg/dL

35.61

35.0

Obstetric score

Gestational age

SARS-CoV-2 vaccination status

COVID-19 symptoms

Disease severity

BMI (kg/m²)

Diabetes

Hypertension

D-dimer before mAb

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Table 1: Comparison of maternal characteristics in cases and controls (Continued).

Maternal characteristics

Cases (n)

Percentage (%)

Controls (n)

Percentage (%)

LDH before mAb <400 IU/L

83.57

92.5

≥400 IU/L

16.43

7.5

<5 mg/dL

83.57

65.0

≥5 mg/dL

16.43

35.0

Abnormal

23.29

5.0

Normal

76.71

95.0

50.69

67.5

<200 mg

36.99

12.5

200–400 mg

5.50

15.0

400–1,200 mg

4.11

5.0

>1,200 mg

2.73

Yes

73.97

30.0

26.03

70.0

CRP before mAb

Chest X-ray findings

Concomitant drugs - Steroids No Yes

Remdesivir

CRP: C-reactive protein; LDH: lactate dehydrogenase; mAb: monoclonal antibody.

Primary Outcomes

Disease progression occurred in 17.50% of controls versus 5.48% of cases. After adjusting for diabetes, the protective effect of monoclonal antibody administration against disease progression remained significant (adjusted odds ratio [OR]: 0.24, 95% CI: 0.06–0.91, p=0.035; Table 2). Oxygen was required in 5.47% of cases compared with 20.00% of controls. The adjusted OR for oxygen requirement was 0.23 (95% CI: 0.06–0.88; p=0.031; Table 2). 162

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Among those requiring oxygen, 12.5% of controls needed non-invasive ventilation and 5.0% invasive ventilation. Among cases, 2.74% required non-invasive ventilation, and none required invasive ventilation (Table 3). Newborn COVID-19 positivity was 7.50% in controls versus 5.48% in cases (p=0.670; Table 2).

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Table 2: Outcome variables.

Outcome

Exposed (n=73)

Unexposed (n=40)

Crude OR (95% CI)

Adjusted ORa (95% CI)

p valueb

COVID-19 disease progression

4 (5.48%)

7 (17.5%)

0.27 (0.07–0.98)

0.24 (0.06–0.91)

0.035

Oxygen requirement

4 (5.48%)

8 (20.0%)

0.23 (0.06–0.83)

0.23 (0.06–0.88)

0.031

Newborn COVID-19 positive

4 (5.48%)

3 (7.5%)

0.72 (0.15–3.37)

0.670

Adjusted for diabetes. p value statistically significant at 5.0% level by using chi-square test.

NA: not applicable; OR: odds ratio.

DISCUSSION On 14th May 2021, the FDA included pregnancy as a qualifying condition for anti-spike mAbs. Guidelines from the National Institutes of Health (NIH), American College of Obstetricians and Gynecologists (ACOG), and Society for Maternal-Fetal Medicine (SMFM) have included pregnant women with risk factors as eligible for mAb therapy.11,12 However, widespread adoption was limited by a lack of clinical data in pregnancy. Available data are limited to retrospective case series and case reports.7-9 These studies suggested that anti-spike mAbs may prevent progression to severe disease in antenatal patients, with no observed adverse events. However, none included a control group. The authors’ study is the first prospective comparative cohort study of CAS and IMD in high-risk pregnant women with COVID-19. In the authors’ study, mAb administration was associated with less disease progression (5.48% versus 17.50%; adjusted odds ratio: 0.24; p=0.035) and lower oxygen requirement (5.47% versus 20.00%; adjusted OR: 0.23; p=0.031). These associations persisted after adjustment for diabetes. Thilagar et al.7 reported no COVID-19 progression in 51 pregnant women receiving mAb, but lacked a comparator.7 The authors’ study extends this by including a control group.

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The higher frequency of remdesivir use in the exposed group (73.97% versus 30.00%) represents a potential confounder that could independently influence outcomes. Although the authors adjusted for diabetes, they could not adjust for remdesivir due to limited outcome events. Therefore, their results should be interpreted as demonstrating an association rather than causation. After mAb administration, D-dimer normalised in 93.15% of cases, suggesting that mAb may reduce inflammatory markers. Newborn COVID-19 positivity did not differ significantly between groups (p=0.670). No hypersensitivity reactions occurred, consistent with prior reports. However, the total number of exposed pregnant women in the literature remains small, precluding firm conclusions about safety. A cost-effectiveness analysis by Ruggeri et al.13 suggested that mAbs may reduce costs and hospital resource use, but the study did not focus on pregnant women. The authors’ institution provided free care, so cost-effectiveness was not assessed.

Limitations •

Observational design with historical controls carries risk of temporal bias, and the authors attempted to minimise this by defining a clear control period before mAb availability and confirming no other protocol changes.

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Table 3: Comparison of oxygen requirement.

Mode of oxygen support

Cases (n)

Percentage (%)

Controls (n)

Percentage (%)

Nasal

2.74

2.5

NIV

2.74

12.5

Invasive ventilator

5.0

No support

94.52

80.0

Total

100.00

100.0

NIV: non-invasive ventilation.

•

Substantial baseline imbalance in remdesivir use (73.97% in cases versus 30.00% in controls) could partly explain better outcomes in the exposed group. Due to small event numbers, the authors could not adjust for remdesivir. Modest sample size and few outcome events (11 for progression, 12 for oxygen) precluded extensive multivariable adjustment or propensity score matching. Residual confounding by other unmeasured factors (e.g., socioeconomic status, timing of presentation) cannot be excluded. Neonatal outcomes beyond SARSCoV-2 status (birth weight, preterm delivery, neonatal ICU admission, respiratory morbidity, breastfeeding) were not systematically collected. The study was conducted during the delta wave, so the findings do not apply to Omicron sublineages, which are not neutralised by CAS and IMD.

References 1.

164

In this prospective observational cohort study, administration of CAS and IMD was associated with reduced COVID-19 progression and lower oxygen requirement in high-risk antenatal patients after adjusting for diabetes. Nevertheless, due to the observational design, modest sample size, and higher concomitant remdesivir use in the exposed group, causal claims of effectiveness cannot be made. The findings suggest a potential benefit that warrants confirmation in larger, randomised, or better-controlled studies. Comprehensive neonatal follow-up should be included in future research. Moreover, CAS and IMD do not neutralise Omicron sublineages, limiting generalisability to current variants.

coronavirus 2 infection in Washington State. Am J Obstet Gynecol. 2021;225(1):77.e1-14.

Cascella M et al., Features, Evaluation, and Treatment of Coronavirus (COVID-19) [Internet] (2020) Treasure Island: StatPearls. Available at: https://www.ncbi.nlm.nih.gov/books/ NBK554776/. Last accessed: 4 August 2022. Lokken EM et al. Disease severity, pregnancy outcomes, and maternal deaths among pregnant patients with severe acute respiratory syndrome

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Magawa S et al. Evaluation of the tolerability of monoclonal antibody therapy for pregnant patients with COVID-19. J Obstet Gynaecol Res. 2022;48(9):2325-33.

Deeks ED. Casirivimab/imdevimab: first approval. Drugs. 2021;81(17):2047-55.

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Central Drugs Standard Control Organisation (CDSCO). List of new drugs (r-DNA origin) approved for import and marketing in India for the Year 2021. Available at: https://cdsco.gov.in/opencms/ resources/UploadCDSCOWeb/2018/ UploadBiologicalrDNA/FormCT-20%20 forthe%20year202%20till02.07.2021. pdf. Last accessed: 26 July 2022.

Brobst B, Borger J. Benefits and risks of administering monoclonal antibody

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therapy for coronavirus (COVID-19) [Internet] (2023) Treasure Island: StatPearls. Available at: https://www. ncbi.nlm.nih.gov/books/NBK574507/. Last accessed: 26 October 2022. 7.

Thilagar BP et al. Anti-Spike monoclonal antibody therapy in pregnant women with mild-tomoderate coronavirus disease 2019 (COVID-19). Obstet Gynecol. 2022;139(4):616-8.

Hirshberg JS et al. Monoclonal antibody treatment of symptomatic COVID-19 in pregnancy: initial report. Am J Obstet Gynecol. 2021;225(6):688-9.

Mayer C et al. Monoclonal antibodies casirivimab and imdevimab in

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pregnancy for coronavirus disease 2019 (COVID-19). Obstet Gynecol. 2021;138(6):937.

12. Society for Maternal-Fetal Medicine (SMFM). Management considerations for pregnant patients with COVID-19. 2021. Available at: https://s3.amazonaws.com/cdn. smfm.org/media/2734/SMFM_COVID_ Management_of_COVID_pos_preg_ patients_2-2-21_(final).pdf. Last accessed: 9 September 2022.

10. Government of Kerala. COVID-19: Treatment Guidelines for Kerala State, Version 3. 2021. Available at: https://dhs.kerala.gov.in/wpcontent/uploads/2021/04/GuidelinesTreatment-Protocol-April-2021merged.pdf. Last accessed: 10 August 2022.

13. Ruggeri M et al. Casirivimab and imdevimab: cost-effectiveness analysis of the treatment based on monoclonal antibodies on outpatients with Covid-19. PLoS One. 2023;18(2):e0279022.

11. American College of Obstetricians & Gynecologists (ACOG). COVID-19 FAQs for obstetrician-gynecologists, obstetrics. Available at: https:// www.acog.org/clinical-information/ physician-faqs/covid-19-faqs-for-obgyns-obstetrics. Last accessed: 14 November 2022.

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Rupture in an Unscarred Uterus: A Rare but Catastrophic Obstetric Emergency Authors:

Parthasarathi Mitra,1 *Antara Chatterjee,1 Dristy Majhi,1 Shreya Adhikari,1 Rahul Patra1 1. Department of Obstetrics and Gynecology, Medical College and Hospital, Kolkata, India *Correspondence to antara9847@gmail.com

Disclosure:

The authors have declared no conflicts of interest. Informed consent was obtained from the patient for the publication of this case report.

Received:

20.11.25

Accepted:

04.06.26

Keywords:

Abdominal pregnancy, live baby, maternal mortality, obstetric emergency, placenta accreta spectrum, ruptured uterus, unscarred uterus.

Citation:

EMJ Repro Health. 2026;12[1]:166-171. https://doi.org/10.33590/emjreprohealth/RFAC188G

Abstract Introduction: Uterine rupture is a rare, life-endangering complication in obstetrics, which is accompanied with high fetal and maternal morbidity and mortality, and occurs most commonly in women with a prior uterine scar, typically from a Caesarean section. However, the incidence of unscarred uterine rupture is extremely rare and poses unique diagnostic and management challenges due to its unpredictability and rapid clinical deterioration. Case Report: Here is a case report on presentation and outcome of a case of rupture in a previously unscarred uterus in the third trimester. Placenta accreta spectrum, a recognised risk factor for uterine rupture, is uncommon in an unscarred uterus. This case has been considered for presentation due to its rarity, co-existence with placenta accreta spectrum, diagnostic dilemmas, and immediate surgical intervention, which led to the most favourable yet unexpected feto-maternal outcome evidenced by real-time photographs supplemented herewith. Discussion: Risk factors for uterine rupture include high parity, uterotonic misuse, obstructed labour, uterine anomalies, connective tissue disorders, placenta accreta spectrum, and traumatic deliveries. Symptoms often manifest abruptly with sudden abdominal pain, fetal distress, vaginal bleeding, and signs of hypovolemic shock. Diagnosis may be clinical or assisted by imaging, though often confirmed intraoperatively. Perinatal mortality remains high and maternal morbidity includes haemorrhage, need for hysterectomy, and end organ damage. Conclusion: This case report may throw some light on how high clinical suspicion, even in low-risk patients, is essential.

Key Points 1. Uterine rupture and placenta accreta spectrum can occur even in an unscarred uterus, although it is a rare event, with significant risks to both mother and the fetus.

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2. In cases of spontaneous uterine rupture, early recognition and immediate surgical intervention are critical to improve maternal survival, reduce morbidity, and improve fetal outcome. In this case, it was observed that a timely intervention led to a successful live delivery followed by the recovery of the mother. 3. A high index of suspicion should be maintained, even in women without conventional risks factors such as previous Caesarean section or uterine surgery.

INTRODUCTION

CASE DESCRIPTION

Uterine rupture is a rare but serious emergency in obstetrics, typically associated with a scarred uterus from previous Caesarean delivery or other uterine surgeries like myomectomy.1 Unprovoked rupture of an unscarred uterus, particularly in the third trimester, is an exceptionally uncommon event, with an estimated incidence of one in 8,000 to one in 15,000 deliveries,2 with higher rates reported in low-resource settings.3 Despite its rarity, it carries significant risks of maternal haemorrhage, fetal compromise, and even mortality if not promptly diagnosed and managed.4

A 40-year-old lady, G2P1A0L1, at 31 weeks 5 days of gestation, was admitted in the Department of Obstetrics and Gynecology after being referred from a peripheral hospital with complains of abdominal pain for 5 days in a suspected case of placenta previa. The pregnancy was spontaneously conceived and antenatal checkups had been uneventful. She had no history of previous Caesarean section, uterine surgery, trauma, or known uterine anomaly. There were also no significant medical or obstetric comorbidities. Ultrasonographies done during antenatal visits were not suggestive of any abnormal lie of the fetus.

The clinical presentation is often nonspecific, ranging from abdominal pain and abnormal fetal heart patterns to signs of hypovolemic shock,5 making early recognition challenging. Known risk factors include high parity, uterine overdistension, obstructed labour, misuse of uterotonics, and trauma;3,6 however, in some instances, no predisposing factors are identified. Most of the cases of uterine rupture are associated with fetal demise, and the rate can be as high as 50–75%, especially in unscarred uterine ruptures or in settings with delayed access to emergency care.4 This case report highlights a rare instance of placenta accreta spectrum causing rupture of an unscarred uterus in the third trimester, underscoring the imperative of maintaining vigilant clinical suspicion, even in low-risk patients, and emphasising the critical role of timely surgical intervention in optimising maternal outcome and delivery of a live fetus from the abdominal cavity.

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On admission, the patient was haemodynamically stable with a BP of 120/70 mmHg, pulse rate of 88/min, and without any pallor. Abdominal examination revealed loss of uterine contour with no tenderness, and the fetal parts were palpable superficially. Fetal heart sound was present and regular, 144 bpm. An ultrasound revealed free fluid in the peritoneal cavity, suggestive of haemoperitoneum, and the presence of fetal cardiac activity in the abdominal cavity outside the uterus. Given the clinical suspicion of uterine rupture, the patient was immediately taken up for emergency laparotomy under general anaesthesia. Intraoperatively, approximately 1 L of haemoperitoneum was noted. A complete rupture of the uterine wall was identified at the fundus of the uterus with the fetus entirely in the abdominal cavity and placenta densely adhered to the fundus of the uterus posteriorly, invading the myometrium with its lower end partially covering the internal os. A live male fetus weighing 1,880 grams was delivered from the left paracolic gutter (Figure 1). An attempt to separate the placenta failed, and an obstetric

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Figure 1: Delivery of a live baby from the left paracolic gutter.

hysterectomy was done (Figure 2). The gross sample of uterus along with the placenta was sent for histopathological examination. The patient received two units of packed red blood cells and other supportive management postoperatively. She was monitored in the high dependency unit for a period of 7 days and she made an uneventful recovery. The baby was kept in the NICU for watchful observation and was free from any morbidity.

DISCUSSION Uterine rupture is a critical obstetric emergency that typically occurs in the context of a previously scarred uterus, most commonly due to prior Caesarean section. However, rupture of an unscarred uterus is exceedingly rare, particularly in the third trimester, and presents significant 168

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diagnostic and management challenges. The present case highlights a spontaneous rupture in an unscarred uterus, in a preterm pregnancy with no identifiable risk factors, emphasising the unpredictable nature of this condition. The incidence of unscarred uterine rupture is estimated at one in 8,000 to one in 15,000 pregnancies.2 The known risk factors include high parity, uterine anomalies, excessive use of uterotonic agents, obstructed labour, external trauma, and connective tissue disorders like Ehlers-Danlos syndrome.3,6 Nevertheless, cases without any predisposing factors, such as the one presented here, have been documented, raising concerns for idiopathic nature. Clinical presentation is often subtle and nonspecific, with symptoms such as abdominal pain, cessation of contractions, vaginal bleeding, or signs of hypovolemic shock.5

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Figure 2: Obstetric subtotal hysterectomy.

Loss of uterine contour, palpable fetal parts, and absence of fetal heart sounds are alarming signs. In this case, the patient complained of moderate abdominal pain, and a differential diagnosis of rupture was presumed after institutional ultrasonography, which was later confirmed intraoperatively. Prompt recognition and immediate surgical intervention are vital to minimise adverse maternal and fetal outcomes. Intraoperative findings often include haemoperitoneum and complete uterine wall disruption, with the fetus possibly expelled into the peritoneal cavity. Uterine repair may be attempted if feasible, and if the patient is haemodynamically stable. In other instances, hysterectomy may be required,7 as in this case. This case is unique in its presentation, as the uterine rupture happened at the fundus of an unscarred uterus with no specific symptoms of uterine rupture and without fetal demise. The histopathological CC BY-NC 4.0 Licence

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examination revealed placenta previa with placenta increta. The rupture of the unscarred uterus could possibly be due to the invasion of the placenta into the myometrium (placenta accreta spectrum), leading to thinning of the myometrium and causing rupture. The survival of the fetus could possibly be justified due to the inseparable placenta densely adhered to the uterus, which probably maintained circulation and blood supply via the umbilical cord. Contrary to the age-old belief of 100% fetal demise in abdominal pregnancy secondary to ruptured uterus, a live baby was delivered from the peritoneal cavity, which was not only rare but also made the case reportable. This case also underlines the importance of sustained clinical alertness for uterine rupture, even in women without typical risk factors. Early diagnosis, rapid resuscitation, and timely surgical management are the keys to favourable outcomes. Additionally, counselling regarding future pregnancies

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and delivery planning is essential, given the increased risk of recurrence. Various cases of uterine rupture have been reported worldwide. Nevertheless, this presentation is exceptionally rare, with only few cases with similar combination of findings documented in the literature. A nationwide population-based cohort study conducted in the Netherlands to assess the incidence of uterine rupture in scarred and unscarred uteri, and its maternal and fetal complications, concluded that 13% of the ruptures occurred in unscarred uteri and 72% occurred during spontaneous labour, and were associated with severe maternal and neonatal morbidity and mortality.8 In a study by Locher et al.,9 the sole potential risk factor was a closed adhesion of the small intestine to the left sacrouterine ligament, indicating persistent inflammation. The authors found that lateral damage to an unscarred uterus increases the likelihood of maternal and fetal problems following rupture. Hence, for the patients presenting with unusual pain, cautious monitoring is important. In another case report, a complete rupture of the posterior wall of the uterus with partial avulsion of the left ovary following induction of labour was noted. The patient underwent subtotal hysterectomy with left salpingectomy. The baby died in utero. The patient’s history of previous medical termination of pregnancies via curettage, resulting in an undiagnosed perforation, may have put her at higher risks. She also had induction of labour for her current pregnancy, which increased her risk.10 Another case was reported in which a primigravida with an unscarred uterus was admitted with preterm pre-labour membrane rupture at 36+4 weeks of gestation, abnormal fetal heart sounds, and sudden onset of severe abdominopelvic pain. Rupture happened before the initiation of regular uterine contractions and without any interventional oxytocin. Despite the immediate Caesarean birth, the newborn showed signs of severe acidosis. 170

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This example emphasises the significance of keeping a high level of suspicion for uterine rupture, even in the unusual scenario of a primigravida with an unscarred uterus. This case also demonstrates a possible link between prelabour rupture of membranes and placental abruption.11 Guèye et al.,12 concluded that the clinical indicators of uterine rupture during pregnancy can be misleading and ambiguous. It can be difficult to differentiate it from other abdominal problems such as pancreatitis, gallstones, and appendicitis. They also found that high parity was a significant risk factor for spontaneous uterine rupture.12 In another instance, a 34-year-old primigravid lady who was 31+3 weeks pregnant got an acute abdomen and preeclampsia. After an emergency laparotomy, the cause of the incident was determined to be a uterine rupture. There was a stillborn girl. The placenta's pathological investigation revealed abruption, which may have contributed to this serious obstetrical problem, along with the pregnancy's potential cornual or angular location.13 Miller et al.,14 in 1997, conducted a retrospective study to examine risk factors, as well as maternal and neonatal outcomes, in 10 cases of intrapartum rupture of unscarred uterus. They concluded that although intrapartum rupture of unscarred uterus is a rare obstetric emergency, the maternal and perinatal outcomes can be optimised by awareness of risk factors, recognition of clinical signs and symptoms, and prompt surgical intervention. A study conducted by Al-Zirki et al.15 in Norway, to follow trends of uterine rupture over a period of 40 years, concluded that there was a sharply increasing trend of uterine rupture associated with obstetric interventions like augmentation with oxytocin, scarred uterus from a previous Caesarean section, and labour induction with prostaglandins or prostaglandins combined with oxytocin. However, the study could not explain the association entirely.15

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CONCLUSION Spontaneous rupture of an unscarred uterus in the third trimester is an extremely rare but potentially fatal obstetric emergency. Placenta accreta spectrum, although rare in unscarred uteri, can manifest as an important risk factor for rupture in such cases. This case highlights the need for clinicians to maintain a high degree of clinical suspicion, even in low-risk patients with no identifiable predisposing factors. Early recognition, prompt surgical intervention,

and appropriate postoperative care are crucial in improving maternal outcomes. Contrary to the age-old idea of 100% fetal demise in secondary abdominal pregnancy, a live baby was delivered from the peritoneal cavity, which was not only rare but also made the case reportable. Furthermore, this case reinforces the importance of postpartum counselling and careful monitoring in subsequent pregnancies due to increased risk of recurrence in case of preservation of the uterus.

References

Schrinsky DC et al. Rupture of the pregnant uterus: a review. Obstet Gynecol Surv. 1978;33(4):217-32.

Walsh CA et al. Rupture of the primigravid uterus: a review. Obstet Gynecol Surv. 2007;62(5):327-34.

Sun HD et al. Spontaneous uterine rupture in the third trimester of pregnancy: a case report and review of the literature. Taiwan J Obstet Gynecol. 2008;47(4):423-6.

Nanda S et al. Spontaneous rupture of unscarred uterus in a term pregnancy: a rare presentation. J Obstet Gynaecol India. 2017;67(Suppl 1):63-5.

Berhe Y et al. Rupture of the unscarred uterus. Obstet Gynecol Surv. 1999;54(7):415-21.

Gibbins KJ et al. Maternal and fetal morbidity associated with uterine rupture of the unscarred uterus. Am J Obstet Gynecol. 2015;213(3):382.e1-6.

Ofir K et al. Uterine rupture: risk factors and outcomes. Am J Obstet Gynecol. 2003;189(4):1042-6.

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11. Mourad WS et al. Spontaneous rupture of unscarred uterus in a primigravida with preterm prelabour rupture of membranes. BMJ Case Rep. 2015;2015:bcr2014207321. 12. Mamour G et al. Spontaneous uterine rupture of an unscarred uterus before labour. Case Rep Obstet Gynecol. 2012;2012:598356.

Zwart JJ et al. Uterine rupture in the Netherlands: a nationwide populationbased cohort study. Am J Obstet Gynecol. 2009;201(6):578.e1-8.

13. Lotte P et al. Uterine rupture in a primigravid patient: a case report. J Med Case Rep. 2017;11:339.

Locher S et al. Spontaneous rupture of an unscarred uterus in a woman at 37 weeks of pregnancy: a case report. Am J Obstet Gynecol Glob Rep. 2022;2:100082.

14. Miller DA et al. Uterine rupture associated with maternal trauma. Am J Obstet Gynecol. 1997;177(4):906-11. 15. Al-Zirqi I et al. Uterine rupture: trends over three decades in a populationbased study. BJOG. 2016;123(5):780-7.

10. Alhubaishi F et al. Uterine rupture in an unscarred uterus: a case report. Crit Care Obst Gyne. 2021;7(5):44.

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Cervical Cytology in Women with Chronic Kidney Disease Authors:

*Winrose Kirui,1 Keitany Kibet,2 Philiph Tonui1 1. Department of Reproductive Health, Moi University, School of Medicine, Eldoret, Kenya 2. Pathology Department, Moi Teaching and Referral Hospital, Eldoret, Kenya *Correspondence to winrosekirui@gmail.com

Disclosure:

The authors have declared no conflicts of interest. The protocol of this study was sought and obtained by Moi University/MTRH IREC Approval reference no. 0004224 and Institution approval from MRTH administration.

Received:

13.10.25

Accepted:

01.07.26

Keywords:

Cervical cytology, chronic kidney disease (CKD), Moi Teaching and Referral Hospital (MTRH).

Citation:

EMJ Repro Health. 2026;12[1]:172-180. https://doi.org/10.33590/emjreprohealth/A62QV9ZQ

Abstract Background: The prevalence of chronic kidney disease (CKD) has been increasing globally (9.1%) and in Kenya (10.6%). There is emerging evidence of an increased risk of cervical dysplasia and cervical cancers in patients with CKD. Cervical cancer screening is part of secondary prevention of cervical cancer that leads to early detection and treatment of premalignant lesions. Despite the high prevalence of CKD, little is known about the patterns and prevalence of cervical cytological abnormalities in this subset of the population in Moi Teaching and Referral Hospital (MTRH), Eldoret, Kenya. Aims: This study aimed to determine the prevalence of abnormal cervical cytology, describe the cervical cytology patterns, and factors associated with abnormal cervical cytology among women with and without CKD at MTRH. Methods: This was a hospital-based cross-sectional study that systematically sampled 176 women (59 with CKD and 117 without CKD) seen at Chandaria Dialysis Unit, Renal Outpatient and Gynecology Outpatient Clinics of MTRH. Data were collected using a structured interviewer-administered questionnaire. Participants who consented underwent cervical cancer screening by conventional Pap smear, and cytological patterns were reported. Categorical variables were summarised as frequencies and percentages, while continuous variables were summarised using means with standard deviation or median with corresponding interquartile ranges. Associations between socio-demographic, obstetric, and clinical characteristics were tested by bivariate analysis using chi-square or Fisher’s exact test, and significance was set at a p value ≤0.05. Variables with a p value of <0.05 were included in the multivariable analytic model, and results were presented as odds ratios and 95% CIs. Results: The prevalence of abnormal cervical cytology was 16.9% in women with CKD and 7.8% in those without CKD. The commonest abnormal cytology pattern in both groups was atypical squamous cells of undetermined significance, with 8.5% occurring in women with CKD and 3.4% in those without CKD. 172

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On multivariable logistic regression analysis, factors that were significantly associated with abnormal cervical cytology included age less than 50 years (adjusted odds ratio [AOR]: 2.74; CI: 0.305–9.289; p=0.029), presence of CKD (AOR: 2.76; CI: 0.980–7.708; p=0.050), multiparity (AOR: 4.42; CI: 0.990–21.07; p=0.006), and lack of tertiary education (AOR: 2.10; CI: 0.649– 8.693; p=0.018). Conclusions: An association was observed between CKD and abnormal cervical cytology, with a higher prevalence of cytological abnormalities among women with CKD. Atypical squamous cells of undetermined significance were reported as the most prevalent abnormality in both groups. Factors associated with abnormal cytology were age <50 years, multiparity, having CKD, and having no tertiary education.

Key Points 1. Women with chronic kidney disease (CKD) had more than double the prevalence of abnormal cervical cytology compared with women without CKD (16.9% versus 7.8%), suggesting this population may benefit from enhanced cervical cancer screening. 2. Atypical squamous cells of undetermined significance were the most frequently observed cytological abnormality in both groups, with higher rates among women with CKD than those without CKD. 3. CKD, age younger than 50 years, multiparity, and lack of tertiary education were independently associated with abnormal cervical cytology, highlighting groups that may warrant prioritised screening and follow-up.

BACKGROUND Chronic kidney disease (CKD) is a major global health problem whose prevalence continues to rise due to increasing rates of hypertension, diabetes, and the use of nephrotoxic herbal medicines. The risk of malignancy increases with the severity of CKD, with kidney transplant recipients showing the highest susceptibility to cancer.1 Although kidney transplantation is the most definitive treatment for end-stage kidney disease (ESKD), dialysis remains the most common modality of renal replacement therapy.2 CKD is defined as an estimated glomerular filtration (eGFR) rate <60 mL/ min/1.73m2. Individuals with CKD are further classified into Stages 1–5 according to the Kidney Disease: Improving Global Outcomes (KDIGO) 2024 guideline as listed below: • Stage 1: kidney damage with normal glomerular filtration (GFR; 90 mL/ min/1.73m2) • Stage 2: mild kidney damage with decreased GFR (60–89 mL/min/1.73m2) • Stage 3: moderately decreased GFR (30–59 mL/min/1.73m2) CC BY-NC 4.0 Licence

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• Stage 4: severely decreased GFR (15–29 mL/min/1.73m2) • Stage 5: ESKD (<15 mL/min/1.73m2) The plasma creatinine value can be used to determine the risk of CKD, as it will approximately double with a 50% reduction in GFR. For example, a rise in plasma creatinine from a baseline value of 0.6 mg/ dL to 1.2 mg/dL in a patient, although still within the adult reference range, actually represents a loss of 50% of functioning nephron mass. In this study, however, those already diagnosed with CKD and on follow-up at renal, dialysis, and kidney transplant outpatient clinics were recruited and sampled. The CKD-EPI Creatinine Equation (2021), the recommended method for estimating GFR in adults by the National Kidney Foundation, estimates GFR from serum creatinine, age, and sex with more accuracy in people with higher levels of GFR. Expressed as a single equation: eGFRcr = 142 x min(Scr/κ, 1)α x max(Scr/κ, 1)1.200 x 0.9938Age x 1.012 [if female]

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where: Scr: standardised serum creatinine in mg/dL κ: 0.7 (females) or 0.9 (males) α: -0.241 (female) or -0.302 (male) min(Scr/κ, 1) is the minimum of Scr/κ or 1.0 max(Scr/κ, 1) is the maximum of Scr/κ or 1.0 Age (years)

METHODS

Cervical cancer, meanwhile, is the fourth most common cancer among women globally, with about 660,000 new cases and 350,000 deaths reported in 2022.3 In Kenya, cervical cancer contributes to 12.9% of new cancer cases and 11.8% of cancer deaths annually, making it the leading cause of cancer-related mortality among women.4 Human papillomavirus (HPV) infection accounts for 99.7% of cervical cancers, predominantly HPV Types 16 and 18.5 Regular screening using cytology or HPV testing remains crucial, particularly among immunocompromised populations, such as those with CKD.6

The study population consisted of 176 women (59 with CKD and 117 without) aged 21–65 years, who presented for follow-up treatment, and those who came for routine screening and met inclusion eligibility criteria for cervical cancer screening by Pap smear.

Despite the prevalence of CKD and cervical cancer in Kenya, there is limited research examining the relationship between CKD and abnormal cervical cytology in this context. Women with CKD are at a higher risk of cervical dysplasia and malignant cervical lesions due to immunosuppression and comorbidities.7 However, screening uptake among women with CKD remains low in low- and middle-income countries. In Kenya, CKD prevalence among medical inpatients has been reported at 10.6%, reflecting a significant disease burden.8 The paucity of local data on the prevalence and cytological patterns of cervical abnormalities among patients with CKD limits the development of targeted preventive strategies and screening guidelines.

AIMS The main objective of this study was to determine the prevalence of abnormal cervical cytology, describe cervical cytological patterns, and identify factors associated with abnormal cervical cytology among women with and without CKD attending Moi Teaching and Referral Hospital (MTRH), Eldoret, Kenya. 174

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This study was conducted at MTRH. This was a hospital-based, analytical crosssectional study to determine cervical cytology amongst women with and without CKD at MTRH.

The sample size was calculated using Fleiss’ formula for comparing two proportions. Based on previous literature reporting a prevalence of abnormal cervical cytology of approximately 27.5% among women with CKD and 9.2% among women without CKD, with 95% confidence level and 80% power, a minimum sample size of 157 participants was obtained. After adjustment for a 10% non-response rate and inadequate cytology specimens, the final sample size was increased to 176 participants. Systematic random sampling was used to select eligible participants. The estimated number of patients with CKD yearly in MTRH between 21–65 years was about 548. The authors then divided the sample size of 59, which therefore led to selecting every ninth patient for the CKD group. On the other hand, the gynaecological patients without CKD were estimated to be about 480 yearly divided by 117 to get every fourth woman in the non-CKD group. Patients were recruited after they gave consent to undergo Pap smears. The Bethesda Pap smear system 2014 was used to report cervical cytology results in this study. This system has been shown to have 85% sensitivity and 90–99% specificity in detecting cervical dysplasia. Its false-negative rate is estimated to be 20%. The majority of false-negative results come from sampling error (60%) and screening error (40%). This study used the conventional Pap smear preparation technique due to its availability.

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Pap smear collection: the slides were labelled with a pencil with the proper patient initials and identifiers on the frosted end of the glass before beginning the procedure. Verbal consent was taken, and the procedure was explained to the patient. Patients were put in the lithotomy position. The vulva was cleaned aseptically. A Cusco speculum was then placed to visualise the cervix using warm saline as lubricant. If the cervix was coated with excessive mucus, inflammatory debris, blood, or other contaminants, a swab with saline was used to remove obscuring substances that will make the smear unsatisfactory for interpretation without disturbing the surface epithelium. The transformational zone or squamocolumnar junction of the cervix were identified (point where the endocervical columnar epithelium and squamous epithelium of the ecto-cervix meet). A cervical spatula was first rotated at 360 degrees near the squamocolumnar junction to scrape the ectocervix and endocervix and smeared on a glass slide. A cytobroom was also used and the central bristles inserted into the endocervix with the outer bristles in contact with the ectocervix; the broom was rotated in the same direction for five turns then smeared in the slide. The slides were fixed in 95% ethyl alcohol solution. Patients were then reassured and counselled on cramping and vaginal bleeding after the procedure. The pap smears were done on a daily basis, and results were reported within 3 weeks according to the Bethesda system 2014. The Pap smear results were conveyed to the patients when they came for their return date reviews in their various clinics, either renal or gynaecology clinics. For those whose results were abnormal, counselling was done by the principal investigator, and the patients were linked to further care and interventions within the dysplasia clinic depending on the results. Cytology slides will be stored for 10 years before being discarded, according to MTRH’s standard of operation for archiving biopsy blocks, slides, and reports in histology. CC BY-NC 4.0 Licence

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Data analysis was done using SPSS version 26.0 (IBM, Armonk, New York, USA). Categorical variables such as parity, comorbidities, and use of immunosuppressant drugs were summarised as frequencies and their corresponding percentages. Continuous variables such as age were summarised using means/ median and their corresponding standard deviation/interquartile ranges using the Mann-Whitney U test. Bivariate analysis was done using the chi-square test and Fisher’s exact test where chi-square assumptions failed. Results were presented as p values, where a p value of ≤0.05 was considered statistically significant. Multivariate analysis was done using logistic regression; results were presented as odds ratios with their corresponding CIs.

FINDINGS Prevalence of Abnormal Cervical Cytology in Women With and Without CKD at MTRH

The overall prevalence of abnormal cervical cytology was 10.9%. Women with CKD had a higher prevalence of 16.9% compared to women without CKD, 7.8% (Table 1). The commonest abnormal cytology was atypical squamous cell of undetermined significance (ASCUS) at 5.1% overall. ASCUS was reported at 8.5% (5/59) among women with CKD and 3.4% (4/116) in women without CKD. The low-grade squamous intraepithelial lesions (LSIL) abnormal cytology accounted for 5.1% (3/59) in women with CKD and 1.7% (2/116) in women without CKD. High-grade squamous intraepithelial lesions (HSIL) were reported at 3.4% (2/59) among CKD women and 1.7% (2/116) among women without CKD (Table 2). The mean age at CKD onset among those with abnormal cytology was 40.1 years versus 33.4 years for those with normal cytology (p=0.119). Diabetes was associated with more abnormal cytology (30.8%) than hypertension (10.2%), with statistical significance (p=0.008). Though systemic lupus erythematosus (33.3%) and

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Table 1: Socio-demographic, clinical, and reproductive characteristics of women with and without CKD at MTRH.

CKD

CKD No N=116

Yes N=59

Total N=175

Parity

p value 0.022

Nulliparous

11 (9.5%)

13 (22.0%)

24 (13.7%)

Multiparous

105 (90.5%)

46 (78.0%)

151 (86.3%)

Number of lifetime sexual partners

0.841

Single

65 (56.0%)

34 (57.6%)

99 (56.6%)

Multiple

51 (44.0%)

25 (42.4%)

76 (43.4%)

Contraceptive

0.041

46 (39.7%)

33 (55.9%)

79 (45.1%)

Yes

70 (60.3%)

26 (44.1%)

96 (54.9%)

Type

0.343

Injectables

18 (25.7%)

11 (42.3%)

29 (30.2%)

Implants

33 (47.1%)

8 (30.8%)

41 (42.7%)

COCs

14 (20.0%)

6 (23.1%)

20 (20.8%)

Others

5 (7.1%)

1 (3.8%)

6 (6.3%)

Age

0.236

Mean (SD)

42.2 (12.1)

39.9 (13.2)

41.4 (12.5)

Range

21–65

Education

0.075

None/primary

30 (25.9)

9 (15.3)

39 (22.3)

Secondary

36 (31.0)

28 (47.5)

64 (36.6)

Tertiary

50 (43.1)

22 (37.3)

72 (41.1)

CKD: chronic kidney disease; COC: combined oral contraceptives; SD: standard deviation; MTRH: Moi Teaching and Referral Hospital.

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chronic glomerulonephritis cases showed higher abnormal cytology rates, these were not statistically significant (p=0.266 and p=0.169, respectively).

prednisolone had abnormal cytology, but this too lacked significance (p=0.313; Table 3).

Patients undergoing dialysis had more abnormal cytology (15.6%) compared to none among transplant recipients, with a significant association (p=0.002). Immunosuppressive regimens including tacrolimus, cyclosporine, mycophenolate mofetil, and steroids were not significantly associated with abnormal cytology (p values >0.3). One participant on

Women with CKD were two times more likely to have abnormal cervical cytology compared to women without CKD, with a significant p value (AOR: 2.762; CI: 0.980–7.708; p=0.05). Factors found to be significantly associated with abnormal cervical cytology were age less than 50 years (AOR: 2.74; CI: 0.305–9.289; p=0.029). Women with no education or

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Table 2: Factors associated with abnormal cytology.

Cervical cytology Normal

Abnormal

N=156

N=19

p value

CKD

0.065

107 (92.2%)

9 (7.8%)

Yes

49 (83.1%)

10 (16.9%)

Age

0.019

Over 50

104 (94.5%)

6 (5.5%)

Below 50

52 (80 %)

13 (20%)

Parity

0.001

Nulliparous

24 (100%)

0 (0.0%)

Multiparous

132 (87.4%)

19 (12.6%)

Lifetime sexual partners

0.086

Single

92 (92.9%)

7 (7.1%)

Multiple

64 (84.2%)

12 (15.8%)

Education level

0.038

None/primary

32 (82.1%)

7 (17.9%)

Secondary

55 (85.9 %)

9 (14.1%)

College/tertiary

69 (95.8 %)

3 (4.2 %)

lower-level education, such as primary, were two times more likely to have abnormal cytology compared to women with college and secondary education (AOR: 2.012; CI: 0.649–8.693; p=0.018). Multiparous women were four times more likely to have abnormal cervical cytology than nulliparous women (AOR: 4.428; CI: 0.99–21.07; p=0.006).

DISCUSSION This study evaluated cervical cytology through the use of Pap smears, as it remains a highly accessible and cost-effective screening tool. This allowed the study to reflect real-world conditions where molecular testing is not readily available while global public health is shifting towards the use of HPV detection due to its superior sensitivity. Australia is on track to eliminate cervical cancer as a public health problem by 2035 by implementing a dual approach through high HPV vaccination rate and HPV screening.

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Prevalence of Abnormal Cervical Cytology

Cervical cancer remains a major public health issue in Kenya, causing 12.2% of all cancer cases and over 3,591 deaths in 2022.4 It accounts for about 3% of post-transplant malignancies, second only to skin cancer in female transplant recipients.8 A study in Denmark found that women with CKD or on dialysis had a higher likelihood of abnormal cytology than the general population.9 In this study, the prevalence of abnormal cervical cytology in women with CKD was 16.9%, compared to 7.8% in those without CKD. This trend may be linked to immunosuppression and chronic inflammation in CKD, impairing HPV clearance and increasing cytological abnormalities. A study at Kenyatta National Hospital, Nairobi, Kenya, reported a comparable prevalence of 12.5%,10 likely due to similar screening approaches and geographical setting. An Ohio study found

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Table 3: Multivariate logistic regression analysis.

Factor

AOR

95% CI

p value

Ref

Yes

2.762

0.980–7.708

0.050

Over 50

Ref

Below 50

2.740

0.305–9.289

0.029

College/university

Ref

None/primary

2.102

0.649–8.693

0.018

Secondary

0.985

0.030–4.221

0.059

Nulliparous

Ref

Multiparous

4.428

0.99–21.07

0.006

Single

Ref

Multiple

0.908

0.054–1.208

0.419

Yes

0.406

0.503–1.000

0.975

Ref

Absent

Ref

Present

0.870

0.221–1.111

0.649

CKD

Age

Education

Parity

Number of sexual partners

RRT

Underlying conditions

AOR: adjusted odds ratio; CKD: chronic kidney disease; RRT: renal replacement therapy.

a higher prevalence (27.5%), possibly due to more frequent screenings per protocol over time.11

age group, including adolescents more prone to transient HPV infections.12

Patterns of Abnormal Cytology

The most common abnormality in this study was ASCUS, found in 8.5% of CKD participants, followed by LSIL (5.1%), and HSIL (3.4%). In contrast, non-CKD women showed ASCUS (3.4%), LSIL (1.7%), HSIL (0.9%), and one case of microinvasive disease. This pattern mirrors findings in a USA study of transplant candidates, where ASCUS was most common.11 However, a study in Türkiye showed LSIL was more frequent, likely due to a younger participant 178

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Factors Associated with Abnormal Cytology

Women with CKD were significantly more likely to have abnormal cytology (AOR: 2.762; CI: 0.980–7.708; p=0.05), consistent with findings by Atılgan et al.,12 where patients with CKD had a threefold higher risk of preinvasive lesions due to immune dysfunction. Conversely, Haberal et al.13 found no such association, likely due to a smaller sample size.

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Age below 50 was also associated with more abnormalities (AOR: 2.740; CI: 0.305– 9.289; p=0.029), aligning with Chaung et al.’s11 study. However, Dalgaard et al.’s9 findings showed a higher risk among women aged 50–64, attributed to better healthseeking behaviours in a well-supported healthcare system. Women with no or primary education had significantly more abnormalities (AOR: 2.012; CI: 0.649–8.693; p=0.018), a trend echoed in Zambia, where tertiary education reduced the risk of abnormal cytology.14 Low education may limit awareness and access to screening. Multiparity was significantly associated with abnormal cytology (AOR: 4.428; CI: 0.99– 21.07; p=0.006), likely due to increased HPV exposure and cervical trauma. This finding is supported by studies in Kenya and Indonesia, although contradicted by Bilgi et al.,16 who found no such link.10,15,16 Lastly, patients undergoing dialysis had more abnormalities (15.6%) than transplant recipients (0%), significant in bivariate but not multivariate analysis. This aligns with Kasiske et al.,17 who noted more cervical abnormalities in patients who underwent dialysis. References 1.

Małyszko J et al. KDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantation. Kidney Int. 2020;98(6):1407-18.

Limitations of the Study

This was a cross-sectional study, and therefore the cause and effects of the risk factors described could not be established. This was a single-centre study, and therefore the results can only be generalised to other similar-level facilities and not to the general population.

CONCLUSIONS Women with CKD have a higher association of abnormal cervical cytology compared to women without CKD at MTRH. ASCUS was the commonest cytology pattern among women with CKD. Factors associated with abnormal cervical cytology were women having CKD, women below the age of 50 years, multiparous women, and women with no or primary education. Increasing cervical cancer screening surveillance among women with CKD, multiparous women, women less than 50 years old, and women with no tertiary education, with frequent follow-up could reduce the high risk of abnormal cervical cytology among this group.

Chesumbai GC et al. Cancer Incidence In Uasin-Gishu County. AMPATH Oncology Institute. 2024;DOI:10.13140/ RG.2.2.19551.84643.

Stengel B. Chronic kidney disease and cancer: a troubling connection. J Nephrol. 2010;23(3):253.

Vajdic CM et al. Cancer incidence before and after kidney transplantation. JAMA. 2006;296(23):2823-31.

Courtney AE et al. The uptake of cervical cancer screening by renal transplant recipients. Nephrol Dial Transplant. 2009;24(2):647-52.

Gultekin M et al. World Health Organization call for action to eliminate cervical cancer globally. Int J Gynecol Cancer. 2020;30(4):426-7.

Sung H et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-49.

Skov Dalgaard L et al. Risk of human papillomavirus-related cancers among kidney transplant recipients and patients receiving chronic dialysis: an observational cohort study. BMC Nephrol. 2013;14(1):137.

World Health Organization (WHO). Human papillomavirus vaccines: WHO position paper. Wkly Epidemiol Rec. 2009;84(15):118-31.

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11. Chaung KV et al. Risk factors for abnormal cervical cytology in women undergoing kidney transplant evaluation. Exp Clin Transplant. 2019;17(1):31-6. 12. Ok Atılgan A et al. Papanicolaou smear findings in solid-organ transplant recipients compared with normal subjects according to the Bethesda 2001 system. Exp Clin Transplant. 2015;13(Suppl 1):S219-22. 13. Haberal AN et al. Pap smear findings in chronic renal failure patients compared with the normal population according to Bethesda 2001. Diagn Cytopathol. 2008;36(11):776-9. 14. Hamoonga ET. Predictors of abnormal cervical lesions among women (1549 years old) in Zambia: a crosssectional study (Doctoral dissertation). [AS1.1]Lusaka: The University of Zambia;2015.

10. Masinde MS. Prevalence of cervical cytological abnormalities and human papilloma virus infection among renal transplant recipients at Kenyatta National Hospital (Doctoral dissertation). Nairobi: University of Nairobi;2015.

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15. Kusuma F et al. Socio-demographic profiles of cervical cancer patients at Cipto Mangunkusumo Hospital, 20092019, and its association with cancer stages at diagnosis. Cermin Dunia Kedokt. 2022;49(5):245-7.

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16. Bilgi A et al. Cervical dysplasia after renal transplantation: a retrospective cohort study. Turk J Obstet Gynecol. 2021;18(1):7-14.

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17. Kasiske BL et al. Cancer after kidney transplantation in the United States. Am J Transplant. 2004;4(6):905-13. 18. Wilbur DC, Nayar R. Bethesda 2014: improving on a paradigm shift. Cytopathology. 2015;26(6):339-42.

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