Elisabet Stener-Victorin, Felice Petraglia, Carlo La Vecchia, and Adam Balen
Infertility Among Healthcare Professionals: A Comprehensive Review Editor's Pick:
Editorial Board 07 Welcome 09 Foreword
Congress Review
10 Review of the European Society of Human Reproduction and Embryology (ESHRE) 40th Annual Meeting, 7th–10th July 2024
Congress Features
23 Editor in Chief’s Highlights from ESHRE 2024 Justin Chu
26 Does Dual and/or Double Trigger Improve IVF Success?
Victoria Antoniou
30 Endometriosis, Endometrial Disorders, and Infertility: From Bench to Bedside Abigail Craig
Abstract Review
34 Tacrolimus Treatment Improved Pregnancy Rate with Euploid Blastocyst in Women with Repeated Implantation Failures and Elevated T Helper 1/2 Cell Ratios Nakagawa et al.
37 Abstract Highlights Congress Interview
42 Karen Sermon
Interviews 45 Elisabet Stener-Victorin 49 Felice Petraglia
52 Carlo La Vecchia 55 Adam Balen
Articles
61 Editor's Pick: Infertility Among Healthcare Professionals: A Comprehensive Review
Richard et al.
69 Colposcopic and Histopathologic Comparative Interpretations Among Patients Undergoing Evaluation for Cervical Dysplasia in Western Kenya
Hassan et al.
75 Fetomaternal Outcomes of Low-Risk Females Presenting with Perceived Reduced Fetal Movements at Moi Teaching and Referral Hospital, Eldoret, Kenya
Chege et al.
83 A Case of Caudal Regression Syndrome From Pakistan
Zameer et al.
88 Fetomaternal Outcomes of Venous Thromboembolism in Pregnancy at Moi Teaching and Referral Hospital, Eldoret, Kenya
Odhiambo et al.
"ESHRE welcomed 11,647 registered participants from 134 countries across the globe"
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
Shterev Hospital, Bulgaria
Dr Melihan Bechir
Columna Medical Center, Romania
Dr Arianna D'Angelo
Wales Fertility Institute, Cardiff University, UK
Dr Monica Muratori
University of Florence, Italy
Dr Galia Oron
Ruth & Bruce Faculty of Medicine, Israel
Dr Kristo Ausmees
Medita Clinic, Estonia
Dr Mátyás Benyó
University of Debrecen, Hungary
Dr Antonio Simone Laganà
University of Palermo, Italy
Dr Ioana Rugescu
Safety and Quality Specialist, Romania
Prof Eduard Ruiz-Castañé
Fundació Puigvert, Spain
Dr Georgios-Sprirodon (George) Anifandis
University of Thessaly, Greece
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.
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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.
Editorial staff have final discretion over any proposed amendments.
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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 2024) and the use of the organisations does not constitute endorsement or media partnership in any form whatsoever. The cover photo is of Amsterdam, the Netherlands, the location of ESHRE 2024.
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Welcome
Dear Readers,
Welcome to this issue of EMJ Reproductive Health, which covers all the exciting developments presented at the European Society of Human Reproduction and Embryology (ESHRE) 40ᵗʰ Annual Meeting. We are delighted to feature the key highlights from this event, including studies on risks associated with pregnancy loss, predictors of success in in vitro fertilisation, and all the latest advancements in assisted reproduction. Be sure not to miss our Editor-in-Chief’s highlights, showcasing the key sessions and findings from the event.
Among the peer-reviewed content is a study from Kenya investigating fetomaternal outcomes of low-risk females presenting with perceived reduced fetal movements, which compares two commonly used diagnostic tools in predicting immediate fetal outcomes in this population. Additionally, we feature a review examining infertility among male and female healthcare professionals, aiming to identify the factors leading to infertility.
In closing, I extend my gratitude to all our contributors, peer reviewers, and Editorial Board for bringing this highly engaging content together, and to the EMJ team for ensuring its timely publication. As always, we welcome your feedback and ratings on our website and look forward to receiving your manuscripts until the next issue!
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Evgenia Koutsouki
Foreword
Welcome back to the latest issue of EMJ Reproductive Health, which presents a selected range of peer-reviewed articles and interviews with field experts, focusing on polycystic ovary syndrome, endometriosis, and reproductive cancers.
This year was the 40th anniversary of the European Society of Human Reproduction and Embryology (ESHRE) Annual Meeting, hosted in Amsterdam, the Netherlands from the 7th–10th July 2024. In this issue, we share the key highlights from ESHRE, which became a meeting place for debate, discussion, and the presentation of new data in the field of fertility. Our review of the Annual Meeting brings you the most significant content from the event, coupled with impactful abstracts and features.
The EMJ team had the pleasure of speaking to various experts in the field, including ESHRE President Karen Sermon, who spoke about the unique challenges associated with providing reproductive healthcare, the impactful initiatives ESHRE has implemented, and her vision for the future of the organisation.
We have selected five peer-reviewed articles for inclusion in this issue, covering aspects of both obstetrics and gynaecology. These include articles investigating pregnancy outcomes from women presenting with reduced fetal movements, obstetric outcomes in women diagnosed with venous thromboembolism in pregnancy, and the accuracy of colposcopic findings in women with cervical dysplasia. Finally, an interesting article is presented exploring the link between infertility and healthcare professionals, which is my Editor’s Pick.
ESHRE became a meeting place for debate, discussion, and the presentation of new data in the field of fertility
I have now been in my role as Editorin-Chief for the past 12 months and I wish to thank all the authors, reviewers, and Editorial Board members for their contributions to this fantastic issue of EMJ Reproductive Health. Enjoy!
Justin Chu
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
ESHRE 2024
ESHRE welcomed 11,647 registered participants from 134 countries across the globe
Congress Review
Review of the European Society of Human Reproduction and Embryology (ESHRE)
WITH its scenic canals and rich history, Amsterdam is a vibrant city and popular travel destination for people across the globe. This year it was also home to the 40th Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE), taking place from 7th–10th July. The event gathered experts, researchers, and practitioners from various parts of the world to share and discuss the latest advancements in reproductive health and embryology.
The opening ceremony was a time of celebration and reflection of all the advancements in the field, and activity of the society in the past year. Karen Sermon, Chair of ESHRE, took the stage, marking several staggering statistics. This year, for instance, ESHRE welcomed 11,647 registered participants (93% in-person and 7% virtual) from 134 countries across the globe. Predominately, attendees come from Europe (57%), followed by Asia (26%), America (11%), and more recently Africa (4%) and Oceania (2%). This figure speaks to the global reputation ESHRE upholds, and the epicentre of its Annual Meeting is for the field of reproductive health and embryology.
As with all congresses, abstract sessions constitute a key component of the programme and are an exciting opportunity to showcase the latest innovations in the field. For ESHRE, this was no exception. With a staggering 2,218 abstracts submitted, a record-breaking figure for the society, this year’s itinerary was packed with a diverse collection of research, ranging in topics from reproductive
endocrinology and fertility preservation, to the ethics and law of reproductive medicine. Intriguing scientific findings discussed at ESHRE include a study identifying a familial endocrine disease linked to an increased risk of pregnancy loss. Moreover, for the first time, researchers have identified patterns of risk for several different types of cancer in men with fertility problems and their families.
Christina Bergh, University of Gothenburg, Sweden, was subsequently recognised as an honourary member of ESHRE, praised for her work as a researcher, educator, clinician, registry expert, and significant contributor to the society. The second ESHRE honorary member, Hans Evers, Professor of Obstetrics and Gynaecology, Maastricht University Medical Centre, the Netherlands, also took the stage, reflecting on his career and research endeavours.
Amidst the awards, the opening ceremony additionally featured a highly entertaining show from Victor Mids, an illusionist and doctor. He engaged the audience through
This clever trick illustrated how easily choices can be influenced and manipulated, providing a thought-provoking interlude
several memory tests, illustrating the use of misdirection and illusion each time. In one exercise, Mids asked an individual from the audience which cup to ‘use’ or ‘get rid of’; one marked an ‘X’ and one without. Mids, as instructed by the audience member, crushed the cup with no ‘X’, later revealing that the ‘X’-marked cup contained a razor underneath. As the actions ‘use’ and ‘get rid of’ have not been specified, the magician could have crushed either cup upon request, whilst maintaining that the audience member made the correct choice. This clever trick illustrated how easily choices can be influenced and manipulated, providing a thought-provoking interlude that blended entertainment with psychological insight.
In conclusion, the 40th Annual Meeting of ESHRE in Amsterdam, the Netherlands, was a resounding success, reflecting the society's ongoing commitment to advancing reproductive health and embryology. The event not only showcased the latest research and innovations but also celebrated the achievements of the global reproductive health community. With its engaging sessions and diverse participation, the 2024 ESHRE Annual Meeting will be remembered as a milestone in the field. For more detailed highlights and insights from the congress, read on.
Familial Endocrine Diseases Linked to Increased Risk of Pregnancy Loss
THE RISK of pregnancy loss could be 6% higher in female patients with a family history of endocrine diseases such as Type 2 diabetes and polycystic ovarian syndrome, according to research presented at the 40th ESHRE Annual Meeting.
The study, from Copenhagen University Hospital Hvidovre, Denmark, examined the data of 366,539 patients and found that women with parents or siblings diagnosed with endocrine diseases had a higher risk of pregnancy loss. Specifically, the risk of pregnancy loss increased by 6% for women with a parental history of endocrine diseases and by 7% if a sister had an endocrine disease.
The study also demonstrated that women with endocrine diseases had a significantly higher risk of experiencing multiple pregnancy losses. Women with one pregnancy loss had a 15% higher risk of having another, those with two losses had a 30% higher risk, and the risk increased to 81% for those with three or more losses.
The lead author, Pia Egerup, Copenhagen University Hospital Hvidovre, Denmark, suggested that a shared genetic background, specifically involving highrisk human leukocyte antigens, could predispose individuals to both endocrine diseases and pregnancy loss. This connection is a previously underexplored risk factor in pregnancy loss, leaving space for further investigation.
It remains pertinent to remember that recurring pregnancy loss affects 2–5% of women and is accompanied by a significant psychological and emotional burden. Future investigations into the genetic mechanisms underlying this association could be key for
The risk of pregnancy loss increased by for women with a parental history of endocrine diseases and by if a sister had an endocrine disease 7% 6 %
both predicting which patients could be at higher risk of experiencing pregnancy loss and the development of prevention strategies.
The results highlight the importance of taking a thorough family history in clinic and represent a marked step forward in prenatal care.
Women with parents or siblings diagnosed with endocrine diseases had a higher risk of pregnancy loss
3D Analysis of Blastocytes for In Vitro Fertilisation
THE SHAPE and structure of blastocysts can predict pregnancy success, aiding blastocyst selection for in vitro fertilisation (IVF). However, selecting the right embryo remains a significant challenge within IVF, as the quality of blastocytes is traditionally assessed with 2D methods which lack depth and comprehensive indicators.
A research team, led by Bo Huang, Huazhong University of Science and Technology, Wuhan, China, aimed to introduce clinically applicable 3D evaluation methods that can reveal previously unrecognised spatial features of blastocytes.
The study, presented at the 40th ESHRE Annual Meeting, included women under 40 years old with an endometrial thickness of 7–16 mm, and no more than one previous embryo transfer failure. Using a device called EmbryoScope+(Vitrolife, Gothenburg, Sweden), researchers took detailed images of 2,141 frozen-thawed single blastocysts. Advanced technology created 3D models of these blastocysts, capturing detailed information about their outer layer (trophectoderm) and inner cell mass. These models were further analysed to find new blastocyst features and determine how these features relate to successful pregnancies.
The model was tested by comparing it with fluorescence imaging of human blastocysts and achieved over 90% accuracy. Key measurements identified include the blastocyst’s size, shape, and cell characteristics. Parameters related to size, such as overall volume, cavity volume, and surface area, were linked to higher
pregnancy rates. Specific features of the inner cell mass and outer layer were also strongly associated with better pregnancy outcomes.
Huang commented: “These results match what we see in clinical outcomes, but we couldn’t previously measure these. This study shows that the 3D shape of the blastocyst’s inner cell mass, its position, and how the surrounding cells are arranged can be important indicators of success, which we didn’t know before.”
Moving forward, the research team plans to collaborate with multiple centres to further validate these findings and invites reproductive centres worldwide to join these efforts. The ultimate goal, explained Huang and team, is to make the 3D evaluation of blastocysts a standard part of clinical practice, bringing new hope to people undergoing IVF.
The ultimate goal is to make the 3D evaluation of blastocysts a standard part of clinical practice, bringing new hope to people undergoing IVF
New Drug Increases Embryo Implantation in Assisted Reproduction
IN A MAJOR advancement for reproductive medicine, OXO-001, a first-in-class oral, non-hormonal drug, significantly enhanced embryo implantation and live birth rates in women experiencing infertility and undergoing in vitro fertilisation or intracytoplasmic sperm injection.
Infertility affects one in six individuals of reproductive age worldwide, leading to over three million in vitro fertilisation cycles annually. Despite technological advancements, embryo implantation failure continues to be a significant hurdle. The Phase II clinical trial, OXOART2, addressed this challenge by evaluating OXO-001, a drug that targets the endometrium to improve implantation and pregnancy outcomes.
The randomised, double-blind, placebocontrolled study was conducted across 28 centres in Europe and recruited 96 women aged up to 40 years who underwent a single embryo transfer. Among them, 42 received a placebo, and 54 were administered OXO001 daily, starting one menstrual cycle before the embryo transfer and continuing until 5 weeks post-transfer.
The results, presented at the 40th ESHRE Annual Meeting showed that the biochemical pregnancy rate in the OXO001 group was 75.9%, compared to 52.4% in the placebo group. Clinically significant improvements were also observed in clinical pregnancy rates (fetal heartbeat 5 weeks post-transfer) and ongoing pregnancy rates (10 weeks post-transfer), with absolute increases of +14.3% (50.0% for OXO-001 versus 35.7% for placebo) and +10.6% (46.3% for OXO-001 versus 35.7% for placebo), respectively. Most notably, live birth rates saw an absolute increase of +6.9% (42.6% for OXO-001 versus 35.7% for placebo).
Agnès Arbat, Chief Executive Officer of OXOLIFE, a specialist biotech focused on women’s fertility, expressed optimism about the findings: “An absolute increase of more than 5 percentage points in ongoing pregnancy is clinically meaningful. We observed an increase higher than +9,
Clinically significant improvements were also observed in clinical pregnancy rates (fetal heartbeat 5 weeks post-transfer) and ongoing pregnancy rates
giving renewed hope to patients and the scientific community.”
The side effects reported were similar between both groups, including mild-tomoderate headaches, nausea, vomiting, gastrointestinal issues, and dizziness. Importantly, a 6-month follow-up indicated no developmental differences in babies between the groups, confirming the drug's safety and tolerability.
These findings mark a significant leap forward in assisted reproduction, offering new hope to women undergoing fertility treatment.
Recurrent Pregnancy Loss and Subsequently Increased Adverse Perinatal Outcomes
A HISTORY of recurrent pregnancy loss (RPL) increases the risk of adverse perinatal outcomes in subsequent pregnancy, according to new data presented at the 40th ESHRE Annual Meeting.
Isabelle Letourneau, University of Ottawa, Canada, and colleagues sought to clarify the implications of RPL on pregnancy outcomes by performing a systematic review and metaanalysis of studies on MEDLINE, EMBASE, Google Scholar, and Cochrane databases that discussed RPL and adverse perinatal outcomes from inception until July 2023.
Two independent reviewers extracted the data, and the estimated effects were pooled using DerSimonian and Laird random effect meta-analyses. Additionally, subgroup analyses were performed for those with unexplained RPL and by the number of pregnancy losses. Risk of bias was assessed using the Newcastle-Ottawa Scale. For the sensitivity analysis, only highquality studies were used, and influence analysis was performed.
Compared to women without a history of RPL, women with a history of RPL had higher odds of adverse perinatal outcomes
In total, 42 studies (n=5,619,124) were included in the meta-analysis. Whilst the authors noted inconsistent confounder adjustment and significant inter-study heterogeneity across the studies, the findings highlighted that compared to women without a history of RPL, women with a history of RPL had higher odds of adverse perinatal outcomes. These included an increased odds of pre-eclampsia (odds ratio [OR]: 1.19; 95% CI: 1.03–1.37), pregnancyinduced hypertension (OR: 1.24; 95% CI: 1.03–1.48), congenital anomalies (OR: 1.25; 95% CI: 1.02–1.53), stillbirth (OR: 1.25; 95% CI: 1.04–1.51), small for gestational age (OR:
From their findings, Letourneau and colleagues concluded that there are increased odds of adverse perinatal outcomes for those with a history of RPL. They suggested that alongside additional monitoring and counselling during subsequent pregnancy, further prospective research to elucidate the relationship between perinatal outcomes and RPL is urgently needed.
Larger Zona Opening Can Reduce Monozygotic
Twin Rates in In Vitro Fertilisation
A RECENT study presented at the 40th ESHRE Annual Meeting has provided new insights into the factors contributing to the occurrence of monozygotic twins in human in vitro fertilisation (IVF) and proposed a potential approach to reduce its rates.
Monozygotic twinning, where a single fertilised egg splits into two embryos, occurs at a rate of 0.5% in spontaneous conceptions, but is significantly higher in IVF treatments. The contributing factors to this phenomenon have been identified to include ovarian stimulation, intracytoplasmic sperm injection, embryo cryopreservation, extended culture, embryo quality, maternal age, genetic factors, and particularly, micromanipulation of the zona pellucida, such as assisted hatching and biopsy. Despite various speculated causes, pinpointing the main reason contributing to monozygotic twinning has proven challenging, and currently there are no effective treatment approaches to lower the rate of occurrence in IVF.
Researchers studied monozygotic twins in 8,063 clinical pregnancies resulting from single blastocyst transfers from 2016–2023. The study specifically looked at the impact of zona pellucida manipulations on monozygotic twinning rates. Blastocytes were either fresh or frozen and were transferred with or without biopsy for preimplantation genetic testing and/or blastocyst collapse. Clinical outcomes such as live birth, ongoing pregnancy, and birth weight were evaluated, alongside clinical pregnancy and embryo implantation.
60.7 of monozygotic twin pregnancies in 56 patients resulted in live twin births, with an overall birth rate of 76.8 % %
The study specifically looked at the impact of zona pellucida manipulations on monozygotic twinning rates
Patients with Polycystic Ovarian Syndrome Show Lower Body Appreciation
NEW research indicates that patients with polycystic ovarian syndrome (PCOS), while not associated with symptoms of anxiety and depression, were more likely to have lower body appreciation.
Routine screening of depression and anxiety in women with PCOS is recommended by the International Guidelines on PCOS. Previous studies have demonstrated that patients with PCOS have a higher chance of developing mental health problems, including concerns regarding body image and anxiety. However, the majority of research evaluating mental health problems in women with PCOS utilises comparison groups composed of healthy women without fertility problems. Tamara Jannik, Amsterdam UMC - University of Amsterdam, the Netherlands, presented research at the 40th ESHRE Annual Meeting examining mental health in women with infertility undergoing fertility treatment.
The study was a cross-sectional survey conducted from May 2021–July 2023. Researchers assessed the mental health and body appreciation of women undergoing fertility treatment in the Netherlands by utilising an online questionnaire. Information about the study was disseminated at fertility clinics through leaflets, posters, and Dutch patient organisations' websites. The study included women with and without PCOS who completed the Hospital Anxiety and
Depression Scale and the Body Appreciation Scale-2 (BAS-2). It comprised 1,025 women undergoing infertility treatment in the Netherlands, with nearly equal representation of those with PCOS (49%) and other infertility diagnoses (51%). Primary outcomes were clinically relevant anxiety and depression symptoms and BAS-2 scores. Logistic and linear regression analyses, adjusted for age, BMI, and duration of infertility, were used for data analysis.
The study found that 33.1% of women with PCOS and 31.0% of women without PCOS reported clinically relevant anxiety symptoms. Depression symptoms were present in 15.5% of women with PCOS and 14.5% of those with other infertility issues. Additionally, women with PCOS showed slightly lower body appreciation. T he findings highlight that anxiety and depression are common among all women undergoing fertility treatments, not just those with PCOS. Researchers recommend that fertility clinics routinely screen and support all patients' mental health as part of standard care.
Researchers recommend that fertility clinics routinely screen and support all patients' mental health as part of standard care
Mild Ovarian Stimulation in Women of an Advanced Maternal Age
IN WOMEN of an advanced maternal age (AMA), aromatase inhibitor letrozole (LTZ) is more effective than clomiphene citrate (CC) for improving blastocyst formation and euploid rates with mild ovarian stimulation (MOS), according to research presented at the 40th ESHRE Annual Meeting.
Previous research has determined that the addition of CC or LTZ can reduce the gonadotropins dose. To optimise this strategy, researchers evaluated MOS outcomes with LTZ and CC in 288 women undergoing assisted reproductive technology between January 2020–April 2021.
Participants received 100 mg of CC (n=153) or 5 mg of LTZ (n=133) daily for 7 days during menstrual cycles three to nine. Additionally, 225 IU of recombinant folliclestimulating hormone was administered during menstrual cycles three, five, seven, and nine. In menstrual cycle ten, a dualmaturation trigger was administered using recombinant human chorionic gonadotropin and a gonadotropin hormone-releasing hormone agonist nasal spray when at least three well-developed follicles (≥ 20 mm in diameter) were confirmed. Oocyte retrieval was then performed 35–36 hours after.
The euploid rate was significantly higher in the LTZ group compared to the CC group
The results revealed that the average number of retrieved oocytes was 7.5±5.3 for women who received CC, and 6.3±4.7 for women who received LTZ (p<0.05). However, the euploid rate was significantly higher in the LTZ group compared to the CC group (p<0.05), with rates of 53.4% and 38.0%, respectively. The average number of blastocysts and morphologically good blastocysts were similar between groups.
The researchers next analysed differences between AMA women only. For AMA
participants treated with LTZ, the blastocyst formation rate was significantly higher, at 58.5%, compared to 46.6% in those treated with CC (p<0.05). Additionally, the euploid rate was significantly higher in AMA women who received LTZ (40.5%), compared to the CC group (16.7%; p<0.05). The average number of blastocysts and rate of good blastocytes were comparable between the two groups.
The study's findings emphasise the importance of considering age-related differences in selecting the optimal ovarian stimulation protocol, especially for women of advanced maternal age. However, it is important to note that not all participants received a trophectoderm biopsy, which may limit the validity and applicability of the findings.
The Link Between the Gut Microbiome and Endometriosis Pathology
THE AETIOLOGY of endometriosis (EM) is convoluted and multifactorial; however, a poster discussion session at the 40th ESHRE Annual Meeting suggested the aetiopathogenesis of endometriosis could be linked to the imbalance of microorganisms in the intestines, marking a step forward in EM research.
Sampson’s hypothesis of retrograde menstruation is the most commonly accepted theory to explain the origin of EM. However, given the characteristics and severe inflammatory response observed as part of EM, questions have been raised about the possibility of human microbiome involvement in the condition’s pathogenesis through the microbiome’s role in immune system modulation.
The study utilised a case-control design and began with 243 female participants who were recruited through a health questionnaire; the Endometriosis Health Profile-5 (EHP-5). After screening with inclusion and exclusion criteria, the resulting cohort consisted of 77 participants, of whom 34 were patients with EM, and the remaining 43 were healthy controls.
Stool samples were analysed using both 16S rRNA gene sequencing and various multivariate approaches. The purpose of the latter was to assess diversity, composition, and abundance of intestinal microbiota. Results revealed 18 significantly different taxa encompassing three families (Bacteroidaceae, Lactobacillaceae, and Desulfovibrionaceae), three genera (Blautia, Anaerostipes, and Lachnospira), and 12 species (Roseburia intestinalis, Bacteroides uniformis, and others).
Patients with EM showed higher diversity at the family and genus levels, while controls exhibited greater species diversity, indicating that a more complex microbial landscape is present in healthy individuals. The work suggests that EM is characterised by a few species from various families and genera, and these microbial differences are linked to molecular pathways involved in inflammation and oestrogen signalling pathways.
Additionally, correlations were found between microbial diversity and clinical parameters from the EHP-5 questionnaire, notably in self-image and infertility, with a strong positive correlation between infertility and the genus Anaerostipes.
Despite its promising results, the study acknowledges limitations, including the potential influence of external factors, although measures were taken to ensure there were no conflicts of interest. Overall, this research underscores the potential role of intestinal dysbiosis in endometriosis and highlights new avenues for targeted microbiota-mediated therapies.
The work suggests that EM is characterised by a few species from various families and genera
Fertility Outcomes for Male Patients with Oncohaematological Disease
TREATMENT-induced fertility difficulties are a pertinent concern for male patients with oncohaematological disease, particularly for those undergoing systemic therapies or haematopoietic stem cell transplantation, which often result in infertility.
A poster presented at the 40th ESHRE Annual Meeting detailed a study that included 424 male patients diagnosed with oncohaematological diseases who preserved their semen between 1987–2018. The median age at the time of sperm banking was 27 years and the most common indication for cryopreservation was lymphoma, accounting for 86% of patients.
A substantial proportion of the cohort (24%) had undergone haematopoietic stem cell transplantation. Initial semen analysis revealed a median sperm concentration of 54 million/mL; however, post-treatment sperm analysis conducted on 57% of the participants showed that 36% were azoospermic. Among those with remaining viable sperm, 38% exhibited normal semen parameters.
The study participants, who survived at least 5 years post-cryopreservation, were assessed for natural and assisted reproductive technology conceptions following treatment. Findings showed that the natural live birth rate rose from 38–61% with the use of frozen semen during assisted reproductive technology cycles.
Of the 424 patients, 188 expressed a desire to father children, 71 of whom achieved this via a natural live birth, while 89 used cryopreserved sperm. Of those who used frozen samples, 51% experienced at least one live birth. Despite attempts, 33 men did not utilise their cryopreserved semen.
Of the 424 patients, 188 expressed a desire to father children, 71 of whom achieved this via a natural live birth, while 89 used cryopreserved sperm
Overall, 114 of the 188 men interested in fatherhood achieved a live birth.
This research highlights the significant impact of fertility preservation on the ability to achieve fatherhood post-treatment. However, the study's single-centre nature and limited illness-specific data are noted limitations, which suggests the need for broader, multi-centre studies to support the wider extrapolation of these results.
Author:
Editor in Chief’s Highlights from ESHRE 2024
Justin Chu1-3
1. Oxford Fertility, UK
2. Birmingham Women’s and Children’s NHS Foundation Trust, UK
3. Institute of Metabolism and Systems Research, University of Birmingham, UK
THERE were several incredible highlights at the 40th European Society of Human Reproduction and Embryology (ESHRE) Annual Meeting. This feature summarises a couple of the presentations that Chu attended in Amsterdam, the Netherlands, for this latest issue of EMJ Reproductive Health. The first was a retrospective cohort study demonstrating a large dataset investigating the effectiveness of pre-implantation genetic testing for aneuploidy. The second was an interesting debate on the use of dual or double triggers in ovarian stimulation in in vitro fertilisation cycles.
PRE-IMPLANTATION GENETIC TESTING FOR ANEUPLOIDY IN WOMEN OVER THE AGE OF 37 YEARS
Pre-implantation genetic testing for aneuploidy (PGT-A) is being increasingly used around the world to optimise the selection of the best quality embryos to give patients the highest chance of pregnancy in as short a time as possible. A huge number of abstracts investigating the merits of PGT-A were submitted to the EHSRE, such that there was a special stream of oral presentations dedicated to ‘Advancing clinical PGT-A: steps towards an evidence-based consensus’.
One of these presentations was to explore the benefits of PGT-A in women above the age of 37 years. This was a multi-centre cohort study of women undergoing in vitro fertilisation (IVF) treatment between 2013–2021 across 33 IVF units.1 The study, which included 9,328 patients, highlighted aneuploidy as the major cause of IVF treatment failure. This included 4,664 patients undergoing PGT-A, and the control
group consisted of 4,664 patients who had standard IVF without embryo biopsy. The two groups were matched by age, BMI, smoking status, number of oocytes, and year of oocyte retrieval. The primary outcome was cumulative live birth rate and secondary outcomes included the time to pregnancy.
The PGT-A group had a slightly higher number of eggs collected
The study found that the PGT-A group had a slightly higher number of eggs collected. A total of 13,153 embryos were biopsied, and the euploidy rate was 29.3%. In the study group, 49.8% (2,324 patients) did not undergo embryo transfer due to a lack of suitable embryos after PGT-A. The clinical pregnancy rate for the PGT-A group was 56.0% compared to 45.8% in the control group. The live birth rates were 47.8% in the PGT-A group and 35.6% in the control group. The differences in pregnancy and live birth rates were statistically significant. It was also found that the miscarriage rate was lower in the PGT-A group. The adjusted odds ratio for live birth after multivariate
logistical regression was performed was 1.56, favouring PGT-A. There was also a shorter time to pregnancy that resulted in live birth in the PGT-A group.
The study group concluded that PGT-A is useful in women over 37 years, and that the finding that an absence of an embryo suitable for transfer after the results of embryo biopsy is a useful clinical finding for counselling and advice for patients to consider the use of donor oocytes.
DUAL OR DOUBLE TRIGGER INJECTIONS FOR IN VITRO FERTILISATION TREATMENT
During the ESHRE Annual Meeting, a great debate was held between Raoul Orvieto, Professor of Obstetrics and Gynaecology, Chaim Sheba Medical Center, Ramat Gan, Israel, who argued for the use of dual and
double triggers in ovarian stimulation, and Anja Pinborg, Professor of Obstetrics and Gynaecology, Rigshospitalet-Copenhagen University Hospital, Denmark, who argued against its use.
Orvieto demonstrated the emerging evidence that ‘dual trigger’ (the use of concomitant gonadotropin-releasing hormone agonist and human chorionic gonadotropin trigger) can lead to the collection of higher numbers of mature oocytes and total oocytes. The evidence, though sparse, has suggested that a higher live birth rate is achievable when a dual trigger is used. In particular, a meta-analysis including four trials showed higher clinical pregnancy rates when a dual trigger is used.2
Further evidence has shown that using a ‘double trigger’ (gonadotropin-releasing hormone agonist trigger 40 hours before oocyte pick up and human chorionic
gonadotropin trigger 34 hours before oocyte pick up) provides better results in women who have previously had a low yield of oocytes and empty follicle syndrome. Additionally, women with low egg-to-follicle rate and high oocyte immaturity rates had improved embryo parameters when a double trigger was used.
The theoretical benefit of dual or double trigger is to mimic the luteinising and follicle stimulating hormone surges seen in a physiological cycle.
Pinborg critically appraised the trials and evidence synthesis investigating the effectiveness of dual and double trigger injections in ovarian stimulation. She presented the latest meta-analysis published in 2023, which extracted data from 10 trials published between 2008–2022.3 They included a total of 1,643 participants. Pinborg showed that all included trials were of small size (60–104
References
1. Casteleiro Alves MF et al. Preimplantation genetic testing for aneuploidies (PGT-A) improves reproductive outcomes in advanced maternal age patients undergoing IVF/ICSI: a multicentre retrospective cohort study with propensity score matching. Abstract O-152. ESHRE
trial participants), which is too small to identify a minimally important difference in live birth rate. There is a high degree of clinical heterogeneity between the included trials, and so, Pinborg suggested that there is insufficient evidence to support the use of dual or double trigger injections. She also suggested that the use of dual or double triggers could also increase the chance of ovarian hyperstimulation syndrome and the costs and complexity of therapy for patients.
There is still no clear signal that a dual or a double trigger for final maturation leads to better clinical outcomes
There is still no clear signal that a dual or a double trigger for final maturation leads to better clinical outcomes. There is a need for further studies to investigate the benefits of using the dual or double-trigger strategy.
Annual Meeting, 7-10 July, 2024.
2. Ding N et al. Dual trigger of final oocyte maturation with a combination of GnRH agonist and hCG versus a hCG alone trigger in GnRH antagonist cycle for in vitro fertilization: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2017;218:92-8.
3. Hsia LH et al. Dual trigger improves the pregnancy rate in fresh in vitro fertilization (IVF) cycles compared with the human chorionic gonadotropin (hCG) trigger: a systematic review and meta-analysis of randomized trials. J Assist Reprod Genet. 2023;40(9):2063-77.
Does Dual and/or Double Trigger Improve In Vitro Fertilisation Success?
DO THE risks of using dual or double trigger in vitro fertilisation (IVF) outweigh the benefits, or do the benefits outweigh the risks? This was the question posed to the audience by co-chairs Nikolaos Polyzos, Dexeus University Hospital, Barcelona, Spain, and Joop Laven, Erasmus Medical Center, Rotterdam, the Netherlands, at the very beginning of a fascinating debate session at the European Society of Human Reproduction and Embryology (ESHRE) 40th Annual Meeting, which took place from 7th–10th July 2024 in Amsterdam, the Netherlands. Though the audience members were initially hesitant to share their thoughts, this first poll demonstrated a strong preference for dual or double trigger as opposed to against. The ensuing talks aimed to convince the crowd one way or the other, as experts in the field joined Laven and Polyzos to debate.
FOR DUAL TRIGGER
Human chorionic gonadotropin (hCG) induces granulosa cells, cumulus expansion, and resumption of meiosis; this much was common knowledge amongst the group of healthcare professionals listening to Raoul Orvieto, Sheba Medical Center (Tel Hashomer), Tel Aviv, Israel, open his argument. Final follicular maturation is usually triggered by one bolus of hCG (5,000–10,000 units), which is administered as close as possible to the time of ovulation. How does the action of hCG compare to that of the luteinising hormone (LH) on the same receptor, however? This is the first question addressed by Orvieto, who went on to present the results of a study in which intracellular signalling was analysed. The results demonstrated that when LH activated the receptor, the cascade responsible for oocyte maturation was more intensely activated, and when hCG was added, the cascade for steroidogenesis was more intensely activated.1 Further studies have shown a higher oocyte recovery rate when utilising hCG and follicle-stimulating hormone (FSH).2 Addition of FSH, Orvieto explained, is therefore highly beneficial in IVF.
Having then established that hCG and gonadotropin-releasing hormone agonist (GnRH-ag) perform the same function as LH, with and without the risk of ovarian hyperstimulation syndrome (OHSS), respectively, Orvieto went on to question whether or not they do the same with regards to the number of oocytes. Comparing the results of multiple studies, Orvieto showed the audience that both methods provided an advantage in oocyte production, with some showing an advantage for the GnRH-ag. If using both hCG and GnRH-ag improves oocyte numbers, he asked the crowd, “why not combine them for a better overall result?”
If using both hCG and GnRH-ag improves oocyte numbers, why not combine them for a better overall result?
To emphasise his point, Orvieto discussed the results of a retrospective study in which dual trigger was tested. The patients receiving dual trigger not only had a higher number of oocytes retrieved, but had a higher live birth rate (41.36%
of patients versus 30.49% in the control group receiving hCG only).3 A further study showed that patients in the dual trigger group more often had patients with at least one top-quality embryo, compared to the group receiving hCG only.4 Several research groups have shown the benefits of dual trigger compared to hCG alone, including, perhaps most importantly, higher pregnancy rate and live birth rate. Orvieto presented a flurry of results from studies throughout the past decade that demonstrated the seemingly clear advantages of using dual trigger, including a case study in which a patient went through seven unsuccessful rounds of IVF before receiving a double trigger on the eighth round, which resulted in conception.
live birth in 41.36% of patients versus 30.49% in the control group receiving hCG only
“By double triggering, we combine the advantages of both prolongation of the time between ovulation triggering and oocyte pickup (OPU), and also the consequent simultaneous induction of an FSH surge,” Orvieto commented.
AGAINST DUAL TRIGGER
Key opinion leader Anja Pinborg, Copenhagen University Hospital, Denmark, was next to take centre stage as she presented her case against the use of dual or double trigger in IVF. She began her argument with a comparison between natural ovulation and the use of dual trigger, detailing how the concurrent administration of GnRH-ag and hCG in dual trigger leads to a surge of LH and FSH, combining the advantages of both components and mimicking the events that occur in the natural cycle. To assess whether or not dual trigger provides a significant advantage, Pinborg discussed the results of a metaanalysis of several randomised control studies between 2008–2022, comparing dual and hCG triggers.5
When looking at these trials, Pinborg highlighted that though there is indeed a difference of 0.82 in the number of mature oocytes collected, all bar one study performed in China included fewer than 100 patients. Additionally, when looking at the clinical pregnancy rate, it is true that there was a statistically significant difference between the two types of triggers, and the same could be said for live birth rate per cycle; however, very few studies actually included analysis of live birth. She added that the studies also appear to show that dual trigger is beneficial in fresh embryo transfer (ET), but there is no statistically significant difference in frozen ET. Additional research has also shown there is no difference between dual trigger and hCG trigger results in women with higher BMIs.6
Pinborg went on to describe the results of a retrospective study that involved giving the hCG trigger for a period of time, followed by giving the dual trigger.7 This research found that patients receiving the dual trigger had a higher number of mature oocytes compared to those receiving the hCG trigger (mean 6.4 versus 6.0), and a higher number of fertilised oocytes (mean 4.7 versus 4.3).7 However, when analysing the pregnancy rate and live birth rate in this cohort, researchers found that both groups yielded the same results.7
Pinborg emphasised the fact that this is real world data, carried out on a large group of patients (8,500 cycles), and stated that:
“The dual trigger is not for all.” She added: “It increases the complexity of a protocol, it increases the cost, and it increases patient discomfort,” highlighting that dual trigger involves multiple injections, which may lead to a higher drop-out rate. Additionally, she emphasised that not all patients may benefit equally and noted that the evidence is still limited, and more research is needed to establish protocols. Pinborg then went on to deliver what she believed to be the most important argument against the use of dual trigger; this method increases the risk of OHSS in patients, even with a low dose of hCG. This is particularly true in patients who are already predisposed to developing OHSS.
Dual trigger increases the complexity of a protocol, it increases the cost, and it increases patient discomfort
This is not to say that the dual trigger should never be used, Pinborg stated. It is a valid option for IVF after a suboptimal response to the agonist trigger, as well as for patients with hypogonadotropic hypogonadism, patients of advanced age who have been through a previous IVF cycle, or those who have low LH after agonist trigger. Pinborg’s conclusion, therefore, was not necessarily ‘con’, but instead errs on the side of caution, suggesting that dual trigger has its place in IVF, but clinicians should not be overtreating patients, and should use this method sparingly.
REBUTTAL: PRO
Pinborg’s arguments were hard to refute, and Orvieto’s rebuttal reflected this. He agreed that dual trigger should not be offered to patients at high risk of OHSS, and that further randomised control trials are needed to establish protocols. The cost, however, of dual trigger should not be considered a reason to not use it, he argued. If increasing the cost by 10 Euros improves the chances of a live birth rate, Orvieto explained, it is worth it.
Everything is ultimately about statistics, he continued. His own research groups have produced several articles, including a randomised control trial, in recent years exploring the benefits of dual trigger compared to hCG trigger. These have not been taken into account by the ESHRE guidelines, which Pinborg had previously highlighted did not recommend using dual trigger. Increasing numbers of randomised trials are additionally showing the benefit of double trigger, he argued, including in predicted normal responders. He presented several studies which supported this argument, responding to Pinborg’s own point about the lack of data to support the benefits of dual trigger on live birth rate; the trials showed by Orvieto showed a clear benefit for most patients.
REBUTTAL: AGAINST
In response, Pinborg urged the audience to consider the history of reproductive medicine. It was once suggested that clinicians practice endometrial scratching, assisted hatching, continuation of the long protocol, and many other ideas which were proven to not be the best approach for all patients after several randomised controlled trials. She implored the crowd to use dual trigger only when other options have been considered, and to not add unnecessary injections for female patients.
References
1. Casarini L et al. LH and hCG action on the same receptor results in quantitatively and qualitatively different intracellular signalling. PLoS One. 2012;7(10):e46682.
2. Lamb J et al. Follicle-stimulating hormone administered at the time of human chorionic gonadotropin trigger improves oocyte developmental competence in in vitro fertilization cycles: a randomized, double-blind, placebo-controlled trial. Fertil Steril. 2011;95(5):1655-60.
THE FINAL VOTE
The second round of voting showed that though some audience members were swayed by the arguments they had heard, the majority of the crowd continued to favour the use of dual or double trigger for IVF.
Regardless of the votes received at ESHRE, it is clear that the topic remains controversial, and that more trials are needed to truly determine the safety of dual trigger compared to hCG trigger, and how this compares to the benefits for patients.
3. Lin MH et al. Dual trigger with combination of gonadotropin-releasing hormone agonist and human chorionic gonadotropin significantly improves the live-birth rate for normal responders in GnRH-antagonist cycles. Fertil Steril. 2013;100(5):1296-302.
4. Decleer W et al. Comparison of hCG triggering versus hCG in combination with a GnRH agonist: a prospective randomized controlled trial. Facts Views Vis Obgyn. 2014;6(4):203-9.
5. Hsia LH et al. Dual trigger improves the pregnancy rate in fresh in vitro fertilization (IVF) cycles compared with the human chorionic gonadotropin (hCG) trigger: a systematic review and meta-analysis of randomized trials. J Assist Reprod Genet. 2023;40(9):206377.
6. Donno V et al. Female BMI and body weight is not associated with oocyte yield and maturation in hCG, agonist or dual trigger cycles: a large observational study including 5000 cycles. J Clin Med. 2023;12(9):3249.
7. Blockeel C et al. O-294 Dual trigger versus hCG-only trigger in ICSI patients: an analysis of 8500 cycles. Human Reprod. 2023;38(Suppl 1):i180.
Endometriosis, Endometrial Disorders, and Infertility: From Bench to Bedside
SPOTLIGHTING endometriosis, a session at the European Society of Human Reproduction and Embryology (ESHRE) Annual Meeting, 2024, held in Amsterdam, the Netherlands, considered the latest advancements in the clinical management of patients with this condition who are trying to conceive. Chaired by Stacey Missmer, Michigan State University, East Lansing, USA, and Noortje van den Boogaard, Flevo Hospital, Almere, the Netherlands, six presentations were delivered to a packed auditorium.
SERUM PROGESTERONE LEVELS IN ENDOMETRIOSIS
The session began with a presentation from Chloé Maignien, Cochin University Hospital, France, reporting that serum progesterone levels do not differ between patients with and without endometriosis who conceived after hormone replacement therapy-frozen embryo transfer (HRT-FET) cycles.1 It is well established that there is a correlation between serum progesterone levels around the time of HRT-FET and live birth rate. Interestingly, when considering endometriosis, which frequently causes infertility, progesterone resistance in the endometrium is common. Subsequently, it is hypothesised that these women require higher progesterone levels to achieve a live birth. Given the absence of evidence of this from controlled studies, Maignien’s research team sought to compare progesterone levels on the day of HRT-FET in patients with endometriosis/adenomyosis to controls who achieved a live birth.
Serum progesterone levels do not differ between patients with and without endometriosis who conceived after hormone replacement therapy-frozen embryo transfer (HRT-FET) cycles
The observational cohort study was conducted between January 2019–December 2021.1 Patients undergoing single autologous blastocyst FET using HRT with exogenous oestrogen and micronised vaginal progesterone were included. Oestrogen treatment commenced on Day 1 of menstruation and continued for approximately 14 days, following which a transvaginal ultrasound and blood testing were performed. If endometrial thickness was above 6 mm and progesterone level was below 1.5 ng/mL, FET was scheduled, with progesterone supplementation commencing 5 days prior. Blastocysts were transferred by senior gynaecologists and if the patient became pregnant, they continued the same luteal phase support until 12 weeks of gestation.
In total, 1,784 patients were included, with 31.4% having endometriosis.1 Mean progesterone levels on the day of FET was 13.2 ng/mL (standard deviation: 4.8).1 The overall live birth rate was 31.4%, and 32% of these patients who achieved a successful live birth had a diagnosis of endometriosis.1 Among women who conceived, there was no significant difference between the mean progesterone levels on the day of FET when comparing patients with endometriosis to those without. Finally, considering patient characteristics and progesterone levels,
neither the presence of endometriosis nor adenomyosis were related with a significant difference. However, factors such as BMI, duration of infertility, and geographic origin significantly affected progesterone levels.
Thus, Maignien concluded that they found no difference between progesterone levels in patients with endometriosis and controls on the day of FET, and therefore, patients with endometriosis do not require higher progesterone levels to achieve a pregnancy.
SUBCUTANEOUS PROGESTERONE SUPPLEMENTATION IN FROZEN EMBRYO TRANSFER
The second talk, delivered by Noémie Sachs-Guedj, Dexeus University Hospital, Barcelona, Spain, also considered serum progesterone in patients with endometriosis, but focused on artificial cycle FET (AC-FET).1 She began by highlighting that several studies report on the best preparation protocol for patients with endometriosis, noting that recent studies suggest AC-FET is the most appropriate protocol, as it may help prevent endometrial alterations by inducing ovarian suppression and reducing inflammation. Due to the absence of a corpus luteum, preparing the endometrium is crucial in these patients. The standard procedure for this is 2 mg oestrogen taken three times per day. If an ultrasound indicates an endometrial thickness of over 7 mm, 200 mg of micronised vaginal progesterone is delivered three times per day. Despite this, recent studies suggest serum progesterone levels of less than 10 ng/mL are linked to poorer outcomes. To combat this, Sachs-Guedj outlined a new protocol that uses subcutaneous progesterone supplementation of 25 mg/ day if the serum progesterone level is not above 10.6 ng/mL the day prior to embryo transfer.2 Specifically considering patients with endometriosis, this protocol may require adjustment as the condition disrupts the balance between progesterone and oestrogen.
Investigating this further, Sachs-Guedj and team sought to consider progesterone levels in patients with endometriosis and whether subcutaneous progesterone would aid those below the progesterone cutoff achieve similar live birth rates to those without endometriosis. A retrospective cohort study between January 2019–December 2022 suggested that mean progesterone levels on the day of transfer were comparable between patients with and without endometriosis.2
Additional analysis of the study data, using a multivariable logistic regression including 985 AC-FET cycles, specifically investigated the effect of subcutaneous progesterone supplementation. Patients with endometriosis and progesterone levels below 10.6 ng/mL receiving subcutaneous supplementation were the reference group. Results showed comparable live birth rates between the reference group and all other test groups, with and without endometriosis, with progesterone levels above or below 10.6 ng/mL, receiving or not receiving supplementation.
Overall, Sachs-Guedj concluded AC-FET cycles in patients with endometriosis requiring subcutaneous progesterone achieve live birth rates comparable to both endometriosis and non-endometriosis cycles with the correct progesterone levels before FET. Thus, supplementation does not need to be altered when delivered to patients with endometriosis and the protocol allows cost-effective and convenient luteal phase individualisation.
DOES ENDOMETRIOSIS AFFECT OOCYTE MORPHOLOGY?
Ipek Nur Balın Duzguner, Istanbul Memorial Hospital, Türkiye, delivered the third research presentation of the session, focusing on whether endometriosis affects oocyte morphology.3 Previous conflicting evidence meant the research team aimed to investigate this relationship using a retrospective, single-centre study between August 2011–March 2023.3
Overall, 29,130 assisted reproductive technology cycles were included in the study.3 There were 4,602 cycles originating from patients with endometriosis and 24,528 cycles from patients without endometriosis, permitting the study of 27,204 oocytes and 178,774 oocytes, respectively. 3 Various parameters, such as presence of vacuole(s) and zona pellucida defects, were assessed individually to identify abnormal oocyte morphology.
Following statistical analysis, the number of previous unsuccessful cycles, duration of infertility, and anti-mullerian hormone levels were significantly different between the two test groups. 3 The oocyte morphological abnormalities evaluated were cytoplasmic granulation, large perivitelline space, zona abnormalities, and polar body defects.3
THE ENDOMETRIOSIS LONGITUDINAL FERTILITY STUDY
Vanessa Ross, Royal Women’s Hospital, Melbourne, Australia, delivered the fourth talk, which outlined the outcomes and interim data of the Endometriosis Longitudinal Fertility Study (ELFS) study, specifically focusing on outcomes for women with moderate or severe endometriosis trying to conceive.4 After reminding the audience that endometriosis is associated with reduced natural and assisted conception rates, she stressed that there is still limited data available to advise treatment recommendations, as studies are commonly retrospective cohort studies thatlack a control group. Whilst laparoscopic
These were significantly increased in patients with endometriosis.
However, when considering the effect size, there was no significant difference between the two groups, due to the large number of oocytes. 3 Further analysis focused on pregnancy results, specifically single blastocyst FET cycles (n=11,116). 3 Clinical and total pregnancy loss was significantly higher in patients with endometriosis, but again, the effect size suggested this result was negligible.
Overall, no significant differences were found between the endometriosis and non-endometriosis groups when oocyte morphological abnormalities were evaluated using effect size.
29,130 4,602
24,528
assisted reproductive technology cycles were included in the study
cycles originating from patients with endometriosis
cycles from patients without endometriosis
surgery has been explored as a treatment option, due to the increased risks associated with surgical intervention robust evidence is required regarding its effectiveness in improving fertility in patients with endometriosis.
Endometriosis is associated with reduced natural and assisted conception rates
Therefore, the research group aimed to explore the role of surgery for infertility in patients with moderate or severe endometriosis, as well as the use of preemptive surgical treatment. The ELFS study,
a multi-site longitudinal cohort study, is currently recruiting women <38 years of age, and aims to assess clinical pregnancy and live birth rates in those with evidence of moderate to severe endometriosis.4
Following enrolment, participants complete a baseline questionnaire, before downloading a smart phone app that delivers periodic cyclical questionnaires. Finally, pregnancy outcome data is collected.4
In total, 868 completed cycles from 151 participants have been captured so far. The majority of participants (70%) elected to undergo surgical treatment during the study period. 4 Furthermore, 54 participants have recorded that they are trying to conceive, with 193 attempted conception cycles recorded (53 of these through in vitro fertilisation). 4 In total, 33 pregnancies were recorded, with a fecundity of 17%, which Ross noted was surprising due to the low average age of the cohort.4 Seven miscarriages and one termination were also recorded.4
References
1. Bourdon M et al. Serum Progesterone levels do not differ between patients with endometriosis and unaffected patients who conceive after Hormone Replacement Therapy-Frozen Embryo Transfer (HRT-FET) cycles. Abstract O-146. ESHRE Annual Meeting, 7-10 July, 2024.
Ross concluded by addressing the study limitations. Namely, as it is not a prospective randomised control trial, cofounders are not accounted for. Furthermore, in the absence of robust data regarding management, clinician scope and practice, and pain symptoms may influence recommendations for patient management.
CONCLUDING REMARKS
In conclusion, the session provided valuable insights into the complexities of endometriosis, endometrial disorders, and infertility. Through a series of detailed presentations, researchers highlighted key findings and advancements in the clinical management of these conditions. Notably, studies on serum progesterone levels revealed no significant differences in patients with endometriosis, challenging the assumption that higher progesterone levels are necessary for successful conception. Overall, there was an emphasis on the need for continued research and individualised treatment approaches to improve fertility outcomes for women with endometriosis and other endometrial disorders.
2. Sachs Guedji N et al. Role of serum progesterone levels and subcutaneous progesterone supplementation in endometriosis patients undergoing Artificial Cycle Frozen Embryo Transfer. Abstract O-147. ESHRE Annual Meeting, 7-10 July, 2024.
3. Duzguner INB et al. Does presence of endometriosis adversely affect oocyte morphology? Evaluation of a large number of oocytes obtained
4. Ross V et al. The Endometriosis Longitudinal Fertility Study (ELFS): Outcomes for women with moderate or severe endometriosis who are trying to conceive. Abstract O-149. ESHRE Annual Meeting, 7-10 July, 2024.
Abstract Review
Read on to learn more about one of the cutting-edge studies presented at the European Society for Human Reproduction and Embryology (ESHRE) 40th Annual Meeting. This abstract explores whether tacrolimus treatment improves pregnancy rate in women with repeated implantation failures.
Tacrolimus Treatment Improved Pregnancy Rate with Euploid Blastocyst in Women with Repeated Implantation Failures and Elevated
T Helper 1/2 Cell Ratios
Authors: *Koji Nakagawa,1 Joanne Kwak-Kim,2
Takashi Horikawa,1 Keiji Kuroda,3 Michi Hisano,4
Rikikazu Sugiyama,1 Koushi Yamaguchi4
1. Sugiyama Clinic Shinjuku, Tokyo, Japan
2. Reproductive Immunology, Obstetrics and Genecology, Clinical Science department, Chicago Medical School at Rosalind Franklin University of Medicine and Science, Vernon Hills, Illinois, USA
3. Sugiyama Clinic Marunouchi, Tokyo, Japan
4. Department of Maternal‐Fetal Biology, National Center for Child Health and Development, Tokyo, Japan
*Correspondence to koji@sugiyama.or.jp
Disclosure: The authors declare no conflicts of interest.
In organ transplantation, the transplanted organ is usually attacked by various lymphocytes. In contrast, a transferred embryo might be attacked by various lymphocytes in treatment with antiretroviral therapy. An underlying mechanism of embryo rejection is considered to be similar to an allograft rejection. According to this
speculation, embryonic rejection is one of the reasons for repeated implantation failure (RIF). Therefore, the authors used the immunosuppressive agent tacrolimus for women with RIF (≥4 times) and elevated T helper (Th) 1/Th2 cell ratios (≥10.3). This resulted in the pregnancy rate being significantly improved.1 However, this first study did not include the use of euploid blastocysts, so embryonic concerns could not be ruled out. In this study, the authors attempted to confirm the effectiveness of the tacrolimus treatment on women with RIF showing elevated Th1/Th2 cell ratios using euploid blastocyst.
MATERIALS AND METHODS
A prospective cohort study was performed, including 569 women who are infertile with RIF four or more times. The study participants received frozen-thawed blastocyst transfer with euploid blastocysts from September 2020–November 2021. All transferred blastocysts were confirmed as euploid or low-frequency mosaic by preimplantation genetic testing for aneuploidy, and the endometrial preparation for embryo transfer (ET) was made by using either hormone replacement cycle or natural ovulatory cycle. All participants were measured for their peripheral blood Th1/Th2 (CD4+IFN-γ+/ CD4+IL-4+) cell ratios in the
secretory phase before ET. Women who had elevated Th1/Th2 cell ratios (≥10.3) received tacrolimus (2–4 mg daily).2 Tacrolimus was started 2 days before ET until the day of pregnancy test.
RESULTS
Among the women, 174 (30.6%) showed a ratio of 10.3 or above were divided into two groups: 148 women received tacrolimus (Tac group) and the others (n=26) did not receive any drugs (no-Tac group). The remaining 395 showed a ratio of 10.3 or less and were considered as controls (control group).
The human chorionic gonadotropin-positive and gestational sac (GS) rates of the Tac group were 73.0% and 64.2%, respectively; similar to the no-Tac group (69.2% and 57.7%, respectively; P is non-significant). Meanwhile, the human chorionic gonadotropin-positive and GS rates of the control group were 70.6% and 60.0%, respectively (P is non-significant).
Recently, the authors reported an adjusted cut-off value of the Th1/Th2 cell ratios (≥11.8) for women with RIF based on the retrospective analysis.3 When the Th1/Th2 cell ratio cut-off value was set to ≥11.8, 123 women of the 569 participants (21.6%) had elevated Th1/Th2 cell ratios (≥11.8). Among them, 112 received tacrolimus (Tac2 group), and 11 did not receive tacrolimus (no-Tac2 group). The remaining 410 women were a control group (Control2 group). The GS rate of the Tac2 group was 67.0%, which was significantly higher than that of the no-Tac group (36.3%; p<0.05, Figure 1), while the GS rate of the Control2 group was 60.5% (P is non-significant).
CONCLUSION
The authors concluded that tacrolimus was an effective treatment for women with RIF showing elevated Th1/Th2 cell ratios using euploid blastocyst, and that the elevated Th1/Th2 cell ratio cut-off value should be set to 11.8. Since then, they have set 11.8 as the new criteria value for tacrolimus treatment.
1: Gestational sac rate after euploid blastocyst transfer between two groups.
Figure
References
1. Nakagawa K et al. Immunosuppressive treatment with tacrolimus improves reproductive outcome for repeated implantation failures patients who have elevated in Th1/Th2 cell ratios. Am J Reprod Immunol. 2015;73(4)353-61.
2. Nakagawa K et al. Immunosuppressive treatment using tacrolimus promotes pregnancye outcome in
infertile women with repeated implantation failure. Am J Reprod Immunol. 2017;DOI:10.1111/aji.12682.
3. Kuroda K et al. Increasing number of implantation failures and pregnancy losses associated with elevated Th1/Th2 cell ratio. Am J Reprod Immunol. 2019;86(3):e13429.
The following highlights spotlight the latest developments in reproductive health, featuring abstracts presented at the European Society of Human Reproduction and Embryology (ESHRE) 40th Annual Meeting in Amsterdam, the Netherlands. From the use of assisted reproduction technology in breast cancer survivors with BRCA 1/2 mutations, to pre-implantation genetic testing for aneuploidies in women of advanced maternal age, the selected highlights bring you groundbreaking research in the field.
Assisted Reproductive Technology Linked to Higher Risk of Congenital Heart Defects
NEW research presented at the ESHRE Annual Meeting 2024 revealed elevated risks of congenital heart defects (CHD) in children conceived with assisted reproductive technology (ART), compared to those conceived through spontaneous conception (SC).
It has already been established that children born with the help of ART have a higher risk of birth defects compared to children born after SC. Notably, CHDs hold the highest prevalence among these defects, accounting for a staggering amount of 50% of all major birth defects and affecting an estimated 1.5% of children in the general population.
The large-scale registry-based cohort study included 7,747,637 live births, of which 171,735 were conceived through ART, spanning data from Denmark, Finland, Norway, and Sweden. The study found that major CHDs occurred in 1.84% of children conceived with ART, compared to 1.15% in those conceived naturally. Additionally, severe CHDs were observed in 0.35% of ART-conceived children versus 0.26% in those conceived through SC. These findings were consistent regardless of whether the children were singletons or multiples, with multiples showing the highest risk.
The analysis revealed that ART was associated with an increased risk in five out of six specific CHD lesion groups, including conotruncal defects, non-conotruncal defects, ventricular septal defects, atrial septal defects, and other CHDs. There were also no significant differences in CHD risks between different ART methods such as intracytoplasmic sperm injection and in vitro fertilisation, or between frozen and fresh embryo transfers for major or severe CHDs.
Although CHDs are rare, they are still associated with severe risks such as morbidity and mortality in both childhood and adulthood. Theses findings suggest that fetal echocardiography screening in ART pregnancies could be beneficial; however, further research is needed to confirm its effectiveness beyond routine obstetric ultrasound.
The study found that major CHDs occurred in 1.84% of children conceived with ART
Is Flexible Progestin-Primed Ovarian Stimulation Inferior to GnRH Antagonists?
THE FIRST freeze-all, randomised controlled trial comparing the long-term outcomes of flexible progestin-primed ovarian stimulation (fPPOS) and gonadotropin-releasing hormone (GnRH) antagonists in sub-optimal responders has been conducted, with results recently presented at the ESHRE Annual Meeting 2024.
The use of medroxyprogesterone acetate for fPPOS has shown to be effective for the prevention of premature ovulation, without reducing oocyte yields. Sub-optimal responders (those with an antral follicle count of less than 10) in particular may benefit from this approach, as fPPOS results in less pituitary gland suppression than standard GnRH approaches, meaning that endogenous follicle-stimulating hormone and luteinising hormone can support follicular development more effectively in sup-optimum responders, potentially leading to a higher oocyte yield.
fPPOS results in less pituitary gland suppression than standard GnRH approaches
Researchers from Northwest Women’s and Children’s Hospital, Assisted Reproductive Technology Center, Xi‘An, China, compared fPPOS with the GnRH antagonist protocol in predicted suboptimal responders in an open-label, freeze-all randomised controlled trial. In a single in vitro fertilisation centre between July 2019–June 2023, 462 women (antral follicle count <10) referred for in vitro fertilisation/intracytoplasmic sperm injection and who did not intend to undergo a fresh transfer, were randomly assigned to fPPOS or GnRH-antagonist protocol. When the leading follicle reached 14 mm, or on the sixth day of stimulation, women in the fPPOS group were given
medroxyprogesterone acetate (10 mg/day), and women in the GnRH-antagonist group were given cetrotide (0.25 mg/day).
The analysis revealed there was no significant difference in serum endocrine profiles and stimulation parameters, including the consumption of gonadotropins between individuals who received fPPOS and those who received the GnRH antagonist protocol. Within 6 months, 79.5% of women in the fPPOS group and 84.02% in the GnRH antagonist group had undergone at least one cycle of frozen embryo transfer (FET; p=0.234). The ongoing pregnancy rates per woman were 48.20% in the fPPOS group versus 52.92% in the GnRHantagonist group (relative risk: 0.91; 95% CI: 0.76–1.09; p=0.311). Additionally, there was no difference in the ongoing pregnancy rate between the two groups regarding the outcomes of the initial FET cycle (49.01% versus 48.37%; relative risk: 1.03; 95% CI: 0.81–1.26; p=0.908). There were no significant differences in biochemical pregnancy rate, clinical pregnancy rate, and miscarriage rate per pregnancy. The results also demonstrated no difference in the number of oocytes, two-pronuclear oocytes, and viable and high-quality embryos retrieved, as well as the total number of embryos cryopreserved.
The results demonstrate that fPPOS is just as effective as the GnRH antagonist protocol in women with a predicted suboptimal response, presenting a valuable alternative for clinicians, especially when patient-specific needs or limitations influence the choice of treatment.
New AI-Enhanced System Outperforms Traditional Fertilisation Techniques
A NOVEL AI-enhanced system developed in a study led by Dimitris Manyas, Gynaecology & Fertility Hospital, Dubai, United Arab Emirates, has shown significant results in improving the rate of fertilisation in comparison to the traditional intracytoplasmic sperm injection (ICSI) method. The research, presented at the ESHRE Annual Meeting 2024, introduced the Sperm Tracer AI system, a novel AI programme that has shown promising results.
The study analysed data from 26 fresh ICSI cycles in 268 sibling oocytes, between September–December 2023. The group looked for statistically significant differences in rates of fertilisation and embryo development on Days 3 and 5. Traditional fertilisation was executed by an embryologist using group embryo culture, while fertilisation in the Sperm Tracer group was conducted through single embryo culture.
Results showed that the Sperm Tracer AI system improved fertilisation rates (odds ratio: 0.46; 95% CI: 0.23, 0.89; p=0.0224); although, there was no significant difference in the cleavage stages, blastocyst formation, or the production of high-quality embryos when compared to traditional methods.
To conduct a correlation analysis, two groups of sperm, Group A and Group B, were created from the population, both of which underwent ICSI with the Sperm Tracer system either successfully or unsuccessfully, respectively. The analysis utilised kinematic parameters including Dance (DNC) and Linearity (LIN). Group A showed a negative association with DNC and multiple linear parameters while Group B showed a negative correlation between DNC and LIN, suggesting potential effects on the linear velocity of the sperm.
Further analysis of Group A also showed robust negative correlations with additional kinematic parameters, indicating a clinical significance in sperm motility. The study results highlight the potential advantage the Sperm Tracer’s system has in improving fertilisation rates.
Results showed that the Sperm Tracer AI system improved fertilisation rates
Despite the promising findings from the study, there are limitations, including small sample size, divergent culture embryo strategies introducing bias, and morphology analysis but no data analysis. These limiting factors could be addressed in further investigation into the efficacy of these methods to validate these results and allow them to be extrapolated.
Nevertheless, the research highlights the potential impact of the Sperm Tracer AI system on in vitro fertilisation outcomes and how the integration of this assist to traditional techniques could improve the efficiency of in vitro fertilisation
Assisted Reproductive Technology in Young BRCA Carriers with a Pregnancy After Treatment
for Breast Cancer
ASSISTED reproductive technology (ART) is safe for breast cancer (BC) survivors with BRCA1/2 pathogenic variants, according to a comprehensive global study presented at the ESHRE Annual Meeting 2024.
This international, multicentre, hospitalbased, retrospective cohort study spanned 78 centres worldwide and included 4,732 women harbouring the BRCA1/2 pathogenic variants, and diagnosed with Stage I–III BC at ≤40 years between 2000–2020. Specifically, 543 women with a pregnancy post-BC diagnosis were analysed, of whom 436 conceived naturally and 107 used ART.
ART procedures varied, including embryo transfer following hormonal replacement therapy, oocyte or embryo cryopreservation at diagnosis, oocyte donation, ovulation induction, in vitro fertilisation, and intracytoplasmic sperm injection postanticancer treatments. The researchers, led by Isotta Martha Magaton, University Hospital of Bern, Switzerland, then compared spontaneous pregnancies with ART-induced pregnancies.
Among 107 ART pregnancies, 42.1% (n=45) used cryopreserved oocytes/embryos, 30.8% (n=33) involved ovarian stimulation
and in vitro fertilisation/intracytoplasmic sperm injection, and 19.6% (n=21) used oocyte donation. ART pregnancies were associated with older maternal age at conception (37.1 versus 34.3 years; p<0.001), more hormone receptorpositive BC cases (43.4% versus 30.8%; p=0.016), and a longer median time from BC diagnosis to conception (4.2 versus 3.3 years; p=0.004). Notably, there was no statistically significant difference observed in pregnancy complications between the two study cohorts (p=0.382), though ART pregnancies had more miscarriages (11.3% versus.8.8%) and fewer induced abortions (0.9% versus 8.3%).
At a median follow-up of 9.1 years, ART showed no significant effect on disease-free survival, with 13 DFS events in the ART group versus 118 in the spontaneous pregnancy group (log-rank p=0.147). Despite limitations, this study is the largest to date, providing reassuring evidence that ART is safe for young BRCA carriers seeking pregnancy.
543 women with a pregnancy post-BC diagnosis were analysed, of whom 436 conceived naturally and 107 used ART
Congress Interview
Karen Sermon, Chair of the European Society of Human Reproduction and Embryology (ESHRE), shared her insights from the 40th ESHRE Annual Meeting. She also discussed her motivation for pursuing a career in reproductive medicine, the unique challenges associated with this field, and her objectives for ESHRE.
Karen Sermon
Vrije Universiteit Brussel, Belgium; Chair, European Society of Human Reproduction and Embryology (ESHRE)
Who or what influenced your decision to pursue a career in reproductive medicine, specifically focusing on genetics and embryology?
I've always been active in ESHRE during my whole professional life
I went to medical school in Brussels, but I knew very early on that I didn't want to practice, I wanted to go into research. So, I looked around on campus to see who was doing research, which is when I found André Van Steirteghem and Inge Liebaers. At that moment, Steirteghem was setting up the in vitro fertilisation (IVF) lab and they had just started having pregnancies, and Liebaers was just starting up the genetic centre there. Once I finished medical school, I became a PhD student there. It's actually Van Steirteghem who pushed me very early on to be involved in the European Society of Human Reproduction and Embryology (ESHRE). My first ESHRE Annual Meeting was in 1988 in Malmö, Sweden, and I didn't have my diploma yet. From then on, I was just going to the conferences and presenting, and gradually, I got involved in organising things for ESHRE. So, I've always been active in ESHRE during my whole professional life.
Q2 What are some of the unique challenges associated with providing care in your field? And how do you think the annual meeting helps to tackle these?
Well, one of the main issues is that, because this is an ethically sensitive area covering topics such as reproduction, abortion, egg donation, sperm donation, surrogacy, and IVF, it is often on the fire. For example, egg and sperm donations are not allowed in every country across Europe. It is therefore a challenge to have an overview across the whole of Europe, especially from the point of view of the patients. What is also challenging is understanding if a patient's need cannot be provided for in their country, they have to travel across borders. One of the things we are trying to do at ESHRE, and I think we've succeeded so far, is to have access to the European Union (EU) and other bodies and councils across Europe to defend patients and their rights.
Q3
As ESHRE's President, what are your main three objectives and vision for the organisation, especially concerning healthcare professionals in reproductive medicine?
To be honest, ESHRE is a very well-oiled machine. So, there are 20 members of the ESHRE staff, and we're constantly modernising. For example, our education, which used to be the classic going to meetings, is now all available online and digitally. We're now trying to make that even better and more streamlined. We also have our accreditation, which is important to us and to the people who receive it. For instance, embryologists now have a recognised diploma and, as such, more security in their jobs. That is important. The science is also important; I'm a scientist and I'm leaving out science! Science is of course the basis and foundation of everything, and we really tried to push this forward. We have plans to help research more in the future than we are at the moment, as we are, of course, advocates of evidence-based medicine with our guidelines and our good practice recommendations.
Q4
What are the most impactful initiatives
ESHRE has implemented recently to advance patient care and research?
We are very proud to have an ongoing EU research project, the EuMAR project, which is a registry for cycle-by-cycle data on all medically assisted reproduction treatments that we introduced about a year and a half ago. So, if a patient or patient couple goes to clinic A and has a number of treatments that don't work or they're not happy with and they go to another clinic, we will have all the data ready. This is also the case if they cross the border from one country to another, we can still follow them. We can track the outcomes, because what is also very important for us, of course, is that it's not just about helping our patients get pregnant and have a baby, but we also want to help them have a healthy baby, a baby that will grow up to be a healthy person. This project will help us, it's going to be a huge database and a huge piece of software.
Q5
Previously, you were instrumental in founding the ESHRE PGD Consortium, and coordinating the ESHRE’s Special Interest Group Reproductive Genetics. How have you seen these groups influence healthcare in Europe?
Genetics is a smaller part of ESHRE. I mean, the large chunk if you look at the lab side of things is, of course, embryology; but genetics has more and more influence now on how embryologists think and practice. Because initially, preimplantation genetic diagnosis (PGD) was just about helping couples who are at risk of having a child with a genetic disease to avoid that by delivering a diagnosis at the level of the embryo. Healthy embryos were then transferred, and that was it. But now, the more we learn about the very specific things that occur in oocytes in embryos; we are cracking the code of the cell biology of the embryo. And that is, of course, largely thanks to the work that the geneticists have done. And of course, now every clinic has a genetic counsellor, specifically for people who have PGD.
Q6
Reflecting on 40 years of the ESHRE Annual Meeting, how instrumental do you believe the society has been in fulfilling its mission statement “to promote interest in infertility care and to aim for a holistic understanding of reproductive biology and medicine”?
I think we've been instrumental, because at this moment we are the first point of contact if the EU wants something that has to do with reproductive medicine, and we've worked hard to get to that place. A very important example is the regulation around the substances of human origin, which originally was about blood and organ transplantations. We were not involved in the first version, and it was a nightmare for the people in the lab. All the oocytes and the sperm were meant to be handled in sterile lab hoods with these thick rubber gloves, which were impossible to work with. Also, if I donate blood to you, that's from person A to person B, it is very simple. But here you have
an oocyte and a sperm that come together to make a third entity that is then going back into person A. The idea was that sperm had to be treated like blood, with the same levels of sterility. So, there were some complications there, and when we became involved, we stressed that it was not going to work that way. Subsequently, the latest version just came out, and we were very instrumental in changing a number of things.
Q7 Are there any sessions that you’re particularly looking forward to?
One that I would highly recommend is our Live Journal Club. We have a journal club every month, and a group of young, enthusiastic people who are very dedicated to ESHRE choose one paper from Human Reproduction, and then they discuss it. Once a year, there's a live session here, and it's always very engaging. This year, it was on the paper discussing our guidelines regarding 'add-ons' in IVF. Then
there was another session I was excited to attend on basic science, which was the ’Molecular Human Reproduction’ symposium. It was about embryo models that we make these days from embryonic stem cells.
Q8
How do you envision the future of reproductive medicine, particularly in terms of patient care and research advancements?
There's been a lot of evolution. We started strictly with the treatment of patients with tubal problems, such as blocks. Then we went on to treat male infertility, and my centre was instrumental in introducing intracytoplasmic sperm injection. Now, our definition of infertility, for instance, is broad enough to include social infertility, such as same-sex couples and single mothers. I think, more and more, we are a very open and very proudly progressive society.
We are a very open and very proudly progressive society
Interviews
Elisabet Stener-Victorin, Felice Petraglia, Carlo La Vecchia, and Adam Balen spoke with EMJ, sharing details about their career and priorities for the future. Topics discussed included cuttingedge research and advocacy work on the most pressing issues in reproductive health today; polycystic ovary syndrome, reproductive cancers, and endometriosis.
Elisabet Stener-Victorin Professor, Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
Q1 What inspired you to dedicate your research career in reproductive endocrinology to polycystic ovary syndrome?
I developed new PCOS-like rodent models and used already established models to enable mechanistic studies
At the beginning of my research career, I investigated whether electrical stimulation could improve blood flow in the uterine arteries before in vitro fertilisation (IVF). In short, we found that we could regulate sympathetic nerve activity and improve blood flow prior to embryo transfer. My PhD supervisor, Per Olof Jansson, suggested that we try this treatment in clomipheneresistant females with polycystic ovary syndrome (PCOS). That was 30 years ago, and I quickly realised how little we knew about the underlying pathophysiology that led to their reproductive, metabolic, and also psychiatric symptoms. Together with clinicians and basic scientists, I set up a cross-sectional study and conducted thorough research on females with and without PCOS. This included measuring insulin sensitivity with the euglycemic hyperinsulinemic clamp, biopsies of adipose tissue, an in-depth characterisation of fat, and MRI
of the trunk to measure body fat distribution as well as the ovaries and uterus. We measured muscle sympathetic nerve activity, and were the first to demonstrate that females with the syndrome have high sympathetic tone. This in-depth phenotyping largely determined my future projects. In parallel, I developed new PCOSlike rodent models and used already established models to enable mechanistic studies.
Today, almost 30 years later, the PCOS research community has made great progress and I hope that we will soon be able to offer more targeted treatment to women with PCOS.
Q2 Can you elaborate on the significance of understanding genetic versus epigenetic heritability in the transmission of PCOS and associated comorbidities across generations?
Like other complex diseases such as Type 2 diabetes, PCOS is a highly hereditary disease. However, only a small part of the heritability can be attributed to the 20 susceptibility loci identified
by genome-wide association studies (GWAS). Nonetheless, reproductive and metabolic phenotypes are associated with specific PCOS susceptibility loci, supporting the role of genetic factors in pathogenesis. A recent study has shown that males with high polygenic PCOS risk scores have an increased risk of obesity, Type 2 diabetes, and cardiovascular disease, as well as hair loss, suggesting that males are also affected by PCOS. However, it is still unclear how PCOS is inherited. Studies suggest that non-genetic factors may play a role. The variability in inheritance could be due to interactions between genetic and epigenetic factors, with the latter being caused by a different maternalfetal environment.
The Barker hypothesis states that early adaptations to suboptimal conditions in utero lead to unfavourable health outcomes later in life, known as the ‘Developmental Origins of Health and Disease’ hypothesis. Females with PCOS have greater weight gain at the beginning of pregnancy and maintain high levels of circulating androgens and anti‐Müllerian hormone throughout pregnancy. These reduce the aromatase activity of the placenta and have a detrimental effect on fetal development, predisposing the children of PCOS mothers to reproductive, metabolic, and psychological disorders. In addition, PCOS per se is an independent risk factor for gestational diabetes and hypertension. Our findings as well
as other findings support the idea that an unfavourable intrauterine environment could cause the same phenotypic heritability as genetic factors via epigenetic processes, but to date the underlying mechanism is unknown.
Q3
Your lab focuses on bridging preclinical and clinical investigations in PCOS. How important is this approach in advancing our understanding of the condition?
This is of fundamental importance as there is no animal model that fully resembles human PCOS. Our animal models are good tools to study the underlying molecular mechanisms and to explore possible epigenetic inheritance. The development
and use of in vitro culture models of human primary tissue have evolved dramatically with the establishment of organoid systems. These are powerful tools that can be used to further investigate identified molecular markers and to test known and new drugs. The combination of preclinical and clinical projects is therefore a powerful tool for all types of research environments.
Q4
Could you explain the main triggers of PCOS that your lab has identified through the use of PCOS-like mice models?
In several of our experiments in which we exposed mice to continuous dihydrotestosterone (DHT), which specifically activates the androgen receptor, from peripuberty to adulthood, and concomitant treatment with flutamide, we observed a complete preventive effect, clearly demonstrating that the PCOSlike reproductive, metabolic, and behavioural phenotypic traits are triggered by activation of the androgen receptor. When we use the same model to study embryonic and placental development, we observe the same phenomena with an almost complete reversal of fetal growth and placental growth and function. In addition, the DHT-induced PCOS-like model negatively affects the populations of immune cells in reproductive, metabolic, and immunological tissues in a PCOS-like mouse model. These results are of great importance as it is known that immune system dysfunction is a major component of the reproductive complications and metabolic diseases that are highly prevalent in females with PCOS. We also show that immune populations in these tissues are differentially affected, which emphasises the importance of studying the
immune system in the right context; immune cells in the blood do not necessarily reflect what is going on in different tissues. Taken together, these findings support the idea of targeting the androgen receptor pathways in the treatment of PCOS.
Q5
In your studies, have you found evidence to suggest that men can also transmit PCOS? If so, what are the implications of this finding?
We have not yet conducted a study to definitively determine whether men can pass the syndrome on to their daughters. However, we have combined studies in humans and mice to determine how and to what extent PCOS-like reproductive and metabolic traits in men are passed on to future generations. A registry-based study and a case-control study show that sons of women with PCOS are three times more likely to be obese and have high LDL cholesterol, which increases their risk of developing insulin resistance and Type 2 diabetes later in life.
Accordingly, the male offspring of pregnant mice fed an obesogenic diet and exposed to DHT (F0), mimicking pregnant women with PCOS, show reproductive and metabolic phenotypes across generations. The offspring were fed a normal diet and followed into adulthood, where their reproductive and metabolic profiles were examined. To find out whether the symptoms are passed on to the next generations, the first-generation male mice (F1) were mated with healthy female mice to study the reproductive and metabolic profile of the second-generation offspring (F2). The whole process was then repeated for a third (F3) generation to investigate whether the phenotype could
be passed on over several generations. In this way, we were able to demonstrate that obesity and high androgen levels during pregnancy can lead to long-term health problems in the male offspring. These problems can affect the metabolism and reproductive system, and can even be passed on to future generations. We also analysed small non-coding RNAs in the sperm of the three generations of mice and found different types of small non-coding RNAs that were differentially expressed in each generation. Moreover, these molecules overlapped with those we found in the bloodstream of PCOS offspring. These results are important because they highlight the risk of inheriting health problems through the male side of a family, a previously unknown risk. However, in this study, we did not follow the female offspring of first- and second-generation males, and therefore cannot conclude that males can also transmit the syndrome to their female offspring.
Q6
What are some of the most promising discoveries or insights that have emerged through your work with tissue biopsies investigating PCOS treatment?
My group was one of the first to demonstrate that in females with PCOS, multiple transcriptional and epigenetic changes in skeletal muscle and adipose tissue are relevant to the development of the disease, and that muscle contractions partially restore the epigenetic and transcriptional changes in these tissues. In addition, our recent study on skeletal muscle suggests that hyperandrogenic females with PCOS have higher levels of extramyocellular lipids and less oxidative and insulin-sensitive
Type I muscle fibres. These may be key factors leading to insulin resistance in PCOS muscle, while electrical stimulation-induced tissue remodelling may be protective. The current singlecell and spatial reference maps of human adipose tissue, skeletal muscle, and endometrium of healthy females provide a rich resource for the study of genes, traits, and cell type-specific functions. Whether adipose tissue, skeletal muscle, and endometrium of females with PCOS have specific and dominant cell types, and how these specific cell types contribute to the pathology of PCOS is still unexplored and a topic we are currently working on.
Q7
One of your most highly cited papers outlines recommendations for the assessment and management of PCOS. Can you summarise the latest developments in our understanding of this?
This publication, along with many others, is a joint effort of the International Evidence Based Guidelines, to which I contributed a section related to emotional well-being and models of care. The international guideline is updated every 5 years. In 2023, the evidence for PCOS was reviewed, synthesised, assessed for quality and integrity, and presented in a 6,000-page technical report with improved certainty of evidence and strength of recommendations. It is a living guideline that responds to rapidly evolving advances in research.
Q8 Considering your hugely successful career to date, what has been your proudest achievement?
It is difficult to choose the proudest achievement because most of what we have done
builds on each other. If I had to pick one particular moment, it would be the publication of our findings in Nature Medicine,1 in which we were able to show that daughters of women with PCOS are more likely to develop PCOS in adulthood. The remarkable discovery that PCOS-like reproductive and metabolic traits induced by exposure of pregnant mice to DHT are passed on from mothers (F0) to daughters (F1), granddaughters (F2), and even great-granddaughters (F3) attracted a lot of attention. In addition, the transcriptional and mitochondrial disorders of oocytes are associated with this transmission. Importantly, several of the transcriptomic signatures were also detectable in the blood of daughters of women with PCOS, suggesting a role in the epigenetic inheritance of the syndrome in humans. Consistent with these findings, we also show that the sons of women with PCOS are more likely to be obese. These intriguing results suggest that epigenetic changes carried by germ cells and/or somatic cells can transmit PCOS across multiple generations. The intriguing questions we must now ask ourselves are how men are affected and what the epigenetic contribution of inheritance is.
References
1. Risal S et al. Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome. Nat Med. 2019;25(12):1894-1904.
Felice Petraglia
Professor of Obstetrics and Gynecology, University of Florence, Italy; Chair of the Maternal-Infancy Department, University Hospital Careggi, Florence, Italy
Can you share the pivotal moments that led you to a career path in Obstetrics and Gynaecology?
At the end of medical school, it is difficult to choose a path for the future, a specialty for the next 50 years!
At the end of medical school, it is difficult to choose a path for the future, a specialty for the next 50 years! Finding a good mentor is very important, and I was lucky to choose one of the youngest and best professors in my medical school. He was a Professor of Obstetrics and Gynecology and he suggested doing the resident programme while also conducting some basic science research. This programme was very stimulating and gave me a great background. Understanding the research was also useful to realise how fascinating the field of reproductive science is; a multidisciplinary area which goes from hormones to cancer, to pregnancy, and the placenta.
Q2
With over 1,000 publications to your name, how has your research focus changed throughout your career?
Yes, I have been an author and co-author for a large number of publications, starting early in my career. Following my mentor’s suggestions, I started working on neuroendocrinology, specifically focusing on the hypothalamus–pituitary ovarian axis and neurotransmitters and neuropeptides involved in the control of reproductive hormones. The priming experience was done in the lab of Pharmacology at the University of Milano, a crucial imprint. After the end of my residency programme, I was a visiting scientist at the Salk
Institute in La Jolla, San Diego, California, USA, and I developed the field of neuroendocrinology of the placenta, opening a new field for research. The discovery of the secretion of corticotropinreleasing hormone, inhibin, and activin from placental cells allowed the most prestigious publications in Nature and Science. Upon my return to Italy, I continued to study the possible clinical implications of placental neuropeptides, particularly those related to stress. Thereafter, as I progressed in my academic career, my scientific and clinical interests in the last 25 years have been focused on endometriosis, abnormal uterine bleeding, uterine fibroids, and polycystic ovary syndrome (PCOS), and their impact on quality of life, fertility, and pregnancy.
Q3
As a pioneer in the exploration of neuroendocrine peptides and growth factors in the placentalfoetal unit, how has this understanding revolutionised the field of reproductive medicine?
Diagnostic and therapeutic applications were suggested from the discovery of these placental peptides. The role of corticotropin-releasing hormone in the mechanisms of parturition and preterm birth opened a large number of research projects all over the world. Later, new studies showed that measuring inhibin and activin in maternal serum or amniotic fluid may be useful for monitoring the function of the fetal placenta unit and in some pathological conditions (preeclampsia, preterm birth, fetal demise).
Q4
As President of the Society of Endometriosis and Uterine Disorders (SEUD), what recent advancements in the understanding and treatment of these conditions excite you the most?
A very exciting and rewarding event was the foundation of the Society of Endometriosis and Uterine Disorders in 2015, in collaboration with my colleague and friend Charles Chapron. The novel idea was to focus on uterine disorders. Uterine fibroids, adenomyosis, and abnormal uterine bleeding were marginal topics in the congresses, and SEUD gave them priority. Therefore, SEUD immediately became a forum for discussing endometriosis and uterine disorders, covering basic and clinical topics and opening up an interdisciplinary debate. Reproductive medicine was traditionally considered the clinical area; however, in the last 20 years, the increased knowledge of the field opened new scientific and clinical investigations. The introduction of new diagnostic imaging tools (ultrasound, MRI), and the increased understanding that these disorders are associated with technological and genetic advancements. Pain mechanisms, stress, and systemic comorbidities (migraine, gastrointestinal disorders, auto-immune disorders, iron deficiency, and anaemia) are of great relevance for these patients. Diagnosis is improved and personalised treatment (not only surgery or drugs) is under development. The field is growing in a really exciting way. More attention to patients and more attention to women's health issues require a multidisciplinary approach. The success of SEUD is largely due to the increased attention devoted to the diagnosis
and treatment of relevant and epidemiologically frequent women’s health issues.
Q5
Managing endometriosis can be challenging due to its chronic nature and the variability of symptoms. Based on your extensive experience, how can healthcare professionals better support these patients?
The interdisciplinary approach is crucial: good interaction with other colleagues is the best way to help patients with endometriosis. It is not simply a gynaecological disease, it is not a lesion to remove surgically or to treat medically, it is a real syndrome. For good management of endometriosis, you have to organise a multidisciplinary centre. Top-class radiology, pain pharmacology, gastroenterology, and urology have to collaborate with gynaecologists who remain the pivot by using appropriate hormonal drugs, the best minimally invasive surgery or assisted reproductive technologies.
Q6
Your research also focuses on polycystic ovary syndrome (PCOS). What are the key challenges in this field, and how can the international research community tackle these?
PCOS is another model of gynaecologic disease that is now considered a syndrome. Like endometriosis, it was discovered by gynaecologists and considered for decades a reproductive disorder affecting fertility. But now it is well recognised as a syndrome because of the metabolic, cardiovascular, and dermatologic components. Therefore, the new diagnostic and therapeutical strategies include a variety of options. The use of anti-diabetic
PCOS is another model of gynaecologic disease that is now considered a syndrome
drugs and cosmetic treatments confirms the multidisciplinary nature of PCOS. The effects on fertility and pregnancy outcomes remain a primary evaluation in obstetrics and gynaecology, but endocrinologists and cardiologists are playing a major role in taking care of these patients.
Q7
You've received numerous awards for your contributions to gynaecology and endocrinology. Which of these recognitions holds the most personal significance to you and why?
There are three major recognitions that hold personal significance. Firstly, becoming president of the Society for Reproductive Investigation (SRI) in the USA in 2008–2009, the first nonAmerican president of the Society (named the Society of Gynecologic Investigation, SGI). Secondly being Editor-in-Chief
of Human Reproduction Update between 2012–2018, the Journal number one in terms of impact factor in the field of obstetrics and gynaecology. During this period of time, HRU reached the IF with double figures! And finally being co-founder of SEUD in 2015 and President between 2018–2021.
Q8 Your major scientific interest is devoted to women's health. How do you see the future of women's health evolving, and what challenges need to be addressed to improve outcomes?
The biggest challenge for future gynaecologists will be to pay more attention to women’s health, to carefully evaluate the symptoms, the risk factors, and the environmental and psychological disruptors which may contribute to the development of a specific disease. To be a good gynaecologist, it will be necessary
to have good skills in surgery and obstetric care, but they will need to have a much wider view and medical culture, to be more familiar with genetic or epigenetic tests, an open mentality for the new molecular and technological advances.
Q9
Reflecting on your career to date, what trends or shifts have you observed in the field of reproductive medicine over the years?
In the last 40 years, reproductive medicine made a great shift. New drugs, new surgical technologies, new assisted reproductive methodologies, and cryopreservation of gametes and embryos are now part of the daily practice. In parallel, patients’ awareness also increased, and associations and social media are contributing to giving more information to women.
Department of Clinical Sciences and Community Health, University of
Milan, Italy
The key finding was a substantial reduction in ovarian cancer risk in women who had used oral contraceptives with a duration-risk relationship
After receiving a Medicine degree from the University of Milan, you completed a Master of Science in Clinical Medicine (Epidemiology) from the University of Oxford. What inspired this career path?
When I graduated from Oxford in the early 80s, epidemiology was a key, innovative discipline. There were several important discoveries at that time, such as quantifying the link between tobacco, asbestos, and lung cancer and a large number of other neoplasms and diseases. The key role of time since first exposure (long latency) to asbestos on mesothelioma, the risks and benefits of oral contraceptives, and the role of human papillomavirus (HPV) on cervical cancer were also being investigated. Furthermore, there was a focus on occupational carcinogens and toxic substances. At that time, epidemiology was a key discipline from a medical and public health viewpoint. That was essentially why I chose to specialise in this field. Epidemiology was very exciting in Oxford because Richard Doll, Richard Peto, Jack Cuzick, Julian Peto, and Nick Wald, were there, so it was great to work with the major figures in the field.
Q2
One of your most highly cited papers is an analysis of 45 epidemiological studies, including over 23,000 women, that specifically investigates the link between ovarian cancer and oral contraceptives. Could you discuss any notable findings or trends in the risk related to oral contraceptive use and its association with ovarian cancer?
This was a major discovery in the field of epidemiology in the 80s. The first papers were published in the early 80s, with larger studies being published in early 2000. The key finding was a substantial reduction in ovarian cancer risk in women who had used oral contraceptives with a duration-risk relationship. There is approximately a 40% risk reduction in people with longterm oral contraceptive use. That is important because ovarian cancer is a very serious disease. In high-income countries, it is the major cause of cancer deaths among gynaecological neoplasms. Early diagnosis is still difficult despite various trials, and the improvements in management have been not substantial. Ovarian cancer remains a serious disease, but it is reassuring that
mortality from ovarian cancer has been appreciably decreasing over the last several decades. A similar pattern of risk has been observed for endometrial cancer. The important message here is that the protection of oral contraceptives on these neoplasms is long-lasting. Oral contraceptives are associated with a modest excess risk of breast and cervical cancer, but that is restricted to current use. Oral contraceptives are mainly used by women aged between 18–35 years; and so, in terms of absolute risk, the excess risk of breast and cervical cancer is minor, cancer at a young age is very rare, while long-term protection against endometrial and ovarian cancer is important.
Q3
How do lifestyle factors such as diet and tobacco impact the development of ovarian and reproductive cancers, based on your extensive research in cancer epidemiology?
These factors do not have as much impact as the favourable effect of oral contraceptives. However, it is possible that dietary factors have some impact on ovarian cancers. Ovarian cancer incidence is a bit lower in Mediterranean countries and in central Northern Europe, so the Mediterranean diet and nutrition (less frequently overweight) have some favourable impact, but this is difficult to quantify and hence difficult to provide specific advice. The association with tobacco is restricted to a minority of ovarian cancers, mucinous ones. Around 20 neoplasms are associated with tobacco smoking besides lung cancer, but the ovary is not one of the most affected by tobacco. Likewise, there is not much you can do regarding diet and lifestyle
to reduce cancer ovarian risk. Other reproductive cancers are more amenable to control by nutrition and diet. For example, endometrial cancer is strongly associated with overweight and obesity, so healthcare professionals can advise women to control their weight to reduce endometrial cancer risk. Cervical cancer is a viral-related disease, it is related to several types of HPV, and hence to sexual habits. However, the issue now is essentially HPV vaccination. Women in high-income countries born after the 1990s have been vaccinated, with vaccination more recently being expanded to men as well. For endometrial cancer, you can reduce your risk if you control your weight; for cervical cancer, you can get vaccinated and tested. However, for other reproductive cancers, this is not possible, with the exception of oral contraceptives to reduce the risk of ovarian cancer–a sort of hormone-prevention.
Q4
In your opinion, what are the key challenges in early detection and screening methods for ovarian cancer, and how do you propose addressing them?
Various trials have been completed over the past several decades, the major one being the PLCO, conducted in the USA. However, there no is evidence that screening can have a favourable impact on ovarian cancer mortality. We have no serum markers. The diagnosis is made when the disease has already spread to the peritoneum. Most ovarian cancers are derived from the surface of the ovary or the fallopian tube and only a few of them give rise to a large mass. This mass can be discovered either through a clinical visit or echography, but most of them are
diagnosed when the disease has already spread. Unfortunately, there is not much to do now in terms of early diagnosis.
Q5 With over 2,650 publications to your name and involvement in international research consortia, what are some global trends or disparities you've observed in the incidence and mortality rates of ovarian and other reproductive cancers?
Ovarian cancer is a common disease particularly in high-income countries as it is more common in middle age. International trends have been largely affected by the wide use of contraceptives, which started with the generations born in the 30s in the UK and North America and those born in the 40s or 50s in most other European countries. That has had a substantial favourable impact on ovarian cancer mortality and these trends remain favourable. Also, we now see the impact of improved surgical management and the development of effective drugs such as chemo- and immunotherapy mainly in highincome countries.
Q6 What are the key priorities of your role as a member of the Research Project Review Panel (RP2), that assists the Sexual and Reproductive Health and Research (SRH) department of the World Health Organization (WHO)?
We essentially review protocols that are proposed. They are mostly from middle- and lowincome countries, covering a wide range of topics involving reproductive health. When I started this role in the 90s, a large number of protocols involved contraception, and not only oral contraceptives
but all types of contraception. Specifically, research was focused on the advantages and risks of contraception in the population, because at that time, a major problem was overpopulation and thus the control of the population. Interestingly, we are now dealing with the opposite, as it is now that we are suffering from a decreasing fertility and number of births. So, the project has shifted from contraception to diseases, including HIV. Apart from that, the project review panel now covers all aspects of reproduction with a key focus on middle- and lowincome countries.
Q7
Another of your research papers with over 3,561 citations explores hormone replacement therapy (HRT) and breast cancer. What has changed in our understanding of the link between the two since its publication in 1997?
Mainly our study, and several other observational studies, case-control studies, and cohort studies, investigated the risk of breast cancer in women who were using HRT. At the end of the 90s, our study but also a large number of other studies conducted in Northern Europe and North America, revealed that HRT, particularly combined oestrogens and progestogens, were associated with some increase in the risk of breast cancer. It is not a large increase, the risk for women using HRT for 5 years increases by around 1.2 to 1.3, and for 10 years it increases from 1.5 to 1.6. Until 2003, until the publication of the Women's Health Initiative, which was not an observational study, but a clinical trial organised and supported by the US Institutes of Health (NIH) showed that HRT, and particularly combined HRT, were not only related to excess cancer risk, which was something
we already had quantified with our observational study, but also with an excess risk of thrombosis. HRT was also shown to have no real benefit, so the risk-benefit evaluation of HRT changed after 2003 and long-term use was discouraged. Now HRTs are used for a few months or a limited number of years for women with serious menopausal symptoms, but not for several years anymore.
Q8 Ahead of Ovarian Cancer Awareness
Month, how can we advance our understanding of ovarian cancer, and what are the priorities for future research in this field?
In the short to medium term, I would like to prioritise innovative treatments. We have several new drugs, mainly immunotherapy, which have shown advantages across several solid cancers and that can be extended to ovarian cancer. Further, genomic characterisation of various neoplasms permits the use of personalised medicine that has been advantageous for several common cancers including lung, colorectal, and also ovarian cancer. However, further research and support is important. I am less optimistic about early diagnosis. It is conceivable that blood tests are developed, there are now several specific blood tests which are undergoing clinical trials. The idea of these tests is to detect signals of early invasive neoplasm, even in the absence of an identification of the site and type of neoplasm. Whole-body screening is then required to detect the site of origin. This may be a possibility for ovarian cancer too, but we have to wait for the results of clinical trials. We may over-diagnose several neoplasms including ovarian cancer leading to increased personal and societal burden.
Q9 Considering your hugely successful career to date, what has been your proudest achievement?
When the original findings were first reported in the mid-90s, there was an association between diabetes and colorectal and liver cancer. At that time, in Italy, we were in a very good position to study liver cancer because it was very common in Italy due to the frequency of hepatitis B and C due to high alcohol consumption. The association with diabetes was important for liver cancer. Another original contribution we published at that time revealed that there was an inverse association between coffee consumption and liver and colorectal cancer. Coffee may have a favourable effect through metabolic pathways, and this was not published before.
Adam Balen
Leeds Centre for Reproductive Medicine, Leeds Teaching Hospitals NHS Trust, UK
After qualifying as a doctor in 1983, who or what inspired you to pursue a career in obstetrics and gynaecology?
The future of medicine lies with genomics, gene therapy, and a more personalised approach
I started off with no particular direction in mind and began training to be a general practitioner (GP). Realising that I needed more stimulation, I decided to go to South Africa for a year in 1985, where I worked in an old Catholic missionary hospital in the middle of the homeland of Lebowa (now Limpopo Province) in the Northern Transvaal. There, I worked as one of three doctors, looking after approximately 350 patients. I was responsible for maternity, paediatrics, and women’s health. In those dark days of apartheid, there was huge deprivation, malnutrition, and heartbreakingly high levels of infant and maternal mortality. Our clinics were huge, with long lines appearing in the early hours. Relatives slept on the floor by their sick family members. Children and babies slept in wooden boxes as there weren’t enough beds.
The conditions were challenging; sometimes operating by torchlight at night when the electricity went out. I regularly performed a whole caesarean delivery as the only doctor present: giving the anaesthetic, doing the operation, delivering and resuscitating the baby, and then completing the surgery. Once, we saved a woman’s life by performing a splenectomy for a ruptured spleen caused when the vehicle she was travelling in tumbled off the dirt track (we were 2 hours from the closest tarmac road). We used
an anatomy textbook in theatre to guide us! Sometimes I was either on my own looking after the hospital when my colleagues had a few days off, or I would drive 2–3 hours on dirt roads to ‘babysit’ another hospital in the group whilst its doctors took a break.
My experiences in the arid homelands of South Africa at St Rita’s Hospital as a very junior doctor were incredible and gave me the confidence to develop pioneering treatments and surgery later in my career when developing my paediatric and adolescent gynaecology work.
In 1986, I returned to London to do 6 months of obstetrics & gynaecology in my GP rotation and realised this was my vocation. So, I stepped into the world of obstetrics and gynaecology and never looked back.
Q2You worked with early pioneers of in vitro fertilisation (IVF), namely Bob Edwards and Howard Jacobs. How did this experience inspire you to create one of the UK’s largest IVF units; Leeds Fertility?
I was very privileged to have spent 4 years working with one of the greatest endocrinologists of our era, Howard Jacobs; both my mentor and a great friend. He was helping develop the ovarian stimulation protocols for IVF in conjunction with the Bourn-Hallam clinics in Cambridge and London. Those were the very early years of IVF, with Louise Brown, the first IVF baby, having been born in 1978, which was the year I had started as a medical student
at St Bartholomew’s Hospital in London, UK. Bob Edwards, Nobel Laureate, and the scientist behind the development of IVF, had initially commuted between Cambridge and Oldham, where the gynaecologist Patrick Steptoe had introduced laparoscopic surgery to the UK and enabled access to the human ovary for the first time. They then founded Bourn Hall, not far from Cambridge, after their successes in Oldham. The Hallam Medical Centre became the London arm of Bourn-Hallam and was a hotbed of research and the training ground for many of us who have developed successful careers in reproductive medicine. Real-time ultrasound was evolving by the time I started doing egg collections, and we were amongst the first to use transvaginal ultrasound, although I also learned to do laparoscopic egg collections in the beginning. Bob was a truly inspirational man, and we enjoyed many fruitful and entertaining conversations.
Howard was then leading the way in the management of polycystic ovary syndrome (PCOS), which is
when my interest evolved and has continued to this day. Therefore, I had a solid grounding in both gynaecology and endocrinology. Having completed my Doctor of Medicine thesis on ‘The hypersecretion of luteinising hormone (LH) in PCOS’, I then went on to complete my clinical training and actually wrote my first book, ‘The CTG in Practice’, on foetal monitoring in labour whilst still a registrar in London. I then went to Oxford to complete subspecialty training in reproductive medicine, where I continued research into the evolution of PCOS in adolescent girls and wrote my second book, ‘Infertility in Practice’, which has recently been revised in its 5th edition and sold worldwide with translations in Chinese and even Greek.
I was attracted to Leeds, which had developed a thriving IVF service and was leading the world with ground-breaking research on ovarian tissue and oocyte freezing, led by Roger Gosden and subsequently Helen Picton, a close friend and collaborator
of many years. I have been a consultant in Leeds since 1996, and with my colleagues, we have developed one of the largest and most comprehensive centres in the UK. I am very proud of all the doctors, nurses, and scientists who have trained with us and I am really pleased that, when I retire, I will be leaving the department in excellent hands.
Q3 Your work has focused on PCOS. Please can you shed light on how this condition affects the quality of life and longterm health of your patients?
PCOS is a multi-faceted condition that affects girls and women throughout their life course with a constellation of symptoms that may change over time and affect general health, reproductive health, and quality of life in a variety of ways. These range from struggling with weight gain, disordered eating patterns, body image issues relating to hirsutism, acne and alopecia, menstrual cycle disturbance, and infertility. And then, as time goes on, there
is an increasing risk of metabolic conditions associated with insulin resistance and diabetes.
I have always worked as a full-time National Health Service (NHS) clinician, and I have considered my research to have been the “icing on the cake,” usually performed out of hours and at weekends. I have looked at many aspects of PCOS, from its evolution in adolescence, its effect on quality of life (we developed a health-related quality of life tool, especially for those with PCOS), and the management of dermatological manifestations. I have been very interested in the ethnic variations, particularly the high prevalence of insulin resistance and PCOS in the South Asian population, and the greater symptomatology at a lower body weight than their White European counterparts, probably a reflection of the ‘thrifty genotype’ hypothesis.
We performed some of the earliest studies on the use of metformin both before and during fertility treatment. We also worked on a range of novel ovulationinduction protocols. The University of Leeds gave me a personal chair in 2004 in recognition of this research and I was awarded a Doctor of Science in 2011, which was also a great honour.
The gonadotrophin preparations we were using were extracted from the urine of menopausal women, and at one stage there was concern, proven later to be unfounded, that there might be a risk of transmission of variant Creutzfeldt–Jakob disease. For a few years, I found myself at meetings with neurologists and Creutzfeldt–Jakob disease specialists trying to ascertain whether there might be a risk; an example of how medicine can expand into so many different pathways.
Q4You have been involved in several international guideline development groups for PCOS and infertility. How do these collaborations influence clinical practice globally, and what has been your most rewarding experience from these efforts?
Collaborations, whether national or international, are the best ways of achieving progress and at the same time learning from others’ experiences and research. I have been so fortunate to have made so many enduring friendships with colleagues from all over the world. I have also been lucky to have travelled the world and given lectures on every continent except Antarctica. I chaired the ESHRE Special Interest Group on Endocrinology for a few years and we took a training course around Europe and into Russia and Ukraine, which was a very rewarding exercise.
Guidelines have to be developed with consensus and an eye not only to the evidence but also a pragmatic approach to what’s achievable and cost-effective. It has been a great privilege to have collaborated with the world’s leading experts in the field of PCOS. I was, I believe, the youngest participant at the Rotterdam Consensus Meeting back in 2003, which gave us the modern definition of PCOS. Since then, some really great groups have evolved, culminating in the Global PCOS Alliance, led by Helena Teede and Rob Norman from Australia, which has produced first-class, evidencebased guidelines covering all aspects of PCOS. My role in this was predominantly in the management of infertility, having previously led the WHO guideline on ovulation induction for PCOS. My various roles in the Royal College of Obstetricians and
Gynaecologists (RCOG) have also enabled me to organise scientific study groups, consensus workshops, and large meetings for a worldwide audience.
I also devised the new International Federation of Gynecology and Obstetrics (FIGO) classification of disorders of ovulation and was the joint first author when we published it in 2022. This, I feel, was a truly important piece of work, replacing the former World Health Organization (WHO) classification, which has developed from a few people agreeing on a rough algorithm rather than a true international consensus process, which we achieved through FIGO. The HypothalamicPituitary-Ovarian-PCOS (HyPO-P) classification provides a clear, logical, and comprehensive overview of every cause of ovulatory disturbance and should act as a learning tool and research aid for, hopefully, generations to come. The detailed review we published on this in Human Reproduction Update earlier this year is one of the longest papers I have written!
Q5 Are there any innovations on the horizon for the treatment of PCOS that you are excited about?
We need to get to the bottom of the genetic and ethnic variations and develop targeted treatments that are fine-tuned to an individual’s needs, whether inducing ovulation or managing the dermatological and metabolic manifestations. Tackling the obesity crisis is also key to managing the ever-increasing numbers of people with PCOS. Some of the newer innovations in weight reduction medicines are exciting but also challenging due to cost and potential
teratogenicity, so they may only be prescribed to people not wishing to conceive. The future of medicine lies with genomics, gene therapy, and a more personalised approach. We do, however, require a significant investment in resources and manpower to be able to deliver the care that we aspire to, and that our populations deserve. PCOS is very common, affecting at least 10% of women, and yet it is underdiagnosed and poorly managed. My work with patient support organisations, in particular Verity and The Fertility Alliance in the UK, brings into sharp focus the distress experienced by many millions of women worldwide with this lifelong and debilitating condition.
Q6You have also developed a multidisciplinary clinic for the management of Paediatric and Adolescent Gynaecology (PAG) problems and congenital development conditions (also known as disorders or differences in sexual development [DSD]), can you please tell us more about that?
This has been another great privilege. When I started, PAG
was an emerging specialty. I co-founded the British Society in 1997 (BritSPAG) as a society representing a range of specialists from gynaecologists, paediatric urologists and surgeons, endocrinologists, psychologists, and specialist nurses, to name a few. We have written national and international guidelines and position papers, and I have edited two textbooks with global leaders in the field. Looking after children with their parents and families during adolescent years as they develop confidence as young adults, and then throughout their reproductive years, helping with their sexual function, fertility, and reconstructive surgery when required, has been one of the most rewarding aspects of my work. Many people I see in my clinic have extremely rare conditions and a range of complex co-morbidities. To help these patients through their life course is not only hugely rewarding but often a humbling experience.
One case that stands out is the case of a young woman aged 16 years who came to see me 25 years ago with pelvic pain and no
periods. She had been born with a uterus but no cervix or vagina, hence the pain as her menstrual blood had nowhere to go. Most specialists would have removed the uterus. But I attempted a reconstruction, creating a neovagina and cervix, thereby enabling menstruation and the potential for fertility. Several years later, she tried to conceive, but without success. We tried fertility treatments including IVF, which sadly didn’t work, and both the NHS and her own funds ran out; many tears were shed. She then conceived naturally, and I helped deliver her baby by caesarean section on her 40th birthday; more tears all around.
Q7 In your role as Chair of the NHS England working group on funding for IVF, what strategies have you implemented to ensure equitable access to fertility treatments across the UK?
We did a huge amount of work developing a benchmark price over the course of about 5 years to form the basis for equitable funding across the UK. Sadly,
we didn’t get where we would like to be. In the UK, we have led the world in the development of IVF and yet we cannot fund a service that provides for our population. Furthermore, we have a ‘postcode lottery’ with huge geographical variations in provision. Scotland is the best, providing three full cycles of IVF on the NHS, as recommended in the National Institute for Health and Care Excellence (NICE) guidance; whereas some areas of the UK provide no funding at all. Having a family is a human right, not a luxury. And, if you want to look at the harsh economics, the contribution to society of any child born as a result of IVF far outweighs the cost of the treatment. I did my best when I was Chair of the British Fertility Society (BFS) to raise these issues within the NHS. I hope to have further opportunities in the future to move this agenda forward.
Q8Looking more broadly at women’s health, what do you consider to be the most pressing issues, and how can the medical community address these?
Women’s health is poorly served in the UK. GPs no longer have to spend time in obstetrics and gynaecology during their training, so girls and women often do not get the care they need. Many conditions, for example, PCOS and endometriosis, are left undiagnosed for years. The term ‘benign gynaecology’ is unhelpful as it almost makes light of the significant symptoms experienced by women with a whole variety of non-malignant conditions, which are nonetheless chronic and debilitating. Furthermore, the gynaecology ward is usually the first to be used for acute medical, surgical, or elderly care patients when hospitals become over-filled during the winter months and
even, these days, at other times of the year. The COVID-19 pandemic also had a disproportionate effect on waiting lists for both gynaecological outpatients and surgical procedures.
We need better prevention and health education rather than the reactive system we have now, which doesn’t provide nearly enough time in GP or hospital appointments to truly get to the bottom of peoples’ problems, encompassing both health, socioeconomic, and psychological needs. There is no doubt that, to coin a phrase, the ‘NHS is broken’ and needs a total overhaul. There are also natural concerns about maternity services; but that’s a topic for another day.
Q9 Can you discuss the importance of preventative care in women's health and what strategies can be employed to encourage more women to engage in regular health screenings?
This is why I founded ‘The Fertility Education Initiative’ when I was Chair of the BFS, and we have managed to change the national curriculum in schools to ensure all young people have a better understanding of their reproductive health and are empowered with the knowledge to, hopefully, have the desired family they want at an appropriate time.
I have also written ‘The Fertility Book’ with my wife Grace Dugdale, who is a nutrition scientist and an expert in preconception health. The book guides people on their fertility journey, whether to conceive naturally or with assistance, and provides evidence-based advice about lifestyle, diet, supplements, and external factors that affect reproductive health.
Nutrition and lifestyle are key and should be learned by families so that children growing up are set on a good trajectory for life. It is a travesty that fresh, nutritious food is so expensive, whereas ready meals with their addictive ingredients are cheap. Far too many women embark on their fertility journey nutritionally depleted, being low in essential vitamins and minerals as well as being overweight, leading not only to problems conceiving but also increased risks for miscarriage, other problems in pregnancy, and importantly, worsened fetal outcomes and the increased risk of children to have health problems that can affect them for life.
Q10Given your media and public speaking experience, how important is the role of media in raising awareness about reproductive health issues, and how do you ensure the information shared is accurate and helpful?
The ‘media’ is vitally important, if we have balanced and not sensationalist reporting. Reproductive medicine is exciting, and some aspects are ethically challenging. Articles need to be appropriately detailed rather than picking up on soundbites that can be misleading and sometimes even frightening to a lay audience. I have done my best to support journalists in their quest for balanced and informative articles.
Modern technology has allowed us to hold webinars and communicate with large audiences. I must confess, however, to not being very good myself at tweeting or using the various other online platforms. It has been an honour to have worked in the whole field of reproductive medicine. I have had some very humbling experiences looking after people who have come to me for help, many of whom have found me via media exposure and public engagement. I hope to be able to continue to communicate my ideas and knowledge for years to come.
Nutrition and lifestyle are key and should be learned by families so that children growing up are set on a good trajectory for life
Infertility Among Healthcare Professionals: A Comprehensive Review
Editor's Pick
As a healthcare professional and fertility specialist, I am biased, but my editor’s pick is this article by Richard et al. It is a fantastic narrative review investigating the intricate link between healthcare professionals and fertility. The impact of shift work and the finding that 76% of female surgeons are seeking medically assisted reproductive treatments are both startling. The delay in child-bearing due to years of demanding training schedules should make all healthcare professionals think about their life goals and the timing of major life events.
Justin Chu
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
Introduction: Infertility globally poses significant physical, emotional, social, and economic challenges. Despite extensive research on infertility in the general population, there needs to be more understanding regarding its prevalence and effects on healthcare professionals. This article addresses this gap by providing a comprehensive overview of infertility in the healthcare industry, highlighting its unique aspects and implications. Methods: The search strategy for this literature review yielded 1,323 studies from the following databases: PubMed, Google Scholar, and ScienceDirect. After duplicate removal and screening of the articles using the authors’ inclusion and exclusion criteria, 54 full-text articles were assessed for eligibility. Of these, 21 articles included surveys, cross-sectional, and cohort studies, followed by reviews.
Results: Female healthcare workers, especially emergency physicians and surgeons, face higher infertility risks due to occupational stressors, with 76% of female surgeons utilising assisted reproductive technology for conception, well above the general population. Sleep deprivation from shift work exacerbates infertility, while long hours increase pregnancy complications. Hazards like radiation and chemicals contribute to menstrual disorders and congenital anomalies. Gender disparities persist, impacting career and lifestyle choices among otolaryngologists.
Discussion: Infertility poses challenges for healthcare professionals, with a limited understanding of male infertility. Female surgeons often delay pregnancy due to training, relying on assisted reproductive technologies. Gender differences in divorce and childbirth rates highlight unique challenges females face, including infertility. Long work hours and occupational hazards further complicate fertility issues. Sleep deprivation affects reproductive hormones, impacting fertility across all ages.
Conclusion: Studies indicate that female surgeons face heightened pregnancy risks, underscoring the need for job changes to prioritise parenthood. Career pressures affect female physicians' decisions to start families, potentially perpetuating gender inequities. Further research on male infertility is crucial for addressing healthcare industry challenges.
Key Points
1. Infertility affects approximately one in six adults, with an estimated one in four female physicians being affected. However, data regarding infertility among male physicians are currently unavailable.
2. This systemic review of 21 papers focusses on the issue of infertility among male and female healthcare professionals, aiming to identify the factors leading to infertility since there is a lack of understanding regarding its prevalence in healthcare workers.
3. The impact infertility poses on healthcare workers reveals a lack of adequate knowledge, as well as increased difficulties, especially in female healthcare workers. The findings of this paper suggest the requirement of policy changes to better support pregnant healthcare workers, and address the overwhelming career pressures that negatively affect family planning among healthcare workers.
INTRODUCTION
The healthcare industry is known for its demanding and stressful working conditions. The complex link between job-related stressors and reproductive outcomes among healthcare workers is an intriguing, yet understudied, field of research, despite the demands of this line of work. Infertility globally poses significant physical, emotional, social, and economic challenges. Despite extensive research on infertility in the general population, there is a lack of understanding regarding its prevalence and effects on healthcare professionals. Although studies have shown the general effects of work stress, the precise influence on fertility continues to be a crucial issue requiring investigation. For instance, female surgeons have been reported to have a higher incidence of infertility and pregnancy difficulties than the general population.1
Also, due to their training and early careers, surgeons frequently put off getting pregnant and having children. However, less is known about the risks of infertility and pregnancy difficulties for female surgeons.2 Numerous studies have also shown a higher incidence of highly educated females not having children. In addition, physical stressors such as shift work, prolonged standing, and lifting have generally been linked to a higher risk of spontaneous abortion or preterm birth.3 Therefore, the conflict between biological and professional clocks may be a very significant problem for many female physicians, and may have serious consequences for career advancement and job happiness.4 This article aims to address this gap by providing a comprehensive overview of infertility in the healthcare industry, highlighting its unique aspects and implications.
METHODOLOGY AND STUDY SELECTION
The search strategy for the literature review yielded 1,323 studies from the following databases: Pubmed, Google Scholar, and ScienceDirect. After duplicate removal, and screening of the articles using the authors’ inclusion and exclusion criteria, 54 full-text articles were assessed for eligibility. Of these, 21 articles included surveys, crosssectional and cohort studies, followed by reviews. Table 1 represents inclusion and exclusion criteria, and Figure 1 represents the identification, screening, and inclusion of studies via databases.
REVIEW
Data that were consistent throughout the literature, and which were selected to understand the factors that led to infertility in healthcare professionals, proceeded with a common trend: female healthcare workers (especially emergency physicians, plastic surgeons, and nurses) were more drastically affected than male healthcare workers. Female physicians, especially emergency physicians, face various psychological and environmental hazards on a day-to-day basis at their workplace.5 Although physicians reported a pregnancy success rate of 84% for all attempts, female emergency physicians had a much lower pregnancy success rate of only 73%, which created a striking indication of the association between occupational stressors and issues related to fertility.5,6
Male infertility in the healthcare profession was a topic that the staff themselves were quite oblivious to.7 Out of 556 people who took part in the study, 89.39% of them reported that “men feel depressed to be associated with infertility”. This ingrained stigma, irrespective of academic background, creates an environment where people refuse to be educated about the issue. A total of 92.81% reported never taking part in any programmes or training regarding male infertility.7
Like female emergency physicians, female surgeons were reported to suffer from emotional hazards that affected pregnancy, and even impaired their fertility.8 Female surgeons were also reported to have fewer biological children when compared to males in their field, due to the stringent requirements of surgical training and the job itself. Female surgeons showed a higher incidence rate of utilising assisted reproductive technology (ART) to conceive. Of the total number (n=1,021) surveyed, 784 females attempted to achieve pregnancy. Of that number, 32% (n=251) reported difficulty with fertility. Of those reporting difficulty with fertility, 84% (n=210) went on to have a formal fertility workup. Seventysix percent (n=180) of the females reporting difficulty with fertility used ART to attempt to achieve pregnancy.
Comparatively, in the general American population, infertility was reported in only 10.9% of females, only 11.0% sought infertility treatment, and only 5.2% utilised ART. Remarkably, at least 13% of the infants born to female surgeons were conceived using ART. In addition, female surgeons had 1.4% biological children, which is lower compared to the normal population. The average age at first pregnancy was 33 years, whereas the national average was 23 years. The implementation of ART increased the surgeon's average age at first birth to 35.4 years. With regard to surgical specialities, otolaryngology recorded the highest rate of infertility (29%), followed by general surgery at 22%, and orthopaedics at 18%.
Complications during pregnancy (such as gestational hypertension and preeclampsia), along with complications after the pregnancy (such as musculoskeletal disorders, nonselective Caesarean delivery, and postpartum depression) were much higher among female surgeons when compared to female non-surgeons.
A study comparing female surgeons with the general population reported greater infertility rates and pregnancy-related complications in female surgeons.10 These complications include spontaneous abortion, preterm delivery, fetal growth, and
Table 1: Inclusion and exclusion criteria.
Inclusion criteria
Studies involving healthcare personnel who have experienced infertility were included. The authors considered studies conducted in various settings and populations.
Studies examining the relationship between work-related stressors and fertility outcomes, pregnancy outcomes, and attitudes toward infertility treatments and donation, and having infertility as the primary outcome, were considered.
Studies published in English language only.
Only peer-reviewed primary research studies, including cross-sectional, cohort, case-control, and longitudinal studies, were considered.
Exclusion criteria
Animal and in vitro studies, as well as studies focused solely on people with other occupations, were excluded, as the primary interest is in healthcare professionals.
Studies that lack sufficient data or information on the link between infertility and healthcare were excluded.
Duplicate studies or overlapping datasets were excluded to avoid data redundancy.
Editorials, conference abstracts, and studies lacking original data were excluded.
inclusion of studies via databases.
Records identified from: PubMed=784
Scopus=315 Science Direct=224
Records screened (n=184)
Reports sought for retrieval (n=91)
Reports assessed for eligibility (n=54)
Studies included in review (n=21)
PICO: population, intervention, control, and outcomes format.
Records removed before screening: Duplicate records removed (n=496)
Records marked as ineligible by automation tools (n=0)
Records excluded (n=93)
Reports not retrieved (n=37)
Reports excluded: Didn't meet with PICO (n=22) Full text unavailable (n=15) Doesn't meet inclusion criteria (n=14)
Figure 1: Identification, screening, and
congenital abnormalities. The factors that contribute to this are exhausting working conditions, older age, and the presence of reproductive hazards such as radiation, surgical smoke, and anaesthetic gasses in operation theatres. Therefore, measures must be taken to control detrimental exposures, and female surgeons should be aware of their potential harms.
Rangel et al.2 and Pfennig et al.5 both illustrate that the most common workrelated stressor is the sheer amount of time spent at the workplace. A significantly higher risk of infertility with long working hours was associated with females younger than 40 years.4 Females who were experienced with contraceptives also exhibited an increase in their risk of infertility with longer durations of work. Younger physicians exhibited higher levels of emotional exhaustion, depersonalisation, and even a lower personal sense of accomplishment, all of which are detrimental to the emotional status of the physician. Physicians without children in their household had much higher emotional exhaustion and depersonalisation scores when compared to those with children (emotional exhaustion subscale of Maslach Burnout Inventory, and depersonalisation subscales were used to gather the scores). Ages between 36–45 years reported the highest percentage (58.2%) of those who fall under moderate-to-high emotional exhaustion. In contrast, the age group below 35 years exhibited the highest percentages for both depersonalisation and lack of personal accomplishment (51.4% and 77.2%, respectively).11 Hazards such as anaesthetic gas and radiation exposure at the workplace affected 30.4% of the pregnancies, and 8.5% were seeking infertility treatments due to the exposure. Female physicians (no specific subspecialty) showed a higher rate of infertility treatment and miscarriages compared to the general population. This increased rate of infertility and miscarriages was attributed to the lack of personal accomplishment and depersonalisation experienced by them.
Succumbing to the demands of the occupation was also faced with the natural limitation of age.
A total of 24.1% of the healthcare professionals from a White background who tried to conceive ended up receiving a diagnosis of infertility.12 This was primarily due to age or diminished ovarian reserve (29.3%), ovulatory dysfunction (29.3%), and male factor infertility (17.2%). It also illustrated how the females mostly underestimated their likelihood of conception at a particularly younger age. According to them, the average estimate regarding the chance of conceiving after a year of unprotected intercourse was 68.3% at age 30, 56.1% at age 35, 33.1% at age 40, and 18.9% at age 45.
Regarding radiology residents, there is an additional hazard of radiation exposure to the fetus during pregnancy.13 Since female physicians represent a minority in the specialty of radiology, programmes may lack formal written policies for fluoroscopy and pregnant workers.
Sleep deprivation is another factor contributing to infertility. Shift work among healthcare workers often involves working at night.14 Hence, the assigned time for sleep coincides with the time of the high circadian alternating signal. This leads to sleep disturbances along with imbalances between the imposed light-dark cycle and endogenous circadian systems. Improper sleep among female shift workers causes pregnancy loss, amenorrhoea, anovulation, and failed embryo implantation. This is thought to be because lack of sleep suppresses the production of melatonin, and excessive hypothalamic-pituitary axis activation. Changes in gonadotropin and sex hormone secretion have also contributed to infertility. In middle-aged and older males, sleeplessness has been associated with decreased testosterone levels.
A cross-sectional study conducted in Japan, among female physicians, demonstrated the relationship between pregnancy complications and long working hours.15 It was found that females who worked 71 hours or more per week had a three-fold greater risk of experiencing threatened abortion in comparison to those who worked 40 hours or less per week. The risk of experiencing preterm birth in
females working 51–70 hours was 2.5 times higher, whereas the risk is 4.2 times greater in those working 71 hours or more.
Regarding the emergency department, it was noted that the frequency of menstrual disorders in clinical staff was greater than that of administrative workers.16 The differences were quite significant, with contributing factors including the physical and emotional exhaustion that comes with the field, along with exposure to hazards such as radiation, anaesthetic gasses, certain chemicals, and drugs.17
There have been increased incidences of congenital anomalies amongst healthcare workers in comparison to non-healthcare workers.18 Increased risk of fetal death is associated with exposure to sterilising agents (glutaraldehyde and ethylene oxide) and, rarely, antineoplastic drugs.
Three research investigations examined how exposure to antineoplastic drugs impacts the likelihood of miscarriage, stillbirth, or both among nurses.19-21 Among the studies focused on miscarriage, one indicated a notable increase in risk linked to antineoplastic drug exposure during pregnancy. Lawson et al.’s19 stratified analyses revealed that this heightened risk specifically pertained to early miscarriages rather than late ones. Similarly, neither of the studies investigating the risk of stillbirth identified a significant correlation with this type of exposure. No association between stress, and fetal death or congenital abnormalities was found. Females working for more than 40 hours per week have a higher risk of irregular menstrual cycles. However, no relationship with the length of the menstrual cycle was found. There has been a small risk of miscarriage associated with longer working hours, and fixed night work. Studies on paternal exposures are rare.
Another study was conducted to identify differences in career and lifestyle factors between male and female otolaryngologists.16 It was found that only 59.9% of the females, from the sample in the study, had children, with the average number of children being 2.4. In males, on the other hand, 82.5% had children with an
average number of children being three. Furthermore, females with more children reduced their work hours.
DISCUSSION
Infertility has become a challenge that has affected the wellbeing of the general population. The effect of infertility on healthcare professionals is yet to be understood. In a few studies, it has been revealed that there is generally a lack of adequate knowledge about, and a negative attitude towards, male infertility.7 The participants were medical students or healthcare professionals from Bangladesh, who were surveyed anonymously on their knowledge, attitude, and perception regarding male infertility. Among the 556 participants, 49.82% did not have a good knowledge of male infertility, and nearly 60.79% had negative attitudes regarding male infertility. Young (23–26 years) healthcare professionals and medical students were more likely to have good knowledge than others (odds ratio: 1.81; 95% CI: 1.099–2.988).7 It has been revealed that female surgeons were more likely to delay pregnancy due to training, utilise ART, and experience pregnancy difficulties.8 Compared to their male coworkers, females are more likely to stay single, get divorced, and have fewer or no children. The observed gender variations in divorce rates and childbirth rates may reflect the unique difficulties females encounter, such as infertility.16
Of female otolaryngologists, 80.4% were married at the time of the survey, compared with 87.3% of males. Females were more likely to be divorced than male otolaryngologists (8.6% versus 2.9%; P=0.001). Males (among those who were spouses or partners) had more children (mean: 3.0 versus 2.4; P<0.001), and were less likely to be without children than females (P<0.001).16 Reducing the number of hours that pregnant doctors work was significantly hampered by a lack of institutional support, which included insufficient maternity leave and difficulty in hiring substitute staff. Pregnancy problems were more likely for surgeons who worked
more than 12 hours a day, averaging over a week during their pregnancies.15 It has been suggested that night shifts, long workdays, prolonged standing, and a heavy physical workload hurt the success of conception and pregnancy.4 However, there is little evidence of lengthy work hours affecting fertility. There are occupational risks due to various exposures in different specialties.5 Workplace risks include night shift work, organic solvents, and heavy metals, which may negatively impact a person’s ability to conceive. Infertility, menstruation problems, and subfertility were shown to be more common in this population.10 Dysmenorrhoea is more common among nurses, and has a significant correlation with ageing and lower BMI.12 Burnout harms both physical and mental health, as well as reproductive health.11 Moreover, working females who use contraceptives may experience a range of obstetrical and gynaecological issues. According to the current investigation, their long workdays put them at risk for infertility.4 Infertility across all ages is affected by quality, timing, and sleep duration.14 Lack of sleep affects the levels of reproductive hormones, which are essential regulators of both male and female fertility.
LIMITATIONS
Although the authors’ review provides valuable insights into the challenges faced by healthcare professionals dealing with infertility, there are some limitations to be acknowledged. During the search, there was little to no evidence of male infertility among physicians, along with a lack of interventions for infertility among male healthcare professionals.7,16 Another significant area for improvement in this review was the reliance on existing research and surveys that may have been conducted on relatively small samples of healthcare professionals.5,7
References
1. Anderson M, Goldman RH. Occupational reproductive hazards for female surgeons in the operating room: a review. JAMA Surg. 2020;155(3):243-9.
Recall biases on pregnancy-related details can manifest within both childbearing and non-childbearing healthcare professionals.2 Questionnaire-based bias may arise when participants engage in self-reporting, potentially leading to hesitancy in responses, or difficulty comprehending the posed questions.2,5 Various studies included in the review consist of unmatched survey times, lack of longitudinal data, challenges in generalising findings due to differences in working conditions and cultural factors, potential influences from age-related factors and healthy worker survivor effects, reliance on limited data sources, and a lack of exploration into long-term trends or associations over time.12-14,17 Additionally, gaps in knowledge or the introduction of new information on specific topics, either not covered during the study or introduced poststudy, can impact data accuracy.
CONCLUSION
Existing studies emphasise how childbearing surgeons are more likely to experience serious pregnancy difficulties and infertility, so the increasing prevalence of infertility and pregnancy-related risks highlights the necessity for a change in their jobs to prioritise pregnancy. Furthermore, female physicians claimed that pressures related to their careers were affected when they had children, and caused significant changes to their career paths to make room for starting a family, and becoming a parent. So, these findings imply that worries about starting families and having children among female doctors may contribute to lingering gender inequities and attrition, and they point to a possible key area for future policy change. Moreover, additional research and interventions about male infertility are required to address the unique challenges and implications of infertility within the healthcare industry.
2. Rangel EL et al. Incidence of infertility and pregnancy complications in US female surgeons. JAMA Surg. 2021;156(10):905-15.
3. Gold EB, Tomich E. Occupational hazards to fertility and pregnancy outcome. Occup Med. 1994;9(3): 435-69.
4. Stentz NC et al. Fertility and childbearing among american female physicians. J Womens Health (Larchmt). 2016;25(10):1059-65.
5. Pfennig CL et al. A comparative analysis on fertility success among physician specialties. Acad Emerg Med. 2022;29(6):792-4.
6. Rooney KL, Domar AD. The relationship between stress and infertility. Dialogues Clin Neurosci. 2018;20(1):41-7.
7. Iktidar MA et al. Knowledge, attitude, and perception among medical students and healthcare professionals regarding male infertility: a crosssectional survey from Bangladesh. BMJ Open. 2022;12(11):e062251.
8. Phillips EA et al. Does a surgical career affect a woman's childbearing and fertility? A report on pregnancy and fertility trends among female surgeons. J Am Coll Surg. 2014;219(5):944-50.
9. Ahn J et al. The association between long working hours and infertility. Saf Health Work. 2021;12(4):517-21.
10. Győrffy Z et al. Reproductive health and burn-out among female physicians: nationwide, representative study from Hungary. BMC Womens Health. 2014;14:121.
11. Blake ME et al. Proposed program guidelines for pregnant radiology residents: a project supported by the American Association for Women Radiologists and the Association of Program Directors in Radiology. Acad Radiol. 2006;13(3):391-401.
12. Lateef OM, Akintubosun MO. Sleep and reproductive health. J Circadian Rhythms. 2020;18:1.
13. Takeuchi M et al. Long working hours and pregnancy complications: women physicians survey in Japan. BMC Pregnancy Childbirth. 2014;14:245.
14. Assadi SN. Is being a health-care worker a risk factor for women's reproductive system? Int J Prev Med. 2013;4(7):852-7.
15. Warembourg C et al. An updated systematic review of fetal death, congenital anomalies, and fertility disorders among health care workers. Am J Ind Med. 2017;60(6):578-90.
16. Grandis JR et al. The gender gap in a surgical subspecialty: analysis of career and lifestyle factors. Arch Otolaryngol Head Neck Surg. 2004;130(6):695-702.
17. Liu Y et al. Awareness of surgical smoke hazards and enhancement of surgical smoke prevention among gynecologists. J Cancer. 2019;10(12):2788-99.
18. Chung F et al. The associations between menstrual function and life style/working conditions among nurses in Taiwan. J Occup Health. 2005;47(2):149-56.
19. Lawson CC et al. Occupational exposures among nurses and risk of spontaneous abortion. Am J Obstet Gynecol. 2012;206(4):327.e1-8.
20. Ratner PA et al. Cancer incidence and adverse pregnancy outcome in registered nurses potentially exposed to antineoplastic drugs. BMC Nurs. 2010;9:15.
21. Fransman W et al. Nurses with dermal exposure to antineoplastic drugs: reproductive outcomes. Epidemiology. 2007;18(1):112-9.
Authors:
Colposcopic and Histopathologic Comparative Interpretations Among Patients Undergoing Evaluation for Cervical Dysplasia in Western Kenya
*Mohamed Ali Hassan,1 Peter Itsura,1 Benjamin Elly Odongo1
1. Moi University School of Medicine, Eldoret, Kenya *Correspondence to mohaali.hassan@yahoo.com
Disclosure: The authors have declared no conflicts of interest.
Received: 24.11.23
Accepted: 30.01.24
Keywords: Colposcopy, histopathology, Reid’s Colposcopic Index (RCI).
Objective: To determine the correlation between colposcopic and final histopathologic results amongst patients undergoing a colposcopic evaluation in cervical dysplasia clinics in Western Kenya.
Methods: This was a cross-sectional study, conducted among 164 females undergoing colposcopic evaluation across several cervical dysplasia clinics in Western Kenya. Colposcopy and histopathology were performed. Colposcopy findings were graded using modified Reid’s Colposcopic Index (RCI). Bayes’ theorem model was used to determine the sensitivity, specificity, positive predictive value, and negative predictive value. An overall ĸ value was calculated as an estimate of the strength of correlation between colposcopy and histopathology.
Results: Mean age of the study participants was 40.6 years. Modified RCI classified 20.7%, 40.2%, and 39.1% between a score of 0–2, 3–5, and 6–8, respectively. Colposcopy classified 0.6%, 38.4%, and 60.1% as normal, cervical intraepithelial neoplasia (CIN) 1 (low risk), and CIN 2–3 (medium–high risk), respectively. Histopathology classified 16.5%, 26.2%, 53.3%, and 3.0% as having normal, CIN 1, CIN 2–3, or carcinoma in situ, respectively. Sensitivity, specificity, positive predictive value, and negative predictive value were 85.3%, 69.7%, 80.3%, and 69.7%, respectively. The estimated strength of correlation between colposcopy and biopsy was relatively strong (ĸ=0.55).
Conclusion: There is an association between the discriminatory powers of colposcopy and histology, but colposcopy had a lower specificity when compared to histopathology.
Key Points
1. Using modified Reid’s Colposcopic Index (RCI) in evaluating the cervix gives a systematic and objective method of colposcopically grading the severity of premalignant cervical lesions.
2. The findings from this study provide information on the sensitivity and specificity of colposcopy in Western Kenya.
3. This study reports an association between the discriminatory power of the two methods; however, colposcopy had a lower specificity when compared to histopathology.
BACKGROUND
Cervical cancer is a consequence of long-term infection with human papillomavirus. It is ranked fourth in both incidence and cancer-related mortality amongst females, with an estimated 569,847 new cases and 311,365 global deaths per annum. This accounts for 13.1% of all new female cancers worldwide. In Eastern Africa, cervical cancer remains the most common cancer in females, with estimated age standardised incidence and mortality rates of 40.1 and 30.0 per 100,000 people.1
Cervical cancer contributes 5,250 (12.9%) of the new cancer cases annually, and 3,286 (11.84%) of all cancer deaths annually in Kenya. It is the leading cause of cancerrelated deaths in Kenya, and the second most common cancer among females.1
Colposcopy is the examination of the epithelia of the cervix, lower genital tract, and anogenital area using magnified illumination, after the application of specific solutions to detect abnormal appearances consistent with dysplasia or neoplasia, or to affirm normality. Integral to the procedure is targeting biopsies to areas of greatest abnormality.2 It is also well documented that colposcopy has significant interperformer variability, and poor reliability. The American Society for Colposcopy and Cervical Pathology (ASCCP) published colposcopy standards to address these, and other concerns.3
Cervical cancer has high morbidity and mortality. In Kenya, it is the second in prevalence, and the first cause of cancerrelated mortality.1 Cervical cancer has a long latent phase, and can be prevented and cured if detected early. The primary method for cervical cancer prevention is through vaccination against human papillomavirus,
while the secondary method of cervical cancer prevention is through cervical cancer screening.4
Cervical cancer initially presents as cervical dysplasia, which may transform into cervical cancer. The diagnosis of cervical dysplasia utilises both colposcopy and histopathology to inform patient management. Although histopathology is the gold standard for diagnosing cervical cancer, its access and utility is limited, due to both cost and limited expertise. There is also a paucity of data on the sensitivity and specificity of colposcopy locally, hence the need to determine the sensitivity and specificity of colposcopy.
OBJECTIVE
The objective is to determine the sensitivity and specificity of colposcopy findings among patients undergoing colposcopy and biopsy in several cervical dysplasia clinics across Western Kenya.
METHODS
This was a cross-sectional, comparative diagnostic study conducted among 164 females undergoing colposcopic evaluation across several cervical dysplasia clinics in Western Kenya, between August 2019–August 2020. Institutional ethical approval was sought, and informed consent obtained from each participant. A colposcope was used to examine the cervix, and findings were graded using the modified Reid’s Colposcopic Index (RCI).5
A colposcopy-guided punch biopsy was then taken for histopathological evaluation when the abnormal area was sighted. Descriptive statistical analysis of mean, with corresponding standard deviation for continuous variables; and frequencies, with corresponding proportions for categorical
variables were calculated, to determine whether differences across groups were statistically significant (P≤0.05). Bayes’ theorem model was used to determine the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), with a corresponding 95% confidence interval. A receiver operating characteristic curve was plotted as sensitivity against 1-specificity, and the area under the curve was computed. An overall ĸ value was calculated as an estimate of the strength of correlation between colposcopy and histopathology.
Permission to conduct the research was sought and obtained from the Institutional Ethics and Research Committee (IREC) of Moi University School of Medicine and Moi Teaching and Referral Hospital, Eldoret, Kenya.
RESULTS
Sociodemographic Characteristics of the Study Participants
The mean age of the study participants was 40.6 years. The majority were married (79.9%), and 51.8% were educated to
primary level. Of the participants, 134 (81.7%) were not post-menopausal, and 106 (64.6%) were HIV-negative.
Colposcopy Findings Using Modified Reid’s Colposcopic Index Among Patients Undergoing Colposcopy in Cervical Dysplasia
Clinics in Western Kenya
Modified RCI classified 20.7%, 40.2%, and 39.1% between a score of 0–2, 3–5, and 6–8, respectively (Table 1). Colposcopy classified 0.6%, 38.4%, and 60.1% as normal, cervical intraepithelial neoplasia (CIN) 1, and CIN 2–3, respectively. Histopathology classified 16.5%, 26.2%, 53.3%, and 3.0% as having normal, CIN 1, CIN 2–3, and carcinoma in situ, respectively.
DISCUSSION
This study involved 164 patients who were subjected to both colposcopy and biopsy diagnostic techniques, to compare the accuracy of the former in approximating the results obtained by biopsy. Biopsy results were considered as the gold standard in this sensitivity–specificity study. A total of 32 subjects were dropped from the
Table 1: Classification by colposcopy impression and classification by modified Reid’s Colposcopic Index.
analysis, as histopathology results classified 27 patients as having a normal cervix. On the contrary, patients who had normal colposcopy results were never subjected to histopathology examination. Comparing the two methods based on this category would have introduced bias by design. Likewise, histopathology results classified five patients as having a carcinoma. Colposcopy was never used to determine carcinoma. Comparing the two diagnostic methods based on this category would have also introduced design bias.
Sensitivity analysis for colposcopy as a diagnostic method was based on its ability to discriminate CIN 2–3 from CIN 1 (Table 2). A χ2 test conducted on the outcome from 132 patients revealed a highly significant association between colposcopy and biopsy in discriminating CIN 2–3 from CIN 1 (p<0.0001; χ2: 37.7; degree of freedom: 1). There was a fairly strong resemblance in the results from colposcopy and biopsy diagnostic techniques (ĸ: 0.55; 95% confidence interval: 0.40–0.70; p<0.0001).
Aue-Aungkul and Suprasert6 compared the results obtained from RCI evaluation and biopsy results. Their study involved the comparison of diagnoses carried out by general and oncologic gynaecologists. They estimated the strength of the correlation (ĸ) between colposcopy impression and biopsy results on diagnoses carried out by the oncologic gynaecologists group to be equal to 0.34, while that of the general gynaecologist group was equal to 0.22.6
In both cases, the estimated strength of correlation was weaker than that which was obtained in this study (ĸ: 0.55).
Colposcopy had a sensitivity of 85.3% and specificity of 69.7% (Table 3). In a prospective, cross-sectional study on the correlation of colposcopy using RCI and histopathology, Durdi et al.7 yielded comparable results on sensitivity. They found a sensitivity of 88.5% with CIN 1 as a disease threshold, and 85.2% with CIN 2 as a disease threshold, with a relatively high specificity of 76.2% with CIN 1 as a disease threshold, and 99.6% with CIN 2 as a disease threshold. The study was conducted in the colposcopy clinic at KLES Dr Prabhakar Kore Hospital & Medical Research Center, Belgaum, Karnakata, India, between January 2008–June 2009, with a sample size of 268. Aue-Aungkul and Suprasert6 estimated a comparable specificity of 70.2% in their study on RCI evaluation, with a sample size of 125 patients. 5 The authors’ study shows that there is a probability of approximately 85.3% that the colposcopy test will return a positive CIN 2–3 result among a population with CIN 2–3. The authors’ study also shows that colposcopy has a 69.7% chance of returning CIN 1 among a population with CIN 1.
The PPV and NPV for colposcopy in discriminating CIN 2–3 from CIN 1 was 85.3% and 69.7%. Durdi et al.7 estimated a PPV of 77.0% and 95.8%, with CIN 1 and CIN 2 as disease thresholds. These estimates
Table 2: Confusion matrix of colposcopy against biopsy.
CIN: cervical intraepithelial neoplasia.
were relatively comparable, especially when CIN 2 was applied as the disease threshold. On the contrary, the study yielded higher NPVs, of 93.5% and 98.5%. Aue-Aungkul and Suprasert7 estimated higher PPV and NPV of 89.0% and 86.0%. The authors’ study estimates that, following a positive colposcopic classification of CIN 2–3 on a patient, there is an 85.3% chance that the patient is in CIN 2–3 stage. It further estimates that, given a colposcopic classification of CIN 1 on a patient, there is a 69.7% chance that the patient is in the CIN 1 stage of cervical cancer. This revelation is in agreement with the conclusion from a prospective, cross-sectional trial on the evaluation of RCI as a predictor of cervical intraepithelial lesion. Using a sample of 125 females aged >20 years, who were scheduled for a colposcopy at
Chiang Mai University Hospital, Thailand, between August 2008–May 2014, the study concluded that the predictive accuracy of colposcopy increased with the increasing severity of the disease.8
Verma et al.8 also estimated the diagnostic accuracy of colposcopy, using RCI, to be 98.4%. This is much higher compared to 80.3%, which is the estimated diagnostic accuracy of colposcopy in discriminating CIN 2–3 from CIN 1 in this study. The authors’ study showed that colposcopy had a 80.3% chance of correctly classifying CIN 2–3 and CIN 1. This also means that it had a 19.7% chance of misclassifying CIN 2–3 as CIN 1, and vice versa. The odds of a positive CIN 2–3 test in those with disease was 13.491 times that of the odds of a positive CIN 2–3 test in those without disease.
Proportion of subjects with their outcome ruled out 0.325 (0.246–0.412)
Proportion of subjects with their outcome ruled in 0.674 (0.587–0.753)
Proportion of false positive 0.302 (0.171–0.461)
Proportion of false negative 0.146 (0.080–0.236)
Table 3: Sensitivity analysis of colposcopy as a diagnostic alternative to biopsy.
This further confirms that colposcopy has a higher chance of returning a positive CIN 2–3 among patients with CIN 2–3, as opposed to those who are not in that stage.
The Youden’s Index associated with colposcopy, using RCI to discriminate between CIN 2–3 and CIN 1, was 0.551 (0.301–0.748). This was relatively fair, as the Youden’s index can only take values between 0–1, signifying poor and good diagnostic tests. The number needed by colposcopy to differentiate between CIN 2–3 and CIN 1 was 1.182. The authors’ study, therefore, showed that colposcopy needed, at the utmost, two patients for it to correctly discriminate CIN 2–3 from CIN 1. This is a relatively good performance for a diagnostic test. This study also estimated an optimal Youden’s Index value of 0.776, with a true positive rate of 69.8%, and a false positive rate of 14.6%. This is synonymous to a sensitivity of 69.8%, and specificity of 85.4%. This also means that in a situation where an investigator deems both sensitivity and specificity as diagnostically important and desirable, the best performance of colposcopy would be noticed at these specificity and sensitivity thresholds.
This study also estimated a positive and negative likelihood ratio of 2.824 (1.779–4.483) and 0.209 (0.122–0.359). The platelet-to-lymphocyte ratio is an important estimate in diagnostics, because it gives the change in odds of having a diagnosis in patients with a positive test. This study revealed that there was a 2.824-times
References
1. Sung H et al. GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-49.
2. Bornstein J et al. 2011 colposcopic terminology of the International Federation for Cervical Pathology and Colposcopy. Obstet Gynecol. 2012;120(1):166-72.
increase in the odds of having CIN 2–3 in a patient who was classified as having CIN 2–3 by colposcopy technique. These odds show that colposcopy has some discriminating ability on CIN 2–3 and CIN 1, hence it is informative. A platelet-tolymphocyte ratio of 1 would mean the odds of a patient having CIN 2–3 do not change, whether colposcopy classifies them as CIN 2–3 or CIN 1.
On the other hand, the neutrophil-tolymphocyte ratio (NLR) defines the change in odds of having a diagnosis in patients who produce a negative test. The NLR of 0.122 indicates an 8.3-times decrease in the odds of having CIN 2–3, in a patient who has been classified as having CIN 1 by colposcopy technique. The smaller the value of the NLR, the more informative the test is. An NLR of 0.122 further shows that colposcopy is an informative diagnostic alternative for biopsy.
CONCLUSIONS
There were nearly equal proportions of intermediate and high Grade disease when modified RCI was used to classify colposcopy findings. Histopathology reported that more than half of all the findings were high Grade disease (CIN 2/ CIN 3). Finally, this study reports that there is an association between the discriminatory power of the two methods; however, colposcopy had a lower specificity when compared to histopathology.
3. Wentzensen N et al. Evidence-based consensus recommendations for colposcopy practice for cervical cancer prevention in the United States. J Low Genit Tract Dis. 2017;21(4):21622.
comparison of general and oncologic gynecologists. Asian Pac J Cancer Prev. 2015;16(12):5001-4.
4. Kaban I et al. Agreement between colposcopy results using the Reid Colposcopic Index and histopathology. Ginekol Pol. 2015;86:537-40.
6. Aue-Aungkul A, Suprasert P. Reid Colposcopic Index evaluation:
7. Durdi GS et al. Correlation of colposcopy using Reid Colposcopic Index with histopathology- a prospective study. J Turk Ger Gynecol Assoc. 2009;10(4):205-7.
8. Verma I et al. Evaluation of Reid’s Combined Colposcopic Index as a predictor of cervical intraepithelial lesion. Int J Reprod Contracept Obstet Gynecol. 2018;7(9):3724-30.
Fetomaternal Outcomes of Low-Risk Females Presenting with Perceived Reduced Fetal Movements at Moi Teaching and Referral Hospital, Eldoret, Kenya
Authors: *Andrew Chege,¹ Philip Kirwa,² Jack Odunga¹
1. Department of Reproductive Health, Moi University School of Medicine, Eldoret, Kenya
2. Moi Teaching and Referral Hospital, Eldoret, Kenya *Correspondence to cheggechege@gmail.com
Disclosure: The authors have declared no conflicts of interest.
Received: 02.12.23
Accepted: 22.02.24
Keywords: Biophysical profile (BPP), Moi Teaching and Referral Hospital (MTRH), non-stress test (NST), reduced fetal movements (RFM).
Objective: To determine the fetomaternal outcomes of low-risk females presenting with perceived reduced fetal movements at Moi Teaching and Referral Hospital (MTRH), Eldoret, Kenya.
Methods: This was a cross-sectional study among 133 females of gestation between 34–41 weeks presenting with a perception of reduced fetal movement, who were consecutively recruited. Pearson χ2 and Fischer’s exact tests of association were used to test the association between the non-stress test (NST) findings, biophysical profile (BPP) scores, and fetomaternal outcomes, where p≤0.05 was considered statistically significant.
Results: A reactive NST finding was seen in 88 (66.2%) participants with 104 (78.2%) of all participants enrolled having a normal BPP score. Active management of the current pregnancy was offered to 89 (66.9%) of the participants, and 81 (60.9%) of the females had a vaginal delivery. Three quarters (76.7%) of the newborns had a 5-minute appearance, pulse, grimace, activity, and respiration (APGAR) score ≥7, 18 (13.5%) were resuscitated, 13 (9.8%) were admitted to the newborn unit, and four (3%) fresh stillbirths were noted. Both NST (p<0.001) and BPP (p<0.001) were good predictors of a 5-minute APGAR score ≥7, but poorly (p=0.086) predicted resuscitation. There was a statistically significant association between the NST findings and admission to newborn unit (p=0.034).
Conclusion: A reactive NST is a good predictor of a 5-minute APGAR score greater than 7, and is associated with a reduced likelihood of both admission to the newborn unit and newborn resuscitation. Both reactive NST and normal BPP are good predictors of vaginal delivery as opposed to Caesarean delivery.
Key Points
1. The findings of this study will influence the diagnosis and management of reduced fetal movements in low-risk pregnancies among expectant females attending both resource-rich and resource-limited public healthcare settings in Kenya.
2. This study therefore aimed to establish the fetomaternal outcomes following a diagnosis of reduced fetal movements among low-risk expectant mothers at Moi Teaching and Referral Hospital (MTRH), Eldoret, Kenya. Furthermore, the study compared two commonly used diagnostic tools, namely the non-stress test and biophysical profile.
3. A non-stress test can be used in place of biophysical profile in low-resource clinical settings, where ultrasound services are not readily accessible, as a good predictor of immediate fetal outcomes among low-risk expectant females with perceived reduced fetal movements.
BACKGROUND
Fetal movements are defined as any discrete kick, flutter, swish, or roll, first perceived between 16–18 weeks in multiparous females and 20–22 weeks among primiparous females, a period long before fetal viability in the current set-up. Also referred to as ‘quickening’, there is considerable variation in the perception of the first movements among expectant females, depending on the parity, as alluded in the above definition. There is no universal definition of reduced fetal movements (RFM); however, the majority of the international bodies, journals, and institutions agree on less than 10 movements in 12 hours,1,2 concurring with the 1976 definition of Pearson and Weaver who developed the Cardiff ‘count-to-ten’ kick chart.3 In that study, the authors noted that intrauterine death was preceded by reduction in perception of fetal movements in the previous 3–4 days, followed by complete cessation of perception of the movements 12–48 hours before eventual fetal demise.3 Soufizadeh et al.4 also reported that while RFM was a predictor of adverse fetal outcomes, perception of normal movements is especially useful to the mother as it allays fears of imminent fetal death. For the obstetrician, it offers assurance of good fetal wellbeing in case postponement of delivery is needed to allow for lung maturity.4
For the expectant female, RFM is a major cause of concern. Consequently, reduced
fetal movements have been shown to be a major indication for hospitalisation, at the detriment of overwhelming the facilities, and crucially, especially in the third world, the already low numbers of the healthcare workers. Despite reduced fetal movements being a common problem among expectant females, the clinical significance of a history of reduced fetal movements remains unclear, and assessment and management of these pregnancies is still controversial.5
RFM is a common reason for admission of expectant females in many reproductive health facilities in Kenya. The majority of the expectant mothers with this complaint are usually apprehensive and anxious to find out about the wellbeing of their babies. There is limited correlation between the surveillance tools used in the evaluation of reduced fetal movements and pregnancy outcomes in many public health facilities, such as Moi Teaching and Referral Hospital (MTRH), Eldoret, Kenya. In addition, the magnitude of undesirable pregnancy outcomes related to reduced fetal movements in low-risk pregnancies has not been adequately documented in Western Kenya. This creates the need for a local study to provide empirical evidence of reduced fetal movements in low-risk pregnancies and the resulting pregnancy outcomes. This study therefore aimed to establish the fetal and maternal outcomes following a diagnosis of reduced fetal movements among low-risk expectant mothers at MTRH. Furthermore, the study compared two commonly used diagnostic tools, namely the non-stress test
(NST) and biophysical profile (BPP). Would the NST alone have the same evaluation benefit for these cohort of patients? The findings of this study will influence the diagnosis and management of reduced fetal movements in low-risk pregnancies among expectant females attending both resourcerich and resource-limited public healthcare settings in Kenya.
STUDY OBJECTIVE
The objective was to describe the fetal and maternal outcomes in low-risk females presenting with perceived reduced fetal movements at MTRH.
METHODS
Study Design
This study adopted a descriptive, crosssectional study design among low-risk expectant females with reduced fetal movements (Figure 1). This was deemed appropriate owing to the small numbers left after excluding high-risk pregnancies, which make the bulk of the females presenting with perceived reduced fetal movements.
Study Setting
The study was conducted at MTRH’s Riley Mother and Baby Hospital (RMBH) labour ward and the newborn unit (NBU).
Study Period
This study was carried for a period of 12 months between June 2019–May 2020.
Study Population
All low-risk expectant females with perceived reduced fetal movements seeking care at MTRH’s maternity unit and their newborns.
Inclusion Criteria
All females with over 34 weeks’ gestation and not more than 41 weeks with complains of reduced fetal movement were included.
Exclusion Criteria
Patients who were in labour and those who declined consent were excluded.
Sampling Technique
Potential study participants were consecutively sampled until the desired sample size was achieved.
Study Procedure
All expectant females who met the eligibility criteria between 27th June 2019–26th June 2020 were approached and told about study objectives. After they consented, they were subjected to both NST and ultrasound examination so as to compute the BPP. The ultrasound was performed by the radiologist on duty or the maternal-fetal medicine consultant. The NST results were computed as either reactive or non-reactive, as per the clinical management guidelines of MTRH’s maternity unit. The BPP was then computed by summing the scores from both the NST and obstetric ultrasound. Following the BPP scoring, participants were managed either actively or expectantly, as per the hospital guidelines. Participants’ sociodemographic and clinical data were collected and documented using an interviewer administered questionnaire. Fetal and maternal outcomes following delivery were obtained by reviewing medical records without meeting the study participant, within 24 hours. These post-delivery outcomes of interest among females with reduced fetal movements were: gestational age, mode of delivery, appearance, pulse, grimace, activity, and respiration (APGAR) score at 5 minutes, need for resuscitation, admission to NBU, or occurrence of fresh stillbirth.
Data Management and Analysis
A pilot study on 10% of the estimated sample size was carried out at RMBH. The questionnaire was tested for its clarity, understandability, length, and completeness. Culturally sensitive questions that needed to be changed before the main study were addressed.
Females with perceived reduced fetal movement
Cardiotocography Active management
Management of current pregnancy
Management of current pregnancy
Management of current pregnancy Ultrasound
Expectant management
Spontaneous vaginal delivery Induction
Emergency Caesarean section
Data were collected using a structured questionnaire. Primary data collected included sociodemographic characteristics. Secondary data included results of evaluations and interventions offered to the participants, as well as the maternal and fetal outcomes. The questionnaires were checked for completeness at the end of each data collection session. Double data entry was then performed to ensure completeness of the data, as well as its accuracy and reliability using the statistical package for social sciences (SPSS) version 24 software (IBM, Armonk, New York, USA). Data were maintained strictly confidential and access was restricted only to the principal investigator and the research assistants. Questionnaires were kept in safe data cabinets with lock and key. The computer databases were password protected to restrict access from unauthorised individuals.
Active management Caesarean section
Expectant management Induced vaginal delivery
Descriptive statistical techniques adopting measures of central tendency and dispersion, such as the mean, interquartile range, and the standard deviation, were used to summarise continuous variables. Categorical variables were summarised as frequencies and the corresponding percentages. Bivariate analysis was carried out to check for association between dependent and independent variables where Pearson’s χ2 and Fisher’s exact tests were used. Variables that were found to be statistically significant at bivariate level were subjected to multivariate logistic regression, and results reported as adjusted odds ratio with a 95% confidence interval. The findings were presented in the form of tables.
Ethical Consideration
Ethical approval to conduct the study was obtained from the Institutional
Figure 1: Study flow chart.
Research Ethics Committee (IREC) at the MTRH and Moi University School of Medicine, Eldoret, Kenya.
RESULTS
This study enrolled 152 expectant females, five of whom did not have cardiotocographic findings, while 14 did not get an obstetric ultrasound done. They were therefore dropped from the final analysis, leaving 133 females with a mean age of 27.8 (±5.1) years. Almost all (98.5%; n=131) the patients had attended antenatal clinic during the course of their pregnancy, and 85 (64.9%) were multiparous, with the rest being primiparous.
Results of Evaluations and Interventions Given to Females Who Present at MTRH with Perceived Reduced Fetal Movements
Among the participants, 85 out of 133 (63.9%) received active management of the current pregnancy, while the remaining 48 (36.1%) were offered expectant management of their current pregnancy. Out of the 133 participants, 88 (66.1%) had a reactive NST, with the remaining
45 (33.8%) recording a non-reactive NST. When the mode of management was compared based on cardiotocographic findings, it was noted that 48 out of the 88 (54.5%) participants with a reactive NST finding received active management, compared to 37 out of 45 (82.2%) of those with a non-reactive NST finding. When BPP scores were categorised as abnormal (≤4), equivocal (6), or normal (>6), 17 out of 19 (89.5%) participants with an abnormal BPP received active management. All the 10 participants (100.0%) with an equivocal BPP received active management, whereas only 58 out of the 104 (55.8%) with a normal BPP received active management. There was a statistically significant relationship between NST findings (p=0.016), BPP score (p=0.001), and management of the current pregnancy (Table 1).
Fetal Outcomes in Females Presenting with Perceived Reduced Fetal Movements at MTRH
When NST and BPP findings were compared to 5-minute APGAR score, 76 out of the 88 (86.4%) participants with a reactive NST finding had neonates with a 5-minute APGAR score ≥7, compared to 26 out of the 45 (57.8%) participants who had a
Table 1: Comparison between reduced fetal movements evaluations and management of current pregnancy. BPP: biophysical profile; N/A:
non-reactive NST finding and neonates with a 5-minute APGAR score of >7. It was found that 89 out of the 104 participants (85.6%) with a BPP score of 8 or 10 (normal) gave birth to neonates with a 5-minute APGAR score >7. In comparison, only six out of the 19 participants (31.6%) with a BPP score of ≤4 (abnormal) had neonates with a 5-minute APGAR score of >7. This relationship between NST findings, BPP score, and 5-minute APGAR score was found to be statistically significant (p<0.001), as shown in Table 2.
There was a higher proportion of resuscitation among neonates for females with a non-reactive NST finding, with 10 out of 45 (22.5%) being resuscitated, compared to those with a reactive NST finding where only eight out of 88 (9.1%) were resuscitated. However, this relationship was not statistically significant (p=0.058). Similarly, the combined proportion of resuscitation among those neonates of participants with abnormal and equivocal BPP was higher compared to those with a normal BPP score, without any statistically significant difference (p=0.086).
In this study, eight out of 45 (17.8%) of the neonates born of participants with a nonreactive NST finding were admitted to the NBU, compared to five out of 88 (7.3%) of those born to mothers with a reactive NST finding. This relationship was found to be statistically significant (p=0.034).
In this study, three out of 45 (6.7%) neonates whose mothers had a nonreactive NST were stillbirths. When analysed against the BPP score, three out of the 19 (15.8%) neonates born of participants with an abnormal score (≤4) were stillbirths. Both NST and BPP findings were significantly (p=0.008) associated with fresh stillbirth.
Among the participants with a reactive NST finding, 78 out of the 88 (88.7%) had neonates with a birth weight of >2,500 g. However, in comparison, 33 out of the 45 (73.3%) of the participants with a non-reactive NST had neonates of <2,500 g. This relationship was found to be statistically significant (p=0.011). BPP score increased with an increase in birthweight. A higher birthweight was significantly associated with a higher BPP score (p<0.001).
Maternal Outcomes in Females Presenting with Perceived Reduced Fetal Movements in MTRH
In this study, 38 out of 85 (44.7%) of the participants who had active management of their current pregnancy had induced vaginal delivery, while 45 out of the 85 (55.3%) participants in this management category had an emergency Caesarean section. Expectant management of the current pregnancy was offered to 48 females with perceived reduced fetal
Table 2: Multivariate logistic regression association between significant variables and fetal outcomes.
movements. Of these patients, 31 (64.6%) had spontaneous vaginal delivery, followed by induced vaginal delivery in 13 out of the 48 (27.1%) participants. The least occurring mode of delivery in the expectant arm was through emergency Caesarean section, which was offered to four out of the 48 (8.3%) participants. The main indication for emergency Caesarean section was a nonreassuring fetal status at 78.7%.
Both NST and BPP were statistically associated with the mode of the management for the current pregnancy (p<0.001; Table 2 and 3).
DISCUSSION
In this study, 88 out of 133 (66.2%) of the participants enrolled had a reactive NST finding, compared to 45 out of 133 (33.8%) participants who had a non-reactive NST finding. This compares to findings from Saudi Arabia,6 which reported that 32.9% of the participants had a non-reactive NST finding. Contrasting findings were observed in studies reviewed from Ireland7 and Kolkata, India,8 which reported a nearly uniform finding of reactive NST among the females enrolled. In Ireland, the proportion
of reactive NST findings was observed to be 94.8%,7 while in India, the authors8 reported that 98.3% of the females enrolled in the prospective study had a reactive NST finding. This higher occurrence of reactive NST finding could be attributed to early health seeking behaviour reported in Europe, as opposed to Sub-Saharan Africa, thus allowing detection of deteriorating fetal status much earlier.
Nearly equal proportions of reactive and non-reactive NST findings were noted in Dhaka, Bangladesh,9 at 49% and 51%, respectively. In Lahore-Pakistan,10 the proportion of reactive and non-reactive NST findings stood at 57.9% and 42.1%, respectively. The lowest proportion of a reactive NST finding was reported in Iran,4 at 15.3%. This was because all the females enrolled had insulin dependent diabetes, compared to this study, which excluded females with comorbidities such as diabetes and hypertension.
In this study, 104 out of 133 (78.2%) participants had a BPP score of 8 or 10, which is considered normal. In comparison, 10 out of 133 (7.5%) of participants had an abnormal (≤4) score, whereas 19 out of the 133 (14.3%) participants had an equivocal
(6); N=10
biophysical profile; N/A: not applicable; NST: non-stress test.
Table 3: Association between evaluations and mode of delivery.
BPP:
(6) BPP score. This trend was also noted in a study conducted in Iran,4 where 70.4% of the females had a normal BPP score. However, there was a higher proportion (26.1%) of equivocal BPP score with the lowest being an abnormal finding (3.5%). The differences in equivocal and abnormal findings could be attributed to the eligibility criteria adopted by the current study, which excluded high-risk females with comorbidities such as hypertensive disease in pregnancy, cardiac disease in pregnancy, and anaemia, as compared to the study conducted in Iran.
The proportion of vaginal delivery among participants with perceived reduced fetal movements enrolled in this study was 61.7% (82 out of 133 participants) with the remaining 51 out of 133 (38.3%) participants delivering via Caesarean section. This is comparable to Ireland, at 68% for vaginal delivery and 32% for Caesarean section.7
However, in Multan, Pakistan,6 the authors noted a lower (27.8%) proportion of vaginal delivery compared to Caesarean section (72.2%).
The authors’ study established that neonates of mothers with a non-reactive NST were more likely to be admitted to the NBU (17.8%), compared to those with a reactive finding (5.7%). This relationship was found to be statistically significant (p=0.034). However, no statistically
References
1. Dutton PJ et al. Predictors of poor perinatal outcome following maternal perception of reduced fetal movements – a prospective cohort study. PLoS One. 2012;7(7):e39784.
3. Pearson JF, Weaver JB. Fetal activity and fetal wellbeing: an evaluation. BMJ. 1976;1(6021):1305-7.
4. Soufizadeh N et al. Diagnostic value of rapid biophysical profile in comparison to biophysical profile in pregnant women with insulin-dependent
significant association (p=0.058) was found between BPP finding and admission to the NBU.
CONCLUSIONS AND RECOMMENDATIONS
A reactive NST is a good predictor of a 5-minute APGAR score greater than 7, and is associated with a reduced likelihood of both admission to the NBU and occurrence of fresh stillbirth. However, it was not significantly associated with the need for neonatal resuscitation among low-risk females with perception of reduced fetal movements. Both reactive NST and normal BPP are good predictors of vaginal delivery as opposed to Caesarean delivery in low-risk females with perceived reduced fetal movements.
Recommendations
An NST can be used in place of BPP in low resource clinical settings, where ultrasound services are not readily accessible, as a good predictor of immediate fetal outcomes among low-risk expectant females with perceived RFM.
Future larger studies adopting longitudinal case-control designs should be conducted to further validate this study’s findings.
diabetes. J Family Reprod Health. 2020;13(4):209-13.
5. Flenady V et al. Detection and management of decreased fetal movements in Australia and New Zealand: a survey of obstetric practice. Aust N Z J Obstet Gynaecol. 2009;49(4):358-63.
6. Rehman A. Frequency of adverse perinatal outcome in patients with poor biophysical profile. Professional Med J. 2020;27(10):2193-8.
7. Daly N et al. Cardiotocography as a predictor of fetal outcome in women presenting with reduced fetal movement. Eur J Obstet Gynecol
Reprod Biol. 2011;159(1):57-61.
8. Sen M. et al. Abnormal cardiotocographic findings and perinatal outcome: a prospective study. Int J Reprod Contracept Obstet Gynecol. 2019;8(11):4261.
9. Jha S, Dangal G. Role of modified biophysical profile in high risk pregnancy in predicting fetal outcome. J Nepal Health Res Counc. 2020;18(3):401-5.
10. Salahuddin N. et al. Obstetrical and fetal outcome in patients with abnormal cardiotocograph. Biomedica. 2017;33(4):309-13.
A Case of Caudal Regression Syndrome From Pakistan
Authors: Sheharyar Zameer,1 Nawal Nasir Khan,1 *Soman Nadim Iqbal,2 Huma Ahmed Khan,1 Shanzay Hummayoun,3 Syed Hashim Zaidi4
1. Department of Surgery, Fauji Foundation Hospital, Rawalpindi, Pakistan
2. Department of Medicine, Fauji Foundation Hospital, Rawalpindi, Pakistan
3. Department of Medicine, Foundation University Medical College, Rawalpindi, Pakistan
4. Department of Paediatric Surgery, Fauji Foundation Hospital, Rawalpindi, Pakistan
*Correspondence to soman@live.com
Disclosure: The authors have declared no conflicts of interest.
Background: Caudal regression syndrome is a group of defects with incomplete development of the terminal vertebral column, with an incidence of 1 in 60,000 live births.
Case presentation: A 12-year-old female presented with dull, cyclical suprapubic abdominal pain occurring every month for the past 4 years. She was operated on for an anorectal malformation at birth. On examination, she had a blind-ending vagina with labial hypoplasia. She was diagnosed with caudal regression syndrome Type I, based upon the author’s findings of left renal agenesis along with low-lying blind ending uterus and sacral hypoplasia. She underwent a hysterectomy with right-sided salpingectomy along with the creation of a neo-vagina using a segment of the sigmoid colon. She was discharged after an uneventful postoperative course.
Conclusion: The condition is irreversible; however, repair and reconstruction of each systemic defect is warranted under a multidisciplinary team.
Key Points
1. Caudal regression syndrome is a rare condition affecting 1 in 60,000 births, presenting with complex congenital abnormalities requiring multidisciplinary management for improved patient outcomes.
2. This case report describes a 12-year-old Pakistani girl with caudal regression syndrome Type I, detailing surgical reconstruction techniques and multidisciplinary approaches to manage multiple congenital anomalies effectively.
3. Early diagnosis and individualised, multidisciplinary treatment strategies, including surgical reconstruction, can significantly enhance the quality of life for patients with caudal regression syndrome, despite the condition's irreversibility.
BACKGROUND
Caudal regression syndrome (CRS) is a group of defects with premature development of the terminal vertebral column, with an incidence of 1 in 60,000 live births.1,2 The term CRS was first coined by Duhamel in 1964.1 The condition may present with a wide range of abnormalities including partial or complete sacral/lumber agenesis, lower limb deformities, anorectal malformations, and urogenital anomalies.1,3 It is also related to vertebral, anal, cardiac, trachea-oesophageal, renal, and limb defects (VACTERL) syndrome.3
The condition occurs due to complex dysraphism with aberrations in gastrulation and failure of notochord development. This defect is attributed to the failure of neurulation along with the failure of the formation of somites being closely linked to the development of the heart and other organs.3 Similarly, the proximity of the caudal neurons, spinal, hindgut, and other elements involved in the closure of the neural tube results in defects of the urogenital, limb, and gastrointestinal systems.1
CASE PRESENTATION
A 12-year-old female of South Asian origin presented to the paediatric surgical outpatient department with complaints of dull, cyclical suprapubic abdominal pain occurring every month for the past 4 years. Her past medical, birth, developmental, and drug history were unremarkable. Her parents were in a consanguineous marriage (marriage between first-degree relatives) and they had three children. Out of these three, the patient was the eldest child. Both of her siblings were healthy and did not report similar complaints. Her mother reported a single-stage procedure at 2.5 months of age. However, medical records were unavailable, and the authors believe, from the appearance, that it was for a recto-perineal fistula.
On examination, her vital signs were stable, with a pulse rate of 85 bpm, blood pressure of 97/65 mmHg, respiratory rate of 17 breaths per minute, temperature of 98 °F,
and blood oxygen saturation of 99% at room air. Her weight was 38 kg, and her review of systems was unremarkable. Her oral exam showed a submucosal cleft of the soft palate, and on genital examination she had a blind-ending vagina with labial hypoplasia.
An ultrasound of the abdomen showed left renal agenesis along with a low-lying blind-ending uterus. The MRI of the pelvis showed a hyperdense area consistent with haematosalpinx, confirming the presence of blood in the right fallopian tube and an absent vagina along with sacral hypoplasia as seen in Figure 1. Her echocardiogram did not reveal any cardiac anomaly.
She was diagnosed with CRS (Type I) and a gynaecological consult was sought to assess for reproductive potential. Intraoperatively, a rudimentary uterus, measuring approximately 2 cm in its greatest dimension, with a right-sided haematosalpinx was identified. The left fallopian tube was absent. The cervix and part of the vagina were also absent (Figure 2). The patient’s exceedingly small rudimentary uterus, absent vagina, and limited reproductive potential as per the intraoperative gynaecology review led to the decision for a hysterectomy with a right-sided salpingectomy. Furthermore, the decision was made keeping in view that the absence of the cervix results in subfertility, a higher chance of miscarriages, and predisposes to ascending infections. Both ovaries were preserved so that in future the child may have the option of egg retrieval and surrogacy. A segment of the sigmoid colon was used as a conduit for the creation of a new vagina in an isoperistaltic fashion. For the reconstructive procedure, the authors utilised a combined lower abdominal and perineal approach. A single lower abdominal incision was made. Approximately 4 cm of the sigmoid colon was used to create the vaginal canal. The segment of the gut was stitched in a discontinuous manner with absorptive sutures to the rudimentary vaginal canal, establishing an anastomosis. The upper end of the segment was closed in a blindending fashion, while the lower end was anastomosed to the rudimentary vaginal canal to ensure continuity.
Figure 1: A) MRI showing sacral agenesis with hypoplastic L3, absent L4, L5, and coccygeal vertebrae. B) MRI showing right-sided haematosalpinx.
A B
She had an uneventful recovery and was discharged on the fourth post-operative day with regular follow-ups. The follow-ups were planned for every 3 weeks in the initial period to monitor for any vaginal stenosis.
It is to be mentioned that during the entire process, careful consideration was taken to keep the confidentiality of the patient safe, and proper written consent was taken.
DISCUSSION
CRS represents a spectrum of structural defects of the caudal region. The defects include premature termination of the vertebral column leading to partial or complete absence of sacrum and/ or lumbar vertebrae.1 Along with that, affected persons may present with associated musculoskeletal anomalies such as dysplastic hips, underdeveloped musculature, club feet, gastrointestinal anomalies like anorectal malformations, oesophagal or duodenal atresia, certain neurological anomalies like defective bladder and bowel control leading to urinary and bowel incontinence, and varying degrees of motor and sensory loss. Urological anomalies may include renal
agenesis or dysgenesis, hydronephrosis, renal ectopia, and genital anomalies like uterine abnormalities and hypospadias. Other associated anomalies include myelomeningocele, congenital heart defects, and facial anomalies such as cleft lip and cleft palate. Nonetheless, the children generally have normal neurodevelopmental outcomes.4
Although the aetiology is poorly understood and most cases are sporadic, a few factors have been identified that may contribute to the development of the defect. The three most important factors are maternal diabetes, vascular hypoperfusion, and genetic predisposition.5,6 Gestational hyperglycaemia is associated with alterations in the closure of the neural tube.7 The genotype of CRS is complex and multigenic with the caudal type homeobox 2 (CDX2) gene playing an important role in sacral morphogenesis.6 At the fetal level, it is believed to occur due to defects in the induction of the caudal elements in the embryo before the 28th day of gestation. This occurs secondary to injury in the posterior medial mesodermal axis causing the absence of development of caudal mesoblastic yolk.7
CRS is also associated with multiple congenital syndromes like VACTERL, OIES syndrome (Omphalocele, imperforate anus, cloacal exstrophy, spinal defects), and Currarino syndrome (a triad of sacral agenesis, presacral mass, and anorectal malformation).1,6
Several classification systems have been suggested for CRS; however, Renshaw provided a classic classification including five subtypes. Type I is total or partial unilateral sacral agenesis. Type II is variable lumbar but total sacral agenesis with the ilia that are articulating alongside the lowest vertebra. Type III is variable lumbar and total sacral agenesis with the caudal end plate of the lowest vertebra resting above either fused ilia or an iliac amphiarthrosis. Type IV is soft tissue fusion of both the lower limbs. Type V also known as sirenomelia or mermaid syndrome, where there is a single femur and tibia (fused bones of lower limb).8,9
The treatment of CRS involves multidisciplinary discussion and planning. The condition itself is permanent and repair
of individual systems is the recommended approach. Each treatment option is tailored to the anatomical, pathological, and social aspects of the patient.1 Orthopaedic treatment includes spinopelvic stabilisation, correction of spinal deformity, correction of scoliosis/kyphosis, and contracture corrections.10 Neurosurgical treatment includes the release of conus in spinal cord tethering and surgery for myelomeningocele.11 Urological treatment includes treatment of neurogenic bladder and surgery for vesicoureteral reflux.12 Gastrointestinal treatment includes the correction of anorectal anomalies with the treatment of faecal incontinence.13 Depending on the type of malformations, patients are also offered plastic and reconstructive options for cosmetic reasons.14
Preserving fertility potential is a key aspect in the treatment of CRS. Based on the underlying anatomy, various options are available. The primary objective is to preserve reproductive and sexual function and to optimise fertility outcomes as much as possible.14
Figure 2: Operative image showing uterus, right fallopian tube, right ovary, and left ovary. There was absence of left fallopian tube, upper vagina, and cervix.
F: right fallopian tube; LO: left ovary; RO: right ovary; U: uterus.
CONCLUSION
CRS is a rare and challenging condition, often presenting with a wide array of defects. The condition is irreversible; however, repair and reconstruction of each systemic defect is warranted under a multidisciplinary team. This case
References
1. Jasiewicz B, Kacki W. Caudal regression syndrome-a narrative review: an orthopedic point of view. Children. 2023;10(3):589.
2. Knight B. Caudal regression syndrome: a case report. AANA Journal. 2011;79(4):281-2.
3. Purbasari U et al. Caudal regression syndrome from radiology and clinical perspective: a case series and a proposed new integrated diagnostic algorithm. Radiol Case Rep. 2023;18(7):2478-86.
4. Israel J et al. Sacral agenesis and associated anomalies. Birth Defects Orig Artic Ser. 1976;12(5):45-51.
5. Chan BW et al. Maternal diabetes
report highlights the unique aspects of the presentation and management of CRS, emphasising the importance of individualised treatment plans. By sharing this case, the authors aim to enhance the understanding of CRS and guide future clinical practice.
increases the risk of caudal regression caused by retinoic acid. Diabetes. 2002;51:2811-6.
6. Allan D et al. RARgamma and Cdx1 interactions in vertebral patterning. Dev. Biol. 2001;240(1):46-60.
7. Duncan MA et al. Caudal regression syndrome: a case report. Medicina Universitaria 2014;16(63):74-7.
8. Renshaw TS. Sacral agenesis. J Bone Joint Surg Am.1978;60(3):373-83.
9. Seidahmed MZ et al. Sirenomelia and severe caudal regression syndrome. Saudi Med J. 2014;35(Suppl 1):S3643.
10. Guille JT et al. Lumbosacral agenesis: a new classification correlating spinal deformity and ambulatory potential. J
Bone Joint Surg Am. 2002;84(1):32-8.
11. Pang D. Sacral agenesis and caudal spinal cord malformations. Neurosurgery. 1993;32(5):755-79.
12. Esposito G et al. Continence management in children with severe caudal regression syndrome: role of multidisciplinary team and longterm follow-up. Pediatr Surg Int. 2022;38(10):1461-72.
13. Dewberry L et al. Sacral agenesis and fecal incontinence: how to increase the index of suspicion. Pediatr Surg Int. 2018;35:239-42.
14. Iozsa DA et al. A case report of a colorectal and caudal duplication syndrome associated with caudal regression syndrome. Gastroenterol. 2021;12(3):319-28.
Fetomaternal Outcomes of Venous Thromboembolism in Pregnancy at Moi Teaching and Referral Hospital, Eldoret, Kenya
Authors: *Dennis Odhiambo,1 Peter Itsura,1 Bett Kipchumba,1 Jack Odunga1
1. Department of Reproductive Health, Moi University School of Medicine, Eldoret, Kenya *Correspondence to dr.dennisodhiambo@gmail.com
Disclosure: The authors have declared no conflicts of interest.
Received: 24.11.23
Accepted: 28.02.24
Keywords: Fetomaternal outcomes, Moi Teaching and Referral Hospital (MTRH), postpartum haemorrhage, pulmonary embolism, venous thromboembolism (VTE).
Objective: To determine the fetomaternal outcome of venous thromboembolism in pregnancy at Moi Teaching and Referral Hospital (MTRH), Eldoret, Kenya.
Methods: This was a prospective cohort study of females with venous thromboembolism (VTE) in pregnancy at MTRH. These patients were followed up, and pregnancy outcomes were compared with a comparison arm of normal pregnant females (non-exposed). Purposive sampling was used for the non-exposed arm. Data were analysed using both descriptive and inferential statistics at 95% confidence level. Categorical variables were summarised as frequencies and percentages. Bivariate analysis was done using Chi square and multivariate analysis using logistic regression, with a confidence level of 95%. A p value of <0.05 was considered to be statistically significant.
Results: The mean age of the participants was 27 and mode of 22 years. Seventy percent of the study population were between the age of 18–35 years, with those below the age of 18 being one in both arms. Fifty-nine percent of females were multiparous. The most common site of deep vein thrombosis was superficial femoral vein, followed by popliteal vein (10 individuals; 5.3%). Multiparty was significantly associated with VTE (p=0.004). Females who were overweight or obese were associated with risk of VTE (p value of 0.001 and 0.003, respectively). There was a significant association between rates of Caesarean section and VTE (p=0.019). Postpartum haemorrhage, admission to newborn unit, and birth weight were associated with VTE with p value of 0.034, 0.025, and 0.018, respectively.
Conclusion: The authors concluded there is no difference in fetomaternal outcome between females with VTE and females without VTE.
Key Points
1. The findings of this study will be able to establish the gestation and mode of delivery that offers the best outcome for both mother and neonate, in females with venous thromboembolism (VTE) in pregnancy.
2. There is limited knowledge on how VTE affects the outcome of pregnancy in the African population. This study explains fetal and maternal outcomes of females diagnosed with VTE, by comparing their outcomes to females without VTE. This study also explains the risks of VTE in pregnancy.
3. The study found no difference in fetal and maternal outcomes between females with and without VTE. Those with VTE in pregnancy should be allowed to deliver at term, and attempt vaginal delivery, if there are no obstetric or medical contraindications.
INTRODUCTION
The development of a blood clot (thrombus) in a deep vein, usually in the lower limbs, is known as deep vein thrombosis (DVT). Pain, swelling, redness, warmth, and engorged superficial veins are examples of nonspecific symptoms.1 A potentially fatal condition known as a pulmonary embolism results from a clot breaking loose, and moving into the lungs. Venous thromboembolism (VTE) is the collective term for the illness process that results from DVT and PE.2
Pregnancy raises a woman’s risk of VTE by a factor of 2–4. According to research by Girish,3 there is a notable tendency for venous thrombi to develop in the left leg during pregnancy. This may be partly because the right iliac artery compresses the left iliac vein when they cross.3
Objectively confirmed DVT appears to occur with similar frequency in each of the three trimesters, despite the fact that leg swelling and calf pain are most common in the third trimester. Therefore, the vast majority of females with leg swelling, with or without calf pain, in the third trimester do not have DVT, whereas when left leg symptoms occur in early pregnancy, DVT is much more likely to be present.4
According to a 2009 study by Galanaud et al.,6 DVT in the lower extremities can be classified as proximal (thigh vein) or distal (calf vein).5 Since proximal vein thrombosis is more frequently linked to serious, chronic diseases, such as active cancer, congestive
failure, respiratory insufficiency, and age greater than 75, it is more significant clinically than distal vein thrombosis, which is more frequently linked to transient risk factors, such as recent surgery, immobilisation, and travel.6
There is clear paucity of data on a number of key areas in the management of VTE in pregnancy. The time to deliver females with VTE in pregnancy and intrapartum management in cases of prolonged induction of labour is one of the major gaps. Very few studies have looked at the impact of VTE on the pregnancy, and how it affects pregnancy outcomes as compared to normal pregnancies.
This study seeks to bring forth a comparative analysis of fetomaternal outcomes between females with and without VTE in pregnancy.
Problem Statement
VTE, though rare, occurs more commonly during pregnancy and puerperium than in the normal population. At a rate of 0.5–2.2 per 1,000 pregnancies, it is a significant contributor to maternal morbidity and mortality, in both industrialised and developing nations, and accounts for 1.1 deaths per 100,000 pregnancies.7 Pulmonary thromboembolism, which is part of the VTE spectrum, has a high fatality rate. VTE is among the causes of near miss, with highest fatality rate of almost 100%; hence, prevention through early treatment of VTE is paramount.8
Pregnancies with VTE can either be allowed to go into spontaneous labour, or are induced at term to allow for continued care of the mother without any further compromise to the mother, especially in pulmonary thromboembolism. An area that is not clearly defined is the duration in which a female on treatment for thromboembolism can stay without anticoagulation during the period of labour, and induction of labour, bearing in mind that the risk of thrombus propagation is increased by the gravid uterus pressing on the pelvic vessels, causing stasis, which is part of the risk factors for VTE.9
A lot of studies have been done on the clinical presentation and patient risk factors for VTE in pregnancy and puerperium, but there is limited knowledge on how VTE affects the outcome of pregnancy in the African population, and locally in Kenya. The maternal outcomes of interest are gestation at delivery, Caesarean section, and postpartum haemorrhage. Fetal outcomes of interest are: preterm birth, 5-minute Apgar score, and admission to newborn unit (NBU).
Study Objective
To determine the fetomaternal outcome of VTE in pregnancy at Moi Teaching and Referral Hospital (MTRH), Eldoret, Kenya.
METHODOLOGY
Study Site
The study was done in Eldoret, Kenya, at Moi Teaching and Referral Hospital (MTRH) in antenatal outpatient clinics, and maternity wards at Riley Mother and Baby Hospital, Eldoret, Kenya, in the gynaecologic ward, and the memorial private maternity wing of MTRH.
Study Design
This was a prospective cohort study. All pregnant females diagnosed with VTE were recruited at first point of contact, and followed up during the entire pregnancy until delivery. Females with no complications during pregnancy were matched with each case of VTE in the cohort arm. Every case was matched with three controls (i.e., 1:3).
The 1:3 ratio was chosen to increase the power of statistics to detect a difference, and to make sure the results did not happen by chance. Matching was done based on parity and age with a margin of error of 5 years and 5 weeks being acceptable. Matching of cases was within 72 whours of case identification.
Sampling Technique
Consecutive sampling was used to recruit patients in the study.
Ethical Consideration
Approval was sought and obtained from the Institutional Research and Ethics Committee (IREC) at MTRH and Moi University School of Medicine, Eldoret, Kenya.
Data Collection
Questionnaires were administered for primary data collection, while patients’ files were used for secondary data collection. Secondary data gaps and inconsistencies were corrected through patient clarification at the time of data cleanup, which was done within 24 hours of attaining the information. For each questionnaire of a VTE case, the matched three subjects were interviewed, to allow for easy data analysis and comparison.
There was a pilot study conducted to test and retest the questionnaire before the main study started. This was done to standardise the data collection tools.
Primary data included bio-data, risk factors and clinical presentation, and pregnancy outcome (maternal and fetal).
Secondary data included how the diagnosis was confirmed, whether based on clinical symptoms or using radiological modalities.
Data Management and Analysis
Descriptive statistics for the measures of central tendency and dispersion, such as the mean and standard deviation, were used to summarise continuous variables, such as age, and Apgar score if normality assumptions will be satisfied. Categorical
variables, such as admission to the NBU, preterm birth, or stillbirth were summarised using frequencies and the corresponding percentages. Continuous variables, such as age, gestational age, weight, and BMI, among others, will be summarised using mean and the corresponding standard deviation.
Maternal outcomes among females with VTE were summarised using the descriptive statistics for the measures of central tendency and dispersion. Frequencies and the corresponding percentages were used to summarise categorical variables, such as postpartum haemorrhage, and mode of delivery, among others.
Neonatal outcomes for females with VTE were summarised using descriptive statistics. Continuous variables, such as birth weight and Apgar score, among others, were summarised using mean and standard. Frequencies and the corresponding percentages were used to summarise categorical variables, such as admission to the NBU, preterm birth, or stillbirth, among others.
Fetomaternal outcomes were compared using appropriate statistical tools (STATA version 12 SE, Statacorp, College Station, Texas, USA). Preterm birth, stillbirth, and admission to NBU, among other categorical outcome variables, were compared between mothers with VTE and those without VTE, using Pearson’s Chi-squared test. Continuous variables, such as birth weight, Apgar score, gestational age, and quantity of blood lost, among other continuous variables, were compared between mothers with VTE and those without, using independent samples t test.
RESULTS
A total of 188 participants were recruited into the study. Of these, 141 were controls, while 47 were cases. Twenty-two of the cases had a previous history of VTE (Table 1).
The majority of the population studies were between the age of 18–35 years in both cases, and control groups, with those
below the age of 18 being one in both arms (assent given).The mean age of the participants was 27 years, with standard deviation of 6.13 years and mode of 22 years (8%). The majority of females studied (59%) were multiparous.
The superficial femoral vein (30%) was the most prevalent site of DVT, followed by the popliteal vein (10%), while 21% of patients had DVT in more than one location. Superficial femoral vein (30%) was most common site of VTE, while deep femoral vein (4%) was the least that occurred in isolation. Twenty-six cases (55%) had proximal VTE, whereas 45% had distal VTE.
Vaginal delivery was the commonest mode of delivery among cases with no statistical difference between proximal and distal VTE. Twenty-four of the cases with proximal VTE (92.3%) had a statistically significant association (p=0.044) with PPH as compared to distal VTE.
Females with proximal VTE had more admission to NBU compared to distal VTE (76.9% and 14.3%, respectively), which was statistically significant (p=0.012) The rest of the outcomes were not statistically significant.
Five percent of cases (24/47) where diagnosed at third trimester, with the lowest number in first trimester (6/47). There was an association between parity and VTE. It clearly came out that multiparity is significantly associated with VTE (p=0.004).
There was no statistically significant difference in the gestational age at delivery for both cases and controls, as most deliveries were term seven (1.6% and 80.9% for controls and cases respectively).
The majority of the population delivered vaginally (148/188). Only one pregnancy was terminated amongst the participants, due to fear of warfarin embryopathy because she conceived while on long term warfarin anticoagulation. The majority of cases had vaginal births (37/47; 78%).
There was a significant association between rates of Caesarean section and VTE
Table 1: Bivariate analysis between venous thromboembolism site and fetomaternal outcomes.
(p=0.019.) There was also a statistically significant association between postpartum haemorrhage and VTE (p=0.034). Admission to NBU and birth weight were also associated with VTE (p value of 0.025 and 0.018, respectively); however, the study found no association between blood group and VTE.
Multivariate analysis showed that the participants with a BMI of more than 30 had a four-times higher risk of having negative outcomes than those with a BMI of 17–25 (Table 2). The results also had a statistically significant P value of 0.001. Similarly, multiparous females were also two-times more likely to have negative outcomes than primiparous, with a significant P value of 0.032.
DISCUSSION
Obesity and Venous Thromboembolism in Females
In this study, obesity with BMI >30 was found to be a strong independent risk factor for VTE (AOR 4.94). This was in agreement with available data that implicate obesity as an even stronger risk factor for VTE than for coronary heart disease and stroke.4 Previous publications from the Hoorn Study showed that obesity is a risk factor for VTE.10
The mechanisms of how obesity increases the risk of VTE was correlated with increased thrombin generation and peripheral conversion of androstenedione to oestrogen in adipocytes (fat cells), particularly in females with obesity.10
Parity
and Risk of Venous Thromboembolism
In this study, multiparity was found to be an independent risk factor for VTE (adjusted odds ratio [AOR]: 2.22). This was in agreement with studies by Jacobsen et al.,13 and Zotz et al.,18 that found multiparity increased the risk of VTE in pregnancy; a study by Waldman et al. also confirmed that multiparity, especially grand multiparity, increases the risk of VTE.12
Gestation Age at Diagnosis
In this study, the gestational age at diagnosis was mainly in the third trimester (51%). These results are in agreement with not only a study done in Nigeria, where majority of the cases were diagnosed during the third trimester, but also another case control study in a referral hospital in Ghana.4,14
Maternal Outcomes
Gestation at delivery
In this study, the majority of the females in both arms delivered at term, and there was no statistically significant association between gestational age at delivery and risk of VTE. These results are supported by Ben-Joseph,15 who found no significant association between gestational age at delivery and VTE. However, several studies have associated gestational age at delivery and VTE risk. Zoller16 found a significant association between gestational age at delivery and VTE, with incidence of venous thromboembolic events being fourfold. Similarly, Galambosi17 also found that the risk of VTE was three-times higher in the females who delivered preterm compared with the females who delivered at term.
Mode of delivery
In this study 19% (nine) of cases compared to 21.39% (30) of controls delivered via Caesaerean section, which was not statistically significant. This was in agreement with studies by Zotz and colleagues,18 who found no relation between mode of delivery and VTE. These findings, however, differ from studies done by Dresang et al.19 whose findings were similar to those of Chang et al.,20 that showed a significant association between VTE and Caesarean section.
Onset of labour
For females on therapeutic anticoagulation, a planned delivery, either through the induction of labour, or by elective Caesarean section, may allow optimal timing of events, or minimise the risks of an unplanned delivery on full anticoagulation. Chan et al.21 found peripartum bleeding risk for females on therapeutic anticoagulation acceptable.
Table 2: Multivariate logistic regression after adjusting for confounding variables.
In this study, PPH was statistically significant at bivariate level, but no association after adjusting for confounders (AOR: 1.11) at multivariate analysis. This was in agreement with Chan,21 who found postpartum bleeding risk for females on therapeutic anticoagulation as acceptable.
In addition, a study by Kominiarek,22 on effect of low molecular weight heparin in pregnancy, showed that bleeding complications, including PPH and transfusion, were not increased when compared to normal controls matched for delivery route.
On the contrary, in a study done by James et al.,23 females with VTE are at an increased risk of postpartum haemorrhage during birth and childbirth.
A cohort study done by Chauleur et al.24 found out there is a risk of PPH during delivery; hence, they studied the relationship between severe PPH and VTE in females during their first pregnancy. Out of the 615 females with VTE recruited, 317 had postpartum haemorrhage, which was statistically significant (p=0.002).24
Fetal Outcomes
Birth weight
In this study, there was a significant association between low birth weight and VTE (p=0.018). A case control study done by Blondon et al.25 had the same insight, and beyond their study found out that delivery of a newborn with low birth weight is associated with a threefold increased risk of maternal postpartum VTE. Their conclusion was that this should be considered when assessing VTE risk at delivery, and during antenatal clinic visits.24
Another study by Tsai26 also had similar results, only in this case, the risk of VTE also affected the newborn, with newborns having a risk of developing VTE either in childhood, teenage years, or adulthood.26
Another study by Chaireti and Bremme27 also came up with the conclusion that there is a significant association between VTE and birth weight. In their study, it was ascertained that there is an association between birth weight and VTE,27 especially in females with antiphospholipid syndrome.
Apgar score at 5 minutes
This study did not find any association between Apgar score and VTE. Apgar score at 5 minutes of both arms was not different between the two groups, as they all had good Apgar score (p=0.433). This is supported by a case control study by Tuckuviene et al.,28 whose study had concluded that other independent infant, obstetrical, and maternal characteristics could be associated with low Apgar score, which may be associated with VTE and Apgar score outcomes.28
Admission to newborn unit
The authors’ study found a significant association between NBU admission and VTE (p=0.025). These results contradict the findings of Tuckuviene et al.,28 whose study found no significant association between admission to the NBU and VTE.28 The above findings could be attributed to the high number of preterm births and low birth weights in this cohort study.
CONCLUSIONS
Females with obesity and higher parity have a higher probability (AOR: 4.94 and 2.22, respectively) of getting VTE than the normal population. However, females with VTE were not at an increased risk of postpartum haemorrhage than those who did not have. There was no difference in gestational age at delivery between the cases and controls. There was no difference in the 5-minute Apgar score and NBU admission among the cases of VTE and controls. Low birth weight was more common among cases of VTE than controls.
The authors recommend larger longitudinal studies that will include the community, and for the major findings to be generalised for both the hospital setting and at the community level.
Strength and Limitations
The strength of this study was in the methodology. The study was powered enough to make sure that the results did not happen by chance. The limitation was that this was a hospital-based study, and the findings may not be the same with a community-based study.
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