Objective To study the preferences and risk tolerance of women suffering from deep endometriosis (DE) with bowel involvement when they have to choose between conservative or surgical. Design Labelled Discrete Choice Experiment (DCE). Setting Dutch academic and non-academic hospitals and online recruitment. Population or Sample A total of 169 patients diagnosed with DE of the bowel. Methods Baseline characteristics and the fear for surgery were collected. Women were asked to rank attributes and choose between hypothetical conservative (medication) or surgical treatment in different choice sets (scenarios). Each choice set offered different levels of all treatment attributes. Data were analysed by using multinomial logistic regression. Main Outcome Measures The following attributes; effect/or risk on pain, fatigue, pregnancy, endometriosis lesions, mood swings, osteoporosis, temporary stoma and permanent intestinal symptoms were used in this DCE. Results In the ranking osteoporosis is the least important attribute, while in the DCE, a lower chance of osteoporosis is one of the most important drivers when choosing a conservative treatment. Women with previous surgery show less fear for surgery compared to women without surgery. The low anterior resection syndrome is almost equally important for patients as the chance of pain reduction. Pain reduction has higher importance than improving fertility chances even in women with a future child wish. Conclusions The risk of suffering from LARS as a result of treatment is almost equally important as the reduction of pain symptoms. Women with previous surgery experience less fear for surgery compared to women without a surgical history.

Title Page Title: Letter to the Editor: ” Gestational weight gain, appetite regulating hormones, and metformin treatment in polycystic ovary syndrome: A longitudinal, placebo- controlled study ”.Article type : Letter to the editor.

Letter to the Editor, BJOG Exchange

Abstract Objective: To investigate serum human epididymis-4 (HE4) as a predictive biomarker of intrauterine progestin response in endometrial cancer and atypical endometrial hyperplasia (AEH). Design: Prospective observational study. Setting: Consecutive sample of women attending a tertiary gynaecological oncology centre in the North West of England. Population: Women with AEH or early stage, low grade endometrial cancer who were unfit or declined primary surgical management; 48 in the discovery cohort and 28 in the validation cohort. Methods: Women were treated with a levonorgestrel intrauterine system (LNG-IUS) for 12 months. Endometrial biopsies and imaging were performed to assess treatment response. Pre-treatment serum HE4 was analysed by chemiluminescence immunoassay and diagnostic accuracy and logistic regression analyses performed. Main outcome measure: Progestin response at 12 months defined by histology and imaging. Results: Baseline serum HE4 was significantly higher in non-responders than responders in both discovery [134.6pmol/L (IQR:94.0-292.4) vs 76.5pmol/L (IQR:59.7-87.3), p<0.001] and validation cohorts [108.2pmol/L (IQR:80.3-119.2) vs 64.4pmol/L (IQR:53.0-73.0), p=0.004]. An HE4≥77pmol/L had a sensitivity and specificity for progestin treatment response of 83.3% and 53.3% in the discovery cohort, and 85.7% and 76.2% and in the validation cohort, respectively. When expressed as a continuous variable, the AUC was 0.81 (95%CI:0.67-0.95) and 0.87 (95%CI:0.73-1.00) for the discovery and validation cohorts, with every 1pmol/L of HE4 increasing the likelihood of progestin treatment failure by 2% and 5%, after adjustment for age and histology, respectively (p=0.02 and p=0.18). Conclusion: Serum HE4 shows promise as a predictive biomarker of progestin treatment response in endometrial cancer and AEH.

Objective: Approximately 50% women who give birth after Obstetric Anal Sphincter Injury (OASI) develop anal incontinence (AI) over their lifetime. We review current evidence for protective benefit of planned cesarean section (CS) to prevent AI after OASI. Design and setting: Systematic review and meta-analysis according to prospectively published methodology. Population and methods: All studies reporting outcomes after an OASI and subsequent birth by any mode. Main outcome measures: AI measurement after OASI and subsequent birth. Total AI, new/worsening AI, quality of life, satisfaction, regret. Results: 86 of 2472 screened studies met inclusion criteria. All studies contributing to meta-analyses were at high risk of bias. There was no evidence of difference in new or worsening AI after subsequent vaginal birth (VB) compared to subsequent CS after OASI across all time periods (p=0.53: CI 0.72-1.19; 9 studies, 2104 participants); ≤2y (p=0.83: CI 0.65-1.72; 7 studies, 569 participants) or ≥5y after subsequent birth (p=0.39: CI 0.65-1.18; 2 studies; 1535 participants). There was no difference between subsequent CS or VB in asymptomatic women or for other AI or QOL outcomes. There was no evidence of difference in AI in women who subsequently delivered vs those who did not (p=0.9: CI 0.71-1.34; 10 studies, 970 participants); or pre- subsequent birth vs post-subsequent birth (p=0.31; CI 0.51-1.25, 13 studies, 5496 participants). Conclusions: Due to evidence quality (majority non-randomised studies) we are unable to determine whether planned cesarean is protective against AI after OASI. Higher quality data is required to guide practice in this area, specifically in asymptomatic women and for long-term outcomes.

Objective: To report on the effectiveness of a standardized core Maternity Waiting Home (MWH) model to increase facility deliveries and access to reproductive health services among women living farthest from a health facility (>10km) using facility-based data. Design: Quasi-experimental design. Setting: Seven rural districts in Zambia. Population: Women delivering at 40 health facilities between June 2016 to August 2018. Methods: 20 intervention sites and 20 comparison sites were used to test if MWHs increased access to reproductive health services for women living in rural Zambia. The difference-in-differences (DID) methodology was used to examine the effectiveness of the core MWH model on our primary outcomes. Main Outcome Measures: Differences in the change from baseline to endline in the percentage of women who: 1) traveled greater than 10 km for delivery, (2) attended a postnatal visit at 6 days postpartum, and (3) were referred to a higher-level health facility between intervention and comparison group. Results: We detected a significant difference for the percentage of deliveries at intervention facilities with the core MWH model for all women living >10km away (p=0.03), adolescent women (<18 years) living >10km away (p=0.002), and primigravida women living >10km away (p=0.01). There were no significant differences for women attending a postnatal care visit at 6 days postpartum (p=0.07) or for women referred to the next level of care (p=0.29). Conclusion: The core MWH model was successful in reaching women with historically low rates of facility delivery, those living >10km from a healthcare facility, including adolescent women and primigravidas.

Dear editor/Sir,We thank Song et al. for their insightful comments (1) on our article (2) and commend them for their study about human papillomavirus (HPV)-genotyping on self-samples and their analysis on different triage strategies for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) (3). They report that cytology on physician-sampled material has a sensitivity of 74.8% for detecting CIN2+, while HPV-genotyping for 16/18 has a sensitivity of 52.6% for detecting CIN2+. This means that HPV-genotyping in their hands, is still inferior to cytology testing and cannot fully replace this triage strategy. However, adding HPV-genotyping to cytology testing could increase the sensitivity, as has been described by others as well. While our study shows that reflex cytology on self-samples cannot replace triage with regular cytology for HPV-positive women, because of the low sensitivity of 29.4% for detecting CIN2+, it is valuable as an additional method for triage (2). With a positive predictive value (PPV) of 68.1% for detecting CIN2+ it is effective to refer HPV-positive women with abnormal cytology on self-sampling directly for colposcopic evaluation without the requirement of an extra visit to the general practitioner. A PPV of 21.2% for HPV-genotyping for 16/18 on self-samples for detecting CIN2+ is not enough to refer these women directly for colposcopy. We agree that cost-effectiveness is important. It is not sure if 15% of direct referral will completely cover the costs for 85% of double cytology testing. As the collection in PreservCyt (Cytyc Corporation, Boxborough, MA, USA) has already been performed for HPV-testing on the self-samples, extra costs will include the use of ThinPrep slides (Hologic Inc, Marlborough, MA, USA) and cytotechnicians’ time for analysing the slides. On the other hand, there will be a reduction in costs for consulting the general practitioner and for regular cytology testing, including material costs (Cervex brush (Rovers® Medical Devices B.V., Oss, the Netherlands), PreservCyt jar, ThinPrep slide), transportation costs, and cytotechnicians’ time for analysing the slides. However, besides cost-effectiveness, patient comfort is at least as important, as well as reduction in loss-to-follow-up and diagnostic delay, in which the latter also positively influences the costs. It remains a challenge to find a triage method on HPV-positive self-samples which could fully replace regular cytology. Molecular tests, such as methylation markers and microRNA detection, are promising future triage methods (4, 5). They are more objective than cytology testing and highly reproducible, however not ready yet for full implementation in cervical cancer screening. Further research on self-samples is warranted to find an optimal triage strategy. Until then, reflex cytology on self-samples could be easily implemented in the current screening programme and improve cervical cancer prevention.Diede L Loopik 1; Willem JG Melchers 2; Judith EM Vedder 3; Adriaan JC van den Brule4; Leon FAG Massuger 1; Ruud LM Bekkers5; Albert G Siebers 3,61 Department of Obstetrics and Gynaecology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, PO Box 9101, 6500HB, Nijmegen, the Netherlands;2 Department of Medical Microbiology, Radboud university medical center, PO Box 9101, 6500HB, Nijmegen, the Netherlands;3 Department of Pathology, Radboud university medical center, PO Box 9101, 6500HB, Nijmegen, the Netherlands;4 Department of Pathology, Lab for Molecular Diagnostics, Pathologie-DNA, Jeroen Bosch Hospital, PO Box 90153, 5200ME,‘s-Hertogenbosch, the Netherlands; 5 Department of Obstetrics and Gynaecology, Catharina Hospital, PO Box 1350, 5602ZA, Eindhoven, the Netherlands; 6 PALGA, the nationwide network and registry of histo- and cytopathology, Randhoeve 225a, 3995 GA, Houten, the NetherlandsPresent address Ruud LM Bekkers: GROW, School for Oncology & Developmental Biology, Maastricht University Medical Centre, PO Box 616, 6200MD, Maastricht, the Netherlands

Letter to the Editor, BJOG Exchange

Obstetric care for women that use antidepressants in pregnancyLine Kolding, MD, PhDVera Ehrenstein, MPH, DSc, ProfessorLars Pedersen, MSc, PhD, ProfessorPuk Sandager, MD, PhD, Associate ProfessorOlav B. Petersen, MD, PhD, ProfessorNiels Uldbjerg, MD, DMSc, ProfessorLars H. Pedersen, MD, PhD, ProfessorCorresponding:Lars Henning PedersenAarhus University Hospital / Aarhus UniversityPalle Juul-Jensens Blvd. 99, 8200 Aarhus N, DenmarkEmail: lhp@clin.au.dkPhone: +45 50526512We are grateful to Drs. Braillon and Bewley for their interest in our recent paper in the BJOG 1 and would like to elaborate on some of the important points they raise.We agree with Braillon and Bewley on the urgent need for improved pharmacovigilance of medication in pregnancy in general, and for antidepressants in particular. There are excellent international collaborations (e.g., the EuroCat) and local initiatives (e.g., the Swedish JanusInfo), but clinically we’re often forced to rely on very limited information indeed. Systematic international recording as suggested by Braillon and Bewley would represent an important step forward.On a smaller scale, we are establishing an automated surveillance system based on curated data that include information on both pre- and postnatally diagnosed malformations. We have, however, faced substantial legal and bureaucratic challenges, and have been forced to use data from the Central Denmark Region only, instead of national data. The surveillance system is consequently based on information on approx. 75,000 pregnancies, and even though it has the potential to aide clinical management, it is a drop in the ocean of the huge potential of for instance a comparable European collaboration.In our study, we used ≥2 redeemed prescriptions to define exposure with a prevalence 1.1%.1 The prevalence of pregnant women that redeemed ≥1 prescription was 3.2% (p. 3/ Table S1), and even though this is likely an overestimation due to non-adherence, the estimates are in line with previously reported prevalences in Scandinavia.2Braillon and Bewley emphasise the need to also consider non-pharmacological treatment of some pregnant women with depression and, further, to provide evidence-based and individualised treatment of women in the reproductive ages. Optimal individualised care will definitely result in non-pharmacological treatment of some pregnant women but, reversely, will cause yet other women to continue or initiate pharmacological treatment. This is in line with what is almost a truism in this field, that the potential harmful foetal effects must be balanced against the potential benefits of a pharmacological treatment, but it is no easy task. Pregnant women might overestimate the foetal risks associated with use of medication3 and discontinue important treatment, on the other hand some may use medication when there may be a better alternative for them. Regardless, we need to provide optimal obstetric care for the pregnant women that choose treatment with antidepressants. If our results are correct, prenatal follow-up of pregnant women treated with venlafaxine may include targeted foetal heart scans, even though the underlying causal explanation for the observed association with cardiac malformations is undetermined.1. Kolding L, Ehrenstein V, Pedersen L, Sandager P, Petersen OB, Uldbjerg N, et al. Antidepressant use in pregnancy and severe cardiac malformations: Danish register-based study. BJOG. 2021 May 25.2. Zoega H, Kieler H, Norgaard M, Furu K, Valdimarsdottir U, Brandt L, et al. Use of SSRI and SNRI Antidepressants during Pregnancy: A Population-Based Study from Denmark, Iceland, Norway and Sweden. PLoS One. 2015;10(12):e0144474.3. Wolgast E, Lindh-Åstrand L, Lilliecreutz C. Women’s perceptions of medication use during pregnancy and breastfeeding—A Swedish cross-sectional questionnaire study. Acta Obstetricia et Gynecologica Scandinavica. 2019;98(7):856-64.

Mini-commentary on BJOG-19-1677.R1: Risk-factors for second-line dactinomycin failure after methotrexate treatment for low-risk gestational trophoblastic neoplasia: a retrospective study

Background: Sub-Saharan African (SSA) countries have high stillbirth rates compared to high-income countries, yet research on risk factors for stillbirth in SSA remain scant. Objectives: To identify the modifiable risk factors of stillbirths in SSA and investigate their strength of association using a systematic review. Search Strategy: EMBASE, MEDLINE, Global Health, and CINAHL Plus databases were searched for literature. Selection Criteria: Observational population- and facility-level studies exploring stillbirth risk factors, published between 2013-2019 were included. Data Collection and Analysis: Narrative synthesis of data was undertaken and the potential risk factors were classified into sub-groups. Main Results: Thirty-seven studies were included, encompassing 20,264 stillbirths. The risk factors were categorized as maternal antepartum (0-4 antenatal care visits, multiple gestations, hypertension, birth interval >3 years, history of perinatal death); socioeconomic factors (maternal lower wealth index and basic education, advanced maternal age, grand multiparity (≥5)); intrapartum (direct obstetric complication, non-vaginal delivery); fetal (low birthweight and gestational age <37weeks) and health systems (poor ANC quality, emergency referrals, ill-equipped facility). The proportion of unexplained stillbirths remained very high. No association was found between stillbirths and HIV, BMI, diabetes, and distance from the facility. Conclusion: The overall quality of evidence was low as many studies were facility-based and did not adjust for confounders. This review identified preventable risk factors for stillbirth. Focused programmatic strategies should be developed to improve antenatal care, emergency obstetric care, maternal perinatal education, referral and outreach systems, and birth attendant training. More population-based high-quality research is needed. Funding: Not externally funded

New insights in diagnostic thresholds for total serum bile acid (TSBA) in intrahepatic cholestasis of pregnancy (ICP)

Retained Products of Conception as an Etiology for EndometritisPietro Bortoletto, MD1, Phillip A. Romanski, MD1, Nina Schatz-Siemers, DO2, Steven D. Spandorfer, MD11 The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical College, 1305 York Ave, 7th Floor, New York, NY 10021, USA.2 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, NY 10021, USA.

Mini commentary on BJOG-21-0235.R1The Project Appropriate Birth: significance of the Robson classification in confronting the caesarean section

Mini-commentary on BJOG-20-0453.R1: Can risk prediction models help us individualise stillbirth prevention? A systematic review and critical appraisal of published risk models

BJOG-22-0382.R1: Implementing Effective Investigations for Cause of StillbirthElizabeth M McClure, PhDRobert L Goldenberg, MDRTI International, Durham, NCColumbia University, New York, NYStillbirth is one of the most common adverse pregnancy outcomes in low and middle-income countries (LMICs), with rates in the range of 40 to 50 per thousand births in some regions [1]. International goals aim for no country to have a rate of >10 per thousand births by 2035 [Hug L, et al. Lancet. 2021;398(10302):772-85]. To achieve this, a better understanding of stillbirth causes often requiring additional investigations is critical. For several reasons, including low prioritization, inadequate resources, and hesitancy by families and providers, investigations on stillbirth causes in LMICs have been limited to date.Bedwell et al used a grounded theory approach to explore the views of women, partners, families, health workers and community leaders in Malawi, Tanzania, and Zambia regarding investigations to determine the cause(s) of stillbirth [Bedwell et al, BJOG (in press)]. While most would like more information regarding the stillbirth, the authors noted cultural and religious obstacles to performing the investigations, including preferences for quick burial, reluctance to disfigure the deceased fetus, concerns about blame, as well as costs.One test to inform cause of stillbirths is minimally invasive tissue sampling (MITS), using needle biopsies to obtain internal organ tissue for histological evaluation and microbial analyses. For a study on causes of stillbirth in Pakistan and India, we explored the acceptability of MITS among parents, relatives, religious leaders, and government officials [Feroz A, et al. Reprod Health.2019;16(1):53]. The perceived benefits included knowing the cause of death, and both personal and societal benefits in preventing subsequent stillbirths. Concerns regarded rapid burial and reluctance to disfigure the stillborn. In Pakistan, with some caveats, religious leaders approved, and, when MITS was undertaken, in both Pakistan and India, approximately 50% of the parents consented for the MITS procedure.Because obstacles to testing in general and to MITS specifically relate to time, cost, and disfigurement, we have considered which examinations feasible in LMICs provide the most information at minimal cost. Page et al., in a similar exercise in a US study, noted that the most useful test was placental histology (65%) followed by full autopsy (42%) [Page JM, Obstet Gynecol 2017;129(4):699-706.]. No other tests were useful for >12% of cases. Similar studies have rarely been performed in LMICs. The prevalence of the causes relates to the frequency of tests’ usefulness. In high-income countries where birth asphyxia and infection have been reduced, congenital and genetic anomalies have assumed a larger proportion of stillbirths, and testing for those conditions using karyotyping and other genetic tests become proportionately more important. However, in many LMICs, birth asphyxia remains the major cause of stillbirth and genetic issues play a smaller proportional role.To develop the most effective methodology to determine cause of stillbirth, the prevalent conditions, and the tests’ usefulness to diagnose those conditions should be considered together. Importantly, the community and other stakeholder’s perceived benefits and obstacles to various tests as described in the Bedwell, et al must be considered to ultimately be successful in implementing the necessary investigations.For LMICs, given that asphyxia and infection appear to be major causes of stillbirth, tests to diagnose these conditions will likely be important to implement, including the obstetric history and histological placental evaluation for diagnosing asphyxia and infection. Of potential information gained from MITS, histology of the fetal lung, and bacteriological assessment of the fetal blood and brain/CSF may be the most useful. Thus, by considering the prevalence of the causes of stillbirth, the usefulness of tests to diagnose the prevalent conditions, and importantly addressing the community’s sense of benefit and obstacles, an effective approach to stillbirth cause of death investigation can be developed.Declaration of Interest: The authors declare no conflicts of interest.

Objective: To evaluate which risk factors for RhD immunization remain, despite adequate routine antenatal and postnatal RhIg prophylaxis (1000 IU RhIg) and additional administration of RhIg. Assessment of the prevalence of RhD immunizations. Design: Prospective cohort Setting: The Netherlands. Population: Two-year nationwide cohort. Methods: RhD-negative women in their first RhD immunized pregnancy and their foregoing non-immunized pregnancy. Risk factors for RhD immunization were compared with population data. Main outcomes measures: Risk factors for FMH and subsequently RhD immunization, prevalence of RhD immunizations. Results: The prevalence of newly detected RhD immunizations was 0.31% (79/25,170) of all RhD-negative pregnant women in the Netherlands. After exclusion, 193 women remained. Significant risk factors found in the group of 113 parous women (previous pregnancy >16 weeks, RhD positive child) were; caesarean section (CS) (OR 1.7, 95% CI 1.1-2.6), perinatal death (OR 3.5, 95% CI 1.1-10.9), gestational age over 42 weeks (OR 6.1, 95% CI 2.2-16.6), postnatal bleeding (>1000mL) (OR 2.0 95% CI 1.1-3.6), surgical removal of the placenta (SRP) (OR 4.3, 95% CI 2.0-9.3). The miscarriage rate in the group of women without a previous RhD positive child was significantly higher than in the Dutch population (35% vs 12.5% p<0.001). Conclusion: Complicated deliveries, including cases of major bleeding and surgical interventions (CS, SRP) need to be recognized as risk factor, requiring determination of FMH volume and adjustment of RhIg dosing. Miscarriage may be an additional risk factor for RhD immunization, requiring further studies. Funding: This research was partly funded by a grant from Sanquin Amsterdam.

Sir, We would like to thank Sharma and colleagues for their interest in our recent study evaluating the effectiveness and safety of surgical interventions for Bartholin’s cyst or abscess.1Their response highlights the unique opportunity offered by randomised trials, and their syntheses into meta‐analyses, to assess patient reported outcomes. We would strongly encourage researchers to select, collect and report patient reported outcomes in future research evaluating interventions for Bartholin’s cyst or abscess.2The primary outcome should be the outcome of greatest therapeutic importance to the study’s prospective hypothesis. There is currently no consensus regarding the selection of outcomes and methods of definition or measurement for randomized trials evaluating interventions for Bartholin’s cyst or abscess.3 In the absence of a standardized approach, researchers have made arbitrary decisions when choosing among several important outcomes.4 It would be useful for healthcare professionals, researchers, and women with lived experience of Bartholin’s cyst or abscess to engage in a formal consensus development process to agree appropriate primary and secondary outcomes.3We agree the use of adjuvant antibiotics is an important consideration. They were not reported by any of the included trials.5We have no experience of marsupialization performed under local anaesthetic. In our opinion, this approach would need to be evaluated within a research setting. The recent COVID-19 pandemic would provide additional impetus to undertake this much needed research.James M. N. Duffy 1,2, Emma Kirk 3, BJG Illingworth 4, K Stocking 5,Marian Showell 61 Institute for Women’s Health, University College London, London, United Kingdom.2 King’s Fertility, Fetal Medicine Research Foundation, London, United Kingdom.3 Department of Obstetrics and Gynaecology, Royal Free London NHS Trust, London, United Kingdom.4 North West Anglia NHS Foundation Trust, Peterborough City Hospital, Peterborough, UK5 Centre for Biostatistics, Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester, UK6 Cochrane Gynaecology and Fertility Group, University of Auckland, Auckland, New Zealand.