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.

Recent trends regarding GDM medication use have not been well described in prior literature. We identified pregnant patients enrolled in Tennessee Medicaid with a GDM diagnosis who a delivered in 2007 to 2019. We studied initial GDM medication use by delivery year (overall and by medication type). Over twenty percent of patients filled at least one prescription for GDM medication in the study period, with a significantly increasing prescribing trend over time. Starting in 2016, metformin replaced glyburide as the most common medication prescribed, which corresponds temporally with the emergence of evidence on the safety and effectiveness of different oral hypoglycemic medications and related changes in ACOG practice recommendations. These findings highlight how practice patterns have potential to shift quickly in response to evolving data.

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.

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.

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.

Objective To investigate perinatal mortality, morbidity and obstetric intervention after introducing universal third-trimester ultrasound scan for growth restriction. Design Prospective cohort study Setting Oxfordshire (OUH), UK Population Women with a non-anomalous singleton pregnancy undergoing pregnancy care and term delivery at OUH with an estimated-date-of-birth between 01/Jan/2014 and 30/Sept/2019. Methods Universal ultrasound for fetal growth restriction between 35+0 and 36+6 weeks was introduced in 2016. The outcomes of the next 18631 eligible term pregnancies were compared, using logistic regression, with the previous 18636 who had clinically-indicated ultrasounds only. ‘Screen positives’ for growth restriction were managed according to a pre-determined protocol. Main Outcome Measures Extended perinatal mortality, a composite of mortality or encephalopathy Grade II-III, and expedited birth. Other outcomes included composite adverse outcomes used elsewhere, detection of birthweight (<10th centile) and birth <39+0 weeks. Results Extended perinatal deaths decreased from 1.7/1000 to 1.2/1000 births (aOR: 0.73; 0.43 -1.25); mortality or severe morbidity decreased from 2.9/1000 to 1.9/1000 births (OR: 0.67; 0.44-1.03). Expedited births increased from 35.2% to 37.7% (OR: 1.08; 1.04 – 1.14). Birth prior to 39+0 weeks fell 10.5% (OR 0.89: 0.85 – 0.94). Birthweight (<10th centile) detection using fetal biometry alone was 31.4%, and rose to 40.5% if all abnormal scan parameters were used. Conclusion Introducing a universal ultrasound for growth restriction has limited impact on mortality and severe morbidity, but only small increases in intervention, and less early-term birth, are possible. The detection of birthweight (<10th c) improved where markers of growth restriction are used.

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

Objective To investigate the clinical outcomes and toxicity in patients with locally advanced cervical cancer treated with supplementary applicator guided-intensity modulated radiation therapy (IMRT) based on conventional intracavitary brachytherapy (IC/IMRT). Population Large high risk clinical target volume (HR-CTV) volume (>40cc) at the time of brachytherapy cervical cancer patients were recruited. Methods This study is a retrospective analysis of 76 patients with locally advanced cervical cancer (FIGO IIB-IVA) treated with concurrent chemo-radiotherapy followed by IC/IMRT between June 2010 and October 2016. External radiotherapy (45 Gy in 25 fractions) with cisplatin chemotherapy treated before IC/IMRT. The prescription dose for HR-CTV and IR-CTV were 6 Gy and 5 Gy per fraction for 5 fractions respectively. Results: Mean HR-CTV was 65.8±23.6 cc at the time of brachytherapy. D90 for HR-CTV and IR-CTV were 88.7±3.6 Gy and 78.1±2.5 Gy. D2cc for bladder, rectum, sigmoid and small intestine were 71.8±3.8 Gy, 64.6±4.9 Gy, 63.9±5.3 Gy and 56.7±8.7 Gy respectively. Median follow-up was 85 months (47.9-124.2 months). Five-year local recurrence free survival rate, metastasis recurrence free survival rate, disease free survival rate and cancer special survival rate were 87.6%, 82.4%, 70.9% and 76.3%, respectively. The grade 1+2 gastrointestinal and urinary late toxicities were 15.8% and 21.1%, while grade 3 late toxicities were 3.9% and 5.2%, respectively. Neither acute nor late grade 4 gastrointestinal or urinary toxicities were seen. Conclusions: The combination of ICBT with an applicator-guided supplementary IMRT boost achieved an excellent local control and overall survival with low toxicity for bulky residual cervical tumor

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

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

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.

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.

A document by Russell Kirby. Click on the document to view its contents.

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

Pregnancy provides optimal opportunities for health promotion and disease prevention. Smoking before and during pregnancy is one of the largest modifiable risk factors for a range of adverse pregnancy outcomes. Concerns over the risks of smoking motivate many pregnant smokers to quit. However, most of their partners continue to smoke throughout pregnancy. More than one-third (35%) of men in the world smoke, and just over 6% of women do (Ritchie et al. Published online at OurWorldInData.org 2020). The impact of paternal smoking, second-hand or third-hand smoking on the perinatal health is largely overlooked. Given the vast majority of studies focusing on the pregnant smokers, less is known about paternal smoking on their future children.In this paper (Zhou et al. BJOG 2020), using a large national prepregnancy registry database, Zhou et al. found that paternal smoking may be associated with birth defects such as congenital heart diseases, limb abnormalities and neural tube defects in the offspring. The result was consistent with previous retrospective studies, but a medium to large effect size was seen. All of the odd ratios exceeded 2.5, with one even over 20 (congenital heart diseases OR=2.51, 95%CI 1.04-6.05; limb abnormalities OR=20.64 95%CI 6.46-68.02; digestive tract anomalies OR=3.67 95%CI 1.44-9.37; neural tube defect OR=4.87,95%CI 1.66-14.28). Such difference might be partially explained by potential confounding factors. For example, the extent of tobacco exposure, in the National Birth Defects Prevention Study (Malik et al. Pediatrics 2008; 121: e810), compared with light smoking exposure (<14 cigarettes per day), heavy smoking women (≥25 cigarettes per day) were more likely to have infants with septal defects (OR 2.06; 95%CI: 1.20-3.54), suggesting a dose-dependent relationship between tobacco exposure and birth defects.In addition, a reduced risk of birth defects after changing smoking behaviors was found in Zhou’s paper. It is no surprise that paternal smoking cessation could improve the adverse outcomes. Limited evidences address whether there is a critical window period by which smoking must be stopped to prevent subsequent adverse perinatal outcomes. Results from a retrospective case-control study indicated that the risk of fetal congenital heart diseases increased as women smoked during the first trimester (Sullivan et al. J Pediatr; 2015; 166:978). In a prospective cohort study (McCowan et al. BMJ 2009; 338: b1081), the authors concluded that stopping smoking early in pregnancy, and certainly by 15-16 weeks’ gestation, may minimize the adverse effects of smoking on late pregnancy complications and should be an important goal for pregnant smokers. Yet, such critical time for paternal smoking cessation remains unknown.Tobacco smoke is also a human germ cell mutagen. It is estimated that with even a modest 25% increase in sperm mutation frequency caused by smoke-exposure, for each generation across the global population there will be millions of smoking-induced de novo mutations transmitted from father to offspring (Beal et al. Mutation Research;2017; 773:26).Therefore, it is strongly recommended that women and men should immediately stop smoking in advance of reproduction.No disclosures: A completed disclosure of interest form is available to view online as supporting information.

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.

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.

Obstetric anal sphincter injury by maternal origin and length of residence: a letterIt gives us great pleasure to read the study entitled “Obstetric anal sphincter injury (OASI) by maternal origin and length of residence: a nation-wide cohort study” by Sorbye and Bains et al1. We appreciate the authors for conducting a large scale multicentric cohort study on this newer aspect of OASI. However, we wish to make certain observations to further help in comprehending the results.Firstly, the eligibility criteria for the recruitment of participants needs clarification as to why foreign-born women with Norwegian-born parents were excluded from enrolment. Keeping them as a separate group could have been beneficial in assessing whether environmental factors due to migrating out of Norway had an impact on the incidence of OASI. Futhermore, the greater odds of OASI among women with foreign-born partners has to be digested with a pinch of salt. A subgroup analysis comparing the newborn birth weight (NBW) and head circumference (HC) could be instrumental in solving this dilemma. Prior studies by Vik et al from Norway had demonstrated similar outcomes in neonatal survival as well2. In the absence of significant difference in NBW and HC, social issues need due consideration. It probably opens up the arena for potential future research in this very field.The study does mention that the mean HC of newborns to foreign-born women with OASI did not differ from Norwegian-born counterparts without OASI. But the p value mentioned alongside in the text is 0.000, which would amount to high significance. This area needs clarification.Table 3 has stratified the association between OASI and the length of residence in Norway. We appreciate this robust comparison as this outcome was vital in hypothesizing the impact of environment and lifestyles on the incidence of OASI. But, it is quite strange to note that women who had childbirth before their lawful residence (probably had immigrated recently) had lesser odds of OASI compared to those who had legal residence upto 4 years. Discrete analysis of this subgroup of patients might give us a better comprehension. Another analysis which can be done is to assess whether the place of delivery (government or private setup) was significantly affecting the prevalence of OASI. It can be thought of as an auxiliary outcome. This will ultimately help in addressing the barriers to optimal utilization of resources and will probably stimulate the health care policy to achieve equitable care across the nation.References:Sorbye IK, Bains S, Vangen S, Sundby J, Lindskog B, Owe KM. Obstetric anal sphincter injury by maternal origin and length of residence: a nation-wide cohort study. BJOG. 2021 Oct 28. doi: 10.1111/1471-0528.16985. Epub ahead of print. PMID: 34710268.Vik ES, Aasheim V, Nilsen RM, Small R, Moster D, Schytt E. Paternal country of origin and adverse neonatal outcomes in births to foreign-born women in Norway: A population-based cohort study. PLoS Med. 2020 Nov;17(11):e1003395.