Objective Assess whether coronavirus disease 2019 (COVID-19) vaccination impacts menstrual bleeding quantity. Design Retrospective cohort Setting Five global regions Populations Vaccinated and unvaccinated regularly cycling individuals using the digital fertility-awareness application “Natural Cycles”. Methods We used prospectively collected menstrual cycle data and multivariable longitudinal Poisson GEE models, multivariable multinomial logistic regression models, and calculated the adjusted difference between vaccination groups. All regression models were adjusted for confounders. Outcome measures Mean number of heavy bleeding days (fewer, no change, more) and changes in bleeding quantity (less, no change, more) at three time points (first dose, second dose, and post-exposure menses). Results We included 9,555 individuals (7,401 vaccinated, 2,154 unvaccinated). About 2/3 of individuals reported no change in the number of heavy bleeding days regardless of vaccination status. After adjusting for confounders, there were no significant differences in the number of heavy bleeding days by vaccination status. A larger proportion of vaccinated individuals experienced an increase in total bleeding quantity (34.5% unvaccinated, 38.4% vaccinated; 4.0% [0.7, 7.2%] adjusted difference). This translates to an estimated 40 additional people per 1,000 normally cycling individuals who experience more total bleeding quantity following the first vaccine dose due to vaccination. Differences resolved in the cycle post-exposure. Conclusion A small increase in the probability of more total bleeding quantity occurs following the first COVID-19 vaccine dose which resolved the cycle post-vaccination cycle. Total number of heavy bleeding days did not differ by vaccination status. Our findings can reassure the public that any changes are small and transie

JOURNAL: BJOGDATE 08_25_2022TITLE: Mini commentary on “Familial aggregation of stillbirth: a pedigree analysis of a matched case control study” BJOG_22-0217Author: Matthew A. Shear, MDa,bAuthor Affiliations:a Department of Obstetrics, Gynecology, & Reproductive Sciences, University of California, San Franciscob Division of Medical Genetics, Department of Pediatrics, University of California, San FranciscoDespite advances in genomics, the underlying cause of many stillbirths remains elusive. The emotional toll that a stillbirth takes on families, as well as the providers caring for them, is hard to overstate. Karyotype may identify a causative aneuploidy or large unbalanced translocation, but only in about 6% of stillbirths. Chromosomal microarray is higher yield, but still only identifies pathogenic copy number variants in about 10% of stillbirth cases (Reddy et al. N Engl J Med. 2012). The addition of exome sequencing to microarray only yielded a plausible genetic explanation in 15 out of 246 cases, or about 6% (Stanley et al. N Engl J Med. 2020). This suggested that non-mendelian mechanisms may play a significant role in stillbirth (Wojcik et al N. Engl J Med. 2020), although single gene pathogenic variants are poorly understood at the fetal level relative to the postnatal setting. The non-genetic mechanisms underlying stillbirth are also poorly understood at present, including viral infections, environmental toxins, and comorbid conditions.Workalemahu and their colleagues present a unique analysis suggesting genomic heritability of stillbirth in some families. Using a robust matched case-control study of over 9000 stillbirths and 390 high-risk pedigrees from the Utah Population Database, they calculated the familial standardized incidence ratio and risk of stillbirth among first, second, and third-degree relatives of the pregnant individuals who had experienced stillbirth. In their adjusted model, among all relatives of an individual who experienced stillbirth, there was a relative risk of stillbirth of 1.1 (95% CI 1.00-1.22). This study adds further evidence there are heritable genetic etiologies of stillbirth not yet fully described.Many non-genetic contributors to stillbirth risk may also cluster in families. In the present study, when adjusting for maternal race/ethnicity, socioeconomic status, and education, the elevations in stillbirth risk became attenuated, although this may be due to collinearity among variables used in the model. Health behaviors are informed through regional and family culture, leading to patterns in diet, nutrition, and exercise. These patterns contribute to modifiable health conditions known to impact stillbirth risk, including hypertension, obesity, diabetes, and smoking status. We also know the incidence of stillbirth is higher in lower income versus higher income countries, higher among individuals of lower educational attainment versus higher education, and higher among African American and Black individuals compared to White, likely complicated by the impacts of systemic racism. This is to say nothing of the additional social determinants of health that may impact families across generations.As Workalemahu and colleagues note, there is still much unknown about complex outcomes such as stillbirth. Their findings support that for a patient with a high-risk pedigree, genomic testing may prove informative. Future epigenetic and functional studies may help understand variants at the tissue level, and the impact of comorbidities on gene expression. Together with fetal genome sequencing, previously unexplained cases of stillbirth might be solved, improving patient counseling, and possibly changing clinical management. While genomic testing offers promise to explain a subset of stillbirths, we should not neglect the “non-mendelian” and non-genetic factors that continue to play a significant role in stillbirth risk.

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 the reasons for COVID-19 vaccine hesitancy during pregnancy from first-person reports. Design: We used regular expressions to identify publicly available social media posts from pregnant people expressing at least one reason for their decision not to accept COVID-19 vaccine. Setting: WhatToExpect and Twitter. Sample: 1017 posts from 945 pregnant people in WhatToExpect and 435 tweets from 345 pregnant people in Twitter Methods: Two annotators manually coded posts according to the Scientific Advisory Group for Emergencies (SAGE) working group’s 3Cs model of vaccine hesitancy (confidence, complacency, and convenience barriers). Within each theme we created subthemes which emerged from the data. Results: Confidence barriers were the most common (75%) and were related to safety, waiting until after the 2nd trimester, birth or breastfeeding, efficacy, misinformation or mistrust. Complacency barriers were also common (52%) with people stating that they did not need the vaccine because they were taking other precautions, were not at risk or had already had COVID-19. Convenience barriers were the least common (13%) with most of these related to medical advice or eligibility. Some women gave more than one reason for their hesitancy and many of the reasons were inter-linked. Conclusion: The reasons for COVID-19 vaccine hesitancy during pregnancy give a clear picture of the public health messages required. Concerns around safety should be addressed in a sensitive manner. The relative effectiveness of the vaccine as compared with other precautions could be better promoted as could the high-risk nature of a COVID-19 infection during pregnancy.

Objective To investigate associations of early and middle adulthood physical activity (PA) with symptoms of pelvic floor disorders (PFD), i.e. stress urinary incontinence (SUI), urge urinary incontinence (UUI), fecal incontinence (FI), constipation or defecation difficulties (CDD), and feeling of pelvic organ prolapse (POP) among middle-aged women. Design A cross-sectional, observational study with retrospective physical activity assessment. Setting University Research Laboratory. Sample A random population sample of 1098 47-to-55-year-old Finnish women. Methods PA history, current PA, and demographical and gynaecological variables were assessed using self-report questionnaires. Logistic regression analyses were applied to study associations of past and current PA with PFDs. Associations of demographical and gynaecological variables with PFDs were studied and their potential confounding effect was controlled in multiple logistic regression models. Main outcome measures Structured questionnaire-assessed retrospective physical activity history at the age of 17–29, current physical activity at middle age, and prevalence of SUI, UUI, FI, CDD and POP. Results Current PA was not independently associated with the occurrence of the PFDs. Middle-aged women with early adulthood history of competitive sports were more likely to experience UUI (OR 2.161, 95% CI 1.102–4.237, p=0.025) but not SUI, FI or POP, while women with history of regular PA were more likely to experience FI (OR 4.405, 95% CI 1.049–18.493, p=0.043) but not other PFDs. Conclusions Competitive sports during early adulthood may increase the risk of UUI at middle age. The history of regular PA may increase the risk of FI. Keywords Pelvic floor function, exercise, menopausal women

Objective: To investigate the compatibility of oxytocin and tranexamic acid injection products when mixed for the purpose of co-administration by intravenous infusion. Population or Sample: Oxytocin and tranexamic acid were collected from hospitals taking part in a multicentre postpartum haemorrhage treatment (E-MOTIVE) trial in Kenya, Nigeria, Tanzania, and South Africa. Methods: The compatibility of two sentinel products of oxytocin injection and tranexamic acid injection in 200mL infusion bags of both 0.9%w/v saline and Ringer’s Lactate was assessed. We analysed all tranexamic acid -oxytocin combinations, and each evaluation was conducted for up to 6hrs. Subsequently, the compatibility of multiple tranexamic acid products with reference oxytocins products when mixed in 0.9%w/v saline over a period of 1 hour was investigated. Results: We found a significant interaction between certain oxytocin and tranexamic acid products after mixing them in vitro and observing for 1 hour. The interaction substantially impacted oxytocin content leading to reduction in concentration (14.8% - 29.0%) immediately on mixing (t=0 minutes). In some combinations, the concentration continued to decline throughout the stability assessment period. Oxytocin loss was observed in 7 out of 22 (32%) combinations tested. Conclusions: In a clinical setting, mixing oxytocin and tranexamic acid may result in an underdosing of oxytocin, compromising care in an emergency life-threatening situation. The mixing of oxytocin and tranexamic acid injection products for co-administration with IV infusion fluids should be avoided until the exact nature of the interaction and its implications are understood.

The effect of antenatal depressive and anxious symptoms on the rate of physiological birthsA comment on the recently published article by Hulsbosch et al:Association between high levels of comorbid anxiety and depressive symptoms and decreased likelihood of birth without intervention: A longitudinal prospective cohort study

Objective: Observational studies have described associations between obesity and adverse outcomes of pregnancy. Mendelian randomization (MR) takes advantage of the ‘natural’ genetic randomization to risk of an exposure such as body mass index (BMI) to study the effects of the exposure on outcomes. Similar to randomization in a clinical trial, this limits the potential for confounding and bias. Design: A two-sample MR study. Setting: Summary statistics from published genome wide association studies (GWAS) in European ancestry populations. Population or Sample: Instrumental variants for body mass index (BMI) were obtained from a study on 434,794 females. Female-specific genetic association estimates for outcomes were extracted from the sixth round of analysis of the FINNGEN cohort data. Methods: Inverse-variance weighted MR was used to assess the association between BMI and all outcomes. Sensitivity analyses with weighted median and MR-Egger were also performed. Results: A 1-SD increase in BMI was associated with higher risk of pre-eclampsia (OR 1.68, 95%CI 1.46-1.94, p=8.74x10-13), gestational diabetes (OR 1.67, 95%CI 1.46-1.92, p=5.35x10-14), polyhydramnios (OR 1.40, 95%CI 1.00-1.96, p=0.049). There was evidence suggestive of a potential association with higher risk of premature rupture of membranes (OR 1.16, 95%CI 1.00-1.36, p=0.050) and postpartum depression (OR 1.12, 95%CI 0.99-1.27, p=0.062). Conclusions: Higher maternal BMI is associated with marked increase in risk of pre-eclampsia, gestational diabetes and polyhydramnios. The relationship between BMI and premature rupture of membranes and postpartum depression should be assessed in further studies. Our study supports efforts to target BMI as a cardinal risk factor for maternal morbidity.

A document by Nicola Curry. Click on the document to view its contents.

Background: Cervical cancer affects 3,197 women in the UK, and 604000 women worldwide annually, with peak incidence seen between 30-34 years of age. For many, fertility-sparing surgery is an appealing option where possible. However, absence of large-scale data, along with a notable variation in reported outcomes in relevant studies may undermine future efforts for consistent evidence synthesis. Objectives: To systematically review the reported outcomes measured in studies that include women who underwent fertility-sparing surgery for cervical cancer and identify whether variation exists. Search Strategy: We searched MEDLINE, EMBASE, and CENTRAL from inception to February 2019. Selection Criteria: Randomised controlled trials, cohort and observational studies, and case studies of more than 10 participants from January 1990 to date. Data Collection and Analysis: Study characteristics and all reported treatment outcomes. Main results: 104 studies with a sum of 9535 participants were identified. Most studies reported on oncological outcomes (97/104), followed by fertility and pregnancy (86/104), post-operative complications (74/104), intra-operative complications (72/104), and quality of life (5). There were huge variation and heterogeneity in reported outcomes, with only 12% being good quality and 87% being of poor quality. Conclusions: There is significant heterogeneity in the reported outcomes. An agreed Core Outcome Set (COS) is necessary for future studies to effectively harmonise reported outcomes that are measurable and relevant to patients, clinicians, and researchers. This systematic review sets the groundwork for the development of a COS for fertility sparing surgery in cervical cancer. Funding: British Medical Association’s Strutt and Harper Grant.

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.

Mini Commentary on manuscript ID BJOG-22-0531.R1

Objective: To investigate reliable biomarkers for predicting histological chorioamnionitis (HCA). Design: In this retrospective study, PPROM mothers were treated with a course of dexamethasone. Blood tests for serum indictors were conducted continuously after first injection. Setting: One Shanghai hospital Population: PPROM mothers before 34 0/7 weeks of gestation Methods: Data were compared by General Linear Model analysis. The diagnostic accuracy in predicting HCA were evaluated with ROC curve. Main Outcome Measures: The response of infectious indictors to dexamethasone treatment; the diagnostic accuracy for CRP and PCT in predicting HCA. Results： We found 98 HCA women (62.42%) and 59 CON women (37.58%) in 157 PPROM mothers. WBC and neutrophil significantly increased 24 hours after the first injection in both groups, followed by a decrease at 72 hours post first injection (P<0.05). No significances were found between two groups in WBC, neutrophil and lymphocyte. Both CRP and PCT were significantly higher in the HCA group after first injection. PCT had both high specificity and sensitivity, especially at the baseline (cutoff, 0.031 ng/ml). Furthermore, the positive predictive values (PPV) of PCT were respectively 0.946 and 0.960 at 48 (cutoff, 0.049 ng/ml) and 72 (cutoff, 0.051 ng/ml) hours, which were better than the corresponding PPV of CRP. Conclusion: The response of WBC, neutrophil and lymphocyte to dexamethasone could be differentiated from uterine infection; PCT could be a reliable biomarker for early diagnosis of HCA. Funding: Shanghai Municipal Commission of Health and Family Planning (GWIV-26, 202040128); Pudong Commission of Health and Family Planning (PW2019D-13).

Commentary for manuscript BJOG 2022 Gurol-Urganci et al (10.1111/1471-0528.17193)

Background: Science integrity initiatives require specific recommendations for randomised clinical trials (RCT). Objective: To prepare a set of statements for RCT integrity through an international multi-stakeholder consensus. Methods: Following prospective registration (https://osf.io/bhncy, https://osf.io/3ursn), the consensus was developed via: multi-country multidisciplinary stakeholder group composition and engagement; evidence synthesis of 55 systematic reviews concerning RCT integrity; anonymised two-round modified Delphi survey with consensus threshold based on the average percent of majority opinions; and, a final consensus development meeting. Results: There were 30 stakeholders representing 14 countries from 5 continents including trialists, ethicists, methodologists, statisticians, consumer representative, industry representative, systematic reviewers, funding body panel members, regulatory experts, authors, journal editors, peer-reviewers and advisors for resolving integrity concerns. Delphi survey response rate was 86.7% (26/30 stakeholders). There were 111 statements (73 stakeholder-provided, 46 systematic review-generated, 8 supported by both) in the initial long list, with 8 additional statements provided during the consensus rounds. Through consensus the final set consolidated 81 statements (49 stakeholder-provided, 41 systematic review-generated, 9 supported by both). The entire RCT life cycle was covered by the set of statements including general aspects (n=6), design and approval (n=11), conduct and monitoring (n=19), reporting of protocols and findings (n=20), post-publication concerns (n=12), and future research and development (n=13). Conclusion: Implementation of this multi-stakeholder consensus statement is expected to enhance RCT integrity.

Objective To test equivalence of two doses of intravenous iron (ferric carboxymaltose) in pregnancy. Design Parallel, two-arm equivalence randomised controlled trial with an equivalence margin of 5%. Setting Single centre in Australia. Population 278 pregnant women with iron deficiency. Methods Participants received either 500 mg (n=152) or 1000mg (n=126) of intravenous ferric carboxymaltose in the second or third trimester. Main outcome measures The proportion of participants requiring additional intravenous iron (500mg) to achieve and maintain ferritin >30ug/L (diagnostic threshold for iron deficiency) at 4 weeks post-infusion, and at 6 weeks, and 3-, 6- and 12-months postpartum. Secondary endpoints included repeat infusion rate, iron status, birth, and safety outcomes. Results The two doses were not equivalent within a 5% margin at any timepoint. At 4 weeks post infusion, 26/73 (36%) participants required a repeat infusion in the 500 mg group compared with 5/67 (8%) in the 1000 mg group (difference in proportions, 0.283 95% confidence interval (0.177, 0.389)). Overall, participants in the 500 mg arm received twice the repeat infusion rate (0.81 (SD= 0.824 vs 0.40 (SD= 0.69), rate ratio 2.05, 95% CI (1.45, 2.91)). Conclusions Administration of 1000mg ferric carboxymaltose in pregnancy maintains iron stores and reduces the need for repeat infusions. A 500 mg dose requires ongoing monitoring to ensure adequate iron stores are reached and sustained.

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.

Objective: To describe clinical and laboratory characteristics of term deliveries complicated by chorioamnionitis, and to assess their association with adverse neonatal outcomes. Design: Cross-sectional cohort study Setting: The study is based on data from the Swedish Pregnancy Register, enriched with clinical data extracted from medical charts. Population and Sample: A random sample of 500 term singleton deliveries in Stockholm County with registered diagnosis of chorioamnionitis in the Swedish Pregnancy Register between 2014 and 2020. Methods: Logistic regression was used to estimate odds ratios (OR) as a measurement of the association between clinical and laboratory characteristics and neonatal complications Main Outcome Measures: Neonatal infection and asphyxia-related complications. Results: Maternal fever, maternal and fetal tachycardia, and elevated inflammatory laboratory markers were frequent signs of chorioamnionitis. The prevalence of neonatal infection and asphyxia-related complications was 10 and 22%, respectively. First leukocyte count in the second tertile (OR 2.14 [95% CI 1.02-4.49]), maximum CRP level in the third tertile (OR 4.01 [95% Cl 1.66-9.68]), and positive cervical culture (OR 2.22 [95% Cl 1.10-4.48]) were associated with an increased risk of neonatal infection. Maximum level of CRP in the third tertile (OR 1.93 [95% Cl 1.09-3.41]), and fetal tachycardia (OR 1.63 [95% Cl 1.01-2.65]) were associated with increased risk of asphyxia-related complications. Conclusions: In addition to maternal intrapartum fever, maternal and fetal tachycardia, and elevated inflammatory laboratory markers were common signs of chorioamnionitis. Elevated inflammatory laboratory markers were associated with both neonatal infection and asphyxia-related complications, and fetal tachycardia was associated asphyxia-related complications.