Objective: Investigate cost effectiveness of first trimester preeclampsia screening using the Fetal Medicine Foundation (FMF) algorithm in comparison to standard care. Design: Retrospective observational study Setting: London tertiary hospital Population: 5957 pregnancies screened for preeclampsia using the National Institute for Health and Care Excellence (NICE) method. Methods: Differences in pregnancy outcomes between those who developed preeclampsia, term preeclampsia and preterm preeclampsia were compared by the Kruskal-Wallis and Chi-square tests. The FMF algorithm was applied retrospectively to the cohort. A decision analytic model was used to estimate costs and outcomes for pregnancies screened using NICE and those screened using the FMF algorithm. The decision point probabilities were calculated using the included cohort. Main outcome measures: Incremental healthcare costs and QALY gained per pregnancy screened. Results: Of 5957 pregnancies, 12.8% and 15.9% were screen positive for the development of preeclampsia using the NICE and FMF methods, respectively. Of those screen positive by NICE recommendations, aspirin was not prescribed in 25%. Across the three groups: pregnancies without preeclampsia, term preeclampsia and preterm preeclampsia, respectively there was a statistically significant trend in rates of emergency caesarean (21%, 43%, 71.4%; p=<0.001), admission to neonatal intensive care unit (NICU) (5.9%, 9.4%, 41%; p=<0.001) and length of stay in NICU. Use of the FMF algorithm was associated with 7 fewer cases of preterm preeclampsia, cost saving of £9.06 and a QALY gain of 0.00006/pregnancy screened. Conclusions: In our cohort, using a conservative approach, application of the FMF algorithm achieved clinical benefit and an economic cost saving.

Thorough Assessment of Pain is the key to diagnosis and Management: Letter to Editor

OBJECTIVE To assess the relationship between allostatic load in early pregnancy and CVD, 2 to 7 years postpartum, and potential pathways contributing to racial disparities in CVDs. DESIGN Secondary analysis of an observational cohort study. SETTING nuMom2b Heart Health Study. POPULATION Pregnant individuals. METHODS Our primary exposure was dichotomous high allostatic load in the first trimester, defined as four or more out of 12 biomarkers in the “worst” quartile. The primary outcome was new diagnosis of composite CVD, consisting of HTN and or MD (fasting glucose greater than 100 mg/dL or medication for diabetes). Each outcome and allostatic load component was analyzed secondarily. Multivariable logistic regression was used to test the association between high allostatic load and CVD adjusted for potential confounders. Mediation and moderation analyses assessed the role of high allostatic load in racial disparities of CVD. MAIN OUTCOME MEASURE Composite CVD. RESULTS Among 4,022 individuals, CVD was identified in 1,462 (36.4%); 26.6% had HTN, and had 15.4% MD. High allostatic load was present in 33.0%. After adjustment for covariates, high allostatic load was associated with CVD (aOR 2.0, 1.8-2.3), HTN (2.1, 1.8-2.4), and MD (1.7, 1.5-2.1). There was a reduction in the magnitude of the relationship between race and CVD with the addition of allostatic load. Self-reported race did not significantly moderate the relationship between allostatic load and CVD. CONCLUSION High allostatic load is associated with CVD. Allostatic load was a partial mediator between race and CVD. Race did not moderate the relationship between allostatic load and CVD.

Objective To examine the association of placental and fetal DNA copy number variants (CNVs) with fetal structural malformations (FSMs) in stillborn fetuses. Design A secondary analysis of stillbirth cases in the Stillbirth Collaborative Research Network (SCRN) study. Setting Multicenter, 59 hospitals in 5 geographic regions in the USA. Population 384 stillbirth cases of the SCRN study (2006-2008). Methods FSMs were grouped by anatomic system and specific malformation type (e.g., central nervous system, thoracic, cardiac, gastrointestinal, skeletal, umbilical cord and craniofacial defects). Single-nucleotide polymorphism array detected CNVs of at least 500kb. CNVs were classified into two groups: normal, defined as no CNVs>500kb or benign CNVs, and abnormal, defined as pathogenic or variants of unknown clinical significance. Main outcome measures The proportions of abnormal CNVs and normal CNVs were compared between stillbirth cases with and without FSMs using the Wald Chi-squared test. Results The proportion of stillbirth cases with any FSMs was higher among those with abnormal CNVs compared with those with normal CNVs (46.7% vs. 19.6%; p-value<0.001). The most common organ system-specific FSMs associated with abnormal CNVs were cardiac defects, followed by craniofacial and skeletal defects. A pathogenic deletion of 1q21.1 involving 46 genes (e.g., CHD1L) and a duplication of 21q22.13 involving 4 genes (SIM2, CLDN14, CHAF1B, HLCS) were associated with a skeletal and cardiac defect, respectively. Conclusion Specific CNVs involving several genes were associated with FSMs in stillborn fetuses. The findings warrant further investigation and may inform counseling and care surrounding pregnancies affected by FSMs at risk for stillbirth.

Reduced fetal movements: time to move on?Lawrence Impey, BA, FRCOG. Department of Fetal Medicine, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, and Nuffield Department of Women’s Reproductive Health, John Radcliffe Hospital, Oxford University, Oxford, OX3 9DU, United KingdomNatalia Abadi-Cuchi MD. Servicio de Ginecologia y Obstetricia, Hospital Clinico Unversitario Lozano Blesa, Avda. San Juan Bosco 15, 50009, Zaragoza, SpainCorresponding author:Lawrence ImpeyEmail: lawrence.impey@ouh.nhs.ukTel: +44 1865 851165ORCID 0000-0002-4462-112XRunning title: Reduced fetal movements: time to move on?The authors declare no conflict of interestsBoth authors contributed to the conception and writing up of this commentaryWord count: 1445 words

Objective: To assess the clinical utility of point of care (POC) capillary blood glucose (CBG) in the assessment of gestational diabetes (GDM) during oral glucose tolerance test (OGTT). Design: Prospective cohort study. Setting: Antenatal clinics at King’s Collage Hospital. Population: Women screening for GDM between March and June 2020. Methods: CBG was measured using POC-StatStrip® (Nova) and venous plasma glucose (VPG) was measured by Roche (Cobas 8000 c702) analyser. GDM was diagnosed based on NICE-2015 criteria. The two methods were compared statistically using Analyse-It (v 5.40.2) Main outcome measures: Diagnostic sensitivity, specificity, positive and negative predictive values (PPV and NPV) for POC-StatStrip® compared to reference laboratory method. Results: 230 women were included. The number and the percentage of women with glucose concentration above the GDM thresholds using POC-StatStrip® vs. Lab-VPG measurement was 15 (6.5%) vs. 8 (3.4%) at fasting and 105 (45%.6) vs. 72 (31.1%) at 2-hour respectively. Sensitivity and specificity for POC-StatStrip® were 88% and 97% at fasting and 97% and 79% at 2-hour respectively. However, the specificity and the NPV for POC-StatStrip® concentrations ≤5.0 mmol/L at fasting or <7.5mmol/L at 2-hour were 100% and the sensitivity and the PPV for concentration >9.5mmol/L at 2-hour was 100 %. Conclusion: In our cohort POC-CBG measurement cannot entirely replace laboratory method in OGTT, however, it can be used to rule out/rule in GDM when the glucose concentrations are ≤5.0mmol/L at fasting or <7.5/>9.5mmol/L at 2-hour. Funding: not applicable. Key Words: Gestational Diabetes Mellitus (GDM), point of care (POC).

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

Objective: To determine SARS-CoV-2 seroprevalence in a UK pregnancy cohort and assess associations with demographic factors and vaccination timing. Design: Observational cohort study. Setting: UK inner-city maternity centre. Sample: 960 pregnant women attending nuchal scans from July 2020-January 2022. Methods: Blood samples were tested for IgG antibodies against SARS-CoV-2 nucleocapsid (N) and spike (S) proteins. Self-reported demographics, vaccination status and previous Covid-19 infection were extracted from health records. Multivariable regression models determined factors associated with seroprevalence and antibody titers. Main outcome measures: IgG N- and S-protein antibody titers. Results: 196/960 (20.4%) women were SARS-CoV-2 seropositive from previous infection. Of these, 70 (35.7%) self-reported previous infection. Amongst unvaccinated women, black women were most likely to be SARS-CoV-2 seropositive (aRR 1.88 [95% CI, 1.35-2.61], P < 0.001). Women from black and mixed ethnic backgrounds were least likely to have a history of vaccination with seropositivity to S-protein (aRR 0.58 [95% CI, 0.40-0.84], P = 0.004 and aRR 0.56 [95% CI, 0.34-0.92], P = 0.021 respectively). Double vaccinated, previously infected women had higher IgG S-protein antibody titers than unvaccinated, previously infected women (mean difference: 4.76, 95% CI = [2.65, 6.86], P < 0.001). Vaccination timing before vs during pregnancy did not significantly affect IgG S antibody titers (F(1, 77) = [0.07], P = 0.785). Conclusions: This inner-city pregnancy cohort demonstrates high rates of asymptomatic SARS-CoV-2 infection with women of black ethnicity having higher infection risk and lower vaccine uptake. SARS-CoV-2 antibody titers were highest among double vaccinated, previously infected women.

Short Commentary: Laser versus Sham for Genitourinary Syndrome of Menopause: a Randomised Controlled Trial

Abstract Objective: To compare rates of urinary retention and postoperative urinary tract infection between women with immediate versus delayed removal of indwelling catheter following benign non-hysterectomy gynecological laparoscopic surgery. Design: This randomized clinical trial was conducted between February 2012 and December 2019, with follow-up to six weeks, in two university-affiliated hospitals in Sydney, Australia. Population: Study participants were 693 women over 18 years of age, undergoing non-hysterectomy laparoscopy for benign gynecological conditions, excluding pelvic floor or concomitant bowel surgery. Methods: 355 participants were randomized to immediate, and 338 to delayed removal of urinary catheter. Main Outcome Measures: The co-primary outcomes were urinary retention (assessed by trial of void and need to re-catheterize) and urinary tract infection. Secondary outcomes included readmission, analgesia requirements, duration of hospitalization and validated bladder function questionnaires. Results: Urinary retention for participants in the immediate removal group was statistically higher at 8.2% (95% CI: 5.7% to 11.4%) vs. 4.2% (95% CI: 2.7% to 7.2%) in the delayed removal group (p=.03). There was no statistically significant difference in the rates of urinary tract infection between the groups at 7.2% (95% CI:4.7% to 10.8%) in the delayed group vs. 4.7% (95% CI: 2.8% to 7.8%) in the immediate group. Conclusions: Rates of urinary retention and urinary tract infection following non-hysterectomy benign gynecological laparoscopy are low. There is a small increased risk of urinary retention with immediate compared with delayed removal of urinary catheter. These findings can be used to counsel patients regarding postoperative bladder care.

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.