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Objective: This sequential, prospective meta-analysis sought to identify risk factors among pregnant and postpartum women with COVID-19 for adverse outcomes related to disease severity, maternal morbidities, neonatal mortality and morbidity, and adverse birth outcomes. Data sources: We prospectively invited study investigators to join the sequential, prospective meta-analysis via professional research networks beginning in March 2020. Study eligibility criteria: Eligible studies included those recruiting at least 25 consecutive cases of COVID-19 in pregnancy within a defined catchment area. Methods: We included individual patient data from 21 participating studies. Data quality was assessed, and harmonized variables for risk factors and outcomes were constructed. Duplicate cases were removed. Pooled estimates for the absolute and relative risk of adverse outcomes comparing those with and without each risk factor were generated using a 2-stage meta-analysis. Results: We collected data from 33 countries and territories, including 21,977 cases of SARS-CoV-2 infection in pregnancy or postpartum. We found that women with comorbidities (preexisting diabetes mellitus, hypertension, cardiovascular disease) vs those without were at higher risk for COVID-19 severity and adverse pregnancy outcomes (fetal death, preterm birth, low birthweight). Participants with COVID-19 and HIV were 1.74 times (95% confidence interval, 1.12-2.71) more likely to be admitted to the intensive care unit. Pregnant women who were underweight before pregnancy were at higher risk of intensive care unit admission (relative risk, 5.53; 95% confidence interval, 2.27-13.44), ventilation (relative risk, 9.36; 95% confidence interval, 3.87-22.63), and pregnancy-related death (relative risk, 14.10; 95% confidence interval, 2.83-70.36). Prepregnancy obesity was also a risk factor for severe COVID-19 outcomes including intensive care unit admission (relative risk, 1.81; 95% confidence interval, 1.26-2.60), ventilation (relative risk, 2.05; 95% confidence interval, 1.20-3.51), any critical care (relative risk, 1.89; 95% confidence interval, 1.28-2.77), and pneumonia (relative risk, 1.66; 95% confidence interval, 1.18-2.33). Anemic pregnant women with COVID-19 also had increased risk of intensive care unit admission (relative risk, 1.63; 95% confidence interval, 1.25-2.11) and death (relative risk, 2.36; 95% confidence interval, 1.15-4.81). Conclusion: We found that pregnant women with comorbidities including diabetes mellitus, hypertension, and cardiovascular disease were at increased risk for severe COVID-19-related outcomes, maternal morbidities, and adverse birth outcomes. We also identified several less commonly known risk factors, including HIV infection, prepregnancy underweight, and anemia. Although pregnant women are already considered a high-risk population, special priority for prevention and treatment should be given to pregnant women with these additional risk factors.

BACKGROUND: Intravaginal washing, practiced by a significant proportion of women globally, is associated with acquisition of human immunodeficiency virus (HIV), sexually transmitted infections, and bacterial vaginosis (BV). A single prior study among women in the United States found that vaginal washing was associated with lower fecundability. OBJECTIVE: To examine the association between vaginal washing and fecundability among Kenyan women. METHODS: HIV-negative Kenyan women who were trying to conceive and reported no history of infertility care-seeking were followed prospectively for incident pregnancy for up to six months. At monthly visits, participants reported the first day of last menstrual period, sexual behavior, vaginal washing behavior, underwent pregnancy testing, and provided vaginal swabs for detection of BV by Gram stain (Nugent score ≥7). Discrete time proportional probabilities models were used to estimate fecundability ratios (FR) and 95% confidence intervals (CI) comparing menstrual cycles when women reported vaginal washing to menstrual cycles when no vaginal washing was reported. RESULTS: Four hundred fifty-eight women contributed 1,376 menstrual cycles and 255 pregnancies. At enrollment, a third (35.2%, 161 of 458) of participants reported vaginal washing with the majority using water only (73.9%, 119 of 161). After adjustment for age, frequency of unprotected intercourse, and study site, vaginal washing in the prior four weeks was associated with a 29% lower fecundability (adjusted FR (aFR) 0.71, 95% CI 0.53, 0.94), which did not change after further adjustment for BV at the visit prior to each pregnancy test (aFR 0.71, 95% CI 0.54, 0.95). CONCLUSIONS: Periconceptual vaginal washing may reduce fecundability. Potential mechanisms include vaginal washing-associated changes in the vaginal microbiota, inflammation, disruption of cervical mucus, and effects on sperm function. Vaginal washing has no known health benefits and cessation may improve women’s likelihood of conceiving.

OBJECTIVE: To examine the association between cultivable vaginal Lactobacillus and fecundability in Kenyan women attempting non-medically assisted conception DESIGN: Prospective preconception cohort SETTING: Nairobi and Mombasa, Kenya PATIENTS: Women trying to conceive who reported ≤3 months of pre-enrollment conception attempt time EXPOSURE: Cultivable Lactobacillus (primary), Lactobacillus morphotypes on Gram stain (secondary) MAIN OUTCOME MEASURES: Participants reported first day of last menstrual period and recent sexual behavior, underwent pregnancy testing, and provided vaginal specimen samples for Lactobacillus culture and Gram stain at ≤6 monthly preconception visits. The outcome was fecundability – the per-menstrual cycle probability of pregnancy. Associations between 1) cultivable Lactobacillus and 2) Lactobacillus morphotypes on Gram stain at the visit prior to each pregnancy test and fecundability were estimated using proportional probabilities models to generate fecundability ratios (FRs). RESULTS: 458 women contributed 1,376 menstrual cycles. At enrollment, 65.3% (n=299) of participants had cultivable Lactobacillus, 47.4% (n=217) had cultivable hydrogen peroxide producing Lactobacillus, and 64.6% (n=296) had Lactobacillus detected on Gram stain. In unadjusted analysis, there was no association between cultivable Lactobacillus at the visit prior and fecundability (FR 0.92, 95%CI 0.73–1.16); results were similar after adjustment for age, frequency of condomless sex, and study site (adjusted FR 0.92, 95%CI 0.72–1.18). Lactobacillus on Gram stain at the visit prior was associated with modestly higher fecundability (adjusted FR 1.18, 95%CI 0.92–1.51). CONCLUSIONS: Cultivable Lactobacillus was not associated with fecundability while Lactobacillus morphotypes detected on Gram stain were somewhat associated with increased fecundability. The relationship between vaginal Lactobacillus and fecundity may be species-specific.

There are minimal data on the BVBlue test for diagnosis of bacterial vaginosis (BV) in Africa. Among 701 Kenyan women, compared with Nugent score ≥7, the BVBlue test had moderate sensitivity (81.9%; 95% confidence interval, 76.5%-86.5%) and high specificity (92.4%; 95% confidence interval, 89.5%-94.6%). This test may provide a complimentary approach to syndromic management.

STUDY QUESTION Is bacterial vaginosis (BV) associated with fecundability? SUMMARY ANSWER Women with BV may be at increased risk for sub-fecundity. WHAT IS KNOWN ALREADY While BV has been associated with poor IVF outcomes, the association between vaginal microbiota disruption and non-medically assisted conception has not been thoroughly explored. STUDY DESIGN, SIZE, DURATION Kenyan women with fertility intent were enrolled in prospective cohort that included monthly preconception visits with vaginal fluid specimen collection and pregnancy testing. Four hundred fifty-eight women attempting pregnancy for ≤3 menstrual cycles at enrollment were eligible for this fecundability analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS At monthly preconception visits, participants reported the first day of last menstrual period and sexual behavior, underwent pregnancy testing and provided vaginal specimens. Discrete time proportional probabilities models were used to estimate fecundability ratios (FRs) and 95% CI in menstrual cycles with and without BV (Nugent score ≥ 7) at the visit prior to each pregnancy test. We also assessed the association between persistent BV (BV at two consecutive visits) and fecundability. MAIN RESULTS AND THE ROLE OF CHANCE Participants contributed 1376 menstrual cycles; 18.5% (n = 255) resulted in pregnancy. After adjusting for age, frequency of condomless sex and study site, BV at the visit prior to pregnancy testing was associated with a 17% lower fecundability (adjusted FR (aFR) 0.83, 95% CI 0.6–1.1). Persistent BV was associated with a 43% reduction in fecundability compared to cycles characterized by optimal vaginal health (aFR 0.57, 95% CI 0.4–0.8). LIMITATIONS, REASONS FOR CAUTION Detection of vaginal microbiota disruption using Gram stain and a point-of-care test for elevated sialidase identified a non-optimal vaginal environment, but these non-specific methods may miss important relationships that could be identified by characterizing individual vaginal bacteria and bacterial communities using molecular methods. In addition, results may be subject to residual confounding by condomless sex as this was reported for the prior month rather than for the fertile window during each cycle. WIDER IMPLICATIONS OF THE FINDINGS Given the high global prevalence of BV and infertility, an association between BV and reduced fecundability could have important implications for a large number of women who wish to conceive. Multi-omics approaches to studying the vaginal microbiota may provide key insights into this association and identify potential targets for intervention. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by a National Institutes of Health grant (NICHD R01 HD087346-R.S.M.). R.S.M. received additional support for mentoring (NICHD K24 HD88229). E.M.L. was supported by pre- and post-doctoral fellowships (NIAID T32 AI07140, NICHD F32 HD100202). Data collection and management were made possible using REDCap electronic data capture tools hosted at the University of Washington’s Institute of Translational Health Science supported by grants from NCATS/NIH (UL1 TR002319). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. R.S.M. receives research funding, paid to the University of Washington, from Hologic Corporation, and has received honoraria for consulting from Lupin Pharmaceuticals. L.E.M. receives research funding, paid to the University of Washington, from Hologic Corporation, and has received honoraria for service on scientific advisory boards from Hologic and Nabriva Therapeutics. TRIAL REGISTRATION NUMBER N/A.

IntroductionBacterial vaginosis (BV) and vaginal microbiota disruption during pregnancy are associated with increased risk of spontaneous preterm birth (SPTB), but clinical trials of BV treatment during pregnancy have shown little or no benefit. An alternative hypothesis is that vaginal bacteria present around conception may lead to SPTB by compromising the protective effects of cervical mucus, colonising the endometrial surface before fetal membrane development, and causing low-level inflammation in the decidua, placenta and fetal membranes. This protocol describes a prospective case-cohort study addressing this hypothesis.Methods and analysisHIV-seronegative Kenyan women with fertility intent are followed from preconception through pregnancy, delivery and early postpartum. Participants provide monthly vaginal specimens during the preconception period for vaginal microbiota assessment. Estimated date of delivery is determined by last menstrual period and first trimester obstetrical ultrasound. After delivery, a swab is collected from between the fetal membranes. Placenta and umbilical cord samples are collected for histopathology. Broad-range 16S rRNA gene PCR and deep sequencing of preconception vaginal specimens will assess species richness and diversity in women with SPTB versus term delivery. Concentrations of key bacterial species will be compared using quantitative PCR (qPCR). Taxon-directed qPCR will also be used to quantify bacteria from fetal membrane samples and evaluate the association between bacterial concentrations and histopathological evidence of inflammation in the fetal membranes, placenta and umbilical cord.Ethics and disseminationThis study was approved by ethics committees at Kenyatta National Hospital and the University of Washington. Results will be disseminated to clinicians at study sites and partner institutions, presented at conferences and published in peer-reviewed journals. The findings of this study could shift the paradigm for thinking about the mechanisms linking vaginal microbiota and prematurity by focusing attention on the preconception vaginal microbiota as a mediator of SPTB.

Background. Adolescents have an increased risk of preterm birth (PTB) and sexually transmitted infections (STIs). We examined the prevalence and impact of STIs (gonorrhea, chlamydia, and trichomonas) on PTB and chorioamnionitis in pregnant adolescents. Methods. This retrospective cohort study utilized the first pregnancy delivered at an urban hospital among patients≤19 years old over a 5-year period. Poisson regression with robust standard errors was used to estimate prevalence ratios (PR) and 95% confidence intervals (CI) of the association between STIs and PTB (Results. 739 deliveries were included. 18.8% (n=139) of births were preterm. The overall prevalence of STIs during pregnancy was 16.5% (Chlamydia trachomatis: 13.1%, n=97; Trichomonas vaginalis: 3.7%, n=27; and Neisseria gonorrheae: 3.1%, n=23). Detection of C. trachomatis, T. vaginalis, or N. gonorrheae was not associated with increased PTB. While infection with N. gonorrheae and C. trachomatis did not increase the likelihood of any chorioamnionitis, infection with T. vaginalis significantly increased the likelihood of any chorioamnionitis diagnosis (aPR 2.19, 95% CI 1.26-3.83). Conclusion. In this adolescent population with a high rate of PTB, in whom most received appropriate STI treatment, we did not find an association between STI during pregnancy and an increased rate of PTB. However, an infection with T. vaginalis was associated with an increased likelihood of chorioamnionitis. Early detection of STIs may prevent adverse pregnancy outcomes. Continued vigilance in STI screening during pregnancy, including consideration of universal Trichomonas vaginalis screening, is merited in this high-risk population.

Some studies suggest that higher body mass index is associated with increased susceptibility to bacterial vaginosis (BV), but results are conflicting. Methods Female sex workers aged 16 to 45 years and participating in an open, prospective cohort study in Mombasa, Kenya between 2000 and 2014 were included in this analysis. Up to 2 years of follow-up were included per woman. Body mass index (BMI) was categorized as underweight (≤18.5), normal (18.5-24.9), overweight (25-29.9), and obese (≥30). Bacterial vaginosis was assessed using Nugent scores. Generalized estimating equations were used to estimate relative risks of the association between BMI and BV. Results At baseline, 32.1% (n = 625) of 1946 women had BV. Half of women were overweight (31.1%, n = 606) or obese (20.1%, n = 391). Participants contributed 14,319 follow-up visits. Adjusting for age, compared to women with normal BMI, overweight (adjusted relative risk, 0.91; 95% confidence interval, 0.81-1.02) and obese (adjusted relative risk, 0.82; 95% confidence interval, 0.71-0.94) women were at lower risk for BV (joint P = 0.03). Conclusions Obese women had a nearly 20% lower risk of BV compared with women with normal BMI. Potential mechanisms for this effect, including possible effects of diet, obesity-associated changes in the gut microbiome, and systemic estrogen levels, should be explored.