A prospective cohort study examining the association between the periconceptual vaginal microbiota and first-trimester miscarriage in Kenyan women.

BACKGROUND: Studies evaluating the association between the vaginal microbiota and miscarriage have produced variable results. OBJECTIVE: This study evaluated the association between periconceptual and first-trimester vaginal microbiota and women's risk for miscarriage. METHODS: At monthly preconception visits and at 9-12 weeks gestation, women collected vaginal swabs for molecular characterisation of the vaginal microbiota. Participants who became pregnant were followed to identify miscarriage versus pregnancy continuing to at least 20 weeks gestation. RESULTS: Forty-five women experienced miscarriage and 144 had pregnancies continuing to ≥20 weeks. A principal component analysis of periconceptual and first-trimester vaginal bacteria identified by 16S rRNA gene PCR with next-generation sequencing did not identify distinct bacterial communities with miscarriage versus continuing pregnancy. Using taxon-directed quantitative PCR assays, increasing concentrations of Megasphaera hutchinsoni, Mageeibacillus indolicus, Mobiluncus mulieris and Sneathia sanguinegens/vaginalis were not associated with miscarriage. In exploratory analyses, these data were examined as a binary exposure to allow for multivariable modelling. Detection of Mobiluncus mulieris in first-trimester samples was associated with miscarriage (adjusted relative risk [aRR] 2.14, 95% confidence interval [CI] 1.08, 4.22). Additional analyses compared women with early first-trimester miscarriage (range 4.7-7.3 weeks) to women with continuing pregnancies. Mobiluncus mulieris was detected in all eight (100%) first-trimester samples from women with early first-trimester miscarriage compared to 101/192 (52.6%) samples from women with continuing pregnancy (model did not converge). Detection of Mageeibacillus indolicus in first-trimester samples was also associated with early first-trimester miscarriage (aRR 4.10, 95% CI 1.17, 14.31). CONCLUSIONS: The primary analyses in this study demonstrated no association between periconceptual or first-trimester vaginal microbiota and miscarriage. Exploratory analyses showing strong associations between first-trimester detection of Mobiluncus mulieris and Mageeibacillus indolicus and early first-trimester miscarriage suggest the need for future studies to determine if these findings are reproducible.

Impact of preconception vaginal microbiota on women's risk of spontaneous preterm birth: protocol for a prospective case-cohort study.

INTRODUCTION: Bacterial 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 ANALYSIS: HIV-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 DISSEMINATION: This 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.

Parallel detection of lactobacillus and bacterial vaginosis-associated bacterial DNA in the chorioamnion and vagina of pregnant women at term.

BACKGROUND: The majority of early preterm births are associated with intrauterine infections, which are thought to occur when microbes traffic into the uterus from the lower genital tract and seed the placenta. Bacterial vaginosis (BV) is associated with heterogeneous bacterial communities in the vagina and is linked to preterm birth. The extent to which trafficking into the uterus of normal and BV-associated vaginal bacteria occurs is unknown. The study objective was to characterize in parallel the distribution and quantities of bacteria in the vagina, uterus, and placental compartments. METHODS: Pregnant women at term (≥37 weeks) presenting for delivery were recruited prospectively. Swabs were collected in parallel from the vagina, chorioamnion. Choriodecidual swabs were collected if a cesarean section was performed. Samples were analyzed by culture, broad-range 16S rRNA gene PCR, and bacterial species-specific quantitative PCR (qPCR) for DNA from Lactobacillus and a panel of BV-associated bacteria. Results were correlated with placental histopathology. RESULTS: Of the 23 women enrolled, 15 were delivered by cesarean section (N = 10 without labor; N = 5 in labor) and eight were delivered vaginally. BV was diagnosed in two women not in labor. Placental histopathology identified chorioamnionitis or funisitis in six cases [1/10 (10%) not in labor; 5/13 (38%) in labor]. Among non-laboring women, broad-range 16S qPCR detected bacteria in the chorioamnion and the choriodecidua (4/10; 40%). Among laboring women, Lactobacillus species were frequently detected in the chorioamnion by qPCR (4/13; 31%). In one case, mild chorioamnionitis was associated with qPCR detection of similar microbes in the chorioamnion and vagina (e.g. Leptotrichia/Sneathia, Megasphaera), along a quantitative gradient. CONCLUSIONS: Microbial trafficking of lactobacilli and fastidious bacteria into the chorioamniotic membranes and choriodecidua occurs at term in normal pregnancies. In one case, we demonstrated a quantitative gradient between multiple bacterial species in the lower genital tract and placenta. Not all bacterial colonization is associated with placental inflammation and clinical sequelae. Further studies of the role of placental colonization with Lactobacillus in normal pregnancy and fastidious bacteria in chorioamnionitis may improve prevention and treatment approaches for preterm labor.

Lower respiratory tract disorder hospitalizations among children born via elective early-term delivery.

OBJECTIVE: We evaluated the hypothesis that elective early-term delivery increases the risk of childhood lower respiratory tract disorder hospitalization. METHODS: Children born via early-term elective inductions were compared to full- or late-term elective inductions in a retrospective cohort study using Washington State birth certificate and hospital discharge data. Outcomes were the odds of lower respiratory disorder hospitalization before age five and cause specific odds ratios for asthma, bronchiolitis, bronchitis, and pneumonia. In addition, a subgroup analysis excluding infants with perinatal complications was conducted. RESULTS: Electively induced early-term children were at significantly increased risk of hospitalization before age five for lower respiratory disorders compared to similar full- or late-term children (adjusted OR: 1.31, 95% CI: 1.11-1.55). Bronchiolitis was the only cause-specific outcome with a statistically significant increase in odds of hospitalization, though comparable increases were found for the less common diagnoses of asthma (adjusted OR: 1.39, 95% CI: 0.93-2.08) and pneumonia (adjusted OR: 1.27, 95% CI: 0.99-1.64). Excluding infants with perinatal complications did not alter the results. CONCLUSIONS: There was an association between electively induced early-term delivery and hospitalization for lower respiratory tract disorders before age five. This reinforces policies discouraging elective early-term delivery.

Antenatal corticosteroid timing: accuracy after the introduction of a rescue course protocol.

BACKGROUND: Antenatal corticosteroid administration is a critical fetal intervention, and the use of a rescue protocol is now standard practice. Rescue antenatal corticosteroid may improve overall accuracy of antenatal corticosteroid administration timing, but this observation and its effect on the initial course is unknown. OBJECTIVE: We sought to compare the accuracy of antenatal corticosteroid administration before and after the implementation of a rescue antenatal corticosteroid protocol. STUDY DESIGN: We performed a retrospective cohort study of patients who received a minimum of 1 dose of antenatal corticosteroid from 2006-2012 at the University of Washington Medical Center with the use of the University of Washington Medical Center Pharmacy Database. For inclusion, subjects were required to be admitted, receive the initial antenatal corticosteroid course at 24-34 weeks gestation, and deliver at University of Washington Medical Center. We designated 2 groups that were based on when rescue antenatal corticosteroid became standard practice at University of Washington Medical Center: before rescue antenatal corticosteroid (2006-2008) and after rescue antenatal corticosteroid (2009-2012). Primary outcome was delivery within any optimal antenatal corticosteroid window, which was defined as 48 hours to 7 days after the first dose or third dose. We also compared delivery within the optimal window of the initial and rescue antenatal corticosteroid courses independently and assessed antenatal corticosteroid timing by the indication for delivery. Chi squared and independent sample t-tests were used to compare results. RESULTS: From 2006-2012, 1356 women met inclusion criteria, 601 before and 755 after rescue antenatal corticosteroid. The study groups demonstrated similar demographics, with the exception of more white women in the group after rescue antenatal corticosteroid (47% vs 60%; P < .01) and delivered at comparable gestational ages (32.7 vs 32.6 weeks; P = .59). Availability of a second course did not increase total subjects who delivered within any optimal window (26.5% vs 28.5%; P = .41). Frequency of delivery within the initial course optimal window did not change after the introduction of the rescue course protocol (26.1% vs 26.4%; P = .92). Similarly, of the 73 subjects who received rescue antenatal corticosteroid, 24.7% delivered in the optimal window of the second course. Delivery within the optimal window varied by indication for antenatal corticosteroid, with highest accuracy among maternal indications (41.2% in any optimal window), followed by preterm premature rupture of membranes (32.1%). Lowest administration accuracy was among women with antenatal cervical shortening and advanced cervical dilation; only 2.8% and 6.3% delivered within the optimal window, respectively. Furthermore, for women with antenatal cervical shortening, the mean gestational age of delivery was 35.1 weeks, and the median interval from antenatal corticosteroid administration to delivery was 55 days (interquartile range, 34-72 days). CONCLUSIONS: The opportunity for a second course of antenatal corticosteroid did not improve the number of women who delivered within any optimal antenatal corticosteroid window. Administration timing was similar for the initial course and the rescue course, with approximately one-quarter of women delivering within the optimal antenatal corticosteroid window. These findings likely reflect the few circumstances in which rescue antenatal corticosteroid is useful and the poor predictability of preterm birth. Future focus should be aimed at tools to predict the timing of preterm birth to optimize antenatal corticosteroid administration.

Racial and Ethnic Disparities in Preterm Birth Among American Indian and Alaska Native Women.

OBJECTIVES: Preterm birth disproportionately affects American Indian/Alaska Native (AI/AN) women. This disparity in birth outcomes may stem from higher levels of exposure to psychosocial, sociodemographic, and medical risk factors. METHODS: This paper reviews relevant research related to preterm birth in American Indian and Alaska Native women. CONCLUSIONS: This narrative review examines disparities in preterm birth rates between AI/AN and other American women, and addresses several maternal risk factors and barriers that contribute to elevated preterm birth rates among this racial minority group. Additionally, this paper focuses on recent evidence that geographical location can significantly impact preterm birth rates among AI/AN women. In particular, access to care among AI/AN women and differences between rural and urban areas are discussed.

Uterine rupture risk after periviable cesarean delivery.

OBJECTIVE: To investigate the risk of uterine rupture in women with prior periviable cesarean delivery and prior term cesarean delivery independent of initial incision type. METHODS: We conducted a retrospective longitudinal cohort study using Washington state birth certificate data and hospital discharge records, identifying primary cesarean deliveries performed at 20-26 weeks and 37-41 weeks of gestation with subsequent delivery between 1989 and 2008. We compared subsequent uterine rupture risk in the two groups considering both primary incision type and subsequent labor induction and augmentation. RESULTS: We identified 456 women with index periviable cesarean delivery and 10,505 women with index term cesarean delivery. Women with index periviable cesarean delivery were younger, more frequently of nonwhite race, more likely to smoke, and more likely to have hypertension. Women in the periviable group had more index classical incisions (42% compared with 1%, P<.001) and fewer subsequent inductions and augmentations (8% compared with 16%, P<.001). Uterine rupture in the subsequent pregnancy occurred more frequently among women in the index periviable group than those in the index term group (8/456 [1.8%] compared with 38/10,505 [0.4%], odds ratio [OR] 4.9, 95% confidence interval [CI] 2.3-10.6). This relationship persisted among women with a low transverse incision (4/228 [1.8%] compared with 36/9,558 [0.4%], OR 4.7, 95% CI 1.7-13.4). CONCLUSION: Cesarean delivery at periviability compared with term is associated with an increased risk for uterine rupture in a subsequent pregnancy, even after low transverse incision. These data support judicious use of cesarean delivery at periviable gestational ages and inform subsequent counseling. LEVEL OF EVIDENCE: II.

Synergy and interactions among biological pathways leading to preterm premature rupture of membranes.

Preterm premature rupture of membranes (PPROM) occurs in 1% to 2% of births. Impact of PPROM is greatest in low- and middle-income countries where prematurity-related deaths are most common. Recent investigations identify cytokine and matrix metalloproteinase activation, oxidative stress, and apoptosis as primary pathways to PPROM. These biological processes are initiated by heterogeneous etiologies including infection/inflammation, placental bleeding, uterine overdistention, and genetic polymorphisms. We hypothesize that pathways to PPROM overlap and act synergistically to weaken membranes. We focus our discussion on membrane composition and strength, pathways linking risk factors to membrane weakening, and future research directions to reduce the global burden of PPROM.

Mode of delivery at periviable gestational ages: impact on subsequent reproductive outcomes.

AIM: The aim of this study was to assess the risk of subsequent delivery complications after extremely preterm deliveries by initial (index) pregnancy mode of delivery (MOD): cesarean (CD) versus vaginal (VD). METHODS: This is a retrospective, longitudinal cohort study using Washington State birth certificate data and International Classification of Diseases, Ninth Revision codes, 1989-2008, identifying women with deliveries 20-26 weeks' gestation and linked subsequent deliveries. Index MOD was considered as a predictor of adverse subsequent maternal and neonatal outcomes, using t-test, χ(2)-test or Fisher's exact test, and regression analysis. RESULTS: Of 2472 women with periviable delivery and subsequent birth, index CD (n=386) and index VD (n=2086) showed similar risks of composite morbidity (16.1% vs. 15.4%, P=0.76) and subsequent hemorrhage (9.6% vs. 11.1%, P=0.39). Women with index CD were more likely than index VD to experience uterine rupture (1.8% vs. 0.1%, P<0.001), to deliver earlier (35.9 vs. 36.9 weeks, P<0.001), and to have lower birth weight (2736 vs. 3014 g, P<0.001) subsequently. Neonatal hospital charges and lengths of stay were also higher after index CD. CONCLUSIONS: MOD at extreme prematurity did not impact subsequent maternal hemorrhage or overall morbidity. However, CD was associated with substantial uterine rupture risk despite evidence of practice to avoid labor (lower birth weight and earlier delivery) in the subsequent pregnancy.

Serious and life-threatening pregnancy-related infections: opportunities to reduce the global burden.

Michael Gravett and colleagues review the burden of pregnancy-related infections, especially in low- and middle-income countries, and offer suggestions for a more effective intervention strategy.