Premature Birth

Preterm birth (PTB) remains a leading cause of neonatal morbidity and mortality worldwide, posing significant challenges to maternal and child health. Recent advances have highlighted the critical role of the maternal microbiome-encompassing vaginal, gut, and oral microbial communities-n influencing pregnancy outcomes. This review comprehensively summarizes the dynamic changes of the pregnancy microbiome and elucidates its association with PTB. During healthy pregnancy, the vaginal microbiome is dominated by Lactobacillus with low diversity, while dysbiosis with fewer Lactobacilli and more anaerobes increases PTB risk. The gut microbiome also shifts, with reduced beneficial bacteria and more pro-inflammatory species linked to adverse outcomes. Changes in the oral microbiome and periodontal disease can promote systemic inflammation contributing to PTB. Microbial imbalance may trigger PTB through inflammation, immune changes, and microbial spread to the uterus. Targeting the microbiome via probiotics shows promise, but more clinical studies are needed. This review highlights the pregnancy microbiome as a key biomarker and intervention target to reduce PTB.

BackgroundExposure to PM2·5 from wildfire smoke during pregnancy has been implicated as a risk factor for preterm birth. We investigated this association in the prospective nationwide US Environmental Influences on Child Health Outcomes (ECHO) Cohort, focusing on prenatal wildfire PM2·5 exposure intensity, duration, and timing.MethodsIn this cohort analysis, we included live singleton births recorded in the ECHO Cohort with available data on gestational age at birth and birthweight and dates of conception between Jan 1, 2006, and March 20, 2020. Census tract-level estimates of daily mean wildfire-derived PM2·5 for the years 2006-20 from a previous machine learning model were linked to residential address history. We calculated the mean concentration of daily wildfire PM2·5, days with wildfire PM2·5 (>0, ≥2·5, ≥5·0, and ≥10·0 μg/m3; termed smoke days) and consecutive smoke days (2, 3, or ≥4 days; termed smoke waves) above the prespecified concentration thresholds across pregnancy. Associations of cumlative pregnancy wildfire PM2·5 exposure with preterm birth (delivery before 37 weeks of gestation) were analysed by adjusted pooled logistic regression in the nationwide ECHO sample and in the US West census region. Associations between smoke days in gestational weeks 0-35 and preterm birth were evaluated by logistic regression in the national sample.FindingsWe included 20 034 births from 30 ECHO Cohort study sites, with residences during pregnancy in all 48 contiguous US states and the District of Columbia. 1687 (8·4%) of the 20 034 infants were preterm. The mean daily wildfire PM2·5 concentration during pregnancy was 0·36 μg/m3 (SD 0·46), with exposure to a mean of 22·2 smoke days (SD 16·6) of any wildfire PM2·5 concentration (>0 μg/m3). Estimates of association between wildfire PM2·5 exposure metrics and preterm birth included the null in nationwide analyses; whereas, in the US West sample (N=5807), we estimated increased odds of preterm birth associated with mean daily wildfire PM2·5 (odds ratio [OR] 1·139 per 1-μg/m3 increase [95% CI 1·001-1·296]), exposure to smoke days with a wildfire PM2·5 concentration of 5·0 μg/m3 or greater (OR 1·018 per additional smoke day [1·003-1·032]) and 10·0 μg/m3 or greater (OR 1·030 [1·006-1·054]), and exposure to ≥4-day smoke waves of 5·0 μg/m3 or greater (OR 1·185 per additional smoke wave [1·044-1·347]) and 10·0 μg/m3 or greater (OR 1·232 [1·029-1·475]). At the national level, by week of gestation, associations with preterm birth were observed in mid-pregnancy for smoke days with wildfire PM2·5 concentrations above 0 μg/m3, of 2·5 μg/m3 or greater, and of 5·0 μg/m3 or greater, and in late pregnancy for smoke days of 10·0 μg/m3 or greater.InterpretationIn a prospective cohort, we observed increased odds of preterm birth associated with wildfire PM2·5 exposure in the western USA, with findings suggesting an exposure-response relationship for increasing exposure intensity and duration. Preterm birth was also associated with exposure to smoke days in mid-to-late pregnancy at the national level. For practice and policy, these findings support the need for public health interventions aimed at reducing exposure to wildfire smoke during pregnancy.FundingECHO Program, US National Institutes of Health Office of the Director.

BackgroundRare damaging genetic variation accounts for a substantial proportion of the risk of rare developmental disorders (DDs), but common genetic variants as well as environmental factors, including prematurity, also contribute. Little is known about the interplay between prematurity and genetic variation in influencing phenotypic outcomes in DDs, nor about how genetic factors may contribute to risk of preterm birth in DDs.MethodsWe leveraged phenotypic and genetic data from 21,712 patients with DDs recruited for clinical sequencing, 16% of whom were born prematurely. Using multivariable regression models, we compared phenotypic features and the prevalence of diagnostic genetic variation in specific genes between preterm and term individuals with DDs. We tested whether the fraction of cases attributable to de novo mutations differed between term and preterm probands. Additionally, we assessed whether associations between common variant contributions to education-related traits and prematurity are explained by direct genetic effects.ResultsPrematurity was associated with more severe clinical phenotypes among these DD patients, including more affected organ systems and more delayed developmental milestones. Prematurity and the presence of a monogenic diagnosis contributed additively to severity. We found that genes associated with fetal anomalies were enriched for diagnostic mutations among preterm individuals (p = 7.83 × 10-5). We also demonstrated an exome-wide enrichment of de novo mutations (DNMs) in both term and preterm probands; the fraction of cases explained by DNMs in known DD-associated genes was higher in term than preterm cases (25% versus 20%) but DNMs in as-yet-undiscovered genes likely contribute approximately equally to both groups (14% versus 13%). Finally, we showed that the positive association between polygenic predisposition to education-related traits and gestational duration is likely to be the result of genetically influenced parental traits or confounders, rather than direct genetic effects in the child, and that a monogenic diagnosis modifies this association.ConclusionsOur findings emphasise the importance of considering environmental factors like prematurity in understanding outcomes in DDs suspected to have a genetic component, and motivate further exploration of the role that genetic variation plays in influencing prematurity.

Preterm birth and socioeconomic status (SES) are associated with brain development in early life, but the contribution of each over time is uncertain. We examined the effects of gestational age (GA) and SES on white matter microstructure in the neonatal period and at five years. Participants included preterm and term children. Diffusion MRI was collected at term-equivalent age (n = 153 preterm, n = 90 term [127/243 female]) and from a subset at five years (n = 26 preterm, n = 32 term [22/58 female]). We assessed linear associations of GA, SES (Scottish Index of Multiple Deprivation [SIMD] and maternal education), and GA×SES interactions on fractional anisotropy (FA) using tract-based spatial statistics. We compared the proportion of voxels with significant associations between timepoints. In preterm neonates, higher GA and higher maternal education, but not SIMD, were associated with higher FA (p corrected for family-wise error rate, pFWER FWER < 0.05). Preterm birth and SES both shape brain development at birth and continue to do so at five years. The SES measure most strongly associated with FA in preterm infants switches from a family-level (i.e. maternal education) to neighborhood-level (i.e. SIMD) measure between birth and five years, which suggests strategies to mitigate adverse effects of social inequalities on development may require adaptation as children grow.