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Marginalized populations experience disproportionate rates of preterm birth and early term birth. Exposure to per- and polyfluoroalkyl substances (PFAS) has been reported to reduce length of gestation, but the underlying mechanisms are unknown. In the present study, we characterized the molecular signatures of prenatal PFAS exposure and gestational age at birth outcomes in the newborn dried blood spot metabolome among 267 African American dyads in Atlanta, Georgia between 2016 and 2020. Pregnant people with higher serum perfluorooctanoic acid and perfluorohexane sulfonic acid concentrations had increased odds of an early birth. After false discovery rate correction, the effect of prenatal PFAS exposure on reduced length of gestation was associated with 8 metabolomic pathways and 52 metabolites in newborn dried blood spots, which suggested perturbed tissue neogenesis, neuroendocrine function, and redox homeostasis. These mechanisms explain how prenatal PFAS exposure gives rise to the leading cause of infant death in the United States. Mechanisms of the impact of PFAS (also known as forever chemicals) on adverse birth outcomes remain largely unknown. Here, authors identified tissue neogenesis, neuroendocrine function, and redox homeostasis as imprints of prenatal PFAS exposures and reduced gestational age in the newborn metabolome.

Gestational per- and polyfluoroalkyl substances (PFAS) exposure may be associated with adiposity and increased risk of obesity among children and adolescents. However, results from epidemiological studies evaluating these associations are inconsistent. We estimated the associations of pregnancy PFAS concentrations with child body mass index (BMI) -scores and risk of overweight/obesity in eight U.S. cohorts. We used data from 1,391 mother-child pairs who enrolled in eight Environmental influences on Child Health Outcomes (ECHO) cohorts (enrolled: 1999-2019). We quantified concentrations of seven PFAS in maternal plasma or serum in pregnancy. We measured child weight and height between the ages of 2 and 5 y and calculated age- and sex-specific BMI -scores; 19.6% children had more than one BMI measurement. We estimated covariate-adjusted associations of individual PFAS and their mixture with child BMI -scores and risk of overweight/obesity using linear mixed models, modified Poisson regression models, and Bayesian approaches for mixtures. We explored whether child sex modified these associations. We observed a pattern of subtle positive associations of PFAS concentrations in pregnancy with BMI -scores and risk of overweight/obesity. For instance, each doubling in perfluorohexane sulfonic acid concentrations was associated with higher BMI -scores ( ; 95% CI: 0.01, 0.12). Each doubling in perfluroundecanoic acid [ ; 95% CI: 1.04, 1.16] and -methyl perfluorooctane sulfonamido acetic acid ( ; 95% CI: 1.00, 1.12) was associated with increased risk of overweight/obesity, with some evidence of a monotonic dose-response relation. We observed weaker and more imprecise associations of the PFAS mixture with BMI or risk of overweight/obesity. Associations did not differ by child sex. In eight U.S.-based prospective cohorts, gestational exposure to higher levels of PFAS were associated with slightly higher childhood BMI -score and risk of overweight or obesity. Future studies should examine associations of gestational exposure to PFAS with adiposity and related cardiometabolic consequences in older children. https://doi.org/10.1289/EHP11545.

Per- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous chemicals associated with risk of adverse birth outcomes. Results of previous studies have been inconsistent. Associations between PFAS and birth outcomes may be affected by psychosocial stress. We estimated risk of adverse birth outcomes in relation to prenatal PFAS concentrations and evaluate whether maternal stress modifies those relationships. We included 3,339 participants from 11 prospective prenatal cohorts in the Environmental influences on the Child Health Outcomes (ECHO) program to estimate the associations of five PFAS and birth outcomes. We stratified by perceived stress scale scores to examine effect modification and used Bayesian Weighted Sums to estimate mixtures of PFAS. We observed reduced birth size with increased concentrations of all PFAS. For a 1-unit higher log-normalized exposure to perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS), we observed lower birthweight-for-gestational-age z-scores of [95% confidence interval (CI): , ], (95% CI: , ), (95% CI: , ), (95% CI: , 0.06), and (95% CI: , ), respectively. We observed a lower odds ratio (OR) for large-for-gestational-age: (95% CI: 0.38, 0.83), (95% CI: 0.35, 0.77). For a 1-unit increase in log-normalized concentration of summed PFAS, we observed a lower birthweight-for-gestational-age z-score [ ; 95% highest posterior density (HPD): , ] and decreased odds of large-for-gestational-age ( ; 95% HPD: 0.29, 0.82). Perfluorodecanoic acid (PFDA) explained the highest percentage (40%) of the summed effect in both models. Associations were not modified by maternal perceived stress. Our large, multi-cohort study of PFAS and adverse birth outcomes found a negative association between prenatal PFAS and birthweight-for-gestational-age, and the associations were not different in groups with high vs. low perceived stress. This study can help inform policy to reduce exposures in the environment and humans. https://doi.org/10.1289/EHP10723.

Background The extent to which past preterm or early term births are risk factors for recurrent shortened gestational age at delivery in the US is unclear. The underlying causes of shortened gestational age and the role of maternal health can vary over time and across the 50 US states. Objectives To estimate differences in the probability of a second live birth being full term (> 38 weeks’ gestation), early term (37–38 weeks’) or preterm (< 37 weeks’) conditional on the gestational age of the first live birth. Study design We used linked birth and hospital discharge records from the state of Georgia to construct a retrospective cohort of individuals whose first and second births resulted in a singleton live birth (2011–2020). Multinomial models were used to estimate the difference in the probability of the second live birth gestational age category (< 32, 32–36, 37–38, ≥ 39 weeks) conditional on the first birth gestational age category. Baseline models were only adjusted for year fixed effects. Subsequent models were adjusted for birthing individual characteristics: race, age at first birth, ethnicity, country of birth, and education at first birth; second birth health, behavioral and socioeconomic risk factors; and, for interpregnancy birth interval and change in paternal characteristics between first and second births. All analyses were completed in Stata 17. Results Individuals whose first live birth was preterm or early term were significantly less likely to have a second full term live birth, compared to individuals who had a first full term live birth. The probability of a full term second live birth following a first preterm live birth at < 32 weeks or 32–36 weeks decreased by 27.7% points (pp) (95% CI -30.0, -25.2) and 22.1 pp (95% CI-23.3, -21.0) respectively. Similarly, the probability of a full term second birth following a first early term birth decreased by 14.9 pp (95% CI − 15.7, -14.2). Individuals who had early term or preterm first births were more likely to have early term and preterm second births, with higher risk for recurrent preterm birth among birthing individuals with earlier preterm first births. For example, following a first birth that is early term, the probability of a second birth at 32–36 weeks increased by 4.7 pp (95% CI 4.2, 5.1), whereas following a first birth at < 32 weeks the probability of a second birth at 32–36 weeks increased by 13.6 pp (95% CI 11.5, 15.6). Conclusions A first live birth that is early term or preterm predicts a higher probability of a second early term or preterm birth. Health information systems that flag these early birth outcomes on the problem list may help clinicians address known risk factors interconceptionally and prenatally in a subsequent pregnancy.

To evaluate the association between the early pregnancy vaginal microbiome and spontaneous preterm birth (sPTB) and early term birth (sETB) among African American women. Vaginal samples collected in early pregnancy (8-14 weeks' gestation) from 436 women enrolled in the Emory University African American Vaginal, Oral, and Gut Microbiome in Pregnancy Study underwent 16S rRNA gene sequencing of the V3-V4 region, taxonomic classification, and community state type (CST) assignment. We compared vaginal CST and abundance of taxa for women whose pregnancy ended in sPTB (N = 44) or sETB (N= 84) to those who delivered full term (N = 231). Nearly half of the women had a vaginal microbiome classified as CST IV (Diverse CST), while one-third had CST III ( dominated) and just 16% had CST I, II, or V (non-iners dominated). Compared to vaginal CST I, II, or V (non-iners dominated), both CST III ( dominated) and CST IV (Diverse) were associated with sPTB with an adjusted odds ratio (95% confidence interval) of 4.1 (1.1, infinity) and 7.7 (2.2, infinity), respectively, in multivariate logistic regression. In contrast, no vaginal CST was associated with sETB. The linear decomposition model (LDM) based on amplicon sequence variant (ASV) relative abundance found a significant overall effect of the vaginal microbiome on sPTB (p=0.034) but not sETB (p=0.320), whereas the LDM based on presence/absence of ASV found no overall effect on sPTB (p=0.328) but a significant effect on sETB (p=0.030). In testing for ASV-specific effects, the LDM found that no ASV was significantly associated with sPTB considering either relative abundance or presence/absence data after controlling for multiple comparisons (FDR 10%), although in marginal analysis the relative abundance of (p=0.011), non-iners (p=0.016), and (p=0.035) and the presence of (p=0.049), BVAB2 (p=0.024), (p=0.011), and (p=0.044) were associated with sPTB. The LDM identified the higher abundance of 7 ASVs and the presence of 13 ASVs, all commonly residents of the gut, as associated with sETB at FDR < 10%. In this cohort of African American women, an early pregnancy vaginal CST III or IV was associated with an increased risk of sPTB but not sETB. The relative abundance and presence of distinct taxa within the early pregnancy vaginal microbiome was associated with either sPTB or sETB.

Background Differential exposure to chronic stressors by race/ethnicity may help explain Black-White inequalities in rates of preterm birth. However, researchers have not investigated the cumulative, interactive, and population-specific nature of chronic stressor exposures and their possible nonlinear associations with preterm birth. Models capable of computing such high-dimensional associations that could differ by race/ethnicity are needed. We developed machine learning models of chronic stressors to both predict preterm birth more accurately and identify chronic stressors and other risk factors driving preterm birth risk among non-Hispanic Black and non-Hispanic White pregnant women. Methods Multivariate Adaptive Regression Splines (MARS) models were developed for preterm birth prediction for non-Hispanic Black, non-Hispanic White, and combined study samples derived from the CDC’s Pregnancy Risk Assessment Monitoring System data (2012–2017). For each sample population, MARS models were trained and tested using 5-fold cross-validation. For each population, the Area Under the ROC Curve (AUC) was used to evaluate model performance, and variable importance for preterm birth prediction was computed. Results Among 81,892 non-Hispanic Black and 277,963 non-Hispanic White live births (weighted sample), the best-performing MARS models showed high accuracy (AUC: 0.754–0.765) and similar-or-better performance for race/ethnicity-specific models compared to the combined model. The number of prenatal care visits, premature rupture of membrane, and medical conditions were more important than other variables in predicting preterm birth across the populations. Chronic stressors (e.g., low maternal education and intimate partner violence) and their correlates predicted preterm birth only for non-Hispanic Black women. Conclusions Our study findings reinforce that such mid or upstream determinants of health as chronic stressors should be targeted to reduce excess preterm birth risk among non-Hispanic Black women and ultimately narrow the persistent Black-White gap in preterm birth in the U.S.

Mechanisms of protein misfolding are of increasing interest in the aetiology of neurodegenerative diseases characterized by protein aggregation and tangles including Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Lewy Body Dementia (LBD), and Progressive Supranuclear Palsy (PSP). Some forms of neurodegenerative illness are associated with mutations in genes which control assembly of disease related proteins. For example, the mouse sticky mutation sti, which results in undetected mischarging of tRNA(Ala) with serine resulting in the substitution of serine for alanine in proteins causes cerebellar Purkinje cell loss and ataxia in laboratory animals. Replacement of serine 422 with glutamic acid in tau increases the propensity of tau aggregation associated with neurodegeneration. However, the possibility that environmental factors can trigger abnormal folding in proteins remains relatively unexplored. We here report that a non-protein amino acid, β-N-methylamino-L-alanine (BMAA), can be misincorporated in place of L-serine into human proteins. We also report that this misincorporation can be inhibited by L-serine. Misincorporation of BMAA into human neuroproteins may shed light on putative associations between human exposure to BMAA produced by cyanobacteria and an increased incidence of ALS.

Background Adverse birth and neonatal outcomes disproportionately affect African American women and infants compared to those of other races/ethnicities. While significant research has sought to identify underlying factors contributing to these disparities, current understanding remains limited, constraining prevention, early diagnosis, and treatment. With the development of next generation sequencing techniques, the contribution of the vaginal microbiome to adverse maternal and neonatal outcomes has come under consideration. However, most microbiome in pregnancy studies include few African American women, do not consider the potential contribution of non-vaginal microbiome sites, and do not consider the effects of sociodemographic or behavioral factors on the microbiome. Methods We conceived our on-going, 5-year longitudinal study, Biobehavioral Determinants of the Microbiome and Preterm Birth in Black Women, as an intra-race study to enable the investigation of risk and protective factors within the disparate group. We aim to recruit over 500 pregnant African American women, enrolling them into the study at 8–14 weeks of pregnancy. Participants will be asked to complete questionnaires and provide oral, vaginal, and gut microbiome samples at enrollment and again at 24–30 weeks. Chart review will be used to identify pregnancy outcomes, infections, treatments, and complications. DNA will be extracted from the microbiome samples and sequencing of the V3 and V4 regions of the 16S rRNA gene will be conducted. Processing and mapping will be completed with QIIME and operational taxonomic units (OTUs) will be mapped to Greengenes version 13_8. Community state types (CSTs) and diversity measures at each site and time will be identified and considered in light of demographic, psychosocial, clinical, and biobehavioral variables. Discussion This rich data set will allow future consideration of risk and protective factors, between and within groups of women, providing the opportunity to uncover the roots of the persistent health disparity experienced by African American families.

This study aimed to investigate the association between sexual activity during pregnancy and adverse birth outcomes among Black women, and to explore whether vaginal cytokine inflammation mediates this association. Data from 397 Black pregnant women through questionnaires on sexual activity and vaginal biosamples during early (8–14 weeks) and late (24–30 weeks) pregnancy, and birth outcomes were analyzed. Using a data-driven approach, the study found that vaginal sex during late pregnancy was associated with spontaneous early-term birth (sETB, 38–39 completed weeks’ gestation) (OR = 0.39, 95% CI: [0.21, 0.72], p-value = 0.003) but not with spontaneous preterm birth (sPTB) (OR = 1.08, p-value = 0.86) compared to full-term birth. Overall, despite vaginal sex in late pregnancy showing an overall positive effect on sETB (total effect = −0.1580, p-value = 0.015), we observed a negative effect of vaginal sex on sETB (indirect effect = 0.0313, p-value = 0.026) due to the fact that having vaginal sex could lead to elevated IL6 levels, which in turn increased the odds of sETB. In conclusion, the study found an overall positive association between sexual activity on ETB and a negative partial mediation effect via increased vaginal cytokine inflammation induced by vaginal sexual activity. This inconsistent mediation model suggested that vaginal sexual activity is a complex behavior that could have both positive and negative effects on the birth outcome.