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Background: Phthalate exposure may contribute to hypertensive disorders of pregnancy (HDP), including preeclampsia/eclampsia (PE/E), but epidemiologic studies are lacking. Objectives: To evaluate associations of pregnancy phthalate exposure with development of PE/E and HDP. Methods: Using data from 3,430 participants in eight Environmental influences on Child Health Outcomes (ECHO) Program cohorts (enrolled from 1999 to 2019), we quantified concentrations of 13 phthalate metabolites (8 measured in all cohorts, 13 in a subset of four cohorts) in urine samples collected at least once during pregnancy. We operationalized outcomes as PE/E and composite HDP (PE/E and/or gestational hypertension). After correcting phthalate metabolite concentrations for urinary dilution, we evaluated covariate-adjusted associations of individual phthalates with odds of PE/E or composite HDP via generalized estimating equations, and the phthalate mixture via quantile-based g-computation. We also explored effect measure modification by fetal sex using stratified models. Effect estimates are reported as odds ratios (OR) with 95% confidence intervals (95% CIs). Results: In adjusted analyses, a doubling of mono-benzyl phthalate (MBzP) and of mono (3-carboxypropyl) phthalate (MCPP) concentrations was associated with higher odds of PE/E as well as composite HDP, with somewhat larger associations for PE/E. For example, a doubling of MCPP was associated with 1.12 times the odds of PE/E (95%CI 1.00, 1.24) and 1.02 times the odds of composite HDP (95%CI 1.00, 1.05). A quartile increase in the phthalate mixture was associated with 1.27 times the odds of PE/E (95%CI 0.94, 1.70). A doubling of mono-carboxy isononyl phthalate (MCiNP) and of mono-carboxy isooctyl phthalate (MCiOP) concentrations were associated with 1.08 (95%CI 1.00, 1.17) and 1.11 (95%CI 1.03, 1.19) times the odds of PE/E. Effect estimates for PE/E were generally larger among pregnancies carrying female fetuses. Discussion: In this study, multiple phthalates were associated with higher odds of PE/E and HDP. Estimates were precise and some were low in magnitude. Interventions to reduce phthalate exposures during pregnancy may help mitigate risk of these conditions.

Abstract Background The development of the face occurs during the early days of intrauterine life by the formation of facial processes from the first Pharyngeal arch. Derangement in these well‐organized fusion events results in Orofacial clefts (OFC). Van der Woude syndrome (VWS) is one of the most common causes of syndromic cleft lip and/or palate accounting for 2% of all cases. Mutations in the IRF6 gene account for 70% of cases with the majority of these mutations located in the DNA‐binding (exon 3, 4) or protein‐binding domains (exon 7–9). The current study was designed to update the list of IRF6 variants reported for VWS by compiling all the published mutations from 2013 to date as well as including the previously unreported VWS cases from Africa and Puerto Rico. Methods We used PubMed with the search terms; "Van der Woude syndrome," “Popliteal pterygium syndrome,” "IRF6," and "Orofacial cleft" to identify eligible studies. We compiled the CADD score for all the mutations to determine the percentage of deleterious variants. Results Twenty‐one new mutations were identified from nine papers. The majority of these mutations were in exon 4. Mutations in exon 3 and 4 had CADD scores between 20 and 30 and mutations in exon 7–9 had CADD scores between 30 and 40. The presence of higher CADD scores in the protein‐binding domain (exon 7–9) further confirms the crucial role played by this domain in the function of IRF6. In the new cases, we identified five IRF6 mutations, three novel missense mutations (p.Phe36Tyr, p.Lys109Thr, and p.Gln438Leu), and two previously reported nonsense mutations (p.Ser424*and p.Arg250*). Conclusion Mutations in the protein and DNA‐binding domains of IRF6 ranked among the top 0.1% and 1% most deleterious genetic mutations, respectively. Overall, these findings expand the range of VWS mutations and are important for diagnostic and counseling purposes.

Abstract The objective of this study was to evaluate the racial and ethnic disparities in delivery hospitalizations involving severe maternal morbidity (SMM) by location of residence and community income. We used the 2016 to 2019 Healthcare Cost and Utilization Project National Inpatient Sample. International Classification of Diseases, Tenth Revision, Clinical Modification codes were used to identify delivery hospitalizations with SMM. Using logistic regression models, we examined the association between race and ethnicity and delivery hospitalizations involving SMM. In adjusted analyses, the models were stratified by location of residence and community income and adjusted for patient and hospital characteristics. In rural areas, non-Hispanic Black women (AOR 1.50; 95% CI 1.25–1.79) and women of other races (AOR 1.32; 95% CI 1.03–1.69) had an increased odds of experiencing a delivery hospitalization involving SMM when compared to non-Hispanic White women. In micropolitan areas, non-Hispanic Black women (AOR 1.88; 95% CI 1.79–1.97), non-Hispanic Asian/Pacific Islander women (AOR 1.54; 95% CI 1.16–2.05), and women of other races (AOR 1.31; 95% CI 1.03–1.67) had an increased odds of experiencing a delivery hospitalization involving SMM when compared to non-Hispanic White women. Non-Hispanic Black women also had increased odds of experiencing a delivery hospitalization involving SMM in communities with the lowest income (quartile 1) (AOR 1.59; 95% CI 1.49–1.66), middle income (quartiles 2 and 3) (AOR 1.81; 95% CI 1.72–1.91), and highest income (AOR 2.09; 95% CI 1.90–2.29) when compared to non-Hispanic White women. We found that location of residence and community income are associated with racial and ethnic differences in SMM in the United States. These factors, outside of individual factors assessed in previous studies, provide a better understanding of some of the structural and systemic factors that may contribute to SMM.

Experiencing a hurricane during pregnancy is associated with increased risk of adverse birth outcomes and poor mental health. Pregnant people from marginalized communities are more susceptible to adverse effects, as they have fewer resources to overcome hardships at a time when shelter and nutrition are essential. When Hurricane Maria (HM) devastated Puerto Rico in September 2017, the archipelago was already burdened with high poverty, health disparities, environmental contamination, and fragile utility infrastructure. We aimed to compare biomarkers of environmental exposures among pregnant participants in the PROTECT cohort before and after HM and to identify hurricane-related sources of exposure. Metals, PAHs, phthalate metabolites, and phenols were measured in urine samples collected from participants at three prenatal visits (2011–2019). Samples were categorized as before, 6 months after HM. Using linear mixed effects models, we found that in the 6 months after HM, participants had higher Co, Ni, and DEHPTP concentrations, indicating increased exposure, and lower concentrations of PAHs, several metals, and phthalates, suggesting decreased exposure, compared to pre-HM levels. Biomarkers were not associated with potential exposure sources assessed through questionnaire or previously measured tap water contaminants. This study provides insight into how extreme weather events may alter environmental exposures among pregnant people in Puerto Rico. As climate change has increased the frequency and magnitude of such events, additional research is needed to clarify the implications for maternal and child health and to identify sources of related environmental exposures within this vulnerable population.

Introduction: This study investigates associations between fine particulate air pollution (PM2.5) exposure and thyroid hormone levels during pregnancy in Puerto Rican individuals, a vulnerable population facing socioeconomic and environmental disparities. Methods: This research draws on data from the PROTECT cohort study and involves 1040 participants to measure the effect of PM2.5 on developmentally important thyroid hormones (TSH, T3, T4, and FT4). Pollution concentrations were linked to participant locations using EPA air quality data and analyzed across two visits during gestational weeks 16–20 and 24–28. Results: The results suggest that PM2.5 exposure is positively associated with maternal T3, T4, and FT4 levels but not TSH. These effects vary by timing, with T3 showing stronger associations later in pregnancy and T4/FT4 earlier. Nonlinear dose–response relationships were observed, suggesting thresholds for certain hormones. Discussion: These findings support previous studies linking altered thyroid hormones to adverse birth outcomes and highlight the potential role of air pollution in disrupting maternal thyroid function and its implications for fetal development, calling for further research into mechanisms and interventions to mitigate these risks.

Preterm birth is a leading cause of neonatal mortality and presents significant public health concerns. Environmental chemical exposures during pregnancy may be partially to blame for disrupted delivery timing. Polycyclic aromatic hydrocarbons (PAHs) are products of incomplete combustion, exposure to which occurs via inhalation of cigarette smoke and automobile exhaust, and ingestion of charred meats. Exposure to PAHs in the US population is widespread, and pregnant women represent a susceptible population to adverse effects of PAHs. We aimed to investigate associations between gestational exposure to PAHs and birth outcomes, including timing of delivery and infant birth size. We utilized data from the PROTECT birth cohort where pregnant women provided spot urine samples at up to three study visits (median 16, 20, and 24 weeks gestation). Urine samples were assayed for eight hydroxylated PAH concentrations. Associations between PAHs and birth outcomes were calculated using linear/logistic regression models, with adjustment for maternal age, education, pre-pregnancy BMI, and daily exposure to environmental tobacco smoke. Models accounted for urine dilution using specific gravity. We also explored effect modification by infant sex. Interquartile range (IQR) increases in all averaged PAH exposures during the second trimester were associated with reduced gestational age at delivery and increased odds of overall PTB, although these associations were not statistically significant (p > 0.05). Most PAHs at the second study visit were most strongly associated with earlier delivery and increased odds of overall and spontaneous PTB, with visit 2 2-hydroxynapthalene (2-NAP) being significantly associated with increased odds of overall PTB (OR:1.55; 95 %CI: 1.05,2.29). Some PAHs resulted in earlier timing of delivery among only female fetuses, specifically 2-NAP on overall PTB (female OR:1.52 95 %CI: 1.02,2.27; male OR:0.78, 95 %CI: 0.53,1.15). Future work should more deeply investigate differential physiological impacts of PAH exposure between pregnancies with male and female fetuses, and on varying developmental processes occurring at different points through pregnancy.

Humans are exposed to complex mixtures of phthalates. Gestational exposure to phthalates has been linked to preeclampsia and preterm birth through potential pathways such as endocrine disruption, oxidative stress, and inflammation. Eicosanoids are bioactive signaling lipids that are related to a variety of homeostatic and inflammatory processes. We investigated associations between urinary phthalates and their mixtures with plasma eicosanoid levels during pregnancy using the PROTECT cohort in Puerto Rico (N = 655). After adjusting for covariates, we estimated pair-wise associations between the geometric mean of individual phthalate metabolite concentrations across pregnancy and eicosanoid biomarkers using multivariable linear regression. We used bootstrapping of adaptive elastic net regression (adENET) to evaluate phthalate mixtures associated with eicosanoids and subsequently create environmental risk scores (ERS) to represent weighted sums of phthalate exposure for each individual. After adjusting for false-discovery, in single-pollutant analysis, 14 of 20 phthalate metabolites or parent compound indices showed significant and primarily negative associations with multiple eicosanoids. In our mixture analysis, associations with several metabolites of low molecular weight phthalates – DEP, DBP, and DIBP – became prominent. Additionally, MEHHTP and MECPTP, metabolites of a new phthalate replacement, DEHTP, were selected as important predictors for determining the concentrations of multiple eicosanoids from different pathway groups. A unit increase in phthalate ERS derived from bootstrapping of adENET was positively associated with several eicosanoids mainly from Cytochrome P450 pathway. For example, an increase in ERS was associated with 11(S)-HETE (β = 1.6, 95% CI: 0.020, 3.180), (±)11,12-DHET (β = 2.045, 95% CI: 0.250, 3.840), 20(S)-HETE (β = 0.813, 95% CI: 0.147, 1.479), and 9 s-HODE (β = 2.381, 95% CI: 0.657, 4.104). Gestational exposure to phthalates and phthalate mixtures were associated with eicosanoid levels during pregnancy. Results from the mixture analyses underscore the complexity of physiological impacts of phthalate exposure and call for further in-depth studies to examine these relationships.

Background The PROTECT Center is a multi-project initiative that studies the relationship between exposure to environmental contaminants and preterm births during the prenatal and postnatal period among women living in Puerto Rico. PROTECT’s Community Engagement Core and Research Translation Coordinator (CEC/RTC) play a key role in building trust and capacity by approaching the cohort as an engaged community that provides feedback about processes, including how personalized results of their exposure to chemicals should be reported back. The goal of the Mi PROTECT platform was to create a mobile-based application of DERBI (Digital Exposure Report-Back Interface) for our cohort that provides tailored, culturally appropriate information about individual contaminant exposures as well as education on chemical substances and approaches to exposure reduction. Methods Participants (N = 61) were presented with commonly used terms in environmental health research related to collected samples and biomarkers, followed by a guided training on accessing and exploring the Mi PROTECT platform. Participants evaluated the guided training and Mi PROTECT platform answering a Likert scale in separated surveys that included 13 and 8 questions, respectively. Results Participants provided overwhelmingly positive feedback on the clarity and fluency of presenters in the report-back training. Most participants reported that the mobile phone platform was both accessible and easy to navigate (83% and 80%, respectively) and that images included in the platform facilitated comprehension of the information. Overall, most participants (83%) reported that language, images, and examples in Mi PROTECT strongly represented them as Puerto Ricans. Conclusions Findings from the Mi PROTECT pilot test informed investigators, community partners and stakeholders by demonstrating a new way to promote stakeholder participation and foster the “research right-to-know.” Author summary The PROTECT Center focuses on studying how contaminants in the environment can affect pregnancy outcomes in women living in the northern Karst of Puerto Rico. In order to facilitate reporting back research results to study participants, the research team decided to develop a mobile based application called Mi PROTECT. Before sharing this application with all study participants, some participants were consulted to ensure that the content was understandable, accessible and culturally appropriate. This was done through in-person meetings where they learned how to navigate the application and revised the content (personal results, definition of contaminants, recommendations to reduce exposure) and provided feedback through an evaluation survey. Results from the survey indicate that participants provided overwhelmingly positive feedback regarding the use of Mi PROTECT. This is an important initiative that demonstrates the relevance of the research right to know and that research participants should be consulted and considered when designing strategies to report back study findings.

Abstract Background Preterm birth (PTB, birth before 37 weeks of gestation) has been associated with adverse health outcomes across the lifespan. Evidence on the association between PTB and prenatal exposure to air pollutants is inconsistent, and is especially lacking for ethnic/racial minority populations. Methods We obtained data on maternal characteristics and behaviors and PTB and other birth outcomes for women participating in the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) cohort, who lived in municipalities located along the North Coast of Puerto Rico. We assessed pre-natal PM2.5 exposures for each infant based on the nearest US Environmental Protection Agency monitor. We estimated prenatal phthalate exposures as the geometric mean of urinary measurements obtained during pregnancy. We then examined the association between PM2.5 and PTB using modified Poisson regression and assessed modification of the association by phthalate exposure levels and sociodemographic factors such as maternal age and infant gender. Results Among 1092 singleton births, 9.1% of infants were born preterm and 92.9% of mothers had at least a high school education. Mothers had a mean (standard deviation) age of 26.9 (5.5) years and a median (range) of 2.0 (1.0–8.0) pregnancies. Nearly all women were Hispanic white, black, or mixed race. Median (range) prenatal PM2.5 concentrations were 6.0 (3.1–19.8) μ g/m3. Median (interquartile range) prenatal phthalate levels were 14.9 (8.9–26.0) and 14.5 (8.4–26.0), respectively, for di-n-butyl phthalate (DBP) and di-isobutyl phthalate (DiBP). An interquartile range increase in PM2.5 was associated with a 1.2% (95% CI 0.4, 2.1%) higher risk of PTB. There was little difference in PTB risk in strata of infant sex, mother’s age, family income, history of adverse birth outcome, parity, and pre-pregnancy body mass index. Pregnancy urinary phthalate metabolite levels did not modify the PM2.5-PTB association. Conclusion Among ethnic minority women in Puerto Rico, prenatal PM2.5 exposure is associated with a small but significant increase in risk of PTB.

Abstract Lipidome-wide metabolites may be useful biomarkers of pregnancy outcomes. We sought to characterize maternal lipidomic signatures associated with preterm birth and neonatal anthropometric parameters. Plasma samples were collected 24–28 weeks gestation, and lipidomic profiling was quantified using high-performance liquid chromatography tandem mass spectrometry. Lipid metabolites were analyzed individually and as whole lipid classes and subgroups based on degree of hydrocarbon chain saturation. Associations were estimated using linear and logistic regression. After false discovery adjustment (q

Abstract Background Preterm birth (PTB; gestational age

Background: A growing number of studies have identified both toxic and essential metals which influence fetal growth. However, most studies have conducted single-cohort analyses, which are often limited by narrow exposure ranges, and evaluated metals individually. The objective of the current study was to conduct an environmental mixture analysis of metal impacts on fetal growth, pooling data from three geographically and demographically diverse cohorts in the United States participating in the Environmental Influences on Child Health Outcomes program. Methods: The pooled sample (N = 1,002) included participants from the MADRES, NHBCS, and PROTECT cohorts. Associations between seven metals (antimony, cadmium, cobalt, mercury, molybdenum, nickel, tin) measured in maternal urine samples collected during pregnancy (median: 16.0 weeks gestation) and birth weight for gestational age z-scores (BW for GA) were investigated using Bayesian Kernel Machine Regression (BKMR). Models were also stratified by cohort and infant sex to investigate possible heterogeneity. Chromium and uranium concentrations fell below the limits of detection for most participants and were evaluated separately as binary variables using pooled linear regression models. Results: In the pooled BKMR analysis, antimony, mercury, and tin were inversely and linearly associated with BW for GA, while a positive linear association was identified for nickel. The inverse association between antimony and BW for GA was observed in both males and females and for all three cohorts but was strongest for MADRES, a predominantly low-income Hispanic cohort in Los Angeles. A reverse j-shaped association was identified between cobalt and BW for GA, which was driven by female infants. Pooled associations were null for cadmium, chromium, molybdenum, and uranium, and BKMR did not identify potential interactions between metal pairs. Conclusions: Findings suggest that antimony, an understudied metalloid, may adversely impact fetal growth. Cohort- and/or sex-dependent associations were identified for many of the metals, which merit additional investigation.

Background/Aim: The association between heavy metal exposure and adverse birth outcomes is well-established. However, there is a paucity of research identifying biomarker profiles that may improve the early detection of heavy metal-induced adverse birth outcomes. Because lipids are abundant in our body and associated with important signaling pathways, we assessed associations between maternal metals/metalloid blood levels with lipidomic profiles among 83 pregnant women in the Puerto Rico PROTECT birth cohort.Methods: We measured 10 metals/metalloid blood levels during 24–28 weeks of pregnancy. Prenatal plasma lipidomic profiles were identified by liquid chromatography–mass spectrometry-based shotgun lipidomics. We derived sums for each lipid class and sums for each lipid sub-class (saturated, monounsaturated, polyunsaturated), which were then regressed on metals/metalloid. False discovery rate (FDR) adjusted p-values (q-values) were used to account for multiple comparisons.Results: A total of 587 unique lipids from 19 lipid classes were profiled. When controlling for multiple comparisons, we observed that maternal exposure to manganese and zinc were negatively associated with plasmenyl-phosphatidylethanolamine (PLPE), particularly those containing polyunsaturated fatty acid (PUFA) chains. In contrast to manganese and zinc, arsenic and mercury were positively associated with PLPE and plasmenyl-phosphatidylcholine (PLPC).Conclusion: Certain metals were significantly associated with lipids that are responsible for the biophysical properties of the cell membrane and antioxidant defense in lipid peroxidation. This study highlighted lipid-metal associations and we anticipate that this study will open up new avenues for developing diagnostic tools.

Loss of basic utilities, such as drinking water and electricity distribution, were sustained for months in the aftermath of Hurricane Maria's (HM) landfall in Puerto Rico (PR) in September 2017. The goal of this study was to assess if there was deterioration in biological quality of drinking water due to these disruptions. This study characterized the microbial composition of drinking water following HM across nine drinking water systems (DWSs) in PR and utilized an extended temporal sampling campaign to determine if changes in the drinking water microbiome were indicative of HM associated disturbance followed by recovery. In addition to monitoring water chemistry, the samples were subjected to culture independent targeted and non-targeted microbial analysis including quantitative PCR (qPCR) and genome-resolved metagenomics. The qPCR results showed that residual disinfectant was the major driver of bacterial concentrations in tap water with marked decrease in concentrations from early to late sampling timepoints. While Mycobacterium avium and Pseudomonas aeruginosa were not detected in any sampling locations and timepoints, genetic material from Leptospira and Legionella pneumophila were transiently detected in a few sampling locations. The majority of metagenome assembled genomes (MAGs) recovered from these samples were not associated with pathogens and were consistent with bacterial community members routinely detected in DWSs. Further, whole metagenome-level comparisons between drinking water samples collected in this study with samples from other full-scale DWS indicated no significant deviation from expected community membership of the drinking water microbiome. Overall, our results suggest that disruptions due to HM did not result in significant and sustained deterioration of biological quality of drinking water at our study sites.

Phthalates have been linked to changes in child neurodevelopment. However, sex-specificity has been reported inconsistently, and little is known about the impact of recent phthalate replacement chemicals. Our analysis included mother–child pairs (N = 274) from the PROTECT birth cohort in Puerto Rico. Phthalate metabolites were measured in multiple maternal urine collected during pregnancy. Neurodevelopment was measured at 6, 12, and 24 months of age using the Battelle Developmental Inventory-2nd edition (BDI), which provides scores for adaptive, personal-social, communication, motor, and cognitive domains. Multivariable linear regression was used to examine associations between phthalate metabolite concentrations and BDI scores, adjusting for maternal age, maternal education, child age, and specific gravity. Sex-specificity was assessed with sex X exposure interaction terms and stratified models. Results show that all five domains were significantly associated with mono-3-carboxypropyl phthalate (MCPP) at age 24 months, suggesting a holistic developmental delay related to this metabolite. Sex-specificity existed for all timepoints (p-interaction < 0.2), in general, showing stronger associations among boys. For example, metabolites of a recent phthalate replacement, di-2-ethylhexyl terephthalate (DEHTP), were differentially associated with the adaptive domain (boys −7.53%/IQR, 95% CI: −14.58, −0.48 vs. girls −0.85%/IQR, 95% CI: −5.08, 3.37), and the cognitive domain (boys −6.05%/IQR, 95% CI: −10.88, −1.22 vs. girls −1.93%/IQR, 95%CI: −4.14, 0.28) at 6 months. To conclude, gestational exposure to phthalates and phthalate replacements was associated with neurodevelopmental delay across multiple domains, with differences by sex and child age.

Exposures to phthalate compounds have been linked to adverse birth outcomes, potentially through oxidative stress mechanisms. We explored associations between mixtures of biomarkers of phthalate and phthalate replacement metabolites and oxidative stress using lipid peroxidation biomarker 8-iso-prostaglandin-F2α (8-iso-PGF2α). As 8-iso-PGF2α can be generated via both chemical (nonenzymatic) and enzymatic lipid peroxidation pathways, we calculated the ratio of 8-iso-PGF2α/prostaglandin F2α in an attempt to distinguish the potential contributions of the two pathways. Urinary biomarker measurements were taken from 775 pregnant women in the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) longitudinal birth cohort at up to three time points during gestation (16–20, 20–24, and 24–28 weeks gestation). Adaptive elastic net with pairwise linear interaction terms (adENET-I) was used to determine individual phthalate metabolites and phthalate interactions that were predictive of lipid oxidative stress biomarkers, and to subsequently create environmental risk scores (ERS) to represent weighted sums of phthalate exposure for each individual at each study visit. Repeated ERS were then used in linear mixed effects models to test for associations between biomarkers of phthalate mixtures and biomarkers of oxidative stress. We also used Bayesian kernel machine regression (BKMR) to explore nonlinearity and interactions between phthalate metabolites within the mixture. An increase from the first to fourth quartile of phthalate ERS derived from adENET-I was associated with a 96.7% increase (95% CI: 74.0, 122) in the hypothesized chemical fraction of 8-iso-PGF2α and a 268% increase (95% CI: 139, 465) in the hypothesized enzymatic fraction of 8-iso-PGF2α. BKMR analyses also suggested strong linear associations between the phthalate mixture and biomarkers of lipid oxidative stress. Various phthalates displayed nonlinear relationships with both chemical and enzymatic fractions of 8-iso-PGF2α, and we observed some evidence of interactions between metabolites in the mixture. In conclusion, exposure to phthalate mixtures was strongly associated with linear increases in biomarkers of lipid oxidative stress, and differences observed between hypothesized chemical and enzymatic lipid peroxidation outcomes highlight the need to critically assess pathways of 8-iso-PGF2α generation in relation to environmental exposures.

In 2017–2019, the March of Dimes convened a workgroup with biomedical, clinical, and epidemiologic expertise to review knowledge of the causes of the persistent Black-White disparity in preterm birth (PTB). Multiple databases were searched to identify hypothesized causes examined in peer-reviewed literature, 33 hypothesized causes were reviewed for whether they plausibly affect PTB and either occur more/less frequently and/or have a larger/smaller effect size among Black women vs. White women. While definitive proof is lacking for most potential causes, most are biologically plausible. No single downstream or midstream factor explains the disparity or its social patterning, however, many likely play limited roles, e.g., while genetic factors likely contribute to PTB, they explain at most a small fraction of the disparity. Research links most hypothesized midstream causes, including socioeconomic factors and stress, with the disparity through their influence on the hypothesized downstream factors. Socioeconomic factors alone cannot explain the disparity's social patterning. Chronic stress could affect PTB through neuroendocrine and immune mechanisms leading to inflammation and immune dysfunction, stress could alter a woman's microbiota, immune response to infection, chronic disease risks, and behaviors, and trigger epigenetic changes influencing PTB risk. As an upstream factor, racism in multiple forms has repeatedly been linked with the plausible midstream/downstream factors, including socioeconomic disadvantage, stress, and toxic exposures. Racism is the only factor identified that directly or indirectly could explain the racial disparities in the plausible midstream/downstream causes and the observed social patterning. Historical and contemporary systemic racism can explain the racial disparities in socioeconomic opportunities that differentially expose African Americans to lifelong financial stress and associated health-harming conditions. Segregation places Black women in stressful surroundings and exposes them to environmental hazards. Race-based discriminatory treatment is a pervasive stressor for Black women of all socioeconomic levels, considering both incidents and the constant vigilance needed to prepare oneself for potential incidents. Racism is a highly plausible, major upstream contributor to the Black-White disparity in PTB through multiple pathways and biological mechanisms. While much is unknown, existing knowledge and core values (equity, justice) support addressing racism in efforts to eliminate the racial disparity in PTB.

BackgroundEarly delivery remains a significant public health problem that has long-lasting impacts on mother and child. Understanding biological mechanisms underlying timing of labor, including endocrine disruption, can inform prevention efforts.MethodsGestational hormones were measured among 976 women in PROTECT, a longitudinal birth cohort in Puerto Rico. We evaluated associations between hormone concentrations at 18 and 26 weeks gestation and gestational age at birth, while assessing effect modification by fetal sex. Exploratory analyses assessed binary outcomes of overall preterm birth (PTB,

Abstract Background Until recently, Zika virus (ZIKV) infections were considered mild and self-limiting. Since 2015, they have been associated with an increase in microcephaly and other birth defects in newborns. While this association has been observed in case reports and epidemiological studies, the nature and extent of the relationship between ZIKV and adverse pregnancy and pediatric health outcomes is not well understood. With the unique opportunity to prospectively explore the full spectrum of issues related to ZIKV exposure during pregnancy, we undertook a multi-country, prospective cohort study to evaluate the association between ZIKV and pregnancy, neonatal, and infant outcomes. Methods At research sites in ZIKV endemic regions of Brazil (4 sites), Colombia, Guatemala, Nicaragua, Puerto Rico (2 sites), and Peru, up to 10,000 pregnant women will be recruited and consented in the first and early second trimesters of pregnancy and then followed through delivery up to 6 weeks post-partum; their infants will be followed until at least 1 year of age. Pregnant women with symptomatic ZIKV infection confirmed by presence of ZIKV RNA and/or IgM for ZIKV will also be enrolled, regardless of gestational age. Participants will be tested monthly for ZIKV infection; additional demographic, physical, laboratory and environmental data will be collected to assess the potential interaction of these variables with ZIKV infection. Delivery outcomes and detailed infant assessments, including physical and neurological outcomes, will be obtained. Discussion With the emergence of ZIKV in the Americas and its association with adverse pregnancy outcomes in this region, a much better understanding of the spectrum of clinical outcomes associated with exposure to ZIKV during pregnancy is needed. This cohort study will provide information about maternal, fetal, and infant outcomes related to ZIKV infection, including congenital ZIKV syndrome, and manifestations that are not detectable at birth but may appear during the first year of life. In addition, the flexibility of the study design has provided an opportunity to modify study parameters in real time to provide rigorous research data to answer the most critical questions about the impact of congenital ZIKV exposure. Trial registration NCT02856984. Registered August 5, 2016. Retrospectively registered.

Abstract Introduction Prenatal exposure to some phenols and parabens has been associated with adverse birth outcomes. Hormones may play an intermediate role between phenols and adverse outcomes. We examined the associations of phenol and paraben exposures with maternal reproductive and thyroid hormones in 602 pregnant women in Puerto Rico. Urinary triclocarban, phenol and paraben biomarkers, and serum hormones (estriol, progesterone, testosterone, sex-hormone-binding globulin (SHBG), corticotropin-releasing hormone (CRH), total triiodothyronine (T3), total thyroxine (T4), free thyroxine (FT4) and thyroid-stimulating hormone (TSH)) were measured at two visits during pregnancy. Methods Linear mixed models with a random intercept were constructed to examine the associations between hormones and urinary biomarkers. Results were additionally stratified by study visit. Results were transformed to hormone percent changes for an inter-quartile-range difference in exposure biomarker concentrations (%Δ). Results Bisphenol-S was associated with a decrease in CRH [(%Δ -11.35; 95% CI: -18.71, − 3.33), and bisphenol-F was associated with an increase in FT4 (%Δ: 2.76; 95% CI: 0.29, 5.22). Butyl-, methyl- and propylparaben were associated with decreases in SHBG [(%Δ: -5.27; 95% CI: -9.4, − 1.14); (%Δ: -3.53; 95% CI: -7.37, 0.31); (%Δ: -3.74; 95% CI: -7.76, 0.27)]. Triclocarban was positively associated with T3 (%Δ: 4.08; 95% CI: 1.18, 6.98) and T3/T4 ratio (%Δ: 4.67; 95% CI: -1.37, 6.65), and suggestively negatively associated with TSH (%Δ: -10.12; 95% CI: -19.47, 0.32). There was evidence of susceptible windows of vulnerability for some associations. At 24–28 weeks gestation, there was a positive association between 2,4-dichlorophenol and CRH (%Δ: 9.66; 95% CI: 0.67, 19.45) and between triclosan and estriol (%Δ: 13.17; 95% CI: 2.34, 25.2); and a negative association between triclocarban and SHBG (%Δ: -9.71; 95% CI:-19.1, − 0.27) and between bisphenol A and testosterone (%Δ: -17.37; 95% CI: -26.7, − 6.87). Conclusion Phenols and parabens are associated with hormone levels during pregnancy. Further studies are required to substantiate these findings.

Background: Metal exposure and psychosocial stress in pregnancy have each been associated with adverse birth outcomes, including preterm birth and low birth weight, but no study has examined the potential interaction between them. Objectives: We examined the modifying effect of psychosocial stress on the association between metals and birth outcomes among pregnant women in Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) birth cohort study. Methods: In our analysis of 682 women from the PROTECT study, we measured 16 essential and non-essential metals in blood samples at two time points. We administered questionnaires to collect information on depression, perceived stress, social support, and life experience during pregnancy. Using K-means clustering, we categorized pregnant women into one of two groups: “good” and “poor” psychosocial status. We then evaluated whether the effect of blood metals (geometric average) on adverse birth outcomes (gestational age, preterm birth [overall and spontaneous], birth weight z-score, small for gestation [SGA], large for gestation [LGA]) vary between two clusters of women, adjusting for maternal age, maternal education, pre-pregnancy body mass index (BMI), and second-hand smoke exposure. Results: Blood manganese (Mn) was associated with an increased odds ratio (OR) of overall preterm birth (OR/interquartile range [IQR] = 2.76, 95% confidence interval [CI] = 1.25, 6.12) and spontaneous preterm birth (OR/IQR: 3.68, 95% CI: 1.20, 6.57) only among women with “poor” psychosocial status. The association between copper (Cu) and SGA was also statistically significant only among women having “poor” psychosocial status (OR/IQR: 2.81, 95% CI: 1.20, 6.57). We also observed associations between nickel (Ni) and preterm birth and SGA that were modified by psychosocial status during pregnancy. Conclusions: Presence of “poor” psychosocial status intensified the adverse associations between Mn and preterm birth, Cu and SGA, and protective effects of Ni on preterm. This provides evidence that prenatal psychosocial stress may modify vulnerability to metal exposure.

The PROTECT research Center funded by the NIH’s National Institute of Environmental Health Sciences (NIEHS) Superfund Research Program was launched in 2010 to explore the impact of exposure to pollutants on the high rate of premature births in Puerto Rico. In September 2017, Hurricanes Irma and María devastated the archipelago, which caused: collapse of the electrical system, collapse of the communication system, limited access to clean water, food, gas, and health services, destruction of public (e.g., hospitals) and private property (e.g., houses) and more than 4500 deaths. Pregnant and postpartum individuals are especially vulnerable to natural disasters. They face difficulty obtaining adequate pre- and post-natal care, are exposed to increased risk of miscarriage, premature delivery, and giving birth to low birth weight babies during and after disasters and are also more likely to suffer physical and mental health problems compared to the general population during and after disasters. A face-to-face questionnaire was administered to PROTECT participants who were pregnant during hurricanes Irma or Maria or who became pregnant shortly after in order to identify hurricane-related sources of stress and other adverse effects. This paper is based on the answers to the open-ended question at the end of the questionnaire where participants were asked to share their experiences during and after the hurricanes. Among the 375 participants who completed the survey, 76 answers to the open-ended question were considered due to data saturation. The answers to the open-ended question were transcribed into a document in order to facilitate the coding process. The transcribed text was analyzed first to identify emerging categories and then coded to identify common themes as well as divergence among participants. The following themes were identified: pregnancy and birth challenges, lack of access to basic services, housing conditions, stressful working conditions, concerns about health, concerns about their children, and positive or protective aspects. The results indicate how the disruption in access to basic services has a unique impact on the physical and mental health of pregnant and post-partum women in an emergency situation. These findings point to the potential benefit of developing specific protocols designed for emergency preparedness aimed at this population, which can inform healthcare providers and community organizations in case of future events.

Background: Metal(loid)s have been associated to adverse birth outcomes in experimental and epidemiological studies, but the underlying mechanism(s) are not well understood. Endocrine disruption may be a mechanism by which the metal(loid)s impact birth outcomes. Methods: Pregnant women were recruited through the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT). Urine, blood, demographic and pregnancy-related data were collected at recruitment and subsequent visits. Sixteen metal(loid)s were analyzed in urine and blood samples, while nine maternal hormones (corticotropin-releasing hormone (CRH), sex-hormone binding globulin (SHBG), estriol (E3), progesterone, testosterone, thyroid-stimulating hormone (TSH), total triiodothyronine (T3), total thyroxine (T4), and free thyroxine (fT4)) were measured in serum samples from 815 singleton pregnancies. Linear mixed models with random intercepts were used to examine associations between metal(loid)s in blood and urine with hormone concentrations. Results: Arsenic blood concentrations were significantly associated with increased levels in CRH (%Δ: 23.0, 95%CI: 8.4–39.6) and decreased levels in testosterone (%Δ: −16.3, 95%CI: −26.2-−5.1). Cobalt, manganese, and lead blood concentrations were associated with small increases in SHBG (%Δ range: 3.3–4.2), E3 (%Δ range: 3.9–8.7) and progesterone (%Δ range: 4.1–6.3) levels, respectively. Nickel blood concentration was inversely associated with testosterone levels (%Δ −13.3, 95%CI: −18.7-−7.6). Significant interactions were detected for the association between nickel and study visit in relation to CRH (p

Background: In previous studies, exposures to heavy metals such as Pb and Cd have been associated with adverse birth outcomes; however, knowledge on effects at low levels of exposure and of other elements remain limited. Method: We examined individual and mixture effects of metals and metalloids on birth outcomes among 812 pregnant women in the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) cohort. We measured 16 essential and non-essential metal(loid)s in maternal blood collected at 16–20 and 24–28 weeks gestation. We used linear and logistic regression to independently examine associations between geometric mean (GM) concentrations of each metal across visits and gestational age, birthweight z-scores, preterm birth, small for gestational age (SGA), and large for gestational age (LGA). We evaluated effect modification with infant sex*metal interaction terms. To identify critical windows of susceptibility, birth outcomes were regressed on visit-specific metal concentrations. Furthermore, average metal concentrations were divided into tertiles to examine the potential for non-linear relationships. We used elastic net (ENET) regularization to construct Environmental Risk Score (ERS) as a metal risk score and Bayesian Kernel Machine Regression (BKMR) to identify individual metals most critical to each outcome, accounting for correlated exposures. Results: In adjusted models, an interquartile range (IQR) increase in GM lead (Pb) was associated with 1.63 higher odds of preterm birth (95%CI = 1.17, 2.28) and 2 days shorter gestational age (95% CI = −3.1, −0.5). Manganese (Mn) and zinc (Zn) were also associated with higher odds of preterm birth and shorter gestational age; the associations were strongest among the highest tertile for Mn and among females for Zn. Mercury (Hg) was associated with higher risk of preterm birth at the later window of pregnancy. Ni measured later in pregnancy was associated with lower odds of SGA. ENET and BKMR models selected similar metals as “important” predictors of birth outcomes. The association between ERS and preterm birth was assessed and the third tertile of ERS was significantly associated with an elevated odds ratio of 2.13 (95% CI = 1.12, 5.49) for preterm birth compared to the first tertile. Conclusion: As the PROTECT cohort has lower Pb concentrations (GM = 0.33 μg/dL) compared to the mainland US, our findings suggest that low-level prenatal lead exposure, as well as elevated Mn and Zn exposure, may adversely affect birth outcomes. Improved understanding on environmental factors contributing to preterm birth, together with sustainable technologies to remove contamination, will have a direct impact in Puerto Rico and elsewhere. Keywords: Metals, Birth outcomes, Biomarkers, Mixtures, Puerto Rico

Background: Understanding important sources and pathways of exposure to common chemicals known or suspected to impact human health is critical to eliminate or reduce the exposure. This is particularly important in areas such as Puerto Rico, where residents have higher exposures to numerous chemicals, as well as higher rates of many adverse health outcomes, compared to the mainland US. Objective: The aim of this study was to assess distributions, time trends, and predictors of urinary triclocarban, phenol, and paraben biomarkers measured at multiple times during pregnancy among women living in Northern Puerto Rico. Methods: We recruited 1003 pregnant women between years 2010 and 2016 from prenatal clinics and collected urine samples and questionnaire data on personal care product use at up to three separate visits, between 16 and 28 weeks gestation. Urine samples were analyzed for triclocarban, seven phenols and four parabens: 2,4-dichlorophenol, 2,5-dichlorophenol, benzophenone-3, bisphenol A (BPA), bisphenol S (BPS), bisphenol F, triclosan, butylparaben, ethylparaben, methylparaben, and propylparaben. Results: Detectable triclocarban, phenol and paraben concentrations among pregnant women were prevalent and tended to be higher than levels measured in women of reproductive age from the general US population, especially triclocarban, which had a median concentration 37 times higher in Puerto Rico participants (2.6 vs 0.07 ng/mL). A decreasing temporal trend was statistically significant for urine concentrations of BPA during the study period, while the BPA substitute BPS showed an increasing temporal trend. Significant and positive associations were found between biomarker concentrations with the products use in the past 48-h (soap, sunscreen, lotion, cosmetics). There was an increasing trend of triclocarban/triclosan urinary concentrations with increased concentrations of triclocarban/triclosan listed as the active ingredient in the bar soap/liquid soap products reported being used. Conclusion: Our results suggest several potential exposure sources to triclocarban, phenols, and parabens in this population and may help inform targeted approaches to reduce exposure. Keywords: Human biomonitoring, Exposure assessment, Pregnancy, Endocrine disruptors, Antimicrobials, Personal care products

Background: Preterm birth is a global public health issue and rates in Puerto Rico are consistently among the highest in the USA. Exposures to environmental contaminants might be a contributing factor. Methods: In a preliminary analysis from the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) cohort (n = 1090), we investigated the association between urinary phthalate metabolite concentrations measured at three study visits (targeted at 20, 24, and 28 weeks of gestation) individually and averaged over pregnancy with gestational age at delivery and preterm birth. We additionally assessed differences in associations by study visit and among preterm births with a spontaneous delivery. Results: Compared to women in the general USA population, urinary concentrations of metabolites of di-n-butyl phthalate (DBP) and di-isobutyl phthalate (DiBP) were higher among pregnant women in Puerto Rico. Interquartile range (IQR) increases in pregnancy-averages of urinary metabolites of DBP and DiBP were associated with shorter duration of gestation and increased odds of preterm birth. An IQR increase in mono-n-butyl phthalate (MBP), a metabolite of DBP, was associated with 1.55 days shorter gestation (95% confidence interval [CI] = −2.68, −0.42) and an odds ratio (OR) of 1.42 (95% confidence interval [CI]: 1.07, 1.88) for preterm birth. An IQR increase in mono-isobutyl phthalate (MiBP), a metabolite of DiBP, was associated with 1.16 days shorter gestation (95% CI = −2.25, −0.08) and an OR of 1.32 (95% CI: 1.02, 1.71) for preterm birth. Associations were greatest in magnitude for urinary concentrations measured at the second study visit (median 23 weeks gestation). DiBP metabolite associations were greatest in magnitude in models of spontaneous preterm birth. No associations were detected with other phthalate metabolites, including those of di-2-ethylhexyl phthalate. Conclusion: Among pregnant women in the PROTECT cohort, DBP and DiBP metabolites were associated with increased odds of preterm birth. These exposures may be contributing to elevated rates of preterm birth observed in Puerto Rico. Keywords: Phthalates, Preterm birth, Gestational age, Puerto Rico, Superfund

Metal exposure has been associated with a wide range of adverse birth outcomes and oxidative stress is a leading hypothesis of the mechanism of action of metal toxicity. We assessed the relationship between maternal exposure to essential and non-essential metals and metalloids in pregnancy and oxidative stress markers, and sought to identify windows of vulnerability and effect modification by fetal sex. In our analysis of 215 women from the PROTECT birth cohort study, we measured 14 essential and non-essential metals in urine samples at three time points during pregnancy. The oxidative stress marker 8-iso-prostaglandin F2α (8-iso-PGF2α) and its metabolite 2,3-dinor-5,6-dihydro-15-15-F2t-IsoP, as well as prostaglandin F2α (PGF2α), were also measured in the same urine samples. Using linear mixed models, we examined the main effects of metals on markers of oxidative stress as well as the visit-specific and fetal sex-specific effects. After adjustment for covariates, we found that a few urinary metal concentrations, most notably cesium (Cs) and copper (Cu), were associated with higher 8-iso-PGF2α with effect estimates ranging from 7.3 to 14.9% for each interquartile range, increase in the metal concentration. The effect estimates were generally in the same direction at the three visits and a few were significant only among women carrying a male fetus. Our data show that higher urinary metal concentrations were associated with elevated biomarkers of oxidative stress. Our results also indicate a potential vulnerability of women carrying a male fetus.

Following publication of the original article [1], the author mentioned that two additional NIH staff were involved in the development of the protocol who did not receive recognition in the Acknowledgments section in their published article.

Abstract Objective: n-3 fatty acid consumption during pregnancy is recommended for optimal pregnancy outcomes and offspring health. We examined characteristics associated with self-reported fish or n-3 supplement intake. Design: Pooled pregnancy cohort studies. Setting: Cohorts participating in the Environmental influences on Child Health Outcomes (ECHO) consortium with births from 1999 to 2020. Participants: A total of 10 800 pregnant women in twenty-three cohorts with food frequency data on fish consumption; 12 646 from thirty-five cohorts with information on supplement use. Results: Overall, 24·6 % reported consuming fish never or less than once per month, 40·1 % less than once a week, 22·1 % 1–2 times per week and 13·2 % more than twice per week. The relative risk (RR) of ever (v. never) consuming fish was higher in participants who were older (1·14, 95 % CI 1·10, 1·18 for 35–40 v.