Pregnancy functions as a “stress test” with implications for women’s long-term health. We hypothesize that maternal biological aging, measured by epigenetic age acceleration (EAA), can be influenced by one-carbon nutritional status (folate, vitamin B₁₂, homocysteine), adherence to the Mediterranean diet, and prenatal multivitamin use. We analyzed data from 742 mothers enrolled in the Boston Birth Cohort (1998–2013). EAA was defined as the difference between the Levine epigenetic clock–DNA methylation–based measure and chronological age at delivery. Mediterranean-diet adherence and prenatal multivitamin use were assessed using a validated food frequency questionnaire administered within 24–72 h postpartum. Blood DNA and plasma samples used to measure folate, B12, and homocysteine were collected concurrently and stored at − 20 °C and − 80 °C, respectively, until biomarker assays. Associations were evaluated using multivariable linear regression adjusting for sociodemographic characteristics. Participants had a median chronological age of 28 (interquartile range, 23–33) years and a median epigenetic age (EA) of 30 (23–36) years; 66

BACKGROUND:Mitochondria, the cell's powerhouse, play a central role in energy homeostasis and may influence obesity risk. Variations in mitochondrial DNA (mtDNA) have been hypothesized to influence early-life metabolic programming; however, prospective evidence remains limited, and no study has jointly examined multiple mtDNA biomarkers. We aimed to investigate the individual and combined associations of cord blood mtDNA heteroplasmy and copy number with the risk of childhood overweight or obesity (OWO). METHODS:Data were obtained from 952 children enrolled at birth and followed longitudinally in the Boston Birth Cohort. Body mass index (BMI) z scores were calculated using U.S. reference data, and OWO was defined as BMI ≥85th percentile for age and sex. Cord blood mtDNA heteroplasmy and copy number were assessed by targeted sequencing, with functional region heteroplasmy defined as heteroplasmic variants in coding regions and classified as inherited or de novo. Mixed-effects models were used to evaluate associations between mtDNA measures and repeated measures of child BMI and OWO. RESULTS:In sex-specific analyses, de novo functional region heteroplasmy was associated with higher BMI z score (β = 0.29, 95% CI: 0.01, 0.57) and increased risk of OWO (RR = 1.46, 95% CI: 1.07, 2.00) among girls, whereas no associations were observed overall. BMI associations were more evident in adolescent girls (aged 10-18 years). MtDNA copy number z score was negatively associated with BMI in children with overall or de novo functional region heteroplasmy but showed modest positive associations in those without specific heteroplasmy (p for interaction < 0.05). CONCLUSIONS:Cord blood mtDNA heteroplasmy and copy number interactively influence the risk of childhood OWO, with associations varying by sex and age. This is the first prospective study to jointly evaluate these mtDNA biomarkers, offering new insight into mitochondrial contributions to the developmental origins of OWO and a potential framework for early-life risk assessment.

Introduction: Cardiovascular disease (CVD) is the leading cause of death for US women. However, female-specific risk factors, especially pregnancy-related factors, are not included in CVD risk assessment for women. Whether alterations in biological pathways after delivery are associated with future CVD is unknown. In this study, we aim to identify postpartum proteomic networks associated with incident CVD. Methods: This case-control study is nested in the Boston Birth Cohort, a predominantly urban, low-income, and multiethnic birth cohort in the US. We included 31 women with incident CVD and 42 controls (up to 21 yrs of follow-up; 74% Black). Maternal postpartum (24-72 hrs after delivery) plasma proteomic profiling was performed using the mass spectrometry-based Seer Proteograph platform; 5,333 proteins were available after quality controls. CVD cases were identified based on International Classification of Diseases codes derived from longitudinal electronic health records, including congestive heart failure (CHF), ischemic heart disease (IHD), and stroke. We defined CVD as a composite of CHF, IHD and stroke. Proteomic networks were identified using WGCNA (Weighted Gene Co-expression Network Analysis), and their associations with incident CVD were examined using Cox proportional-hazards models. Results: Women developed CVD had higher pre-pregnancy body mass index and higher prevalence of preterm delivery and hypertensive disorders of pregnancy (HDP). WGCNA identified 22 proteomic network modules; 6 modules were associated with at least one CVD outcomes (p<0.05) in the fully adjusted model, and these modules consist of proteins involved in estrogen signaling, brain aging, lipid metabolism, coagulation, inflammation, and immune function. The observed associations slightly attenuated after additionally adjusting for adverse pregnancy outcomes for 3 modules, but not for others. Notably, for one module consisting of 10 proteins (mostly keratins that are highly expressed in skin, arteries, and female reproductive organs), the association with CVD remained after Bonferroni correction for 22 modules (p<0.0023), and 8 constituting proteins (6 are keratins) were associated with CVD. This module mediates 20% of the association between HDP and incident CVD. Conclusions: Network-based analysis identified postpartum plasma proteomic modules associated with incident CVD in women and suggested a mechanistic link between HDP and future CVD risk. Our findings need to be validated.

Abstract Background Hormonal changes throughout life in women are associated with menarche, pregnancy, lactation, and menopause. Cardiometabolic multimorbidity (CMM) has become increasingly common with population aging. However, the impact of such fluctuations on CMM has not been evaluated. This study aims to investigate the associations of female sex-specific risk factors with CMM and four cardiometabolic diseases. Methods A total of 248,623 women from the UK Biobank without pre-existing cardiometabolic disease were included. Cox proportional hazard models were used to evaluate the association between female-specific risk factors and the incidence of CMM and the four cardiometabolic diseases. The UpSet plots were used to visualize combinations of female-specific risk factors, and then to evaluate the association between the combinations and accumulations of female risk factors and CMM. Results The average age of participants was 56.4 years, with a median follow-up period of 13.6 years. After adjusting for multiple variables, early menarche was associated with an 11% higher risk for CMM incidence (HR, 1.11; 95% CI, 1.06–1.15). Early menopause (age < 35 years: HR, 1.80; 95% CI, 1.58–2.06; age 35–44 years: HR, 1.24; 95% CI, 1.17–1.32; age 45–49 years: HR, 1.09; 95% CI, 1.04–1.15), younger maternal age at first (age < 21 years: HR, 1.35; 95% CI, 1.28–1.42; age 21–25 years: HR, 1.13; 95% CI, 1.08–1.18) and last (age < 26 years: HR, 1.12; 95% CI, 1.06–1.18) live birth were associated with increased CMM risk, respectively. Women with three or more children had a higher risk of developing CMM (3 children: HR, 1.05; 95% CI, 1.00–1.10; ≥ 4 children HR, 1.19; 95% CI, 1.13–1.27). Additionally, a history of two or more stillbirths (HR, 1.30; 95% CI, 1.07–1.59) or spontaneous miscarriages (HR, 1.24; 95% CI, 1.15–1.34) was associated with elevated CMM risk, with similar findings for each cardiometabolic disease. Combinations or accumulations of sex-specific risk factors are associated with an increased risk of CMM. Conclusions In summary, female sex-specific factors significantly influence the incidence of both CMM and each cardiometabolic disease.

Introduction and Objective: We aimed to identify cord blood metabolomic signatures of GDM and their associations with childhood insulin levels. Methods: We studied 943 mother-child dyads from the Boston Birth Cohort. We ascertained GDM via ICD codes, medication history, and plasma glucose profiles and excluded women with pregestational diabetes mellitus. We measured 378 metabolites in cord blood and random plasma insulin levels in childhood (median [IQR]: 1.34 y [0.84-3.10]). We identified metabolites associated with GDM using linear regression with False Discovery Rate (FDR) correction (FDR < 0.05). In children with insulin data (n = 401), we examined associations between cord blood metabolites and childhood insulin using linear regression. We adjusted for covariates listed in the Figure Footnote. Results: Among 943 women (58% Black, 24% Hispanic; 9% with GDM), GDM was associated with alterations in 32 cord blood metabolites spanning 13 classes, including higher diacylglycerol (DAG) and triacylglycerol (TAG) metabolites, and lower cholesteryl ester (CE) and phospholipid (PC, PE) metabolites (Panel A). In the subset, TAGs and DAGs were associated with higher childhood insulin levels, while CE and PE were associated with lower insulin levels (Panel B). Conclusion: Fetal lipid dysregulation may underlie the intergenerational transmission of cardiometabolic risk. Further work should investigate the long-term prognostic significance of these metabolites. Disclosure B. Grobman: None. G. Wang: None. X. Hong: None. L.H. Ngo: None. S. Juraschek: None. X. Wang: None. M. Zhang: None. Funding American Diabetes Association (7-24-ICTSWH-10)

BACKGROUND:Elevated prepregnancy body mass index (ppBMI) and excessive gestational weight gain (GWG) may contribute to the development of childhood overweight or obesity (COWO), potentially by altering the intrauterine metabolic environment. OBJECTIVES:This study aimed to evaluate the impact of maternal obesity phenotypes on maternal and umbilical cord blood metabolomic profiles, both individually and collectively, and to further examine their association with COWO incidence from preschool through adolescence. METHODS:We analyzed 1253 mother-child dyads with maternal metabolomic data collected 1 to 3 d postpartum and 856 dyads with cord metabolomic data from a prospective multiethnic birth cohort. Metabolomics was profiled using liquid chromatography-tandem mass spectrometry. COWO was defined as a BMI ≥ 85th percentile for a specific age and sex. Metabolomic signatures of maternal obesity and scores were derived using linear regression and elastic net regression, and their associations with COWO were assessed via logistic regression. RESULTS:Most maternal metabolites were significantly correlated with corresponding cord metabolites (Spearman's ρ: 0.11-0.67; adjusted P < 0.05), except for steroids and certain phospholipids. ppBMI was significantly associated with broad-based alterations in maternal metabolite profiles, particularly medium-chain acylcarnitines, saturated sphingomyelins, triacylglycerols, and phospholipids carrying PUFAs. We further developed ppBMI-related multi-metabolite scores (Pearson's r = 0.43-0.64) that were associated with higher birthweight (β = 0.07-0.11; P < 0.013) and increased COWO risk (odds ratio: 1.18-1.61; all P < 0.05) from preschool through adolescence. A similar pattern was observed for GWG. In mediation analyses, the maternal metabolite score explained 12.3% (95% confidence interval: 2.18, 24.5; P = 0.02) of the association between ppBMI and BMI z-score at the last well-child visit. CONCLUSIONS:Metabolomic profiles are associated with and may partly mediate the association between maternal obesity, particularly ppBMI, and an increased risk of COWO. These findings warrant validation in independent cohorts.

Blood DNA methylation patterns are highly predictive of prenatal exposure to smoking, and differential methylation has been associated with maternal alcohol use. We extended this to determine whether DNA methylation patterns in cord blood are associated with prenatal exposure to opioids, cannabis, and polysubstance use. We also evaluated whether DNA methylation patterns have predictive utility. We examined 932 mother-child pairs in the Boston Birth Cohort between 1998 and 2020 with cord blood DNA methylation data. For each substance self-reported within 72 hr after birth, we performed an adjusted linear regression analysis at 865,859 CpG sites to identify related methylation differences. We generated polyepigenetic scores using summary statistics for each exposure and assessed predictive ability using cross-validation and receiver operating characteristic curves. Specificity of methylation associations was evaluated by assessing overlap across exposure summary statistics and using logistic regression for methylation scores, adjusted for concurrent use. We identified methylation changes at 72, 21, and 1 CpG suggestively associated with prenatal exposure to opioids, cannabis, and polysubstance use, respectively (p < 1e-6), in cord blood, reported for the first time for these exposures. We identified two loci associated at epigenome-wide significance with opioids and one with polysubstance use (p < 1e-8). Methylation scores were highly predictive and exposure-specific, with area under the curve accuracy of 91% for opioids, 90% for cannabis, and 93%-98% depending on polysubstance number. These CpGs provide biologic insights for reducing the impact of substance exposure, and these findings may serve as a biomarker of prenatal substance exposure for future studies and potential clinical utility.

BACKGROUND:The biological mechanisms underlying preterm birth (PTB) are not fully understood. This study examined the individual and joint associations of mitochondrial DNA (mtDNA) heteroplasmy and copy number (mtDNA-CN) in maternal and cord blood with PTB. METHODS:This study analyzed 998 mother-infant dyads (18% PTB). MtDNA heteroplasmy and mtDNA-CN were measured by a targeted DNA sequencing approach using umbilical cord blood collected at birth and maternal blood collected 24-72 hours postpartum. Multivariable logistic regressions were used to evaluate the associations with PTB. RESULTS:Maternal predicted pathogenic heteroplasmy was associated with a twofold increased risk of PTB (adjusted OR (95% CI) = 2.08 (1.07, 4.05)), whereas no significant associations were observed for maternal overall or functional heteroplasmy. No significant associations were observed for cord blood heteroplasmy measures. A U-shaped association between maternal mtDNA-CN and PTB was observed. Higher cord mtDNA-CN were associated with increased PTB odds (1.36 (1.14, 1.62)). Notably, a significant interaction between maternal and cord mtDNA-CN was found for PTB risk. CONCLUSION:Maternal, but not fetal, mtDNA heteroplasmy was associated with increased PTB risk. Both maternal and cord blood mtDNA-CN demonstrated individual and interactive associations with PTB, suggesting that maternal and fetal mitochondrial genomic variations may jointly influence PTB risk. IMPACT:We found that maternal predicted pathogenic mtDNA heteroplasmy was associated with increased PTB risk; maternal mtDNA-CN showed a U-shaped association with PTB; and higher cord blood mtDNA-CN was positively associated with PTB. This study provides the first evidence from a large birth cohort simultaneously assessing maternal and fetal mtDNA heteroplasmy and mtDNA-CN in relation to PTB, adding a mitochondrial genetics perspective to PTB research. This study highlights mitochondrial genomic variation as a novel pathway in PTB pathogenesis and suggests the potential utility of mtDNA measures as biomarkers for early risk assessment and as a basis for future mitochondria-targeted interventions.

OBJECTIVE:To investigate whether maternal diabetes in pregnancy was associated with altered neonatal global IgG repertoire and early-life infections in offspring. RESEARCH DESIGN AND METHODS:This study included 2,702 mother-infant pairs enrolled at birth and followed longitudinally at the Boston Medical Center. Maternal diabetes and infant infections were extracted from electronic medical records. Cord blood IgG antibodies against a wide range of microbes were quantified using Phage ImmunoPrecipitation Sequencing. RESULTS:Overall, 327 infants (12.1%) were born to mothers with gestational diabetes mellitus (GDM) and 138 (5.1%) to mothers with pregestational diabetes mellitus (PDM). Of these, 416 infants (15.4%) and 1,425 infants (52.7%) had at least one infection in the neonatal period and the first 6 months of life, respectively. Compared with no diabetes, both maternal GDM (risk ratio [RR] 1.20, 95% CI 1.09-1.32) and PDM (RR 1.28, 95% CI 1.12-1.47) were significantly associated with an elevated risk of infections in infants during the first 6 months. These associations were particularly pronounced among infants born preterm, delivered via cesarean section, or with lower IgG repertoire diversity. Additionally, PDM was associated with a lower newborn's global IgG repertoire diversity, compared with no diabetes, with the effect more marked among infants whose mothers had prepregnancy overweight or obesity. CONCLUSIONS:This study provides strong evidence of an increased infection risk in the infants of mothers with diabetes and a reduced IgG repertoire diversity in those of PDM mothers. Lower IgG diversity exacerbated the diabetes-infection link. These findings suggest that maternal metabolic conditions may impact an infant's passive immunity and susceptibility to infections.

OBJECTIVES:To examine the immediate and long-term effect of the pandemic on clinical encounters in predominantly low-income, racially and ethnically diverse mothers. METHODS:This is a longitudinal study of 3,073 predominantly low-income, racially, and ethnically diverse mothers in the Boston Birth Cohort. We conducted descriptive and random-effects negative binomial regression to examine the impact of the COVID-19 pandemic on medical and mental health care encounters of the study mothers, using comprehensive electronic health record data before and during the pandemic (January 2019-December 2021). We also conducted a qualitative survey in a subsample (N ∼200) to assess pandemic-related stressors. RESULTS:Compared with 2019 (prepandemic), mental health encounter incidence increased by 56% in 2020 (incidence rate ratio [IRR]: 1.56, 95% confidence interval [CI]: 1.29-1.88) and 37% in 2021 (IRR: 1.37, CI: 1.14-1.64). In contrast, primary care and non-mental health subspecialty care decreased in 2020 (IRRs: 0.91 and 0.73, CIs: 0.85-0.97 and 0.67-0.8) and recovered in 2021 (IRRs: 1.24 and 1.48, CIs: 1.17-1.32 and 1.37-1.61), whereas emergency department encounters decreased in both 2020 (IRR: 0.64, CI: 0.57-0.71) and 2021 (IRR: 0.74, CI: 0.67-0.82). Telemedicine was utilized the most for mental health. Consistently, 38.4% of the mothers reported higher levels of stress during the pandemic. CONCLUSIONS:COVID-19 imposed significant mental distress on this sample of racially and ethnically diverse mothers, with an increase in mental health encounters. Telemedicine was a major modality for mental health services. POLICY IMPLICATIONS:The study findings draw attention to the profound adverse impact of the pandemic on mental health in racially and ethnically diverse mothers and highlights the need to develop current and long-term strategies for addressing mental distress in this population and for future preparedness.

Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) may damage newborn mitochondrial function indicated by lower mitochondrial DNA copy number (mtDNAcn), which may help explain the mechanisms underlying adverse health outcomes in offspring. Adequate maternal folate levels may offer protection. We investigated associations between maternal PFAS exposures and newborn mtDNAcn and examined effect modification by maternal folate levels in 572 mother-newborn dyads from the Boston Birth Cohort. We measured eight PFAS in maternal plasma collected 24-72 h postpartum using HPLC-MS/MS and mtDNAcn in cord blood using targeted sequencing. We used multivariable linear regression and Bayesian kernel machine regression models to estimate associations between PFAS and mtDNAcn Z-score, overall and stratified by newborn sex and maternal folate level. We observed that associations varied by PFAS species, including an inverse association with PFOS and nonlinear associations with Me-PFOSA-AcOH, PFDeA, and PFNA. Associations of PFHxS and PFOS with mtDNAcn differed by sex. Notably, we found inverse associations of Me-PFOSA-AcOH, PFOS, and the PFAS mixture only among newborns whose mothers had low folate levels. In conclusion, prenatal exposures to specific PFAS and the PFAS mixture were associated with altered cord blood mtDNAcn, with adequate maternal folate levels potentially mitigating the associations.

BACKGROUND:Early-life microbial exposure to microbes may play a role in asthma development. This study tests the hypothesis that mothers born in low-income countries might have been exposed to diverse microbes-leading to greater diversity and higher levels of transplacental anti-microbial antibodies, thereby conferring protection against asthma in offspring. METHODS:In the prospective Boston Birth Cohort, IgG antibody reactome against microbes (2740 species; 1311 genera) was profiled in cord blood, using Phage ImmunoPrecipitation Sequencing. Multinomial regression models were applied to examine the associations of cord blood IgG reactome with child risk of physician-diagnosed atopy and asthma. Mediation analysis was performed to examine the inter-relationships among maternal nativity, IgG reactome and risk of developing childhood asthma. RESULTS:This report included 943 mother-child dyads enrolled at birth and followed prospectively. Compared to children of US-born mothers, children of foreign-born mothers had a lower prevalence of asthma (17.5% vs. 30.5%) and greater diversity of cord blood IgG antibodies against hundreds of microbes (FDR < 0.05). Cord blood seropositivity to peptides or proteins from 6 microbes was inversely associated with the risk of asthma in children, and children with more seropositivity to these microbes were at a lower risk of developing asthma (p < 0.001). IgG seropositivity to A. actinomycetemcomitans, H. pylori, S. flexneri, and T. parva each mediated 17%-62% of the association between maternal nativity and child risk of asthma. CONCLUSION:In this US prospective birth cohort, maternal transplacental IgG reactivity to four microbes (A. actinomycetemcomitans, H. pylori, S. flexneri and T. parva) was associated with a lower risk of childhood asthma, and partly explains the lower risk of asthma in children of mothers born outside the US.

Introduction and Objective: Metals may increase the risk of GDM, while certain elements may be protective. We examined the associations of a mixture of metals and elements during pregnancy with GDM risk in a predominantly Black and Hispanic cohort. Methods: In the Boston Birth Cohort, we measured Pb, Hg, Cd, Se, and Mn in maternal red blood cells collected postpartum. GDM cases were identified using ICD codes and plasma glucose profiles. Women with pre-existing diabetes were excluded. We used modified Poisson regression to assess individual associations and probit BKMR to assess mixture effects. Results: Among 1,256 women (58% Black, 22% Hispanic; median age 27.9y), Black women had higher Pb and Hg levels than Hispanic or White women (Panel A). A doubling of Hg and Mn was associated with 1.16 (95% CI: 1.03-1.31) and 0.65 (95% CI: 0.50-0.86) times the GDM risk, respectively (Panel B). Se showed a trend toward higher GDM risk. Associations of Hg and Mn with GDM did not vary by race. BKMR showed non-linear associations for Hg and linear ones for Se and Mn with GDM (Panel C) and did not identify exposure interactions. Conclusion: Women with higher Hg or lower Mn levels during pregnancy were more likely to develop GDM. Future research should explore interventions to mitigate the effects of prior Hg exposure or increase pregnancy Mn levels. Z. Li: None. G. Wang: None. X. Hong: None. S.P. Juraschek: None. L.H. Ngo: None. M. Zhang: None. American Diabetes Association (7-24-ICTSWH-10); National Institutes of Health (2R01HD041702, R01HD098232, R01ES031272, R01ES031521, and U01ES034983)

INTRODUCTION:Research on in-utero heavy metal exposure shows inconsistent results on offspring pubertal timing. We aim to contribute to understanding the association between heavy metal exposures and age at peak height velocity (APHV), an indicator of pubertal timing, and to investigate the joint associations of heavy metal concentrations and previously known risk factors. METHODS:We included 956 mother-child dyads from the Boston Birth Cohort. Heavy metal concentrations were measured in maternal red blood cells collected 24-72 h after delivery. Offspring APHV was calculated using mixed-effects growth curve models based on repeated height measurements over time. Firstly, we investigated maternal lead, cadmium and mercury level in association with APHV using multivariate linear regression models. Secondly, we estimated the joint associations of maternal pre-pregnancy overweight/obesity (or race/ethnicity) and heavy metal concentrations with APHV, after adjusting for confounders. Thirdly, we applied a Bayesian kernel machine regression (BKMR) model to investigate the association between the heavy metal mixture and APHV. RESULTS:Overall, prenatal heavy metal exposure was modestly inversely (but not statistically significantly) associated with earlier offspring APHV. Both childhood and maternal pre-pregnancy overweight/obesity were associated with an earlier APHV. Non-Hispanic Black males had an earlier APHV than other race/ethnicity males. Moreover, high lead and cadmium concentrations and maternal pre-pregnancy overweight/obesity were jointly associated with APHV in males only and females only, respectively. The joint exposure of maternal pre-pregnancy overweight/obesity and high lead concentrations were associated with earlier APHV among males, and likewise maternal pre-pregnancy overweight/obesity and high cadmium concentrations with earlier APHV among females. The joint associations of non-Hispanic Black race/ethnicity and high concentrations of lead and mercury with APHV were observed in males. CONCLUSIONS:Our findings suggest that maternal pre-pregnancy overweight/obesity prevention and environmental toxic chemicals control may help attenuate the secular trend of early puberty, particularly among non-Hispanic Black individuals.

We investigated the associations of pregnancy levels of heavy metals and trace elements with the risk of gestational diabetes mellitus (GDM). Participating pregnant women were from the Boston Birth Cohort. We measured levels of mercury, lead, cadmium, selenium, and manganese in maternal red blood cells collected after delivery. We verified the GDM diagnosis using ICD codes, medication history, and plasma glucose profile abstracted from medical records. We used modified Poisson regression and Bayesian kernel machine regression models to examine associations of metals and elements, individually and as a mixture, with GDM. We stratified the analyses by race and ethnicity. Among 1256 pregnant women, 58% were non-Hispanic Black and 22% were Hispanic. Overall, each doubling of mercury and manganese levels was associated with 1.14 (95% CI: 1.01-1.28) and 0.65 (95% CI: 0.50-0.84) times the risk of GDM, respectively. In the race- and ethnicity-stratified analyses, the mercury-GDM association was stronger among Black women, and higher selenium levels were associated with higher GDM risk only among Hispanic women (Pinteraction = 0.01). In conclusion, women with higher mercury or lower manganese levels during pregnancy were more likely to develop GDM. An increased GDM risk associated with higher selenium levels was observed only in Hispanic women.

In-utero and the first few years of life represent critical windows for immune development, and early life exposures to microbes and environmental pollutants may have a profound impact on future risk of allergic diseases. However, few studies have examined the interplay among early life exposures, immune responses, and multi-omics on allergic outcomes across the critical developmental windows. Funded by the National Institute of Health, we launched a prospective study in the Boston Birth Cohort (BBC) to investigate the impact of early-life exposure to environmental pollutants and immune response to a broad array of microbes on the development and prognosis of allergic diseases from birth up to age 18 years and their underlying molecular pathways (referred as "The BBC IDeaL study"). The objective of this paper is to describe the study rationale, hypotheses, and study design of the BBC IDeaL study. This study included a total of 990 mother-child dyads, with almost equal number of boys and girls. About 58% mothers self-identified as Black, 6% as White, 22% as Hispanic and 14% as others. These children were followed from birth onwards, with an average of 12 ± 5 years of follow-up. The incident rate for food allergy and asthma was 8% and 21%, respectively. The key strengths of this study include its prospective birth cohort design, large sample size, diverse race/ethnicity, comprehensive and high-quality exposure assessment, standardized clinical outcome ascertainment, cutting-edge immune and multi-omics assays. We anticipate that successful completion of the BBC IDeaL study will help identify important early life risk and protective factors, along with novel biomarkers for prediction or therapeutic targets. Ultimately, the expected findings may contribute to identification of high-risk newborns and can inform effective interventions during the earliest developmental windows when they may have the greatest lifelong benefit.

BACKGROUND:Previous studies suggest that per- and polyfluoroalkyl substances (PFAS) may act as immune suppressants. However, research about the impact of PFAS exposure on antibody responses to the measles, mumps, rubella (MMR) vaccine is limited and inconsistent. METHODS:This report includes 748 mother-child pairs from the Boston Birth Cohort, with 8 PFAS compounds measured in maternal plasma shortly after delivery. IgG reactivities to measles and rubella were profiled in cord blood and venous blood plasma during early childhood, using Phage ImmunoPrecipitation Sequencing. Linear regression models were applied to assess the relationships between log2-transformed PFAS and IgG reactivities as measured by Viral Aggregate Reactivity score (VARscore, with inverse normal transformation) for measles and rubella. Quantile g-computation was applied to evaluate the PFAS mixture - VARscore associations. RESULTS:The detection rate for 8 PFAS compounds ranged from 90 % to 100 % in maternal plasma. Maternal PFAS burden score (P = 0.01), but not individual PFAS compounds, was associated with lower VARscore for measles in cord blood. In 348 children after receiving the MMR vaccine, three maternal PFAS compounds (Me-PFOSA-AcOH, PFHpS and PFHxS) were significantly associated with lower measles VARscore (P < 0.05). Me-PFOSA-AcOH and PFHxS were significantly associated with higher risk of having low reactivity to measles defined as VARscore < 25th percentile. PFAS mixture analysis revealed a significant inverse association between quantile of the PFAS mixture and measles VARscore (P = 0.025) in children after vaccination, with PFHxS as an important contributor to this association. These inverse associations were more pronounced in Black children (compared to non-Black children) and in preterm children (compared to term children). In comparison, no associations were found for rubella VARscore. CONCLUSIONS:This prospective birth cohort study provides suggestive evidence that maternal PFAS exposure is associated with a reduced immune response to the measles vaccine, especially, among Black or preterm children.

Importance:Preterm children face a higher risk of cardiovascular conditions, including hypertension. However, studies have not isolated the associations of prematurity with cardiovascular conditions from the associations of subsequent complications with cardiovascular conditions, especially among those admitted to a neonatal intensive care unit (NICU). Objective:To investigate prospective associations of prematurity and NICU complications with childhood hypertension while accounting for prenatal and perinatal factors. Design, Setting, and Participants:This cohort study analyzed longitudinal data from the Boston Birth Cohort on 2459 infants (695 preterm, 468 with NICU admission) born between January 1, 1999, and December 31, 2014. Statistical analysis was performed from January 1, 1999, to December 31, 2020. Main Outcomes and Measures:Children were categorized into 5 subgroups based on preterm birth status, NICU admission, and major complications (sepsis, chronic lung disease, necrotizing enterocolitis, and intraventricular hemorrhage). The primary end point was hypertension (episodic and persistent) per American Academy of Pediatrics guidelines, with elevated blood pressure (BP) and BP percentiles as secondary end points. Modified Poisson and proportional hazards regression were used to determine crude and adjusted relative risks (RRs) and hazard ratios (HRs). Secondary analyses used linear generalized estimating equations to assess repeated BP measurements over time, standardized to population-based BP percentiles. Results:Of the 2459 infants (695 preterm: mean [SD] gestational age, 33.2 [3.5] weeks; 358 boys [51.5%]; and 1764 full term: mean [SD] gestational age, 39.4 [1.3] weeks; 879 boys [49.7%]) in this study, 468 (19.0%) were admitted to the NICU. The incidence of persistent hypertension was higher among children born preterm compared with those born at full term (25.2% [175 of 695] vs 15.8% [278 of 1764]). Preterm infants and infants admitted to the NICU had a greater risk of developing persistent hypertension compared with full term-born children without NICU admission or neonatal complications, independent of pertinent maternal and infant characteristics. Preterm infants with an NICU stay, both with (adjusted RR, 1.87 [95% CI, 1.19-2.94]) and without (adjusted RR, 1.62 [95% CI, 1.27-2.07]) a neonatal complication, had the greatest risk for persistent hypertension. Cox proportional hazards regression analysis identified preterm infants with an NICU stay, particularly those with a complication, as having the highest risk of developing persistent hypertension (adjusted HR, 2.37 [95% CI, 1.44-3.89]). On average, infants born prematurely without an NICU admission or complication (β, 2.74 percentile points [95% CI, 0.38-5.10 percentile points]) and those born prematurely with an NICU admission but no complications (β, 4.06 percentile points [95% CI, 2.11-6.02 percentile points]) had higher systolic BP percentiles and those born prematurely with an NICU admission but no complications had higher diastolic BP percentiles (β, 4.01 percentile points [95% CI, 2.52-5.49 percentile points]) during follow-up up to 18 years of age. Conclusions and Relevance:This prospective cohort study found incrementally stronger associations for NICU admission, prematurity, and prematurity-related complications with the risk of developing persistent hypertension in childhood. These findings support the need for hypertension screening, coordinated primary and specialist care, and cardiovascular health promotion among children born preterm.

Background Prenatal per‐ and polyfluoroalkyl substance (PFAS) exposures may influence offspring blood pressure (BP), but long‐term studies in diverse populations remain limited. Methods Participants were from the Boston Birth Cohort. We measured PFAS in maternal plasma collected 24 to 72 hours after delivery and extracted children's BP from medical records. We calculated age‐, sex‐, and height‐specific BP percentiles and defined elevated BP as systolic/diastolic BP ≥90th percentile (ages 3 to <13 years) or ≥120/80 mm Hg (ages 13 to <18 years). We used adjusted mixed‐effects linear and modified Poisson models to examine associations of PFAS with BP percentiles and elevated BP. We used linear spline mixed‐effects models to predict BP trajectories at ages 3 to 18 years by PFAS levels. Results We included 13 404 BP measurements from 1094 children (median follow‐up: 12 years [interquartile range, 9–15 years]; 61% Black and 22% Hispanic). Overall, higher perfluorodecanoic acid (PFDeA), perfluorononanoic acid (PFNA), and perfluoroundecanoic acid (PFUnA) were associated with higher systolic BP percentile. The associations differed by child life stage, sex, race and ethnicity. For example, associations of PFDeA with systolic BP percentile were stronger in older (β3–5y=0.40; β6–12y=1.06; β13–18y=2.55), male (βmale=1.51; βfemale=0.52), and Black (βBlack=1.75; βHispanic=0.45) children. In male children, each doubling of perfluoroheptanesulfonic acid (PFHpS) was associated with a 9% higher risk of elevated BP at ages 6 to 12 years and a 17% higher risk at 13 to 18 years, with no increased risk at 3 to 5 years. PFHpS was associated with a dose‐dependent divergence in BP trajectories beginning at age 13 years. Conclusions Prenatal exposures to certain PFAS were associated with offspring BP, with stronger associations in adolescents, male children, and Black children. Prenatal PFAS exposures may have intergenerational, long‐term, and latent hypertensive effects.