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Abstract Background Gestational age (GEAA) estimated by newborn DNA methylation (GAmAge) is associated with maternal prenatal exposures and immediate birth outcomes. However, the association of GAmAge with long-term overweight or obesity (OWO) trajectories is yet to be determined. Methods GAmAge was calculated for 831 children from a US predominantly urban, low-income, multi-ethnic birth cohort based on cord blood DNA methylation profile using Illumina EPIC array. Repeated anthropometric measurements aligned with pediatric primary care schedule allowed us to calculate body-mass-index percentiles (BMIPCT) at specific age and to define long-term weight trajectories from birth to 18 years. Results GAmAge was associated with BMIPCT trajectories, defined by 4 groups: stable (consistent OWO: “early OWO”; constant normal weight: “NW”) or non-stable (OWO by year 1 of follow-up: “late OWO”; OWO by year 6 of follow-up: “NW to very late OWO”). GAmAge differentiated between the group with consistently normal BMIPCT pattern and the non-stable groups with late and very late OWO development. Such differentiation was observed in the age periods of birth to 1year, 3years, 6years, 10years, and 14years (p

Abstract Background Gestational DNA methylation age (GAmAge) has been developed and validated in European ancestry samples. Its applicability to other ethnicities and associations with fetal stress and newborn phenotypes such as inflammation markers are still to be determined. This study aims to examine the applicability of GAmAge developed from cord blood samples of European decedents to a racially diverse birth cohort, and associations with newborn phenotypes. Methods GAmAge based on 176 CpGs (Haftorn GAmAge) was calculated for 940 children from a US predominantly urban, low-income, multiethnic birth cohort. Cord blood DNA methylation was profiled by Illumina EPIC array. Newborn phenotypes included anthropometric measurements and, for a subset of newborns (N = 194), twenty-seven cord blood inflammatory markers (sandwich immunoassays). Results GAmAge had a stronger correlation with GEAA in boys (r = 0.89, 95% confidence interval (CI) [0.87,0.91]) compared with girls (r = 0.83, 95% CI [0.80,0.86]), and was stronger among extremely preterm to very preterm babies (r = 0.91, 95% CI [0.81,0.96]), compared with moderate (r = 0.48, 95% CI [0.34,0.60]) and term babies (r = 0.58, 95% CI [0.53,0.63]). Among White newborns (N = 51), the correlation between GAmAge vs. GEAA was slightly stronger (r = 0.89, 95% CI [0.82,0.94]) compared with Black/African American newborns (N = 668; r = 0.87, 95% CI [0.85,0.89]) or Hispanic (N = 221; r = 0.79, 95% CI [0.74,0.84]). Adjusting for GEAA and sex, GAmAge was associated with anthropometric measurements, cord blood brain-derived neurotrophic factor (BDNF), and monocyte chemoattractant protein-1 (MCP-1) (p

Abstract Background Biologic strain such as oxidative stress has been associated with short leukocyte telomere length (LTL), as well as with preeclampsia and spontaneous preterm birth, yet little is known about their relationships with each other. We investigated associations of postpartum maternal LTL with preeclampsia and spontaneous preterm birth. Methods This pilot nested case control study included independent cohorts of pregnant people with singleton gestations from two academic institutions: Cohort 1 (hereafter referred to as Suburban) were enrolled prior to 20 weeks’ gestation between 2012 and 2018; and Cohort 2 (hereafter referred to as Urban) were enrolled at delivery between 2000 and 2012. Spontaneous preterm birth or preeclampsia were the selected pregnancy complications and served as cases. Cases were compared with controls from each study cohort of uncomplicated term births. Blood was collected between postpartum day 1 and up to 6 months postpartum and samples were frozen, then simultaneously thawed for analysis. Postpartum LTL was the primary outcome, measured using quantitative polymerase chain reaction (PCR) and compared using linear multivariable regression models adjusting for maternal age. Secondary analyses were done stratified by mode of delivery and self-reported level of stress during pregnancy. Results 156 people were included; 66 from the Suburban Cohort and 90 from the Urban Cohort. The Suburban Cohort was predominantly White, Hispanic, higher income and the Urban Cohort was predominantly Black, Haitian, and lower income. We found a trend towards shorter LTLs among people with preeclampsia in the Urban Cohort (6517 versus 6913 bp, p = 0.07), but not in the Suburban Cohort. There were no significant differences in LTLs among people with spontaneous preterm birth compared to term controls in the Suburban Cohort (6044 versus 6144 bp, p = 0.64) or in the Urban Cohort (6717 versus 6913, p = 0.37). No differences were noted by mode of delivery. When stratifying by stress levels in the Urban Cohort, preeclampsia was associated with shorter postpartum LTLs in people with moderate stress levels (p = 0.02). Conclusion Our exploratory results compare postpartum maternal LTLs between cases with preeclampsia or spontaneous preterm birth and controls in two distinct cohorts. These pilot data contribute to emerging literature on LTLs in pregnancy.

Lower respiratory tract infections (LRTIs) remain the leading cause of infant morbidity and mortality worldwide and affect long-term respiratory health. Identifying immunological determinants of LRTI susceptibility may help stratify disease risk and identify therapies. This study aimed to identify neonatal immunological factors predicting LRTI risk in infancy. Cord blood plasma from 191 neonates from the Boston Birth Cohort was analyzed for 28 soluble immune factors. LRTI was defined as bronchiolitis, bronchitis, or pneumonia during the first year of life. Welch’s t-test demonstrated significantly higher log10 transformed concentrations of IL-17 and IFNγ in the LRTI group compared to neonates without LRTI in the first year of life (p < 0.05). Risk associations were determined using multivariate survival models. There were 29 infants with LRTIs. High cord blood levels of IFNγ (aHR = 2.35, 95% CI 1.07–5.17), TNF-β (aHR = 2.86, 95% CI 1.27–6.47), MIP-1α (aHR = 2.82, 95% CI 1.22–6.51), and MIP-1β (aHR = 2.34, 95% CI 1.05–5.20) were associated with a higher risk of LRTIs. RANTES was associated with a lower risk (aHR = 0.43, 95% CI 0.19–0.97). Soluble immune factors linked to antiviral immunity (IFNγ) and cytokines mediating inflammatory responses (TNF-β), and cell homing (MIP-1α/b), at birth were associated with an increased risk of LRTIs during infancy.

Background: The coronavirus 2019 (COVID-19) pandemic fundamentally changed how populations interface with the healthcare system. Despite historical spikes in US mortality during the pandemic, emergency department (ED) visits were paradoxically low. This is a concerning phenomenon that raises a red flag regarding access to care, especially among vulnerable populations. In this study we sought to understand how ED utilization evolved during the COVID-19 pandemic among traditionally understudied, low-income, racially diverse US- and foreign-born mothers. Methods: This is a secondary analysis of a pre-existing dataset of 3,073 participants enrolled in the Boston Birth Cohort at birth and followed prospectively. We obtained ED visit diagnoses from 2019 and 2020 via electronic health records, categorized according to the International Classification of Diseases, 10th Revision, and compared them using graph plots, chi-square, and negative binomial regression. Results: The number of ED visits decreased by 29.1% (P US born) and mental health- (US-born only) related visits. Our findings demonstrate that EDs remain a critical access point for care for minority populations and have implications for preparedness, resources, and services of EDs in urban settings to better address the needs of communities. However, alternative avenues for healthcare services for these populations, particularly during health crises, warrant further investigation.

Abstract Background Antenatal corticosteroids are considered the standard of care for pregnant women at risk for preterm birth, but studies examining their potential risks are scarce. We aimed to estimate the associations of antenatal corticosteroids with three severe adverse events: sepsis, heart failure, and gastrointestinal bleeding, in pregnant women. Methods Of 2,157,321 pregnant women, 52,119 at 24 weeks 0/7 days to 36 weeks 6/7 days of gestation were included in this self-controlled case series study during the study period of 2009–2018. We estimated incidence rates of three severe adverse events: sepsis, heart failure, and gastrointestinal bleeding. Conditional Poisson regression was used to calculate incidence rate ratios (IRRs) for comparing incidence rates of the adverse events in each post-treatment period compared to those during the baseline period among pregnant women exposed to a single course of antenatal corticosteroid treatment. Results Among 52,119 eligible participants who received antenatal corticosteroid treatment, the estimated incidence rates per 1000 person-years were 0.76 (95% confidence interval (CI): 0.69–0.83) for sepsis, 0.31 (95% CI: 0.27–0.36) for heart failure, and 11.57 (95% CI: 11.27–11.87) for gastrointestinal bleeding. The IRRs at 5 ~ 60 days after administration of antenatal corticosteroids were 5.91 (95% CI: 3.10–11.30) for sepsis and 4.45 (95% CI: 2.63–7.55) for heart failure, and 1.26 (95% CI: 1.02–1.55) for gastrointestinal bleeding; and the IRRs for days 61 ~ 180 were 2.00 (95% CI: 1.01–3.96) for sepsis, 3.65 (95% CI: 2.14–6.22) for heart failure, and 1.81 (95% CI: 1.56–2.10) for gastrointestinal bleeding. Conclusions This nationwide population-based study suggests that a single course of antenatal corticosteroids is significantly associated with a 1.3- to 5.9-fold increased risk of sepsis, heart failure, and gastrointestinal bleeding in pregnant women. Maternal health considerations, including recommendations for adverse event monitoring, should be included in future guidelines for antenatal corticosteroid treatment.

Abstract Background Maternal pre-pregnancy obesity is an established risk factor for childhood obesity. Investigating epigenetic alterations induced by maternal obesity during fetal development could gain mechanistic insight into the developmental origins of childhood obesity. While obesity disproportionately affects underrepresented racial and ethnic mothers and children in the USA, few studies investigated the role of prenatal epigenetic programming in intergenerational obesity of these high-risk populations. Methods This study included 903 mother–child pairs from the Boston Birth Cohort, a predominantly urban, low-income minority birth cohort. Mother-infant dyads were enrolled at birth and the children were followed prospectively to age 18 years. Infinium Methylation EPIC BeadChip was used to measure epigenome-wide methylation level of cord blood. We performed an epigenome-wide association study of maternal pre-pregnancy body mass index (BMI) and cord blood DNA methylation (DNAm). To quantify the degree to which cord blood DNAm mediates the maternal BMI-childhood obesity, we further investigated whether maternal BMI-associated DNAm sites impact birthweight or childhood overweight or obesity (OWO) from age 1 to age 18 and performed corresponding mediation analyses. Results The study sample contained 52.8% maternal pre-pregnancy OWO and 63.2% offspring OWO at age 1–18 years. Maternal BMI was associated with cord blood DNAm at 8 CpG sites (genome-wide false discovery rate [FDR]

Abstract Background Acetaminophen is a commonly used medication by pregnant women and is known to cross the placenta. However, little is known about the biological mechanisms that regulate acetaminophen in the developing offspring. Cytochrome 2E1 (CYP2E1) is the primary enzyme responsible for the conversion of acetaminophen to its toxic metabolite. Ex vivo studies have shown that the CYP2E1 gene expression in human fetal liver and placenta is largely controlled by DNA methylation (DNAm) at CpG sites located in the gene body of CYP2E1 at the 5’ end. To date, no population studies have examined the association between acetaminophen metabolite and fetal DNAm of CYP2E1 at birth. Methods We utilized data from the Boston Birth Cohort (BBC) which represents an urban, low-income, racially and ethnically diverse population in Boston, Massachusetts. Acetaminophen metabolites were measured in the cord plasma of newborns enrolled in BBC between 2003 and 2013 using liquid chromatography-tandem mass spectrometry. DNAm at 28 CpG sites of CYP2E1 was measured by Illumina Infinium MethylationEPIC BeadChip. We used linear regression to identify differentially methylated CpG sites and the “DiffVar” method to identify differences in methylation variation associated with the detection of acetaminophen, adjusting for cell heterogeneity and batch effects. The false discovery rate (FDR) was calculated to account for multiple comparisons. Results Among the 570 newborns included in this study, 96 (17%) had detectable acetaminophen in cord plasma. We identified 7 differentially methylated CpGs (FDR

Background Lower respiratory tract infections (LRTIs) are the leading cause of infant morbidity and mortality worldwide, and altered metabolite production is recognised as a critical factor in LRTI pathogenesis. Methods This study aimed to identify prenatal metabolic changes associated with LRTI risk in infancy, using liquid chromatography-mass spectrometry unbiased metabolomics analysis on cord blood from 810 full-term newborns. Results We identified 22 compounds linked to LRTIs in infancy, enriched for purine degradation pathway (PDP) metabolites. High cord blood PDP metabolites, including xanthine, hypoxanthine, xanthosine and inosine, were linked to reduced LRTI risk during infancy. Notably, a low xanthine to uric acid ratio at birth predicted a four-fold increased LRTI risk. Conclusion This study is the first to reveal that high cord blood PDP metabolites identify newborns at lower LRTI risk, stratifying disease risk at birth. Moreover, our results prompt further study on PDP enzymes as pharmacological targets to decrease LRTI morbidity and mortality for at-risk newborns.

Abstract Background In utero exposure to diabetes has been shown to contribute to preterm birth, though the underlying biological mechanisms are yet to be fully elucidated. Fetal epigenetic variations established in utero may be a possible pathway. This study aimed to investigate whether in utero exposure to diabetes was associated with a change in newborn DNA methylation, and whether the identified CpG sites mediate the association between diabetes and preterm birth in a racially diverse birth cohort population. Methods This study included 954 mother–newborn pairs. Methylation levels in the cord blood were determined using the Illumina Infinium MethylationEPIC BeadChip 850 K array platform. In utero exposure to diabetes was defined by the presence of maternal pregestational or gestational diabetes. Preterm birth was defined as gestational age at birth less than 37 weeks. Linear regression analysis was employed to identify differentially methylated CpG sites. Differentially methylated regions were identified using the DMRcate Package. Results 126 (13%) newborns were born to mothers with diabetes in pregnancy and 173 (18%) newborns were born preterm, while 41 newborns were born both preterm and to mothers with diabetes in pregnancy. Genomic-wide CpG analysis found that eighteen CpG sites in cord blood were differentially methylated by maternal diabetes status at an FDR threshold of 5%. These significant CpG sites were mapped to 12 known genes, one of which was annotated to gene Major Histocompatibility Complex, Class II, DM Beta (HLA-DMB). Consistently, one of the two identified significant methylated regions overlapped with HLA-DMB. The identified differentially methylated CpG sites mediated the association between diabetes in pregnancy and preterm birth by 61%. Conclusions In this US birth cohort, we found that maternal diabetes was associated with altered fetal DNA methylation patterns, which substantially explained the link between diabetes and preterm birth.

Abstract Background The mother–child inheritance of DNA methylation (DNAm) variations could contribute to the inheritance of disease susceptibility across generations. However, no study has investigated patterns of mother–child associations in DNAm at the genome-wide scale. It remains unknown whether there are sex differences in mother–child DNAm associations. Results Using genome-wide DNAm profiling data (721,331 DNAm sites, including 704,552 on autosomes and 16,779 on the X chromosome) of 396 mother–newborn pairs (54.5% male) from the Boston Birth Cohort, we found significant sex differences in mother–newborn correlations in genome-wide DNAm patterns (Spearman’s rho = 0.91–0.98; p = 4.0 × 10–8), with female newborns having stronger correlations. Sex differences in correlations were attenuated but remained significant after excluding X-chromosomal DNAm sites (Spearman’s rho = 0.91–0.98; p = 0.035). Moreover, 89,267 DNAm sites (12.4% of all analyzed, including 88,051 [12.5% of analyzed] autosomal and 1,216 [7.2% of analyzed] X-chromosomal sites) showed significant mother–newborn associations in methylation levels, and the top autosomal DNAm sites had high heritability than the genome-wide background (e.g., the top 100 autosomal DNAm sites had a medium h 2 of 0.92). Additionally, significant interactions between newborn sex and methylation levels were observed for 11 X-chromosomal and 4 autosomal DNAm sites that were mapped to genes that have been associated with sex-specific disease/traits or early development (e.g., EFHC2, NXY, ADCYAP1R1, and BMP4). Finally, 18,769 DNAm sites (14,482 [77.2%] on the X chromosome) showed mother–newborn differences in methylation levels that were significantly associated with newborn sex, and the top autosomal DNAm sites had relatively small heritability (e.g., the top 100 autosomal DNAm sites had a medium h 2 of 0.23). These DNAm sites were mapped to 2,532 autosomal genes and 978 X-chromosomal genes with significant enrichment in pathways involved in neurodegenerative and psychological diseases, development, neurophysiological process, immune response, and sex-specific cancers. Replication analysis in the Isle of Wight birth cohort yielded consistent results. Conclusion In two independent birth cohorts, we demonstrated strong mother–newborn correlations in whole blood DNAm on both autosomes and ChrX, and such correlations vary substantially by sex. Future studies are needed to examine to what extent our findings contribute to developmental origins of pediatric and adult diseases with well-observed sex differences.

Background Pregnancy complications are risk factors for cardiovascular disease (CVD). Little is known about the role of renal biomarkers measured shortly after delivery, individually or in combination with pregnancy complications, in predicting subsequent severe maternal CVD. Methods and Results This study included 566 mothers of diverse races and ethnicities from the Boston Birth cohort, enrolled at delivery and followed prospectively. Plasma creatinine and CysC (cystatin C) were measured 1 to 3 days after delivery. CVD during follow‐up was defined by physician diagnoses in electronic medical records. Associations of renal biomarkers and pregnancy complications with time‐to‐CVD events were assessed using Cox proportional hazards models. During an average of 10.3±3.2 years of follow‐up, 30 mothers developed 1 or more CVDs. Only a modest association was observed between creatinine and risk of CVD. In comparison, we found that per 0.1 mg/L increase of CysC was associated with a hazard ratio (HR) of 1.2 (95% CI, 1.1–1.4) for CVD after adjusting for covariates. Compared with those without preeclampsia and with normal CysC level (≤75th percentile), mothers with preeclampsia and elevated CysC (>75th percentile) had the highest risk of CVD (HR, 4.6 [95% CI, 1.7–17.7]), whereas mothers with preeclampsia only or with elevated CysC only did not have significantly increased CVD risk. Similar synergistic effects for CVD were observed between CysC and preterm delivery. Conclusions In this sample of US, traditionally underrepresented multiracial and multiethnic high‐risk mothers, elevated maternal plasma CysC, independently and jointly with pregnancy complications, increased risk of CVD later in life. These findings warrant further investigation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03228875.

A comprehensive genetic analysis of the relationship between childhood obesity and childhood asthma identifies shared mechanisms and potential mediators linking the two pediatric disorders.

Most genetic studies of autism spectrum disorder (ASD) have focused on the nuclear genome. Here, the authors show that variations in mitochondrial DNA, detectable at birth, are also associated with risk of ASD.

Abstract Alterations in tryptophan and serotonin have been implicated in various mental disorders; but studies are limited on child neurodevelopmental disabilities such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). This prospective cohort study examined the associations between levels of tryptophan and select metabolites (5-methoxytryptophol (5-MTX), 5-hydroxytryptophan (5-HTP), serotonin, N-acetyltrytophan) in cord plasma (collected at birth) and physician-diagnosed ASD, ADHD and other developmental disabilities (DD) in childhood. The study sample (n = 996) derived from the Boston Birth Cohort, which included 326 neurotypical children, 87 ASD, 269 ADHD, and 314 other DD children (mutually exclusive). These participants were enrolled at birth and followed-up prospectively (from October 1, 1998 to June 30, 2018) at the Boston Medical Center. Higher levels of cord 5-MTX was associated with a lower risk of ASD (aOR: 0.56, 95% CI: 0.41, 0.77) and ADHD (aOR: 0.79, 95% CI: 0.65, 0.96) per Z-score increase, after adjusting for potential confounders. Similarly, children with cord 5-MTX ≥ 25th percentile (vs.

Summary: Background: DNA methylation (DNAm) in cord blood has been associated with various prenatal factors and birth outcomes. This study sought to fill an important knowledge gap: the link of cord DNAm with child postnatal growth trajectories from birth to age 18 years (y). Methods: Using data from a US predominantly urban, low-income, multi-ethnic birth cohort (N = 831), we first applied non-parametric methods to identify body-mass-index percentile (BMIPCT) trajectories from birth to age 18 y (the outcome); then, conducted epigenome-wide association study (EWAS) of the outcome, interrogating over 700,000 CpG sites profiled by the Illumina Infinium MethylationEPIC BeadChip. Multivariate linear regression models and likelihood ratio tests (LRT) were applied to examine the DNAm-outcome association in the overall sample and sex strata. Findings: We identified four distinct patterns of BMIPCT trajectories: normal weight (NW), Early overweight or obesity (OWO), Late OWO, and normal to very late OWO. DNAm at CpG18582997 annotated to TPGS1, CpG15241084 of TLR7, and cg24350936 of RAB31 were associated with BMIPCT at birth-to-3 y, 10 y, and 14 y, respectively (LRT FDR < 0.05 for all). Interpretation: In this prospective birth cohort study, we identified 4 distinct and robust patterns of growth trajectories from birth to 18 y, which were associated with variations in cord blood DNAm at genes implicated in inflammation induction pathways. These findings, if further replicated, raise the possibility that these DNAm markers along with early assessment of BMIPCT trajectories may help identify young children at high-risk for obesity later in life. Funding: Detailed in the Acknowledgements section.

Abstract Background Given the trend of increasing maternal age and associated adverse reproductive outcomes in the US, this study aimed to assess whether this association is due to an independent aging or confounded by sociodemographic, biomedical, or behavioral determinants in a predominantly Black US population. Methods Data was from 8509 women enrolled in the Boston Birth Cohort. Adverse reproductive outcomes included spontaneous preterm delivery, cesarean delivery, and low birth weight. Covariates included sociodemographic (parity, race/ethnicity, education, marital status, income, receipt of public assistance, nativity); biomedical (obesity, hypertensive disorders, diabetes mellitus); and behavioral (consistent intake of multivitamin supplements, support from father of baby, support from family, major stress in pregnancy, cigarette smoking, alcohol intake). Analysis included Lowess and marginal probability plots, crude and adjusted sequential logistic regression models to examine age-outcome associations and to what degree the association can be explained by the above covariables. Result Overall, the study sample had high levels of spontaneous preterm birth (18%), cesarean delivery (33%) and low birth weight (26%). Unadjusted models showed no significant difference odds of spontaneous preterm birth by maternal age but higher odds of cesarean section (aOR: 1.77, 95% CI: 1.60, 1.95) and low birth weight (aOR: 1.15, 95% CI: 1.04, 1.28) among women 30 years or older. Adjustment for sociodemographic factors, biomedical conditions and behavioral factors revealed higher odds of spontaneous preterm birth: (aOR: 1.30, 95% CI: 1.14, 1.49), cesarean section deliveries (aOR: 1.68, 95% CI: 1.51, 1.87) and low birth weight (aOR: 1.36, 95% CI: 1.21, 1.53). Across all ages, optimal BMI status and consistent multivitamin supplement intake were protective of spontaneous preterm birth and low birth weight. Conclusion In this high-risk minority population, we demonstrated that the association between increasing maternal age and adverse pregnancy outcomes was due to an independent aging effect and the presence of confounding by sociodemographic, biomedical, and behavioral factors. Some modifiable risk factors to counteract aging effect, include optimizing BMI and consistent intake of multivitamin supplement. A fundamental change in how care is provided to women, particularly low income Black women, is needed with emphasis on the protective role of optimal nutritional status. Trial registration ClinicalTrials.gov Identifier: NCT03228875

Abstract The prevalence of maternal obesity has increased dramatically with adverse consequences on infant health. Prior studies have reported associations between maternal obesity and childhood wheeze, asthma as well as lower respiratory tract infections (LRTI). However, studies examining the association of obesity with early-life LRTIs in low-income urban minority populations are still lacking. This is a critical gap because both obesity and infant respiratory morbidity are more prevalent and severe in these communities. We examined mother‐child dyads from the Boston Birth Cohort (BBC) to define the longitudinal association of maternal pre‐pregnancy BMI and LRTI in infancy, defined as the presence of bronchiolitis, bronchitis, or pneumonia during the first year of life (

Background Preeclampsia is a major cause of maternal and fetal morbidity and mortality. Given its large public health burden, there is a need to identify modifiable factors that can be targeted for preeclampsia prevention. In this study, we examined whether a Mediterranean‐style diet is protective for preeclampsia in a large cohort of racially and ethnically diverse, urban, low‐income women. Methods and Results We used data from the Boston Birth Cohort. Maternal sociodemographic and dietary data were obtained via interview and food frequency questionnaire within 24 to 72 hours postpartum, respectively. Additional clinical information, including physician diagnoses of preexisting conditions and preeclampsia, were extracted from medical records. We derived a Mediterranean‐style diet score from the food frequency questionnaire and performed logistic regression to examine the association of the Mediterranean‐style diet score with preeclampsia. Of 8507 women in the sample, 848 developed preeclampsia. 47% were Black, 28% were Hispanic, and the remaining were White/Other. After multivariable adjustment, greatest adherence with MSD was associated with lower preeclampsia odds (adjusted odds ratio comparing tertile 3 to tertile 1, 0.78; 95% CI, 0.64–0.96). A subgroup analysis of Black women demonstrated a similar benefit with an adjusted odds ratio comparing tertile 3 to tertile 1 of 0.74 (95% CI, 0.76–0.96). Conclusions Self‐report of higher adherence to a Mediterranean‐style diet is associated with lower preeclampsia odds, and benefit of this diet is present among Black women as well.

Abstract Background Preeclampsia and preterm delivery (PTD) are believed to affect women’s long-term health including cardiovascular disease (CVD), but the biological underpinnings are largely unknown. We aimed to test whether maternal postpartum metabolomic profiles, especially CVD-related metabolites, varied according to PTD subtypes with and without preeclampsia, in a US urban, low-income multi-ethnic population. Methods This study, from the Boston Birth Cohort, included 980 women with term delivery, 79 with medically indicated PTD (mPTD) and preeclampsia, 52 with mPTD only, and 219 with spontaneous PTD (sPTD). Metabolomic profiling in postpartum plasma was conducted by liquid chromatography-mass spectrometry. Linear regression models were used to assess the associations of each metabolite with mPTD with preeclampsia, mPTD only, and sPTD, respectively, adjusting for pertinent covariates. Weighted gene coexpression network analysis was applied to investigate interconnected metabolites associated with the PTD/preeclampsia subgroups. Bonferroni correction was applied to account for multiple testing. Results A total of 380 known metabolites were analyzed. Compared to term controls, women with mPTD and preeclampsia showed a significant increase in 36 metabolites, mainly representing acylcarnitines and multiple classes of lipids (diacylglycerols, triacylglycerols, phosphocholines, and lysophosphocholines), as well as a decrease in 11 metabolites including nucleotides, steroids, and cholesteryl esters (CEs) (P

Background: Exposure to metals lead (Pb), mercury (Hg), and cadmium (Cd) and trace elements selenium (Se) and manganese (Mn) has been linked to the developmental origins of cardiometabolic diseases, but the mechanisms are not well-understood. Objective: Conduct a metabolome-wide association study to understand how in utero exposure to Pb, Hg, Cd, Se, and Mn affects the metabolic programming of fetuses. Methods: We used data from the Boston Birth Cohort, which enrolled mother-child pairs from Boston, MA. We measured metals and trace elements in maternal red blood cells (RBCs) collected 24–72 h after delivery, and metabolites in cord blood collected at birth. We used multivariable linear regression to examine associations of metals and trace elements with metabolites and Bonferroni correction to account for multiple comparisons. We assessed non-linear associations of metals and trace elements with metabolites using restricted cubic spline plots. Results: This analysis included 670 mother-child pairs (57% non-Hispanic Black and 24% Hispanic). After Bonferroni correction, there were 25 cord metabolites associated with at least one of the metals or trace elements. Pb was negatively associated with the xenobiotic piperine, Cd was positively associated with xenobiotics cotinine and hydroxycotinine, and Hg was associated with 8 lipid metabolites (in both directions). Se and Mn shared associations with 6 metabolites (in both directions), which mostly included nucleotides and amino acids; Se was additionally associated with 7 metabolites (mostly amino acids, nucleotides, and carnitines) and Mn was additionally associated with C36:4 hydroxy phosphatidylcholine. Restricted cubic spline plots showed that most associations were linear. Discussion: Maternal RBC metal and trace element concentrations were associated in a dose-dependent fashion with cord blood metabolites. What remains to be determined is whether these metals- and trace elements-associated changes in cord metabolites can influence a child’s risk of cardiometabolic diseases.

Background Preeclampsia increases women's risks for maternal morbidity and future cardiovascular disease. The aim of this study was to identify opportunities for prevention by examining the association between cardiometabolic risk factors and preeclampsia across 2 pregnancies among women in a high‐risk US birth cohort. Methods and Results Our sample included 618 women in the Boston Birth Cohort with index and subsequent pregnancy data collected using standard protocols. We conducted log‐binomial univariate regression models to examine the association between preeclampsia in the subsequent pregnancy (defined as incident or recurrent preeclampsia) and cardiometabolic risk factors (ie, obesity, hypertension, diabetes mellitus, preterm birth, low birth weight, and gestational diabetes mellitus) diagnosed before and during the index pregnancy, and between index and subsequent pregnancies. At the subsequent pregnancy, 7% (36/540) had incident preeclampsia and 42% (33/78) had recurrent preeclampsia. Compared with women without obesity, women with obesity had greater risk of incident preeclampsia (unadjusted risk ratio [RR], 2.2 [95% CI, 1.1–4.5]) and recurrent preeclampsia (unadjusted RR, 3.1 [95% CI, 1.5–6.7]). Preindex pregnancy chronic hypertension and diabetes mellitus were associated with incident, but not recurrent, preeclampsia (hypertension unadjusted RR, 7.9 [95% CI, 4.1–15.3]; diabetes mellitus unadjusted RR, 5.2 [95% CI, 2.5–11.1]. Women with new interpregnancy hypertension versus those without had a higher risk of incident and recurrent preeclampsia (incident preeclampsia unadjusted RR, 6.1 [95% CI, 2.9–13]); recurrent preeclampsia unadjusted RR, 2.4 [95% CI, 1.5–3.9]). Conclusions In this diverse sample of high‐risk US women, we identified modifiable and treatable risk factors, including obesity and hypertension for the prevention of preeclampsia.

Abstract Background Low-dose mercury (Hg) exposure has been associated with cardiovascular diseases, diabetes, and obesity in adults, but it is unknown the metabolic consequence of in utero Hg exposure. This study aimed to investigate the association between in utero Hg exposure and child overweight or obesity (OWO) and to explore if adequate maternal folate can mitigate Hg toxicity. Methods This prospective study included 1442 mother-child pairs recruited at birth and followed up to age 15 years. Maternal Hg in red blood cells and plasma folate levels were measured in samples collected 1–3 days after delivery (a proxy for third trimester exposure). Adequate folate was defined as plasma folate ≥ 20.4 nmol/L. Childhood OWO was defined as body mass index ≥ 85% percentile for age and sex. Results The median (interquartile range) of maternal Hg levels were 2.11 (1.04–3.70) μg/L. Geometric mean (95% CI) of maternal folate levels were 31.1 (30.1–32.1) nmol/L. Maternal Hg levels were positively associated with child OWO from age 2–15 years, independent of maternal pre-pregnancy OWO, diabetes, and other covariates. The relative risk (RR = 1.24, 95% CI 1.05–1.47) of child OWO associated with the highest quartile of Hg exposure was 24% higher than those with the lowest quartile. Maternal pre-pregnancy OWO and/or diabetes additively enhanced Hg toxicity. The highest risk of child OWO was found among children of OWO and diabetic mothers in the top Hg quartile (RR = 2.06; 95% CI 1.56–2.71) compared to their counterparts. Furthermore, adequate maternal folate status mitigated Hg toxicity. Given top quartile Hg exposure, adequate maternal folate was associated with a 34% reduction in child OWO risk (RR = 0.66, 95% CI 0.51–0.85) as compared with insufficient maternal folate. There was a suggestive interaction between maternal Hg and folate levels on child OWO risk (p for interaction = 0.086). Conclusions In this US urban, multi-ethnic population, elevated in utero Hg exposure was associated with a higher risk of OWO in childhood, and such risk was enhanced by maternal OWO and/or diabetes and reduced by adequate maternal folate. These findings underscore the need to screen for Hg and to optimize maternal folate status, especially among mothers with OWO and/or diabetes.

Objective: To investigate to what extent paternal involvement and support during pregnancy were associated with preterm (PTB) and small-for-gestational age (SGA) births. Methods: Using data from the Boston Birth Cohort (n = 7047), multiple logistic regression models were performed to estimate the log odds of either PTB or SGA birth, with paternal involvement, paternal social support, and family and friend social support variables as the primary independent variables. Results: About 10% of participating mothers reported their husbands not being involved or supportive during their pregnancies. Lack of paternal involvement was associated with 21% higher risk of PTB (OR = 1.21, 95% CI: 1.01–1.45). Similarly, lack of paternal support was borderline associated with PTB (OR = 1.13, 95% CI: 0.94–1.35). Also marginally significant, lack of paternal involvement (OR = 1.18, 95% CI: 0.95–1.47) and father’s support (OR = 1.19, 95% CI: 0.96–1.48) were associated with higher odds of SGA birth. No associations were found between familial and friend support during pregnancy and PTB or SGA. Conclusions: Among predominantly low-income African Americans, lack of paternal involvement and lack of paternal support during pregnancy were associated with an increased risk of PTB, and suggestive of SGA birth. These findings, if confirmed in future research, underscore the important role a father can play in reducing PTB and/or SGA.

Diabetes mellitus (pregestational (PDM) and gestational (GDM)) is associated with adverse pregnancy outcomes (APOs). However, studies exploring the association of APOs with maternal glycemia among women without PDM/GDM are limited. We utilized data from 4119 women (307—PDM; 582—GDM; 3230—non-PDM/GDM) in the Boston Birth Cohort (1998–2016). Women in the non-PDM/GDM group were subdivided by tertiles of 1 h, 50 g oral glucose load test at 24–32 weeks: T1: 50–95 mg/dL (n = 1166), T2: 96–116 mg/dL (n = 1151), T3: 117–201 mg/dL (n = 913). Using multivariable logistic regression, we examined the association of maternal glycemia with APOs—preterm birth (PTB) and hypertensive disorders of pregnancy (HDP)—and adverse perinatal outcomes—high birth weight (HBW), cesarean section (CS), and sub-analyses by race-ethnicity. Compared to women in T1, women in T2 and T3 had a higher prevalence of pre-existing hypertension (T1: 2.8% vs. T2: 5.2% vs. T3: 6.3%) and obesity (T1: 13.3% vs. T2: 18.1% vs. T3: 22.9%). Women in T2 and T3 had higher odds of HBW (adjusted odds ratio aOR T2: 1.47 [1.01–2.19] T3: 1.68 [1.13–2.50]) compared to women in T1. Additionally, women in T2, compared to T1, had higher odds of HDP (aOR 1.44 [1.10–1.88]). Among non-Hispanic Black (NHB) women, those in T2 and T3 had higher odds of HDP compared to T1 (aOR T2 1.67 [1.13–2.51]; T3: 1.68 [1.07–2.62]). GDM and PDM were associated with higher odds of HBW, CS, PTB, and HDP, compared to women in T1. In this predominantly NHB and Hispanic cohort, moderate maternal glycemia without PDM/GDM was associated with higher odds of HBW and HDP, even more strongly among NHB women. If confirmed, a review of current guidelines of glucose screening and risk stratification in pregnancy may be warranted.

The molecular machinery controlling immune development has been extensively investigated. Studies in animal models and adult individuals have revealed fundamental mechanisms of disease and have been essential to understanding how humans sense and respond to cellular stress, tissue damage, pathogens and their environment. Nonetheless, our understanding of how immune responses originate during human development is just starting to emerge. In particular, studies to unveil how environmental and other non-heritable factors shape the immune system at the beginning of life offer great promise to yield important knowledge about determinants of normal inter-individual immune variation and to prevent and treat many human diseases. In this review, we summarize our current understanding of some of the mechanisms determining early life antibody production as a model of an immune process with sequential molecular checkpoints susceptible to influence by non-heritable factors. We discuss the potential of epigenomics as a valuable approach that may reveal not only relevant gene-environment interactions but important clues about immune developmental processes and homeostasis in early life. We then highlight the novel paradigm of human immunology as a complex field that nowadays requires a longitudinal systems-biology approach to understand normal variation and developmental changes during the first few years of life.

Maternal smoking during pregnancy may affect newborn DNA methylation (DNAm). However, little is known about how these associations vary by a newborn’s sex and/or maternal nutrition. To fill in this research gap, we investigated epigenome-wide DNAm associations with maternal smoking during pregnancy in African American mother-newborn pairs. DNAm profiling in cord (n = 379) and maternal blood (n = 300) were performed using the Illumina HumanMethylation450 BeadChip array. We identified 12 CpG sites whose DNAm levels in cord blood were associated with maternal smoking, at a false discovery rate 19.2 nmol/L), the DNAm level was about 0.03 lower (P = 3.6 × 10−4) in exposed newborns with a high maternal folate level, but was 0.08 lower (P = 1.2 × 10−8) in exposed newborns with a low maternal folate level. Our data suggest that adequate maternal folate levels may partly counteract the impact of maternal smoking on DNAm. These findings may open new avenues of inquiry regarding sex differences in response to environmental insults and novel strategies to mitigate their intergenerational health effects through optimization of maternal nutrition.

Preterm birth (PTB) affects one in six Black babies in the United States. Epigenetics is believed to play a role in PTB; however, only a limited number of epigenetic studies of PTB have been reported, most of which have focused on cord blood DNA methylation (DNAm) and/or were conducted in white populations. Here we conducted, by far, the largest epigenome-wide DNAm analysis in 300 Black women who delivered early spontaneous preterm (sPTB, n = 150) or full-term babies (n = 150) and replicated the findings in an independent set of Black mother-newborn pairs from the Boston Birth Cohort. DNAm in maternal blood and/or cord blood was measured using the Illumina HumanMethylation450 BeadChip. We identified 45 DNAm loci in maternal blood associated with early sPTB, with a false discovery rate (FDR)

There is increasing recognition on the role of early life metabolic programming in childhood obesity. This study sought to investigate whether newborn cord blood metabolome can predict future BMI. It included 946 children in the Boston Birth Cohort, a sample of high-risk yet understudied US urban, low-income, predominantly Black and Hispanic children, who were enrolled at birth and followed prospectively up to age 18 years. A total of 376 metabolites were measured in cord blood plasma. Longitudinal BMI trajectories were defined and categorized into three distinct patterns: early onset overweight and obesity (early-OWO), late onset OWO (late-OWO), and normal weight trajectory (NW). Multinomial logistic regression models were used to identify metabolites individually or as network modules associated with BMI trajectories. Of the 946 children, 388, 254, and 304 were classified as early-OWO, late-OWO, and NW, respectively. Of the seven co-metabolomic network modules defined, two were inversely correlated with early-OWO. Among the 68 metabolites within the two modules, 22 triacylglycerols and diacylglycerols were negatively associated with early-OWO; 5 cholesterol esters were positively associated with early-OWO. In this prospective birth cohort, we demonstrated distinctive longitudinal BMI trajectories and identified multiple cord plasma metabolites in relevant biological pathways that were associated with early-OWO.

Oxidative stress mechanisms may explain associations between perinatal acetaminophen exposure and childhood attention-deficit hyperactivity disorder (ADHD). We investigated whether the changes in umbilical cord plasma amino acids needed to synthesize the antioxidant glutathione and in the oxidative stress biomarker 8-hydroxy-deoxyguanosine may explain the association between cord plasma acetaminophen and ADHD in the Boston Birth Cohort (BBC). Mother–child dyads were followed at the Boston Medical Center between 1998 and 2018. Cord plasma analytes were measured from archived samples collected at birth. Physician diagnoses of childhood ADHD were obtained from medical records. The final sample consisted of 568 participants (child mean age [SD]: 9.3 [3.5] years, 315 (52.8%) male, 248 (43.7%) ADHD, 320 (56.3%) neurotypical development). Cord unmetabolized acetaminophen was positively correlated with methionine (R = 0.33, p < 0.001), serine (R = 0.30, p < 0.001), glycine (R = 0.34, p < 0.001), and glutamate (R = 0.16, p < 0.001). Children with cord acetaminophen levels >50th percentile appeared to have higher risk of ADHD for each increase in cord 8-hydroxy-deoxyguanosine level. Adjusting for covariates, increasing cord methionine, glycine, serine, and 8-hydroxy-deoxyguanosine were associated with significantly higher odds for childhood ADHD. Cord methionine statistically mediated 22.1% (natural indirect effect logOR = 0.167, SE = 0.071, p = 0.019) and glycine mediated 22.0% (natural indirect effect logOR = 0.166, SE = 0.078, p = 0.032) of the association between cord acetaminophen >50th percentile with ADHD. Our findings provide some clues, but additional investigation into oxidative stress pathways and the association of acetaminophen exposure and childhood ADHD is warranted.

Food allergy is an increasing public health problem. In a genome-wide scan of children diagnosed by oral food challenge, Marenholz et al. find new genetic associations underlying food allergy, implicating the immune system and the epithelial barrier.

Preterm birth (PTB) has high prevalence and PTB infants have greater risk for mortality. Here, Hong and colleagues perform a genome-wide gene × environment interaction analysis and find that maternalCOL24A1variants have a significant interaction with maternal pre-pregnancy obesity in increasing PTB risk.

Background Preeclampsia is a leading contributor to maternal and perinatal morbidity and mortality. In mice experiments, manganese (Mn) and selenium (Se) are protective whereas cadmium (Cd) is promotive for preeclampsia. Epidemiologic findings on these chemical elements have been inconsistent. To confirm experimental findings in mice, we examined associations of trace minerals (Mn and Se) and heavy metals (Cd, lead [Pb], and mercury [Hg]) with preeclampsia in a birth cohort. Methods and Results A total of 1274 women from the Boston Birth Cohort (enrolled since 1998) had complete data on the exposures and outcome. We measured Mn, Se, Cd, Pb, and Hg from red blood cells collected within 24 to 72 hours after delivery. We ascertained preeclampsia diagnosis from medical records. We used Poisson regression with robust variance models to estimate prevalence ratios (PRs) and 95% CIs. A total of 115 (9.0%) women developed preeclampsia. We observed evidence of a dose–response trend for Mn (P for trend

Findings on the role of Mediterranean-style diet (MSD) on duration of pregnancy and birth weight have been inconsistent and based largely on Non-Hispanic white populations, making it unclear as to whether they could extend to African Americans who are at a higher risk of unfavorable birth outcomes. Our study addresses this gap using a large urban, multiethnic, predominantly low-income cohort of mother-infant dyads from Boston, MA, USA. Dietary information was obtained via food frequency questionnaires; health information including birth outcomes were extracted from medical records. A Mediterranean-style diet score (MSDS) was formulated based on intake history, and linear and log-binomial regressions were performed to assess its association with birth outcomes. After adjustment, the lowest MSDS quintile from the overall sample was found to be associated with an increased relative risk (RR) of overall preterm birth (RR 1.18; 95% CI: 1.06–1.31), spontaneous preterm birth (1.28; 1.11–1.49), late preterm birth (1.21; 1.05–1.39), and low birth weight (1.11; 1.01–1.22), compared to the highest quintile. The findings were similar for the African American sample. Our study adds to the current understanding of the diet’s influence on birth outcomes by demonstrating that adherence to MSD may improve birth outcomes for African American women.

DNA methylation (DNAm) is an essential mechanism governing normal development in humans. Although most DNAm patterns in blood cells are established in utero, the genes associated with immune function undergo postnatal DNAm modifications, and the characterization of this subset of genes is incomplete. Accordingly, we used available longitudinal DNAm datasets from a large birth cohort in the U.S. to further identify postnatal DNAm variation in peripheral leukocytes from 105 children (n = 105) between birth and the first two years of life, as determined by postnatal changes in β values (with the percentage of methylation ranging from 0 to 1.0 at individual CpG sites). Our study is an extension of a previous analysis performed by our group and identified that: (1) as previously described, DNAm patterns at most CpG sites were established before birth and only a small group of genes underwent DNAm modifications postnatally, (2) this subset includes multiple immune genes critical for lymphocyte development, and (3) several members of the tumor necrosis factor receptor and cytokine superfamilies with essential roles in immune cell activation, survival, and lymphoid tissue development were among those with a larger postnatal variation. This study describes the precise epigenetic DNA methylation marks in important immune genes that change postnatally and raises relevant questions about the role of DNAm during postnatal immune development in early childhood.

Plasma homocysteine (Hcy) is a modifiable, independent risk factor for cardiovascular disease (CVD) and is affected by both environmental and genetic factors. This study aimed to describe the gender- and age-specific distribution of Hcy concentration for 1117 subjects aged 10–66 years, a subset of a community-based rural Chinese twin cohort. In addition, we examined environmental and genetic contributions to variances in Hcy concentration by gender and age groups. We found that the distribution pattern for Hcy varied by both age and gender. Males had higher Hcy than females across all ages. Elevated Hcy was found in 43% of male adults and 13% of female adults. Moreover, nearly one fifth of children had elevated Hcy. Genetic factors could explain 52%, 36% and 69% of the variation in Hcy concentration among children, male adults and female adults, respectively. The MTHFR C677T variant was significantly associated with Hcy concentrations. Smokers with the TT genotype had the highest Hcy levels. Overall, our results indicate that elevated Hcy is prevalent in the children and adults in this rural Chinese population. The early identification of elevated Hcy will offer a window of opportunity for the primary prevention of CVD and metabolic syndrome.

Previous studies have suggested a positive association between self-reported maternal acetaminophen use during pregnancy and risk of attention deficit hyperactivity disorder (ADHD) in offspring. We sought to examine the prospective association between maternal plasma biomarkers of acetaminophen intake and ADHD diagnosis in the offspring. This report analyzed 1180 children enrolled at birth and followed prospectively as part of the Boston Birth Cohort, including 188 with ADHD diagnosis based on electronic medical record review. Maternal biomarkers of acetaminophen intake were measured in plasma samples obtained within 1–3 days postpartum. Odds ratios for having ADHD diagnosis or other developmental disorders were estimated using multinomial logistic regression models, adjusting for pertinent covariables. Compared to neurotypical children, we observed significant positive dose-responsive associations with ADHD diagnosis for each maternal acetaminophen biomarker. These dose–responsive associations persisted after adjusting for indication of acetaminophen use and other pertinent covariates; and were specific to ADHD, rather than other neurodevelopmental disorders. In the stratified analyses, differential point estimates of the associations were observed across some strata of covariates. However, these differences were not statistically significant. Maternal acetaminophen biomarkers were specifically associated with increased risk of ADHD diagnosis in offspring. Additional clinical and mechanistic investigations are warranted.

Growing evidence suggests that maternal cholesterol levels are important in the offspring’s brain growth and development. Previous studies on cholesterols and brain functions were mostly in adults. We sought to examine the prospective association between maternal cholesterol levels and the risk of attention deficit hyperactivity disorder (ADHD) in the offspring. We analyzed data from the Boston Birth Cohort, enrolled at birth and followed from birth up to age 15 years. The final analyses included 1479 mother-infant pairs: 303 children with ADHD, and 1176 neurotypical children without clinician-diagnosed neurodevelopmental disorders. The median age of the first diagnosis of ADHD was seven years. The multiple logistic regression results showed that a low maternal high-density lipoprotein level (≤60 mg/dL) was associated with an increased risk of ADHD, compared to a higher maternal high-density lipoprotein level, after adjusting for pertinent covariables. A “J” shaped relationship was observed between triglycerides and ADHD risk. The associations with ADHD for maternal high-density lipoprotein and triglycerides were more pronounced among boys. The findings based on this predominantly urban low-income minority birth cohort raise a new mechanistic perspective for understanding the origins of ADHD and the gender differences and future targets in the prevention of ADHD.

Growing evidence suggests that maternal exposures to endocrine disrupting chemicals during pregnancy may lead to poor pregnancy outcomes and increased fetal susceptibility to adult diseases. Polybrominated diphenyl ethers (PBDEs), which are ubiquitously used flame-retardants, could leach into the environment; and become persistent organic pollutants via bioaccumulation. In the United States, blood PBDE levels in adults range from 30-100 ng/g- lipid but the alarming health concern revolves around children who have reported blood PBDE levels 3 to 9-fold higher than adults. PBDEs disrupt endocrine, immune, reproductive and nervous systems. However, the mechanism underlying its adverse health effect is not fully understood. Epigenetics is a possible biological mechanism underlying maternal exposure-child health outcomes by regulating gene expression without changes in the DNA sequence. We sought to examine the relationship between maternal exposure to environmental PBDEs and promoter methylation of a proinflammatory gene, tumor necrosis factor alpha (TNFα). We measured the maternal blood PBDE levels and cord blood TNFα promoter methylation levels on 46 paired samples of maternal and cord blood from the Boston Birth Cohort (BBC). We showed that decreased cord blood TNFα methylation associated with high maternal PBDE47 exposure. CpG site-specific methylation showed significantly hypomethylation in the girl whose mother has a high blood PBDE47 level. Consistently, decreased TNFα methylation associated with an increase in TNFα protein level in cord blood. In conclusion, our finding provided evidence that in utero exposure to PBDEs may epigenetically reprogram the offspring's immunological response through promoter methylation of a proinflammatory gene.

BACKGROUND: Sufficient sleep during childhood is essential to ensure a transition into a healthy adulthood. However, chronic sleep loss continues to increase worldwide. In this context, it is imperative to make sleep a high-priority and take action to promote sleep health among children. The present series of studies aimed to shed light on sleep patterns, on the longitudinal association of sleep with school performance, and on practical intervention strategy for Chinese school-aged children. METHODS AND FINDINGS: A serial sleep researches, including a national cross-sectional survey, a prospective cohort study, and a school-based sleep intervention, were conducted in China from November 2005 through December 2009. The national cross-sectional survey was conducted in 8 cities and a random sample of 20,778 children aged 9.0±1.61 years participated in the survey. The five-year prospective cohort study included 612 children aged 6.8±0.31 years. The comparative cross-sectional study (baseline: n = 525, aged 10.80±0.41; post-intervention follow-up: n = 553, aged 10.81±0.33) was undertaken in 6 primary schools in Shanghai. A battery of parent and teacher reported questionnaires were used to collect information on children's sleep behaviors, school performance, and sociodemographic characteristics. The mean sleep duration was 9.35±0.77 hours. The prevalence of daytime sleepiness was 64.4% (sometimes: 37.50%; frequently: 26.94%). Daytime sleepiness was significantly associated with impaired attention, learning motivation, and particularly, academic achievement. By contrast, short sleep duration only related to impaired academic achievement. After delaying school start time 30 minutes and 60 minutes, respectively, sleep duration correspondingly increased by 15.6 minutes and 22.8 minutes, respectively. Moreover, intervention significantly improved the sleep duration and daytime sleepiness. CONCLUSIONS: Insufficient sleep and daytime sleepiness commonly existed and positively associated with the impairment of school performance, especially academic achievement, among Chinese school-aged children. The effectiveness of delaying school staring time emphasized the benefits of optimal school schedule regulation to children's sleep health.

We examined the tracking of blood glucose, the development of prediabetes, and estimated their genetic contributions in a prospective, healthy, rural Chinese twin cohort. This report includes 1,766 subjects (998 males, 768 females) aged 6-21 years at baseline who completed a 6-year follow-up study. Oral glucose tolerance test was performed for all subjects at both baseline and follow-up. We found that subjects with low fasting plasma glucose (FPG) or 2 h post-load glucose (PG) levels at baseline tended to remain at the low level at follow-up. Subjects in the top tertile of baseline plasma glucose tended to have a higher risk of developing prediabetes at follow-up compared to the low tertile: in males, 37.6% vs. 27.6% for FPG and 37.2% vs. 25.7% for 2hPG, respectively; in females, 31.0% vs. 15.4% for FPG and 28.9% vs. 15.1% for 2 h PG, respectively. Genetic factors explained 43% and 41% of the variance of FPG, and 72% and 47% for impaired fasting glucose for males and females, respectively; environmental factors substantially contribute to 2hPG status and impaired glucose tolerance. In conclusion, in this cohort of healthy rural Chinese children and adolescents, we demonstrated that both FPG and 2hPG tracked well and was a strong predictor of prediabetes. The high proportion of children with top tertile of blood glucose progressed to prediabetes, and the incidence of prediabetes has a male predominance. Genetic factors play more important role in fasting than postload status, most of which was explained by unique environmental factors.

BACKGROUND: The impact of methylation gestational age (GAmAge; a biomarker of fetal maturity) at birth on childhood blood pressure (BP) trajectories is unknown. METHODS: This cohort study included 500 boys and 440 girls with data on cord blood DNA methylation and BP at 3 to 15 years of age. Systolic BP (SBP) and diastolic BP percentiles were calculated based on clinical guidelines. Time-series K-means clustering identified 4 distinct SBP and diastolic BP percentile trajectories: high-steady, high-decrease, normal-increase, and normal-steady. GAmAge was estimated using an existing pediatric epigenetic clock. Extrinsic age acceleration was calculated as residuals of associations between GAmAge and chronological gestational age. Intrinsic age acceleration was calculated using the same method adjusting for cord blood cell compositions. RESULTS: Extrinsic age acceleration and intrinsic age acceleration were inversely associated with repeated measures of BP percentiles. Significant inverse associations were observed between extrinsic age acceleration and SBP percentiles in boys (β=-2.02; P=0.02) but not in girls (β=-0.49; P=0.58). Both extrinsic age acceleration and intrinsic age acceleration were inversely associated with SBP percentiles in girls born preterm (<37 weeks; βEAA=-2.95; βIAA=-3.00; P<0.05). Compared with the normal-steady SBP trajectory, significant inverse associations were observed between intrinsic age acceleration and high-steady, high-decrease, and normal-increase SBP trajectories in boys (odds ratio, 0.73--0.81; P<0.03), and significant positive associations were observed for high-decrease and normal-increase SBP trajectories in girls (odds ratio, 1.26-1.38; P<0.01). Significant sex differences were observed (Psex-interaction <2x10-16). CONCLUSIONS: GAmAge acceleration at birth was inversely associated with child BP, and such association was more pronounced in boys than in girls. Our findings may shed new light on the developmental origins of high BP and sex differences in cardiovascular risk. [ABSTRACT FROM AUTHOR]