First trimester plasma PER- AND Polyfluoroalkyl Substances (PFAS) and blood pressure trajectories across the second and third trimesters of pregnanacy.

BACKGROUND: Evidence suggests that exposure to per- and polyfluoroalkyl substances (PFAS) increases risk of high blood pressure (BP) during pregnancy. Prior studies did not examine associations with BP trajectory parameters (i.e., overall magnitude and velocity) during pregnancy, which is linked to adverse pregnancy outcomes. OBJECTIVES: To estimate associations of multiple plasma PFAS in early pregnancy with BP trajectory parameters across the second and third trimesters. To assess potential effect modification by maternal age and parity. METHODS: In 1297 individuals, we quantified six PFAS in plasma collected during early pregnancy (median gestational age: 9.4 weeks). We abstracted from medical records systolic BP (SBP) and diastolic BP (DBP) measurements, recorded from 12 weeks gestation until delivery. BP trajectory parameters were estimated via Super Imposition by Translation and Rotation modeling. Subsequently, Bayesian Kernel Machine Regression (BKMR) was employed to estimate individual and joint associations of PFAS concentrations with trajectory parameters - adjusting for maternal age, race/ethnicity, pre-pregnancy body mass index, income, parity, smoking status, and seafood intake. We evaluated effect modification by age at enrollment and parity. RESULTS: We collected a median of 13 BP measurements per participant. In BKMR, higher concentration of perfluorooctane sulfonate (PFOS) was independently associated with higher magnitude of overall SBP and DBP trajectories (i.e., upward shift of trajectories) and faster SBP trajectory velocity, holding all other PFAS at their medians. In stratified BKMR analyses, participants with ≥ 1 live birth had more pronounced positive associations between PFOS and SBP velocity, DBP magnitude, and DBP velocity - compared to nulliparous participants. We did not observe significant associations between concentrations of the overall PFAS mixture and either magnitude or velocity of the BP trajectories. CONCLUSION: Early pregnancy plasma PFOS concentrations were associated with altered BP trajectory in pregnancy, which may impact future cardiovascular health of the mother.

Associations of Childhood Adiposity and Cardiometabolic Biomarkers With Adolescent PCOS.

OBJECTIVE: Polycystic Ovary Syndrome (PCOS) is common among females, with significant metabolic and reproductive comorbidities. We describe PCOS development in a pediatric population. METHODS: We assessed cardiometabolic biomarkers and adiposity at the midchildhood (mean 7.9 y), early teen (mean 13.1 y), and midteen (mean 17.8 y) visits among 417 females in the prospective Project Viva cohort. We defined PCOS via self-reported diagnosis or ovulatory dysfunction with hyperandrogenism in midlate adolescence. We used multivariable logistic regression to assess associations of metabolic and adiposity markers at each visit with PCOS. RESULTS: Adolescents with PCOS (n = 56, 13%) versus without had higher mean (SD) BMI z-score and truncal fat mass at the midchildhood (0.66 [0.99] vs 0.30 [1.04]; 3.5 kg [2.6] vs 2.7 [1.5]), early teen (0.88 [1.01] vs 0.25 [1.08]; 9.4 kg [6.7] vs 6.1 [3.4]), and midteen (0.78 [1.03] vs 0.33 [0.97]; 11.6 kg [7.2] vs 9.1 [4.9]) visits as well as lower adiponectin to leptin ratio at the early (0.65 [0.69] vs 1.04 [0.97]) and midteen (0.33 [0.26] vs 0.75 [1.21]) visits. In models adjusted for maternal PCOS, education and child race and ethnicity (social factors), we found higher odds of PCOS per 1-SD increase in truncal fat at midchildhood (odds ratio [OR] 1.42; 95% confidence interval [CI] 1.03-1.95) and early teen visits (OR 1.61; 95% CI 1.14-2.28) and lower odds per 1-SD increase in adiponectin/leptin ratio at the midteen visit (OR 0.14; 95% CI 0.03-0.58). CONCLUSIONS: Childhood excess adiposity and adipose tissue dysfunction may be a first signs of later PCOS risk.

History of Infertility and Midlife Cardiovascular Health in Female Individuals.

Importance: Fertility status is a marker for future health, and infertility has been associated with risk for later cancer and diabetes, but associations with midlife cardiovascular health (CVH) in female individuals remain understudied. Objective: To evaluate the association of infertility history with CVH at midlife (approximately age 50 years) among parous individuals. Design, Setting, and Participants: Project Viva is a prospective cohort study of pregnant participants enrolled between 1999 and 2002 who delivered a singleton live birth in the greater Boston, Massachusetts, area. Infertility history was collected at a midlife visit between 2017 and 2021, approximately 18 years after enrollment. Data analysis was performed from January to June 2023. Exposures: The primary exposure was any lifetime history of infertility identified by self-report, medical record, diagnosis, or claims for infertility treatment. Main Outcomes and Measures: The American Heart Association's Life's Essential 8 (LE8) is a construct for ranking CVH that includes scores from 0 to 100 (higher scores denote better health status) in 4 behavioral (diet, physical activity, sleep, and smoking status) and 4 biomedical (body mass index, blood pressure, blood lipids, and glycemia) domains to form an overall assessment of CVH. Associations of a history of infertility (yes or no) with mean LE8 total, behavioral, biomedical, and blood biomarker (lipids and glycemia) scores were examined, adjusting for age at outcome (midlife visit), race and ethnicity, education, household income, age at menarche, and perceived body size at age 10 years. Results: Of 468 included participants (mean [SD] age at the midlife visit, 50.6 [5.3] years) with exposure and outcome data, 160 (34.2%) experienced any infertility. Mean (SD) LE8 scores were 76.3 (12.2) overall, 76.5 (13.4) for the behavioral domain, 76.0 (17.5) for the biomedical domain, and 78.9 (19.2) for the blood biomarkers subdomain. In adjusted models, the estimated overall LE8 score at midlife was 2.94 points lower (95% CI, -5.13 to -0.74 points), the biomedical score was 4.07 points lower (95% CI, -7.33 to -0.78 points), and the blood subdomain score was 5.98 points lower (95% CI, -9.71 to -2.26 points) among those with vs without history of infertility. The point estimate also was lower for the behavioral domain score (ß = -1.81; 95% CI, -4.28 to 0.66), although the result was not statistically significant. Conclusions and Relevance: This cohort study of parous individuals found evidence for an association between a history of infertility and lower overall and biomedical CVH scores. Future study of enhanced cardiovascular preventive strategies among those who experience infertility is warranted.

Pediatric Features of Genetic Predisposition to Polycystic Ovary Syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) has historically been conceptualized as a disorder of the reproductive system in women. However, offspring of women with PCOS begin to show metabolic features of PCOS in childhood, suggestive of childhood manifestations. OBJECTIVE: To identify childhood manifestations of genetic risk for PCOS. METHODS: We calculated a PCOS polygenic risk score (PRS) for 12 350 girls and boys in 4 pediatric cohorts-ALSPAC (UK), COPSAC (Denmark), Project Viva (USA), and The HOLBÆK Study (Denmark). We tested for association of the PRS with PCOS-related phenotypes throughout childhood and with age at pubarche and age at peak height velocity and meta-analyzed effects across cohorts using fixed-effect models. RESULTS: Higher PRS for PCOS was associated with higher body mass index in midchildhood (0.05 kg/m2 increase per 1 SD of PRS, 95% CI 0.03, 0.07, P = 3 × 10-5) and higher risk of obesity in early childhood (OR 1.34, 95% CI 1.13, 1.59, P = .0009); both persisted through late adolescence (P all ≤.03). Higher PCOS PRS was associated with earlier age at pubarche (0.85-month decrease per 1 SD of PRS, 95% CI -1.44, -0.26, P = .005) and younger age at peak height velocity (0.64-month decrease per 1 SD of PRS, 95% CI -0.94, -0.33, P = 4 × 10-5). CONCLUSION: Genetic risk factors for PCOS are associated with alterations in metabolic, growth, and developmental traits in childhood. Thus, PCOS may not simply be a condition that affects women of reproductive age but, rather, a possible manifestation of an underlying condition that affects both sexes starting in early life.

Associations of prenatal maternal depressive symptoms with cord blood glucocorticoids and child hair cortisol levels in the project viva and the generation R cohorts: a prospective cohort study.

BACKGROUND: Prior studies have reported conflicting results regarding the association of prenatal maternal depression with offspring cortisol levels. We examined associations of high levels of prenatal depressive symptoms with child cortisol biomarkers. METHODS: In Project Viva (n = 925, Massachusetts USA), mothers reported their depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS) during pregnancy, cord blood glucocorticoids were measured at delivery, and child hair cortisol levels were measured in mid-childhood (mean (SD) age: 7.8 (0.8) years) and early adolescence (mean (SD) age: 13.2 (0.9) years). In the Generation R Study (n = 1644, Rotterdam, The Netherlands), mothers reported depressive symptoms using the Brief Symptom Inventory (BSI) during pregnancy, and child hair cortisol was measured at a mean (SD) age of 6.0 (0.5) years. We used cutoffs of ≥ 13 for the EPDS and > 0.75 for the BSI to indicate high levels of prenatal depressive symptoms. We used multivariable linear regression models adjusted for child sex and age (at outcome), and maternal pre-pregnancy BMI, education, social support from friends/family, pregnancy smoking status, marital status, and household income to assess associations separately in each cohort. We also meta-analyzed childhood hair cortisol results from both cohorts. RESULTS: 8.0% and 5.1% of women respectively experienced high levels of prenatal depressive symptoms in Project Viva and the Generation R Study. We found no associations between high levels of maternal depressive symptoms during pregnancy and child cortisol biomarkers in either cohort. CONCLUSIONS: The present study does not find support for the direct link between high levels of maternal depressive symptoms and offspring cortisol levels.

Maternal glycemia in pregnancy is longitudinally associated with blood DNAm variation at the FSD1L gene from birth to 5 years of age.

BACKGROUND: In utero exposure to maternal hyperglycemia has been associated with an increased risk for the development of chronic diseases in later life. These predispositions may be programmed by fetal DNA methylation (DNAm) changes that persist postnatally. However, although some studies have associated fetal exposure to gestational hyperglycemia with DNAm variations at birth, and metabolic phenotypes in childhood, no study has yet examined how maternal hyperglycemia during pregnancy may be associated with offspring DNAm from birth to five years of age. HYPOTHESIS: Maternal hyperglycemia is associated with variation in offspring DNAm from birth to 5 years of age. METHODS: We estimated maternal hyperglycemia using the area under the curve for glucose (AUCglu) following an oral glucose tolerance test conducted at 24-30 weeks of pregnancy. We quantified DNAm levels in cord blood (n = 440) and peripheral blood at five years of age (n = 293) using the Infinium MethylationEPIC BeadChip (Illumina). Our total sample included 539 unique dyads (mother-child) with 194 dyads having DNAm at both time-points. We first regressed DNAm M-values against the cell types and child age for each time-point separately to account for the difference by time of measurement for these variables. We then used a random intercept model from the linear mixed model (LMM) framework to assess the longitudinal association between maternal AUCglu and the repeated measures of residuals of DNAm. We adjusted for the following covariates as fixed effects in the random intercept model: maternal age, gravidity, smoking status, child sex, maternal body mass index (BMI) (measured at first trimester of pregnancy), and a binary variable for time-point. RESULTS: In utero exposure to higher maternal AUCglu was associated with lower offspring blood DNAm levels at cg00967989 located in FSD1L gene (ß = - 0.0267, P = 2.13 × 10-8) in adjusted linear regression mixed models. Our study also reports other CpG sites for which DNAm levels were suggestively associated (P < 1.0 × 10-5) with in utero exposure to gestational hyperglycemia. Two of these (cg12140144 and cg07946633) were found in the promotor region of PRDM16 gene (ß: - 0.0251, P = 4.37 × 10-07 and ß: - 0.0206, P = 2.24 × 10-06, respectively). CONCLUSION: Maternal hyperglycemia is associated with offspring DNAm longitudinally assessed from birth to 5 years of age.

DNA methylation age at birth and childhood: performance of epigenetic clocks and characteristics associated with epigenetic age acceleration in the Project Viva cohort.

BACKGROUND: Epigenetic age acceleration (EAA) and epigenetic gestational age acceleration (EGAA) are biomarkers of physiological development and may be affected by the perinatal environment. The aim of this study was to evaluate performance of epigenetic clocks and to identify biological and sociodemographic correlates of EGAA and EAA at birth and in childhood. In the Project Viva pre-birth cohort, DNA methylation was measured in nucleated cells in cord blood (leukocytes and nucleated red blood cells, N = 485) and leukocytes in early (N = 120, median age = 3.2 years) and mid-childhood (N = 460, median age = 7.7 years). We calculated epigenetic gestational age (EGA; Bohlin and Knight clocks) and epigenetic age (EA; Horvath and skin & blood clocks), and respective measures of EGAA and EAA. We evaluated the performance of clocks relative to chronological age using correlations and median absolute error. We tested for associations of maternal-child characteristics with EGAA and EAA using mutually adjusted linear models controlling for estimated cell type proportions. We also tested associations of Horvath EA at birth with childhood EAA. RESULTS: Bohlin EGA was strongly correlated with chronological gestational age (Bohlin EGA r = 0.82, p < 0.001). Horvath and skin & blood EA were weakly correlated with gestational age, but moderately correlated with chronological age in childhood (r = 0.45-0.65). Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males. When comparing self-reported Asian, Black, Hispanic, and more than one race or other racial/ethnic groups to White, we identified significant differences in EGAA and EAA at birth and in mid-childhood, but associations varied across clocks. Horvath EA at birth was positively associated with childhood Horvath and skin & blood EAA. CONCLUSIONS: Maternal smoking during pregnancy and child sex were associated with EGAA and EAA at multiple timepoints. Further research may provide insight into the relationship between perinatal factors, pediatric epigenetic aging, and health and development across the lifespan.

Non-essential and essential trace element mixtures and kidney function in early pregnancy - A cross-sectional analysis in project viva.

Some trace elements are established nephrotoxicants, yet their associations with kidney function remain understudied in the context of pregnancy, a time of substantial change in kidney physiology and function. We aimed to estimate the individual and joint associations of trace element mixtures with maternal kidney function during the 1st trimester of pregnancy (mean 9.7 gestational weeks). 1040 women from Project Viva contributed blood samples which were assessed for erythrocyte non-essential [arsenic (As), cadmium (Cd), cesium (Cs), mercury (Hg), lead (Pb)] and essential [barium (Ba), magnesium (Mg), manganese (Mn), selenium (Se), and Zinc (Zn)] trace elements, and plasma creatinine for kidney function. We estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration (eGFRCKD-EPI) equation without race-adjustment factors. We examined associations of eGFRCKD-EPI with individual trace elements using multivariable linear regression and their mixtures using quantile-based g-computation, adjusting for sociodemographics, pregnancy characteristics, and diet. Participants in our study were predominantly White (75%), college graduates (72%), and had household income >$70,000/year (63%). After adjusting for covariates, higher Pb (ß -3.51 ml/min/1.73 m2; 95% CI -5.83, -1.18) concentrations were associated with lower eGFRCKD-EPI, while higher Mg (ß 10.53 ml/min/1.73 m2; 95% CI 5.35, 15.71), Se (ß 5.56 ml/min/1.73 m2; 95% CI 0.82, 10.31), and Zn (ß 5.88 ml/min/1.73 m2; 95% CI 0.51, 11.26) concentrations were associated with higher eGFRCKD-EPI. In mixture analyses, higher non-essential trace elements mixture concentration was associated with reduced eGFRCKD-EPI (Ψ -1.03 ml/min/1.73 m2; 95% CI: 1.92, -0.14). Conversely, higher essential trace elements mixture concentration was associated with higher eGFR (Ψ 1.42; 95% CI: 0.48, 2.37). Exposure to trace elements in early pregnancy may influence women's kidney function although reverse causation cannot be eliminated in this cross-sectional analysis. These findings have important implications for long-term cardiovascular and postpartum kidney health that warrant additional studies.

A meta-analysis of pre-pregnancy maternal body mass index and placental DNA methylation identifies 27 CpG sites with implications for mother-child health.

Higher maternal pre-pregnancy body mass index (ppBMI) is associated with increased neonatal morbidity, as well as with pregnancy complications and metabolic outcomes in offspring later in life. The placenta is a key organ in fetal development and has been proposed to act as a mediator between the mother and different health outcomes in children. The overall aim of the present work is to investigate the association of ppBMI with epigenome-wide placental DNA methylation (DNAm) in 10 studies from the PACE consortium, amounting to 2631 mother-child pairs. We identify 27 CpG sites at which we observe placental DNAm variations of up to 2.0% per 10 ppBMI-unit. The CpGs that are differentially methylated in placenta do not overlap with CpGs identified in previous studies in cord blood DNAm related to ppBMI. Many of the identified CpGs are located in open sea regions, are often close to obesity-related genes such as GPX1 and LGR4 and altogether, are enriched in cancer and oxidative stress pathways. Our findings suggest that placental DNAm could be one of the mechanisms by which maternal obesity is associated with metabolic health outcomes in newborns and children, although further studies will be needed in order to corroborate these findings.

History of infertility and pregnancy outcomes in Project Viva: a prospective study.

BACKGROUND: Infertility has been associated with the risk of adverse pregnancy outcomes. It is not clear whether infertility and underlying causes of infertility or the use of medically assisted reproduction (MAR) therapies are responsible for the observed associations. In this study, we aimed to evaluate the association of history of infertility with pregnancy outcomes and identify whether the associations, if present, differed by subgroups defined by the use of MAR. METHODS: Prospective study of 2201 pregnant women from the Boston-area Project Viva cohort. The exposure was history of infertility based on self-reported time to pregnancy ≥12 mo (or ≥ 6 mo if ≥35 y) or use of MAR; a diagnosis of infertility or claims for infertility treatments from medical records. The outcomes included: gestational glucose tolerance (gestational diabetes, impaired glucose tolerance, isolated hyperglycemia vs. normoglycemia), hypertensive disorders (gestational hypertension/preeclampsia vs. normotension), gestational weight gain (inadequate/excessive vs. adequate), systolic (SBP) and diastolic blood pressure, birthweight-for-gestational age z-score (tertile 2 and 3 vs. 1), preterm birth (<37 vs. ≥37 weeks at delivery), and birth outcome (pregnancy loss vs. live birth). We performed linear and logistic/multinomial regression analyses adjusted for age, race/ethnicity, age at menarche, pre-pregnancy BMI, and prenatal smoking. RESULTS: Mean (SD) age was 32.0 (5.0) years, and 18.8% of women had history of infertility, 32.6% of whom used MAR. SBP across pregnancy was 0.72 mmHg higher in women with vs. without infertility (95% CI 0.02, 1.42). The associations were stronger among women who used MAR (ß 1.32 mmHg, 95% CI 0.21, 2.44), especially among those who used gonadotropins or gonadotropin-releasing hormone [GnRH] agonists (ß 1.91 mmHg, 95% CI 0.48, 3.35). Other outcomes were not associated with history of infertility. CONCLUSIONS: A history of infertility was associated with higher SBP during pregnancy, with stronger associations among those who used gonadotropins or GnRH agonists. Future studies are needed to confirm these findings and determine their clinical implications.

Gestational Perfluoroalkyl Substance Exposure and DNA Methylation at Birth and 12 Years of Age: A Longitudinal Epigenome-Wide Association Study.

BACKGROUND: DNA methylation alterations may underlie associations between gestational perfluoroalkyl substances (PFAS) exposure and later-life health outcomes. To the best of our knowledge, no longitudinal studies have examined the associations between gestational PFAS and DNA methylation. OBJECTIVES: We examined associations of gestational PFAS exposure with longitudinal DNA methylation measures at birth and in adolescence using the Health Outcomes and Measures of the Environment (HOME) Study (2003-2006; Cincinnati, Ohio). METHODS: We quantified serum concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), and perfluorohexane sulfonate (PFHxS) in mothers during pregnancy. We measured DNA methylation in cord blood (n=266) and peripheral leukocytes at 12 years of age (n=160) using the Illumina HumanMethylation EPIC BeadChip. We analyzed associations between log2-transformed PFAS concentrations and repeated DNA methylation measures using linear regression with generalized estimating equations. We included interaction terms between children's age and gestational PFAS. We performed Gene Ontology enrichment analysis to identify molecular pathways. We used Project Viva (1999-2002; Boston, Massachusetts) to replicate significant associations. RESULTS: After adjusting for covariates, 435 cytosine-guanine dinucleotide (CpG) sites were associated with PFAS (false discovery rate, q<0.05). Specifically, we identified 2 CpGs for PFOS, 12 for PFOA, 8 for PFHxS, and 413 for PFNA; none overlapped. Among these, 2 CpGs for PFOA and 4 for PFNA were replicated in Project Viva. Some of the PFAS-associated CpG sites annotated to gene regions related to cancers, cognitive health, cardiovascular disease, and kidney function. We found little evidence that the associations between PFAS and DNA methylation differed by children's age. DISCUSSION: In these longitudinal data, PFAS biomarkers were associated with differences in several CpGs at birth and at 12 years of age in or near genes linked to some PFAS-associated health outcomes. Future studies should examine whether DNA methylation mediates associations between gestational PFAS exposure and health. https://doi.org/10.1289/EHP10118.

Maternal Mediterranean diet in pregnancy and newborn DNA methylation: a meta-analysis in the PACE Consortium.

Higher adherence to the Mediterranean diet during pregnancy is related to a lower risk of preterm birth and to better offspring cardiometabolic health. DNA methylation may be an underlying biological mechanism. We evaluated whether maternal adherence to the Mediterranean diet was associated with offspring cord blood DNA methylation.We meta-analysed epigenome-wide association studies (EWAS) of maternal adherence to the Mediterranean diet during pregnancy and offspring cord blood DNA methylation in 2802 mother-child pairs from five cohorts. We calculated the relative Mediterranean diet (rMED) score with range 0-18 and an adjusted rMED excluding alcohol (rMEDp, range 0-16). DNA methylation was measured using Illumina 450K arrays. We used robust linear regression modelling adjusted for child sex, maternal education, age, smoking, body mass index, energy intake, batch, and cell types. We performed several functional analyses and examined the persistence of differential DNA methylation into childhood (4.5-7.8 y).rMEDp was associated with cord blood DNA methylation at cg23757341 (0.064% increase in DNA methylation per 1-point increase in the rMEDp score, SE = 0.011, P = 2.41 × 10-8). This cytosine-phosphate-guanine (CpG) site maps to WNT5B, associated with adipogenesis and glycaemic phenotypes. We did not identify associations with childhood gene expression, nor did we find enriched biological pathways. The association did not persist into childhood.In this meta-analysis, maternal adherence to the Mediterranean diet (excluding alcohol) during pregnancy was associated with cord blood DNA methylation level at cg23757341. Potential mediation of DNA methylation in associations with offspring health requires further study.

Analysis of Early-Life Growth and Age at Pubertal Onset in US Children.

Importance: Earlier pubertal onset may be associated with an increased risk of chronic diseases. However, the extent to which growth in the first 5 years of life-an important developmental life stage that lays the foundation for later health outcomes-is associated with pubertal onset remains understudied. Objective: To assess whether changes in weight, length or height, and body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) during the first 5 years of life are associated with earlier pubertal onset. Design, Setting, and Participants: This cohort study used data from 36 cohorts participating in the Environmental Influences on Child Health Outcomes program from January 1, 1986, to December 31, 2015. Participant inclusion required at least 1 anthropometric measure in the first 5 years of life and at least 1 measure of pubertal onset. Data were analyzed from January 1 to June 30, 2021. Exposures: Standardized velocities of weight, length or height, and BMI gain in early infancy (0-0.5 years), late infancy (0.5-2 years), and early childhood (2-5 years). Main Outcomes and Measures: Markers of pubertal onset for boys and girls, including age at peak height velocity (APHV), time to puberty score greater than 1, time to Tanner pubic hair stage greater than 1, and time to menarche. Multivariable regression models were used to estimate mean differences in APHV by growth periods. Results: Of 7495 children included in the study, 3772 (50.3%) were girls, 4505 (60.1%) were White individuals, and 6307 (84.1%) were born during or after the year 2000. Girls had a younger APHV (10.8 vs 12.9 years) than boys. In boys, faster weight gain (per 1-SD increase) in early infancy (ß, -0.08 years; 95% CI, -0.10 to -0.06), late infancy (ß, -0.10 years; 95% CI, -0.12 to -0.08), and early childhood (ß, -0.07 years; 95% CI, -0.08 to -0.05) was associated with younger APHV after adjusting for the child's birth year, race, and Hispanic ethnicity as well as maternal age at delivery; educational level during pregnancy; annual household income during pregnancy; prenatal cigarette smoking; whether the mother was nulliparous; whether the mother had gestational diabetes, hypertension, or preeclampsia; mode of delivery; prepregnancy BMI; gestational weight gain; and gestational age at delivery. Similar associations were observed for length or height and BMI gains during the same age periods. In girls, faster gains (per 1-SD increase) in weight (ß, -0.03 years; 95% CI, -0.05 to -0.01) and height (ß, -0.02 years; 95% CI, -0.04 to 0.00) in early childhood were associated with younger APHV. Faster BMI gain in late infancy was associated with earlier time to menarche, whereas faster BMI gain in early childhood was associated with earlier time to Tanner pubic hair stage greater than 1. Conclusions and Relevance: This cohort study found that faster gains in weight, length or height, or BMI in early life were associated with earlier pubertal onset. The results suggest that children who experience faster early growth should be monitored closely for earlier onset of puberty and referred as appropriate for supportive services.

Early-pregnancy maternal body mass index is associated with common DNA methylation markers in cord blood and placenta: a paired-tissue epigenome-wide association study.

Women entering pregnancy with elevated body mass index (BMI) face greater risk of adverse outcomes during pregnancy, delivery, and for their offspring later in life, potentially via epigenetics. If epigenetic programming occurs early during in utero development, the differential marks should be detectable in multiple tissues despite the known unique epigenetic profile in each.We used early-pregnancy BMI as reflection of maternal metabolic milieu exposure in peri-conception and early-pregnancy period. We analysed DNA methylation in paired cord blood and placenta samples among 437 newborns from Gen3G, a pre-birth prospective cohort of primarily European descent. We measured DNA methylation in both tissues across the genome in >720,000 CpG sites using the Illumina MethylationEPIC array. At each site, we used linear mixed models (LMMs) with an unstructured variance-covariance matrix to test for an association between maternal early-pregnancy BMI and DNA methylation in both tissues (modelled as M-values). We adjusted for tissue-specific covariates, offspring sex, gestational age at delivery, and maternal smoking and age.Women had a mean (SD) BMI of 25.4 (5.7) kg/m2 measured at first trimester visit (mean=9.9 weeks). Early-pregnancy BMI was associated with differential DNA methylation levels in paired-tissue analyses at two sites: cg10593758 (ß=0.0126, SE=0.0025; P=4.07e-7), annotated to CRHBP, and cg0762168 (ß=-0.0094, SE=0.0018; P=2.78e-7), annotated to CCDC97.Application of LMMs in DNA methylation data from distinct fetal-origin tissues allowed us to identify CpG sites at which early-pregnancy BMI may have an epigenetic 'programming' effect on overall fetus development. One site (CRHBP) may play a role in hypothalamic-pituitary-adrenal axis regulation.

Association of Mode of Obstetric Delivery With Child and Adolescent Body Composition.

Importance: Although the literature on the association between birth by cesarean delivery and children's anthropometry has continued to increase, only a few studies have examined the association of cesarean delivery with measures of body composition assessed using dual-energy x-ray absorptiometry (DXA), which allows the differentiation of fat and lean mass overall and in specific regions of the body. Objective: To investigate whether differences exist in DXA-measured body composition between children and adolescents born by cesarean delivery and those born by vaginal delivery. Design, Setting, and Participants: This prospective cohort study included singleton children of mothers enrolled between April 1999 and July 2002 in Project Viva, a longitudinal prebirth cohort of mother-child pairs in Massachusetts. The children had at least 1 DXA scan at a follow-up visit during middle childhood (2007-2010) and/or early adolescence (2013-2016). Data analysis was performed from October 16, 2020, to May 9, 2021. Exposures: Mode of delivery (cesarean vs vaginal). Main Outcomes and Measures: Total lean mass index, total and truncal fat mass indexes, visceral adipose tissue (VAT), subcutaneous abdominal adipose tissue, and total abdominal adipose tissue (TAAT) were estimated using DXA. Multivariable linear regression models were used to estimate the association between mode of delivery and DXA-derived outcomes with adjustment for confounders. Stabilized inverse probability weights were used to control for potential selection bias owing to loss to follow-up. Results: A total of 975 mother-child pairs were included in the study. The mean (SD) maternal age at study entry was 32.0 (5.5) years, and the mean (SD) self-reported prepregnancy body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) was 25.0 (5.4). Of the children included in the study, 491 (50%) were female; 212 (22%) were born by cesarean delivery and 763 (78%) by vaginal delivery. Body composition in middle childhood as measured by DXA did not differ by mode of delivery. In early adolescence, participants born by cesarean delivery had a significantly greater total lean mass index (ß, 0.4; 95% CI, 0.0-0.7), total fat mass index (ß, 0.6; 95% CI, 0.1-1.1), truncal fat mass index (ß, 0.3; 95% CI, 0.0-0.5), VAT area (ß, 4.7; 95% CI, 0.9-8.6), and TAAT area (ß, 23.8; 95% CI, 0.8-46.8) in a model adjusted for child sex and age at the time of DXA measurements; maternal age, educational level, race and ethnicity, total gestational weight gain, and smoking status during pregnancy; birth-weight-per-gestational-age z score; and paternal BMI. Associations between mode of delivery and measures of adiposity were found for cesarean deliveries performed in the absence of labor (total fat mass index: ß, 1.3; 95% CI, 0.3-2.3; truncal fat mass index: ß, 0.6; 95% CI, 0.1-1.0; VAT area: ß, 10.7; 95% CI, 3.1-18.3; TAAT area: ß, 47.3; 95% CI, 2.3-92.2). There were no associations after adjustment for maternal self-reported prepregnancy BMI (total lean mass index: ß, 0.2; 95% CI, -0.1 to 0.6; total fat mass index: ß, 0.4; 95% CI, -0.1 to 0.9; truncal fat mass index: ß, 0.2; 95% CI, -0.1 to 0.4; VAT area: ß, 3.0; 95% CI, -0.6 to 6.7; TAAT area: ß, 13.6; 95% CI, -8.2 to 35.3). Conclusions and Relevance: In this cohort study, adolescents born by cesarean delivery had significantly higher measures of lean mass, fat mass, and central adiposity compared with those born by vaginal delivery, but associations did not remain after adjustment for the mothers' self-reported prepregnancy BMI. The findings suggest that the association between birth by cesarean delivery and adolescent adiposity may partly be explained by maternal self-reported prepregnancy BMI.

Placental DNA methylation signatures of maternal smoking during pregnancy and potential impacts on fetal growth.

Maternal smoking during pregnancy (MSDP) contributes to poor birth outcomes, in part through disrupted placental functions, which may be reflected in the placental epigenome. Here we present a meta-analysis of the associations between MSDP and placental DNA methylation (DNAm) and between DNAm and birth outcomes within the Pregnancy And Childhood Epigenetics (PACE) consortium (N = 1700, 344 with MSDP). We identify 443 CpGs that are associated with MSDP, of which 142 associated with birth outcomes, 40 associated with gene expression, and 13 CpGs are associated with all three. Only two CpGs have consistent associations from a prior meta-analysis of cord blood DNAm, demonstrating substantial tissue-specific responses to MSDP. The placental MSDP-associated CpGs are enriched for environmental response genes, growth-factor signaling, and inflammation, which play important roles in placental function. We demonstrate links between placental DNAm, MSDP and poor birth outcomes, which may better inform the mechanisms through which MSDP impacts placental function and fetal growth.

Associations of maternal insulin resistance during pregnancy and offspring inflammation at birth and at 5 years of age: A prospective study in the Gen3G cohort.

BACKGROUND: Maternal insulin resistance is associated with greater maternal inflammation during pregnancy, but its relation to inflammation in offspring remains unclear. The goal of this study was to assess the relationship of gestational insulin resistance and other glycemic markers with offspring inflammation at birth and at 5 years of age. METHODS: We included 653 mother-child pairs from the prospective pre-birth Gen3G cohort. We examined maternal insulin and glucose levels measured during the second trimester of pregnancy, from which we derived the homeostatic model of assessment of insulin resistance (HOMA-IR) and the Matsuda index. We assessed offspring inflammation at birth and at 5 years of age by measuring plasma tumor necrosis factor-α (TNFα) concentrations. We conducted multivariable regression models to evaluate associations of each insulin and glucose marker with offspring inflammation adjusting for confounding variables. RESULTS: Higher levels of fasting insulin were associated with lower TNFα levels at birth (-0.78, 95% CI [-1.45, -0.11]), in the fully adjusted model. We observed similar associations with the HOMA-IR and opposite direction with the Matsuda index. We did not find persistence of the association between maternal fasting insulin and offspring TNFα at 5 years of age. CONCLUSIONS: Greater maternal insulin resistance during pregnancy was associated with lower cord blood TNFα levels in newborns. The mechanisms by which maternal insulin resistance may promote lower inflammatory levels in newborns are not fully understood and more research is needed to deepen our understanding of these mechanisms.

DNA methylation of blood cells is associated with prevalent type 2 diabetes in a meta-analysis of four European cohorts.

BACKGROUND: Type 2 diabetes (T2D) is a heterogeneous disease with well-known genetic and environmental risk factors contributing to its prevalence. Epigenetic mechanisms related to changes in DNA methylation (DNAm), may also contribute to T2D risk, but larger studies are required to discover novel markers, and to confirm existing ones. RESULTS: We performed a large meta-analysis of individual epigenome-wide association studies (EWAS) of prevalent T2D conducted in four European studies using peripheral blood DNAm. Analysis of differentially methylated regions (DMR) was also undertaken, based on the meta-analysis results. We found three novel CpGs associated with prevalent T2D in Europeans at cg00144180 (HDAC4), cg16765088 (near SYNM) and cg24704287 (near MIR23A) and confirmed three CpGs previously identified (mapping to TXNIP, ABCG1 and CPT1A). We also identified 77 T2D associated DMRs, most of them hypomethylated in T2D cases versus controls. In adjusted regressions among diabetic-free participants in ALSPAC, we found that all six CpGs identified in the meta-EWAS were associated with white cell-types. We estimated that these six CpGs captured 11% of the variation in T2D, which was similar to the variation explained by the model including only the common risk factors of BMI, sex, age and smoking (R2 = 10.6%). CONCLUSIONS: This study identifies novel loci associated with T2D in Europeans. We also demonstrate associations of the same loci with other traits. Future studies should investigate if our findings are generalizable in non-European populations, and potential roles of these epigenetic markers in T2D etiology or in determining long term consequences of T2D.

Per- and polyfluoroalkyl substances and calcifications of the coronary and aortic arteries in adults with prediabetes: Results from the diabetes prevention program outcomes study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are endocrine disrupting chemicals that have been associated with cardiovascular risk factors including elevated body weight and hypercholesterolemia. Therefore, PFAS may contribute to the development of atherosclerosis and cardiovascular disease (CVD). However, no previous study has evaluated associations between PFAS exposure and arterial calcification. METHODS AND RESULTS: This study used data from 666 prediabetic adults enrolled in the Diabetes Prevention Program trial who had six PFAS quantified in plasma at baseline and two years after randomization, as well as measurements of coronary artery calcium (CAC) and ascending (AsAC) and descending (DAC) thoracic aortic calcification 13-14 years after baseline. We performed multinomial regression to test associations between PFAS and CAC categorized according to Agatston score [low (<10), moderate (11-400) and severe (>400)]. We used logistic regression to assess associations between PFAS and presence of AsAC and DAC. We adjusted models for baseline sex, age, BMI, race/ethnicity, cigarette smoking, education, treatment assignment (placebo or lifestyle intervention), and statin use. PFAS concentrations were similar to national means; 53.9% of participants had CAC > 11, 7.7% had AsAC, and 42.6% had DAC. Each doubling of the mean sum of plasma concentrations of linear and branched isomers of perfluorooctane sulfonic acid (PFOS) was associated with 1.49-fold greater odds (95% CI: 1.01, 2.21) of severe versus low CAC. This association was driven mainly by the linear (n-PFOS) isomer [1.54 (95% CI: 1.05, 2.25) greater odds of severe versus low CAC]. Each doubling of mean plasma N-ethyl-perfluorooctane sulfonamido acetic acid concentration was associated with greater odds of CAC in a dose-dependent manner [OR = 1.26 (95% CI:1.08, 1.47) for moderate CAC and OR = 1.37 (95% CI:1.07, 1.74) for severe CAC, compared to low CAC)]. Mean plasma PFOS and n-PFOS were also associated with greater odds of AsAC [OR = 1.67 (95% CI:1.10, 2.54) and OR = 1.70 (95% CI:1.13, 2.56), respectively], but not DAC. Other PFAS were not associated with outcomes. CONCLUSIONS: Prediabetic adults with higher plasma concentrations of select PFAS had higher risk of coronary and thoracic aorta calcification. PFAS exposure may be a risk factor for adverse cardiovascular health among high-risk populations.

A prospective study of maternal adiposity and glycemic traits across pregnancy and mid-childhood metabolomic profiles.

BACKGROUND: Fetal exposure to maternal excess adiposity and hyperglycemia is risk factors for childhood adverse metabolic outcomes. Using data from a prospective pre-birth cohort, we aimed to further understand the prenatal determinants of fetal metabolic programming based on analyses of maternal adiposity and glycemic traits across pregnancy with childhood metabolomic profiles. METHODS: This study included 330 mother-child pairs from the Gen3G cohort with information on maternal adiposity and glycemic markers at 5-16 (visit 1) and 24-30 (visit 2) weeks of pregnancy. At mid-childhood (4.8-7.2 years old), we collected fasting plasma and measured 1116 metabolites using an untargeted approach. We constructed networks of interconnected metabolites using a weighted-correlation network analysis algorithm. We estimated Spearman's partial correlation coefficients of maternal adiposity and glycemic traits across pregnancy with metabolite networks and individual metabolites, adjusting for maternal age, gravidity, race/ethnicity, history of smoking, and child's sex and age at blood collection for metabolite measurement. RESULTS: We identified a network of 16 metabolites, primarily glycero-3-phosphoethanolamines (GPE) at mid-childhood that showed consistent negative correlations with maternal body mass index, waist circumference, and body-fat percentage at visits 1 and 2 (ρadjusted = -0.14 to -0.21) and post-challenge glucose levels at visit 2 (ρadjusted = -0.10 to -0.13), while positive correlations with Matsuda index (ρadjusted = 0.13). Within this identified network, 1-palmitoyl-2-decosahexaenoyl-GPE and 1-stearoyl-2-decosahexaenoyl-GPE appeared to be driving the associations. In addition, a network of 89 metabolites, primarily phosphatidylcholines, plasmalogens, sphingomyelins, and ceramides showed consistent negative correlations with insulin at visit 1 and post-challenge glucose at visit 2, while positive correlation with adiponectin at visit 2. CONCLUSIONS: Prenatal exposure to maternal higher adiposity and hyperglycemic traits and lower insulin sensitivity markers were associated with a unique metabolomic pattern characterized by low serum phospho- and sphingolipids in mid-childhood.