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.

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.

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.

Precipitation and Adolescent Respiratory Health in the Northeast United States.

Rationale: With more frequent and intense precipitation events across the globe due to a changing climate, there is a need to understand the relationship between precipitation and respiratory health. Precipitation may trigger asthma exacerbations, but little is known about how precipitation affects lung function and airway inflammation in early adolescents. Objectives: To determine if short-term precipitation exposure is associated with lung function and airway inflammation in early adolescents and if ever having a diagnosis of asthma modifies associations of precipitation with lung function and airway inflammation. Methods: In a prospective prebirth cohort, Project Viva, that included 1,019 early adolescents born in the northeastern United States, we evaluated associations of 1-, 2-, 3-, and 7-day moving averages of precipitation in the preceding week and forced expiratory volume in 1 second, forced vital capacity, and fractional exhaled nitric oxide (FeNO) using linear regression. We used log-transformed FeNO with effect estimates presented as percentage change. We adjusted for maternal education and household income at enrollment; any smoking in the home in early adolescence; child sex, race/ethnicity, and ever asthma diagnosis; and age, height, weight, date, and season (as sine and cosine functions of visit date) at the early adolescent visit and moving averages for mean daily temperature (same time window as exposure). Results: In fully adjusted linear models, 3- and 7-day moving averages for precipitation were positively associated with FeNO but not lung function. Every 2-mm increase in the 7-day moving average for precipitation was associated with a 4.0% (95% confidence interval, 1.1, 6.9) higher FeNO. There was evidence of effect modification by asthma status: Precipitation was associated with lower forced vital capacity and higher FeNO among adolescents with asthma. We also found that outdoor aeroallergen sensitization (immunoglobulin E against common ragweed, oak, ryegrass, or silver birch) modified associations of precipitation with FeNO, with higher FeNO in sensitized adolescents compared with nonsensitized adolescents. The associations of precipitation with FeNO were not explained by relative humidity or air pollution exposure. Conclusions: We found that greater short-term precipitation may trigger airway inflammation in adolescents, particularly among those with asthma.

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.

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.

Self-Reported Total Screen Time and Viewing Modes Are Associated with Body Dissatisfaction, Disordered Eating, and Cosmetic Surgery Intentions among Young Adults.

While numerous studies have shown that media exposure is linked to body dissatisfaction and disordered eating behavior, limited research has examined these associations by screen-viewing mode. This study examined associations of total screen-time and screen-viewing modes with body dissatisfaction, disordered eating, and cosmetic surgery intention among young adults. Men (n = 3466) and women (n = 7300), aged 19 to 34 years, self-reported their screen-time on various TV viewing modes, and their body dissatisfaction, overeating, disordered weight control behaviors, and cosmetic surgery intentions. We fit linear, logistic, and multivariate models to examine cross-sectional associations between total screen-time and screen-viewing modes and body dissatisfaction, disordered eating, and cosmetic surgery intention. Handheld viewing was associated with body dissatisfaction for women only, and online viewing was associated with greater body dissatisfaction among both men (߈ = 0.40; 95% CI, 0.15 to 0.65) and women (߈ = 0.25; 95% CI, 0.10 to 0.40). Downloaded viewing was associated with higher odds of overeating behaviors among both men (OR = 1.24; 95% CI, 1.10 to 1.40) and women (OR = 1.21; 95% CI, 1.12 to 1.32), respectively. Although total screen time was associated with greater cosmetic surgery intention for both men (߈ = 0.24; 95% CI, 0.09 to 0.39) and women (߈ = 0.43; 95% CI, 0.28 to 0.58), sex differences were found for the viewing modes. Our results suggest that different viewing modes may be differently associated with men and women's body image, disordered eating behavior, and cosmetic surgery intention. Future research should consider all modes of screen-viewing in our media environment.

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.

Associations of maternal non-nutritive sweetener intake during pregnancy with offspring body mass index and body fat from birth to adolescence.

BACKGROUND/OBJECTIVE: The evidence that maternal non-nutritive sweetener (NNS) intake during pregnancy increases childhood obesity risk is conflicting. A potential reason for this is that all prior studies examined childhood body mass index (BMI) at only one timepoint and at different ages. We examined the extent to which NNS intake during pregnancy is associated with offspring BMI z-score and body fat longitudinally from birth to 18 years. SUBJECTS: A total of 1683 children from Project Viva, a prospective pre-birth cohort, were recruited from 1999 to 2002 in Massachusetts. METHODS: We assessed maternal NNS intake in the first and second trimesters of pregnancy using a semiquantitative food frequency questionnaire. Our outcomes were offspring BMI z-score, (at birth, infancy (median 6.3 months), early childhood (3.2 years), mid-childhood (7.7 years), and early adolescence (12.9 years)), sum of skinfolds (SS), fat mass index (FMI) measured by dual x-ray absorptiometry, and BMI z-score trajectory from birth to 18 years. We adjusted models for maternal pre-pregnancy BMI, age, race/ethnicity, education, parity, pre-pregnancy physical activity, smoking, and paternal BMI and education. RESULTS: A total of 70% of mothers were white and pre-pregnancy BMI was 24.6 ± 5.2 kg/m2. The highest quartile of NNS intake (Q4: 0.98 ± 0.91 servings/day) was associated with higher BMI z-score in infancy (ß 0.20 units; 95% CI 0.02, 0.38), early childhood (0.21; 0.05, 0.37), mid-childhood (0.21; 0.02, 0.40), and early adolescence (0.14; -0.07, 0.35) compared with Q1 intake (Q1: 0.00 ± 0.00 servings/day). Q4 was also associated with higher SS in early childhood (1.17 mm; 0.47, 1.88), mid-childhood (2.33 mm; 0.80, 3.87), and early adolescence (2.27 mm; -0.06, 4.60) and higher FMI in mid-childhood (0.26 kg/m2; -0.07, 0.59). Associations of maternal NNS intake with offspring BMI z-score became stronger with increasing age from 3 to 18 years (Pinteraction < 0.0001). CONCLUSIONS: Maternal NNS intake during pregnancy is associated with increased childhood BMI z-score and body fat from birth to teenage years. This is relevant given the escalating obesity epidemic, and popularity of NNS.

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.

Maternal Midpregnancy Leptin and Adiponectin Levels as Predictors of Autism Spectrum Disorders: A Prenatal Cohort Study.

CONTEXT: Autism spectrum disorders (ASDs) are a group of conditions characterized by impaired social function and repetitive behaviors. Their etiology is largely unknown. OBJECTIVE: This work aims to examine the associations of maternal second-trimester and cord blood leptin and adiponectin levels with ASDs in offspring. METHODS: We used data from 1164 mother-child pairs enrolled in Project Viva, a prospective prebirth cohort. We used logistic regression analysis to examine the associations of leptin and adiponectin levels in maternal second-trimester blood and cord blood obtained at birth with ASDs. Additionally, we examined the association of maternal prepregnancy body mass index (BMI) as an exposure. Main outcome measures included doctor-diagnosed ASDs reported by mothers using questionnaires in midchildhood and early adolescence. RESULTS: The cumulative incidence of ASDs was 3.4%. Maternal prepregnancy BMI (per 5 points) was positively associated with ASDs in a logistic regression model adjusted for maternal race/ethnicity, education, smoking status and child sex (adjusted odds ratio [OR] 1.38; 95% CI, 1.06-1.79). Higher second-trimester adiponectin was associated with lower odds of ASD in offspring (unadjusted OR 0.49; 95% CI, 0.30-0.78; and OR 0.54; 95% CI, 0.32-0.91 after adjusting for maternal race/ethnicity, education, child sex, OR 0.55; 95% CI, 0.33-0.93 after adjusting for BMI, gestational weight gain, gestational diabetes, and smoking status). Maternal leptin and cord blood leptin and adiponectin levels were not associated with ASDs. CONCLUSION: Prepregnancy BMI and adiponectin during pregnancy may be useful as a tool to monitor the risk of autism. Increasing adiponectin levels prenatally may play a role in the prevention of ASDs.

Contributions of asthma, rhinitis and IgE to exhaled nitric oxide in adolescents.

Exhaled nitric oxide fraction (F eNO) is an indicator of allergic airway inflammation. However, it is unknown how asthma, allergic rhinitis (AR) and allergic sensitisation relate to F eNO, particularly among adolescents and in overlapping conditions. We sought to determine the associations between asthma, AR, and aeroallergen immunoglobulin (Ig)E and F eNO in adolescents. We measured F eNO among 929 adolescents (aged 11-16 years) in Project Viva, an unselected prebirth cohort in Massachusetts, USA. We defined asthma as ever asthma physician diagnosis plus wheezing in the past year or taking asthma medications in the past month, AR as a physician diagnosis of hay fever or AR, and aeroallergen IgE as any IgE >0.35 IU·mL-1 among 592 participants who provided blood samples. We examined associations of asthma, AR and IgE with percent difference in F eNO in linear regression models adjusted for sex, race/ethnicity, age and height, maternal education and smoking during pregnancy, and household/neighbourhood demographics. Asthma (14%) was associated with 97% higher F eNO (95% CI 70-128%), AR (21%) with 45% higher F eNO (95% CI 28-65%), and aeroallergen IgE (58%) with 102% higher F eNO (95% CI 80-126%) compared to those without each condition, respectively. In the absence of asthma or AR, aeroallergen IgE was associated with 75% higher F eNO (95% CI 52-101), while asthma and AR were not associated with F eNO in the absence of IgE. The link between asthma and AR with F eNO is limited to those with IgE-mediated phenotypes. F eNO may be elevated in those with allergic sensitisation alone, even in the absence of asthma or AR.

Maternal glucose tolerance in pregnancy and child cognitive and behavioural problems in early and mid-childhood.

BACKGROUND: Maternal abnormal glucose tolerance during pregnancy may adversely affect offspring cognition and behaviour, but few prospective studies investigated this association at multiple points throughout childhood. OBJECTIVES: We hypothesised that maternal abnormal glucose tolerance is associated with child cognitive and behavioural outcomes in early and mid-childhood. METHODS: We examined the associations of maternal abnormal glucose tolerance at 26-28 weeks of pregnancy with offspring cognitive and behavioural scores in 1421 children in the Project Viva pre-birth cohort. In early (mean 3.3 years) and mid-childhood (mean 7.9 years), we measured child cognition using validated instruments, the Kaufman Brief Intelligence Test, Wide Range Assessment of Memory and Learning, and the Wide Range Assessment of Visual Motor Abilities (WRAVMA); we assessed parent- and teacher-rated behavioural outcomes with the Strengths and Difficulties Questionnaire and the Behavioural Rating Inventory of Executive Function. We used linear regression models adjusted for potential confounders (maternal race/ethnicity, pre-pregnancy BMI, intelligence, age, parity, smoking status, education, and household income at enrolment, in addition to child's sex and age at assessment). RESULTS: Of 1421 mothers, 69 (4.9%) had gestational diabetes mellitus, 43 (3.0%) impaired glucose tolerance, 122 (8.6%) isolated hyperglycaemia, and 1187 (83.5%) normal glucose tolerance. Offspring born to women with gestational diabetes mellitus had lower total WRAVMA scores (-3.09 points; 95% CI -6.12, -0.05) in early childhood compared with offspring of women with normal glucose tolerance. None of the abnormal glucose tolerance categories during pregnancy were associated with any of the cognitive outcomes (verbal, non-verbal, and visual motor scores) or behavioural measures in mid-childhood. CONCLUSIONS: Children born to mothers who had gestational diabetes mellitus had slightly lower scores on one cognitive test in early childhood. We found no evidence to support that maternal abnormal glucose tolerance was associated with cognitive or behavioural development in mid-childhood.

Longitudinal associations of modifiable risk factors in the first 1000 days with weight status and metabolic risk in early adolescence.

BACKGROUND: Many studies have identified early-life risk factors for childhood overweight/obesity (OwOb), but few have evaluated how they combine to influence later cardiometabolic health. OBJECTIVES: We aimed to examine the association of risk factors in the first 1000 d with adiposity and cardiometabolic risk in early adolescence. METHODS: We studied 1038 mother-child pairs in Project Viva. We chose 6 modifiable early-life risk factors previously associated with child adiposity or metabolic health in the cohort: smoking during pregnancy (yes compared with no); gestational weight gain (excessive compared with nonexcessive); sugar-sweetened beverage consumption during pregnancy (≥0.5 compared with <0.5 servings/d); breastfeeding duration (<12 compared with ≥12 mo); timing of complementary food introduction (<4 compared with ≥4 mo); and infant sleep duration (<12 compared with ≥12 h/d). We computed risk factor scores by calculating the cumulative number of risk factors for each child. In early adolescence (median: 13.1 y) we measured indicators of adiposity [BMI, fat mass index (FMI), trunk fat mass index (TFMI)]. We also calculated OwOb prevalence and metabolic syndrome (MetS) risk z score of adolescents. RESULTS: Among 1038 adolescents, 71% had >1 early-life risk factor. In covariate-adjusted models, we observed positive monotonic increases in BMI, FMI, TFMI, and MetS z scores with increasing risk factor score. Children with 5‒6 risk factors (compared with 0-1 risk factors) had the highest risk of OwOb [risk ratio (RR): 2.53; 95% CI: 1.63, 3.91] and being in the highest MetS quartile (RR: 2.46; 95% CI: 1.43, 4.21). The predicted probability of OwOb in adolescence varied from 9.4% (favorable levels for all factors) to 63.6% (adverse levels for all factors), and for being in the highest MetS quartile from 9.6% to 56.6%. CONCLUSIONS: Early-life risk factors in the first 1000 d cumulatively predicted higher adiposity and cardiometabolic risk in early adolescence. Intervention strategies to prevent later obesity and cardiometabolic risk may be more effective if they concurrently target multiple modifiable factors.

Pregnancy Per- and Polyfluoroalkyl Substance Concentrations and Postpartum Health in Project Viva: A Prospective Cohort.

CONTEXT: Per- and polyfluoroalkyl substances (PFAS) are environmental chemicals linked to weight gain and type 2 diabetes. OBJECTIVE: We examined the extent to which PFAS plasma concentrations during pregnancy were associated with postpartum anthropometry and biomarkers. DESIGN, PATIENTS, AND MEASURES: We studied women recruited between 1999 and 2002 in the Project Viva prospective cohort with pregnancy plasma concentrations of PFAS, including perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and 2-(N-ethyl-perfluorooctane sulfonamide) acetic acid (EtFOSAA). Three-year postpartum anthropometry measurements were available from 786 to 801 women, blood pressure from 761 women, and blood biomarkers from 450 to 454 women. We used multivariable regression to evaluate the association of log2-transformed PFAS with postpartum anthropometry, blood pressure, and blood biomarkers (leptin, adiponectin, sex hormone binding globulin [SHBG], hemoglobin A1c, interleukin-6 [IL-6], C-reactive protein), adjusting for age, prepregnancy body mass index, marital status, race/ethnicity, education, income, smoking, parity, and breastfeeding history. RESULTS: Pregnancy concentrations of certain PFAS were associated with greater adiposity (eg, 0.4 cm [95% confidence interval [95%CI]: -0.1, 0.9] greater waist circumference per doubling in EtFOSAA; 0.2 cm [95%CI: -0.1, 0.5] greater mid-upper arm circumference per doubling in PFOA; 1.2 mm [95%CI: 0.1, 2.2] thicker sum of subscapular and triceps skinfolds per doubling in PFOS) and higher systolic blood pressure (eg, 1.2 mm Hg [95%CI: 0.3, 2.2] per doubling in PFOS) at 3 years postpartum. Higher EtFOSAA concentrations were also associated with 10.8% higher IL-6 (95%CI: 3.3, 18.9) and 6.1% lower SHBG (95%CI: 0.7, 11.2) per doubling. CONCLUSIONS: Pregnancy concentrations of EtFOSAA, PFOS, and PFOA were associated with adverse postpartum cardiometabolic markers.

Associations of α- and γ-tocopherol during early life with lung function in childhood.

BACKGROUND: Tocopherol isoforms may regulate child lung growth and spirometric measures. OBJECTIVE: Our aim was to determine the extent to which plasma α-tocopherol (α-T) or γ-tocopherol (γ-T) isoform levels in early childhood or in utero are associated with childhood lung function. METHODS: We included 622 participants in the Project Viva cohort who had lung function at a mid-childhood visit (age 6-10 years). Maternal and child tocopherol isoform levels were measured by HPLC at the second trimester and 3 years of age, respectively. Multivariable linear regression models (adjusted for mid-childhood body mass index z scores, maternal education, smoking in pregnancy, and prenatal particulate matter with diameter of <2.5 micrometers (PM2.5) particulate exposure) stratified by tertiles of child γ-T level were used to assess the association of α-T levels with FEV1 and forced vital capacity (FVC) percent predicted. Similarly, models stratified by child α-T tertile evaluated associations of γ-T levels with lung function. We performed similar analyses with maternal second trimester tocopherol isoform levels. RESULTS: The median maternal second trimester α-T level was 63 µM (interquartile range = 47-82). The median early-childhood level was 25 µM (interquartile range = 20-33 µM). In the lowest tertile of early-childhood γ-T, children with a higher α-T level (per 10 µM) had a higher mid-childhood FEV1 percent predicted (ß = 3.09; 95% CI = 0.58-5.59 and a higher FVC percent predicted (ß = 2.77; 95% CI = 0.47-5.06). This protective association of α-T was lost at higher γ-T levels. We did not see any consistent associations of second trimester levels of either α-T or γ-T with mid-childhood FEV1 or FVC. CONCLUSION: When γ-T levels were in the lowest tertile, a higher early-childhood α-T level was associated with better lung function at mid-childhood. Second trimester maternal plasma α-T concentration was 3-fold higher than in the adult nonpregnant female population.

Prenatal and childhood predictors of hair cortisol concentration in mid-childhood and early adolescence.

BACKGROUND: Hair cortisol concentration (HCC) is an increasingly used measure of systemic cortisol concentration. However, determinants of HCC in children and adolescents are unclear because few prospective studies have been conducted to date. STUDY DESIGN: We followed 725 children in Project Viva, a pre-birth cohort study of mothers and children, who provided hair samples at mid-childhood (median age: 7.7 years) or early adolescence (median age: 12.9 years). We examined associations of various factors measured from pregnancy to mid-childhood with HCC in mid-childhood and early adolescence, as well as change in HCC between these time points (ΔHCC). RESULTS: There were 426 children with HCC measurements in both mid-childhood and early adolescence, 173 children with measures only in mid-childhood, and 126 with measures only in early adolescence. HCC was lower in mid-childhood (median 1.0pg/mg [interquartile range, IQR: 0.5, 2.4]) than early adolescence (2.2pg/mg [1.1, 4.4]). In multivariable-adjusted regression models, female sex (ß = -0.41, 95% CI: -0.67, -0.15) and birth weight-for-gestational age z-score (ß = -0.19, 95% CI: -0.33, -0.04) were associated with lower mid-childhood HCC, while prenatal smoking was associated with higher mid-childhood HCC (ß = 0.53, 95% CI: 0.04, 1.01). In early adolescence, child age (ß = 0.34 per year, 95% CI: 0.21, 0.46) female sex (ß = 0.33, 95% CI: 0.10, 0.57), and maternal pre-pregnancy body mass index (ß = 0.15 per 5-kg/m2, 95% CI: 0.01, 0.29) were positively associated with HCC. Child anthropometric measures and biomarker concentrations were not associated with HCC. CONCLUSION: Maternal pre-pregnancy BMI, maternal prenatal smoking, and low birth weight were associated with higher mid-childhood and adolescent HCC. However, few postnatal characteristics were associated with HCC.

Associations of acetaminophen use during pregnancy and the first year of life with neurodevelopment in early childhood.

BACKGROUND: Over-the-counter analgesic use during pregnancy, particularly acetaminophen, may be associated with negative developmental outcomes in children. OBJECTIVE: Estimate associations of prenatal and early-life exposure to acetaminophen in early childhood with cognitive, motor, and language skills in two birth cohorts. METHODS: The American Project Viva cohort (1217 mother-child pairs enrolled 1999-2002) assessed cognition at approximately 3 years using the Peabody Picture Vocabulary Test and the Wide Range Achievement of Visual Motor Abilities (WRAVMA). The Brazilian 2015 Pelotas Birth Cohort (3818 mother-child pairs) assessed cognition at 2 years using the INTERGROWTH-21st Neurodevelopment Assessment. We used linear regression to estimate associations of acetaminophen use during pregnancy (Project Viva and Pelotas) and infancy (Project Viva) with children's cognitive scores adjusted for maternal age, pre-pregnancy body mass index, education, parity, race/ethnicity, smoking and alcohol use during pregnancy, depression during pregnancy, antibiotic and ibuprofen use during pregnancy, household income, and child's sex. RESULTS: In Project Viva, exposure to acetaminophen in both the 1st and 2nd trimester of pregnancy was associated with lower WRAVMA drawing scores (ß -1.51, 95% CI -2.92, -0.10). However, in Pelotas, exposure to acetaminophen in both the 1st and 2nd trimester of pregnancy was not associated with INTER-NDA motor scores (ß 0.02; 95% CI -0.05, 0.09) and was associated with higher INTER-NDA total scores (ß 0.08, 95% CI 0.01, 0.16). Other comparisons did not show evidence for any associations. CONCLUSIONS: Inconsistencies and lack of specificity of the findings did not clarify the research question considering that we still have a large variability and uncertainty to define the risk or safety in the use of acetaminophen related to cognition in early childhood. More studies using better exposure assessment and better confounding variables are needed to clarify these associations.