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OBJECTIVE Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are suspected endocrine disruptors widely detected across populations. We examine the extent to which PFASs are associated with diabetes incidence and microvascular disease. Secondarily, we tested whether a lifestyle intervention modifies associations and decreases concentrations. RESEARCH DESIGN AND METHODS We analyzed data from a prospective cohort of 957 participants from the Diabetes Prevention Program (DPP) trial and Diabetes Prevention Program Outcomes Study (DPPOS). At baseline, participants were randomized to an intensive lifestyle intervention of diet, physical activity, and behavior modification or a placebo medication. We quantified plasma concentrations of six PFASs at baseline and 2 years after randomization. Participants were monitored for ∼15 years, repeatedly tested for diabetes, and evaluated for microvascular disease at the end of the follow-up. RESULTS A doubling in baseline branched perfluorooctanoic acid concentration was associated with a 14% increase in diabetes risk for the placebo (hazard ratio [HR] 1.14, 95% CI 1.04, 1.25) but not in the lifestyle intervention group (HR 1.01, 95% CI 0.92, 1.11, Pinteraction = 0.11). Mean change in plasma baseline branched perfluorooctanoic acid concentration was greater for the placebo (0.96 ng/mL; 95% CI 0.71, 1.22) compared with the lifestyle intervention group (0.31 ng/mL; 95% CI 0.14, 0.48) 2 years after randomization. Each doubling in N-ethyl-perfluorooctane sulfonamido acetic acid was associated with 17% greater odds of prevalent microvascular disease (OR 1.17, 95% CI 1.05, 1.31), and a similar association was observed for perfluorodimethylhexane sulfonic acid (OR 1.18, 95% CI 1.04, 1.35), regardless of treatment. CONCLUSIONS Some plasma PFASs were associated with diabetes and microvascular disease. Our results suggest that exercise and diet may attenuate the diabetogenic association of PFASs.

BackgroundPer- 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 resultsThis 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 13-14years after baseline. We performed multinomial regression to test associations between PFAS and CAC categorized according to Agatston score [low (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.ConclusionsPrediabetic 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.

Context Per- and polyfluoroalkyl substances (PFAS) may alter body composition by lowering anabolic hormones and increasing inflammation, but data are limited, particularly in adolescence when body composition is rapidly changing. Objective To evaluate associations of PFAS plasma concentrations in childhood with change in body composition through early adolescence. Methods A total of 537 children in the Boston-area Project Viva cohort participated in this study. We used multivariable linear regression and Bayesian kernel machine regression (BKMR) to examine associations of plasma concentrations of 6 PFAS, quantified by mass spectrometry, in mid-childhood (mean age, 7.9 years; 2007-2010) with change in body composition measured by dual-energy x-ray absorptiometry from mid-childhood to early adolescence (mean age, 13.1 years). Results In single-PFAS linear regression models, children with higher concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorodecanoate (PFDA), and perfluorohexane sulfonate (PFHxS) had less accrual of lean mass (eg, −0.33 [95% CI: −0.52, −0.13] kg/m2 per doubling of PFOA). Children with higher PFOS and PFHxS had less accrual of total and truncal fat mass (eg, −0.32 [95% CI: −0.54, −0.11] kg/m2 total fat mass per doubling of PFOS), particularly subcutaneous fat mass (eg, −17.26 [95% CI −32.25, −2.27] g/m2 per doubling of PFOS). Children with higher PFDA and perfluorononanoate (PFNA) had greater accrual of visceral fat mass (eg, 0.44 [95% CI: 0.13, 0.75] g/m2 per doubling of PFDA). Results from BKMR mixture models were consistent with linear regression analyses. Conclusion Early life exposure to some but not all PFAS may be associated with adverse changes in body composition.

Background: Per- and polyfluoroalkyl substances (PFAS) are widely used chemicals, some of which have been linked to type 2 diabetes. We tested whether PFAS concentrations were cross-sectionally associated with metabolites previously shown to predict incident type 2 diabetes using the Diabetes Prevention Program (DPP), a trial of individuals at high risk of type 2 diabetes. Methods: We evaluated 691 participants enrolled in the DPP with baseline measures of 10 PFAS (including total perfluorooctanesulfonic acid (PFOS), total perfluorooctanoic acid (PFOA), and Sb-PFOA [branched isomers of PFOA]) and 77 metabolites. We used log2-transformed PFAS concentrations as exposures and standardized metabolite concentrations as outcomes in linear regression models adjusted for age, sex, race/ethnicity, use of anti-hyperlipidemic or triglyceride-lowering medication, income, years of education, marital status, smoking, and family history of diabetes, with Benjamini-Hochberg linear step-up false discovery rate correction. Results: Sb-PFOA was associated with the largest number of tested metabolites (29 of 77). Each doubling in Sb-PFOA was associated with higher leucine (β=0.07 [95%CI: 0.02, 0.11] SD) and lower glycine (-0.08 [95%CI: -0.03, -0.13] SD). Each doubling of either total PFOA or n-PFOA was associated with -0.13 [95%CI: -0.04, -0.22] SD lower glycine. PFOA and Sb-PFOA were positively associated with multiple triacylglycerols and diacylglycerols, and total PFOS, total PFOA, and Sb-PFOA were positively associated with phosphatidylethanolamines.Conclusions: PFAS concentrations are associated with metabolites linked to type 2 diabetes (particularly amino acid, glycerolipid and glycerophospholipid pathways). Further prospective research is needed to test whether these metabolites mediate associations of PFAS and type 2 diabetes.

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.

Background Exposure to ionizing radiation increases the risk of chronic metabolic disorders such as insulin resistance and type 2 diabetes. Internal ionizing radiation from inhaled radioactive aerosol may contribute to the associations between fine particulate matter (PM2.5) and gestational diabetes mellitus (GDM). Methods We used the Massachusetts Registry of Vital Records to study 1,061,937 pregnant women from 2001 to 2015 with a singleton pregnancy without pre-existing diabetes. Gross β activity measured by seven monitors of the U.S. Environmental Protection Agency's RadNet monitoring network was utilized to represent ambient particle radioactivity (PR). We obtained GDM status from birth certificates and used logistic regression analyses adjusted for socio-demographics, maternal comorbidities, PM2.5, temperature and relative humidity. We also examined effect modification by smoking habits. Results Ambient particle radioactivity exposure during first and second trimester of pregnancy was associated with higher odds of GDM (OR: 1.18 (95% CI 1.10 to 1.22). Controlling for PM2.5 did not substantially change the effects of PR on GDM. In women that reported being former or current smokers, the association between PR and GDM was null. In the full cohort, the overall effect of PM2.5 on GDM without adjusting for PR was not significant. Conclusion This is the first population-based study to examine the association between particle radioactivity and gestational diabetes mellitus - one of the most common pregnancy-related diseases with lifelong effects for the mother and the fetus. This finding has important public health policy implications because it enhances our understanding about the toxicity of PR, a modifiable risk factor, which to date, has been considered only as an indoor and occupational air quality risk.

Background: Growing evidence suggests that exposure to per- and polyfluoroalkyl substances (PFASs) may disrupt lipid homeostasis and liver function, but data in children are limited. Objective: We examined the association of prenatal and mid-childhood PFAS exposure with lipids and alanine aminotransferase (ALT) levels in children. Methods: We studied 682 mother-child pairs from a Boston-area pre-birth cohort. We quantified PFASs in maternal plasma collected in pregnancy (median 9.7weeks gestation, 1999–2002) and in child plasma collected in mid-childhood (median age 7.7years, 2007–2010). In mid-childhood we also measured fasting total (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and ALT. We then derived low-density lipoprotein cholesterol (LDL-C) from TC, HDL-C, and TG using the Friedewald formula. Results: Median (interquartile range, IQR) perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorodecanoate (PFDeA) concentrations in child plasma were 6.2 (5.5), 4.3 (3.0), and 0.3 (0.3) ng/mL, respectively. Among girls, higher child PFOS, PFOA, and PFDeA concentrations were associated with detrimental changes in the lipid profile, including higher TC and/or LDL-C [e.g., β per IQR increment in PFOS=4.0mg/dL (95% CI: 0.3, 7.8) for TC and 2.6mg/dL (−0.5, 5.8) for LDL-C]. However, among both boys and girls, higher plasma concentrations of these child PFASs were also associated with higher HDL-C, which predicts better cardiovascular health, and slightly lower ALT, which may indicate better liver function. Prenatal PFAS concentrations were also modestly associated with improved childhood lipid and ALT levels. Conclusions: Our data suggest that prenatal and mid-childhood PFAS exposure may be associated with modest, but somewhat conflicting changes in the lipid profile and ALT levels in children. Keywords: Per- and polyfluoroalkyl substances, Lipids, Liver function, Pregnancy, Childhood

Maternal smoking during pregnancy is associated with low fetal growth and adverse cardiometabolic health in offspring. However, hormonal pathways underlying these associations are unclear. Therefore, we examined maternal smoking habits and umbilical cord blood hormone profiles in a large, prospective cohort.We studied 978 mother/infant pairs in Project Viva, a Boston-area cohort recruited 1999-2002. We categorized mothers as early pregnancy smokers, former smokers, or never smokers. Outcomes were cord blood concentrations of IGF-1, IGF-2, IGFBP-3, leptin, adiponectin, insulin, and C-peptide. We used linear regression models adjusted for maternal pre-pregnancy body mass index (BMI), race/ethnicity, parity, education, and infant sex. We conducted analyses in the full cohort and stratified by infant sex.Thirteen percent of women were early pregnancy smokers, 20% former smokers, and 68% never smokers. Infants of early pregnancy smokers had lower IGF-1 adjusted for IGFBP-3 [-5.2ng/mL (95% CI: -8.6, -1.7)], with more pronounced associations in girls [-10.7ng/mL (95% CI: -18.5, -2.9) vs. -4.0ng/mL (95% CI: -8.4, 0.4) for boys]. Early pregnancy smoking was not associated with cord blood hormones other than IGF-1. Infants of former smokers had a cord blood hormone profile similar to infants of never smokers.As compared to mothers who never smoked, early pregnancy smokers had infants with lower cord blood IGF-1 which could prime adverse metabolic outcomes. This provides further reason to support smoking cessation programs in women of reproductive age.

Background: Perfluoroalkyl substances (PFASs) are synthetic chemicals that may persist in the environment and in humans. There is a possible association between early-life PFAS exposure and metabolic dysfunction in later life, but data are limited. Methods: We studied 665 mother–child pairs in Project Viva, a Boston, Massachusetts-area cohort recruited 1999–2002. We quantified concentrations of PFASs [perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), perfluorohexane sulfonate (PFHxS), and perfluorodecanoate (PFDeA)] in maternal plasma collected at the first prenatal visit (median, 9.6 weeks gestation) and in child plasma from the mid-childhood research visit (median, 7.7 years). We assessed leptin, adiponectin, and homeostatic model assessment of insulin resistance (HOMA-IR) in mid-childhood. We fit covariate-adjusted linear regression models and conducted stratified analyses by child sex. Results: Children with higher PFAS concentrations had lower HOMA-IR [e.g., –10.1% (95% CI: –17.3, –2.3) per interquartile range increment in PFOA]. This inverse association between child PFAS and HOMA-IR was more pronounced in females [e.g., PFOA: –15.6% (95% CI: –25.4, –4.6) vs. –6.1% (95% CI: –16.2, 5.2) for males]. Child PFAS plasma concentrations were not associated with leptin or adiponectin. Prenatal PFAS plasma concentrations were not associated with leptin, adiponectin, or HOMA-IR in offspring. Conclusions: We found no evidence for an adverse effect of early-life PFAS exposure on metabolic function in mid-childhood. In fact, children with higher PFAS concentrations had lower insulin resistance. Antecedentes: las sustancias perfluoroalquilo (PFAS) son sustancias químicas sintéticas que pueden persistir en el medio ambiente y en los seres humanos. Existe una posible asociación entre la exposición temprana al PFAS y la disfunción metabólica en la edad adulta, pero los datos son limitados. Métodos: Estudiamos 665 parejas de madre e hijo en el Proyecto Viva, una cohorte del área de Boston, Massachusetts, reclutada en 1999-2002. Se cuantificaron las concentraciones de PFAS [perfluorooctanoato (PFOA), sulfonato de perfluorooctano (PFOS), perfluorononanoato (PFNA), sulfonato de perfluorohexano (PFHxS) y perfluorodecanoato (PFDeA)] en el plasma materno recolectado en la primera visita prenatal (mediana de 9,6 semanas), y en el plasma infantil de la visita de investigación de la niñez media (mediana, 7,7 años). Evaluamos la leptina, la adiponectina y la evaluación del modelo homeostático de la resistencia a la insulina (HOMA-IR) en la infancia media. Ajustamos modelos de regresión lineal ajustados por covariables y realizamos análisis estratificados por sexo del niño. Resultados: Los niños con concentraciones más altas de PFAS tenían HOMA-IR más bajo [por ejemplo, –10,1% (IC del 95%: –17,3, –2,3) por incremento de rango intercuartílico en PFOA]. Esta asociación inversa entre PFAS infantil y HOMA-IR fue más pronunciada en las mujeres [p. Ej., PFOA: –15,6% (IC del 95%: –25,4, –4,6) frente a –6,1% (IC del 95%: –16,2, 5,2) para machos]. Las concentraciones plasmáticas de PFAS en niños no se asociaron con leptina o adiponectina. Las concentraciones plasmáticas prenatales de PFAS no se asociaron con leptina, adiponectina o HOMA-IR en la descendencia. Conclusiones: No encontramos evidencia de un efecto adverso de la exposición temprana al PFAS sobre la función metabólica en la niñez media. De hecho, los niños con concentraciones más altas de PFAS tenían menor resistencia a la insulina. Antecedentes: As substâncias perfluoroalquílicas (PFASs) são produtos químicos sintéticos que podem persistir no meio ambiente e nos seres humanos. Há uma possível associação entre a exposição precoce ao PFAS e disfunção metabólica na vida adulta, mas os dados são limitados. Métodos: Estudamos 665 pares de mãe e filho no Projeto Viva, uma coorte da área de Boston, Massachusetts, recrutada em 1999–2002. Quantificamos as concentrações de PFASs [perfluorooctanoato (PFOA), perfluorooctano sulfonato (PFOS), perfluorononanoato (PFNA), sulfonato de perfluorohexano (PFHxS) e perfluorodecanoato (PFDeA)] no plasma materno coletado na primeira visita pré-natal (mediana). e no plasma infantil da visita de pesquisa do meio da infância (mediana, 7,7 anos). Avaliamos a leptina, a adiponectina e a avaliação do modelo homeostático de resistência à insulina (HOMA-IR) no meio da infância. Ajustamos modelos de regressão linear ajustados por covariável e conduzimos análises estratificadas por sexo da criança. Resultados: Crianças com concentrações mais altas de PFAS tiveram menor HOMA-IR [por exemplo, –10,1% (IC 95%: –17,3, –2,3) por incremento do intervalo interquartil no PFOA]. Esta associação inversa entre crianças PFAS e HOMA-IR foi mais pronunciada em mulheres [por exemplo, PFOA: –15,6% (IC 95%: –25,4, –4,6) vs. –6,1% (IC 95%: –16,2, 5,2) para machos]. As concentrações plasmáticas de crianças PFAS não foram associadas à leptina ou adiponectina. As concentrações plasmáticas de PFAS pré-natal não foram associadas à leptina, adiponectina ou HOMA-IR na prole. Conclusões: Não encontramos evidências de um efeito adverso da exposição precoce ao PFAS sobre a função metabólica na metade da infância. Na verdade, crianças com concentrações mais altas de PFAS apresentaram menor resistência à insulina. Boston Children’s Hospital, United States Harvard Medical School, United States Harvard Pilgrim Health Care Institute, United States Boston University School of Public Health, United States Universidad Nacional, Costa Rica National Center for Environmental Health, United States Harvard School of Public Health, United States University of California, United States Instituto Regional de Estudios en Sustancias Tóxicas

BackgroundHair 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 designWe 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).ResultsThere 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 (β = -0.41, 95% CI: -0.67, -0.15) and birth weight-for-gestational age z-score (β = -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 (β = 0.53, 95% CI: 0.04, 1.01). In early adolescence, child age (β = 0.34 per year, 95% CI: 0.21, 0.46) female sex (β = 0.33, 95% CI: 0.10, 0.57), and maternal pre-pregnancy body mass index (β = 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.ConclusionMaternal 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.

OBJECTIVE To examine associations of hair cortisol concentration (HCC) in mid-childhood and change in HCC from mid-childhood to early adolescence (ΔHCC) with early adolescent adiposity and cardiometabolic biomarker measures. METHODS In Project Viva, a pre-birth cohort of mothers and children, we measured HCC in 599 white children in mid-childhood and in 426 of these participants in early adolescence. We used multivariable linear regression to examine associations of mid-childhood HCC and ΔHCC with BMI-for-age-and-sex z score, waist circumference, waist-height ratio, dual X-ray absorptiometry total and trunk fat mass, a metabolic risk z score, adiponectin, HOMA-IR, high-density lipoprotein, C-reactive protein, interleukin-6, leptin, and systolic blood pressure. RESULTS Over a mean (SD) follow-up of 5.2 (0.8) years, we did not find associations of mid-childhood HCC with BMI-for-age-and-sex z score (β = 0.00 per 1-interquartile range of HCC, 95% confidence interval [CI], -0.08 to 0.07), waist circumference (β = -0.04 cm, 95% CI, -0.83 to 0.74), metabolic risk z score (β = 0.04, 95% CI, -0.03 to 0.11), or other cardiometabolic measures except for an increase in log-transformed HOMA-IR (β = 0.10, 95% CI, 0.04-0.17). ΔHCC was not associated with any outcome measures. CONCLUSIONS We found that mid-childhood HCC was not associated with early adolescent adiposity or cardiometabolic biomarkers except for a slight increase in HOMA-IR.

The purpose of this study was to test the extent to which pregnancy per- and polyfluoroalkyl substance (PFAS) concentrations were associated with gestational weight gain and postpartum weight changes.This study was composed of 1,614 women recruited between 1999 and 2002 via the Project Viva cohort with pregnancy plasma concentrations of six PFAS, including perfluorooctanesulfonic acid, perfluorooctanoic acid (PFOA), and 2-(N-ethyl-perfluorooctane sulfonamido) acetic acid. Gestational weight gain was defined as the difference between last pregnancy weight and prepregnancy weight, 1-year postpartum weight retention as the difference between 1-year postpartum weight and prepregnancy weight, and 3-year postpartum weight change as the difference between 3-year postpartum weight and prepregnancy weight.During pregnancy, women gained 0.37 kg (95% CI: 0.11-0.62) more weight per doubling of 2-(N-ethyl-perfluorooctane sulfonamido) acetic acid. At 1 year post partum, women retained 0.55 kg (95% CI: 0.07-1.04) more weight per doubling of PFOA. At 3 years post partum, women gained 0.91 kg (95% CI: 0.25-1.56) more weight per doubling in PFOA. Findings were similar after adjustment for all PFAS. Other PFAS were not associated with weight changes. Postpartum associations were stronger among women with higher prepregnancy BMI. Models were adjusted for demographics.Pregnancy PFAS were associated with greater gestational weight gain, weight retention, and weight gain years after pregnancy.

Background Few studies have examined sex-specific associations of maternal gestational glycemia with cord blood hormones, which might predict later health. Methods In 976 women without pre-existing diabetes in the Project Viva cohort, we used linear regression to examine associations of maternal gestational glycemia with cord hormone concentrations, adjusted for maternal characteristics and stratified by infant sex. Results A total of 6.1% of women had gestational diabetes mellitus (GDM), 8.8% isolated hyperglycemia, 3.2% gestational impaired glucose tolerance, and 81.9% were normoglycemic. In boys, compared with infants of normoglycemic mothers, infants of GDM mothers had higher cord levels of IGF-2 (β 35.55 ng/mL; 95% CI: 2.60, 68.50), IGFBP-3 (111.2 ng/mL; 5.53, 216.8), insulin (4.66 uU/mL; 2.38, 6.95), C-peptide (0.46 ng/mL; 0.25, 0.67), and leptin (3.51 ng/mL; 1.37, 5.64), but lower IGF-1 (−6.71 ng/mL; −12.7, − 0.76, adjusted for IGFBP-3). In girls, GDM offspring had higher cord blood levels of IGF-1 adjusted for IGFBP-3 (12.45 ng/mL; 4.85, 20.04). Boys, but not girls, of mothers with abnormal glucose tolerance but not GDM also had higher levels of some hormones. Conclusion GDM was associated with growth factors and adipokines in cord blood from boys, but only IGF-1 in girls. These findings suggest sex differences in responses to fetal overnutrition.

SummaryBackground Prenatal exposure to traffic pollution has been associated with faster infant weight gain, but implications for cardiometabolic health in later childhood are unknown. Methods Among 1418 children in Project Viva, a Boston-area pre-birth cohort, we assessed anthropometric and biochemical parameters of cardiometabolic health in early (median age 3.3 years) and mid- (median age 7.7 years) childhood. We used spatiotemporal models to estimate prenatal and early life residential PM2.5 and black carbon exposure as well as traffic density and roadway proximity. We performed linear regression analyses adjusted for sociodemographics. Results Children whose mothers lived close to a major roadway at the time of delivery had higher markers of adverse cardiometabolic risk in early and mid-childhood. For example, total fat mass was 2.1 kg (95%CI: 0.8, 3.5) higher in mid-childhood for children of mothers who lived

Many studies have found associations of particulate and gaseous air pollution during late pregnancy with reduced measures of fetal growth at birth.1, 2 Pollution components of particle mass with an aerodynamic diameter of less than 2.5 μm (PM2.5) readily enter the lower airways and have been hypothesized to adversely influence fetal growth and development by inducing maternal oxidative stress, blood coagulation, vascular dysfunction, or inflammation, potentially inhibiting nutrient transfer from mother to fetus.3 Indirect evidence also suggests that air pollution exposure may promote obesity after birth. Prenatal exposure to tobacco smoke4 (a complex mix of particulate matter, gases and toxins) and to polycyclic aromatic hydrocarbons5 (a combustion byproduct of fossil fuel and biomass burning with hormonal properties) have both been associated with increased odds of childhood obesity. In rodent models, adult mice developed visceral adipocyte hypertrophy and increased central adiposity following long-term postnatal exposure to fine particulate matter.6 Reduced fetal growth and development of childhood obesity may have common mechanistic origins during the prenatal period.7 Also, the phenotype of reduced fetal growth followed by greater weight gain during infancy predicts cardiovascular disease risk later in life.8, 9 However, whether exposure to fine particulate matter during late pregnancy increases risk for childhood obesity in addition to reduced fetal growth is unknown. In the present analysis of a large cohort of women and their offspring residing in the greater Boston area, our objective was to evaluate the extent to which neighborhood traffic density, home roadway proximity, and third-trimester exposures to PM2.5 and black carbon (a traffic-related component of PM2.5) were associated with fetal growth at birth, weight gain from 0 to 6 months of age, and the phenotype of reduced fetal growth and rapid infant weight gain. We hypothesized that prenatal air pollution exposure would be associated with both reduced fetal growth and greater postnatal weight gain.

Associations of prenatal exposure to perfluoroalkyl substances (PFAS), ubiquitous chemicals used in stain- and water-resistant products, with adverse birth outcomes may be confounded by pregnancy hemodynamics. We measured plasma concentrations of 4 PFAS in early pregnancy (median length of gestation, 9 weeks) among 1,645 women in Project Viva, a study of a birth cohort recruited during 1999-2002 in eastern Massachusetts. We fitted multivariable models to estimate associations of PFAS with birth weight-for-gestational age z score and length of gestation, adjusting for sociodemographic confounders and 2 hemodynamic markers: 1) plasma albumin concentration, a measure of plasma volume expansion, and 2) plasma creatinine concentration, used to estimate glomerular filtration rate. Perfluorooctane sulfonate (PFOS) and perfluorononanoate (PFNA) were weakly inversely associated with birth weight-for-gestational age z scores (adjusted β = -0.04 (95% confidence interval (CI): -0.08, 0.01) and adjusted β = -0.06 (95% CI: -0.11, -0.01) per interquartile-range increase, respectively). PFOS and PFNA were also associated with higher odds of preterm birth (e.g., for highest PFOS quartile vs. lowest, adjusted odds ratio = 2.4, 95% CI: 1.3, 4.4). Adjusting for markers of pregnancy hemodynamics (glomerular filtration rate and plasma albumin), to the extent that they accurately reflect underlying pregnancy physiology, did not materially affect associations. These results suggest that pregnancy hemodynamics may not confound associations with birth outcomes when PFAS are measured early in pregnancy.

Background: Prenatal exposure to dietary protein may program growth-regulating hormones, consequently influencing early-life growth patterns and later risk of associated chronic diseases. The insulin-like growth factor (IGF) axis is of particular interest in this context given its influence on pre- and postnatal growth and its sensitivity to the early nutritional environment.Objective: Our objective was to examine associations of maternal protein intake during pregnancy with cord blood concentrations of IGF-I, IGF-II, IGF binding protein-3 (IGFBP-3), and insulin.Methods: We studied 938 mother-child pairs from early pregnancy through delivery in the Project Viva cohort. Using multivariable linear regression models adjusted for maternal race/ethnicity, education, income, smoking, parity, height, and gestational weight gain and for child sex, we examined associations of second-trimester maternal protein intake [grams per kilogram (weight before pregnancy) per day], as reported on a food frequency questionnaire, with IGF-I, IGF-II, IGFBP-3, and insulin concentrations in cord blood. We also examined how these associations may differ by child sex and parity.Results: Mothers were predominantly white (71%), college-educated (64%), and nonsmokers (67%). Mean ± SD protein intake was 1.35 ± 0.35 g ⋅ kg-1 ⋅ d-1 Each 1-SD increment in second-trimester protein intake corresponded to a change of -0.50 ng/mL (95% CI: -2.26, 1.26 ng/mL) in IGF-I and -0.91 μU/mL (95% CI: -1.45, -0.37 μU/mL) in insulin. Child sex and parity modified associations of maternal protein intake with IGF-II and IGFBP-3: protein intake was inversely associated with IGF-II in girls (P-interaction = 0.04) and multiparous mothers (P-interaction = 0.05), and with IGFBP-3 in multiparous mothers (P-interaction = 0.04).Conclusions: In a cohort of pregnant women with relatively high mean protein intakes, higher intake was associated with lower concentrations of growth-promoting hormones in cord blood, suggesting a pathway that may link higher protein intake to lower fetal growth. This trial was registered at clinicaltrials.gov as NCT02820402.

Objective To identify metabolite patterns associated with childhood obesity, to examine relations of these patterns with measures of adiposity and cardiometabolic risk, and to evaluate associations with maternal peripartum characteristics. Methods Untargeted metabolomic profiling was used to quantify metabolites in plasma of 262 children (6-10 years). Principal components analysis was used to consolidate 345 metabolites into 18 factors and identified two that differed between obese (BMI ≥ 95‰; n = 84) and lean children (BMI

Background: Childhood lead exposure has been associated with growth delay. However, the association between blood lead levels (BLLs) and insulin-like growth factor 1 (IGF-1) has not been characterized in a large cohort with low-level lead exposure. Methods: We recruited 394 boys 8–9 years of age from an industrial Russian town in 2003–2005 and followed them annually thereafter. We used linear regression models to estimate the association of baseline BLLs with serum IGF-1 concentration at two follow-up visits (ages 10–11 and 12–13 years), adjusting for demographic and socioeconomic covariates. Results: At study entry, median BLL was 3 μg/dL (range, < 0.5–31 μg/dL), most boys (86%) were prepubertal, and mean ± SD height and BMI z-scores were 0.14 ± 1.0 and –0.2 ± 1.3, respectively. After adjustment for covariates, the mean follow-up IGF-1 concentration was 29.2 ng/mL lower (95% CI: –43.8, –14.5) for boys with high versus low BLL (≥ 5 μg/dL or < 5 μg/dL); this difference persisted after further adjustment for pubertal status. The association of BLL with IGF-1 was stronger for mid-pubertal than prepubertal boys (p = 0.04). Relative to boys with BLLs < 2 μg/dL, adjusted mean IGF-1 concentrations decreased by 12.8 ng/mL (95% CI: –29.9, 4.4) for boys with BLLs of 3–4 μg/dL; 34.5 ng/mL (95% CI: –53.1, –16.0) for BLLs 5–9 μg/dL; and 60.4 ng/mL (95% CI: –90.9, –29.9) for BLLs ≥ 10 μg/dL. Conclusions: In peripubertal boys with low-level lead exposure, higher BLLs were associated with lower serum IGF-1. Inhibition of the hypothalamic–pituitary–growth axis may be one possible pathway by which lead exposure leads to growth delay.

Background Excessive gestational weight gain (GWG) during pregnancy is associated with adverse outcomes for mothers and offspring. Early, mid, and late pregnancy GWGs have different associations with fetal growth and later life adiposity, but associations with cord blood hormones, which might predict later health, are not well studied. Methods In 978 pregnant women from the pre-birth Project Viva cohort, we calculated trimester-specific GWG using clinically recorded prenatal weights. Outcomes were levels of umbilical cord blood hormones related to fetal and postnatal growth. We used linear regression models adjusted for maternal race/ethnicity, pre-pregnancy BMI, parity, education, pregnancy smoking status and child sex; 2nd and 3rd trimester models were additionally adjusted for GWG in prior trimesters. Results Mean ± SD pre-pregnancy BMI was 24.9 ± 5.5 kg/m 2 , 30% were non-white, and 63% were college graduates. Mean ± SD cord blood hormone levels were insulin-like growth factor [IGF]-1 (56.4 ± 24.3 ng/mL), IGF-2 (408.5 ± 92.7 ng/mL), IGFBP-3 (1084 ± 318 ng/mL), insulin (6.5 ± 7.2 uU/mL), C-peptide (1.0 ± 0.6 ng/mL), leptin (9.0 ± 6.6 ng/mL) and adiponectin (28.7 ± 6.8 μg/mL). Mean ± SD 1st, 2nd and 3rd trimester GWG rates were 0.22 ± 0.22, 0.49 ± 0.19 and 0.46 ± 0.22 kg/wk. Greater 1st trimester GWG (per 0.2 kg/wk) was associated with higher insulin (0.5 uU/mL; 95% CI 0.1, 0.9) and C-peptide (0.06 ng/mL; 95% CI 0.02, 0.09) and lower adiponectin (−0.4 μg/mL; 95% CI − 0.9, 0.0). Greater 2nd trimester GWG (per 0.2 kg/wk) was associated with higher IGF-1 (2.3 ng/mL; 95% CI 0.6, 4.0), IGF-2 (7.9 ng/mL; 95% CI 1.2, 14.6), IGFBP-3 (41.6 ng/mL; 95% CI 19.4, 63.7) and leptin (0.9 ng/mL; 0.4, 1.4). 3rd trimester GWG was not associated with cord blood hormones. Conclusion 1st trimester weight gain appears to matter more for cord blood hormones related to offspring glucose/insulin regulation, whereas 2nd trimester gain matters more for hormones related to growth and adiposity.

Background: Growing evidence suggests that exposure to per- and polyfluoroalkyl substances (PFASs) may disrupt lipid and liver enzyme regulation, but data in children are limited. We examined the a...

Importance Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are ubiquitous synthetic chemicals that are suspected endocrine disruptors. Objectives To determine the extent to which PFASs are associated with increases in weight and body size and evaluate whether a lifestyle intervention modifies this association. Design, Setting, and Participants This prospective cohort study included 957 individuals who participated in the Diabetes Prevention Program trial, conducted from July 1996 to May 2001, and the Diabetes Prevention Program Outcomes Study, conducted from September 2002 to January 2014. Statistical analysis was conducted from September 1, 2017, to May 25, 2018. Interventions and Exposures The initial lifestyle intervention consisted of training in diet, physical activity, and behavior modification, with the major goals of achieving 7% weight loss with subsequent maintenance and a minimum of 150 minutes per week of physical activity. Participants randomized to placebo received standard information about diet and exercise. A total of 6 plasma PFASs were quantified at baseline and 2 years after randomization, means were calculated from baseline and year 2 concentrations, and means were summed to assess total PFAS burden. Main Outcomes and Measures Weight, waist circumference, and hip girth were measured at baseline and at scheduled visits. Results Of the 957 participants, 625 (65.3%) were women and 731 participants (76.4%) were between 40 and 64 years of age; 481 participants were randomized to the lifestyle intervention and 476 participants were randomized to the placebo arm. The PFAS concentrations were not different by treatment arm and were similar to concentrations reported for the US population in 1999-2000. The association of PFAS and weight change differed by treatment. Each doubling in total PFAS concentration was associated with an increase of 1.80 kg (95% CI, 0.43-3.17 kg; P = .01) from baseline to 9 years after randomization for the placebo group but not the lifestyle intervention group (−0.59 kg; 95% CI, –1.80 to 0.62 kg; P = .34). Similarly, each doubling in PFAS was associated with a 1.03-cm increase in hip girth in the Diabetes Prevention Program trial for the placebo group (95% CI, 0.18-1.88 cm; P = .02) but not the lifestyle intervention group (−0.09 cm; 95% CI, −0.82 to 0.63 cm; P = .80). No associations were observed for changes in mean waist circumference. Conclusions and Relevance Among adults at high risk for diabetes, higher plasma PFAS concentration was associated with increases in weight and hip girth over time, but a lifestyle intervention attenuated these associations. Diet and exercise may mitigate the obesogenic effects of environmental chemicals. Trial Registration ClinicalTrials.gov Identifier: NCT00004992 and NCT00038727, This cohort study from the Diabetes Prevention Program trial and Outcomes Study determines the extent to which perfluoroalkyl and polyfluoroalkyl substances are associated with increases in body weight and size and evaluates whether a lifestyle intervention modifies this association., Key Points Question Are synthetic perfluoroalkyl and polyfluoroalkyl substances associated with changes in weight, body size, and adiposity in adults? Findings In this follow-up cohort study of 957 participants in the the Diabetes Prevention Program Outcomes Study for 15 years, plasma concentrations of perfluoroalkyl and polyfluoroalkyl substances were associated with increases in weight gain and body size among individuals initially randomized to placebo. However, for participants randomized to a lifestyle intervention of exercise and diet, no detrimental associations were observed. Meaning Plasma concentration of perfluoroalkyl and polyfluoroalkyl substances is associated with increases in weight and body size in adults; however, exercise and diet may modify and attenuate the obesogenic effects of perfluoroalkyl and polyfluoroalkyl substances.

Background Rodent and human studies suggest an association between air pollution exposure and type 2 diabetes mellitus, but the extent to which air pollution is associated with gestational diabetes mellitus (GDM) is less clear. Methods We used the Massachusetts Registry of Vital Records to study primiparous women pregnant from 2003-2008 without pre-existing diabetes. We used satellite-based spatiotemporal models to estimate first and second trimester residential particulate (PM2.5) exposure and geographic information systems to estimate neighborhood traffic density. We obtained GDM status from birth records. We performed logistic regression analyses adjusted for sociodemographics on the full cohort and after stratification by maternal age and smoking habits. Results Of 159,373 women, 5,381 (3.4 %) developed GDM. Residential PM2.5 exposure ranged 1.3–19.3 μg/m3 over the second trimester. None of the exposures were associated with GDM in the full cohort [e.g. OR 0.99 (95 % CI: 0.95, 1.03) for each interquartile range (IQR) increment in second trimester PM2.5]. There were also no consistent associations after stratification by smoking habits. When the cohort was stratified by maternal age, women less than 20 years had 1.36 higher odds of GDM (95 % CI: 1.08, 1.70) for each IQR increment in second trimester PM2.5 exposure. Conclusions Although we found no evidence of an association between air pollution exposure and GDM among all women in our study, greater exposure to PM2.5 during the second trimester was associated with GDM in the youngest age stratum. Electronic supplementary material The online version of this article (doi:10.1186/s12940-016-0121-4) contains supplementary material, which is available to authorized users.

Objective To identify metabolite patterns associated with childhood obesity, and to examine their relations with cardiometabolic risk biomarkers. Methods We quantified 350 metabolites in serum of 262 children 7-10 y with an untargeted mass spectrophotometry approach. Using principal component analysis, we characterized 18 metabolite patterns. Next, we compared factor scores for each pattern between obese (BMI 蠅 95 %tile; n = 84) and lean children (BMI < 85 %tile; n = 150) to identify patterns related to obesity. Using multivariable linear regression we examined relations of the metabolite factor scores with ln transformed HOMA-IR, leptin, adiponectin, triglycerides, CRP, and IL-6. Results Approximately half (50.6%) of the sample were boys; 58.9% were white. Compared to lean children, obese children had higher factor scores for a branched chain amino acid (BCAA) and an androstene steroid (AS) pattern. After adjustment for age, sex, and race, every 1 unit increment in the BCAA score corresponded to 7% (1%, ...

To assess whether adding liothyronine (LT3) to levothyroxine (LT4) monotherapy normalizes serum thyrotropin (TSH) and thyroxine (T4) concentrations in children with congenital hypothyroidism and central resistance to thyroid hormone.We retrospectively studied 12 patients with congenital hypothyroidism and central resistance to thyroid hormone (6 treated with LT3+LT4 combined therapy and 6 treated with LT4 monotherapy). In patients receiving combined therapy, we compared serum concentrations of TSH, T4, and triiodothyronine before and after addition of LT3. We used repeated measures analysis to compare thyroid function in participants receiving combined therapy vs monotherapy, while accounting for age and intrasubject correlation.In patients receiving combined therapy, the addition of LT3 was associated with normalization of mean TSH (9.2 vs 4.5 mIU/L, P = .002), a lower proportion of TSH values greater than 10 mIU/L (35% vs 8%, P = .03), and a decrease in mean serum T4 by 23 ± 9% (P .001). Compared with patients receiving LT4 monotherapy, patients receiving combined therapy had lower mean TSH (8.5 ± 0.9 vs 4.3 ± 0.4, P .001), lower odds of TSH elevation greater than 10 mIU/L (OR 0.20, 95% CI 0.10-0.41, P .001), and lower odds of T4 elevation (OR 0.21, 95% CI 0.04-1.09, P = .06). LT3 treatment did not increase serum T3 levels significantly.The addition of LT3 to LT4 monotherapy facilitates normalization of both serum TSH and T4 in patients with congenital hypothyroidism and central resistance to thyroid hormone. Larger prospective studies are needed to confirm these findings and to determine the effect of combined therapy on neurodevelopmental outcomes.

We report 2 cases of extensive methicillin-resistant Staphylococcus aureus (MRSA) retropharyngeal abscesses in young infants. In 1 case, the abscess was associated with a reactive thrombosis of the jugular vein. Based on the existing literature and the rapid emergence of MRSA skin and soft tissue infections, it is possible that similar severe infections will occur with increasing frequency in young infants.

Objective To examine the relationship between energy intake during a buffet meal and indexes of insulin dynamics in overweight children. Study design Ninety-five nondiabetic, overweight (body mass index ≥95th percentile) children (age 10.3 ± 1.4 years) selected lunch from a 9835-kcal buffet eaten ad libitum after an overnight fast. The associations between energy intake and measures of insulin dynamics, in the postabsorptive state and during a 2-hour hyperglycemic clamp, were determined. Covariates in the statistical model included race, sex, skeletal age, fat-free mass, fat mass, socioeconomic status, and number of foods in the buffet rated as acceptable. Results Energy intake was positively associated with the fasting homeostasis model assessment for insulin resistance index (β = 0.24, P = .042), fasting insulin/glucose ratio (β = 0.24, P = .044), first-phase insulin (β = 0.23, P = .032), and first-phase C-peptide (β = 0.21, P = .046); energy intake was negatively associated with clamp-derived insulin sensitivity (β = −0.29, P = .042). Each 10% decrease in clamp-derived insulin sensitivity predicted a 27-kcal greater energy intake. Conclusions Insulin resistance and hyperinsulinemia are associated with greater energy intake after an overnight fast in overweight children. These associations suggest mechanisms whereby insulin resistance may contribute to excessive weight gain in children.

We report an adolescent boy with poor growth and delayed skeletal age who was found to have pulmonary arteriovenous malformations (PAVMs) consistent with hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome). While a host of chronic diseases, including a number of cardiopulmonary diseases, have previously been associated with poor growth or short stature, to our knowledge this is the first documented case of PAVM presenting with poor growth, manifesting as weight loss and delayed adolescence. This case highlights the importance of a thorough physical examination for identifying rare, occult, chronic diseases in patients who present with poor growth.

Our objective was to examine serum leptin prospectively as a predictor of weight and body fat growth in children at high risk for adult obesity. We hypothesized that leptin measurements would be positively associated with increased growth of adipose tissue because children with high baseline leptin for their body fat mass have greater leptin resistance and thus would have greater susceptibility to weight gain.Children ages 6-12 yr at high risk for adult obesity because of early-onset childhood overweight and/or parental overweight were recruited from 1996-2004. Growth in body mass index (BMI) was studied in 197 children, and growth in total body fat mass was examined in 149 children over an average follow-up interval of 4.4 yr (range, 1-8 yr). Longitudinal analyses accounted for sex, race, socioeconomic status, initial body composition, age, skeletal age, and physical activity and included all available interim visits for each individual so that a total of 982 subject visits were included in the analysis.At baseline, 43% of children studied were overweight (BMIor = 95th percentile); during follow-up, an additional 14% became overweight. Independent of initial body composition, baseline leptin was a statistically significant positive predictor of increased BMI (P = 0.0147) and increased total body fat mass (P0.007).High serum leptin, independent of body fat, may be an indicator of increased leptin resistance, which predisposes children at high risk for adult obesity to somewhat greater growth in weight and body fat during childhood.