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Linear regression is often used to estimate associations between chemical exposures and neurodevelopment at the mean of the outcome. However, the potential effect of chemicals may be greater among individuals at the 'tails' of outcome distributions. Here, we investigated distributional effects on the associations between gestational phthalate exposure and child Autism Spectrum Disorder (ASD)-related behaviors using quantile regression. We harmonized data from the Early Autism Risk Longitudinal Investigation (EARLI) (n = 140) Study, an enriched-risk cohort of mothers who had a child with ASD, and the Health Outcomes and Measures of the Environment (HOME) Study (n = 276), a general population cohort. We measured concentrations of 9 phthalate metabolites in urine samples collected twice during pregnancy. Caregivers reported children's ASD-related behaviors using the Social Responsiveness Scale (SRS) at age 3-8 years; higher scores indicate more ASD-related behaviors. In EARLI, associations between phthalate concentrations and SRS scores were predominately inverse or null across SRS score quantiles. In HOME, positive associations of mono-n-butyl phthalate, monobenzyl phthalate, mono-isobutyl phthalate, and di-2-ethylhexyl phthalate concentrations with SRS scores increased in strength from the median to 95th percentile of SRS scores. These results suggest associations between phthalate concentrations and SRS scores may be stronger in individuals with higher SRS scores.

Maternal nutrition during gestation has been investigated for its role in child neurodevelopment. However, little is known about the potential impact of gestational caffeine exposure on child autistic behaviors. Here, we assess the relation between maternal caffeine intake during pregnancy and children's behavioral traits related to Autism Spectrum Disorder (ASD). We harmonized data from two pregnancy cohorts, Early Autism Risk Longitudinal Investigation (EARLI) (n = 120), an enriched-risk cohort of mothers who previously had a child with ASD, from Pennsylvania, Maryland, and Northern California (2009-2012), and the Health Outcomes and Measures of the Environment (HOME) Study (n = 269), a general population cohort from Cincinnati, Ohio (2003-2006). Mothers self-reported caffeine intake twice during pregnancy. Caregivers reported child behavioral traits related to ASD using the Social Responsiveness Scale (SRS) when children were aged 3-8 years. Higher scores indicate more ASD-related behaviors. We estimated covariate-adjusted differences in continuous SRS T-scores per interquartile range increase in caffeine intake. Self-reported caffeine intake during pregnancy was positively associated with SRS T-scores among children in EARLI (β: 2.0; 95% CI -0.1, 4.0), but to a lesser extent in HOME (β: 0.6; 95% CI -0.5, 1.6). In HOME, pre-pregnancy body mass index (BMI) modified the association between caffeine intake and SRS T-scores, where more positive associations were observed among women with higher BMIs. Our findings suggest gestational caffeine intake may represent a marker of vulnerability to childhood ASD-related behaviors. Additional studies are warranted to extend these findings.

Executive functioning (EF) abilities develop through childhood, but this development can be impacted by various psychosocial environmental influences. Using longitudinal data from the Health Outcome and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort study, we examined if psychosocial environmental factors were significant predictors of EF development. Study participants comprised 271 children and their primary caregivers (98.5% mothers) followed from birth to age 12. We identified four distinct EF developmental trajectory groups comprising a consistently impaired group (13.3%), a descending impairment group (27.7%), an ascending impairment group (9.95%), and a consistently not impaired group (49.1%). Higher levels of maternal ADHD and relational frustration appear to be risk factors for increased EF difficulty over time, while higher family income may serve as a protective factor delaying predisposed EF impairment. Important intervention targets might include teaching positive and effective parenting strategies to mothers whose children are at risk for EF dysfunction. [ABSTRACT FROM AUTHOR]

Background: Pregnancy may stress calcium economy in women through fetal calcium requirements, and increasing maternal body weight. Bone is stimulated by compression forces. Playing tennis may decrease bone resorption through intermittent mechanical loading. This study tests the thesis that maternal bone mineral changes during pregnancy in women who play tennis are less compromised compared with nontennis playing controls. Methods: This is a prospective cohort study, a pilot study of 18 healthy pregnant women: 8 tennis players and I 0 controls, ages 18 to 39 years. Calcanei bone mineral density (BMD) and ultrasound (Stiffness Index (St)) measurements, were made at 12 weeks gestation and 2 to 4 weeks postpartum. SI was also measured at 20 to 24, and 33 to 36 weeks gestation. Statistical analysis included analysis of variance and covariance. Results: Age. height, and weight at study entry were not different between tennis players and controls. At 12 weeks, BMD was higher in tennis players versus controls 0.57 ± 0.02, 0.43 ± 0.03 g/cm², (P = .003); but not postpartum. SI Z-scores fell significantly during pregnancy in both groups, but were consistently higher in tennis players. Conclusions: Bone measures dropped overall during pregnancy, but were significantly higher in tennis players versus controls at 12 weeks and through gestation. [ABSTRACT FROM AUTHOR]

Objective To determine the association between placental weight (PW) and large for gestational age (LGA) in women with type 1 diabetes mellitus (T1DM) and whether glycemic control modifies the association. Study Design In a retrospective analysis of a cohort of women with T1DM, poor glycemic control was defined as glycohemoglobin A1(HbA1) ≥ 8.5% (≥2 standard deviations [SD] above mean), and LGA as birth weight > 90th percentile, according to gestation, race, and sex. Multivariable logistic regression was used for analysis. Stratified analyses (HbA1 < 8.5% vs. HbA1 ≥ 8.5%) assessed the role of glycemic control on association between PW and LGA. Results PW in 302 pregnancies was positively associated with LGA (first vs. fourth quartile of PW; odds ratio [OR] = 9.56; 95% confidence interval [CI]: 4.14-22.08). Association varied significantly by glycemic control in the first trimester, but not in the second and third trimesters. For women with first trimester HbA1 concentration < 8.5%, there was no statistically significant association; however, with HbA1 ≥ 8.5%, there was a strong association (OR = 13.40, 95% CI: 3.31, 54.27). Conclusion There was a significant positive association between PW and LGA in infants of women with T1 DM, particularly evident in pregnancies with poor glycemic control during the first trimester, highlighting the importance of achieving good glycemic control early in gestation. [ABSTRACT FROM AUTHOR]

Objective To identify phenotypes of type 1 diabetes control and associations with maternal/neonatal characteristics based on blood pressure (BP), glucose, and insulin curves during gestation, using a novel functional data analysis approach that accounts for sparse longitudinal patterns of medical monitoring during pregnancy. Methods We performed a retrospective longitudinal cohort study of women with type 1 diabetes whose BP, glucose, and insulin requirements were monitored throughout gestation as part of a program-project grant. Scores from sparse functional principal component analysis (fPCA) were used to classify gestational profiles according to the degree of control for each monitored measure. Phenotypes created using fPCA were compared with respect to maternal and neonatal characteristics and outcome. Results Most of the gestational profile variation in the monitored measures was explained by the first principal component (82-94%). Profiles clustered into three subgroups of high, moderate, or low heterogeneity, relative to the overall mean response. Phenotypes were associated with baseline characteristics, longitudinal changes in glycohemoglobin A1 and weight, and to pregnancy-related outcomes. Conclusion Three distinct longitudinal patterns of glucose, insulin, and BP control were found. By identifying these phenotypes, interventions can be targeted for subgroups at highest risk for compromised outcome, to optimize diabetes management during pregnancy. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) has increased dramatically in the past 20 years together with the obesity epidemic. Mirroring the increase in incidence of GDM is increasing use of endocrine disrupting chemicals (EDCs). EDCs are structurally similar to endogenous hormones and interfere with synthesis, secretion, activity, or elimination of natural hormones, resulting in adverse health effects, including diabetes, obesity, developmental disorders, etc. Although the association between bisphenol A (BPA), a well-studied EDC, and type 2 diabetes has been repeatedly investigated in epidemiological and animal studies, there is a dearth of studies examining EDCs and GDM. In fact, the impact of environmental toxins on perinatal health outcomes has largely been overlooked. Recognizing this research gap, the American College of Obstetricians and Gynecologists, American Society for Reproductive Medicine, and International Federation of Gynecology and Obstetrics recently joined leading scientists and clinicians in a call for action to prioritize research in the consequences of exposure to toxic environmental agents on women's health. Evidence is emerging to suggest signaling molecules and EDCs are involved in the control of microRNA (miRNA) expression in trophoblast cells. We reviewed existing scientific evidence of EDCs as a risk factor for GDM as well as the potential role of miRNA in this association. [ABSTRACT FROM AUTHOR]

Objective This study aims to evaluate the association between gestational weight gain (GWG) defined by the current Institute of Medicine (IOM) guidelines and pregnancy outcomes in women with type 1 diabetes mellitus (DM). Study design This is a secondary analysis of a cohort of 293 pregnancies of women with type 1 DM between 24 and 41 weeks' gestation. Women were categorized according to GWG per week over the second and third trimester: below, within, and above the IOM guidelines. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were calculated for maternal and neonatal outcomes, controlling for covariates and confounders (referent: GWG within the IOM guidelines). Results Of the 293 women, there were 49 women (16.7%) with the GWG below the IOM guidelines, 86 women (29.4%) with the GWG within the IOM guidelines, and 158 women (53.9%) with the GWG above the IOM guidelines. Women with the GWG above the IOM guidelines had a higher risk of macrosomia and neonatal hyperbilirubinemia (aOR: 2.78; 95% CI: 1.23-6.30 and 2.31; 1.22-4.35, respectively). Conclusion GWG above the IOM guidelines is associated with an increased risk of macrosomia and neonatal hyperbilirubinemia. Maintaining GWG within the IOM guidelines may decrease the risk of excessive fetal growth and neonatal hyperbilirubinemia in infants of women with type 1 DM. [ABSTRACT FROM AUTHOR]

Prenatal exposure to organophosphate pesticides, which is ubiquitous, may be detrimental to neurological development. We examined 327 mother/infant pairs in Cincinnati, Ohio, between 2003 and 2006 to determine associations between prenatal exposure to organophosphate pesticides and neurodevelopment. Twice during pregnancy urinary concentrations of 6 common dialkylphosphates, nonspecific metabolites of organophosphate pesticides, were measured. Aggregate concentrations of diethylphosphates, dimethylphosphates, and total dialkylphosphates were calculated. Bayley Scales of Infant Development, Second Edition-Mental and Psychomotor Developmental indices were administered at ages 1, 2, and 3 years, the Clinical Evaluation of Language Fundamentals-Preschool, Second Edition, at age 4, and the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, at age 5. Mothers with higher urinary total dialkylphosphate concentrations reported higher levels of socio-economic status and increased fresh fruit and vegetable intake. We found no associations between prenatal exposure to organophosphate pesticides and cognition at 1-5 years of age. In our cohort, exposure to organophosphate pesticides during pregnancy was not associated with cognition during early childhood. It is possible that a higher socioeconomic status and healthier diet may protect the fetus from potential adverse associations with gestational organophosphate pesticide exposure, or that dietary exposure to the metabolites is innocuous and not an ideal measure of exposure to the parent compound. [ABSTRACT FROM AUTHOR]

Background: Early-life exposure to bisphenol A (BPA) may increase childhood obesity risk, but few prospective epidemiological studies have investigated this relationship. Objective: We sought to determine whether early-life exposure to BPA was associated with increased body mass index (BMI) at 2–5 years of age in 297 mother–child pairs from Cincinnati, Ohio (HOME Study). Methods: Urinary BPA concentrations were measured in samples collected from pregnant women during the second and third trimesters and their children at 1 and 2 years of age. BMI z-scores were calculated from weight/height measures conducted annually from 2 through 5 years of age. We used linear mixed models to estimate BMI differences or trajectories with increasing creatinine-normalized BPA concentrations. Results: After confounder adjustment, each 10-fold increase in prenatal (β = –0.1; 95% CI: –0.5, 0.3) or early-childhood (β = –0.2; 95% CI: –0.6, 0.1) BPA concentrations was associated with a modest and nonsignificant reduction in child BMI. These inverse associations were suggestively stronger in girls than in boys [prenatal effect measure modification (EMM) p-value = 0.30, early-childhood EMM p-value = 0.05], but sex-specific associations were imprecise. Children in the highest early-childhood BPA tercile had lower BMI at 2 years (difference = –0.3; 95% CI: –0.6, 0.0) and larger increases in their BMI slope from 2 through 5 years (BMI increase per year = 0.12; 95% CI: 0.07, 0.18) than children in the lowest tercile (BMI increase per year = 0.07; 95% CI: 0.01, 0.13). All associations were attenuated without creatinine normalization. Conclusions: Prenatal and early-childhood BPA exposures were not associated with increased BMI at 2–5 years of age, but higher early-childhood BPA exposures were associated with accelerated growth during this period. [ABSTRACT FROM AUTHOR]

Background: National data suggest widespread gestational exposure to organophosphate pesticides (OPs) based on the detection of OP metabolites in the urine of pregnant women. Associations with early infant neurobehavior are largely understudied, with only two studies reporting abnormal reflexes in newborns in association with gestational exposure to OPs. Our objective was to utilize biological markers of OP metabolites in pregnant women and a comprehensive assessment of infant neurobehavior to determine the association of gestational exposure to OPs with neurobehavioral outcomes during early infancy. Methods: Among a cohort of 350 mother/infant pairs, we measured six common dialkylphosphate metabolites of OP pesticides in maternal urine, at two times during pregnancy (16 w & 26 w gestation), then calculated aggregate concentrations of diethylphosphate, dimethylphosphate, and total dialkyphosphate metabolites. We measured infant neurobehavior at about five weeks of age using the NICU Network Neurobehavioral Scale (NNNS), a comprehensive assessment of neurobehavior in young infants. Analyses of associations between gestational exposure to OPs and neurobehavior at five weeks included multiple linear and logistic regression. Results: After adjustment for covariates, higher creatinine-corrected urinary concentrations of diethylphosphate metabolites were associated with improved attention and reduced lethargy and hypotonia in young infants. Higher creatinine-corrected urinary concentrations of total dialkylphosphate metabolites were associated with fewer signs of autonomic stress. Women who were white, married, had advanced education, and reported more frequent consumption of fresh fruits and vegetables had higher concentrations of OP metabolites during pregnancy. Conclusions: In this sample of pregnant women whose urinary concentrations of dialkylphosphate metabolites are representative of national exposure levels, we found no detrimental effects of gestational exposure to OPs on neurobehavioral outcomes among young infants. These results are important as they suggest there may be minimal to no detectable adverse impact of low level prenatal OP exposure on the neurobehavior of young infants. [ABSTRACT FROM AUTHOR]

Summary: Recent studies from our laboratory have indicated that the transcription factor activator protein-2α plays a critical role in the differentiation of human villous cytotrophoblast cells to syncytiotrophoblast cells. However, little is known about the expression of activator protein-2α in placentas from pathologic pregnancies. This study compares the expression of activator protein-2α in placentas from high-risk pregnancies to gestational age–matched controls. Paracentral sections from grossly unremarkable areas of 10 placentas from each group of pregnancies complicated by mild preeclampsia, severe preeclampsia, diabetes mellitus, chronic hypertension, and fetal growth restriction and 10 control cases of placentas from normal pregnancies matched for gestational age were double immunostained for activator protein-2α and E-cadherin. The total numbers of cytotrophoblast cells and syncytiotrophoblast nuclei and the numbers of activator protein-2α–positive and activator protein-2α–negative nuclei in both of these cell types were counted by 2 pathologists blinded to disease status, in 10 representative ×40 high-power fields for each placenta. Abnormal placental maturation in most of pathologic pregnancies was evidenced by a 1.5- to 1.7-fold lower expression ratio of syncytiotrophoblast cell to cytotrophoblast cell. Activator protein-2α in syncytiotrophoblast cells was lower in mild preeclampsia, diabetes mellitus, hypertension, and fetal growth restriction (P <.0001 in each instance) and was higher by 2-fold in severe preeclampsia, although this increase was not statistically significant (P =.3). Because activator protein-2α has been shown to be critical for villous cytotrophoblast cell differentiation, our findings suggest that abnormalities in the activator protein-2α cascade of transcription factors and/or signaling molecules may contribute to the pathogenesis of the abnormal maturation in placentas in certain types of high-risk pregnancies. The different pattern of activator protein-2α expression in mild and severe preeclampsia clearly suggests that these conditions may have 2 independent pathogenic mechanisms. [Copyright &y& Elsevier]

Objective: To determine whether the second stage of labor affects the progression of retinopathy in women with type I diabetes mellitus (DM). Research and Design: The study is a secondary analysis of 192 pregnant women with type I DM who participated in an interdisciplinary diabetes in pregnancy intervention program between 1978 and 1993. Evaluation for diabetic retinopathy (DR) was performed each trimester and 6-12 weeks postpartum by the same two ophthalmologists. Women were divided into three groups: (i) elective cesarean delivery ( n == 60), (ii) cesarean delivery prior to the second stage of labor ( n == 69) and (iii) vaginal or cesarean delivery in the second stage ( n == 63). Progression of DR during pregnancy and between pregnancy and postpartum was compared among the groups. Results: Maternal demographics, glycemic control and pregnancy complications were similar among groups. Progression of retinopathy from early and late pregnancy to postpartum did not differ between the three groups. Conclusion: With close follow-up and good glycemic control, expulsive efforts in the second stage of labor do not affect the progression of retinopathy in women with type I DM. Our data support the premise that pregnant women with type I DM and stable retinopathy should not be denied vaginal delivery, if otherwise not contraindicated. [ABSTRACT FROM AUTHOR]

We sought to examine neonatal morbidity in four groups of offspring (asymmetric large for gestational age [LGA], symmetric LGA, asymmetric non-LGA, symmetric non-LGA) exposed in utero to maternal type 1 diabetes, and the association between rate of fetal abdominal circumference growth and asymmetric LGA. We performed a secondary analysis of 302 singleton pregnancies. Neonatal morbidity (respiratory distress syndrome, polycythemia, hypoglycemia, hyperbilirubinemia, acidosis, and composite morbidity [any of the five]) was assessed. Serial ultrasound examinations after 20 weeks' gestation were available for 35 fetuses. Logistic regression and general linear mixed modeling were used for analysis. Asymmetric LGA infants had 3.5-, 2.2-, and 3.2-fold greater odds of hypoglycemia, hyperbilirubinemia, and composite morbidity, respectively, compared with symmetric non-LGA infants. The rate of growth of the abdominal circumference in asymmetric LGA infants (1.11 cm/wk) was greater than for both the symmetric LGA infants (0.87 cm/wk, p = 0.09) and the symmetric non-LGA infants (0.87 cm/wk, p = 0.03). Asymmetric LGA infants are at higher risk for morbidity than symmetric LGA and non-LGA infants. Intrauterine growth rate of the abdominal circumference may potentially be used as a marker to identify the asymmetric LGA and thereby aid in the identification of newborns at greatest risk for perinatal complications. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to test whether vasculopathy in type 1 diabetes mellitus (DM) is associated with fetal growth abnormalities. Study Design: Women with type 1 DM (n = 340) were enrolled in a prospective study of diabetes in pregnancy and classified according to vascular status: NV (no vasculopathy, n = 181), HBR (hypertension or background retinopathy, n = 79), PR (proliferative retinopathy only, n = 16), NEP (nephropathy only, n = 40), and PRN (proliferative retinopathy and nephropathy, n = 24). Association of vascular status with low birthweight (LBW) and small for gestational age (SGA) infants was analyzed. Results: The odds ratios for delivery of a LBW infant compared to women without vasculopathy after controlling for maternal age, gestational age and race were: HBR 1.0, PR 2.2, NEP 3.7, and PRN 5.5. The odds ratios for delivery of a SGA infant were: HBR 0.7, PR 10.4, NEP 1.9, and PRN 9.9. Conclusion: Diabetic vasculopathy is associated with increased odds for delivery of low-birthweight or SGA infants. [Copyright &y& Elsevier]

Polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental chemicals used as flame retardants in commercial and consumer products. Gestational PBDE concentrations are associated with adverse behaviors in children; however, the persistence of these associations into adolescence remains understudied. We estimated the association of gestational PBDE serum concentrations with early adolescent self- and caregiver-reported behaviors at age 12 years and determined the consistency with previously observed associations in childhood with caregiver-reported behaviors in a prospective pregnancy and birth cohort. We measured maternal serum concentrations of five individual PBDE congeners and created a summary exposure variable (∑ 5 BDE: 28, −47, −99, −100 and −153) during pregnancy. At age 12 years, we assessed behaviors for 237 adolescents using self- and caregiver-reports with the Behavioral Assessment System for Children-3 (BASC3). We used multivariable linear regression models to estimate covariate-adjusted associations of lipid standardized, log 10 -transformed gestational PBDE concentrations with BASC3 scores. We obtained estimates and 95% confidence intervals through a bootstrapping approach. We evaluated potential effect measure modification (EMM) of adolescent sex by examining sex-stratified regression models and estimating the EMM p-values. Gestational PBDE concentrations were positively associated with adolescent-reported BASC3 composite indices for inattention & hyperactivity (BDE-28, -47, −99, −100, ∑ 5 BDE), internalizing problems (BDE-28, -47, −99), functional impairment (BDE-28, ∑ 5 BDE), and emotional symptoms (BDE-28). Gestational PBDE concentrations were positively associated with caregiver-reported BASC3 composite indices for externalizing problems (BDE-28, -47, −99, −100, −153, ∑ 5 BDE) and behavioral symptoms (BDE-99). For caregiver reported behaviors, we observed stronger associations with gestational BDE concentrations among males, especially for executive functioning (BDE-28, -47, −99, −100, ∑ 5 BDE). Gestational PBDE serum concentrations were associated with self-reported internalizing and externalizing behavior problems in early adolescence. Caregiver-reported externalizing behaviors recognized during childhood remain associated with gestational PBDE concentrations and persist into early adolescence. Internalizing behaviors were less recognized by caregivers. • Gestational BDE serum concentrations were associated with internalizing and externalizing behaviors in adolescence. • Gestational BDE concentrations were related to adolescent-reported internalizing behaviors, not caregiver-reported measures. • Caregiver-reported childhood externalizing behaviors remained associated with gestational BDE concentrations in adolescence. • Gestational BDE and caregiver-reported measures had stronger associations for externalizing than internalizing behaviors. [ABSTRACT FROM AUTHOR]

To determine the incidence and obstetric implications and to identify prospectively women with a poor response to hMG with a normal clomiphene citrate challenge test (CCCT) result.Retrospective chart review.Tertiary fertility center.One hundred sixty-three women who underwent ovulation induction with hMG for IUI, and 266 women who underwent ovulation induction with GnRH analogue and hMG for IVF. All had a CCCT before stimulation. Seventy-five percent of IUI patients (123 of 163) and 89% of IVF patients (238 of 266) had normal CCCT results. A poor response to hMG was defined as a response less than the 90th percentile of women with an abnormal CCCT result (peak E2 [pg/mL] level per ampule hMG used: 90th percentile ≤30).Clomiphene citrate challenge test and ovulation induction for IUI or IVF.Response to gonadotropins and pregnancy outcome after treatment.Thirty-five percent of IUI patients (43 of 123) and 52% of IVF patients (123 of 238) with a normal CCCT result had a poor response to hMG. Intrauterine insemination patients with a poor response to hMG had significantly lower delivery rates than IUI patients with a normal response (19% vs. 39%). In vitro fertilization patients with a poor response to hMG had similar delivery rates compared with IVF patients with a normal response (32% vs. 35%). For both groups of patients, an FSH >12 mIU/mL (IMx assay) on either day 3 or day 10 (normal ≤14.5 IMx) was highly predictive of a poor response to hMG, the elevated FSH level being a much better predictor than the woman''s age.A poor response to hMG with a normal CCCT result (false negative) is a common event. A day-3 or day-10 FSH >12 mIU/mL (IMx assay) or 20 mIU/mL (converted to the original RIA) will identify approximately 80% (IUI) and approximately 94% (IVF) of the women who will experience a poor response to hMG. When identified, the data suggest that these patients will benefit significantly from the more aggressive IVF. [Copyright &y& Elsevier]