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BackgroundPrenatal exposure to increased androgens has been suggested as a risk factor for autism spectrum disorder (ASD). This hypothesis has been examined by measurement of steroids in amniotic fluid, cord blood, saliva, and blood with mixed results.MethodsTo provide an orthogonal measure of fetal exposure, this study used meconium, the first stool of a newborn, to measure prenatal androgen exposure from infants in the Early Autism Risk Longitudinal Investigation (EARLI). EARLI is a familial-enriched risk cohort that enrolled pregnant mothers who already had a child with an ASD diagnosis. In the younger child, we investigated the association between meconium unconjugated (u) and total (t) concentrations of major androgens testosterone (T), dehydroepiandrosterone (DHEA), and androstenedione (A4), and ASD-related traits at 12 and 36 months of age. Traits were measured at 12 months with Autism Observation Scale for Infants (AOSI) and at 36 months with total score on the Social Responsiveness Scale (SRS). One hundred and seventy children had meconium and AOSI, 140 had meconium and SRS, and 137 had meconium and both AOSI and SRS.ResultsSeparate robust linear regressions between each of the log-transformed androgens and log-transformed SRS scores revealed three-way interaction between sex of the child, sex of the proband, and testosterone concentration. In the adjusted analyses, t-T, u-A4, and u-DHEA (P ≤ 0.01) were positively associated with AOSI scores, while u-T (P = 0.004) and u-DHEA (P = 0.007) were positively associated with SRS total score among females with female probands (n = 10). Additionally, higher concentrations of u-T (P = 0.01) and t-T (P = 0.01) predicted higher SRS total score in males with male probands (n = 63). Limitations Since we explored three-way interactions, this resulted in a limited sample size for some analyses. This study was from an enriched-risk cohort which may limit generalizability, and this study used ASD-assessment scales as outcomes instead of diagnostic categories. Additionally, the novel use of meconium in this study limits the ability to compare the results in this cohort to others due to the paucity of research on meconium.ConclusionsThis study supports the utility of meconium for studies of endogenous fetal metabolism and suggests the sex of older siblings with autism should be considered as a biological variable in relevant studies.

BackgroundAutism spectrum disorder (ASD) is a neurodevelopmental disorder that affects more than 1% of children in the USA. ASD risk is thought to arise from both genetic and environmental factors, with the perinatal period as a critical window. Understanding early transcriptional changes in ASD would assist in clarifying disease pathogenesis and identifying biomarkers. However, little is known about umbilical cord blood gene expression profiles in babies later diagnosed with ASD compared to non-typically developing and non-ASD (Non-TD) or typically developing (TD) children.MethodsGenome-wide transcript levels were measured by Affymetrix Human Gene 2.0 array in RNA from cord blood samples from both the Markers of Autism Risk in Babies-Learning Early Signs (MARBLES) and the Early Autism Risk Longitudinal Investigation (EARLI) high-risk pregnancy cohorts that enroll younger siblings of a child previously diagnosed with ASD. Younger siblings were diagnosed based on assessments at 36 months, and 59 ASD, 92 Non-TD, and 120 TD subjects were included. Using both differential expression analysis and weighted gene correlation network analysis, gene expression between ASD and TD, and between Non-TD and TD, was compared within each study and via meta-analysis.ResultsWhile cord blood gene expression differences comparing either ASD or Non-TD to TD did not reach genome-wide significance, 172 genes were nominally differentially expressed between ASD and TD cord blood (log2(fold change) > 0.1, p

BackgroundAutism spectrum disorder (ASD) affects more than 1% of children in the USA. The male-to-female prevalence ratio of roughly 4:1 in ASD is a well-recognized but poorly understood phenomenon. An explicit focus on potential etiologic pathways consistent with this sex difference, such as those involving prenatal androgen exposure, may help elucidate causes of ASD. Furthermore, the multi-threshold liability model suggests that the genetic mechanisms in females with ASD may be distinct and may modulate ASD risk in families with female ASD in the pedigree.MethodsWe examined umbilical cord blood from 137 children in the Early Autism Risk Longitudinal Investigation (EARLI) cohort. EARLI is an ASD-enriched risk cohort with all children having an older sibling already diagnosed with ASD. Fetal testosterone (T), androstenedione (A4), and dehyroepiandrosterone (DHEA) levels were measured in cord blood using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Robust linear regression models were used to determine associations between cord blood androgen levels and 12-month Autism Observation Scales for Infants (AOSI) scores and 36-month Social Responsiveness Scale (SRS) scores adjusting for potential confounders.ResultsIncreasing androgens were not associated with increasing 12-month AOSI score or 36-month total SRS score in either boys or girls. However, the association between T and autistic traits among subjects with a female older affected sibling was greater at 12 months (test of interaction, P = 0.008) and deficits in reciprocal social behavior at 36 months were also greater (test of interaction, P = 0.006) than in subjects whose older affected sibling was male.ConclusionsWhile increased prenatal testosterone levels were not associated with autistic traits at 12 or 36 months, our findings of a positive association in infants whose older ASD-affected siblings were female suggests an androgen-related mechanism that may be dependent on, or related to, genetic liability factors present more often in families containing female ASD cases. However, this initial finding, based on a small subgroup of our sample, should be interpreted with considerable caution.

Prenatal metabolism exerts profound effects on development. The first stool of the newborn, meconium, provides a window into the prenatal metabolic environment. The objective of this study was to examine the feasibility of meconium as a novel matrix to quantify prenatal steroid levels. We quantified parameters of analytical interest regarding the use of meconium, including sample stability. We hypothesized that meconium steroid content would differ by sex, prompting analysis of meconium to test effects of prenatal steroid metabolism. Meconium from 193 newborns enrolled in the Early Autism Risk Longitudinal Investigation (EARLI) study, including 107 males, and 86 females, were analyzed by isotope dilution-liquid chromatography-high resolution mass spectrometry (ID-LC-HRMS) while blinded to identity for testosterone (T), androstenedione (AD), and dehydroepiandrosterone (DHEA). Steroid levels were compared by sex, and investigations of potential trends resulting from sample storage or processing was conducted. The unconjugated steroid content of meconium in ng/g (mean, standard deviation) was for males: T (2.67, 8.99), AD (20.01, 28.12), DHEA (13.96, 23.57) and for females: T (0.82, 1.63), AD (22.32, 24.38), DHEA (21.06, 43.49). T was higher in meconium from males (p=0.0333), and DHEA was higher in meconium from females (p=0.0202). 6 female and 3 male T values were below the limit of detection. No extreme variability in hydration or trend in steroid levels by storage time was detected. Sexually dimorphic levels of hormones may reflect gestational differentiation, and future studies should consider meconium analysis.

Background: The optimal timing of induction for those undergoing a trial of labor after cesarean section has not been established. The little data which supports the consideration of induction at 39 weeks gestation excludes those with a history of prior cesarean section. Objective: To determine the risks and benefits of elective induction of labor (IOL) at 39 weeks compared with expectant management (EM) until 42 weeks in pregnancies complicated by one previous cesarean delivery. Study design: This is a retrospective cohort analysis of singleton non-anomalous pregnancies in the United States between January 2015 and December 2017. Data was provided by the CDC National Center for Health Statistics, Division of Vital Statistics. Analyses included only pregnancies with a history of one previous cesarean delivery (CD). Perinatal outcomes of pregnancies electively induced at 39 weeks (IOL) were compared to pregnancies that were induced, augmented or underwent spontaneous labor between 40 and 42 weeks (EM). Unlabored cesarean deliveries were excluded. Outcomes of interest included: cesarean delivery, intra-amniotic infection, blood transfusion, adult intensive care unit (ICU) admission, uterine rupture, hysterectomy, 5-minute Apgar score -3, prolonged neonatal ventilation, neonatal ICU (NICU) admission, neonatal seizure, perinatal/neonatal death. Log-binomial regression analysis was performed to calculate the relative risk (RR) for each outcome of interest, adjusting for confounding variables. Results: There were 50,136 pregnancies included for analysis with 9,381 women in the IOL group. Compared with EM, IOL at 39 weeks decreased the risk of intra-amniotic infection (1.7% vs 3.0%, p<.001; aRR: 0.58, 95% CI: [0.49-0.68]), blood transfusion (0.3% vs. 0.5%, p=.03; aRR: 0.66, 95% CI: [0.45-0.98]), and low 5-minute Apgar score (0.31% vs 0.47%, p=.031; aRR: 0.66, 95% CI: [0.44-0.97]). Conversely, IOL increased the risk of cesarean delivery (49.0% vs 27.6%, p<.001; aRR: 1.72, 95% CI: [1.68-1.77]). Furthermore, in the EM group, 919 pregnancies developed preeclampsia and 42 progressed to eclampsia. There were no differences in other perinatal outcomes. Conclusion: In pregnancies complicated by one previous cesarean delivery, elective induction of labor at 39 weeks reduced the risk of intra-amniotic infection, blood transfusion, and low 5-minute Apgar score while increased the risk of repeat cesarean delivery. [ABSTRACT FROM AUTHOR]

Objective: Obesity and pregestational diabetes (PGDM) may interact to further increase the risk of stillbirth than either risk factors independently. The objective of this study was to determine the risk of stillbirth in pregnancies complicated by both conditions.Method: This was a retrospective cohort analysis of singleton nonanomalous births using the updated Texas vital records database between 2006 and 2014. Gestational diabetes and hypertensive diseases were additionally excluded from analysis. Analysis was stratified into 10 strata based on BMI class: underweight, normal weight, overweight, obese and morbidly obese, and PGDM. Furthermore, gestational age was stratified into the four periods for analysis: 24-33, 34-36, 37-39, and 40-42 weeks. The rate of stillbirth per 10,000 pregnancies were calculated for each stratum. The risks of stillbirth associated with each BMI class and PGDM were compared to normal weight nondiabetic pregnancies for each gestational period using proportional hazard regression models.Result: After all exclusions, 3,097,123 births remained for analysis, including 5997 stillbirths. The overall rate of stillbirth increased from 15.0 per 10,000 pregnancies in normal weight pregnancies to 26.7 per 10,000 pregnancies in the morbidly obese group. The rate of stillbirth further increased with coexistence of PGDM to 119.9 per 10,000 pregnancies in the normal weight group and 209.8 per 10,000 pregnancies in the morbidly obese group. Compared to normal weight nondiabetic pregnancies the overall adjusted hazard ratio (aHR) of stillbirth associated with morbid obesity without PGDM was 1.57 [1.38, 1.79]. However, when further complicated by PGDM, the aHR was 6.67 [5.05, 8.81] in normal weight pregnancies and 12.86 [9.36, 17.67] in morbidly obese pregnancies. The highest risk of stillbirth was seen between 37 and 39 weeks, when the aHR in the diabetic normal weight group was 9.63 [5.65, 16.40] and the aHR in the diabetic morbidly obese group was 25.34 [15.58, 41.22].Conclusion: PGDM and obesity both independently increased the risk of stillbirth. The joint effect of obesity and PGDM is stronger than the summation or multiplication of the individual effects of each risk factor. [ABSTRACT FROM AUTHOR]

A growing body of evidence suggests that prenatal environment is important in Autism Spectrum Disorder (ASD) etiology. In this study, we compare placental shape features in younger siblings of children with ASD, who themselves are at high ASD risk, to a sample of low risk peers. Digital photographs of the fetal placenta surface and of the sliced placental disk from 129 high ASD risk newborns and from 267 newborns in the National Children’s Study Vanguard pilot were analysed to extract comparable measures of placental chorionic surface shape, umbilical cord displacement and disk thickness. Placental thickness measures were moderately higher in siblings of ASD cases. The placentas of ASD-case siblings were also rounder and more regular in perimeter than general population placentas. After stratification by sex, these across-group differences persisted for both sexes but were more pronounced in females. No significant differences were observed in cord insertion measures. Variations in placental shape features are generally considered to reflect flexibility in placental growth in response to changes in intrauterine environment as the placenta establishes and matures. Reduced placental shape variability observed in high ASD risk siblings compared to low-risk controls may indicate restricted ability to compensate for intrauterine changes. [ABSTRACT FROM AUTHOR]

Background: Maternal obesity has been associated with higher birth weight. Small for gestational age (SGA) neonates born to obese women may be associated with pathological growth with increased neonatal complications.Methods: This was a retrospective cohort study of all non-anomalous singleton neonates born in Texas from 2006-2011. Analyses were limited to births between 34 and 42 weeks gestation with birth weight ≤10th percentile. Results were stratified by maternal pre-pregnancy BMI class. The risk for stillbirth, neonatal death, neonatal intensive care unit (NICU) admission and five minute Apgar scores <7 were estimated for each obesity class and compared to the normal weight group. Multivariable logistic regression analyses were performed to control for potential confounding variables.Results: The rate of stillbirth was 1.4/1000 births for normal weight women, and 2.9/1000 among obese women (p < 0.001, aOR: 1.83 [1.43, 2.34]). The rate of neonatal deaths among normal weight women was 4.3/1000 births, whereas among obese women it was 4.7/1000 (p = 0.94, aOR: 1.10 [0.92, 1.30]). A dose-dependent relationship between maternal obesity and stillbirths was seen, but not for other neonatal outcomes.Conclusion: Among SGA neonates, maternal pre-pregnancy obesity was associated with increased risks for stillbirth, NICU admission and low Apgar scores but not neonatal death. [ABSTRACT FROM AUTHOR]

Background  Wildfires produce air pollutants that have been associated with complications during pregnancy. This study examined the association between wildfire exposure before and during pregnancy and the odds of congenital heart defect (CHD) in the offspring. Methods  This retrospective cohort study used the California Linked Birth File and the Forestry and Fire Protection data between 2007 and 2010. Patients living within 15 miles of wildfire during pregnancy were considered exposed. Multivariate logistic regression models were used to estimate the association between wildfire exposure by these various exposure metrics and atrial septal defect (ASD) or ventricular septal defect (VSD) types of CHD compared to pregnancies without wildfire exposure. Results  Compared to births without wildfire exposure, those with first-, second-, and third-trimester exposure were associated with a higher risk of ASD with a first-trimester adjusted odds ratio (aOR) of 1.11 (95% confidence interval (CI): 1.04-1.18), second-trimester aOR of 1.12 (95% CI: 1.07-1.18), and third-trimester aOR of 1.08 (95% CI: 1.02-1.14). Wildfire exposure during the critical window of fetal heart development (weeks 3-8) was associated with aOR of 1.12 (95% CI: 1.02-1.23). Conclusion  Wildfire exposure during pregnancy appears to increase the risk of developing ASD. Key points Wildfire exposure during critical periods in pregnancy are associated with congenital cardiac malformation.Pre-pregnancy exposure to wildfire is not associated with increased risk of congenital cardiac malformation.Pregnant individuals should avoid wildfire exposure., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)