Placental transcriptomic signatures of prenatal and preconceptional maternal stress.

Prenatal exposure to maternal psychological stress is associated with increased risk for adverse birth and child health outcomes. Accumulating evidence suggests that preconceptional maternal stress may also be transmitted intergenerationally to negatively impact offspring. However, understanding of mechanisms linking these exposures to offspring outcomes, particularly those related to placenta, is limited. Using RNA sequencing, we identified placental transcriptomic signatures associated with maternal prenatal stressful life events (SLEs) and childhood traumatic events (CTEs) in 1 029 mother-child pairs in two birth cohorts from Washington state and Memphis, Tennessee. We evaluated individual gene-SLE/CTE associations and performed an ensemble of gene set enrichment analyses combing across 11 popular enrichment methods. Higher number of prenatal SLEs was significantly (FDR < 0.05) associated with increased expression of ADGRG6, a placental tissue-specific gene critical in placental remodeling, and decreased expression of RAB11FIP3, an endocytosis and endocytic recycling gene, and SMYD5, a histone methyltransferase. Prenatal SLEs and maternal CTEs were associated with gene sets related to several biological pathways, including upregulation of protein processing in the endoplasmic reticulum, protein secretion, and ubiquitin mediated proteolysis, and down regulation of ribosome, epithelial mesenchymal transition, DNA repair, MYC targets, and amino acid-related pathways. The directional associations in these pathways corroborate prior non-transcriptomic mechanistic studies of psychological stress and mental health disorders, and have previously been implicated in pregnancy complications and adverse birth outcomes. Accordingly, our findings suggest that maternal exposure to psychosocial stressors during pregnancy as well as the mother's childhood may disrupt placental function, which may ultimately contribute to adverse pregnancy, birth, and child health outcomes.

Characterization of Xenobiotic and Steroid Disposition Potential of Human Placental Tissue and Cell Lines (BeWo, JEG-3, JAR, and HTR-8/SVneo) by Quantitative Proteomics.

The placenta is a fetal organ that performs critical functions to maintain pregnancy and support fetal development, including metabolism and transport of xenobiotics and steroids between the maternal-fetal unit. In vitro placenta models are used to study xenobiotic and steroid disposition, but how well these models recapitulate the human placenta is not well understood. We first characterized the abundance of proteins involved in xenobiotic and steroid disposition in human placental tissue. In pooled human placenta, the following xenobiotic and steroid disposition proteins were detected (highest to lowest), 1) enzymes: glutathione S-transferase P, carbonyl reductase 1, aldo-keto reductase 1B1, hydroxysteroid dehydrogenases (HSD3B1 and HSD11B1), aromatase, epoxide hydrolase 1 (EPHX1) and steryl-sulfatase, and 2) transporters: monocarboxylate transporters (MCT1 and 4), organic anion transporting polypeptide 2B1, organic anion transporter 4, and breast cancer resistance protein (BCRP). Then, the tissue proteomics data were compared with four placental cell lines (BeWo, JEG-3, JAR, and HTR-8/SVneo). The differential global proteomics analysis revealed that the tissue and cell lines shared 1420 cytosolic and 1186 membrane proteins. Although extravillous trophoblast and cytotrophoblast marker proteins were detected in all cell lines, only BeWo and JEG-3 cells expressed the syncytiotrophoblast marker, chorionic somatomammotropin hormone 1. BeWo and JEG-3 cells expressed most target proteins including aromatase, HSDs, EPHX1, MCT1, and BCRP. JEG-3 cells treated with commonly detected phthalates in human biofluids showed dysregulation of steroid pathways. The data presented here show that BeWo and JEG-3 cells are closer to the placental tissue for studying xenobiotic and steroid disposition. SIGNIFICANCE STATEMENT: This is the first study to compare proteomics data of human placental tissue and cell lines (BeWo, JAR, JEG-3, and HTR-8/SVneo). The placental cell line and tissue proteomes are vastly different, but BeWo and JEG-3 cells showed greater resemblance to the tissue in the expression of xenobiotic and steroid disposition proteins. These data will assist researchers to select an optimum cell model for mechanistic investigations on xenobiotic and steroid disposition in the placenta.

Placental transcriptomic signatures of spontaneous preterm birth.

BACKGROUND: Spontaneous preterm birth accounts for most preterm births and leads to significant morbidity in the newborn and childhood period. This subtype of preterm birth represents an increasing proportion of all preterm births when compared with medically indicated preterm birth, yet it is understudied in omics analyses. The placenta is a key regulator of fetal and newborn health, and the placental transcriptome can provide insight into pathologic changes that lead to spontaneous preterm birth. OBJECTIVE: This analysis aimed to identify genes for which placental expression was associated with spontaneous preterm birth (including early preterm and late preterm birth). STUDY DESIGN: The ECHO PATHWAYS consortium extracted RNA from placental samples collected from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood and the Global Alliance to Prevent Prematurity and Stillbirth studies. Placental transcriptomic data were obtained by RNA sequencing. Linear models were fit to estimate differences in placental gene expression between term birth and spontaneous preterm birth (including gestational age subgroups defined by the American College of Obstetricians and Gynecologists). Models were adjusted for numerous confounding variables, including labor status, cohort, and RNA sequencing batch. This analysis excluded patients with induced labor, chorioamnionitis, multifetal gestations, or medical indications for preterm birth. Our combined cohort contained gene expression data for 14,023 genes in 48 preterm and 540 term samples. Genes and pathways were considered statistically significantly different at false discovery rate-adjusted P value of <.05. RESULTS: In total, we identified 1728 genes for which placental expression was associated with spontaneous preterm birth with more differences in expression in early preterm samples than late preterm samples when compared with full-term samples. Of those, 9 genes were significantly decreased in both early and late spontaneous preterm birth, and the strongest associations involved placental expression of IL1B, ALPL, and CRLF1. In early and late preterm samples, we observed decreased expression of genes involved in immune signaling, signal transduction, and endocrine function. CONCLUSION: This study provides a comprehensive assessment of the differences in the placental transcriptome associated with spontaneous preterm birth with robust adjustment for confounding. Results of this study are in alignment with the known etiology of spontaneous preterm birth, because we identified multiple genes and pathways for which the placental and chorioamniotic membrane expression was previously associated with prematurity, including IL1B. We identified decreased expression in key signaling pathways that are essential for placental growth and function, which may be related to the etiology of spontaneous preterm birth. We identified increased expression of genes within metabolic pathways associated exclusively with early preterm birth. These signaling and metabolic pathways may provide clinically targetable pathways and biomarkers. The findings presented here can be used to understand underlying pathologic changes in premature placentas, which can inform and improve clinical obstetrics practice.

Familial aggregation of stillbirth: A pedigree analysis of a matched case-control study.

OBJECTIVE: To determine whether stillbirth aggregates in families and quantify its familial risk using extended pedigrees. DESIGN: State-wide matched case-control study. SETTING: Utah, United States. POPULATION: Stillbirth cases (n = 9404) and live birth controls (18 808) between 1978 and 2019. METHODS: Using the Utah Population Database, a population-based genealogical resource linked with state fetal death and birth records, we identified high-risk pedigrees with excess familial aggregation of stillbirth using the Familial Standardised Incidence Ratio (FSIR). Stillbirth odds ratio (OR) for first-degree relatives (FDR), second-degree relatives (SDR) and third-degree relatives (TDR) of parents with a stillbirth (affected) and live birth (unaffected) were estimated using logistic regression models. MAIN OUTCOME MEASURES: Familial aggregation estimated using FSIR, and stillbirth OR estimated for FDR, SDR and TDR of affected and unaffected parents using logistic regression models. RESULTS: We identified 390 high-risk pedigrees with evidence for excess familial aggregation (FSIR ≥2.00; P-value <0.05). FDRs, SDRs and TDRs of affected parents had 1.14-fold (95% confidence interval [CI]: 1.04-1.26), 1.22-fold (95% CI 1.11-1.33) and 1.15-fold (95% CI 1.08-1.21) higher stillbirth odds compared with FDRs, SDRs and TDRs of unaffected parents, respectively. Parental sex-specific analyses showed male FDRs, SDRs and TDRs of affected fathers had 1.22-fold (95% CI 1.02-1.47), 1.38-fold (95% CI 1.17-1.62) and 1.17-fold (95% CI 1.05-1.30) higher stillbirth odds compared with those of unaffected fathers, respectively. FDRs, SDRs and TDRs of affected mothers had 1.12-fold (95% CI 0.98-1.28), 1.09-fold (95% CI 0.96-1.24) and 1.15-fold (95% CI 1.06-1.24) higher stillbirth odds compared with those of unaffected mothers, respectively. CONCLUSIONS: We provide evidence for familial aggregation of stillbirth. Our findings warrant investigation into genes associated with stillbirth and underscore the need to design large-scale studies to determine the genetic architecture of stillbirth.

Associations of perinatal exposure to PM2.5 with gestational weight gain and offspring birth weight.

BACKGROUND: PM2.5 have been associated with weight change in animal models and non-pregnant populations. Evidence of associations between PM2.5 and gestational weight gain (GWG), an important determinant of course and outcomes of pregnancy, and subsequent birth outcomes is limited. METHODS: The study was conducted among a subset of participants from the Omega Study, a prospective pregnancy cohort. Exposure to PM2.5 (µg/m3) was ascertained for participants (N = 855) based on their residential address using a validated national spatiotemporal model. Adjusted multivariable linear regression models were used to estimate associations of trimester-specific and pregnancy-month PM2.5 exposures with early (<20 weeks gestation), late (≥20 weeks gestation), and total GWG and infant birth weight. Stratified models and product terms were used to examine whether pre-pregnancy BMI (ppBMI) and infant sex modified the associations. RESULTS: Average monthly PM2.5 exposure during the first, second, and third trimesters were 7.3 µg/m3, 7.9 µg/m3, and 7.7 µg/m3, respectively. Higher third trimester PM2.5 exposure was associated with higher late (0.40 kg per 5 µg/m (McDowell et al., 2018); 95%CI: 0.12, 0.67) and total (0.35 kg; 95%CI: 0.01, 0.70) GWG among participants with normal ppBMI. Higher second month PM2.5 exposure was associated with lower early (-0.70 kg; 95%CI: 1.22, -0.18), late (-0.84 kg; 95% CI: 1.54, -0.14), and total (-1.70 kg; 95%CI: 2.57, -0.82) GWG among participants with overweight/obese ppBMI. Product terms between PM2.5 and ppBMI were significant for second month PM2.5 exposure and early (p-value = 0.01) and total GWG (p-value<0.01). Higher third trimester PM2.5 exposure was associated with higher birth weight, though higher fourth month PM2.5 exposure was associated with lower birth weight, particularly among those with normal ppBMI and male infants. CONCLUSIONS: Associations of PM2.5 with GWG vary by exposure window and ppBMI, while associations of PM2.5 with birth weight potentially vary by exposure window, ppBMI and infant sex. Further exploration of associations between PM2.5 and maternal/child health outcomes are needed.

Association of prenatal exposure to ambient air pollution with adverse birth outcomes and effect modification by socioeconomic factors.

BACKGROUND: Maternal exposure to air pollution has been associated with birth outcomes; however, few studies examined biologically critical exposure windows shorter than trimesters or potential effect modifiers. OBJECTIVES: To examine associations of prenatal fine particulate matter (PM2.5), by trimester and in biologically critical windows, with birth outcomes and assess potential effect modifiers. METHODS: This study used two pregnancy cohorts (CANDLE and TIDES; N = 2099) in the ECHO PATHWAYS Consortium. PM2.5 was estimated at the maternal residence using a fine-scale spatiotemporal model, averaged over pregnancy, trimesters, and critical windows (0-2 weeks, 10-12 weeks, and last month of pregnancy). Outcomes were preterm birth (PTB, <37 completed weeks of gestation), small-for-gestational-age (SGA), and continuous birthweight. We fit multivariable adjusted linear regression models for birthweight and Poisson regression models (relative risk, RR) for PTB and SGA. Effect modification by socioeconomic factors (maternal education, household income, neighborhood deprivation) and infant sex were examined using interaction terms. RESULTS: Overall, 9% of births were PTB, 10.4% were SGA, and mean term birthweight was 3268 g (SD = 558.6). There was no association of PM2.5 concentration with PTB or SGA. Lower birthweight was associated with higher PM2.5 averaged over pregnancy (ß -114.2, 95%CI -183.2, -45.3), during second (ß -52.9, 95%CI -94.7, -11.2) and third (ß -45.5, 95%CI -85.9, -5.0) trimesters, and the month prior to delivery (ß -30.5, 95%CI -57.6, -3.3). Associations of PM2.5 with likelihood of SGA and lower birthweight were stronger among male infants (p-interaction ≤0.05) and in those with lower household income (p-interaction = 0.09). CONCLUSIONS: Findings from this multi city U.S. birth cohort study support previous reports of inverse associations of birthweight with higher PM2.5 exposure during pregnancy. Findings also suggest possible modification of this association by infant sex and household income.

The mediating role of anxiety/depression symptoms between adverse childhood experiences (ACEs) and somatic symptoms in adolescents.

INTRODUCTION: This study examines the relationships among recent adverse childhood experiences (ACEs), somatic symptoms, and anxiety/depression symptoms during adolescence and whether anxiety/depression symptoms mediate the relationship between ACEs and somatic symptoms. METHODS: Longitudinal prospective data from the Longitudinal Studies of Child Abuse and Neglect study of 1354 children and their primary caregivers in the United States was used in this study. A longitudinal cross-lagged path analysis among recent ACEs, anxiety/depression symptoms, and somatic symptoms at three points during adolescence (ages 12, 14, and 16 years) was conducted. RESULTS: The sample was 51% female and 53% African American. The results indicated significant concurrent associations between recent ACEs and increased anxiety/depression symptoms at ages 12, 14, and 16 (ß = .27, p < .001; ß = .15, p < .001; ß = .07, p < .05) and between anxiety/depression symptoms and increased somatic symptoms at ages 12, 14, and 16 years (ß = .44, p < .001; ß = .39, p < .001; ß = .49, p < .001). Moreover, anxiety/depression symptoms significantly mediated the relationship between recent ACEs and concurrent somatic symptoms at ages 12, 14, and 16 years (ß = .12, p < .001; ß = .06, p < .001; ß = .04, p < .05). However, there was no significant relationship between recent ACEs and somatic symptoms. CONCLUSION: The findings suggest that anxiety/depression symptoms mediate the concurrent relationships between recent ACEs and somatic symptoms at ages 12, 14, and 16. Clinicians should consider assessing anxiety/depression symptoms and possible concurrent exposure to ACEs when caring for adolescents who present with somatic symptoms.

Neonatal Vital Sign Trajectories and Risk Factors During Transport Within a Regional Care Network.

OBJECTIVE: The aim of this study was to characterize vital sign abnormalities, trajectories, and related risk factors during neonatal transport. METHODS: We performed a retrospective analysis of neonates transported within a US regional care network in 2020 to 2021. Demographic and clinical data were collected from electronic records. Group-based trajectory modeling was applied to identify groups of neonates who followed distinct vital sign trajectories during transport. Patients with conditions likely to impact the assessed vital were excluded. Risk factors for trajectories were examined using modified Poisson regression models. RESULTS: Of the 620 neonates in the study, 92% had one abnormal systolic blood pressure (SBP) measure, approximately half had an abnormal heart rate (47%) or temperature (56%), and 28% had an abnormal oxygen saturation measure during transport. Over half (53%) were in a low and decreasing SBP trajectory, and 36% were in a high and increasing heart rate trajectory. Most infants ≤ 28 weeks postmenstrual age had 2 or more concerning vital sign trajectories during transport. CONCLUSION: Abnormal vital signs were common during neonatal transport, and potentially negative trajectories in heart rate and SBP were more common than temperature or oxygen saturation. Transport teams should be trained and equipped to detect concerning trends and respond appropriately while en route.

Maternal Plasma 25-Hydroxyvitamin D during Gestation Is Positively Associated with Neurocognitive Development in Offspring at Age 4-6 Years.

BACKGROUND: Vitamin D is critical to embryonic neuronal differentiation and other developmental processes that may affect future neurocognitive function. However, observational studies have found inconsistent associations between gestational vitamin D and neurocognitive outcomes. OBJECTIVES: We examined the association of gestational 25-hydroxyvitamin D [25(OH)D] with children's IQ at 4-6 y, and explored whether associations differed by race. METHODS: This study used data from the CANDLE (Conditions Affecting Neurocognitive Development and Learning in Early Childhood) cohort. Between 2006 and 2011, CANDLE recruited 1503 women in their second trimester of healthy singleton pregnancies. Inclusion criteria for this analysis were gestation of ≥34 wk and availability of 25(OH)D and IQ data. Associations between second-trimester 25(OH)D plasma concentration and Stanford-Binet IQ scores in offspring at 4-6 y were examined using multivariable linear regression; interaction terms were used to explore possible effect modification by race. RESULTS: Mean ± SD 25(OH)D concentration among 1019 eligible dyads was 21.6 ± 8.4 ng/mL, measured at a mean ± SD gestational age of 23.0 ± 3.0 wk. Vitamin D deficiency [25(OH)D < 20 ng/mL] was observed in 45.6%. Maternal 25(OH)D differed by race with a mean ± SD of 19.8 ± 7.2 ng/mL in Blacks sand 25.9 ± 9.3 ng/mL in Whites ( P  < 0.001). In adjusted models a 10-ng/mL increase in 25(OH)D was associated with a 1.17-point higher Full Scale IQ (95% CI: 0.27, 2.06 points), a 1.17-point higher Verbal IQ (95% CI: 0.19, 2.15 points), and a 1.03-point higher Nonverbal IQ (95% CI: 0.10, 1.95 points). We observed no evidence of effect modification by race. CONCLUSIONS: Second-trimester maternal 25(OH)D was positively associated with IQ at 4-6 y, suggesting that gestational vitamin D status may be an important predictor of neurocognitive development. These findings may help inform prenatal nutrition recommendations and may be especially relevant for Black and other dark-skinned women at high risk of vitamin D deficiency.

Associations Between Maternal Nutrition in Pregnancy and Child Blood Pressure at 4-6 Years: A Prospective Study in a Community-Based Pregnancy Cohort.

BACKGROUND: The intrauterine environment may influence offspring blood pressure, with effects possibly extending into adulthood. The associations between prenatal nutrition and offspring blood pressure, alone or in combination with other sociodemographic or behavioral factors, are unclear. OBJECTIVES: To investigate the associations of maternal dietary patterns and plasma folate concentrations with blood pressure in children aged 4-6 years, and assess the potential effect modifications by child sex, maternal race, pre-pregnancy overweight or obesity, maternal smoking, and breastfeeding. METHODS: Participants were 846 mother-child dyads from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) study. Maternal nutrition was characterized by the Healthy Eating Index 2010 (HEI) scores and plasma folate concentrations in pregnancy. We calculated the systolic blood pressure (SBP) and diastolic blood pressure percentiles, incorporating sex, age, and height, and categorized children as either having high blood pressure (HBP; ≥90th percentile) or normal blood pressure. Linear regressions were performed to quantify the associations between maternal nutrition and continuous blood pressure percentiles, and Poisson regressions were used to estimate the incidence rate ratio (IRR) of binary HBP. We examined the effect modifications using interaction models. RESULTS: Mean HEI scores and folate concentrations were 60.0 (SD, 11.3) and 23.1 ng/mL (SD, 11.1), respectively. Based on measurements at 1 visit, 29.6% of the children were defined as having HBP. Maternal HEI scores and plasma folate concentrations were not associated with child blood pressure percentiles or HBP in the full cohort. Among mothers self-identified as white, there was an inverse relationship between maternal HEI score and child SBP percentile (ß, -0.40; 95%CI: -0.75 to -0.06). A maternal HEI score above 59 was associated with a reduced risk of HBP in girls (IRR, 0.53; 95% CI: 0.32-0.88). No modified associations by pre-pregnancy overweight or obesity, maternal smoking, or breastfeeding were indicated. CONCLUSIONS: We found little evidence for effects of maternal nutrition during pregnancy on childhood blood pressure, but detected sex- and race-specific associations. The study contributes to the evolving scientific inquiry regarding developmental origins of disease.

Association of Antidepressant Continuation in Pregnancy and Infant Birth Weight.

PURPOSE: The aim of the study was to evaluate the association of antidepressant continuation in pregnancy with infant birth weight among women using antidepressants before pregnancy. METHODS: This retrospective cohort study used electronic health data linked with state birth records. We identified singleton live births (2001-2014) to enrolled women with 1 or more antidepressant prescriptions filled 6 months or less before pregnancy, including "continuers" (≥1 antidepressant fills during pregnancy, n = 1775) and "discontinuers" (no fill during pregnancy, n = 1249). We compared birth weight, small or large for gestational age (SGA or LGA), low birth weight (LBW; <2500 g), and macrosomia (>4500 g) between the 2 groups, using inverse probability of treatment weighting to account for pre-pregnancy characteristics, including mental health conditions. RESULTS: After weighting, infants born to antidepressant continuers weighed 71.9 g less than discontinuers' infants (95% confidence interval [CI], -115.5 to -28.3 g), with a larger difference for female infants (-106.4 g; 95% CI, -164.6 to -48.1) than male infants (-48.5 g; 95% CI, -107.2 to 10.3). For female infants, SGA risk was greater in continuers than discontinuers (relative risk [RR],1.54; 95% CI, 1.02 to 2.32). Low birth weight risk was greater in continuers with 50% or more of days covered (RR, 1.69; 95% CI, 1.11 to 2.58) and exposure in the second trimester (RR, 1.53; 95% CI, 1.02 to 2.29), as compared with discontinuers. CONCLUSIONS: Depending on infant sex, as well as duration and timing of use, continuation of antidepressant use during pregnancy may be associated with lower infant birth weight, with corresponding increases in LBW and SGA.

Maternal Gestational Weight Gain in Relation to Antidepressant Continuation in Pregnancy.

OBJECTIVE: Both excessive and inadequate gestational weight gain (GWG) are associated with adverse health outcomes for the woman and her child. Antidepressant use in pregnancy could affect GWG, based on evidence in nonpregnant women that some antidepressants may cause weight gain and others weight loss. Previous studies of antidepressant use and GWG were small with limited ability to account for confounding, including by maternal mental health status and severity. We assessed the association of antidepressant continuation in pregnancy with GWG among women using antidepressants before pregnancy. STUDY DESIGN: Our retrospective cohort study included singleton livebirths from 2001 to 2014 within Kaiser Permanente Washington, an integrated health care system. Data were obtained from electronic health records and linked Washington State birth records. Among women with ≥1 antidepressant fill within 6 months before pregnancy, women who filled an antidepressant during pregnancy were considered "continuers;" women without a fill were "discontinuers." We calculated mean differences in GWG and relative risks (RR) of inadequate and excessive weight gain based on Institute of Medicine guidelines. Using inverse probability of treatment weighting with generalized estimating equations, we addressed differences in maternal characteristics, including mental health conditions. RESULTS: Among the 2,887 births, 1,689 (59%) were to women who continued antidepressants in pregnancy and 1,198 (42%) were to discontinuers. After accounting for confounding, continuers had similar weight gain to those who discontinued (mean difference: 1.3 lbs, 95% confidence interval [CI]: -0.1 to 2.8 lbs) and similar risks of inadequate and excessive GWG (RR: 0.95, 95% CI: 0.80-1.14 and RR: 1.06, 95% CI: 0.98-1.14, respectively). Findings were comparable for specific antidepressants and trimesters of exposure. CONCLUSION: We did not find evidence that continuation of antidepressants in pregnancy led to differences in GWG. KEY POINTS: · Antidepressant use is associated with weight change in nonpregnant populations.. · Prior evidence on whether antidepressant use in pregnancy affects gestational weight gain is sparse.. · We accounted for confounding by characteristics such as mental health conditions and their severity.. · We found no association between pregnancy antidepressant continuation and gestational weight gain..

Maternal Education in Early Life and Risk of Metabolic Syndrome in Young Adult American Females and Males: Disentangling Life Course Processes Through Causal Models.

BACKGROUND: Maternal education in a child's early life may directly affect the child's adult cardiometabolic health, but this is difficult to disentangle from biological, social, and behavioral life course processes that are associated with maternal education. These processes may also differ between males and females. METHODS: Using data from the National Longitudinal Study of Adolescent to Adult Health (1995-2009) (N = 4,026 females and 3,192 males), we estimated sex-stratified associations between maternal attainment of less than high school (

Antidepressant continuation in pregnancy and risk of gestational diabetes.

PURPOSE: Previous studies observed modestly higher risk of gestational diabetes (GDM) associated with antidepressant use in pregnancy, potentially due to confounding by indication. We assessed the association of antidepressant continuation in pregnancy with GDM, as well as blood glucose levels, after accounting for confounding. METHODS: We conducted a retrospective cohort study of singleton live births from 2001 to 2014 to women enrolled in Kaiser Permanente Washington, an integrated health care delivery system, utilizing electronic health data and linked Washington State birth records. We required that women have ≥1 antidepressant prescription fills ≤6 months before pregnancy. Women with an antidepressant fill during pregnancy were categorized as "continuers" (n = 1634); those without a fill were "discontinuers" (n = 1211). We calculated relative risks (RRs) for GDM and mean differences in screening blood glucose levels using generalized estimating equations with inverse probability of treatment weighting to account for baseline characteristics, including mental health conditions and indicators of mental health severity. RESULTS: Compared with discontinuers, antidepressant continuers had comparable risk of GDM (RR: 1.10; 95% confidence interval [CI], 0.84-1.44) and blood glucose levels (mean difference: 2.3 mg/dL; 95% CI, -1.5 to 6.1 mg/dL). We observed generally similar results for specific antidepressants, with the potential exceptions of risk of GDM associated with sertraline (RR: 1.30; 95% CI, 0.90-1.88) and venlafaxine (RR: 1.52; 95% CI, 0.87-2.68), but neither association was statistically significant. CONCLUSIONS: Our study suggests that overall, women who continue antidepressants in pregnancy are not at increased risk for GDM or higher blood glucose, although further study may be warranted for sertraline and venlafaxine.

Racial disparities in the transgenerational transmission of low birthweight risk.

Objective: To examine the association of maternal low birthweight (LBW) with infant LBW and infant LBW subgroups (i.e. moderate and very LBW), overall and among non-Hispanic (NH) white and NH black mothers. Design: We conducted a population-based cohort study in Allegheny County, Pennsylvania, using linked birth record data of NH white and NH black mother-infant pairs (N = 6,633) born in 1979-1998 and 2009-2011, respectively. The exposure of interest was maternal LBW (birthweight <2500 grams) while the outcomes were infant LBW and LBW subgroups - moderate LBW (1,500-2,499 grams) or very LBW (<1,500 grams). Logistic regression (binomial and multinomial) models were used to estimate adjusted Odds Ratios (ORs), Relative Risk Ratios (RRRs), and related 95% confidence intervals (CI). Stratified analyses were conducted to assess effect modification by mothers' race. Results: Maternal LBW was associated with 1.53 (95%CI: 1.15-2.02) and 1.75 (95%CI: 1.29-2.37) -fold increases in risk of infant LBW and MLBW, respectively, but not VLBW (RRR = 0.86; 95%CI: 0.44-1.70). In race-stratified models, maternal LBW-infant LBW associations were observed among NH blacks (OR = 1.88; 95%CI: 1.32-2.66) and not among NH whites (OR = 1.03; 95%CI: 0.62-1.73) (P for interaction = 0.07). Among NH blacks, maternal LBW was associated with a 2.18 (95%CI: 1.49, 3.20) -fold increase in risk of infant MLBW, but not VLBW (RRR = 1.12; 95%CI: 0.54, 2.35). Among NH whites, LBW subgroup analyses could not be performed due to small numbers of VLBW infants among LBW mothers. Conclusion: Mothers who were LBW at their own birth were more likely to have MLBW infants. Maternal race modified associations of maternal LBW with infant LBW, particularly infant MLBW. Further research is needed in this area to understand the potential mechanisms involved in the transgenerational transmission of LBW risk and race-specific differences in the transmission.

Abruptio placentae risk and genetic variations in mitochondrial biogenesis and oxidative phosphorylation: replication of a candidate gene association study.

BACKGROUND: Abruptio placentae is a complex multifactorial disease that is associated with maternal and neonatal death and morbidity. Abruptio placentae's high recurrence rate, high prevalence of heritable thrombophilia among women with abruptio placentae, and aggregation of cases in families of women with the disease support the possibility of a genetic predisposition. Previous genome-wide and candidate gene association studies have identified single nucleotide polymorphisms in mitochondrial biogenesis and oxidative phosphorylation genes that potentially are associated with abruptio placentae risk. Perturbations in mitochondrial biogenesis and oxidative phosphorylation, which results in mitochondrial dysfunction, can lead to the impairment of differentiation and invasion of the trophoblast and to several obstetrics complications that include abruptio placentae. OBJECTIVE: The purpose of this study was to determine whether the results of a candidate genetic association study that indicated a link between DNA variants (implicated in mitochondrial biogenesis and oxidative phosphorylation) and abruptio placentae could be replicated. STUDY DESIGN: The study was conducted among participants (507 abruptio placentae cases and 1090 control subjects) of the Placental Abruption Genetic Epidemiology study. Weighted genetic risk scores were calculated with the use of abruptio placentae risk-increasing alleles of 11 single nucleotide polymorphisms in 9 mitochondrial biogenesis and oxidative phosphorylation genes (CAMK2B, NR1H3, PPARG, PRKCA, THRB, COX5A, NDUFA10, NDUFA12, and NDUFC2), which previously was reported in the Peruvian Abruptio Placentae Epidemiology study, a study with similar design and study population to the Placental Abruption Genetic Epidemiology study. Logistic regression models were fit to examine associations of weighted genetic risk scores (quartile 1, <25th percentile; quartile 2, 25-50th percentile; quartile 3, 50-70th percentile, and quartile 4, >75th percentile) with risk of abruptio placentae, adjusted for population admixture (the first 4 principal components), maternal age, infant sex, and preeclampsia. The weighted genetic risk score was also modeled as a continuous predictor. To assess potential effect modification, analyses were repeated among strata that were defined by preeclampsia status, maternal age (≥35 vs 18-34 years), and infant sex. RESULTS: Abruptio placentae cases were more likely to have preeclampsia, shorter gestational age, and lower infant birthweight. Participants in quartile 2 (score, 12.6-13.8), quartile 3 (score, 13.9-15.0) and quartile 4 (score, ≥15.1) had a genetic risk score of 1.45-fold (95% confidence interval, 1.04-2.02; P=.03), a 1.42-fold (95% confidence interval, 1.02-1.98; P=.04), and a 1.75-fold (95% confidence interval, 1.27-2.42; P=7.0E-04) higher odds of abruptio placentae, respectively, compared with those in quartile 1 (score,<12.6; P-for trend=.0003). The risk of abruptio placentae was 1.12-fold (95% confidence interval, 1.05-1.19; P=3.0×1004) higher per 1-unit increase in the score. Among women with preeclampsia, those in quartile 4 had a 3.92-fold (95% confidence interval, 1.48-10.36; P=.01) higher odds of abruptio placentae compared with women in quartile 1. Among normotensive women, women in quartile 4 had a 1.57-fold (95% confidence interval, 1.11-2.21; P=.01) higher odds of abruptio placentae compared with those in quartile 1 (P-for interaction=.12). We did not observe differences in associations among strata defined by maternal age or infant sex. CONCLUSION: In this study, we replicated previous findings and provide strong evidence for DNA variants that encode for genes that are involved in mitochondrial biogenesis and oxidative phosphorylation pathways, which confers risk for abruptio placentae. These results shed light on the mechanisms that implicate DNA variants that encode for proteins in mitochondrial function that are responsible for abruptio placentae risk. Therapeutic efforts to reduce risk of abruptio placentae can be enhanced by improved biologic understanding of maternal mitochondrial biogenesis/oxidative phosphorylation pathways and identification of women who would be at high risk for abruptio placentae.

Maternal sedentary behavior during pre-pregnancy and early pregnancy and mean offspring birth size: a cohort study.

BACKGROUND: Sedentary behavior is associated with adverse health outcomes in the general population. Whether sedentary behavior during pregnancy is associated with newborn outcomes, such as birth size, is not established, and previous studies have been inconsistent. While previous research suggests that male and female fetuses respond differently to maternal behaviors, such as physical activity, the role of infant sex in sedentary behavior-birth size associations has not been examined. METHODS: Participants in the Omega study, a cohort in Washington State (1996-2008), reported leisure time sedentary behavior (non-work time spent sitting), light intensity physical activity, and moderate/vigorous leisure time physical activity duration in the year before pregnancy (N = 1373) and in early pregnancy (N = 1535, mean 15 weeks). Offspring birth size was abstracted from delivery records. Non-parametric calibration weighting was used to assign adjustment weight (matching the distribution of sociodemographic and medical characteristics of the full cohort (N = 4128)) to participants with available sedentary behavior data. Weighted linear regression models were used to estimate mean differences in offspring birthweight, head circumference, and ponderal index (birthweight/length3) associated with leisure time sedentary behavior. Regression models were run overall and stratified by offspring sex. Isotemporal substitution modeling was used to determine mean differences in birthweight associated with replacing sedentary behavior with light or moderate/vigorous physical activity. RESULTS: On average, women spent 2.3 and 2.6 h/day in leisure time sedentary behavior during pre- and early pregnancy, respectively. There were no associations of pre-pregnancy leisure time sedentary behavior with mean birthweight, head circumference, or ponderal index (adjusted ß = - 12, 95% CI: -28, 4.1; ß = 0.0, 95% CI: -0.04, 0.1; and ß = 0.1, 95% CI: -0.2, 0.4, respectively). Early pregnancy sedentary behavior was not associated with mean birth size. Associations of sedentary behavior with mean birth size did not differ by offspring sex. Replacing sedentary time with light or moderate/vigorous physical activity was not associated with mean birthweight. CONCLUSIONS: We did not observe associations of maternal sedentary behavior during pre- or early pregnancy with mean offspring birth size. Pre-pregnancy and early pregnancy sedentary behavior may have important adverse effects on maternal health, but our results do not support associations with mean offspring birth size.

Dental enamel defects predict adolescent health indicators: A cohort study among the Tsimane' of Bolivia.

OBJECTIVES: Bioarchaeological findings have linked defective enamel formation in preadulthood with adult mortality. We investigated how defective enamel formation in infancy and childhood is associated with risk factors for adult morbidity and mortality in adolescents. METHODS: This cohort study of 349 Amerindian adolescents (10-17 years of age) related extent of enamel defects on the central maxillary incisors (none, less than 1/3, 1/3 to 2/3, more than 2/3) to adolescent anthropometrics (height, weight) and biomarkers (hemoglobin, glycated hemoglobin, white blood cell count, and blood pressure). Risk differences and 95% confidence intervals were estimated using multiple linear regression. Enamel defects and stunted growth were compared in their ability to predict adolescent health indicators using log-binomial regression and receiver operating characteristics (ROCs). RESULTS: Greater extent of defective enamel formation on the tooth surface was associated with shorter height (-1.35 cm, 95% CI: -2.17, -0.53), lower weight (-0.98 kg, 95% CI: -1.70, -0.26), lower hemoglobin (-0.36 g/dL, 95% CI: -0.59, -0.13), lower glycated hemoglobin (-0.04 %A1c , 95% CI: -0.08, -0.00008), and higher white blood cell count (0.74 109 /L, 95% CI: 0.35, 1.14) in adolescence. Extent of enamel defects and stunted growth independently performed similarly as risk factors for adverse adolescent outcomes, including anemia, prediabetes/type II diabetes, elevated WBC count, prehypertension/hypertension, and metabolic health. CONCLUSIONS: Defective enamel formation in infancy and childhood predicted adolescent health outcomes and may be primarily associated with infection. Extent of enamel defects and stunted growth may be equally predictive of adverse adolescent health outcomes.

Parent-of-Origin Effects of the APOB Gene on Adiposity in Young Adults.

Loci identified in genome-wide association studies (GWAS) of cardio-metabolic traits account for a small proportion of the traits' heritability. To date, most association studies have not considered parent-of-origin effects (POEs). Here we report investigation of POEs on adiposity and glycemic traits in young adults. The Jerusalem Perinatal Family Follow-Up Study (JPS), comprising 1250 young adults and their mothers was used for discovery. Focusing on 18 genes identified by previous GWAS as associated with cardio-metabolic traits, we used linear regression to examine the associations of maternally- and paternally-derived offspring minor alleles with body mass index (BMI), waist circumference (WC), fasting glucose and insulin. We replicated and meta-analyzed JPS findings in individuals of European ancestry aged ≤50 belonging to pedigrees from the Framingham Heart Study, Family Heart Study and Erasmus Rucphen Family study (total N≅4800). We considered p<2.7x10-4 statistically significant to account for multiple testing. We identified a common coding variant in the 4th exon of APOB (rs1367117) with a significant maternally-derived effect on BMI (ß = 0.8; 95%CI:0.4,1.1; p = 3.1x10-5) and WC (ß = 2.7; 95%CI:1.7,3.7; p = 2.1x10-7). The corresponding paternally-derived effects were non-significant (p>0.6). Suggestive maternally-derived associations of rs1367117 were observed with fasting glucose (ß = 0.9; 95%CI:0.3,1.5; p = 4.0x10-3) and insulin (ln-transformed, ß = 0.06; 95%CI:0.03,0.1; p = 7.4x10-4). Bioinformatic annotation for rs1367117 revealed a variety of regulatory functions in this region in liver and adipose tissues and a 50% methylation pattern in liver only, consistent with allelic-specific methylation, which may indicate tissue-specific POE. Our findings demonstrate a maternal-specific association between a common APOB variant and adiposity, an association that was not previously detected in GWAS. These results provide evidence for the role of regulatory mechanisms, POEs specifically, in adiposity. In addition this study highlights the benefit of utilizing family studies for deciphering the genetic architecture of complex traits.

Healthy Lifestyle During Early Pregnancy and Risk of Gestational Diabetes Mellitus.

Previous studies have found associations between individual healthy behaviors and reduced risk of gestational diabetes mellitus (GDM); however, the association of composite healthy lifestyle during pregnancy with GDM has not been examined. Participants in the Omega Study (n = 3,005), a pregnancy cohort study conducted in Washington State (1996-2008), reported information on diet, physical activity, smoking, and stress during early pregnancy. Lifestyle components were dichotomized into healthy/unhealthy and then combined into a total lifestyle score (range, 0-4). Regression models were used to determine relative risk of GDM (n = 140 cases) in relation to healthy lifestyle. Twenty percent of participants had a healthy diet, 66% were physically active, 95% were nonsmokers, and 55% had low stress. Each 1-point increase in lifestyle score was associated with a 21% lower risk of GDM (95% confidence interval: 0.65, 0.96) after adjustment for age, race, and nulliparity. Adjustment for prepregnancy body mass index, prepregnancy physical activity, and prepregnancy smoking attenuated the associations slightly. Associations were similar in normal-weight and overweight/obese women. In this study, a composite measure of healthy lifestyle during early pregnancy was associated with substantially lower GDM risk. Public health messaging and interventions promoting multiple aspects of a healthy lifestyle during early pregnancy should be considered for GDM prevention.