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BackgroundAn extensive body of animal literature supports the premise that maternal obesity during pregnancy can alter the development of the fetal hypothalamus (HTH, a critical regulator of energy balance) with implications for offspring obesity risk (i.e., long-term energy imbalance). Yet, the relationship in humans between maternal overweight/obesity during pregnancy and fetal hypothalamic development remains largely unknown. Here, using an international (Finland and California, USA) multi-site diffusion tensor imaging (DTI) dataset, we test the hypothesis that maternal pre-pregnancy BMI is associated with newborn offspring HTH mean diffusivity (HTH MD, a replicable neural correlate of BMI in adults).MethodsHTH MD was independently quantified in two separate BMI-matched cohorts (up to class II obesity; BMIRange = 17-35) using a high-resolution atlas-based definition of HTH. A total of n = 231 mother-child dyads were available for this analysis (nSite,1 = 152, age at MRI = 26.7 ± 8.1 days, gestational age at birth = 39.9 ± 1.2 weeks, nM/F = 82/70, BMI = 24.2 ± 3.8; nSite,2 = 79, age at MRI = 25.6 ± 12.5 days, gestational age at birth = 39.3 ± 1.5 weeks, nM/F = 45/34, BMI = 25.1 ± 4.0). The association between maternal pre-pregnancy BMI and newborn offspring HTH MD was examined separately in each cohort using linear regression adjusting for gestational age at birth, postnatal age at scan, sex, whole white matter mean diffusivity, and DTI quality control criteria. In post hoc analyses, additional potentially confounding factors including socioeconomic status, ethnicity, and obstetric risk were adjusted where appropriate.ResultsThe distribution of maternal pre-pregnancy BMI was comparable across sites but differed by ethnicity and socioeconomic status. A positive linear association between maternal pre-pregnancy BMI and newborn offspring HTH MD was observed at both sites ([Formula: see text]Site,1 = 0.17, pSite,1 = 0.01; [Formula: see text]Site,2 = 0.22, pSite,2 = 0.03) and remained significant after adjusting for cohort-relevant covariates.ConclusionsThese findings translate the preclinically established association between maternal obesity during pregnancy and offspring hypothalamic microstructure to the human context. In addition to further replication/generalization, future efforts to identify biological mediators of the association between maternal obesity and fetal HTH development are warranted to develop targeted strategies for the primary prevention of childhood obesity.

ContextHispanic women are at elevated risk of gestational glucose intolerance and postpartum type 2 diabetes compared with non-Hispanic White women. Identification of potentially modifiable factors contributing to this trajectory of beta-cell dysfunction is warranted.ObjectiveWe aimed to determine the association between rate of gestational weight gain (rGWG) and glucose-insulin metabolism in Hispanic pregnant women with overweight and obesity.MethodsThis cross-sectional, observational study, conducted from 2018-2020 at the clinical research center at University of California, Irvine, included 33 nondiabetic Hispanic pregnant women at 28 to 30 weeks' gestation with pre-pregnancy body mass index (BMI) 25.0 to 34.9 kg/m2. Participants consumed a standardized liquid mixed meal after an overnight fast. Serial blood samples were collected at fasting and up to 2 hours postprandial. The glucose and insulin area under the curve (AUC), insulin sensitivity index (ISI) and insulin secretion sensitivity index (ISSI)-2 were computed.ResultsAverage rGWG (0.36 ± 0.22 kg/week) was classified as excessive in 60% of women. While rGWG was not associated with the glucose or insulin AUC or ISI, it accounted for 13.4% of the variance in ISSI-2 after controlling for covariates (maternal age, parity, and pre-pregnancy BMI); for each 1 unit increase in rGWG, ISSI-2 decreased 2.1 units (P = 0.015).ConclusionEven in the absence of gestational diabetes, rGWG was inversely associated with beta-cell function in a high-risk population of Hispanic pregnant women with overweight and obesity. Beta-cell decline is an established risk factor for transition to type 2 diabetes, and these cross-sectional findings highlight rGWG as a potentially modifiable contributor to this process.

BackgroundThe association of acculturation with health among immigrant populations is believed to be mediated, in part, by acculturation-related stress and stress biology.ObjectivesTo review and qualitatively synthesize empirical findings on the relationship of acculturation with stress-related inflammatory and endocrine biomarkers and composite allostatic load (AL) scores.MethodsA literature search was performed in the PubMed and PsycInfo databases. Article titles, abstracts or full-texts were screened and checked for match with the search criteria. Studies were eligible if they empirically tested the relationship between acculturation and inflammatory/endocrine stress biomarkers or composite AL scores, and were published in the English language.ResultsAmong the 41 articles identified as relevant and included in this review, the majority were published after 2010, included adult Hispanic U.S.-based populations, used cross-sectional study designs, operationalized acculturation as a unidimensional construct, and varied considerably in the selection of covariates in the analyses. Acculturation was significantly associated with stress biomarkers in 29 studies, but the direction of effects varied across studies. Specifically, acculturation, operationalized as a higher orientation towards the host culture, was associated with inflammatory biomarkers in 10 of 14 studies, with endocrine stress biomarkers in 12 of 20 studies, and with composite AL scores in 7 of 8 studies. Overall, language-based proxy measures of acculturation were related to higher levels of stress-related inflammatory and endocrine biomarkers and to lower levels of AL scores, whereas nativity-, generation status- and length of stay-based proxy measures of acculturation were related to higher levels of inflammatory biomarkers and AL score.DiscussionThe majority of studies reported associations between measures of acculturation and stress biomarkers, however the directions of effects varied across studies. We suggest this heterogeneity may, in part, be a function of limitations imposed by cross-sectional research designs and unidimensional measures of acculturation measures, and we highlight the need for longitudinal studies and use of multidimensional measures of acculturation to better uncover the biobehavioral mechanisms and pathways linking acculturation with health outcomes.

ProblemThe immune system represents a leading pathway of interest in the pathophysiology of preterm birth. The majority of human clinical studies interrogating this pathway have utilized circulating immune biomarkers; however, these concentrations typically reflect only basal production but not key functional properties of the immune system, particularly variation in the pro-inflammatory response to antigen challenge and the regulation of this response. Thus, in this study, we utilized an ex vivo stimulation protocol that quantifies these processes, and we examined their prospective association with the gestation length and risk of preterm birth.Method of studyImmune responsiveness and regulation were assessed in 128 pregnant women in mid-gestation using an ex vivo stimulation protocol. Maternal pro-inflammatory responsivity of leukocytes was quantified by assessing the release of the pro-inflammatory cytokines IL-6, TNF-α, and IL-1β in response to antigen stimulation, and regulation of the pro-inflammatory response was quantified by assessing the suppression of stimulated cytokine response upon co-incubation with increasing dexamethasone concentrations (ie, glucocorticoid receptor resistance; GRR).ResultsHigher maternal GRR, indicating impaired regulation of the pro-inflammatory response, was significantly and independently associated with shorter gestational length (β = -0.42, p = .0091) and a 3.0-fold increase in risk for preterm birth (OR = 3.01, 95% CI = 1.17-7.70, p = .0218). Basal circulating IL-6 and TNF-α were not associated with either outcome.ConclusionThe association of maternal GRR with length of gestation and preterm birth risk suggests that the processes represented by this measure-maternal pro-inflammatory propensity and immune regulation-may provide further mechanistic insight into the pathophysiology of preterm birth.

ObjectiveIn the context of the importance of elucidating the determinants of the initial, newborn setting of telomere length (TL), it is increasingly evident that maternal stress and stress-related processes during pregnancy play a major role. Although psychological resilience may function as a buffer, research in this area has not yet examined its potential role vis-à-vis that of stress. The authors examined the relationship between maternal psychological resilience during pregnancy and newborn TL.MethodsIn a sample of 656 mother-child dyads from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction cohort, multiple serial assessments were conducted over the course of pregnancy to quantify maternal stress, negative and positive emotional responses to pregnancy events, positive affect, and perceived social support. Principal component analysis identified two latent factors: stress and positivity. A measure of resilience was computed by regressing the positivity factor on the stress factor, in order to quantify positivity after accounting for stress. TL was measured using quantitative polymerase chain reaction in leukocytes extracted from cord blood shortly after birth. Linear regression was used to predict newborn TL from maternal resilience during pregnancy, adjusting for other potential determinants.ResultsMaternal stress significantly predicted shorter newborn TL (β=-0.079), and positivity significantly predicted longer TL (β=0.135). Maternal resilience (positivity accounting for stress) was significantly and positively associated with newborn TL (β=0.114, 95% CI=0.035, 0.189), with each standard deviation increase in resilience predicting 12% longer newborn TL.ConclusionsThe results indicate that maternal psychological resilience may exert a salubrious effect on offspring telomere biology and highlight the importance of enhancing maternal mental health and well-being during pregnancy.

BackgroundAlthough the linkage between psychological stress and cortisol is believed to mediate the association of stress with health outcomes, several studies have been unable to demonstrate this association. We suggest this inability may be a consequence of limitations in the measurement approach and/or reliance on analytic strategies that focus on associations across, rather than within individuals. The link between psychological stress and cortisol is of particular interest in the context of pregnancy and fetal development. Using an ecological momentary assessment (EMA) design, we examined the association between psychological stress and cortisol at the between- and the within-person level.Methods152 participants completed a 4-day long EMA protocol serially in early, mid and late pregnancy to provide momentary stress appraisals (average of 150 measures/subject) and saliva samples (average of 55 samples/subject) for quantification of cortisol. The association between stress and cortisol was estimated using linear mixed models.ResultsAfter accounting for the effects of key determinants of variation in cortisol, momentary stress was significantly and positively associated with cortisol at the within-person level (B = .030, p = .031), but not at the between-person level. No association was evident for traditional retrospective measures of stress with cortisol at either the between- or the within-person level.ConclusionsOur study highlights the value of EMA methods and linear mixed-modeling approaches in linking maternal psychological and physiological states across pregnancy. These findings may have important implications for the development of personalized risk identification and "just-in-time" intervention strategies to optimize maternal and child health.

Parenting quality is associated with child cognitive and executive functions (EF), which are important predictors of social and academic development. However, children vary in their susceptibility to parenting behaviors, and the neurobiological underpinnings of this susceptibility are poorly understood. In a prospective longitudinal study, we examined whether neonatal total brain volume (TBV) and subregions of interest (i.e., hippocampus (HC) and anterior cingulate gyrus (ACG)) moderate the association between maternal sensitivity and cognitive/EF development across early childhood. Neonates underwent a brain magnetic resonance imaging scan. Their cognitive performance and EF was characterized at 2.0 ± 0.1 years (N = 53) and at 4.9 ± 0.8 years (N = 36) of age. Maternal sensitivity was coded based on observation of a standardized play situation at 6-mo postpartum. Neonatal TBV moderated the association between maternal sensitivity and 2-year working memory as well as all 5-year cognitive outcomes, suggesting that the positive association between maternal sensitivity and child cognition was observed only among children with large or average but not small TBV as neonates. Similar patterns were observed for TBV-corrected HC and ACG volumes. The findings suggest that larger neonatal TBV, HC and ACG may underlie susceptibility to the environment and affect the degree to which parenting quality shapes long-term cognitive development.

The development of biological markers of aging has primarily focused on adult samples. Epigenetic clocks are a promising tool for measuring biological age that show impressive accuracy across most tissues and age ranges. In adults, deviations from the DNA methylation (DNAm) age prediction are correlated with several age-related phenotypes, such as mortality and frailty. In children, however, fewer such associations have been made, possibly because DNAm changes are more dynamic in pediatric populations as compared to adults. To address this gap, we aimed to develop a highly accurate, noninvasive, biological measure of age specific to pediatric samples using buccal epithelial cell DNAm. We gathered 1,721 genome-wide DNAm profiles from 11 different cohorts of typically developing individuals aged 0 to 20 y old. Elastic net penalized regression was used to select 94 CpG sites from a training dataset (n = 1,032), with performance assessed in a separate test dataset (n = 689). DNAm at these 94 CpG sites was highly predictive of age in the test cohort (median absolute error = 0.35 y). The Pediatric-Buccal-Epigenetic (PedBE) clock was characterized in additional cohorts, showcasing the accuracy in longitudinal data, the performance in nonbuccal tissues and adult age ranges, and the association with obstetric outcomes. The PedBE tool for measuring biological age in children might help in understanding the environmental and contextual factors that shape the DNA methylome during child development, and how it, in turn, might relate to child health and disease.

Microbes and their metabolic products influence early-life immune and microbiome development, yet remain understudied during pregnancy. Vaginal microbial communities are typically dominated by one or a few well-adapted microbes which are able to survive in a narrow pH range and are adapted to live on host-derived carbon sources, likely sourced from glycogen and mucin present in the vaginal environment. We characterized the cervicovaginal microbiomes of 16 healthy women throughout the three trimesters of pregnancy. Additionally, we analyzed saliva and urine metabolomes using gas chromatography-time of flight mass spectrometry (GC-TOF MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) lipidomics approaches for samples from mothers and their infants through the first year of life. Amplicon sequencing revealed most women had either a simple community with one highly abundant species of Lactobacillus or a more diverse community characterized by a high abundance of Gardnerella, as has also been previously described in several independent cohorts. Integrating GC-TOF MS and lipidomics data with amplicon sequencing, we found metabolites that distinctly associate with particular communities. For example, cervicovaginal microbial communities dominated by Lactobacillus crispatus have high mannitol levels, which is unexpected given the characterization of L. crispatus as a homofermentative Lactobacillus species. It may be that fluctuations in which Lactobacillus dominate a particular vaginal microbiome are dictated by the availability of host sugars, such as fructose, which is the most likely substrate being converted to mannitol. Overall, using a multi-"omic" approach, we begin to address the genetic and molecular means by which a particular vaginal microbiome becomes vulnerable to large changes in composition.IMPORTANCE Humans have a unique vaginal microbiome compared to other mammals, characterized by low diversity and often dominated by Lactobacillus spp. Dramatic shifts in vaginal microbial communities sometimes contribute to the presence of a polymicrobial overgrowth condition called bacterial vaginosis (BV). However, many healthy women lacking BV symptoms have vaginal microbiomes dominated by microbes associated with BV, resulting in debate about the definition of a healthy vaginal microbiome. Despite substantial evidence that the reproductive health of a woman depends on the vaginal microbiota, future therapies that may improve reproductive health outcomes are stalled due to limited understanding surrounding the ecology of the vaginal microbiome. Here, we use sequencing and metabolomic techniques to show novel associations between vaginal microbes and metabolites during healthy pregnancy. We speculate these associations underlie microbiome dynamics and may contribute to a better understanding of transitions between alternative vaginal microbiome compositions.

BackgroundThe association of socioeconomic status (SES) with health and disease risk is well established. Low-grade inflammation represents a key pathway believed to underlie this association. Previous research has suggested that subjective social standing (SSS) is more consistently associated with health outcomes than objective measures of SES such as income and education. Given the importance of maternal inflammatory state in a wide array of pregnancy, birth and fetal/child developmental and health outcomes, we examine here the independent association of maternal SSS relative to objective SES with pro-inflammatory state during pregnancy.MethodsWe conducted a longitudinal study of an ethnically diverse sample of 250 pregnant women with 3 study visits in early, mid and late gestation. We obtained objective measures of SES (income, education), and SSS with reference to the community and to the nation using the MacArthur Scale of Subjective Social Status. At each study visit, a composite maternal pro-inflammatory score was derived from circulating levels of inflammatory markers (IL-6, CRP, TNF-α).ResultsIn hierarchical linear models, SSS but not objective SES was significantly and negatively associated with maternal inflammatory state. Moreover, the relationship between SSS and inflammatory state remained significant after accounting for objective SES. SSS with reference to the community was a stronger predictor of inflammatory state than SSS with reference to the nation.DiscussionOur finding adds to the scientific literature on SSS and health, highlights the importance of including SSS measures in this context, and supports future research on the relative role and biological pathways by which SSS may impact pregnancy, birth and fetal/child development and health.

We sought to replicate and expand upon previous work demonstrating antenatal TTC9B and HP1BP3 gene DNA methylation is prospectively predictive of postpartum depression (PPD) with ~80% accuracy. In a preterm birth study from Emory, Illumina MethylEPIC microarray derived 1st but not 3rd trimester biomarker models predicted 3rd trimester Edinburgh Postnatal Depression Scale (EPDS) scores ≥ 13 with an AUC=0.8 (95% CI: 0.63-0.8). Bisulfite pyrosequencing derived biomarker methylation was generated using bisulfite pyrosequencing across all trimesters in a pregnancy cohort at UC Irvine and in 3rd trimester from an independent Johns Hopkins pregnancy cohort. A support vector machine model incorporating 3rd trimester EPDS scores, TTC9B, and HP1BP3 methylation status predicted 4 week to 6 week postpartum EPDS ≥ 13 from 3rd trimester blood in the UC Irvine cohort (AUC=0.78, 95% CI: 0.64-0.78) and from the Johns Hopkins cohort (AUC=0.84, 95% CI: 0.72-0.97), both independent of previous psychiatric diagnosis. Technical replicate predictions in a subset of the Johns Hopkins cohort exhibited strong cross experiment correlation. This study confirms the PPD prediction model has the potential to be developed into a clinical tool enabling the identification of pregnant women at future risk of PPD who may benefit from clinical intervention.

There is inconsistent evidence that healthy dietary interventions can effectively mitigate the risk of adverse outcomes associated with elevated insulin resistance in pregnancy, suggesting that other moderating factors may be at play. Maternal psychological state is an important factor to consider in this regard, because stress/mood state can directly influence glycemia and a bidirectional relationship may exist between nutrition and psychological state. The objective of this study was to examine the interaction between maternal negative affect and diet quality on third trimester insulin resistance. We conducted a prospective longitudinal study of N = 203 women with assessments in early and mid-pregnancy, which included an ecological momentary assessment of maternal psychological state, from which a negative affect score (NAS) was derived, and 24-h dietary recalls, from which the Mediterranean Diet Score (MDS) was computed. The homeostasis model assessment of insulin resistance (HOMA-IR) was computed from third trimester fasting plasma glucose and insulin values. Early pregnancy MDS was inversely associated with the HOMA-IR, but this did not maintain significance after adjusting for covariates. There was a significant effect of the mid-pregnancy MDS*NAS interaction term with the HOMA-IR in the adjusted model, such that a higher negative affect was found to override the beneficial effects of a Mediterranean diet on insulin resistance. These results highlight the need to consider nutrition and affective state concurrently in the context of gestational insulin resistance.

ObjectiveWomen exposed to childhood maltreatment (CM) are more likely to exhibit insensitive parenting, which may have consequences for their offspring's development. Variation in the oxytocin-receptor gene (OXTR) moderates risk of CM-associated long-term sequelae associated with mother-child attachment, although functionality of previously investigated single nucleotide polymorphisms (SNPs) remained elusive. Here, we investigated the role of OXTR rs237895, a brain tissue expression quantitative trait locus (eQTL), as a moderator of the relationship between CM and maternal behavior (MB) and the association between MB and offspring attachment security.MethodOf 110 women with information on rs237895 genotype (T-allele = 64, CC = 46), 107 had information on CM (CTQ) and 99 on standardized observer-based ratings of MB at 6 months postpartum (responsivity and detachment), which were used in principal component analysis to obtain a latent factor representing MB. Offspring (n = 86) attachment was evaluated at 12 months of age. Analyses predicting MB were adjusted for socioeconomic status, age, postpartum depression, and genotype-based ethnicity. Analyses predicting child attachment were adjusted for infant sex, socioeconomic status, and postpartum depression.Resultsrs237895 significantly moderated the relationship between CM and MB (F1;66 = 7.99, p < .01), indicating that CM was associated with maternal insensitivity only in high-OXTR-expressing T-allele carriers but not in low-OXTR-expressing CC homozygotes. Moreover, maternal insensitivity predicted offspring insecure attachment (B = -0.551; p < .05).ConclusionWomen with a high OXTR expressing genotype are more susceptible to CM-related impairments in MB that, in turn, predict attachment security in their children, supporting the role of the OT system in the intergenerational transmission of risk associated with maternal CM.

IntroductionTelomere biology plays a fundamental role in maintaining the integrity of the genome and cell, and shortened telomeres have been linked to several age-related diseases. The initial (newborn) telomere length (TL) represents a critically important feature of the telomere biology system. Exposure to a variety of adverse prenatal conditions such as maternal stress, suboptimal diet, obesity, and obstetric complications, is associated with shorter offspring TL at birth and in adult life. Many, if not all, of these exposures are believed to have an inflammatory component. In this context, stress-related immunological processes during pregnancy may constitute a potential additional biological pathway because they can affect telomere length and telomerase activity via transcriptions factors such as cyclic adenosine monophosphate-dependent transcription factor (ATF7) and nuclear factor-kappa B (NF-κB). Thus, in the present study we examined the hypothesis that maternal pro-inflammatory state across pregnancy, operationalized as the balance between tumor necrosis factor (TNF)-α, a major pro-inflammatory cytokine, and interleukin-10 (IL-10), the major anti-inflammatory cytokine, is associated with newborn leukocyte telomere length (LTL) at birth.Methods and materialsParticipants were healthy women (N = 112) recruited in early pregnancy. Concentrations of TNF- α and IL-10 were quantified in early, mid and late pregnancy from maternal blood samples. Telomere length was assessed in newborn blood samples soon after birth.ResultsAfter adjusting for maternal age, maternal pre-pregnancy BMI, birth weight percentile, and infant sex, a higher mean TNF-α/IL-10 ratio across pregnancy was significantly associated with shorter newborn TL (β = -.205, p = .030). Newborn TL was, on average, 10% shorter in offspring of women in the upper compared to lower quartile of the TNF-α/IL-10 ratio during pregnancy.DiscussionThese findings provide new evidence in humans for a potential "programming" mechanism linking maternal systemic pro-inflammatory processes during pregnancy with the initial (newborn) setting of her offspring's telomere system.

Maternal behavior (MB) is observable across mammals and represents an important feature of environmental variation during early postnatal development. Oxytocin (OT) plays a crucial role in MB. Even prior to childbirth, pregnancy induces epigenetic and other downstream changes in the maternal OT-system, likely mediated by the actions of steroid hormones. However, little is known about the nature and consequences of epigenetic modifications in the maternal OT-encoding gene (OXT) during pregnancy. Our study aims to investigate temporal dynamics of OXT promoter DNA methylation (DNAm) throughout pregnancy in predicting MB in humans. In 107 mother-child dyads, maternal OXT DNAm was serially analyzed in whole blood in early, mid and late pregnancy. MB was coded based on standardized mother-child interactions at six months postpartum. After controlling for cellular heterogeneity, race/ethnicity, age, and socioeconomic status, OXT-promoter DNAm exhibited a dynamic profile during pregnancy (b = 0.026, t=-3.37, p

ScopeThe fetal programming paradigm posits that the origins of obesity can be traced, in part, to the intrauterine period of life. However, the mechanisms underlying fetal programming are not well understood, and few studies have measured offspring adiposity in the neonatal period. The aim of this study is to identify maternal metabolites, and their determinants, that are associated with neonatal adiposity.Methods and resultsA targeted metabolomics approach is applied to analyze plasma samples collected across gestation from a well-characterized cohort of 253 pregnant women participating in a prospective study at the University of California, Irvine. Whole-body dual X-ray absorptiometry (DXA) imaging of body composition is obtained in N = 121 newborns. Statistical models are adjusted for potential confounders and multiple testing. The authors identify six alkyl-linked phosphatidylcholines (PCae), containing fatty acid 20:4, that are significantly and negatively associated with neonatal body fat percentage. Factors indicating higher socioeconomic status, non-Hispanic ethnicity, and higher nonesterified fatty acid percentages are positively associated with these PCae.ConclusionsThe polyunsaturated fatty acid 20:4 contained in PCae may exert a beneficial effect with respect to future propensity for obesity development. Prepregnancy and early pregnancy factors are determinants of these PCae, highlighting the importance of addressing preconceptional conditions for fetal programming of newborn adiposity.

BACKGROUND:Maternal cortisol during pregnancy has the potential to influence rapidly developing fetal brain systems that are commonly altered in neurodevelopmental and psychiatric disorders. Research examining maternal cortisol concentrations across pregnancy and offspring neurodevelopment proximal to birth is needed to advance understanding in this area and lead to insight into the etiology of these disorders. METHODS:Participants were 70 adult women recruited during early pregnancy and their infants born after 34 weeks gestation. Maternal cortisol concentrations were assessed serially over 4 days in early, mid, and late gestation. Resting state functional connectivity magnetic resonance imaging of the neonatal amygdala was examined. Mothers reported on children's internalizing behavior problems at 24 months of age. RESULTS:Maternal cortisol concentrations during pregnancy were significantly associated with neonatal amygdala connectivity in a sex-specific manner. Elevated maternal cortisol was associated with stronger amygdala connectivity to brain regions involved in sensory processing and integration, as well as the default mode network in girls, and with weaker connectivity to these brain regions in boys. Elevated maternal cortisol was associated with higher internalizing symptoms in girls only, and this association was mediated by stronger neonatal amygdala connectivity. CONCLUSIONS:Normative variation in maternal cortisol during pregnancy is associated with the coordinated functioning of the amygdala soon after birth in a sex-specific manner. The identified pathway from maternal cortisol to higher internalizing symptoms in girls via alterations in neonatal amygdala connectivity may be relevant for the etiology of sex differences in internalizing psychiatric disorders, which are more prevalent in women.

To evaluate the association between psychotropic medication and inflammatory biomarkers in women with antenatal depressive symptoms (ADS). In this cross-sectional secondary analysis of a prospective multicenter observational study, 723 pregnant women underwent a depression screen using the Center for Epidemiologic Studies Depression Scale (CES-D) between 12 and 21 weeks gestation. Self-reported use of medications for depression and/or anxiety was corroborated with the medical record to document exposure to pharmacotherapy. Serum was collected and inflammatory biomarkers (IFNγ, IL13, IL6, IL8, TNFα, CRP) were measured concomitantly. Women were included if they fell into one of three categories: ADS responsive to treatment (CES-D

BackgroundThe process of acculturation (post-migration acquisition of host culture and/or loss of heritage culture) likely represents a key mediator of the observed post-migration decline in health that is evident among immigrant populations such as Mexican Americans. The observations that migrant health declines progressively as not only a function of length of stay in the U.S. but also across generations, and that this inter-generational decline in health is evident as early as at the time of birth itself, supports the concept of fetal programming of acculturation's effects. However, the underlying mechanisms remain to be elucidated. Inflammation during pregnancy represents a candidate pathway of particular interest for 2 reasons: it represents a key biological mediator of the psychosocial and/or behavioral sequelae of acculturation on health, and it represents a key pathway by which maternal states and conditions during pregnancy may influence fetal development and subsequent birth and child developmental and health outcomes. Therefore, the aim of this study was to examine the relationship between acculturation and inflammation across pregnancy in a population of Mexican-American women. Specifically, we tested the hypothesis that a higher level of acculturation is associated with higher circulating concentrations across pregnancy of the pro-inflammatory cytokine interleukin-6 (IL-6).Methods75 pregnant first- or second-generation Mexican-American women constituted the study population. Acculturation was quantified using a commonly-used and previously validated measure - the Acculturation Rating Scale for Mexican Americans (ARSMA). Maternal blood samples were collected during early, mid and late pregnancy for analysis of circulating IL-6 concentrations.ResultsHierarchical linear models indicated a significantly and positive main effect of acculturation on IL-6 concentrations across pregnancy after adjusting for key covariates including gestational age(s) at blood sampling, socioeconomic status, pre-pregnancy BMI, and presence of obstetric risk conditions.ConclusionsMaternal inflammation during pregnancy may represent a biological pathway of interest in the context of the inter-generational effects of acculturation from a mother to her as-yet-unborn child.

Maternal inflammation during pregnancy is known to adversely impact fetal development, birth outcomes, and offspring physical and mental health. Diet and stress have been identified as important determinants of inflammation, yet their combined effects have not been examined in the context of pregnancy. The aim of this study was to examine the relationship between maternal diet with inflammatory potential and psychological stress, and to determine their interaction effect on concentrations of tumor necrosis factor (TNF)-α across pregnancy. We conducted a prospective longitudinal study of n = 202 women with three assessments during pregnancy, which included: ecological momentary assessment (EMA) of maternal stress using the perceived stress scale (PSS) short version; 24-h dietary recalls from which the dietary inflammatory index (DII) was computed; and serum measurements of TNF-α. Across pregnancy, higher perceived stress was associated with consumption of a more pro-inflammatory diet (r = 0.137; p < 0.05). In a linear regression model adjusted for covariates, DII was positively associated with TNF-α (B = 0.093, p = 0.010). The effect of the pro-inflammatory diet on concentrations of TNF-α was more pronounced in women reporting higher levels of stress (B = 0.134, p = 0.018 for DII*PSS interaction). These results highlight the need to consider nutrition and stress concurrently in the context of inflammation during pregnancy.

BackgroundHispanic Americans consistently exhibit an intergenerational increase in the prevalence of many noncommunicable chronic physical and mental disorders.MethodsWe review and synthesize evidence suggesting that a constellation of prenatal and postnatal factors may play crucial roles in explaining this trend. We draw from relevant literature across several disciplines, including epidemiology, anthropology, psychology, medicine (obstetrics, neonatology), and developmental biology.ResultsOur resulting model is based on evidence that among women, the process of postmigration cultural adjustment (i.e., acculturation) is associated, during pregnancy and after delivery, with psychological and behavioral states that can affect offspring development in ways that may alter susceptibility to noncommunicable chronic disease risk in subsequent-generation Hispanic Americans. We propose one integrated process model that specifies the biological, behavioral, psychological, and sociocultural pathways by which maternal acculturation may influence the child's long-term health. We synthesize evidence from previous studies to describe how acculturation among Hispanic American mothers is associated with alterations to the same biobehavioral systems known to participate in the processes of prenatal and postnatal developmental programming of disease risk. In this manner, we focus on the concepts of biological and cultural mother-to-child transmission across the prenatal and postnatal life phases. We critique and draw from previous hypotheses that have sought to explain this phenomenon (of declining health across generations). We offer recommendations for examining the transgenerational effects of acculturation.ConclusionA life course model with a greater focus on maternal health and well-being may be key to understanding transgenerational epidemiological trends in minority populations, and interventions that promote women's wellness may contribute to the elimination or reduction of health disparities.

ObjectiveTo evaluate the association between prenatal stress and gestational weight gain (GWG).Study designThis was an analysis of women recruited between 2013-2015 from four sites in the US. We tested associations between responses at 32-35 weeks to the Life Experiences Survey (LES), a 37-item measure of events and perceived stress, and GWG categories. Bivariable comparisons and logistic regression were used to estimate the association between the total LES score and the odds of achieving adequate GWG.ResultAmong the 725 women, those with adequate GWG had lower median LES scores (5) compared to women with inadequate (7) and excessive (7) GWG, p = 0.02. After adjusting for age, initial BMI, income, education, marital status and gestational diabetes, lower LES scores (multiples of the median) were associated with adequate GWG (aOR 0.81, 95% CI 0.67-0.98).ConclusionLower reported stress, as measured by the LES, was associated with a greater chance of women achieving adequate GWG. This relationship highlights the potential for interventions directed toward psychosocial support to have salutary effects upon GWG.

The goal of this study was to develop and validate a measure of maximal telomerase activity capacity (mTAC) for use in human studies of telomere biology, and to determine its association with measures of stress and stress responsivity. The study was conducted in a population of 28 healthy young women and men who were assessed serially across two separate days, at multiple time points, and in response to a standardized laboratory stressor. Venous blood was collected at each of these multiple assessments, and an in vitro mitogen challenge (phytohaemagglutinin supplemented with interleukin-2) was used to stimulate telomerase activity in leucocytes. After first establishing the optimal post-stimulation time course to characterize mTAC, we determined the within-subject stability and the between-subject variability of mTAC. The major findings of our study are as follows: (i) the optimal time point to quantify human leucocyte mTAC appears to be at 72 h after mitogen stimulation; (ii) mTAC exhibits substantial within-subject stability (correlations were in the range of r 0.68-0.82) and between-subject variability, with a high intra-class coefficient (0.70), indicating greater between-subject relative to within-subject variability; (iii) mTAC is not influenced by situational factors including time of day, cortisol, acute stress exposure and immune cell distribution in the pre-stimulation blood sample; and (iv) a significant proportion of the between-subject variability in mTAC is associated with measures of stress and stress responsivity (mTAC is lower in subjects reporting higher levels of perceived (chronic) stress and exhibiting higher psychophysiological stress reactivity). Based collectively on these findings, it appears that mTAC, as proposed and operationalized, empirically meets the key criteria to represent a potentially useful individual difference measure of telomerase activity capacity of human leucocytes.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.

BackgroundChildhood maltreatment (CM) confers deleterious long-term consequences, and growing evidence suggests some of these effects may be transmitted across generations. We examined the intergenerational effect of maternal CM exposure on child brain structure and also addressed the hypothesis that this effect may start during the child's intrauterine period of life.MethodsA prospective longitudinal study was conducted in a clinical convenience sample of 80 mother-child dyads. Maternal CM exposure was assessed using the Childhood Trauma Questionnaire. Structural magnetic resonance imaging was employed to characterize newborn global and regional brain (tissue) volumes near the time of birth.ResultsCM exposure was reported by 35% of the women. Maternal CM exposure was associated with lower child intracranial volume (F1,70 = 6.84, p = .011), which was primarily due to a global difference in cortical gray matter (F1,70 = 9.10, p = .004). The effect was independent of potential confounding variables, including maternal socioeconomic status, obstetric complications, obesity, recent interpersonal violence, pre- and early postpartum stress, gestational age at birth, infant sex, and postnatal age at magnetic resonance imaging scan. The observed group difference between offspring of CM-exposed mothers versus nonexposed mothers was 6%.ConclusionsThese findings represent the first report to date associating maternal CM exposure with variation in newborn brain structure. These observations support our hypothesis of intergenerational transmission of the effects of maternal CM exposure on child brain development and suggest this effect may originate during the child's intrauterine period of life, which may have downstream neurodevelopmental consequences.

BackgroundMaternal inflammation during pregnancy increases the risk for offspring psychiatric disorders and other adverse long-term health outcomes. The influence of inflammation on the developing fetal brain is hypothesized as one potential mechanism but has not been examined in humans.MethodsParticipants were adult women (N = 86) who were recruited during early pregnancy and whose offspring were born after 34 weeks' gestation. A biological indicator of maternal inflammation (interleukin-6) that has been shown to influence fetal brain development in animal models was quantified serially in early, mid-, and late pregnancy. Structural and functional brain magnetic resonance imaging scans were acquired in neonates shortly after birth. Infants' amygdalae were individually segmented for measures of volume and as seeds for resting state functional connectivity. At 24 months of age, children completed a snack delay task to assess impulse control.ResultsHigher average maternal interleukin-6 concentration during pregnancy was prospectively associated with larger right amygdala volume and stronger bilateral amygdala connectivity to brain regions involved in sensory processing and integration (fusiform, somatosensory cortex, and thalamus), salience detection (anterior insula), and learning and memory (caudate and parahippocampal gyrus). Larger newborn right amygdala volume and stronger left amygdala connectivity were in turn associated with lower impulse control at 24 months of age, and mediated the association between higher maternal interleukin-6 concentrations and lower impulse control.ConclusionsThese findings provide new evidence in humans linking maternal inflammation during pregnancy with newborn brain and emerging behavioral phenotypes relevant for psychiatric disorders. A better understanding of intrauterine conditions that influence offspring disease susceptibility is warranted to inform targeted early intervention and prevention efforts.

We examined the prospective associations of objective and subjective measures of stress during pregnancy with infant stress reactivity and regulation, an early-life predictor of psychopathology. In a racially and ethnically diverse low-income sample of 151 mother-infant dyads, maternal reports of stressful life events (SLE) and perceived stress (PS) were collected serially over gestation and the early postpartum period. Infant reactivity and regulation at 6 months of age was assessed via maternal report of temperament (negativity, surgency, and regulation) and infant parasympathetic nervous system physiology (respiratory sinus arrhythmia [RSA]) during the Still Face Paradigm. Regression models predicting infant temperament showed higher maternal prenatal PS predicted lower surgency and self-regulation but not negativity. Regression models predicting infant physiology showed higher numbers of SLE during gestation predicted greater RSA reactivity and weaker recovery. Tests of interactions revealed SLE predicted RSA reactivity only at moderate to high levels of PS. Thus, findings suggest objective and subjective measures of maternal prenatal stress uniquely predict infant behavior and physiology, adjusting for key pre- and postnatal covariates, and advance the limited evidence for such prenatal programming within high-risk populations. Assessing multiple levels of maternal stress and offspring stress reactivity and regulation provides a richer picture of intergenerational transmission of adversity.

Research suggests the health consequences of economic hardship can be transmitted across generations. Some of these disparities are thought to be passed to offspring during gestation. But this hypothesis has not been tested in contemporary American samples, and the mechanisms of transmission have not been characterized. Accordingly, this study had two goals: first, to determine if women exposed to economic hardship during childhood showed higher rates of adverse birth outcomes; and second, to evaluate the contribution of inflammation, psychosocial, lifestyle, and obstetric characteristics to this phenomenon. This prospective study enrolled 744 women with singleton pregnancies (59.1% White; 16.3% Black; 18.7% Latina; 5.9% Other). Childhood economic hardship was measured by self-report. Birth outcomes included length of gestation and incidence of preterm birth; birth weight percentile and small for gestational age; length of hospital stay and admission to Special Care Nursery. Analyses revealed that mothers' childhood economic hardship was independently associated with multiple adverse birth outcomes, even following adjustment for demographics, maternal education, and obstetrical confounders. Women raised in economically disadvantaged conditions had shorter gestation length and higher preterm delivery rates. Their babies had lower birth weights, were more likely to be small for gestational age, stayed in the hospital longer, and had more Special Care Nursery admissions. Mediation analyses suggested these associations arose through multiple pathways, and highlighted roles for inflammation, education, adiposity, and obstetric complications. Collectively, these findings suggest that childhood economic hardship predisposes women to adverse birth outcomes, and highlights likely behavioral and biological mechanisms.

The critical importance of thyroid hormones for fetal development is well established. The developing fetus is dependent on the mother for adequate thyroid hormone supply, and maternal thyroid dysfunction in pregnancy may result in suboptimal fetal development. Because exposure to childhood maltreatment (CM) has been associated with thyroid dysfunction in the non-pregnant state, we sought to test the hypothesis that exposure to CM may represent a risk factor for the development of maternal hypothyroidism in pregnancy. The study was conducted in a healthy cohort of 102 pregnant mothers who were followed across the entire course of pregnancy. At each trimester thyroid-stimulating hormone (TSH) and free thyroxine (fT4) were measured in maternal serum. Experience of CM was assessed using the Childhood Trauma Questionnaire. After adjusting for potentially confounding variables, CM exposure was associated with increased TSH concentrations across pregnancy (F1,94.6=11.52, p=0.001) and with a 4- to 7-fold increased risk of TSH levels above the trimester-specific clinical cut-off values. Women with clinically elevated TSH concentrations did not differ in fT4 concentrations from women with normal TSH concentrations (p>0.1), suggesting subclinical hypothyroidism. Our findings suggest that there is a substantial and clinically relevant increased risk for thyroid dysfunction during pregnancy among women exposed to abuse or neglect in their childhood. This could potentially have adverse consequences for fetal brain development. Thus, these findings highlight the critical importance of considering CM exposure as a potential risk factor for (subclinical) hypothyroidism in pregnancy.

BackgroundThe significance of periconceptional nutrition for optimizing offspring and maternal health and reducing social inequalities warrants greater understanding of diet quality among US women.ObjectiveOur objective was to evaluate racial or ethnic and education inequalities in periconceptional diet quality and sources of energy and micronutrients.DesignCross-sectional analysis of data from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be cohort.Participants and settingNulliparous women (N=7,511) were enrolled across eight US medical centers from 2010 to 2013.Main outcome measuresA semiquantitative food frequency questionnaire assessing usual dietary intake during the 3 months around conception was self-administered during the first trimester. Diet quality, measured using the Healthy Eating Index-2010 (HEI-2010), and sources of energy and micronutrients were the outcomes.Statistical analysesDifferences in diet quality were tested across maternal racial or ethnic and education groups using F tests associated with analysis of variance and χ2 tests.ResultsHEI-2010 score increased with higher education, but the increase among non-Hispanic black women was smaller than among non-Hispanic whites and Hispanics (interaction P value

ContextGlucocorticoids play a key role during intrauterine development in cellular growth and differentiation. Evidence suggests that exposure to inappropriate concentrations of glucocorticoids during sensitive developmental periods may produce alterations in physiological systems that impact obesity risk.ObjectiveTo elucidate the magnitude and stage-of-gestation-specific association of maternal cortisol concentrations during pregnancy with infant adiposity.Design, participants, and settingSixty-seven mother-child dyads recruited in early pregnancy at university-based obstetric clinics in Southern California were followed with serial assessments from early gestation through birth until 6 months postnatal age. Maternal cumulative cortisol production was assessed over each of 4 consecutive days in early (≅13 weeks), mid (≅24 weeks), and late pregnancy (≅30 weeks) (5 saliva samples/d × 4 days × 3 trimesters = 60 saliva samples/subject). Infant body composition was serially assessed in newborns (at ∼25 days postnatal age) and at ∼6 months age with dual-energy X-ray absorptiometry imaging.ResultsAfter adjusting for key prenatal, birth, and postnatal covariates, higher maternal cortisol during the early third trimester (conditioned on prior early and midgestation cortisol concentrations) was significantly associated with a greater change in infant percent body fat from 1 to 6 months of age [partial r (adjusted for covariates) = 0.379, P = 0.007], accounting for ∼14% of the variance in this measure of childhood obesity risk.ConclusionThe present findings suggest a stage-of-gestation-specific effect of maternal cortisol on infant adiposity gain in early postnatal life and provide evidence in humans to support the role of glucocorticoids in fetal programming of childhood obesity risk.

BackgroundSeveral studies about humans and animals have separately examined the effects of prenatal nutrition and stress on fetal development, pregnancy, and birth outcomes, and subsequent child health and disease risk. Although substantial evidence from non-pregnant literature supports the presence of bidirectional interactions between nutrition and stress at various psychological, behavioral, and physiological levels, such interaction effects have not yet been systematically examined in the context of pregnancy.SummaryThis paper discusses the multifaceted and multilevel relationship between nutrition and stress. It then reviews the currently available observational and experimental evidence in animals and humans regarding the interplay between maternal psychosocial stress, dietary intake, and nutritional state during pregnancy, and implications for maternal and child health-related outcomes. Key Messages: During pregnancy, maternal psychosocial stress, dietary behavior, and nutritional state likely regulate and counter-regulate one another. Emerging evidence suggests that omega-3 fatty acids may attenuate maternal psychosocial stress, and that high maternal pre-pregnancy body mass index exacerbates unhealthy dietary behaviors under high-stress conditions. Longitudinal studies are warranted in order to understand the interplay between prenatal psychosocial stress, diet, and stress- and nutrition-related biomarkers to obtain further insight and inform the development and design of future, more effective intervention trials for improved maternal and child health outcomes.

Background The aim of this study was to determine whether racial/ethnic differences in psychosocial measures, independent of economic status, exist among a large population of pregnant nulliparas. Methods Between October 2010 and September 2013, nulliparous women at eight U.S. medical centers were followed longitudinally during pregnancy and completed validated instruments to quantify several psychosocial domains: Cohen Perceived Stress Scale, trait subscale of the Spielberger Anxiety Inventory, Connor-Davidson Resilience Scale, Multidimensional Scale of Perceived Social Support, Krieger Racism Scale, Edinburgh Postnatal Depression Scale, and the Pregnancy Experience Scale. Scores were stratified and compared by self-reported race, ethnicity, and income. Results Complete data were available for 8,128 of the 10,038 women enrolled in the study. For all measures, race and ethnicity were significantly associated (p  0.05) except on the Krieger racism survey and the Edinburgh depression survey, which were exacerbated among NHB women with higher income (interaction, p

Characterization of cortisol production, regulation and function is of considerable interest and relevance given its ubiquitous role in virtually all aspects of physiology, health and disease risk. The quantification of cortisol concentration in hair has been proposed as a promising approach for the retrospective assessment of integrated, long-term cortisol production. However, human research is still needed to directly test and validate current assumptions about which aspects of cortisol production and regulation are reflected in hair cortisol concentrations (HCC). Here, we report findings from a validation study in a sample of 17 healthy adults (mean±SD age: 34±8.6 yrs). To determine the extent to which HCC captures cumulative cortisol production, we examined the correspondence of HCC, obtained from the first 1cm scalp-near hair segment, assumed to retrospectively reflect 1-month integrated cortisol secretion, with 30-day average salivary cortisol area-under-the curve (AUC) based on 3 samples collected per day (on awakening, +30min, at bedtime) and the average of 4 weekly 24-h urinary free cortisol (UFC) assessments. To further address which aspects of cortisol production and regulation are best reflected in the HCC measure, we also examined components of the salivary measures that represent: (1) production in response to the challenge of awakening (using the cortisol awakening response [CAR]), and (2) chronobiological regulation of cortisol production (using diurnal slope). Finally, we evaluated the test-retest stability of each cortisol measure. Results indicate that HCC was most strongly associated with the prior 30-day integrated cortisol production measure (average salivary cortisol AUC) (r=0.61, p=0.01). There were no significant associations between HCC and the 30-day summary measures using CAR or diurnal slope. The relationship between 1-month integrated 24-h UFC and HCC did not reach statistical significance (r=0.30, p=0.28). Lastly, of all cortisol measures, test-retest correlations of serial measures were highest for HCC (month-to-month: r=0.84, p

BackgroundThe effects of exposure to childhood trauma (CT) may be transmitted across generations; however, the time period(s) and mechanism(s) have yet to be clarified. We address the hypothesis that intergenerational transmission may begin during intrauterine life via the effect of maternal CT exposure on placental-fetal stress physiology, specifically placental corticotropin-releasing hormone (pCRH).MethodsThe study was conducted in a sociodemographically diverse cohort of 295 pregnant women. CT exposure was assessed using the Childhood Trauma Questionnaire. Placental CRH concentrations were quantified in maternal blood collected serially over the course of gestation. Linear mixed effects and Bayesian piece-wise linear models were employed to test hypothesized relationships.ResultsMaternal CT exposure (CT+) was significantly associated with pCRH production. Compared with nonexposed women, CT+ was associated with an almost 25% increase in pCRH toward the end of gestation, and the pCRH trajectory of CT+ women exhibited an approximately twofold steeper increase after the pCRH inflection point at 19 weeks gestation.ConclusionsTo the best of our knowledge, this finding represents the first report linking maternal CT exposure with placental-fetal stress physiology, thus identifying a potential novel biological pathway of intergenerational transmission that may operate as early as during intrauterine life.

Background/aimsTelomere biology plays a fundamental role in genomic integrity and cell physiology. The newborn setting of telomere length (TL) likely has important implications for telomere dynamics over the lifespan; however, its determinants are poorly understood. Folate is essential for DNA integrity. The maternal compartment is the only source of folate for the developing fetus. We, therefore, tested the hypothesis that variation in maternal folate during pregnancy is associated with newborn TL.MethodsA prospective, longitudinal study was conducted in 119 mother-newborn dyads. Eligible mothers were enrolled at 9.5 (SD ±2.1) weeks gestation and followed through birth. Concentrations of maternal serum folate were measured in the first trimester of pregnancy. Newborn telomere length was measured in cord blood mononuclear cells (CBMC).ResultsAfter accounting for the effects of other established determinants of newborn TL, each 10 ng/ml increase in maternal total folate was associated with a 5.8% increase in median TL (p = 0.03). The median TL in newborns of mother in the lowest quartile of total folate levels was approximately 10% shorter than that of newborns of mothers in the highest folate quartile.ConclusionsOur findings suggest that fetal TL exhibits developmental plasticity, and provide evidence that maternal nutrition may exert a 'programming' effect on this system.

In the past decade, the growing field of telomere science has opened exciting new avenues for understanding the cellular and molecular substrates of stress and stress-related aging processes over the lifespan. Shorter telomere length is associated with advancing chronological age and also increased disease morbidity and mortality. Emerging studies suggest that stress accelerates the erosion of telomeres from very early in life and possibly even influences the initial (newborn) setting of telomere length. In this review, we highlight recent empirical evidence linking stress and mental illnesses at various times across the lifespan with telomere erosion. We first present findings in the developmental programming of telomere biology linking prenatal stress to newborn and adult telomere length. We then present findings linking exposure to childhood trauma and to certain mental disorders with telomere shortening. Last, we review studies that characterize the relationship between related health-risk behaviors with telomere shortening over the lifespan, and how this process may further buffer the negative effects of stress on telomeres. A better understanding of the mechanisms that govern and regulate telomere biology throughout the lifespan may inform our understanding of etiology and the long-term consequences of stress and mental illnesses on aging processes in diverse populations and settings.

The effects of maternal stress during pregnancy may depend, in part, on the timing in gestation of the occurrence of stress. The aim of the present study was to examine the effect of stage of gestation on maternal psychophysiological responses to stress using a standardized laboratory paradigm and on the cortisol response to awakening (CAR). A longitudinal design was employed to quantify maternal psychophysiological stress reactivity [changes in heart rate (HR), blood pressure, salivary cortisol, and psychological distress in response to the trier social stress test (TSST)] and the CAR at approximately 17 and 31 weeks gestation in a sample of 148 women. To account for the possible effects of habituation when being exposed to the same stress protocol twice, a non-pregnant comparison group (CG, N = 36) also underwent these assessments at two time points, with a comparable time interval between the assessments. In both groups, the TSST elicited significant changes in maternal HR, mean arterial pressure, and psychological distress levels but not a significant increase in cortisol levels. Among the pregnant women (pregnant group(PG)), the stressor-induced increases in HR, blood pressure, and psychological distress were significantly lower at the second (31 weeks gestation) compared to the first (17 weeks gestation) assessment of pregnancy (all p < 0.01). The maternal CAR was also significantly attenuated in later compared to earlier gestation (p = 0.003). In the CG, there were no significant differences in psychophysiological stress responses and in the CAR across the two assessments. Among pregnant women there is a progressive attenuation of psychophysiological stress responses with advancing gestation. This attenuation is unlikely to be attributable to habituation. Individual differences in the degree of attenuation of stress responses over gestation may represent a novel marker of stress susceptibility in human pregnancy.

ObjectiveThe purpose of this study was to examine the relationship between intraindividual changes in cortisol responsiveness over pregnancy and the length of human gestation.Study designPregnancy-related changes in the cortisol awakening response (CAR), which is a measure of hypothalamic-pituitary-adrenal axis responsiveness, were assessed prospectively in 101 pregnant women at 16.8 +/- 1.4 weeks' and 31.4 +/- 1.3 weeks' (+/-SD) gestation. Cortisol was measured in saliva that was collected immediately and +30, +45 and +60 minutes after awakening.ResultsThe CAR was significant in pregnancy and exhibited progressive attenuation over the course of gestation. A larger CAR in late pregnancy and reduced attenuation of the CAR from early to late gestation were associated significantly with shorter gestational length.ConclusionThe findings are the first to suggest that the hormonal (cortisol) response to a naturally occurring challenge (awakening) and the degree of attenuation of this response over the course of gestation may represent a novel biomarker of increased vulnerability for earlier birth.

ObjectivesRecent advances in the physiology of human pregnancy have implicated placental corticotropin-releasing hormone (CRH) as one of the primary endocrine mediators of parturition and possibly also of fetal development. The aim of this study was (1) to prospectively assess the relationship of maternal plasma concentrations of CRH in the early third trimester of gestation with two prematurity-related outcomes-spontaneous preterm birth (PTB), and small-for-gestational age birth (SGA), and (2) to determine whether the effects of CRH on each of these outcomes are independent from those of other established obstetric risk factors.Study designIn a sample of 232 women with a singleton, intrauterine pregnancy, maternal plasma was collected at 33 weeks' gestation and CRH concentrations were determined by radioimmunoassay. Each pregnancy was dated on the basis of last menstrual period and early ultrasonography. Parity, obstetric risk conditions for prematurity, mode of delivery, and birth outcomes were abstracted from the medical record.ResultsAfter adjusting for the effects of established obstetric risk factors, elevated CRH levels at 33 weeks' gestation were significantly associated with a 3.3-fold increase in the adjusted relative risk (RR) for spontaneous preterm birth and with a 3.6-fold increase in the adjusted relative risk for fetal growth restriction. Women who delivered postterm had significantly lower CRH levels in the early third trimester than those who delivered at term. When outcomes were stratified by gestational length and birth weight, the lowest CRH levels at 33 weeks' gestation were associated with the term non-SGA births, intermediate and approximately equal CRH levels were associated with the preterm non-SGA and term SGA births, and the highest CRH levels were associated with the preterm SGA births.ConclusionFor deliveries occurring after 33 weeks' gestation (the time of CRH sampling in this study), our findings support the notion that in humans placental CRH may play an impending, direct role in not only the physiology of parturition but also in processes related to fetal growth and maturation. Our results also support the notion that the timing of onset of parturition may be determined or influenced by events occurring earlier in gestation rather than those close to the time of actual onset of labor (ie, the notion of a "placental clock").

ObjectiveIt has been demonstrated that physiological responses to stress are diminished late in pregnancy. This study investigates whether emotional responding is diminished as well by measuring affective responses to specific life events during pregnancy.MethodsA total of 292 pregnant women reported the occurrence of and affective responses to a range of major life events during gestation. Two analyses were conducted (across events and within events) on these responses to determine whether life events occurring in the first trimester were rated as more stressful than those that occurred in the third trimester.ResultsBoth within-event and across-events analyses of responses to life events demonstrated that events occurring early in pregnancy were perceived as more stressful than events occurring later in pregnancy.ConclusionResponses to stress and affective state are progressively altered in pregnant women, suggesting that timing of stress exposure during gestation may be critical in determining its impact.

Maternal peptides from the hypothalamic-pituitary-adrenal (HPA) axis rise during human pregnancy. The effects of circulating maternal adrenocorticotropin (ACTH) and beta-endorphin (BE) on human fetal behavior was determined in 135 women during their 32nd week of gestation. Fetal behavior was measured by assessing heart rate habituation to a series of repeated vibroacoustic stimuli. Individual differences in habituation were determined by computing the number of consecutive responses above the standard deviation during a control period. There was no significant relation between levels of ACTH, BE and the rate of fetal heart rate habituation. However, an index of HPA disregulation (uncoupling of ACTH and BE) was related significantly to fetal behavior. Fetal exposure to high levels of maternal BE relative to ACTH was associated with significantly lower rates of habituation. Results indicate that maternal stress and stress-related peptides influence fetal response patterns. It is possible that this influence persists over the life span.

ObjectiveCorticotropin releasing hormone, a hypothalamic neuropeptide, plays a major role in regulating pituitary-adrenal function and the physiologic response to stress. During pregnancy corticotropin-releasing hormone is synthesized in large amounts by the placenta and released into the maternal and fetal circulations. Various endocrine, autocrine, and paracrine roles have been suggested for placental corticotropin-releasing hormone. The aim of this study was to prospectively assess the relationship between maternal plasma concentrations of corticotropin-releasing hormone in the early third trimester of pregnancy and the length of gestation in two groups of deliveries, with and without spontaneous labor.Study designIn a sample of 63 women with singleton intrauterine pregnancies, maternal plasma samples were collected between 28 and 30 weeks' gestation and corticotropin-releasing hormone concentrations were determined by radioimmunoassay. Each pregnancy was dated on the basis of last menstrual period and early ultrasonography. Parity, antepartum risk conditions, presence or absence of spontaneous labor, and birth outcomes were abstracted from the medical record.ResultsMaternal corticotropin-releasing hormone levels between 28 and 30 weeks' gestation significantly and negatively predicted gestational length (P < .01) after adjustment for antepartum risk. Moreover, subjects who were delivered preterm had significantly higher corticotropin-releasing hormone levels in the early third trimester (P < .01) than did those who were delivered at term. In deliveries preceded by spontaneous onset of labor, maternal third-trimester corticotropin-releasing hormone levels significantly and independently predicted earlier onset of labor (P < .01) and preterm labor (P < .05), whereas in deliveries effected by induction of labor or cesarean delivery, maternal corticotropin-releasing hormone levels were a marker of antepartum risk but not a statistically independent predictor of gestational length.ConclusionThese findings support the premise that placental corticotropin-releasing hormone is potentially implicated in the timing of human delivery in at least two ways. First, placental corticotropin-releasing hormone may play a role in the physiology of parturition. Premature or accelerated activation of the placental corticotropin-releasing hormone system, as reflected by precocious elevation of maternal corticotropin-releasing hormone levels, may therefore be associated with earlier onset of spontaneous labor and resultant delivery. Second, placental corticotropin-releasing hormone may be a marker of antepartum risk for preterm delivery and therefore an indirect predictor of earlier delivery. The implications of these findings are discussed in the context of the neuroendocrinology of placental corticotropin-releasing hormone and human parturition. Furthermore, the role of corticotropin-releasing hormone as a possible effector of prenatal stress in producing alterations in the timing of normal delivery is detailed.

In a prospective study, third trimester plasma levels of BE and ACTH were determined in 58 women who delivered vaginally. Peptide regulation was compared between subjects who used conduction anesthesia at delivery and subjects who did not. Third trimester levels of maternal BE and ACTH were significantly related; however, the relationship was significant only in subjects who did not receive conduction anesthesia (n = 24) at delivery. The normal co-release pattern between BE and ACTH in subjects receiving conduction anesthesia (n = 34) during birth was uncoupled. The use of conduction analgesia during vaginal delivery was significantly related to a disregulation index created to quantify the BE-ACTH release pattern. Uncoupled ACTH and BE patterns may result from modified control of pro-opiomelanocortin (POMC) expression during pregnancy or unique proteolytic processing of POMC, and may alter pain tolerance during delivery.

ObjectiveThe aim was to test a model of the influence of maternal prenatal psychosocial stress on birth outcomes after controlling for biomedical risk.Study designIn a prospective study a sociodemographically homogeneous sample of 90 women was assessed during the third trimester with standard, reliable questionnaires that measured episodic and chronic stress, strain (response to stress), and pregnancy-related anxiety. Birth outcomes included infant birth weight, gestational age at birth, and intrapartum complications. Parity and biomedical (antepartum) risk was also coded. Bivariate and multivariate analyses were performed after controlling for the effects of biomedical risk factors.ResultsIndependent of biomedical risk, each unit increase of prenatal life event stress (from a possible sample range of 14.7 units) was associated with a 55.03 gm decrease in infant birth weight and with a significant increase in the likelihood of low birth weight (odds ratio 1.32), and each unit increase of prenatal pregnancy anxiety (from a possible sample range of 5 units) was associated with a 3-day decrease in gestational age at birth.ConclusionIndependent of biomedical risk, maternal prenatal stress factors are significantly associated with infant birth weight and with gestational age at birth.