Demographic and health characteristics associated with fish and n-3 fatty acid supplement intake during pregnancy: results from pregnancy cohorts in the ECHO programme.

OBJECTIVE: n-3 fatty acid consumption during pregnancy is recommended for optimal pregnancy outcomes and offspring health. We examined characteristics associated with self-reported fish or n-3 supplement intake. DESIGN: Pooled pregnancy cohort studies. SETTING: Cohorts participating in the Environmental influences on Child Health Outcomes (ECHO) consortium with births from 1999 to 2020. PARTICIPANTS: A total of 10 800 pregnant women in twenty-three cohorts with food frequency data on fish consumption; 12 646 from thirty-five cohorts with information on supplement use. RESULTS: Overall, 24·6 % reported consuming fish never or less than once per month, 40·1 % less than once a week, 22·1 % 1-2 times per week and 13·2 % more than twice per week. The relative risk (RR) of ever (v. never) consuming fish was higher in participants who were older (1·14, 95 % CI 1·10, 1·18 for 35-40 v. <29 years), were other than non-Hispanic White (1·13, 95 % CI 1·08, 1·18 for non-Hispanic Black; 1·05, 95 % CI 1·01, 1·10 for non-Hispanic Asian; 1·06, 95 % CI 1·02, 1·10 for Hispanic) or used tobacco (1·04, 95 % CI 1·01, 1·08). The RR was lower in those with overweight v. healthy weight (0·97, 95 % CI 0·95, 1·0). Only 16·2 % reported n-3 supplement use, which was more common among individuals with a higher age and education, a lower BMI, and fish consumption (RR 1·5, 95 % CI 1·23, 1·82 for twice-weekly v. never). CONCLUSIONS: One-quarter of participants in this large nationwide dataset rarely or never consumed fish during pregnancy, and n-3 supplement use was uncommon, even among those who did not consume fish.

Gestational and postnatal age associations for striatal tissue iron deposition in early infancy.

Striatal development is crucial for later motor, cognitive, and reward behavior, but age-related change in striatal physiology during the neonatal period remains understudied. An MRI-based measure of tissue iron deposition, T2*, is a non-invasive way to probe striatal physiology neonatally, linked to dopaminergic processing and cognition in children and adults. Striatal subregions have distinct functions that may come online at different time periods in early life. To identify if there are critical periods before or after birth, we measured if striatal iron accrued with gestational age at birth [range= 34.57-41.85 weeks] or postnatal age at scan [range= 5-64 days], using MRI to probe the T2* signal in N = 83 neonates in three striatal subregions. We found iron increased with postnatal age in the pallidum and putamen but not the caudate. No significant relationship between iron and gestational age was observed. Using a subset of infants scanned at preschool age (N = 26), we show distributions of iron shift between time points. In infants, the pallidum had the least iron of the three regions but had the most by preschool age. Together, this provides evidence of distinct change for striatal subregions, a possible differentiation between motor and cognitive systems, identifying a mechanism that may impact future trajectories.

Gestational and postnatal age associations for striatal tissue iron deposition in early infancy.

Striatal development is crucial for later motor, cognitive, and reward behavior, but age-related change in striatal physiology during the neonatal period remains understudied. An MRI-based measure of tissue iron deposition, T2*, is a non-invasive way to probe striatal physiology neonatally, linked to dopaminergic processing and cognition in children and adults. Striatal subregions have distinct functions that may come online at different time periods in early life. To identify if there are critical periods before or after birth, we measured if striatal iron accrued with gestational age at birth [range=34.57-41.85 weeks] or postnatal age at scan [range=5-64 days], using MRI to probe the T2* signal in N=83 neonates in three striatal subregions. We found iron increased with postnatal age in the pallidum and putamen but not the caudate. No significant relationship between iron and gestational age was observed. Using a subset of infants scanned at preschool age (N=26), we show distributions of iron shift between timepoints. In infants, the pallidum had the least iron of the three regions but had the most by preschool age. Together, this provides evidence of distinct change for striatal subregions, a possible differentiation between motor and cognitive systems, identifying a mechanism that may impact future trajectories. Highlights: Neonatal striatal tissue iron can be measured using the T2* signal from rsfMRInT2* changed with postnatal age in the pallidum and putamen but not in the caudatenT2* did not change with gestational age in any of the three regionsPatterns of iron deposition (nT2*) among regions shift from infancy to preschool.

Exposure to childhood maltreatment and systemic inflammation across pregnancy: The moderating role of depressive symptomatology.

BACKGROUND: Childhood maltreatment (CM) has long-term consequences for dysregulation of the immune system which is particularly pronounced when mental and physical health sequelae have manifested. Higher proinflammatory state has been shown in non-pregnant state in association with CM as well as with depression, one of the most frequent and pernicious psychiatric sequelae of CM. During pregnancy, however, this association is less clear. Given the important role of maternal inflammatory state during pregnancy for fetal, pregnancy, and birth outcomes, we sought to examine the association between CM and proinflammatory state during pregnancy considering the moderating role of maternal depressive symptoms characterized serially across pregnancy. METHODS: A prospective, longitudinal study of 180 healthy pregnant women was conducted with serial assessments in early (12.98 ± 1.71 weeks gestation), mid (20.53 ± 1.38 weeks gestation) and late (30.42 ± 1.4 weeks gestation) pregnancy. Maternal history of CM was assessed with the Childhood Trauma Questionnaire (CTQ) and the total score was used as an indicator of CM experience. Maternal depressive symptoms were assessed at each pregnancy visit with the Center for Epidemiologic Studies Depression Scale (CES-D). Serum concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-6 were obtained at each pregnancy visit and combined to a composite maternal proinflammatory score. Linear mixed effects models were employed to assess the association between CTQ score, CES-D score, and proinflammatory score during pregnancy, adjusting for potential confounders. RESULTS: Gestational age was associated with the proinflammatory score (B = 0.02; SE = 0.00; p < .001), indicating an increase in inflammation across gestation. Neither CTQ score nor depressive symptoms were independently associated with the proinflammatory score (ps > 0.28). However, the interaction between CTQ score and depressive symptoms was associated with the proinflammatory score (B = 0.03, SE = 0.01, p < .05), indicating higher inflammation across pregnancy with increasing levels of depressive symptoms during pregnancy in women with higher CTQ scores. Exploratory analyses suggested that this interaction was mainly driven by CTQ subscale scores assessing experiences of abuse rather than neglect. CONCLUSIONS: These findings suggest a moderating role of maternal depressive symptoms during pregnancy on the association of early life stress with inflammation and thus highlight the importance of the timely assessment of both CM exposure and depressive symptoms which might allow for the development of targeted and individualized interventions to impact inflammation during pregnancy and to ameliorate the detrimental long-term effects of CM. The current findings add to a better understanding of the prenatal biological pathways that may underlie intergenerational transmission of maternal CM.

The intersection of race and socioeconomic status is associated with inflammation patterns during pregnancy and adverse pregnancy outcomes.

BACKGROUND: Preterm birth rates are higher among individuals of lower socioeconomic status and non-White race, which is possibly related to life-course stressors. It is important to understand the underlying mechanisms of these health disparities, and inflammation is a possible pathway to explain the disparities in birth outcomes. OBJECTIVE: In this study, we aimed to determine whether patterns of inflammation differed by maternal race and socioeconomic status. STUDY DESIGN: Seven hundred and forty-four participants in a multi-site, prospective study of pregnancy and birth outcomes provided biological and psychological data between 12'0-20'6 weeks gestation. Participants with recent infection, fever, antibiotics or steroid treatment were excluded. Cytokines including INFÉ£, IL-10, IL-13, IL-6, IL-8, and TNFα, and the acute phase protein CRP were measured in serum and values and were log-transformed for normality when appropriate, and a non-orthogonal rotation (Oblimid) was performed to allow the extracted factor to inter-correlate. IFNγ, IL-8, IL-10, IL-6, TNF-a, and IL-13 loaded onto Inflammatory Factor 1 (IF-1), while CRP and IL-6 loaded onto Inflammatory Factor 2 (IF-2). Race and education were collected via self-report during an in-person study visit. Multivariable models were used to determine the association of race and SES with IF-1 and IF-2 during the second trimester, and a mediation model was used to examine if inflammation is on the causal pathway. Models were adjusted for study site, prenatal age, pre-pregnancy BMI, smoking during pregnancy, and gestational age at the time of blood collection. RESULTS: Six hundred and five participants were included in our final analysis, with 61.2% of low or moderate SES, and 35.5% identifying as a person of color (POC). Identifying as a POC, being of low and moderate SES, and being both low-SES and POC or moderate-SES and POC were associated with higher odds of preterm birth and lower birth weight percentile infants. Low SES POC participants had significantly higher IF-1 and IF-2 scores when compared to high-SES White participants. Additionally, higher IF-1 and IF-2 were associated with shorter gestation. In the mediation analysis, we observed a significant direct effect of race/SES on preterm birth; however, the results did not support an indirect pathway where IF-1 or IF-2 acted as mediators. CONCLUSION: Maternal race and SES are significantly associated with inflammatory biomarkers during pregnancy, and when race and SES are considered in combination, they are stronger predictors of adverse pregnancy outcomes than when evaluated separately.

Neuroanatomical Correlates Underlying the Association Between Maternal Interleukin 6 Concentration During Pregnancy and Offspring Fluid Reasoning Performance in Early Childhood.

BACKGROUND: Maternal inflammation during pregnancy can alter offspring brain development and influence risk for disorders commonly accompanied by deficits in cognitive functioning. We therefore examined associations between maternal interleukin 6 (IL-6) concentrations during pregnancy and offspring cognitive ability and concurrent magnetic resonance imaging-based measures of brain anatomy in early childhood. We further examined newborn brain anatomy in secondary analyses to consider whether effects are evident soon after birth and to increase capacity to differentiate effects of pre- versus postnatal exposures. METHODS: IL-6 concentrations were quantified in early (12.6 ± 2.8 weeks), mid (20.4 ± 1.5 weeks), and late (30.3 ± 1.3 weeks) pregnancy. Offspring nonverbal fluid intelligence (Gf) was assessed at 5.2 ± 0.6 years using a spatial reasoning task (Wechsler Preschool and Primary Scale of Intelligence-Matrix) (n = 49). T1-weighted magnetic resonance imaging scans were acquired at birth (n = 89, postmenstrual age = 42.9 ± 2.0 weeks) and in early childhood (n = 42, scan age = 5.1 ± 1.0 years). Regional cortical volumes were examined for a joint association between maternal IL-6 and offspring Gf performance. RESULTS: Average maternal IL-6 concentration during pregnancy was inversely associated with offspring Gf performance after adjusting for socioeconomic status and the quality of the caregiving and learning environment (R2 = 13%; p = .02). Early-childhood pars triangularis volume was jointly associated with maternal IL-6 and childhood Gf (pcorrected < .001). An association also was observed between maternal IL-6 and newborn pars triangularis volume (R2 = 6%; p = .02). CONCLUSIONS: These findings suggest that the origins of variation in child cognitive ability can, in part, trace back to maternal conditions during the intrauterine period of life and support the role of inflammation as an important component of this putative biological pathway.

Using principal component analysis to examine associations of early pregnancy inflammatory biomarker profiles and adverse birth outcomes.

OBJECTIVE: Inflammation as a risk factor for preterm birth is well-established. The primary objective of this analysis was to examine whether individual cytokines versus a composite indicator of mid-pregnancy inflammation are significantly associated with risk for adverse birth outcomes. STUDY DESIGN: A multi-site prospective study was conducted in a socio-demographically diverse cohort of 610 pregnant participants. At a study visit between 12 and 20 6/7 weeks' gestation, low-grade inflammation was measured via log-transformed serum concentrations of the biomarkers IFN-γ, IL-10, IL-13, IL-6, IL-8, TNF-α, and CRP. Principal component analysis (PCA) was used to identify underlying dimensions of inflammatory activity from the seven biomarkers measured. Gestational age and birth weight at delivery were obtained from medical chart review. The associations between inflammatory profiles and birth outcomes were assessed via linear and logistic regression models. Results were compared with those from individual inflammatory biomarkers, and model fit was assessed using Akaike's Information Criterion (AIC). RESULTS: Principal component analysis analysis yielded a two-factor solution, with the first factor (IF1) composed of IL-8, IL-10, IL-13, IFN-É£, and TNF-α, and the second factor (IF2) containing IL-6 and CRP. When adjusted for race, education, BMI, smoking status, gestational age at time of blood draw, and study site, a one standard deviation (SD) increase in IF1 remained significantly associated with a decrease in standardized gestational age (ß = -.13, 95% CI: -.21, -.05) and an increase in odds of preterm delivery (OR = 1.46, 95% CI: 1.13, 1.88) (Table 3). A one SD increase in IF2 was similarly associated with a decrease in standardized gestational age at delivery (ß = -.13, 95% CI: -.23, -.04) and an increase in odds of preterm delivery (OR: 1.46, 95% CI: 1.04, 2.05). Neither IF1 nor IF2 was associated with measures of fetal growth. AIC identified that IL-6 was a slightly better fit for length of gestation compared to either composite measure, though all performed similarly. CONCLUSION: Independent of known sociodemographic risk factors, an elevated mid-pregnancy inflammatory profile was associated with a nearly 50% increase in odds of preterm delivery. The composite performed similarly to IL-6. These results suggest that maternal low-grade inflammation is a risk factor for preterm delivery, and that mid-pregnancy inflammatory biomarkers may be useful in predicting risk for preterm delivery.

Prospective association of maternal psychosocial stress in pregnancy with newborn hippocampal volume and implications for infant social-emotional development.

Maternal psychosocial stress during pregnancy can impact the developing fetal brain and influence offspring mental health. In this context, animal studies have identified the hippocampus and amygdala as key brain regions of interest, however, evidence in humans is sparse. We, therefore, examined the associations between maternal prenatal psychosocial stress, newborn hippocampal and amygdala volumes, and child social-emotional development. In a sample of 86 mother-child dyads, maternal perceived stress was assessed serially in early, mid and late pregnancy. Following birth, newborn (aged 5-64 postnatal days, mean: 25.8 ± 12.9) hippocampal and amygdala volume was assessed using structural magnetic resonance imaging. Infant social-emotional developmental milestones were assessed at 6- and 12-months age using the Bayley-III. After adjusting for covariates, maternal perceived stress during pregnancy was inversely associated with newborn left hippocampal volume (ß = -0.26, p = .019), but not with right hippocampal (ß = -0.170, p = .121) or bilateral amygdala volumes (ps > .5). Furthermore, newborn left hippocampal volume was positively associated with infant social-emotional development across the first year of postnatal life (B = 0.01, p = .011). Maternal perceived stress was indirectly associated with infant social-emotional development via newborn left hippocampal volume (B = -0.34, 95% CIBC [-0.97, -0.01]), suggesting mediation. This study provides prospective evidence in humans linking maternal psychosocial stress in pregnancy with newborn hippocampal volume and subsequent infant social-emotional development across the first year of life. These findings highlight the importance of maternal psychosocial state during pregnancy as a target amenable to interventions to prevent or attenuate its potentially unfavorable neural and behavioral consequences in the offspring.

Racial differences across pregnancy in maternal pro-inflammatory immune responsivity and its regulation by glucocorticoids.

BACKGROUND: The distribution of adverse pregnancy, birth and subsequent child developmental and health outcomes in the U.S. is characterized by pronounced racial (particularly Black-white) disparities. In this context, chronic stress exposure represents a variable of considerable importance, and the immune/inflammatory system represents a leading candidate biological pathway of interest. Previous pregnancy studies examining racial disparities in immune processes have largely utilized circulating cytokine levels, and have yielded null or mixed results. Circulating cytokines primarily represent basal secretion and do not necessarily represent functional features of immune responsivity and regulation. Thus, in order to conduct a more in-depth characterization of racial differences in functional immune properties during pregnancy, we utilized an ex vivo stimulation assay, a dynamic measure of immune function at the cellular level, to investigate Black-white racial differences in in mid- and late-gestation in i) pro-inflammatory (IL-6) responsivity of leukocytes to antigen [lipopolysaccharide (LPS)] challenge, and ii) regulation (dampening) of this pro-inflammatory response by glucocorticoids. METHOD: 177 women (N = 42 Black (24%), n = 135 white (76%)) with a singleton, intrauterine pregnancy provided 20 mL venous blood in mid- (16.6 ± 2.4 wks) and late (33.3 ± 1.1 wks) pregnancy. Maternal pro-inflammatory responsivity of leukocytes was quantified by assessing the release of the pro-inflammatory cytokine IL-6 in response to LPS stimulation, and regulation of the pro-inflammatory response was quantified by assessing the suppression of the stimulated IL-6 response after co-incubation with progressively increasing levels of dexamethasone [10-7, 10-6, 10-5 M] (i.e., glucocorticoid receptor resistance (GRR)). A priori model covariates included maternal age, parity, SES (socioeconomic status), and pre-pregnancy BMI. RESULTS: Maternal pro-inflammatory responsivity (LPS-stimulated IL-6) and GRR increased significantly across mid- and late gestation (adjusted ß = 0.157, p = 0.007; ß = 0.627, p < 0.001, respectively). Across both time points in pregnancy Black women exhibited significantly higher LPS-stimulated IL-6 release and reduced glucocorticoid regulation of the IL-6 response (i.e., higher GRR) relative to white women, before and after adjusting for covariates (ß = 0.381, p = 0.0030; ß = 0.391, p = 0.0075, respectively). There was no racial difference in the concentrations of circulating IL-6 (p = 0.9199). CONCLUSION: Our findings support the hypothesis postulating significant racial (Black-white) differences in key functional properties of the maternal immune system in pregnancy, which were not apparent using circulating cytokine measures. These data elucidate a potentially important physiological mechanism underlying the transduction of environmental conditions into racial disparities in reproductive and subsequent child health outcomes, and the use of these ex vivo measures should be considered in future studies.

Childhood adversity correlates with stable changes in DNA methylation trajectories in children and converges with epigenetic signatures of prenatal stress.

Childhood maltreatment (CM) is an established major risk factor for a number of negative health outcomes later in life. While epigenetic mechanisms, such as DNA methylation (DNAm), have been proposed as a means of embedding this environmental risk factor, little is known about its timing and trajectory, especially in very young children. It is also not clear whether additional environmental adversities, often experienced by these children, converge on similar DNAm changes. Here, we calculated a cumulative adversity score, which additionally to CM includes socioeconomic status (SES), other life events, parental psychopathology and epigenetic biomarkers of prenatal smoking and alcohol consumption. We investigated the effects of CM alone as well as the adversity score on longitudinal DNAm trajectories in the Berlin Longitudinal Child Study. This is a cohort of 173 children aged 3-5 years at baseline of whom 86 were exposed to CM. These children were followed-up for 2 years with extensive psychometric and biological assessments as well as saliva collection at 5 time points providing genome-wide DNAm levels. Overall, only a few DNAm patterns were stable over this timeframe, but less than 10 DNAm regions showed significant changes. At baseline, neither CM nor the adversity score associated with DNAm changes. However, in 6 differentially methylated regions (DMRs), CM and the adversity score significantly moderated DNAm trajectories over time. A number of these DMRs have previously been associated with adverse prenatal exposures. In our study, children exposed to CM also presented with epigenetic signatures indicative of increased prenatal exposure to tobacco and alcohol, as compared to non-CM exposed children. These epigenetic signatures of prenatal exposure strongly correlate with DNAm regions associated with CM and the adversity score. Finally, weighted correlation network analysis revealed a module of CpGs exclusively associated with CM. While our study identifies DNAm loci specifically associated with CM, especially within long non-coding RNAs, the majority of associations were found with the adversity score with convergent association with indicators of adverse prenatal exposures. This study highlights the importance of mapping not only of the epigenome but also the exposome and extending the observational timeframe to well before birth.

Prospective association of maternal immune pro-inflammatory responsivity and regulation in pregnancy with length of gestation.

PROBLEM: The 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 STUDY: Immune 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-1ß 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). RESULTS: Higher maternal GRR, indicating impaired regulation of the pro-inflammatory response, was significantly and independently associated with shorter gestational length (ß = -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. CONCLUSION: The 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.

Lifetime Psychosocial Stress Exposure Associated with Hypertensive Disorders of Pregnancy.

OBJECTIVE: Hypertensive disorders of pregnancy (HDP) complicate 5 to 10% of all pregnancies and are a major cause of pregnancy-related morbidity. Exposure to psychosocial stress has been associated with systemic inflammation and adverse birth outcomes in pregnant women. Thus, it is probable that psychosocial stress and inflammation play a role in the development of HDP. The primary objective of this analysis was to determine if a woman's lifetime psychosocial stress exposure was associated with an increased risk of HDP. Additionally, we examined whether serum inflammation was an underlying biological mediator for this relationship. STUDY DESIGN: A multisite prospective study was conducted in a sociodemographically diverse cohort of 647 pregnant women. At a study visit between 12 and 206/7 weeks' gestation, maternal psychosocial stress was assessed with six validated assessments and inflammation was measured via log-transformed serum concentrations of interferon-γ, interleukin (IL)-10, IL-13, IL-6, IL-8, and tumor necrosis factor-α. A composite stress score was calculated for each participant from the six stress assessments. The diagnosis of HDP was abstracted from the medical record and was defined as the presence of gestational hypertension after 20 weeks of pregnancy and/or preeclampsia. The association between composite stress and HDP was determined using binary logistic regression. Inflammation, using the six inflammatory biomarkers, was tested as a potential mediator between stress and HDP. RESULTS: Participants with higher composite stress scores were more likely to develop HDP (odds ratio [OR]: 1.50, 95% confidence interval [CI]: 1.06-2.12). When adjusted for known risk modifiers, including maternal age, race/ethnicity, parity, pre-pregnancy body mass index, diabetes, chronic hypertension, and smoking during pregnancy, the risk remained unchanged (OR: 1.50, 95% CI: 1.03-2.20). No mediation effect by inflammation was observed. CONCLUSION: Independent of known risk factors, women exposed to greater composite stress burden across the life course are at increased risk of developing HDP. KEY POINTS: · This study was conducted to determine if women with high levels of psychosocial stress have differences in risk for hypertensive disorders of pregnancy (HDP).. · Independent of known risk factors, women with increased lifetime psychosocial burden are at higher risk for HDP.. · A model that captures multiple domains of life stress may better predict HDP than a unimodal stress assessment..

DCC gene network in the prefrontal cortex is associated with total brain volume in childhood.

BACKGROUND: Genetic variation in the guidance cue DCC gene is linked to psychopathologies involving dysfunction in the prefrontal cortex. We created an expression-based polygenic risk score (ePRS) based on the DCC coexpression gene network in the prefrontal cortex, hypothesizing that it would be associated with individual differences in total brain volume. METHODS: We filtered single nucleotide polymorphisms (SNPs) from genes coexpressed with DCC in the prefrontal cortex obtained from an adult postmortem donors database (BrainEAC) for genes enriched in children 1.5 to 11 years old (BrainSpan). The SNPs were weighted by their effect size in predicting gene expression in the prefrontal cortex, multiplied by their allele number based on an individual's genotype data, and then summarized into an ePRS. We evaluated associations between the DCC ePRS and total brain volume in children in 2 community-based cohorts: the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) and University of California, Irvine (UCI) projects. For comparison, we calculated a conventional PRS based on a genome-wide association study of total brain volume. RESULTS: Higher ePRS was associated with higher total brain volume in children 8 to 10 years old (ß = 0.212, p = 0.043; n = 88). The conventional PRS at several different thresholds did not predict total brain volume in this cohort. A replication analysis in an independent cohort of newborns from the UCI study showed an association between the ePRS and newborn total brain volume (ß = 0.101, p = 0.048; n = 80). The genes included in the ePRS demonstrated high levels of coexpression throughout the lifespan and are primarily involved in regulating cellular function. LIMITATIONS: The relatively small sample size and age differences between the main and replication cohorts were limitations. CONCLUSION: Our findings suggest that the DCC coexpression network in the prefrontal cortex is critically involved in whole brain development during the first decade of life. Genes comprising the ePRS are involved in gene translation control and cell adhesion, and their expression in the prefrontal cortex at different stages of life provides a snapshot of their dynamic recruitment.

Are personality traits associated with smoking and alcohol use prior to and during pregnancy?

Cigarette smoking and alcohol consumption during pregnancy can have detrimental effects on the developing fetus, including fetal alcohol syndrome and low birth weight. Surprisingly little is known about the association of personality traits with smoking and alcohol consumption in the specific subpopulation of pregnant women. This study analyzed data from a geographically diverse sample of 603 pregnant women, aged 18 years and older, who provided information regarding their smoking and drinking habits before and during pregnancy. We compared women who consumed alcohol or smoked cigarettes before pregnancy with women who quit or continued smoking or drinking during pregnancy. Associations between personality and maladaptive behaviors prior to and during pregnancy were modeled using logistic regression. The study revealed that women who scored high on openness to experience were significantly more likely to continue alcohol consumption during pregnancy (OR = 1.07, 95% CI 1.01, 1.14, p = .02). This association was maintained after adjusting for potential confounds. This study demonstrated a significant relationship between personality traits and women's likelihood of continued alcohol consumption prior to and during pregnancy. Understanding personality-based determinants of health-detrimental behavior is important in order to design interventions that aim at decreasing rates of maladaptive health behaviors among pregnant women.

The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells.

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.

Maternal pro-inflammatory state during pregnancy and newborn leukocyte telomere length: A prospective investigation.

INTRODUCTION: Telomere 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 MATERIALS: Participants 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. RESULTS: After 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 (ß = -.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. DISCUSSION: These 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.

Dynamic DNA methylation changes in the maternal oxytocin gene locus (OXT) during pregnancy predict postpartum maternal intrusiveness.

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 < .001), with decreases in DNAm from early to mid-pregnancy and no further change until late pregnancy. Moreover, dynamic DNAm trajectories of the OXT-promoter region predicted MB (intrusiveness) at six months postpartum (b = 0.006, t = 2.0, p < 0.05), with 6% higher OXT DNAm in late pregnancy in intrusive compared to non-intrusive mothers. We here demonstrate that OXT promoter DNAm changes significantly throughout gestation in peripheral blood and that these changes are associated with variability in MB, providing a novel potential biomarker predicting postnatal MB.

Maternal Interleukin-6 concentration during pregnancy is associated with variation in frontolimbic white matter and cognitive development in early life.

Maternal inflammation during pregnancy can alter the trajectory of fetal brain development and increase risk for offspring psychiatric disorders. However, the majority of relevant research to date has been conducted in animal models. Here, in humans, we focus on the structural connectivity of frontolimbic circuitry as it is both critical for socioemotional and cognitive development, and commonly altered in a range of psychiatric disorders associated with intrauterine inflammation. Specifically, we test the hypothesis that elevated maternal concentration of the proinflammatory cytokine interleukin-6 (IL-6) during pregnancy will be associated with variation in microstructural properties of this circuitry in the neonatal period and across the first year of life. Pregnant mothers were recruited in early pregnancy and maternal blood samples were obtained for assessment of maternal IL-6 concentrations in early (12.6 ±â€¯2.8 weeks [S.D.]), mid (20.4 ±â€¯1.5 weeks [S.D.]) and late (30.3 ±â€¯1.3 weeks [S.D.]) gestation. Offspring brain MRI scans were acquired shortly after birth (N = 86, scan age = 3.7 ±â€¯1.7 weeks [S.D.]) and again at 12-mo age (N = 32, scan age = 54.0 ±â€¯3.1 weeks [S.D.]). Diffusion Tensor Imaging (DTI) was used to characterize fractional anisotropy (FA) along the left and right uncinate fasciculus (UF), representing the main frontolimbic fiber tract. In N = 30 of the infants with serial MRI data at birth and 12-mo age, cognitive and socioemotional developmental status was characterized using the Bayley Scales of Infant Development. All analyses tested for potentially confounding influences of household income, prepregnancy Body-Mass-Index, obstetric risk, smoking during pregnancy, and infant sex, and outcomes at 12-mo age were additionally adjusted for the quality of the postnatal caregiving environment. Maternal IL-6 concentration (averaged across pregnancy) was prospectively and inversely associated with FA (suggestive of reduced integrity under high inflammatory conditions) in the newborn offspring (bi-lateral, p < 0.01) in the central portion of the UF proximal to the amygdala. Furthermore, maternal IL-6 concentration was positively associated with rate of FA increase across the first year of life (bi-lateral, p < 0.05), resulting in a null association between maternal IL-6 and UF FA at 12-mo age. Maternal IL-6 was also inversely associated with offspring cognition at 12-mo age, and this association was mediated by FA growth across the first year of postnatal life. Findings from the current study support the premise that susceptibility for cognitive impairment and potentially psychiatric disorders may be affected in utero, and that maternal inflammation may constitute an intrauterine condition of particular importance in this context.

Maternal Stress Potentiates the Effect of an Inflammatory Diet in Pregnancy on Maternal Concentrations of Tumor Necrosis Factor Alpha.

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.

Acculturation and interleukin (IL)-6 concentrations across pregnancy among Mexican-American women.

BACKGROUND: The 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). METHODS: 75 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. RESULTS: Hierarchical 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. CONCLUSIONS: Maternal 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.