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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 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.

Prevalences of non-communicable diseases such as depression and a range of somatic diseases are continuously increasing requiring simple and inexpensive ways to identify high-risk individuals to target with predictive and preventive approaches. Using k-mean cluster analytics, in study 1, we identified biochemical clusters (based on C-reactive protein, interleukin-6, fibrinogen, cortisol, and creatinine) and examined their link to diseases. Analyses were conducted in a US American sample (from the Midlife in the US study, N = 1234) and validated in a Japanese sample (from the Midlife in Japan study, N = 378). In study 2, we investigated the link of the biochemical clusters from study 1 to childhood maltreatment (CM). The three identified biochemical clusters included one cluster (with high inflammatory signaling and low cortisol and creatinine concentrations) indicating the highest disease burden. This high-risk cluster also reported the highest CM exposure. The current study demonstrates how biomarkers can be utilized to identify individuals with a high disease burden and thus, may help to target these high-risk individuals with tailored prevention/intervention, towards personalized medicine. Furthermore, our findings raise the question whether the found biochemical clusters have predictive character, as a tool to identify high-risk individuals enabling targeted prevention. The finding that CM was mostly prevalent in the high-risk cluster provides first hints that the clusters could indeed have predictive character and highlight CM as a central disease susceptibility factor and possibly as a leverage point for disease prevention/intervention.

Objective: In 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. Methods: In 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. Results: Maternal 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. Conclusions: The 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.

Exposure to child maltreatment increases the risk for psychiatric and physical diseases. Inflammation has been proposed as a mechanism through which early adverse experiences become biologically embedded. However, most studies providing evidence for the link between early adverse exposures and inflammation have been retrospective or cross-sectional in design, or did not assess inflammation immediately after maltreatment in young children. In the present study we investigated the association between childhood maltreatment and salivary C-reactive protein (CRP) concentrations in a population of N = 173 children, 3–5 years of age, who were recruited in the immediate aftermath of maltreatment and followed-up longitudinally every 6 months over a period of 2 years. We found that the association between maltreatment and CRP concentrations was significantly moderated by child sex, such that in girls, CRP concentrations were higher in the maltreated compared to the control group, and this difference was stable across the 2-year follow-up-period, while in boys, there was no association between maltreatment and CRP. Our findings suggest that the effect of maltreatment on inflammation may already emerge right after exposure at a very young age in girls and manifest over time. Our study provides important evidence for the development of personalized, early interventions strategies targeting the early-life period.

Background The 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. Methods We 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). Results In 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. Discussion Our 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.

Context Across pregnancy, maternal serum cortisol levels increase up to 3-fold. It is not known whether maternal peripheral cortisol metabolism and clearance change across pregnancy or influence fetal cortisol exposure and development. Objectives The primary study objective was to compare maternal urinary glucocorticoid metabolites, as markers of cortisol metabolism and clearance, between the second and third trimester of pregnancy. Secondary objectives were to test associations of total maternal urinary glucocorticoid excretion, with maternal serum cortisol levels and offspring birth weight z score. Design, Participants, and Setting A total of 151 women with singleton pregnancies, recruited from prenatal clinic at the Pittsburgh site of the Measurement of Maternal Stress (MOMS) study, had 24-hour urine collections during both the second and third trimesters. Results Between the second and third trimester, total urinary glucocorticoid excretion increased (ratio of geometric means [RGM] 1.37, 95% CI 1.22-1.52, P < .001), and there was an increase in calculated 5β-reductase compared to 5α-reductase activity (RGM 3.41, 95% CI 3.04-3.83, P < .001). During the third trimester total urinary glucocorticoid excretion and serum cortisol were negatively correlated (r = –0.179, P = .029). Mean total urinary glucocorticoid excretion across both trimesters and offspring birth weight z score were positively associated (β = 0.314, P = .001). Conclusions The estimated activity of maternal enzymes responsible for cortisol metabolism change between the second and third trimester of pregnancy. Additionally, maternal peripheral metabolism and clearance of cortisol may serve as a novel mechanism affecting fetal cortisol exposure and growth.

Contains fulltext : 219496.pdf (Publisher’s version ) (Closed access) DNA methylation is the most studied modification in human population epigenetics. Its information content can be explored in 2 principal ways - epigenome-wide association studies and epigenetic age. The latter likely reflects cellular/biological age and works with impressive accuracy across most tissues. In adults, it associates with various environments and health. However, current epigenetic clocks are not very accurate in the pediatric age range perhaps because DNA methylation changes much faster in children. Addressing this crucial gap, we created a precise tool to estimate DNA methylation age specific to pediatric buccal epithelial cells. This tool has the potential to become the standard reference for epigenetic studies broadly relevant to child development across the spectrum from health to disease.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. 7 p.

From early to middle childhood, brain regions that underlie memory consolidation undergo profound maturational changes. However, there is little empirical investigation that directly relates age-related differences in brain structural measures to the memory consolidation processes. The present study examined system-level memory consolidations of intentionally studied object-location associations after one night of sleep (short delay) and after two weeks (long delay) in normally developing 5-to-7-year-old children (n = 50) and young adults (n = 39). Behavioural differences in memory consolidation were related to structural brain measures. Our results showed that children, in comparison to young adults, consolidate correctly learnt object-location associations less robustly over short and long delay. Moreover, using partial least squares correlation method, a unique multivariate profile comprised of specific neocortical (prefrontal, parietal, and occipital), cerebellar, and hippocampal subfield structures was found to be associated with variation in short-delay memory consolidation. A different multivariate profile comprised of a reduced set of brain structures, mainly consisting of neocortical (prefrontal, parietal, and occipital), and selective hippocampal subfield structures (CA1-2 and subiculum) was associated with variation in long-delay memory consolidation. Taken together, the results suggest that multivariate structural pattern of unique sets of brain regions are related to variations in short- and long-delay memory consolidation across children and young adults.RESEARCH HIGHLIGHTSShort- and long-delay memory consolidation is less robust in children than in young adultsShort-delay brain profile comprised of hippocampal, cerebellar, and neocortical brain regionsLong-delay brain profile comprised of neocortical and selected hippocampal brain regions.Brain profiles differ between children and young adults.

The association between maternal immune activation (MIA) during pregnancy and risk for offspring neuropsychiatric disorders has been increasingly recognized over the past several years. Among the mechanistic pathways that have been described through which maternal inflammation during pregnancy may affect fetal brain development, the role of mitochondria has received little attention. In the current review the role of mitochondria as a potential mediator of the association between MIA during pregnancy and offspring brain development and risk for psychiatric disorders will be proposed. As a basis for this postulation convergent evidence is presented supporting the obligatory role of mitochondria in brain development, the role of mitochondria as mediators and initiators of inflammatory processes, and evidence of mitochondrial dysfunction in pre-clinical MIA exposure models and human neurodevelopmental disorders. Elucidating the role of mitochondria as a potential mediator of MIA-induced alterations in brain development and neurodevelopmental disease risk may not only provide new insight into the pathophysiology of mental health disorders that have their origins in exposure to infection/immune activation during pregnancy but may also offer new therapeutic targets.

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.

Prevalences of non-communicable diseases such as depression and a range of somatic diseases are continuously increasing requiring simple and inexpensive ways to identify high-risk individuals to target with predictive and preventive approaches. Using k-mean cluster analytics, in study 1, we identified biochemical clusters (based on C-reactive protein, interleukin-6, fibrinogen, cortisol, and creatinine) and examined their link to diseases. Analyses were conducted in a U.S. American sample (from Midlife in the United States study, N = 1,234) and validated in a Japanese sample (from Midlife in Japan study, N = 378). In study 2, we investigated the link of clusters to childhood maltreatment (CM). The three identified biochemical clusters included one cluster (with high inflammatory signaling and low cortisol and creatinine concentrations) indicating the highest disease burden. This high-risk cluster also reported the highest CM exposure. The current study demonstrates how biomarkers can be utilized to identify individuals with a high disease burden and thus, may help to target these high-risk individuals with tailored prevention/intervention, towards personalized medicine. Furthermore, our findings raise the question whether the found biochemical clusters have predictive character; as a tool to identify high-risk individuals enabling targeted prevention. The finding that CM was mostly prevalent in the high-risk cluster provides first hints that the clusters could indeed have predictive character and highlight CM as a central disease susceptibility factor and possibly as a leverage point for disease prevention/intervention.

BackgroundThe 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.Method177 women (N=42 Black (24%), n=135 white (76%)) with a singleton, intrauterine pregnancy provided 20mL 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.ResultsMaternal pro-inflammatory responsivity (LPS-stimulated IL-6) and GRR increased significantly across mid- and late gestation (adjusted β=0.157, p=0.007; β=0.627, p&nbsp

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-ɣ, 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 (β = -.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 (β = -.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.

Very preterm infants are at risk for cerebellar injury and impaired cerebellar growth with adverse neurodevelopmental outcome. Ultrasound through the mastoid fontanel (MF) with a curved-array or sector probe is the most established method for the sonographic examination of the cerebellum. The goal of our study was to examine the validity of transnuchal ultrasound through the foramen occipitale magnum (FOM) with a linear probe for monitoring postnatal cerebellar growth. Retrospective analysis of routine ultrasound scans through FOM and MF in 105 preterm infants born between 23 and 36 weeks of gestation with a birthweight of less than 1500 g. Diameters of the cerebellar hemispheres obtained through the two acoustic windows mastoid fontanel and foramen occipitale magnum showed high correlations (r's = 0.981 and 0.983, p's 0.001). Corrected gestational age was significantly associated with transverse cerebellar diameter (TCD) on the first scan (r = 0.908, p 0.001) as well as postnatal cerebellar growth (r = 0.920, p 0.001). Postnatal growth was slightly decreased resulting in cerebellar growth restriction on serial scans. Both associations exceeded the calculated ratio of TCD to head circumference (r = 0.657, p 0.001) and TCD to biparietal diameter with gestational age (r = 0.705, p 0.001). Transnuchal ultrasound is feasible for examination of the preterm cerebellum and improves image quality compared to scans through the MF with higher resolution at a very short distance. Monitoring cerebellar growth during early postnatal life via transnuchal ultrasound can help to identify children at high risk for neurodevelopmental impairment.ZIEL: Bei extrem Frühgeborenen besteht das Risiko für Kleinhirnschädigungen und für eine Beeinträchtigung des Kleinhirnwachstums mit nachteiligen Auswirkungen auf die neurologische Entwicklung. Ultraschall durch die Mastoid-Fontanelle (MF) mit einer gekrümmten Array- oder Sektorsonde ist die etablierteste Methode zur sonografischen Untersuchung des Kleinhirns. Ziel unserer Studie war es, die Validität von transnuchalem Ultraschall durch das Foramen occipitale magnum (FOM) mittels Linear-Schallkopf zur Überwachung des postnatalen Kleinhirnwachstums zu untersuchen. Retrospektive Analyse von Routine-Ultraschalluntersuchungen durch FOM und MF bei 105 Frühgeborenen zwischen 23 und 36 Schwangerschaftswochen mit einem Geburtsgewicht von weniger als 1500 g. Die Durchmesser der Kleinhirnhemisphären, die durch die beiden akustischen Fenster von MF und FOM gemessen wurden, zeigten hohe Korrelationen (r’s = 0,981 und 0,983; p 0,001). Das korrigierte Gestationsalter war signifikant mit dem transversalen Kleinhirndurchmesser (TCD) beim ersten Scan (r = 0,908; p 0,001) sowie dem postnatalen Kleinhirnwachstum (r = 0,920; p 0,001) assoziiert. Das postnatale Wachstum war leicht vermindert, was zu einer Einschränkung des Kleinhirnwachstums bei seriellen Scans führte. Beide Assoziationen übertrafen die berechnete Ratio von TCD zum Kopfumfang (r = 0,657; p 0,001) und von TCD zum biparietalen Durchmesser (r = 0,705; p 0,001) gegenüber dem Gestationsalter. Transnuchaler Ultraschall kann für die Untersuchung des Zerebellums des Frühgeborenen eingesetzt werden und verbessert, im Vergleich zu Aufnahmen durch die MF, die Bildqualität bei höherer Auflösung in sehr kurzer Distanz. Die Überwachung des Kleinhirnwachstums mittels transnuchalem Ultraschall in der frühpostnatalen Phase kann helfen, Kinder mit hohem Risiko für neurologische Entwicklungsstörungen zu identifizieren.

BackgroundStudies reporting accelerated ageing in children with affective disorders or maltreatment exposure have relied on algorithms for estimating epigenetic age derived from adult samples. These algorithms have limited validity for epigenetic age estimation during early development. We here use a pediatric buccal epigenetic (PedBE) clock to predict DNA methylation-based ageing deviation in children with and without internalizing disorder and assess the moderating effect of maltreatment exposure. We further conduct a gene set enrichment analysis to assess the contribution of glucocorticoid signaling to PedBE clock-based results.MethodDNA was isolated from saliva of 158 children [73 girls, 85 boys; mean age (SD)=4.25 (0.8) years] including children with internalizing disorder and maltreatment exposure. Epigenetic age was estimated based on DNA methylation across 94 CpGs of the PedBE clock. Residuals of epigenetic age regressed against chronological age were contrasted between children with and without internalizing disorder. Maltreatment was coded in 3 severity levels and entered in a moderation model. Genome-wide dexamethasone-responsive CpGs were derived from an independent sample and enrichment of these CpGs within the PedBE clock was identified.ResultsChildren with internalizing disorder exhibited significant acceleration of epigenetic ageing as compared to children without internalizing disorder (F1,147=6.67, p=.011). This association was significantly moderated by maltreatment severity (b=0.49, 95% CI [0.073, 0.909], t=2.322, p=.022). Children with internalizing disorder who had experienced maltreatment exhibited ageing acceleration relative to children with no internalizing disorder (1-2 categories: b=0.50, 95% CI [0.170, 0.821], t=3.008, p=.003; 3 or more categories: b=0.99, 95% CI [0.380, 1.593], t=3.215, p=.002). Children with internalizing disorder who were not exposed to maltreatment did not show epigenetic ageing acceleration. There was significant enrichment of dexamethasone-responsive CpGs within the PedBE clock (OR=4.36, p=1.65*10-6). Among the 94 CpGs of the PedBE clock, 18 (19%) were responsive to dexamethasone.ConclusionUsing the novel PedBE clock, we show that internalizing disorder is associated with accelerated epigenetic ageing in early childhood. This association is moderated by maltreatment severity and may, in part, be driven by glucocorticoids. Identifying developmental drivers of accelerated epigenetic ageing after maltreatment will be critical to devise early targeted interventions.

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.

Early adversity influences brain development and emerging behavioral phenotypes relevant for psychiatric disorders. Understanding the effects of adversity before and after conception on brain development has implications for contextualizing current public health crises and pervasive health inequities. The use of functional magnetic resonance imaging (fMRI) to study the brain at rest has shifted understanding of brain functioning and organization in the earliest periods of life. Here we review applications of this technique to examine effects of early life stress (ELS) on neurodevelopment in infancy, and highlight targets for future research. Building on the foundation of existing work in this area will require tackling significant challenges, including greater inclusion of often marginalized segments of society, and conducting larger, properly powered studies.

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 (β = −0.26, p = .019), but not with right hippocampal (β = −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., Highlights • Maternal perceived stress predicted smaller neonatal left hippocampal volume (HCV). • Neonatal left HCV was positively associated with infant social-emotional function. • Variation in HCV may mediate maternal stress-related effects on child mental health.

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-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). Results Higher 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. 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.

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

Context Variation in fetal liver blood flow influences fetal growth and postnatal body composition. Placental corticotrophin-releasing hormone has been implicated as a key mediator of placental-fetal perfusion. Objective To determine whether circulating levels of placental corticotrophin-releasing hormone across gestation are associated with variations in fetal liver blood flow. Design Prospective cohort study. Methods Fetal ultrasonography was performed at 30 weeks’ gestation to characterize fetal liver blood flow (quantified by subtracting ductus venosus flow from umbilical vein flow). Placental corticotrophin-releasing hormone was measured in maternal circulation at approximately 12, 20, and 30 weeks’ gestation. Multiple regression analysis was used to determine the proportion of variation in fetal liver blood flow explained by placental corticotrophin-releasing hormone. Covariates included maternal age, parity, pre-pregnancy body mass index, gestational weight gain, and fetal sex. Results A total of 79 uncomplicated singleton pregnancies were analyzed. Fetal liver blood flow was 68.4 ± 36.0 mL/min (mean ± SD). Placental corticotrophin-releasing hormone concentrations at 12, 20, and 30 weeks were 12.5 ± 8.1, 35.7 ± 24.5, and 247.9 ± 167.8 pg/mL, respectively. Placental corticotrophin-releasing hormone at 30 weeks, but not at 12 and 20 weeks, was significantly and positively associated with fetal liver blood flow at 30 weeks (r = 0.319; P = 0.004) and explained 10.4% of the variance in fetal liver blood flow. Conclusions Placental corticotrophin-releasing hormone in late gestation is a possible modulator of fetal liver blood flow and may constitute a biochemical marker in clinical investigations of fetal growth and body composition.

OBJECTIVES: Suboptimal diet quality has been reported in Hispanic pregnant women in the US, but the potential moderating role of maternal psychological state has not been considered. The aim of this study is to test whether maternal perceived stress in pregnancy moderates the association between ethnicity and the Dietary Inflammatory Index (DII), a validated marker of the inflammatory potential of the diet. METHODS: N = 195 pregnant women underwent detailed assessment of diet and psychological state at the beginning of the second trimester (mean(SD) = 13(1.7) weeks). Dietary intake data from 24-hr diet recalls on 3 non-consecutive days were used to compute a mean DII score. Ecological Momentary Assessment of psychological state was performed in ambulatory settings using an electronic diary, with multiple daily entries over 4 consecutive days, from which a mean composite Perceived Stress Score (PSS) was derived. Maternal age, socioeconomic status (SES) score and self-reported pre-pregnancy body mass index (BMI) were included as covariates in the analysis of the effects of PSS, ethnicity, and PSS*ethnicity interaction on DII score. RESULTS: Hispanic pregnant women (N = 87) had higher mean DII (0.56(1.81) vs −0.001(1.82), P = 0.034) and PSS scores (1.14(0.61) vs 1.00(0.55), P = 0.093) compared to women of non-Hispanic ethnicity (N = 108). Hispanic women were also younger (26.33(6.30) vs 28.62(4.76) years, P = 0.004) and of lower SES (2.67(0.83) vs 3.62(0.86), p =

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.

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.

Background Although 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. Methods 152 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. Results After 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. Conclusions Our 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.

To evaluate the association between prenatal stress and gestational weight gain (GWG). This 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. Among 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). Lower 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.

Understanding of the effects of in utero opioid exposure on neurodevelopment is a priority given the recent dramatic increase in opioid use among pregnant individuals. However, opioid abuse does not occur in isolation-pregnant individuals abusing opioids often have a significant history of adverse experiences in childhood, among other co-occurring factors. Understanding the specific pathways in which these frequently co-occurring factors may interact and cumulatively influence offspring brain development in utero represents a priority for future research in this area. We highlight maternal history of childhood adversity (CA) as one such co-occurring factor that is more prevalent among individuals using opioids during pregnancy and which is increasingly shown to affect offspring neurodevelopment through mechanisms beginning in utero. Despite the high incidence of CA history in pregnant individuals using opioids, we understand very little about the effects of comorbid prenatal opioid exposure and maternal CA history on fetal brain development. Here, we first provide an overview of current knowledge regarding effects of opioid exposure and maternal CA on offspring neurodevelopment that may occur during gestation. We then outline potential mechanistic pathways through which these factors might have interactive and cumulative influences on offspring neurodevelopment as a foundation for future research in this area.

This study included 168 and 85 mother–infant dyads from Asian and United States of America cohorts to examine whether a genomic profile risk score for major depressive disorder (GPRSMDD) moderates the association between antenatal maternal depressive symptoms (or socio-economic status, SES) and fetal neurodevelopment, and to identify candidate biological processes underlying such association. Both cohorts showed a significant interaction between antenatal maternal depressive symptoms and infant GPRSMDD on the right amygdala volume. The Asian cohort also showed such interaction on the right hippocampal volume and shape, thickness of the orbitofrontal and ventromedial prefrontal cortex. Likewise, a significant interaction between SES and infant GPRSMDD was on the right amygdala and hippocampal volumes and shapes. After controlling for each other, the interaction effect of antenatal maternal depressive symptoms and GPRSMDD was mainly shown on the right amygdala, while the interaction effect of SES and GPRSMDD was mainly shown on the right hippocampus. Bioinformatic analyses suggested neurotransmitter/neurotrophic signaling, SNAp REceptor complex, and glutamate receptor activity as common biological processes underlying the influence of antenatal maternal depressive symptoms on fetal cortico-limbic development. These findings suggest gene–environment interdependence in the fetal development of brain regions implicated in cognitive–emotional function. Candidate biological mechanisms involve a range of brain region-specific signaling pathways that converge on common processes of synaptic development.

Thyroid hormones (THs) play an obligatory role in many fundamental processes underlying brain development and maturation. The developing embryo/fetus is dependent on maternal supply of TH. The fetal thyroid gland does not commence TH synthesis until mid gestation, and the adverse consequences of severe maternal TH deficiency on offspring neurodevelopment are well established. Recent evidence suggests that even more moderate forms of maternal thyroid dysfunction, particularly during early gestation, may have a long-lasting influence on child cognitive development and risk of neurodevelopmental disorders. Moreover, these observed alterations appear to be largely irreversible after birth. It is, therefore, important to gain a better understanding of the role of maternal thyroid dysfunction on offspring neurodevelopment in terms of the nature, magnitude, time-specificity, and context-specificity of its effects. With respect to the issue of context specificity, it is possible that maternal stress and stress-related biological processes during pregnancy may modulate maternal thyroid function. The possibility of an interaction between the thyroid and stress systems in the context of fetal brain development has, however, not been addressed to date. We begin this review with a brief overview of TH biology during pregnancy and a summary of the literature on its effect on the developing brain. Next, we consider and discuss whether and how processes related to maternal stress and stress biology may interact with and modify the effects of maternal thyroid function on offspring brain development. We synthesize several research areas and identify important knowledge gaps that may warrant further study. The scientific and public health relevance of this review relates to achieving a better understanding of the timing, mechanisms and contexts of thyroid programing of brain development, with implications for early identification of risk, primary prevention and intervention.

Glucocorticoids (cortisol in humans) are the end product of the hypothalamic-pituitary-adrenocortical (HPA) axis and are proposed as a key mechanism for programming fetal brain development. The present prospective longitudinal study evaluates the association between prenatal maternal cortisol concentrations and child neurodevelopment. Participants included a low risk sample of 91 mother-child pairs. Prenatal maternal plasma cortisol concentrations were measured at 19 and 31 gestational weeks. Brain development and cognitive functioning were assessed when children were 6–9 years of age. Structural magnetic resonance imaging scans were acquired and cortical thickness was determined. Child cognitive functioning was evaluated using standardized measures (Wechsler Intelligence Scale for Children IV and Expressive Vocabulary Test, Second Edition). Higher maternal cortisol concentrations during the third trimester were associated with greater child cortical thickness primarily in frontal regions. No significant associations were observed between prenatal maternal cortisol concentrations and child cortical thinning. Elevated third trimester maternal cortisol additionally was associated with enhanced child cognitive performance. Findings in this normative sample of typically developing children suggest that elevated maternal cortisol during late gestation exert lasting benefits for brain development and cognitive functioning 6–9 years later. The benefits of fetal exposure to higher maternal cortisol during the third trimester for child neurodevelopment are consistent with the role cortisol plays in maturation of the human fetus. It is plausible that more extreme elevations in maternal cortisol concentrations late in gestation, as well as exposure to pharmacological levels of synthetic glucocorticoids, may have neurotoxic effects on the developing fetal brain.

Childhood obesity constitutes a major global public health challenge. A substantial body of evidence suggests that conditions and states experienced by the embryo/fetus in utero can result in structural and functional changes in cells, tissues, organ systems and homeostatic set points related to obesity. Furthermore, growing evidence suggests that maternal conditions and states experienced prior to conception, such as stress, obesity and metabolic dysfunction, may spill over into pregnancy and influence those key aspects of gestational biology that program offspring obesity risk. In this narrative review, we advance a novel hypothesis and life-span framework to propose that maternal exposure to childhood maltreatment may constitute an important and as-yet-underappreciated risk factor implicated in developmental programming of offspring obesity risk via the long-term psychological, biological and behavioral sequelae of childhood maltreatment exposure. In this context, our framework considers the key role of maternal-placental-fetal endocrine, immune and metabolic pathways and also other processes including epigenetics, oocyte mitochondrial biology, and the maternal and infant microbiomes. Finally, our paper discusses future research directions required to elucidate the nature and mechanisms of the intergenerational transmission of the effects of maternal childhood maltreatment on offspring obesity risk.

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.

Stress during pregnancy affects maternal health and well-being, as well as the health and well-being of the next generation, in part through the hypothalamic-pituitary-adrenal (HPA) axis. Although most studies have focused solely on proximal experiences (i.e., during the pregnancy) as sources of prenatal stress, there has been a recent surge in studies that examine maternal early life adversity as a source of stress system dysregulation during pregnancy. The current study of 178 pregnant women examined the association of economic and life stress experienced during two time periods (i.e., childhood and pregnancy) with maternal HPA axis activity during the third trimester of pregnancy. Findings indicated that a current annual income of less than $15,000 and greater childhood disadvantage were associated with a flatter diurnal cortisol slope. Childhood maltreatment, particularly sexual abuse, was associated with a higher cortisol awakening response (CAR), even when controlling for recent adversity. We found some evidence that past adversity moderates the relationship between current adversity and diurnal cortisol, specifically for economic adversity and waking cortisol. Overall, our findings indicate that early life stressors play an important and underappreciated role in shaping stress biology during pregnancy.

This review integrates scientific knowledge obtained over the past few decades on the biological mechanisms that contribute to the profound association between exposure to early adversity, including childhood trauma and prenatal stress, and the lifelong elevated risk to develop a broad range of diseases. We further discuss insights into gene-environment interactions moderating the association between early adversity and disease manifestation and we discuss the role of epigenetic and other molecular processes in the biological embedding of early adversity. Based on these findings, we propose potential mechanisms that may contribute to the intergenerational transmission of risk related to early adversity from the mother to the fetus. Finally, we argue that basic research knowledge on the biological embedding of early adversity must now be translated into novel intervention strategies that are mechanism-driven and sensitive to developmental timing. Indeed, to date, there are no diagnostic biomarkers of risk or mechanism-informed interventions that we can offer to victims of early adversity in order to efficiently prevent or reverse adverse health outcomes. Such translational efforts can be expected to have significant impact on both clinical practice and the public health system, and will promote precision medicine in pediatrics and across the lifespan.

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 (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. 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.

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 ± 2.8 weeks [S.D.]), mid (20.4 ± 1.5 weeks [S.D.]) and late (30.3 ± 1.3 weeks [S.D.]) gestation. Offspring brain MRI scans were acquired shortly after birth (N = 86, scan age = 3.7 ± 1.7 weeks [S.D.]) and again at 12-mo age (N = 32, scan age = 54.0 ± 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

Growing evidence supports an important role for the intrauterine environment in shaping fetal development and subsequent child health and disease risk. The fetal brain is particularly plastic, whereby even subtle changes in structure and function produced by in utero conditions can have long-term implications. Based on the consideration that conditions related to energy substrate and likelihood of survival to reproductive age are particularly salient drivers of fetal programming, maternal nutrition and stress represent the most commonly, but independently, studied factors in this context. However, the effects of maternal nutrition and stress are context dependent and may be moderated by one another. Studies examining the effects of the bidirectional nutrition-stress interplay in pregnancy on fetal programming of brain development are beginning to emerge in the literature. This review incorporates all currently available animal and human studies of this interplay and provides a synthesis and critical discussion of findings. Nine of the 10 studies included here assessed nutrition-stress interactions and offspring neurodevelopmental or brain development outcomes. Despite significant heterogeneity in study design and methodology, two broad patterns of results emerge to suggest that the effects of prenatal stress on various aspects of brain development may be mitigated by 1) higher fat diets or increased intake and/or status of specific dietary fats and 2) higher dietary intake or supplementation of targeted nutrients. The limitations of these studies are discussed, and recommendations are provided for future research to expand on this important area of fetal programming of brain development.

SummaryBackground Newborns exhibit substantial variation in gestational age-adjusted and sex-adjusted fat mass proportion. The antecedent characteristics of fetal body composition that are associated with newborn fat mass proportion are poorly understood. Objective The aim of this study was to determine whether a composite measure of fetal fat mass is prospectively associated with newborn adiposity. Methods In a longitudinal study of 109 low-risk pregnancies, fetal ultrasonography was performed at approximately 12, 20 and 30 weeks gestation. Estimated fetal adiposity (EFA) was derived by integrating cross-sectional arm and thigh per cent fat area and anterior abdominal wall thickness. Newborn per cent body fat was quantified by Dual Energy X-Ray Absorptiometry. The association between EFA and newborn per cent body fat was determined by multiple linear regression. Results After controlling for confounding factors, EFA at 30 weeks was significantly associated with newborn per cent body fat (standardized β = 0.41, p