Associations of radiologic characteristics of the neonatal hypothalamus with early life adiposity gain.

BACKGROUND: The mediobasal hypothalamus (MBH) is a key brain area for regulation of energy balance. Previous neuroimaging studies suggest that T2-based signal properties indicative of cellular inflammatory response (gliosis) are present in adults and children with obesity, and predicts greater adiposity gain in children at risk of obesity. OBJECTIVES/METHODS: The current study aimed to extend this concept to the early life period by considering if, in full-term healthy neonates (up to n = 35), MRI evidence of MBH gliosis is associated with changes in early life (neonatal to six months) body fat percentage measured by DXA. RESULTS: In this initial study, neonatal T2 signal in the MBH was positively associated with six-month changes in body fat percentage. CONCLUSION: This finding supports the notion that underlying processes in the MBH may play a role in early life growth and, by extension, childhood obesity risk.

Segmenting hypothalamic subunits in human newborn magnetic resonance imaging data.

Preclinical evidence suggests that inter-individual variation in the structure of the hypothalamus at birth is associated with variation in the intrauterine environment, with downstream implications for future disease susceptibility. However, scientific advancement in humans is limited by a lack of validated methods for the automatic segmentation of the newborn hypothalamus. N = 215 healthy full-term infants with paired T1-/T2-weighted MR images across four sites were considered for primary analyses (mean postmenstrual age = 44.3 ± 3.5 weeks, nmale /nfemale = 110/106). The outputs of FreeSurfer's hypothalamic subunit segmentation tools designed for adults (segFS) were compared against those of a novel registration-based pipeline developed here (segATLAS) and against manually edited segmentations (segMAN) as reference. Comparisons were made using Dice Similarity Coefficients (DSCs) and through expected associations with postmenstrual age at scan. In addition, we aimed to demonstrate the validity of the segATLAS pipeline by testing for the stability of inter-individual variation in hypothalamic volume across the first year of life (n = 41 longitudinal datasets available). SegFS and segATLAS segmentations demonstrated a wide spread in agreement (mean DSC = 0.65 ± 0.14 SD; range = {0.03-0.80}). SegATLAS volumes were more highly correlated with postmenstrual age at scan than segFS volumes (n = 215 infants; RsegATLAS 2 = 65% vs. RsegFS 2 = 40%), and segATLAS volumes demonstrated a higher degree of agreement with segMAN reference segmentations at the whole hypothalamus (segATLAS DSC = 0.89 ± 0.06 SD; segFS DSC = 0.68 ± 0.14 SD) and subunit levels (segATLAS DSC = 0.80 ± 0.16 SD; segFS DSC = 0.40 ± 0.26 SD). In addition, segATLAS (but not segFS) volumes demonstrated stability from near birth to ~1 years age (n = 41; R2 = 25%; p < 10-3 ). These findings highlight segATLAS as a valid and publicly available (https://github.com/jerodras/neonate_hypothalamus_seg) pipeline for the segmentation of hypothalamic subunits using human newborn MRI up to 3 months of age collected at resolutions on the order of 1 mm isotropic. Because the hypothalamus is traditionally understudied due to a lack of high-quality segmentation tools during the early life period, and because the hypothalamus is of high biological relevance to human growth and development, this tool may stimulate developmental and clinical research by providing new insight into the unique role of the hypothalamus and its subunits in shaping trajectories of early life health and disease.

A global multicohort study to map subcortical brain development and cognition in infancy and early childhood.

The human brain grows quickly during infancy and early childhood, but factors influencing brain maturation in this period remain poorly understood. To address this gap, we harmonized data from eight diverse cohorts, creating one of the largest pediatric neuroimaging datasets to date focused on birth to 6 years of age. We mapped the developmental trajectory of intracranial and subcortical volumes in ∼2,000 children and studied how sociodemographic factors and adverse birth outcomes influence brain structure and cognition. The amygdala was the first subcortical volume to mature, whereas the thalamus exhibited protracted development. Males had larger brain volumes than females, and children born preterm or with low birthweight showed catch-up growth with age. Socioeconomic factors exerted region- and time-specific effects. Regarding cognition, males scored lower than females; preterm birth affected all developmental areas tested, and socioeconomic factors affected visual reception and receptive language. Brain-cognition correlations revealed region-specific associations.

Maternal Perinatal Stress Trajectories and Negative Affect and Amygdala Development in Offspring.

OBJECTIVE: Maternal psychological stress during pregnancy is a common risk factor for psychiatric disorders in offspring, but little is known about how heterogeneity of stress trajectories during pregnancy affect brain systems and behavioral phenotypes in infancy. This study was designed to address this gap in knowledge. METHODS: Maternal anxiety, stress, and depression were assessed at multiple time points during pregnancy in two independent low-risk mother-infant cohorts (N=115 and N=2,156). Trajectories in maternal stress levels in relation to infant negative affect were examined in both cohorts. Neonatal amygdala resting-state functional connectivity MRI was examined in a subset of one cohort (N=60) to explore the potential relationship between maternal stress trajectories and brain systems in infants relevant to negative affect. RESULTS: Four distinct trajectory clusters, characterized by changing patterns of stress over time, and two magnitude clusters, characterized by severity of stress, were identified in the original mother-infant cohort (N=115). The magnitude clusters were not associated with infant outcomes. The trajectory characterized by increasing stress in late pregnancy was associated with blunted development of infant negative affect. This relationship was replicated in the second, larger cohort (N=2,156). In addition, the trajectories that included increasing or peak maternal stress in late pregnancy were related to stronger neonatal amygdala functional connectivity to the anterior insula and the ventromedial prefrontal cortex in the exploratory analysis. CONCLUSIONS: The trajectory of maternal stress appears to be important for offspring brain and behavioral development. Understanding heterogeneity in trajectories of maternal stress and their influence on infant brain and behavioral development is critical to developing targeted interventions.

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.

Sleep across the first year of life is prospectively associated with brain volume in 12-months old infants.

Objective: Longer sleep duration in infancy supports cognitive and affective functioning - likely through effects on brain development. From childhood through old age, there is evidence for a close link between sleep and brain volume. However, little is known about the association between sleep duration and brain volume in infancy, a developmental period of unprecedented brain maturation. This study aimed to close this gap by assessing sleep duration across the first year of life and gray and white matter volume at 12-mo age. Method: Infant sleep duration trajectories across the first year of life were based on maternal reports at 1, 3, 6, 9, and 12 months of age. Infant specific trajectories were generated by running a logarithmic regression for each infant and residualizing the resulting slopes for their intercept. Structural magnetic resonance imaging (MRI) scans were acquired at 12-mo age. Gray and white matter volume estimates were residualized for intracranial volume and age at scan. Results: Data to calculate sleep trajectories was available for 112 infants. Overall, sleep duration decreased over the course of the first year of life and was best described by a logarithmic function. Of these infants, data on brain volume was available for 45 infants at 12-mo age. Infants whose sleep duration decreased less during the first year of life relative to their intercept had, on average, greater white matter volume (ß = .36, p = .02). Furthermore, average sleep duration across the first year of life, and sleep duration specifically at 6 and 9 months were positively associated with white matter volume. Sleep duration during the first year of life was not significantly associated with gray matter volume at 12-mo age. Conclusion: Sufficient sleep duration may benefit infant white matter development - possibly by supporting myelination. The fact that sleep duration was not associated with gray matter volume is in line with preclinical studies suggesting that sleep may be crucial for the balance between synaptogenesis and synaptic pruning but not necessarily relate to a net increase in gray matter volume. Supporting sleep during periods of rapid brain development and intervening in case of sleep problems may have long-term benefits for cognitive function and mental health.

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.

Maternal exposure to childhood maltreatment and adverse birth outcomes.

Exposure to traumatic events during pregnancy may influence pregnancy and birth outcomes. Growing evidence suggests that exposure to traumatic events well before pregnancy, such as childhood maltreatment (CM), also may influence the course of pregnancy and risk of adverse birth outcomes. We aimed to estimate associations between maternal CM exposure and small-for-gestational-age birth (SGA) and preterm birth (PTB) in a diverse US sample, and to examine whether common CM-associated health and behavioral sequelae either moderate or mediate these associations. The Measurement of Maternal Stress (MOMS) Study was a prospective cohort study that enrolled 744 healthy English-speaking participants ≥ 18 years with a singleton pregnancy, who were < 21 weeks at enrollment, between 2013 and 2015. CM was measured via the Childhood Trauma Questionnaire (CTQ) and participants above the moderate/severe cut-off for any of the five childhood abuse and neglect scales were assigned to the CM-exposed group. Common CM-associated health (obesity, depressive symptoms, hypertensive disorders) and behavioral (substance use) sequelae were obtained from standardized questionnaires and medical records. The main outcomes included PTB (gestational age < 37 weeks at birth) and SGA (birthweight < 10%ile for gestational age) abstracted from the medical record. Multivariable logisitic regression was used to test associations between CM, sequeale, and birth outcomes, and both moderation and mediation by CM-related sequelae were tested. Data were available for 657/744 participants. Any CM exposure was reported by 32% of participants. Risk for SGA birth was 61% higher among those in the CM group compared to the non-CM group (14.1% vs. 7.6%), and each subsequent form of CM that an individual was exposed to corresponded with a 27% increased risk for SGA (aOR 1.27, 95% CI 1.05, 1.53). There was no significant association between CM and PTB (9.3% vs. 13.0%, aOR 1.07, 95% CI 0.58, 1.97). Of these sequelae only hypertensive disorders were associated with both CM and SGA and hypertensive disorders of pregnancy did not mediate the association between CM and SGA. Our findings indicate that maternal CM exposure is associated with increased risk for SGA birth and highlight the importance of investigating the mechanisms whereby childhood adversity sets the trajectory for long-term and intergenerational health issues.

Maximal telomerase activity capacity (mTAC) underlies the link between the cortisol response to stress and telomere length.

Exposure to various forms of stress has been associated with shorter telomere length (TL). However, the molecular underpinnings of this effect are poorly understood. Based on an understanding of the key role of the reverse transcriptase enzyme telomerase in regulating TL, and building upon our previous work in developing and validating a biomarker of the capacity of cells to express telomerase (maximal telomerase activity capacity (mTAC)), we examine here the hypotheses that mTAC is positively associated with TL and that the effect of stress on TL is mediated by individual differences in mTAC. In a proof-of-principle study of 28 healthy women and men we quantified the cortisol response to a standardized stress challenge, the Trier Social Stress Test (TSST), and we concurrently assessed peripheral blood mononuclear cell (PBMC) mTAC and TL. Our results indicated that higher mTAC levels were associated with longer TL (r = 0.50, p = .01). Moreover, mediational analysis suggested that the effect of the cortisol stress response on TL was mediated by mTAC (completely standardized ß = -0.17, bootstrap CI95 %: -0.44 to -0.01). Thus, our findings support the premise that individual differences in the capacity of cells to up-regulate telomerase may represent a key mediator in the link between stress and TL.

Maternal pre-pregnancy body mass index is associated with newborn offspring hypothalamic mean diffusivity: a prospective dual-cohort study.

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

Intergenerational transmission of the effects of maternal exposure to childhood maltreatment in the USA: a retrospective cohort study.

BACKGROUND: Childhood maltreatment is associated with adverse health outcomes and this risk can be transmitted to the next generation. We aimed to investigate the association between exposure to maternal childhood maltreatment and common childhood physical and mental health problems, neurodevelopmental disorders, and related comorbidity patterns in offspring. METHODS: We conducted a retrospective cohort study using data from the Environmental influences on Child Health Outcomes (ECHO) Program, which was launched to investigate the influence of early life exposures on child health and development in 69 cohorts across the USA. Eligible mother-child dyads were those with available data on maternal childhood maltreatment exposure and at least one child health outcome measure (autism spectrum disorder, attention-deficit hyperactivity disorder [ADHD], internalising problems, obesity, allergy, and asthma diagnoses). Maternal history of childhood maltreatment was obtained retrospectively from the Adverse Childhood Experiences or Life Stressor Checklist questionnaires. We derived the prevalence of the specified child health outcome measures in offspring across childhood and adolescence by harmonising caregiver reports and other relevant sources (such as medical records) across cohorts. Child internalising symptoms were assessed using the Child Behavior Checklist. Associations between maternal childhood maltreatment and childhood health outcomes were measured using a series of mixed-effects logistic regression models. Covariates included child sex (male or female), race, and ethnicity; maternal and paternal age; maternal education; combined annual household income; maternal diagnosis of depression, asthma, ADHD, allergy, or autism spectrum disorder; and maternal obesity. Two latent class analyses were conducted: to characterise patterns of comorbidity of child health outcomes; and to characterise patterns of co-occurrence of childhood maltreatment subtypes. We then investigated the association between latent class membership and maternal childhood maltreatment and child health outcomes, respectively. FINDINGS: Our sample included 4337 mother-child dyads from 21 longitudinal cohorts (with data collection initiated between 1999 and 2016). Of 3954 mothers in the study, 1742 (44%) had experienced exposure to abuse or neglect during their childhood. After adjustment for confounding, mothers who experienced childhood maltreatment were more likely to have children with internalising problems in the clinical range (odds ratio [OR] 2·70 [95% CI 1·95-3·72], p<0·0001), autism spectrum disorder (1·70 [1·13-2·55], p=0·01), ADHD (2·09 [1·63-2·67], p<0·0001), and asthma (1·54 [1·34-1·77], p<0·0001). In female offspring, maternal childhood maltreatment was associated with a higher prevalence of obesity (1·69 [1·17-2·44], p=0·005). Children of mothers exposed to childhood maltreatment were more likely to exhibit a diagnostic pattern characterised by higher risk for multimorbidity. Exposure to multiple forms of maltreatment across all subtypes of maternal childhood maltreatment was associated with the highest risk increases for most offspring health outcomes, suggesting a dose-response relationship. INTERPRETATION: Our findings suggest that maternal childhood maltreatment experiences can be a risk factor for disease susceptibility in offspring across a variety of outcomes and emphasise the need for policies focusing on breaking the intergenerational transmission of adversity. FUNDING: Environmental influences on Child Health Outcomes Program, Office of the Director, National Institutes of Health.

Maternal insulin resistance in pregnancy is associated with fetal fat deposition: findings from a longitudinal study.

BACKGROUND: Newborns exhibit substantial variation in fat mass accretion over gestation. These individual differences in newborn adiposity extend into infancy and childhood and relate to subsequent risk of obesity and metabolic dysregulation. Maternal glucose homeostasis in pregnancy has been proposed as an underlying mechanism; however, the timing in gestation when maternal glucose regulation influences the progression of fetal fat deposition remain unclear. OBJECTIVE: This study aimed to investigate the cross-sectional and longitudinal association of maternal insulin resistance in early, mid, and late pregnancy with fetal fat deposition in uncomplicated pregnancies. We hypothesized that maternal insulin resistance at early, mid, and late gestation is positively associated with fetal fat deposition, and that the magnitude of the association is greater for the mid and late gestation measures than for the early gestation measure. STUDY DESIGN: In a longitudinal study of 137 low-risk pregnancies, a fasting maternal blood sample was obtained and fetal ultrasonography was performed at ≈ 12, 20, and 30 weeks' gestation. Maternal insulin resistance was quantified using the homeostasis model assessment of insulin resistance (fasting insulin×fasting glucose/405). Estimated fetal adiposity was calculated by integrating measurements of cross-sectional arm and thigh percentage fat area and anterior abdominal wall thickness. The associations between maternal homeostasis model assessment of insulin resistance and estimated fetal adiposity and estimated fetal weight were determined by multiple linear regression adjusted for potential confounding factors including maternal age, parity, race and ethnicity, prepregnancy body mass index, gestational weight gain per week, fetal sex, and gestational age at assessments. RESULTS: Maternal homeostasis model assessment of insulin resistance at ≈ 12, 20, and 30 weeks was 2.79±1.79 (±standard deviation), 2.78±1.54, and 3.76±2.30, respectively. Homeostasis model assessment of insulin resistance at 20 weeks was positively associated with estimated fetal adiposity at 20 weeks (r=0.261; P=.005). Homeostasis model assessment of insulin resistance at 20 weeks (r=0.215; P=.011) and 30 weeks (r=0.285; P=.001) were also positively associated with estimated fetal adiposity at 30 weeks. These relationships remained significant after adjustment for confounding factors. There was no significant correlation between homeostasis model assessment of insulin resistance and estimated fetal weight at 20 and 30 weeks' gestation. CONCLUSION: In low-risk pregnancies, maternal insulin resistance at mid and late but not early pregnancy is significantly associated with fetal adiposity but not with fetal weight. Maternal insulin resistance in mid-gestation could provide a basis for risk identification and interventions that target child adiposity.

The association between history of prenatal loss and maternal psychological state in a subsequent pregnancy: an ecological momentary assessment (EMA) study.

BACKGROUND: Prenatal loss which occurs in approximately 20% of pregnancies represents a well-established risk factor for anxiety and affective disorders. In the current study, we examined whether a history of prenatal loss is associated with a subsequent pregnancy with maternal psychological state using ecological momentary assessment (EMA)-based measures of pregnancy-specific distress and mood in everyday life. METHOD: This study was conducted in a cohort of N = 155 healthy pregnant women, of which N = 40 had a history of prenatal loss. An EMA protocol was used in early and late pregnancy to collect repeated measures of maternal stress and mood, on average eight times per day over a consecutive 4-day period. The association between a history of prenatal loss and psychological state was estimated using linear mixed models. RESULTS: Compared to women who had not experienced a prior prenatal loss, women with a history of prenatal loss reported higher levels of pregnancy-specific distress in early as well as late pregnancy and also were more nervous and tired. Furthermore, in the comparison group pregnancy-specific distress decreased and mood improved from early to late pregnancy, whereas these changes across pregnancy were not evident in women in the prenatal loss group. CONCLUSION: Our findings suggest that prenatal loss in a prior pregnancy is associated with a subsequent pregnancy with significantly higher stress and impaired mood levels in everyday life across gestation. These findings have important implications for designing EMA-based ambulatory, personalized interventions to reduce stress during pregnancy in this high-risk group.

Maternal free fatty acid concentration during pregnancy is associated with newborn hypothalamic microstructure in humans.

OBJECTIVE: This study tested the hypothesis, in a prospective cohort study design, that maternal saturated free fatty acid (sFFA) concentration during pregnancy is prospectively associated with offspring (newborn) hypothalamic (HTH) microstructure and to explore the functional relevance of this association with respect to early-childhood body fat percentage (BF%). METHODS: In N = 94 healthy newborns (born mean 39.3 [SD 1.5] weeks gestation), diffusion-weighted magnetic resonance imaging was performed shortly after birth (25.3 [12.5] postnatal days), and a subgroup (n = 37) underwent a dual-energy x-ray absorptiometry scan in early childhood (4.7 [SD 0.7] years). Maternal sFFA concentration during pregnancy was quantified in fasting blood samples via liquid chromatography-mass spectrometry. Infant HTH microstructural integrity was characterized using mean diffusivity (MD). Multiple linear regression was used to test the association between maternal sFFA and HTH MD, accounting for newborn sex, age at scan, mean white matter MD, and image quality. Multiple linear regression models also tested the association between HTH MD and early-childhood BF%, accounting for breastfeeding status. RESULTS: Maternal sFFA during pregnancy accounted for 8.3% of the variation in newborn HTH MD (ß-std = 0.25; p = 0.006). Furthermore, newborn HTH MD prospectively accounted for 15% of the variation in early-childhood BF% (ß-std = 0.32; p = 0.019). CONCLUSIONS: These findings suggest that maternal overnutrition during pregnancy may influence the development of the fetal hypothalamus, which, in turn, may have clinical relevance for childhood obesity risk.

Transmission of the adverse consequences of childhood maltreatment across generations: Focus on gestational biology.

Childhood maltreatment (CM) has well-established consequences for the mental and physical health of the exposed individual. Accumulating evidence now suggests that the detrimental sequelae of CM may be transmitted from one generation to the next, thereby extending the long-term ramifications of early adverse experiences and constituting intergenerational continuity in poor health outcomes. In this review, the current state of knowledge on the intergenerational effects of maternal exposure to CM is summarized and transmission pathways are discussed, specifically direct as well as indirect pathways involving variation in gestational biology. The review begins with a definition of CM and an overview of the clinical and neurobiological consequences of CM in the exposed and the offspring generation. The intrauterine period and variation in gestational biology are identified as a potential time window and a mechanism of transmission, respectively. Furthermore, a summary of the available evidence supporting both direct and indirect effects of gestational biological variation on offspring development is included. Finally, knowledge gaps and challenges in the investigation of the role of gestational biological mechanisms in the intergenerational transmission of CM sequelae are addressed and considerations for future study designs along with experiences from our current studies are provided.

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.

Rate of Gestational Weight Gain and Glucose-Insulin Metabolism Among Hispanic Pregnant Women With Overweight and Obesity.

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

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.

Fetal programming of human energy homeostasis brain networks: Issues and considerations.

In this paper, we present a transdisciplinary framework and testable hypotheses regarding the process of fetal programming of energy homeostasis brain circuitry. Our model proposes that key aspects of energy homeostasis brain circuitry already are functional by the time of birth (with substantial interindividual variation); that this phenotypic variation at birth is an important determinant of subsequent susceptibility for energy imbalance and childhood obesity risk; and that this brain circuitry exhibits developmental plasticity, in that it is influenced by conditions during intrauterine life, particularly maternal-placental-fetal endocrine, immune/inflammatory, and metabolic processes and their upstream determinants. We review evidence that supports the scientific premise for each element of this formulation, identify future research directions, particularly recent advances that may facilitate a better quantification of the ontogeny of energy homeostasis brain networks, highlight animal and in vitro-based approaches that may better address the determinants of interindividual variation in energy homeostasis brain networks, and discuss the implications of this formulation for the development of strategies targeted towards the primary prevention of childhood obesity.