Prenatal Cannabis Exposure and The Risk for Neuropsychiatric Anomalies in the Offspring: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the association between cannabis use during pregnancy and the risk for long-term neuropsychiatric pathology in the offspring. DATA SOURCES: MEDLINE, EMBASE, and Cochrane library databases were systematically searched until January 22, 2024, with no language or date restrictions. STUDY ELIGIBILITY CRITERIA: Studies were eligible for inclusion if they reported quantitative data on any long-term neuropsychiatric outcome in offspring whose mothers used cannabis during pregnancy for medical or recreational use, by any route and at any trimester, in comparison to offspring of women who abstained from cannabis use during pregnancy. All observational study designs were included in the analysis. STUDY APPRAISAL AND SYNTHESIS METHODS: A systematic review and meta-analysis were performed according to the PRISMA and MOOSE guidelines. The data was extracted independently by two reviewers. The following offspring outcomes were of interest: attention-deficit/ hyperactivity disorder (ADHD), autism spectrum disorder (ASD), depression, anxiety, psychotic disorders, as well as cannabis and other substance use. Odds ratios (OR) and 95% confidence intervals (CI) were pooled for each neuropsychiatric outcome in the offspring of women exposed to cannabis during pregnancy compared with non-exposed. Data were pooled using random-effects models. RESULTS: Eighteen eligible observational studies were included in the systematic review, and seventeen were included in the final quantitative analysis, representing 534,445 participants. After adjusting for confounders, the pooled OR for ADHD was 1.13 (95% CI 1.01-1.26); for ASD, the pooled OR was 1.04 (95% CI 0.74-1.46); for psychotic symptoms, the pooled OR was 1.29 (95% CI 0.97-1.72); for anxiety, the pooled OR was 1.34 (95% CI 0.79-2.29); for depression, the pooled OR was 0.72 (95% CI 0.11-4.57); and for offspring's cannabis use the pooled OR was 1.20 (95% CI 1.01-1.42). CONCLUSIONS: Prenatal cannabis exposure is not associated with an increased risk of ASD, psychotic symptoms, anxiety, or depression in offspring. However, it may slightly elevate the risk of ADHD and predispose offspring to cannabis consumption. Despite these findings, caution is warranted regarding cannabis use during pregnancy. Further research is imperative, especially given the increasing potency of cannabis in recent years.

Mapping Early Brain-Body Interactions: Associations of Fetal Heart Rate Variation with Newborn Brainstem, Hypothalamic, and Dorsal Anterior Cingulate Cortex Functional Connectivity.

The autonomic nervous system (ANS) regulates the body's physiology, including cardiovascular function. As the ANS develops during the second to third trimester, fetal heart rate variability (HRV) increases while fetal heart rate (HR) decreases. In this way, fetal HR and HRV provide an index of fetal ANS development and future neurobehavioral regulation. Fetal HR and HRV have been associated with child language ability and psychomotor development behavior in toddlerhood. However, their associations with postbirth autonomic brain systems, such as the brainstem, hypothalamus, and dorsal anterior cingulate cortex (dACC), have yet to be investigated even though brain pathways involved in autonomic regulation are well established in older individuals. We assessed whether fetal HR and HRV were associated with the brainstem, hypothalamic, and dACC functional connectivity in newborns. Data were obtained from 60 pregnant individuals (ages 14-42) at 24-27 and 34-37 weeks of gestation using a fetal actocardiograph to generate fetal HR and HRV. During natural sleep, their infants (38 males and 22 females) underwent a fMRI scan between 40 and 46 weeks of postmenstrual age. Our findings relate fetal heart indices to brainstem, hypothalamic, and dACC connectivity and reveal connections with widespread brain regions that may support behavioral and emotional regulation. We demonstrated the basic physiologic association between fetal HR indices and lower- and higher-order brain regions involved in regulatory processes. This work provides the foundation for future behavioral or physiological regulation research in fetuses and infants.

Associations between individual and structural level racism and gestational age at birth in the Nulliparous Pregnancy Outcomes Study: Monitoring mothers-to-be.

The purpose of this study was to investigate the associations between multilevel racism and gestational age at birth among nulliparous non-Hispanic Black, non-Hispanic White and Hispanic women. We conducted a secondary analysis of data of the nuMoM2b Study (2010-2013) to examine the associations between individual and structural-level experiences of racism and discrimination and gestational age at birth among nulliparous women (n=7,732) at eight sites across the U.S. Measures included the individual Experiences of Discrimination (EOD) scale and the Index of Concentration (ICE) at the Extremes to measure structural racism. After adjustment,we observed a significant individual and structural racism interaction on gestational length (p=0.03). In subgroup analyses, we found that among these with high EOD scores, women who were from households concentrated in the more privileged group had significantly longer gestations (ß = 1.07, 95% CI: 0.24, 1.90). Women who reported higher EOD scores and more economic privilege had longer gestations, demonstrating the moderating effect of ICE as a measure of structural racism. In conclusion, ICE may represent a modifiable factor in the prevention of adverse birth outcomes in nulliparas.

Co-location of specialized mental health services in an intimate partner violence advocacy organization.

Historically, services for intimate partner violence (IPV) survivors predominantly focused on advocacy, resulting in service gaps for IPV survivors who need mental health care. When mental health services are offered, there are several barriers that limit treatment engagement. To address these gaps, a novel, integrated care model, comprised of psychiatrists, clinical psychologists, and social workers were embedded into the five New York City (NYC) Family Justice Centers (FJCs), to provide free co-located mental health care to adult survivors of IPV alongside the existing advocacy, social, and legal services. This article reports on the evaluation of the Health + Hospitals Family Justice Center Mental Health Program (FJCMHP) via: (i) seven focus groups with FJC clients and staff and Health + Hospitals (H+H) clinicians; and (ii) de-identified online surveys completed by 53 FJC clients and 130 FJC staff. Clients reported increased access to care, with 67.2% seeing a mental health clinician within two weeks of a request, and improvement in symptom relief, including sleep, mood, irritability, reduction in thoughts of self-harm, improved relationships with others, especially their children, and improved self-efficacy in parenting skills. Additionally, FJC staff reported satisfaction with the FJCMHP model, and increased understanding of clients' mental health needs. The evaluation results highlight the feasibility and tolerability of integrated mental health services in a non-medical setting. The evaluation also identifies areas for improvement, as well as the strengths of an integrated, multidisciplinary mental health service program for IPV survivors co-located in a non-medical, advocacy setting.

Maternal childhood trauma and observed maternal care behaviors with 4-month-old infants.

OBJECTIVE: To examine the relationship between maternal childhood trauma and early maternal caregiving behaviors (MCB). METHOD: Participants included 74 mother-infant dyads (maternal age 20-45 years; ethnicity 64.9% Latina) from a longitudinal pregnancy cohort study. Maternal childhood trauma was assessed during pregnancy with the childhood trauma questionnaire (CTQ). Observed mother-infant interactions at infant age 4 months were coded utilizing modified Ainsworth's MCB rating scales that assessed a range of behaviors (e.g., acceptance, soothing, and delight) which we analyze grouped together and will summarize using the term "maternal sensitivity." Linear regressions tested the associations between maternal childhood trauma and MCB. Primary analyses examined the relationships of MCB with (a) any maternal childhood trauma (moderate or greater exposure to physical abuse, sexual abuse, emotional abuse, physical neglect, and/or emotional neglect) and (b) cumulative childhood trauma. Secondary analyses examined the relationships between each type of childhood trauma and MCB. RESULTS: Exposure to childhood trauma was not associated with MCB (p = .88). Cumulative childhood trauma score was associated with lower scores on MCB (ß = -1.88, p < .05). Emotional abuse and emotional neglect were individually associated with lower scores on MCB (ß = -1.78, p = .04; ß = -1.55, p = .04, respectively). Physical abuse, sexual abuse, and physical neglect were not associated with MCB. CONCLUSIONS: Many mothers exposed to childhood trauma may be resilient to negative effects on parenting behaviors, while specific experiences of childhood trauma (emotional abuse, emotional neglect, and cumulative childhood trauma) may predict less sensitive early parenting behaviors. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The effects of experience of discrimination and acculturation during pregnancy on the developing offspring brain.

The experience of ethnic, racial, and structural inequalities is increasingly recognized as detrimental to health, and early studies suggest that its experience in pregnant mothers may affect the developing fetus. We characterized discrimination and acculturation experiences in a predominantly Hispanic sample of pregnant adolescent women and assessed their association with functional connectivity in their neonate's brain. We collected self-report measures of acculturation, discrimination, maternal distress (i.e., perceived stress, childhood trauma, and depressive symptoms), and socioeconomic status in 165 women. Then, we performed a data-driven clustering of acculturation, discrimination, perceived stress, depressive symptoms, trauma, and socioeconomic status variables during pregnancy to determine whether discrimination or acculturation clustered into distinct factors. Discrimination and acculturation styles loaded onto different factors from perceived stress, depressive symptoms, trauma, and socioeconomic status, suggesting that they were distinct from other factors in our sample. We associated these data-driven maternal phenotypes (discrimination and acculturation styles) with measures of resting-state functional MRI connectivity of the infant amygdala (n = 38). Higher maternal report of assimilation was associated with weaker connectivity between their neonate's amygdala and bilateral fusiform gyrus. Maternal experience of discrimination was associated with weaker connectivity between the amygdala and prefrontal cortex and stronger connectivity between the amygdala and fusiform of their neonate. Cautiously, the results may suggest a similarity to self-contained studies with adults, noting that the experience of discrimination and acculturation may influence amygdala circuitry across generations. Further prospective studies are essential that consider a more diverse population of minoritized individuals and with a comprehensive assessment of ethnic, racial, and structural factors.

Prenatal Exposure to Nonpersistent Environmental Chemicals and Postpartum Depression.

Importance: Postpartum depression (PPD) affects up to 20% of childbearing individuals, and a significant limitation in reducing its morbidity is the difficulty in modifying established risk factors. Exposure to synthetic environmental chemicals found in plastics and personal care products, such as phenols, phthalates, and parabens, are potentially modifiable and plausibly linked to PPD and have yet to be explored. Objective: To evaluate associations of prenatal exposure to phenols, phthalates, parabens, and triclocarban with PPD symptoms. Design, Setting, and Participants: This was a prospective cohort study from 5 US sites, conducted from 2006 to 2020, and included pooled data from 5 US birth cohorts from the National Institutes of Health Environmental Influences on Child Health Outcomes (ECHO) consortium. Participants were pregnant individuals with data on urinary chemical concentrations (phenols, phthalate metabolites, parabens, or triclocarban) from at least 1 time point in pregnancy and self-reported postnatal depression screening assessment collected between 2 weeks and 12 months after delivery. Data were analyzed from February to May 2022. Exposures: Phenols (bisphenols and triclosan), phthalate metabolites, parabens, and triclocarban measured in prenatal urine samples. Main Outcomes and Measures: Depression symptom scores were assessed using the Edinburgh Postnatal Depression Scale (EPDS) or the Center for Epidemiologic Studies Depression Scale (CES-D), harmonized to the Patient-Reported Measurement Information System (PROMIS) Depression scale. Measures of dichotomous PPD were created using both sensitive (EPDS scores ≥10 and CES-D scores ≥16) and specific (EPDS scores ≥13 and CES-D scores ≥20) definitions. Results: Among the 2174 pregnant individuals eligible for analysis, nearly all (>99%) had detectable levels of several phthalate metabolites and parabens. PPD was assessed a mean (SD) of 3 (2.5) months after delivery, with 349 individuals (16.1%) and 170 individuals (7.8%) screening positive for PPD using the sensitive and specific definitions, respectively. Linear regression results of continuous PROMIS depression T scores showed no statistically significant associations with any chemical exposures. Models examining LMW and HMW phthalates and di (2-ethylhexyl) phthalate had estimates in the positive direction whereas all others were negative. A 1-unit increase in log-transformed LMW phthalates was associated with a 0.26-unit increase in the PROMIS depression T score (95% CI, -0.01 to 0.53; P = .06). This corresponded to an odds ratio (OR) of 1.08 (95% CI, 0.98-1.19) when modeling PPD as a dichotomous outcome and using the sensitive PPD definition. HMW phthalates were associated with increased odds of PPD (OR, 1.11; 95% CI, 1.00-1.23 and OR, 1.10; 95% CI, 0.96-1.27) for the sensitive and specific PPD definitions, respectively. Sensitivity analyses produced stronger results. Conclusions and Relevance: Phthalates, ubiquitous chemicals in the environment, may be associated with PPD and could serve as important modifiable targets for preventive interventions. Future studies are needed to confirm these observations.

Editorial: In Utero Exposure to Maternal Affective Symptoms: Prenatal Programming of Child Psychopathology Is Independent of Shared Genes of Risk.

The womb is an influential first home. This felicitous phrase is attributed to David Barker, often called the father of the late 20th century developmental origins of health and disease hypothesis, which asserts that maternal experiences during pregnancy are biologically transmitted to, and embedded in, the fetus, shaping child development.1 Specifically, Barker focused on maternal inadequate nutrition as a key in utero exposure to which the fetus biologically adapts, leading to biologically programmed changes, meaning long-lasting, that potentially put the offspring at risk for future metabolic diseases.1 In more recent developmental origins of health and disease publications, the impact of affective symptoms in pregnant women-defined broadly to include perceived stress, depression, and anxiety-on fetal and infant brain and behavior development has been identified. There is a third pathway for the familial inheritance of risk for psychiatric illness beyond shared genes and compromised parental postnatal mental health and caregiving: prenatal programming of risk for psychopathology originating in mental health symptoms of mothers.1 However, despite decades of experimental preclinical studies demonstrating maternal prenatal stress predicting altered offspring outcomes,2 the alternative interpretation-that shared genes of risk account for the outcomes-has remained challenging to disprove for human studies, perhaps particularly when the mother reports on her own and her child's mental health (a common study design further addressed below). In this context, the article by Chen et al.3 using polygenic risk scores to provide a single measure of genomic risk for complex phenotypes reports rigorous and original results demonstrating effects of maternal affective symptoms on child psychiatric outcomes while controlling for genomic risk.

Sociocultural Risk and Resilience in the Context of Adverse Childhood Experiences.

Importance: Knowledge about childhood resilience factors relevant in circumstances of marginalization and high numbers of adverse childhood experiences (ACEs) can improve interventions. Objective: To identify sociocultural resilience factors in childhood that are associated with better young adult mental health in the context of ACEs. Design, Setting, and Participants: This cohort study examined 4 waves of data from the Boricua Youth Study, which included Puerto Rican children from the South Bronx, New York, and San Juan, Puerto Rico. Participants were aged 5 to 17 years at waves 1 through 3 (2000-2003) and aged 15 to 29 years at wave 4 (2013-2017). Linear and logistic regression models tested the associations of 7 childhood resilience factors and their interaction with ACEs on young adult mental health outcomes. Data were analyzed from June 2021 to October 2023. Main Outcomes and Measures: Perceived stress, major depressive disorder and/or generalized anxiety disorder (MDD/GAD), and substance use disorder (SUD) in young adulthood. Results: Among a total 2004 participants, the mean (SD) age at wave 4 was 22.4 (2.9) years; 1024 participants (51.1%) were female, and 980 (48.9%) were male. Positive parent-child relationships and nonparental adult support during childhood were associated with both lower perceived stress (ß = -0.14; SE = 0.02; P < .001; ß = -0.08; SE = 0.03; P = .003, respectively) and lower odds of MDD/GAD (adjusted odds ratio [aOR], 0.84; 95% CI, 0.73 to 0.97; aOR = 0.81; 95% CI, 0.69 to 0.95, respectively) in young adulthood. Maternal warmth reported during childhood was also associated with lower young adult perceived stress (ß = -0.11; SE = 0.02; P < .001). None of the resilience factors were associated with SUD. The resilience factors familism, friendships, and family religiosity were not associated with any of the mental health outcomes. ACEs were associated with poorer mental health outcomes; however, none of the resilience factors exhibited interactions consistent with being protective for ACEs. Unexpectedly, higher family religiosity was associated with more perceived stress in the presence of higher ACEs. Conclusions and Relevance: The results of this study suggest that promoting positive relationships with adults during childhood may reduce later young adulthood stress and MDD/GAD. However, there is still a need to identify sociocultural childhood protective factors for ACEs. Caution should be taken in assuming what resilience factors are relevant for a given group, as higher family religiosity (one postulated resilience factor) was unexpectedly associated with a stronger, rather than a weaker, association between ACEs and perceived stress in young adulthood.

Prenatal sleep health and risk of offspring ADHD symptomatology and associated phenotypes: a prospective analysis of timing and sex differences in the ECHO cohort.

Background: Sleep difficulties are common in pregnancy, yet poor prenatal sleep may be related to negative long-term outcomes for the offspring, including risk for attention-deficit/hyperactivity disorder (ADHD). Existing studies are few and have not examined timing of exposure effects or offspring sex moderation. We thus aimed to test the hypotheses that poor sleep health in pregnancy is associated with increased risk for ADHD symptoms and offspring sleep problems at approximately 4 years of age. Methods: Participants were 794 mother-child dyads enrolled in the NIH Environmental Influences on Child Health Outcomes Study (ECHO). Participants self-reported on sleep duration, quality, and disturbances during pregnancy and on children's ADHD symptoms and sleep problems on the Child Behaviour Checklist. Findings: Pregnant participants were 32.30 ± 5.50 years and children were 46% female. 44 percent of pregnant participants identified as Hispanic or Latine; 49% identified as White. Second-trimester sleep duration was associated with offspring ADHD symptoms (b = -0.35 [95% CI = -0.57, -0.13], p = 0.026), such that shorter duration was associated with greater symptomatology. Poorer sleep quality in the second trimester was also associated with increased ADHD symptomatology (b = 0.66 [95% CI = 0.18, 1.14], p = 0.037). Greater sleep disturbances in the first trimester were associated with offspring ADHD (b = 1.03 [95% CI = 0.32, 1.03], p = 0.037) and in the second trimester with sleep problems (b = 1.53 [95% CI = 0.42, 2.92], p = 0.026). We did not document substantial offspring sex moderation. Interpretation: Poor prenatal sleep health, particularly quality and duration in the second trimester, may be associated with offspring risk of neurodevelopmental disorders and sleep problems in early childhood. Further research is needed to understand mechanisms, yet our study suggests that prenatal maternal sleep may be a modifiable target for interventions aimed at optimizing early neurodevelopment. Funding: NIH grants U2COD023375, U24OD023382, U24OD023319, UH3OD023320, UH3OD023305, UH3OD023349, UH3OD023313, UH3OD023272, UH3OD023328, UH3OD023290, K08MH117452 and NARSAD Young Investigator Award 28545.

Stress and DNA Methylation of Blood Leukocytes among Pregnant Latina Women.

Latinas experience physical and psychological stressors in pregnancy leading to increased morbidity and higher risk for adverse birth outcomes. Epigenetic changes, including DNA methylation (DNAm), have been proposed as markers to create more refined risk stratification, yet few of these studies have examined these changes in Latinas. We conducted a secondary analysis of stored blood leukocytes of Latina women (n = 58) enrolled in a larger National Institutes of Health funded R01 project (2011-2016). We examined DNAm on eight candidate stress genes to compare physically and psychologically stressed participants to healthy (low stress) participants. We found unique CpGs that were differentially methylated in stressed women early- and mid-pregnancy compared to the healthy group, though none remained significant after FDR correction. Both physical and psychological stress were associated with hypomethylation at two consecutive CpG sites on NR3C1 in early pregnancy and one CpG site on NR3C1 in mid-pregnancy before adjustment. Stress was also associated with hypomethylation at two CpG sites on FKBP5 in early and mid-pregnancy but were no longer significant after FDR adjustment. Though we did not find statistically significant differences in DNAm during pregnancy between stressed and healthy women in this sample, signals were consistent with previous findings. Future work in larger samples should further examine the associations between stress and DNAm in pregnancy as this mechanism may explain underlying perinatal health inequities.

Maternal childhood maltreatment: associations to offspring brain volume and white matter connectivity.

The deleterious effects of adversity are likely intergenerational, such that one generation's adverse experiences can affect the next. Epidemiological studies link maternal adversity to offspring depression and anxiety, possibly via transmission mechanisms that influence offspring fronto-limbic connectivity. However, studies have not thoroughly disassociated postnatal exposure effects nor considered the role of offspring sex. We utilized infant neuroimaging to test the hypothesis that maternal childhood maltreatment (CM) would be associated with increased fronto-limbic connectivity in infancy and tested brain-behavior associations in childhood. Ninety-two dyads participated (32 mothers with CM, 60 without; 52 infant females, 40 infant males). Women reported on their experiences of CM and non-sedated sleeping infants underwent MRIs at 2.44 ± 2.74 weeks. Brain volumes were estimated via structural MRI and white matter structural connectivity (fiber counts) via diffusion MRI with probabilistic tractography. A subset of parents (n = 36) reported on children's behaviors at age 5.17 ± 1.73 years. Males in the maltreatment group demonstrated greater intra-hemispheric fronto-limbic connectivity (b = 0.96, p= 0.008, [95%CI 0.25, 1.66]), no differences emerged for females. Fronto-limbic connectivity was related to somatic complaints in childhood only for males (r = 0.673, p = 0.006). Our findings suggest that CM could have intergenerational associations to offspring brain development, yet mechanistic studies are needed.

Maternal prenatal immune activation associated with brain tissue microstructure and metabolite concentrations in newborn infants.

Importance: Few translational human studies have assessed the association of prenatal maternal immune activation with altered brain development and psychiatric risk in newborn offspring. Objective: To identify the effects of maternal immune activation during the 2nd and 3rd trimesters of pregnancy on newborn brain metabolite concentrations, tissue microstructure, and longitudinal motor development. Design: Prospective longitudinal cohort study conducted from 2012 - 2017. Setting: Columbia University Irving Medical Center and Weill Cornell Medical College. Participants: 76 nulliparous pregnant women, aged 14 to 19 years, were recruited in their 2nd trimester, and their children were followed through 14 months of age. Exposure: Maternal immune activation indexed by maternal interleukin-6 and C-reactive protein in the 2nd and 3rd trimesters of pregnancy. Main Outcomes and Measures: The main outcomes included (1) newborn metabolite concentrations, measured as N-acetylaspartate, creatine, and choline using Magnetic Resonance Spectroscopy; (2) newborn fractional anisotropy and mean diffusivity measured using Diffusion Tensor Imaging; and (3) indices of motor development assessed prenatally and postnatally at ages 4- and 14-months. Results: Maternal interleukin-6 and C-reactive protein levels in the 2nd or 3rd trimester were significantly positively associated with the N-acetylaspartate, creatine, and choline concentrations in the putamen, thalamus, insula, and anterior limb of the internal capsule. Maternal interleukin-6 was associated with fractional anisotropy in the putamen, insula, thalamus, precuneus, and caudate, and with mean diffusivity in the inferior parietal and middle temporal gyrus. C-reactive protein was associated with fractional anisotropy in the thalamus, insula, and putamen. Regional commonalities were found across imaging modalities, though the direction of the associations differed by immune marker. In addition, a significant positive association was observed between offspring motor development and both maternal interleukin-6 and C-reactive protein (in both trimesters) prenatally and 4- and 14-months of age. Conclusions and Relevance: Using a healthy sample, these findings demonstrate that levels of maternal immune activation in mid- to late pregnancy associate with tissue characteristics in newborn brain regions primarily supporting motor integration/coordination and behavioral regulation and may lead to alterations in motor development.

Intergenerational transmission of cognitive control capacity among children at risk for depression.

A maternal history of major depressive disorder (MDD) is a well-known risk factor for depression in offspring. However, the mechanism through which familial risk is transmitted remains unclear. Cognitive control alterations are common in MDD, and thus, the current study investigated whether altered control capacity is transmitted intergenerationally, and whether it then contributes to the developmental pathways through which depression is passed from mothers to children. We recruited children (N = 65) ages 4-10-years-old, of which 47.7 % (n = 31) reported a maternal history of MDD, and their biological mother (N = 65). Children performed a child-friendly Go/NoGo task while electroencephalography (EEG) data were recorded, and mothers performed a Flanker task. Children exhibited heightened sensitivity to error versus correct responses, which was characterized by an error-related negativity (ERN), error positivity (Pe) as well as prominent delta and frontal midline theta (FMT) oscillations. Interestingly, worse maternal performance on the Flanker task associated with an increased Go/NoGo error rate and a smaller ERN and Pe in children. However, there was no association between maternal or child control indices with child depression symptoms. Our results suggest a familial influence of cognitive control capacity in mother-child dyads, but it remains unclear whether this confers risk for depressive symptoms in children. Further research is necessary to determine whether alterations in cognitive control over time may influence symptom development in at-risk children.

Stage 2 Registered Report: Epigenetic Intergenerational Transmission: Mothers' Adverse Childhood Experiences and DNA Methylation.

OBJECTIVE: Individual differences in risk for mental disorders over the lifespan are shaped by forces acting before the individual is born-in utero, but likely even earlier, during the mother's own childhood. The environmental epigenetics hypothesis proposes that sustained effects of environmental conditions on gene expression are mediated by epigenetic mechanisms. Recent human studies have shown that adversities in childhood are correlated with DNA methylation (DNAm) in adulthood. In the current study, we tested the following pre-registered hypotheses: Mothers' adverse childhood experiences (ACEs) are correlated with DNAm in peripheral blood during pregnancy (hypothesis 1) and in cord blood samples from newborn infants (hypothesis 2), and women's depression and anxiety symptoms during pregnancy mediate the association between mothers' ACE exposure and prenatal/neonatal DNA methylation (hypothesis 3). METHOD: Data were from the Avon Longitudinal Study of Parents and Children Accessible Resource for Integrated Epigenomic Studies substudy. Women provided retrospective self-reports during pregnancy of ACE exposure. We conducted an epigenome-wide association study testing whether mothers' ACE exposure, cumulative score (0-10), was associated with DNAm in maternal antenatal blood and infant cord blood in more than 450,000 CpG (point on DNA sequence where cytosine and guanine base pairs are linked by a phosphate, where methylation usually occurs) sites on the Illumina 450K BeadChip. Analyses for cord blood were separated by infant sex, a pre-registered analysis. RESULTS: Hypothesis 1: In 896 mother-infant pairs with available methylation and ACE exposure data, there were no significant associations between mothers' ACE score and DNAm from antenatal peripheral blood, after controlling for covariates. Hypothesis 2: In infant cord blood, there were 5 CpG sites significantly differentially methylated in relation to mothers' ACEs (false discovery rate [FDR] < .05), but only in male offspring. Effect sizes were medium, with partial eta squared values ranging from 0.060 to 0.078. CpG sites were in genes related to mitochondrial function and neuronal development in the cerebellum. Hypothesis 3: There was no mediation by maternal anxiety/depression symptoms found between mothers' ACEs score and DNAm in the significant CpG sites in male cord blood. Mediation was not tested in antenatal peripheral blood, because no direct association between mothers' ACE score and antenatal peripheral blood was found. CONCLUSION: Our results show that mothers' ACE exposure is associated with DNAm in male offspring, supporting the notion that DNAm could be a marker of intergenerational biological embedding of mothers' childhood adversity. STUDY REGISTRATION INFORMATION: Epigenetic Intergenerational Transmission: Mothers' Adverse Childhood Experiences and DNA Methylation; https://doi.org/10.1016/j.jaac.2020.03.008.

Intergenerational Transmission of Maternal Childhood Maltreatment Prior to Birth: Effects on Human Fetal Amygdala Functional Connectivity.

OBJECTIVE: Childhood maltreatment (CM) is a potent risk factor for developing psychopathology later in life. Accumulating research suggests that the influence is not limited to the exposed individual but may also be transmitted across generations. In this study, we examine the effect of CM in pregnant women on fetal amygdala-cortical function, prior to postnatal influences. METHOD: Healthy pregnant women (N = 89) completed fetal resting-state functional magnetic resonance imaging (rsfMRI) scans between the late second trimester and birth. Women were primarily from low socioeconomic status households with relatively high CM. Mothers completed questionnaires prospectively evaluating prenatal psychosocial health and retrospectively evaluating trauma from their own childhood. Voxelwise functional connectivity was calculated from bilateral amygdala masks. RESULTS: Connectivity of the amygdala network was relatively higher to left frontal areas (prefrontal cortex and premotor) and relatively lower to right premotor area and brainstem areas in fetuses of mothers exposed to higher CM. These associations persisted after controlling for maternal socioeconomic status, maternal prenatal distress, measures of fetal motion, and gestational age at the time of scan and at birth. CONCLUSION: Pregnant women's experiences of CM are associated with offspring brain development in utero. The strongest effects were found in the left hemisphere, potentially indicating lateralization of the effects of maternal CM on the fetal brain. This study suggests that the time frame of the Developmental Origins of Health and Disease research should be extended to exposures from mothers' childhood, and indicates that the intergenerational transmission of trauma may occur prior to birth.

Association of Gestational Diabetes Mellitus and Perinatal Maternal Depression with Early Childhood Behavioral Problems: An Environmental Influences on Child Health Outcomes (ECHO) Study.

This study examined the association of gestational diabetes mellitus (GDM), prenatal, and postnatal maternal depressive symptoms with externalizing, internalizing, and autism spectrum problems on the Preschool Child Behavior Checklist in 2379 children aged 4.12 ± 0.60 (48% female; 47% White, 32% Black, 15% Mixed Race, 4% Asian, <2% American Indian/Alaskan Native, <2% Native Hawaiian; 23% Hispanic). Data were collected from the NIH Environmental influences on Child Health Outcomes (ECHO) Program from 2009-2021. GDM, prenatal, and postnatal maternal depressive symptoms were each associated with increased child externalizing and internalizing problems. GDM was associated with increased autism behaviors only among children exposed to perinatal maternal depressive symptoms above the median level. Stratified analyses revealed a relation between GDM and child outcomes in males only.