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Objective: To investigate whether parenting or neonatal brain volumes mediate associations between prenatal social disadvantage (PSD) and cognitive/language abilities and whether these mechanisms vary by level of disadvantage., Study Design: Pregnant women were recruited prospectively from obstetric clinics in St Louis, Missouri. PSD encompassed access to social (eg, education) and material (eg, income to needs, health insurance, area deprivation, and nutrition) resources during pregnancy. Neonates underwent brain magnetic resonance imaging. Mother-child dyads (n = 202) returned at age 1 year for parenting observations and at age 2 years for cognition/language assessments (Bayley Scales of Infant and Toddler Development, Third Edition). Generalized additive and mediation models tested hypotheses., Results: Greater PSD associated nonlinearly with poorer cognitive/language scores. Associations between parenting and cognition/language were moderated by disadvantage, such that supportive and nonsupportive parenting behaviors related only to cognition/language in children with lesser PSD. Parenting mediation effects differed by level of disadvantage: both supportive and nonsupportive parenting mediated PSD-cognition/language associations in children with lesser disadvantage, but not in children with greater disadvantage. PSD-associated reductions in neonatal subcortical grey matter (β = 0.19; q = 0.03), white matter (β = 0.23; q = 0.02), and total brain volume (β = 0.18; q = 0.03) were associated with lower cognition, but did not mediate the associations between PSD and cognition., Conclusions: Parenting moderates and mediates associations between PSD and early cognition and language, but only in families with less social disadvantage. These findings, although correlational, suggest that there may be a critical threshold of disadvantage, below which mediating or moderating factors become less effective, highlighting the importance of reducing disadvantage as primary prevention., Competing Interests: Declaration of Competing Interest This study was funded by R01MH113883, K01MH122735, T32NS121881, and T32 MH100019 from the NIH, the March of Dimes Foundation, grant MI-II-2018-725 from the Children's Discovery Institute, grant P50 HD103525 from the Washington University Intellectual and Developmental Disability Research Center, and National Alliance for Research on Schizophrenia & Depression Young Investigator Grant 28521 from the Brain and Behavior Research Foundation, and grant KL2 TR00234. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Prenatal exposure to heightened maternal inflammation has been associated with adverse neurodevelopmental outcomes, including atypical brain maturation and psychiatric illness. In mothers experiencing socioeconomic disadvantage, immune activation can be a product of the chronic stress inherent to such environmental hardship. While growing preclinical and clinical evidence has shown links between altered neonatal brain development and increased inflammatory states in utero, the potential mechanism by which socioeconomic disadvantage differentially impacts neural-immune crosstalk remains unclear. In the current study, we investigated associations between socioeconomic disadvantage, gestational inflammation, and neonatal white matter microstructure in 320 mother-infant dyads over-sampled for poverty. We analyzed maternal serum levels of four cytokines (IL-6, IL-8, IL-10, TNF-α) over the course of pregnancy in relation to offspring white matter microstructure and socioeconomic disadvantage. Higher average maternal IL-6 was associated with very low socioeconomic status (SES; INR < 200% poverty line) and lower neonatal corticospinal fractional anisotropy (FA) and lower uncinate axial diffusivity (AD). No other cytokine was associated with SES. Higher average maternal IL-10 was associated with lower FA and higher radial diffusivity (RD) in corpus callosum and corticospinal tracts, higher optic radiation RD, lower uncinate AD, and lower FA in inferior fronto-occipital fasciculus and anterior limb of internal capsule tracts. SES moderated the relationship between average maternal TNF-α levels during gestation and neonatal white matter diffusivity. When these interactions were decomposed, the patterns indicated that this association was significant and positive among very low SES neonates, whereby TNF-α was inversely and significantly associated with inferior cingulum AD. By contrast, among the more advantaged neonates (lower-to-higher SES [INR ≥ 200% poverty line]), TNF-α was positively and significantly associated with superior cingulum AD. Taken together, these findings suggest that the relationship between prenatal cytokine exposure and white matter microstructure differs as a function of SES. These patterns are consistent with a scenario where gestational inflammation's effects on white matter development diverge depending on the availability of foundational resources in utero., (© 2024. The Author(s).)

Early life adversity (social disadvantage and psychosocial stressors) is associated with altered microstructure in fronto-limbic pathways important for socioemotional development. Understanding when these associations begin to emerge may inform the timing and design of preventative interventions. In this longitudinal study, 399 mothers were oversampled for low income and completed social background measures during pregnancy. Measures were analyzed with structural equation analysis resulting in two latent factors: social disadvantage (education, insurance status, income-to-needs ratio [INR], neighborhood deprivation, and nutrition) and psychosocial stress (depression, stress, life events, and racial discrimination). At birth, 289 healthy term-born neonates underwent a diffusion MRI (dMRI) scan. Mean diffusivity (MD) and fractional anisotropy (FA) were measured for the dorsal and inferior cingulum bundle (CB), uncinate, and fornix using probabilistic tractography in FSL. Social disadvantage and psychosocial stress were fitted to dMRI parameters using regression models adjusted for infant postmenstrual age at scan and sex. Social disadvantage, but not psychosocial stress, was independently associated with lower MD in the bilateral inferior CB and left uncinate, right fornix, and lower MD and higher FA in the right dorsal CB. Results persisted after accounting for maternal medical morbidities and prenatal drug exposure. In moderation analysis, psychosocial stress was associated with lower MD in the left inferior CB among the lower-to-higher socioeconomic status (SES) (INR ≥ 200%) group, but not the extremely low SES (INR < 200%) group. Increasing access to social welfare programs that reduce the burden of social disadvantage and related psychosocial stressors may be an important target to protect fetal brain development in fronto-limbic pathways.

Background: Maternal exposure to adversity during pregnancy has been found to affect infant brain development; however, the specific effect of prenatal crime exposure on neonatal brain connectivity remains unclear. Based on existing research, we hypothesized that living in a high-crime neighborhood during pregnancy would affect neonatal frontolimbic connectivity over and above other individual- and neighborhood-level adversity and that these associations would be mediated by maternal psychosocial stress., Methods: Participants included 399 pregnant women, recruited as part of the eLABE (Early Life Adversity, Biological Embedding, and Risk for Developmental Precursors of Mental Disorders) study. In the neonatal period, 319 healthy, nonsedated infants were scanned using resting-state functional magnetic resonance imaging (repetition time = 800 ms; echo time = 37 ms; voxel size = 2.0 × 2.0 × 2.0 mm 3 ; multiband = 8) on a Prisma 3T scanner and had at least 10 minutes of high-quality data. Crime data at the block group level were obtained from Applied Geographic Solution. Linear regressions and mediation models tested associations between crime, frontolimbic connectivity, and psychosocial stress., Results: Living in a neighborhood with high property crime during pregnancy was related to weaker neonatal functional connectivity between the thalamus-anterior default mode network (aDMN) (β = -0.15, 95% CI = -0.25 to -0.04, p = .008). Similarly, high neighborhood violent crime was related to weaker functional connectivity between the thalamus-aDMN (β = -0.16, 95% CI = -0.29 to -0.04, p = .01) and amygdala-hippocampus (β = -0.16, 95% CI = -0.29 to -0.03, p = .02), controlling for other types of adversity. Psychosocial stress partially mediated relationships between the thalamus-aDMN and both violent and property crime., Conclusions: These findings suggest that prenatal exposure to crime is associated with weaker neonatal limbic and frontal functional brain connections, providing another reason for targeted public policy interventions to reduce crime., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Importance: Exposure to early-life adversity alters the structural development of key brain regions underlying neurodevelopmental impairments. The association between prenatal exposure to adversity and brain structure at birth remains poorly understood., Objective: To examine whether prenatal exposure to maternal social disadvantage and psychosocial stress is associated with neonatal global and regional brain volumes and cortical folding., Design, Setting, and Participants: This prospective, longitudinal cohort study included 399 mother-infant dyads of sociodemographically diverse mothers recruited in the first or early second trimester of pregnancy and their infants, who underwent brain magnetic resonance imaging in the first weeks of life. Mothers were recruited from local obstetric clinics in St Louis, Missouri from September 1, 2017, to February 28, 2020., Exposures: Maternal social disadvantage and psychosocial stress in pregnancy., Main Outcomes and Measures: Confirmatory factor analyses were used to create latent constructs of maternal social disadvantage (income-to-needs ratio, Area Deprivation Index, Healthy Eating Index, educational level, and insurance status) and psychosocial stress (Perceived Stress Scale, Edinburgh Postnatal Depression Scale, Everyday Discrimination Scale, and Stress and Adversity Inventory). Neonatal cortical and subcortical gray matter, white matter, cerebellum, hippocampus, and amygdala volumes were generated using semiautomated, age-specific, segmentation pipelines., Results: A total of 280 mothers (mean [SD] age, 29.1 [5.3] years; 170 [60.7%] Black or African American, 100 [35.7%] White, and 10 [3.6%] other race or ethnicity) and their healthy, term-born infants (149 [53.2%] male; mean [SD] infant gestational age, 38.6 [1.0] weeks) were included in the analysis. After covariate adjustment and multiple comparisons correction, greater social disadvantage was associated with reduced cortical gray matter (unstandardized β = -2.0; 95% CI, -3.5 to -0.5; P = .01), subcortical gray matter (unstandardized β = -0.4; 95% CI, -0.7 to -0.2; P = .003), and white matter (unstandardized β = -5.5; 95% CI, -7.8 to -3.3; P < .001) volumes and cortical folding (unstandardized β = -0.03; 95% CI, -0.04 to -0.01; P < .001). Psychosocial stress showed no association with brain metrics. Although social disadvantage accounted for an additional 2.3% of the variance of the left hippocampus (unstandardized β = -0.03; 95% CI, -0.05 to -0.01), 2.3% of the right hippocampus (unstandardized β = -0.03; 95% CI, -0.05 to -0.01), 3.1% of the left amygdala (unstandardized β = -0.02; 95% CI, -0.03 to -0.01), and 2.9% of the right amygdala (unstandardized β = -0.02; 95% CI, -0.03 to -0.01), no regional effects were found after accounting for total brain volume., Conclusions and Relevance: In this baseline assessment of an ongoing cohort study, prenatal social disadvantage was associated with global reductions in brain volumes and cortical folding at birth. No regional specificity for the hippocampus or amygdala was detected. Results highlight that associations between poverty and brain development begin in utero and are evident early in life. These findings emphasize that preventive interventions that support fetal brain development should address parental socioeconomic hardships.

Background: A major challenge in prenatal drug exposure research concerns the balance of measurement quality with sample sizes necessary to address confounders. To inform the selection of optimal exposure measures for the HEALthy Brain and Child Development (HBCD) Study, we employed integrated analysis to determine how different methods used to characterize prenatal tobacco exposure influence the detection of exposure-related risk, as reflected in normal variations in birth weight., Methods: Participants were N = 2323 mother-infant dyads derived from 7 independent developmental cohorts harmonized on measures of exposure, outcome (birthweight), and covariates. We compared estimates of PTE-related effects on birthweight derived from linear regression models when PTE was categorized dichotomously based on any fetal exposure (30% exposed; 69% not exposed); versus categorically, based on common patterns of maternal smoking during pregnancy (never smoked 69%; quit smoking 16%; smoked intermittently 2%; smoked persistently 13%). We secondarily explored sex differences in PTE-birthweight associations across these categorization methods., Results: When PTE was categorized dichotomously, exposure was associated with a - 125-g difference in birthweight (95% C.I. -173.7 - -76.6, p < .0001). When PTE was characterized categorically based on maternal smoking patterns, however, exposure was associated with either no difference in birthweight if mothers quit smoking by the end of the first trimester (B = -30.6, 95% C.I. -88.7-27.4, p = .30); or a - 221.8 g difference in birthweight if mothers did not [95% C.I. (-161.7 to -282.0); p < .001]. Qualitative sex differences were also detected though PTE x sex interactions did not reach statistical significance. Maternal smoking cessation during pregnancy was associated with a 239.3 g increase in birthweight for male infants, and a 114.0 g increase in birthweight for females infants (p = .07)., Conclusions: Categorization of PTE based on patterns of maternal smoking rather than the presence or absence of exposure alone revealed striking nuances in estimates of exposure-related risk. The described method that captures both between-individual and within-individual variability in prenatal drug exposure is optimal and recommended for future developmental investigations such as the HBCD Study., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Importance: In light of increasing cannabis use among pregnant women, the US Surgeon General recently issued an advisory against the use of marijuana during pregnancy., Objective: To evaluate whether cannabis use during pregnancy is associated with adverse outcomes among offspring., Design, Setting, and Participants: In this cross-sectional study, data were obtained from the baseline session of the ongoing longitudinal Adolescent Brain and Cognitive Development Study, which recruited 11 875 children aged 9 to 11 years, as well as a parent or caregiver, from 22 sites across the United States between June 1, 2016, and October 15, 2018., Exposure: Prenatal cannabis exposure prior to and after maternal knowledge of pregnancy., Main Outcomes and Measures: Symptoms of psychopathology in children (ie, psychotic-like experiences [PLEs] and internalizing, externalizing, attention, thought, and social problems), cognition, sleep, birth weight, gestational age at birth, body mass index, and brain structure (ie, total intracranial volume, white matter volume, and gray matter volume). Covariates included familial (eg, income and familial psychopathology), pregnancy (eg, prenatal exposure to alcohol and tobacco), and child (eg, substance use) variables., Results: Among 11 489 children (5997 boys [52.2%]; mean [SD] age, 9.9 [0.6] years) with nonmissing prenatal cannabis exposure data, 655 (5.7%) were exposed to cannabis prenatally. Relative to no exposure, cannabis exposure only before (413 [3.6%]) and after (242 [2.1%]) maternal knowledge of pregnancy were associated with greater offspring psychopathology characteristics (ie, PLEs and internalizing, externalizing, attention, thought and, social problems), sleep problems, and body mass index, as well as lower cognition and gray matter volume (all |β| > 0.02; all false discovery rate [FDR]-corrected P < .03). Only exposure after knowledge of pregnancy was associated with lower birth weight as well as total intracranial volume and white matter volumes relative to no exposure and exposure only before knowledge (all |β| > 0.02; all FDR-corrected P < .04). When including potentially confounding covariates, exposure after maternal knowledge of pregnancy remained associated with greater PLEs and externalizing, attention, thought, and social problems (all β > 0.02; FDR-corrected P < .02). Exposure only prior to maternal knowledge of pregnancy did not differ from no exposure on any outcomes when considering potentially confounding variables (all |β| < 0.02; FDR-corrected P > .70)., Conclusions and Relevance: This study suggests that prenatal cannabis exposure and its correlated factors are associated with greater risk for psychopathology during middle childhood. Cannabis use during pregnancy should be discouraged.