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.

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.

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

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

Psychological stress and cortisol during pregnancy: An ecological momentary assessment (EMA)-Based within- and between-person analysis.

BACKGROUND: Although the linkage between psychological stress and cortisol is believed to mediate the association of stress with health outcomes, several studies have been unable to demonstrate this association. We suggest this inability may be a consequence of limitations in the measurement approach and/or reliance on analytic strategies that focus on associations across, rather than within individuals. The link between psychological stress and cortisol is of particular interest in the context of pregnancy and fetal development. Using an ecological momentary assessment (EMA) design, we examined the association between psychological stress and cortisol at the between- and the within-person level. METHODS: 152 participants completed a 4-day long EMA protocol serially in early, mid and late pregnancy to provide momentary stress appraisals (average of 150 measures/subject) and saliva samples (average of 55 samples/subject) for quantification of cortisol. The association between stress and cortisol was estimated using linear mixed models. RESULTS: After accounting for the effects of key determinants of variation in cortisol, momentary stress was significantly and positively associated with cortisol at the within-person level (B = .030, p = .031), but not at the between-person level. No association was evident for traditional retrospective measures of stress with cortisol at either the between- or the within-person level. CONCLUSIONS: Our study highlights the value of EMA methods and linear mixed-modeling approaches in linking maternal psychological and physiological states across pregnancy. These findings may have important implications for the development of personalized risk identification and "just-in-time" intervention strategies to optimize maternal and child health.

Maternal subjective social standing is related to inflammation during pregnancy.

BACKGROUND: The association of socioeconomic status (SES) with health and disease risk is well established. Low-grade inflammation represents a key pathway believed to underlie this association. Previous research has suggested that subjective social standing (SSS) is more consistently associated with health outcomes than objective measures of SES such as income and education. Given the importance of maternal inflammatory state in a wide array of pregnancy, birth and fetal/child developmental and health outcomes, we examine here the independent association of maternal SSS relative to objective SES with pro-inflammatory state during pregnancy. METHODS: We conducted a longitudinal study of an ethnically diverse sample of 250 pregnant women with 3 study visits in early, mid and late gestation. We obtained objective measures of SES (income, education), and SSS with reference to the community and to the nation using the MacArthur Scale of Subjective Social Status. At each study visit, a composite maternal pro-inflammatory score was derived from circulating levels of inflammatory markers (IL-6, CRP, TNF-α). RESULTS: In hierarchical linear models, SSS but not objective SES was significantly and negatively associated with maternal inflammatory state. Moreover, the relationship between SSS and inflammatory state remained significant after accounting for objective SES. SSS with reference to the community was a stronger predictor of inflammatory state than SSS with reference to the nation. DISCUSSION: Our finding adds to the scientific literature on SSS and health, highlights the importance of including SSS measures in this context, and supports future research on the relative role and biological pathways by which SSS may impact pregnancy, birth and fetal/child development and health.

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

BACKGROUND: The process of acculturation (post-migration acquisition of host culture and/or loss of heritage culture) likely represents a key mediator of the observed post-migration decline in health that is evident among immigrant populations such as Mexican Americans. The observations that migrant health declines progressively as not only a function of length of stay in the U.S. but also across generations, and that this inter-generational decline in health is evident as early as at the time of birth itself, supports the concept of fetal programming of acculturation's effects. However, the underlying mechanisms remain to be elucidated. Inflammation during pregnancy represents a candidate pathway of particular interest for 2 reasons: it represents a key biological mediator of the psychosocial and/or behavioral sequelae of acculturation on health, and it represents a key pathway by which maternal states and conditions during pregnancy may influence fetal development and subsequent birth and child developmental and health outcomes. Therefore, the aim of this study was to examine the relationship between acculturation and inflammation across pregnancy in a population of Mexican-American women. Specifically, we tested the hypothesis that a higher level of acculturation is associated with higher circulating concentrations across pregnancy of the pro-inflammatory cytokine interleukin-6 (IL-6). METHODS: 75 pregnant first- or second-generation Mexican-American women constituted the study population. Acculturation was quantified using a commonly-used and previously validated measure - the Acculturation Rating Scale for Mexican Americans (ARSMA). Maternal blood samples were collected during early, mid and late pregnancy for analysis of circulating IL-6 concentrations. RESULTS: Hierarchical linear models indicated a significantly and positive main effect of acculturation on IL-6 concentrations across pregnancy after adjusting for key covariates including gestational age(s) at blood sampling, socioeconomic status, pre-pregnancy BMI, and presence of obstetric risk conditions. CONCLUSIONS: Maternal inflammation during pregnancy may represent a biological pathway of interest in the context of the inter-generational effects of acculturation from a mother to her as-yet-unborn child.

Prenatal and Postnatal Mother-to-Child Transmission of Acculturation's Health Effects in Hispanic Americans.

BACKGROUND: Hispanic Americans consistently exhibit an intergenerational increase in the prevalence of many noncommunicable chronic physical and mental disorders. METHODS: We review and synthesize evidence suggesting that a constellation of prenatal and postnatal factors may play crucial roles in explaining this trend. We draw from relevant literature across several disciplines, including epidemiology, anthropology, psychology, medicine (obstetrics, neonatology), and developmental biology. RESULTS: Our resulting model is based on evidence that among women, the process of postmigration cultural adjustment (i.e., acculturation) is associated, during pregnancy and after delivery, with psychological and behavioral states that can affect offspring development in ways that may alter susceptibility to noncommunicable chronic disease risk in subsequent-generation Hispanic Americans. We propose one integrated process model that specifies the biological, behavioral, psychological, and sociocultural pathways by which maternal acculturation may influence the child's long-term health. We synthesize evidence from previous studies to describe how acculturation among Hispanic American mothers is associated with alterations to the same biobehavioral systems known to participate in the processes of prenatal and postnatal developmental programming of disease risk. In this manner, we focus on the concepts of biological and cultural mother-to-child transmission across the prenatal and postnatal life phases. We critique and draw from previous hypotheses that have sought to explain this phenomenon (of declining health across generations). We offer recommendations for examining the transgenerational effects of acculturation. CONCLUSION: A life course model with a greater focus on maternal health and well-being may be key to understanding transgenerational epidemiological trends in minority populations, and interventions that promote women's wellness may contribute to the elimination or reduction of health disparities.

Acculturation and health: the moderating role of socio-cultural context.

Acculturation represents an important construct for elucidating the determinants and consequences of health disparities in minority populations. However, the processes and mechanisms underlying acculturation's effects on health are largely undetermined and warrant further study. We integrate concepts from anthropology and statistics to describe the role of sociocultural context as a putative modifier of the relationship between acculturation and health. Sociocultural context may influence the extent to which exposure to host culture leads to internalization of host cultural orientation, and may influence the extent to which acculturation leads to stress and adoption of unhealthy behaviors. We focus on specific aspects of sociocultural context: (1) neighborhood ethno-cultural composition; (2) discrimination; (3) discrepancy between origin and host environments; (4) discrepancy between heritage and host cultures; (5) origin group, host group, and individual attitudes towards assimilation; (6) variation in targets of assimilation within host community; (7) public policy and resources; (8) migration selection bias. We review and synthesize evidence for these moderation effects among first- and later-generation immigrants, refugees, and indigenous populations. Furthermore, we propose best-practices data-collection and statistical-analysis methods for this purpose, in order to improve our understanding of the complex, multilevel aspects of the relationship between acculturation and health.

Effects of Antenatal Maternal Depressive Symptoms and Socio-Economic Status on Neonatal Brain Development are Modulated by Genetic Risk.

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

Racial or Ethnic and Socioeconomic Inequalities in Adherence to National Dietary Guidance in a Large Cohort of US Pregnant Women.

BACKGROUND: The significance of periconceptional nutrition for optimizing offspring and maternal health and reducing social inequalities warrants greater understanding of diet quality among US women. OBJECTIVE: Our objective was to evaluate racial or ethnic and education inequalities in periconceptional diet quality and sources of energy and micronutrients. DESIGN: Cross-sectional analysis of data from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be cohort. PARTICIPANTS AND SETTING: Nulliparous women (N=7,511) were enrolled across eight US medical centers from 2010 to 2013. MAIN OUTCOME MEASURES: A semiquantitative food frequency questionnaire assessing usual dietary intake during the 3 months around conception was self-administered during the first trimester. Diet quality, measured using the Healthy Eating Index-2010 (HEI-2010), and sources of energy and micronutrients were the outcomes. STATISTICAL ANALYSES: Differences in diet quality were tested across maternal racial or ethnic and education groups using F tests associated with analysis of variance and χ2 tests. RESULTS: HEI-2010 score increased with higher education, but the increase among non-Hispanic black women was smaller than among non-Hispanic whites and Hispanics (interaction P value <0.0001). For all groups, average scores for HEI-2010 components were below recommendations. Top sources of energy were sugar-sweetened beverages, pasta dishes, and grain desserts, but sources varied by race or ethnicity and education. Approximately 34% of energy consumed was from empty calories (the sum of energy from added sugars, solid fats, and alcohol beyond moderate levels). The primary sources of iron, folate, and vitamin C were juices and enriched breads. CONCLUSIONS: Diet quality is suboptimal around conception, particularly among women who are non-Hispanic black, Hispanic, or who had less than a college degree. Diet quality could be improved by substituting intakes of refined grains and foods empty in calories with vegetables, peas and beans (legumes), seafood, and whole grains.

Assessment of acculturation in minority health research.

Acculturation represents an important construct in the context of health disparities. Although several studies have reported relationships between various aspects of acculturation and health in minority populations, crucial inconsistencies remain. One likely reason for these inconsistencies may relate to limitations in the conceptualization and operationalization of acculturation, particularly in the context of health research. The acculturation construct underwent major conceptual and operational change when it was adapted from anthropology to psychology, and we argue another major shift is now required for use of this construct in health research. Issues include determining whether acculturation measures should focus on an individual's internal attitudes or overt behaviors; whether they should characterize cultural orientation status at a given point in time or change over time; whether measures should be culture-specific or more global in nature; how the issue of multiculturalism should be addressed; how measures can optimally incorporate multiple dimensions of acculturation; and whether proxy measures should be used. These issues are important in the context of health research because of their implications for determining the direct and indirect effects of cultural change on health-related biological and behavioral processes. We elaborate on and address each of these issues from a perspective that spans multiple disciplines across the biological and social sciences, and offer concrete recommendations with the ultimate goal of achieving a better understanding of the role of acculturation in minority health and health disparities.

Racial/Ethnic Disparities in Measures of Self-reported Psychosocial States and Traits during Pregnancy.

Background The aim of this study was to determine whether racial/ethnic differences in psychosocial measures, independent of economic status, exist among a large population of pregnant nulliparas. Methods Between October 2010 and September 2013, nulliparous women at eight U.S. medical centers were followed longitudinally during pregnancy and completed validated instruments to quantify several psychosocial domains: Cohen Perceived Stress Scale, trait subscale of the Spielberger Anxiety Inventory, Connor-Davidson Resilience Scale, Multidimensional Scale of Perceived Social Support, Krieger Racism Scale, Edinburgh Postnatal Depression Scale, and the Pregnancy Experience Scale. Scores were stratified and compared by self-reported race, ethnicity, and income. Results Complete data were available for 8,128 of the 10,038 women enrolled in the study. For all measures, race and ethnicity were significantly associated (p < 0.001) with survey scores. Non-Hispanic black (NHB) women were most likely to score in the most unfavorable category for all measures, with the exception of the Pregnancy Experience Scale. The magnitude of these differences did not differ by income status (interaction, p > 0.05) except on the Krieger racism survey and the Edinburgh depression survey, which were exacerbated among NHB women with higher income (interaction, p < 0.001). Conclusion Significant racial/ethnic disparities, independent of income status, exist in psychosocial measures during pregnancy.

Intergenerational transmission of the effects of acculturation on health in Hispanic Americans: a fetal programming perspective.

We propose a transdisciplinary, life span framework for examining the underlying cause of the observed intergenerational decline in health among Hispanic Americans. We focus on acculturation, and we posit that acculturation-related processes in first-generation Hispanic immigrant mothers may affect the intrauterine development of an unborn child, via the process of fetal programming, to produce phenotypic effects that may alter the susceptibility for noncommunicable chronic diseases. In this manner, an intergenerational cascade of perpetuation may become established. Our framework may shed light on the biological, behavioral, and social causes of intergenerational cycles of vulnerability among immigrant minority groups, with public health and policy implications for primary prevention and intervention.

Ecological momentary assessment of maternal cortisol profiles over a multiple-day period predicts the length of human gestation.

OBJECTIVE: Biobehavioral models of prenatal stress highlight the importance of the stress-related hormone cortisol. However, the association between maternal cortisol levels and the length of human gestation requires further investigation because most previous studies have relied on one-time cortisol measures assessed at varying gestational ages. This study assessed whether ecological momentary assessment (EMA) of cortisol sampling improves the ability to predict the length of human gestation. In addition, associations between EMA-based measures of psychological state (negative affect) with cortisol levels during pregnancy were assessed. METHODS: For a 4-day period, 25 healthy pregnant women (mean gestational age at assessment = 23.4 [standard deviation = 9.1] weeks) collected seven salivary samples per day for the assessment of cortisol and provided a rating of negative affect every waking hour using an electronic diary. RESULTS: Higher salivary cortisol concentrations at awakening and throughout the day (p = .001), as well as a flatter cortisol response to awakening (p = .005), were associated with shorter length of gestation. Women who delivered an infant at 36 weeks of gestations had 13% higher salivary cortisol levels at awakening than women who delivered an infant at 41 weeks of gestation. The EMA-based measure of negative affect was associated with higher cortisol throughout the day (p = .006) but not to gestational length (p = .641). The one-time measure of cortisol was not associated with length of gestation, and traditional retrospective recall measures of negative affect were not associated with cortisol. CONCLUSIONS: Our findings support the ecological validity of repeated ambulatory assessments of cortisol in pregnancy and their ability to improve the prediction of adverse birth outcomes.