Maternal Iron and Vitamin D Status during the Second Trimester Is Associated with Third Trimester Depression Symptoms among Pregnant Participants in the APrON Cohort.

BACKGROUND: The maternal status of multiple micronutrients during pregnancy and postpartum and their potential associations with maternal health outcomes are largely undescribed. OBJECTIVES: This study aimed to examine associations between maternal iron and vitamin D status, individually and in combination, on depression symptoms in pregnant individuals. METHODS: The Alberta Pregnancy Outcomes and Nutrition cohort study included pregnant participants and their children from Calgary and Edmonton, Canada. Iron biomarkers (serum ferritin [SF], soluble transferrin receptor, and hepcidin) were measured via immunoassays and vitamin D [25-hydroxyvitamin D3 (25(OH)D3) and 3-epi-25-hydoxyvitamin D3 (3-epi-25(OH)D3)] metabolites were quantifed using liquid chromatography with tandem mass spectroscopy. Four categories of maternal iron and vitamin D status during the second trimester were conceptualized using concentrations of SF and total 25-hydoxyvitamin D [25(OH)D], respectively. Maternal Edinburgh Postnatal Depression Scale (EPDS) scores during the third trimester (n = 1920) and 3 mo postpartum (n = 1822) were obtained. RESULTS: Concentrations of maternal 25(OH)D3, 3-epi-25(OH)D3, and the ratio of both metabolites were significantly higher during the second trimester compared with their status at 3 mo postpartum. Higher second trimester maternal concentrations of SF (ß: -0.8; 95% confidence interval [CI]: -1.5, -0.01), hepcidin (ß: -0.5; 95% CI: -0.9, -0.2), and 25(OH)D3 (ß: -0.01; 95% CI: -0.02, -0.004) predicted lower maternal EPDS scores during the third trimester. Pregnant individuals with a low iron (SF <15 µg/L) and replete vitamin D (25(OH)D ≥75 nmol/L) (ß: 1.1; 95% CI: 0.03, 2.1) or low iron (SF <15 µg/L) and vitamin D (25(OH)D <75 nmol/L) (ß: 2.2; 95% CI: 0.3, 4.2) status during midpregnancy had higher third trimester EPDS scores compared with those that were replete in both micronutrients. CONCLUSIONS: A higher midpregnancy maternal iron and vitamin D status, independently or in combination, predicted fewer maternal depression symptoms in the third trimester. Concentrations of maternal 25(OH)D3 and 3-epi-25(OH)D3 may be lower in the postpartum period compared with midpregnancy.

Prenatal maternal diabetes, comorbidities, and risk for neurodevelopmental impairment in the first two years.

BACKGROUND: Maternal diabetes is a known risk for neurodevelopmental delay in offspring, and often presents with comorbid metabolic conditions, such as obesity and hypertension. However, their combined effects on neurodevelopmental outcomes remain unclear. We investigated the independent and combined associations of maternal diabetes and comorbidities with the risk of neurodevelopmental delay in children aged 12 and 24 months. METHODS: A prospective longitudinal cohort of children from Pregnancy during the COVID-19 Pandemic study. Neurodevelopmental screening at 12 and 24 months was conducted using the Ages and Stages Questionnaire, which assesses domain-specific development. RESULTS: Maternal diabetes was not associated with neurodevelopmental risks either at 12 or 24 months. However, in combined analyses, maternal diabetes and pre-pregnancy overweight were associated with an increased risk of neurodevelopmental delay in personal-social skills (odds ratio [OR], 1.75 [95%CI,1.01-3.01]) at 24 months, though not at 12 months. Maternal diabetes and pre-pregnancy obesity were also associated with an increased risk for neurodevelopmental delay in communication (OR, 1.71 [95%CI,1.01-2.82]) and personal-social skills (OR, 2.01 [95%CI,1.03-3.73]) at 24 months. Furthermore, maternal diabetes and hypertensive disorders of pregnancy (HDP) had higher rates of positive screening for delay in fine-motor skills (OR, 3.54 [95%CI, 1.28-8.41]) at 12 months but not at 24 months. Post-hoc analysis revealed an independent association of maternal pre-pregnancy obesity, but not overweight, with an increased risk of neurodevelopmental delay in communication, fine-motor, and personal-social skills (ORs ranging from 1.44 to 1.71) at 24 months but not 12 months. Similarly, there was an independent association of maternal HDP with an increased risk of neurodevelopmental delay in fine-motor and and personal-social skills (ORs ranging from 2.01 to 2.19) at 24 months. CONCLUSION: Maternal diabetes with comorbid conditions is likely to increase the risk of neurodevelopmental delay during infancy than individual exposure, suggesting the persistent influence of prenatal exposure on offspring neurodevelopment. IMPACT: 1. Identifying modifiable prenatal risk factors for neurodevelopmental impairment in offspring is crucial for targeted interventions and providing support to mothers during pregnancy, which can lead to improved child health outcomes. 2. Maternal diabetes was not associated with neurodevelopmental delays in children at 12 or 24 months. 3. Maternal diabetes in combination with pre-pregnancy overweight or obesity increased the risk of cognitive delay at 24 months. 4. Maternal pre-pregnancy obesity but not overweight, and hypertensive disorders of pregnancy independently increased risks of cognitive and motor delays at 24 months.

Language learning in the context of a global pandemic: proximal and distal factors matter.

BACKGROUND: Public health measures implemented during the COVID-19 pandemic fundamentally altered the socioecological context in which children were developing. METHODS: Using Bronfenbrenner's socioecological theory, we investigate language acquisition among 2-year-old children (n = 4037) born during the pandemic. We focus on "late talkers", defined as children below the 10th percentile on the MacArthur-Bates Communicative Development Inventories-III. RESULTS: Overall, the proportion of late talkers declined as a function of pandemic wave, with 13.0% of those born during the first wave classified as late talkers compared to 10.4% born in wave two, and 8.0% born during wave three. In sex-based analysis, we observed a 15.9% prevalence of late talking among female toddlers, which was significantly different from the norming sample. In contrast, the prevalence of late talking among male toddlers was 9.1%. Using hierarchical logistic regression to identify both proximal and distal factors associated with being a late talker, we found that male sex, lower socioeconomic status, greater screen time, receiving childcare at home, disruptions to childcare, and experiencing greater exposure to public health restrictions were associated with increased odds for being a late talker. CONCLUSION: We interpret the findings in relation to the need to consider the special needs of young children in disaster preparation and response. IMPACT: Two-year-old children acquiring language in the context of the COVID-19 pandemic have vocabulary size similar to historical norms. A higher-than-expected prevalence of late talkers (below the 10th percentile) was observed among females and children born during the first wave of the pandemic. Motivated by Bronfenbrenner's socioecological theory, we show that both proximal and distal environmental factors are associated with vocabulary size. Infants exposed to stricter public measures had reduced vocabulary size. The findings suggest a need to recognize the developmental needs of children as part of the public health response to emergencies.

Maternal pre-pregnancy diet and prenatal depression: the mediating role of pre-pregnancy weight status and prenatal inflammation.

Depression is a common prenatal psychological complication. We aimed to investigate if maternal pre-pregnancy diet can impact prenatal depressive symptoms and the mediating role of pre-pregnancy BMI and inflammation. We used data (N 1141) from the Alberta Pregnancy Outcomes and Nutrition cohort study. We calculated Mediterranean diet adherence (MED) and dietary inflammatory index (DII) scores using data from pre-pregnancy FFQ. In the third-trimester, we assessed depressive symptoms using Edinburgh Postpartum Depression Scale (EPDS) and inflammation through serum C-reactive protein (CRP) levels. BMI was calculated from self-reported pre-pregnancy weight. Race-stratified analyses (white and people of colour) were run. We observed no association between MED or DII tertiles and depressive symptoms. However, white participants in the MED tertile-3 had lower risk of depression (EPDS < 10) compared with tertile-1 (OR = 0·56, 95 % CI, 0·33, 0·95). White individuals in MED tertile-3 had lower BMI (MD = -1·08; 95 % CI, -1·77, -0·39) and CRP (MD = -0·53; 95 % CI, -0·95, -0·11) than tertile-1, and those in DII tertile-2 (MD = 0·44; 95 % CI, 0·03, 0·84) and tertile-3 (MD = 0·42; 95 % CI, 0·01, 0·83) had higher CRP than tertile-1. Among people of colour, neither MED nor DII was associated with BMI or CRP, but BMI was negatively associated with depressive symptoms (ß = -0·25, 95 % CI, -0·43, -0·06). We found no association between diet and depressive symptoms through BMI or CRP, in either race. Pre-pregnancy diet might affect the risk of prenatal depression in a race-specific way. Further research is required to explore the racial differences in the association between maternal diet and prenatal depressive symptoms/depression risk.

Early Life Surgency, but not Effortful Control or Negative Affectivity, Is a Mediating Variable Between Maternal Pre-Pregnancy Body Mass Index and Childhood Obesity Risk.

Maternal gestational obesity is related to risk of obesity in the child. This risk may be in part mediated by altered child temperament, which can affect mother-child interactions, including feeding and soothing behaviors that affect obesity risk. Our objective was to examine the association between maternal pre-pregnancy BMI and child zBMI and determine if child temperament, specifically positive Affectivity/Surgency, mediates this association. Using conditional process modeling, we analyzed data from 408 mother-child dyads enrolled in the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Child temperament was assessed at 3 years of age via a parent report measure, the Child Behavior Questionnaire (CBQ), and child zBMI was calculated from in-person measurements of child height and weight at 4-5 years of age. Bivariate correlations showed that there was a significant positive correlation between zBMI and Surgency (r = 0.11, p = 0.03), and zBMI was also correlated with maternal pre-pregnancy BMI (r = 0.12, p = 0.02). Multivariable regression revealed that maternal pre-pregnancy BMI (adjusted ß = 0.15, 95% confidence interval [CI]; 0.00-0.05, p = 0.02) and Surgency scores (adjusted ß = 0.14, 95% CI; 0.02-0.28, p = 0.03) were associated with higher child zBMI at 4-5 years of age. Mediation analysis showed that Surgency mediated the association between pre-pregnancy BMI and child zBMI. Our models controlled for maternal gestational weight gain, gestational diabetes, socioeconomic status, maternal anxiety and depression, and gestational age at birth. Overall, maternal pre-pregnancy BMI was positively associated with child zBMI, and this association was mediated by higher child Surgency scores.

Prenatal depressive symptoms and childhood development of brain limbic and default mode network structure.

Prenatal depressive symptoms are linked to negative child behavioral and cognitive outcomes and predict later psychopathology in adolescent children. Prior work links prenatal depressive symptoms to child brain structure in regions like the amygdala; however, the relationship between symptoms and the development of brain structure over time remains unclear. We measured maternal depressive symptoms during pregnancy and acquired longitudinal T1-weighted and diffusion imaging data in children (n = 111; 60 females) between 2.6 and 8 years of age. Controlling for postnatal symptoms, we used linear mixed effects models to test relationships between prenatal depressive symptoms and age-related changes in (i) amygdala and hippocampal volume and (ii) structural properties of the limbic and default-mode networks using graph theory. Higher prenatal depressive symptoms in the second trimester were associated with more curvilinear trajectories of left amygdala volume changes. Higher prenatal depressive symptoms in the third trimester were associated with slower age-related changes in limbic global efficiency and average node degree across childhood. Our work provides evidence that moderate symptoms of prenatal depression in a low sociodemographic risk sample are associated with structural brain development in regions and networks implicated in emotion processing.

Maternal Iron Status Is Dynamic Throughout Pregnancy and Might Predict Birth Outcomes in a Sex Dependent Manner: Results from the Alberta Pregnancy Outcomes and Nutrition (APrON) Cohort Study.

BACKGROUND: Developmental responses to nutrient deprivation may differ by fetal sex. Despite this, relationships between maternal prenatal iron biomarkers and birth outcomes when stratifying by offspring sex are poorly described, especially in healthy cohorts. OBJECTIVES: This study aimed to determine associations between maternal iron biomarkers and birth weights (BWs) and birth head circumferences (BHCs) among female and male newborns to assess whether the potential predictive ability of iron biomarkers on birth outcomes differs by offspring sex. METHODS: The Alberta Pregnancy Outcomes and Nutrition (APrON) cohort study recruited 2189 pregnant individuals from Calgary and Edmonton, Canada. Maternal blood was drawn at each trimester and 3 mo postpartum. Maternal serum ferritin (SF) concentrations were measured using chemiluminescent immunoassays and erythropoietin (EPO), hepcidin, and soluble transferrin receptor (sTfR) using enzyme-linked immunosorbent assays. Ratios of sTfR:SF and hepcidin:EPO were calculated and birth outcomes accessed through delivery records. Directed acyclic graphs informed multivariate regression models. RESULTS: The risk of maternal iron deficiency increased throughout pregnancy because ∼61% showed depleted iron stores (SF < 15 µg/L) by the third trimester. Maternal hepcidin, SF, sTfR, and sTfR:SF concentrations changed across time (P < 0.01), and participants carrying female fetuses consistently (across 6 biomarkers) showed a lower iron status during the third trimester compared with those with male fetuses (P < 0.05). Higher maternal SF and hepcidin:EPO during the third trimester was associated with lower BWs in males (P = 0.006 for SF; P = 0.03 for hepcidin:EPO) and females (P = 0.02 for SF; P = 0.02 for hepcidin:EPO). There were additional inverse associations between BWs and third trimester maternal hepcidin (P = 0.03) and hemoglobin (P = 0.004) and between BHCs and maternal SF (second trimester; P < 0.05) and Hb (third trimester P = 0.02) but only in males. CONCLUSIONS: Relationships between maternal iron biomarkers and BWs and BHCs may depend on the timing of pregnancy and offpsring sex. There was a high risk of third trimester iron storage depletion among generally healthy pregnant individuals.

Binge-spectrum symptoms in their association with higher gestational weight gain.

OBJECTIVE: Gestational weight gain (GWG) above or below recommendations is common and has implications for parent and infant health. Bulimia nervosa and binge-eating disorder during pregnancy have been associated with higher GWG. Yet, little research has examined the associations between binge-spectrum symptoms and GWG. Likewise, few interventions exist to adequately prevent GWG. The current study investigated a broad range of predictors of GWG, with the goal of identifying potentially modifiable risk factors. METHOD: We conducted secondary data analyses of a subsample of individuals from the Alberta Pregnancy Outcome and Nutrition (APrON) longitudinal cohort study. Multinomial logistic regression estimated the odds of gestational weight gain (GWG) outside of Institute of Medicine (IOM) recommendations and linear regression was used to examine total GWG continuously. RESULTS: Of the 1644 participants included, 848 (51.6%) exceeded the IOM's guidelines for GWG, and 272 (16.5%) gained below these recommendations. Binge-spectrum symptom symptomatology during pregnancy was not associated with exceeding GWG recommendations after accounting for post-secondary education, identifying as European Canadian, and higher pre-pregnancy body mass index (BMI). However, greater self-reported binge-spectrum symptomatology during pregnancy was associated with higher total GWG after accounting for age, parity, and pre-pregnancy BMI. CONCLUSIONS: In addition to replicating identified predictors of higher GWG, we found that greater binge-spectrum symptomatology was associated with higher total GWG. These findings suggest that routine screening for eating pathology during pregnancy may identify those at risk for excess GWG. PUBLIC SIGNIFICANCE: Gestational weight gain (GWG) outside of recommended ranges is associated with adverse outcomes. Little work has examined the associations between eating disorder symptoms and GWG. This study found that bulimia and binge-eating symptoms were uniquely associated with higher GWG beyond known risk factors. These findings support routine screening of eating disorder symptoms and interventions to help individuals gain within GWG recommendations during pregnancy.

The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells.

The development of biological markers of aging has primarily focused on adult samples. Epigenetic clocks are a promising tool for measuring biological age that show impressive accuracy across most tissues and age ranges. In adults, deviations from the DNA methylation (DNAm) age prediction are correlated with several age-related phenotypes, such as mortality and frailty. In children, however, fewer such associations have been made, possibly because DNAm changes are more dynamic in pediatric populations as compared to adults. To address this gap, we aimed to develop a highly accurate, noninvasive, biological measure of age specific to pediatric samples using buccal epithelial cell DNAm. We gathered 1,721 genome-wide DNAm profiles from 11 different cohorts of typically developing individuals aged 0 to 20 y old. Elastic net penalized regression was used to select 94 CpG sites from a training dataset (n = 1,032), with performance assessed in a separate test dataset (n = 689). DNAm at these 94 CpG sites was highly predictive of age in the test cohort (median absolute error = 0.35 y). The Pediatric-Buccal-Epigenetic (PedBE) clock was characterized in additional cohorts, showcasing the accuracy in longitudinal data, the performance in nonbuccal tissues and adult age ranges, and the association with obstetric outcomes. The PedBE tool for measuring biological age in children might help in understanding the environmental and contextual factors that shape the DNA methylome during child development, and how it, in turn, might relate to child health and disease.

Associations of peripheral blood DNA methylation and estimated monocyte proportion differences during infancy with toddler attachment style.

Attachment is a motivational system promoting felt security to a caregiver resulting in a persistent internal working model of interpersonal behavior. Attachment styles are developed in early social environments and predict future health and development outcomes with potential biological signatures, such as epigenetic modifications like DNA methylation (DNAm). Thus, we hypothesized infant DNAm would associate with toddler attachment styles. An epigenome-wide association study (EWAS) of blood DNAm from 3-month-old infants was regressed onto children's attachment style from the Strange Situation Procedure at 22-months at multiple DNAm Cytosine-phosphate-Guanine (CpG) sites. The 26 identified CpGs associated with proinflammatory immune phenotypes and cognitive development. In post-hoc analyses, only maternal cognitive-growth fostering, encouraging intellectual exploration, contributed. For disorganized children, DNAm-derived cell-type proportions estimated higher monocytes -cells in immune responses hypothesized to increase with early adversity. Collectively, these findings suggested the potential biological embedding of both adverse and advantageous social environments as early as 3-months-old.

Associations Between the Gut Microbiota and Internalizing Behaviors in Preschool Children.

OBJECTIVE: Emerging evidence points toward a connection between mental health and the gut microbiota and its metabolites (e.g., short-chain fatty acids). It is unknown whether the gut microbiota is associated with the development of mental health problems (e.g., internalizing or externalizing behaviors) in preschool children. The objective of this study was to evaluate associations between the gut microbiota and internalizing and externalizing behaviors in preschool-aged children. METHODS: A community sample of 248 typically developing children (3-5 years of age) provided a stool sample for gut microbiota and SCFA analysis. Parents reported child internalizing and externalizing behaviors using the Child Behavior Checklist. Associations between child behaviors and gut microbiota measures were analyzed using Spearman correlations followed by an adjustment for multiple testing, with subanalysis conducted in children clinically "at risk" for behavioral problems compared with those who were not. RESULTS: There was a correlation between Shannon alpha diversity with internalizing behaviors (rs = -0.134, p = .035) and its subscale somatic complaints (rs = -0.144, p = .023). In addition, children clinically "at risk" for internalizing problems had decreased alpha diversity (U = 551, p = .017). Internalizing behaviors correlated with valerate and isobutyrate (rs = -0.147, p = .021; rs = -0.140, p = .028, respectively). Furthermore the somatic complaints subscale additionally correlated with acetate and butyrate (rs = -0.219, p = .001; rs = -0.241, p < .001, respectively). These findings were also present in children "at risk" for internalizing problems (U = 569, p = .026; U = 571, p = .028) and somatic complaints (U = 164, p = .004; U = 145, p = .001). CONCLUSIONS: These analyses reveal novel associations between internalizing behaviors and the gut microbiota in preschool children. Furthermore, a relationship between somatic complaints and acetate and butyrate was identified, indicating that interventions that increase SCFA production warrant future investigation.

Latent class trajectories of infant temperament and associations with problem behavior at two years of age.

Individual differences in temperament have been well-described, but individual differences in temperament trajectories require elaboration. Specifically, it is unknown if subgroups of infants display different developmental patterns and if these patterns relate to later behavioral problems. The aims were to identify distinct developmental patterns in broad dimensions of temperament among typically developing infants, to determine whether these developmental patterns differ by sex, to evaluate how developmental patterns within each dimension of temperament relate to developmental patterns within other dimensions of temperament, and to determine whether developmental patterns of infant temperament are associated with internalizing and externalizing behavior at 2 years of age. Data from the longitudinal Alberta Pregnancy Outcomes and Nutrition study (n = 1,819) were used to model latent class trajectories of parent-reported infant temperament at 3, 6, and 12 months. Four to five unique latent trajectories were identified within each temperament dimension. Sex was not associated with trajectory groups. Developmental coordination was observed between trajectories of negative emotionality and regulatory capacity, and between regulatory capacity and positive affect, but not between positive affect and negative emotionality. Negative emotionality and regulatory capacity predicted internalizing and externalizing behavior. Patterns of development in infant temperament, and not just intensity of temperament, contribute toward later problem behavior.

Pregnancy during the COVID-19 pandemic: a qualitative examination of ways of coping.

The COVID-19 pandemic and related public health restrictions have impacted the mental health and coping strategies of many population groups, including people who are pregnant. Our study sought to explore the ways that pregnant people described coping with stressors associated with the pandemic. N = 5879 pregnant individuals completed the pan-Canadian Pregnancy During the COVID-19 Pandemic Survey between April and December 2020. We used descriptive statistics to quantify sociodemographic characteristics and thematic analysis (Braun & Clarke, 2006, 2019) to analyze n = 3316 open-ended text responses to the question "Can you tell us what things you are doing to cope with the COVID-19 pandemic?" The average age of participants was 32 years (SD = 4.4), with the majority identifying as White (83.6%), female (99.7%), married (61.5%), having completed post-secondary education (90.0%), and working full-time (75.4%). We categorized participant responses into two overarching thematic dimensions: (1) ways of coping and (2) coping challenges. Ways of coping included the following main themes: (1) taking care of oneself, (2) connecting socially, (3) engaging in pandemic-specific coping strategies, (4) keeping busy, (5) taking care of others, (6) creating a sense of normalcy, (7) changing perspectives, and (8) practicing spirituality. Coping challenges included the following: (1) the perception of coping poorly, (2) loss of coping methods, (3) managing frontline or essential work, and (4) worries about the future. Findings highlight important implications for targeted prenatal supports delivered remotely, including opportunities for social support, prenatal care, and mental health strategies.

Amygdala-Prefrontal Structural Connectivity Mediates the Relationship between Prenatal Depression and Behavior in Preschool Boys.

Prenatal depression is common, underrecognized, and undertreated. It has negative consequences on child behavior and brain development, yet the relationships among prenatal depression, child behavior, and children's brain structure remain unclear. The aim of this study was to determine whether altered brain connectivity mediates relationships between prenatal maternal depressive symptoms and child behavior. This study included 54 human mother-child pairs. Mothers completed the Edinburgh Postnatal Depression Scale during the second and third trimesters of pregnancy and 3 months postpartum. Their children had diffusion MRI at age 4.1 ± 0.8 years, and children's behavior was assessed using the Child Behavior Checklist within 6 months of their MRI scan. Structural brain connectivity of the amygdala, fornix, uncinate fasciculus, and cingulum was assessed using fractional anisotropy and mean diffusivity and analyzed with maternal prenatal depressive symptoms as well as child behavior. Third trimester maternal Edinburgh Postnatal Depression Scale scores were positively associated with mean diffusivity in the amygdala-frontal tract and the cingulum, controlling for postpartum depression. Externalizing behavior had a sex interaction in the amygdala-frontal pathway; weaker connectivity (lower fractional anisotropy, higher mean diffusivity) was associated with worse behavior in boys. Amygdala-frontal connectivity mediated the relationship between third trimester depressive symptoms and child externalizing behavior in males. These findings suggest that altered brain structure is a mechanism via which prenatal depressive symptoms can impact child behavior, highlighting the importance of both recognition and intervention in prenatal depression.SIGNIFICANCE STATEMENT Understanding how prenatal maternal depression impacts child behavior is critical for appropriately treating prenatal maternal mental health problems and improving child outcomes. Here, we show white matter changes in young children exposed to maternal prenatal depressive symptoms. Children of mothers with worse depressive symptoms had weaker white matter connectivity between areas related to emotional processing. Furthermore, connectivity between the amygdala and prefrontal cortex mediated the relationship between maternal depressive symptoms and externalizing behavior in boys, showing that altered brain structure is a possible mechanism via which maternal prenatal depression impacts children's behavior. This provides important information for understanding why children of depressed mothers may be more vulnerable to depression themselves and may help shape future guidelines on maternal prenatal care.

Postnatal BPA is associated with increasing executive function difficulties in preschool children.

BACKGROUND: Early bisphenol exposure may have consequences for executive function development, but less is known about potential sex effects. We hypothesized that early bisphenol A (BPA) and bisphenol S (BPS) exposures would be associated with sex-dependent changes in preschool executive function. METHODS: A subsample of the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort (n = 312) provided maternal second trimester (prenatal) and 3-month postpartum (postnatal) urine samples, from which BPA and BPS concentrations were quantified. When children were age 2 and 4, mothers completed the Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P). Changes in standardized T scores on the BRIEF-P indexes of inhibitory self-control, flexibility, and emergent metacognition were investigated. RESULTS: Adjusted multivariate regression analyses showed that child sex modified the associations between maternal postnatal BPA and changes in executive function. Higher maternal postnatal BPA concentrations predicted increasing difficulties from age 2 to 4 in the domains of inhibitory self-control and emergent metacognition in female, but not male children. The other bisphenol concentrations were not associated with changes in executive function. CONCLUSION: Due to the ubiquity of BPA exposure among breastfeeding women, these findings justify further investigation on the effects of postnatal bisphenol exposure on child cognitive development. IMPACT: Higher concentrations of maternal BPA at 3-month postpartum were associated with increasing difficulties in inhibitory self-control and emergent metacognition from age 2 to 4 in girls, but not boys. Prenatal BPA and prenatal/postnatal BPS were not significant predictors of changes in executive function in boys and girls. The current study extends previous research to show that maternal postnatal BPA could also impact child executive function. Due to the ubiquity of BPA exposure among breastfeeding women, the current findings suggest that additional precautions may be needed to protect infants' neurodevelopment from indirect exposure to BPA.

The role of HPA-axis function during pregnancy in the intergenerational transmission of maternal adverse childhood experiences to child behavior problems.

The current study aimed to understand the mediating and/or moderating role of prenatal hypothalamic-pituitary-adrenal (HPA) axis function in the association between maternal adverse childhood experiences (ACEs) and child internalizing and externalizing behavior problems at age 4. The influence of timing and child sex were also explored. Participants were 248 mother-child dyads enrolled in a prospective longitudinal cohort study (the Alberta Pregnancy Outcomes and Nutrition Study). Maternal ACEs were retrospectively assessed while maternal self-reported depression and diurnal salivary cortisol were assessed prospectively at 6-26 weeks gestation (T1) and 27-37 weeks gestation (T2). Maternal report of child internalizing and externalizing problems was assessed at 4 years (T3). Results revealed that there was a negative indirect association between maternal ACEs and child internalizing behavior via a higher maternal cortisol awakening response (CAR). Maternal diurnal cortisol slope moderated the association between maternal ACEs and child behavior problems. Some of these effects were dependent on child sex, such that higher ACEs and a flatter diurnal slope at T1 was associated with more internalizing behavior in female children and more externalizing behavior in male children. There were timing effects such that the mediating and moderating effects were strongest at T1.

Prenatal maternal distress and immune cell epigenetic profiles at 3-months of age.

BACKGROUND: Prenatal maternal distress predicts altered offspring immune outcomes, potentially via altered epigenetics. The role of different kinds of prenatal maternal distress on DNA methylation profiles is not understood. METHODS: A sample of 117 women (APrON cohort) were followed from pregnancy to the postpartum period. Maternal distress (depressive symptoms, pregnancy-specific anxiety, stressful life events) were assessed mid-pregnancy, late-pregnancy, and 3-months postpartum. DNA methylation profiles were obtained from 3-month-old blood samples. Principal component analysis identified two epigenetic components, characterized as Immune Signaling and DNA Transcription through gene network analysis. Covariates were maternal demographics, pre-pregnancy body mass index, child sex, birth gestational age, and postpartum maternal distress. Penalized regression (LASSO) models were used. RESULTS: Late-pregnancy stressful life events, b = 0.006, early-pregnancy depressive symptoms, b = 0.027, late-pregnancy depressive symptoms, b = 0.014, and pregnancy-specific anxiety during late pregnancy, b = -0.631, were predictive of the Immune Signaling component, suggesting that these aspects of maternal distress could affect methylation in offspring immune signaling pathways. Only early-pregnancy depressive symptoms was predictive of the DNA Transcription component, b = -0.0004, suggesting that this aspect of maternal distress is implicated in methylation of offspring DNA transcription pathways. CONCLUSIONS: Exposure timing and kind of prenatal maternal distress could matter in the prediction of infant immune epigenetic profiles.

Paternal adverse childhood experiences: Associations with infant DNA methylation.

Adverse childhood experiences (ACEs), or cumulative childhood stress exposures, such as abuse, neglect, and household dysfunction, predict later health problems in both the exposed individuals and their offspring. One potential explanation suggests exposure to early adversity predicts epigenetic modification, especially DNA methylation (DNAm), linked to later health. Stress experienced preconception by mothers may associate with DNAm in the next generation. We hypothesized that fathers' exposure to ACEs also associates with their offspring DNAm, which, to our knowledge, has not been previously explored. An epigenome-wide association study (EWAS) of blood DNAm (n = 45) from 3-month-old infants was regressed onto fathers' retrospective ACEs at multiple Cytosine-phosphate-Guanosine (CpG) sites to discover associations. This accounted for infants' sex, age, ethnicity, cell type proportion, and genetic variability. Higher ACE scores associated with methylation values at eight CpGs. Post-hoc analysis found no contribution of paternal education, income, marital status, and parental postpartum depression, but did with paternal smoking and BMI along with infant sleep latency. These same CpGs also contributed to the association between paternal ACEs and offspring attention problems at 3 years. Collectively, these findings suggested there were biological associations with paternal early life adversity and offspring DNAm in infancy, potentially affecting offspring later childhood outcomes.

Cerebral blood flow increases across early childhood.

Adequate cerebral blood flow (CBF) is essential to proper brain development and function. Detailed characterization of CBF developmental trajectories will lead to better understanding of the development of cognitive, motor, and sensory functions, as well as behaviour in children. Previous studies have shown CBF increases during infancy and decreases during adolescence; however, the trajectories during childhood, and in particular the timing of peak CBF, remain unclear. Here, we used arterial spin labeling to map age-related changes of CBF across a large longitudinal sample that included 279 scans on 96 participants (46 girls and 50 boys) aged 2-7 years. CBF maps were analyzed using hierarchical linear regression for every voxel inside the grey matter mask, controlling for multiple comparisons. The results revealed a significant positive linear association between CBF and age in distributed brain regions including prefrontal, temporal, parietal, and occipital cortex, and in the cerebellum. There were no differences in developmental trajectories between males and females. Our findings show that CBF continues to increase until the age of 7 years, likely supporting ongoing improvements in behaviour, cognition, motor, and sensory functions in early childhood.

Depressed mood and anxiety as risk factors for hypertensive disorders of pregnancy: a systematic review and meta-analysis.

BACKGROUND: Psychosocial factors have been implicated as both a cause and consequence of hypertension in the general population but are less understood in relation to hypertensive disorders of pregnancy (HDP). The aims of this review were to (1) synthesize the existing literature examining associations between depression and/or anxiety in pregnancy and HDP and (2) assess if depression and/or anxiety in early pregnancy was a risk factor for HDP. METHODS: A comprehensive search of Medline, Embase, CINAHL, and PsycINFO was conducted from inception to March 2020 using terms related to 'pregnancy', 'anxiety', 'depression', and 'hypertensive disorders'. English-language cohort and case-control studies were included if they reported: (a) the presence or absence of clinically significant symptoms of depression/anxiety, or a medical record diagnosis of depression or an anxiety disorder in pregnancy; (b) diagnosis of HDP; and/or (c) data comparing the depressed/anxious group to the non-depressed/anxious group on HDP. Data related to depression/anxiety, HDP, study characteristics, and aspects related to study quality were extracted independently by two reviewers. Random-effects meta-analyses of estimated pooled relative risks (RRs) were conducted for depression/anxiety in pregnancy and HDP. RESULTS: In total, 6291 citations were retrieved, and 44 studies were included across 61.2 million pregnancies. Depression and/or anxiety were associated with HDP [RR = 1.39; 95% confidence interval (CI) 1.25-1.54]. CONCLUSIONS: When measurement of anxiety or depression preceded diagnosis of hypertension, the association remained (RR = 1.27; 95% CI 1.07-1.50). Women experiencing depression or anxiety in pregnancy have an increased prevalence of HDP compared to their non-depressed or non-anxious counterparts.