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.

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 body mass index (BMI) and inflammation. We used data (N=1141) from the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort study. We calculated Mediterranean diet adherence (MED) and dietary inflammatory index (DII) scores using data from pre-pregnancy food frequency questionnaire (FFQ). In the 3rd-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 color) 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 to 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 color, neither MED nor DII were 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.

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.

Effects of inulin supplementation on inflammatory biomarkers and clinical symptoms of women with obesity and depression on a calorie-restricted diet: a randomised controlled clinical trial.

Major depressive disorder (MDD) is regarded as an inflammatory disorder. Gut microbiota dysbiosis, observed in both MDD and obesity, leads to endotoxemia and inflammatory status, eventually exacerbating depressive symptoms. Manipulation of gut microbiota by prebiotics might help alleviate depression. The present study aimed to investigate the effects of inulin supplementation on psychological outcomes and biomarkers of gut permeability, endotoxemia, inflammation, and brain-derived neurotrophic factor (BDNF) in women with obesity and depression on a calorie-restricted diet. In a double-blind randomised clinical trial, forty-five women with obesity and MDD were allocated to receive 10 g/d of either inulin or maltodextrin for 8 weeks; all the patients followed a healthy calorie restricted diet as well. Anthropometric measures, dietary intakes, depression, and serum levels of zonulin, lipopolysaccharide (LPS), inflammatory biomarkers (TNF-α, IL-10, monocyte chemoattractant protein-1, toll-like receptor-4 and high-sensitivity C-reactive protein), and BDNF were assessed at baseline and end of the study. Weight and Hamilton Depression Rating Scale (HDRS) scores decreased in both groups; between-group differences were non-significant by the end of study (P = 0·333 for body weight and P = 0·500 for HDRS). No between-group differences were observed for the other psychological outcomes and serum biomarkers (P > 0·05). In this short-term study, prebiotic supplementation had no significant beneficial effects on depressive symptoms, gut permeability, or inflammatory biomarkers in women with obesity and depression.

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.

Maternal pre-pregnancy weight status and gestational weight gain in association with child behavior: The mediating role of prenatal systemic inflammation.

BACKGROUND AND AIMS: Maternal pre-pregnancy obesity and excessive gestational weight gain (EGWG) may predispose children to behavioral problems through increased prenatal inflammation. We investigated the association between maternal body mass index (BMI) and gestational weight gain (GWG), and child behavioral problems (primary aim), and the mediating role of prenatal inflammation (secondary aim). METHODS: We used self-reported pre-pregnancy BMI and estimated-GWG data (N = 1137) from a longitudinal cohort study. Maternal serum C-reactive protein (CRP) was measured in the 3rd-trimester. Parent-reported Child Behavior Checklist (CBCL) was used to assess child internalizing and externalizing behaviors at 3-years-of-age. We used analysis of covariance (ANCOVA), multiple linear regression, and mediation analyses for data analysis. RESULTS: Maternal obesity (F = 21.98, df 3836), EGWG (F = 6.53, df 2764), and their combination (F = 18.51, df 3764) were associated with the 3rd trimester CRP, but not child behavior in the whole sample. Maternal underweight was associated with withdrawal problems in all children (ß = 0.56, 95%CI, 0.11,1.00) and aggressive behaviors in female children (ß = 2.59, 95%CI, 0.28,4.91). Obesity had a significant association with externalizing behaviors in female children after controlling for maternal CRP (ß = 3.72, 95%CI, 0.12,7.32). Both inadequate and EGWG were associated with somatic complaints in male children (ß = 0.50, 95%CI, 0.05,0.95; ß = 0.36, 95%CI, 0.01,0.71, respectively). Combined obesity/EGWG was associated with externalizing (ß = 6.12, 95%CI, 0.53,11.70) and aggressive (ß = 4.23, 95%CI, 0.90,7.56) behaviors in female children. We found no significant effects through CRP. CONCLUSIONS: Maternal pre-pregnancy BMI and GWG showed sex-specific associations with child behavioral problems. Prenatal CRP, although increased in obesity and EGWG, did not mediate these associations.

Cluster-specific associations between the gut microbiota and behavioral outcomes in preschool-aged children.

BACKGROUND: The gut microbiota is recognized as a regulator of brain development and behavioral outcomes during childhood. Nonetheless, associations between the gut microbiota and behavior are often inconsistent among studies in humans, perhaps because many host-microbe relationships vary widely between individuals. This study aims to stratify children based on their gut microbiota composition (i.e., clusters) and to identify novel gut microbiome cluster-specific associations between the stool metabolomic pathways and child behavioral outcomes. METHODS: Stool samples were collected from a community sample of 248 typically developing children (3-5 years). The gut microbiota was analyzed using 16S sequencing while LC-MS/MS was used for untargeted metabolomics. Parent-reported behavioral outcomes (i.e., Adaptive Skills, Internalizing, Externalizing, Behavioral Symptoms, Developmental Social Disorders) were assessed using the Behavior Assessment System for Children (BASC-2). Children were grouped based on their gut microbiota composition using the Dirichlet multinomial method, after which differences in the metabolome and behavioral outcomes were investigated. RESULTS: Four different gut microbiota clusters were identified, where the cluster enriched in both Bacteroides and Bifidobacterium (Ba2) had the most distinct stool metabolome. The cluster characterized by high Bifidobacterium abundance (Bif), as well as cluster Ba2, were associated with lower Adaptive Skill scores and its subcomponent Social Skills. Cluster Ba2 also had significantly lower stool histidine to urocanate turnover, which in turn was associated with lower Social Skill scores in a cluster-dependent manner. Finally, cluster Ba2 had increased levels of compounds involved in Galactose metabolism (i.e., stachyose, raffinose, alpha-D-glucose), where alpha-D-glucose was associated with the Adaptive Skill subcomponent Daily Living scores (i.e., ability to perform basic everyday tasks) in a cluster-dependent manner. CONCLUSIONS: These data show novel associations between the gut microbiota, its metabolites, and behavioral outcomes in typically developing preschool-aged children. Our results support the concept that cluster-based groupings could be used to develop more personalized interventions to support child behavioral outcomes. Video Abstract.

Long-term and trimester-specific effects of prenatal stress on the child gut microbiota.

OBJECTIVE: Stress is common among pregnant individuals and is associated with an altered gut microbiota composition in infants. It is unknown if these compositional changes persist into the preschool years when the gut microbiota reaches an adult-like composition. This study aimed to investigate if indicators of prenatal stress (i.e., psychological distress and stress-related physiology) are associated with children's gut microbiota composition and metabolites at 3-4 years of age. METHODS: Maternal-child pairs (n = 131) were from the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort. Each trimester, psychological distress was measured as symptoms of anxiety (Symptom Checklist-90-R) and depressed mood (Edinburgh Postnatal Depression Scale), whereas salivary cortisol was quantified as a measure of stress-related physiology. Child stool samples were collected at 3-4 years to evaluate gut microbiota composition using 16S rRNA gene sequencing and fecal metabolome using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Associations between prenatal distress and cortisol with the gut microbiota were determined using Pearson and Spearman correlations and corrected for multiple testing. Associations between prenatal distress and cortisol with the fecal metabolome were assessed using Metaboanalyst. RESULTS: Symptoms of depressed mood during the 2nd and 3rd trimesters and anxiety during the 2nd trimester of pregnancy were associated with increased alpha diversity of the child's gut microbiota. Cortisol levels during the 1st trimester were also associated with increased Faith PD diversity (r = 0.32), whereas cortisol levels during the 2nd trimester were associated with reduced Shannon diversity (r = -0.27). Depression scores during the 2nd and 3rd trimesters were associated with reductions in the relative abundances of Eggerthella, Parasutterella, and increases in Ruminococcaceae (rs = -0.28, rs = -0.32, rs = 0.32, respectively), as well as the fecal metabolome (e.g., branched-chain amino acid metabolism). Cortisol levels during the 2nd trimester correlated with 7 bacterial taxa, whereas 1st-trimester cortisol levels were associated with the child's fecal metabolome. CONCLUSIONS: Prenatal distress and cortisol were associated with both child gut microbiota composition and fecal metabolome at preschool age. Understanding these associations may allow for the identification of microbiota-targeted interventions to support child developmental outcomes affected by prenatal stress.

Exploring associations between the gut microbiota and full-scale intelligence in preschool children.

The relationship between the gut microbiota and neurocognitive outcomes is becoming increasingly recognized; however, findings in humans are inconsistent. In addition, few studies have investigated the gut microbial metabolites that may mediate this relationship. The objective of this study was to investigate associations between full-scale intelligence (FSIQ) and the composition of the gut microbiota and metabolome in preschool children. Stool samples were collected from a community sample of 245 typically developing children (3-5 years) from the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort. The faecal microbiome was assessed using 16S rRNA sequencing and the metabolome using LC-MS/MS. FSIQ and scores on the Verbal Comprehension, Visual Spatial, Working Memory indices of the Wechsler Preschool and Primary Scale of Intelligence-IV were used to assess neurocognition. Associations between the gut microbiota and FSIQ were determined using Pearson and Spearman correlations, which were corrected for multiple testing and relevant covariates. Verbal Comprehension correlated negatively with both Shannon alpha diversity (r = -0.14, p = 0.032) and the caffeine-derived metabolite paraxanthine (r = -0.22, p < 0.001). No other significant correlations were observed. Overall, the weak to modest correlations between Verbal Comprehension with alpha diversity and paraxanthine provide limited evidence of an association between the gut microbiota and neurocognitive outcomes in typically developing preschool children.

Sleep and the gut microbiota in preschool-aged children.

Sleep plays a significant role in the mental and physical development of children. Emerging evidence in animals and human adults indicates a relationship between sleep and the gut microbiota; however, it is unclear whether the sleep of preschoolers during a key developmental period, associates with features of their gut microbiota. The objective of this study was to assess the relationship between sleep and gut microbiota in preschool-aged children (4.37 ± 0.48 years, n = 143). Sleep measures included total night-time sleep (TST), sleep efficiency (SE), and wake-time after sleep onset (WASO) assessed using actigraphy. Beta-diversity differences between children with low and high TST (p = .048) suggest gut microbiota community differences. Particularly, relative abundance of Bifidobacterium was higher in the high TST group and Bacteroides, was higher in children who had greater SE and less WASO (LDA score >2). In contrast, some Lachnospiraceae members including Blautia and Coprococcus 1 were associated with shorter night-time sleep duration and less efficiency, respectively. We also found a group of fecal metabolites, including specific neuroactive compounds and immunomodulating metabolites were associated with greater sleep efficiency and less time awake at night. Notably, tryptophan and its metabolizing products were higher in children who had higher SE or lower WASO (LDA score >2); concentration of propionate was higher in children with less WASO (p = .036). Overall, our results reveal a novel association between sleep and gut microbiota in preschool-aged children. Longer night-time sleep and greater sleep efficiency were associated with specific commensal bacteria that may regulate sleep through modulating neurotransmitter metabolism and the immune system.

Dietary changes among pregnant individuals compared to pre-pandemic: A cross-sectional analysis of the Pregnancy during the COVID-19 Pandemic (PdP) study.

Introduction: Dietary changes are common in pregnancy and may affect pregnancy outcomes, yet these changes and the associated contributory factors during the COVID-19 pandemic have been understudied. We aimed to investigate the association between dietary change and socioeconomic variables, pre-pregnancy BMI, and mental health symptoms; the change in intake of seven food categories and their reasons; and the association between intake of these food categories and mental health symptoms. Materials and methods: In this cross-sectional analysis, we used data from the Pregnancy during the COVID-19 Pandemic (PdP) cohort study that collected data from pregnant Canadian individuals (n = 9,870, gestational age ≤ 35 weeks) on socioeconomic factors, pandemic-related hardships, pre-pregnancy body mass index (BMI), dietary changes compared to pre-pandemic and the reasons for these changes. We assessed depressive and anxiety symptoms using the Edinburgh Postpartum Depression Scale (EPDS) and Patient-Reported Outcomes Measurement Information System (PROMIS)-Anxiety, respectively. Results: 54.3% of the participants reported a change in their diet. Non-white ethnicity (OR = 1.33), job loss (OR = 1.29), clinically elevated depressive and anxiety symptoms (OR = 1.26 and 1.14, respectively), self-isolation (OR = 1.20), pre-pregnancy BMI (OR = 1.19), fear of COVID-19 (OR = 1.15), and pandemic phase at enrolment (OR = 0.90) significantly predicted dietary change. Most participants ate about the same amounts of dairy, meats and canned foods/dried goods as pre-pandemic (61.5, 61.7, and 60.2%, respectively), increased their intake of fresh vegetables/fruits and sweets/snacks (43.2 and 54.5%, respectively), and decreased fast-food and take-out/home delivery (53.2 and 43.1%, respectively). Changes in consumption of the food categories had a curvilinear association with mental health symptoms (except resilience) indicating greater symptoms with either decreased or increased intakes. Changes in craving, having more time for cooking/preparing foods, and being unable to go grocery shopping frequently (but not reduced affordability) were the main reasons driving these dietary changes. Conclusion: Some factors increase the odds of dietary change among pregnant individuals during the pandemic, with some changes toward a healthy and others toward an unhealthy diet. Given the importance of a healthy diet during gestation, identifying the risk and protective factors might be the first essential step in reducing the detrimental effects of unfavorable dietary changes during the pandemic on this vulnerable population.

The association of depression with metabolic syndrome parameters and malondialdehyde (MDA) in obese women: A case-control study.

Background: There is evidence for a bidirectional association between obesity and depression, and obesity is the main risk factor for metabolic syndrome (MetS). This study aimed to compare oxidative stress and MetS features between depressed and non-depressed obese women and study the association of depressive symptoms, oxidative stress, and components of MetS. Methods: In this case-control study conducted in Tabriz (East Azarbaijan, Iran), obese women (body mass index [BMI]: 30-40 kg/m2 ) with a primary diagnosis of major depressive disorder (MDD; based on diagnostic interview with a psychiatrist; n=75) and their age-matched non-depressed controls (n=150) were enrolled. Beck Depression Inventory-version II (BDI-II) was used to assess depressive symptoms in both groups. Anthropometric parameters, blood pressure, fasting blood sugar (FBS), lipid profile and malondialdehyde (MDA) were measured. Results: No significant differences in anthropometric parameters and blood pressure were observed between the two groups. However, FBS of the MDD group was significantly higher than the control (P <0.05). FBS was significantly correlated with BDI-II scores (r=0.158, P =0.017). No significant difference in lipid profile was observed between the groups. Serum MDA level was significantly lower in the MDD group and was inversely associated with BDI-II scores (r=-0.328, P <0.001). Overall, MDD was not significantly associated with MetS in our study (OR=0.848, 95% CI: 0.484, 1.487; P =0.566). Conclusion: Although we found a correlation between higher depressive symptoms and some adverse metabolic outcomes, our findings do not support a significant association between MDD and MetS.

The role of maternal nutrition during pregnancy in the intergenerational transmission of childhood adversity.

Adverse childhood experiences (ACEs) of a woman can lead to dysregulated hypothalamus-pituitary-adrenal (HPA) axis during pregnancy, which can in turn adversely affect her offspring HPA axis function. Choline and docosahexaenoic acid (DHA) are dietary factors with the potential to favorably modify the stress response system. The current study aimed to investigate whether maternal choline intake and DHA status moderate the effects of maternal ACEs exposure on maternal and infant HPA axes function. Participants were a sub-sample of the prospective longitudinal Alberta Pregnancy Outcomes and Nutrition (APrON) study consisting of 340 mothers and 238 infants. We collected data on maternal ACEs, maternal choline intake (24-hour dietary recall) and serum phospholipid DHA concentrations (at each trimester). Women self-collected saliva samples on two consecutive days (at waking, +30 min, 1100 h, and 2100 h) in each trimester to calculate the cortisol awakening response (CAR) and total daytime cortisol. Infants' salivary cortisol was measured before and after (20, and 40 min) exposure to a blood draw stressor 3 months postpartum. During pregnancy, choline intake moderated (reduced) the association between maternal ACEs and CAR (ß = -0.003; 95% CI -0.006, -0.003), but not total daytime cortisol. DHA status did not moderate the association between ACEs and CAR or total daytime cortisol. Choline intake also moderated (reduced) the association between maternal CAR and infant cortisol during a stress task (ß = -0.0001; 95% CI -0.0002, -0.00003). Maternal DHA status revealed no modifying effects on these associations. Our findings suggest that maternal choline intake, but not DHA status, can buffer the associations between ACEs and maternal HPA axis, as well as maternal and infant HPA axes function.