Maternal Iron and Vitamin D Status During and After Pregnancy and Their Relationships With Maternal and Child Health Outcomes: Evidence From the APrON Cohort Study

Background: Investigations that assess how maternal iron or vitamin D status biomarkers change across pregnancy and postpartum, and their relationships with maternal and offspring outcomes, in cohorts of healthy pregnant individuals from high-income countries are limited. Recent reports suggest that the prevalence of iron or vitamin D insufficiencies among pregnant people are underestimated. Further, evidence supporting associations between maternal iron and vitamin D status and prospective maternal and child health outcomes is mixed, and the possible combined impact of both micronutrients is poorly described. Objectives: The first objective was to determine how maternal concentrations of iron and vitamin D biomarkers changed across pregnancy into postpartum and to assess the combined maternal status of iron and vitamin D during the 2nd trimester (mid-pregnancy). Relationships between maternal iron biomarkers and birth weights (BWs) and birth head circumferences (BHCs) were examined. Lastly, relationships between maternal iron and vitamin D biomarkers and maternal depression symptoms along with internalizing and externalizing behaviours in children at age 5 were determined. Methods: The Alberta Pregnancy Outcomes and Nutrition (APrON) prospective cohort study recruited 2,189 generally healthy pregnant individuals from Calgary and Edmonton, Alberta. Maternal blood was drawn at each trimester of pregnancy and at 3 months postpartum, and maternal hemoglobin (Hb) concentrations were immediately quantified. Concentrations of maternal serum ferritin (SF) were measured using chemiluminescent microparticle immunoassays, and erythropoietin (EPO), hepcidin and soluble transferrin receptor (sTfR) using enzyme-linked immunosorbent assays. Maternal 25-hydroxyvitamin D3 (25(OH)D3) and 3-epi-25-hydroxyvitamin D3 (3-epi-25(OH)D3) concentrations were quantified by liquid chromatography with tandem mass spectroscopy. Ratios of sTfR:SF and hepcidin:EPO were calculated, and four categories of maternal iron and vitamin D status conceptualized. Neonatal BWs (n=2,022) and BHCs (n=1,873) were obtained. Maternal Edinburgh Postnatal Depression Scale (EPDS) scores, collected during the 3rd trimester (n=1,920) and at 3 months postpartum (n=1,822), and the Behavior Assessment System for Children 2nd Edition internalizing and externalizing T-scores from children at age 5 (n=662) were also assessed. Child outcome models were stratified by offspring sex. Directed acyclic graphs and change-in-estimate rules determined multivariate linear regression model adjustment. Results: Concentrations of maternal Hb, hepcidin and SF decreased, and sTfR and sTfR:SF increased as pregnancy progressed, with Hb and SF rebounding by 3 months postpartum (all p<0.001). Maternal 25(OH)D3 and 3-epi-5(OH)D3 concentrations decreased between the 2nd trimester and 3 months postpartum (p<0.01). In 627 pregnant participants with 2nd trimester SF and 25-hydroxyvitamin D data, 63% were replete in both micronutrients, 15% were iron replete but low in vitamin D, 18% were vitamin D replete but low in iron and 4% were low in both. Higher maternal 3rd trimester SF and hepcidin:EPO concentrations were linearly associated with lower BWs in male (SF: p<0.01; hepcidin:EPO: p=0.03) and female newborns (SF: p=0.02; hepcidin:EPO: p=0.02). There were inverse associations between BWs and 3rd trimester maternal hepcidin (p=0.03) and Hb (p<0.01), and BHCs and maternal 2nd trimester SF (p<0.05) and 3rd trimester Hb (p=0.02), but only in the male models. Higher 2nd trimester maternal SF (p<0.05), hepcidin (p<0.01) and 25(OH)D3 (p<0.01) concentrations predicted lower 3rd trimester maternal EPDS scores. Pregnant individuals that were vitamin D replete but low in iron (p=0.04) or low in iron and vitamin D (p=0.02) during mid-pregnancy had higher 3rd trimester EPDS scores compared to those that were replete in both micronutrients. An inverse association between 3rd trimester maternal sTfR:SF and externalizing T-scores was observed in female children (p=0.04), whereas in male children a negative relationship was observed between maternal 3-epi-25(OH)D3 concentrations at 3 months postpartum and externalizing T-scores (p=0.02). Child externalizing T-scores differed depending on the combined maternal iron and vitamin D status during mid-pregnancy (all p<0.04). Conclusions: Iron and vitamin D biomarker concentrations were dynamic across gestation and into the postpartum period in generally healthy pregnant individuals. Maternal SF concentrations were inversely related to BWs, BHCs, prenatal maternal depression symptoms and child externalizing behaviours at age 5, but these associations may be time and offspring sex dependent. Negative relationships were also observed between maternal vitamin D biomarkers and maternal prenatal depression symptoms as well as child externalizing behaviours at age 5. The potential impact of concurrent micronutrient deficiencies on maternal and offspring health outcomes should be explored in future research.

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