The Effect of Antenatal Multiple Micronutrient Supplementation on Placental Angiogenesis and Fetal Growth Factors in Rural Bangladesh

Abstract

Objectives: Pathways by which micronutrients may influence birth size are not well understood. To elucidate these, we assessed markers of placental angiogenesis and fetal growth factors in a substudy of a community-based, double blinded, cluster-randomized trial of maternal multiple micronutrient (MM) supplementation versus iron and folic acid (IFA) in rural Bangladesh. Methods: We collected maternal blood (n=395) at 10 and 32 weeks gestation and cord blood (n=325) at home deliveries, where infant and placental weight were measured. Angiogenic factors assessed in maternal plasma were placental growth factor (PlGF), angiopoietin 2 (Ang-2), vascular endothelial growth factor (VEGF), and VEGF receptor 1 (VEGFR-1). Insulin, insulin-like growth factor-1 (IGF-1), and IGF binding protein-1 (IGFBP-1) were measured in cord plasma. Results: Mothers had a mean (SD) BMI in early pregnancy of 19.5 (2.5) kg/m2 and infants weighed 2.68 (0.41) kg at birth. Ang-2 at 32 weeks gestation was 3.1 (95% CI: 0.20, 6.0) ng/mL higher in mothers taking MM vs. IFA suggesting improved vascular remodeling. Other angiogenic factors and insulin, IGF-1, and IGFBP-1 did not differ by maternal supplementation, but significant interactions were observed with infant sex and maternal height. For male fetuses, change in VEGF from 10 to 32 weeks was lower by 7.5 (95% CI: -13.3, -1.7) pg/mL for MM vs. IFA groups reflecting improved angiogenesis across pregnancy. Among shorter women (<145 cm), MM increased insulin by 1.8 (95% CI: 1.0, 3.1) µIU/ML indicating improved fetal energy metabolism. Conclusions: MM supplementation has a biologic basis for improving fetal growth beyond improved micronutrient status of the fetus.