Mediating and Interacting Effects of Birth Outcomes on the Relationship between Prenatal Manganese Exposure and Cognitive Outcome among 2-3 years-old Bangladeshi Children

Abstract

Background/Aim: We investigated the mediating and interacting influence of physical measurements at birth on the relationship between prenatal exposure to manganese and cognitive status among 2-3 years-old Bangladeshi children. Methods: Pregnant mothers were enrolled in a prospective birth cohort in rural Bangladesh between 2008-2011 and children followed longitudinally. Manganese was measured in umbilical cord blood metal by ICP-MS. Anthropometric measurements (weight, length, head circumference) were assessed at delivery. Cognitive status of the children was assessed by translated and culturally appropriate version of the Bayley Scales of Infant and Toddler Development Third Edition at age 20-40 months. We assessed the effect of cord blood manganese on neurodevelopment considering whether physical measures at birth mediated the association with cognitive score or whether these measures modified the association between cord blood manganese and cognitive score. Recently developed statistical approaches allow for estimating mediation and effect modification effects simultaneously. Results: 764 mother-child pairs were included. Higher cord blood manganese concentration was associated with lower cognitive score [β=-0.31, standard error (SE)=0.12, p=0.008]. Among the birth measures, mediating and modifying effects of birth length were identified. We found a significant mediation effect through birth length (β =-0.08, SE=0.03). We found evidence of interaction between manganese and birth length (β =0.11, SE=0.03) and of mediated interaction (both mediation and interaction)(β =-0.04, SE=0.01)(all p≤0.01). The overall proportion mediated by birth length was 38.2% and the proportion attributed to interaction was 21.7%. Conclusions: Our findings confirm that birth length significantly contributes to the overall effect of manganese exposure on child’s cognitive score. This suggests that manganese may have effects on global nutritional status that contributes to neurotoxicity, as opposed to effects that are specific to brain development. In addition, our analysis suggests that birth length (a marker of growth stunting) also partly modifies the effect of manganese on neurodevelopment.