Prenatal Lead Exposure, Genetic Factors, and Cognitive Developmental Delay

Abstract

Importance: Although the effects of lead (Pb) exposure on neurocognition in children have been confirmed, the individual associations of prenatal Pb exposure and its interaction with genetic factors on cognitive developmental delay (CDD) in children remain unclear.

Objective: To investigate the association of prenatal Pb exposure and its interaction with genetic factors with CDD risk.

Design, setting, and participants: Women in Wuhan, China, who had an expected delivery date between March 2014 and December 2017, were recruited for this prospective cohort study. Children were assessed for cognitive development at approximately 2 years of age (March 2016 to December 2019). Maternal venous blood, cord blood, and venous blood from children were collected in a longitudinal follow-up. Data analysis was performed from March 2022 to February 2023.

Exposure: Prenatal Pb exposure, and genetic risk for cognitive ability evaluated by polygenic risk score constructed with 58 genetic variations.

Main outcomes and measures: Cognitive developmental delay of children aged approximately 2 years was assessed using the Chinese revision of the Bayley Scale of Infant Development. A series of multivariable logistic regressions was estimated to determine associations between prenatal Pb exposure and CDD among children with various genetic backgrounds, adjusting for confounding variables.

Results: This analysis included 2361 eligible mother-child pairs (1240 boys [52.5%] and 1121 girls [47.5%]; mean [SD] ages of mothers and children, 28.9 [3.6] years and 24.8 [1.0] months, respectively), with 292 children (12.4%) having CDD. Higher maternal Pb levels were significantly associated with increased risk of CDD (highest vs lowest tertile: odds ratio, 1.55; 95% CI, 1.13-2.13), adjusting for demographic confounders. The association of CDD with maternal Pb levels was more evident among children with higher genetic risk (highest vs lowest tertile: odds ratio, 2.59; 95% CI, 1.48-4.55), adjusting for demographic confounders.

Conclusions and relevance: In this cohort study, prenatal Pb exposure was associated with an increased risk of CDD in children, especially in those with a high genetic risk. These findings suggest that prenatal Pb exposure and genetic background may jointly contribute to an increased risk of CDD for children and indicate the possibility for an integrated strategy to assess CDD risk and improve children's cognitive ability.

Figure 1.. Distributions of Lead (Pb) Concentrations Among Mother-Child Pairs

The geometric mean (geometric SD) of plasma Pb concentrations in mothers and blood Pb concentrations in children are 7.32 (0.12) ng/mL (to convert ng/mL to g/L, multiply by 1 × 10⁻⁶) and 4.39 (0.04) μg/dL (to convert μg/dL to g/L, multiply by 1 × 10⁻⁵), respectively. Circles and whiskers represent the median and IQR, respectively. CDD indicates cognitive developmental delay.

Figure 2.. Risk for Cognitive Developmental Delay According to Prenatal Lead (Pb) Exposure and Genetic Categories of Children

Odds ratios (ORs) for cognitive developmental delay were estimated according to Pb and genetic risk categories using logistic regression. Model 1 is the unadjusted model. Model 2 was adjusted for characteristics of the child (sex, gestational age at birth), mother (age, education status, prepregnancy body mass index, passive smoking status, number of deliveries, mode of delivery), father (education status), family (annual family income), and the top 10 principal components of ancestry and genotyping batch. Model 3 was adjusted for covariates in model 2 and blood Pb levels in children. NA indicates not applicable.