Bellinger, David C.

Importance Data are limited on the longitudinal implications of socioeconomic status (SES) for neurodevelopmental outcomes among persons with complex congenital heart disease (CHD). Objectives To examine the association of family SES, maternal educational level, and maternal IQ with the neurodevelopment of individuals with dextro-transposition of the great arteries (d-TGA) from age 1 to 16 years and to identify how SES-related disparities change with age. Design, Setting, and Participants This cohort study analyzed data of participants enrolled in the Boston Circulatory Arrest Study, a randomized clinical trial conducted in Boston, Massachusetts, from 1988 to 1992. Participants were infants with d-TGA who underwent arterial switch operation and, after operation, underwent in-person neurodevelopmental status evaluations at ages 1, 4, 8, and 16 years. Analyses were conducted from April 2021 to August 2024. Exposures Mean Hollingshead scores at birth, age 1 year, and age 4 years were used to assign participants to SES tertiles (lowest, middle, or highest). Main Outcomes and Measures Age-appropriate neurodevelopmental outcomes assessed at 4 study time points (ages 1, 4, 8, and 16 years) via in-person administration of a range of well-validated measures. Standardized neurodevelopmental composite scores from each evaluation were derived from principal component analysis and compared across SES tertiles, adjusting for birth and medical characteristics. These scores were used to categorize the sample into latent classes; patient and medical factors for a 3-class model were used to estimate latent class using multinomial regression. Results The sample included 164 patients with d-TGA (123 males [75%]; mean [SD] gestational age at birth, 39.8 [1.2] weeks; 3 with Asian [2%], 6 with Black [4%], 5 with Hispanic [3%], and 146 with White [89%] race and ethnicity) and their mothers (mean [SD] age at birth, 28.5 [5.2] years). Lower SES tertile was associated with worse scores on most individual neurodevelopmental tests and worse neurodevelopmental composite scores at ages 4, 8, and 16 years. For example, mean (SD) neurodevelopmental composite scores at age 4 years were –0.49 [0.83] for lowest, 0.00 [0.81] for middle, and 0.47 [1.10] for highest SES tertile ( F 2 = 15.5; P < .001). When measured at consecutive time points, differences between SES tertiles were of similar magnitude. A latent class analysis produced 2- and 3-class models representing patients with stable (103 [64%] and 85 [53%]), improving (20 [13%]), and declining (57 [36%] and 55 [34%]) neurodevelopmental status. Those experiencing declines in neurodevelopmental status were more likely to have younger maternal age at childbirth (26.6 [5.1] vs 29.6 [4.9] and 29.1 [5.1] years; P = .002), lower maternal IQ (91.0 [14.1] vs 100.1 [11.1] and 96.2 [11.0]; P < .001), and lower SES (35.2 [10.8] vs 40.9 [9.9] and 35.8 [10.1]; P = .003) compared with those with stable or improving status. Conclusions and Relevance This cohort study of individuals with d-TGA found an association between lower family SES and worse neurodevelopmental outcomes in childhood and continuing throughout adolescence as well as greater decline in neurodevelopmental status over time. Effective strategies are needed to improve access to neurodevelopmental monitoring and intervention services for children with CHD from lower socioeconomic backgrounds.

Greater understanding of the pathways through which an environmental mixture operates is important to design effective interventions. We present new methodology to estimate natural direct and indirect effects and controlled direct effects of a complex mixture exposure on an outcome through a mediator variable. We implement Bayesian Kernel Machine Regression (BKMR) to allow for all possible interactions and nonlinear effects of (1) the co‐exposures on the mediator, (2) the co‐exposures and mediator on the outcome, and (3) selected covariates on the mediator and/or outcome. From the posterior predictive distributions of the mediator and outcome, we simulate counterfactuals to obtain posterior samples, estimates, and credible intervals of the mediation effects. Our simulation study demonstrates that when the exposure‐mediator and exposure‐mediator‐outcome relationships are complex, BKMR‐Causal Mediation Analysis performs better than current mediation methods. We applied our methodology to quantify the contribution of birth length as a mediator between in utero co‐exposure to arsenic, manganese, and lead, and children's neurodevelopmental scores, in a prospective birth cohort in Bangladesh. Among younger children, we found a negative (adverse) association between the metal mixture and neurodevelopment. We also found evidence that birth length mediates the effect of exposure to the metal mixture on neurodevelopment for younger children. If birth length were fixed to its percentile value, the harmful effect of the metal mixture on neurodevelopment is attenuated, suggesting nutritional interventions to help increase fetal growth, and thus birth length, could potentially block the harmful effect of the metal mixture on neurodevelopment.