Causal inference between neurodevelopmental disorders and brain structure among individuals with congenital heart disease: Insights from meta-analysis and Mendelian randomization

To systematically review and meta-analyze the evidence on neurodevelopmental outcomes from infancy to adolescence among patients with congenital heart disease (CHD) and to explore the causal relationships among CHD, neurodevelopmental (ND) and brain structure. The PubMed, Embase, and Web of Science databases were searched for relevant studies. Genetic variants from genome-wide association studies (GWASs) were used to elucidate the causal relationships between CHD, ND, and brain structure. A total of 5824 studies were initially retrieved; ultimately, 23 studies were included (2069 CHD cases). Nine studies used the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) to assess language, motor and cognitive skills; 10 studies used the Wechsler Intelligence Scale (WIS) to assess the intelligence quotient (IQ); 3 studies used the Social Reactive Score (SRS) to assess social communication; and 1 study used both the SRS and the WIS. We found that the CHD group had worse language (mean 94.40, 95% CI 92.98–95.81) and motor (mean 95.35, 95% CI 92.11–98.59) skills during infancy as well as lower IQ (mean 95.94, 95% CI 93.59 ~ 98.29) and worse social communication abilities (mean 53.82, 95% CI 51.75–55.90) in the preschool and adolescence periods than did the age-matched healthy group. There were no significant genetic associations between CHD, ND and brain structure. We observed causal links between brain structure and both cognitive function and behavioral functions. ND delay is common among non-genetic CHD patients from infancy to young adulthood.