Placental hypoplasia and vascular malperfusion are associated with reduced brain volumes in fetal congenital heart disease.

Background Critical congenital heart disease (CHD) is associated with poor neurodevelopmental outcomes and long-term psychosocial morbidity. The pre-natal environment is increasingly recognized as a critical effector. However, the association of specific placental lesions with fetal brain volume in CHD remains unexamined. Methods This was a multi-site prospective, nested case-control study, that recruited pregnant women with typical fetal development and prenatally diagnosed fetal CHD. Fetal brain MRI was performed at 32.8 ± 3.0 weeks gestation. Placentas were examined pathologically after delivery. Clinical characteristics were gathered from self-reports and medical charts. Multiple linear regression modeling was performed in R with p < 0.05 considered significant. Results Placental hypoplasia (weight <10th %ile) was associated with lower total fetal intracranial volume in CHD ( p = 0.006) and combined (CHD + non-CHD) cohorts ( p = 0.001). Maternal and/or fetal vascular malperfusion was also associated with lower total fetal intracranial volume in combined ( p = 0.026), and non-CHD cohorts ( p = 0.020). Presence of any placental pathology was associated with reduced total fetal intracranial volume ( p = 0.047), an effect moderated by the presence of CHD (interaction term p = 0.037). Conclusion Placental hypoplasia, vascular malperfusion, and the presence of any placental pathology are associated with decreased total intracranial volumes in-utero. Fetuses with CHD and concomitant placental lesions appear particularly susceptible. Impact Placental vascular malperfusion is associated with reduced fetal intracranial volume. Placental hypoplasia (weight <10th %ile) is associated with smaller intracranial volumes in fetal congenital heart disease. Placental pathologies uniquely affect in-utero brain development in congenital heart disease. This study is the first to link fetal brain development to specific placental pathologies using standardized, reproducible criteria (Amsterdam) with comparative inclusion of a non-congenital heart disease cohort. Evidence builds that the in-utero environment impacts neurodevelopment in congenital heart disease; this study points to specific placental lesions that may mediate the pathophysiology underlying these observations.