In their article, Barbu et al reported increased rates of microcephaly in neonates with congenital heart defects such as tetralogy of Fallot or coarctation/aortic arch hypoplasia. The authors interpret their findings as “strong evidence in support of intrauterine hypoxic central nervous system damage.” They thereby argue that it is heart defect–induced hypoxia that causes a developmental defect of the brain and thus microcephaly. Moreover, they call for “potential changes in prenatal management including aggressive antepartum surveillance and earlier delivery.”

Although the study has merit, and the core results are in line with those of others who have indicated similar developmental disturbances of the brain in children with congenital heart defects, we strongly caution against the 1-sided causation alluded to by the authors. First, neither tetralogy of Fallot nor aortic arch hypoplasia impair oxygen delivery to the brain during intrauterine life. Second, reduced oxygen supply before birth (eg, by high altitude) may reduce birthweight substantially but has little effect on head circumference. Third, congenital heart defects (especially those mentioned in the study) and congenital microcephaly share common genetic pathways. The development of the mammalian heart is critically shaped by a subpopulation of neural crest cells that migrate to and from specific regions of the heart, the pulmonary artery, and the ascending aorta early in embryogenesis. Neural crest cells further regulate heart development through microenvironmental effects. Molecular perturbation of these neural crest cells leads to conotruncal heart defects (ie, outflow defects ranging from tetralogy of Fallot to interrupted aortic arch/coarctation). In mice, mutations in various genes encoding proteins that are important for neuronal survival, differentiation, and migration both in the developing brain and in the neural crest cells lead to conotruncal heart defects. Typical examples are neurotrophin-3 and connexin-43 deficiencies. Based on this train of thought, we propose that a concurrent observation of microcephaly and a conotruncal heart defect in infants warrants the search for a common pathomechanism rather than a simple chain of causation. Earlier delivery that is aggressively pursued, as suggested by authors, not only exposes the infant’s brain to the problems caused by prematurity but also increases the risks of cardiopulmonary bypass during open heart surgery.