The Role of Abnormal Placentation in Congenital Heart Disease; Cause, Correlate, or Consequence?

Congenital heart disease (CHD) is the most common birth defect, affecting ~1% of all live births (van der Linde et al., 2011). Despite improvements in clinical care, it is the leading cause of infant mortality related to birth defects (Yang et al., 2006) and burdens survivors with significant morbidity (Gilboa et al., 2016). Furthermore, CHD accounts for the largest proportion (26.7%) of birth defect-associated hospitalization costs-up to $6.1 billion in 2013 (Arth et al., 2017). Yet after decades of research with a primary focus on genetic etiology, the underlying cause of these defects remains unknown in the majority of cases (Zaidi and Brueckner, 2017). Unexplained CHD may be secondary to undiscovered roles of noncoding genetic, epigenetic, and environmental factors, among others (Russell et al., 2018). Population studies have recently demonstrated that pregnancies complicated by CHD also carry a higher risk of developing pathologies associated with an abnormal placenta including growth disturbances (Puri et al., 2017), preeclampsia (Auger et al., 2015; Brodwall et al., 2016), preterm birth (Laas et al., 2012), and stillbirth (Jorgensen et al., 2014). Both the heart and placenta are vascular organs and develop concurrently; therefore, shared pathways almost certainly direct the development of both. The involvement of placental abnormalities in congenital heart disease, whether causal, commensurate or reactive, is under investigated and given the common developmental window and shared developmental pathways of the heart and placenta and concurrent vasculature development, we propose that further investigation combining clinical data, in vitro, in vivo, and computer modeling is fundamental to our understanding and the potential to develop therapeutics.