Unveiling of Placental–Fetal Heart Interplay: A Novel Etiologic and Therapeutic Insight—A Narrative Review

Congenital heart disease (CHD) is the most common fetal anomaly worldwide. The definite etiology of most CHD is not recognized. A direct genetic etiology is considered for a minority of patients. Most etiologies are attributed to epigenetic and environmental factors. Placental malformation is an overlooked cause of CHD that has recently received attention. This narrative review presents a hypothesis based on clinical reports and animal studies. The placenta and fetal heart have concomitant developmental regulatory pathways, and their diseases have a two-way communication. Placental insufficiency may result in cardiac remodeling. Conversely, placental diseases are more frequent in association with fetal CHD. Fetal vascular malperfusion and genetic defects may play a role in placental and fetal heart disorders. Disturbed embryonic blood flow, such as syncytialization deformities and umbilical cord disorders, may lead to cardiac underdevelopment. Genetic, epigenetic, hormonal, and regulatory factors, including the NOTCH signaling pathway, SUMO-modulated stress responses, and autophagy-related genes, can affect both placental and fetal heart development. This novel information about the interplay between the placenta and fetal heart provides a new perspective on the etiologic factors of CHD and placental insufficiency. The current study aims to clarify the common causes of placental and fetal heart disorders.