Abnormalities of placental development and function are associated with the different fetal growth patterns of hypoplastic left heart syndrome and transposition of the great arteries.

Background: Birthweight is a critical predictor of congenital heart disease (CHD) surgical outcomes. Hypoplastic left heart syndrome (HLHS) is cyanotic CHD with known fetal growth restriction and placental abnormalities. Transposition of the great arteries (TGA) is cyanotic CHD with normal fetal growth. Placental development, growth and function is vital for appropriate fetal growth and recent studies have suggested abnormal placentation in cases of CHD. Comparison of the placenta in these diagnoses may provide insights on the fetal growth abnormality of CHD as well as identify any shared placental abnormalities in these two forms of CHD. Methods: Clinical data and placental histology from placentas associated with Transposition of the Great Arteries (TGA) were analyzed for gross pathology, morphology, maturity and vascularity and compared to both control and previously analyzed HLHS placentas. RNA was isolated from HLHS, TGA and control placentas and sequenced by Illumina HiSeq.Gene, analysis was performed using TopHat, R and MSigDB. Cluster analysis was performed using GoElite and Pathway analysis performed using PANTHERdb Overrepresentation Test. Immunohistochemistry was utilized to assess placental nutrient transporter expression in all three groups. Results: Placental weight was reduced in TGA cases, and placentas demonstrated reduced villous vasculature, immature terminal villi, and increased fibrin deposition in the parenchyma compared to controls and reflected our previous data from HLHS placentas. However, birth weight was not reduced in TGA cases compared to controls in contrast to the HLHS cohort and placental efficiency was significantly increased in TGA cases but not HLHS compared to control. Clustering and Pathway analysis identified both similarities and differences in placental transcriptomes between TGA and HLHS with term controls. Immunohistochemical analysis highlighted substantial differences between TGA and HLHS placentas in the protein expression and localization of nutrient transporters previously associated with impaired fetal growth.Conclusions: This study identifies the disruption of multiple placental mechanisms in two subtypes of CHD. Despite common vascular and structural disturbances in placentas from HLHS and TGA, these do not account for the differences seen in fetal growth which are likely due to perturbations in placental transport capabilities and efficiency seen in HLHS but not in TGA.