impact In situations where the inner cell mass of the blastocyst is imperfectly aligned at implantation, a smaller region of syncytiotrophoblast invasion takes place, resulting in a smaller placenta and a degree of fetal growth restriction.5 Smaller placentas are also seen when the umbilical cord inserts at the margin or into fetal membranes instead of the central placental mass Infants with such placentas have been found to be proportionally smaller.11 Even when the umbilical cord insertion is eccentric but not marginal, the efficiency of the placental circulation is reduced and birth weight is smaller than would be expected for the placental weight.11 Placental insufficiency is a multifactorial failure of the maternal and fetal tissues to form the placenta Suboptimal uterine preparation, impaired decidualization, atypical maternal immune response to trophoblast invasion, and a host of potential aberrancies in the complex signaling involved in placental development contribute to the spectrum of clinical disease.8 Placenta in Congenital Heart Disease A growing body of data demonstrates that the placentas of fetuses with CHD are abnormal An emerging theory points to the existence of a “fetal heart-placental axis,” in which shared signaling factors and genes lead to the abnormal development of both organs—heart and placenta—early in fetal life.12 Placental abnormalities develop alongside CHD and are a part of the disease state.12,13 However, the precise nature of these abnormalities, and how they may vary with the form of structural heart disease present, is not well understood The placenta is intrinsically challenging to assess and study in utero It is a unique organ, which develops, functions, and is discarded over the course of less than a year, and is intimately tied to the delicate process of fetal growth and development Investigating the placenta in CHD has been approached in a number of ways Several large epidemiologic studies have compellingly demonstrated a significant relationship between fetuses with CHD and preeclampsia, especially early preeclampsia.14,15 One study of over 1.9 million pregnancies in Denmark demonstrated a sixfold increase in the risk of early preeclampsia when the fetus had structural heart disease; this effect was consistent across different forms of CHD.15 Prior history of early preeclampsia was associated with a sevenfold increase in risk of CHD in subsequent pregnancy, while a history of late-term preeclampsia also doubled the risk In addition, mothers who had a prior child with CHD increased the risk of early and late preeclampsia in subsequent pregnancies.15 These observations not only demonstrate the strong association between fetal CHD and placental insufficiency, but also point to the existence of maternal or genetic factors in the pathogenesis of both disease processes There are limited data examining the gross and microscopic pathology of placental abnormalities in CHD One study noted abnormal placental cord insertion associated with CHD, especially in the setting of intrauterine growth restriction.16 Another study of the placentas of fetuses with hypoplastic left heart syndrome demonstrated gross findings of significantly reduced placental weight and increased fibrin deposition Histologically, the placentas had increased syncytial nuclear aggregates, decreased terminal villi, reduced vasculature, and increased leptin expression in syncytiotrophoblast and endothelial cells.17 On a biomarker level, an imbalance between angiogenic and antiangiogenic factors in the maternal and fetal circulations has been implicated in the development of CHD, and may cause abnormal angiogenesis in the placenta.13 Interestingly, although these strong associations between CHD and placental anomalies have been demonstrated, the placental weight to birth weight ratio or placental size has not been consistently found to be significantly different in CHD.16,18 A recent large-scale population multicenter study in Denmark compared birth weights and placental weights of 7569 infants born with CHD over a 14-year period to those of individuals without CHD Only three types of CHD lesions, large ventricular septal defects, double-outlet right ventricle, and tetralogy of Fallot, were found to be associated with significantly smaller placental size at birth.18 In a study performed at The Children's Hospital of Philadelphia, we found the placenta-to-birth weight ratios of 120 fetuses with complex CHD consisting primarily of single ventricle and conotruncal anomalies to be significantly lower than normal.19 Differences in findings between these studies may be related to the specific populations of the type of CHD investigated, or perhaps variability in consistency of methodology in weighing the postnatal placenta Placental size alone may be an insufficient proxy for the complex changes of the fetal heart– placental axis in CHD In our Children's Hospital of Philadelphia study, for the 120 subjects overall, placental-to-birth weight ratios were less than the 10th percentile for 77% and less than the third percentile for 49% of subjects (Fig 11.2).19 Chorangiosis is the pathologic finding of an abnormally increased capillary density in the placental villi and is a reflection of tissue hypoxia We found abnormalities of chorangiosis in 18% and hypomature villi in 15% Subjects were categorized based on the type of cardiac structural malformation (single ventricle with aortic obstruction, single ventricle with pulmonic obstruction, two-ventricle conotruncal anomaly, and transposition of the great arteries) The lowest placenta-to-birthweight ratios and the greatest percentage of subjects with of chorangiosis and hypomature villi were noted in the newborns with transposition of the great arteries Also of great interest was the finding that important placental thrombosis was present overall in 41% with infarction of placental tissue in 17% Infarction was focused predominantly in the periphery of the placenta in the vascular watershed regions (Fig 11.3) There was no association between these placental abnormalities and fetal echocardiography-derived Doppler tracings of the umbilical artery pulsatility index Thus it appears that detecting placental structural abnormalities is not readily achievable by assessing