Mechanisms and Conditions of Placental Dysfunction
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maternal arteries normally extends beyond the spiral arteries and the decidual border into the radial arteries of the myometrium.8,9 Arteriovenous shunts also form in the maternal myometrium underneath the placenta, which support placental circulation by decreasing maternal systemic vascular resistance.4 Thus the human placenta forms from the interweaving of maternal and fetal tissues, guided by a complex interplay of hormones, cytokines, and growth factors.3,7 By the end of the first trimester the placenta has developed into its definitive state Although trophoblast invasion continues through 19 to 20 weeks, the fetus has become dependent on the uteroplacental circulation.2 Mechanisms and Conditions of Placental Dysfunction Placental dysfunction is the direct consequence of impaired placental development It can trigger a myriad of conditions affecting both mother and fetus, including miscarriage, premature rupture of membranes, fetal growth restriction, and the hypertensive disorders of pregnancy, including preeclampsia For definition purposes, preeclampsia is a disorder of pregnancy believed to develop due to placental dysfunction and is characterized by the onset of maternal hypertension and proteinuria As severity progresses it can lead to thrombocytopenia, hemolysis, hepatic dysfunction, renal dysfunction, peripheral edema, and visual disturbances In this advanced form, some refer to the condition as HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) If untreated, preeclampsia can lead to seizures, at which point it is then known as eclampsia Many of these clinical symptoms are believed to result from a maternal inflammatory reaction to placental dysfunction with maternal endothelial dysfunction and increased vascular reactivity.4,8 Many pathologic findings are associated with placental dysfunction, which can be loosely grouped into three categories: defective trophoblast invasion and failure of spiral artery dilation, vascular lesions termed “atherosis,” and lesions of the mature placenta However, how these findings are interrelated, and the roles they play in the mechanisms of the various clinical manifestations, is still somewhat unclear Defective trophoblast invasion and subsequent failure of spiral artery dilation have been shown to be associated in particular with early-onset preeclampsia, fetal growth restriction, and premature rupture of membranes.2,4 Beginning even before fertilization, if the uterine decidua is insufficiently prepared, trophoblast invasion may be suboptimal.8,10 Abnormal trophoblast invasion prevents adequate spiral artery remodeling and dilation, not only leading to decreased flow into the placenta but loss of the potentially oxygen-driven deep trophoblastic invasion and arterial remodeling.8,9 In severe preeclampsia, deep placentation is severely affected, with few spiral arteries demonstrating full transformation, compared to 90% transformation in normal pregnancies.10 Premature loss of the spiral artery trophoblast plugs can result in miscarriage or preeclampsia, depending on the location and timing.8 Normally, blood flow from spiral arteries begins at the center of the placenta first, and spreads to the margins; flow that begins at the margins instead may result in high oxidative stress and villous regression Conversely, if intervillous flow does not reach the placental margins, there can be chorionic regression and subsequently a small placenta.8 Atherosis is another common finding in states of placental dysfunction It can be seen in preeclampsia, hypertensive disease without preeclampsia, fetal growth restriction without maternal hypertension, and systemic lupus erythematosus.2,9 Lipophage plaques and fibrin accumulate in spiral arteries, and fibrinoid necrosis occurs In addition to physically obstructing flow, the resulting vasculopathy leads to endothelial disruption and a prothrombotic state, as well as aneurysm formation in the weakened arterial walls.2,9 Over time, macroscopic lesions develop in the placenta Without adequate dilation of the spiral arteries, maternal arterial blood flow enters the intravillous space with greater velocity, creating intervillous lakes These abnormal pockets often become lined with thrombus due to altered flow dynamics When severe, anchoring villi can be ruptured, pushing the chorionic plate away from the basal plate This perpetuates further placental disorder as fewer extravillous trophoblasts are able to reach the maternal surface to remodel the spiral arteries.4 As the structure of the placenta is disrupted, the delicate balance of oxygen and nutrient exchange is also affected In the classic state of fetal growth restriction, uterine venous blood has higher oxygen content than normal, which may be due to the higher velocity of arterial blood entering a structurally disrupted intervillous space resulting in suboptimal gas exchange.4 Moreover, without spiral artery remodeling, the vasocontractility of the vessels remains intact These arteries are less able to provide adequate flow to keep up with increasing fetal demand as pregnancy progresses.2 Their vasoreactivity can also cause episodes of placental hypoxia and reperfusion, leading to oxidative stress, apoptosis, and necrosis This, in turn, can trigger or promote a maternal hyperinflammatory response.8 Not every pregnancy with imperfect placentation results in clinically significant disease, and the clinical manifestations of diseases are not consistent Although many of these findings can be seen in intrauterine growth restriction and preeclampsia, not all fetuses of preeclamptic pregnancies are growth restricted.9 Less dramatic aberrancies in placental development nevertheless have an