Women with more than one fetus, and women with molar pregnancies are more disposed to develop preeclampsia, suggesting that placental tissue, rather than the fetus itself, causes the disease. As early as 1939, Page thought the placenta contributed to the pathology of preeclampsia.¹⁰ He observed infarcts, sclerotic vessels, and thrombosis in the placentas he studied from hydatid moles. He even ground up placental tissue to inject into dogs, where a marked pressor effect was seen. Many years later, and with a better understanding of the vascular endothelium, it seems that Page was correct: Abnormal placentation is part of the etiology of preeclampsia. In a normal placenta, extravillous cytotrophoblasts invade the decidua and the maternal spiral arterioles, replacing both the endothelium and the muscular tunica media. This process, which begins in the first trimester, converts the spiral arterioles into large capacitance, low resistance vessels, and is thought to be complete by 18 to 20 weeks. This transformation is necessary to allow the large blood flow needed to support the fetal placental unit. In the preeclamptic placenta, this invasion by cytotrophoblasts is shallow and leads to reduced perfusion. Underperfusion of the placenta, and subsequent ischemia, appear to cause the generalized vascular and endothelial changes of preeclampsia. Curiously, the maternal manifestations of the disease usually present in the third trimester, well after the abnormal placentation occurs. Therefore preeclampsia is a two-stage disease. This raises further questions: Is the maternal response to the placenta immune-mediated, or a result of inflammation due to the release of vasogenic factors by the ischemic placenta? Even more curious is the fact that a placenta can be ischemic and the growth of the fetus retarded, without any manifestations of preeclampsia. There must be an interaction between the ischemic placenta and the maternal vascular and immune system to produce the widespread changes seen in the brain, kidney, liver, and vasculature of preeclamptic women.

Any medical online search will reveal a host of studies that find markers of endothelial cell injury circulating in preeclamptics. Many investigators have sought to find one that might be a reliable predictive marker, but thus far, no one marker has fit the bill. Ischemic tissue produces a host of free radicals and factors, both inflammatory and vasogenic. Increased lipid peroxidation has been shown in the placentas of preeclamptic women in a number of studies, and may be associated with elevated diastolic BP.¹¹ Superoxide dismutase and glutathione—potent, free radical scavengers—have been found in below-normal levels in preeclamptic placentas, presumably because of consumption in ongoing peroxidation. It is this evidence that has spurred interest in antioxidants as preventive treatment, as will be discussed. Tumor necrosis factor α (TNF-α), plasminogen activator, von Willebrand factor, fibronectin, and a host of vascular endothelial growth factors (VEGFs) have been found circulating in preeclamptics—but again, no one is clearly implicated as responsible for the disease.

A reliable marker would allow both prediction and possible prevention or early treatment of the disease. Levine and Karumanchi have reviewed and studied the leading angiogenic factors implicated in preeclampsia.¹² Attention is focused on VEGF, placental growth factor
(PlGF), and soluble fms-like tyrosine kinase 1 (sFlt-1). VEGF and PlGF both promote angiogenesis; sFlt-1, which is antiangiogenic, binds both VEGF and PlGF and prevents their interaction with endothelial cell receptors, producing endothelial dysfunction. sFlt-1 has been found in both the placentas and blood of preeclamptic women, and is increased 5 weeks before the onset of preeclampsia. Circulating PlGF is reduced in preeclampsia, probably because the increased concentrations of sFlt-1 have bound it, further contributing to placental and endothelial dysfunction. Circulating VEGF is found to be decreased, as one would expect if “mopped up” by sFlt-1 in some studies but not in others. PlGF can also be found in urine; this, too, has been studied as a possible marker. Buhimschi et al. have studied sFlt-1 and PlGF in urine and showed an increase in sFlt-1 and a decrease in PlGF.¹³ They also demonstrated a urinary ratio of the two that may be useful as a marker for preeclampsia. However, yet another study by Powers et al. found that circulating PlGF is not increased in all women with preeclampsia.¹⁴

Traditionally, increased thromboxane and decreased prostacyclin were thought to be major contributors to the clinical picture, and many textbooks show a “seesaw” imbalance of the two, as described by Walsh in 1985.¹⁵ Thromboxane, a potent vasoconstrictor has been found to be increased in preeclamptics in some studies, but Sibai’s group, during their low-dose aspirin study, found that reducing thromboxane levels did not prevent or lessen the severity of preeclampsia.⁶ Nitric oxide, another potent vasodilator, has been studied with difficulty because of its evanescence, and again there is no firm conclusion. A number of other circulatory and urinary factors, such as β-natriuretic peptide and homocysteine, are under observation, but it may be years yet before a reliable marker is discovered, and thus far sFlt-1, PlGF, and VEGF seem promising.

A curious phenomenon is the marked reduction of preeclampsia in smokers. This has been noted since the 1960s, when investigators collected data on smoking, low birth weight, and spontaneous abortion. It seems odd that regular exposure to a host of toxins and a potent vasoconstrictor such as nicotine would prevent a hypertensive, vasoactive disease, but such is the case. Sibai et al. found this true in a prospective multicenter study in 1995.⁹ Zhang et al. looked at a large study group and found a dose-response reduction in preeclampsia in smokers.¹⁶ The physiologic mechanisms behind this observation remain unclear.

An immunologic basis for preeclampsia has been postulated since the 1970s. Clearly, pregnancy is an unusual immunologic state in that two different genetic beings, with different human leukocyte antigen (HLA) markers, coexist without mounting an immune response to each other. The fact that most preeclampsia occurs in first pregnancies led investigators to think that a first pregnancy somehow “primed” a woman for the next immunologic assault, provided the paternity of the second fetus was the same. Others have considered preeclampsia a partial immune rejection of the fetus, and that complete rejection results in abortion. This does not explain the number of multiparas who develop preeclampsia, and the fact that having preeclampsia in a first pregnancy is a risk factor for developing the disease in a second pregnancy. There is, however, evidence that fetal cells and free DNA are shed into the maternal circulation—and in greater numbers in the preeclamptic. The first observation of fetal cells in the lungs of women who had died of eclampsia was made in the 19th century, by Schmorl.¹⁷ Hahn and Holzgreve reviewed (and conducted) some of the recent studies of fetal cell traffic in the preeclamptic.¹⁷ They note that in pregnancies with donated eggs—where both the ova and sperm are antigenically different from the pregnant host—preeclampsia is vastly increased. Perhaps the initial placental defect in the first trimester—ischemia as the result of faulty vascular development—leads to this increase in fetal cellular and DNA traffic, which then produces the second maternal stage of preeclampsia in the third trimester. Cotter et al. have studied a small number of RhD-negative women who went on to develop preeclampsia, and matched them to Rh-negative controls.¹⁸ Increased amounts of the fetal RhD gene was found in the women who developed preeclampsia at 15-weeks gestation. This work is significant, not because fetal RhD genes will be a reliable marker—only a small percentage of white women are RhD negative, and even fewer African or Asian women—but because it demonstrates an immune contribution to the disease. All women in the study had circulating fetal RhD genes, but the amount was increased in those who became preeclamptic. This tells us that fetal DNA does cross the placenta in normal and abnormal pregnancies, and that the maternal immune response to this material may be one of the factors that causes the disease. Zhong et al. demonstrated not only an increase in fetal DNA in the preeclamptic, but also an increase in maternal DNA.¹⁹ The presumed mechanism for this free DNA of maternal and fetal origin is cell death. It is not known whether this cell death is causative, or simply another marker for the process underlying preeclampsia.

Placentation depends on the invasion of maternal tissue by cytotrophoblasts. The HLA-G is a molecule expressed by extravillous trophoblast cells, and may protect these cells from the maternal immune response. Yie et al. have postulated that the reduced expression of this gene could play a role in preeclampsia.²⁰ The HLA-G is found in the placenta and circulation and is almost exclusively produced by trophoblasts. It was consistently lower in the first and second trimester in those women who developed preeclampsia versus matched controls. No statistical difference was seen in third trimester levels, although an earlier study by this group²⁰ did demonstrate a difference. Finding a marked difference early in pregnancy supports the concept that it is an early defect in placental implantation that leads to the later maternal manifestation of preeclampsia. Moreover, it is not known whether this reduced expression of the HLA-G gene is the cause, because it protects trophoblasts from the maternal immune response, or another marker, but it may have predictive value.

The cytokine TNF-α and its variants have been studied in many disease states. It is released by macrophages and mast cells, and is a potent immune modulator responsible for lymphocyte and interleukin activation. Schipper et al. focused their attention on TNF in their study of high-risk women.²¹ In their cohort study, TNF levels were monitored throughout pregnancy in 68 women with a history of severe preeclampsia, intrauterine growth retardation, or hypertension. The levels rose throughout pregnancy, but no significant differences were noted between normotensive, hypertensive, or preeclamptic women in any trimester. This is in contrast to several studies that found increased TNF and TNF-receptor (TNF-r) levels in the third trimester in preeclamptic women. In the Schipper study, TNF-r levels were higher in the second trimester in women with both preeclampsia and intrauterine growth retardation, but not in women affected by preeclampsia without fetal growth restriction. TNF-r was also high in women with severe preeclampsia. These varied outcomes may be the result of a small sample size, or more likely that there are many mechanisms and influences at work in preeclampsia.