If we know so much about preeclampsia, why haven't we cured the disease?

Abstract

Preeclampsia has been recognized for at least 100 years. In the last 20 years, the consideration of the disorder as more than simply hypertension in pregnancy has led to an explosion in knowledge about preeclampsia pathophysiology. It is now evident that for most cases of preeclampsia, the root cause is the placenta. Relatively reduced placental perfusion leads to inflammation, oxidative stress, and endoplasmic reticulum stress, which converge to modify maternal physiology, with endothelium an important target. Although preeclampsia is characteristically diagnosed in the last third of pregnancy, it is evident that many of these pathophysiological changes can be detected long before clinically evident disease. Furthermore, it is evident that the "maternal constitution," including genetic, behavioral, and metabolic factors, influences the maternal response to the abnormal placentation of preeclampsia. These insights would seem to provide a guide for the prediction of the disorder in early pregnancy, along with targets for intervention. However, this has not been the case. Predictive tests guided by this knowledge do not predict well and several interventions guided by the expanded understanding of pathophysiology do not prevent the disease. We propose that these failures are secondary to the fact that preeclampsia is more than one disorder. Further, we suggest that future progress toward prediction and prevention will require research guided by this concept.

Keywords: Pathophysiology; Prediction; Preeclampsia; Prevention; Translation.

Figure 1. The two-stage model of preeclampsia

It is proposed that the initiating insult in preeclampsia is a relative reduction of the perfusion of the placenta, Stage 1. This insult leads to the generation of materials (arrow) that act on the maternal constitution to result in the maternal pathophysiology of preeclampsia, Stage 2. Reprinted from Roberts & Hubel (2009), with permission from Elsevier.

Figure 2. Failed spiral artery remodeling in preeclampsia

During pregnancy, the spiral arteries that underlie the placenta, which in nonpregnant women are typical, small muscular arteries containing smooth muscle and an inner elastic lamina, undergo physiological remodeling. This includes terminal dilatation, the loss of the internal elastic lamina, and the loss of smooth muscle. This change extends into the inner third of the myometrium, resulting in the loss of a condensation of vascular smooth muscle near the myometrial decidual junction. This “sphincter” is proposed to be responsible for terminating blood flow at the time of menses. In preeclampsia, this process is not complete. The terminal dilatation is not as extensive and the removal of smooth muscle is not complete and does not extend beyond the decidua, leaving the functional vascular sphincter intact. Reprinted with permission. Parham 2004).

Figure 3. The heterogeneity of laboratory findings in preeclampsia

Scattergrams indicate three well-established pathophysiological findings in preeclampsia. A and B indicate triglycerides and malondialdehyde concentrations before and 24 h after delivery in women with preeclampsia (PE) or without preeclampsia (Norm). C demonstrates the concentration of s-Flt in women with severe or mild preeclampsia and normal pregnancy. The wide scatter of the findings, and the overlapping of the data from women with and without preeclampsia, is typical of findings with many analytes in preeclampsia. A and B reprinted from Hubel et al. (1996), with permission from Elsevier. C reprinted from Powers et al. (2005), with permission from Elsevier.

Figure 4. Phosphatidylinositol-glycan biosynthesis class F (PIGF) concentrations across pregnancy

PIGF was measured across pregnancy in 50 women who later developed preeclampsia (□) or 250 women who did not develop preeclampsia (◆). Between 15 and 22 weeks of pregnancy, values are significantly lower in women who later developed preeclampsia (p < 0.04). However, the ROC curve for these data had an area under the curve of 0.64, and if a cut off value was selected that resulted in a 20% false=positive rate, the accompanying sensitivity was 40%. In a population in which preeclampsia developed in 5% of pregnancy, the positive predictive value would be 9.5%.

Figure 5. Longitudinal pattern of PIGF concentrations

The data presented in Figure 4 were examined as longitudinal values for individual women. In 27 of the women who went on to develop preeclampsia, (A) the concentration of PIGF was similar to that in women with normal pregnancy outcome, prior to and with clinical preeclampsia. Normal pregnancy findings are illustrated in gray as median (solid line) or 95% confidence intervals (dashed line) in both A and B. In A, the results from women with preeclampsia are in blue (median solid. 95% confidence interval, dashed). The other 23 women who developed preeclampsia manifested a very different pattern (B), with no overlap with normal values, being less than the 95% confidence intervals of normal results from 15 weeks’ gestational age. Results from these women with preeclampsia are in red (Median solid 95% confidence intervals, dashed.) Reprinted from Powers et al. 2012, with permission from Wolters Kluwer Health.