Pre-eclampsia: pathogenesis, novel diagnostics and therapies

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Abstract

Pre-eclampsia is a complication of pregnancy that is associated with substantial maternal and fetal morbidity and mortality. The disease presents with new-onset hypertension and often proteinuria in the mother, which can progress to multi-organ dysfunction, including hepatic, renal and cerebral disease, if the fetus and placenta are not delivered. Maternal endothelial dysfunction due to circulating factors of fetal origin from the placenta is a hallmark of pre-eclampsia. Risk factors for the disease include maternal comorbidities, such as chronic kidney disease, hypertension and obesity; a family history of pre-eclampsia, nulliparity or multiple pregnancies; and previous pre-eclampsia or intrauterine fetal growth restriction. In the past decade, the discovery and characterization of novel antiangiogenic pathways have been particularly impactful both in increasing understanding of the disease pathophysiology and in directing predictive and therapeutic efforts. In this Review, we discuss the pathogenic role of antiangiogenic proteins released by the placenta in the development of pre-eclampsia and review novel therapeutic strategies directed at restoring the angiogenic imbalance observed during pre-eclampsia. We also highlight other notable advances in the field, including the identification of long-term maternal and fetal risks conferred by pre-eclampsia.

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Circulating angiogenic factors and the risk of preeclampsia.

Richard J. Levine, Sharon E. Maynard, Cong Qian … (2004)

The cause of preeclampsia remains unclear. Limited data suggest that excess circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), may have a pathogenic role. We performed a nested case-control study within the Calcium for Preeclampsia Prevention trial, which involved healthy nulliparous women. Each woman with preeclampsia was matched to one normotensive control. A total of 120 pairs of women were randomly chosen. Serum concentrations of angiogenic factors (total sFlt-1, free PlGF, and free VEGF) were measured throughout pregnancy; there were a total of 655 serum specimens. The data were analyzed cross-sectionally within intervals of gestational age and according to the time before the onset of preeclampsia. During the last two months of pregnancy in the normotensive controls, the level of sFlt-1 increased and the level of PlGF decreased. These changes occurred earlier and were more pronounced in the women in whom preeclampsia later developed. The sFlt-1 level increased beginning approximately five weeks before the onset of preeclampsia. At the onset of clinical disease, the mean serum level in the women with preeclampsia was 4382 pg per milliliter, as compared with 1643 pg per milliliter in controls with fetuses of similar gestational age (P<0.001). The PlGF levels were significantly lower in the women who later had preeclampsia than in the controls beginning at 13 to 16 weeks of gestation (mean, 90 pg per milliliter vs. 142 pg per milliliter, P=0.01), with the greatest difference occurring during the weeks before the onset of preeclampsia, coincident with the increase in the sFlt-1 level. Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeclampsia was associated with a small-for-gestational-age infant. Increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent development of preeclampsia. Copyright 2004 Massachusetts Medical Society

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Global and regional estimates of preeclampsia and eclampsia: a systematic review.

Edgardo Abalos, Cristina Cuesta, Ana L. Grosso … (2013)

Reduction of maternal mortality is a target within the Millennium Development Goals. Data on the incidence of preeclampsia and eclampsia, one of the main causes of maternal deaths, are required at both national and regional levels to inform policies. We conducted a systematic review of the incidence of hypertensive disorders of pregnancy (HDP) with the objective of evaluating its magnitude globally and in different regions and settings. We selected studies using pre-specified criteria, recorded database characteristics and assessed methodological quality of the eligible studies reporting incidence of any HDP during the period 2002-2010. A logistic model was then developed to estimate the global and regional incidence of HDP using pre-specified predictor variables where empiric data were not available. We found 129 studies meeting the inclusion criteria, from which 74 reports with 78 datasets reporting HDP were analysed. This represents nearly 39 million women from 40 countries. When the model was applied, the overall estimates are 4.6% (95% uncertainty range 2.7-8.2), and 1.4% (95% uncertainty range 1.0-2.0) of all deliveries for preeclampsia and eclampsia respectively, with a wide variation across regions. The figures we obtained give a general idea of the magnitude of the problem and suggest that some regional variations might exist. The absence of data in many countries is of concern, however, and efforts should be made to implement data collection and reporting for substantial statistics. The implementation of large scale surveys conducted during a short period of time could provide more reliable and up-to-date estimations to inform policy. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

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Soluble endoglin and other circulating antiangiogenic factors in preeclampsia.

Richard Levine, Chun Lam, Cong Qian … (2006)

Alterations in circulating soluble fms-like tyrosine kinase 1 (sFlt1), an antiangiogenic protein, and placental growth factor (PlGF), a proangiogenic protein, appear to be involved in the pathogenesis of preeclampsia. Since soluble endoglin, another antiangiogenic protein, acts together with sFlt1 to induce a severe preeclampsia-like syndrome in pregnant rats, we examined whether it is associated with preeclampsia in women. We performed a nested case-control study of healthy nulliparous women within the Calcium for Preeclampsia Prevention trial. The study included all 72 women who had preterm preeclampsia ( or =37 weeks), 120 women with gestational hypertension, 120 normotensive women who delivered infants who were small for gestational age, and 120 normotensive controls who delivered infants who were not small for gestational age. Circulating soluble endoglin levels increased markedly beginning 2 to 3 months before the onset of preeclampsia. After the onset of clinical disease, the mean serum level in women with preterm preeclampsia was 46.4 ng per milliliter, as compared with 9.8 ng per milliliter in controls (P<0.001). The mean serum level in women with preeclampsia at term was 31.0 ng per milliliter, as compared with 13.3 ng per milliliter in controls (P<0.001). Beginning at 17 weeks through 20 weeks of gestation, soluble endoglin levels were significantly higher in women in whom preterm preeclampsia later developed than in controls (10.2 ng per milliliter vs. 5.8 ng per milliliter, P<0.001), and at 25 through 28 weeks of gestation, the levels were significantly higher in women in whom term preeclampsia developed than in controls (8.5 ng per milliliter vs. 5.9 ng per milliliter, P<0.001). An increased level of soluble endoglin was usually accompanied by an increased ratio of sFlt1:PlGF. The risk of preeclampsia was greatest among women in the highest quartile of the control distributions for both biomarkers but not for either biomarker alone. Rising circulating levels of soluble endoglin and ratios of sFlt1:PlGF herald the onset of preeclampsia. Copyright 2006 Massachusetts Medical Society.