What causes pre-eclampsia?

doi:10.1053/beog.1999.0005

Best Practice & Research Clinical Obstetrics & Gynaecology

Volume 13, Issue 1, March 1999, Pages 41-57

https://doi.org/10.1053/beog.1999.0005 Get rights and content

Abstract

Pre-eclampsia remains a leading cause of maternal and fetal morbidity and mortality. Despite extensive research, the mechanisms that cause pre-eclampsia are unknown and it has been considered to be the ‘disease of theories’. Hippocrates wrote in one of his Aphorisms that ‘convulsions take place from either repletion or depletion’. Since then, obstetricians have been divided on the question of which factor accounted for the convulsions observed during childbirth. Some considered that a sudden reduction in intra-abdominal pressure at delivery led to a pooling of blood diverted from the brain, causing collapse of the cerebral blood vessels and convulsions. Others postulated that cerebral congestion, secondary to compression of the abdominal organs by the large uterus, diverted blood to the brain, causing eclamptic convulsions. It is the purpose of this review to examine those theories about the cause of pre-eclampsia for which modern evidence is available. At present, it is believed that the pathological chain of events leading to pre-eclampsia is scheduled in two steps: an absolute or relative placental ischaemia is followed by a diffuse endothelial cell activation, which causes the clinical features of the disease.

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Cited by (26)

Protocol for measurement of mean arterial pressure at 10–40 weeks’ gestation
2017, Pregnancy Hypertension
Citation Excerpt :
In preeclampsia, hypertension develops as a result of vasoconstriction and reduced peripheral vascular compliance [1].
The study aimed to identify the simplest protocol for the measurement of mean arterial pressure (MAP) across 10–40 weeks’ gestation. 2726 women with uncomplicated singleton pregnancy attending for their routine hospital visit between 10 and 40 weeks’ gestation were recruited prospectively. The blood pressure (BP) was measured according to the National Heart Foundation of Australia (NHFA) protocol using automated devices. Linearizing regression models were determined for MAP derived from single, repeat and average measurements taken in the left and right arms using the same polynomial power of the best fit model determined using the NHFA protocol. Z-scores were used to compare the differences between the smoothed 50th percentiles. The first measurements taken in the left and right arms were on average 0.15SD and 0.12SD, respectively, higher than those obtained from the NHFA protocol. The second measurements taken in the left and right arms were both 0.26SD lower than the first measurement taken in the same arm and these values were lower than those from the NHFA protocol. The median MAP determined by the protocol of the average of two measurements taken in both arms was similar to the median MAP determined using the NHFA protocol (Z-score 0.0194SD). MAP derived by the average of two measurements in both arms had a quadratic relationship with gestation, with the measurement being the lowest in the mid-trimester. In conclusion, our study has demonstrated that at 10–40 weeks’ gestation, BP recordings can be obtained by a simpler protocol using the average of two measurements in both arms.
A case-control study of placental lesions associated with pre-eclampsia
2013, International Journal of Gynecology and Obstetrics
Citation Excerpt :
The findings of the present study have potentially enabled pathology examinations of the placenta to be systematized. The fact that the number of pathology findings significantly associated with pre-eclampsia has been reduced to 5 elementary lesions after multivariate analysis could be useful for understanding the mechanisms that lead to this disease, which many researchers consider to be multiple [22,23]. It is possible that some types of pre-eclampsia, depending on the timing of their onset or their association with HELLP syndrome, involve different pathophysiologic mechanisms.
To investigate gross and microscopic placental lesions associated with pre-eclampsia and to determine which lesions are most strongly linked to serious pregnancy complications.
A retrospective case–control study of 173 placentas from women with pre-eclampsia and 173 placentas from healthy normotensive women was conducted.
The mean placental weight in the pre-eclampsia group was lower than that recorded for the control group (280 g vs 360 g; P < 0.001). Infarcts (65.9% vs 13.2%; P < 0.001) and placental abruption (P < 0.001) were most frequent among women with pre-eclampsia. Microscopic findings showed the following lesions to be associated with pre-eclampsia: hypermature villi, defined by absence of intermediate villi (72% vs 16%; P < 0.001), excessive syncytial knots (90% vs 9%; P < 0.001), decidual vasculopathy (51% vs 8%; P < 0.001), villous fibrosis (6% vs 0%; P < 0.001), erythroblastosis (11% vs 4%; P < 0.01), and avascular terminal villi (9% vs 3%; P < 0.05). Increased syncytial knots, infarcts, basal decidual vasculopathy, hypermature villi, and placental erythroblastosis were still associated with pre-eclampsia after logistic regression modeling.
Placental lesions most strongly associated with pre-eclampsia were all causes or expressions of placental hypoxia or ischemia, which appears as the primary mechanism of pre-eclampsia.
HCG, Hyperglycosylated hCG, and Free ß-Subunit in Predicting Down Syndrome Pregnancies and Preeclampsia
2010, Human Chorionic Gonadotropin (hCG)
Screening pregnancies for Down syndrome was the first application found for hCG-H. hCG and hCG-H take on different profiles in Down syndrome pregnancies. The limited fusion of trophoblast cells in Down syndrome causes an unduly high proportion of cytotrophoblast cells to remain unfused. This leads to an unduly high production of hCG-H in Down syndrome pregnancies. This chapter presents the procedures involved in screening for Down syndrome pregnancies. Trisomy 21, also referred to as Down syndrome, is the most common genetic abnormality that complicates pregnancies. Trisomy 21 and other genetic monosomies, trisomies, and triploidies can be detected through a cytogenetic analysis procedure. Amniocentesis is performed at 14–26 weeks of gestation and can lead to late pregnancy termination between 16 and 30 weeks of gestation. Amniocentesis is complicated by an approximate 1 in 300 failure rate in which the fetus is aborted by the procedure. Chorionic villous sampling can determine cytogenetics at 9–11 weeks gestation. The prenatal risk for analysis by chorionic villous sampling is approximately 2 times higher; approximately 1 in 150 failures, depending on the expertise of the center performing the procedure. In terms of predicting a Down syndrome pregnancy, the hCG-H, PAPP-A, and nuchal translucency combination are the best methods available today. Impending hypertensive disorders can be predicted by measuring hCG-H in serum or urines during the first and second trimesters of pregnancy. As such, hCG-H presents itself as an ideal marker for predicting pregnancy hypertensive disorders.
Evolution of HCG, Evolution of Humans, and Evolution of Human Pregnancy Disorders and Cancer
2010, Human Chorionic Gonadotropin (hCG)
This chapter deals with CG evolution, the evolution of humans and human CG, and the complications humans now face because of the tremendous evolution of these molecules. The evolution of chorionic gonadotropin (CG) is a biological marvel in which two separate molecules evolved from a single deletion mutation in early primates. Dozens of incredible changes in amino acid sequences occurred during the development of CG and hyperglycosylated CG (CG-H) in early primates, advanced primates, and humans. These changes took CG and CG-H from nonacidic molecules with minimal activity in early primates to very acidic molecules with a long circulating half-life and maximal activity in humans. In so doing, they made human CG and CG-H ultrapotent. Although CG promotes differentiation of cytotrophoblast cells to syncytiotrophoblast cells, CG-H promotes the formation of cytotrophoblast columns and their extensions into primitive villi in early primates. Together, CG and CG-H drive the formation of trophoblast villi, the root structures of hemochorial placentation. CG drives angiogenesis in uterine vasculature so that invading villi are met with maternal blood. Both CG and CG-H drive the efficient nutrient system that we call hemochorial placentation. Seemingly, it is the evolution of ultraefficient CG and CG-H that drove hemochorial placentation to its maximum potential. In turn, an increasingly efficient transfer of fetal nutrients eventually led to an increased amount of nutrients needed to form the human brain.
Signs of maternal vascular dysfunction precede preeclampsia in women with type 1 diabetes
2007, Journal of Diabetes and its Complications
Citation Excerpt :
The pathological mechanism(s) leading to preeclampsia is unclear, but a reduction in uteroplacental perfusion with a subsequent placental ischemia is hypothesized to be the initial insult. According to this hypothesis, the ischemia results in the release of placental factors harmful to endothelium/vascular smooth muscle cells, causing a maternal vascular dysfunction responsible for the clinical characteristics of the syndrome (Salas, 1999; Roberts & Cooper, 2001). Known risk factors for the development of preeclampsia include hypertension, insulin resistance, dyslipidemia, and increased plasma homocysteine concentration, and in the diabetic pregnancy, other risk factors are diabetes duration, poor glycemic control, microalbuminuria, and diabetic nephropathy (Dunne et al., 1999; Ekbom et al., 2001; Garner, 1995; Roberts & Cooper, 2001; Rosenn et al., 1993; Sibai et al., 2000).
This study aims to test the hypothesis that vascular dysfunction is present early in pregnancy in women with type 1 diabetes who subsequently develop preeclampsia.
Eighty-three women with type 1 diabetes of more than 10 years duration were followed up prospectively during pregnancy. External ultrasound was used to measure the dilatory response of the brachial artery to postischemic increased blood flow (endothelium-dependent, flow-associated dilatation) and to nitroglycerin (NTG) [endothelium-independent, NTG-induced dilatation (NID)] at Gestational Weeks 11 and 29. Plasma concentrations of the vascular markers vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin, and von Willebrand factor antigen were also measured together with 24-h urinary albumin excretion (UAE), blood pressure (BP), and HbA_1C.
Fourteen (17%) of the 83 women developed preeclampsia. NID was significantly impaired at Week 29 in women prone to preeclampsia (108.8±7.0% vs. 116.8±8.9%, mean±S.D., P<.05), and the plasma concentrations of VCAM-1 and ICAM-1 were significantly elevated at Gestational Week 11 (612±82 vs. 516±109 μg/l, P<.005 and 293±67 vs. 255±57 μg/l, P<.05, respectively). Women who later developed preeclampsia were also characterized by higher UAE, higher BP, and higher HbA_1C than women who did not [Gestational Week 11: 194 (3–1104) vs. 7 (0–412) mg/24 h, median (range), P=.0003; 122±12/75±6 vs. 111±11/69±9 mmHg, mean±S.D., P<.01; and 8.2% (5.9–10.5%) vs. 7.2% (5.3–10.9%), P=.008, respectively].
This prospective study indicates that signs of maternal vascular dysfunction precede development of preeclampsia in women with type 1 diabetes.
Maternal autoantibodies from preeclamptic patients activate angiotensin receptors on human mesangial cells and induce interleukin-6 and plasminogen activator inhibitor-1 secretion
2005, American Journal of Hypertension
Preeclampsia affects 3–5% of all pregnancies. It is a major cause of maternal and fetal morbidity and mortality. Recent studies demonstrate that autoantibodies against the angiotensin II type 1 (AT₁) receptor are present in the serum of preeclamptic patients. In this study, we investigated the role of AT₁ receptor-agonistic autoantibody (AT1-AA) regarding interleukin-6 (IL-6) and plasminogen activator inhibitor–1 (Pai-1) secretion in human mesangial cells.
The study included ten patients: five severely preeclamptic and five normotensive pregnant women. Immunoglobulin-G (IgG) was purified from each individual. The presence of AT1-AA was determined based on its ability to stimulate an increase in the contraction rate of rat neonatal cardiomyocytes. Primary human mesangial cells were chosen to study IgG-induced secretion of IL-6 and Pai-1. Losartan and epitope peptides were used to determine whether AT1-AA interaction with AT₁ receptor was associated with stimulation of IL-6 and Pai-1 secretion and was mediated through AT₁ receptor activation.
The IgG from preeclamptic patients stimulated an increased contraction rate in rat neonatal cardiomyocytes. The IgG from preeclamptic patients induced the AT₁ receptor-specific secretion of IL-6 and Pai-1 from human mesangial cells at a significantly higher level than that achieved with IgG from normotensive patients. Competition with an epitope peptide suggested that the AT₁ receptor was stimulated by AT1-AA.
Our findings suggest that a maternal autoantibody with the ability to activate AT₁ receptors may account for the development of renal damage seen in preeclamptic patients.

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Abstract

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What causes pre-eclampsia?