Women's Health - Obstetrics & Gynecology
Pre-eclampsia (previously called toxemia) is a hypertensive disorder of pregnancy with associated protein loss in the urine. Early identification may prevent progression, to the convulsions of eclampsia or multisystem effects of HELLP syndrome, that are potentially fatal to both mother and fetus.


Pre-eclampsia is diagnosed when a pregnant woman develops high blood pressure (two separate readings taken at least 6 hours apart of 140/90 or more) and 300 mg of protein in a 24 hour urine sample (proteinuria). Swelling or edema (especially in the hands and face) was originally considered an important sign for a diagnosis of pre-eclampsia, but in current medical practice only hypertension and proteinuria are necessary for a diagnosis.

Some women develop high blood pressure without the proteinuria; this is called Pregnancy-induced hypertension (PIH) or gestational hypertension. Both pre-eclampsia and PIH are regarded as very serious conditions and require careful monitoring of mother and baby.


Pre-eclampsia is much more common in the first pregnancy (3-5% of births) and usually becomes evident in the third trimester (and virtually always after the 20th week of pregnancy). It is also more common in women who have preexisting hypertension, diabetes, autoimmune diseases like lupus, various inherited thrombophilias like Factor V Leiden, or renal disease, in women with a family history of pre-eclampsia, and in women with a multiple gestation (twins, triplets and more).

Pre-eclampsia may also occur in the immediate post-partum period or up to 6-8 weeks post-partum. This is referred to as "postpartum pre-eclampsia".


Pre-eclampsia is thought to be caused by a shallowly implanted placenta which becomes hypoxic, leading to upregulated inflammatory mediators secreted by the placenta and acting on the vascular endothelium. If severe, it progresses to fulminant pre-eclampsia, with headaches, visual disturbances, and epigastric pain, and further to HELLP syndrome and eclampsia. Placental abruption is associated with hypertensive pregnancies. These are life-threatening conditions for both the developing fetus and the mother.


Despite extensive research, the exact aetiology and pathophysiology of the condition remain unclear. It is likely, however, that inadequate placental perfusion resulting from inadequate placental invasion precipitates the release of some form of chemical trigger which, in susceptible mothers, leads to endothelial damage, metabolic changes and a form of inflammatory response.

Recent studies suggest that hypoxia resulting from inadequate perfusion upregulates sFlt-1, a VEGF and PlGF antagonist, leading to a damaged maternal endothelium and restriction of placental growth.[1]

Placental invasion

In normal pregnancy trophoblastic invasion of the maternal spiral arteries causes the diameter of these arteries to increase around five-fold, converting the supply from a high resistance low flow system to one with a low resistance and high flow. In pre-eclampsia adequate invasion does not seem to occur, or is limited to the decidual portions of the vessels, and the result is inadequate placental blood flow. Inadequate placental invasion is also associated with fetal growth restriction, but not all those with this form of growth restriction develop pre-eclampsia.

As the degree of trophoblastic invasion is regulated by the maternal decidual barrier, probably by the action of a specific form of leucocyte, it has been suggested that the primary aetiological factor in pre-eclampsia may be immunological in origin. The predominance of pre-eclampsia in first pregnancies, and the protective effect of parity, further supports an immunological mechanism but the exact nature of this has yet to be elucidated. Nonetheless inadequate placental invasion certainly occurs and may be the trigger to release some factor, or alter the level of some factor, which brings about a response in a susceptible mother. SFlt-1 upregulated in response to placental hypoxia is a current front-runner for this factor.

Maternal susceptibility

As noted above, placentally mediated growth restriction can occur in isolation, but is also common with pre-eclampsia. It is therefore reasonable to assume that, while inadequate invasion occurs in both, only mothers who develop pre-eclampsia have a susceptibility to the placental stimulus. This susceptibility may be genotypic or phenotypic.

The evidence for genotypic susceptibility is strong. It has long been recognised that there is a familial pattern to pre-eclampsia and studies of pregnant women who have developed eclamptic seizures show that these women are more likely to have had sisters, mothers or grandmothers who have suffered from the same problem. Analysis suggests a single gene inheritance, either recessive with high penetrance, or dominant with incomplete penetrance. A number of genes on a variety of chromosomes have been found to be associated with pre-eclampsia, as has an angiotensin gene variant on chromosome 4. A genetic pre-disposition is also observed in those with certain congenital thrombophilias.

Certain phenotypes are also more susceptible. Those with insulin resistance and central obesity are at increased risk of pre-eclampsia, possibly on account of an exaggerated metabolic response. Those with systemic lupus erythematosus are also at increased risk, possibly because of an exaggerated immune response, and it has already been noted that those with a congenital thrombophilia are more likely to develop problems, possibly because of an increased coagulation response. These associations suggest that the pathophysiology involves a significant inter-relation between metabolic processes, an immunological response and coagulation problems, possibly mediated through endothelial damage. These maternal responses are now considered.

Metabolic changes, inflammatory response and endothelial damage

In normal pregnancy there is increased biosynthesis of eicosanoids - particularly prostacyclin (PGI2), a vasodilator with platelet inhibitory properties, and thromboxane A2, a vasoconstrictor with a tendency to stimulate platelet aggregation. As both usually increase in proportion to each other, there is a net neutralization and homeostasis is maintained. This homeostasis is disrupted in pre-eclampsia because of a relative deficiency in prostacyclin due either to a decrease in its synthesis and/or an increase in the production of thromboxane A2. This imbalance leads to vasoconstriction, hypertension, and platelet stimulation. These observations form the theoretical basis behind the use of low-dose aspirin, a prostaglandin inhibitor, in preventing pre-eclampsia. The dose of aspirin required to inhibit thromboxane synthesis is less than that required for prostacyclin inhibition and it should, in theory, therefore reduce the vascular and thrombotic effects.

Normal pregnancy is also associated with an increase in angiotensin II, a potent vasoconstrictor, yet despite this it is usual in pregnancy for the peripheral vascular resistance to fall. This appears to be because of a resistance to effects of angiotensin II in normal pregnancy, a phenomenon which seems to be lost in women who are destined to develop pregnancy-induced hypertension. This suggests that abnormalities in the renin-angiotensin-aldosterone system may play a role in the pathogenesis of the condition. Most agree that it seems unlikely, however, that derangements in this system are the primary cause of the pre-eclampsia.

In addition to these changes, there also appears to be some form of inflammatory process. There is an increase in the pro-inflammatory cytokines, evidence of neutrophil activation, and an increase in substances capable of causing inflammatory damage, particularly proteases and oxygen radicals. These are also recognised to damage vessel walls. Other systemic metabolic changes include hypertriglyceridaemia and a significant increase in free fatty acids, both associated with acute atherosis.

Some of these metabolic changes may cause endothelial damage, which in turn promotes platelet adhesion, stimulates clotting activity and disturbs the normal physiological modulation of vascular tone, further amplifying the response. The resulting secondary damage to other organs gives rise to the clinical features of gestational hypertension, pre-eclampsia, eclampsia and the HELLP syndrome.


The only known treatment for eclampsia or advancing preeclampsia is delivery, either by induction or Caesarean section. Hypertension can be sometimes be controlled with anti-hypertensive medication, but any effect this might have on the progress of the underlying disease is unknown. In some cases women with preeclampsia or eclampsia can be stabilized temporarily with magnesium sulfate intravenously to forestall seizures while steroid shots are administered to promote fetal lung maturation. As of 2006, Pfizer's Viagra (sildenafil citrate) was in Phase II clinical trials for the treatment of pre-eclampsia. Attempts will be made to delay delivery until the fetus has matured, but in severe cases where the mother's life is threatened, delivery must occur as soon as possible.

Recent studies into supplementation with antioxidant vitamins C and E found no change in preeclampsia rates.[2] Calcium supplementation in women with low-calcium diets found no change in preeclampsia rates but did find a decrease in the rate of severe preeclamptic complications.[3] Aspirin supplementation is still being evaluated as to dosage, timing, and population and may provide a slight preventative benefit.[4] There is insufficient evidence to recommend either exercise[5] or bedrest[6] as treatments. Studies of protein/calorie supplementation have found no effect on preeclampsia rates, and dietary protein restriction does not appear to increase preeclampsia rates.

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