Pre-eclampsia

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Editor(s)-in-Chief: C. Michael Gibson, M.S.,M.D. [mailto:mgibson@perfuse.org] Phone:617-632-7753; Stacie Zelman, M.D. [mailto:szelman@wfumbc.edu]

Overview
Pre-eclampsia (US: preeclampsia) is a medical condition where hypertension arises in pregnancy (pregnancy-induced hypertension) in association with significant protein in the urine. Its cause remains unclear, although the principal cause appears to be a substance or substances from the placenta causing endothelial dysfunction in the maternal blood vessels. While blood pressure elevation is the most visible sign of the disease, it involves generalized damage to the maternal endothelium and kidneys and liver, with the release of vasopressive factors only secondary to the original damage.

Pre-eclampsia may develop at varying times within pregnancy and its progress differs among patients; most cases are diagnosed pre-term. It has no known cure apart from ending the pregnancy (induction of labor or abortion). It may also occur up to six weeks post-partum. Of dangerous pregnancy complications, it is the most common; it may affect both the mother and the fetus.

Diagnosis
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). A rise in baseline BP of 20 systolic or 15 diastolic, while not meeting the absolute criteria of 140/90 is still considered important to note but no longer diagnostic. 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. However, unusual swelling, particularly of the hands, feet, or face, notable by leaving an indentation when pressed on, can be significant and should be reported to your health-care provider.

Pre-eclampsia is usually asymptomatic, hence its detection depends on signs or investigations. Nonetheless, one symptom is crucially important because it is so often misinterpreted. The epigastric pain, which reflects hepatic involvement and is typical of the HELLP syndrome, may easily be confused with heartburn, a very common problem of pregnancy. However, it is not burning in quality, does not spread upwards towards the throat, is associated with hepatic tenderness, may radiate through to the back, and is not relieved by giving antacids. It is often very severe, described by sufferers as the worst pain that they have ever experienced. Affected women are not uncommonly referred to general surgeons as suffering from an acute abdomen, for example acute cholecystitis.

In general, none of the signs of pre-eclampsia is specific; even convulsions in pregnancy are more likely to have causes other than eclampsia in modern practice. Diagnosis, therefore, depends on finding a coincidence of several pre-eclamptic features, the final proof being their regression after delivery.

Some women develop high blood pressure without the proteinuria (protein in urine); 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.

Epidemiology
Pre-eclampsia occurs in 6% of pregnancies, usually in the second or third trimester, and after the 32nd week. Some women will experience pre-eclampsia as early as 20 weeks, though this is rare. It is much more common in women who are pregnant for the first time.

Pre-eclampsia 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, obese women, and in women with a multiple gestation (twins, triplets, and more). The single most significant risk for developing pre-eclampsia is having had pre-eclampsia in a previous pregnancy.

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." The most dangerous time for the mother is the 24-48 hours postpartum and careful attention should be paid to pre-eclampsia signs and symptoms.

Causes
The pre-eclampsia syndrome is thought in some cases 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. The shallow implantation is thought to stem from the maternal system's response to the placenta. But in some cases of preeclampsia, the placenta appears to have implanted normally. Possibly women with higher baseline levels of inflammation stemming from underlying conditions such as chronic hypertension may have normally implanted placentae, but less tolerance for the inflammatory burden of pregnancy.

If severe, preeclampsia 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 baby and the mother.

Many theories have attempted to explain why the preeclampsia syndrome arises in some pregnancies:
 * vitamin D deficiency J Clinical Endorcinol Metabolism  Sept 2007  92(9) 3517-22
 * endothelial cell injury
 * rejection phenomenon
 * compromised placental perfusion
 * altered vascular reactivity
 * imbalance between prostacyclin and thromboxane
 * decreased glomerular filtration rate with retention of salt and water
 * decreased intravascular volume
 * increased central nervous system irritability
 * disseminated intravascular coagulation
 * uterine muscle stretch (ischemia)
 * dietary factors
 * genetic factors

The current understanding of the disease is as a two-stage process, with a variable first stage which predisposes the placenta to hypoxia, followed by the release of soluble factors which result in many of the other observed phenomena. Many of the older theories can be subsumed under this umbrella, as the soluble factors have been shown to cause, for example, endothelial cell injury, altered vascular reactivity, the classic lesion of glomerular endotheliosis, decreased intravascular volume, etc. Underlying maternal susceptibility to the damage is likely implicated as well.

Pathogenesis
Although much research into the etiology and mechanism of pre-eclampsia has taken place, its exact pathogenesis remains uncertain. Most studies support the notion of inadequate blood supply to the placenta making it release particular hormones or chemical agents that, in mothers predisposed to the condition, leads to damage of the endothelium (lining of blood vessels), alterations in metabolism, and inflammation.

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. In addition, endoglin, a TGF-beta antagonist, is elevated in pregnant women who develop preeclampsia. Soluble endoglin is likely upregulated by the placenta in response to an upregulation of cell-surface endoglin produced by the maternal immune system, although there is also the potential that sEng is produced by the maternal endothelium. Levels of both sFlt-1 and sEng increase as severity of disease increases, with levels of sEng surpassing levels of sFlt-1 in HELLP syndrome cases.

Both sFlt-1 and sEng are upregulated in all pregnant women to some extent, supporting the idea that hypertensive disease in pregnancy is a normal pregnancy adaptation gone awry. As natural killer cells are intimately involved in placentation and as placentation involves a degree of maternal tolerance for a foreign placenta which requires maternal resources for its support, it is not surprising that the maternal immune system might respond more negatively to the arrival of placentae under certain circumstances, such as a placenta which is more invasive than normal. Initial maternal rejection of the placental cytotrophoblasts may be the cause of the inadequately remodeled spiral arteries in those cases of preeclampsia associated with shallow implantation, leading to downstream hypoxia and the appearance of maternal symptoms in response to upregulated sFlt-1 and sEng. (See parent-offspring conflict.)

It has been documented that fetal cells such as fetal erythroblasts as well as cell-free fetal DNA are increased in the maternal circulation in women who develop preeclampsia. These findings have given rise to the hypothesis that preeclampsia is a disease process by which a placental lesion such as hypoxia allows increased fetal material into maternal circulation that leads to an inflammatory response and endothelial damage ultimately resulting in preeclampsia and eclampsia.

Differential diagnosis
Preeclampsia-eclampsia can mimic and be confused with many other diseases, including chronic hypertension, chronic renal disease, primary seizure disorders, gallbladder and pancreatic disease, immune or thrombotic thrombocytopenic purpura, and hemolytic-uremic syndrome. It must always be considered a possibility in any pregnant woman beyond 20 weeks of gestation. It is particularly difficult to diagnose when preexisting disease such as hypertension is present.

Complications
Eclampsia can occur after the onset of pre-eclampsia. Eclampsia, which is a more serious condition, complicates 1 in 2000 maternities in the United Kingdom and carries a maternal mortality of 1.8 per cent. The HELLP syndrome is more common, probably about 1 in 500 maternities, but may be as dangerous as eclampsia itself. These two major maternal crises can present unheralded by prodromal signs of pre-eclampsia.

Cerebral hemorrhage is a lesion that can kill women with pre-eclampsia or eclampsia. In that cerebral haemorrhage is a known complication of severe hypertension in other contexts, it must be assumed that this is a major predisposing factor in this situation, although this has not been proved. Adult respiratory distress syndrome appears to have become more common, it is not known whether this is a consequence of modern methods of respiratory support rather than of the disease itself.

Therapy
The only known treatment for eclampsia or advancing preeclampsia is delivery, either by induction or Caesarean section. However, post-partum pre-eclampsia may occur up to 6 weeks following delivery even if symptoms were not present during the pregnancy. Post-partum pre-eclampsia is dangerous to the health of the mother since she may ignore or dismiss symptoms as simple post-delivery headaches and edema. Hypertension can sometimes be controlled with anti-hypertensive medication, but any effect this might have on the progress of the underlying disease is unknown. Studies have suggested that the father's semen when introduced into the mother, most effectively orally but also through intercourse, prior to pregnancy reduces chances of preeclampsia, as it exposes the mother to foreign proteins of her partner.

Magnesium sulfate
In some cases women with preeclampsia or eclampsia can be stabilized temporarily with magnesium sulfate intravenously to forestall seizures while steroid injections are administered to promote fetal lung maturation. Magnesium sulfate as a possible treatment was considered at least as far back as 1955, but only in recent years did its use in the UK replace the use of diazepam or phenytoin. Evidence for the use of magnesium sulphate came from the international MAGPIE study. When induced delivery needs to take place before 37 weeks gestation, it is accepted that there are additional risks to the baby from premature birth that will require additional monitoring and care.

Other investigated treatments
Maternal Vitamin D Deficiency Increases the Risk of Preeclampsia. Studies into supplementation with antioxidant vitamins C and E found no change in preeclampsia rates. Drs. Padayatty and Levine with NIH in a "Letter to the Editor" stated that the studies and another "Letter to the Editor" ''overlooked a key reason for the lack of vitamin C on the prevention of preeclampsia. Because plasma ascorbate concentrations were not reported, we estimated them from known data, the placebo and treatment groups in the study probably had similar plasma and tissue ascorbate concentrations. Doses of 1 g per day have little effect on plasma or intracellular ascorbate concentrations.'' 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. Aspirin supplementation is still being evaluated as to dosage, timing, and population and may provide a slight preventative benefit in some women, however significant research has been done on aspirin and the results thus far are unimpressive. There is insufficient evidence to recommend either exercise or bedrest as preventative measures. Studies of protein/calorie supplementation have found no effect on preeclampsia rates, and dietary protein restriction does not appear to increase preeclampsia rates.

It has been suggested that fellatio may, through "immune modulation", have a beneficial role in preventing dangerous complications during pregnancy. Specifically, a research group reported that pre-eclampsia, a life threatening complication that sometimes arises in pregnancy, is much less frequent in couples who have practiced oral sex, and even more rare in couples where fellatio ended with the semen swallowed. Both results were statistically significant. This is consistent with other evidence that semen contains an agent that prevents preeclampsia, and with the theory that preeclampsia is an immunological condition. According to that view, preeclampsia is caused by a failure of the mother organism to accept the fetus and placenta, which both contain "foreign" proteins from the father's genes. Regular exposure to the father's semen might cause her immune system to gradually "grow accustomed" to their proteins. Other studies also found that, while any exposure to the partner's sperm during sex appears to decrease the chances of various disorders, women in couples who have practiced "other sex acts" than intercourse are half as likely to suffer pre-eclampsia. It is not known whether this represents a protective effect of "other sex acts" including oral sex, or a correlation between these sexual practices and some other protective factor: for example, greater overall frequency of sex. The standard way to resolve such questions (confounding) in medical science would be through a randomized trial, but there are unique challenges to research in sexual health.

When reporting the findings of the first research group mentioned above, New Scientist magazine thought it worth mentioning that some of the research team were women (including the lead author). Candidates for a protective agent in semen may include serum hormone leutinizing agent and transforming growth factor beta.[verification needed]

Additional Resources

 * NIH Working Group Report on High Blood Pressure in Pregnancy
 * NIH Working Group Report on High Blood Pressure in Pregnancy

لا ارتعاج Präeklampsie Preeclampsia Pré-éclampsie Preeclampsia Pre-eclampsie Preeklampsi Havandeskapsförgiftning