Pre-eclampsia (US: preeclampsia) is a medical condition where hypertension arises in pregnancy (pregnancy-induced hypertension) in association with significant amounts of protein in the urine. Because pre-eclampsia refers to a set of symptoms rather than any causative factor, it is established that there are many different causes for the syndrome. It also appears likely that there is a substance or substances from the placenta that may cause endothelial dysfunction in the maternal blood vessels of susceptible women. 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 from 20 weeks gestation (it is considered early onset before 32 weeks, which is associated with increased morbidity) and its progress differs among patients; most cases are diagnosed pre-term. Apart from abortion, Caesarean section, or induction of labor, and therefore delivery of the placenta, there is no known cure. It may also occur up to six weeks post-partum. It is the most common of the dangerous pregnancy complications; it may affect both the mother and the fetus.
Although eclampsia is potentially fatal, pre-eclampsia is often 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.
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.
In many cases of the pre-eclampsia syndrome, however, the maternal response to the placenta appears to have allowed for normal implantation. It is possible that women with higher baseline levels of inflammation stemming from underlying conditions such as chronic hypertension or autoimmune disease may have 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 preeclampsia arises, and have linked the syndrome to the presence of the following:
The current understanding of the syndrome is as a two-stage process, with a highly 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, inflammation, etc. Underlying maternal susceptibility to the damage is likely implicated as well.
Some 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 some 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 immune response and endothelial damage ultimately resulting in preeclampsia and eclampsia.
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 hemorrhage 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.
Many studies have also suggested the importance of a woman's immunological tolerance to her baby's father, whose genes are present in the young fetus and its placenta and which may pose a challenge to her immune system. As the theory is gaining support, researchers are increasingly recognizing the importance of a woman's continued exposure to her partner's semen as early as several years before conception. One study published in the American Journal of Obstetrics and Gynecology involved several hundreds of women and found that "women with a short period of cohabitation (less than 4 months) who used barrier methods for contraception had a substantially elevated risk for the development of pre-eclampsia compared with women with more than 12 months of cohabitation before conception." The study was also statistically significant at a desired 99.6% confidence level.
Results from research conducted in the past two decades strongly suggest the importance of repeated exposure to the father's semen throughout the full length of the pregnancy due to the immune-modulating effects of key factors in semen.
Women with underlying inflammatory disorders such as chronic hypertension or autoimmune diseases would likely benefit from aggressive treatment of those conditions prior to conception, tamping down the overactive immune system. Diagnosis of thrombophilias can allow for the administration of blood thinners, which may minimize clotting and improve blood flow through the placenta, minimizing the number of preeclampsia cases which apparently result from placental infarction.
Studies conducted on the effect of supplementation with antioxidants such as vitamin C and E found no change in pre-eclampsia rates. However, Drs. Padayatty and Levine with the NIH criticized the studies for overlooking several key factors that would have been important to the success of the supplementation. Because plasma ascorbate concentrations were not reported, they were estimated from known data, and the placebo and treatment groups in the study probably had similar plasma and tissue ascorbate concentrations. Some of the smaller doses of 1 g per day would have had little effect on plasma or intracellular ascorbate concentrations,'' so the studies should have been conducted with higher dosages of vitamin C in order for there to have been any beneficial effects.
Low levels of vitamin D may be a risk factor for preeclampsia, and 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. Low selenium status is associated with higher incidence of pre-eclampsia. Some other vitamin may also play a role.
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.
Research on the immunological basis for pre-eclampsia has indicated that continued exposure to a partner's semen has a strong protective effect against pre-eclampsia, largely due to the absorption of several immune modulating factors present in seminal fluid. Studies also showed that long periods of sexual cohabitation with the same partner fathering a woman's child significantly decreased her chances of suffering pre-eclampsia. Several other studies have since investigated the strongly decreased incidence of pre-eclampsia in women who had received blood transfusions from their partner, those with long, preceding histories of sex without barrier contraceptives, and in women who had been regularly performing oral sex, with one study concluding that "induction of allogeneic tolerance to the paternal HLA molecules of the fetus may be crucial. Data collected strongly suggests that exposure, and especially oral exposure to soluble HLA from semen can lead to transplantation tolerance."
Other studies have investigated the roles of semen in the female reproductive tracts of mice, showing that "insemination elicits inflammatory changes in female reproductive tissues," concluding that the changes "likely lead to immunological priming to paternal antigens or influence pregnancy outcomes." A similar series of studies confirmed the importance of immune modulation in female mice through the absorption of specific immune factors in semen, including TGF-Beta, lack of which is also being investigated as a cause of miscarriage in women and infertility in men.
According to the theory, some cases of pre-eclampsia are caused by an abnormal maternal immune response to the fetus and placenta, which both contain "foreign" proteins from paternal genes, but regular exposure to the father's semen promotes implantation, a process which is significantly supported by as many as 93 currently identified immune regulating factors in seminal fluid.
Having already noted the importance of a woman's immunological tolerance to her baby's paternal genes, several Dutch reproductive biologists decided to take their research a step further. Consistent with the fact that human immune systems tolerate things better when they enter the body via the mouth, the Dutch researchers conducted a series of studies that confirmed a surprisingly strong correlation between a diminished incidence of pre-eclampsia and a woman's practice of oral sex, and noted that the protective effects were strongest if she swallowed her partner's semen. The researchers concluded that while any exposure to a partner's semen during sexual activity appears to decrease a woman's chances for the various immunological disorders that can occur during pregnancy, immunological tolerance could be most quickly established through oral introduction and gastrointestinal absorption of semen. Recognizing that some of the studies potentially included the presence of confounding factors, such as the possibility that women who regularly perform oral sex and swallow semen also engage in more frequent intercourse, the researchers also noted that, either way, the data still overwhelmingly supports the main theory behind all their studies--that repeated exposure to semen establishes the maternal immunological tolerance necessary for a safe and successful pregnancy.
A team from the University of Adelaide has also investigated to see if men who have fathered pregnancies which have ended in miscarriage or pre-eclampsia had low seminal levels of critical immune modulating factors such as TGF-Beta. The team has found that certain men, dubbed "dangerous males," are several times more likely to father pregnancies that would end in either preeclampsia or miscarriage. Among other things, most of the "dangerous males" seemed to lack sufficient levels of the seminal immune factors necessary to induce immunological tolerance in their partners.
If the theory of pre-eclampsia as a symptom of immune intolerance in some cases is officially accepted, women who suffer repeated pre-eclampsia, miscarriages, or In Vitro Fertilization failures could potentially be administered key immune factors such as TGF-beta along with the father's foreign proteins, possibly either orally, as a sublingual spray, or as a vaginal gel to be applied onto the vaginal wall before intercourse.