Pre-eclampsia

Pre-eclampsia is a medical condition in which hypertension arises in pregnancy (pregnancy-induced hypertension) in association with significant amounts of protein in the urine.

Pre-eclampsia refers to a set of symptoms rather than any causative factor, and there are many different causes for the condition. It appears likely that there are substances from the placenta that can 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, kidneys, and liver, with the release of vasoconstrictive factors being 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). Its progress differs among patients; most cases are diagnosed pre-term. Pre-eclampsia may also occur up to six weeks post-partum. Apart from Caesarean section or induction of labor (and therefore delivery of the placenta), there is no known cure. It is the most common of the dangerous pregnancy complications; it may affect both the mother and the unborn child.

Diagnosis
Pre-eclampsia is diagnosed when a pregnant woman develops high blood pressure (two separate readings taken at least six hours apart of 140/90 or more) and 300 mg of protein in a 24-hour urine sample (proteinuria). A rise in baseline blood pressure (BP) of 30 mmHg systolic or 15 mmHg diastolic, while not meeting the absolute criteria of 140/90, is still considered important to note, but is not considered 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. Pitting edema (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 a health care provider.

"Severe pre-eclampsia" involves a BP over 160/110, and additional symptoms.

Pre-eclampsia may progress to eclampsia, characterized by the appearance of tonic-clonic seizures. This happens only very rarely with proper treatment.

Although eclampsia is potentially fatal, pre-eclampsia is often asymptomatic, and so its detection depends on signs or investigations. Nonetheless, one symptom is crucially important because it is 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. It can be distinguished from heartburn when 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 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 are specific, and 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 proteinuria (protein in urine), which 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 fetus.

Epidemiology
Pre-eclampsia affects approximately 3% of all pregnancies worldwide, with onset of symptoms in the late second or third trimester, most commonly 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, and its frequency drops significantly in second pregnancies. While change of paternity in a subsequent pregnancy is now thought to lower risk except in those with a family history of hypertensive pregnancy, since increasing maternal age raises risk, it has been difficult to evaluate how significant paternity change actually is and studies are providing conflicting data on this point.

Pre-eclampsia is also more common in women who have preexisting hypertension, diabetes, autoimmune diseases such as lupus, various inherited thrombophilias such as Factor V Leiden, renal disease, women with a family history of pre-eclampsia, obese women, and women with a multiple gestation (twins or multiple birth). 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. 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 many cases to be caused by a shallowly implanted placenta which becomes hypoxic, leading to an immune reaction characterized by secretion of upregulated inflammatory mediators from the placenta, and acting on the vascular endothelium. The shallow implantation is thought to stem from the maternal immune system's response to the placenta. This theory emphasizes the role of the maternal immune system, and refers to evidence suggesting a lack of established immunological tolerance in pregnancy, resulting in an immune response against paternal antigens from the fetus and its placenta. In some cases of pre-eclampsia it is thought that the mother lacks the receptors for the proteins the placenta is using to downregulate the maternal immune system's response to it. This view is also consistent with evidence showing many miscarriages to be an immunological disorder where the mother's immune system "unleashes a destructive attack on the tissues of the developing child."

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, pre-eclampsia 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 pre-eclampsia arises, and have linked the syndrome to the presence of the following:
 * endothelial cell injury
 * immune rejection of the placenta
 * 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, including vitamin deficiency
 * genetic factors
 * air pollution
 * obesity
 * unfamiliar sperm theory
 * Thyroid dysfunction: Subclinical hypothyroidism in early pregnancy, compared with normal thyroid function, has been estimated to increase the risk of pre-eclampsia with an odds ratio of 1.7.

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...

Pathogenesis
Although much research into the etiology and mechanism of pre-eclampsia has taken place, its exact pathogenesis remains uncertain. Some studies support notions 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, inflammation, and other possible reactions.

Abnormalities in the maternal immune system and insufficiency of gestational immune tolerance seem to play major roles in pre-eclampsia. One of the main differences found in pre-eclampsia is a shift toward Th1 responses and the production of IFN-γ. The origin of IFN-γ is not clearly identified and could be the natural killer cells of the uterus, the placental dendritic cells modulating responses of T helper cells, alterations in synthesis of or response to regulatory molecules, or changes in the function of regulatory T cells in pregnancy. Aberrant immune responses promoting pre-eclampsia may also be due to an altered fetal allorecognition or to inflammatory triggers. 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 pre-eclampsia. These findings have given rise to the hypothesis that pre-eclampsia 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 pre-eclampsia and eclampsia.

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 pre-eclampsia. 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. Recent data indicate that Gadd45a stress signaling regulates elevated sFlt-1 expression in pre-eclampsia.

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 immune 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 pre-eclampsia associated with shallow implantation, leading to downstream hypoxia and the appearance of maternal symptoms in response to upregulated sFlt-1 and sEng.

Differential diagnosis
Pre-eclampsia-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, antiphospholipid syndrome 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 percent. 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 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 proven. 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.

Uric acid levels may help to predict maternal complications among patients with pre-eclampsia according to a systematic review and decision analysis. In this study, the sensitivity was 68% and specificity was 68%. In this study which assumed a prevalence of maternal complications was 5%, the positive predictive value of 6.2% and negative predictive value of 98.6% ( click here to adjust these results for patients at higher or lower risk of maternal complications). In their clinical decision analysis, they presumed initially a distress ratio of 10 (defined as being the expected distress of severe complications valued as 10 times worse than the expected distress of a caesarean section), and under these assumptions, they concluded that there would be the least expected distress from using serum uric acid for clinical decision making. The writers of this study acknowledged that there were significant limitations to their review due to heterogeneity of the individual studies they examined with regards to several variables.

Treatment and prevention
The only known treatments for eclampsia or advancing pre-eclampsia are abortion or delivery, either by labor induction or Caesarean section. However, post-partum pre-eclampsia may occur up to six 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.

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.

Thrombophilias may be weakly linked to pre-eclampsia. There are no high quality studies to suggest that blood thinners will prevent pre-eclampsia in thrombophilic women.

In low-risk pregnancies the association between cigarette smoking and a reduced risk of pre-eclampsia has been consistent and reproducible across epidemiologic studies. High-risk pregnancies (those with pregestational diabetes, chronic hypertension, history of pre-eclampsia in a previous pregnancy, or multifetal gestation) showed no significant protective effect. The reason for this discrepancy is not definitively known; research supports speculation that the underlying pathology increases the risk of pre-eclampsia to such a degree that any measurable reduction of risk due to smoking is swamped. A study into the effects of smoking on the incidence of pre-eclampsia in African-American women found a significantly lower incidence of pre-eclampsia with higher measured levels of nicotine. When adjusted for age, parity, and medical comorbidities the association was still observable, but no longer significant. Medical authorities and anti-smoking advocates discourage smoking in general during pregnancy.

Antihypertensive therapy
Antihypertensives may reduce maternal and fetal mortality among pregnancy patients with hypertension as compared to placebo according to a randomized controlled trial. Overall, after three weeks of treatment, MAP was lower in the isradipine group, but when compared with the placebo group, the difference in MAP did not have statistical significance. After treatment with isradipine, those patients with no proteinuria experienced a decrease of between 8.5 and 11.3 mmHg, whereas those with proteinuria experienced about only 1 mmHg difference in systolic blood pressure. Those treated with placebo in both groups did not experience much change in systolic blood pressure, regardless of proteinuria being present or not. Therefore, the authors concluded proteinuric patients may respond differently from nonproteinuric patients to this treatment, where the nonproteinuric patients responded the most to treatment with isradipine.

Labetolol or Nifedipine are often the antihypertensives of choice for eclampsia or pre-eclampsia according to the CHEST 2007 study, especially Labetolol as it has little placental transfer.

Magnesium sulfate
In some cases, women with pre-eclampsia 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 sulfate 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.

Dietary and nutritional factors
Studies of protein/calorie supplementation have found no effect on pre-eclampsia rates, and dietary protein restriction does not appear to increase pre-eclampsia rates. No mechanism by which protein or calorie intake would affect either placentation or inflammation has been proposed.

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.

The La Universida Nacional Autonoma de Mexico study also used a combination other antioxidant vitamins, such as vitamin C and E, in addition to L-arginine in the hopes of prevention of pre eclampsia in high-risk women. In this double blind placebo controlled trial of approximately 700 women, the results indicated that those who supported their diet with a combination of arginine and antioxidant vitamins experienced the preventative effects and reduced incidence of pre eclampsia during their pregnancy.

Low levels of vitamin D may be a risk factor for pre-eclampsia, and calcium supplementation in women with low-calcium diets found no change in pre-eclampsia 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
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.

Exercise
There is insufficient evidence to recommend either exercise or bedrest as preventative measures.

Induction of paternal tolerance
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 further investigated, researchers are increasingly studying 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". However, the results from a study conducted in 2004 show that the theory is still not conclusive. In that study, the researchers found that after adjustment and stratification, the effect of barrier contraceptive use on the development of pre-eclampsia had disappeared, with both arms having identical rates of pre-eclampsia. Although the study has since been criticized for its subjective adjustment of data, it remains important because it demonstrates that there is still some contention over the degree to which failure of tolerance induction can be attributed to prior exposure to the partner's sperm.

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.

Long periods of sexual cohabitation with the same partner fathering a woman's child significantly decreased her chances of suffering pre-eclampsia. As one early study described, "although pre-eclampsia is a disease of first pregnancies, the protective effect of multiparity is lost with change of partner". The study also concluded that although women with changing partners are strongly advised to use condoms to prevent sexually transmitted diseases, "a certain period of sperm exposure within a stable relation, when pregnancy is aimed for, is associated with protection against 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 "induction of allogeneic tolerance to the paternal human leukocyte antigen (HLA) molecules of the fetus may be crucial. Data collected strongly suggest 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, the fetus and placenta both contain "foreign" proteins from paternal genes, but regular, preceding and coincident exposure to the father's semen may promote immune acceptance and subsequent 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 pre-eclampsia 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.

Administration of immune factors
As the theory of immune intolerance as a cause of pre-eclampsia has become 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.

In 2006, researchers at the University of Adelaide developed a gel containing TGF-Beta for use in human populations. Later, GroPep, the company which was awarded the patent on a TGF-Beta3 variant, conducted trials where the miscarriage rate was halved in the mice studied. According to a GroPep news release later published, "a faulty immune response is implicated in the etiology of as many as 50% of all miscarriages." Their drug, PV903, was "targeted to treat recurrent miscarriages caused by an abnormal immune response to the foetus, a condition for which there is no current [drug] treatment." Stage I clinical trials of their vaginal gel were partly successful, succeeding in establishing the safety of the drug, but failing in their aim of increasing the number of specific immune cells measured in circulation, the necessary condition for affecting a desired immunological desensitization. The trials were later criticized for failing to recognize the synergistic effects of a large variety of immune factors naturally present in seminal fluid, which, acting together and with the localized presence of the foreign paternal proteins, modulate the female immune response so as to allow for implantation, and then the subsequent immune acceptance of the (foreign) fetus throughout a successful pregnancy. GroPep was later acquired by the large biotechnology company Novozymes. The development of the PV903 drug has since been suspended.