Inflammation

Keradangan

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.[citation needed] 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.[27] 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.[28] 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.[29] Medical authorities and anti-smoking advocates discourage smoking in general during pregnancy. [edit] Antihypertensive therapy Antihypertensives may reduce maternal and fetal mortality among pregnancy patients with hypertension as compared to placebo according to a randomized controlled trial .[30] 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. [edit] 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,[31] but only in recent years did its use in the UK replace the use of diazepam or phenytoin.[32] Evidence for the use of magnesium sulfate came from the international MAGPIE study.[33] 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. [edit] Dietary and nutritional factors The Farm (Tennessee) is a vegan community in Tennessee, famous for their successful natural birth outcomes. Pre-eclampsia is virtually unknown in this community, with one study of 775 vegan mothers showing one only case meeting the clinical criteria for pre-eclampsia. The study's authors concluded that "it is possible that a vegan diet could alleviate most, if not all, of the signs and symptoms of preeclampsia."[34] 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.[35] 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.[36] 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.[37] The Universidad Nacional Autonoma de Mexico study[38] 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,[38] 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.[39] Low selenium status is associated with higher incidence of pre-eclampsia.[40][41] Some other vitamin may also play a role.[42] [edit] 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.[43] [edit] Exercise There is insufficient evidence to recommend either exercise[44] or bedrest[45] as preventative measures. [edit] 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.[12][46] As the theory is further investigated,[47] 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".[48] 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.[49] 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.[50][51] Long periods of sexual cohabitation with the same partner fathering a woman's child significantly decreased her chances of suffering pre-eclampsia.[48][51] 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".[52] 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".[52] 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,[53][54] 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."[54] 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",[55] 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.[12][46] 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.[53][54][56][57][58][59] 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.[54][56] 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.[51][56] 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.[51] 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.[60] [edit] 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.[51] In 2006, researchers at the University of Adelaide developed a gel containing TGF-Beta for use in human populations.[61] 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."[62] 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." [62] 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.[62][63] 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.

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