Pre-eclampsia
Encyclopedia
Pre-eclampsia or preeclampsia 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
, kidney
s, 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.
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 seizure
s. This happens only very rarely with proper treatment.
Although eclampsia is potentially fatal (20% of cases), 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.
In November 2011, doctors working at the Mayo Clinic
announced that a new test had been discovered which involves checking patients' urine for specific cells called podocytes. Out of the 300 women tested, all the women who went on to have pre-eclampsia were found to have podocytes in their urine, whilst none of the women who had a normal pregnancy, or who suffered from pregnancy-induced hypertension
, tested positive for podocytes. Doctors said that this test appears to be extremely accurate and should become a recognised medical test soon.
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.
, 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 headache
s, 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:
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...
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 cell
s 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 cell
s 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.
, 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.
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.
, 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.
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.
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.
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."
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.
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.
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.
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
arises in pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
(pregnancy-induced hypertension
Pregnancy-induced hypertension
Gestational hypertension or pregnancy-induced hypertension is defined as the development of new arterial hypertension in a pregnant woman after 20 weeks gestation without the presence of protein in the urine.-Conditions:...
) in association with significant amounts of protein in the urine
Proteinuria
Proteinuria means the presence of anexcess of serum proteins in the urine. The protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine , retrograde ejaculation, pneumaturia due to a fistula, or drugs such as pyridium.- Causes...
.
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
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
that can cause endothelial dysfunction
Endothelial dysfunction
Endothelial dysfunction is a systemic pathological state of the endothelium and can be broadly defined as an imbalance between vasodilating and vasoconstricting substances produced by the endothelium...
in the maternal blood vessels of susceptible women. While blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
elevation is the most visible sign of the disease, it involves generalized damage to the maternal endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
, kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s, and liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, 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
Caesarean section
A Caesarean section, is a surgical procedure in which one or more incisions are made through a mother's abdomen and uterus to deliver one or more babies, or, rarely, to remove a dead fetus...
or induction of labor (and therefore delivery of the placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
), 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 pregnantPregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
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
Proteinuria
Proteinuria means the presence of anexcess of serum proteins in the urine. The protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine , retrograde ejaculation, pneumaturia due to a fistula, or drugs such as pyridium.- Causes...
). 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
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
(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
Eclampsia
Eclampsia , an acute and life-threatening complication of pregnancy, is characterized by the appearance of tonic-clonic seizures, usually in a patient who had developed pre-eclampsia...
, characterized by the appearance of tonic-clonic seizure
Tonic-clonic seizure
Tonic–clonic seizures are a type of generalized seizure that affects the entire brain...
s. This happens only very rarely with proper treatment.
Although eclampsia is potentially fatal (20% of cases), pre-eclampsia is often asymptomatic
Asymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...
, 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
HELLP syndrome
HELLP syndrome is a life-threatening obstetric complication usually considered to be a variant of pre-eclampsia. Both conditions usually occur during the later stages of pregnancy, or sometimes after childbirth.HELLP is an abbreviation of the main findings:...
, may easily be confused with heartburn
Heartburn
Heartburn, also known as pyrosis or acid indigestion is a burning sensation in the chest, just behind the breastbone or in the epigastrium...
, 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
Cholecystitis
-Signs and symptoms:Cholecystitis usually presents as a pain in the right upper quadrant. This is known as biliary colic. This is initially intermittent, but later usually presents as a constant, severe pain. During the initial stages, the pain may be felt in an area totally separate from the site...
).
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
Pregnancy-induced hypertension
Gestational hypertension or pregnancy-induced hypertension is defined as the development of new arterial hypertension in a pregnant woman after 20 weeks gestation without the presence of protein in the urine.-Conditions:...
(PIH) or gestational hypertension. Both pre-eclampsia and PIH are regarded as very serious conditions and require careful monitoring of mother and fetus.
In November 2011, doctors working at the Mayo Clinic
Mayo Clinic
Mayo Clinic is a not-for-profit medical practice and medical research group specializing in treating difficult patients . Patients are referred to Mayo Clinic from across the U.S. and the world, and it is known for innovative and effective treatments. Mayo Clinic is known for being at the top of...
announced that a new test had been discovered which involves checking patients' urine for specific cells called podocytes. Out of the 300 women tested, all the women who went on to have pre-eclampsia were found to have podocytes in their urine, whilst none of the women who had a normal pregnancy, or who suffered from pregnancy-induced hypertension
Pregnancy-induced hypertension
Gestational hypertension or pregnancy-induced hypertension is defined as the development of new arterial hypertension in a pregnant woman after 20 weeks gestation without the presence of protein in the urine.-Conditions:...
, tested positive for podocytes. Doctors said that this test appears to be extremely accurate and should become a recognised medical test soon.
Epidemiology
Pre-eclampsia affects approximately 6-8% 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
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, diabetes, autoimmune diseases such as lupus
Lupus erythematosus
Lupus erythematosus is a category for a collection of diseases with similar underlying problems with immunity . Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs...
, various inherited thrombophilias such as Factor V Leiden
Factor V Leiden
Factor V Leiden is the name given to a variant of human factor V that causes a hypercoagulability disorder. In this disorder the Leiden variant of factor V cannot be inactivated by activated protein C. Factor V Leiden is the most common hereditary hypercoagulability disorder amongst Eurasians...
, renal disease
Chronic renal failure
Chronic kidney disease , also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. The symptoms of worsening kidney function are unspecific, and might include feeling generally unwell and experiencing a reduced appetite...
, women with a family history of pre-eclampsia, obese women, and women with a multiple gestation (twins
TWINS
Two Wide-Angle Imaging Neutral-Atom Spectrometers are a pair of NASA instruments aboard two United States National Reconnaissance Office satellites in Molniya orbits. TWINS was designed to provide stereo images of the Earth's ring current. The first instrument, TWINS-1, was launched aboard USA-184...
or multiple birth
Multiple birth
A multiple birth occurs when more than one fetus is carried to term in a single pregnancy. Different names for multiple births are used, depending on the number of offspring. Common multiples are two and three, known as twins and triplets...
). 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 hypoxicHypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
, leading to an immune reaction characterized by secretion of upregulated inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
mediators from the placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
, and acting on the vascular endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
. 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
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
, 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 headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
s, visual disturbances, and epigastric pain, and further to HELLP syndrome
HELLP syndrome
HELLP syndrome is a life-threatening obstetric complication usually considered to be a variant of pre-eclampsia. Both conditions usually occur during the later stages of pregnancy, or sometimes after childbirth.HELLP is an abbreviation of the main findings:...
and eclampsia
Eclampsia
Eclampsia , an acute and life-threatening complication of pregnancy, is characterized by the appearance of tonic-clonic seizures, usually in a patient who had developed pre-eclampsia...
. Placental abruption
Placental abruption
Placental abruption is a complication of pregnancy, wherein the placental lining has separated from the uterus of the mother. It is the most common pathological cause of late pregnancy bleeding. In humans, it refers to the abnormal separation after 20 weeks of gestation and prior to birth...
is associated with hypertensive pregnancies. These are life-threatening conditions
Medical emergency
A medical emergency is an injury or illness that is acute and poses an immediate risk to a person's life or long term health. These emergencies may require assistance from another person, who should ideally be suitably qualified to do so, although some of these emergencies can be dealt with by the...
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 prostacyclinProstacyclinProstacyclin is a member of the family of lipid molecules known as eicosanoids.As a drug, it is also known as "epoprostenol". The terms are sometimes used interchangeably.-History:...
and thromboxaneThromboxaneThromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring.... - 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
- ThyroidThyroidThe thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
dysfunction: Subclinical hypothyroidism in early pregnancy, compared with normal thyroid function, has been estimated to increase the risk of pre-eclampsia with an odds ratioOdds ratioThe odds ratio is a measure of effect size, describing the strength of association or non-independence between two binary data values. It is used as a descriptive statistic, and plays an important role in logistic regression...
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
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
, 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 etiologyEtiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....
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
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
(lining of blood vessels), alterations in metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
, inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
, and other possible reactions.
Abnormalities in the maternal immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
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 cell
Natural killer cell
Natural killer cells are a type of cytotoxic lymphocyte that constitute a major component of the innate immune system. NK cells play a major role in the rejection of tumors and cells infected by viruses...
s 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 cell
Regulatory T cell
Regulatory T cells , sometimes known as suppressor T cells, are a specialized subpopulation of T cells which suppresses activation of the immune system and thereby maintains tolerance to self-antigens. The existence of regulatory T cells was the subject of significant controversy among...
s 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
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
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
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
resulting from inadequate perfusion upregulates sFlt-1, a VEGF
Vascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
and PlGF antagonist, leading to a damaged maternal endothelium and restriction of placental growth. In addition, endoglin
Endoglin
Endoglin is a type I membrane glycoprotein located on cell surfaces and is part of the TGF beta receptor complex.The protein consists of a homodimer of 180 kDA with disulfide links....
, 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
HELLP syndrome
HELLP syndrome is a life-threatening obstetric complication usually considered to be a variant of pre-eclampsia. Both conditions usually occur during the later stages of pregnancy, or sometimes after childbirth.HELLP is an abbreviation of the main findings:...
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
Immune tolerance in pregnancy
Immune tolerance in pregnancy or gestational/maternal immune tolerance is the absence of a maternal immune response against the fetus and placenta, which thus may be viewed as unusually successful allografts, since they genetically differ from the mother. In the same way, many cases of spontaneous...
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 diseasePancreatic disease
-Pancreatitis:Pancreatitis is inflammation of the pancreas. There are two forms of pancreatitis, which are different in causes and symptoms, and require different treatment:...
, immune or thrombotic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura is a rare disorder of the blood-coagulation system, causing extensive microscopic thromboses to form in small blood vessels throughout the body...
, antiphospholipid syndrome
Antiphospholipid syndrome
Antiphospholipid syndrome or antiphospholipid antibody syndrome , often also Hughes syndrome, is an autoimmune, hypercoagulable state caused by antibodies against cell-membrane phospholipids that provokes blood clots in both arteries and veins as well as pregnancy-related complications such as...
and hemolytic-uremic syndrome
Hemolytic-uremic syndrome
Hemolytic-uremic syndrome , abbreviated HUS, is a disease characterized by hemolytic anemia, acute renal failure and a low platelet count . It predominantly, but not exclusively, affects children. Most cases are preceded by an episode of diarrhea caused by E. coli O157:H7, which is acquired as a...
. 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
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
is present.
Complications
EclampsiaEclampsia
Eclampsia , an acute and life-threatening complication of pregnancy, is characterized by the appearance of tonic-clonic seizures, usually in a patient who had developed pre-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
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
levels may help to predict maternal complications among patients with pre-eclampsia according to a systematic review
Systematic review
A systematic review is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. Systematic reviews of high-quality randomized controlled trials are crucial to evidence-based medicine...
and decision analysis
Decision analysis
Decision analysis is the discipline comprising the philosophy, theory, methodology, and professional practice necessary to address important decisions in a formal manner...
. 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
Positive predictive value
In statistics and diagnostic testing, the positive predictive value, or precision rate is the proportion of subjects with positive test results who are correctly diagnosed. It is a critical measure of the performance of a diagnostic method, as it reflects the probability that a positive test...
of 6.2% and negative predictive value
Negative predictive value
In statistics and diagnostic testing, the negative predictive value is a summary statistic used to describe the performance of a diagnostic testing procedure. It is defined as the proportion of subjects with a negative test result who are correctly diagnosed. A high NPV means that when the test...
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 deliveryChildbirth
Childbirth is the culmination of a human pregnancy or gestation period with the birth of one or more newborn infants from a woman's uterus...
, either by labor induction or Caesarean section
Caesarean section
A Caesarean section, is a surgical procedure in which one or more incisions are made through a mother's abdomen and uterus to deliver one or more babies, or, rarely, to remove a dead fetus...
. 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
Smoking
Smoking is a practice in which a substance, most commonly tobacco or cannabis, is burned and the smoke is tasted or inhaled. This is primarily practised as a route of administration for recreational drug use, as combustion releases the active substances in drugs such as nicotine and makes them...
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 hypertensionHypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
as compared to placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
according to a randomized controlled trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
. Overall, after three weeks of treatment, MAP was lower in the isradipine
Isradipine
Isradipine is a calcium channel blocker of the dihydropyridine class. It is usually prescribed for the treatment of high blood pressure in order to reduce the risk of stroke and heart attack...
group, but when compared with the placebo group, the difference in MAP did not have statistical significance
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
. After treatment with isradipine
Isradipine
Isradipine is a calcium channel blocker of the dihydropyridine class. It is usually prescribed for the treatment of high blood pressure in order to reduce the risk of stroke and heart attack...
, those patients with no proteinuria experienced a decrease of between 8.5 and 11.3 mmHg, whereas those with proteinuria
Proteinuria
Proteinuria means the presence of anexcess of serum proteins in the urine. The protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine , retrograde ejaculation, pneumaturia due to a fistula, or drugs such as pyridium.- Causes...
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
Proteinuria
Proteinuria means the presence of anexcess of serum proteins in the urine. The protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine , retrograde ejaculation, pneumaturia due to a fistula, or drugs such as pyridium.- Causes...
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
Nifedipine
Nifedipine is a dihydropyridine calcium channel blocker...
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 sulfateMagnesium sulfate
Magnesium sulfate is a chemical compound containing magnesium, sulfur and oxygen, with the formula MgSO4. It is often encountered as the heptahydrate epsomite , commonly called Epsom salt, from the town of Epsom in Surrey, England, where the salt was distilled from the springs that arise where the...
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
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
or phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
.
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
Premature birth
In humans preterm birth refers to the birth of a baby of less than 37 weeks gestational age. The cause for preterm birth is in many situations elusive and unknown; many factors appear to be associated with the development of preterm birth, making the reduction of preterm birth a challenging...
that will require additional monitoring and care.
Dietary and nutritional factors
The Farm (Tennessee)The Farm (Tennessee)
The Farm is an intentional community in Lewis County, Tennessee, near the town of Summertown, Tennessee, based on principles of nonviolence and respect for the Earth. It was founded in 1971 by Stephen Gaskin and 320 San Francisco hippies; The Farm is well known amongst hippies and other members of...
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."
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
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
may be a risk factor for pre-eclampsia,
and calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
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
Selenium
Selenium is a chemical element with atomic number 34, chemical symbol Se, and an atomic mass of 78.96. It is a nonmetal, whose properties are intermediate between those of adjacent chalcogen elements sulfur and tellurium...
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
Oral sex
Oral sex is sexual activity involving the stimulation of the genitalia of a sex partner by the use of the mouth, tongue, teeth or throat. Cunnilingus refers to oral sex performed on females while fellatio refer to oral sex performed on males. Anilingus refers to oral stimulation of a person's anus...
, with one study concluding "induction of allogeneic tolerance to the paternal human leukocyte antigen
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
(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
Miscarriage
Miscarriage or spontaneous abortion is the spontaneous end of a pregnancy at a stage where the embryo or fetus is incapable of surviving independently, generally defined in humans at prior to 20 weeks of gestation...
in women and infertility
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
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
University of Adelaide
The University of Adelaide is a public university located in Adelaide, South Australia. Established in 1874, it is the third oldest university in Australia...
has also investigated to see if men who have fathered pregnancies which have ended in miscarriage
Miscarriage
Miscarriage or spontaneous abortion is the spontaneous end of a pregnancy at a stage where the embryo or fetus is incapable of surviving independently, generally defined in humans at prior to 20 weeks of gestation...
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
Miscarriage
Miscarriage or spontaneous abortion is the spontaneous end of a pregnancy at a stage where the embryo or fetus is incapable of surviving independently, generally defined in humans at prior to 20 weeks of gestation...
. 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
University of Adelaide
The University of Adelaide is a public university located in Adelaide, South Australia. Established in 1874, it is the third oldest university in Australia...
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
Miscarriage
Miscarriage or spontaneous abortion is the spontaneous end of a pregnancy at a stage where the embryo or fetus is incapable of surviving independently, generally defined in humans at prior to 20 weeks of gestation...
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
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
throughout a successful pregnancy. GroPep was later acquired by the large biotechnology company Novozymes
Novozymes
Novozymes is a biotech-based company, headquartered in Denmark and employing approximately 5,400 people in 30 countries. Novozymes A/S’ B shares are listed on the NASDAQ OMX Nordic.-Business areas:...
. The development of the PV903 drug has since been suspended.
Further reading
- A Mom and Dad's Guide to Pre-eclampsia By David Papandreas