Pre-eclampsia

Pre-eclampsia

A micrograph showing hypertrophic decidual vasculopathy, a finding seen in gestational hypertension and pre-eclampsia. H&E stain.
Classification and external resources
Specialty Obstetrics
ICD-10 O10–O14
ICD-9-CM 642.4–642.7
OMIM 189800
DiseasesDB 10494
MedlinePlus 000898
eMedicine med/1905 ped/1885
MeSH D011225
Orphanet 275555

Pre-eclampsia or preeclampsia (PE) is a disorder of pregnancy characterized by high blood pressure and a large amount of protein in the urine.[1] The disorder usually occurs in the third trimester of pregnancy and worsens over time.[2][3] In severe disease there may be red blood cell breakdown, a low blood platelet count, impaired liver function, kidney dysfunction, swelling, shortness of breath due to fluid in the lungs, or visual disturbances.[2][3] Preeclampsia increases the risk of poor outcomes for both the mother and the baby.[3] If left untreated, it may result in seizures at which point it is known as eclampsia.[2]

Risk factors for preeclampsia include: obesity, prior hypertension, older age, and diabetes mellitus.[2][4] It is also more frequent in a woman's first pregnancy and if she is carrying twins.[2] The underlying mechanism involves abnormal formation of blood vessels in the placenta amongst other factors.[2] Most cases are diagnosed before delivery. Rarely, preeclampsia may begin in the period after delivery.[3] While historically both high blood pressure and protein in the urine were required to make the diagnosis, some definitions also include those with hypertension and any associated organ dysfunction.[3][5] Blood pressure is defined as high when it is greater than 140 mmHg systolic or 90 mmHg diastolic at two separate times, more than four hours apart in a woman after twenty weeks of pregnancy.[3] Preeclampsia is routinely screened for during prenatal care.[6]

Recommendations for prevention include: aspirin in those at high risk, calcium supplementation in areas with low intake, and treatment of prior hypertension with medications.[4][7] In those with preeclampsia delivery of the fetus and placenta is an effective treatment.[4] When delivery becomes recommended depends on how severe the preeclampsia and how far along in pregnancy a person is.[4] Blood pressure medication, such as labetalol and methyldopa, may be used to improve the mother's condition before delivery.[8] Magnesium sulfate may be used to prevent eclampsia in those with severe disease.[4] Bedrest and salt intake have not been found to be useful for either treatment or prevention.[3][4]

Preeclampsia affects 2–8% of pregnancies worldwide.[4] Hypertensive disorders of pregnancy (which include preeclampsia) are one of the most common causes of death due to pregnancy.[8] They resulted in 29,000 deaths in 2013 – down from 37,000 deaths in 1990.[9] Preeclampsia usually occurs after 32 weeks; however, if it occurs earlier it is associated with worse outcomes.[8] Women who have had preeclampsia are at increased risk of heart disease and stroke later in life.[6] The word eclampsia is from the Greek term for lightning.[10] The first known description of the condition was by Hippocrates in the 5th century BC.[10]

Signs and symptoms

Swelling (especially in the hands and face) was originally considered an important sign for a diagnosis of preeclampsia. However, because swelling is a common occurrence in pregnancy, its utility as a distinguishing factor in preeclampsia is not high. 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.

In general, none of the signs of preeclampsia are specific, and even convulsions in pregnancy are more likely to have causes other than eclampsia in modern practice. Further, a symptom such as epigastric pain may be misinterpreted as heartburn. Diagnosis, therefore, depends on finding a coincidence of several preeclamptic features, the final proof being their regression after delivery.

Causes

There is no definitive known cause of preeclampsia, though it is likely related to a number of factors. Some of these factors include:[2][6]

Those with long term high blood pressure have a risk 7 to 8 times higher than those without.[12]

Physiologically, research has linked preeclampsia to the following physiologic changes: alterations in the interaction between the maternal immune response and the placenta, placental injury, endothelial cell injury, altered vascular reactivity, oxidative stress, imbalance among vasoactive substances, decreased intravascular volume, and disseminated intravascular coagulation.[6][13]

While the exact cause of preeclampsia remains unclear, there is strong evidence that a major cause predisposing a susceptible woman to preeclampsia is an abnormally implanted placenta.[2][6] This abnormally implanted placenta may result in poor uterine and placental perfusion, yielding a state of hypoxia and increased oxidative stress and the release of anti-angiogenic proteins along with inflammatory mediators into the maternal plasma.[6] A major consequence of this sequence of events is generalized endothelial dysfunction.[1] The abnormal implantation may stem from the maternal immune system's response to the placenta, specifically a lack of established immunological tolerance in pregnancy. Endothelial dysfunction results in hypertension and many of the other symptoms and complications associated with preclampsia.[2] Those with preeclampsia may have a lower risk of breast cancer.[14]

Risk factors

Known risk factors for preeclampsia include:[8][15]

Pathogenesis

Although much research into mechanism of preeclampsia has taken place, its exact pathogenesis remains uncertain. Preeclampsia is thought to result from an abnormal placenta, the removal of which ends the disease in most cases.[2] During normal pregnancy, the placenta vascularizes to allow for blood flow between the mother and fetus.[13] Abnormal development of the placenta leads to poor placental perfusion. The placenta of women with preeclampsia is abnormal and characterized by poor trophoblastic invasion.[13] It is thought that this results in oxidative stress, hypoxia, and the release of factors that promote endothelial dysfunction, inflammation, and other possible reactions.[1][13][20]

The clinical manifestations of preeclampsia are associated with general endothelial dysfunction, including vasoconstriction and end-organ ischemia.[13] Implicit in this generalized endothelial dysfunction may be an imbalance of angiogenic and anti-angiogenic factors.[2] Both circulating and placental levels of soluble fms-like tyrosine kinase-1 (sFlt-1) are higher in women with preeclampsia than in women with normal pregnancy.[13] sFlt-1 is an anti-angiogenic protein that antagonizes vascular endothelial growth factor (VEGF) and placental growth factor (PIGF), both of which are proangiogenic factors.[6] Soluble endoglin (sEng) has also been shown to be elevated in women with preeclampsia and has anti-angiogenic properties, much like sFlt-1 does.[13]

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 placentation involves a degree of maternal immune tolerance for a foreign placenta, 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.

Oxidative stress may also play an important part in the pathogensis of pre-eclampsia. The main source of reactive oxygen species (ROS) is the enzyme xanthine oxidase (XO) and this enzyme mainly occurs in the liver. One hypothesis is that the increased purine catabolism from placental hypoxia results in increased ROS production in the maternal liver and release into the maternal circulation that causes endothelial cell damage.[21]

Abnormalities in the maternal immune system and insufficiency of gestational immune tolerance seem to play major roles in pre-eclampsia. One of the main differences found in pre-eclampsia is a shift toward Th1 responses and the production of IFN-γ. The origin of IFN-γ is not clearly identified and could be the natural killer cells of the uterus, the placental dendritic cells modulating responses of T helper cells, alterations in synthesis of or response to regulatory molecules, or changes in the function of regulatory T cells in pregnancy.[22] Aberrant immune responses promoting pre-eclampsia may also be due to an altered fetal allorecognition or to inflammatory triggers.[22] 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 in turn leads to an immune response and endothelial damage, and that ultimately results in pre-eclampsia and eclampsia.

One hypothesis for vulnerability to preeclampsia is the maternal-fetal conflict between the maternal organism and fetus.[23] After the first trimester trophoblasts enter the spiral arteries of the mother to alter the spiral arteries and thereby gain more access to maternal nutrients.[23] Occasionally there is impaired trophoblast invasion that results in inadequate alterations to the uterine spiral arteries.[23] It is hypothesized that the developing embryo releases biochemical signals that result in the woman developing hypertension and preeclampsia so that the fetus can benefit from a greater amount of maternal circulation of nutrients due to increased blood flow to the impaired placenta.[23] This results in a conflict between maternal and fetal fitness and survival because the fetus is invested in only its survival and fitness while the mother is invested in this and subsequent pregnancies.[23]

Another evolutionary hypothesis for vulnerability to preeclampsia is the idea of ensuring pair-bonding between the mother and father and paternal investment in the fetus.[24] Researchers posit that preeclampsia is an adaptation for the mother to terminate investment in a fetus that might have an unavailable paternal donor, as determined by repeated semen exposure of the paternal donor to the mother.[24] Various studies have shown that women who frequently had exposure to partners’ semen before conception had a reduced risk of preeclampsia.[24] Also, subsequent pregnancies by the same paternal donor had a reduced risk of preeclampsia while subsequent pregnancies by a different paternal donor had a higher risk of developing preeclampsia.[24]

Diagnosis

Preeclampsia laboratory values
Diagnostics

LDH/Uric Acid/AST/ALT/Plt/Cr

Shorthand for laboratory values commonly used in preeclampsia. LDH=Lactate dehydrogenase, Uric acid=Uric acid, AST=Aspartate aminotransferase, ALT=Alanine aminotransferase, Plt=Platelets, Cr=Creatinine.
MeSH D007770
Reference range LDH: 105–333 IU/L
Uric Acid: 2.4–6.0 mg/dL
AST: 5–40 U/L
ALT: 7–56 U/L
Plt: 140–450 x 109/L
Cr: 0.6–1.2 mg/dL
LOINC Codes for preeclampsia

Diagnostic criteria

Pre-eclampsia is diagnosed when a pregnant woman develops:[25]

Suspicion for preeclampsia should be maintained in any pregnancy complicated by elevated blood pressure, even in the absence of proteinuria. Ten percent of individuals with other signs and symptoms of preeclampsia and 20% of individuals diagnosed with eclampsia show no evidence of proteinuria.[13] In the absence of proteinuria, the presence of new-onset hypertension (elevated blood pressure) and the new onset of one or more of the following is suggestive of the diagnosis of preeclampsia:[3][8]

Preeclampsia is a progressive disorder and these signs of organ dysfunction are indicative of severe preeclampsia. A systolic blood pressure ≥160 or diastolic blood pressure ≥110 and/or proteinuria >5g in a 24-hour period is also indicative of severe preeclampsia.[8] Clinically, individuals with severe preeclampsia may also present epigastric/right upper quadrant abdominal pain, headaches, and vomiting.[8] Severe preeclampsia is a significant risk factor for intrauterine fetal death.

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 important to note but is not considered diagnostic.

Predictive tests

There have been many assessments of tests aimed at predicting preeclampsia, though no single biomarker is likely to be sufficiently predictive of the disorder.[6] Predictive tests that have been assessed include those related to placental perfusion, vascular resistance, kidney dysfunction, endothelial dysfunction, and oxidative stress. Examples of notable tests include:

Differential diagnosis

Pre-eclampsia can mimic and be confused with many other diseases, including chronic hypertension, chronic renal disease, primary seizure disorders, gallbladder and pancreatic disease, immune or thrombotic thrombocytopenic purpura, antiphospholipid syndrome and hemolytic-uremic syndrome. It must 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.[29] Women with acute fatty liver of pregnancy may also present with elevated blood pressure and protein in the urine, but differ by the extent of liver damage. Other disorders that can cause high blood pressure include thyrotoxicosis, pheochromocytoma, and drug misuse.[8]

Prevention

Preventative measures against preeclampsia have been heavily studied. Because the pathogensis of preeclampsia is not completely understood, prevention remains a complex issue. Below are some of the currently accepted recommendations.

Diet

Protein or calorie supplementation have no effect on preeclampsia rates, and dietary protein restriction does not appear to increase preeclampsia rates.[30] Further, there is no evidence that changing salt intake has an effect.[31]

Supplementation with antioxidants such as vitamin C and E has no effect on preeclampsia incidence,[32] nor does supplementation with vitamin D.[33] Therefore, supplementation with vitamins C, E, and D is not recommended for reducing the risk of pre-eclampsia.[33]

Calcium supplementation of at least 1 gram per day is recommended during pregnancy as it prevents preeclampsia where dietary calcium intake is low, especially for those at high risk.[33][34] Low selenium status is associated with higher incidence of preeclampsia.[35]

Aspirin

Taking aspirin is associated with a 1% to 5% reduction in preeclampsia and a 1% to 5% reduction in premature births in women at high risk.[7][36] The World Health Organization recommends low-dose aspirin for the prevention of preeclampsia in women at high risk and recommend it be started before 20 weeks of pregnancy.[33] The United States Preventive Services Task Force recommends a low-dose regimen for women at high risk beginning in the 12th week.[37]

Physical activity

There is insufficient evidence to recommend either exercise[38] or strict bedrest[39] as preventative measures of pre-eclampsia.

Smoking cessation

In low-risk pregnancies the association between cigarette smoking and a reduced risk of preeclampsia has been consistent and reproducible across epidemiologic studies. High-risk pregnancies (those with pregestational diabetes, chronic hypertension, history of preeclampsia 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 preeclampsia to such a degree that any measurable reduction of risk due to smoking is masked.[40] However, the damaging effects of smoking on overall health and pregnancy outcomes outweighs the benefits in decreasing the incidence of preeclampsia.[6] It is recommended that smoking be stopped prior to, during and after pregnancy.[41]

Treatment

The only known definitive treatment for preeclampsia is delivery of the fetus and placenta. The timing of delivery should balance the desire for optimal perinatal outcomes for the fetus while reducing maternal risks.[6] The severity of disease and the maturity of the fetus are primary considerations.[42] These considerations are situation-specific and management will vary with situation, location, and institution. Treatment can range from expectant management to expedited delivery of the fetus and placenta by induction of labor or Caesarian section, in addition to pharmaceutical interventions. Important in management is the assessment of vulnerable maternal organ systems when possible, management of severe hypertension, and prevention and treatment of eclamptic seizures.[6] Separate interventions directed at the fetus may also be necessary.

Blood pressure

The World Health Organization recommends that women with severe hypertension during pregnancy should receive treatment with anti-hypertensive agents.[4] Severe hypertension is generally considered systolic BP of at least 160 or diastolic BP of at least 110.[3] Evidence does not support the use of one anti-hypertensive over another.[6] The choice of which agent to use should be based on the prescribing clinician's experience with a particular agent, its cost, and its availability.[4] Diuretics are not recommended for prevention of preeclampsia and its complications.[4] Labetolol, Hydralazine and Nifedipine are commonly used antihypertensive agents for hypertension in pregnancy.[8] ACE inhibitors and angiotensin receptor blockers are contraindicated as they affect fetal development.[25]

The goal of treatment of severe hypertension in pregnancy is to prevent cardiovascular, kidney, and cerebrovascular complications.[3] The target blood pressure has been proposed to be 140–160 mmHg systolic and 90–105 mmHg diastolic, although values are variable.[43]

Prevention of eclampsia

The intrapartum and postpartum administration of magnesium sulfate is recommended in severe preeclampsia for the prevention of eclampsia.[4][6] Further, magnesium sulfate is recommended for the treatment of eclampsia over other anticonvulsants.[4] Magnesium sulfate acts by interacting with NMDA receptors.[25]

Epidemiology

Pre-eclampsia affects approximately 2–8% of all pregnancies worldwide,[1][2][44] The incidence of pre-eclampsia has risen in the USA since the 1990s, possibly as a result of increased prevalence of predisposing disorders, such as chronic hypertension, diabetes, and obesity.[6]

Preeclampsia is one of the leading causes of maternal and perinatal morbidity and mortality worldwide.[1] Nearly one tenth of all maternal deaths in Africa and Asia and one quarter in Latin America are associated with hypertensive diseases in pregnancy, a category that encompasses preeclampsia.[4]

Preeclampsia is much more common in women who are pregnant for the first time.[45] Women who have previously been diagnosed with preeclampsia are also more likely to experience preeclampsia in subsequent pregnancies.[8] Preeclampsia is also more common in women who have preexisting hypertension, obesity, diabetes, autoimmune diseases such as lupus, various inherited thrombophilias such as Factor V Leiden, renal disease, multiple gestation (twins or multiple birth), and advanced maternal age.[8] Preeclampsia is also more common in some ethnic groups (e.g. African-Americans, Sub-Saharan Africans, Latin Americans African Caribbeans and Filipinos).[6][46] Change of paternity in a subsequent pregnancy has been implicated as affecting risk, except in those with a family history of hypertensive pregnancy[47]

Eclampsia is a major complication of preeclampsia. Eclampsia affects 0.56 per 1000 pregnant women in developed countries and almost 10–30 times as many women in low-income countries as in developed countries.[8]

Complications

Complications of preeclampsia can affect both the mother and the fetus. Acutely, preeclampsia can be complicated by eclampsia, the development of HELLP syndrome, hemorrhagic or ischemic stroke, liver damage and dysfunction, acute kidney injury, and acute respiratory distress syndrome (ARDS).[8][13]

Preeclampsia is also associated with increased frequency of Caesarian section, preterm delivery, and placental abruption. Furthermore, an elevation in blood pressure can occur in some individuals in the first week postpartum attributable to volume expansion and fluid mobilization.[13] Fetal complications include fetal growth restriction and potential fetal or perinatal death.[13]

Long-term, an individual with preeclampsia is at increased risk for recurrence of preeclampsia in subsequent pregnancies.

Eclampsia

Eclampsia is the development of new convulsions in a preeclamptic patient that may not be attributed to other cause. Eclampsia is a serious complication of preeclampsia and results in high rates of perinatal and maternal morbidity and mortality.[4] Warning symptoms for eclampsia in an individual with current preeclampsia may include headaches, visual disturbances, and right upper quadrant or epigastric abdominal pain, with headache being the most consistent symptom.[6][48] Magnesium sulfate is used to prevent convulsions in cases of severe preeclampsia.

HELLP Syndrome

HELLP syndrome is defined as hemolysis (microangiopathic), elevated liver enzymes (liver dysfunction), and low platelets (thrombocytopenia). This condition may occur in 10–20% of patients with severe preeclampsia and eclampsia[6] and is associated with increased maternal and fetal morbidity and mortality. In 50% of instances, HELLP syndrome develops preterm, while 20% of cases develop in late gestation and 30% during the post-partum period.[8]

Long term

There is also an increased risk for cardiovascular complications, including hypertension and ischemic heart disease, and kidney disease.[13] Other risks include stroke and venous thromboembolism.[49][50] It seems pre-eclampsia does not increase the risk of cancer.[49]

History

The word eclampsia is from the Greek term for lightning.[10] The first known description of the condition was by Hippocrates in the 5th century BC.[10]

An outdated medical term for pre-eclampsia is toxemia of pregnancy, a term that originated in the mistaken belief that the condition was caused by toxins.[51]

Research

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.[52][53] As the theory is further investigated,[54] 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".[55] 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.[56] Although the study has since been criticized for its subjective adjustment of data, it remains important because it demonstrates that there is still debate 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.[57][58]

Long periods of sexual cohabitation with the same partner fathering a woman's child significantly decreased her chances of suffering pre-eclampsia.[55][58] 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".[59] 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".[59]

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,[60][61] 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."[61]

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.[52][53]

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.[60][61][62][63][64][65] 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.[61][62] 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.[58][62]

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.[58] 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.[66]

As the theory of immune intolerance as a cause of pre-eclampsia has become accepted, women who with 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.[58]

It was reported that patients with pre-eclampsia have higher levels of endothelial microparticles than healthy controls. Concentration of endothelial microparticles has been proposed as a biomarker for pre-eclampsia severity.[67]

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