Pre-eclampsia
Pre-eclampsia is a multi-system disorder specific to pregnancy, characterized by the onset of high blood pressure and often a significant amount of protein in the urine.[1][8][9] When it arises, the condition begins after 20 weeks of pregnancy.[2][3] In severe cases of the 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] Pre-eclampsia increases the risk of undesirable as well as lethal outcomes for both the mother and the fetus including preterm labor.[10][11][3] If left untreated, it may result in seizures at which point it is known as eclampsia.[2]
Pre-eclampsia
Preeclampsia toxaemia (PET)
Red blood cell breakdown, low blood platelet count, impaired liver function, kidney problems, swelling, shortness of breath due to fluid in the lungs, eclampsia[2][3]
After 20 weeks of pregnancy[2]
Obesity, prior hypertension, older age, diabetes mellitus[2][4]
Aspirin, calcium supplementation, treatment of prior hypertension[4][5]
2–8% of pregnancies[4]
46,900 hypertensive disorders in pregnancy (2015)[7]
Risk factors for pre-eclampsia 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 mechanisms are complex and involve abnormal formation of blood vessels in the placenta amongst other factors.[2] Most cases are diagnosed before delivery, and may be categorized depending on the gestational week at delivery.[10] Commonly, pre-eclampsia continues into the period after delivery, then known as postpartum pre-eclampsia.[12][13] Rarely, pre-eclampsia 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][9] 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] Pre-eclampsia is routinely screened during prenatal care.[14][15]
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][5] In those with pre-eclampsia, delivery of the baby and placenta is an effective treatment[4] but full recovery can take days or weeks.[12] When delivery becomes recommended depends on how severe the pre-eclampsia and how far along in pregnancy a woman is.[4] Blood pressure medication, such as labetalol and methyldopa, may be used to improve the mother's condition before delivery.[6] Magnesium sulfate may be used to prevent eclampsia in those with severe disease.[4] Bed rest and salt intake have not been found to be useful for either treatment or prevention.[3][4]
Pre-eclampsia affects 2–8% of pregnancies worldwide.[4][16][11] Hypertensive disorders of pregnancy (which include pre-eclampsia) are one of the most common causes of death due to pregnancy.[6] They resulted in 46,900 deaths in 2015.[7] Pre-eclampsia usually occurs after 32 weeks; however, if it occurs earlier it is associated with worse outcomes.[6] Women who have had pre-eclampsia are at increased risk of high blood pressure, heart disease and stroke later in life.[14][17] Further, those with pre-eclampsia may have a lower risk of breast cancer.[18]
Etymology[edit]
The word "eclampsia" is from the Greek term for lightning.[19] The first known description of the condition was by Hippocrates in the 5th century BC.[19]
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.[20]
Signs and symptoms[edit]
Edema (especially in the hands and face) was originally considered an important sign for a diagnosis of pre-eclampsia. However, because edema is a common occurrence in pregnancy, its utility as a distinguishing factor in pre-eclampsia 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.
Further, a symptom such as epigastric pain may be misinterpreted as heartburn. Common features of pre-eclampsia which are screened for during pre-natal visits include elevated blood pressure and excess protein in the urine. Additionally, some women may develop severe headache as a sign of pre-eclampsia.[21] 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.[22] Diagnosis depends on finding a coincidence of several pre-eclamptic features, the final proof being their regression within the days and weeks after delivery.[12]
Pathogenesis[edit]
Although much research into mechanism of pre-eclampsia has taken place, its exact pathogenesis remains uncertain. Pre-eclampsia 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 the exchange of water, gases, and solutes, including nutrients and wastes, between maternal and fetal circulations.[25] Abnormal development of the placenta leads to poor placental perfusion. The placenta of women with pre-eclampsia is abnormal and characterized by poor trophoblastic invasion.[25] 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][25][46]
In normal early embryonic development, the outer epithelial layer contains cytotrophoblast cells, a stem cell type found in the trophoblast that later differentiates into the fetal placenta. These cells differentiate into many placental cells types, including extravillous trophoblast cells. Extravillous trophoblast cells are an invasive cell type which remodel the maternal spiral arteries by replacing the maternal epithelium and smooth muscle lining the spiral arteries, thus causing and maintaining spiral artery dilation. This prevents maternal vasoconstriction in the spiral arteries and allows for continued blood and nutrient supply to the growing fetus with low resistance and high blood flow.[27]
The clinical manifestations of pre-eclampsia are associated with general endothelial dysfunction, including vasoconstriction and end-organ ischemia.[25] 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 pre-eclampsia than in women with normal pregnancy.[25] 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.[14] Soluble endoglin (sEng) has also been shown to be elevated in women with pre-eclampsia and has anti-angiogenic properties, much like sFlt-1 does.[25]
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 pathogenesis 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.[47]
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.[48] Aberrant immune responses promoting pre-eclampsia may also be due to an altered fetal allorecognition or to inflammatory triggers.[48] 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 the 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 pre-eclampsia is the maternal-fetal conflict between the maternal organism and fetus.[49] 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.[49] Occasionally there is impaired trophoblast invasion that results in inadequate alterations to the uterine spiral arteries.[49] It is hypothesized that the developing embryo releases biochemical signals that result in the woman developing hypertension and pre-eclampsia so that the fetus can benefit from a greater amount of maternal circulation of nutrients due to increased blood flow to the impaired placenta.[49] 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.[49]
Another evolutionary hypothesis for vulnerability to pre-eclampsia is the idea of ensuring pair-bonding between the mother and father and paternal investment in the fetus.[50] Researchers posit that pre-eclampsia is an adaptation for the mother to terminate investment in a fetus that might have an unavailable father, as determined by repeated semen exposure of the father to the mother.[50] Various studies have shown that women who frequently had exposure to partners' semen before conception had a reduced risk of pre-eclampsia.[50] Also, subsequent pregnancies by the same father had a reduced risk of pre-eclampsia while subsequent pregnancies by a different father had a higher risk of developing pre-eclampsia.[50]
In pre-eclampsia, abnormal expression of chromosome 19 microRNA cluster (C19MC) in placental cell lines reduces extravillus trophoblast migration.[28][29] Specific microRNAs in this cluster which might cause abnormal spiral artery invasion include miR-520h, miR-520b, and 520c-3p. This impairs extravillus trophoblast cells invasion to the maternal spiral arteries, causing high resistance and low blood flow and low nutrient supply to the fetus.[27] There is tentative evidence that vitamin supplementation can decrease the risk.[51]
Immune factors may also play a role.[52][48]
Pre-eclampsia laboratory values
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
Epidemiology[edit]
Pre-eclampsia affects approximately 2–8% of all pregnancies worldwide.[1][2][85] The incidence of pre-eclampsia has risen in the U.S. since the 1990s, possibly as a result of increased prevalence of predisposing disorders, such as chronic hypertension, diabetes, and obesity.[14]
Pre-eclampsia 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 pre-eclampsia.[4]
Pre-eclampsia is much more common in women who are pregnant for the first time.[86] Women who have previously been diagnosed with pre-eclampsia are also more likely to experience pre-eclampsia in subsequent pregnancies.[6] Pre-eclampsia is also more common in women who have pre-existing 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.[6] Women who live at high altitude are also more likely to experience pre-eclampsia.[87][88] Pre-eclampsia is also more common in some ethnic groups (e.g. African-Americans, Sub-Saharan Africans, Latin Americans, African Caribbeans, and Filipinos).[14][89][90] Change of paternity in a subsequent pregnancy has been implicated as affecting risk, except in those with a family history of hypertensive pregnancy.[91]
Eclampsia is a major complication of pre-eclampsia. Eclampsia affects 0.56 per 1,000 pregnant women in developed countries and almost 10 to 30 times as many women in low-income countries as in developed countries.[6]
Postpartum preeclampsia[edit]
Preeclampsia can also occur in the postpartum period or after delivery. There are currently no clear definitions or guidelines for postpartum preeclampsia, but experts have proposed a definition of new-onset preeclampsia that occurs between 48 hours after delivery up to 6 weeks after delivery. [100]
The diagnostic criteria otherwise are essentially the same as for preeclampsia diagnosed during pregnancy. Similarly, many of the risk factors are the same, except that not having been pregnant previously does not seem to be a risk factor for postpartum preeclampsia.[101] There are other risk factors related to the labor and/or delivery that are associated with postpartum preeclampsia like cesarean delivery and higher rates of intravenous fluids.[100]
The American College of Obstetricians and Gynecologists recommends blood pressure evaluation for patients who have any hypertensive disorder of pregnancy within 7-10 days after delivery. Home blood pressure monitoring may increase the likelihood of measuring blood pressure during these recommended time periods. [102]
In general, the treatment of postpartum preeclampsia is the same as during pregnancy, including using anti-hypertensive medications to lower blood pressure and magnesium sulfate to prevent eclampsia. The same blood pressure medications that are used during pregnancy can be used in the postpartum period. There may be other medications that can be used, when there is no longer concern for the developing fetus. In general, ACE inhibitors, beta-blockers, and calcium channel blockers all appear to be safe in lactating patients.[103] There is no data showing that any one medication is most effective for postpartum blood pressure management.[102] In addition, there is evidence that the use of a diuretic, furosemide, may shorten the duration of hypertension in patients with postpartum preeclampsia. [102]
Other animals[edit]
Primates can also rarely experience pre-eclampsia.[104] In 2024, a female western lowland gorilla was diagnosed with pre-eclampsia and had a successful caesarean section.[105]