Pre-eclampsia

The word "eclampsia" is from the Greek term (éklămpsĭs, "sudden development, violent onset", literally "brightness"). The first known description of the condition was by Hippocrates in the 5th century BC. ==Signs and symptoms==

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 healthcare provider. Further, a symptom such as epigastric pain may be misinterpreted as heartburn. Standard features of pre-eclampsia, which are screened for during prenatal visits, include elevated blood pressure and excess protein in the urine. Additionally, some women may develop severe headaches as a sign of pre-eclampsia. 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 depends on finding a coincidence of several pre-eclamptic features, the final proof being their regression within the days and weeks after delivery. ==Causes==

The cause of preeclampsia is not fully understood. It is likely related to factors such as: • Infection (for which there is much evidence), including at the time of conception. Those with long-term high blood pressure have a 7 to 8 times higher risk than those without. Physiologically, research has linked pre-eclampsia 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. While the exact cause of pre-eclampsia remains unclear, there is strong evidence that a major cause predisposing a susceptible woman to pre-eclampsia is an abnormally implanted placenta. Abnormal chromosome 19 microRNA cluster (C19MC) impairs extravillus trophoblast cell invasion to the spiral arteries, causing high resistance, low blood flow, and low nutrient supply to the fetus. Genetic factors Despite a lack of knowledge of the specific causal mechanisms of pre-eclampsia, strong evidence suggests it results from both environmental and heritable factors. A 2005 study showed that women with a first-degree relative who had a pre-eclamptic birth are twice as likely to develop it themselves. Furthermore, men related to someone with an affected birth have an increased risk of fathering a pre-eclamptic pregnancy. Fetuses affected by pre-eclampsia have a higher chance of later pregnancy complications including growth restriction, prematurity, and stillbirth. The onset of pre-eclampsia is thought to be caused by several complex interactions between genetics and environmental factors. Our current understanding of the specifically heritable cause involves an imbalance of angiogenic factors in the placenta. Angiogenesis involves the growth of new blood vessels from existing vessels. An imbalance during pregnancy can affect the vascularization, growth, and biological function of the fetus. The irregular expression of these factors is thought to be controlled by multiple loci on different chromosomes. Research on the topic has been limited because of the heterogeneous nature of the disease. Maternal, paternal, and fetal genotypes play a role, as do complex epigenetic factors such as whether the parents smoke, maternal age, sexual cohabitation, and obesity. Furthermore, in this locus region, several single-nucleotide polymorphisms (SNPs) have been observed to impact the overexpression of sFL1. Specifically, SNPs rs12050029 and rs4769613's risk alleles are linked with low red blood cell counts and an increased risk of late-onset pre-eclampsia. Patau syndrome, or Trisomy 13, is also associated with the upregulation of sFLT1 due to the extra copy of the 13th chromosome. Because of this upregulation of an antiangiogenic factor, women with trisomy 13 pregnancies often experience reduced placental vascularization and are at higher risk for developing pre-eclampsia. Beyond fetal loci, some maternal loci have been identified as effectors of pre-eclampsia. Alpha-ketoglutarate-dependent hydroxylase expression on chromosome 16 in the q12 region is also associated with pre-eclampsia. Specifically, allele rs1421085 heightens the risk of not just pre-eclampsia but also an increase in BMI and hypertension. When paternally inherited, DLX5 and its SNP rs73708843 are shown to play a role in trophoblast proliferation, affecting vascular growth and nutrient delivery. Besides specific loci, several important genetic regulatory factors contribute to the development of pre-eclampsia. Micro RNAs, or miRNAs, are noncoding mRNAs that downregulate posttranscriptional gene expression through RNA-induced silencing complexes. In the placenta, miRNAs are crucial for regulating cell growth, angiogenesis, cell proliferation, and metabolism. These placental-specific miRNAs are clustered in large groups, mainly on chromosomes 14 and 19, and irregular expression of either is associated with an increased risk of an affected pregnancy. For instance, miR-16 and miR-29 are vascular endothelial growth factors (VEGFs) and play a role in upregulating sFLT-1. In particular, the overexpression of miRNA miR-210 has been shown to induce hypoxia, which affects spiral artery remodeling, an important part of the pathogenesis of pre-eclampsia. • Endometriosis • Obesity • Having sub-clinical hypothyroidism or thyroid antibodies • Placental abnormalities such as placental ischemia • Socioeconomics play a large role in the prevalence of these risk factors, and, like other processes, each risk factor plays a role in the likelihood of increased consequences (morbidity) to, and the complexity of care for, the hospitalized patient ==Pathogenesis==

Although much research into the 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. 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 cell types, including extravillous trophoblast cells. Extravillous trophoblast cells are an invasive cell type that remodels 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. 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 the synthesis of or response to regulatory molecules, or changes in the function of regulatory T cells in pregnancy. Aberrant immune responses promoting pre-eclampsia may also be due to an altered fetal allorecognition or to inflammatory triggers. 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. Immune factors may also play a role. ==Diagnosis==

Testing for pre-eclampsia is recommended throughout pregnancy via measuring a woman's blood pressure. • Blood pressure ≥140 mmHg systolic or ≥90 mmHg diastolic on two separate readings taken at least four to six hours apart after 20 weeks of gestation in an individual with previously normal blood pressure. • In a woman with essential hypertension beginning before 20 weeks of gestational age, the diagnostic criteria are an increase in systolic blood pressure (SBP) of ≥30 mmHg or an increase in diastolic blood pressure (DBP) of ≥15 mmHg. • Proteinuria ≥ or more of protein in a 24-hour urine sample or a SPOT urinary protein to creatinine ratio ≥0.3 or a urine dipstick reading of 1+ or greater (dipstick reading should only be used if other quantitative methods are not available). This approach is now officially recommended by the International Federation of Gynecologists & Obstetricians (FIGO). However, this model specializes in predicting pre-eclampsia with onset before 34 weeks of gestation, while the prediction of pre-eclampsia with later onset remains challenging. • 2011 studies have shown that looking for podocytes (specialized cells of the kidney) in the urine has the potential to aid in the prediction of pre-eclampsia. Studies have demonstrated that finding podocytes in the urine may serve as an early marker of and diagnostic test for pre-eclampsia. 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 in any pregnant woman beyond 20 weeks of gestation. It is difficult to diagnose when pre-existing conditions such as hypertension are present. 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. ==Prevention==

Preventive measures against pre-eclampsia have been heavily studied. Because the pathogenesis of pre-eclampsia is not completely understood, prevention remains a complex issue. Some currently accepted recommendations are: Diet Supplementation with a balanced protein and energy diet does not appear to reduce the risk of pre-eclampsia. Further, no evidence suggests that changing salt intake has an effect. Supplementation with antioxidants such as vitamin C, D and E has no effect on pre-eclampsia incidence; therefore, supplementation with vitamins C, E, and D is not recommended for reducing the risk of pre-eclampsia. However, updated evidence indicates that calcium supplements may have little or no effect on preventing pre-eclampsia or related complications for mothers or babies. Most studies started supplementation in the second trimester, so the effectiveness of earlier supplementation remains unclear. Higher selenium level is associated with a lower incidence of pre-eclampsia. Higher cadmium level is associated with higher incidence of pre-eclampsia. The World Health Organization recommends low-dose aspirin for the prevention of pre-eclampsia in women at high risk and recommends it be started before 20 weeks of pregnancy. Benefits are less if started after 16 weeks. Since 2018 the American College of Obstetricians and Gynecologists has recommended low-dose aspirin therapy as standard preventive treatment for pre-eclampsia. There is a reported problem of its efficacy when combined with paracetamol. Early (< 32 week) PE was reduced by 80% and there was no change in term PE rates. Additional analysis of ASPRE data suggests that aspirin works by delaying the development of PE. Physical activity There is insufficient evidence to recommend either exercise or strict bedrest as preventive measures of pre-eclampsia. Smoking cessation 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 masked. However, the damaging effects of smoking on overall health and pregnancy outcomes outweigh the benefits in decreasing the incidence of pre-eclampsia. Immune modulation Observational studies have suggested the importance of a woman's gestational immunological tolerance to her baby's father, as the baby and father share genetics. More specifically, it was proposed that some cases of pre-eclampsia may be linked to a breakdown of maternal T-cell tolerance for the fetus. However, more recent studies (as of 2019) have found no evidence that this is a risk factor for pre-eclampsia or other adverse pregnancy outcomes. There is a decreased incidence of pre-eclampsia in women who have received blood transfusions from their partner, those with long preceding histories of sex without barrier contraceptives, and women who have been regularly performing oral sex. Having noted the potential importance of a woman's immunological tolerance to her baby's paternal genes, several Dutch reproductive biologists decided to take their research 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. 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. As the theory of immune intolerance as a cause of pre-eclampsia has gained prominence, women 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. Immunogenetic studies have further revealed the importance of EVT recognition by uNK. uNKs appear to play a role in remodeling the spinal arteries of the placenta, but not much is known about what they do exactly in normal and abnormal pregnancies. ==Treatment==

The definitive treatment for pre-eclampsia is the delivery of the baby and placenta. The danger to the mother persists after delivery, and full recovery can take days or weeks. These considerations are situation-specific, and management will vary with situation, location, and institution. Treatment can range from expectant management to expedited delivery by induction of labor or caesarean section. In the case of preterm delivery, additional treatments, including corticosteroid injection to accelerate fetal pulmonary maturation and magnesium sulfate for prevention of cerebral palsy, should be considered. Important in management is the assessment of the mother's organ systems, management of severe hypertension, and prevention and treatment of eclamptic seizures. Blood pressure The World Health Organization recommends that women with severe hypertension during pregnancy should receive treatment with anti-hypertensive agents. Severe hypertension is generally considered systolic BP of at least 160 or diastolic BP of at least 110. Prevention of eclampsia The intrapartum and postpartum administration of magnesium sulfate is recommended in severe pre-eclampsia for the prevention of eclampsia. Further, magnesium sulfate is recommended for the treatment of eclampsia over other anticonvulsants. Magnesium sulfate acts by interacting with NMDA receptors. ==Epidemiology==

Pre-eclampsia affects approximately 2–8% of all pregnancies worldwide. The incidence of pre-eclampsia has risen in the U.S. since the 1990s, possibly as a result of an increased prevalence of predisposing disorders, such as chronic hypertension, diabetes, and obesity. Women who have previously been diagnosed with pre-eclampsia are also more likely to experience pre-eclampsia in subsequent pregnancies. Pre-eclampsia is also more common in some ethnic groups (e.g. African-Americans, Sub-Saharan Africans, Latin Americans, African Caribbeans, and Filipinos). 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. ==Complications==

Complications of pre-eclampsia can affect both the mother and the fetus. Acutely, pre-eclampsia 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). Magnesium sulfate is used to prevent convulsions in cases of severe pre-eclampsia. 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 pre-eclampsia and eclampsia Other risks include stroke, chronic hypertension, kidney disease and venous thromboembolism. It seems that pre-eclampsia does not increase the risk of cancer. Because pre-eclampsia leads to a mismatch between the maternal energy supply and fetal energy demands, pre-eclampsia can lead to IUGR in the developing fetus. Infants with IUGR are prone to have poor neuronal development and are at increased risk for adult disease according to the Barker hypothesis. Associated adult diseases of the fetus due to IUGR include, but are not limited to, coronary artery disease (CAD), type 2 diabetes mellitus (T2DM), cancer, osteoporosis, and various psychiatric illnesses. The risk of pre-eclampsia and the development of placental dysfunction has also been shown to be recurrent cross-generationally on the maternal side and most likely on the paternal side. Fetuses born to mothers who were born small for gestational age (SGA) were 50% more likely to develop pre-eclampsia. Fetuses born to both SGA parents were threefold more likely to develop pre-eclampsia in future pregnancies. == Postpartum preeclampsia ==

Preeclampsia can also occur in the postpartum period or after delivery. There are currently no clear definitions or guidelines for postpartum preeclampsia. Experts have proposed a definition of new-onset preeclampsia that occurs between 48 hours after delivery and up to six weeks after delivery. 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. 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. 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 used during pregnancy can be used postpartum. Other medications can be used when there is no longer a concern for the developing fetus. In general, ACE inhibitors, beta-blockers, and calcium channel blockers all appear to be safe in lactating patients. No data show that any one medication is most effective for postpartum blood pressure management. In addition, there is evidence that the use of a diuretic, furosemide, may shorten the duration of hypertension in patients with postpartum preeclampsia. == Other animals ==

Primates can also rarely experience pre-eclampsia. In 2024, a female western lowland gorilla was diagnosed with pre-eclampsia and had a successful caesarean section. == Two-kinds of pre-eclampsia ==

As far back as 1996, it was implied that various pathological events can lead to hypertension combined with organ dysfunction during the second half of pregnancy. Over time, increasing levels of research results support this opinion. Early findings, challenging the homogenous disease conception, reported higher than average maternal blood volume (suggesting yet another pathway to hypertension), high fetal weight (excluding placental insufficiency), and increased cerebral blood flow (contrary to vasoconstriction) among patients afflicted with pre-eclampsia. Since 2003, it has been recommended to separate pre-eclampsia cases into early- or late-onset subtypes based on the onset of clinical symptoms (before or at/following 34 weeks of gestation), as early-onset cases bear a much worse outcome than when compared with late-onset cases. Clinically, two (sub)types of pre-eclampsia can be distinguished by main characteristics: Early-onset (also referred to as hypovolemic, type I, preterm, placental) pre-eclampsia is basically characterized with contracted blood volume, vasoconstriction, thrombotic microangiopathy, fetal growth restriction and oligohydramnios. Late-onset (also signaled as hypervolemic, type II, term, maternal) pre-eclampsia is associated with augmented blood volume, vasodilatation, marked venous stasis, and normal or increased fetal weight. The late-onset type is much more common than the early-onset type. Obesity is a high-risk factor, especially in the case of late-onset pre-eclampsia. Aspirin can effectively delay and alleviate symptoms in early-onset cases; diuretics show promise in late-onset, hypervolemic pre-eclampsia. ==See also==