Pre-eclampsia

Pre-eclampsia is a multi-system disorder specific to pregnancy, characterized by the new onset of high blood pressure and often a significant amount of protein in the urine (proteinuria) or by the new onset of high blood pressure along with significant end-organ damage, with or without the proteinuria.<ref>Template:Cite journal</ref><ref name="Ei2012">Template:Cite journal</ref><ref>Template:Cite book</ref><ref name="Lambert etal 2021" /> When it arises, the condition begins after 20 weeks of pregnancy.<ref name="Al2020">Template:Cite journal</ref><ref name="ACOG2020" /> 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.<ref name="Al2020" /><ref name="ACOG2020" /> Pre-eclampsia increases the risk of undesirable as well as lethal outcomes for both the mother and the fetus including preterm labor.<ref name="Magee etal 2022">Template:Cite journal</ref><ref name="Role of B1 and B2 lymphocytes in pl">Template:Cite journal</ref><ref name="ACOG2013">Template:Cite journal</ref> If left untreated, it may result in seizures at which point it is known as eclampsia.<ref name="Al2021" />

Risk factors for pre-eclampsia include obesity, prior hypertension, older age, and diabetes mellitus.<ref name="Al2022" /><ref name="WHO2011" /> It is also more frequent in a woman's first pregnancy and if she is carrying twins.<ref name="Al2021" /> The underlying mechanisms are complex and involve abnormal formation of blood vessels in the placenta amongst other factors.<ref name="Al2021" /> Most cases are diagnosed before delivery, and may be categorized depending on the gestational week at delivery.<ref name="Magee etal 2022" /> Commonly, pre-eclampsia continues into the period after delivery, then known as postpartum pre-eclampsia.<ref name="propublica201808">Template:Cite web</ref><ref name="propublica201705">Template:Cite web</ref> Rarely, pre-eclampsia may begin in the period after delivery.<ref name="ACOG2020" /> 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.<ref name="ACOG2020" /><ref name="Lambert etal 2014">Template:Cite journal</ref> 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.<ref name="ACOG2021" /> Pre-eclampsia is routinely screened during prenatal care.<ref name="Lancet2020" /><ref name="USPSTF2017">Template:Cite journal</ref>

Recommendations for prevention include: aspirin in those at high risk, calcium supplementation in areas with low intake, and treatment of prior hypertension with medications.<ref name="WHO2020" /><ref name="Hend2014">Template:Cite journal</ref> In those with pre-eclampsia, delivery of the baby and placenta is an effective treatment<ref name="WHO2011" /> but full recovery can take days or weeks.<ref name="propublica201808" /> The point at which delivery becomes recommended depends on how severe the pre-eclampsia is and how far along in pregnancy a woman is.<ref name="WHO2011" /> Blood pressure medication, such as labetalol and methyldopa, may be used to improve the mother's condition before delivery.<ref name="Aru2021" /> Magnesium sulfate may be used to prevent eclampsia in those with severe disease.<ref name="WHO2011" /> Bed rest and salt intake are not useful for either treatment or prevention.<ref name="ACOG2020" /><ref name="WHO2011" />

Pre-eclampsia affects 2–8% of pregnancies worldwide.<ref name="WHO2011">Template:Cite book</ref><ref>Template:Cite journal</ref><ref name="Role of B1 and B2 lymphocytes in pl" /> Hypertensive disorders of pregnancy (which include pre-eclampsia) are one of the most common causes of death due to pregnancy.<ref name="Aru2020">Template:Cite journal</ref> They resulted in 46,900 deaths in 2015.<ref name="GBD2015De">Template:Cite journal</ref> Pre-eclampsia usually occurs after 32 weeks; however, if it occurs earlier it is associated with worse outcomes.<ref name="Aru2021" /> Women who have had pre-eclampsia are at increased risk of high blood pressure, heart disease and stroke later in life.<ref name="Lancet2020">Template:Cite journal</ref><ref>Template:Cite journal</ref> Further, those with pre-eclampsia may have a lower risk of breast cancer.<ref>Template:Cite journal</ref>

Etymology

The word "eclampsia" is from the Greek term Template:Lang (éklămpsĭs, “sudden development, violent onset”, literally “brightness”).<ref>Template:Cite web</ref><ref name="Em2006">Template:Cite book</ref> The first known description of the condition was by Hippocrates in the 5th century BC.<ref name="Em2006" />

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.<ref>Template:Cite encyclopedia</ref>

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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite web</ref> Diagnosis depends on finding a coincidence of several pre-eclamptic features, the final proof being their regression within the days and weeks after delivery.<ref name="propublica201808" />

Causes

The cause of preeclampsia is not fully understood. It is likely related to factors such as:<ref name="Al2014" /><ref name="Lancet2010">Template:Cite journal</ref>

• Abnormal placentation (formation and development of the placenta)
• Immunologic factors
• Prior or existing maternal pathologyTemplate:Sndpre-eclampsia is seen more at a higher incidence in individuals with pre-existing hypertension, obesity, or antiphospholipid antibody syndrome, or those with a history of pre-eclampsia
• Dietary factors, e.g., calcium supplementation in areas where dietary calcium intake is low, have been shown to reduce the risk of pre-eclampsia<ref name="WHO2011" />
• Environmental factors, e.g. air pollution<ref name="EHP">Template:Cite journal</ref>
• Infection (for which there is much evidence),<ref>Template:Cite journal</ref> including at the time of conception.<ref>Template:Cite journal</ref>

Those with long-term high blood pressure have a 7 to 8 times higher risk than those without.<ref>Template:Cite journal</ref>

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.<ref name="Lancet2010" /><ref name="Mustafa 2012 1–19">Template:Cite journal</ref>

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.<ref name="Al2014" /><ref name="Lancet2010" /> 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.<ref name="Lancet2010" /> A major consequence of this sequence of events is generalized endothelial dysfunction.<ref name="Ei2012" /> 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 pre-eclampsia.<ref name="Al2014" /> When pre-eclampsia develops in the last weeks of pregnancy or a multiple pregnancy, the causation may, in some cases, partly be due to a large placenta outgrowing the capacity of the uterus, eventually leading to the symptoms of pre-eclampsia.<ref>Template:Cite journal</ref>

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.<ref name="Chen D., Wang W. 2013 1–11">Template:Cite journal</ref><ref name="Ouyang etal 2014">Template:Cite journal</ref><ref name="C19MC MicroRNAs Regulate the Migrat">Template:Cite journal</ref>

Genetic factors

Despite a lack of knowledge on specific causal mechanisms of pre-eclampsia, there is strong evidence to suggest 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 affected birth have an increased risk of fathering a pre-eclamptic pregnancy.<ref name="Skjaerven R., 2005">Template:Cite journal</ref> Fetuses affected by pre-eclampsia have a higher chance of later pregnancy complications including growth restriction, prematurity, and stillbirth.<ref name="Ehret G., 2018">Template:Cite journal</ref>

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.<ref name="Phipps EA., Thadhani R., Benzing T., Karumanchi SA., 2019">Template:Cite journal</ref> 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.<ref name="McGinnis R., 2017">Template:Cite journal</ref><ref name="Ehret G., 2018"/><ref name="Steinthorsdottir V., McGinnis R., Williams NO., 2020">Template:Cite journal</ref> 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.<ref name="Phipps EA., Thadhani R., Benzing T., Karumanchi SA., 2019" /> There is very little understanding of the mechanisms of these interactions. Due to the polygenic nature of pre-eclampsia, a majority of the studies that have been conducted thus far on the topic have utilized genome-wide association studies.<ref name="Skjaerven R., 2005"/>

One known effector of pre-eclampsia is the fetal locus FLT1. Located on chromosome 13 in the q12 region, FLT1 codes for Fms-like tyrosine kinase 1, an angiogenic factor expressed in fetal trophoblasts.<ref name="McGinnis R., 2017"/> Angiogenic factors are crucial for vascular growth in the placenta. An FLT1 soluble isoform caused by a splice variant is sFLT1, which works as an antiangiogenic factor, reducing vascular growth in the placenta. A healthy, normotensive pregnancy is characterized by a balance between these factors. However, upregulation of this variant and overexpression of sFL1 can contribute to endothelial dysfunction. Reduced vascular growth and endothelial dysfunction manifest primarily in maternal symptoms such as kidney failure, swelling, and seizures. However, these factors can also lead to inadequate oxygen, nutrient, or blood supply to the fetus.<ref name="Maynard S., Venkatesha S., Thadhani R. 2005">Template:Cite journal</ref> 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 carry 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.<ref name="Chen CP., 2009">Template:Cite journal</ref>

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.<ref name="Steinthorsdottir V., McGinnis R., Williams NO., 2020" /> This pleiotropy is one of the reasons why these traits are considered to be a risk factor. Furthermore, ZNF831 (zinc finger protein 831) and its loci on chromosome 20q13 were identified as another significant factor in pre-eclampsia. The risk allele rs259983 is also associated with both pre-eclampsia and hypertension, further evidence that the two traits are possibly linked.

While the current understanding suggests that maternal alleles are the main hereditary cause of pre-eclampsia, paternal loci have also been implicated. In one study, paternal DLX5 (Distal-Less Homeobox 5) was identified as an imprinted gene. Located on chromosome 7 in the q21 region, DLX5 serves as a transcription factor often linked with the developmental growth of organs.<ref name="Ensembl Release 89">Template:Cite web</ref> When paternally inherited, DLX5 and its SNP rs73708843 are shown to play a role in trophoblast proliferation, affecting vascular growth and nutrient delivery.<ref name="Zadora J., Singh M., Herse F., 2018">Template:Cite journal</ref>

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.<ref name="Bounds KR, Chiasson VL, Pan LJ, Gupta S, Chatterjee P., 2017">Template:Cite journal</ref> 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.<ref name="Chen D., Wang W. 2013 1–11"/>

Risk factors

Known risk factors for pre-eclampsia include:<ref name="Aru2013">Template:Cite journal</ref><ref name="Cunningham_2010">Template:Cite book</ref>

• Having never previously given birth
• Diabetes mellitus<ref name="BMJ2016">Template:Cite journal</ref>
• Endometriosis<ref name="PMID28181672">Template:Cite journal</ref>
• Obesity<ref name="BMJ2016" />
• Advanced maternal age (>35 years)
• Kidney disease
• Untreated hypertension<ref name="BMJ2016" />
• Prior history of pre-eclampsia<ref name="BMJ2016" />
• Family history of pre-eclampsia
• Antiphospholipid antibody syndrome<ref name="BMJ2016" />
• Multiple gestation<ref name="BMJ2016" />
• Having donated a kidney<ref name="GargNevis2014">Template:Cite journal</ref>
• Having sub-clinical hypothyroidism or thyroid antibodies<ref name="vandenBoogard2011">Template:Cite journal</ref><ref name="Vissenberg2012">Template:Cite journal</ref>
• 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.<ref name="Al2014" /> 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.<ref name="Mustafa 2012 1–19" /> 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.<ref name="Mustafa 2012 1–19" /> It is thought that this results in oxidative stress, hypoxia, and the release of factors that promote endothelial dysfunction, inflammation, and other possible reactions.<ref name="Ei2012" /><ref name="Mustafa 2012 1–19" /><ref name="DrifeMagowan">Template:Cite book</ref>

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.<ref name="Chen D., Wang W. 2013 1–11" />

The clinical manifestations of pre-eclampsia are associated with general endothelial dysfunction, including vasoconstriction and end-organ ischemia.<ref name="Mustafa 2012 1–19" /> Implicit in this generalized endothelial dysfunction may be an imbalance of angiogenic and anti-angiogenic factors.<ref name="Al2014" /> 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.<ref name="Mustafa 2012 1–19" /> 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.<ref name="Lancet2010" /> 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.<ref name="Mustafa 2012 1–19" />

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, which causes endothelial cell damage.<ref>Template:Cite journal</ref>

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.<ref name="Laresgoiti-Servitje">Template:Cite journal</ref> Aberrant immune responses promoting pre-eclampsia may also be due to an altered fetal allorecognition or to inflammatory triggers.<ref name="Laresgoiti-Servitje" /> 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, which 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.<ref name="Redman2005">Template:Cite journal</ref> 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.<ref name="Redman2005" /> Occasionally there is impaired trophoblast invasion that results in inadequate alterations to the uterine spiral arteries.<ref name="Redman2005" /> 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.<ref name="Redman2005" /> 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.<ref name="Redman2005" />

In pre-eclampsia, abnormal expression of chromosome 19 microRNA cluster (C19MC) in placental cell lines reduces extravillus trophoblast migration.<ref name="Ouyang etal 2014" /><ref name="C19MC MicroRNAs Regulate the Migrat" /> 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 of the maternal spiral arteries, causing high resistance and low blood flow, and low nutrient supply to the fetus.<ref name="Chen D., Wang W. 2013 1–11" /> There is tentative evidence that vitamin supplementation can decrease the risk.<ref>Template:Cite journal</ref>

Immune factors may also play a role.<ref>Template:Cite journal</ref><ref name="Laresgoiti-Servitje" />

Diagnosis

Testing for pre-eclampsia is recommended throughout pregnancy via measuring a woman's blood pressure.<ref name="USPSTF2017" />

Diagnostic criteria

Pre-eclampsia is diagnosed when a pregnant woman develops:<ref name="Harrison's">Template:Cite book</ref>

• 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 ≥ Template:Convert 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).<ref name="ACOG2013" />

Suspicion for pre-eclampsia 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 pre-eclampsia and 20% of individuals diagnosed with eclampsia show no evidence of proteinuria.<ref name="Mustafa 2012 1–19" /> 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 pre-eclampsia:<ref name="ACOG2013" /><ref name="Aru2013" />

• Evidence of kidney dysfunction (oliguria, elevated creatinine levels)
• Impaired liver function (noted by liver function tests)
• Thrombocytopenia (platelet count <100,000/microliter)
• Pulmonary edema
• Ankle edema (pitting type)
• Cerebral or visual disturbances

Pre-eclampsia is a progressive disorder, and these signs of organ dysfunction are indicative of severe pre-eclampsia. A systolic blood pressure ≥160 or diastolic blood pressure ≥110 and/or proteinuria >5g in 24 hours is also indicative of severe pre-eclampsia.<ref name="Aru2013" /> Clinically, individuals with severe pre-eclampsia may also present epigastric/right upper quadrant abdominal pain, headaches, and vomiting.<ref name="Aru2013" /> Severe pre-eclampsia 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 pre-eclampsia, though no single biomarker is likely to be sufficiently predictive of the disorder.<ref name="Lancet2010" /> 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:

• Doppler ultrasonography of the uterine arteries to investigate for signs of inadequate placental perfusion. This test has a high negative predictive value among those individuals with a history of prior pre-eclampsia.<ref name="Mustafa 2012 1–19" />
• Some use elevations in serum uric acid (hyperuricemia) to "define" pre-eclampsia,<ref name="Cunningham_2010" /> though it is a poor predictor of the disorder.<ref name="Mustafa 2012 1–19" /> Elevated levels in the blood (hyperuricemia) are likely due to reduced uric acid clearance secondary to impaired kidney function.
• Angiogenic proteins such as vascular endothelial growth factor (VEGF) and placental growth factor (PIGF) and anti-angiogenic proteins such as soluble fms-like tyrosine kinase-1 (sFlt-1) have shown promise for potential clinical use in diagnosing pre-eclampsia. The evidence is insufficient to recommend a clinical use for these markers.<ref name="Cunningham_2010" />

A recent study, ASPRE, known to be the largest multi-country prospective trial, has reported a significant performance in identifying pregnant women at high risk of pre-eclampsia during the first trimester of pregnancy. Utilizing a combination of maternal history, mean arterial blood pressure, intrauterine Doppler, and PlGF measurement, the study has shown a capacity to identify more than 75% of the women who will develop pre-eclampsia, allowing early intervention to prevent the development of later symptoms.<ref name="pubmed.ncbi.nlm.nih.gov">Template:Cite journal</ref> This approach is now officially recommended by the International Federation of Gynecologists & Obstetricians (FIGO),<ref>Template:Cite journal</ref> However this model particularly predict pre-eclampsia with onset before 34 weeks' of gestation, while prediction of pre-eclampsia with later onset remains challenging.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

• Recent 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.<ref>Template:Cite journal</ref><ref name="BBC News – Pre-eclampsia predicted using test during pregnancy">Template:Cite news</ref><ref name="Brown_2011">Template:Cite journal</ref>

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.<ref name="AMN1">Template:Cite web</ref> 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.<ref name="Aru2013" />

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.<ref>Template:Cite journal</ref> Further, no evidence suggests that changing salt intake has an effect.<ref>Template:Cite journal</ref>

Supplementation with antioxidants such as vitamin C, D and E has no effect on pre-eclampsia incidence;<ref name="NEJM2006-Rumbold">Template:Cite journal</ref><ref name="WHO recommendations 2011">Template:Cite book</ref> therefore, supplementation with vitamins C, E, and D is not recommended for reducing the risk of pre-eclampsia.<ref name="WHO recommendations 2011" />

Calcium supplementation of at least 1 gram per day is recommended during pregnancy as it prevents pre-eclampsia where dietary calcium intake is low, especially for those at high risk.<ref name="WHO recommendations 2011" /><ref>Template:Cite journal</ref> Higher selenium level is associated with a lower incidence of pre-eclampsia.<ref name="pmid14634566">Template:Cite journal</ref><ref name="Liu etal 2019">Template:Cite journal</ref> Higher cadmium level is associated with higher incidence of pre-eclampsia.<ref name="Liu etal 2019" />

Aspirin

Taking aspirin is associated with a 1 to 5% reduction in pre-eclampsia and a 1 to 5% reduction in premature births in women at high risk.<ref>Template:Cite journal</ref> 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.<ref name="WHO recommendations 2011" /> The United States Preventive Services Task Force recommends a low-dose regimen for women at high risk beginning in the 12th week.<ref>Template:Cite web</ref> Benefits are less if started after 16 weeks.<ref>Template:Cite journal</ref> Since 2018 the American College of Obstetricians and Gynecologists has recommended low-dose aspirin therapy as standard preventive treatment for pre-eclampsia.<ref name="Walsh">Template:Cite journal</ref> There is a reported problem of its efficacy when combined with paracetamol.<ref name="Walsh" /> Supplementation of aspirin with L-Arginine has shown favourable results.<ref name="Walsh" />

The study ASPRE, besides its efficacy in identifying women suspected to develop pre-eclampsia, has also demonstrated a strong drop in the rate of early pre-eclampsia (-82%) and preterm pre-eclampsia (-62%). The efficacy of aspirin is due to screening to identify high-risk women, adjusted prophylaxis dosage (150 mg/day), the timing of the intake (bedtime), and must start before week 16 of pregnancy.<ref name="pubmed.ncbi.nlm.nih.gov" />

Physical activity

There is insufficient evidence to recommend either exercise<ref name="Cochrane2006-Meher-exercise">Template:Cite journal</ref> or strict bedrest<ref name="Cochrane2006-Meher-rest">Template:Cite journal</ref> 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.<ref name="pmid18566591">Template:Cite journal</ref> However, the damaging effects of smoking on overall health and pregnancy outcomes outweigh the benefits in decreasing the incidence of pre-eclampsia.<ref name="Lancet2010" /> It is recommended that smoking be stopped before, during, and after pregnancy.<ref>Template:Cite journal</ref>

Immune modulation

Template:AnchorSome studies have suggested the importance of a woman's gestational immunological tolerance to her baby's father, as the baby and father share genetics. However, more recent studies have found no evidence that this is a risk factor for pre-eclampsia or other adverse pregnancy outcomes.<ref name="auto">Template:Cite journal</ref>

Several other studies have since investigated the 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 women who had been regularly performing oral sex.<ref name="Bonney 2007">Template:Cite journal</ref>

Having noted the 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.<ref name="Bonney 2007" /><ref name = mattar_sexual_behavior>Template:Cite journal</ref> 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.<ref name="SeminalPriming">Template:Cite journal</ref> 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.<ref name="Dekker_Partner_Role">Template:Cite journal</ref>

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.<ref name="SeminalPriming" />

More recent studies, though, have called these concepts into question. The human body contains a placental barrier to prevent the immune cells of the mother from destroying the cells of the placenta,<ref>Template:Cite journal</ref> and no definitive link has been found between partner selection and adverse pregnancy outcomes, despite many attempts by researchers.<ref name="auto"/>

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.<ref name="propublica201808" /> The timing of delivery should balance the desire for optimal outcomes for the baby while reducing risks for the mother.<ref name="Lancet2010" /> The severity of the disease and the maturity of the baby are primary considerations.<ref>Template:Cite bookTemplate:Page needed</ref> 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.<ref name="Lancet2010" /> Separate interventions directed at the baby may also be necessary. Bed rest is not useful and is thus not routinely recommended.<ref>Template:Cite journal</ref>

Blood pressure

The World Health Organization recommends that women with severe hypertension during pregnancy should receive treatment with anti-hypertensive agents.<ref name="WHO2011" /> Severe hypertension is generally considered systolic BP of at least 160 or diastolic BP of at least 110.<ref name="ACOG2013" /> Evidence does not support the use of one anti-hypertensive over another.<ref name="Lancet2010" /> 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.<ref name="WHO2011" /> Diuretics are not recommended for prevention of pre-eclampsia and its complications.<ref name="WHO2011" /> Labetalol, hydralazine and nifedipine are commonly used antihypertensive agents for hypertension in pregnancy.<ref name="Aru2013" /> ACE inhibitors and angiotensin receptor blockers are contraindicated as they affect fetal development.<ref name="Harrison's" />

The goal of the treatment of severe hypertension in pregnancy is to prevent cardiovascular, kidney, and cerebrovascular complications.<ref name="ACOG2013" /> The target blood pressure has been proposed to be 140–160 mmHg systolic and 90–105 mmHg diastolic, although values are variable.<ref>Hypertensive Disorders in Pregnancy. Version 2.0. Template:Webarchive at Nederlandse Vereniging voor Obstetrie en Gynaecologie. Date of approval: 20-05-2005</ref>

Prevention of eclampsia

The intrapartum and postpartum administration of magnesium sulfate is recommended in severe pre-eclampsia for the prevention of eclampsia.<ref name="WHO2011" /><ref name="Lancet2010" /> Further, magnesium sulfate is recommended for the treatment of eclampsia over other anticonvulsants.<ref name="WHO2011" /> Magnesium sulfate acts by interacting with NMDA receptors.<ref name="Harrison's" />

Epidemiology

Pre-eclampsia affects approximately 2–8% of all pregnancies worldwide.<ref name="Ei2012" /><ref name="Al2014" /><ref>World Health Organization (WHO). World Health Report 2005: make every mother and child count. Geneva: WHO; 2005, p. 63</ref> 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.<ref name="Lancet2010" />

Pre-eclampsia is one of the leading causes of maternal and perinatal morbidity and mortality worldwide.<ref name="Ei2012" /> 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.<ref name="WHO2011" />

Pre-eclampsia is much more common in women who are pregnant for the first time.<ref>Robbins and Cotran, Pathological Basis of Disease, 7th ed.</ref> Women who have previously been diagnosed with pre-eclampsia are also more likely to experience pre-eclampsia in subsequent pregnancies.<ref name="Aru2013" /> 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.<ref name="Aru2013" /> Women who live at high altitude are also more likely to experience pre-eclampsia.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Pre-eclampsia is also more common in some ethnic groups (e.g. African-Americans, Sub-Saharan Africans, Latin Americans, African Caribbeans, and Filipinos).<ref name="Lancet2010" /><ref>Template:Cite journal</ref><ref name="propublica201712">Template:Cite web</ref>

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.<ref name="Aru2013" />

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).<ref name="Aru2013" /><ref name="Mustafa 2012 1–19" />

Pre-eclampsia is also associated with increased frequency of caesarean 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.<ref name="Mustafa 2012 1–19" /> Fetal complications include fetal growth restriction and potential fetal or perinatal death.<ref name="Mustafa 2012 1–19" />

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

Eclampsia

Eclampsia is the development of new convulsions in a pre-eclamptic patient that may not be attributed to other causes. It is a sign that the underlying pre-eclamptic condition is severe and is associated with high rates of perinatal and maternal morbidity and mortality.<ref name="WHO2011" /> Warning symptoms for eclampsia in an individual with current pre-eclampsia may include headaches, visual disturbances, and right upper quadrant or epigastric abdominal pain, with a headache being the most consistent symptom.<ref name="Lancet2010" /><ref name="Cunningham_2010" /> During pregnancy brisk or hyperactive reflexes are common, however, ankle clonus is a sign of neuromuscular irritability that usually reflects severe pre-eclampsia and also can precede eclampsia.<ref>Template:Cite journal</ref> 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<ref name="Lancet2010" /> 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.<ref name="Aru2013" />

Long term

Preeclampsia predisposes to future cardiovascular disease, and a history of preeclampsia/eclampsia doubles the risk for cardiovascular mortality later in life.<ref name="Mustafa 2012 1–19" /><ref name="Cardiovascular sequelae of preeclam">Template:Cite journal</ref> Other risks include stroke, chronic hypertension, kidney disease and venous thromboembolism.<ref name="Bellamy 2007">Template:Cite journal</ref><ref name="Cardiovascular sequelae of preeclam" /> Preeclampsia and cardiovascular disease share many risk factors such as age, elevated BMI, family history, and certain chronic diseases.<ref>Template:Cite journal</ref>

It seems that pre-eclampsia does not increase the risk of cancer.<ref name="Bellamy 2007" />

Lowered blood supply to the fetus in pre-eclampsia causes lowered nutrient supply, which could result in intrauterine growth restriction (IUGR) and low birth weight.<ref name="Chen D., Wang W. 2013 1–11" /> The fetal origins hypothesis states that fetal undernutrition is linked with coronary heart disease later in adult life due to disproportionate growth.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref> Infants with IUGR are prone to have poor neuronal development and in 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.<ref>Template:Cite journal</ref>

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, while fetuses born to both SGA parents were threefold more likely to develop pre-eclampsia in future pregnancies.<ref>Template:Cite journal</ref>

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.<ref name="Hauspurg Jeyabalan 2022">Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref> 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.<ref name="Hauspurg Jeyabalan 2022" />

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.<ref name="Steele etal 2023">Template:Cite report</ref>

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.<ref>Template:Cite journal</ref> No data show that any one medication is most effective for postpartum blood pressure management.<ref name="Steele etal 2023" /> In addition, there is evidence that the use of a diuretic, furosemide, may shorten the duration of hypertension in patients with postpartum preeclampsia.<ref name="Steele etal 2023" />

Other animals

Primates can also rarely experience pre-eclampsia.<ref>Template:Cite journal</ref> In 2024, a female western lowland gorilla was diagnosed with pre-eclampsia and had a successful caesarean section.<ref>Template:Cite news</ref>

Two-kinds of pre-eclampsia

As far back as 1996, it was implied, various pathological events can lead to hypertension combined with organ dysfunction during the second half of pregnancy.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Since 2003, it has been recommended to separate pre-eclampsia cases into early- or late-onset subtypes based on the onset of clinical symptoms (prior to or at/following 34 weeks of gestation), as early-onset cases bear a much worse outcome than when compared with late-onset cases.<ref>Template:Cite journal</ref>

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.<ref name=":0">Template:Cite journal</ref><ref name="Masini2021">Template:Cite journal </ref><ref>Template:Cite journal </ref> 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.<ref name=":0" /><ref name="Masini2021" /><ref name="Gyselaers2019">Template:Cite journal </ref>

The late-onset type is much more common than the early-onset type.<ref>Template:Cite journal </ref> Obesity is a high risk factor, especially in the case of late-onset pre-eclampsia.<ref>Template:Cite journal </ref> Aspirin can effectively delay and alleviate symptoms in early-onset cases; diuretics show promise in late-onset, hypervolemic pre-eclampsia.<ref>Template:Cite journal </ref><ref>Template:Cite journal </ref>

See also

Gestational hypertension

External links

• MedlinePlus entry on high blood pressure in pregnancy
• Mayo Clinic fact sheet on pre-eclampsia