Pre-eclampsia
Pre-eclampsia | |
---|---|
Other names | Preeclampsia toxaemia (PET) |
Treatment | Delivery, medications[4] |
Medication | Labetalol, methyldopa, magnesium sulfate[4][6] |
Frequency | 2–8% of pregnancies[4] |
Deaths | 46,900 hypertensive disorders in pregnancy (2015)[7] |
Pre-eclampsia is a multi-system disorder specific to
Risk factors for pre-eclampsia include
Recommendations for prevention include:
Pre-eclampsia affects 2–8% of pregnancies worldwide.
Etymology
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An outdated medical term for pre-eclampsia is
Signs and symptoms
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]
Causes
There is no definitive known cause of pre-eclampsia, though it is likely related to a number of factors. Some of these factors include:[2][14]
- Abnormal placentation (formation and development of the placenta)
- Immunologic factors
- Prior or existing maternal pathology—pre-eclampsia is seen more at a higher incidence in individuals with pre-existing antiphospholipid antibody syndromeor those with a history of pre-eclampsia
- Dietary factors, e.g. calcium supplementation in areas where dietary calcium intake is low has been shown to reduce the risk of pre-eclampsia[4]
- Environmental factors, e.g. air pollution[23]
Those with long term high blood pressure have a risk 7 to 8 times higher than those without.[24]
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,
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
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.[30] Fetuses affected by pre-eclampsia have a higher chance of later pregnancy complications including growth restriction, prematurity, and stillbirth.[31]
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.
One known effector of pre-eclampsia is the fetal loci
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.[36]
Beyond fetal loci, there have been some maternal loci identified as effectors of pre-eclampsia.
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.[37] When paternally inherited, DLX5 and its SNP rs73708843 are shown to play a role in trophoblast proliferation, affecting vascular growth and nutrient delivery.[38]
Besides specific loci, several important genetic regulatory factors contribute to the development of pre-eclampsia. Micro RNAs, or
Risk factors
Known risk factors for pre-eclampsia include:[6][40]
- Having never previously given birth
- Diabetes mellitus[41]
- Endometriosis[42]
- Obesity[41]
- Advanced maternal age (>35 years)
- Kidney disease
- Untreated hypertension[41]
- Prior history of pre-eclampsia[41]
- Family history of pre-eclampsia
- Antiphospholipid antibody syndrome[41]
- Multiple gestation[41]
- Having donated a kidney[43]
- Having sub-clinical hypothyroidism or thyroid antibodies[44][45]
- Placental abnormalities such as placental ischemia
- morbidity) to, and the complexity of care for, the hospitalized patient
Pathogenesis
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
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
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
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]
Diagnosis
Pre-eclampsia laboratory values | |
---|---|
Platelets, Cr=Creatinine. | |
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 |
MeSH | D007770 |
LOINC | Codes for pre-eclampsia |
Testing for pre-eclampsia is recommended throughout pregnancy via measuring a woman's blood pressure.[15]
Diagnostic criteria
Pre-eclampsia is diagnosed when a pregnant woman develops:[53]
- Blood pressure ≥140 mmHg systolic or ≥90 mmHg diastolic on two separate readings taken at least four to six hours apart after 20 weeks' gestation in an individual with previously normal blood pressure.
- In a woman with essential hypertension beginning before 20 weeks' 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 ≥ 0.3 grams (300 mg) 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).[3]
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.[25] 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:[3][6]
- 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 a 24-hour period is also indicative of severe pre-eclampsia.[6] Clinically, individuals with severe pre-eclampsia may also present epigastric/right upper quadrant abdominal pain, headaches, and vomiting.[6] Severe pre-eclampsia is a significant risk factor for intrauterine fetal death.
A rise in baseline blood pressure (BP) of 30
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.
- 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.[25]
- Elevations in serum uric acid (hyperuricemia) is used by some to "define" pre-eclampsia,[40] though it has been found to be a poor predictor of the disorder.[25] 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, though evidence is insufficient to recommend a clinical use for these markers.[40]
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 yet 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 that will develop pre-eclampsia, allowing early intervention to prevent development of later symptoms.[54] This approach is now officially recommended by the International Federation of Gynecologists & Obstetricians (FIGO),[55] However this model particularly predict pre-eclampsia with onset before 34 weeks' of gestation, while prediction of pre-eclampsia with later onset remains challenging.[56][57]
- 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.[58][59][60]
Differential diagnosis
Pre-eclampsia can mimic and be confused with many other diseases, including chronic hypertension, chronic renal disease, primary seizure disorders, gallbladder and
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.[62] Further, there is no evidence that changing salt intake has an effect.[63]
Supplementation with antioxidants such as vitamin C, D and E has no effect on pre-eclampsia incidence;[64][65] therefore, supplementation with vitamins C, E, and D is not recommended for reducing the risk of pre-eclampsia.[65]
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.[65][66] Higher selenium level is associated with lower incidence of pre-eclampsia.[67][68] Higher cadmium level is associated with higher incidence of pre-eclampsia.[68]
Aspirin
Taking
The study ASPRE, besides its efficacy in identifying women suspected to develop pre-eclampsia, has also been able to demonstrate 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), timing of the intake (bedtime) and must start before week 16 of pregnancy.[54]
Physical activity
There is insufficient evidence to recommend either exercise[73] or strict bedrest[74] 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.[75] However, the damaging effects of smoking on overall health and pregnancy outcomes outweighs the benefits in decreasing the incidence of pre-eclampsia.[14] It is recommended that smoking be stopped prior to, during and after pregnancy.[76]
Immune modulation
Some studies have suggested the importance of a woman's gestational immunological tolerance to her baby's father, as the baby and father share genetics. There is tentative evidence that ongoing exposure either by vaginal or oral sex to the same semen that resulted in the pregnancy decreases the risk of pre-eclampsia.[77] 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".[78] 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".[78]
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 in women who had been regularly performing oral sex.[79]
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.
As the theory of immune intolerance as a cause of pre-eclampsia has become accepted, 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.[77]
Treatment
The definitive treatment for pre-eclampsia is the delivery of the baby and placenta, but danger to the mother persists after delivery, and full recovery can take days or weeks.[12] The timing of delivery should balance the desire for optimal outcomes for the baby while reducing risks for the mother.[14] The severity of disease and the maturity of the baby are primary considerations.[82] 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 addition to medications. Important in management is the assessment of the mother's organ systems, management of severe hypertension, and prevention and treatment of eclamptic seizures.[14] Separate interventions directed at the baby may also be necessary. Bed rest has not been found to be useful and is thus not routinely recommended.[83]
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.[14] 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 pre-eclampsia and its complications.[4] Labetalol, hydralazine and nifedipine are commonly used antihypertensive agents for hypertension in pregnancy.[6] ACE inhibitors and angiotensin receptor blockers are contraindicated as they affect fetal development.[53]
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.[84]
Prevention of eclampsia
The intrapartum and postpartum administration of magnesium sulfate is recommended in severe pre-eclampsia for the prevention of eclampsia.[4][14] Further, magnesium sulfate is recommended for the treatment of eclampsia over other anticonvulsants.[4] Magnesium sulfate acts by interacting with NMDA receptors.[53]
Epidemiology
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.
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]
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).[6][25]
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.[25] Fetal complications include fetal growth restriction and potential fetal or perinatal death.[25]
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.[4] 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.[14][40] 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.[92] 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[14] 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.[6]
Long term
Preeclampsia predisposes for future cardiovascular disease and a history of preeclampsia/eclampsia doubles the risk for cardiovascular mortality later in life.
[25][93] Other risks include stroke, chronic hypertension, kidney disease and venous thromboembolism.[94][93] Preeclampsia and cardiovascular disease share many risk factors such as age, elevated BMI, family history and certain chronic diseases.[95]
It seems that pre-eclampsia does not increase the risk of cancer.[94]
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.[27] The fetal origins hypothesis states that fetal undernutrition is linked with coronary heart disease later in adult life due to disproportionate growth.[96]
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.[97] 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.[98]
The risk of pre-eclampsia and 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
Postpartum preeclampsia
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
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]
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