Preeclampsia occurs in 2% to 7% of healthy nulliparous women and 1% to 5% of parous women. The incidence is higher in twin pregnancies (14%) and for women with a history of preeclampsia (18%). It is the third leading cause of maternal mortality, responsible for over 17% of maternal deaths, and a major cause of neonatal morbidity and mortality.
Risk factors for preeclampsia include the following:
Nulliparity
Multiple gestation
Obesity
Chronic hypertension
Systemic lupus erythematosus or other autoimmune disorder
Thrombophilia
Pregestational diabetes
Kidney disease
History of preeclampsia or eclampsia
Low socioeconomic status
Family history of preeclampsia, eclampsia, or cardiovascular disease
Molar pregnancy
Conception via assisted reproductive technologies
Advanced maternal age (>40 years)
The pathophysiology of preeclampsia has been studied extensively over the past decade. It is clear that preeclampsia is a systemic disease, and the placenta is the root cause of preeclampsia. The proposed insult to the placenta is an immunologic alteration in trophoblastic function and reduction in trophoblast invasion. This in turn reduces vascular remodeling, reducing perfusion, and increasing velocity of blood in the intervillous space. This leads to both inflammation and endothelial damage and dysfunction. Due to this, angiogenesis and angiogenic factors have been studied extensively. Two particular proteins of interest are soluble fms-like tyrosine kinase 1 (sFlt-1), which is an antiangiogenic agent, and placental growth factor. The sFlt-1 particularly has been shown to be increased 4 to 5 weeks prior to any clinical manifestations of preeclampsia (see “Prediction of Preeclampsia” under “Preeclampsia” section).
It has also been hypothesized that alteration in the prostacyclin-thromboxane balance plays a role in preeclampsia. Given this, low-dose aspirin (81 mg), which blocks thromboxane production, has been studied as a preventative agent for preeclampsia. Small initial studies showed promising results but larger randomized trials showed nonsignificant reduction in preeclampsia. The largest meta-analysis showed a 17% risk reduction in women at high risk for the disease. Patients at high risk for preeclampsia include those with the following:
Previous preeclamptic pregnancy
Chronic hypertension
Renal disease
Multifetal pregnancy
Pregestational diabetes
Systemic lupus erythematosus or other autoimmune disorder (antiphospholid syndrome)
For pregnancies at high risk for preeclampsia (those that meet the above criteria), we recommend initiating low-dose aspirin between 12 and 28 weeks (ideally before 16 wk) and continue until delivery. No increased risk of significant bleeding or abruptio placentae has been noted with low-dose aspirin.
Other factors that increase preeclampsia risk include nulliparity, family history of preeclampsia, low sociodemographic factors (low socioeconomic status, African American ethnicity), maternal age >35 years, obesity, in vitro fertilization, and previously poor pregnancy outcomes. It is unclear if prophylactic aspirin provides any benefit in these conditions. If a patient has two or more of these aforementioned factors, an informed discussion with the patient about the possible benefits of low-dose aspirin should take place.
Other important measures for preeclampsia prevention are early evaluation and risk reduction through optimizing prepregnancy and maternal health. Women with preeclampsia in the second trimester have a recurrence rate as high as 65%. In patients at high risk for development of preeclampsia, supplementation with fish oil and vitamins C and E has been studied and has been shown to be ineffective. Strict hypertension goals have not been shown to decrease preeclampsia risks either. Calcium supplementation in patients who have a deficiency has been shown to decrease the risk of preeclampsia development, although it is very unlikely that a patient would be calcium deficient in the United States and calcium supplementation is, at this time, not recommended. Dietary salt restriction has also been studied in preeclampsia prevention; however, it has not been shown to provide benefit.
Prediction of preeclampsia has been an area of growing research and debate. Uterine artery velocity Doppler and various biomarkers (sFlt-1, soluble endoglin, placental growth factor) have been shown in small studies to be predictive of future preeclampsia development, especially when studied in the second trimester; however, use of these biomarkers has yet to show improvement in either maternal or fetal outcomes during pregnancy and none is approved by the US Food and Drug Administration for clinical use. There are ongoing studies evaluating the combination of biomarkers plus uterine artery Doppler studies to create a prediction algorithm, and ongoing research is warranted.
Uric acid: A test that is readily available is uric acid, and a recent prospective study showed a uric acid level of 5.2 mg/dL correlated with a positive predictive value of 91.4%. Using uric acid in rare circumstances to evaluate a patient with worsening gestational hypertension for possible progression to preeclampsia is a reasonable option, although regularly checking uric acid levels should not be part of routine care and should not be the principle guiding force in patient management.
Diagnosis of preeclampsia is by symptoms and signs, including elevated blood pressure, proteinuria, and abnormal laboratory findings (described above).
Definitive management for gestational hypertension, preeclampsia, and eclampsia is delivery because the placenta is the insulting agent and removal of the placenta will lead to resolution of the disease process.
In general, preeclampsia without severe features (also known as mild preeclampsia, see definitions above) at term is treated by delivery, typically at 37 weeks or at time of diagnosis if after 37 weeks.
Optimal treatment prior to 37 weeks is usually expectant management. The benefits of antihypertensive medications and early hospitalization are not clearly established. There is no role for bed rest in the management of preeclampsia without severe features.
Close maternal and fetal observation is essential, but there is no standard protocol for testing or frequency.
Fetal monitoring can include growth ultrasound and amniotic fluid assessment every 3 to 4 weeks, umbilical artery Doppler velocimetry, and once or twice weekly NST or BPP.
Maternal monitoring can include weekly or semiweekly blood pressure check and evaluation, and periodic lab testing such as 24-hour urine protein or urine protein/creatinine ratio, serum creatinine, platelet count, and serum transaminases to detect progression to severe preeclampsia.
A gestational age of >34 weeks with uncontrolled hypertension and abnormal fetal testing should warrant further investigation, and if severe features identified, prompt delivery.
The first priority in treating preeclampsia with severe features is to assess and stabilize the mother.
At ≥34 weeks, delivery is indicated, although immediate cesarean delivery is not usually warranted, rather urgent delivery after maternal stabilization is indicated.
Patients with a vertex fetus and no contraindication to labor can deliver vaginally.
Careful monitoring, at least hourly assessments, and strict intake/output recordings should be maintained. Furthermore, assessment of labs such as CBC and comprehensive metabolic panel should be checked serially (typically every 6-12 h) during an induction of a severely preeclamptic patient to monitor for development of HELLP syndrome.
Between 24 and 34 weeks expectant management is acceptable if blood pressure is adequately controlled with antihypertensive agents, fetal status is reassuring, and the mother is not developing worsening HELLP syndrome.
Magnesium sulfate (MgSO4) and IV antihypertensives may be given initially while betamethasone is administered for fetal lung maturity.
Fluid status should be monitored.
The CBC, platelets, and liver function tests should be checked daily.
Fetal surveillance with NST or BPP should be performed at least weekly, and patients should be instructed regarding maternal assessment of fetal movement.
Delivery is indicated by the following: worsening IUGR, nonreassuring fetal tracing, eclampsia, neurologic deficits, pulmonary edema, right upper quadrant/epigastric pain, worsening renal status, disseminated intravascular coagulation, HELLP, placental abruption, or uncontrolled severe blood pressure.
Prior to 24 weeks' gestation, expectant management is associated with high maternal morbidity and limited perinatal benefit.
Expectant management of severe preeclampsia with IUGR has been associated with increased risk of fetal death (rate of perinatal death is 5.4%) and should be performed cautiously.
Seizure prophylaxis during labor and for 24-hour postpartum is recommended for patients with preeclampsia. Some patients with severe persistent preeclampsia may need seizure prophylaxis for longer periods before and after delivery.
Magnesium sulfate is the agent of choice for eclamptic seizure prophylaxis. The MgSO4 has been shown to decrease the risk of eclampsia by more than 50%.
For prophylaxis, we administer a loading dose of 6 g MgSO4 intravenously over 15 to 20 minutes.
Maintenance dose is 2 g/hr intravenously (dose should be titrated down if the patient has poor urine output, poor kidney function, or an elevated serum creatinine).
If there is no IV access, the loading dose is 5 g MgSO4 (50% solution) administered intramuscularly in each buttock (10 g total), with a maintenance dose of 5 g in alternating buttocks every 4 hours.
The therapeutic serum magnesium level for seizure prophylaxis depends on the laboratory. In general, the therapeutic range is 4.8 to 8.4 mg/dL or 4 to 6 mEq/L. However, it is our practice to follow magnesium levels only for those patients in whom we are unusually concerned for developing supratherapeutic levels. For such patients, check serum magnesium level 4 hours after the loading dose and then every 6 hours as needed or if symptoms suggest magnesium toxicity.
Patients are monitored hourly for signs and symptoms of magnesium toxicity:
Loss of patellar reflexes at 8 to 10 mEq/L
Respiratory depression or arrest at 12 mEq/L
Mental status changes at >12 mEq/L followed by ECG changes and arrhythmias
If magnesium toxicity develops, check the patient's vital signs, stop magnesium and check plasma levels, administer 1-g calcium gluconate IV over 3 minutes, and consider diuretics (eg, furosemide, mannitol).
Phenytoin (Dilantin) is a secondary agent for eclamptic seizure prophylaxis. Magnesium was clearly superior in a large randomized clinical trial and is preferred. It may, however, be contraindicated, as in patients with myasthenia gravis.
The loading dose is maternal weight based. For <50 kg, load 1000 mg; for 50 to 70 kg, load 1250 mg; and for >70 kg, load with 1500 mg phenytoin.
The first 750 mg of the loading dose should be given at 25 mg/min and the rest at 12.5 mg/min. If the patient maintains normal cardiac rhythm and has no history of heart disease, ECG monitoring is not necessary at this infusion rate.
Check the serum phenytoin level at 30 to 60 minutes after infusion.
A therapeutic level is >12 μg/mL; recheck level in 12 hours.
If the level is <10 μg/mL, reload with 500 mg and check again in 30 to 60 minutes.
If the level is 10 to 12 μg/mL, reload with 250 mg and check again in 30 to 60 minutes.
Antihypertensive therapy is indicated for patients with a systolic blood pressure of 160 mm Hg or greater or diastolic blood pressure of 110 mm Hg or greater. Acute treatment aims to reduce blood pressure in a controlled manner without compromising uteroplacental perfusion.
It is reasonable to reduce the patient's systolic blood pressure to 140 to 155 mm Hg and the diastolic blood pressure to 90 to 100 mm Hg.
While administering magnesium, useful antihypertensive agents for acute management include the following:
Immediate release oral nifedipine: This is particularly useful in patients without IV access. It has an onset of action of 15 minutes and reaches a peak by 1 hour. Initial dose should be 10 mg orally. Subsequent doses can be given every 20 minutes. Subsequent doses should be 20 mg. A total of three doses every 20 minutes can be attempted to reduce blood pressure. If at any point the patient's blood pressure is reduced below 160/110 mm Hg, she can be observed. While administering short-acting antihypertensives, the blood pressure should be checked at least every 20 minutes. Once blood pressure is below 160/110 mm Hg, the blood pressure should be checked every 10 minutes for 1 hour, then every 15 minutes for 1 hour, then every 30 minutes for 1 hour, and then every hour for at least the next 4 hours. If three doses of nifedipine do not improve the patient's blood pressures, you should use one of the two following agents.
Hydralazine hydrochloride: Administered intravenously, it has an onset of action within 10 to 20 minutes. The duration of action is 4 to 6 hours.
Begin with a 5- to 10-mg IV bolus or push over 2 minutes, and recheck a blood pressure in 20 minutes. If severe blood pressures persist, an additional 10 mg should be administered. No more than 20 mg should be administered over a 20-minute time period. If the blood pressure remains elevated after two doses, an additional antihypertensive should be used. If the blood pressure is reduced below 160/110 mm Hg, the blood pressure monitoring as described above should be initiated.
Labetalol hydrochloride: Administered intravenously, it has an onset of action within 5 to 10 minutes and has a duration of 3 to 6 hours. It is contraindicated in greater than first-degree maternal heart block and should be used cautiously in severe asthmatics.
Begin with a 20-mg IV bolus or push over 2 minutes and then check a repeat blood pressure in 20 minutes. If severe range blood pressures persist, 40 mg intravenously should be administered (over 2 or more minutes) and blood pressures checked in 20 minutes. If severe range blood pressures persist, administer 80 mg intravenously. If the blood pressure remains elevated at this time, an additional antihypertensive should be used. If the blood pressure is reduced below 160/110 mm Hg, the blood pressure monitoring as described above should be initiated.
When administering IV labetalol, there should be a maximum dosing of 300 mg/24 hr.
Fluid management: Patients with preeclampsia are frequently hypovolemic due to third spacing from low serum oncotic pressure and increased capillary permeability. These same abnormalities also increase risk for pulmonary edema. Diuretics may be used to treat pulmonary edema but should not be used as the primary antihypertensive in preeclamptic patients.
Oliguria is defined as urine output of <100 mL in 4 hours. It is treated with 500-mL crystalloid bolus if the lungs are clear. If there is no response, another 500-mL bolus can be administered. If there is no response after 1 L, central hemodynamic monitoring can be considered.
Central venous pressure monitoring does not correlate well with pulmonary capillary wedge pressure. Rarely, a Swan-Ganz catheter may be required to help guide fluid management and prevent flash pulmonary edema. More practically, evaluation with lung exam every 2 hours can help identify onset of pulmonary edema.
Patients usually begin to effectively diurese about 12 to 24 hours after delivery. In cases of severe renal compromise, it may take 72 hours or more for adequate diuresis to resume.
Maternal complications of severe preeclampsia require a high index of clinical suspicion and include renal failure, acute cardiac failure, pulmonary edema, thrombocytopenia, disseminated intravascular coagulopathy, and cerebrovascular accidents.
Perinatal outcome: There is a high perinatal morbidity and mortality in pregnancies complicated by severe preeclampsia. Fetal mortality rates range from 5% to more than 70% depending on the gestational age.