Current Diagnosis & Treatment Obstetrics & Gynecology, 11th Ed.

26. Hypertension in Pregnancy

David A. Miller, MD

Hypertension is a common medical disorder that affects 20–30% of adults in the United States and complicates as many as 5–8% of all pregnancies. Hypertensive disorders of pregnancy rank among the leading causes of maternal morbidity and mortality. Approximately 15% of maternal deaths are attributable to hypertension, making it the second leading cause of maternal mortality in the United States. Severe hypertension increases the mother’s risk of heart attack, cardiac failure, cerebral vascular accidents, and renal failure. The fetus and neonate also are at increased risk from complications such as poor placental transfer of oxygen, fetal growth restriction, preterm birth, placental abruption, stillbirth, and neonatal death.

Hypertension is defined as a sustained blood pressure higher than 140/90 mm Hg. In the nonpregnant patient, essential hypertension accounts for more than 90% of cases; however, many other conditions must be considered (Table 26–1). In the pregnant patient, hypertension may be attributable to any of the conditions summarized in Table 26–1. In addition, unique forms of hypertension, gestational hypertension and preeclampsia, occur only during pregnancy. Gestational hypertension is characterized by elevated blood pressure diagnosed for the first time during pregnancy in patients without evidence of proteinuria. Preeclampsia is characterized by the onset of hypertension and proteinuria, usually during the third trimester of pregnancy. The National High Blood Pressure Education Program Working Group stated that edema occurs too frequently in normal pregnant women to be a useful marker in the diagnosis of preeclampsia. Therefore, edema is no longer recommended as a diagnostic criterion for preeclampsia. Management of preeclampsia differs from the management of other forms of hypertension during pregnancy. Therefore, it is important to distinguish preeclampsia from other forms of hypertension that may complicate pregnancy.

Table 26–1. Causes of chronic hypertension.


Classification of hypertension during pregnancy can be viewed as a continuum. On one end of the spectrum is the patient with hypertension that was present before pregnancy (or was recognized during the first half of pregnancy), does not worsen appreciably during pregnancy, and persists after delivery. This condition would be classified as chronic hypertension. On the other end of the spectrum is the patient with no evidence of chronic hypertension who experiences the abrupt onset of hypertension and proteinuria late in pregnancy followed by complete resolution postpartum. In this case, the hypertension observed during pregnancy may be the result of factors related entirely to pregnancy and not to an underlying medical cause. This condition would be classified as preeclampsia. Between these 2 extremes are gestational hypertension and cases in which varying degrees of preeclampsia are superimposed upon varying degrees of chronic hypertension. These broad categories have some value in estimating risk. Isolated mild to moderate chronic hypertension may have little effect on pregnancy outcome. On the other hand, severe hypertension of any cause may increase the risk to mother and fetus. The highest risks are associated with preeclampsia or eclampsia. The classification system of hypertension in pregnancy proposed by the National High Blood Pressure Education Program Working Group is summarized in Table 26–2.

Table 26–2. Classification of hypertension in pregnancy.





Images Hypertension with onset before pregnancy or before 20th week of gestation

Images Persistence of hypertension beyond 12 weeks postpartum

Images Blood pressure ≥140 mm Hg systolic or ≥90 mm Hg diastolic


Chronic hypertension complicates as many as 5% of pregnancies. It is characterized by a history of high blood pressure before pregnancy, elevation of blood pressure during the first half of pregnancy, or high blood pressure that lasts for longer than 12 weeks after delivery. The pathogenesis of chronic hypertension or essential hypertension is poorly understood. Factors that may contribute to the development of chronic hypertension are derangements in sympathetic neural activity or angiotensin II activity. There appears to be a genetic component in that hypertension is more common in individuals with a family history of hypertension. Other risk factors that predispose one to develop chronic hypertension during a person’s lifetime are African American race, obesity, dyslipidemia, and physical inactivity.

Clinical Findings

Chronic hypertension is defined as women who have a blood pressure of ≥140 mmHg systolic or ≥90 mmHg diastolic before pregnancy, during the first 20 weeks of pregnancy, or >12 weeks after pregnancy. During the first trimester of pregnancy, women with a history of chronic hypertension will likely manifest blood pressure elevations. However, during normal pregnancy, maternal blood volume increases by 40–60%. Cardiac output and renal blood flow increase significantly. Blood pressure normally decreases throughout the first half of pregnancy under the influence of progesterone, reaching a nadir in midpregnancy and returning to prepregnancy levels by the end of the third trimester. For this reason, blood pressure may normalize during the second trimester in women with underlying chronic hypertension.

Evaluation of the patient with chronic hypertension is directed at end organs and systems most likely to be affected by hypertension, including the eyes, heart, kidneys, uteroplacental circulation, and the fetus. Laboratory tests include a complete blood count, glucose screen, electrolyte panel, serum creatinine, urinalysis, and urine culture. In some cases, additional tests may be needed. In patients with possible renal disease (serum creatinine ≥0.8 mg/dL, urine protein >1+ on dipstick), a 24-hour urine collection for creatinine clearance and total protein will provide baseline information that may be helpful in diagnosing the onset of preeclampsia later in pregnancy. An electrocardiogram may reveal left ventricular hypertrophy in the patient with long-standing hypertension. Chest radiography with abdominal shielding or echocardiogram may reveal cardiomegaly.

Differential Diagnosis

In women with hypertension, underlying disorders must be excluded (Table 26–1). The search for an underlying cause should include a complete history and physical examination, taking into account the normal changes that accompany pregnancy. Blood pressure should be measured in both arms with the patient in a sitting position and the arm at the level of the heart, and multiple measurements should be obtained on different occasions. If possible, measurements should be obtained outside of the office setting. The fifth Korotkoff sound should be used to determine diastolic pressure. Auscultation of the flanks may reveal a renal artery bruit. Funduscopic examination may reveal typical findings associated with long-standing hypertension or possibly diabetes. An enlarged thyroid gland may indicate thyroid disease. Absent peripheral pulses suggest coarctation of the aorta. Heart, skin, and joints should be evaluated thoroughly. Antinuclear antibody may help suggest a diagnosis of collagen vascular disease. A suppressed thyroid-stimulating hormone level suggests hyperthyroidism. Rarely, elevated urinary catecholamine levels may point to pheochromocytoma.


Complications related to chronic hypertension include superimposed preeclampsia, fetal growth restriction, pre-term birth, and placental abruption. The risk of developing one of these complications correlates with the degree of maternal blood pressure elevation; the higher the blood pressure, the greater the risk of one of these complications. Unfortunately, the benefit of maternal blood pressure control appears to be limited to preventing maternal morbidities and does not appear to extend to reducing the risk of these obstetric complications.


Management of the chronic hypertensive patient during pregnancy is targeted to 2 goals: (1) maternal blood pressure control to minimize the risk of maternal complications related to blood pressure elevations such as stroke and myocardial infarction, and (2) early detection of any obstetrical or fetal complications related to chronic hypertension.

A number of antihypertensives have been shown to be safe and effective during pregnancy in controlling maternal blood pressure. Treatment of elevated blood pressure with antihypertensives reduces the risk of maternal morbidities related to hypertension but does not reduce the risk of fetal complications such as intrauterine growth restriction, preeclampsia, and placental abruption.

A. Treatment of Mild Chronic Hypertension

In pregnant women with mild hypertension and no evidence of renal disease, serious medical complications are rare. Moreover, there is no consensus that antihypertensive medication can reduce the risk of fetal death, growth restriction, placental abruption, preeclampsia, or eclampsia in these women. Therefore, antihypertensive medication is not usually necessary. Avoidance of alcohol and tobacco is encouraged. Sodium restriction may be considered (2–3 g/d). Rigorous activity should be avoided, as should weight reduction. Despite the lack of evidence supporting the benefit of antihypertensive therapy in women with blood pressure <180/110 mm Hg, many clinicians are reluctant to withhold medication when the blood pressure remains ≥150/100 mm Hg despite lifestyle modifications. A practical management algorithm using a blood pressure of 150/100 mm Hg as the threshold for initiation of antihypertensive therapy in women without evidence of end-organ involvement and 140/90 mm Hg as the threshold in women with evidence of renal involvement is summarized in Figure 26–1. Prenatal visits are scheduled every 2–4 weeks until 34–36 weeks and weekly thereafter. At each visit, blood pressure, urine protein, and fundal height are evaluated. Patients are questioned regarding signs and symptoms of preeclampsia, including headache, abdominal pain, blurred vision, scotomata, rapid weight gain, or marked swelling of the hands and/or face. Antepartum fetal monitoring usually is started around 32–34 weeks, and, in most cases, delivery is accomplished by 39–40 weeks’ gestation.


Figure 26–1. Management algorithm for chronic hypertension in pregnancy. DBP, diastolic blood pressure; SBP, systolic blood pressure.

B. Treatment of Severe Chronic Hypertension

Women with sustained blood pressure ≥180/110 mm Hg or those with evidence of renal disease may be at higher risk for serious complications, such as heart attack, stroke, or progression of renal disease, and are candidates for anti-hypertensive medication. As summarized in Figure 26–1, many clinicians would use a lower threshold of 150/100 mm Hg for instituting antihypertensive therapy during pregnancy.

Frequent prenatal visits may be needed to check the effectiveness of the medication. Fetal growth, blood pressure, and proteinuria are assessed at each visit, and evidence of superimposed preeclampsia is aggressively sought. Management of preeclampsia is described later in this chapter. In women with evidence of renal disease, some clinicians measure creatinine clearance and 24-hour urinary protein excretion each trimester. Sonographic assessment of fetal growth is performed every 2–4 weeks, antepartum testing is initiated by 32–34 weeks, and delivery is accomplished after 38 weeks or when fetal lung maturity is demonstrated. In some cases, hypertension worsens significantly during pregnancy without the development of overt preeclampsia. If exacerbation of chronic hypertension necessitates preterm delivery, corticosteroids should be considered in attempt to accelerate fetal maturity.

C. Antihypertensive Therapy in Chronic Hypertension

Several choices for initial antihypertensive therapy during pregnancy are available. Methyldopa has been studied extensively and is recommended by many as the first-line antihypertensive agent in pregnancy. It is a centrally acting alpha-adrenergic agonist that appears to inhibit vasoconstricting impulses from the medullary vasoregulatory center. The total daily dosage of 500 mg to 2 g is administered in 2–4 divided doses. Peak plasma levels occur 2–3 hours after administration, and the maximum effect occurs 4–6 hours after an oral dose. The agent is excreted primarily by the kidney. Sedation and postural hypotension are the most common side effects. A positive direct Coombs’ test may be seen, usually after 6–12 months of therapy. Hemolytic anemia may occur in these patients and is an indication to stop the medication. Fever, liver function abnormalities, granulocytopenia, and thrombocytopenia are rare side effects.

Labetalol is an alpha1-adrenergic blocker and a nonselective beta-adrenergic blocker. The beta-blockade/alpha-blockade ratio is 7:1. A large body of clinical evidence suggests that use of labetalol is safe during pregnancy. It appears to lack teratogenicity and crosses the placenta in small amounts. One randomized study showed no advantages of labetalol over methyldopa. Another study reported a higher incidence of small for gestational age newborns in patients treated with labetalol. The usual starting dose is 100 mg twice per day (BID), and the dose can be increased weekly to a maximum of 2400 mg daily. Titration increments should not exceed 200 mg BID.

Nifedipine is a calcium channel blocker that has been used during pregnancy for tocolysis and treatment of hypertension. Several reports suggest that nifedipine use is safe during pregnancy; however, the cumulative experience with this agent is not as extensive as with methyldopa and labetalol. When nifedipine is used for treatment of chronic hypertension during pregnancy, the long-acting formulation (Procardia XL, Adalat CC) may improve patient compliance. The principal benefit of this agent is once-daily dosing. The usual starting dose is 30 mg daily. If necessary, the dose may be increased to 60–90 mg daily. The neuro-muscular-blocking action of magnesium may be potentiated by simultaneous calcium channel blockade; therefore, nifedipine should be used with caution in patients receiving magnesium sulfate. The sublingual route of administration is associated with unpredictable blood levels and should be avoided.

Other antihypertensive medications used in pregnancy include atenolol, metoprolol, prazosin, minoxidil, hydralazine, thiazide diuretics, and clonidine. Published experience with these agents is limited, and they should not supplant methyldopa, labetalol, or nifedipine as first-line agents in pregnancy.

Use of angiotensin-converting enzyme inhibitors (enalapril, captopril) during pregnancy is associated with fetal hypocalvaria, renal defects, anuria, and fetal and neonatal death. These agents are contraindicated in pregnancy. With few exceptions, diuretics (furosemide, hydrochlorothiazide) should be avoided during pregnancy. Fetal bradycardia, growth retardation, and neonatal hypoglycemia have been reported in patients treated with blockers.

D. Fetal Assessment in Chronic Hypertension

Pregnancies complicated by chronic hypertension, regardless of the cause, are at increased risk for poor fetal growth. An initial ultrasound examination should be performed as early as possible to confirm the due date and to ensure that no obvious fetal anomalies are present. Thereafter, fetal growth may be assessed by ultrasound as needed, usually no more frequently than every 2–4 weeks. Antepartum fetal monitoring usually is started by 32–34 weeks. If the nonstress test is used as the method of surveillance, it should be accompanied by assessment of amniotic fluid volume. Doppler velocimetry of the umbilical, uterine, and middle cerebral arteries are helpful in optimizing the timing of delivery, particularly in cases of suspected fetal growth restriction.


Pregnancy outcome usually is good in patients with mild chronic hypertension and no other serious medical conditions. Fetal growth restriction, superimposed preeclampsia, placental abruption, and preterm delivery are the most common complications. The outlook is less favorable in women with severe hypertension early in pregnancy and in those with evidence of end-organ compromise, such as renal insufficiency and/or cardiovascular disease. By necessity, management is individualized. Close monitoring for development of fetal growth restriction and superimposed preeclampsia is indicated.

American College of Obstetricians and Gynecologists. Chronic hypertension in pregnancy. ACOG Practice Bulletin No. 29. Obstet Gynecol 2001;98:177. PMID 11508256.

Report of the National High Blood Pressure Education Program Working Group on high blood pressure in pregnancy. Am J Obstet Gynecol 2000;183:S1. PMID 10920346.



Images Maternal blood pressure elevation of ≥140 mm Hg systolic or ≥90 mm Hg diastolic on 2 occasions 6 hours apart in a previously normotensive woman ≥20 weeks’ gestation

Images No evidence of proteinuria


Gestational hypertension appears to affect approximately 6% of pregnancies. The pathogenesis of gestational hypertension is unclear, and it is equally unclear whether gestational hypertension represents an early stage of preeclampsia or whether it is an entirely separate disease entity. Gestational hypertension is considered to be a provisional diagnosis as many women with gestational hypertension will go on to be diagnosed with either preeclampsia or chronic hypertension. If preeclampsia has not developed and the maternal blood pressure has returned to normal by 12 weeks postpartum, then a diagnosis of transient hypertension of pregnancy is made.

Clinical Findings

A diagnosis of gestational hypertension is made when (1) maternal blood pressure is elevated to ≥140 mm Hg systolic or ≥90 mm Hg diastolic on 2 occasions 6 hours apart in a previously normotensive woman ≥20 weeks’ gestation, and (2) there is no evidence of proteinuria. Gestational hypertension is classified as mild or severe based on the degree of blood pressure elevation. It is considered to be severe when the systolic blood pressure is persistently ≥160 mm Hg or the diastolic blood pressure is persistently ≥110 mm Hg.


Approximately 15–25% of women diagnosed with gestational hypertension go on to develop preeclampsia. Women with mild gestational hypertension do not appear to be at increased risk of preterm birth, intrauterine growth restriction, abruption, or stillbirth. Women with severe gestational hypertension, however, are at increased risk of adverse outcomes, including preterm birth, intrauterine growth restriction, and placental abruption.


Given the 15–25% risk of progression to preeclampsia, treatment includes close surveillance for signs and symptoms of preeclampsia. Patient education regarding symptoms of preeclampsia (headache, visual changes, epigastric or abdominal pain) is recommended. Initial evaluation includes 24-hour urine collection to confirm the absence of significant proteinuria and serum laboratory evaluation to evaluate hepatic transaminases, creatinine, hematocrit, platelets, and lactic acid dehydrogenase. Derangements in any of these serum laboratories would be indicative of a diagnosis of preeclampsia as opposed to gestational hypertension.

For the patient with mild gestational hypertension, fetal surveillance with ultrasound for fetal growth approximately once per month and weekly biophysical profiles can assess fetal well-being. Antihypertensives are not recommended in women with mild gestational hypertension, as they have not been shown to improve outcomes. Delivery is recommended at 39–40 weeks’ gestation.

Because severe gestational hypertension is associated with an increased risk of adverse outcomes at a rate similar to that of severe preeclampsia, women with severe gestational hypertension are generally managed the same way as women with severe preeclampsia (see Treatment section under Preeclampsia, later).


Most women experience normalization of their blood pressure within 2 weeks after delivery. Approximately 15% of women diagnosed with gestational hypertension will have persistently elevated blood pressure >12 weeks after delivery and will meet a diagnosis of chronic hypertension. The recurrence rate of gestational hypertension in future pregnancies is approximately 25%.



Images Maternal blood pressure elevation of ≥140 mm Hg systolic or ≥90 mm Hg diastolic on 2 occasions 6 hours apart

Images Proteinuria ≥300 mg in a 24-hour urine specimen


Preeclampsia complicates 5–7% of all pregnancies. Preeclampsia occurs with increased frequency among young, nulliparous women. However, the frequency distribution is bimodal, with a second peak occurring in multiparous women greater than 35 years of age. Among daughters of preeclamptic women, the risk of preeclampsia is significantly higher than the population risk. Other predisposing factors for preeclampsia are listed in Table 26–3.

Table 26–3. Risk factors for preeclampsia.


Normal pregnancy is associated with decreased maternal sensitivity to endogenous vasopressors. Apparent early in gestation, this effect leads to expansion of the maternal intravascular space and a decline in blood pressure throughout the first half of pregnancy, with a nadir at midgestation. Thereafter, continued expansion of intravascular volume leads to a gradual rise in the blood pressure to prepregnancy levels by term. Women destined to develop preeclampsia do not exhibit normal refractoriness to endogenous vasopressors. As a result, normal expansion of the intravascular space does not occur, and the normal decline in blood pressure during the first half of pregnancy may be absent or attenuated. Despite normal to elevated blood pressure, intravascular volume is reduced.

The etiology of preeclampsia is not known; however, a growing body of evidence suggests that maternal vascular endothelial injury plays a central role in the disorder. Some reports suggest that endothelial damage in preeclampsia results in decreased endothelial production of prostaglandin I2 (prostacyclin), a potent vasodilator and inhibitor of platelet aggregation. Endothelial cell injury exposes subendothelial collagen and can trigger platelet aggregation, activation, and release of platelet-derived thromboxane A2 (TXA2), a potent vasoconstrictor and stimulator of platelet aggregation. Decreased prostacyclin production by dysfunctional endothelial cells and increased TXA2 release by activated platelets and trophoblast may be responsible for reversal of the normal ratio of prostacyclin and TXA2 observed in preeclampsia. The predominance of TXA2 may contribute to the vasoconstriction and hypertension that are central features of the disorder. Elevated intravascular pressure combined with damaged vascular endothelium results in movement of fluid from the intravascular to the extravascular spaces, leading to edema in the brain, retinae, lungs, liver, and subcutaneous tissues. Hypertension and glomerular endothelial damage lead to proteinuria. The resultant decrease in intravascular colloid oncotic pressure contributes to further loss of intravascular fluid. Hemoconcentration is reflected in a rising hematocrit. Consumption of platelets and activation of the clotting cascade at the sites of endothelial damage may lead to thrombocytopenia and disseminated intravascular coagulation (DIC). Soluble fibrin monomers produced by the coagulation cascade may precipitate in the microvasculature, leading to microangiopathic hemolysis and elevation of the serum lactate dehydrogenase level. Cerebral edema, vasoconstriction, and capillary endothelial damage may lead to hyperreflexia, clonus, convulsions, or hemorrhage. Hepatic edema and/or ischemia may lead to hepatocellular injury and elevation of serum transaminases and lactate dehydrogenase levels. The right upper quadrant or epigastric pain observed in severe preeclampsia is thought to be caused by stretching of Glisson’s capsule by hepatic edema or hemorrhage. Intravascular fluid loss across damaged capillary endothelium in the lungs may result in pulmonary edema. In the retinae, vasoconstriction and/or edema may lead to visual disturbances, retinal detachment, or blindness. Movement of fluid from the intravascular space into the subcutaneous tissues produces the characteristic nondependent edema of preeclampsia.

Endothelial damage appears to be capable of triggering a cascade of events culminating in the multiorgan system dysfunction observed in preeclampsia. However, the mechanism of endothelial injury remains speculative. In one theory, decreased placental oxygenation triggers the placenta to release an unknown factor into the maternal circulation. This circulating factor is capable of damaging or altering the function of maternal endothelial cells and triggering the cascade of events described. In support of this theory, cultured trophoblasts exposed to a hypoxic environment release a variety of potentially vaso-active factors, including thromboxane, interleukin-1, and tumor necrosis factor. Moreover, serum from preeclamptic women, when applied to human endothelial cell cultures, alters the release of a variety of procoagulant, vasoactive, and mitogenic factors, including endothelin, nitric oxide, and prostacyclin. Serum from the same woman 6 weeks after delivery does not produce this effect. Likewise, serum from a nonpreeclamptic woman at the same gestational age fails to trigger these endothelial changes. In many cases, reduced placental oxygenation may be explained by maternal vasculopathy (chronic hypertension, renal disease, collagen vascular disease) and in others by abnormal placental mass (multiple gestation, diabetes, hydatidiform mole). In another subset of patients, reduced placental oxygenation late in pregnancy may be the result of abnormal endovascular trophoblast invasion early in pregnancy. In the first trimester of a normal pregnancy, proliferating trophoblast invades the decidual segments of the maternal spiral arteries, replacing endothelium and destroying the medial elastic and muscular tissue of the arterial wall. The arterial wall is replaced by fibrinoid material. During the second trimester, a second wave of endovascular trophoblastic invasion extends down the lumen of the spiral arteries deeper in the myometrium. The endothelium and musculoelastic architecture of the spiral arteries are destroyed, resulting in dilated, thin-walled, funnel-shaped vessels that are passive conduits of the increased uteroplacental blood flow of pregnancy. In some women destined to develop preeclampsia, the first wave of endovascular trophoblastic invasion may be incomplete, and the second wave does not occur. As a result, the deeper segments of the spiral arteries are not remodeled but instead retain their musculoelastic architecture and their ability to respond to endogenous vasoconstrictors, reducing maternal perfusion of the placenta and predisposing to relative placental hypoxia later in pregnancy. In addition, myometrial portions of the spiral arteries exhibit a unique abnormality characterized by vessel wall damage, fibrinoid necrosis, lipid deposition, and macrophage and mononuclear cell infiltration of vessel walls and surrounding tissues. These changes, histologically similar to those observed in atherosclerosis, are referred to as acute atherosis and may lead to vascular lumen obliteration and placental infarction. Importantly, these changes are attributed to abnormal endovascular trophoblastic invasion during the second trimester of pregnancy, predisposing the fetus to suboptimal placental perfusion early in gestation. Interestingly, the clinical manifestations are observed most often in the third trimester, possibly due to increasing fetal and placental oxygen demands with advancing gestation.

The reason that endovascular trophoblastic invasion progresses normally in most pregnancies but abnormally in others is unclear. One theory maintains that maternal antibodies directed against paternal antigens on invading trophoblasts are necessary to shield those antigens from recognition by decidual natural killer cells, protecting the invading trophoblast from attack and rejection by the cellular arm of the maternal immune system. Supporting this theory is the observation that preeclampsia appears to be associated with primi-paternity and the presumed lack of previous maternal exposure and sensitization to paternal trophoblast antigens in a previous pregnancy. Additional support for this theory is provided by the observation that preeclampsia is more common among women using barrier contraception than among those using nonbarrier forms of contraception before pregnancy. This suggests that maternal exposure (and presumably sensitization) to paternal antigens on sperm is protective against preeclampsia. The observed inverse relationship between duration of cohabitation before pregnancy and the incidence of preeclampsia provides further evidence that maternal sensitization to paternal antigens is protective against preeclampsia. The interplay between immunology and genetics is underscored by the observation that preeclampsia may be more common in pregnancies in which the father was the product of a preeclamptic pregnancy. Applied to the theory under discussion, this suggests that some genetically determined paternal antigens are less antigenic than others and therefore less likely to provoke an antibody response in an exposed mother, decreasing maternal production of “blocking” antibodies and increasing the likelihood of abnormal placental invasion and preeclampsia. Alternatively, paternally inherited genes may code for altered fetal production of insulin-like growth factor-2, an insulin homologue related to placental invasion. Other genes that may be inherited from the father and play a role in the development of preeclampsia include genes coding for angiotensinogen, methylenetetrahydrofolate reductase, and the factor V Leiden mutation.

Some studies have demonstrated that invading trophoblastic cells in normal pregnancy undergo an “antigenic shift” to resemble vascular endothelial antigens, masking them from recognition and rejection by decidual natural killer cells. Invading trophoblasts in preeclamptic pregnancies may fail to make this antigenic shift, exposing them to recognition by natural killer cells and halting normal invasion.

Recent work has demonstrated that soluble fms-like tyrosine kinase-1 (sFlt-1) is increased in the placenta and serum of women with preeclampsia. This protein adheres to placental growth factor and vascular endothelial growth factor (VEGF), preventing their interaction with endothelial receptors and causing endothelial dysfunction. Interrupted angiogenesis may contribute to faulty placental invasion early in pregnancy and subsequent risk for placental hypoxia–ischemia and preeclampsia. Unbound placental growth factor and VEGF have been found in decreased concentration during and even before the development of clinical preeclampsia.

Genetic, immunologic, and other factors govern the complex interaction between the maternal host and the invading trophoblast. Detailed discussion of these and other possible etiologies of the entity of preeclampsia are beyond the scope of this chapter. Regardless of the etiology, thorough familiarity with the clinical aspects of the disorder can help guide thoughtful and coherent management.

Preeclampsia exerts an effect on many different maternal organ systems:

A. Brain

Pathologic findings in preeclampsia-induced cerebral injury include fibrinoid necrosis, thrombosis, microinfarcts, and petechial hemorrhages, primarily in the cerebral cortex. Cerebral edema may be observed. Head computed tomographic findings include focal white matter hypodensities in the posterior cerebral hemispheres, temporal lobes, and brain stem, possibly reflecting petechial hemorrhage with resultant local edema. Magnetic resonance imaging may reveal occipital and parietal abnormalities in the watershed distribution of the major cerebral arteries, as well as lesions in the brain stem and basal ganglia. Subarachnoid or intraventricular hemorrhage may occur in severe cases.

B. Heart

Preeclampsia is characterized by the absence of normal intravascular volume expansion, a reduction in normal circulating blood volume, and a loss of normal refractoriness to endogenous vasopressors, including angiotensin II. Invasive hemodynamic monitoring in preeclamptic patients has yielded conflicting information. Depending on disease severity, effects of previous therapy, and other factors, preeclampsia has been described variously as a state of abnormally high cardiac output and low systemic vascular resistance, a state of abnormally low cardiac output and high systemic vascular resistance, or a state of high cardiac output and high systemic vascular resistance. These divergent observations underscore the complexity of the disorder.

C. Lungs

Alterations in colloid oncotic pressure, capillary endothelial integrity, and intravascular hydrostatic pressure in preeclampsia predispose to noncardiogenic pulmonary edema. In women with preeclampsia superimposed on chronic hypertension, preexisting hypertensive cardiac disease may exacerbate the situation, superimposing cardiogenic pulmonary edema on noncardiogenic, preeclampsia-related pulmonary edema. Excessive administration of intravenous (IV) fluid and postpartum mobilization of accumulated extravascular fluid also increase the risk of pulmonary edema. In eclampsia, pulmonary injury may result from aspiration of gastric contents, leading to pneumonia, pneumonitis, or adult respiratory distress syndrome.

D. Liver

Histologic lesions in the liver are characterized by sinusoidal fibrin deposition in the periportal areas with surrounding hemorrhage and portal capillary thrombi. Centrilobular necrosis may result from reduced perfusion. Inflammation is not characteristic. Subcapsular hematomas may develop. In severe cases involving hepatocellular necrosis and DIC, intrahepatic hematomas may progress to liver rupture. Right upper quadrant pain or epigastric pain are classic symptoms attributed to stretching of Glisson’s capsule. Elevation of serum transaminases is a hallmark of HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome.

E. Kidneys

Distinct histologic changes have been described in the kidneys of women with preeclampsia. The classic renal lesion of preeclampsia, glomeruloendotheliosis, is characterized by swelling and enlargement of glomerular capillary endothelial cells, leading to narrowing of the capillary lumen. There is an increased amount of cytoplasm containing lipid-filled vacuoles. Mesangial cells may be swollen as well. Immunoglobulins, complement, fibrin, and fibrin degradation products have been observed in the glomeruli, but their presence is variable.

F. Eyes

Retinal vasospasm, retinal edema, serous retinal detachment, and cortical blindness may occur in the setting of preeclampsia. Blindness is uncommon and usually transient, resolving within hours to days of delivery.


The observed alteration in the ratio of vasoconstrictive and vasodilatory prostaglandins in preeclampsia led investigators to study the effectiveness of prostaglandin synthesis inhibitors in preventing the disorder. Several small trials of low-dose aspirin reported significant reductions in the incidence of preeclampsia in high-risk populations. However, in 1994 the Collaborative Low-Dose Aspirin Study in Pregnancy (CLASP) Collaborative Group reported a large randomized trial comparing low-dose aspirin with placebo in more than 9300 high-risk patients. Low-dose aspirin did not reduce the incidence of preeclampsia in this high-risk population. Because the risks of the regimen are few, some physicians may reasonably choose to use it.

Calcium is essential in the synthesis of nitric oxide, a potent vasodilator believed to contribute to the maintenance of reduced vascular tone in pregnancy. Calcium supplementation during pregnancy has been proposed as a means to prevent preeclampsia. Although individual studies have demonstrated mixed results regarding the efficacy of calcium supplementation, a meta-analysis concluded that calcium supplementation of at least 1 gram daily during pregnancy appears to reduce the risk of preeclampsia by approximately 50%.

Clinical Findings

A diagnosis of preeclampsia is made based on 2 criteria: (1) elevated maternal blood pressure of ≥140 mm Hg systolic or ≥90 mm Hg diastolic on 2 occasions 6 hours apart, and (2) proteinuria ≥300 mg in a 24-hour urine specimen. In the past, the classic diagnostic triad included hypertension, proteinuria, and edema. Recently, the National High Blood Pressure Education Working Group recommended eliminating edema as a diagnostic criterion because it is too frequent an observation during normal pregnancy to be useful in diagnosing preeclampsia. In addition to the classic findings of hypertension and proteinuria, women with preeclampsia may complain of scotomata, blurred vision, or pain in the epigastrium or right upper quadrant. Examination often reveals brisk patellar reflexes and clonus. Laboratory abnormalities include elevated levels of hematocrit, lactate dehydrogenase, serum transaminases and uric acid, and thrombocytopenia. Although biochemical evidence of DIC may be detected with increased fibrin degradation products, hypofibrinogenemia and prolongation of the prothrombin time and activated partial thromboplastin time usually are seen only in cases complicated by abruption or multiple organ failure.

Preeclampsia is classified into mild or severe based on the degree of hypertension and proteinuria and the presence of other findings (Table 26–4). The HELLP syndrome is a variant of preeclampsia that is characterized by hemolysis, elevated liver enzymes, and low platelets. It complicates 10% of cases of severe preeclampsia and up to 50% of cases of eclampsia. Right upper quadrant pain, nausea, vomiting, and malaise are common. Hypertension and proteinuria are variable. The hallmark of the disorder is microangiopathic hemolysis leading to elevation of serum lactate dehydrogenase level and fragmented red blood cells on peripheral smear. Transaminase levels are elevated, thrombocytopenia is present, and DIC may be evident. Management is similar to that of severe preeclampsia. (See Chapter 29, Gastrointestinal Disorders in Pregnancy, for a more extensive review of HELLP syndrome.)

Table 26–4. Classification of preeclampsia.



Complications related to preeclampsia include preterm birth, intrauterine fetal growth restriction, placental abruption, maternal pulmonary edema, and eclampsia. The estimated incidence of eclampsia is 1–3 per 1000 preeclamptic patients. Eclampsia is defined as one or more generalized convulsions in the setting of preeclampsia.


In the management of preeclampsia, with few exceptions, maternal interests are best served by immediate delivery. However, this approach may not be in the best interest of the fetus. In the case of extreme prematurity, for example, the fetus may benefit from a period of expectant management during which corticosteroids are administered to accelerate fetal maturation. The decision to proceed with immediate delivery versus expectant management is based on several factors, including disease severity, fetal maturity, maternal and fetal condition, and cervical status.

A. Mild Preeclampsia

Women with mild preeclampsia are hospitalized for further evaluation and, if indicated, delivery. If mild preeclampsia is confirmed and the gestational age is 40 weeks or greater, delivery is indicated. At gestational ages of 37–40 weeks, cervical status is assessed and, if favorable, induction is initiated. If the cervical status is unfavorable, preinduction cervical ripening agents are used as needed. Occasionally, women with very unfavorable cervical examinations between 37 and 40 weeks may be managed expectantly for a limited time with bed rest, antepartum fetal surveillance, and close monitoring of maternal condition, including blood pressure measurement every 4–6 hours and daily assessment of patellar reflexes, weight gain, protein-uria, and symptoms. A complete blood count and levels of serum transaminases, lactate dehydrogenase, and uric acid should be checked weekly to twice weekly. Delivery is indicated if the cervical status becomes favorable, antepartum testing is abnormal, the gestational age reaches 40 weeks, or evidence of worsening preeclampsia is seen. If expectant management is undertaken after 37 weeks, the patient should understand that the only known benefit is a possible reduction in the rate of caesarean birth.

Women with mild preeclampsia before 37 weeks’ gestation are managed expectantly with bed rest, twice-weekly antepartum testing, and maternal evaluation as described. Corticosteroids are administered if the gestational age is <34 weeks; amniocentesis is performed as needed to assess fetal pulmonary maturity. When extended expectant management is undertaken, fetal growth is assessed with ultrasound every 3–4 weeks. Occasionally, outpatient management is reasonable in carefully selected, reliable, asymptomatic patients with minimal proteinuria and normal laboratory test results. This approach includes bed rest at home, daily fetal movement counts, twice-weekly antepartum testing, serial evaluation of fetal growth, and frequent assessment, often by a visiting nurse, of blood pressure, proteinuria, weight gain, patellar reflexes, and symptoms. Any evidence of disease progression constitutes an indication for hospitalization and consideration of delivery. The benefit of prophylactic intrapartum magnesium sulfate in preventing convulsions in patients with mild preeclampsia has not been demonstrated conclusively in the literature.

B. Severe Preeclampsia

Severe preeclampsia mandates hospitalization. Delivery is indicated if the gestational age is 34 weeks or greater, fetal pulmonary maturity is confirmed, or evidence of deteriorating maternal or fetal status is seen. Acute blood pressure control may be achieved with hydralazine, labetalol, or nifedipine. The goal of antihypertensive therapy is to achieve a systolic blood pressure <160 mm Hg and a diastolic blood pressure <105 mm Hg. Overly aggressive control of the blood pressure may compromise maternal perfusion of the intervillous space and adversely affect fetal oxygenation. Hydralazine is a peripheral vasodilator that can be given in doses of 5–10 mg administered intravenously (IV). The onset of action is 10–20 minutes, and the dose can be repeated in 20–30 minutes if necessary. Labetalol can be administered in doses of 5–20 mg by slow IV push. The dose can be repeated in 10–20 minutes. Nifedipine is a calcium channel blocker that can be used in doses of 5–10 mg orally. The sublingual route of administration should not be used. The dose can be repeated in 20–30 minutes, as needed.

Management of severe preeclampsia before 34 weeks is controversial. In some institutions, delivery is accomplished regardless of fetal maturity. In others, delivery is delayed for a limited period of time to permit the administration of corticosteroids. Four large randomized controlled trials comparing magnesium sulfate with other methods of treatment to prevent convulsions in women with severe preeclampsia have demonstrated that magnesium sulfate is associated with a significantly lower rate of eclampsia than either no treatment or nimodipine. Lucas and colleagues reported no seizures among 1049 preeclamptic women receiving magnesium sulfate prophylaxis. Nonetheless, tonic–clonic convulsions may occur despite magnesium sulfate therapy. Magnesium sulfate is initiated, fetal status is monitored continuously, and antihypertensive agents are used as needed to maintain a systolic blood pressure <160 mm Hg and a diastolic blood pressure <105 mm Hg. Between 33 and 35 weeks, consideration should be given to amniocentesis for pulmonary maturity studies. If mature, immediate delivery is indicated. If immature, corticosteroids are administered and, if possible, delivery is delayed 24–48 hours. Between 24 and 32 weeks, antihypertensive therapy is instituted as indicated, corticosteroids are administered, and extensive maternal counseling is undertaken to clarify the risks and benefits of pregnancy prolongation. Neonatology consultation is helpful to delineate the neonatal risks specific to gestational age and estimated fetal weight. The duration of expectant management is determined on an individual basis, taking into account maternal wishes, estimated fetal weight, gestational age, and maternal and fetal status. Expectant management is contraindicated in the presence of fetal compromise, uncontrollable hypertension, eclampsia, DIC, HELLP syndrome, cerebral edema, pulmonary edema, or evidence of cerebral or hepatic hemorrhage. When severe preeclampsia is diagnosed before 24 weeks of gestation, the likelihood of a favorable outcome is low. Thorough counseling should address realistically the risks and anticipated benefits of expectant management and should include the option of pregnancy termination. If an appropriately informed patient declines the option of pregnancy termination, expectant management should proceed as outlined previously.

C. Intrapartum Management of Preeclampsia

In women with preeclampsia without contraindications to labor, vaginal delivery is the preferred approach. Cervical ripening agents and oxytocin are used as needed. If magnesium sulfate is used for seizure prophylaxis, it is administered as an IV loading dose of 4–6 g over 20–60 minutes, followed by a maintenance dose of 1–2 g/h. Urine output and serum creatinine level are monitored, and the magnesium dose is adjusted accordingly to prevent hypermagnesemia. Patellar reflexes and respiratory rate should be assessed frequently. In the presence of patellar reflexes, serum magnesium levels usually are unnecessary. Therapeutic magnesium levels range from 4–8 mg/dL. Loss of patellar reflexes is observed at magnesium levels of 10 mg/dL or higher, respiratory paralysis may occur at levels of 15 mg/dL or above, and cardiac arrest is possible with levels in excess of 25 mg/dL. Calcium gluconate (10 mL of 10% solution) should be available in the event of hypermagnesemia. To avoid pulmonary edema, total IV fluids should not exceed 100 mL/h. Pain control is achieved with regional anesthesia or with intramuscular or IV narcotic analgesics. Invasive hemodynamic monitoring is reserved for refractory pulmonary edema, adult respiratory distress syndrome, or oliguria unresponsive to fluid challenge. If caesarean section is required, platelets should be available for possible transfusion for patients with platelet counts <50,000/mm3. Use of other blood products is guided by clinical and laboratory findings.

D. Management of Eclampsia

In most cases eclamptic seizures are self-limited, lasting 1–2 minutes. The first priorities are to ensure that the airway is clear and to prevent injury and aspiration of gastric contents. Diazepam or lorazepam should be used only if seizures are sustained. Nearly all tonic–clonic seizures are accompanied by a prolonged fetal heart rate deceleration that resolves after the seizure has ended. Once the patient has been stabilized, delivery is indicated. If possible, a 10- to 20-minute period of in utero resuscitation should be permitted before delivery. Convulsions alone do not constitute an indication for caesarean section. However, if vaginal birth is not possible within a reasonable period of time, caesarean delivery is performed in most cases. A number of studies suggest that magnesium sulfate is superior to phenytoin, diazepam, and a lytic cocktail at preventing recurrent seizures in women with eclampsia.

Altman D, Carroli G, Duley L, et al. Magpie Trial Collaboration Group: Do women with preeclampsia, and their babies, benefit from magnesium sulfate? The Magpie Trial: A randomized placebo-controlled trial. Lancet2002;359:1877–1890. PMID 12057549.

American College of Obstetricians and Gynecologists. Diagnosis and management of preeclampsia and eclampsia. ACOG Practice Bulletin No. 33. Obstet Gynecol 2002;99:159. PMID 16175681.

Belfort M, Anthony J, Saade G. The Nimodipine Study Group: A comparison of magnesium sulfate and nimodipine for the prevention of preeclampsia. N Engl J Med 2003;348:304–311. PMID 12540643.

Caritis S, Sibai B, Hauth J, et al. Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Units. N Engl J Med1998;338:701–705. PMID: 9494145.

CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group. CLASP: A randomized trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. Lancet1994;343:619–629. PMID: 7906809.

Chambers JC, Fusi L, Malik IS, et al. Association of maternal endothelial dysfunction with preeclampsia. JAMA 2001;285:1607. PMID 11268269.

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Duley L, Gulmezoglu AM, Henderson-Smart DJ. Magnesium sulphate and other anticonvulsants for women with pre-eclampsia. Cochrane Database Syst Rev 2003;CD000025. PMID 12804383.

Duley L, Henderson-Smart DJ, Knight M, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 2004:CD004659. PMID 14974075.

Esplin MS, Fausett MB, Fraser A, et al. Paternal and maternal components of the predisposition to preeclampsia. N Engl J Med 2001;344:867. PMID 11259719.

Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev 2010;CD001059. PMID: 20687064.

Isler CM, Barrilleaux PS, Magann EF, Bass JD, Martin JN Jr. A prospective, randomized trial comparing the efficacy of dexamethasone and betamethasone for the treatment of antepartum HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. Am J Obstet Gynecol 2001;184:1332. PMID 11408849.

Lain KY, Roberts JM. Contemporary concepts in the pathogenesis and management of preeclampsia. JAMA 2002;287:3183. PMID 12076198.

Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004;350:672. PMID 14764923.

Livingston JC, Livingston LW, Ramsey R, Mabie BC, Sibai BM. Magnesium sulfate in women with mild preeclampsia: A randomized controlled trial. Obstet Gynecol 2003;101:217–220. PMID 12576241.

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Hypertensive disorders of pregnancy remain among the most common causes of adverse maternal and perinatal outcome. These disorders can be regarded as a spectrum of disease, ranging from isolated chronic hypertension to pure preeclampsia–eclampsia. Isolated mild or moderate chronic hypertension appears to have little effect on pregnancy outcome. Morbidity and mortality are highest among patients with severe preeclampsia or eclampsia.

Appropriate management of newly diagnosed chronic hypertension entails a thorough search for an underlying cause. Close maternal and fetal surveillance is necessary, and a high index of suspicion must be maintained for the development of superimposed preeclampsia.

The management of preeclampsia is influenced by many factors, including disease severity, gestational age, and fetal condition. Optimal management requires an appreciation of the complexity of the disease process and familiarity with its manifestations in multiple organ systems. Maternal and fetal risks and benefits must be assessed thoroughly. Individualized treatment plans should be formulated and discussed with the patient, and she should be encouraged to participate in major decisions regarding her care. In atypical cases, alternative diagnoses must be considered.