Chapter 43. Hypertension in High-Risk Populations

General Considerations

Hypertension is a persistent and frequently progressive elevation in blood pressure. The level of systolic and/or diastolic blood pressure at which the elevation assumes the diagnosis of hypertension depends on the presence or absence of coexisting comorbidities. The current classification of blood pressure and the level of blood pressure that defines hypertension for the major comorbid conditions as recommended in the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of high blood pressure are shown in Table 43–1. The prevalence of hypertension varies with age and sex. It is estimated that 23% of adult Americans between the ages of 20 and 74 years have hypertension. About 75% of women aged 75 years and over have hypertension and about 64% of men aged 75 years and over have hypertension. At all ages and in both sexes African-Americans have the highest prevalence of hypertension in the United States. In African-Americans hypertension tends to develop at an earlier age and tends to be more severe than in other races. Some patients with systemic hypertension will have a specific identifiable cause for the elevated systemic blood pressure. The estimated proportion of the cases of secondary hypertension among patients with systemic hypertension ranges from about 5% to 10% and has not been shown to exhibit racial predilection. Patients with secondary hypertension usually exhibit suggestive constellations of signs and/or symptoms on initial evaluation and should undergo further evaluation for specific causes of hypertension regardless of their race and/or ethnicity.

Hypertension is one of the major risk factors for cardiovascular disease. Uncontrolled hypertension leads to specific target organ damage that contributes to overall cardiovascular morbidity and mortality. African-Americans exhibit a greater increase in target organ damage than other racial and ethnic groups. In fact, the heart disease mortality rate is 50% higher, the stroke mortality rate is 80% higher, and the incidence of hypertension-related end-stage renal disease (ESRD) is 6-fold higher in African-Americans than in whites. It is apparent that hypertension along with its cardiovascular morbidity and mortality is an even greater challenge for the African-American community than it is for the rest of the nation. Many of the factors responsible for the disparities in the incidence, prevalence, detection, treatment, and control of hypertension have been well described and can be useful in the design and development of programs and policies targeted to the diagnosis and control of hypertension within the population.

Pathogenesis

Blood pressure is a continuous variable determined by multiple factors and demonstrates a fairly normal distribution within the population. Some of the factors that determine blood pressure level are genetic and may account for about 30–50% of the blood pressure variation in the general population. The development of essential or idiopathic hypertension, however, is believed to require a genetic predisposition and an environmental precipitation in most instances. The search for specific genes responsible for hypertension has resulted in the discovery of some rare monogenetic causes of both high and low blood pressure. While several physiologic characteristics such as low renin levels, lower bioavailability of nitric oxide, increased salt sensitivity, and increased aldosterone levels are more prevalent in African-Americans, specific genetic underpinnings have yet to be identified. In spite of popular expectation there is still no identified genetic basis for the excess prevalence of hypertension in the African-American community. However, several lifestyle and environmental risk factors for hypertension have been identified with important differences among racial and ethnic groups.

Excess body fat, particularly in the upper body, is an important risk factor for hypertension. Whether expressed as overweight or obesity, excess body fat is more common among African-Americans, Hispanics, and several other ethnic minorities. Dietary salt intake in the form of sodium chloride has been associated with the level of blood pressure and the rise in blood pressure with age. As a group, African-Americans have higher salt intake and greater sensitivity to changes in blood pressure in response to dietary salt intake. In contrast a low potassium intake has been associated with hypertension and there is evidence that high dietary potassium, particularly in the form of fresh fruits and vegetables, may offer protection from hypertension and perhaps reduce the need for antihypertensive drug therapy. The diets of many African-Americans are generally low in fruits and vegetables and the average dietary potassium intake among African-Americans is less than that of other major racial and ethnic groups in the United States.

Physical inactivity is a risk factor for hypertension and cardiovascular mortality. Optimum physical activity requires 20–60 minutes of rhythmic and aerobic large-muscle activity such as walking, running, and cycling 3–5 days a week for blood pressure control and cardiorespiratory fitness. Physical activity is suboptimal in over 60% of the U.S. adults, about 25% of whome are totally inactive. Physical inactivity is more common among older adults, women, less affluent people, and Hispanic and African-American adults.

The intake of three or more standard drinks of alcohol per day, where a standard drink is defined as 14 g of ethanol and is contained in 1.5 oz of distilled spirit, a 5-oz glass of table wine, or a 12-oz glass of beer, has been associated with serious adverse psychosocial and health consequences including hypertension. It is estimated that about 60% of Americans ages 18 years and over ingest alcohol and about 30% have five or more standard drinks on the same occasion at least once in that year. Many of these Americans are African-Americans.

The low educational status and high unemployment rate prevalent among minority populations in the United States predispose many minority communities, including African-American, to adverse political and socioeconomic conditions that contribute to environmental and psychosocial stress as well as reduced access to quality health care. Acute stress can transiently raise blood pressure, while chronic stress has been associated with sustained hypertension. The job-strain model of psychosocial conflict, designed to assess the impact of occupational stress on the health of the worker, characterizes jobs into high and low strain jobs. Workers with high decision latitudes exhibit little or no distress because they have more flexibility in deciding how best to meet their work-related demands, while those in occupations that combine high demands with low decision latitudes exhibit high stress levels and its attendant cardiovascular morbidity. African-Americans are more likely to be employed in these positions. Indeed, men employed in these typically blue-collar jobs have a 3-fold increase in hypertension and those who remain in these jobs for 3 or more years have a reported blood pressure that is 11/7 mm Hg higher than men in low strain jobs.

While genetic and biological differences may influence the distribution of blood pressure levels within a population, the prevailing body of evidence seems to suggest that lifestyle and socioeconomic disparities have a greater influence on the expression of hypertension and the disproportionate burden of hypertension and cardiovascular disease in African-Americans. This suggests that it is not genetics alone but the gene–environment interaction that is responsible for the higher prevalence of hypertension among African-Americans. Further evidence supporting the unique role of environment is the fact that the excess risk for hypertension in African-Americans is more strongly linked to being born and living in the United States than with African ancestry.

Racial and/or ethnic differences in combined cardiovascular endpoints assume less significance in hypertensive-treated patients after an adjustment for differences in socioeconomic and demographic factors. The treatment and control of hypertension for optimal outcomes require an appropriate sensitivity to and an understanding of the unique sociocultural aspects of race/ethnicity to maximize effective access to care, adherence to treatment, and scheduled follow-ups. Such approaches will ultimately assist in overcoming many of the barriers to the control of hypertension and will lead to improved cardiovascular outcomes for all Americans.

Treatment Strategies

Hypertension

Severe hypertension and suboptimal blood pressure control rates perpetuate the disproportionate burden of cardiovascular disease (CVD) and premature death among African-Americans. Biobehavioral and socioeconomic factors frequently cited as plausible explanations for the lack of awareness and treatment of high blood pressure among African-Americans may not fully explain the failure to achieve recommended blood pressure goals. Several large-scale multicenter studies with substantial enrollment of African-American patients have demonstrated that blood pressure can be treated to goal levels, although more aggressive therapy may be needed. African-Americans seem to have a slightly greater blood pressure response to diuretics and calcium channel blockers than do other ethnic groups and less response to angiotensin-converting enzyme inhibitors (ACEIs) and β-blockers. Nevertheless, these differences do not seem to translate into different clinical outcomes based on class of antihypertensive therapy as long as target blood pressure levels are achieved. Thus, the search for cardiovascular risk factors and target organ damage, both of which are more prevalent among hypertensive African-Americans, and the selection of the appropriate therapeutic agent by compelling indication based on the coexisting comorbidities should supersede the search for specific agents for blood pressure control among African-Americans.

Cardiovascular and Related Complications of Hypertension

Hypertension is not only a major risk factor for CVD, but often occurs with one or more cardiovascular risk factors such as obesity, diabetes, and/or dyslipidemia in a syndrome known as the metabolic syndrome. A race-specific role for emerging cardiovascular risk factors such as aldosterone and inflammatory mediators has yet to be determined. The clinical and laboratory search for cardiovascular risk factors and target-organ damage is particularly important for African-American hypertensive patients. The awareness and identification of specific end-organ damage and coexisting cardiovascular risk factors should help prioritize nonpharmacologic recommendations, the selection of compelling evidenced-based medical treatment, and the establishment of appropriate target goals.

Left Ventricular Hypertrophy

Left ventricular hypertrophy is a common complication of hypertension and an independent predictor of increased mortality among hypertensive patients. It is more common among female and African-American patients with hypertension and may account for some of the ethnic and gender differences in cardiovascular mortality rates.

The treatment and control of hypertension by β-blockade and renin–angiotensin inhibition have been associated with regression of left ventricular hypertrophy. The blood pressure reduction and left ventricular mass regression associated with both of these treatments in most studies were similar in African-American and other racial and ethnic participants. A diminished response among African-Americans treated with angiotensin receptor blocker (ARB) therapy in one study may have been related to fewer African-Americans achieving target blood pressure goals, but a differential outcome based on race cannot be excluded.

Congestive Heart Failure

Congestive heart failure (CHF) in blacks is characterized by a higher frequency of hypertension as the etiology, a worse prognosis, and perhaps less of a response to evidenced-based CHF medical therapy in comparison to their white counterparts. There is abundant evidence that β-blockade and renin–angiotensin inhibition are beneficial for improving both mortality and hospitalization outcomes among patients with CHF, and overall these treatment strategies when adjusted for other covariates appear similar for both African-American and other racial/ethnic patients. While there are reports of higher readmission rates for African-American patients receiving these treatments, posthospitalization mortality data suggest that when quality care is provided, the apparent racial disparities in CHF outcomes dissipate. The treatment of CHF patients should therefore encompass class-specific therapy (eg, ACEI, ARB, β-blocker) in combination with diuretics as indicated for the general population regardless of race or ethnicity. The addition of aldosterone blockade has also led to improved CHF outcomes, although there are no data on racial differences. However, isosorbide dinitrate and hydralazine have been shown to reduce CHF mortality by 43% compared to placebo for African-Americans.

Stroke

African-American patients with hypertension exhibit the highest stroke rates of any racial or ethnic group. The recent decline in stroke mortality observed in other racial and ethnic groups is attenuated for African-American patients with hypertension. Blood pressure control and antiplatelet therapy remain the principal strategies for reducing stroke events among patients with hypertension. The degree of protection conferred by blood pressure control may vary for different classes of antihypertensive medications. A relative-risk reduction in stroke as high as 40% has been reported for African-Americans with diuretic therapy compared to therapy with ACEIs. Diuretics and calcium channel blockers (CCBs) have emerged as the preferred antihypertensive treatment for reducing stroke events for all hypertensive patients, including African-Americans. There are no reported racial and/or ethnic differences in the prevention of recurrent stroke and myocardial infarction with ticlopidine and aspirin. Aspirin is more cost effective and should therefore be the preferred agent for antiplatelet therapy. Ticlopidine should be reserved for patients with aspirin intolerance and allergy.

Chronic Kidney Disease

ESRD secondary to hypertension is six times more common in African-Americans than in the general population. The use of ACEIs in comparison to β-blockers and dihydropyridine CCBs was associated with a reduction in adverse clinical outcomes (doubling of creatinine, ESRD, or death) for African-American patients with hypertensive nephrosclerosis. Thus, the existing body of evidence suggests that optimal clinical outcomes are achieved when inhibition of the renin–angiotensin system is used as initial antihypertensive therapy with diuretics in African-Americans with hypertensive nephrosclerosis. Diabetes is the leading cause of ESRD for all racial and ethnic groups and over 90% of patients with diabetic nephropathy have hypertension. Multiple studies support the use of ACEIs and ARBs as the mainstay of therapy. The inclusion of nearly 15% African-American participants in two of the pivotal prospective randomized trial studies, suggests that the positive outcomes extend to blacks as well as nonblacks. Thus, interruption of the renin–angiotensin system has emerged as the initial recommended therapy in combination with diuretics for treating hypertensive and diabetic nephropathy, and usually represents the minimum treatment regimen needed to achieve the more aggressive recommended treatment goal of 130/80 mm Hg for patients with chronic kidney disease.

Therapeutic Lifestyle Changes

Therapeutic lifestyle changes are equally effective across racial and ethnic groups and sometimes even more effective among African-American patients. These changes are particularly important for African-American patients with hypertension because many of the major risk factors for hypertension in these patients are behavioral and modifiable. The identification and communication of risk-attributable behaviors (such as dietary indiscretion, physical inactivity, excessive alcohol intake, and smoking), particularly within the context of the established burden of cardiovascular disease, should engage and encourage the patient to be proactive in the implementation of therapeutic lifestyle changes.

Practical suggestions for the effective implementation of therapeutic lifestyle changes are listed in Table 43–2. Many of the barriers to successful implementation of therapeutic lifestyle changes among African-Americans are listed in Table 43–3. The recommendations for therapeutic lifestyle changes, such as weight control, dietary salt reduction, regular physical activity, and adherence to clinic visits and a medication regimen, should be provided in specific detail with a practical design, making it possible to break through some of these common barriers and achieve successful implementation. This may frequently necessitate the inclusion of additional healthcare professionals (eg, dietitian, pharmacist, social worker) and/or family members in the dialogue.

Prognosis

The mainstay of hypertensive therapy for African-Americans remains diuretics and therapeutic lifestyle changes. The selection of supplemental antihypertensive agents should be tailored to the presence of coexisting risk factors, comorbid medical conditions, and/or the presence of hypertension-related target organ damage. Many of these patients will need two to four antihypertensive agents to achieve target blood pressure goals. The preference for agents that block the renin–angiotensin system as supplemental antihypertensive agents among patients with CHF, diabetes, and kidney disease cannot be overemphasized. It is, however, pertinent to note that the use of some of these agents among African-Americans is associated with a slightly higher rate of side effects, such as angioedema with ACEIs. Thus, strategies for the treatment of hypertension should be driven by the prevalence of coexisting cardiovascular risk factors and an understanding of sociocultural influences that impact access to care and adherence to evidenced-based treatment rather than minor differences in blood pressure response by racial and ethnic categories. Such approaches will ultimately reduce the disproportionate impact of hypertension and CVD within the African-American community.

General Considerations

In the past few years there has been a major paradigm shift in thinking about hypertension, with systolic blood pressure (BP) now accepted as the primary clinical concern in adults. Systolic hypertension is generated principally by functional and structural changes in the aorta and large arteries and can be viewed as a condition that differs distinctly from diastolic hypertension. Isolated systolic hypertension is considerably more difficult to treat than diastolic hypertension and expert clinical judgment is often required in establishing acceptable BP targets and in choosing optimal drug therapy.

Age-related BP patterns in industrialized societies are complex (Figure 43–1): Systolic BP increases linearly with age, while diastolic BP increases until about age 50 years and then declines. Mean arterial pressure (MAP) thus increases until about age 50 years and then plateaus, whereas pulse pressure (PP) is constant until age 50 years and then increases. In adults, systolic hypertension is thus the predominant form of the condition. Contrary to popular belief, systolic hypertension is not just “burned out” diastolic hypertension. Rather, it can arise de novo at any age, either preceding or without the presence of diastolic hypertension. Aging is not inexorably associated with systolic hypertension: In primitive or cloistered societies there is no relationship between age and BP.

Aging and hypertension dramatically increase the risk for cardiovascular disease (CVD). Overall, each 20 mm Hg increase in systolic BP (or 10 mm Hg increase in diastolic BP) at least doubles the risk of cardiovascular disease or stroke over the range of 115/75 to 185/115 mm Hg. The risk associated with systolic BP is robust and log-linear irrespective of age, while the relationship between diastolic BP and risk is weaker and more complex; the risk for CVD is proportional to diastolic BP until about age 50 years, after which decreased diastolic BP and “wide pulse pressure hypertension” are the major markers of increased risk for CVD.

The value of therapy in isolated systolic hypertension has been clearly established for thiazide-based therapy in the Systolic Hypertension in the Elderly Program (SHEP) and for calcium antagonist-based therapy in the Systolic Hypertension in Europe (Syst-EUR) study. In both of these studies, individuals over age 60 years with stage 2 isolated systolic hypertension (pretreatment systolic BP values >160 mm Hg with diastolic BP values <90 mm Hg) experienced a relative reduction in stroke by about one-third when active therapy was compared to placebo. The net differences in systolic BP between the active and control arms in SHEP and Syst-EUR were about 10–12 mm Hg. To date, no study has been completed that demonstrates an outcome benefit of treating stage 1 systolic hypertension (140–159 mm Hg), but it has recently been found that treating prehypertension (systolic BP 120–139 mm Hg) for 2 years with an angiotensin blocker reduces the subsequent incidence of hypertension for at least 2 years after cessation of therapy.

Pathogenesis

The predominant clinical form of hypertension in middle-aged and elderly individuals is isolated systolic hypertension (ISH); combined systolic–diastolic hypertension (SDH) is much less common and isolated diastolic hypertension (IDH) is increasingly rare (Figure 43–2). These clinical subtypes are related to the underlying hemodynamic abnormalities, which are quite heterogeneous from a pathophysiologic perspective. In the past, the pathogenesis of hypertension was oversimplified as a syndrome of arteriolar vasoconstriction and vascular smooth muscle hypertrophy leading to high systemic vascular resistance (SVR) with normal cardiac output.

In reality, hypertension is a collection of hemodynamic anomalies that includes various proportions of (1) increased impedance in large arteries (generating systolic or wide pulse pressure hypertension), (2) decreased luminal diameter of distal arterioles (generating diastolic or mean arterial hypertension), (3) inappropriately high cardiac output, and (4) increased blood pressure reactivity to environmental stimuli, most commonly recognized as the “white-coat syndrome.” In contrast to IDH, the characteristic sign of increased SVR, ISH is associated with significant increases in aortic impedance and sometimes with increased stroke volume, with only minimal to moderate increases in SVR (Figure 43–3). In some cases, especially in women and smaller people, increased aortic impedance can be caused by a relatively small aortic diameter with normal aortic wall elastic properties, whereas in older people the aortic wall is stiffer because of thickening and a reduced elastin:collagen ratio. In either case, the widened pulse pressure is the result of the net imbalance between pressure and flow during peak systole. Isolated increases in cardiac output are rare, but in many cases stroke volume is higher than would have been expected given the elevated systemic BP. Understanding which of these anomalies is present is important because each requires different treatment strategies for optimum results.

Increases in large and small arterial impedances usually have opposing effects on diastolic BP. Increased distal impedance (ie, SVR) usually exacerbates systolic hypertension (Figure 43–2) because diastolic BP is the basis of any accompanying systolic elevation in BP. In contrast, increased aortic impedance tends to lower diastolic BP because stiffer central arteries have reduced capacitance function and less elastic recoil. Thus, of each stroke volume less is stored by the aorta during systole and less is available to be delivered by elastic recoil during diastole to sustain distal flow and pressure.

Arm cuff systolic BP values are not fully representative of systolic BP (or pulse pressure) values in other parts of the body. Altered transmission of systolic BP from the heart to the periphery is causally related to changes in BP seen with aging and hypertension. In young people, peak systolic BP in the arm is almost always higher than that measured at the aortic root due to the impedance gradient caused by the progressive taper of peripheral conduit arteries. Yet older or hypertensive individuals often have equal aortic and brachial systolic BP values due to the added dimension of enhanced pressure wave reflection. In these individuals, the increased magnitude of the reflected pressure wave in late systole causes late systolic pressure augmentation (where there is summation of the forward and reflected pressure waves). This added systolic BP burden increases cardiac loading and promotes left ventricular hypertrophy.

Treatment

Blood Pressure Measurement Issues

For the majority of older patients, the accuracy of brachial cuff BP values is no worse than that of younger people. Peak brachial systolic BP is principally determined by the interaction of the heart and large arteries in early systole (at about 80–90 milliseconds after ventricular contraction begins). Arm cuff BP readings are generally not affected by reflected waves because the primary reflected wave appears much later in systole (about 140 milliseconds), after peak systolic flow has begun to decline rapidly. Pseudohypertension (spuriously high systolic BP readings due to abnormally stiff calcified peripheral arteries) has been reported, but this phenomenon is quite rare in usual medical practice. In fact, older individuals with hypertension often have normal or increased peripheral arterial compliance values.

Goal Pressures

Despite the continuous relationship between risk and BP, current guidelines have maintained rigid cutoff values for therapy at 140/90 mm Hg in patients without complications or 130/80 mm Hg in patients with diabetes or chronic kidney disease. The value of intensive lowering of BP to values substantially below 140/90 mm Hg has not been tested and some experts still question whether there is a clinically relevant “J-curve” that limits the degree of safe lowering of BP; overall, however, most experts believe that “lower is better.” In all cases, sound clinician judgment is needed to individualize therapy.

One useful rule to establish a BP goal in an individual with wide pulse pressure is to calculate the estimated mean arterial pressure (MAP = diastolic + 1/3 pulse pressure) and compare this value to a theoretical threshold value of 100 mm Hg (equivalent to a BP of 140/80 or 130/85 mm Hg). Using this method, if BP is lowered from 170/70 (MAP = 103) mm Hg to 150/70 (MAP = 97) mm Hg, the risk for cardiovascular disease can be reduced hypothetically by as much as 50%. In some cases it may be necessary to proceed more slowly, having established an intermediate level of BP control during an initial stabilization period with systolic BP values <160 mm Hg.

Nonpharmacologic Therapy

Controversy still abounds regarding the utility of hygienic measures in older individuals and no clinical study has demonstrated unequivocal outcome benefits of lifestyle modification in older individuals or in ISH. Nevertheless, current guidelines recommend that all individuals with hypertension be instructed in lifestyle modifications that lower BP. Weight loss is probably most important, but sustained weight loss is not usually achieved without some form of increased physical activity. Smoking cessation, moderation of alcohol intake, salt restriction, and increased dietary potassium intake are also recommended.

Drug Choices

In general, any drug that lowers BP satisfactorily and does not cause untoward side effects is an appropriate antihypertensive agent for a patient of any age. Choosing among individual drug classes is less important for BP control than it is for the treatment of concomitant conditions or hypertensive complications present in that patient. Yet certain trends have emerged suggesting that each class of antihypertensive drugs has a slightly different profile of optimal outcome benefits.

The most consistently effective and reliable drugs for elderly patients are thiazide diuretics and calcium antagonists, which have been shown to cause effective reduction of BP, stroke, and cardiovascular disease. Yet these same drugs do not appear to protect against chronic kidney disease. Thiazides are safe and effective in modest doses (up to 25 mg hydrochlorothiazide daily). Angiotensin-converting enzyme (ACE) inhibitors or angiotensin blockers are recommended as first-line therapy for individuals with diabetes or chronic kidney disease. These agents have also achieved outcome benefits in ischemic heart disease and heart failure. ACE inhibitors have an inconsistent record in preventing primary or secondary strokes, but angiotensin blockers have demonstrated stroke protection. The reason for the apparent outcome differences between ACE inhibitors and angiotensin blockers is unclear, but inadequate ACE inhibitor dosing has plagued clinical trials with these agents. The least attractive antihypertensives are β-blockers, which are less effective than the other major classes in lowering peripheral and central systolic BP, in protecting the kidney, or in preventing strokes and cardiovascular disease. For these reasons, β-blockers are not ideal choices unless overt ischemic heart disease or heart failure is present.

Ultimately, combination drug therapy is almost unavoidable because the majority of individuals at any age require more than one drug to achieve and sustain a meaningful reduction in BP. The most effective two-drug regimens combine a thiazide diuretic or calcium antagonist with an ACE inhibitor or an angiotensin blocker. Optimal three-drug regimens in the elderly often combine a thiazide diuretic, calcium antagonist, and either an ACE inhibitor or an angiotensin blocker.

Barriers to Blood Pressure Control in the Elderly

In general, elderly individuals are more receptive to treatment than their younger counterparts. Nevertheless, there are several specific biological barriers to effective therapy.

Central Arterial Stiffness

With the exception of β-blockers, standard antihypertensive drugs (thiazides, calcium antagonists, ACE inhibitors, and angiotensin blockers) work by directly or indirectly causing arteriolar (and to a lesser degree venous) relaxation. Unfortunately, currently available agents do relatively little to reverse the aortic stiffness that causes isolated systolic hypertension. For this reason, idealized BP targets cannot always be attained in older individuals with longstanding systolic hypertension and very wide pulse pressure. Because the diastolic BP value is relatively fixed in most individuals with wide pulse pressures, the effects of antihypertensive drugs (except β-blockers) are seen mainly in the form of decreases in systolic BP; in the majority of patients, systolic BP can be brought down to levels below 160 mm Hg. Even if ideal goals are not achieved in these patients, substantial benefit can be derived because of the log-linear association between risk and systolic BP.

Orthostatic Hypotension

Many elderly individuals have impaired postural adaptation reflexes and thus can exhibit clinically significant orthostatic decreases (>20 mm Hg systolic or 10 mm Hg diastolic) in blood pressure. Cardiovascular disease risk is elevated by over 64% in such individuals compared to age-matched controls. Thus, it would be desirable to treat such patients aggressively. Unfortunately, the presence of orthostatic hypotension usually limits aggressive therapy in these individuals due to symptoms such as dizziness and weakness, along with an increased risk of falling. Although there are no formal studies testing individual drug classes in individuals with orthostatic hypotension, it is wise to avoid drugs that can affect postural adaptation, including potent venodilators such as α-blockers, α-β-blockers, organic nitrates, and phosphodiesterase inhibitors. It is also wise to avoid loop diuretics and high doses of thiazide diuretics, which exacerbate orthostatic hypotension by reducing venous return and cardiac filling.

Increased Blood Pressure Variability

Because of the low blood flow during diastole in individuals with wide pulse pressure, diastolic BP is relatively fixed. The wide range of variability in BP seen in this group thus occurs mainly in systolic BP, which responds to ambient physiologic stress levels. Regardless of whether the stimulus tends to increase cardiac stroke volume (eg, aerobic exercise) or arteriolar constriction (eg, isotonic exercise), the systolic BP responds. Furthermore, elderly individuals with stiff carotid arteries have reduced baroreflex sensitivity and thus cannot maintain buffered control of sympathetic nervous outflow. The result is often a marked increase in systolic BP variability that is often seen in the form of increased home-office BP differences (including white-coat hypertension). Therapy in these individuals is often difficult and confusing because home BP monitoring may reveal normal BP readings, whereas office values may be very high. In such patients it is important to note that standard antihypertensive drugs have minimal effects on these acute stress-induced changes in BP. Thus, attempts to treat high “office” pressures can be met with episodes of symptomatic hypotension at home. In most instances, the clinician should carefully assess whether target organ damage (TOD) is present (especially left ventricular hypertrophy or signs of chronic kidney disease). In patients without significant TOD, therapy can be less aggressive. In patients with TOD, every attempt should be made to lower BP with agents appropriate for that individual.

General Considerations

Hypertension is the most common medical disorder of pregnancy and complicates a reported 6–10% of pregnancies. Of four million women giving birth in the United States each year, an estimated 240,000 are affected by hypertension. Hypertension and preeclampsia can cause serious maternal and fetal problems and account for ˜15% of maternal deaths in the United States. Worldwide, preeclampsia causes at least 63,000 maternal deaths yearly.

There are four major hypertensive disorders in pregnancy: (1) Chronic hypertension, (2) preeclampsia, which is pregnancy-induced hypertension associated with proteinuria, (3) preeclampsia superimposed on chronic hypertension, and (4) gestational hypertension. All four types may lead to maternal and perinatal complications, although preeclampsia with severe hypertension is associated with the highest maternal and fetal risks. The diagnosis essentially depends on the gestational age at presentation of hypertension and the presence or absence of proteinuria (Figure 43–4).

Chronic Hypertension

Chronic hypertension is blood pressure (BP) >140/90 mm Hg that either predates pregnancy or presents earlier than 20 weeks of pregnancy. It is not associated with proteinuria and complicates approximately 3% of pregnancies.

Preeclampsia–Eclampsia

Preeclampsia, a pregnancy-specific syndrome that develops in the latter half of pregnancy (after 20 weeks) in 5–6% of all pregnant women, and is characterized by increased BP (>140/90 mm Hg) and new onset proteinuria (>0.3 g daily) in a woman who had normal BP before 20 weeks. Eclampsia is the occurrence of seizures that cannot be attributed to other causes and complicates approximately 3% of preeclamptic women.

A severe variant of preeclampsia that features hemolysis, elevated liver enzymes, and low platelets (the HELLP syndrome) occurs in 1 in 1000 pregnancies.

Preeclampsia Superimposed on Chronic Hypertension

Women with chronic hypertension are at increased risk for the development of superimposed preeclampsia, which complicates 25% of chronic hypertensive pregnancies (versus 5% of nonhypertensive pregnancies). The diagnosis of superimposed preeclampsia is made if proteinuria develops for the first time after 20 weeks in association with an (even higher) increase in BP. In women with both hypertension and proteinuria before 20 weeks of gestation (for example, patients with diabetic nephropathy and proteinuria), superimposed preeclampsia is diagnosed (1) when there is a sudden increase in proteinuria or a sudden increase in BP in the latter half of pregnancy in a woman whose hypertension had previously been well controlled or (2) as part of the HELLP syndrome when there is new onset thrombocytopenia with hemolysis and elevated levels of alanine aminotransferase or aspartate aminotransferase.

Gestational Hypertension

Gestational hypertension, seen in 6% of pregnancies, develops in the latter half of pregnancy and is not associated with features of preeclampsia (eg, proteinuria). Some women may ultimately develop signs of preeclampsia, so the final diagnosis can only be made postpartum.

Clinical Findings

Maternal Risks

Women with chronic hypertension in pregnancy may develop superimposed preeclampsia; morbidity and mortality rates (both maternal and fetal) are greater in these women than in women with other forms of hypertension in pregnancy. The risk of abruptio placenta is increased 3-fold in women with chronic hypertension. Other risks include accelerated hypertension and cerebrovascular catastrophe; if preeclampsia is superimposed, risks are even worse for accelerated hypertension and fatal intracerebral hemorrhage, which account for 15% of maternal deaths.

Women with secondary hypertension due to renal disease or collagen vascular disease may experience irreversible deterioration in renal function or multiorgan system morbidity regardless of the development of superimposed preeclampsia. If significant azotemia is present (creatinine >1.9 mg/dL, 168 μmol/L), the maternal and fetal outcomes are poor, with worsening azotemia, proteinuria, and hypertension in the mother and growth restriction in the fetus. Finally, pregnancies in women with uncomplicated chronic hypertension are usually successful, but such women are more likely to undergo cesarean delivery and be hospitalized for high BP.

Fetal Risks

Perinatal death is higher in pregnancies of women with chronic hypertension than in normotensive women, and superimposed preeclampsia is associated with an even greater risk. Maternal chronic hypertension is a risk factor for intrauterine growth restriction (IUGR, defined as birth weight <10th percentile), which is seen in 5–13% of cases. With superimposed preeclampsia IUGR is seen in 35% of cases and delivery resulting in prematurity occurs in up to 54% of cases; fetal death is the outcome in <1%. Thus, chronic hypertension is associated with increased risk of perinatal death, IUGR, and premature delivery, which are considerably magnified in the presence of superimposed preeclampsia.

Differential Diagnosis

The prevalence of hypertension in premenopausal women is close to 25% and increases with age. Approximately 2–5% of pregnancies are complicated by chronic hypertension. Preexisting hypertension may be more common, particularly in industrialized urban areas where women often postpone child bearing to later years.

If hypertension was clearly documented before conception, the diagnosis of chronic hypertension in pregnancy is straightforward (Figure 43–4). Chronic hypertension is also the most likely diagnosis when hypertension (and no proteinuria) is present before 20 weeks of gestation. In normotensive patients, BP falls in early pregnancy. Systolic pressure changes little, whereas diastolic pressure falls by ˜10 mm Hg within 13–20 weeks, with a nadir at 24 weeks, and then rises again to prepregnancy levels in the third trimester (weeks 28–40) (Figure 43–5). This physiologic fall may be even more exaggerated in women with chronic hypertension, and difficulties in diagnosis arise when pregnant women with undiagnosed chronic hypertension are seen for the first time in the second trimester, during the time of the physiologic decrease in BP. In this circumstance, women may appear normotensive (when it is really the physiologic decrease in BP); later they are inaccurately diagnosed with gestational hypertension or preeclampsia when BP rises to prepregnancy levels in the third trimester. In such cases the diagnosis of preeclampsia is ruled out by the absence of proteinuria (greater than “trace” on dipstick is abnormal) and the absence of other classic laboratory abnormalities of preeclampsia or HELLP syndrome such as uric acid greater than 5.5 mg/dL (325 μmol/L), elevated liver function tests, and decreased platelets.

White-coat hypertension (elevated office BP with normal BP outside the medical setting) may be seen in up to 29% of women without preexisting hypertension. A noninvasive 24-hour blood pressure monitor can distinguish white-coat hypertension from true hypertension in the pregnant patient. White-coat hypertension does not appear to predispose paatients to preeclampsia.

Women who present with hypertension before gestational week 20 likely have chronic hypertension. Young women may have secondary hypertension (eg, renal disease, renovascular hypertension, primary aldosteronism, Cushing's syndrome, pheochromocytoma). When secondary hypertension is suspected, noninvasive evaluation may be appropriate (Figure 43–6). For example, if proteinuria is documented in early pregnancy, noninvasive evaluation for renal disease is indicated. This might include 24-hour urinary protein excretion, creatinine clearance, renal ultrasound, and serologic testing to rule out systemic lupus erythematosus if there are suggestive symptoms. Another form of secondary hypertension that should be considered is pheochromocytoma, which although rare is associated with a high rate of morbidity and mortality during pregnancy. This entity should be considered in women with severe hypertension, especially when associated with symptoms such as headache, palpitations, pallor, and sweats. Significant hypokalemia (potassium <3.2 mEq/L) may be a sign of primary aldosteronism.

Baseline laboratory tests including uric acid, platelets, liver function tests, urea, creatinine, and 24-hour urine for protein should be performed in women with early pregnancy hypertension, as this is helpful in determining the clinical significance of later increases in BP accompanied by abnormal laboratory tests.

Distinguishing between chronic hypertension (that is first noted in pregnancy) and gestational hypertension is not possible until after delivery. In some instances, women with undocumented hypertension before pregnancy will have normal BP throughout their entire pregnancy, only to return to prepregnancy hypertensive levels in the postpartum period; this accounts for the mysterious cases of isolated postpartum hypertension.

Treatment

Preconception

Management of the pregnant woman with chronic hypertension begins before conception to establish the diagnosis and to rule out forms of secondary hypertension such as renal disease and renovascular hypertension (Figure 43–7). Patients who have had hypertension for longer than 5 years, older women, and women with chronic illnesses such as diabetes may be evaluated for target organ damage such as left ventricular hypertrophy, fundoscopic changes, azotemia, and cardiac disease. Ideally, medications should be adjusted before pregnancy, and medications with deleterious fetal effects, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), can be assessed. Preconception is also the time to discuss the risks posed by pregnancy. Women should be informed of the likelihood of a favorable outcome if they have chronic hypertension, but should be apprised of the risks of superimposed preeclampsia and fetal complications. Patient education regarding these issues helps to increase compliance and may improve outcome, and frequent visits will increase the likelihood of detecting preeclampsia and other complications before they become life threatening.

Postconception

Nonpharmacologic Management

Treatment of hypertension in the gravid patient represents a departure from guidelines for treastment of nonpregnant hypertensive women. Patients are not advised to exercise vigorously as the concern is that women with chronic hypertension are at risk for preeclampsia, a condition characterized by decreased uteroplacental blood flow that vigorous exercise may further compromise. Of note, women who work outside the home had both higher blood pressure and an increased risk of preeclampsia in one study. Decreased work hours and more rest may theoretically increase placental blood flow and decrease BP.

Excessive weight loss during pregnancy is not advisable, even in obese women. Salt restriction is an important component of the management of many nonpregnant hypertensive individuals, but extremely low sodium intake (<2 g sodium) is not advisable during pregnancy. Calcium supplementation in excess of the recommended dietary allowance has not been shown to reduce the incidence of superimposed preeclampsia; however, in the developing world, in women with low dietary intake, calcium supplementation may prevent preeclampsia.

Pharmacologic Management

In nonpregnant adults, control of BP can decrease the long-term incidence of cardiovascular disease and mortality. During the 9 months of pregnancy, however, untreated mild to moderate hypertension is unlikely to lead to adverse maternal outcomes. An important issue for women with chronic hypertension is the prevention of preeclampsia; however, there is little evidence that the treatment of mild to moderate hypertension in pregnancy reduces the incidence of superimposed preeclampsia.

The appropriate level of BP in a pregnant woman with hypertension is consensus rather than evidence based. International guidelines vary concerning both the thresholds for starting treatment and the targeted BP goals. Recommendations here are in accord with those of the National High Blood Pressure Education Programs' (NHBEP) working Group Report on High Blood Pressure in pregnancy. When maternal BP reaches levels ≥150/90–95 mm Hg, treatment should be instituted to avoid hypertensive vascular damage, with BP generally targeted to 140/90 mm Hg.

As BP normally drops in the first two trimesters of pregnancy, including women with chronic hypertension, clinicians can consider discontinuing antihypertensive drugs and monitoring. Therapy can then be initiated at a BP of ≥150/90 mm Hg for otherwise healthy pregnant women with mild to moderate hypertension, regardless of type. A wide variety of reasonable agents are available for use (Table 43–4). The Food and Drug Administration classification of drugs in pregnancy designates most antihypertensive medications as category C, indicating that the drug should be given only if potential benefits justify potential risks to the fetus. This category cannot be interpreted as no risk, and is so broad that it is not clinically useful. The most recent evidence assessing the risks and benefits of drugs useful in treating hypertension in pregnancy will be reviewed. These medications have the longest history of safe use in pregnancy; however, they are rarely used in the nonpregnant population due to side effects or inconvenient dosing.

Central Adrenergic Agonists

Methyldopa

Methyldopa remains the drug of first choice for treatment of hypertension in pregnancy; it has not been found to be teratogenic after a 40-year history of use. In treated patients it has been found to be useful in decreasing the occurrence of severe hypertension and hospital admissions compared with untreated patients. Birth weight and development in the first year as well as development to the age of 7 years were similar in children exposed to methyldopa compared to children in the placebo group. Methyldopa is metabolized to α-methylnorepinephrine and replaces norepinephrine to decrease sympathetic tone centrally. The adverse effects are due to its action at the brainstem and include decreased mental alertness, impaired sleep, and decreased salivation leading to xerostomia. It can cause elevated liver enzymes in 5% of patients, with hepatitis or hepatic necrosis rarely reported. It has been associated with Coombs' positivity without (except rarely) hemolytic anemia as well as a positive antinuclear antibody (ANA).

Clonidine

Clonidine is another α2-adrenergic agonist comparable to methyldopa, although it is not used in preference to methyldopa given the proven safety of the latter. There is a greater potential for rebound hypertension when this drug is abruptly discontinued, and its use is reserved for individuals who cannot tolerate the other medications.

β-Adrenoceptor Blockers

β-Adrenoceptor blockers have been studied extensively in pregnancy and none has been associated with teratogenicity. Individual agents are not distinguishable with the exception of atenolol, which has been associated with decreased fetal weight compared to placebo. Oral and parenteral β-blockade have been associated with neonatal bradycardia, which was not clinically significant for the most part.

Maternal outcomes have been found to improve with the use of β-blockers, which control maternal BP and decrease both the incidence of severe hypertension and the rate of admission to hospital prior to delivery. They have been compared and found to be equivalent to methyldopa in 15 trials. Adverse effects due to β-blockade include fatigue, lethargy, exercise intolerance, sleep disturbance, and bronchoconstriction in patients with asthma.

Labetalol, a nonselective β-blocker with vascular α1-receptor blocking capabilities, has gained wide acceptance for use in pregnancy. When administered orally in patients with chronic hypertension, it is as safe and effective as methyldopa. Parenterally it is used to treat severe hypertension, and when compared to hydralazine has been associated with a lower incidence of maternal hypotension and other side effects.

Calcium Channel Blockers

Calcium channel blockers have been used to treat chronic hypertension, mild preeclampsia, and urgent hypertension in preeclampsia. Orally administered nifedipine and verapamil do not appear to pose teratogenic risk to fetuses exposed in the first trimester. Maternal side effects of the calcium channel blockers include palpitations, peripheral edema, headaches, and facial flushing. Most investigators have focused on the use of nifedipine, although there are reports on nicardipine, isradipine, felodipine, and verapamil as well; amlodipine is still unstudied in pregnancy.

A concern with the use of calcium antagonists for control of BP in preeclampsia is the concomitant use of magnesium sulfate to prevent seizures; drug interactions with nifedipine and magnesium sulfate have been reported to cause neuromuscular blockade, myocardial depression, or circulatory collapse, although in practice these medications are commonly used together and the actual risk appears to be low.

Diuretics

Although diuretics are widely used in the treatment of nonpregnant hypertensive patients, obstetricians are reluctant to use diuretics because of a concern that they will interfere with the physiologic volume expansion of normal pregnancy. However, in a meta-analysis of trials involving >7000 subjects diuretics appeared to prevent preeclampsia. While volume contraction might be expected to limit fetal growth, data have not supported this concern. Of note, mild volume contraction with diuretic therapy may lead to hyperuricemia, and in so doing may invalidate serum uric acid levels as a laboratory marker in the diagnosis of superimposed preeclampsia.

Diuretics are commonly prescribed in essential hypertension prior to conception and, given their apparent safety, the NHBEP Working Group on High Blood Pressure in Pregnancy concluded that they may be continued through gestation or used in combination with other agents, especially for women deemed likely to have salt-sensitive hypertension. Hydrochlorothiazide may be continued; utilization of low doses, no more than 25 mg daily, can minimize the side effects of impaired glucose tolerance and hypokalemia. Spironolactone is not recommended due to theoretic antiandrogen effects during fetal development.

Direct Vasodilators

Hydralazine is effective orally, intramuscularly, or intravenously; parenteral administration is useful for rapid control of severe hypertension. Adverse effects, mostly due to excessive vasodilation or sympathetic activation, include headache, nausea, flushing, or palpitations. In rare cases, chronic use can lead to a pyridoxine-responsive polyneuropathy or to a drug-induced lupus syndrome.

Hydralazine has been used in all trimesters of pregnancy and is not associated with teratogenicity. It has been widely used for chronic hypertension in the second and third trimesters, but use has been supplanted by agents with more favorable side effect profiles. For acute severe hypertension later in pregnancy, intravenous hydralazine has been associated with more maternal and perinatal adverse effects than intravenous labetalol or oral nifedipine, such as maternal hypotension, oliguria, cesarean sections, placental abruptions, and APGAR scores <7. Furthermore, the common side effects such as headache, nausea, and vomiting mimic the symptoms of deteriorating preeclampsia. A recent meta-analysis of the use of intravenous hydralazine for severe hypertension in pregnancy does not support its use first line, and suggests that parenteral labetalol or oral nifedipine may be preferable.

Nitroprusside is seldom used in pregnancy; it is used only as a last resort in cases of life-threatening hypertension with heart failure. Adverse effects include excessive vasodilation and syncope in the mother and a risk of cyanide toxicity in the fetus.

Isosorbide dinitrate has been investigated in a small study of gestational hypertensive and preeclamptic patients. It was found to lower BP but not cerebral perfusion, thus decreasing the risk for ischemia and infarction when BP is lowered.

Serotonin2 Receptor Blockers

Ketanserin is a selective S2 receptor-blocking drug that appears to be safe and useful in the treatment of chronic hypertension in pregnancy, preeclampsia, and HELLP syndrome. Ketanserin is used in Australia and South Africa, but has not been approved by the Food and Drug Administration for use in the United States.

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Antagonists

ACEIs and angiotensin receptor agents are contraindicated in pregnancy due to toxicity associated with reduced perfusion of the fetal kidneys; their use is associated with a fetopathy similar to that observed in Potter's syndrome, ie, bilateral renal agenesis, oligohydramnios due to fetal oliguria, calvarial hypoplasia, pulmonary hypoplasia, intrauterine growth retardation, and neonatal anuric renal failure leading to death. Use of ARBs in pregnancy has also caused fetal demise amid the same pathogenic features.

The available evidence on first trimester exposure to ACEIs is not consistent with high teratogenic risk, although a small risk cannot be ruled out. Most cases of malformations have been associated with second or third trimester use. As such, inadvertent first trimester drug exposure is not considered to be an indication for elective termination of the pregnancy. Of note, many women at risk for hypertension during pregnancy, particularly those with underlying diabetes mellitus, may benefit from use of ACEIs prior to conception. Since all cases of ACEI-associated fetopathy or renal failure occurred with drug use in the latter two trimesters, it seems reasonable to use these drugs when appropriate and to counsel women to switch to alternate agents either while attempting to conceive or as soon as the pregnancy is diagnosed.

Preeclampsia

Clinical Features and Diagnosis

Preeclampsia is the development of hypertension in association with new-onset proteinuria (>0.3 g daily), edema, and hyperuricemia after 20 weeks of gestation. Edema alone has been abandoned as a marker of preeclampsia because it is present in too many normal pregnant women to be a specific indicator of disease. Mild preeclampsia can be distinguished from severe preeclampsia: features of severe preeclampsia include severe hypertension (systolic pressure greater than 160/110 mm Hg on two occasions), eclampsia (seizures), pulmonary edema, cortical blindness, proteinuria >5 g/24 hours, renal failure or oliguria (<500 mL/24 hours), hepatocellular injury (serum transaminase levels ≥2 × normal), thrombocytopenia (<100,000 platelets/mm3), coagulopathy, or HELLP syndrome.

Important findings on physical examination in addition to elevated BP include hyperreflexia, generalized edema, and vasospasm on fundoscopic examination.

It is important to determine which women are at increased risk for preeclampsia, because such individuals need to be followed more closely during pregnancy. Those at increased risk for preeclampsia include women with chronic hypertension, women who had early (before 34 weeks of gestation) or severe preeclampsia in a previous pregnancy, and women with diabetes, collagen vascular disease, renovascular disease, renal parenchymal disease, or a multifetal pregnancy, or women who were the product of a pregnancy complicated by preeclampsia (Table 43–5). Such women should have a baseline laboratory evaluation performed early in gestation. Recommended tests that are helpful to compare and to discriminate preeclampsia from chronic or transient hypertension later in pregnancy include hematocrit, hemoglobin, platelet count, serum creatinine, uric acid, alanine aminotransferase, and aspartate aminotransferase. If qualitative dipstick proteinuria is documented, a 24-hour urine collection should be performed for the determination of protein and creatinine clearance. There is an extensive literature reporting the ability of various clinical signs or laboratory tests to predict, early in pregnancy, which patients will later develop preeclampsia. While many of these tests reflect important pathophysiologic features of preeclampsia, none is considered sensitive or specific enough to use at this time.

Prevention

Strategies to prevent preeclampsia, including sodium restriction, diuretics, high protein diets, low dose aspirin, calcium supplementation, fish oil, magnesium, antioxidants, and antihypertensive medication, have been largely ineffective. Baby aspirin is a relatively benign drug that is still used in select cases, although in large meta analyses its utility appears uncertain.

Pathophysiology

The pathophysiology of preeclampsia can be divided into two stages: Alterations in placental perfusion and the maternal syndrome. Abnormalities begin in the vascular supply of the developing placenta, leading to placental ischemia and production of vasculogenic substances, which upon reaching the maternal circulation produce the maternal clinical syndrome. There is evidence for the importance of the placenta in the pathogenesis of preeclampsia, which can develop without a fetus in the case of molar pregnancies (a rapidly growing placenta with trophoblastic tissue) and in multiple gestations (increased placental mass).

There is an increased incidence of preeclampsia in women with medical conditions associated with microvascular disease such as hypertension, diabetes, and collagen vascular disease, as the impaired placental perfusion leading to ischemia may be the common starting point of this disease.

Impaired placental perfusion appears to cause the release of “factors” into the maternal circulation. Angiogenic proteins such as placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), which are both required for normal angiogenesis and endothelial function in pregnancy, are reduced in women with preeclampsia. Recent studies report elevated maternal serum levels of a protein that appears to scavenge these factors and induce endothelial dysfunction: sFlt-1, a soluble fms-like tyrosine kinase. This molecule functions to neutralize VEGF and PlGF. In experimental studies, increased serum levels of sFlt-1 and reduced levels of PlGF have been found to predict the development of preeclampsia in humans. The mechanism for the upregulation of sFlt-1 and whether normalization of VEGF and PlGF levels might halt progression of preeclampsia are yet unknown.

Blood Pressure

High BP in preeclampsia is due mainly to a reversal of the vasodilation of normal pregnancy, replaced by a marked increase in peripheral vascular resistance. Preeclamptic patients do not develop overt hypertension until late gestation (after week 20, and usually not until the third trimester-weeks 28–40), but vasoconstrictor influences may be present much earlier. For instance, longitudinal and epidemiologic surveys show that women destined to develop preeclampsia have slightly higher “normal” blood pressure (eg, diastolic levels >70 mm Hg) as early as the second trimester.

BP in preeclampsia is characteristically labile, and there is a reversal of the normal circadian rhythm, with BP levels often being higher at night. These changes should be kept in mind when evaluating a woman with preeclampsia, because two observers may obtain different readings, reflecting lability and not measurement error. In addition, increases in peripheral vascular resistance and BP that characterize preeclampsia have been found to be mediated by an increase in sympathetic vasoconstrictor activity, which reverts to normal after delivery. These observations lend mechanistic support to the use of methyldopa and labetalol.

Treatment

Most cases of preeclampsia present close to term. They are managed by obstetricians with an approach that includes bed rest, consideration of the use of antihypertensive medications, and delivery of the fetus, followed by seizure prophylaxis with magnesium sulfate. Although there are no proven strategies for the prevention of preeclampsia, early diagnosis is important to avoid severe complications. When early signs of preeclampsia are detected, hospitalization should be strongly considered to permit close monitoring of the patient. If preeclampsia is diagnosed early, bed rest and close monitoring of maternal and fetal conditions may enable prolongation of pregnancy and improve maternal and fetal outcomes.

Lowering BP does not cure preeclampsia but may prolong the pregnancy, because uncontrolled hypertension is frequently an indication for delivery. In a woman with preeclampsia it prevents the maternal cerebrovascular and cardiovascular complications that result from elevated BP. There is a consensus that severe hypertension, defined as >160/110 mm Hg, requires treatment because these women are at increased risk of intracerebral hemorrhage and because lowering BP leads to a decrease in maternal death. Women with hypertensive encephalopathy, hemorrhage, or eclampsia (seizures) require treatment with parenteral agents to lower mean arterial pressure (two-thirds diastolic + one-third systolic BP) by 25% over minutes to hours, and then to further lower BP to ≤160/100 mm Hg over subsequent hours. In women with preeclampsia, treatment of acute severe hypertension should be initiated at lower doses, as these patients may be intravascularly volume depleted and are at increased risk for hypotension. The parenteral medications used to treat acute hypertension in women with preeclampsia are listed in Table 43–6. If delivery is not anticipated immediately (within 24–48 hours) antihypertensive therapy should be considered when diastolic BP reaches 100 mm Hg; in this instance, oral agents are appropriate.

Maternal factors that may signal the time for delivery in preeclampsia include gestational age over 38 weeks, platelet count <100 × 103, progressive deterioration in liver and renal function, suspected abruptio placenta, and uncontrolled severe hypertension despite medication. Fetal factors include fetal growth restriction, nonreassuring fetal testing results, and oligohydramnios.

Renal function is usually well preserved, and because relative oliguria is often a manifestation of renal vasoconstriction rather than impaired glomerular filtration rate it is not advisable to “push fluids” in such circumstances to increase urine output. Aggressive hydration of women with preeclampsia may result in acute pulmonary edema, a rare manifestation that may develop when abundant intravenous fluids are administered or on the backdrop of preexisting coronary disease. Decreased urinary output will usually resolve within 24 hours of delivery and will not be associated with acute tubular necrosis.

Some, although not all women develop considerable peripheral edema in association with preeclampsia. The mechanisms are likely a combination of hypoalbuminemia, increased renal sodium reabsorption, and local tissue factors such as increased capillary permeability. Despite the presence of edema, plasma volume is reduced in most cases, presumably as a consequence of vasoconstriction as opposed to underfilling of the arterial circulation. In view of the reduced plasma volume, there is a reluctance to administer diuretic therapy to women with preeclampsia, even when edema is present, because diuretics may further reduce plasma volume and potentially compromise uteroplacental perfusion. However, in the postpartum period, edema may become considerably worse due to administration of intravenous fluids during surgery. Moreover, hypertension may be worse in the first postpartum week, and tends to reach its maximum by the fifth postpartum day. Thus, on occasion, it may be necessary to administer small doses of diuretics when edema becomes marked and causes discomfort, particularly when BP is elevated.

Seizures are generally preceded with complaints of headache. The contribution of uncontrolled hypertension to the eclamptic seizure has been disputed. Some have argued that eclampsia is a manifestation of hypertensive encephalopathy, while others cite data indicating that many women who seize have BP levels that are only mildly elevated. However, uncontrolled hypertension may lower the seizure threshold, and although the treatment of hypertension does not necessarily prevent eclamptic seizures, BP levels should be maintained in a “safe” range of 130–150/80–100 mm Hg. Most of the cases of intracerebral hemorrhage and death due to eclampsia have occurred in women with preexisting hypertension and uncontrolled BP. Antihypertensive therapy should be combined with intravenous magnesium sulfate in the postpartum period, because it is the anticonvulsant of choice to prevent eclamptic seizures. Reversible posterior leukencephalopathy (transient cortical blindness) resolves with BP management as above.

The liver may be involved in severe cases of preeclampsia, usually in association with hemolysis and thrombocytopenia (the HELLP syndrome). The HELLP syndrome is associated with a poor prognosis and is usually an indication for urgent delivery. Women with liver involvement may develop epigastric or right upper quadrant pain resulting from hepatocellular necrosis, edema, and ischemia leading to stretching of the Glisson capsule. Periportal hemorrhagic necrosis in the periphery of the liver lobule results in elevations in liver enzymes. On rare occasions, there may be bleeding from these lesions, and hepatic rupture is a fatal complication of preeclampsia if not recognized early and treated aggressively with supportive therapy and surgery. The consultant should be familiar with these complications of preeclampsia and should recognize the potential severity of the development of epigastric, chest, or abdominal pain in a woman with preeclampsia.

Obstetric Issues: Fetal Monitoring and Delivery

Once preeclampsia is diagnosed, monitoring of the fetusis indicated to identify fetal distress, which, if present, would be an indication for urgent delivery. One of the most difficult management issues in preeclampsia is the timing of delivery in cases in which fetal maturity is questionable. Delivery is always appropriate therapy for the mother. However, delivery is not indicated for a preterm fetus with no evidence of fetal compromise in a woman with only mild preeclampsia. Important decisions are based on whether the fetus is more likely to survive without significant neonatal complications in utero or in the nursery and whether maternal safety will be jeopardized by the postponement of delivery.

Delivery is always indicated when preeclampsia develops at term and should be strongly considered in women who have severe preeclampsia beyond 32–34 weeks of gestation. In women with preeclampsia remote from term (23–32 weeks) prolongation of pregnancy is possible in only a select group of women with easily controlled hypertension, no evidence of fetal distress, and no indication of serious maternal disease (headache, abdominal pain, and signs of the HELLP syndrome).

Prognosis

Hypertension frequently persists after delivery in women with antenatal hypertension or preeclampsia, and BP may be labile in the weeks postpartum. BP may increase even higher if patients are treated with nonsteroidal anti-inflammatory agents. The goals of treatment are to prevent severe hypertension (and its consequences of cerebral hemorrhage and eclampsia). Antihypertensive treatment given antenatally should be reordered postpartum and then discontinued in days to weeks after BP normalizes. If BP was normal prior to conception, then normalization is likely to return after 2–12 weeks. Hypertension that persists beyond that may represent previously undiagnosed chronic hypertension or secondary hypertension and should be evaluated and followed.

Evaluation should also be considered postpartum for patients who developed preeclampsia early (at less than 34 weeks of gestation), who had severe preeclampsia, who had a recurrence of this condition, or who continue to have persistent proteinuria. In these cases, renal disease, secondary hypertension, and thrombophilias (eg, factor V Leiden) may be evaluated.

Counseling for future pregnancies requires consideration of different recurrence rates for preeclampsia depending on the pathogenesis and population. The earlier in gestation, the higher the risk of recurrence; before week 30, recurrence may be as high as 40%. If preeclampsia has developed in a nulliparous woman close to term (ie, after 36 weeks), the risk of recurrence is thought to be 10%. Patients who had HELLP syndrome appear to have a high risk of subsequent obstetric complications, with preeclampsia occurring in 55%; however, the rate of recurrent HELLP appears to be low, only 6%.

Hypertensive diseases of pregnancy have been associated with the risk of hypertension and stroke later in life. In one study, gestational hypertension was associated with a relative risk (RR) of 3.72 for later hypertension, and preeclampsia with a RR of 3.98 for later hypertension and 3.59 for stroke. Preeclampsia is also a risk factor for coronary disease when studied retrospectively. These associations serve to increase awareness for the need to monitor patients for future hypertensive and cardiovascular disorders.

In general, antihypertensive drugs that are bound to plasma protein are not transferred to breast milk. Lipid-soluble drugs achieve concentrations higher than water-soluble drugs. Neonatal exposure to methyldopa, labetalol, captopril, and nifedipine via nursing is low, and these medications are considered safe in breastfeeding. Atenolol and metoprolol are concentrated in breast milk, possibly to levels that could affect the infant, and are not recommended. Finally, although the concentration of diuretics in breast milk is usually low, these agents may reduce milk production due to mild volume contraction and may interfere with the ability to successfully breast feed.