Hypertensive renal diseases are the most common medical disorders seen in pregnancy. Whereas preeclampsia (acute pregnancy-induced hypertension) is the etiology of hypertension in most (approximately 70%), chronic hypertension or renal disease is the etiology in the remaining patients (30%). Unfortunately, the correct etiology may be difficult to determine in the patient who is first seen late in pregnancy. The subject of acute pregnancy-induced hypertension is discussed elsewhere in these volumes (see index). This discussion focuses on the effects of chronic hypertension concurrent with pregnancy.

Chronic hypertension concurrent with pregnancy is associated with increased perinatal and maternal morbidity and mortality, although these complications can be decreased with proper obstetric and neonatal management.^1,2,3 The incidence of chronic hypertension in pregnancy varies among different populations and hospitals, but overall, the National Blood Pressure Education Program Working Group has estimated that up to 5% of pregnancies are affected.¹

The diagnosis of chronic hypertension in pregnancy is usually made on the basis of either a documented history of high blood pressure antedating pregnancy or persistent elevation of blood pressure (at least 140/90 mmHg) on two occasions more than 24 hours apart before the 20th week of gestation.

When either or both of the aforementioned findings cannot be documented, other findings that an astute clinician might identify that would be suggestive of the presence of chronic hypertension include retinal changes on funduscopic examination, cardiac enlargement on chest x-ray or electrocardiogram, compromised renal function or associated renal disease, presence of medical disorders known to lead to hypertension, multiparity with previous history of hypertensive pregnancies, and evidence of persistent hypertension beyond the 42nd day postpartum.

This diagnosis is frequently difficult to establish as a result of the marked and variable changes that are seen with blood pressure during midpregnancy. The physiologic decrease in blood pressure that all patients experience during the first and second trimesters is also present in many chronic hypertensive patients. Indeed, Chesley and Annitto observed that women with chronic hypertension show greater decreases in their blood pressure during pregnancy than do normotensive patients.⁴ They reported a marked decrease in 39% of 301 pregnancies studied, noting that during mid pregnancy, the blood pressure was in the normal range in women who were severely hypertensive before pregnancy. Similar findings were observed by Sibai and colleagues when reporting the course of pregnancy in 211 patients with mild chronic hypertension.⁵ Such changes become problematic in patients with no previous medical care who are first seen in the late second and early third trimesters.

Essential hypertension is by far the most common cause of chronic hypertension during pregnancy. Despite their added risks for both mother and fetus, a description of all causes of hypertension is beyond the scope of this chapter (Table 1).

Table 1. Causes of Chronic Hypertension

Chronic hypertension in pregnancy is classified as mild or severe depending on the systolic and diastolic blood pressure readings. The hypertension is classified as either mild or severe. Mild hypertension has been traditionally defined by a systolic blood pressure less than 160 mmHg, and diastolic blood pressure less than 110 mmHg,1,2 although the American College of Obstetricians and Gynecologists has recently changed its definition to include a systolic blood pressure less than 180 mmHg.^6,7 Beyond this, patients are further classified as either having low- or high-risk hypertension. Patients with uncomplicated mild essential hypertension are considered to be at low risk, whereas patients with severe hypertension or having associated complicating factors are classified as being at high risk (Table 2). Classification in this way will help to direct management and initiation of antihypertensive medication. Most women with chronic hypertension in pregnancy have the mild form of the disease.

Table 2. Criteria for High-Risk Chronic Hypertension

Superimposed preeclampsia is a condition in which patients preeclampsia develops in patients with preexisting hypertension. Although a clear-cut definition is difficult to establish, this is best defined by the following findings¹: new-onset proteinuria of .3 g of protein in a 24-hour specimen; in women with hypertension and proteinuria before 20 weeks' gestation any of the following are seen: sudden increase in proteinuria, sudden increase in blood pressure in a woman whose hypertension has previously been controlled, thrombocytopenia (platelet count less than 100,000 cells/mm³), abnormal alanine aminotransferase or aspartate aminotransferase.

Pregnancies complicated by chronic hypertension are at increased risk for the development of superimposed preeclampsia, abruptio placentae, and poor perinatal outcome. The reported incidence of superimposed preeclampsia ranges from 4.7% to 52%, depending on the severity of hypertension at the onset of pregnancy and on the criteria used to make the diagnosis.^{1,2,4,5,8–16} The rate of superimposed preeclampsia varies across studies depending on diagnostic criteria. In general, the incidence of this complication will be high if only exacerbation of blood pressure is used in the diagnosis, whereas this incidence will be lower if significant proteinuria (more than1 g/24 hr) is added to make such a diagnosis.¹⁵ In addition, some pregnant chronic hypertensive women may have silent undiagnosed chronic renal disease and may experience urinary protein excretion that increases with advancing gestation, particularly in the third trimester (usually more than 300 mg but less than 1 g/24 hr); many such women will demonstrate an increase in either their systolic (more than 30 mmHg) or their diastolic (more than 15 mmHg) blood pressure with advancing gestation. Formerly, an elevation of 30 mmHg for systolic or 15 mmHg for diastolic was considered significant. If these criteria are used, the incidence of superimposed preeclampsia will be extremely high.¹⁷ Thus, strict cutoffs such as were formerly recommend have been abandoned, and superimposed preeclampsia should be diagnosed on the basis of exacerbated hypertension to severe levels or the development of either substantial proteinuria (more than 1 g/24 hr) or significant laboratory abnormalities, such as thrombocytopenia or elevated transaminases. In women using antihypertensive medications in whom exacerbation of blood pressure is less common, the diagnosis should be based on the development of substantial proteinuria, symptoms, or laboratory abnormalities.

In general, pregnancies complicated only by exacerbation of blood pressure have perinatal outcomes similar to those of normotensive women, whereas the appearance of proteinuria is more significant for fetal prognosis, because in such pregnancies most of the poor perinatal outcomes are associated with proteinuria. Because many obstetricians consider superimposed preeclampsia as an indication for delivery, it is important to use strict criteria to avoid potentially unnecessary preterm delivery.

Rates of adverse pregnancy outcomes are described in Tables 3 and 4. The incidence of abruptio placentae is reportedly increased and ranges from .45% to 5%, depending on the duration and the severity of hypertension.^18,19,20 For those with mild uncomplicated disease, the incidence ranges from .45% to 1.9%,^9,13 whereas in cases of severe hypertension the incidence is markedly increased 2.3% to 5%.^4,12 This incidence is not influenced by the use of antihypertensive medications.¹³ Notably, in cases complicated by superimposed preeclampsia, abruptio placentae is associated with higher perinatal mortality than when preeclampsia is absent.²¹ Also, this incidence is substantially increased in those with a history of abruptio in previous pregnancies.²¹ Acute renal failure is an extremely rare complication of hypertensive pregnancies. It is usually caused by acute tubular necrosis or, rarely, bilateral cortical necrosis. Its development is associated with high maternal–perinatal mortality and morbidity. Usually, it develops in pregnancies with severe chronic hypertension complicated by abruptio placentae that is severe enough to cause fetal demise and disseminated intravascular coagulation, or it is seen with significant antepartum/postpartum hemorrhage in the presence of superimposed preeclampsia.²²

Table 3. Rates of Adverse Pregnancy Outcome in Mild and Severe Chronic Hypertension

Table 4. Preeclampsia and Abruptio in Chronic Hypertension

These complications are responsible for most of the perinatal deaths, as well as the increased incidence of fetal growth retardation and premature delivery in such pregnancies 18,23,24,25 (Table 5). In addition, these pregnancies are reportedly associated with increased fre-quency of midtrimester losses, particularly in those not receiving antihypertensive therapy.^10,15 In general, perinatal mortality and morbidity are not increased in patients with uncomplicated mild chronic hypertension, whereas they are markedly increased in patients with severe disease, those with renal disease, and those with superimposed preeclampsia.^5,22

Table 5. Effects of Chronic Hypertension on IUGR and Preterm Delivery (<37 Weeks).

In the nonpregnant patient, the goal of hypertensive management is to prevent long-term vascular complications such as stroke and cardiovascular disease.²⁶ Treating patients with mild to moderate hypertension, for example, may yield benefits after 5 years of treatment.²⁶ Such goals are reasonable because of the long-term nature of the disease. In pregnant women, however, the duration of the condition (pregnant and hypertensive) is finite and relatively short, so that no maternal benefits could be expected from antihypertensive therapy for mild chronic hypertension during the 9-month period of pregnancy.

Low-Risk Hypertension: Maternal Outcome

In the presence of mild elevations of blood pressure, and in the absence of end-organ involvement, women are considered to be at low risk. In such cases, the benefit of pharmacologic management for the mother is unclear, and whether such treatment improves perinatal outcome is a matter of controversy. There have been a number of prospective randomized trials to evaluate the whether antihypertensive treatment improves maternal or perinatal outcome in such women.^{8,9,13,15,16,27,28,29,30,31,32,33,34}

In a study of 264 women, Sibai and colleagues prospectively randomized patients between 6 and 13 weeks' gestation to either receive no medication (n = 90), methyldopa (n = 88), or labetalol (n = 86), and compared resultant pregnancy outcomes. The incidences of superimposed preeclampsia (15.6%, 18.4%, and 16.3%, respectively) and abruptio placentae (2.2%, 1.1%, and 2.3%, respectively) were similar among the three groups.¹³

The impact of routine treatment with nifedipine in mild-to-moderate hypertensive patients was studied among 283 women in Italy. Women were assigned to treatment with 10 mg of extended release nifedipine twice daily (n = 145) or were administered no treatment (n = 138). The rate of preeclampsia was unchanged in the treated group and the authors concluded that routine treatment of mild hypertension did not improve pregnancy outcome.²⁸

Hirsch and colleagues evaluated the beta-blocker pindolol in a placebo-controlled trial, which included 30 chronic hypertensive pregnancies, and found the incidence of superimposed preeclampsia to be statistically similar between the groups.²⁹ A prospective randomized trial of ketanserin (a selective serotonin-2-receptor blocker) and aspirin versus placebo in the prevention of superimposed preeclampsia among 138 chronic hypertensive patients has shown a decreased incidence of preeclampsia in the treated patients (3% vs 19%). The authors also reported a decreased rate of abruptio (1% vs 8%), although this was not statistically significant.³³ Overall, there has been no clearly demonstrable benefit of antihypertensive treatment in women with mild hypertension with regards to preeclampsia and abruptio. The two largest studies, however, have found contradictory results regarding preeclampsia,^13,35 although neither study had a demonstrable benefit with regards to the prevention of abruptio.

Low-Risk Hypertension: Perinatal Outcome

In a recent meta-analysis of trials of antihypertensive medications in patients with mild-to-moderate hypertension investigated, von Dadelszen and colleagues studied the decrease in mean arterial blood pressure and related it to the delivery of SGA infants.³⁶ The authors concluded that antihypertensive medications induce a decrease in blood pressure, which may adversely affect fetal growth. Before this, antihypertensive medications studied had not been shown to be associated with abnormal fetal growth, with the exception of atenolol, whose use has repeatedly been shown to have a relationship to birth weight.^37,38,39

In summary, analysis of the maternal and perinatal data indicates that, regardless of the treatment used, perinatal mortality is not improved by the use of antihypertensive medications, and the indiscriminate use of such medications may, in fact, have deleterious effects. Consequently, antihypertensive medications should not be routinely used in patients at low risk.^12,40,41

Severe Hypertension in Pregnancy

Because maternal mortality and morbidity are increased in pregnant women with diastolic blood pressures of 110 mmHg or higher (Table 6),^12,22 there are potential maternal and fetal benefits from treating severe chronic hypertension during pregnancy.¹² Three early retrospective studies, conducted before modern advances in obstetric and neonatal care, described pregnancy outcome in untreated women with severe chronic hypertension early in pregnancy.^4,14,42 The reported perinatal survival ranged from 19% to 50%, and most of the fetal losses occurred in women with superimposed preeclampsia. In addition, the studies reported a high frequency of maternal mortality and morbidity (acute and long term). As a result, concerns about the risk of acute renal failure and cerebrovascular accidents led many obstetricians to recommend early termination of such pregnancies.

Table 6. Maternal Risks of Severe Hypertension in Pregnancy

In 1966, Kincaid-Smith and colleagues reported pregnancy outcome in 32 patients with severe hypertension who were treated with methyldopa during their pregnancy.⁴³ The perinatal survival was 90.7%, and there were no maternal complications. The authors attributed this good outcome to the control of maternal blood pressure with methyldopa. Sibai and Anderson later documented pregnancy outcome in 44 patients with severe hypertension who were seen during the first trimester.¹² Each was treated with methyldopa and oral hydralazine as needed to keep diastolic blood pressure below 110 mmHg. The patients were observed closely throughout pregnancy, with frequent prenatal visits and intensive monitoring of the clinical status of both mother and fetus. Twenty-three women (52%) had superimposed preeclampsia and one (2.3%) had abruptio placentae, but there were no maternal deaths. One subject had pleural effusion and one had postpartum hypertensive encephalopathy. The total perinatal survival was 75%; 31 infants (70%) were delivered preterm and 19 (43%) were small for gestational age. Among subjects without superimposed preeclampsia, there were no perinatal deaths and only one infant (5%) was small for gestational age. However, such women should be counseled regarding the potential maternal risks, and they must be observed and managed at a tertiary care center with adequate maternal–neonatal care facilities. Interestingly, however, although controlling hypertension in such women may help to prolong pregnancy, there is no evidence that it reduces the rates of preeclampsia or abruptio.^41,44

Many drugs are available for treating hypertension in pregnancy. Some have been studied extensively whereas others are used infrequently. The drugs used most often in pregnancy are adrenoreceptor blocking agents, thiazide diuretics, hydralazine, and calcium channel blockers. There are potential adverse effects from the chronic use of any drug during pregnancy. When using antihypertensives, one must weigh the benefits of such treatment against the potential adverse effects on the mother, fetus, and the neonate.

Frequently Used Medications

METHYLDOPA

Although methyldopa is no longer commonly used in nonpregnant patients, for many obstetricians it is the first-line agent for treatment of chronic hypertension in pregnancy.¹ It has an excellent safety record in both short-term and long-term follow-up of children exposed in utero.⁴⁵ Many studies have been performed using this medication to manage mild-to-moderate hypertension, without evidence of adverse maternal or fetal outcome.⁴⁵

Methyldopa lowers blood pressure by stimulation of central alpha-2-receptors via alpha-methylnorepinephrine, which is its active form. In addition, it might act as an alpha-2-peripheral blocker via a false neurotransmitter effect. It reduces systemic vascular resistance without causing physiologically significant changes in heart rate or cardiac output while renal blood flow is maintained. Maternal side effects include dry mouth, lethargy, and drowsiness. Other side effects include liver function abnormalities, postural hypotension, hemolytic anemia, and a positive Coombs test.

The usual oral dosage is 1 to 2 g per day administered in four divided doses, which can be increased to 4 g as needed. The plasma half-life is approximately 2 hours, and peak plasma levels occur within 2 hours after oral administration. The decrease in blood pressure is maximal approximately 4 hours after an oral dose. Most of the drug is excreted via the kidney. It is considered a weak antihypertensive that is best suited for cases with mild hypertension, and if adequate blood pressure control is not achieved with the maximum dosage, additional antihypertensive agents, such as hydralazine, beta-blockers, or nifedipine may be added.

CALCUIM CHANNEL BLOCKERS

These drugs act by inhibiting transmembrane calcium ion influx from the extracellular space into the cytoplasm, thus blocking excitation–contraction coupling in smooth muscle fibers, and thereby causing vasodilation and reduction in the peripheral resistance. Calcium channel blockers, primarily nifedipine, have been studied both as antihypertensive medications (primarily in the second and third trimesters) and as tocolytic agents. Evaluation of teratogenicity has been based on 211 first-trimester pregnancy exposures. The Michigan Medicaid Surveillance Program reported140 first trimester exposures to nifedipine (n = 37), verapamil (n = 76), and diltiazem (n = 27), with major birth defects in 5%, 1.3%, and 14.8%, respectively.⁴⁶ A prospective multicenter cohort in which 78 women were exposed to calcium channel blockers (mainly nifedipine and verapamil) during the first trimester did not demonstrate an increased rate of birth defects.⁴⁷

A prospective randomized trial of 283 women in which 47% of patients had chronic hypertension evaluated the benefit of nifedipine on pregnancy outcome. Women were enrolled between 12 and 34 weeks (mean: 24 weeks) with no improvement in maternal or neonatal outcome.²⁸ Follow-up at 18 months of 94 infants exposed in utero to nifedipine has not shown any adverse effects on development.⁴⁸ Nifedipine is effective in controlling maternal blood pressure during episodes of acute hypertension, although potentially severe adverse outcomes have been reported with the use of sublingual nifedipine and intravenous nicardipine, including myocardial infarction and severe hypotension with resultant fetal distress.⁴⁶ Common side effects include headache, flushing, tachycardia, and fatigue. Care should be exercised when using nifedipine with magnesium sulfate (which is a calcium channel blocker itself), because the use of both agents together could potentiate the antihypertensive action.

BETA-BLOCKERS

Beta-blockers have been extensively used since their introduction in the 1960s to treat thyroid disease, mitral valve prolapse, migraine headache, glaucoma, and chronic hypertension. The drugs in this category have different hemodynamic effects that depend on their receptor selectivity, presence of intrinsic sympathomimetic activity, and their lipid solubility. Drugs without intrinsic sympathomimetic activity reduce both cardiac output and heart rate in association with their antihypertensive effects. However, drugs with intrinsic sympathomimetic activity reduce mean arterial blood pressure without influencing either cardiac output or heart rate. Beta-blocking agents have been widely studied, mainly as a treatment for hypertension in the third trimester, and in this situation they are effective in controlling blood pressure. Limited data exist for the treatment of mild hypertension with beta-blockers, with most studies showing no beneficial effect on outcomes.(Table 7).^{13,27,28,29,49,50,51}

Table 7. Randomized Trials of Beta-Blockers for Mild Hypertension in Pregnancy

Although most data would appear to support the safety of the beta-blockers, atenolol appears to be an exception. In a series of 105 pregnant women registered in the Michigan Medicaid Surveillance Program, first trimester use of atenolol has been associated with an increased incidence (11.4%) of birth defects.⁴⁶ Specifically, detailed analysis has revealed a possible relationship between its use and hypospadias. The authors, however, have cautioned that this relationship may not be clear, because multiple drugs have been used concomitantly in these pregnancies. In addition, the use of atenolol begun during early pregnancy and continued for a long duration has been associated with lower birth weights and fetal growth restriction.^37,38,39 Therefore, the use of atenolol in such women should be avoided if possible.

Side effects in the nonpregnant state include bronchial spasm, hypoglycemia, cold extremities, and disturbance in the lipid metabolism. Their use in pregnancy has been reportedly associated with neonatal bradycardia, hypoglycemia, fetal growth retardation, altered adaptation to perinatal asphyxia, and neonatal respiratory depression,⁵² although most of these neonatal effects could be attributed to maternal disease as well.

Alpha-Beta Blocker: Labetalol

In addition to its beta-blocking effect, labetalol provides the additional benefit of alpha-adrenergic blockade. This offers the theoretical advantage of vasodilation, which is not seen with traditional beta-blockers.

The Michigan Medicaid Surveillance Program has documented the first trimester exposure to labetalol in 29 fetuses. Four of these (13.8%) had unspecified malformations that were not in the categories of cardiovascular defects, oral clefts, spina bifida, polydactyly, limb reductions, or hypospadias.⁴⁶ In contrast, 86 mildly hypertensive patients in a randomized controlled trial treated with labetalol therapy beginning between 6 and 13 weeks had no major congenital malformations identified.¹³

The literature regarding a possible association between the use of labetalol and SGA infants is contradictory. Whereas some studies have documented an increased risk for SGA in patients treated in the second and third trimesters for mild pregnancy-induced hypertension, this association has not been documented in women with chronic hypertension.¹²

Treatment with labetalol is initiated at 100 mg twice per day, with a maximum daily dose of 2400 mg. Common side effects include headache and tremulousness.

Thiazide Diuretics

Thiazide diuretics are among the first line agents used in the treatment of nonpregnant hypertensive patients. Consequently, many women with chronic hypertension become pregnant while using diuretics. In the first 3 to 5 days of treatment, these drugs result in reduction (5% to 10%) in both plasma and extracellular fluid volumes, with a concomitant decrease in the cardiac output and lowering of the blood pressure. However, these changes tend to return to pretreatment levels within 4 to 6 weeks. These effects are followed by a long-term reduction in peripheral resistance, which is thought to be related to reduced intracellular sodium concentration in vascular smooth muscle cells.

With regard to safety of thiazide diuretics, data are available for chlorothiazide, hydrochlorothiazide, and chlorthalidone. Although these medications are rarely used during the first trimester, the Collaborative Perinatal Project reported on 233 pregnancies exposed to thiazide or related diuretics during the first trimester.⁵³ Birth defects were increased with chlorthalidone, but not with hydrochlorothiazide. This was not confirmed by the Michigan Medicaid Surveillance Program, in which 635 patients were exposed to diuretics in the first trimester (20 chlorothiazide, 48 chlorthalidone, and 567 hydrochlorothiazide), with major malformation rates of 10%, 4.2%, and 4.2%, respectively.⁴⁶ Although the number of exposed infants for the former two medications is limited, these rates were statistically similar to the expected rates, and these data do not support an increased risk for major congenital defects in first trimester exposures.

Later in pregnancy, only one study has evaluated the benefit of diuretics on plasma volume expansion and perinatal outcome in women with chronic hypertension.⁵⁴ Unfortunately, this study was small, including only 20 patients, and the specific diuretics used are not provided. However, the diuretics did, in fact, reduce plasma volume expansion without affecting perinatal outcome.

The usual dose of hydrochlorothiazide is 25 mg once daily in the morning. Adverse maternal effects reported with the use of diuretics during pregnancy include hypokalemia, hyponatremia, hyperglycemia, hyperuricemia, hyperlipidemia, hemorrhagic pancreatitis, and even death. Reported neonatal adverse effects include electrolyte imbalance, thrombocytopenia, and small size for gestation. The neonatal thrombocytopenia that was reported after the use of thiazide diuretics was associated with the death of two babies.⁴⁶ Other studies, however, have not found an increased risk of thrombocytopenia related to diuretics.^54,55

Infrequently Used Medications

CLONIDINE

Clonidine is rarely used in pregnancy. It is a potent alpha-2-adrenoreceptor central stimulant, used primarily for treatment of mild-to-moderate hypertension. Approximately 40% to 60% of the oral dose is excreted in unaltered form in the urine. Its potential side effects include sedation, dry mouth, and rebound hypertension after abrupt discontinuation. The usual oral dose in pregnancy is .1 to .3 mg per day administered in two divided doses, which can be increased up to 1.2 mg per day as needed. Its safety during pregnancy is not well established.

Horvath and colleagues reported a randomized study in 100 pregnant hypertensive women comparing clonidine to methyldopa.⁵⁶ They found no significant difference in blood pressure control or maternal and fetal outcome. The authors concluded that clonidine was a safe and effective antihypertensive agent to use in pregnancy.

HYDRALAZINE

Hydralazine is a potent vasodilator that acts directly on the vascular smooth muscle. Although hydralazine is rarely used for maintenance control of hypertension, it is frequently used to control severe hypertension in preeclampsia, when it is administered intravenously in bolus injections. After its intravenous use, the hypotensive effect of this drug develops gradually over 15 to 30 minutes, peaking at 20 minutes. The elimination half-life is approximately 3 hours.

The usual bolus dose of 5 mg to 10 mg may be repeated every 20 to 30 minutes as needed. Its main side effects are fluid retention, tachycardia, palpitation, headache, and a lupus-like syndrome, as well as neonatal thrombocytopenia. Many of these side effects are common with high chronic doses and are usually minimized when it is used in combination with other antihypertensives. Because oral hydralazine when used as a monotherapy is a weak antihypertensive, it is usually combined with diuretics, methyldopa, or beta-blockers. The usual oral dose is 10 mg administered four times daily, but this can be increased up to 300 mg per day.

Contraindicated Medications

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS

These agents induce vasodilation by inhibiting the enzyme that converts angiotensin I to angiotensin II (potent vasoconstrictor), without reflex increase in the cardiac output. In addition, they increase the synthesis of vasodilating prostaglandins and diminish the rate of bradykinin inactivation (potent vasodilator). Because of their efficacy and infrequent side effects, these agents are becoming widely used as first-line therapy for chronic hypertension in the nonpregnant state.

The data regarding the use of angiotensin-converting enzyme (ACE) inhibitors are largely limited to captopril, enalapril, and lisinopril. The Michigan Medicaid Surveillance Program has reported 141 cases of exposure to ACE inhibitors during the first trimester, with birth defects identified in 7%.⁴⁶ Indeed, use of ACE inhibitors during the first trimester, before the start of renal tubular function, did not result in a teratogenic effect.⁵⁷ However, exposure to ACE inhibitors during the second and third trimesters appears to alter renal development,^58,59,60 which may be a consequence of tubular dysfunction resulting from persistent inhibition of the renin-angiotensin system. Indeed, among 85 cases exposed after 16 weeks' gestation, anuria was seen in 15%, and oligohydramnios in 14%.⁶⁰ Further, ACE inhibitors have been associated with neonatal renal failure and death, renal dysgenesis, pulmonary hypoplasia, and fetal growth restriction.^46,59,60 Clearly, the teratogenic effect of ACE inhibitors is both timing- and dose-dependent, and these agents are contraindicated in the second and third trimesters. Similarly, we would recommend that the newer ACE II blocking medications be avoided as well. Their safety in pregnancy is not established, and we would expect a similar array of effects as are seen with the ACE inhibitors.⁶¹

The primary objective in the management of pregnancies complicated with chronic hypertension is to reduce maternal risks and achieve optimal perinatal survival. This objective can be achieved by formulating a rational approach that includes preconceptional evaluation and counseling, early antenatal care, frequent antepartum visits to monitor both maternal and fetal well-being, timely delivery with intensive intrapartum monitoring, and proper postpartum management.

Preconceptional Evaluation

Management of patients with chronic hypertension should ideally begin before pregnancy, whereby extensive evaluation and complete work-up is undertaken to assess the etiology, the severity, the presence of other medical illnesses (see Table 1), and to rule out the presence of target organ damage of long-standing hypertension. The initial evaluation will allow the classification as either low-risk or high-risk hypertension.

An in-depth history should delineate in particular the duration of hypertension, the use of antihypertensive medications, their type, and the response to these medications. Because some medications that have potentially harmful effects on both the fetus and the mother are frequently used in the nonpregnant state, it is prudent to change these drugs to others with well documented safety and to monitor the response of the patients to these medications. Also, attention should be given to the presence of cardiac or renal disease, diabetes, thyroid disease, and a history of cerebrovascular accident, or congestive heart failure. A detailed obstetric history should include maternal, as well as neonatal, outcome of previous pregnancies with stresses on history of development of abruptio placentae, superimposed preeclampsia, preterm delivery, small-for-gestation infants, intrauterine fetal death, and neonatal morbidity and mortality. A detailed physical examination should include the following: general physical examination, funduscopic examination, measurement of blood pressure in the four extremities, measurement of blood pressure with changes in posture and after rest, detailed auscultation of chest and flanks, and checking of pulses in the four extremities.

Laboratory evaluation is obtained to assess the function of different organ systems that are likely to be affected by chronic hypertension, and as a baseline for future assessments. For all patients, these should include the following: urine analysis, urine culture and sensitivity, 24-hour urine evaluation for protein, and creatinine clearance, complete blood count, and glucose tolerance test.

Selectively, the following assessments should be made: (1) if hyperglycemia or wide blood pressure swings are evident, a 24-hour urine evaluation for vanillylmandelic acid and metanephrines may should be considered to rule out pheochromocytoma; (2) for patients with severe hypertension or significant proteinuria, chest x-ray, electrocardiogram, antinuclear antibody, and serum complement studies may be indicated; (3) for patients with severe long-standing hypertension or if there is a suspicion of heart disease, an echocardiogram may be considered; (4) women with a history of poor pregnancy outcome (repetitive midpregnancy losses), and those with recent thromboembolic disease, should be evaluated for the presence of lupus anticoagulants and anticardiolipin antibodies;⁶² and (5) for patients with persistent hypokalemia (serum K⁺ less than 3 mEq/L) evaluation for hypoaldosteronism should be considered.

Pregnancies in women with chronic hypertension and renal insufficiency are associated with increased perinatal loss and higher incidence of superimposed preeclampsia, preterm delivery, and fetal growth restriction. These risks increase in proportion to the severity of the renal insufficiency; women with severe renal insufficiency, particularly primary glomerular disease, risk rapid progression to end-stage renal disease during pregnancy or postpartum.^63,64,65 Thus, women with renal disease desiring pregnancy should be counseled to conceive before renal insufficiency becomes severe. For women with hypertension and severe renal insufficiency in the first trimester, the decision to continue pregnancy should not be made without extensive counseling regarding the potential maternal and fetal risks, particularly the potential need for dialysis during pregnancy.^64,65 Women who elect to continue their pregnancies must be observed and managed at a tertiary care center with adequate maternal–neonatal care facilities.

Initial and Subsequent Prenatal Visits

Early prenatal care will ensure accurate determination of gestational age, as well as the severity of hypertension in the first trimester, which has prognostic values for the outcome of such pregnancies. Furthermore, patients who are seen for the first time during pregnancy should be evaluated as discussed previously. At the time of initial and subsequent visits, the patient should be counseled regarding the following aspects as they pertain to her pregnancy: instructed by a nutritionist regarding nutritional requirements, weight gain, and sodium intake; instructed regarding the negative impact of maternal anxiety, smoking, and caffeine, as well as drugs on maternal blood pressure and perinatal outcome; counseled regarding the possible adverse effects and complications of hypertension during pregnancy; and counseled regarding the importance of frequent prenatal visits and their impact on preventing or minimizing the aforementioned adverse effects.

If the patient is well-motivated, she can be instructed in self-determination of blood pressure, as recommended by Zuspan and Rayburn.⁶⁶ This approach avoids the phenomenon of white coat hypertension, which is associated with a visit to the physician's office and avoids the unnecessary need for starting or increasing the dose of antihypertensive medications. It is recommended that patient-recorded measurements of blood pressure be used to supplement those recorded in the doctor's office.

During the course of pregnancy, the patient should be seen every 2 to 3 weeks in the first two trimesters; thereafter, it should be adjusted based on maternal and fetal conditions. Systolic and diastolic blood pressure readings should be carefully measured at each visit. At each visit, the urine should be checked for proteinuria. Patients with significant end-organ disease may require serial measurements of hematocrit, serum creatinine, as well as urine culture and sensitivity once every trimester. Other tests are obtained as needed. The occurrence of one or more of the following is an indication for prompt maternal hospitalization: pyelonephritis, significant elevations in blood pressure with levels in the range of severe hypertension, new onset of proteinuria (usually an early sign of developing superimposed preeclampsia), and severe fetal growth restriction.

As stated previously, most patients with uncomplicated mild chronic hypertension will have a good perinatal outcome, irrespective of the use of antihypertensive drugs. These data suggest that the use of antihypertensive drugs is not necessary to achieve a good pregnancy outcome. It is of interest to note that 49% of patients will demonstrate a decrease in mean arterial pressure and an additional 34% will demonstrate no change in mean arterial pressure at 20 to 26 weeks' gestation without the use of antihypertensive medications.⁵ Furthermore, only 13% of patients will require antihypertensive medications for exacerbation of hypertension during the third trimester. In the same report, we found that most of the poor outcome was related to the development of superimposed preeclampsia in such pregnancies. Indeed, in the absence of superimposed preeclampsia, the perinatal outcome in patients with mild chronic hypertension was similar to that in the general obstetric population. These findings are similar to those reported by Chesley and Annitto using a similar management approach.⁴ We attribute the good perinatal outcome in these pregnancies to early onset of perinatal care, frequent prenatal visits, intensive antepartum and intrapartum monitoring, and timely delivery. Thus, it is our policy to discontinue all antihypertensive medications in all such patients at the time of the first prenatal visit. Antihypertensive therapy is subsequently started only if the blood pressure exceeds 180 mmHg systolic or 110 mmHg diastolic. These patients are usually treated with methyldopa, nifedipine, labetalol, or a thiazide diuretic (Table 8) administered as needed to keep diastolic blood pressure consistently below 100 mmHg. In some patients, the choice of medication will be guided by other factors related to the hypertension (Table 9). It is important to emphasize that the development of exacerbated hypertension alone is not an indication for delivery. The pregnancy in these patients may be continued until term or until the onset of superimposed preeclampsia. In the absence of superimposed preeclampsia or fetal jeopardy, routine induction before 40 weeks' gestation is not warranted. Superimposed preeclampsia or fetal growth retardation is an indication for hospitalization and close evaluation of maternal and fetal well-being. Subsequent management is similar to that in the high-risk group and will depend on the fetal gestational age and the result of antepartum fetal testing (Table 10). Mild superimposed preeclampsia is an indication for delivery if the gestational age is at least 37 weeks. Otherwise, the pregnancy can be managed conservatively in the hospital until the cervix is ripe for induction, the onset of labor, or completion of 39 weeks' gestation.

Table 8. Treatment of Chronic Hypertension in Pregnancy

Table 9. Medical Factors Guiding Antihypertensive Selection in Pregnancy

Table 10. Antepartum Fetal Evaluation in Mild Chronic Hypertension*

Pregnancies in women at high risk are associated with increased maternal and perinatal complications.^1,2,11,12 As a result, these patients should be managed in consultation with a maternal–fetal medicine specialist. Furthermore, patients with chronic renal disease, particularly those with primary glomerular diseases and significant renal function impairment (serum creatinine more than 2.5 mg/dL) should be managed in consultation with a nephrologist. All these patients should be hospitalized at the time of first prenatal visit for evaluation of cardiovascular and renal status and for regulation of antihypertensive medications, as well as other prescribed medications (insulin, thyroid drugs, cardiac drugs) if needed. Antihypertensive medications should be used to keep systolic blood pressure between 130 and 140 mmHg and diastolic blood pressure between 80 and 90 mmHg. Typical first-line medications for blood pressure control are beta-blockers, thiazide diuretics, calcium channel blockers, or methyldopa. In some instances, blood pressure may be difficult to control, demanding the use of multiple oral and intravenous therapy.^11,12 Antihypertensives should be used in all women with high-risk hypertension. For patients with significant proteinuria in the first trimester, antinuclear antibody and serum complement are performed to rule out the presence of lupus nephritis. Early and frequent prenatal care is the key to a successful outcome for patients with high-risk characteristics. These women need close monitoring throughout pregnancy and may require multiple hospital admissions for control of blood pressure or associated medical complication. Fetal evaluation should be started as early as 28 weeks, and repeated as needed (Table 11). Superimposed preeclampsia is an indication for immediate hospitalization. Subsequent management will depend on the severity of preeclampsia and fetal gestational age.

Table 11. Antepartum Fetal Evaluation in Severe Chronic Hypertension**

On rare occasions, pregnant women may present with life-threatening clinical conditions that require immediate control of blood pressure such as the following: hypertensive encephalopathy; acute left ventricular failure; acute aortic dissection; or increased circulating catecholamines (pheochromocytoma, clonidine withdrawal, cocaine ingestion). Patients at highest risk for these complications include those with underlying cardiac disease, chronic glomerular renal disease, patients that require multiple drugs to control their hypertension, patients with superimposed preeclampsia in the second trimester, and those with abruptio placenta complicated by disseminated intravascular coagulation. Although a diastolic blood pressure of 115 mmHg or more is usually considered a hypertensive emergency, this level is actually arbitrary, and the rate of change of blood pressure may be more important than absolute level.⁶⁷ The association of elevated blood pressure with evidence of new or progressive end organ damage determines the seriousness of the clinical situation.⁵⁶

Hypertensive Encephalopathy

Hypertensive encephalopathy is a rare complication of hypertension in pregnancy, seen in only three of 79,301 pregnancies,⁶⁸ having an unknown cause. The rapid increase in blood pressure appears to be caused by a massive overproduction of renin and angiotensin II in response to renal ischemia. This is followed by pressure natriuresis, which stimulates additional renin-angiotensin-aldosterone release.⁶⁹ Hypertensive encephalopathy is usually seen in patients with systolic blood pressure greater than 250 mmHg and/or diastolic blood pressure greater than 130 mmHg.⁷⁰ Patients with acute onset of hypertension may have encephalopathy at pressure levels that are generally tolerated by those with chronic hypertension. Normally, cerebral blood flow is approximately 50 mL per 100 g of tissue per minute. When the blood pressure decreases, cerebral arterioles normally dilate, whereas when blood pressure increases, they constrict to maintain constant cerebral blood flow.⁷¹ This mechanism usually remains operative between 60 and 120 mmHg diastolic blood pressure. Hypertensive encephalopathy is currently considered to be a derangement of the autoregulation of the cerebral arterioles, which occurs when the upper limit of autoregulation is exceeded.⁷⁰ As cerebral perfusion pressure exceeds130 to 150 mmHg, cerebral blood vessels constrict as much as possible and then reflex cerebral vasodilatation occurs, resulting in overperfusion, damage to small blood vessels, cerebral edema, and increased intracranial pressure (breakthrough theory). Others believe that hypertensive encephalopathy results from an exaggerated vasoconstrictive response of the arterioles, resulting in cerebral ischemia (overregulation theory). Patients who have impaired autoregulation involving the cerebral arterioles may experience necrotizing arteriolitis, microinfarcts, petechial hemorrhages, multiple small thrombi, or cerebral edema.⁷⁰ Typically, hypertensive encephalopathy has a subacute onset (over 24–72 hours).⁷¹ Table 12 describes the presenting signs and symptoms.^67,70,71

Table 12. Clinical Features of Hypertensive Encephalopathy

During a hypertensive crisis, other evidence for end-organ damage may be present: cardiac, renal, or retinal dysfunction secondary to impaired organ perfusion and loss of autoregulation of blood flow. Ischemia of the retina with flame-shape retinal hemorrhages, retinal infarcts, or papilledema may occur, causing decreased visual acuity.⁷⁰ Impaired regulation of coronary blood flow and marked increase in ventricular wall stress may result in angina, myocardial infarction, congestive heart failure, malignant ventricular arrhythmia, pulmonary edema, or dissecting aortic aneurysm.^21,70 Necrosis of the afferent arterioles of the glomerulus results in hemorrhages of the cortex and medulla; fibrinoid necrosis and proliferative endarteritis result in elevated serum creatinine(more than 3 mg/dL), proteinuria, oliguria, hematuria, hyaline or red blood cell casts, and progressive azotemia.⁷⁰ Such severe hypertension may result in abruptio placentae with resultant disseminated intravascular coagulopathy. In addition, high levels of angiotensin II, norepinephrine, and vasopressin accompany ongoing vascular damage. These circulating hormones increase relative efferent arteriolar tone, resulting in sodium pressure diuresis and hypovolemia. Because levels of renin and angiotensin II are increased, the aldosterone level is also elevated. The impact of these endocrine changes may be important in maintaining the hypertensive crisis.

The ultimate goal of therapy is to prevent the occurrence of a hypertensive emergency. Patients at risk for hypertensive crisis should receive intensive management during labor and for a minimum of 48 hours after delivery. In the presence of hypertensive crisis, diagnostic procedures and therapy are essential. Although pregnancy may complicate the diagnosis, once the life-threatening conditions are recognized, pregnancy does not, in any way, slow or alter the mode of therapy. The only reliable clinical criterion for confirming the diagnosis of hypertensive encephalopathy is prompt response of the patient to antihypertensive therapy. The headache and sensorium often clear dramatically, sometimes within 1 to 2 hours after the treatment although recovery may be somewhat slower in patients with uremia and in whom the symptoms have been present for a prolonged period before the therapy is administered. Sustained cerebrovascular deficits should suggest other diagnoses.⁷¹

Patients with hypertensive encephalopathy or other hypertensive crisis should be hospitalized for bedrest. Intravenous lines should be inserted for fluids and medications. Although there is a tendency to restrict sodium intake in patients with hypertensive emergency, volume contraction from sodium pressure diuresis may be present. A marked decrease in diastolic blood pressure with an increase in heart rate on standing from the supine position is evidence of volume contraction. Infusion of normal saline solution during the first 24 to 48 hours to achieve volume expansion should be considered. Saline infusion may help decrease the activity of the renin-angiotensin-aldosterone axis and result in better blood pressure control. Simultaneous repletion of potassium losses and continuous monitoring of blood pressure, volume status, urinary output, electrocardiographic readings, and mental status is mandatory. An intraarterial line may provide the most accurate blood pressure information. Laboratory studies include complete blood count, differential, reticulocyte count, platelets, and a renal profile. A urinalysis should be obtained for protein, glucose, blood, cells, casts, and bacteria. Assessment for end-organ damage (central nervous system, retina, renal, cardiovascular) should be performed periodically. Antepartum patients should have continuous fetal monitoring.^1,2,67,70,71

Lowering Blood Pressure

There are risks associated with too rapid or excessive reduction of elevated blood pressure. The aim of therapy is to lower mean blood pressure by no more than 15% to 25%. Small reductions in blood pressure in the first 60 minutes, working toward a diastolic level of 100 to 110 mmHg have been recommended.^1,67,70,71 Although cerebral blood flow is maintained constant over a wide range of blood pressures, there is a lower and an upper limit to autoregulation. In chronic hypertensives, a rightward shift of the cerebral autoregulation curve secondary to medial hypertrophy of the cerebral vasculature may result in cerebral ischemia, stroke, or coma if blood pressure is lowered too rapidly. Coronary blood flow, renal perfusion, and uteroplacental perfusion also may deteriorate, resulting in acute renal failure, myocardial infarction, fetal distress, or death. If the hypertension proves increasingly difficult to control blood pressure escapes, this is an indication to end the pregnancy by elective delivery. If the patient's outcome appears to be grave, consideration of perimortem cesarean delivery should be made.⁶⁷

The drug of choice in the treatment of hypertensive crisis has traditionally been sodium nitroprusside, although beta-blocking agents may have the advantage of preserving cerebral blood flow in these patients.⁷² Other drugs such as hydralazine, nicardipine, and nitroglycerin can also be used (Table 13).

Table 13. Parenteral Medications for the Treatment of Severe Hypertension

Sodium nitroprusside causes arterial and venous relaxation by interfering with both influx and the intracellular activation of calcium. It is administered as an intravenous infusion of .25 to 5 mg/kg per minute. The onset of action is immediate and its effect may last 3 to 5 minutes after discontinuing the infusion. Hypotension caused by nitroprusside should resolve within a few minutes of stopping the infusion because the drug's half-life is so short. If it does not resolve, other causes for hypotension should be suspected. The effect of nitroprusside on uterine blood flow is controversial. Nitroprusside is metabolized into thiocyanate, which is excreted in the urine. Cyanide can accumulate if there is either increased production caused by large doses (more than 10 mg/kg per minute), prolonged administration (more than 48 hours), or if there is renal insufficiency or decreased metabolism in the liver. Signs of toxicity include anorexia, disorientation, headache, fatigue, restlessness, tinnitus, delirium, hallucinations, nausea, vomiting, and metabolic acidosis. When it is infused at less than 2 mg/kg per minute, cyanide toxicity is unlikely. Animal experiments and the few reported cases of nitroprusside use in pregnancy have revealed that thiocyanate toxicity to mother and fetus rarely occur if used at usual pharmacologic doses. Before toxicity manifests, usually tachyphylaxis to nitroprusside effect develops. Whenever toxicity is suspected, therapy should be initiated with 3% sodium nitrite at a rate not exceeding 5 mL/min up to a total dose of 15 mL. Then, infusion of 12.5 g of sodium thiosulfate in 50 mL of 5% dextrose in water over a 10-minute period should be started.⁷³

Nitroglycerin

Nitroglycerine is an arterial and venous dilator (mostly venous). It is administered as an intravenous infusion of 5 μg per minute, which is gradually increased every 3 to 5 minutes to titrate blood pressure up to a maximum dose of 100 μg per minute. It is the drug of choice in preeclampsia associated with pulmonary edema and for control of hypertension associated with tracheal manipulation. Side effects such as headache, tachycardia, and methemoglobinemia may develop. It is contraindicated in hypertensive encephalopathy because it increases cerebral blood flow and intracranial pressure.⁷⁰

Lowering Increased Intracranial Pressure

The following steps should be considered whenever increased intracranial pressure is diagnosed: (1) elevate the head to 30- to 45-degree angle; (2) intubate, with subsequent hyperventilation (target PaCO₂ of 25–30 mmHg); (3) correct hyponatremia; administer mannitol 250 mL to 500 mL of a 20% solution over 20 to 30 minutes (target serum osmolarity: 310); and (4) withdraw cerebrospinal fluid with a catheter.⁶⁷

Treating Target Organ Damage

AORTIC DISSECTION

Patients with dissecting aortic aneurysm present with pain, which is maximal at onset, history of myocardial infarction, or acute neurologic deficits. It is diagnosed by blood pressure differences between arms, asymmetric carotid impulses, transthoracic or transesophageal echocardiography, computed tomography scan of the chest with contrast, or invasive aortography. The most important feature of therapy is to reduce the shear force, rate of blood pressure increase, and left ventricular stroke work. Consultation with a cardiologist and a thoracic surgeon is mandatory. For patients with type-B aortic dissection (distal to the left subclavian artery), antihypertensive therapy should be administered within 30 minutes. The drug of choice in this setting is an agent that has a negative inotropic effect and alters the pulse wave contour such as a beta-blocker every 5 minutes to lower the heart rate to 60 beats per minute, and nitroprusside to lower blood pressure to 100 mmHg to 110 mmHg range unless myocardial infarction or cerebral edema limits attainment of the goal.⁷⁰

PULMONARY EDEMA

A bedside echocardiogram might disclose the cause. Cardiogenic pulmonary edema caused by systolic dysfunction (impaired myocardial contractility) is the usual mechanism of pulmonary edema in patients with severe hypertension caused by increased afterload. Impaired left ventricular systolic function results in increased left atrial pressure with a concomitant increase in pulmonary capillary wedge pressure and a decrease in the oncotic–hydrostatic pressure gradient. Diastolic dysfunction or impaired ventricular relaxation has been described in obese, chronically hypertensive women with superimposed preeclampsia. These women with stiff ventricles require high filling pressures and are thus predisposed to have pulmonary edema with the expanded blood volume of pregnancy. Diastolic dysfunction occurs in patients with left ventricular hypertrophy and often coexists with normal systolic function. Combined systolic and diastolic dysfunction occurs in elderly multiparas with long-standing severe hypertension.⁶⁷ Other mechanisms involved in the pathogenesis of pulmonary edema are described in Table 14. In patients with systolic heart failure, reduction of blood pressure decreases the workload of the failing left ventricle. Nitroprusside is the drug of choice for this situation since it reduces both afterload and preload. Intravenous furosemide, morphine, nitrates, enalapril maleate, oral hydralazine, and digitalis are also used. In diastolic heart failure, the use of beta-blocker or verapamil hydrochloride is recommended. Nitrates and hydralazine may be dangerous because they can further reduce the volume that primes the left ventricle.

Table 14. Mechanisms Involved in the Pathogenesis of Pulmonary Edema

Normalization of urinary findings and improvement in creatinine clearance with adequate control of blood pressure suggest malignant nephrosclerosis as the cause of azotemia. With overzealous treatment of malignant hypertension, kidney function may worsen. If renal findings do not improve after blood pressure control, other causes of renal injury such as nephritis should be considered. Ultrasound of kidneys is indicated to rule out obstruction. Dialysis or hemofiltration may be necessary with oliguric renal failure.⁷⁰

INTRACEREBRAL HEMORRHAGE

Intracerebral hemorrhage is the most common cause of death in the eclamptic patient (60%). It is more likely to occur in the older parturient and is correlated better with advancing maternal age and long-standing hypertension than with seizure activity. When hemorrhage does occur, it often does not coincide with the onset of seizures but rather is usually manifested at least 6 hours after the onset of convulsions. Intracerebral hemorrhage may occur antepartum or postpartum. It may occur spontaneously or complicate cocaine abuse, thrombocytopenia, or disseminated intravascular coagulation. Intracerebral hemorrhage into the putamen, basal ganglia, and internal capsule usually results from rupture of a Charcot-Bouchard aneurysm. Patients with intracerebral hemorrhage usually present with daytime neurologic deficits that worsen over several hours.⁷⁰ Table 15 describes the prognostic indicators for intracerebral hemorrhage.

Table 15. Prognosis in Patients With Intracerebral Hemorrhage

Pheochromocytoma is an extremely rare complication of pregnancy. Pheochromocytoma produces similar signs and symptoms in both pregnant and nonpregnant patients,⁷⁴ although the occurrence of hypertension and the classical pheochromocytoma symptoms are less frequent than in nonpregnant patients.⁷⁵ Patients with pheochromocytoma usually present with wide blood pressure swings, headache, pallor, anxiety, hot flashes, excessive perspiration, palpitations, tachycardia, arrhythmias, postural hypertension, chest or abdominal pain, abdominal masses, unusual response to drugs that affect the release and actions of circulating catecholamines, hyperglycemia, visual disturbances, dilated pupils, convulsions, sudden collapse, and death. Hypertension may be absent.^74,75,76,77 The diagnosis may be overlooked in pregnancy because the condition often mimics that of preeclampsia. Antepartum diagnosis was made only in 53% of the reported cases in one series.⁷⁵ It is advisable to think of pheochromocytoma in patients with severe or intermittent hypertension, hypertension associated with paroxysmal symptoms, hypertension in the first half of pregnancy, hypertension with abnormal glucose tolerance or diabetes mellitus, and hypertension with thyrotoxicosis. Furthermore, because pheochromocytoma occurs in 1% to 2% of patients with neurofibromatosis and is associated with familial multiple endocrine neoplasia II syndrome, hypertension in these patients should raise the suspicion of an underlying pheochromocytoma.⁷⁴ An unrecognized pheochromocytoma is particularly dangerous because potentially fatal hypertensive crisis may be precipitated by anesthesia, vaginal delivery, the mechanical effects of the gravid uterus, uterine contractions, and even vigorous fetal movements. Maternal and perinatal outcome are poor if the condition is not identified and treated during pregnancy

Maternal death has been reported in up to 50% to 60% of cases when the diagnosis is not made before the onset of labor, but in only 2% to 20% of cases when the diagnosis is made earlier in pregnancy. Most maternal deaths occur intrapartum or within 72 hours postpartum because the events of labor and delivery are associated with the most severe elevations of blood pressure.^77,78 Although fetal mortality can be kept low by medications, fetal loss occasionally occurs in the second and third trimesters even though seemingly adequate alpha-blockade has been administered.^75,79 Fetal growth restriction or death may occur secondary to reduced uteroplacental perfusion and fetal hypoxia from complications arising from malignant tumor, hypotension in the postoperative course, or hypertensive crisis. Decreasing intravascular volume characteristic of pheochromocytoma can also lead to oligohydramnios. Patients with pheochromocytoma medically treated during pregnancy or after tumor resection should have twice weekly testing and amniotic fluid index, in addition to serial ultrasound for growth.

The diagnosis of pheochromocytoma in pregnancy can be made by estimation of urinary metanephrines in a properly collected 24-hour urine sample, preferably obtained during or immediately after a hypertensive episode. Pregnancy does not alter the diagnostic levels of these tests. Assays using high-pressure liquid chromatography or the catecholomethyl transferase radioenzymatic technique have considerably improved the diagnostic accuracy. Pharmacologic tests, such as the phentolamine suppression tests, are unnecessary and have been associated with maternal and fetal death. Preoperative tumor localization is desirable; 90% of pheochromocytomas arise in the adrenal medulla and 98% occur within the abdomen. Bilateral adrenal tumors occur in 10% of the cases, especially in multiple endocrine neoplasia II syndrome. The most sensitive imaging test for localization of the tumor is magnetic resonance imaging,⁸⁰ and this test offers the advantage of safety in pregnancy.

Management during pregnancy consists of medical control of signs and symptoms followed by surgical excision of the tumor.^75,76,77,79 Table 16 outlines the drugs that can be used in this setting. Surgical intervention is advisable in all patients with diagnosis before 20 weeks' gestation. Between 20 and 24 weeks, treatment will depend on the uterine size in terms of tumor access. After 24 weeks, abdominal exploration and access to the tumor is difficult unless the patient is first delivered. Optimum results are obtained if surgery is delayed until fetal maturity is reached.^75,81,82 It is understandable that the longer the time that passes, the more hazardous it becomes to harbor a functioning pheochromocytoma, even under protection of an alpha-blocker. The mode of delivery is still controversial. Because vaginal delivery has a higher maternal mortality than cesarean section, most cases diagnosed but not removed antenatally were delivered by cesarean section with concurrent or delayed surgical removal of the tumor.^75,82 If vaginal delivery is attempted, epidural anesthesia is advisable for vaginal delivery to establish pain-free labor and decrease catecholamine responses.

Table 16. Medical Treatment of Pheochromocytoma

Women with high-risk chronic hypertension are at risk for postpartum complications such as pulmonary edema, hypertensive encephalopathy, and renal failure.⁶ This is particularly true among women with target organ involvement, superimposed preeclampsia, abruptio placentae, morbid obesity, or long-standing hypertension. In these patients, blood pressure must be closely monitored and controlled for at least 48 hours after delivery. Intravenous labetalol or hydralazine can be used for acute elevations of blood pressure,⁸³ in addition to diuretics in women with circulatory congestion and pulmonary edema.⁸⁴

After delivery, oral antihypertensive therapy may be needed to maintain blood pressure control. In choosing the appropriate agent, it is important to consider whether factors compel the choice of one medication over another. For patients with a history of myocardial infarction, beta-blockers, and ACE inhibitors are excellent choices to decrease mortality.⁸⁵ In patients with diabetes mellitus, ACE inhibitors offer a renal-protective effect.²⁶

Another significant consideration in the postpartum patient is the mother who wishes to breastfeed her infant. All antihypertensive medications are found in breast milk to varying degrees,⁸⁶ and the long-term effect of these medications on breastfeeding infants has not been specifically studied. Concentrations of methyldopa in milk are low and considered safe, and this remains the first-line agent for patients without compelling indications to choose another antihypertensive. Because concentrations of labetalol and propranolol in breast milk are low, these may be better choices than atenolol and metoprolol, which are concentrated in breast milk.⁸⁷ The concentrations of diuretic agents in milk are also low, but they may, unfortunately, induce a decrease in milk production.⁸⁶ Although little information exists regarding the excretion of calcium channel blockers in breast milk, there have been no apparent untoward effects.⁴⁶

ACE inhibitors and angiotensin II receptor antagonists should be avoided because of the potential of deleterious effects on neonatal renal function, even though their concentrations in breast milk appear to be low. If ACE inhibitors are indicated for the breastfeeding mother, current data suggest that captopril and enalapril are safe treatments.⁸⁸

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