Hypertensive disorders are the most common medical conditions during pregnancy and are a leading cause of maternal and perinatal morbidity and mortality worldwide. Hypertension complicates 6% to 10% of pregnancies and, of 4 million women giving birth in the United States each year, an estimated 240,000 are affected by hypertension. Of concern, hypertension is the most important risk factor for stroke and there has been an overall rise in the incidence of pregnancy-related stroke and subsequent morbidity in the past 20 years. Although maternal mortality rates are reduced considerably in developed compared with developing nations, hypertension still accounts for 15% of maternal deaths in the U.S., mostly as a result of intracerebral hemorrhage.
Although the obstetrician manages most cases of hypertension during pregnancy, the internist, cardiologist, or nephrologist may be consulted if hypertension precedes conception, if end organ damage is present, or when accelerated hypertension occurs. This chapter assumes a medical perspective focusing on nonobstetrical diagnostic and therapeutic issues in the care of pregnant women with hypertension.
Classification and Definitions
Hypertension in pregnancy generally refers to a blood pressure (BP) of 140/90 mm Hg or above. In most obstetric guidelines it is broken down into two categories of severity: mild-moderate (140 to 159/90 to 109 mm Hg) and severe (≥160/110 mm Hg). Four major hypertensive disorders in pregnancy have been described by the American College of Obstetricians and Gynecologists (ACOG) : (1) chronic hypertension; (2) preeclampsia-eclampsia; (3) chronic hypertension with superimposed preeclampsia; and (4) gestational hypertension.
Based on the 1980 to 2010 national hospital discharge survey data sets, out of 120 million births, 3.8% were complicated by preeclampsia; of these patients, 0.97% had chronic hypertension (0.24% had superimposed preeclampsia), and 2% had gestational hypertension All four types may lead to maternal and perinatal complications, however, the syndrome of preeclampsia is associated with the highest maternal and fetal risks.
Chronic Hypertension
Chronic hypertension is defined as blood pressure (BP) 140/90 or higher mm Hg that either predates pregnancy or develops before 20 weeks. Chronic hypertension complicates 3.6% to 9.1% of pregnancies and is usually (88.8%) attributed to essential hypertension. Higher rates may be seen in older women, obese women, and African Americans.
Preeclampsia-Eclampsia
This syndrome occurs in 2% to 5% of pregnancies and is responsible for up to 12% to 15% of maternal deaths. The morbidity and mortality risks seem to be higher in women of African-American descent.
Preeclampsia is a pregnancy-specific syndrome that develops in the latter half of pregnancy. It is characterized by a de novo onset of hypertension (BP ≥ 140/90 mm Hg) after 20 weeks of gestation and traditionally, proteinuria (>0.3 g per day). More recently, it has been recognized that nonproteinuric forms of preeclampsia exist, and guidelines have updated their diagnostic criteria of preeclampsia to include additional signs/symptoms: neurological symptoms, thrombocytopenia (platelets < 100,000/μL), pulmonary edema, transaminitis (alanine aminotransferase [ALT], or aspartate aminotransferase [AST] above twice the normal range) and renal insufficiency (creatinine > 1.1 mg/dL or doubling). In the absence of proteinuria, a woman can still be diagnosed with preeclampsia if she has any of the above listed signs/symptoms assuming these findings cannot be attributed to another illness.
A severe variant of preeclampsia features hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, which occurs in 1 in 1000 pregnancies. Eclampsia complicates approximately 3% of cases of preeclampsia and is the occurrence of seizures that cannot be attributed to other causes.
Chronic Hypertension With Superimposed Preeclampsia
Women with chronic hypertension are at an increased risk to develop superimposed preeclampsia, which complicates 25% of chronic hypertensive pregnancies (versus 5% of nonhypertensive pregnancies). The diagnosis of superimposed preeclampsia is made in women with chronic hypertension if proteinuria or a severe feature of preeclampsia develops for the first time after 20 weeks, in association with an increase in BP.
In women with both hypertension and proteinuria before 20 weeks of gestation, 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 of thrombocytopenia with hemolysis and elevated levels of ALT or AST.
Gestational Hypertension
Gestational hypertension, seen in 6% of pregnancies, is hypertension developing after 20 weeks not associated with the systemic features of preeclampsia (e.g., proteinuria). Some women (up to 25%) may ultimately develop signs of preeclampsia, so the final diagnosis of gestational hypertension can only be made postpartum.
Clinical Features and Management of Chronic Hypertension During Pregnancy
Clinical Features and Diagnosis
The prevalence of hypertension in women of reproductive age (18 to 44 years old) is close to 9.3% in whites, 19.2% in African Americans, and 8.2% in Hispanics and increases with age. Nearly 2% of all pregnancies are complicated by chronic hypertension.
If hypertension is clearly documented before conception, the diagnosis of chronic hypertension in pregnancy is straightforward ( Figs. 39.1, 39.2 ). Chronic hypertension is also the most likely diagnosis when hypertension is present before 20 weeks of gestation. Routine laboratory tests including platelets, liver function tests, blood urea nitrogen, creatinine, uric acid; and quantification of proteinuria should be performed at baseline in women with early pregnancy hypertension, to determine the clinical significance of any later changes in BP or laboratory tests.
The distinction between chronic hypertension (first noted in pregnancy) and gestational hypertension may be difficult to establish until after delivery. In some patients with undocumented chronic hypertension BPs will run normal throughout the entire pregnancy and then return to prepregnancy hypertensive levels in the postpartum period, accounting for the unusual but mysterious cases of isolated postpartum hypertension.
BP normally falls in early pregnancy; systolic blood pressure (SBP) changes little, whereas diastolic blood pressure (DBP) falls by approximately 10 mm Hg by 13 to 20 weeks, with a nadir at 24 weeks, and then rises again to prepregnancy levels in the third trimester (weeks 28 to 40). This physiologic fall may be more exaggerated in women with chronic hypertension. The BP usually rises in the third trimester to prepregnancy values and the differential in these patients includes undiagnosed chronic hypertension, gestational hypertension, or preeclampsia. In such cases, the diagnosis of preeclampsia should be ruled out by verifying the absence of proteinuria or other signs/symptoms of preeclampsia or HELLP syndrome. The patient should be asked about cerebral or visual symptoms; abdominal pain and laboratory testing for serum uric acid, liver function tests, renal function, complete blood count, and urine protein/creatinine should be done.
Although early onset hypertension (before 20 weeks gestation) is most often a result of chronic hypertension, it may, on rare occasions, be an indication of early-onset preeclampsia; such women require urine protein measurements and preeclampsia labs. They should be treated to target (see later) and followed closely, particularly if they had no history of previous hypertension. When blood pressure increases in mid pregnancy (16 to 24 weeks), early preeclampsia should be considered because in healthy pregnancies, blood pressure usually decreases at this time.
White coat hypertension (elevated office BP with normal BP outside the medical setting) is more likely to be present in the first, rather than the second trimester, with an estimated prevalence of 32% and 3% to 4% respectively. White coat hypertension does not appear to predispose to preeclampsia or to worsen overall pregnancy outcomes. Home BP monitoring or a noninvasive 24-hour BP monitor can distinguish white coat from true hypertension in the pregnant patient.
Although most women with chronic or preexisting hypertension have essential hypertension, consider the possibility of secondary hypertension. Young women with hypertension may be somewhat more likely (compared with middle-aged women) to have secondary hypertension (e.g., intrinsic renal disease, renovascular hypertension, primary aldosteronism, Cushing syndrome, pheochromocytoma). In select patients with severely elevated BP or with attributable symptoms or laboratory abnormalities, secondary hypertension may be considered in women planning a pregnancy or even in early pregnancy, as secondary hypertension is potentially curable and some forms are associated with increased morbidity during pregnancy ( Fig. 39.3 ). For example, if proteinuria is documented in early pregnancy, then noninvasive evaluation for renal disease may be indicated, including 24-hour urinary protein excretion or creatinine clearance, renal ultrasound, and serologic testing to rule out secondary glomerulopathies.
Primary aldosteronism is the most common form of curable hypertension. The hallmarks of this disorder are an increased aldosterone production, a suppressed plasma renin activity (PRA), and hypokalemia. Diagnosis in pregnancy is very difficult, as progesterone (the hormone of pregnancy) acts as an aldosterone blocker, so aldosterone levels are physiologically elevated in the normal pregnant woman; in those with secondary hyperaldosteronism who are also pregnant, they are even more so. As a result of normal volume expansion, plasma renin is physiologically increased in pregnancy; however, PRA may be lowered between 1 ng per mL per hour and 4 ng per mL per hour in primary aldosteronism. During pregnancy, the clinical manifestations of primary aldosteronism are heterogeneous and range from an improvement of hypertension/hypokalemia to difficult-to-control hypertension and hypokalemia. In cases when primary aldosteronism is quiescent during pregnancy, clinicians need to be vigilant of a rebound in hypertension and hypokalemia after delivery. If the disease is diagnosed early in pregnancy, the patient may undergo laparoscopic adrenalectomy in the late first trimester or in the second trimester.
Another form of secondary hypertension that may be considered is pheochromocytoma, which, although rare, is associated with high morbidity and mortality rates during pregnancy, particularly if undiagnosed. This should be considered in pregnant women with severe hypertension, especially when associated with headache, anxiety, palpitations, pallor, and sweats.
Maternal Risks
Pregnancies in women with uncomplicated chronic hypertension are usually successful although such women are more likely to undergo cesarean delivery and be hospitalized for worsening hypertension. In addition to the previously mentioned increased risk for superimposed preeclampsia, women with chronic hypertension are at a three-fold increased risk of abruptio placentae which can lead to life-threatening maternal hemorrhage. Other risks include accelerated hypertension with potential target organ damage and cerebrovascular catastrophes. Both maternal and fetal morbidity and mortality are greater when superimposed preeclampsia develops with an increased risk of fatal intracerebral hemorrhage, particularly if posterior reversible encephalopathy is present.
Women with chronic hypertension caused by advanced chronic kidney disease (CKD) may experience irreversible deterioration in kidney function during pregnancy regardless of the development of superimposed preeclampsia. If advanced CKD is present, (e.g., serum creatinine > 1.9 mg/dL, or 168 μmol/L), maternal hypertension, worsening proteinuria, and evolution to end-stage renal disease requiring dialysis are common. Fetal complications include growth restriction and preterm delivery.
Fetal Risks
Perinatal death rates are higher in pregnancies of women with chronic hypertension than in those without, and superimposed preeclampsia confers 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% to 13% of pregnancies of women with chronic hypertension. When superimposed preeclampsia develops, all complications are magnified; IUGR is reported in 35% of pregnancies, delivery resulting in prematurity occurs in 13% to 54%, and fetal death is the outcome in less than 1%.
Data from large surveys suggest that infants born to mothers with chronic hypertension may have as much as a 30% increased risk for congenital malformations, especially cardiac malformations. This risk is not significantly altered by antihypertensive therapy.
Management
Management of the pregnant woman with chronic hypertension is ideally before conception, to establish the diagnosis and to rule out secondary hypertension.
Preconception is also the appropriate time to discuss the risks of hypertension in pregnancy: a high likelihood of a favorable outcome despite risks of superimposed preeclampsia (25%) and fetal complications. Adherence to appointment keeping is essential, because frequent visits increase the likelihood of detecting preeclampsia and other complications before they become life threatening. Similarly, home BP monitoring by the patient, especially in the latter half of pregnancy, is advised. The use of medications with deleterious fetal effects, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and direct renin inhibitors should be addressed (see “Medications” section). Finally, in complicated conditions such as kidney transplantation or diabetes mellitus (DM) with renal disease, a multidisciplinary team consisting of obstetricians and internists familiar with the care of pregnant women can optimize the chances of a successful outcome. Before conception, we also recommend the modification of certain risk factors; for example, women with obesity are at a higher risk for gestational hypertension and women who are underweight (body mass index below 18.5 kg/m 2 ) are at a higher risk for preterm labor.
Nonpharmacologic Management
The approach to hypertension in the gravid patient represents a departure from accepted guidelines for nonpregnant hypertensive individuals. Patients are not advised to exercise vigorously because of the concern that extreme physical exertion may potentially decrease uteroplacental blood flow, and is associated with a higher rate of preeclampsia. Although this has not been extensively studied, one clinical trial showed that aerobic exercise thrice weekly may reduce the risk of developing hypertension and prevent excessive weight gain during pregnancy. Moderate intensity walking probably does not impair placental flow, however strenuous exercise remains contraindicated in pregnancy. Of note, women who work outside the home have both higher BP and an increased risk of preeclampsia compared with those who report not working. Decreased work hours and more rest may theoretically increase placental blood flow and decrease BP.
Excessive weight gain (of 36 lbs or more) has been associated with an increased risk of hypertensive diseases of pregnancy in all race/ethnicity or baseline body mass index (BMI) subgroups. Excessive weight loss during pregnancy is not advisable though, even in obese women because it may compromise fetal growth and increase the risk for small for gestational age infants. It is therefore advisable for women to limit their weight gain during pregnancy to the 2009 Institute of Medicine (IOM) recommendation because there is currently no proven weight gain limitation strategy that would improve pregnancy outcomes. The IOM recommends a weight gain of 1 lb per week (in the second and third trimesters) for women with a normal BMI or underweight before pregnancy. This weight gain is limited to 0.6 lb per week in women with a prepregnancy BMI 25 to 29.9 kg/m 2 and to 0.5 lb per week in those with a BMI 30 kg/m or above.
Significant salt restriction is not advisable during pregnancy. because of concerns that the normal, physiologic plasma volume expansion would not occur. It is however reasonable for women adhering to a low-sodium diet before conception to continue their dietary habits.
Blood Pressure Treatment Targets
In nonpregnant adults, BP control decreases the long-term incidence of cardiovascular (CV) disease and mortality. During the 9 months of pregnancy, however, untreated mild (stage 1) hypertension is unlikely to lead to detectable adverse outcomes and antihypertensive drugs, in this setting, are used primarily to protect the mother from acute CV or cerebrovascular events.
With regards to prevention of preeclampsia, there is unfortunately little evidence that the treatment of mild to moderate hypertension early in pregnancy reduces the incidence of superimposed preeclampsia, preterm birth, or small-for-gestational age neonates. A major benefit of BP medication use in all hypertensive pregnancies is to decrease the incidence of severe hypertension and possibly decrease the risk for other fetal or maternal complications. In women who ultimately develop preeclampsia, the risk of cerebrovascular events increases sharply with severe hypertension.
There is widespread consensus among national and international guidelines to treat any BP 160/110 or higher mm Hg. The ACOG and American Heart Association/American Stroke Association (AHA/ASA) recommend initiating hypertension treatment when BP 160/105 or higher mm Hg (if either value is reached). The Society of Obstetricians and Gynaecologists of Canada has the same systolic threshold in its guidelines but tolerates a DBP up to 110 mm Hg before initiation of therapy. The AHA/ASA further suggests considering pharmacologic therapy for BPs 150 to 159/100 to 109 mm Hg to prevent worsening hypertension and strokes. These numbers are aligned with the targets set by the European and British guidelines. However, the European Society of Cardiology (ESC) goes even further to recommend treatment of BP 140/90 mm Hg or above in women with organ damage, symptoms or superimposed gestational hypertension on chronic hypertension.
For women without end organ damage, current guidelines vary, with recommendations to initiate treatment for BP thresholds ranging from 140/90 to 160/110 mm Hg or higher. Summarized recommendations in accordance with those of the National High Blood Pressure Education Program (NHBEP) Working Group on High Blood Pressure in Pregnancy in 2000 advising when maternal BP reaches levels 150/90 to 100 mm Hg or higher, treatment should be initiated to avoid hypertensive vascular damage. As BP normally falls in early pregnancy, even in women with chronic hypertension, if there is no known organ damage, clinicians can consider discontinuing antihypertensive drugs and monitoring BP in those with stage 1 hypertension. Therapy can then be restarted at a BP of 145 to 150/90 to 100 mm Hg, regardless of the type of hypertension. Orally administered antihypertensive agents should be used in standard doses in pregnancy as discussed later in this chapter. Overly aggressive, acute blood pressure lowering is not advised because this may lead to reductions in uteroplacental perfusion.
A recent large clinical trial, the Control of Hypertension In Pregnancy Study (CHIPS), has addressed treatment targets for BP in 987 pregnant women with hypertension in pregnancy. The majority of participants had preexisting hypertension but the study also included women with nonproteinuric gestational hypertension. This study demonstrated that women treated to lower blood pressure targets (130 to 140/85 mm Hg) had fewer episodes of severe hypertension. Importantly, there were no adverse fetal effects in the lower blood pressure target group, challenging the previous concern that lowering blood pressure to ‘normal’ might be associated with reduced fetal growth. The incidence of preeclampsia was similar in women treated to standard, less-tight control (target DBP, 100 mm Hg) or tight control (target DBP, 85 mm Hg).
The ACOG recommends adjusting therapy to maintain BP in the 120 to 160/80 to 105 mm Hg range during pregnancy. The target range is narrower in the Canadian guidelines and is further divided into 130 to 155/80 to 105 mm Hg for women with chronic hypertension without comorbidities and less than 140/90 if comorbidities are present.
Pharmacologic Management
Many women with chronic hypertension in pregnancy have stage 1 hypertension, and if, as expected, BP decreases below 130 to 140/90 mm Hg by the end of the first trimester, reduced doses or discontinuation of antihypertensive medication may be possible. When pharmacologic treatment is required to control BP, the choices for antihypertensives is limited by their safety data in pregnancy. The United States Food and Drug Administration (FDA) classification of drugs in pregnancy designates most antihypertensive drugs as category C, stating 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 it is so broad as to preclude its usefulness in clinical practice. The most recent evidence assessing risks and benefits for the drugs to treat hypertension in pregnancy is reviewed later and in Table 39.1 . These medications have the longest history of safe use in pregnancy, although some are rarely used in the nonpregnant population, because of side effects or inconvenient dosing schedules. The ACOG recommends labetalol, nifedipine, or methyldopa as first-line therapy.
| Drug (FDA Risk) c | Dose | Concerns or Comments |
|---|---|---|
| Preferred Agent | ||
| Methyldopa (B) | 0.5-3 g/day in 2-3 divided doses | Drug of choice according to NHBEP working group; safety after first trimester well documented, including 7-year follow-up of offspring. |
| Second-Line Agents d | ||
| Labetalol (C) | 200-1200 mg/day in 2-3 divided doses | May be associated with fetal growth restriction and neonatal bradycardia. |
| Nifedipine (C) | 30-90 mg/day of a slow-release preparation | |
| Hydralazine (C) | 50-300 mg/day in 2-4 divided doses | Few controlled trials, but long experience with few adverse events documented; useful only in combination with sympatholytic agent. May cause neonatal thrombocytopenia. |
| β-Receptor blockers (C) | Depends on specific agent | May cause fetal bradycardia; this effect may be less for agents with partial agonist activity. May impair fetal response to hypoxic stress; possible risk for lower birth weight when started in first or second trimester (especially atenolol). |
| Hydrochlorothiazide (C) | 25 mg/day | May cause volume depletion and electrolyte disorders. May be useful in combination with methyldopa and vasodilator to mitigate compensatory fluid retention. |
| Contraindicated | ||
| ACE inhibitors and AT1 receptor antagonists (D) e | Leads to fetal loss in animals; human use in second and third trimester associated with fetopathy, oligohydramnios, growth restriction, and neonatal anuric renal failure, which may be fatal. | |
a No antihypertensive has been proven safe for use during the first trimester.
b Drug therapy indicated for uncomplicated chronic hypertension when diastolic blood pressure ≥100 mm Hg (using Korotkoff V phase for diastolic measurement). Treatment at lower levels may be indicated for patients with diabetes mellitus, renal disease, or target organ damage.
c United States Food and Drug Administration classification.
d Some agents are omitted (e.g., clonidine, alpha blockers) as a result of limited data on use for chronic hypertension in pregnancy.
e Authors would classify in category X during second and third trimeesters.
Central Adrenergic Agonists
Methyldopa continues to be widely used for treatment of hypertension in pregnancy; it has been found to be nonteratogenic during a 40-year history of use and has no known adverse uteroplacental or fetal effects. Birth weight and development in the first year are similar in children exposed in utero to methyldopa compared with placebo, as is neurocognitive development up to the age of 7 years. In trials, methyldopa has compared favorably with placebo agents in decreasing the occurrence of severe hypertension, in pregnancy, as well as hospital admissions. Recent posthoc analysis from the CHIPS trial suggests that methyldopa may be associated with less preterm delivery, severe hypertension, and perinatal loss or high-level neonatal care for more than 48 hours compared with labetalol. Prior studies comparing methyldopa with labetalol failed to reveal a clear outcomes advantage to either therapy.
The adverse effects of methyldopa are primarily as a result of its action at the brainstem and include decreased mental alertness, drowsiness, impaired sleep, and decreased salivation. It can cause elevated liver enzymes in 5%, with hepatitis or hepatic necrosis rarely reported, and has been associated with Coombs positivity, with (or more commonly without) associated hemolytic anemia.
Clonidine is another alpha-2 adrenergic agonist comparable with methyldopa with respect to safety and efficacy; of some concern is a reported transient hypertension and excess of sleep disturbance in exposed infants without sequelae at 1 year of age. Clonidine should be avoided in early pregnancy because of suspected embryopathy; there is little justification for its use in preference to methyldopa, given the proven safety of the latter. There is potential for rebound hypertension when clonidine is abruptly discontinued, so it is reserved for individuals who develop rash or liver dysfunction with methyldopa.
Beta-Adrenoceptor Blockers
Beta-blockers have been studied extensively in pregnancy and none have been associated with teratogenicity. Atenolol in one very small study resulted in clinically significant fetal growth restriction compared with placebo. Parenteral beta-blockade has been associated with neonatal bradycardia which rarely has required intervention. Reassurance is derived from a 1-year follow-up study, which showed normal development of infants exposed to beta-blockers in utero.
Maternal outcomes improve with the use of beta-blockers, which controls maternal BP and decreases both the incidence of severe hypertension and the rate of admission to hospital before delivery. Beta-blockers have been compared with, and found equivalent to, methyldopa in 13 trials. Adverse effects resulting from beta-blockade include fatigue, lethargy, exercise intolerance, sleep disturbance, and bronchoconstriction.
Labetalol, a nonselective beta-blocker with vascular alpha 1 -receptor–blocking properties has gained wide acceptance in pregnancy, and is as safe and effective as methyldopa. Labetalol does not decrease uterine blood flow but has been associated with fetal growth restriction in one placebo-controlled study. It is used parenterally to treat severe hypertension and has been associated with a lower incidence of maternal hypotension and other side effects compared with hydralazine. Prescribers should be aware of the rare, but potentially dangerous, association with hepatic injury.
Alpha-Adrenergic Blockers
Alpha-adrenergic blockers are indicated during pregnancy in the management of pheochromocytoma. Both prazosin and phenoxybenzamine have been used, along with β-blockers as adjunctive agents only if sufficient alpha blockade has been achieved. There is limited experience with these agents in pregnancy.
Calcium Channel Blockers
Calcium channel blockers (CCBs) have been used to treat chronic hypertension, mild preeclampsia presenting late in gestation, and severe hypertension associated with preeclampsia. Orally administered nifedipine and verapamil do not appear to pose teratogenic risk to fetuses exposed in the first trimester. Although the numbers of treated patients are small, these data are reassuring, as women with hypertension associated with kidney disease or transplantation may be difficult to manage during pregnancy without CCBs. Maternal side effects include tachycardia, palpitations, peripheral edema, and headaches (which tend to resolve after a few doses).
Long-acting nifedipine is commonly used in pregnancy without causing a detectable decrease in uterine blood flow, and is considered to be a safe first-line agent in the treatment of severe hypertension. Short-acting nifedipine has been withdrawn from the market in several countries and is not recommended in older patients because of its association with an increased incidence of myocardial infarction and death in hypertensive (nonpregnant) patients with coronary artery disease. In pregnancy, short acting nifedipine continues to be used by some, although it has been associated with maternal hypotension and fetal distress. Our preference is to use long-acting preparations; onset of action is similar to the short-acting preparations.
There are several reports documenting the safety of other calcium channel blockers including: amlodipine, nicardipine, isradipine, felodipine, diltiazem, and verapamil.
Diuretics
Although diuretics are widely used in the treatment of nonpregnant hypertensives, there is reluctance on the part of obstetricians to use diuretics because of the concern that they will interfere with the physiologic volume expansion of normal pregnancy. Of interest, a 1985 meta-analysis of trials involving more than 7000 subjects suggested that diuretics prevented preeclampsia, and were not associated with adverse effects. Although volume contraction might be expected to limit fetal growth, outcome data do not support these concerns. Diuretics are commonly prescribed in essential hypertension before conception and, given their apparent safety, NHBEP concluded that they may be continued through gestation or used in combination with other agents. The use of the loop diuretic furosemide in the postpartum period in women with preeclampsia has been reported to be beneficial for blood pressure control while in the hospital and potentially even after discharge. More studies are required and in progress to determine the role for loop diuretics in the treatment of postpartum hypertension in women with preeclampsia.
Hydrochlorothiazide can be used throughout pregnancy in low doses (12.5 to 25 mg/day), to minimize the side effects of impaired glucose tolerance and hypokalemia. Triamterene and amiloride are not teratogenic, based on small numbers of case reports. Spironolactone is not recommended because of antiandrogenic effects during fetal development in animal models, but does not seem to cause adverse outcomes in small human cohorts. We do not recommend its use during pregnancy, and based on limited data, if a potassium-sparing diuretic is needed amiloride is recommended.
Direct Vasodilators
Hydralazine is effective orally, intramuscularly, or intravenously (IV). Adverse effects are mostly those associated with vasodilation and sympathetic nervous system activation and include headache, nausea, flushing, and palpitations. In rare cases, chronic use can lead to a polyneuropathy or to a drug-induced lupus syndrome (typically with high doses). Hydralazine has been used in all trimesters of pregnancy and has not been associated with teratogenicity, although neonatal thrombocytopenia and lupus have been reported. Other adverse effects associated with hydralazine include a decrease in uterine blood flow and an increased risk for prolonged severe hypotension. In acute severe hypertension during pregnancy, IV hydralazine is useful for rapid BP control, but has been associated with more adverse events compared with IV labetalol or oral nifedipine, including maternal hypotension, cesarean section, placental abruption, Apgar scores lower than 7, and oliguria. Furthermore, side effects of hydralazine (headache, nausea, and vomiting) mimic the symptoms of deteriorating preeclampsia.
Oral hydralazine has been used for chronic hypertension in the second and third trimesters but has been largely supplanted by medications with more favorable side effect profiles.
Nitroprusside is seldom used in pregnancy; its use is limited to cases of life-threatening refractory hypertension associated with heart failure. Adverse effects include vasodilation and syncope in volume-depleted preeclamptic women. The risk of fetal cyanide intoxication is unknown but is a concern. Given the availability of safer medications, this drug is considered a last resort.
Isosorbide dinitrate has been investigated in two small studies in women with gestational hypertension and preeclampsia. It was found to lower BP while maintaining cerebral perfusion, thus decreasing the risk for ischemia and infarction.
Serotonin 2 -Receptor Blockers
Although not approved by the FDA in the United States, Ketanserin is a selective serotonin 2 -receptor–blocking drug that decreases systolic and diastolic BP in nonpregnant patients with acute or chronic hypertension. Ketanserin has been found to be nonteratogenic in animals and humans and has been studied primarily in Australia and South Africa in small trials of pregnant women. These studies suggest it may be safe and useful in treatment of chronic hypertension in pregnancy, preeclampsia, and HELLP syndrome. However Ketanserin does not control BP as well as hydralazine in women with severe hypertension in pregnancy and is not considered a drug of choice in this clinical context.
Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers
ACE inhibitors and ARBs are contraindicated in the second or third trimesters because of toxicity associated with reduced perfusion to the fetal kidneys; their use is associated with a fetopathy similar to that observed in Potter syndrome (i.e., bilateral renal agenesis) including renal dysgenesis, oligohydramnios as a result of fetal oliguria, calvarial and pulmonary hypoplasia, IUGR, and neonatal anuric renal failure, leading to death of the fetus. ARB use in pregnancy has also been associated with fetal demise.
ACE inhibitor use and exposure in the first trimester is controversial for many physicians and requires counselling prepregnancy regarding the risks and benefits of this treatment up to the first trimester, as well as the need for vigilance in stopping ACE inhibitors before the second trimester.
In 2006, a report linked first trimester exposure to ACE inhibitors with a greater incidence of malformations of the CV and central nervous systems. Since this time, other reports, including a meta-analysis, have emerged describing an increase in cardiac malformations in fetuses exposed to all classes of antihypertensive drugs. As such, current evidence does not suggest that ACE inhibitors in the first trimester are associated with a greater risk of fetal malformations than any other antihypertensives, and women in whom ACE inhibitors are of distinct benefit (e.g., diabetic nephropathy) should be counselled prepregnancy regarding the risks and benefits of this treatment up to the first trimester, as well as the need for vigilance in stopping ACE inhibitors before the second trimester. However, given the controversy and potential for risk, ACE inhibitor exposure in first trimester must be counselled and managed carefully, and in some cases where adherence to advice may be unreliable, switching to alternate agents before conception may be advisable.
Clinical Features and Management of Preeclampsia
Preeclampsia is characterized by the development of hypertension in association with new-onset proteinuria, after 20 weeks gestation. It is recognized that not all women with preeclampsia will have proteinuria; therefore, additional signs and symptoms of organ dysfunction are sufficient to make the diagnosis. These newly recognized diagnostic criteria include: neurological symptoms (headaches, abnormal vision, altered mental status, etc), pulmonary edema, hepatocellular injury (serum transaminase levels ≥ 2 times normal), thrombocytopenia (<100,000 platelets/mm 3 ), and renal insufficiency (creatinine > 1.1mg/dL or doubling). Edema has been abandoned as a marker of preeclampsia, because it is present in many normal pregnant women and lacks specificity. Nonproteinuric preeclampsia is associated with better outcomes than proteinuric preeclampsia but worse outcomes than gestational hypertension.
The most recent ACOG guidelines and the International Society for the study of Hypertension in Pregnancy (ISSHP) guidelines have set 300 mg of urinary protein in a 24-hour collection or a urine protein/creatinine ratio of 0.3 in a spot sample as a cutoff value to diagnose proteinuria. Although protein to creatinine ratios determined on spot urines are considered to be adequate for quantification of proteinuria, some obstetricians remain reluctant to abandon 24-hour urine collections. Proteinuria should be quantified in all patients suspected of having preeclampsia. If quantitative assays are not available, then at least 1+ proteinuria on dipstick testing is considered sufficient for a diagnosis.
The recent ACOG has recommended that the term “mild” preeclampsia be abandoned because preeclampsia can always lead to a rapidly deteriorating clinical status. All women with preeclampsia should be continuously evaluated for signs of severe features of preeclampsia. These severe features include the signs/symptoms listed above in addition to BP 160/110 or higher mm Hg (measured at least twice within 4 hours). The HELLP syndrome is considered to be a manifestation of severe preeclampsia. The magnitude of proteinuria has not been shown to correlate with adverse maternal or perinatal outcomes, and thus, is probably not a reliable indicator of the severity of preeclampsia.
Risk Factors for Preeclampsia
Women at an increased risk for preeclampsia include those with chronic hypertension especially secondary forms of hypertension (renovascular hypertension, pheochromocytoma, primary aldosteronism), early preeclampsia (before 34 weeks gestation) in a previous pregnancy, diabetes mellitus (DM), obesity, collagen-vascular disease, chronic kidney disease, a multifetal pregnancy, and women who themselves are the product of a pregnancy complicated by preeclampsia ( Box 39.1 ). Recommended tests to discriminate preeclampsia from chronic or gestational hypertension later in pregnancy include hematocrit/hemoglobin, platelet count, serum creatinine and uric acid, and liver function tests. If qualitative dipstick proteinuria is documented, then protein quantification should be performed. We recommend obtaining baseline laboratory evaluation early in gestation in women with any of these risk factors.
