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Update on the Use of Antihypertensive Drugs in Pregnancy

2008; Lippincott Williams & Wilkins; Volume: 51; Issue: 4 Linguagem: Inglês

10.1161/hypertensionaha.106.075895

1524-4563

Tiina Podymow, Phyllis August,

Pregnancy and Medication Impact

HomeHypertensionVol. 51, No. 4Update on the Use of Antihypertensive Drugs in Pregnancy Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBUpdate on the Use of Antihypertensive Drugs in Pregnancy Tiina Podymow and Phyllis August Tiina PodymowTiina Podymow From the Division of Nephrology (T.P.), McGill University Health Center, Royal Victoria Hospital, Montreal, Quebec, Canada; and the Division of Nephrology and Hypertension (P.A.), Weill Medical College of Cornell University, New York, NY. and Phyllis AugustPhyllis August From the Division of Nephrology (T.P.), McGill University Health Center, Royal Victoria Hospital, Montreal, Quebec, Canada; and the Division of Nephrology and Hypertension (P.A.), Weill Medical College of Cornell University, New York, NY. Originally published7 Feb 2008https://doi.org/10.1161/HYPERTENSIONAHA.106.075895Hypertension. 2008;51:960–969Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: February 7, 2008: Previous Version 1 As the most common medical disorder of pregnancy, hypertension is reported to complicate 1 in 10 pregnancies1,2 and affects an estimated 240 000 women in the United States each year.3 Antihypertensive treatment rationale in this group represents a departure from the nonpregnant adult Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines.4 First, during pregnancy, the priority regarding hypertension is in making the correct diagnosis, with the emphasis on distinguishing preexisting (chronic) from pregnancy induced (gestational hypertension and the syndrome of preeclampsia). Second, much of the obstetric literature distinguishes blood pressure (BP) levels as either mild (140 to 159/90 to 109 mm Hg) or severe (≥160/110 mm Hg), rather than as stages (as in Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; Table 1). Third, in contrast to hypertension guidelines in adults, which emphasize the importance of systolic BP, much of the obstetric literature focuses on diastolic rather than systolic BP, in part because of the lack of clinical trials to support one approach versus another. The focus of treatment is the 9 months of pregnancy, during which untreated mild-to-moderate hypertension is unlikely to lead to unfavorable long-term maternal outcomes. In this setting, antihypertensive agents are mainly used to prevent and treat severe hypertension; to prolong pregnancy for as long as safely possible, thereby maximizing the gestational age of the infant; and to minimize fetal exposure to medications that may have adverse effects. During pregnancy, the challenge is in deciding when to use antihypertensive medications and what level of BP to target. The choice of antihypertensive agents is less complex, because only a small proportion of currently available drugs have been adequately evaluated in pregnant women, and many others are contraindicated. Appropriate use of antihypertensive drugs in specific pregnancy-associated hypertensive disorders, including therapeutic BP goals and criteria for selecting specific antihypertensive drugs, are discussed in this review. Table 1. BP Classification: JNC-7 vs NHBPEPJNC-7 BP Classification (Nonpregnant), mm HgNHBPEP BP Classification (Pregnant), mm HgJNC-7 indicates the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure4; NHBPEP, National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy.1NormalNormal/acceptable in pregnancySBP≤120 and DBP≤80SBP≤140 and DBP≤90PrehypertensionSBP 120 to 139 or DBP 80 to 89Stage 1 hypertensionMild hypertensionSBP 140 to 159 or DBP 90 to 99SBP 140 to 150 or DBP 90 to 109Stage 2 hypertensionSevere hypertensionSBP 160 to 179 or DBP 100 to 110≥160 systolic or ≥110 diastolicStage 3 hypertensionSBP 180 to 209 or DBP 110 to 119Principles of Treatment of Specific Hypertensive DisordersThere are 4 major hypertensive disorders in pregnancy, each with unique pathophysiologic features that have implications for antihypertensive therapy, as described below.Chronic hypertension, defined as BP >140/90 mm Hg either predating pregnancy or developing before 20 weeks' gestation, complicates ≈3% of pregnancies. Because the cause is largely essential hypertension, it is more frequent in African American patients and women who are of advanced maternal age or who are obese. Women of childbearing age with stage 1 essential hypertension (Table 1) who are free of target organ damage and are in good health have an excellent prognosis for pregnancy. Although at increased risk for superimposed preeclampsia (see below), many will experience a physiological lowering of BP during pregnancy and a reduction in the requirement for antihypertensive medication. The goal of treatment is to maintain BP at a level that minimizes maternal cardiovascular and cerebrovascular risk. Prevention of preeclampsia is desirable; however, current evidence has not shown that either specific BP targets in pregnancy or specific antihypertensive agents modify the risk of superimposed preeclampsia in women with preexisting hypertension.5Preeclampsia-eclampsia is a syndrome that manifests clinically as new-onset hypertension in later pregnancy (any time after 20 weeks, but usually closer to term), with associated proteinuria: 1+ on dipstick and, officially, ≥300 mg per 24-hour urine collection. This syndrome occurs in 5% to 8% of all pregnancies and is thought to be a consequence of abnormalities in the maternal vessels supplying the placenta, leading to poor placental perfusion and release of factors6,7 causing widespread endothelial dysfunction with multiorgan system clinical features, such as hypertension, proteinuria, and cerebral (edema, occipital headaches, or seizures) and hepatic dysfunction (extension to hemolysis elevation of liver enzymes, low platelets).6 As currently understood, the hypertension of preeclampsia is secondary to placental underperfusion, thus, lowering systemic BP is not believed to reverse the primary pathogenic process, and antihypertensive medication has never been demonstrated to "cure" or reverse preeclampsia. Nevertheless, because preeclampsia may develop suddenly in young, previously normotensive women, prevention of cardiovascular and cerebrovascular consequences of severe and rapid elevations of BP is an important goal of clinical management, often requiring judicious use of antihypertensive medication.Superimposed preeclampsia complicates 25% of pregnancies in women with chronic hypertension, a much higher risk than that observed in the general population.8 Principles of management are similar to those outlined above for preeclampsia, although women with preexisting hypertension and superimposed preeclampsia may be more likely to develop severe hypertension requiring multiple antihypertensive medications.Gestational hypertension occurs in ≈6% of pregnancies and is hypertension developing in the latter half of pregnancy not associated with the systemic features of preeclampsia (eg, proteinuria). The precise diagnosis is frequently made in hindsight; if laboratory tests remain normal and BP decreases postpartum, then the diagnosis is gestational hypertension (formerly called "transient hypertension" in previous texts and guidelines). Women with gestational hypertension should be considered to be at risk for preeclampsia, which may develop at any time, including the first postpartum week. Approximately 15% to 45% of women initially diagnosed with gestational hypertension will develop preeclampsia, and this is more likely with earlier presentation, previous miscarriage, and previous hypertensive pregnancy, as well as higher BP.9,10 As in women with chronic hypertension, antihypertensive medications should be prescribed with the goal of preventing maternal consequences of severe hypertension, because there is no evidence that targeted BP control prevents preeclampsia.Occasionally, women with apparent gestational hypertension remain hypertensive after delivery. These women most likely have pre-existing chronic hypertension, which was masked in early pregnancy by physiological vasodilation. The natural history of hypertension in the postpartum period and the maximum time to normalization (beyond which chronic hypertension should be diagnosed) are not known. In general, hypertension >140/90 mm Hg persisting beyond 3 months postpartum is diagnosed as chronic hypertension. This is further discussed in a later section.Although all 4 types of hypertension in pregnancy may lead to maternal and perinatal complications, preeclampsia (regardless of BP level) and severe hypertension (regardless of type) are those associated with the highest maternal and perinatal risks. The main risks to the mother are placental abruption, accelerated hypertension leading to hospitalization, and target organ damage, such as cerebral vascular catastrophe.1 Fetal risks include growth restriction and prematurity because of worsening of maternal disease necessitating early delivery.11Principles for Treatment of Mild-to-Moderate Hypertension in PregnancyThe benefits of antihypertensive therapy for mild-to-moderately elevated BP in pregnancy (≤160/110 mm Hg), either chronic or pregnancy induced, have not been demonstrated in clinical trials. Recent reviews, including a Cochrane meta-analysis, concluded that there are insufficient data to determine the benefits and risks of antihypertensive therapy for mild-to-moderate hypertension (defined as 140 to 169 mm Hg systolic BP and 90 to 109 mm Hg diastolic BP).5,12–15 Of note, with antihypertensive treatment, there seems to be less risk of developing severe hypertension (risk ratio: 0.50, with a number needed to treat of 10) but no difference in outcomes of preeclampsia, neonatal death, preterm birth, and small-for-gestational-age babies with treatment.5International guidelines for the treatment of hypertension in pregnancy vary with respect to thresholds for starting treatment and targeted BP goals, but all are higher than the Joint National Committee guidelines for treatment of (nonobstetric) hypertension. Therapy is recommended in the United States for a BP of ≥160/105 mm Hg1 with no set treatment target; in Canada, therapy is considered at ≥140/90 mm Hg targeting diastolic pressure to 80 to 90 mm Hg,16 and in Australia, elevations ≥160/90 mm Hg are treated to a target of ≥110 systolic.17 A recent retrospective review of 28 patients who suffered stroke in the setting of preeclampsia demonstrated that the cause of stroke was usually arterial hemorrhage, that the average BP before stroke was 159 to 198 mm Hg systolic and 81 to 133 mm Hg diastolic, and that 54% of women died.18 Of note, systolic hypertension (155 to 160 mm Hg) was more prevalent than diastolic hypertension (most women did not reach a diastolic BP of 110 mm Hg) in women who suffered strokes. This case series underscores the need for clinical trials and evidence-based guidelines for antihypertensive treatment in pregnant women. Our practice is to initiate treatment when BP is ≥150 systolic and 90 to 100 mm Hg diastolic.When the diagnosis is preeclampsia, the gestational age, as well as the level of BP, influences the use of antihypertensive therapy. At term, women with preeclampsia are likely to be delivered, treatment of hypertension (unless severe) can be delayed, and BP can be reevaluated postpartum. If preeclampsia develops remote from term, and expectant management is undertaken, treatment of severe hypertension is initiated, and BP can usually be safely lowered to 140/90 mm Hg with oral medications as described below. It should be emphasized that there are no studies addressing safe BP treatment targets for pregnant women, and guidelines and reviews generally recommend treating to BP levels that are likely to be protective against acute adverse cerebrovascular or cardiovascular events, which is usually in the range of 140 to 155/90 to 105 mm Hg.19 When antihypertensive therapy is used in women with preeclampsia, fetal monitoring is helpful to recognize any signs of fetal distress that might be attributable to reduced placental perfusion. Indeed, temporizing management of early onset preeclampsia ( 160/110 mm Hg, requires treatment, because these women are at an increased risk of intracerebral hemorrhage, and that treatment decreases the risk of maternal death.1,22 Those with hypertensive encephalopathy, hemorrhage, or eclampsia require treatment with parenteral agents to lower mean arterial pressure (2/3 diastolic +1/3 systolic BP) by 25% over minutes to hours and then to further lower BP to 160/100 mm Hg over subsequent hours.1 In treating severe hypertension, it is important to avoid hypotension, because the degree to which placental blood flow is autoregulated is not established, and aggressive lowering may cause fetal distress. In women with preeclampsia, consideration should be given to initiating agents for treatment of acute severe hypertension at lower doses, because these patients may be intravascularly volume depleted and may be at increased risk for hypotension. Principles of treatment are outlined in Table 3; of note, a recent meta-analysis of 24 trials (2949 women) in which different antihypertensive drugs were compared for the treatment of severe hypertension in pregnancy concluded that there is insufficient data to favor one agent over another,23 although others have concluded that agents other than parenteral hydralazine (eg, parenteral labetalol or oral nifedipine) are preferable because of reduced maternal and fetal adverse effects.24Table 3. Drugs for Urgent Control of Severe Hypertension in PregnancyDrug (FDA Risk*)Dose and RouteConcerns or Comments†Drugs indicated for acute elevation of diastolic BP≥105 mm Hg; the goal is gradual reduction to 90 to 100 mm Hg. NHBPEP indicates National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy; FDA, Food and Drug Administration.*Food and Drug Administration classification, C indicates that either studies in animals have revealed adverse effects on the fetus (teratogenic, embryocidal, or other) and/or there are no controlled studies in women or studies in women and animals are not available. Drugs should only be given if the potential benefits justify the potential risk to the fetus.†Adverse effects for all of the agents, except as noted, may include headache flushing, nausea, and tachycardia (primarily because of precipitous hypotension and reflex sympathetic activation).‡We would classify in category D: there is positive evidence of human fetal risk, but the benefits of the use in pregnant women may be acceptable despite the risk (eg, if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs can not be used or are ineffective).Labetalol (C)10 to 20 mg IV, then 20 to 80 mg every 20 to 30 minutes, maximum of 300 mg; for infusion: 1 to 2 mg/minBecause of a lower incidence of maternal hypotension and other adverse effects, its use now supplants that of hydralazine; avoid in women with asthma or congestive heart failureHydralazine (C)5 mg, IV or IM, then 5 to 10 mg every 20 to 40 minutes; once BP controlled repeat every 3 hours; for infusion: 0.5 to 10.0 mg/h; if no success with 20 mg IV or 30 mg IM, consider another drugA drug of choice according to NHBEP; long experience of safety and efficacyNifedipine (C)Tablets recommended only: 10 to 30 mg PO, repeat in 45 minutes if neededWe prefer long-acting preparations; although obstetric experience with short acting has been favorable, it is not approved by the FDA for management of hypertensionDiazoxide (C)30 to 50 mg IV every 5 to 15 minutesUse is waning; may arrest labor; causes hyperglycemiaRelatively contraindicated nitroprusside (C)‡Constant infusion of 0.25 to 5.00 μg/kg per minutePossible cyanide toxicity if used for >4 hours; agent of last resortChoice of Antihypertensive Drug for Use in PregnancyThe Food and Drug Administration reviews human and animal data to assign letter grades corresponding with risk of fetal exposure in pregnancy. Most antihypertensive agents used in pregnancy are designated as "category C," which states that human studies are lacking, animal studies are either positive for fetal risk or are lacking, and the drug should be given only if potential benefits justify potential risks to the fetus.25 This category cannot be interpreted as no evidence of risk and is so broad to preclude usefulness in practice, leading some groups to suggest that the Food and Drug Administration classification be abandoned.26,27 Information is, thus, based on clinical cases, small studies, and meta-analyses.Sympathetic Nervous System InhibitionMethyldopa remains one of the most widely used drugs for the treatment of hypertension in pregnancy. It is a centrally acting α2-adrenergic agonist prodrug, which is metabolized to α-methyl norepinephrine and then replaces norepinephrine in the neurosecretory vesicles of adrenergic nerve terminals. BP control is gradual, over 6 to 8 hours, because of the indirect mechanism of action. It is not thought to be teratogenic based on limited data and a 40-year history of use in pregnancy. It has been assessed in a number of prospective trials in pregnant women compared with placebo28–30 or with alternative antihypertensive agents.30–33 Treatment with methyldopa has been reported to prevent subsequent progression to severe hypertension in pregnancy34 and does not seem to have adverse effects on uteroplacental or fetal hemodynamics35 or on fetal well being.29 One placebo-controlled trial (>200 women with diastolic BP >90 mm Hg at entry) noted fewer midpregnancy losses in patients randomly assigned to methyldopa,28 but this observation was not confirmed in a more recent trial of a similar size.29 Importantly, birth weight, neonatal complications, and development during the first year were similar in children exposed to methyldopa as in the placebo group.36,37 In a follow-up study of offspring who were exposed to methyldopa in utero, at 7.5 years of age, the children exhibited intelligence and neurocognitive development similar to control subjects.38Adverse effects are consequences of central α2-agonism or decreased peripheral sympathetic tone. These drugs act at sites in the brain stem to decrease mental alertness and impair sleep, leading to a sense of fatigue or depression in some patients. Frequently, decreased salivation, leading to xerostomia, is experienced. Methyldopa can also cause elevated liver enzymes in 5%; hepatitis and hepatic necrosis have also been reported.39 Some patients will develop a positive antinuclear antigen or antiglobulin (Coombs') test with chronic use, and this is occasionally associated with clinical hemolytic anemia. In these cases, medications from other classes are substituted.Clonidine, a selective α2-agonist, acts similarly and is comparable to methyldopa with respect to safety and efficacy,40 but of some concern is a small controlled follow-up study of 22 neonates that reported an excess of sleep disturbance in clonidine-exposed infants.41 In pregnancy, it is mainly used as a third-line agent for multidrug control of refractory hypertension.Peripherally Acting Adrenergic Receptor Antagonistsβ-Blockers have been used extensively in pregnancy. Although several randomized trials comparing β-blockers with either placebo or other agents have been conducted,31,32,42,43 there are still some unresolved issues regarding their use in pregnancy, largely a result of a few small studies that suggest an association with lower birth weight infants. None of the β-blockers have been associated with teratogenicity. In meta-analysis and Cochrane review,44 individual agents were not distinguishable in their perinatal effects with the exception of atenolol, which in 1 small study was started at 12 to 24 weeks' gestation and resulted in clinically significant fetal growth restriction and decreased placental weight compared with placebo.45 This observation was supported in a subsequent retrospective review comparing atenolol with alternative therapies.46 Given differences in β-blockers with respect to lipid solubility and receptor specificity, the potential for clinically relevant differences between agents exists but has not been investigated in pregnancy. Oral β-blockade had been associated with nonclinically significant neonatal bradycardia,14,47 although in a systematic review of trials, labetalol does not (along with oral methyldopa, nifedipine, or hydralazine) seem to cause neonatal heart rate effects.48 Parenteral therapy has been found to increase the risk of neonatal bradycardia, requiring intervention in 1 of 6 newborns.14 Further reassurance is derived from a 1-year postpartum follow-up study, which showed normal development of infants exposed to atenolol in utero.49 Maternal outcomes are improved with the use of β-blockers, with effective control of maternal BP, decreased incidence of severe hypertension, and decreased rate of preterm admission to hospital14; they have been found in a recent Cochrane analysis to be more effective in lowering BP compared with methyldopa in 10 trials.5Labetalol, a nonselective β-blocker with vascular α1-receptor blocking capabilities, has gained wide acceptance in pregnancy. When administered orally to women with chronic hypertension, it seems as safe29,33,50,51 and effective as methyldopa, although neonatal hypoglycemia with higher doses has been reported.52 Of some concern, 1 placebo controlled study reported an association with fetal growth restriction in the management of preeclampsia remote from term.51 Parenterally it is used to treat severe hypertension, and because of a lower incidence of maternal hypotension and other adverse effects, its use now supplants that of hydralazine.24Adverse effects may be predicted as consequences of β-receptor blockade. Fatigue, lethargy, exercise intolerance (because of β2-blocking effects in skeletal muscle vasculature), peripheral vasoconstriction, sleep disturbance (with use of more lipid-soluble drugs), and bronchoconstriction may be seen; however, discontinuation because of adverse effects is uncommon.5Peripherally acting α-adrenergic antagonists are second-line antihypertensive drugs in nonpregnant adults. These are indicated during pregnancy in the management of hypertension because of suspected pheochromocytoma, and both prazosin and phenoxybenzamine have been used, with β-blockers used as adjunctive agents after α-blockade is accomplished.53,54 Because there is but limited experience with these agents in pregnancy, their routine use cannot be advocated.Calcium Channel AntagonistsCalcium channel antagonists have been used to treat chronic hypertension, mild preeclampsia presenting late in gestation, and urgent hypertension associated with preeclampsia. Orally administered nifedipine and verapamil do not seem to pose teratogenic risks to fetuses exposed in the first trimester.55 Most investigators have focused on the use of nifedipine, although there are reports of nicardipine,56,57 isradipine,58 felodipine,59 and verapamil.60 Although used in pregnancy, the dihydropyridine amlodipine is yet unstudied in this population. Maternal adverse effects of the calcium channel blockers include tachycardia, palpitations, peripheral edema, headaches, and facial flushing.61 Nifedipine does not seem to cause a detectable decrease in uterine blood flow.62,63 Short-acting dihydropyridine calcium antagonists, particularly when administered sublingually, are now not recommended for the treatment of hypertension in nonpregnant patients because of reports of myocardial infarction and death in hypertensive patients with coronary artery disease.64 Administration of short-acting nifedipine capsules has been, in case reports, associated with maternal hypotension and fetal distress.65,66 If rapid BP control is desired, then we recommend using parenteral labetalol or hydralazine until the desired target is achieved. One study has shown efficacy and safety of long-acting oral nifedipine in pregnant patients with severe hypertension in pregnancy,67 and given possible untoward fetal effects of short-acting sublingual nifedipine,65,66 we also advocate use of the long-acting preparation.A concern with the use of calcium antagonists for BP control in preeclampsia has been the concomitant use of magnesium sulfate to prevent seizures; drug interactions between nifedipine and magnesium sulfate were reported to cause neuromuscular blockade, myocardial depression, or circulatory collapse in some cases.68–70 In practice21,71,72 and in a recent evaluation,73 these medications are commonly used together without increased risk.DiureticsDiuretics are commonly prescribed in essential hypertension before conception and, given their apparent safety, the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy concluded that they may be continued through gestation (with an attempt made to lower the dose) or used in combination with other agents, especially for women deemed likely to have salt-sensitive hypertension.1 Older anecdotal studies suggested that diuretics might prevent preeclampsia, a finding that was supported by a meta-analysis (published in 1985) of 9 randomized trials involving >7000 subjects.74 Although volume contraction might be expected to limit fetal growth, outcome data have not supported these concerns.74 However, mild volume contraction with diuretic therapy may lead to hyperuricemia and in so doing invalidate serum uric acid levels as a laboratory marker in the diagnosis of superimposed preeclampsia.Hydrochlorothia