Antihypertensive Drugs in

Tiina Podymow, MD, FRCPC,* Phyllis August, MD, MPH†

Summary: Blood pressure targets and medications that are safe differ in pregnant women compared with nonpregnant individuals. The principles of treatment for mild, moderate, and severe in pregnancy, chronic versus gestational versus preeclampsia, and women hypertensive at term versus remote from term are reviewed. The choice of antihy- pertensive drugs also is discussed; methyldopa, labetalol, and nifedipine, among others, appear safe for use in pregnancy, whereas angiotensin converting enzyme inhibitors and angiotensin receptor blockers should be avoided. The management of increased blood pressure in the postpartum period, and agents to use in lactation, are also discussed. Semin Nephrol 31:70-85 © 2011 Elsevier Inc. All rights reserved. Keywords: Hypertension, pregnancy, antihypertensive drugs, postpartum, lactation

ypertension, the most common medical months of pregnancy, a time frame that permits disorder of pregnancy, is reported to the trade-off of slightly higher blood pressures Hcomplicate 1 in 10 gestations,1,2 and af- than targeted in nonpregnant individuals to min- fects an estimated 240,000 women in the imize fetal exposure to antihypertensive medica- United States each year.3 The principles of an- tions. In this setting, antihypertensive medica- tihypertensive treatment in pregnancy represents tions are mainly used to prevent or treat severe a departure from the nonpregnant adult (7th Re- hypertension, to prolong pregnancy for as long as port of the Joint National Committee on Preven- safely possible thereby maximizing the gestational tion, Detection, Evaluation, and Treatment of age of the infant, and to minimize fetal exposure High Blood Pressure [JNC-7]) guidelines.4 First, to medications that may have adverse effects. Dur- during pregnancy the priority is to distinguish ing pregnancy, the challenge is in deciding when pre-existing (chronic) from hypertension specific to use antihypertensive medications, and what to pregnancy (gestational hypertension and pre- level of blood pressure to target. The choice of eclampsia). Second, much of the obstetric litera- antihypertensive agents is less complex because ture categorizes blood pressure levels as either only a small proportion of currently available mild (140-159/90-109 mm Hg) or severe (Ն160/ drugs have been evaluated adequately in pregnant 110 mm Hg), rather than by stages (as in JNC-7) women and many are contraindicated; some (Table 1). Third, in contrast to hypertension carry Food and Drug Administration (FDA) classi- guidelines in adults, which emphasize the impor- fications that suggest or demand their avoidance tance of systolic blood pressure, much of the in pregnancy (classes D and X). Appropriate use obstetric literature focuses on diastolic blood of antihypertensive drugs in specific pregnancy- pressure, in part because of a lack of clinical trials associated hypertensive disorders, including ther- to support one approach versus another. Finally, apeutic blood pressure goals and criteria for se- the focus of treatment is primarily limited to the 9 lecting specific antihypertensive drugs, are discussed in this review.

*Division of Nephrology, McGill University Health Center, Royal Victoria Hospital, Montreal Quebec Canada. TREATMENT OF †Division of Nephrology and Hypertension, Weill Medical College of Cornell University, New York, NY. SPECIFIC HYPERTENSIVE DISORDERS Address reprint requests to Tiina Podymow, MD, FRCPC, Division of Ne- phrology, McGill University Health Center, Royal Victoria Hospital, 687 There are four major hypertensive disorders in Pine Ave W, Ross 2.38, Montreal, Quebec, Canada H3A 1A1. E-mail: pregnancy, each with unique pathophysiologic [email protected] 0270-9295/ - see front matter features that have implications for antihyper- © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2010.10.007 tensive therapy:

70 Seminars in Nephrology, Vol 31, No 1, January 2011, pp 70-85 Antihypertensive drugs in pregnancy 71

Table 1. Blood Pressure Classification: JNC-7 Compared With NHBPEP JNC-7 Blood Pressure Classification NHBPEP Blood Pressure (Nonpregnant), mm Hg Classification (Pregnant), mm Hg Normal: SBP Յ120 DBP Յ80 Normal/acceptable in pregnancy: SBP Յ140 and DBP Յ90 Prehypertension: SBP 120-139 or DBP 80-89 — Stage 1 hypertension: SBP 140–159 or DBP 90–99 Mild hypertension: SBP 140-150 or DBP 90-109 Stage 2 hypertension: SBP 160-179 or DBP 100-110 Severe hypertension: Ն160 systolic or Ն110 diastolic Stage 3 hypertension: SBP 180-209 or DBP 110-119 — JNC-7, The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.4 NHBPEP, National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy.1

Chronic Hypertension term), with associated proteinuria: 1ϩ on dipstick Chronic hypertension, defined as blood pres- and by definition at least 300 mg/24-hour urine. sure (BP) of 140/90 mm Hg or greater either This syndrome occurs in 5% to 8% of all pregnan- predating pregnancy or developing earlier than cies, and is thought to be a consequence of ab- 20 weeks’ gestation, complicates approxi- normalities in the maternal vessels supplying the , leading to poor placental perfusion and mately 3% of . The cause is largely 6,7 essential hypertension, which is more frequent release of factors. This leads to widespread en- in African American patients and women who dothelial dysfunction with multi-organ system are of advanced maternal age, or who are clinical features, such as hypertension, protein- obese. Women of childbearing age with stage 1 uria, and cerebral (edema, occipital headaches, (mild) essential hypertension (Table 1) who are seizures) and hepatic dysfunction (extension to free of target organ damage and are in good hemolysis elevation of liver enzymes, low plate- 6 health have an excellent prognosis for preg- lets). As currently understood, the hypertension nancy. Although at increased risk for superim- of preeclampsia is a consequence of placental posed preeclampsia (see later), many will natu- underperfusion, thus lowering systemic blood rally experience a physiologic lowering of pressure is not believed to reverse the primary blood pressure during pregnancy, and a reduc- pathogenic process, and antihypertensive medi- tion in the requirement for any previously pre- cation has never been shown to cure or reverse scribed antihypertensive medication. The goal preeclampsia. Nevertheless, control of hyperten- of treatment is to maintain blood pressure at a sion may allow for expectant management of pre- level that minimizes maternal cardiovascular eclampsia, prolonging pregnancy remote from and cerebrovascular risk. Prevention of pre- term. As well, in women with preeclampsia-ec- eclampsia is desirable, however, current evi- lampsia, intracerebral hemorrhage remains the 8 dence has not shown that either specific blood most common cause of death, so control of se- pressure targets in pregnancy or specific anti- vere and rapid increases of blood pressure is the hypertensive agents modify the risk of superim- main goal of clinical management, often requiring posed preeclampsia in women with pre-exist- the use of antihypertensive medication. ing hypertension.5 Superimposed Preeclampsia Preeclampsia-Eclampsia Superimposed preeclampsia complicates ap- Preeclampsia-eclampsia is a syndrome character- proximately 25% of pregnancies in women ized by new-onset hypertension in later preg- with chronic hypertension, five times the rate nancy (usually after 20 weeks, but often closer to observed in the general population.9 At times it 72 T. Podymow and P. August may be difficult to distinguish exacerbation of sisting beyond 3 months postpartum. This is chronic hypertension from superimposed pre- discussed further in a later section. eclampsia, but it is usually prudent to err to- Although all four types of hypertension in ward treating the latter. Principles of manage- pregnancy may lead to maternal and perinatal ment are similar to those outlined earlier for complications, preeclampsia (regardless of preeclampsia, although women with pre-exist- blood pressure level) and severe hyperten- ing hypertension and superimposed preeclamp- sion (regardless of type) are those associated sia may be more likely to develop severe hyper- with the highest maternal and perinatal risks. tension, requiring multiple antihypertensive The mothers usually do well, but the main medications. risks are , accelerated hy- pertension leading to hospitalization, and tar- get organ damage, such as cerebral vascular Gestational Hypertension catastrophe.1 The fetus is far more vulnera- Gestational hypertension, formerly called tran- ble; risks include growth restriction and pre- sient hypertension in previous texts and guide- maturity owing to worsening of maternal dis- lines, occurs in approximately 6% of pregnan- ease necessitating early delivery.12 cies and is defined as de novo hypertension developing in the latter half of pregnancy not MILD TO MODERATE associated with the systemic features of pre- HYPERTENSION IN PREGNANCY eclampsia (eg, proteinuria). The precise diagno- The benefits of antihypertensive therapy for sis frequently is made in hindsight; if laboratory mild to moderately increased blood pressure tests remain normal, and blood pressure de- in pregnancy (Յ160/110 mm Hg), either creases postpartum, then the diagnosis was ges- chronic or de novo, have not been shown in tational hypertension rather than preeclampsia clinical trials. Recent reviews, including a Co- or chronic hypertension. Women with gesta- chrane meta-analysis, concluded that there tional hypertension should be considered to be are insufficient data to determine the benefits at risk for preeclampsia because approximately and risks of antihypertensive therapy for mild 15% to 45% of women initially in the gestational to moderate hypertension (defined as blood hypertension category develop preeclampsia. pressure 140-160 mm Hg systolic or diastolic Progression to preeclampsia is more likely if blood pressure 90–109 mm Hg).5,13-16 Of gestational hypertension appears early, there is note, with antihypertensive treatment, there a history of prior miscarriage or hypertension seems to be less risk of developing severe during a previous pregnancy, as well as in those hypertension (relative risk, 0.50; with a num- 10,11 with higher blood pressure. As in women ber needed to treat of 10) but no difference in with chronic hypertension, antihypertensive outcomes of preeclampsia, neonatal death, medications should be prescribed with the goal , and small for of preventing maternal consequences of severe babies with treatment.5 hypertension because there is no evidence that International guidelines for the treatment of targeted blood pressure control prevents pre- hypertension in pregnancy vary with respect to eclampsia. thresholds for starting treatment and targeted BP Occasionally, women with apparent gesta- goals, but all are higher than the Joint National tional hypertension remain hypertensive after Committee guidelines for treatment of (nonob- delivery. These women most likely have pre- stetric) hypertension. Therapy is recommended existing chronic hypertension that was masked in the United States for a BP of 160/105 mm Hg or in early pregnancy by physiologic vasodilation. greater,1 with no set treatment target; in Canada The natural history of hypertension in the post- for women with no comorbid conditions therapy partum period, and the maximum time to nor- is recommended for blood pressure of 140 to malization (beyond which chronic hyperten- 150/90 mm Hg or greater, targeting diastolic pres- sion should be diagnosed), appears to be sure to 80 to 90 mm Hg17,18 and in those with hypertension of 140/90 mm Hg or greater per- comorbid conditions targeting 130 to 139/80 to Antihypertensive drugs in pregnancy 73

89 mm Hg; and in Australia increases of 160/90 sia (Ͻ34 wk) includes judicious use of antihy- mm Hg or greater are treated to a target of no less pertensive medications, avoiding both high than 110 systolic.19 A retrospective review of 28 (Ͼ160/110 mm Hg) as well as low (Ͻ120/80 patients who suffered stroke in the setting of mm Hg) blood pressures. Although not found preeclampsia (54% died) showed that the cause to be effective by Cochrane and other analyses, of stroke was usually arterial hemorrhage, and the bed rest, and close in-hospital maternal and average blood pressure prestroke was 159 to fetal monitoring, frequently are prescribed. 198/81 to 133 mm Hg.20 In this case series, Control of hypertension and careful monitoring systolic hypertension (155-160 mm Hg) was have been shown to permit postponement of more prevalent than diastolic hypertension (ie, delivery in selected cases for an average of 2 most women did not reach a diastolic BP of 110 weeks, which has been associated with im- mm Hg). This report underscores the need for proved outcomes later in childhood.22 It must clinical trials and evidence-based guidelines for be emphasized that daily assessment of both antihypertensive treatment in pregnant maternal (review of symptoms, BP, and blood women. Our practice is to initiate treatment work) and fetal well-being are necessary in such when blood pressure is 150 systolic or greater cases, and delivery may be necessary if either or 90 to 100 mm Hg diastolic. Other clinicians deteriorate. may wait until diastolic BPs reach 100 mm Hg For women with chronic hypertension and before treating. One should note that in the mild to moderately increased BP before preg- presence of any signs of end-organ damage nancy, it is reasonable to expect that pressures (electrocardiogram or imaging changes suggest- may decrease early in pregnancy, owing to ing cardiac hypertrophy, alterations in the optic physiologic vasodilation, and if there is no fundi, borderline high or frankly abnormal cre- known target organ damage, clinicians can con- atinine levels) the patient’s hypertension is sider discontinuing antihypertensive treatment treated as if she were not pregnant. and monitoring, provided patients are followed When the diagnosis is preeclampsia, the ges- up closely. Therapy then can be initiated if the tational age, as well as the level of BP, influence BP again increases to 140 to 150/90 to 100 mm 23 the use of antihypertensive therapy. At or near Hg. In women with underlying renal dysfunc- term, women with preeclampsia are likely to be tion, it is reasonable to choose a slightly lower 9 delivered. Severe hypertension should always threshold for treatment. There are a wide va- be treated, but the treatment of moderate hy- riety of agents available for use, and orally ad- pertension can be reassessed postpartum. If ministered antihypertensives can be used in preeclampsia develops remote from term, and standard doses in pregnancy (Table 2). First-line expectant management is undertaken, treat- recommended agents for nonsevere hyperten- ment of severe hypertension should be initi- sion are methyldopa and labetalol, with nifedi- ated, and blood pressure lowered to 140/90 pine as second-line, although the latter is now mm Hg with oral medications, as described used quite commonly. later. It should be emphasized that there are no studies addressing safe blood pressure treat- SEVERE HYPERTENSION ment targets for pregnant women, and guide- There is consensus that treatment is indicated lines and reviews generally recommend treat- for severe hypertension in pregnancy, de- ing to blood pressure levels that are likely to be fined as 160/110 mm Hg or greater, to pre- protective against acute adverse cerebrovascu- vent intracerebral hemorrhage and maternal lar or cardiovascular events, which is usually in death.1,24 Those with hypertensive encepha- the range of 135 to 155/85 to 90 mm Hg.18,21 lopathy, hemorrhage, or eclampsia require When antihypertensive therapy is used in treatment with parenteral agents to lower women with preeclampsia, fetal monitoring is mean arterial pressure (two-thirds diastolic ϩ advisable to recognize fetal distress, which one-third systolic blood pressure) by 25% might be attributable to reduced placental per- over minutes to hours, and then to further fusion. Management of early onset preeclamp- lower blood pressure to 160/100 mm Hg over 74 T. Podymow and P. August

Table 2. Drugs for Gestational or Chronic Hypertension in Pregnancy Drug (FDA Risk Classification) Dose (oral) Concerns or Comments Preferred agent 0.5-3.0 g/d in 2-4 divided doses Drug of choice according to NHBPEP methyldopa (B) working group; safety after first trimester well documented, including 7-year follow-up evaluation of offspring Second-line agents* 200-1,200 mg/d in 2-3 divided May be associated with fetal growth Labetalol (C) doses restriction Nifedipine (C) 30-120 mg/d of a slow-release May inhibit labor; little experience preparation with other calcium entry blockers Hydralazine (C) 50-300 mg/d in 2-4 divided Few controlled trials, long doses experience with few adverse events documented; useful in combination with sympatholytic agent; may cause neonatal thrombocytopenia ␤-receptor Depends on specific agent May decrease uteroplacental blood blockers (C) flow; may impair fetal response to hypoxic stress; risk of growth restriction when started in first or second trimester (Atenolol); may be associated with neonatal hypoglycemia at higher doses Hydrochlorothiazide 12.5-25 mg/d Majority of controlled studies in (C)† normotensive pregnant women rather than hypertensive patients; can cause volume contraction and electrolyte disorders; may be useful in combination with methyldopa and vasodilator to mitigate compensatory fluid retention Contraindicated — Leads to fetal loss in animals; human ACE-Is and AT1- use associated with cardiac defects, receptor fetopathy, oligohydramnios, antagonists, growth restriction, and neonatal direct renin anuric renal failure, which may be inhibitors (D)† fatal; direct renin inhibitors—no reports in pregnancy: avoid No antihypertensive agent has been proven safe for use during the first trimester. Drug therapy indicated for uncomplicated chronic hypertension when diastolic BP was 100 mm Hg or greater (Korotkoff V). Treatment at lower levels may be indicated for patients with mellitus, renal disease, or target organ damage. Abbreviation: NHBPEP, National High Blood Pressure Education Program. Modified from reference 113. *We omitted some agents (eg, clonidine, ␣-blockers) because of limited data on use for chronic hypertension in pregnancy. †We would classify in category X.

subsequent hours.1 In treating severe hyper- aggressive lowering may cause fetal distress. tension, it is important to avoid hypotension In women with preeclampsia, treatment of because the degree to which placental blood acute severe hypertension should be initiated flow is autoregulated likely is limited, and at lower than usual doses because these pa- Antihypertensive drugs in pregnancy 75

Table 3. Drugs for Urgent Control of Severe Hypertension in Pregnancy Drug (FDA Risk)* Dose and Route Concerns or Comments† Labetalol (C) 10-20 mg IV, then 20-80 mg Because of a lower incidence of every 20-30 min, maximum, maternal hypotension and 300 mg; for infusion, 1-2 other side effects, its IV use mg/min IV now supplants that of hydralazine; avoid in women with asthma or congestive failure Hydralazine (C) 5 mg, IV or IM, then 5-10 mg A drug of choice according to every 20-40 min; once BP NHBPEP working group; long controlled repeat every 3 h; experience of safety and for infusion, 0.5-10 mg/h; if efficacy no success with 20 mg IV or 30 mg IM, consider another drug Nifedipine (C) Tablets recommended only: We prefer long-acting 10-30 mg oral dose, repeat preparations; although in 45 min if needed obstetric experience with short-acting preparations has been favorable it is not approved by US FDA for management of hypertension Diazoxide (C) 30-50 mg IV every 5-15 min Use is waning; may arrest labor; causes hyperglycemia Relatively contraindicated Constant infusion of 0.25-5 Possible cyanide toxicity if used nitroprusside (C)‡ ␮g/kg/min IV for Ͼ4 h; agent of last resort Indicated for acute increase of diastolic BP of 105 mm Hg or greater; goal is gradual reduction to 90 to 100 mm Hg. Abbreviation: IM, intramuscular; IV, intravenous; NHBPEP, National High Blood Pressure Education Program. Modified from reference 113. *US Food and Drug Administration classification, C indicates that 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 be given only if the potential benefits justify the potential risk to the fetus. †Adverse effects for all agents, except as noted, may include headache flushing, nausea, and tachycardia (primarily owing to precipitous hypotension and reflex sympathetic activation). ‡We would classify in category D: there is positive evidence of human fetal risk, but the benefits of 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 cannot be used or are ineffective).

tients may be intravascularly volume depleted CHOICE OF ANTIHYPERTENSIVE DRUGS and at increased risk for hypotension. Princi- ples of treatment are outlined in Table 3;of The FDA reviews human and animal data to note, a meta-analysis of 24 trials (2,949 assign letter grades corresponding to risk of women) in which different antihypertensive fetal exposure in pregnancy. Most antihyper- drugs were compared for the treatment of tensive agents used in pregnancy are desig- severe hypertension in pregnancy concluded nated as category C, which states that human that there are insufficient data to favor one studies are lacking and animal studies are either agent over another,25 although other studies positive for fetal risk or are lacking, and that the have concluded that agents other than paren- drug should be given only if potential benefits teral hydralazine (eg, parenteral labetalol or justify potential risks to the fetus.27 This cate- oral nifedipine) are preferable owing to re- gory cannot be interpreted as no evidence of duced maternal and fetal adverse effects.26 risk, and is so broad to preclude usefulness in 76 T. Podymow and P. August practice, leading some groups to suggest that pathetic tone. These drugs act at sites in the the FDA classification be abandoned, or at least brainstem to decrease mental alertness and modified so as to be more useful to the clini- impair sleep, leading to a sense of fatigue or cian.28,29 The following information is thus to depression in some patients. Frequently, based on clinical case series, small studies, and decreased salivation leading to xerostomia is meta-analyses. experienced. Methyldopa also can cause liver enzyme increases in 5% of patients; both hep- SYMPATHETIC atitis and hepatic necrosis have been re- NERVOUS SYSTEM INHIBITORS ported.41 Some patients will develop a posi- tive antinuclear antigen, or antiglobulin Methyldopa is still widely used for treatment of (Coombs) test with chronic use, and this oc- hypertension in pregnancy and remains one of casionally is associated with clinical hemo- the only drugs for which a 7.5-year follow-up lytic anemia. In these cases, medications from evaluation of the newborn of treated mothers is other classes are substituted. available. It is a centrally acting ␣ -adrenergic 2 Clonidine (Catapres; Boehringer Ingelheim agonist prodrug, which is metabolized to Pharmaceuticals, Inc, Ridgefield, CT), a selec- ␣-methyl norepinephrine and then replaces tive ␣ -agonist, acts similarly and is comparable norepinephrine in the neurosecretory vesicles 2 with methyldopa with respect to safety and of adrenergic nerve terminals. Blood pressure efficacy,42 but of some concern is a small con- control is gradual, over 6 to 8 hours, owing to trolled follow-up study of 22 neonates that re- the indirect mechanism of action. It is not ported an excess of sleep disturbance in cloni- thought to be teratogenic based on limited data dine-exposed infants.43 In pregnancy, it is and a more than 40-year history of use in preg- mainly used as a third-line agent for multidrug nancy. It has been assessed in a number of control of refractory hypertension. prospective trials in pregnant women, com- pared with placebo30-32 or with alternative an- tihypertensive agents.32-35 Treatment with PERIPHERALLY ACTING methyldopa has been reported to prevent sub- ADRENERGIC-RECEPTOR ANTAGONISTS sequent progression to severe hypertension in ␤-blockers have been used extensively in preg- pregnancy36 and does not appear to have ad- nancy. Although several randomized trials com- verse effects on uteroplacental or fetal hemo- paring ␤-blockers with either placebo or other dynamics37 or on fetal well being.31 One place- agents have been conducted,33,34,44,45 there are bo-controlled trial (Ͼ200 women with diastolic still unresolved issues regarding their use in preg- BP Ն90 mm Hg at entry) noted fewer midpreg- nancy because of a few small studies that sug- nancy losses in patients randomized to methyl- gested an association with lower birth weight dopa30 but this observation was not confirmed infants. None of the ␤-blockers have been associ- in a more recent trial of similar size.31 Impor- ated with teratogenicity. In a meta-analysis and tantly, birth weight, neonatal complications, Cochrane review,46 individual agents were not and development during the first year were distinguishable in their perinatal effects with the similar in children exposed to methyldopa as in exception of atenolol (Tenormin; AstraZeneca the placebo group.38,39 Also in the earlier-noted Pharmaceuticals), which in one small study was follow-up study of offspring who were exposed started at 12 to 24 weeks’ gestation and resulted to methyldopa in utero, at 7.5 years of age, in clinically significant fetal growth restriction intelligence and neurocognitive development and decreased placental weight compared with were similar to controls.40 It is unfortunate that placebo.47 This observation was supported by a this landmark 1993 study did not result in a subsequent retrospective review comparing standard method of evaluation applied to all atenolol with alternative therapies.48 Given dif- antihypertensive drugs prescribed to pregnant ferences in ␤-blockers with respect to lipid sol- women. ubility and receptor specificity, the potential Adverse effects are consequences of cen- for clinically relevant differences between tral ␣2-agonism or decreased peripheral sym- agents exists, but has not been investigated in Antihypertensive drugs in pregnancy 77 pregnancy. Oral ␤-blockade had been associ- prazosin (Minipres; Pfizer Inc, New York, NY) ated with non–clinically significant neonatal and phenoxybenzamine (Dibenzyline; Well- bradycardia15,49; though in a systematic review Spring Pharmaceutical Corp) have been used, of trials, labetalol did not (along with oral meth- with ␤-blockers as adjunctive agents after yldopa, nifedipine, or hydralazine) appear to ␣-blockade is accomplished.55,56 Because there cause neonatal heart rate effects.50 Parenteral is limited experience with these agents in preg- therapy has been found to increase the risk of nancy, their routine use cannot be advocated. neonatal bradycardia, requiring intervention in one of six newborns.15 Further reassurance is CALCIUM-CHANNEL BLOCKERS derived from a 1-year postpartum follow-up Calcium-channel antagonists have been used to study that showed normal development of in- 51 treat chronic hypertension, mild preeclampsia fants exposed to atenolol in utero. presenting late in gestation, and urgent hyper- Maternal outcomes are improved with the tension associated with preeclampsia. Orally ␤ use of -blockers, with effective control of ma- administered nifedipine (Adalat [Bayer Health- ternal blood pressure, decreased incidence of Care Pharmaceuticals, Calgary, Alberta], Procar- severe hypertension, and decreased rate of pre- dia [Pfizer Inc]) and verapamil (Isoptin; Ranb- 15 term admission to the hospital ; they have axy Pharmaceuticals Inc) do not appear to pose been found in a recent Cochrane analysis to be a teratogenic risk to fetuses exposed in the first more effective in lowering blood pressure com- trimester.57 Most investigators have focused on 5 pared with methyldopa in 10 trials. the use of nifedipine, although there are reports Labetalol (Trandate; Prometheus Laborato- of nicardipine (Cardene; EKR Therapeutics, ries, Inc, San Diego, CA), a nonselective Inc),58,59 isradipine,60 felodipine (Plendil [Astra- ␤ ␣ -blocker with vascular 1-receptor blocking Zeneca Pharmaceuticals], Renedil [Sanofi-Aven- capabilities has gained wide acceptance in tis]),61 and verapamil (Isoptin).62 Amlodipine pregnancy. When administered orally to (Norvasc; Pfizer Inc), the dihydropyridine calci- women with chronic hypertension, it appears um-channel blocker widely used for treatment 31,35,52,53 as safe and effective as methyldopa, of hypertension in nonpregnant hypertensive although neonatal hypoglycemia with higher patients, has not been studied extensively in doses has been reported.54 Of some concern, pregnancy. We are only aware of one small case one placebo-controlled study reported an as- series in pregnancy, however, it is commonly sociation with fetal growth restriction in the used in pregnancy and appears safe.63 Maternal management of preeclampsia remote from side effects of the calcium-channel blockers in- term.53 Parenterally it is used to treat severe clude tachycardia, palpitations, peripheral hypertension, and because of a lower inci- edema, headaches, and facial flushing.64 Nifed- dence of maternal hypotension and other side ipine does not appear to cause a detectable effects, many find this drug preferable to hy- decrease in uterine blood flow.65,66 Short-acting dralazine.26 dihydropyridine calcium antagonists, particu- Adverse effects may be predicted as conse- larly when administered sublingually, are now quences of ␤-receptor blockade. Fatigue, leth- not recommended for the treatment of hyper- argy, exercise intolerance (owing to ␤2-blocking tension in nonpregnant patients because of re- effects in skeletal muscle vasculature), peripheral ports of and death in hy- , sleep disturbance (with use of pertensive patients with coronary artery more lipid-soluble drugs), and bronchoconstric- disease.67 Administration of short-acting nifedi- tion may be seen, however, discontinuation ow- pine capsules has been, in case reports, associ- ing to side effects is uncommon.5 ated with maternal hypotension and fetal dis- 68,69 Peripherally acting ␣1-adrenergic antagonists tress. If rapid blood pressure control is are second-line antihypertensive drugs in non- desired, then we recommend using parenteral pregnant adults. These are indicated during labetalol or hydralazine until the desired target is pregnancy in the management of hypertension achieved. One study has shown efficacy and owing to suspected pheochromocytoma; both safety of long-acting oral nifedipine in pregnant 78 T. Podymow and P. August patients with severe hypertension in pregnancy,70 though this was not borne out in an isolated and given possible untoward fetal effects of short- clinical case.78 acting sublingual nifedipine,68,69 we also advocate use of the long-acting preparation. SEROTONIN -RECEPTOR BLOCKERS A concern with the use of calcium antago- 2 nists for BP control in preeclampsia relates to Serotonin-induced vasodilation is mediated by the concomitant use of magnesium sulfate to S1 receptors and subsequent release of prosta- prevent seizures; additive effects between ni- cyclin and nitric oxide. Endothelial dysfunction fedipine and magnesium sulphate were ob- and loss of endothelial S1 receptors allows se- served in a few cases, leading to neuromus- rotonin, whose levels are greatly increased in cular blockade, myocardial depression, or pregnancy, to react only with S2 receptors, re- circulatory collapse.71-73 However, these sulting in vasoconstriction and platelet aggrega- agents are commonly used together in prac- tion. Ketanserin is a selective S2-receptor– tice23,74,75 and a recent evaluation76 provided blocking drug that decreases systolic and evidence that they may be used together diastolic BP in nonpregnant patients with acute without increased risk. or chronic hypertension. Ketanserin has not been found to be teratogenic in animals or Diuretics human beings, and has been studied during pregnancy primarily in Australia and South Af- Diuretics commonly are prescribed in patients rica in small trials, which suggest it may be safe with essential hypertension and, given their ap- and useful in the treatment of chronic hyper- parent safety, the National High Blood Pressure tension in pregnancy, preeclampsia, and hemo- Education Program Working Group on High lysis elevation of liver enzymes, low platelets Blood Pressure in Pregnancy concluded that syndrome.79,80 Ketanserin has not been FDA they may be continued during pregnancy (with approved in the United States. an attempt made to decrease the dose; see later) or used in combination with other agents, especially for women deemed likely to have DIRECT VASODILATORS salt-sensitive hypertension.1 Older anecdotal Hydralazine (Apresoline; Novartis Pharmaceuti- studies suggested that diuretics might prevent cals Corp) selectively relaxes arteriolar smooth preeclampsia, a finding that was supported by a muscle by an as yet unknown mechanism. Its (now discredited) meta-analysis (published in greatest utility is in the urgent control of severe 1985) of nine randomized trials involving more hypertension, or as a third-line agent for multi- than 7,000 subjects.77 Although volume con- drug control of refractory hypertension. It is ef- traction might be expected to limit fetal fective orally, intramuscularly, or intravenously; growth, outcome data have not supported parenteral administration is useful for rapid con- these concerns.77 However, mild volume con- trol of severe hypertension. Adverse effects are traction with diuretic therapy may lead to hy- mostly those caused by excessive vasodilation or peruricemia, and in so doing invalidate serum reflex sympathetic activation, and include head- uric acid levels as a laboratory marker in the ache, nausea, flushing, or palpitations. Chronic diagnosis of superimposed preeclampsia. use can lead, in rare cases, to a pyridoxine-respon- In women already taking, hydrochlorothia- sive polyneuropathy or to immunologic reactions zide may be continued during pregnancy; the including a drug-induced, lupus-like syndrome. use of low doses (12.5-25 mg/d) may minimize Hydralazine has been used in all trimesters of untoward metabolic effects such as impaired pregnancy and data have not shown an associa- glucose tolerance and hypokalemia.23 Tri- tion with teratogenicity, although neonatal throm- amterene and amiloride do not appear to be bocytopenia and lupus have been reported.81 It teratogenic based on a small number of case has been widely used for chronic hypertension in reports.23 Spironolactone is not recommended the second and third trimesters, but its use has because of its antiandrogenic effects noted dur- been supplanted by agents with more favorable ing fetal development in animal models, al- side-effect profiles.82 For acute severe hyperten- Antihypertensive drugs in pregnancy 79 sion later in pregnancy, intravenous hydralazine or oral calcium-channel blockers, this drug is has been associated with more maternal and peri- considered as a last resort. natal adverse effects than intravenous labetalol or oral nifedipine,26 such as maternal hypotension, ANGIOTENSIN CONVERTING cesarean deliveries, placental abruptions, Apgar ENZYME INHIBITORS AND scores less than 7, and oliguria.15 Furthermore, ANGIOTENSIN RECEPTOR ANTAGONISTS common side effects of hydralazine, such as head- Angiotensin converting enzyme inhibitors (ACE-I) ache, nausea, and vomiting, mimic the symptoms and angiotensin-receptor blockers (ARBs) are of deteriorating preeclampsia. Effects on uteropla- both class D drugs according to FDA classifica- cental blood flow are unclear, likely owing to tion, although we approach them as if contrain- variation in the degree of reflex sympathetic acti- dicated, especially in the second or third trimes- vation, and fetal distress may result via a precipi- ters, because of toxicity associated with reduced tous decrease in maternal pressure.83-85 perfusion of the fetal kidneys. Use is associated Isosorbide dinitrate (Isordil; Valeant Pharma- with a fetopathy similar to that observed in Pot- ceuticals International), a nitric oxide donor ter’s syndrome (ie, bilateral renal agenesis) includ- acting primarily on capacitance vessels, has ing renal dysgenesis, oligohydramnios as a result been investigated in a small study of gestational of fetal oliguria, calvarial and pulmonary hyp- hypertensive and preeclamptic pregnant pa- oplasia, intrauterine growth restriction, and tients. It did not affect cerebral perfusion pres- fatal neonatal anuric renal failure.90,91 ARB sure despite significant changes in maternal use in pregnancy also has caused similar fetal blood pressure, thus decreasing the risk for renal abnormalities, as well as fetal demise, and infarction when blood pressure is attributed primarily to renal failure.92-94 decreased.86 First trimester exposure to ACE-I recently Sodium nitroprusside is a direct nitric ox- has been associated with a greater incidence ide donor that nonselectively relaxes both of malformations of the cardiovascular and arteriolar and venular vascular smooth mus- central nervous systems. Of 29,096 pregnan- cle. Administered only by continuous intrave- cies analyzed, 209 were exposed to ACE-I in nous infusion, it is easily titrated because it the first trimester alone, associated with a has a near-immediate onset of action and du- relative risk of congenital malformation of ration of effect of 3 minutes. Nitroprusside 2.71, when compared with no antihyperten- sive medication or other types of antihyper- metabolism releases cyanide, which can tensive medication.95 Whether adverse out- reach toxic levels with high infusion rates; comes are owing to a hemodynamic effect in cyanide is metabolized to thiocyanate, whose the fetus or to specific (nonhemodynamic) own toxicity usually occurs after 24 to 48 requirements for angiotensin II as a fetal hours of infusion unless its excretion is de- growth factor is unknown. A more recent layed owing to renal insufficiency. Nitroprus- study of pregnancies recorded in the Swedish side is seldom used in pregnancy, usually only Birth Registry reported an increase in cardiac in cases of life-threatening refractory hyper- malformations in fetuses exposed to ACE-Is in 87 tension in the moments before delivery. Ad- the first trimester, however, similar risks also verse effects include excessive vasodilation were observed in women who reported tak- and cardioneurogenic (ie, paradoxic brady- ing other antihypertensive drugs, particularly cardia) syncope in volume-depleted pre- ␤-blockers.96 As such, first trimester use of eclamptic women.88 The risk of fetal cyanide ACE-I and ARB medications should be intoxication remains unknown; in one litera- avoided. Because exposure to ACE-Is during ture review of 24 exposed fetuses there did the first trimester cannot be considered safe, not appear to be an association between so- it may be best to counsel women to switch to dium nitroprusside use and fetal demise.89 alternate agents while attempting to con- Given the long experience with hydralazine ceive. However, in those who inadvertently and alternative utility of parenteral labetalol become pregnant while taking ACE-I or ARBs, 80 T. Podymow and P. August

Table 4. Maternal Antihypertensive Medications Usually Compatible With Breastfeeding ACE-I Calcium-Channel Blocker ␤-Blocker Diuretics Other Captopril Diltiazem Labetalol Furosemide Hydralazine Enalapril Nifedipine Nadolol Hydrochlorothiazide Methyldopa Quinapril Verapamil Oxprenolol Spironolactone Minoxidil Propranolol Timolol Diuretics (furosemide, hydrochlorothiazide, spironolactone) may reduce milk production. Metoprolol is classified as compatible with breastfeeding, although it is concentrated in human milk. Acebutolol and atenolol should not be used in nursing mothers. Data from the American Academy of Pediatrics.111

the risk of birth defects increases from 3% to postpartum period often is influenced by breast 7%95; it has not been our practice to recom- feeding,101 but in general the agents commonly mend pregnancy termination. Of note, direct used in the antepartum period may be contin- renin inhibitors might be expected to have ued postpartum (Table 4). similar effects as ACE-Is and ARBs in preg- In select cases of women with severe pre- nancy, however, we are unaware of any re- eclampsia, there appears to be some benefit to ports of their use in pregnancy; they should a brief course of furosemide diuresis in the days be avoided in this setting. postpartum in those patients with hypertension accompanied by symptomatic pulmonary or pe- 102 POSTPARTUM HYPERTENSION ripheral edema. A few case reports have reported that non- In the postpartum period, previously normo- steroidal anti-inflammatory agents may contrib- tensive women have been noted to have an ute to postpartum hypertension,103 and hyper- increase in BP that reaches a maximum on the tensive effects in nonpregnant individuals are fifth postpartum day, and in one study 12% of well documented. Thus, in postpartum patients patients had a diastolic BP exceeding 100 mm who already are hypertensive, nonsteroidal an- 97 Hg. This is thought to be a consequence of ti-inflammatory agents should be used cau- physiologic volume expansion and fluid mobi- tiously, or should perhaps be avoided. lization in the postpartum period. Postpartum there are currently no management guidelines (as also noted in a recent Cochrane analysis98), BREASTFEEDING but Tan and de Swiet99 suggested that antihy- We could locate no well-designed studies as- pertensive drugs should be given if the blood sessing neonatal effects of maternally adminis- pressure exceeds 150 mm Hg systolic or 100 tered antihypertensive drugs delivered via mm Hg diastolic in the first four days postpar- breast milk. The pharmacokinetic principles tum. Medications may be continued until blood that govern drug distribution to milk and ensu- pressure normalizes and then may be stopped. ing exposure to the infant are well estab- This may occur days to several weeks postpar- lished.104,105 Milk, secreted by alveolar cells, is a tum, and home blood pressure monitoring suspension of fat globules in a protein-contain- by the patient may be helpful in this regard. In ing aqueous solution with a pH lower than that the postpartum period, hypertension as a result of maternal plasma. Factors that favor drug pas- of gestational hypertension and preeclampsia sage into milk are a small maternal volume of appears to normalize by 3 months.100 Beyond distribution, low plasma protein binding, high this period, if patients continue to require anti- lipid solubility, and lack of charge at physio- hypertensive agents to maintain a normal blood logic pH. Even when drugs are ingested by pressure, chronic hypertension may be diag- nursing infants, exposure depends on volume nosed. Choice of antihypertensive agent in the ingested, intervals between drug administration Antihypertensive drugs in pregnancy 81 and nursing, oral bioavailability, and the capac- yldopa, labetalol, and nifedipine, in standard ity of the infant to clear the drug.106 Neonatal doses. ACE-Is and angiotensin-receptor block- exposure to methyldopa via nursing is likely ers should be avoided in all trimesters; when low and it generally is considered safe (Table administered in the second and third trimesters 4). Atenolol and metoprolol are concentrated in they are associated with a characteristic fetopa- breast milk, possibly to levels that could affect thy, neonatal renal failure, and death, and thus the infant; by contrast, exposure to labetalol are contraindicated. Cohort data lead to recom- and propranolol appears low.107 Although milk mendations to avoid in the first trimester as concentrations of diuretics are low and consid- well. Finally, control of severe hypertension in ered safe, these agents, by inducing volume pregnancy has been studied in a recent meta- contraction in the mother, can decrease milk analysis, and this suggests that intravenous la- production significantly.108 There are reports of betalol or oral nifedipine are as effective as calcium-channel blocker transfer into breast intravenous hydralazine, with fewer side ef- milk,109 but relative infant doses of nifedipine, fects. verapamil, and diltiazem are low, and all are Many research questions surrounding hyper- safe during breast feeding. Sufficient data exist tension in pregnancy and preeclampsia remain for the safety of three ACE-Is: captopril, enal- unanswered. Preconception management of april, and quinapril; the concentrations are 1% hypertension, the necessity for antihyperten- to 2% of that found in blood, with the infant sive agents, specific drug agents, racial differ- receiving approximately 0.03% of the regular ences, and blood pressure levels for initiation of dose.106,110 Based on these findings the Ameri- therapy and treatment targets all remain to be can Academy of Pediatrics deems these drugs determined. Current guidelines rely only on ev- compatible with breast feeding.111 There are idence from small, largely underpowered trials currently insufficient data on angiotensin II– and expert opinion. Finally, studies of antihy- receptor blockers; varied animal data show de- pertensive medication in pregnancy often eval- tectable milk levels and at this time our recom- uate the effectiveness of a drug without exam- mendation is not to use. ining fetal outcomes associated with harm.112 Future studies must include detailed outcomes CONCLUSIONS of risk and benefit for both the mother and baby. Better surveillance systems to routinely Use of antihypertensive agents in pregnancy for monitor adverse events and the number of control of mild to moderate hypertension or for women exposed to particular agents are re- control of severe hypertension is summarized quired to guide treatment efficacy, advance our in Tables 2 and 3. 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