No epidemiological studies of spironolactone (Aldactone) in pregnant women have been published. Spironolactone was not a.s.sociated with an increased frequency of malformations in offspring of rats (Miyakubo et al et al., 1977), but feminization of the genitalia in the male offspring of rats that received this diuretic in doses five times that normally used in humans was reported (Hecker et al et al., 1980). This diuretic is not recommended for use during human pregnancy because of the theoretical risk of feminization of male genitalia.

This specific complication has not been reported in humans. Spironolactone for the treatment of pregnant women with Bartter's disease (Groves and Corenblum, 1995; Rigo et et al al., 1996) has been reported. None of the three male infants or two female infants had any demonstrable adverse effects, including undervirilization of the male infant.

TRIAMTERENE.

Triamterene (Direnium) is another pota.s.sium-sparing diuretic. Of 271 pregnant women included in the Collaborative Perinatal Project who were treated with this diuretic (Heinonen et al et al., 1977), only a few received this diuretic in the first months of pregnancy. The frequency of congenital malformations was not increased in the offspring of these women; neither was the frequency of malformations increased in the offspring of animals who received triamterene (Ellison and Maren, 1972).

64.Cardiovascular drugs during pregnancy Thiazides Thiazides comprise the largest group of diuretics (Box 3.5). Thiazides function by preventing reabsorption of sodium at the distal renal tubules. No increase in frequency of congenital anomalies in the offspring of over 500 women who took thiazide diuretics in the first trimester of pregnancy was noted (Kraus et al et al., 1966).

BENDROFLUMETHIAZIDE.

Among more than 1000 women included in the Collaborative Perinatal Project who received bendroflumethiazide (Naturetin), only 13 received this diuretic in early pregnancy (Heinonen et al et al., 1977). In a study of diuretics to prevent preeclampsia, no increase in the frequency of malformations or stillbirths was found in the offspring of over 1000 women who received this diuretic after the first trimester. No increased frequency of congenital anomalies was found among offspring of rats given hundreds of times the usual human dose (Stevens et al et al., 1984).

BENZTHIAZIDE.

There are no epidemiological studies on the use of this diuretic in pregnant women. No animal teratology studies are available regarding benzthiazide.

CHLOROTHIAZIDE.

Chlorothiazide (Diuril) is the most commonly used thiazide diuretic. The frequency of congenital anomalies was not increased over the expected rate reported among offspring of 63 women who took this diuretic in early pregnancy and of over 5000 women who took this drug after the first trimester of pregnancy (Heinonen et al et al., 1977).

Neonatal thrombocytopenia was reported in the offspring of several mothers who received chlorothiazide during pregnancy (Rodriguez et al et al., 1964), but not among infants in another series (Finnerty and a.s.sali, 1964). An increased frequency of hypertension was reported in the offspring of rats treated with chlorothiazide at doses 30 times those employed in humans (Grollman and Grollman, 1962). No increase in malformations in offspring of rats treated with this agent in doses up to 12 times that used in humans was found by another group of investigators (Maren and Ellison, 1972).

HYDROCHLOROTHIAZIDE.

Hydrochlorothiazide is a very commonly used thiazide diuretic. Birth defects were not increased in frequency among offspring of more than 200 women who received this diuretic in early pregnancy (Heinonen et al et al., 1977; Jick et al et al., 1981). Neonatal thrombocytopenia was observed with hydrochlorothiazide, as with other thiazide diuretics (Rodriguez et al et al., 1964). Hydrochlorothiazide was not teratogenic in the offspring of rats who received this agent in doses many times that of the human adult dose (George et al et al., 1995; Maren and Ellison, 1972).

HYDROFLUMETHIAZIDE.

No human epidemiological studies or animal teratology studies are published for hydroflumethiazide (Diucardin, Saluron). It is reasonable to a.s.sume that the potential risks of this diuretic are similar to those of other thiazides.

Calcium channel blockers 65.METHYCLOTHIAZIDE, POLYTHIAZIDE, AND TRICHLORMETHIAZIDE.

No information is available on which to base a risk estimate for these thiazide drugs.

For example, the Collaborative Perinatal Project database included only three women treated with methyclothiazide (Aquatensen, Enduran), 10 women treated with polythiazide (Renese), and only two women treated with trichlormethiazide (Metahydrin, Naqua, Trichlorex) in the first 4 months of pregnancy (Heinonen et al et al., 1977). There are no available animal teratology studies with these three thiazide diuretics.

Nonetheless, based upon information for a closely related and better-studied drug, chlorothiazide, it is reasonable to state that the risk of birth defects with these drugs is low, if it exceeds background risk.

Other thiazide-like diuretics Chlorthalidone (Hygroton, Thalitone), metolazone (Diulo, Zaroxolyn), and quinethazone (Hydromox) are not true thiazide diuretics from the standpoint of chemical structure, although their mode of action is very similar to the thiazide group. There is little available information regarding the use of chlorthalidone in women in the first trimester of pregnancy. Over 1300 women who used thiazide diuretics were included in the Collaborative Perinatal Project database, but only 20 used chlorthalidone during the first trimester (Heinonen et al et al., 1977). Although there was an increased frequency of congenital dislocation of the hip in this latter group, it is difficult if not impossible to draw valid conclusions from such numbers. Tervila and Vartianen (1971) reported no significant differences in offspring of mothers exposed to chlorthalidone after 15 weeks gestation, compared to controls. Only eight pregnant women were exposed to quinethi-azone in the Collaborative Perinatal Project database, and none who received metolazone (Heinonen et al et al., 1977). No published reports are available on congenital anomalies in the offspring of women who took either of these two diuretics during pregnancy.

Metolazone was not found to be teratogenic in one animal study (Nakajima et al et al., 1978), and no animal teratology studies are available for quinethazone.

CALCIUM CHANNEL BLOCKERS.

Calcium channel blockers are used to treat hypertension and supraventricular tachycardia.

Verapamil This calcium channel antagonist was discussed under Antiarrhythmics.

Nifedipine Nifedipine was used 'off-label' as a tocolytic agent and an antihypertensive medication.

Nifedipine was teratogenic in rats given 30 times the usual human dose (data from the manufacturer's insert). There are no studies of nifedipine use during the first trimester of pregnancy. No adverse maternal or fetal effects were reported for the use of nifedipine to treat preeclapmsia or hypertension, respectively (Sibai et al et al., 1992). The frequency 66 66 Cardiovascular drugs during pregnancy of congenital anomlies was not increased among 64 infants born to women treated with nifedipine (or a related calcium channel blocker) (Magee et al et al., 1996). It is regarded as the 'second line' antihypertensive therapy in pregnant women. Nifedipine use during pregnancy is probably safe with 'little teratogenic or fetotoxic potential' (Childress and Katz, 1994).

Nicardipine Treatment of hypertension in pregnancy with nicardipine was more effective than metoprolol in decreasing blood pressure, and neonatal outcomes were not different (Jannet et al et al., 1994). One study of 40 pregnant women with hypertension reported that intravenous nicardipine 'seems to be safe' (Carbonne et al et al., 1993). Nicardipine was not teratogenic in rats given an oral dose many times the recommended human dose (Sato et al et al., 1979).

Isradipine Isradipine, a dihydropyridine calcium channel blocker, is used as an antihypertensive agent. Isradipine was not teratogenic in rats given several times the human dose (data from the manufacturer's insert). No human reproduction studies have been published on isradipine. This calcium channel blocker was evaluated for the treatment of hypertension in pregnancy and reported to be effective for the treatment of nonproteinuric hypertension.

No adverse fetal effects were mentioned in this report (Wide-Swensson et al et al., 1995).

Diltiazem, nimodipine, and amlodipine There is little information regarding the use of these calcium channel blockers during pregnancy. Nimodipine was teratogenic in rabbits (data from the manufacturer's insert).

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS.

Angiotensin-converting enzyme (ACE) inhibitors are a cla.s.s of drugs used to treat hypertension (see Table 3.4). The ACE inhibitor group should be considered contraindicated for use during pregnancy because of the risks discussed below (Shotan et al et al., 1994).

Risks a.s.sociated with ACE inhibitors are second and third trimester events. First trimester exposures do not seem to present a significant risk for congenital anomalies, but this is an unknown area.

Captopril Captopril (Capoten) is an ACE inhibitor used as an oral antihypertensive agent. No epidemiological studies of this antihypertensive agent in pregnant women have been published. There were no malformations among 22 infants born to mothers who received captopril during the first trimester (Kreft-Jais and Boutroy, 1988), but no controlled studies have addressed whether or not captopril is a potent human teratogen. Case report evidence strongly suggests that captopril and other ACE inhibitors may be a.s.sociated with Angiotensin-converting enzyme inhibitors Angiotensin-converting enzyme inhibitors 67.Table 3.4 Summary of cardiovascular drugs: Teratogen Information Service (TERIS) and Food and Drug Administration (FDA) risk estimates Summary of cardiovascular drugs: Teratogen Information Service (TERIS) and Food and Drug Administration (FDA) risk estimates Drug Risk Risk rating Acebutolol Unlikely B *

m Amiloride Undetermined B *

m Amiodarone Neonatal thyroid dysfunction or goiter: small to moderate Dm Congenital anomalies: undetermined Atenolol Undetermined Dm Betaxolol Undetermined C *

m Bendroflumethiazide Undetermined C *

m Benzthiazide Undetermined C*

b.u.metanide Undetermined C *

m Captopril First-trimester use: undetermined C *

m Use later in pregnancy: moderate Chlorothiazide Unlikely C *

m Chlorthalidone Unlikely B *

m Clonidine Undetermined Cm Diazoxide Undetermined Cm Digoxin Unlikely Cm Diltiazem Undetermined Cm Disopyramide Undetermined Cm Enalapril First-trimester use: undetermined C *

m Use later in pregnancy: moderate Encainide Undetermined Bm Flecainide Undetermined Cm Furosemide Undetermined C *

m Heparin Unlikely Cm Hydralazine Undetermined Cm Hydrochlorothiazide Unlikely B *

m Lidocaine Local administration: none intravenous Bm Administration: undetermined Lisinopril First-trimester use: none to minimal C *

m Second or third trimester: moderate Methclothiazide Unlikely NA.

Methyldopa Undetermined Bm Metolazone Undetermined B *

m Nadolol Undetermined C *

m Nifedipine None to minimal Cm Pindolol Unlikely B *

m Polythiazide Undetermined C*

Procainamide Undetermined Cm Propranolol Undetermined C *

m Quinethazone Undetermined D*

Quinidine Undetermined Cm Spironolactone Undetermined C *

m Streptokinase Undetermined Cm Timolol Undetermined C *

m Tocainide Undetermined Cm Continued 68.Cardiovascular drugs during pregnancy Table 3.4 Continued Continued Drug Risk Risk rating Triamterene Undetermined C *

m Trichlormethiazide Undetermined C*

Urokinase Undetermined Bm Verapamil Undetermined Cm NA, not available.

Compiled from: Friedman et al., Obstet Gynecol 1990; 75 75: 594; Briggs et al., 2005; Friedman and Polifka, 2006.

anuria, renal failure, and hypocalvaria, possibly contributing to perinatal death (Anonymous, 1989; Barr and Cohen, 1991; Boutroy, 1989; Boutroy et al et al., 1984; Rosa and Bosco, 1991; Rothberg and Lorenz, 1984). Of 29 infants with neonatal renal failure, nine were born to women who had used captopril throughout pregnancy (Rosa and Bosco, 1991). The other 20 were born to women who used other ACE inhibitors. These antihypertensives are, therefore, contraindicated for use during pregnancy, and should be avoided if possible. No animal teratology studies have been published for captopril, but an increased frequency of fetal deaths was reported in two animal studies (Pipkin et al et al., 1980, 1982).

Enalapril This drug is an ACE inhibitor. Of 29 cases of perinatal renal failure, 18 occurred following maternal therapy with enalapril during pregnancy (Rosa and Bosco, 1991). This drug in contraindicated in the second and third trimesters.

Lisinopril Lisinopril is another ACE inhibitor. Among 29 infants with neonatal renal failure, two were born to women who used lisinopril during pregnancy (Rosa and Bosco, 1991).

This drug is contraindicated in the second and third trimesters.

Quinapril, ramipril, and fosinapril These ACE inhibitors theoretically carry the same risks of adverse fetal/neonatal effects as the other ACE inhibitors. They should be contraindicated in the second and third trimesters.

Angiotensin II receptor blockers Angiotensin II receptor blockers (ARBs) are a new cla.s.s of ACE inhibitors used to treat hypertension. The ARBs include: valsartan, losartan, telmisartan, candesartan, omlesartan, tasosartan, and eprosartan. Based upon case reports, the ARBs have a collection of fetal complications strikingly similar to the ACE inhibitor fetopathy. The risk of congenital anomalies following use during the first trimester is unknown, but use during the Special considerations Special considerations 69.second and third trimesters is a.s.sociated with a significant risk of fetal-neonatal complications. The complications include: oligohydramnios, fetal/neonatal renal failure, and decreased calcification of the cranium (Friedman and Polifka, 2006).

SPECIAL CONSIDERATIONS.

Cardiac arrhythmias and hypertension are the two most common cardiovascular diseases that require therapy during pregnancy. A complete review of these disorders is beyond the scope of this book. Only a few of the more common clinical problems are discussed below.

Cardiac arrhythmias Fortunately, life-threatening cardiac arrhythmias are uncommon during pregnancy.

However, certain less serious arrhythmias may actually be increased in frequency during pregnancy (Brown and Wendel, 1989).

Paroxysomal supraventricular tachycardia Paroxysmal supraventricular tachycardia occurs among 12 per 500 young women, and frequently occurs in those without overt heart disease (Brown and Wendel, 1989). The disease frequently presents with heart rates of over 200 beats per minute. Symptoms include palpitations, light-headedness, and rarely, angina and syncope. Pregnancy may increase risk for this type of arrhythmia (Meller and Goldman, 1982; Szekely and Snaith, 1953). Most cases of paroxysmal supraventricular tachycardia are a.s.sociated with AV-nodal reentry mechanisms, which can be managed in most patients with maneuvers of vagal stimulation to include carotid ma.s.sage or Valsalva techniques (Brown and Wendel, 1989; Josephson and Kaster, 1977; Wu et al et al., 1978). If vagal stimulation is unsuccessful, verapamil at 510 mg intravenously will prove successful in most cases in pregnant women. Because of reports of adverse neonatal cardiac effects Box 3.6 Treatment of acute episodes of paroxysmal Box 3.6 Treatment of acute episodes of paroxysmal supraventricular tachycardia in the pregnant patient without cardiac decompensation cardiac decompensation Vagal stimulation Carotid sinus ma.s.sage Valsalva Verapamil, 510 mg IVa Adenosine, 6 mg as a rapid intravenous bolus Digoxin, 0.51.0 mg IV over 15 min (total dose not to exceed 1.5 mg in 24 h) Propranolol, 0.51.0 mg/min (total dose not to exceed 3.0 mg)b See manufacturer's recommendations for dosing.

aSee text regarding possible fetal effects.

bCaution in patients with heart disease or asthma.

70.Cardiovascular drugs during pregnancy (including cardiac arrest), verapamil should be used with extreme caution during pregnancy, only after other agents have failed.

Cardioversion appears to be safe for the fetus (Clark et al et al., 1994). Digoxin and propranolol may also be utilized (Box 3.6). Recently adenosine, in a dose of 6 mg given as a rapid intravenous bolus, has been recommended for the treatment of supraventricular tachycardia. As previously mentioned, there is little information regarding the safety of this agent during pregnancy. However, there are several reports regarding its efficacy in pregnant women (Afridi et al et al., 1992; Hagley and Cole, 1994; Mason et al et al., 1992).

Electrical cardioversion should be reserved for patients with cardiac decompensation in whom medical therapy has failed.

Patients with frequent recurrences of this arrhythmia can usually be treated with digitalis and/or verapamil, quinidine, and propranolol as needed (Brown and Wendel, 1989; Zipes, 1988).

Atrial fibrillation Atrial fibrillation is uncommon in pregnant women, and this event points to underlying cardiac or thyroid disease. Mitral valve disease, secondary to rheumatic heart disease, is the most commonly encountered underlying cause of atrial fibrillation in the pregnant patient. Chronic atrial fibrillation treatment is generally directed at slowing the ventricular rate through medical therapy, with such medications as digitalis, with or without verapamil or propranolol (Brown and Wendel, 1989). Such gravidas may also require heparinization to prevent embolization.

Electrical cardioversion is indicated for significant cardiac decompensation and has been utilized in pregnant women without apparent adverse effects (Schroeder and Harrison, 1971).

Ventricular arrhythmias Premature ventricular contractions (PVCs) are relatively common and may actually be increased during pregnancy (Brown and Wendel, 1989). They generally do not require therapy, especially in asymptomatic pregnant women. Frequent PVCs should alert the clinician to possible organic heart disease, but medical therapy is rarely necessary for infrequent PVCs. Agents such as lidocaine, procainamide, quinidine, or disopyramide can be utilized for frequent or symptomatic PVCs.

Ventricular tachycardia is a life-threatening arrhythmia as it may lead to ventricular fibrillation, cardiac decompensation, and death. Fortunately, this arrhythmia is rarely encountered during pregnancy, especially in the absence of specific cardiac disease such as myocardial infarction. Therapy consists primarily of electric cardioversion, especially if the patient is hemodynamically unstable. Lidocaine, in a dose of 75100 mg IV bolus followed by 14 mg/min infusion, should be utilized in conjunction with countershock and as initial therapy in the stable patient (Brown and Wendel, 1989). Lidocaine, procainamide, or bretylium may be used to prevent recurrence of tachycardia.

Ventricular fibrillation is a medical emergency of the highest magnitude. Treatment is primarily electrical cardioversion followed by lidocaine or bretylium to prevent further fibrillation.

Special considerations 71.Hypertension Hypertension is one of the most common medical complications encountered during pregnancy and presents as chronic hypertension, pregnancy-induced hypertension, or preeclampsia. In the case of chronic hypertension, an underlying and potentially cor-rectable etiology should be ruled out.

CHRONIC HYPERTENSION.

Chronic hypertension is hypertension that was present before pregnancy or prior to 20 weeks gestational age, and occurs most frequently among multiparous patients. No unanimity of opinion has been reached regarding the most appropriate antihypertensive for use during pregnancy or the efficacy of such treatment with regard to pregnancy outcome.

Methyldopa (Aldomet) is one of the most commonly used antihypertensives in pregnant women. The initial dose of this agent is 250 mg twice a day with increases up to 2 g per day and a maximum recommended daily dose of 3 g (PDR, 2004).

Beta-adrenergic blockers such as atenolol, propranolol, or labetolol, as well as the calcium channel blockers and the centrally acting agent, clonidine, can also be used during pregnancy to treat hypertensions. However, no scientific evidence indicates that they offer any advantage over methyldopa during pregnancy.

A variety of thiazide diuretics may also be utilized as an adjunct in the treatment of hypertension. However, they should not be initiated after 20 weeks gestation because they may interfere with the 'normal' pregnancy expansion of blood volume and thus placental perfusion.

PREGNANCY-INDUCED HYPERTENSION.

Antihypertensives are generally not indicated for the treatment of hypertension a.s.sociated with preeclampsia except in severe preeclampsia. In the event of severe, acute hypertension (i.e., diastolic blood pressures greater than 110 mmHg) intravenous hydralazine in 510 mg doses will usually be effective. This dose can be increased and repeated every 1520 min, as necessary. The treatment goal of medical therapy is to achieve a diastolic blood pressure less than 110 mmHg, and in the range of 90100 mmHg. Caution must be exercised at the lower range to ensure adequate placental perfusion. Labetolol 10 mg IV may also be utilized every 10 min. Increasing doses (up to a total dose of 300 mg) may be necessary in some women.

Diuretics are generally contraindicated in women with preeclampsia because they may significantly interfere with utero-placental blood flow by further decreasing intravascular volume.

Prophylaxis of subacute bacterial endocarditis Pregnant women with significant cardiac lesions should receive antibiotic prophylaxis for invasive procedures, including v.a.g.i.n.al and Caesarean delivery, as prophylaxis for endocarditis (see Box 3.7).

72.Cardiovascular drugs during pregnancy Box 3.7 American Heart a.s.sociation prophylaxis for bacterial endocarditis guidelines endocarditis guidelines Nonpenicillin allergic Ampicillin 2.0 g IM or IV Gentamicin 1.5 mg/kg IM or IV To be given 30 min before delivery and repeated once 8 h later Penicillin allergic Vancomycin 1.0 g IV given over 60 min Gentamicin 1.5 mg/kg IM or IV To be given 60 min before delivery and repeated once 812 h later Box 3.8 Fetal arrythmias Box 3.8 Fetal arrythmias Tachycardia Supreventricular tachycardia (sinus or atrial), rate >180 bpm Atrial flutter, rate 400500 bpm Atrial fibrillation Ventricular tachycardia, rate 180400 Bradycardia Sinus bradycardia Complete heart block Irregular rhythms Premature atrial contractions Premature ventricular contractions From Kleinman and Copel, 1991; Pinsky et al., 1991.

Fetal cardiac arrhythmias A variety of fetal arrhythmias may be detected during pregnancy (Box 3.8). Not all such arrhythmias need to be or can be treated in utero in utero. Factors that influence in utero in utero therapy include the type and etiology of the arrhythmia, the potential for fetal compromise (i.e., heart failure or hydrops) and the gestational age of the fetus. Although virtually all antiarrhythmic drugs cross the placenta, it is often difficult to achieve adequate blood concentrations in both the mother and fetus with standard therapeutic doses. therapy include the type and etiology of the arrhythmia, the potential for fetal compromise (i.e., heart failure or hydrops) and the gestational age of the fetus. Although virtually all antiarrhythmic drugs cross the placenta, it is often difficult to achieve adequate blood concentrations in both the mother and fetus with standard therapeutic doses.

Supraventricular tachycardia Supraventricular tachycardia is probably the most common fetal arrhythmia a.s.sociated with fetal congestive heart failure, especially if the condition is long-standing (Chitkara et al et al., 1980; Kleinman et al et al., 1985a,b; Pinsky et al et al., 1991). The drug of choice for the initial treatment of supraventricular tachycardia is maternal digitalis therapy (Pinsky et et al al., 1991). This drug crosses the placenta readily and is safe for the fetus, although it is sometimes difficult to achieve therapeutic levels in the fetus. Recommended maternal doses are summarized in Table 3.5.

Key references 73.Table 3.5 Maternal dose and serum level of medications for fetal supraventricular tachycardia Maternal dose and serum level of medications for fetal supraventricular tachycardia Maternal dose Serum level Digoxin 0.250.75 mg 0.52 ng/mL (loading dose 1.02.5 ng pO) (or 0.52.0 ng IV) Propranolol 20160 ng q 68 h IV 20100 ng/mL Procainamide 6 mg/kg q 4 h IV 414 ng/mL If above fail: Verapamil 80120 mg q 68 h IV 50100 ng/mL From Kleinman et al., 1985a, 1985b; Pinsky et al., 1991.

Two other drugs that can be used are propranolol and procainamide. Verapamil, which has been utilized for this purpose, should be used with extreme caution and probably only after other therapeutic modalities have failed because of adverse events. Other agents that may used include quinidine, disopyramide, flecainide, and amiodarone, depending on the suspected etiology of the tachycardia (Kleinman and Copel, 1991).

Atrial flutter Atrial flutter and fibrillation are uncommon during the fetal period and are often difficult to diagnose. The fetal heart rate may reach 400500 bpm with atrial flutter. Control of the ventricular rate via atrioventricular nodal blocks with digoxin or verapamil may be inadequate and may actually worsen fetal hemodynamic status (Kleinman and Copel, 1991). Unless the atrial flutter itself is controlled, 'there will continue to be actual contractions against a closed or partially closed atrioventricular valve. ...' (Kleinman and Copel, 1991). A type I agent, such as procainamide or quinidine, should be included in the treatment regimen. Atrial fibrillation is even more rare than flutter and is treated similarly (Kleinman and Copel, 1991).

Key references Bhagwat AR, Engel PJ. Heart disease and pregnancy. Cardiol Clin 1995; 13 13: 163.

Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves. A systematic review of the literature. Arch Intern Med 2000; 160 160: 1916.