Markedly prolonged duration of action potential IV.

Blockade of slow inward (calciumsodium channel) depolarization current Brown and Wendel, 1989; Vaughan-Williams EM, 1984.

This cla.s.sification may prove useful in predicting both the efficacy and the toxicity of a specific agent (Brown and Wendel, 1989).

Table 3.3 Cla.s.sification of antiarrhythmic agents Drug Cla.s.sification of antiarrhythmic agents Drug Brand names Vaughan Williams cla.s.sification Amiodarone Cardarone III.

Bretylium Bretylol III.

Disopyramide Norpace I.

Encainide Enkaid IC.

Esomolola Brevibloc II.

Flecainide Tambocar IC.

Lidocaine Xylocaine, LidoPen IB.

Mexiletine Mexitil IB.

Mibefradila Posicor IV.

Procainamide Procan, p.r.o.nestyl, Promine, Rhthmin I.

Propranolol Inderal II.

Quinidine Cardioquin, Quindex, Quinaglute IA.

Sotalola Betapace II, III.

Tocainide Tanocard IB.

Verapamil Isoptin, Calan IV.

From Vaughan Williams, 1984.

aNo data on use of esomolol, sotalol, or mibefradil during pregnancy have been published.

women without known heart disease. Antiarrhythmics have been cla.s.sified into six cla.s.ses according to their major mode of action or effect (Vaughan Williams, 1984), as shown in Tables 3.2 and 3.3.

Lidocaine Commonly used as an amide local anesthetic, lidocaine is also effective in the treatment of ventricular and supraventricular tachycardias. Lidocaine rapidly crosses the placenta and fetal levels reach about 50 percent of maternal levels within less than an hour 54 54 Cardiovascular drugs during pregnancy (Rotmensch et al et al., 1983). Lidocaine's half-life is twice as long in the fetus/neonate (3 h) than in the mother (1.52 h) (Brown et al et al., 1976). Lidocaine persists for as long as 48 h after birth (Garite and Briggs, 1987). Importantly, most information available regarding pharmac.o.kinetics of lidocaine in pregnant and postpartum women and newborns is from studies of regional or local anesthesia (Rotmensch et al et al., 1983). No published data are available on lidocaine from women who received the drug for cardiac arrhythmias.

However, local anesthetics given in toxic doses may result in central nervous system and cardiac side effects in both the mother and the fetus. Lidocaine is not known to be teratogenic at acute therapeutic levels in humans or in chronic doses in animals (Fujinaga and Mazze, 1986; Heinonen et al et al., 1977; Rotmensch et al et al., 1983). Toxicity risk is minimal when maternal lidocaine levels are maintained at less than 4 mg/mL (Bhagwat and Engel, 1995). Amide-type local anesthetics given for paracervical block are a.s.sociated with spasm of the uterine arteries, causing decreased uterine blood flow.

Procainamide Another amide compound, procainamide, is used to treat ventricular tachycardia. There is little information regarding the pharmac.o.kinetics of this drug during pregnancy.

However, it has been estimated that fetal levels are approximately one-fourth the maternal levels (Garite and Briggs, 1987). Scientific evidence of the safety of procainamide for use during pregnancy does not address possible human teratogenicity. However, given the safety profile of a closely related drug (lidocaine), procainamide seems to not pose a great risk when used during pregnancy (Little and Gilstrap, 1989). Chronic use of this drug should be avoided, unless necessary for life-threatening conditions, because a lupus-like syndrome may occur (Rotmensch et al et al., 1987). Breastfeeding is not contraindicated in mothers on procainamide (American Academy of Pediatrics, 1994).

Encainide and flecainide Two other lidocaine-related antiarrhythmic medications are encainide and flecainide.

Encainide was not teratogenic in rats and rabbits when given at doses up to 9 and 13 times the human dose (data from the manufacturer's insert). Flecainide has been reported to cause teratogenic and embryotoxic effects in some species of rabbits when given in doses four times the usual adult dose. It was not, however, teratogenic in rats, mice, and other species of rabbits when given in the usual adult dose, according to its manufacturer. One case report suggested an a.s.sociation with birth defects with flecainide. Flecainide has been used to treat fetal arrhythmias, but fetal deaths have occurred with this treatment. Given the alternative related medications available, flecainide should be avoided, or at least the drug of last resort when others have failed.

Tocainide Tocainide is another amide antiarrhythmic agent, closely related to lidocaine. It was not teratogenic in animals at doses several times the usual adult dose, but it may be embryotoxic. There are no human studies during pregnancy, but it is closely related to lidocaine and its data may be extrapolated to tocainide.

Antiarrhythmics 55.Disopyramide Similar in action to quinidine, disopyramide is used to treat supraventricular and ventricular arrhythmias. Dysopyramide crosses the placenta readily, with fetal levels approximately half those of the mother (Rotmensch et al et al., 1983). The drug was embryotoxic in laboratory animals when given at several times the human dose, but no pattern or specific malformations were noted (data from the manufacturer's insert).

Disopyramide use during the third trimester has been a.s.sociated with premature onset of labor (Leonard et al et al., 1978; Rotmensch et al et al., 1983).

Bretylium This drug is primarily indicated for life-threatening ventricular arrhythmias, such as ventricular tachycardia and ventricular fibrillation. No human data are published regarding safety of the drug during pregnancy. Bretylium was reported to be 'without effect' in one rat study published by West (1962).

Amiodarone This drug is used primarily to treat life-threatening ventricular arrhythmias (e.g., ventricular fibrillation, tachycardia). Amiodarone has limited ability to cross the placenta, with newborn concentrations reaching only 1025 percent of maternal serum levels (Rotmensch et al et al., 1987). Of six pregnancies exposed to amiodarone after 10 weeks gestation, hypothyroidism (n = 2) and small size for gestational age (n = 4) was observed (Magee et al. et al. , 1995). Amiodarone contains a large amount (37 percent by weight) of iodine. Learning disabilities were unusually frequent in two small series of children exposed to amiodarone during gestation (Bartalena , 1995). Amiodarone contains a large amount (37 percent by weight) of iodine. Learning disabilities were unusually frequent in two small series of children exposed to amiodarone during gestation (Bartalena et al et al., 2001; Magee et al et al., 1999).

When administered chronically during pregnancy, fetal goiter is a major risk after 10 weeks gestation. Fetal death is consistently reported in animal studies of the drug during pregnancy. A possible a.s.sociation between fetal cretinism has also been suggested, especially from direct fetal injection (Pinsky et al et al., 1991). Otherwise, the frequency of congenital anomalies was not increased among 30 infants exposed to amiodarone during the first trimester (Bartalena et al et al., 2001).

Mexiletine Similar in action to lidocaine, mexiletine is a local anesthetic type of antiarrhythmic agent (Zipes and Troup, 1978). Mexiletine is used primarily to treat ventricular arrhythmias (ventricular tachycardia, premature ventricular contractions). No studies of congenital anomalies in infants exposed to mexiltene have been published. A few anecdotal case reports suggest no adverse effects on the fetus or on labor, but the importance of such observations is not clear. Mexiletine was not teratogenic in various laboratory animals (data from the manufacturer's insert). Cord blood concentrations of this drug were similar to maternal levels, and therapeutic levels may be found in breast milk (Timmis et al et al., 1980). However, breastfeeding is not contraindicated when the mother is using mexiletine (American Academy of Pediatrics, 1994).

56.Cardiovascular drugs during pregnancy Verapamil A calcium channel blocker that is used as an antiarrhythmic, antihypertensive, and antianginal treatment, verapamil is especially efficacious for the treatment of paroxysmal supraventricular tachycardia.

Verapamil is used to transplacentally treat fetal supraventricular tachycardia (Klein and Repke, 1984; Rey et al et al., 1985; Wolff et al et al., 1980). Verapamil should be used with caution in pregnant patients because it might reduce uterine blood flow by 25 percent or more (Murad et al et al., 1985). Importantly, 1020 percent of neonates who received this drug intraveneously for supraventricular tachycardia and congestive heart failure developed cardiac depression and cardiac arrest (Kleinman and Copel, 1991). Therefore, verapamil is not recommended for use in infants of less than 1 year (Garson, 1987).

Verapamil might have adverse effects in the fetal heart, especially in the presence of heart failure and hydrops (Shen et al et al., 1995). Among 33 infants exposed to verapamil in the first trimester, no increase in congenital anomalies was reported (Magee et al et al., 1996).

Verapamil is not contraindicated in breastfeeding mothers (American Academy of Pediatrics, 1994).

Propranolol Propranolol is a beta-adrenergic blocker used to treat supraventricular and ventricular tachycardias, hypertension, hyperthyroidism, and migraine headaches. It is also used in the intrauterine treatment of fetal arrhythmias (Bhagwat and Engel, 1995; Eibeschitz, 1975). Propranolol is probably the best studied of all the agents in this group. The majority of this information is derived from the treatment of hypertension during pregnancy.

Nonetheless, no controlled human teratology studies of propranolol have been published.

The drug was not teratogenic in at least two animal studies (Fuji and Nishimura, 1974; Speiser et al et al., 1983). No reports of malformations in either animals or humans have been published. Adverse fetal effects have been reported with the use of propranolol during pregnancy. Intrauterine growth r.e.t.a.r.dation and use of propranolol were a.s.sociated in one study (Pruyn et al et al., 1979). However, other studies have not found this a.s.sociation (Rotmensch et al et al., 1987). Importantly, it is also possible that the maternal hypertension, and not propranolol therapy per se per se, is responsible for decrease in fetal growth.

In addition to intrauterine growth restriction (IUGR), fetal effects of beta-blockers include apnea, bradycardia, and hypoglycemia (Bhagwat and Engel, 1995; Habib and McCarthy, 1977; Pruyn et al et al., 1979; Rubin, 1981; Turnstall, 1969), as summarized in Box 3.1.

Several other beta-adrenergic blocking agents are available but are used primarily for the treatment of hypertension. These are discussed below under Antihypertensives.

Box 3.1 Possible adverse fetal effects of maternal beta-blocker therapy therapy Apnea and respiratory depression Intrauterine growth r.e.t.a.r.dation Bradycardia Jaundice Hypoglycemia Anticoagulants and thrombolytics 57.Quinidine Primarily ventricular arrhythmias and supraventricular tachycardias are treated with quinidine. It was successfully used for the intrauterine treatment of fetal tachycardias (Spinnato et al et al., 1984). Quinidine was also used to treat fetal hydrops from reciprocat-ing tachycardia that did not convert with maternal digitalization (Guntheroth et al et al., 1985). There have been no controlled studies in human pregnancies. Among fewer than 20 pregnancies, quinidine exposure during the first trimester was not a.s.sociated with an increased frequency of congenital anomalies (Rosa, personal communication, cited in Briggs et al et al., 2002).

Adenosine Adenosine is a purine nucleoside approved by the Food and Drug Administration (FDA) for the treatment of supraventricular tachycardia (Mason et al et al., 1992). It has also been reported to be effective in the treatment of supraventricular tachycardia in pregnant women (Afridi et al et al., 1992; Hagley and Cole, 1994; Mason et al et al., 1992). There are no published studies regarding the teratogenic effects of this adenosine.

CARDIAC GLYCOSIDES.

Cardiac glycosides are used to treat atrial fibrillation, other supraventricular tachycardias, and treatment of fetal tachycardias.

Cardiac glycosides are effective because of their inotropic effects on the heart and antiarrhythmic effects. Various digitalis preparations cross the placenta readily, resulting in significant fetal levels with cord levels that are 5080 percent of maternal levels (Chan et al et al., 1978; Rogers et al et al., 1972). No scientific studies regarding the safety of cardiac glycosides in pregnant women have been published. Fetal digitalis toxicity has occurred, but this was secondary to maternal overdose (Sherman and Locke, 1960). In this latter report, it is estimated that the mother ingested 8.9 mg of digitoxin, resulting in significant fetal toxicity and neonatal death. Available information supports the view that cardiac glycosides are probably safe for use during pregnancy.

ANTICOAGULANTS AND THROMBOLYTICS.

Heparin is used in pregnant women primarily for the treatment of thromboembolic disease or for prophylaxis in women with artificial heart valves. Low-molecular-weight heparin is also used to treat thromboembolism in pregnancy, and does not cross the placenta (Feijgin and Lourwood, 1994; Macklon et al et al., 1995; Schneider et al et al., 1995).

Warfarin derivatives are contraindicated for use during pregnancy Coumarin derivatives, including warfarin, are contraindicated for use during pregnancy. Coumarin derivatives, including warfarin, are contraindicated for use during pregnancy.

The fetal warfarin syndrome is comprised of skeletal and brain defects. Use after the first trimester includes brain and eye defects, and other anomalies a.s.sociated with vascular disruption.

58.Cardiovascular drugs during pregnancy No controlled trials investigating the use of thrombolytics, such as streptokinase or urokinase, during pregnancy have been published. However, in a review of 172 pregnant women from published reports, Turrentine and a.s.sociates (1995) found no increase in congenital anomalies and a pregnancy loss rate of 5.8 percent. Hemorrhagic complications occurred in 8 percent of the women. Among more than 140 infants exposed to heparin during the first trimester, the frequency of congenital anomalies was not increased (Chan et al et al., 2000). Similarly, in a literature review among more than 440 infants exposed to low molecular weight heparins during pregnancy, including nearly 200 infants whose mothers were treated during the first trimester, no congenital anomalies were noted (Sanson et al et al., 1999). Seven to 10 infant defects would have been expected to occur in the absence of any drug exposure. Therefore, ascertainment bias may confound the detection of birth defects in their study.

Protamine sulfate is used to reverse the anticoagulant effects of heparin prior to surgery (e.g., Caesarean section). No studies regarding use of protamine in pregnancy have been published. One infant with neonatal depression following maternal protamine sulfate injection was reported Wittmaack et al et al., 1994).

ANTIANGINAL AGENTS.

Antianginal agents, potent vasodilators, are listed in Box 3.2. Organic nitrites are the most commonly used agents in this group, and nitroglycerin is the prototype organic nitrite agent. No human studies of organic nitrites in pregnant women have been published, although these agents were not teratogenic in animal studies.

Box 3.2 Antianginal agents Organic nitrites Nifedipine (Procardia Adalat) Amyl nitrate Nisoldipinea Dipyramidole (Persantine) Posicora Erythrityl tetranitrate (Cardilate) Verapamil (Calan, Isoptin) Isosorbide dinitrate (Isordil, Sorbitrate) Nitroglycerin Beta blockers Pentaerythritol tetranitrate (Pentritol, Atenolol Peritrate) Bisoprolola Bucindolola Calcium antagonists Labetalol Aminodipinea Metoprolol Bepridila Propranolol Diltiazem (Cardizem) Feldopinea New cla.s.s Mibefradila Ranolazinea Nicardipine (Cardene) Adapted in part from the USP DI, 2003.

aNot studied during pregnancy.

Antihypertensives 59.Intravenous nitroglycerin has also been utilized to blunt the hypertensive effect of endotracheal intubation in women with severe preeclampsia undergoing Caesarean section (Cheek and Samuels, 1996; Longmire et al et al., 1991).

The calcium channel blocker verapamil has been discussed above. Other calcium antagonists, such as diltiazem, nicardipine, and nifedipine, may also be useful as antianginal agents and have not been reported to be a.s.sociated with an increase in malformation rates in animal studies (Ariyuki, 1975). No studies of the use of other calcium channel antagonists use during pregnancy have been published.

No information has been published on the use of dipyramidole, a selective coronary vasodilator, in pregnant women. The beta-blockers are discussed above, as well as in the Antihypertensives section below.

ANTIHYPERTENSIVES.

Methyldopa Methyldopa (Aldomet) is a commonly utilized alpha-adrenergic blocking agent for the treatment of chronic hypertension in pregnant women. No epidemiologic studies are published on methyldopa use during pregnancy. Nonetheless, the available data suggest that methyldopa does not pose a significant risk of birth defects, and postnatal growth and development seems unaffected by prenatal exposure.

In summary, it would appear that methyldopa is not a human teratogen and is probably one of the safest antihypertensives for use during pregnancy.

Hydralazine One of the commonly used antihypertensive drugs is hydralazine, especially for acutely lowering of blood pressure in women with severe preeclampsia. It is thought to work primarily as a peripheral vasodilator (i.e., smooth muscle relaxant). No epidemiological studies of congenital anomalies in children born to women who took hydralazine during pregnancy have been published. Transient neonatal thrombocytopenia was reported.

Box 3.3 Antihypertensive drugs Acebutolol (Sectral) Lisinopril Atenolol (Tenormin) Methyldopa (Aldomet) Betaxolol (Kerlane) Metoprolol (Lopressor) Captopril (Capoten) Nadolol (Corgard) Carteolol (Cartol) Penbutolol (Levatol) Clonidine (Catapres) Propranolol (Inderal) Diazoxide (Hyperstat) Quinapril Enalapril Ramipril FosinaprilHydralazine (Apresoline) Sodium nitroprusside (Nipride, Nitropress) Hydralazine (Apresoline) Timolol (Blocadren) Labetolol (Normodyne, Trandate) 60.Cardiovascular drugs during pregnancy Beta-adrenergic blockers Several beta-blockers are available for the treatment of hypertension (Box 3.3) and have been used in pregnant women. Propranolol has been discussed above. Although there are no large human reproduction studies for labetolol, metaprolol, or atenolol use in pregnant women, there are reports of their use without apparent adverse fetal effects.

There are no reports of human teratogenicity for any of the beta-adrenergic blockers.

LABETOLOL.

Investigators who studied drug-free, methyldopa, and labetolol groups reported a higher frequency of fetal growth r.e.t.a.r.dation in the labetolol group with no obvious improvement in neonatal outcome (Sibai et al et al., 1987, 1990); neither was there an increase in congenital anomalies or any adverse effects in the offspring of 85 women with severe hypertension who were treated with labetolol during pregnancy (Michael, 1979). Comparing oral labetolol to intravenous diazoxide for hypertensive crisis during pregnancy, no significant maternal or fetal side effects were observed (Michael, 1986). Among 104 labetolol- versus methyldopa-treated women with pregnancy-induced hypertension, labetolol caused fewer side effects than methyldopa (el-Qarmalawi et al et al., 1995). Labetolol is the agent of choice to blunt the hypertensive response to endotracheal intubation, with few maternal, fetal or neonatal side effects (Cheek and Samuels, 1996).

METOPROLOL AND ATENOLOL.

Metoprolol (Lopressor) and atenolol (Tenormin) are beta-blockers that are used to treat hypertension during pregnancy. No studies on the use of these agents during the first trimester of pregnancy are published. No increase in adverse maternal or fetal effects, including no significant differences in birth weight, were reported in 120 women treated with atenolol or placebo during pregnancy (Rubin et al et al., 1983a,b). Similarly, no adverse fetal effects or pregnancy outcomes a.s.sociated with metoprolol or metprolol/hydralazine treatment in second and third trimesters of pregnancy were noted (Sundstrom, 1978). According to the manufacturer, it was not teratogenic in several animal studies.

Breastfeeding is allowed during maternal therapy with either metoprolol or atenolol (American Academy of Pediatrics, 1994), despite a case report of toxicity in a neonate whose mother was receiving atenolol while breastfeeding (Schmimmel et al et al., 1989).

ACEBUTOLOL.

No studies of acebutolol (Sectral) use in the first trimester of pregnancy have been published, but several reports of acebutolol treatment for hypertension during pregnancy ( n n = 56 infants) have been published that were without adverse maternal or fetal effects (Dubois et al et al., 1980, 1982; Williams and Morrissey, 1983). Neonatal hemodynamic adaptation failure occurred in five of 11 infants whose mothers were treated with acebutolol during pregnancy (Ya.s.sen et al et al., 1992). It seems unlikely that this drug is a.s.sociated with an increased risk of congenital anomalies.

PINDOLOL.

No studies regarding the use of pindolol during the first trimester of pregnancy have been published. Among 51 women with pregnancy-induced hypertension randomized to Antihypertensives Antihypertensives 61.hydralazine, hydralazine and propranolol, or hydralazine and pindolol, pindolol was a.s.sociated with fewer maternal and fetal side effects (Paran et al et al., 1995). However, infants born to mothers who received propranolol had smaller birth weights. In a comparative study of atenolol or pindolol on uterine/fetal hemodynamics and fetal cardiac function, investigators found that pindolol was preferable to atenolol for the treatment of pregnancy-induced hypertension based upon maternal and fetal cardiovascular function (Rasanen and Jouppila, 1995).

BETAXOLOL, CARTEOLOL, NADOLOL, PENBUTOLOL, AND TIMOLOL.

No human teratology or reproduction studies with betaxolol, carteolol, nadolol, penbutolol, or timolol have been published. No increase in congenital malformations was noted in the offspring of pregnant mice who received up to 150 mg/kg.day of carteolol (Tanaka et al et al., 1979). Also, no increase in the frequency of malformations was found among the offspring of rats, rabbits, and hamsters that had received nadolol in doses several times higher than the usual human dose (Sibley et al et al., 1978; Stevens et al et al., 1984).

No increased frequency of adverse fetal effects was found in the offspring of mice treated with penbutolol (Sugisaki et al et al., 1981).

CLONIDINE.

Clonidine (Catapres) is a centrally acting antihypertensive that blocks alpha-adrenergic receptors. No epidemiologic studies of the frequency of congenital anomalies and clonidine use during early pregnancy have been published. Anecdotal case reports of clonidine use during pregnancy suggest no adverse fetal effects (Horvath et al et al., 1985). Head size and neurologic examination of 22 children whose mothers received clonidine during pregnancy were normal (Huisjes et al et al., 1986; Raftos et al et al., 1973). One rat teratology study found no increased frequency of birth defects (Angelova et al et al., 1975), but one study found an increase in growth r.e.t.a.r.dation and cleft palates in offspring of mice treated with large doses of this antihypertensive (Chahoud et al et al., 1985). Clonidine is probably not a.s.sociated with an increased risk of congenital anomalies when used therapeutically.

DIAZOXIDE.

Diazoxide is a thiazide (Hyperstat) that is used parenterally as an antihypertensive. An oral form of this drug (Proglycem) is also used to treat hypoglycemia secondary to hyperinsulin-ism. No epidemiologic studies of diazoxide have been published. An anecdotal case report of abnormalities of body and scalp hair, including alopecia, in four neonates of women who received oral diazoxide during the last trimester of pregnancy has been published (Milner and Chonskey, 1972). Maternal diazoxide therapy was also reportedly a.s.sociated with hyperglycemia in the neonate (Milsap and Auld, 1980). No animal teratology studies are available. Pancreatic islet cell damage was found in the offspring of sheep and goats treated with intravenous diazoxide (Boulos et al et al., 1971). Diazoxide may inhibit uterine contractions (Landesman et al et al., 1969) and was used in the past by some clinicians as a tocolytic agent.

SODIUM NITROPRUSSIDE.

A potent vasodilator, sodium nitroprusside (Nipride, Nitropress), is used primarily for hypertensive emergencies. It is also used to induce hypotension during certain types of 62 62 Cardiovascular drugs during pregnancy Box 3.4 Loop and pota.s.sium-sparing diuretics Loop diuretics Pota.s.sium-sparing diuretics b.u.metanide (b.u.mex) Amiloride (Midamor) Ethacrynic acid (Edecrin) Spironolactone (Aldactone) Furosemide (Lasix, Myrosemide) Triamterene (Direnium) Box 3.5 Thiazide diuretics Bendroflumethiazide (Naturetin) Hydroflumethiazide (Diucardin, Saluron) Benzthiazide (Exna, Hydrex) Methyclothiazide (Aquatensen, Enduran) Chlorothiazide (Diuril) Metolazone (Diulo, Zaroxolyn, Mykrox) Cyclothiazide (Anhydron) Polythiazide (Renese) Hydrochlorothiazide (Esidrix, Hydro-Chlor, Quinethazone (Hydromox) Hydro-D, Hydrodiuril) Trichlomethiazide (Metahydrin, Naqua, Trichlorex) surgical procedures, especially neurosurgical procedures. No epidemiological studies of congenital anomalies in a.s.sociation with nitroprusside use during pregnancy have been published. Nitroprusside was reported to be a.s.sociated with cyanide toxicity in animals (Lewis et al et al., 1977), but this is apparently not a significant risk in the human fetus when recommended human doses are used in the mother (Shoemaker and Meyers, 1984).

Nonetheless, it is prudent to avoid use of nitroprusside during pregnancy because of the theoretical acc.u.mulation of cyanide in the fetal liver. Chronic use of sodium nitroprusside is logically a.s.sociated with a much higher risk than acute usage.

DIURETICS.

Diuretics are used to treat hypertension, sometimes alone or in conjunction with another drug regimen. Three basic categories of diuretics are: (1) loop diuretics; (2) pota.s.sium-sparing diuretics; and (3) thiazide diuretics. Agents in these categories are listed in Boxes 3.4 and 3.5.

Loop diuretics Loop diuretics act primarily by inhibiting sodium and water reabsorption by the loop of Henle. Loop diuretics include b.u.metanide, ethracrynic acid, and furosemide.

b.u.mETANIDE.

No epidemiological studies of b.u.metanide (b.u.mex) during pregnancy have been published. No increase in malformations was found in offspring of animals receiving several times the usual adult human dose of b.u.metanide (McClain and Dammers, 1981).

ETHACRYNIC ACID.

No animal or human teratology studies of ethacrynic acid (Edecrin) have been reported.

Diuretics 63.FUROSEMIDE.

Among 350 infants born to women who used furosemide during pregnancy, the frequency of congenital anomalies was not increased (Rosa, personal communication, cited in Briggs et al et al., 2002). Diuretics given after the first trimester of pregnancy may interfere with normal plasma volume expansion. An adverse effect on plasma volume, no improvement in perinatal outcome (Sibai et al et al., 1987), and decreased placental perfusion were reported with the use of diuretics during pregnancy (Shoemaker et al et al., 1973).

Furosemide also displaces bilirubin from alb.u.min, increasing the risk for fetal hyperbilirubinemia (Turmen et al et al., 1982). In animal studies, furosemide exposure in pregnancy was a.s.sociated with an increase in fetal loss and skeletal anomalies in offspring (G.o.dde and Grote, 1975; Mallie et al et al., 1985). Furosemide crosses the placenta and a.s.sists in a.s.sessing fetal urinary tract obstruction and fetal urine production (Barrett et et al al., 1983; Wladimiroff, 1975). Furosemide is probably not a.s.sociated with an increased risk of birth defects.

Pota.s.sium-sparing diuretics Pota.s.sium-sparing diuretics include amiloride, spironolactone, and triamterene, and result in sodium and water loss while sparing pota.s.sium. Spironolactone is a compet.i.tive inhibitor of aldosterone, while ameloride and triamterene function at the level of the collecting tubules.

AMILORIDE.

No epidemiological studies regarding the use of amiloride in pregnant women are published. No increase in malformations in offspring of pregnant hamsters that received small doses of ameloride was found (Storch and Layton, 1973).

SPIRONOLACTONE.