Journal of Human (2002) 16, 293–298  2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh REVIEW ARTICLE The effect of antihypertensive drugs on the fetus

T Rosenthal1 and S Oparil2 1Chorley Hypertension Research Institute, Chaim Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Israel; 2Department of Medicine, Division of Cardiovascular Disease, Vascular Biology and Hypertension Program, University of at Birmingham Alabama School of Medicine Birmingham, AL, USA

A critical review of the literature on the effects of antihy- scores that some antihypertensive drugs can be used pertensive drugs on the fetus in pregnant women is safely at certain stages of , while others are presented. The survey covers the alpha-adrenergic suspect and to be avoided at all costs. The lack of pla- receptor agonists, beta-blockers including topical eye cebo-controlled studies on the treatment of severe medications, alpha-beta blockers, calcium antagonists, hypertension in pregnancy due to ethical consider- diuretics, and angiotensin-converting enzyme (ACE) ations is discussed against the background of the inhibitors. The lack of data on angiotensin II receptor pressing need to treat these women despite the poss- blockers is noted although effects are considered to be ible deleterious effects of antihypertensive drugs similar to those reported with ACE inhibitors and there- Journal of Human Hypertension (2002) 16, 293–298. DOI: fore to be avoided. Analysis of the literature under- 10.1038/sj/jhh/1001400

Keywords: hypertension in pregnancy; antihypertensive drugs and fetus; and antihypertensive drugs

Introduction Methyldopa The use of antihypertensive drugs in pregnant On the basis of reports of stable uteroplacental blood women with chronic hypertension remains contro- flow and fetal haemodynamics,6 methyldopa has versial in light of the usual fall in blood pressure become the preferred agent as first-line therapy and that occurs during the first half of pregnancy,1 and has been used most commonly in randomised the probable deleterious effects on fetal growth and trials.7 It is considered the safest and most effi- development of antihypertensive drugs and treat- cacious for use in pregnancy ment-induced blood pressure declines.2,3 Whether and is therefore recommended by all working or not pre-eclampsia develops, the presence of pro- groups.8 Kirsten and colleagues9 consider it the only teinuria early in pregnancy puts women with acceptable drug during the first trimester of preg- chronic hypertension at higher risk for adverse neo- nancy. natal outcomes.4 Rey and Couturier5 retrospectively evaluated the course of 298 pregnant women with chronic hypertension whose antihypertensive medi- Alpha-and beta-adrenergic blocking cations had been discontinued or reduced in doses agents – labetalol early in pregnancy. Neither superimposed pre- When methyldopa causes somnolence and cannot eclampsia, preterm delivery, abrupto placentae, nor be tolerated, alternatives such as the alpha-beta- perinatal death was less frequent than in treated adrenergic blocking agent, labetalol, may be used. women. Although placebo-controlled trials on anti- Clinical experience with labetalol is extensive and hypertensive drug treatment in pregnancy are lack- it is among the most widely used antihypertensive ing, considerable data have accumulated on this drugs in pregnancy.10 Blood pressure and pro- topic (Table 1). teinuria fell significantly in a placebo controlled trial of labetalol in a cohort of 144 women with preg- nancy-induced mild and moderate hypertension. However, gestation was not significantly prolonged Correspondence: T Rosenthal, MD, Chorley Hypertension and measures of clinical outcome were not signifi- 11 Research Institute, Chaim Sheba Medical Center, Tel Hashomer cantly altered in these women. Possible advan- 52621, Israel. E-mail: trosenthȰsheba.health.govil tages and no evidence of disadvantages for the fetus Antihypertensive drugs and the fetus T Rosenthal and S Oparil 294 Table 1 Antihypertensive therapy of chronic hypertension in later stages. A randomised trial in which atenolol or pregnancy placebo was given before 24 weeks of gestation to normotensive pregnant women with high cardiac Drug Dosage Additional comments output in an attempt to prevent pre-eclampsia revealed similar results, namely smaller babies than Methyldopa 500–3000 mg Considered to be drug of choice 17 18 in 2–4 divided because of extensive experience those getting placebo. Churchill et al, on the doses other hand, found little difference in fetal growth Labetalol 200–1200 mg Similar in efficacy and safety to between women who began atenolol in the second in 2–3 divided methyldopa trimester, women on other antihypertensive drugs, doses and those using no medication. Beta-blockers variable Possibility of fetal bradycardia, A basic concern of these and other authors is the lower birth weight (when used level at which blood pressure should be treated and early in pregnancy) to which blood pressure should be lowered in preg- Calcium variable Accumulating data support nancy. Magee19 raises this question, noting that channel maternal and fetal safety; may many factors are likely to affect fetal growth other blockers interact with magnesium than maternal blood pressure. He points to the con- sulfate nection between antihypertensive treatment and the Alpha- variable Scant data for use in pregnancy goal of best perinatal outcome, which remains to be blockers addressed. An international multicentre randomised Clonidine 0.1–0.8 mg in Limited data controlled trial, Control of Hypertension in Preg- 2–4 divided doses nancy and small for (SGA) Infants (CHIPS), is currently being designed to answer Thiazide variable May be associated with these questions.20 diuretics diminished volume expansion in pregnancy; may be necessary Since topical eye medications are absorbed in salt-sensitive hypertensives through the nasopharyngeal mucosa and can there- at lower doses fore enter the systemic circulation, beta-blocker eye Angiotensin- contraindicated Contraindicated in pregnancy; drops should be avoided in the first trimester of converting neonatal anuric renal failure pregnancy. This is especially noteworthy because enzyme glaucoma can occur during the second to the fifth inhibitors decade of life, a time when women are at risk for Angiotensin contraindicated Contraindicated in pregnancy; pregnancy. Indeed, Wagebvoort et al21 reported a receptor neonatal anuria renal failure. case in which timolol eye drops were associated antagonists with bradycardia and arrhythmia in the fetus, a From: August P, Falkner B. Hypertension in pregnancy and in phenomenon observed also in sheep by Van 22 children. In: Antman E (ed). Cardiovascular Therapeutics: A Tetten. The literature on the use of other forms of Modified Companion to Braunwald’s Disease. W.B. Saund- eye drops, such as betaxolol and levobunolol in ers Company: Philadelphia, PA, Chapter 38, 2001 (published pregnant women, is lacking.23 last week).

were reported in another trial with labetalol, this Alpha adrenergic blocking agents time a double-blind controlled study in 152 women.12 Thus labetalol is generally not considered Although prazosin is rarely used in pregnancy, it to adversely affect the fetus during the third trimes- was recently reported that in the third trimester, ter of pregnancy, and is commonly used to treat fetal concentrations of prazosin are 10–20% of the hypertension at that stage.10 maternal concentrations, suggesting the possibility that prazosin may affect the fetus.24 Prazosin has Beta-adrenergic blocking agents been associated with transverse limb defects in the fetus in a case report.25 Prazosin taken from day 7 The beta-adrenergic receptor antagonists, including of gestation resulted in limb defects, hypoxic renal metoprolol and atenolol, are also considered safe damage, and intrauterine death at 20 weeks. These and effective in late gestation, but have been authors25 attributed the anomalies to drug-induced reported to cause some fetal problems when given in hypotension in the mother, with resultant dimin- early or mid-gestation.13,14 Beta-blockers, especially ished uteroplacental blood flow, fetal hypotension atenolol, have been linked with fetal growth retar- and hypoxia. This is only a speculation, and if this dation when given early in pregnancy.15 A large- were the case, we would expect to see more limb scale retrospective study of atenolol in 78 preg- reduction defects in the population treated with nancies showed that the drug was associated with antihypertensive drugs than we actually do. One fetal growth retardation, particularly when it was should be cautious about drawing conclusions con- given early in pregnancy and continued for a long cerning the adverse effects of drugs on the fetus time.16 These authors urge avoiding atenolol in the based on isolated case reports since fetal defects early stages of pregnancy and exercising caution at occur in a sporadic case in the general population of

Journal of Human Hypertension Antihypertensive drugs and the fetus T Rosenthal and S Oparil 295 pregnant women independent of both hypertension 7000 pregnant women receiving diuretics, revealed and antihypertensive therapy. a decrease in the tendency of the women to develop oedema and/or hypertension. Pre-eclampsia, Vasodilators appeared to have been prevented even when oedema was not a diagnostic criterion. This may The potent vasodilator minoxidil26 has been shown reflect the blood pressure-lowering action of to adversely affect the fetus causing hypertrichosis diuretics. There was little difference in postnatal of the back and extremities in a 38-week-old infant survival between diuretic treated and untreated born to a woman administered a daily regimen of groups: stillbirths were about one-third less with minoxidil, captopril and propranolol. Additional treatment, but small numbers made the difference pathologic features included dysmorphic facial fea- statistically insignificant. There was no increased tures, bilateral fifth finger clinodactyly, and an incidence of adverse fetal effects. omphalocele containing bowel loops. The hypertri- Although data concerning the use of diuretics in chosis was considered evidence of the transpla- pregnant women with essential hypertension are cental effect of minoxidil, but does not necessarily sparse, the Working Group Report on High Blood account for the other pathologic features. The con- Pressure in Pregnancy, 20001 concluded that ges- genital abnormalities might be attributable to an tation does not preclude use of diuretics to reduce interaction among the three drugs. Animal safety or control blood pressure in women whose hyper- studies27 of the effects of minoxidil in pregnant rats tension predated conception or manifested before and rabbits revealed no teratogenic effects in rats mid-pregnancy. These safe and efficacious agents, when given at 20 and 70 times routine human doses can markedly potentiate the response to other anti- on gestation days 6 to 15, while rabbits given those hypertensive agents, and are not contraindicated in doses on days 6–18 had smaller litter sizes and pregnancy except in settings where uteroplacental higher rates of fetal absorption. perfusion is already reduced (pre-eclampsia and intrauterine growth restriction). Calcium channel blocking agents Angiotensin-converting enzyme Calcium antagonists generally constitute second- line agents, usually administered late in pregnancy. inhibitors A small multicentre prospective cohort study of first Animal studies have found angiotensin-converting trimester exposures to calcium channel blockers enzyme inhibitors (ACEIs) to be associated with reported no increase in major teratogenic risk.28 This fetal anomalies. Captopril administered to two near- study suggests that calcium channel blockers term pregnant guinea pigs reduced fetal ACE (especially nifedipine and verapamil) do not rep- activity below levels seen in control animals,33 indi- resent a major teratogenic risk. The prematurity and cating that the drug can adversely affect blood press- lower birth weight that have been reported with ure control during both fetal and neonatal life. increased frequency among offspring of patients Administration of enalapril to ewes34 produced treated with calcium channel blockers may be due unexpected fetal deaths, skeletal abnormalities, and to the serious maternal hypertension and not to the an unexplained stillbirth. Histological examination therapy per se. A larger multicentre study random- of the lungs of this last fetus showed inadequate ised 145 pregnant women with mild to moderate lung expansion indicative of severe intrapartum hypertension to slow release nifedipine or no treat- asphyxia and/or possibly a surfactant deficiency. ment. Neither benefit nor harm from the treatment When given to lambs and rabbits late in preg- was reported in the 138 women who began treat- nancy,35 captopril resulted in a high percentage of ment in the second trimester.29 The literature is too stillbirths in the former and prolonged gestation in sparse, however, to draw any definite conclusions the latter. These studies point to the rapid passage of about the safety of calcium channel blockers admin- captopril across the . Captopril in pregnant istered early during pregnancy. rabbits in another study36 reduced blood pressure, slowed uterine blood flow, and drastically decreased Diuretics uterine vein prostaglandin E (PGE). The importance of PGE synthesis in maintaining uterine blood flow The known association of pre-eclampsia with and the survival of the fetus evidenced by these fin- reduced plasma volume and worse fetal outcome in dings raises the possibility that uterine PGE syn- women with chronic hypertension, who failed to thesis is dependent on angiotensin II. expand their plasma volume appropriately in preg- Experience with ACEIs in humans confirms much nancy argues against use of diuretics in pregnancy.30 of the data from animal studies. Fiocchi and co- Indeed, plasma volume expansion was found to be workers,37 in a letter to the editor in the Lancet, minimal in women using diuretics from early preg- described a case in which captopril was given nancy compared with normotensive pregnant throughout pregnancy to a 47-year-old hypertensive women.31 A meta-analysis of nine randomised trials woman with no untoward events until weeks 32– performed by Collins et al,32 involving more than 36, when there was progressive retardation in fetal

Journal of Human Hypertension Antihypertensive drugs and the fetus T Rosenthal and S Oparil 296 growth according to imaging and biochemical para- exposed to these drugs during pregnancy.51,52 Lip et meters. This baby was born with no abnormalities al53 further stated that there is no justification to despite continuous administration of captopril continue using ACEIs once pregnancy is docu- throughout the pregnancy. With some exceptions,38 mented, and recommended that they should be despite early case reports supporting the safety of stopped or changed to an alternative agent. ACEIs in pregnancy, the literature is generally not in favour of using ACEIs because of associated sev- Angiotensin II receptor antagonists ere fetal and neonatal disease.39 A number of reviews and reports addressed to clinical tetralogy Adverse effects of angiotensin II receptor antagonists counsellors cited oligohydramnios and/or neonatal on fetal kidneys have been documented in rats and anuria, pulmonary hydroplasia, mild to severe intra- sheep,54–56 and recent case reports have provided uterine growth retardation, and fetal death associa- data on their effects on humans. Losartan, hydro- ted with ACEIs. Persistent anuria in neonates was chlorothiazide, felodipine and metoprolol given to attributed to maternal intake of captopril40 and to a a 42-year-old woman from the beginning of preg- battery of antihypertensive drugs including enala- nancy57 resulted in a baby with varus deformation, pril.41 Neonatal renal failure and some dysmorphic of the left foot, clubbed right foot and fixed external features were described following captopril;42 the rotation of right knee, Potter’s facies, and patent death of a child from pulmonary hypoplasia was ductus arteriosus. This anuric baby died on the 4th attributed to oligohydramnios following enalapril;43 postnatal day. Microscopy revealed renal tubular and acute renal failure was reported in a premature dysgenesis. newborn following enalapril.44 In another case,58 a woman on candesartan gave Two cases of bone hypocalvaria were reported by birth to a baby girl with left sided facial palsy and Barr and Cohen,45 one in the fetus of a woman who plexus paresis who was anuric at 24 h postpartum, received captopril and another in a woman who with steadily rising creatinine that dropped at 1 received lisinopril both fetuses had fetopathy with month of age. The authors suspect that the candesar- renal tubular dysgenesis and severely underdevel- tan was responsible for the acute perinatal renal fail- oped calvarial bone. Other cases of underdeveloped ure in this case. calvaria induced by captopril were described by Three patients59 on valsartan at the time of con- Duminy and Burger46 and Mheta and Modi.47 The ception delivered babies that showed no congenital anomalies described in these cases—fetal and neo- abnormalities or evidence of renal dysfunction, one natal mortality, neonatal anuria, intrauterine growth of which had growth retardation. The authors con- retardation,and calvarial hypoplasia—are connected cluded that activation of the AT1 receptor by angio- with severe fetal hypotension during the second and tensin II plays a role in vascular development and third trimester. The morphologic findings and/or growth, so an AT1 antagonist should not be given to signs of fetal growth restriction attest to utero women already pregnant or planning pregnancy. hypotension/hypoxia. 48 A French group reported fetal death, preterm Conclusions delivery, and small-for-age newborns in women tak- ing captopril or enalapril during pregnancy, but also The high risk of hypertension, particularly severe noted that in seven cases in which ACEIs were com- hypertension, to the pregnant woman, mandates the bined with diuretics, perinatal outcome was unre- use of antihypertensive treatment despite possible markable. Brent39 considered it important to alert detrimental effects on the fetus. While antihyperten- physicians to the possibility of fetal and neonatal sive therapy is indicated for maternal benefit, it may disease following transplacental passage of captop- also permit prolongation of the pregnancy and ril, especially since a report suggesting that capto- thereby improve fetal maturity. However, severely pril is not teratogenic49 raised the likelihood of hypertensive women are usually delivered soon physicians prescribing it during pregnancy. after their blood pressure is controlled, since the Although there is agreement that ACEIs can pose reduction in uteroplacental blood flow following the a risk to the fetus,39 there is controversy over the quick and dramatic reduction in maternal blood timing and duration of exposure in relation to fetal pressure adversely affects the fetus. risk and the magnitude of the risk during the unsafe Diagnosing any drug-related disorder can be dif- stages. While an editorial in The Lancet in 198950 ficult. The relationship between a drug and an effect cautioned that most of the pregnant women reported can be definitively established only by withdrawal in the various studies were also receiving other of the suspected offending agent and rechallenge— drugs, there is no question that oligohydramnios, clearly out of the question in most cases. Studies fetal death, neonatal anuria, intrauterine growth that attempt to establish a cause and effect relation- retardation and fetal calvarial hypoplasia are direct ship based on clinical data are done on cohorts of effects of ACEIs on the fetus. ACEIs are absolutely varying sizes and are usually very small. The effects contraindicated in women with child-bearing poten- of treating severe hypertension in pregnancy have tial, based on the evidence of a high degree of mor- been investigated in only a few placebo-controlled bidity and mortality in fetuses or newborn infants trials. There is a pressing need for well-designed,

Journal of Human Hypertension Antihypertensive drugs and the fetus T Rosenthal and S Oparil 297 controlled studies carried out by multidisciplinary 19 Magee L. Authors reply. Lancet 2000; 355: 1367. teams of obstetricians, hypertension specialists, epi- 20 Magee LA et al. The generalizability of trial data; a demiologists, and even geneticists. More infor- comparison of trial participants with a mation about the risks and safety of specific drugs, prospective cohort of women taking beta blockers in dosages and combinations should enable the phys- pregnancy. Eur J Obstet Gynecol Reprod Biol 2001; 94: 205–210. ician to be bolder in attempting to treat this con- 21 Wagebvoort AM et al. Topical timolol therapy in preg- dition which if left unattended, will harm both the nancy: is it safe for the fetus? Teratology 1998; 58: mother and fetus. 258–262. 22 Van Tetten GR. Cardiovascular effects of timolol in the References anesthetized pregnant ewe and fetus. Proc West Phar- macol Soc 1980; 23: 191–195. 1 Working Group Report on High Blood Pressure in 23 Kooner KS, Zimmerman TJ. Antiglaucoma therapy Pregnancy. Am J Obstet Gynecol 1990; 163: 1691– during pregnancy – Part I. Ann Ophthalmol 1988; 20: 1712. NIH publication N000–3029. Revised July 2000. 166–169. 2 De Swiet M Maternal blood pressure and birthweight 24 Bourget P et al. Weak placental passages of prazosin (editorial). Lancet 2000; 355: 81. (Alpress) during the third trimester of pregnancy. J 3 Von Dadelszen P et al. Fall in mean arterial pressure Gynecol Obstet Biol Reported Paris 1993; 22: 871–874. and fetal growth restriction in pregnancy hyperten- 25 Hurst JA et al. Transverse limb deficiency, facial cleft- sion: a meta-analysis. Lancet 2000; 355:87–92. ing and hypoxic renal damage: an association with 4 Sibai BM et al. Risk factors for preeclampsia abruption treatment of maternal hypertension? Clin Dysmorphol placental, and adverse neonatal outcomes among 1995; 4: 359–363. women with chronic hypertension. N Engl J Med 1998; 26 Kaler SG et al. Hypertrichosis and congenital anomal- 338: 701–705. ies associated with maternal use of minoxidil. Pedi- 5 Rey E, Couturier A. The prognosis of pregnancy in atrics 1987; 79: 434–436. women with chronic hypertension. Am J Obstet Gyn- 27 Carlson RG, Feenstra ES. Toxicologic studies with the ecol 1994; 171: 410–416. hypotensive agent minoxidil. Toxicol Appl Pharmacol 6 Montan S et al. Effects of methyldopa on uteroplacen- 1977; 39:1–11. tal and fetal hemodynamics in pregnancy-induced 28 Magee LA et al. The safety of calcium channel blockers hypertension. Am J Obstet Gynecol 1993; 168: 152– in human pregnancy: A prospective, multicenter 156. cohort study. Am J Obstet Gynecol 1996; 174: 823–828. 7 Sibai BM. Treatment of hypertension in pregnant 29 Gruppo di studio Ipertensione in Gravidanze. Nifedip- women. N Engl J Med 1996; 335: 257–265. ine versus expectant management in mild to moderate 8 Lindheimer MD. Hypertension in pregnancy. Hyper- hypertension in pregnancy. Br J Obstet Gynaecol 1998; tension 1993; 22: 127–137. 105: 718–722. 9 Kirsten R, Nelson K, Kirsten D, Heintz B. Clinical phar- 30 Sibai BM, Grossman RA, Grossman HG. Effects of makokinetics of vasodilators – Part II. Clin Pharmaco- diuretics on plasma volume in with long kinet 1998; 35:9–36. term hypertension. Am J Obstet Gynecol 1984; 150: 10 Sibai MB et al. A comparison of no medication versus 831–835. methyldopa or labetalol in chronic hypertension dur- 31 Arias F, Zamora J. Antihypertensive treatment and ing pregnancy. Am J Obstet Gynecol 1990; 162: 960– pregnancy outcome in patients with mild chronic 967. hypertension. Obstet Gynecol 1979; 53: 489–494. 11 Pickles CJ, Symonds EM, Pipkin FB. The fetal outcome 32 Collins R, Yusuf S, Peto R. Overview of randomised in a randomized double blind controlled trial of labet- alol versus placebo in pregnancy-induced hyperten- trials of diuretics in pregnancy. BMJ 1985; 290:17–23. sion. Br J Obstet Gynecol 1989; 96:38–43. 33 Davidson D, Stalcup SA, Mellins RB. Captopril admin- 12 Pickles CJ, Broughton Pipkin F, Symonds EM. A ran- istration to the pregnant guinea pig inhibits fetal angi- domized placebo controlled trial of labetalol in the otensin converting enzyme activity. Pediatr Res 1981; treatment of mild to moderate pregnancy induced 15: 658. hypertension. Br J Obstet Gynecol 1992; 99: 964–968. 34 Broughton-Pipkin F, Wallace CP. The effect of enala- 13 Butters L, Kennedy S, Rubin PC. Atenolol in essential pril (MK421), an angiotensin converting enzyme hypertension during pregnancy. BMJ 1990; 301: 587– inhibitor, on the conscious pregnant ewe and her foe- 589. tus. Br J Pharmacol 1986; 87: 533–542. 14 Lip GYH et al. Effect of atenolol on birth weight. Am 35 Broughton-Pipkin F, Symonds EM, Turner SR. The J Cardiol 1997; 79: 1436–1438. effect of captopril (SQ14,255) upon mother and fetus 15 Magee LA, Omstein MP, von Dsadelszen P. Fortnightly in the chronically cannulated ewe and in the pregnant review: management of hypertension in pregnancy. rabbit. J Physiol 1982; 323: 415–422. BMJ 1999; 318: 1332–1336. 36 Ferris TF, Weir EK. Effect of captopril on uterine blood 16 Lydakis C et al. Atenolol and fetal growth in preg- flow and prostaglandin synthesis in the pregnant rab- nancies complicated by hypertension. Am J Hypertens bit. J Clin Invest 1983; 71: 809–815. 1999; 12: 541–547. 37 Fiocchi R et al. Captopril during pregnancy. Lancet 17 Easterling TR et al. Prevention of preeclampsia a ran- 1984; 2: 1153. domized trial of atenolol in hyperdynamic patients 38 Coen G et al. Successful treatment of long lasting before onset of hypertension. Obstet. Gynecol 1999; 93: severe hypertension with captopril during a twin 725–733. pregnancy. Nephron 1985; 40: 498–500. 18 Churchill D, Bayliss H, Beevers G. Fetal growth restric- 39 Brent RL. Angiotensin-converting enzyme inhibitors, tion. Lancet 2000; 355: 1366–1367. an embryopathic class of drugs with unique proper-

Journal of Human Hypertension Antihypertensive drugs and the fetus T Rosenthal and S Oparil 298 ties: information for clinical tetralogy counselors. ogic factors and their role in prevention. N Engl J Med Tetralogy 1991; 43: 543–546. 1983; 308: 491–497. 40 Guignard JP. Burgener F, Calame A. Persistent anuria 50 Are ACE inhibitors safe in pregnancy? (editorial) in a neonate: a side effect of captopril? J Pediatr Lancet 1989; 2: 482–483. Nephrol 1981; 2: 133. 51 Shotan A et al. Risks of angiotensin converting enzyme 41 Scott AA, Purohit DM. Neonatal renal failure: a com- inhibition during pregnancy: experimental and clini- plication of maternal antihypertensive therapy. Am J cal evidence, potential mechanisms and recommen- Obstet Gynecol 1989; 160: 1223–1224. dations for use. Am J Med 1994; 96: 451–456. 42 Rothberg AD, Lorenz R. Can captopril cause fetal and 52 Calhoun DA, Oparil S. High blood pressure in women. neonatal renal failure? Pediatr Pharmacol 1984; 4: Int J Fertil 1997; 42: 198–205. 189–192. 53 Lip GYH et al. Angiotensin converting enzyme inhibi- 43 Cuniff C et al. Oligohydramnios sequence and renal tors in early pregnancy. Lancet 1997; 350: 1446–1447. tubular malformation associated with maternal enala- 54 Forhead AJ et al. Changes in maternal and fetal renin- pril use. Am J Obstet Gynecol 1990; 162: 187–189. angiotensin system in response to angiotensin II type 1 44 Schubiger G, Flury G, Nussberger J. Enalapril for preg- receptor blockade and angiotensin converting enzyme nancy induced hypertension: Acute renal failure in inhibitor in pregnant sheep during late gestation. Exp neonate. Ann Intern Med 1988; 108: 215–216. Phys 1997; 82: 761–776. 45 Barr M Jr, Cohen MM Jr. ACE inhibitor fetopathy and 55 Spence SG et al. Toxicokinetic analysis of losartan hypocalvaria: the kidney-skull connection. Teratology during gestation and lactation in the rat. Teratology 1991; 44: 485–495. 1996; 53: 245–252. 46 Duminy PC, Burger P du T. Fetal anbormality associa- 56 Lambot MA, Vermeylen D, Noel JC. Angiotensin II ted with the use of captopril during pregnancy. receptor inhibitors in pregnancy. Lancet 2001; 357: (Letter). SAfrMedJ1981; 60: 805. 1619–1620. 47 Mheta N, Modi N. ACE inhibitors in pregnancy. 57 Saji H, Yamanaka M, Hagiwara A, Ijiri R. Losartan and (Letter) Lancet 1989; 2: 96. fetal toxic effects (Letter) Lancet 2001; 357: 363. 48 Kreft-Jais C et al. Angiotensin-converting enzyme 58 Hinsberger A, Wingen AM, Hoyer PF. (Letter). Lancet inhibitors during pregnancy: a survey of 22 patients 2001; 357: 1620. given captopril and nine given enalapril. Br J Obstet 59 Chung NA, Lip GH, Beevers M, Beevers DG. Outcomes Gynecol 1988; 95: 420–422. in women given valsortam early in pregnancy. (Letter). 49 Kalter H, Warkany J. Congenital malformations: etiol- Lancet 2001; 357: 1620.

Journal of Human Hypertension