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Journal of Human Hypertension (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 fetusT Rosenthal1 and S Oparil21Chorley 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-pertensive drugs on the fetus in pregnant women is

presented. The survey covers the alpha-adrenergicreceptor agonists, beta-blockers including topical eyemedications, alpha-beta blockers, calcium antagonists,diuretics, and angiotensin-converting enzyme (ACE)inhibitors. The lack of data on angiotensin II receptorblockers is noted although effects are considered to besimilar to those reported with ACE inhibitors and there-fore to be avoided. Analysis of the literature under-

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

Introduction

The use of antihypertensive drugs in pregnantwomen with chronic hypertension remains contro-versial in light of the usual fall in blood pressurethat occurs during the first half of pregnancy,1 andthe probable deleterious effects on fetal growth anddevelopment of antihypertensive drugs and treat-ment-induced blood pressure declines.2,3 Whetheror not pre-eclampsia develops, the presence of pro-teinuria early in pregnancy puts women withchronic hypertension at higher risk for adverse neo-natal outcomes.4 Rey and Couturier5 retrospectivelyevaluated the course of 298 pregnant women withchronic hypertension whose antihypertensive medi-cations had been discontinued or reduced in dosesearly in pregnancy. Neither superimposed pre-eclampsia, preterm delivery, abrupto placentae, norperinatal death was less frequent than in treatedwomen. Although placebo-controlled trials on anti-hypertensive drug treatment in pregnancy are lack-ing, considerable data have accumulated on thistopic (Table 1).

Correspondence: T Rosenthal, MD, Chorley HypertensionResearch Institute, Chaim Sheba Medical Center, Tel Hashomer52621, Israel. E-mail: trosenthsheba.health.govil

scores that some antihypertensive drugs can be usedsafely at certain stages of pregnancy, while others are

suspect and to be avoided at all costs. The lack of pla-cebo-controlled studies on the treatment of severehypertension in pregnancy due to ethical consider-ations is discussed against the background of thepressing need to treat these women despite the poss-ible deleterious effects of antihypertensive drugsJournal of Human Hypertension (2002) 16, 293–298. DOI:10.1038/sj/jhh/1001400

Methyldopa

On the basis of reports of stable uteroplacental bloodflow and fetal haemodynamics,6 methyldopa has become the preferred agent as first-line therapy andhas been used most commonly in randomisedtrials.7 It is considered the safest and most effi-cacious antihypertensive drug for use in pregnancyand is therefore recommended by all workinggroups.8 Kirsten and colleagues9 consider it the onlyacceptable drug during the first trimester of preg-nancy.

Alpha-and beta-adrenergic blockingagents – labetalol

When methyldopa causes somnolence and cannot be tolerated, alternatives such as the alpha-beta-adrenergic blocking agent, labetalol, may be used.Clinical experience with labetalol is extensive andit is among the most widely used antihypertensivedrugs in pregnancy.10 Blood pressure and pro-teinuria fell significantly in a placebo controlledtrial of labetalol in a cohort of 144 women with preg-nancy-induced mild and moderate hypertension.However, gestation was not significantly prolongedand measures of clinical outcome were not signifi-cantly altered in these women.11 Possible advan-tages and no evidence of disadvantages for the fetus



Antihypertensive drugs and the fetusT Rosenthal and S Oparil

294

Journal of Human Hypertension

Table 1 Antihypertensive therapy of chronic hypertension inpregnancy

Drug Dosage Additional comments

Methyldopa 500–3000 mg Considered to be drug of choicein 2– 4 divided because of extensive experience

dosesLabetalol 200–1200 mg Similar in ef ficacy and safety to

in 2–3 divided methyldopadoses

Beta-blockers variable Possibility of fetal bradycardia,lower birth weight (when usedearly in pregnancy)

Calcium variable Accumulating data supportchannel maternal and fetal safety; may blockers interact with magnesium

sulfate

Alpha- variable Scant data for use in pregnancy blockers

Clonidine 0.1–0.8 mg in Limited data

2– 4 divideddoses

Thiazide variable May be associated withdiuretics diminished volume expansion

in pregnancy; may be necessaryin salt-sensitive hypertensivesat lower doses

Angiotensin- contraindicated Contraindicated in pregnancy;converting neonatal anuric renal failureenzymeinhibitors

Angiotensin contraindicated Contraindicated in pregnancy;receptor neonatal anuria renal failure.antagonists

From: August P, Falkner B. Hypertension in pregnancy and inchildren. In: Antman E (ed). Cardiovascular Therapeutics: AModified Companion to Braunwald’s Heart Disease. W.B. Saund-ers Company: Philadelphia, PA, Chapter 38, 2001 (publishedlast week).

were reported in another trial with labetalol, thistime a double-blind controlled study in 152women.12 Thus labetalol is generally not consideredto adversely affect the fetus during the third trimes-ter of pregnancy, and is commonly used to treathypertension at that stage.10

Beta-adrenergic blocking agents

The beta-adrenergic receptor antagonists, includingmetoprolol and atenolol, are also considered safeand effective in late gestation, but have beenreported to cause some fetal problems when given inearly or mid-gestation.13,14 Beta-blockers, especiallyatenolol, have been linked with fetal growth retar-dation when given early in pregnancy.15 A large-scale retrospective study of atenolol in 78 preg-nancies showed that the drug was associated withfetal growth retardation, particularly when it wasgiven early in pregnancy and continued for a longtime.16 These authors urge avoiding atenolol in theearly stages of pregnancy and exercising caution at

later stages. A randomised trial in which atenolol orplacebo was given before 24 weeks of gestation tonormotensive pregnant women with high cardiacoutput in an attempt to prevent pre-eclampsiarevealed similar results, namely smaller babies thanthose getting placebo.17 Churchill et al ,18 on the

other hand, found little difference in fetal growth between women who began atenolol in the secondtrimester, women on other antihypertensive drugs,and those using no medication.

A basic concern of these and other authors is thelevel at which blood pressure should be treated andto which blood pressure should be lowered in preg-nancy. Magee19 raises this question, noting thatmany factors are likely to affect fetal growth otherthan maternal blood pressure. He points to the con-nection between antihypertensive treatment and thegoal of best perinatal outcome, which remains to beaddressed. An international multicentre randomisedcontrolled trial, Control of Hypertension in Preg-

nancy and small for gestational age (SGA) Infants(CHIPS), is currently being designed to answerthese questions.20

Since topical eye medications are absorbedthrough the nasopharyngeal mucosa and can there-fore enter the systemic circulation, beta-blocker eyedrops should be avoided in the first trimester of pregnancy. This is especially noteworthy becauseglaucoma can occur during the second to the fifthdecade of life, a time when women are at risk forpregnancy. Indeed, Wagebvoort et al 21 reported acase in which timolol eye drops were associatedwith bradycardia and arrhythmia in the fetus, aphenomenon observed also in sheep by VanTetten.22 The literature on the use of other forms of eye drops, such as betaxolol and levobunolol inpregnant women, is lacking.23

Alpha adrenergic blocking agents

Although prazosin is rarely used in pregnancy, itwas recently reported that in the third trimester,fetal concentrations of prazosin are 10–20% of thematernal concentrations, suggesting the possibilitythat prazosin may affect the fetus.24 Prazosin has been associated with transverse limb defects in the

fetus in a case report.25

Prazosin taken from day 7of gestation resulted in limb defects, hypoxic renaldamage, and intrauterine death at 20 weeks. Theseauthors25 attributed the anomalies to drug-inducedhypotension in the mother, with resultant dimin-ished uteroplacental blood flow, fetal hypotensionand hypoxia. This is only a speculation, and if thiswere the case, we would expect to see more limbreduction defects in the population treated withantihypertensive drugs than we actually do. Oneshould be cautious about drawing conclusions con-cerning the adverse effects of drugs on the fetus based on isolated case reports since fetal defectsoccur in a sporadic case in the general population of




295pregnant women independent of both hypertensionand antihypertensive therapy.

Vasodilators

The potent vasodilator minoxidil26 has been shown

to adversely affect the fetus causing hypertrichosisof the back and extremities in a 38-week-old infant born to a woman administered a daily regimen of minoxidil, captopril and propranolol. Additionalpathologic features included dysmorphic facial fea-tures, bilateral fifth finger clinodactyly, and anomphalocele containing bowel loops. The hypertri-chosis was considered evidence of the transpla-cental effect of minoxidil, but does not necessarilyaccount for the other pathologic features. The con-genital abnormalities might be attributable to aninteraction among the three drugs. Animal safetystudies27 of the effects of minoxidil in pregnant ratsand rabbits revealed no teratogenic effects in rats

when given at 20 and 70 times routine human doseson gestation days 6 to 15, while rabbits given thosedoses on days 6–18 had smaller litter sizes andhigher rates of fetal absorption.

Calcium channel blocking agents

Calcium antagonists generally constitute second-line agents, usually administered late in pregnancy.A small multicentre prospective cohort study of firsttrimester exposures to calcium channel blockersreported no increase in major teratogenic risk.28 Thisstudy suggests that calcium channel blockers(especially nifedipine and verapamil) do not rep-resent a major teratogenic risk. The prematurity andlower birth weight that have been reported withincreased frequency among offspring of patientstreated with calcium channel blockers may be dueto the serious maternal hypertension and not to thetherapy per se. A larger multicentre study random-ised 145 pregnant women with mild to moderatehypertension to slow release nifedipine or no treat-ment. Neither benefit nor harm from the treatmentwas reported in the 138 women who began treat-ment in the second trimester.29 The literature is toosparse, however, to draw any definite conclusionsabout the safety of calcium channel blockers admin-

istered early during pregnancy.

Diuretics

The known association of pre-eclampsia withreduced plasma volume and worse fetal outcome inwomen with chronic hypertension, who failed toexpand their plasma volume appropriately in preg-nancy argues against use of diuretics in pregnancy.30

Indeed, plasma volume expansion was found to beminimal in women using diuretics from early preg-nancy compared with normotensive pregnantwomen.31 A meta-analysis of nine randomised trialsperformed by Collins et al ,32 involving more than


7000 pregnant women receiving diuretics, revealeda decrease in the tendency of the women to developoedema and/or hypertension. Pre-eclampsia,appeared to have been prevented even whenoedema was not a diagnostic criterion. This mayreflect the blood pressure-lowering action of

diuretics. There was little difference in postnatalsurvival between diuretic treated and untreatedgroups: stillbirths were about one-third less withtreatment, but small numbers made the differencestatistically insignificant. There was no increasedincidence of adverse fetal effects.

Although data concerning the use of diuretics inpregnant women with essential hypertension aresparse, the Working Group Report on High BloodPressure in Pregnancy, 20001 concluded that ges-tation does not preclude use of diuretics to reduceor control blood pressure in women whose hyper-tension predated conception or manifested beforemid-pregnancy. These safe and ef ficacious agents,

can markedly potentiate the response to other anti-hypertensive agents, and are not contraindicated inpregnancy except in settings where uteroplacentalperfusion is already reduced (pre-eclampsia andintrauterine growth restriction).

Angiotensin-converting enzymeinhibitors

Animal studies have found angiotensin-convertingenzyme inhibitors (ACEIs) to be associated withfetal anomalies. Captopril administered to two near-term pregnant guinea pigs reduced fetal ACEactivity below levels seen in control animals,33 indi-cating that the drug can adversely affect blood press-ure control during both fetal and neonatal life.Administration of enalapril to ewes34 producedunexpected fetal deaths, skeletal abnormalities, andan unexplained stillbirth. Histological examinationof the lungs of this last fetus showed inadequatelung expansion indicative of severe intrapartumasphyxia and/or possibly a surfactant deficiency.When given to lambs and rabbits late in preg-nancy,35 captopril resulted in a high percentage of stillbirths in the former and prolonged gestation inthe latter. These studies point to the rapid passage of captopril across the placenta. Captopril in pregnant

rabbits in another study36

reduced blood pressure,slowed uterine blood flow, and drastically decreaseduterine vein prostaglandin E (PGE). The importanceof PGE synthesis in maintaining uterine blood flowand the survival of the fetus evidenced by these fin-dings raises the possibility that uterine PGE syn-thesis is dependent on angiotensin II.

Experience with ACEIs in humans confirms muchof the data from animal studies. Fiocchi and co-workers,37 in a letter to the editor in the Lancet ,described a case in which captopril was giventhroughout pregnancy to a 47-year-old hypertensivewoman with no untoward events until weeks 32–36, when there was progressive retardation in fetal




296


growth according to imaging and biochemical para-meters. This baby was born with no abnormalitiesdespite continuous administration of captoprilthroughout the pregnancy. With some exceptions,38

despite early case reports supporting the safety of ACEIs in pregnancy, the literature is generally not

in favour of using ACEIs because of associated sev-ere fetal and neonatal disease.39 A number of reviews and reports addressed to clinical tetralogycounsellors cited oligohydramnios and/or neonatalanuria, pulmonary hydroplasia, mild to severe intra-uterine growth retardation, and fetal death associa-ted with ACEIs. Persistent anuria in neonates wasattributed to maternal intake of captopril40 and to a battery of antihypertensive drugs including enala-pril.41 Neonatal renal failure and some dysmorphicfeatures were described following captopril;42 thedeath of a child from pulmonary hypoplasia wasattributed to oligohydramnios following enalapril;43

and acute renal failure was reported in a premature

newborn following enalapril.44Two cases of bone hypocalvaria were reported by

Barr and Cohen,45 one in the fetus of a woman whoreceived captopril and another in a woman whoreceived lisinopril both fetuses had fetopathy withrenal tubular dysgenesis and severely underdevel-oped calvarial bone. Other cases of underdevelopedcalvaria induced by captopril were described byDuminy and Burger46 and Mheta and Modi.47 Theanomalies described in these cases—fetal and neo-natal mortality, neonatal anuria, intrauterine growthretardation,and calvarial hypoplasia—are connectedwith severe fetal hypotension during the second andthird trimester. The morphologic findings and/orsigns of fetal growth restriction attest to uterohypotension/hypoxia.

A French group48 reported fetal death, pretermdelivery, and small-for-age newborns in women tak-ing captopril or enalapril during pregnancy, but alsonoted that in seven cases in which ACEIs were com- bined with diuretics, perinatal outcome was unre-markable. Brent39 considered it important to alertphysicians to the possibility of fetal and neonataldisease following transplacental passage of captop-ril, especially since a report suggesting that capto-pril is not teratogenic49 raised the likelihood of physicians prescribing it during pregnancy.

Although there is agreement that ACEIs can posea risk to the fetus,39 there is controversy over thetiming and duration of exposure in relation to fetalrisk and the magnitude of the risk during the unsafestages. While an editorial in The Lancet in 198950

cautioned that most of the pregnant women reportedin the various studies were also receiving otherdrugs, there is no question that oligohydramnios,fetal death, neonatal anuria, intrauterine growthretardation and fetal calvarial hypoplasia are directeffects of ACEIs on the fetus. ACEIs are absolutelycontraindicated in women with child-bearing poten-tial, based on the evidence of a high degree of mor- bidity and mortality in fetuses or newborn infants

exposed to these drugs during pregnancy.51,52 Lip et al 53 further stated that there is no justification tocontinue using ACEIs once pregnancy is docu-mented, and recommended that they should bestopped or changed to an alternative agent.

Angiotensin II receptor antagonistsAdverse effects of angiotensin II receptor antagonistson fetal kidneys have been documented in rats andsheep,54–56 and recent case reports have provideddata on their effects on humans. Losartan, hydro-chlorothiazide, felodipine and metoprolol given toa 42-year-old woman from the beginning of preg-nancy57 resulted in a baby with varus deformation,of the left foot, clubbed right foot and fixed externalrotation of right knee, Potter’s facies, and patentductus arteriosus. This anuric baby died on the 4thpostnatal day. Microscopy revealed renal tubulardysgenesis.

In another case,58 a woman on candesartan gave birth to a baby girl with left sided facial palsy andplexus paresis who was anuric at 24 h postpartum,with steadily rising creatinine that dropped at 1month of age. The authors suspect that the candesar-tan was responsible for the acute perinatal renal fail-ure in this case.

Three patients59 on valsartan at the time of con-ception delivered babies that showed no congenitalabnormalities or evidence of renal dysfunction, oneof which had growth retardation. The authors con-cluded that activation of the AT1 receptor by angio-tensin II plays a role in vascular development andgrowth, so an AT1 antagonist should not be given towomen already pregnant or planning pregnancy.

Conclusions

The high risk of hypertension, particularly severehypertension, to the pregnant woman, mandates theuse of antihypertensive treatment despite possibledetrimental effects on the fetus. While antihyperten-sive therapy is indicated for maternal benefit, it mayalso permit prolongation of the pregnancy andthereby improve fetal maturity. However, severelyhypertensive women are usually delivered soonafter their blood pressure is controlled, since the

reduction in uteroplacental blood flow following thequick and dramatic reduction in maternal bloodpressure adversely affects the fetus.

Diagnosing any drug-related disorder can be dif-ficult. The relationship between a drug and an effectcan be definitively established only by withdrawalof the suspected offending agent and rechallenge—clearly out of the question in most cases. Studiesthat attempt to establish a cause and effect relation-ship based on clinical data are done on cohorts of varying sizes and are usually very small. The effectsof treating severe hypertension in pregnancy have been investigated in only a few placebo-controlledtrials. There is a pressing need for well-designed,




297controlled studies carried out by multidisciplinaryteams of obstetricians, hypertension specialists, epi-demiologists, and even geneticists. More infor-mation about the risks and safety of specific drugs,dosages and combinations should enable the phys-ician to be bolder in attempting to treat this con-

dition which if left unattended, will harm both themother and fetus.

References

1 Working Group Report on High Blood Pressure inPregnancy. Am J Obstet Gynecol 1990; 163: 1691–1712. NIH publication N000–3029. Revised July 2000.

2 De Swiet M Maternal blood pressure and birthweight(editorial). Lancet 2000; 355: 81.

3 Von Dadelszen P et al . Fall in mean arterial pressureand fetal growth restriction in pregnancy hyperten-sion: a meta-analysis. Lancet 2000; 355: 87–92.

4 Sibai BM et al . Risk factors for preeclampsia abruptionplacental, and adverse neonatal outcomes among

women with chronic hypertension. N Engl J Med 1998;338: 701–705.

5 Rey E, Couturier A. The prognosis of pregnancy inwomen with chronic hypertension. Am J Obstet Gyn-ecol 1994; 171: 410– 416.

6 Montan S et al . Effects of methyldopa on uteroplacen-tal and fetal hemodynamics in pregnancy-inducedhypertension. Am J Obstet Gynecol 1993; 168: 152–156.

7 Sibai BM. Treatment of hypertension in pregnantwomen. N Engl J Med 1996; 335: 257–265.

8 Lindheimer MD. Hypertension in pregnancy. Hyper-tension 1993; 22: 127–137.

9 Kirsten R, Nelson K, Kirsten D, Heintz B. Clinical phar-makokinetics of vasodilators – Part II. Clin Pharmaco-

kinet 1998; 35: 9–36.10 Sibai MB et al . A comparison of no medication versus

methyldopa or labetalol in chronic hypertension dur-ing pregnancy. Am J Obstet Gynecol 1990; 162: 960–967.

11 Pickles CJ, Symonds EM, Pipkin FB. The fetal outcomein a randomized double blind controlled trial of labet-alol versus placebo in pregnancy-induced hyperten-sion. Br J Obstet Gynecol 1989; 96: 38– 43.

12 Pickles CJ, Broughton Pipkin F, Symonds EM. A ran-domized placebo controlled trial of labetalol in thetreatment of mild to moderate pregnancy inducedhypertension. Br J Obstet Gynecol 1992; 99: 964–968.

13 Butters L, Kennedy S, Rubin PC. Atenolol in essentialhypertension during pregnancy. BMJ 1990; 301: 587–

589.14 Lip GYH et al . Effect of atenolol on birth weight. Am

J Cardiol 1997; 79: 1436–1438.15 Magee LA, Omstein MP, von Dsadelszen P. Fortnightly

review: management of hypertension in pregnancy.BMJ 1999; 318: 1332–1336.

16 Lydakis C et al . Atenolol and fetal growth in preg-nancies complicated by hypertension. Am J Hypertens1999; 12: 541–547.

17 Easterling TR et al . Prevention of preeclampsia a ran-domized trial of atenolol in hyperdynamic patients

before onset of hypertension. Obstet. Gynecol 1999; 93:725–733.

18 Churchill D, Bayliss H, Beevers G. Fetal growth restric-tion. Lancet 2000; 355: 1366–1367.


19 Magee L. Authors reply. Lancet 2000; 355: 1367.20 Magee LA et al . The generalizability of trial data; a

comparison of beta blocker trial participants with aprospective cohort of women taking beta blockers inpregnancy. Eur J Obstet Gynecol Reprod Biol 2001; 94:205–210.

21 Wagebvoort AM et al . Topical timolol therapy in preg-

nancy: is it safe for the fetus? Teratology 1998; 58:258–262.

22 Van Tetten GR. Cardiovascular effects of timolol in theanesthetized pregnant ewe and fetus. Proc West Phar-macol Soc 1980; 23: 191–195.

23 Kooner KS, Zimmerman TJ. Antiglaucoma therapyduring pregnancy – Part I. Ann Ophthalmol 1988; 20:166–169.

24 Bourget P et al . Weak placental passages of prazosin(Alpress) during the third trimester of pregnancy. J Gynecol Obstet Biol Reported Paris 1993; 22: 871–874.

25 Hurst JA et al . Transverse limb deficiency, facial cleft-ing and hypoxic renal damage: an association withtreatment of maternal hypertension? Clin Dysmorphol 1995; 4: 359–363.

26 Kaler SG et al . Hypertrichosis and congenital anomal-ies associated with maternal use of minoxidil. Pedi-atrics 1987; 79: 434 –436.

27 Carlson RG, Feenstra ES. Toxicologic studies with thehypotensive agent minoxidil. Toxicol Appl Pharmacol 1977; 39: 1–11.

28 Magee LA et al . The safety of calcium channel blockersin human pregnancy: A prospective, multicentercohort study. Am J Obstet Gynecol 1996; 174: 823–828.

29 Gruppo di studio Ipertensione in Gravidanze. Nifedip-ine versus expectant management in mild to moderatehypertension in pregnancy. Br J Obstet Gynaecol 1998;105: 718–722.

30 Sibai BM, Grossman RA, Grossman HG. Effects of diuretics on plasma volume in pregnancies with longterm hypertension. Am J Obstet Gynecol 1984; 150:831–835.

31 Arias F, Zamora J. Antihypertensive treatment andpregnancy outcome in patients with mild chronichypertension. Obstet Gynecol 1979; 53: 489– 494.

32 Collins R, Yusuf S, Peto R. Overview of randomisedtrials of diuretics in pregnancy. BMJ 1985; 290: 17–23.

33 Davidson D, Stalcup SA, Mellins RB. Captopril admin-istration to the pregnant guinea pig inhibits fetal angi-otensin converting enzyme activity. Pediatr Res 1981;15: 658.

34 Broughton-Pipkin F, Wallace CP. The effect of enala-pril (MK421), an angiotensin converting enzymeinhibitor, on the conscious pregnant ewe and her foe-

tus. Br J Pharmacol 1986; 87: 533–542.35 Broughton-Pipkin F, Symonds EM, Turner SR. Theeffect of captopril (SQ14,255) upon mother and fetusin the chronically cannulated ewe and in the pregnantrabbit. J Physiol 1982; 323: 415– 422.

36 Ferris TF, Weir EK. Effect of captopril on uterine bloodflow and prostaglandin synthesis in the pregnant rab-

bit. J Clin Invest 1983; 71: 809–815.37 Fiocchi R et al . Captopril during pregnancy. Lancet

1984; 2: 1153.38 Coen G et al . Successful treatment of long lasting

severe hypertension with captopril during a twinpregnancy. Nephron 1985; 40: 498–500.

39 Brent RL. Angiotensin-converting enzyme inhibitors,an embryopathic class of drugs with unique proper-



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Antihipertensive drug fetal.pdf