A 22-year old woman, pregnant since 7-8 weeks, is treated with Renitec (enalapril) 5 mg/day. What a

Fråga: A 22-year old woman, pregnant since 7-8 weeks, is treated with Renitec (enalapril) 5 mg/day. What are the risks when ACE-inhibitors are used during pregnancy? Can the drug therapy be continued or at the other extreme, is there a significant risk for malformation in which case therapeutic abortion should be considered?

Sammanfattning: The use of ACE inhibitors during pregnancy may be harmful to the fetus by several mechanisms. Fetal and neonatal ACE activity can be severely suppressed, causing oligohydramnios, neonatal anuria and hypotension. Growth retardation and preterm delivery can occur, especially if the treatment is continued throughout pregnancy. The relative frequency of normal outcomes is unknown, since most information available is based on individual cases. Possible teratogenic effects of ACE inhibitors cannot be excluded, but case reports in which the use of these drugs is associated with observed malformations are very scarce and not conclusive. Thus, there is no indication for therapeutic abortion when pregnancy is diagnosed whilst on treatment with ACE inhibitors. However, ACE inhibitors should be avoided or withdrawn during pregnancy, unless their use is strongly indicated and no safer alternatives can be found.

Svar: The use of ACE-inhibitors during pregnancy may have potential risks to the fetus. This question was evaluated by the Drug Information Centre about one year ago (1). As there is now more concern about possible hazards, a new review has been made. By alterations in placental perfusion, fetal growth or survival may be affected. A retrospective study (2) concerning prenatal exposure to ACE-inhibitors described 31 pregnancies, during which 22 patients were treated with captopril (25-200 mg/day) and 9 were treated with enalapril (10-30 mg/day), mostly because of chronic essential or renovascular hypertension, unresponsive to alternative treatment. Preterm delivery occurred in 11 women. Of the 26 babies liveborn, 6 were small for gestational age. Two pregnancies exposed to enalapril miscarried. Two fetal deaths occurred with captopril and one with enalapril, but all three were associated with severe proteinuric hypertension. Since this group consisted of high-risk pregnancies, both the severity of maternal disease, as well as the ACE inhibitors could account for the fetal death, growth retardation or preterm delivery observed.

The presence of these so called confounding factors in such studies makes the evaluation of a possible cause-effect relationship more difficult.

By crossing the placental barrier (3), captopril and enalapril can also decrease fetal and neonatal ACE activity, with consequent alterations in systemic and renal haemodynamics. Cases of severe oligohydramnios, neonatal anuria, hypotension and a persistent ductus arteriosus during maternal treatment with ACE inhibitors have been reported. For instance a woman taking enalapril 20 mg/day, was 17 days later delivered of a 35 weeks´ gestation preterm infant (4). The infant was anuric from birth, probably due to the suppressed angiotensin converting enzyme activity. The plasma renin values were ten-fold higher than in normal newborns. Cases of fatal respiratory distress syndrome, due to oligohydramnios, have been reported as well (5,6).

It seems that, when ACE inhibitors are withdrawn in the first trimester, the infant is likely to be born at or near term and to be of normal birthweight, whereas continued treatment carries a risk of early delivery and neonatal complications (7). On the other hand, pregnancies have gone very successfully to term (8), even though captopril (100 mg/day) was administered throughout the third trimester. The infants delivered were in good health and showed no signs of renal failure or hypotension. In these cases ACE inhibitors proved to be valuable in preventing the recurrence of preeclamptic episodes.

Another question of concern is the possibility of teratogenic effects. There seem to be no reports of direct teratogenicity in animals treated with ACE inhibitors, although an increased rate of stillbirths has been observed (9). A single case has been reported of a 30-year old woman who became pregnant while on treatment with captopril, propranolol and amiloride (10). The pregnancy was terminated and a malformed fetus was delivered with the left leg ending in the mid-thigh and a defective vault of the skull. The possibility was raised by the authors that this malformation could be associated with the use of captopril. Another case report (11) mentions a rare ossification defect of the occipital skull of an infant whose mother was on treatment with enalapril, azathioprine, atenolol and prednisolone throughout pregnancy. These two cases are worth noting, but do not seem to offer any base to assume a cause-effect relationship (12). Recently, a case has been reported of a child who died of pulmonary hypoplasia as a result of oligohydramnios (13). The mother was taking enalapril 20 mg/day, as well as propranolol 40 mg/day and hydrochlorothiazide 50 mg/day. Autopsy examination also revealed severe renal tubular malformation. It was considered to be unclear whether the renal defects were due to reduced renal blood flow as a secondary effect of enalapril, or to a direct teratogenic effect. 1 Drugline nr 06724 (år 1989) 2 Kreft-Jais C: Angiotensin-converting enzyme inhibitors during pregnancy: a survey of 22 patients given captopril and nine given enalapril. Br J Obstet Gynecol 1988; 95: 420-422 3 FASS 1990, sid 193, 807 4 Schubiger G, Flury G, Nussberger J: Enalapril for pregnancy-induced hypertension: acute renal failure in a neonate. Ann Intern Med 1988; 108: 215-216 5 Scott AA, Purohit DM: Neonatal renal failure: a complication of maternal antihypertensive therapy. Am J Obstetr Gynecol 1989; 160 (part 1): 1223-1224 6 Broughton Pipkin F, Symonds FM, Turner SR: The effect of captopril upon mother and fetus in the chronically cannulated ewe and in the pregnant rabbit. J Physiol 1982; 323: 415-422 7 Are ACE inhibitors safe in pregnancy? Lancet 1989; II: 482-483 8 Coehn G, Cugini P, Gerlini G, Finistauri D, Cinotti GA: Successful tratment of long-lasting severe hypertension with captopril during a twin pregnancy. Nephron 1985; 40: 498-500 9 Broughton Pipkin F, Turner SR, Symonds EM: Possible risk with captopril in pregnancy: some animal data. Lancet 1980; I: 1256 10 Duminy PC, Burger PdT: Fetal abnormality associated with the use of captopril during pregnancy. S Afr Med J 1981; 60: 805 11 Mehta N, Modi N: ACE inhibitors in pregnancy. Lancet 1989; II: 96 12 Prof Bengt Källen, Embryologiska institutionen, Lund, personal communication 13 Cunniff C, Lyons Jones K, Phillipson J, Benirschke K, Short S, Wujek J: Oligohydramnios sequence and renal tubular malformation associated with maternal enalapril use. Am J Obstet Gynecol 1990; 162: 187-189