Publications

Published: December 1998

ACE Inhibitors in Early Pregnancy

Prescriber Update 17: 25–27
December 1998

Medsafe Editorial Team

Oligohydramnios, renal failure, bony malformations and prolonged hypotension have been associated with the use of ACE inhibitors in the second and third trimesters of pregnancy. However, recent case series suggest that teratogenicity or toxicity may not be a problem if a woman becomes pregnant while taking an ACE inhibitor.

Among a total of 93 completed pregnancies (including one twin) exposed to an ACE inhibitor during the first trimester, only one case of congenital anomaly was identified (congestive cardiomyopathy), and no cases of neonatal renal dysfunction occurred. Preterm birth, low birthweight and intrauterine growth retardation were common; possible causes were medication, more serious maternal illness and twin pregnancy. Two babies died in the perinatal period.

ACE inhibitors need not be contraindicated in women of childbearing potential, but women intending to become pregnant should switch from an ACE inhibitor in anticipation. A contraindication applies after the first trimester.

Foetal toxicity occurs with ACE inhibitor therapy in 2nd and 3rd trimesters
Outcome from use in the first trimester generally good
Negative outcomes may be cause by the woman's disease or medication
Contraindication not necessary in women of childbearing potential
Advise according to foetal exposure and maternal disease
References

Foetal toxicity occurs with ACE inhibitor therapy in 2nd and 3rd trimesters

The use of an ACE inhibitor during the second and third trimesters of pregnancy has been associated with a number of serious foetal malformations including oligohydramnios, foetal and neonatal renal failure, bony malformations, limb contractures, pulmonary hypoplasia, prolonged hypotension and neonatal death.1,2 ACE inhibitors are contraindicated after week 12 of pregnancy.

However, several recently published case series are reassuring about outcome when exposure to an ACE inhibitor occurred only in the first trimester. In these series the women were treated for hypertension or prevention of diabetic nephropathy.

Outcome from use in the first trimester generally good

From the computerised records of an antenatal hypertension clinic, Lip et al3 identified 18 women who had taken an ACE inhibitor during pregnancy. ACE inhibitor treatment was stopped at a mean gestation of 10.3 weeks (range 6-25; 6 continued beyond 12 weeks). Alternative antihypertensives were used throughout pregnancy by 12 women, and one woman had therapy initiated at 33 weeks. Two women had missed abortions, but the remaining pregnancies proceeded to the delivery of a live infant at a mean gestational age of 34.1 (28-41) weeks. The examining paediatrician found no congenital anomalies or neonatal renal dysfunction. Follow-up of 10 babies after discharge also failed to identify any problems.

The US Centres for Disease Control and Prevention4 reported the foetal outcome in 66 women who took an ACE inhibitor during the first 14 weeks of pregnancy only. Spontaneous abortion occurred in 23% of these women (background rate approximately 15%). In the 48 live-born neonates there was no evidence of renal tubular dysfunction, but there were 3 cases of intrauterine growth retardation (one case was a twin born at 36 weeks), and one case of patent ductus arteriosus in the baby of a woman treated with digoxin throughout pregnancy.

Another series from Israel5 included 8 women with nine newborns who were exposed to an ACE inhibitor for 2-12 weeks during the first trimester. Eight babies were born alive, and the mean gestation was 34.5 (range 26-40) weeks with a mean birthweight of 2288g. The lowest birthweights and earliest preterm deliveries occurred in the twin pregnancy and in babies of two women with severe disease. In one of these cases the baby had intrauterine growth retardation and died before delivery. No neonate had any detected malformations. All women were taking additional antihypertensive agents.

A fourth study6 used Danish health records and searched for discharge diagnoses of congenital malformations or renal failure in babies born to 21 women who had received a prescription for an ACE inhibitor during the first trimester of pregnancy. No babies were stillborn, and there were no cases of neonatal renal failure. However, one infant, delivered at 27 weeks’ gestation (birthweight 725g) to a diabetic mother died at one week, and another neonate had congestive cardiomyopathy without structural malformations.

Negative outcomes may be caused by the woman’s disease or medication

Several conclusions can be drawn from these four studies. Firstly, it is not possible to be certain whether the low birthweights, preterm deliveries and intrauterine growth retardation were associated with the mothers’ treatment or disease. Secondly, although foetopathy from use of ACE inhibitors during the first trimester cannot be excluded with the total sample of 93 completed pregnancies in these studies, the outcome of these pregnancies does not give cause for alarm.

Contraindication not necessary in women of childbearing potential

Present data do not give reason to contraindicate ACE inhibitors in women of childbearing potential. However, if pregnancy is planned in a woman taking an ACE inhibitor, it is best to switch medication in advance, unless there are specific advantages of ACE inhibitor therapy.

Advise according to foetal exposure and maternal disease

If pregnancy is confirmed in a woman taking an ACE inhibitor, she should be referred promptly to a specialist for a switch to an alternative means of management for her condition. The woman should be advised not to discontinue her medication prior to the consultation because of the risk to mother and foetus of inadequately controlled hypertension. With regard to the safety of the foetus, the woman should be counselled according to the exposure of the foetus and the seriousness of her disease. A woman whose foetus has been exposed to an ACE inhibitor only during the first trimester can be assured that the foetus is unlikely to be harmed. Nevertheless, the woman should not be led to believe that the safety of the baby is guaranteed.

Women who are not found to be pregnant until their use of an ACE inhibitor has continued into the second trimester should be advised that there is a significant risk of foetal toxicity which increases as the pregnancy advances. The consequences of continuing the pregnancy should be discussed and a referral made for assessment and appropriate management.

References
  1. Shotan A, Widerhorn J, Hurst A, Elkayam U. Risks of angiotensin-converting enzyme inhibition during pregnancy: experimental and clinical evidence, potential mechanisms, and recommendaions for use. Amer J Med 1994;96:451-6.
  2. ACE inhibitors contraindicated in pregnancy. Clinical Services Letter No.266, Aug 1992, p.5
  3. Lip GYH, Churchill D, Beevers M, Auckett A, Beevers DG. Angiotensin-converting-enzyme inhibitors in early pregnancy. Lancet 1997;350:1446-7.
  4. Centres for Disease Control and Prevention. Postmarketing surveillance for angiotensin-converting enzyme inhibitor use during the first trimester of pregnancy—United States, Canada, and Israel, 1987-1995. JAMA 1997;277:1193-4.
  5. Bar J, Hod M, Merlob P. Angiotensin converting enzyme inhibitors use in the first trimester of pregnancy. Intern J Risk & Safety in Med 1997;10:23-6.
  6. Steffensen FH, Nielsen GL, Sørensen HT, Olesen C, Olsen J. Pregnancy outcome with ACE-inhibitor use in early pregnancy. Lancet 1998;351:596.