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ACE Inhibitors in Early Pregnancy

Web site: December 1998Prescriber Update No.17:25-27

Medsafe Editorial Team

Oligohydramnios, renal failure, bony malformations and prolongedhypotension have been associated with the use of ACE inhibitors in thesecond and third trimesters of pregnancy. However, recent case seriessuggest that teratogenicity or toxicity may not be a problem if a womanbecomes pregnant while taking an ACE inhibitor.

Among a total of 93 completed pregnancies (including one twin) exposedto an ACE inhibitor during the first trimester, only one case of congenitalanomaly was identified (congestive cardiomyopathy), and no cases ofneonatal renal dysfunction occurred. Preterm birth, low birthweight and

intrauterine growth retardation were common; possible causes weremedication, more serious maternal illness and twin pregnancy. Two babiesdied in the perinatal period.

ACE inhibitors need not be contraindicated in women of childbearingpotential, but women intending to become pregnant should switch from anACE inhibitor in anticipation. A contraindication applies after the firsttrimester.

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 pregnancyhas been associated with a number of serious foetal malformations includingoligohydramnios, foetal and neonatal renal failure, bony malformations, limbcontractures, pulmonary hypoplasia, prolonged hypotension and neonataldeath.1,2 ACE inhibitors are contraindicated after week 12 of pregnancy.

However, several recently published case series are reassuring about outcomewhen exposure to an ACE inhibitor occurred only in the first trimester. In theseseries the women were treated for hypertension or prevention of diabeticnephropathy.

Outcome from use in the first trimester generally good

From the computerised records of an antenatal hypertension clinic, Lip et al 3identified 18 women who had taken an ACE inhibitor during pregnancy. ACEinhibitor treatment was stopped at a mean gestation of 10.3 weeks (range 6-25; 6continued beyond 12 weeks). Alternative antihypertensives were usedthroughout pregnancy by 12 women, and one woman had therapy initiated at 33weeks. Two women had missed abortions, but the remaining pregnancies

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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 orneonatal renal dysfunction. Follow-up of 10 babies after discharge also failed toidentify any problems.

The US Centres for Disease Control and Prevention

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reported the foetal outcomein 66 women who took an ACE inhibitor during the first 14 weeks of pregnancyonly. Spontaneous abortion occurred in 23% of these women (background rateapproximately 15%). In the 48 live-born neonates there was no evidence of renaltubular dysfunction, but there were 3 cases of intrauterine growth retardation(one case was a twin born at 36 weeks), and one case of patent ductusarteriosus in the baby of a woman treated with digoxin throughout pregnancy.

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

A fourth study6 used Danish health records and searched for dischargediagnoses of congenital malformations or renal failure in babies born to 21women who had received a prescription for an ACE inhibitor during the firsttrimester of pregnancy. No babies were stillborn, and there were no cases ofneonatal 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 womans disease or medication

Several conclusions can be drawn from these four studies. Firstly, it is notpossible to be certain whether the low birthweights, preterm deliveries andintrauterine growth retardation were associated with the mothers treatment ordisease. Secondly, although foetopathy from use of ACE inhibitors during the firsttrimester cannot be excluded with the total sample of 93 completed pregnanciesin these studies, the outcome of these pregnancies does not give cause foralarm.

Contraindication not necessary in women of childbearing potential

Present data do not give reason to contraindicate ACE inhibitors in women ofchildbearing potential. However, if pregnancy is planned in a woman taking an

ACE inhibitor, it is best to switch medication in advance, unless there are specificadvantages of ACE inhibitor therapy.

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Advise according to foetal exposure and maternal disease

If pregnancy is confirmed in a woman taking an ACE inhibitor, she should bereferred promptly to a specialist for a switch to an alternative means ofmanagement for her condition. The woman should be advised not to discontinue

her medication prior to the consultation because of the risk to mother and foetusof inadequately controlled hypertension. With regard to the safety of the foetus,the woman should be counselled according to the exposure of the foetus and theseriousness 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 isunlikely to be harmed. Nevertheless, the woman should not be led to believe thatthe safety of the baby is guaranteed.

Women who are not found to be pregnant until their use of an ACE inhibitor hascontinued into the second trimester should be advised that there is a significantrisk of foetal toxicity which increases as the pregnancy advances. Theconsequences of continuing the pregnancy should be discussed and a referralmade for assessment and appropriate management.