Antihypertensive
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 2nd and 3rd Trimesters
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
The fetal toxicity of benazepril in the 2nd and 3rd trimesters is similar to other angiotensin-converting enzyme (ACE) inhibitors. The use of this drug during the 2nd and 3rd trimesters may cause teratogenicity and severe fetal and neonatal toxicity. Fetal toxic effects may include anuria, oligohydramnios, fetal hypocalvaria, intrauterine growth restriction (IUGR), prematurity, and patent ductus arteriosus. Stillbirth or neonatal death may occur. Anuria-associated oligohydramnios may produce fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Severe anuria and hypotension, which is resistant to both pressor agents and volume expansion, may occur in the newborn following in utero exposure. Newborn renal function and blood pressure should be closely monitored.
FETAL RISK SUMMARY
Benazepril is an ACE inhibitor. It is indicated for the treatment of hypertension. It is metabolized to benazeprilat, a more potent active metabolite. The effective half-life of accumulation of benazeprilat is 10–11 hours (1).
Reproduction studies have been conducted in mice, rats, and rabbits. No teratogenic effects were observed at doses that were 9, 60, and >0.8 times, respectively, the maximum recommended human dose based on BSA (assuming a 50-kg woman) (1).
Benazepril crosses the human placenta (1). This is consistent with the molecular weight (about 425 for the free base of the parent drug) and suggests that its active metabolite also will cross.
A 1997 report described the use of benazepril (40 mg/day) in a 35-year-old woman with chronic hypertension (2). Treatment began several years before conception. Anhydramnios was noted at 27 weeks’ gestation and the drug was discontinued. Twelve days later, complete resolution of the severe oligohydramnios was documented and the woman eventually delivered a healthy 2600-g (10th percentile) male infant at 38 weeks’ gestation. No signs or symptoms of impaired renal function were observed in the healthy infant (2).
A retrospective study using pharmacy-based data from the Tennessee Medicaid program identified 209 infants born between 1985 and 2000 who had 1st trimester exposure to ACE inhibitors (3). Infants of mothers with evidence of diabetes, either before or during pregnancy, were excluded, as were those exposed to angiotensin-receptor antagonists (ARBs), ACE inhibitors, or other antihypertensives beyond the 1st trimester, and known teratogens. The subject group (N=209) was compared with two groups, other antihypertensives (N=202) and no antihypertensives (N=29,096). The number of major birth defects in each of the three groups was 18 (8.6%), 4 (2%), and 834 (2.9%), respectively. Compared with the no antihypertensives group, exposure to ACE inhibitors was associated with a significantly increased risk of major defects (relative risk [RR] 2.71, 95% confidence interval [CI] 1.72–4.27). When the analysis was conducted by the type of defect, the highest rates were with cardiovascular defects, 9, 2, and 294, respectively, RR 3.72, 95% CI 1.89–7.30, and with CNS defects, 3, 0, and 80, respectively, RR 4.39, 95% CI 1.37–14.02. The major defects observed in the subject group were atrial septal defect (N = 6) (includes three with pulmonic stenosis and/or three with patent ductus arteriosus [PDA]), renal dysplasia (N = 2), PDA alone (N = 2), and one each of ventricular septal defect, spina bifida, microcephaly with eye anomaly, coloboma, hypospadias, intestinal and choanal atresia, Hirschsprung disease, and diaphragmatic hernia (3). In an accompanying editorial, it was noted that neither previous reports of 1st trimester exposure to ACE inhibitors nor the animal studies had observed an increased risk of birth defects (4). It also was noted that no mechanism for ACE inhibitor-induced teratogenicity was known. A subsequent communication raising concerns about the validity of the study in terms of adequate exclusion of diabetes, charting and coding errors in busy medical practices, and the effects of maternal obesity (5) was addressed by the investigators (6).
Benazepril and other ACE inhibitors are human teratogens when used in the 2nd and 3rd trimesters, producing fetal hypocalvaria and renal defects. The cause of the defects and other toxicity is probably related to fetal hypotension and decreased renal blood flow. The compromise of the fetal renal system may result in severe, and at times fatal, anuria, both in the fetus and in the newborn. Anuria-associated oligohydramnios may produce pulmonary hypoplasia, limb contractures, persistent PDA, craniofacial deformation, and neonatal death (7,8). IUGR, prematurity, and severe neonatal hypotension may also be observed.
Two reviews of fetal and newborn renal function indicated that both renal perfusion and glomerular plasma flow are low during gestation and that high levels of angiotensin II may be physiologically necessary to maintain glomerular filtration at low perfusion pressures (9,10). Benazepril prevents the conversion of angiotensin I to angiotensin II and, thus, may lead to in utero renal failure. Since the primary means of removal of the drug is renal, the impairment of this system in the newborn prevents elimination of the drug resulting in prolonged hypotension. Newborn renal function and blood pressure should be closely monitored. If oligohydramnios occurs, stopping benazepril may resolve the problem but may not improve infant outcome because of irreversible fetal damage (7).
In those cases in which benazepril must be used to treat the mother’s disease, the lowest possible dose should be used combined with close monitoring of amniotic fluid levels and fetal well-being. Guidelines for counseling exposed pregnant patients have been published and should be of benefit to health professionals faced with this task (7,11). However, the observation in Tennessee Medicaid data of an increased risk of major congenital defects after 1st trimester exposure to ACE inhibitors raises concerns about teratogenicity that have not been seen in other studies (4). Medicaid data are a valuable tool for identifying early signals of teratogenicity, but are subject to a number of shortcomings and their findings must be considered hypotheses until confirmed by independent studies.
In a 2002 case report, a woman with chronic hypertension presented at about 24 weeks’ gestation with severe oligohydramnios (amniotic fluid index <2) (12). Her medications included benazepril, carvedilol, amiodarone, and furosemide. The fetus had a misshapen cranium with overlapping sutures, pericardial effusion, small bladder, echogenic focus in the heart, echogenic bowel, and normal-appearing kidneys. All the drugs except carvedilol were discontinued. An examination 18 days later revealed normal amniotic fluid volume and normal cranial anatomy. At about 37 weeks, she gave birth to a 2060-g (<3rd percentile) female infant with Apgar scores of 7 and 9 at 1 and 5 minutes, respectively. The infant’s initial physical examination was normal. Except for bilious vomiting on day 1, that resolved by day 2, the infant’s hospital course was normal. At 1 year of age, the infant was healthy and weighed 18 lb (5th percentile) (12).
A 2012 review of the use of ACE inhibitors and ARBs in the 1st trimester concluded that there may be an elevated teratogenic risk, but the risk appeared to be related to other factors (13). The factors, that typically coexist with hypertension in pregnancy, included diabetes, advanced maternal age, and obesity.
BREASTFEEDING SUMMARY
Benazepril and benazeprilat are excreted into human breast milk (14). Nine women were given benazepril 20 mg/day for 3 days. At 1 hour after a dose, peak milk concentrations of benazepril were 0.9 mcg/L, whereas the peak level of benazeprilat was 2 mcg/L at 1.5 hours postdose. The estimated infant dose as a percentage of the mother’s weight-adjusted dose was <0.14% (14). These results are consistent with the data from other ACE inhibitors (see Captopril and Enalapril) that have found low amounts in milk and no adverse effects in nursing infants.
References
1.Product information. Benazepril Hydrochloride. Andrx Pharmaceuticals, 2005.
2.Chisholm CA, Chescheir NC, Kennedy M. Reversible oligohydramnios in a pregnancy with angiotensin-converting enzyme inhibitor exposure. Am J Perinatol 1997;14:511–3.
3.Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, Hall K, Ray WA. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006;354:2443–51.
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6.Cooper WO, Ray WA. Reply—ACE inhibitors and major congenital malformations. N Engl J Med 2006;355:1281.
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8.Shotan A, Widerhorn J, Hurst A, Elkayam U. Risks of angiotensin-converting enzyme inhibition during pregnancy: experimental and clinical evidence, potential mechanisms, and recommendations for use. Am J Med 1994;96:451–6.
9.Robillard JE, Nakamura KT, Matherne GP, Jose PA. Renal hemodynamics and functional adjustments to postnatal life. Semin Perinatol 1988;12:143–50.
10.Guignard J-P, Gouyon J-B. Adverse effects of drugs on the immature kidney. Biol Neonate 1988;53:243–52.
11.Brent RL, Beckman DA. Angiotensin-converting enzyme inhibitors, an embryopathic class of drugs with unique properties: information for clinical teratology counselors. Teratology 1991;43:543–6.
12.Muller PR, James A. Pregnancy with prolonged fetal exposure to an angiotensin-converting enzyme inhibitor. J Perinatol 2002;22:582–4.
13.Polifka JE. Is there an embryopathy associated with first-trimester exposure to angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists? A critical review of the evidence. Birth Defects Res (Part A) 2012;94:576–98.
14.Kaiser G, Ackerman R, Dieterle W, Fleiss PM. Benazepril and benazeprilat in human plasma and breast milk (abstract). Eur J Clin Pharmacol 1989;36(Suppl):A303. As cited by National Library of Medicine LactMed database, September 7, 2013.