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 perindopril 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
Perindopril, an ACE inhibitor, is a prodrug that is hydrolyzed in vivo to the active agent, perindoprilat. The agent is used in the management of essential hypertension.
Reproduction studies have been conducted with perindopril in mice, rats, rabbits, and cynomolgus monkeys (1). No evidence of teratogenicity was observed in these species at doses 6, 670, 50, and 17 times, respectively, the maximum recommended human dose based on BSA for a 50-kg adult (MRHD). At 6 times the MRHD in rats, no adverse effects on reproductive performance or fertility were observed in male and female rats (1).
It is not known if either perindopril or its metabolite, perindoprilat, crosses the human placenta to the fetus. The molecular weights of perindopril (about 368 for the free acid or 442 for the salt form) and perindoprilat (less than the prodrug) suggest that transfer to the embryo and fetus will occur.
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 (2). 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 exposure to known teratogens. Two comparison groups, other antihypertensives (N = 202) and no antihypertensives (N = 29,096), were formed. 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 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 (2). 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 (3). 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 (4) was addressed by the investigators (5).
Perindopril 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 (6,7). 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 (8,9). Perindopril 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 perindopril may resolve the problem but may not improve infant outcome because of irreversible fetal damage (6). In those cases in which perindopril 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 (6,10).
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 (3). 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.
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 (11). The factors, that typically coexist with hypertension in pregnancy, included diabetes, advanced maternal age, and obesity.
BREASTFEEDING SUMMARY
No reports describing the use of the prodrug perindopril during human lactation have been located. The molecular weights of perindopril (about 368 for the free acid and 442 for the salt form) and its active metabolite, perindoprilat (molecular weight less than perindopril), suggest that both will be excreted into breast milk. The effects on a nursing infant from exposure to perindopril or perindoprilat in milk are unknown. However, other agents in this class are excreted into milk and, because the amounts are low and no adverse effects have been observed in nursing infants, are classified as compatible with breastfeeding by the American Academy of Pediatrics (see also Captopril and Enalapril).
References
1.Product information. Aceon. Solvay Pharmaceuticals, 2000.
2.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.
3.Friedman JM. ACE inhibitors and congenital anomalies. N Engl J Med 2006;354:2498–500.
4.Scialli AR, Lione A. ACE inhibitors and major congenital malformations. N Engl J Med 2006;355:1280.
5.Cooper WO, Ray WA. Reply—ACE inhibitors and major congenital malformations. N Engl J Med 2006;355:1281.
6.Barr M Jr. Teratogen update: angiotensin-converting enzyme inhibitors. Teratology 1994;50:399–409.
7.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.
8.Robillard JE, Nakamura KT, Matherne GP, Jose PA. Renal hemodynamics and functional adjustments to postnatal life. Semin Perinatol 1988;12:143–50.
9.Guignard J-P, Gouyon J-B. Adverse effects of drugs on the immature kidney. Biol Neonate 1988;53:243–52.
10.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.
11.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.