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 ramipril 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
Ramipril is an ACE inhibitor. Reproduction studies in rats, rabbits, and monkeys at doses 400, 2, and 400 times, respectively, the recommended human dose based on BSA revealed no teratogenic effects (1).
It is not known if ramipril crosses the human placenta. The molecular weight (about 417) is low enough that exposure of the embryo–fetus should be expected.
A 2005 case report described the pregnancy outcome of a 33-year-old woman treated with ramipril in the first 8 weeks of an unplanned pregnancy (2). Diseases in the patient included hypertension, morbid obesity, type 2 diabetes mellitus, and hypercholesterolemia. Other drugs used by the woman were glimepiride, orlistat, thiocolchicoside (a muscle relaxant), simvastatin, metformin, ciprofloxacin, and aspirin. When pregnancy was diagnosed at 8 weeks, all medications were stopped and she was started on methyldopa and insulin. She gave birth at 38 weeks to a 3470-g female infant with Apgar scores of 5 and 7 at 1 and 5 minutes, respectively. No minor or major malformations were observed in the 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 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 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).
A 2005 case report described a 28-year-old woman with chronic renal disease and hypertension (7). She presented at 25.5 weeks’ gestation and had been taking before and throughout pregnancy ramipril 50 mg/day, nifedipine 60 mg/day, atenolol 50 mg/day, and hydroxychloroquine 200 mg/day. Severe oligohydramnios was noted and estimated fetal weight was at the 15th percentile. Ramipril was stopped and the dose of atenolol was increased. Three weeks later, the amniotic fluid volume had returned to normal (amniotic fluid index 15.3). At 30 weeks, worsening hypertension and renal function was noted and the woman gave birth by cesarean section to an 880-g female infant with Apgar scores of 8 and 9. The infant had respiratory distress, but there was no evidence of cerebral hemorrhage and her renal impairment was resolving (7).
In a 2009 case report, a 42-year-old woman with type 2 diabetes and hypertension was treated during the first 17 weeks’ gestation with gliclazide 30 mg/day and ramipril 10 mg/day (8). This therapy was discontinued and replaced with insulin and methyldopa. At 36 weeks’, she gave birth by cesarean section to a healthy 3200-g female infant with Apgar scores of 8 and 10. No malformations were noted and the infant was doing well at 1.5 years of age (8).
Ramipril 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 (9,10). 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 (11,12). Ramipril 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 ramipril may resolve the problem but may not improve infant outcome because of irreversible fetal damage (9). In those cases in which ramipril 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 (9,13).
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.
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 (14). The factors, that typically coexist with hypertension in pregnancy, included diabetes, advanced maternal age, and obesity.
BREASTFEEDING SUMMARY
No reports describing the use of ramipril during lactation have been located. The molecular weight (about 417) is low enough that excretion into breast milk should be expected. Other ACE inhibitors are excreted into breast milk and the American Academy of Pediatrics classifies them as compatible with breastfeeding (see Captopril and Enalapril).
References
1.Product information. Altace. Monarch Pharmaceuticals, 2000.
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13.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.
14.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.