Lisinopril

 Risk Factor: CM*
 Class: CARDIOVASCULAR DRUGS / Antihypertensives / Angiotensin-Converting Enzyme Inhibitors

Contents of this page:

Fetal Risk Summary
Breast Feeding Summary
References
Questions and Answers

Fetal Risk Summary

Lisinopril is a long-acting angiotensin I-converting enzyme (ACE) inhibitor used for the treatment of hypertension (see also Captopril and Enalapril). The drug is not teratogenic in mice, rats, and rabbits treated with doses up to 55, 33, and 0.15 times, respectively, the maximum recommended human daily dose based on body surface area (1).

Use of lisinopril limited to the 1st trimester does not appear to present a significant risk to the fetus, but fetal exposure after this time has been associated with teratogenicity and severe toxicity in the fetus and newborn, including death. The pattern of fetal toxicity, including teratogenicity, appears to be similar to that experienced with captopril and enalapril.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 15 newborns had been exposed to lisinopril during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Two (13.3%) major birth defects were observed (0.6 expected), one of which was polydactyly (none expected). No anomalies were observed in five other categories of defects (cardiovascular defects, oral clefts, spina bifida, limb reduction defects, and hypospadias) for which specific data were available.

Two cases of lisinopril-induced perinatal renal failure in newborns were published in a 1991 abstract (2). Additional details were not provided other than that both infants had been exposed in utero to the agent. The authors noted, however, that the effects of angiotensin-converting enzyme inhibitors in the newborn are prolonged unless removed by dialysis, because 95% of the active metabolites are eliminated by renal excretion (2).

In a 2000 report, a woman with normal amniotic fluid volume and fetal measurements by ultrasound consistent with 18 weeks' gestation presented with severe chronic hypertension (3). She had been treated before conception and during the first 16 weeks with lisinopril but had self-stopped therapy 2 weeks before presentation. Because a combination of methyldopa, nifedipine, and labetalol failed to control her blood pressure, lisinopril was re-added to her regimen. At 22 weeks' gestation, the amniotic fluid index was 8 but declined to 0 at 24 weeks. A cesarean section was performed at about 27 weeks because of deteriorating maternal and fetal condition. The growth retarded, 680-g (3rd percentile) female infant had minimal respiratory distress syndrome. Severe renal impairment (maximum urine output 0.3 mL/kg/hr) was present during the first 6 days before improving after corrective surgery for bowel perforations secondary to necrotizing enterocolitis. She was discharged home on day 102 (3).

An 18-year-old woman received lisinopril, 10 mg/day, throughout gestation for the treatment of essential hypertension (4). No mention of amniotic fluid levels during pregnancy was made in this brief report. She delivered a premature, 1.48-kg, anuric infant at 33 weeks' gestation. Fetal calvarial hypoplasia was present. The normal-sized kidneys showed no evidence of perfusion on renal ultrasonography. An open biopsy at 11 weeks of age showed extensive atrophy and loss of tubules with interstitial fibrosis. The findings were compatible with exposure to a nephrotoxic agent. Peritoneal dialysis was instituted on day 8. Measurements of the drug in the dialysate indicated that removal of lisinopril was occurring. At 12 months of age, the infant continued to require dialysis (4).

Three cases of in utero exposure to ACE inhibitors, one of which was lisinopril, were reported in a 1992 abstract (5). The infant, delivered at 32 weeks' gestation because of severe oligohydramnios and fetal distress, suffered from intrauterine growth retardation, hypocalvaria, renal tubular dysplasia, and persistent renal insufficiency. The profound neonatal hypotension and anuria observed at birth improved only after dialysis. At the time of the report, the 15-month-old infant was maintained on dialysis.

A 1992 Reference described the effects of ACE inhibitors on pregnancy outcome (6). Among 106,813 women enrolled in the Tennessee Medicaid program who delivered either a liveborn or stillborn infant, 19 had taken either lisinopril, captopril, or enalapril during gestation. Two of the infants had adverse outcomes (see Enalapril and Captopril for details).

Six pregnancies treated with lisinopril were reported in a 1997 study of 19 pregnancies exposed to ACE inhibitors (7). Lisinopril therapy was stopped in the 1st trimester in four pregnancies and at 20 and 25 weeks, respectively, in the others. No congenital anomalies or renal dysfunction were noted in the six neonates (7).

A case of lisinopril-induced fetopathy and hypocalvaria was included in a study examining the causes of fetal skull hypoplasia (8). Among 14 known cases of hypocalvaria or acalvaria, 5 were caused by ACE inhibitors. The authors speculated that the underlying pathogenetic mechanism in these cases is fetal hypotension (8).

A 1991 article examining the teratogenesis of ACE inhibitors cited evidence linking fetal calvarial hypoplasia with the use of these agents after the 1st trimester (9). The proposed mechanism was drug-induced oligohydramnios that allowed the uterine musculature to exert direct pressure on the fetal skull. This mechanical insult, combined with drug-induced fetal hypotension, could inhibit peripheral perfusion and ossification of the calvaria (9).

In summary, ACE inhibitors present a major risk to the fetus in terms of toxicity, including fetal and neonatal renal failure, intrauterine growth retardation, prematurity, severe neonatal hypotension, and fetal and neonatal death. Oligohydramnios may occur resulting in pulmonary hypoplasia, limb contractures, persistent patent ductus arteriosus, craniofacial deformation, and neonatal death (10,11). These agents appear to be teratogenic when used in the 2nd and 3rd trimesters, causing fetal calvarial hypoplasia and renal anomalies (see also Captopril and Enalapril). The cause of these defects is probably related to fetal hypotension and decreased renal blood flow. Because of these reports, some investigators contend that drugs in this class should not be used in pregnancy (10,11,12 and 13). In those cases in which lisinopril must be used to treat the mother's disease, close monitoring of amniotic fluid levels and fetal well-being are required. Newborn renal function and blood pressure should also be monitored. If oligohydramnios occurs, stopping the drug may resolve the problem but may not improve infant outcome because of irreversible fetal damage (10). Guidelines for counseling exposed pregnant patients have been published and should be of benefit to health professionals faced with this task (9,10).

[*Risk Factor DM if used in 2nd or 3rd trimesters.]

Breast Feeding Summary

No reports describing the use of lisinopril during human lactation have been located. The drug is excreted in the milk of lactating rats (1). The molecular weight (about 442) is low enough that excretion into breast milk should be expected. Two similar agents are present in milk in low concentrations and are classified by the American Academy of Pediatrics as compatible with breast feeding (see Captopril and Enalapril).

References

1. Product information. Prinivil. Merck, 2001.
2. Rosa F, Bosco L. Infant renal failure with maternal ACE inhibition (abstract). Am J Obstet Gynecol 1991;164:273.
3. Tomlinson AJ, Campbell J, Walker JJ, Morgan C. Malignant primary hypertension in pregnancy treated with lisinopril. Ann Pharmacother 2000;34:1802.
4. Bhatt-Mehta V, Deluga KS. Chronic renal failure (CRF) in a neonate due to in-utero exposure to lisinopril. Presented at the 12th Annual Meeting of the American College of Clinical Pharmacy, Minneapolis, MN, August 20, 1991, Abstract No. 43.
5. Pryde PG, Nugent CE, Sedman AB, Barr M Jr. ACE inhibitor fetopathy (abstract). Am J Obstet Gynecol 1992;166:348.
6. Piper JM, Ray WA, Rosa FW. Pregnancy outcome following exposure to angiotensin-converting enzyme inhibitors. Obstet Gynecol 1992;80:42932.
7. Lip GYH, Churchill D, Beevers M, Auckett A, Beevers DG. Angiotensin-converting-enzyme inhibitors in early pregnancy. Lancet 1997;350:14467.
8. Barr M Jr, Cohen MM Jr. ACE inhibitor fetopathy and hypocalvaria: the kidney-skull connection. Teratology 1991;44:48595.
9. Brent RL, Beckman DA. Angiotensin-converting enzyme inhibitors, an embryopathic class of drugs with unique properties: information for clinical teratology counselors. Teratology 1991;43:5436.
10. Barr M Jr. Teratogen update: angiotensin-converting enzyme inhibitors. 1994;50:399409.
11. 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;96:4516.
12. Lindheimer MD, Katz AI. Hypertension in pregnancy. N Engl J Med 1985;313:67580.
13. Lindheimer MD, Barron WM. Enalapril and pregnancy-induced hypertension. Ann Intern Med 1988;108:91.