Enalapril]]>

Risk Factor: CM*
Class: Cardiovascular drugs/ Antihypertensives/ Angiotensin-converting enzyme inhibitors

Contents of this page:
Fetal Risk Summary
Breast Feeding Summary
References

Fetal Risk Summary

Enalapril, a competitive inhibitor of angiotensin I-converting enzyme (ACE inhibitor), is used for the treatment of hypertension (see also Captopril). Following oral administration, the prodrug enalapril is bioactivated by hydrolysis to the active agent, enalaprilat. Use of the drug in pregnant rats produced fetal growth retardation and, in two fetuses, incomplete skull ossification (1).

Enalaprilat crosses the human placenta. In an in vitro experiment using a human placental lobe, enalaprilat crossed from to the fetal side with a mean transfer of 2.99% (2). The maximum concentration on the fetal side was about 2048 ng/mL.

A number of References on the use of enalapril during pregnancy have appeared (3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21 and 22). A 1991 review summarized the cases of enalapril-exposed pregnancies published prior to January 1, 1990 (23). Use of enalapril 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. Of interest, an apparent autosomal recessive syndrome of renal tubular dysplasia with fetal/neonatal anuric renal failure, intrauterine growth retardation, and skull ossification defects, but without exposure to ACE inhibitors, has been described in five infants from two separate kindreds (24).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 40 newborns had been exposed to enalapril during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Four (10.0%) major birth defects were observed (two expected), including (observed/expected) 2/0.4 cardiovascular defects, and 1/0.1 polydactyly. No anomalies were observed in four other categories of defects (oral clefts, spina bifida, limb reduction defects, and hypospadias) for which specific data were available.

A European survey on the use of ACE inhibitors in pregnancy briefly reviewed the results obtained in nine motherchild pairs (3). Two spontaneous abortions occurred: one at 7 weeks in a 44-year-old woman and one at 11 weeks in a 41-year-old diabetic patient. Enalapril, 20 mg/day, had been used from conception until abortion in the first case and from conception until 6 weeks’ gestation in the second. In both cases, factors other than the drug therapy were probably responsible for the pregnancy losses. In a third case, enalapril (30 mg/day) was started at 24 weeks; the patient, with severe glomerulopathy, delivered a stillborn infant 2 weeks later. It is not known whether enalapril therapy was associated with the adverse outcome. The remaining six women were being treated at the time of conception with 1020 mg/day for essential hypertension or lupus-induced hypertension. Therapy was discontinued by 7 weeks’ gestation in four pregnancies, and at 28 weeks in one, and enalapril was continued throughout gestation (40 weeks) in one. Two infants were small for gestational age; one had been exposed only during the first 4 weeks, and one was exposed throughout (40 weeks). No anomalies were mentioned, nor were any other problems in the exposed liveborn infants. The growth retardation was probably due to the severe maternal disease (3).

A 1988 case report described a woman with pregnancy-induced hypertension who was treated with methyldopa and verapamil for 6 weeks with poor control of her blood pressure (4). At 32 weeks’ gestation, methyldopa was discontinued and enalapril (20 mg/day) was combined with verapamil (360 mg/day), resulting in good control. An elective cesarean section was performed after 17 days of combination therapy. Oligohydramnios was noted, as was meconium staining. The 2100-g female infant was anuric during the first 2 days, although tests indicated normal kidneys without obstruction. A renal biopsy showed hyperplasia of the juxtaglomerular apparatus. She began producing urine on the 3rd day (2 mL in a period of 24 hours), 12 hours after the onset of peritoneal dialysis. She remained oliguric when dialysis was stopped at age 10 days, producing only 30 mL of urine in a period of 24 hours. By the 19th postnatal day, her urine output had reached 125 mL/24 hours. The plasma enalaprilat concentration was 28 ng/mL before dialysis and then fell to undetectable (130 (day 90). Angiotensin II concentrations (normal 182 fmol/mL) were still suppressed (39.8) on day 31; plasma renin activity, active renin, and total renin were all markedly elevated until day 90. By this time, renal function had returned to normal. Clinical followup at 1 year of age was normal (4).

A renal transplant patient was treated with enalapril, azathioprine, atenolol, and prednisolone (doses not given) throughout pregnancy (5). Ultrasound at 32 weeks’ gestation indicated oligohydramnios and asymmetrical growth retardation. A 1280-g (10th percentile) male infant with a head circumference of 25.7 cm (3rd percentile) was delivered by cesarean section. Severe hypotension (mean 25 mm Hg), present at birth, was resistant to volume expansion and pressor agents. The newborn was anuric for 72 hours, then oliguric, passing only 2.5 mL during the next 36 hours. Ultrasonography revealed a normal-sized kidney and a normal urinary tract. Peritoneal dialysis was commenced on day 8, but the infant died 2 days later. Defects secondary to oligohydramnios were squashed facies, contractures of the extremities, and pulmonary hypoplasia. Ossification of the occipital skull was absent. A chromosomal abnormality was excluded based on a normal male karyotype (46,XY). The renal failure and skull hypoplasia were probably caused by enalapril (5).

A 24-year-old woman with malignant hypertension and familial hypophosphatemic rickets was treated from before conception with enalapril (10 mg/day), furosemide (40 mg/day), calciferol, and slow phosphate (6). Blood pressure was normal at 15 weeks’ gestation as was fetal growth. However, oligohydramnios developed 2 weeks later; by 20 weeks’ gestation, virtually no fluid was present. Fetal growth retardation was also evident at this time. Enalapril and furosemide therapy were slowly replaced by labetalol over the next week, and a steady improvement in amniotic fluid volume was noted by 24 weeks. Volume was normal at 27 weeks’ gestation, but shortly thereafter, abruptio placentae occurred, requiring an emergency cesarean section. A 720g (below 3rd percentile) male infant was delivered who died on day 6. A postmortem examination indicated a normal urogenital tract (6).

An 18-year-old woman with severe chronic hypertension had four pregnancies over an approximately 4-year period, all while taking ACE inhibitors and other antihypertensives (7). During her first pregnancy, she had been maintained on captopril and she delivered a premature, growth-retarded, but otherwise healthy female infant who survived. In the postpartum period, captopril was discontinued and enalapril (10 mg/day) was started while continuing atenolol (100 mg/day) and nifedipine (40 mg/day). She next presented in the 13th week of her second pregnancy with unchanged antihypertensive therapy. Fetal death occurred at 18 weeks’ gestation. The 340-g male fetus was macerated but otherwise normal. Her third and fourth pregnancies, again with basically unchanged antihypertensive therapy except for the addition of aspirin (75 mg/day) at the 10th week, resulted in the delivery of an 1170-g female and a 1540-g male, both at 29 weeks (7).

The case of a 27-year-old woman with scleroderma renal disease who was treated with both enalapril and captopril at different times in her pregnancy was published in 1989 (8). Treatment with enalapril (10 mg/day) and nifedipine (60 mg/day) had begun approximately 4 years before the woman presented at an estimated 29 weeks’ gestation. Because of concerns for the potential fetal harm induced by the current treatment, therapy was changed to methyldopa. This agent failed to control the woman’s hypertension and therapy with captopril (150 mg/day) was initiated at approximately 33 weeks’ gestation, 4 weeks prior to delivery of a normal male infant weighing 1740 g. No evidence of renal impairment was observed in the infant (8).

A woman with active systemic lupus erythematosus became severely hypertensive at 22 weeks’ gestation (9). Therapy included prednisone, phenytoin (for one episode of tonic clonic seizure activity), and the antihypertensive agents enalapril, hydralazine (used only briefly), clonidine, nitroprusside, nifedipine, and propranolol. A 600-g male infant with hyaline membrane disease was delivered by cesarean section at 26 weeks’ gestation. Severe, persistent hypotension (mean blood pressure during first 24 hours 1823 mm Hg) was observed that was resistant to volume expansion and dopamine. Both kidneys were normal by ultrasonography but no urine was visualized in the bladder. The infant died on the 7th day. Gross and microscopic examination of the kidneys at autopsy revealed no abnormalities. Nephrogenesis was appropriate for gestational age (9).

A 1710-g male infant, delivered by cesarean section for fetal distress at 35 weeks’ gestation, had been exposed to enalapril (20 mg/day) and diazepam (5 mg/day) from the 32nd week of pregnancy for the treatment of maternal hypertension (10). Prior to this, treatment had consisted of a 2-week course of methyldopa and amiloride plus hydrochlorothiazide. Except for a few drops, the growth-retarded infant produced no urine, and peritoneal dialysis was started at 86 hours of age. Renal ultrasonography indicated normal kidneys without evidence of obstruction. Renal function slowly improved following dialysis, but some impairment was still present at 18 months of age (10).

Investigators at the FDA reviewed five cases of enalapril-induced neonatal renal failure, one of which had been published previously in a 1989 report (11). Enalapril doses ranged from 1045 mg/day. Two of the mothers were treated throughout gestation, one was treated from 2734 weeks’ gestation, and one was treated during the last 3 weeks only. All of the infants required dialysis for anuria. Renal function eventually recovered in two infants, it was still abnormal 1 month after birth in one, and tubular acidosis occurred in the fourth infant 60 days after delivery. Hypotension was reported in three of the four newborns. The authors cautioned that if enalapril was used during pregnancy, then preparations should be made for neonatal hypotension and renal failure (11).

In a 1991 abstract, the FDA investigators updated their previous report on ACE inhibitors and perinatal renal failure by listing a total of 29 cases: 18 were caused by enalapril, 9 captopril, and 2 lisinopril (12). Of the 29 cases, 12 (41%) were fatal (another fatal case was listed but it was apparently not caused by renal failure), 9 recovered, and 8 had persistent renal impairment. Only 2 deaths occurred among dialyzed patients. Two cases of oligohydramnios resolved when therapy was stopped before delivery, but one of the infants was stillborn (12).

A 1990 case report suggested that structural kidney defects may be a consequence of enalapril therapy (13). A 22-year-old mother, with systemic lupus erythematous and severe chronic hypertension, was treated throughout gestation with enalapril 20 mg/day, propranolol 40 mg/day, and hydrochlorothiazide 50 mg/day. Blood pressure was well controlled on this regimen, and no evidence of active lupus occurred during pregnancy. Normal amniotic fluid volume was documented at 16 weeks’ gestation followed by severe oligohydramnios at 27 weeks. Although normal fetal growth was observed, the male infant was delivered at 34 weeks’ gestation by emergency cesarean section because thick meconium was found on amniocentesis. No meconium was found below the vocal cords. The profound neonatal hypotension induced by enalapril required aggressive treatment with fluids and pressor agents. The newborn had the characteristic features of the oligohydramnios sequence. Both kidneys were morphologically normal by renal ultrasonogram, but no urine output was observed, and no urine was found in the bladder. The infant died at about 25 hours of age. Pulmonary hypoplasia, a condition secondary to oligohydramnios, was found at autopsy. Except for their large size, approximately 1.5 times the expected weight, the kidneys were grossly normal with normal vessels and ureters and a contracted bladder. Microscopic examination revealed a number of kidney abnormalities: irregular corticomedullary junctions; glomerular maldevelopment with a decreased number of lobulations in many of the glomeruli, and some congested glomeruli; a reduced number of tubules in the upper portion of the medulla with increased mesenchymal tissue; and tubular distension in the cortex and medulla. The investigators could not determine whether the renal defects were due to reduced renal blood flow secondary to enalapril, a direct teratogenic effect of the drug, or an effect of the specific drug combination. However, no renal anomalies have been reported after use of the other two drugs (see Hydrochlorothiazide and Propranolol), and similar renal defects have not been reported as a complication of maternal lupus (13).

Three cases of in utero exposure to ACE inhibitors, one of which was enalapril, were reported in a 1992 abstract (14). The infant, delivered at 32 weeks’ gestation because of severe oligohydramnios and fetal distress, had growth retardation, hypocalvaria, short limbs, and renal tubular dysplasia. Profound neonatal hypotension and anuria was observed at birth and improved only with dialysis, but the infant died at 9 days of age due to the renal failure (14).

A woman took enalapril (10 mg/day) and furosemide (80 mg/day) throughout gestation for hypertension and delivered a 2.76-g male infant at 37 weeks’ gestation (19). An ultrasound at 20 weeks’ had noted oligohydramnios, multicystic kidneys, a small thorax, and no visible bladder. The newborn died a few minutes after birth. Autopsy revealed low set ears, small epicanthic folds, bilateral talipes, a markedly bell-shaped thorax, grossly cystic kidneys and no apparent normal renal tissue. The karyotype was normal (19).

A 1997 case report described the pregnancy outcome of a woman who was treated with enalapril (20 mg/day) for gestational hypertension from about 28 weeks’ gestation to delivery at 36 weeks’ (20). Severe oligohydramnios had developed shortly before delivery. The growth retarded, 2000-g male infant had hypocalvaria, anuria, and profound hypotension. Peritoneal dialysis was started at age 3 days. Before dialysis, the serum ACE level was 7.4 m/mL (normal 2030 m/mL). After dialysis, the level was 20.5 m/mL, whereas enalaprilat concentrations in the infant’s serum and dialysate were 6.92 and 3.3 g/mL, respectively. Blood pressure normalized after 4 days of dialysis but chronic renal failure persisted. At 8 months of age, expansion of the calvarial bones with gradual closing of the fontanelles was evident and development, other than growth, was normal. However, the renal failure had worsened and the infant was on the waiting list for a renal transplant (20).

Ten pregnancies treated with enalapril were reported in a 1997 study of 19 pregnancies exposed to ACE inhibitors (21). Enalapril therapy was stopped in the 1st trimester in eight pregnancies and at 14 and 15 weeks’, respectively, in the others. No congenital anomalies or renal dysfunction were noted in the 10 neonates (21).

The outcomes of 21 pregnancies exposed to ACE inhibitors between 1991 and 1996 were reported using data from the Danish birth registry (22). Exposure to the agents occurred at a median of 8 weeks’ gestation (range 515 weeks’). No fetal or neonatal complications attributable to the drug therapy were discovered (22).

A 1992 Reference described the effects of ACE inhibitors on pregnancy outcome (25). Among 106,813 women enrolled in the Tennessee Medicaid program who delivered either a liveborn or stillborn infant, 19 had taken either enalapril, captopril, or lisinopril during gestation. One newborn, exposed in utero to enalapril, was delivered at 29 weeks’ gestation for severe oligohydramnios, intrauterine growth retardation, and fetal distress. Gradual resolution of the infant’s renal failure occurred following dialysis (25).

Fourteen cases of fetal hypocalvaria or acalvaria were reviewed in a 1991 Reference, one of which was due to enalapril (26). The authors speculated that the underlying pathogenetic mechanism in these cases was fetal hypotension.

In an article examining the teratogenesis of ACE inhibitors, the authors cited evidence linking fetal calvarial hypoplasia with the use of these agents after the 1st trimester (27). They speculated that the mechanism was related to 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 (27).

Investigators in a study published in 1992 examined microscopically the kidneys of nine fetuses from chronically hypertensive mothers, one of whom was taking enalapril (28). The researchers concluded that the renal defects associated with ACE inhibitors were due to decreased renal perfusion and are similar to the defects seen in other conditions related to reduced fetal renal blood flow.

The severe enalapril-induced fetal/neonatal renal failure and neonatal hypotension are a consequence of its pharmacologic effect in the fetus (see also Captopril). Two reviews of fetal and newborn renal function, published in 1988, 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 (29,30). Enalapril 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 and its active metabolite, enalaprilat, resulting in prolonged hypotension.

In summary, enalapril and other ACE inhibitors appear to be teratogenic when used in the 2nd and 3rd trimesters, producing fetal hypocalvaria and renal defects. The cause of the defects and other toxicity associated with ACE inhibitors is probably related to fetal hypotension and decreased renal blood flow. The use of enalapril during pregnancy may compromise the fetal renal system and 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 patent ductus arteriosus, craniofacial deformation, and neonatal death (31,32). Intrauterine growth retardation, prematurity, and severe neonatal hypotension have also been observed after use of these drugs. Because of these effects, some investigators have stated that ACE inhibitors should not be used in pregnancy (31,32,33 and 34). In those cases when enalapril 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 (31). Guidelines for counseling exposed pregnant patients have been published and should be of benefit to health professionals faced with this task (27,31).

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

Breast Feeding Summary

A study published in 1989 was unable to demonstrate the excretion of enalapril and enalaprilat in breast milk (35). Direct concentrations of enalapril, however, were not measured in this study. Three women, 345 days postpartum, were treated with enalapril for hypertension. One woman with chronic glomerulonephritis and slightly impaired renal function was treated with 5 mg twice daily for 40 days before the study. The other two women, both with essential hypertension and normal renal function, were treated with 10 mg (duration not specified). ACE activity in the serum of the women was markedly depressed 4 hours after treatment with activity dropping from 18.724.0 U/mL to 0.40.7 U/mL (Reference value in controls 28.0 U/mL). ACE activity in milk samples was not affected: 11.718.6 U/mL before the dose vs. 12.415.4 U/mL 4 hours after the dose (Reference value in controls 9.122.6 U/mL), indicating that little if any of the drug was excreted into milk. Concentrations of enalaprilat in maternal serum ranged from 23.9 to 48.0 ng/mL in the two women with normal renal function and 179 ng/mL in the woman with renal impairment. Milk levels were all
In contrast to the above study, concentrations of both enalapril and enalaprilat were measured in a study published in 1991 (36). A woman, 12 months postpartum, had been treated with enalapril (10 mg/day) for essential hypertension for 11 months. Twenty-four hours after her last dose, she was given 10 mg, and milk samples were drawn at 0, 4, 8.75, and 24 hours. Serum samples were also drawn at various times over the next 24 hours. The total amount of the enalapril and enalaprilat measured in the milk over the 24-hour sample period was 81.9 ng and 36.1 ng, respectively. These values corresponded to 1.44 ng/mL and 0.63 ng/mL, respectively. The peak concentration of enalapril, 2.05 ng/mL, occurred in the 4-hour sample, whereas that of enalaprilat, 0.75 ng/mL, occurred in the 8.75-hour sample. When milk levels were compared to serum concentrations at these sampling times, the milk:serum ratios were 0.14 and 0.02, respectively (36).

In a third study, milk and serum concentrations of enalapril and enalaprilat were measured in five women at 0, 4, 6, and 24 hours after a single 20-mg dose (37). The mean maximum milk concentration of enalapril was 1.74 ng/mL, whereas that of enalaprilat was 1.72 ng/mL. No enalapril was measured in the milk of one patient. The milk:serum ratio for the parent compound and the metabolite varied from 00.043 and 0.0210.031, respectively (37).

Based on the above data, the amount of enalapril and enalaprilat that could potentially be ingested by a breast-feeding infant appears to be negligible and is probably clinically insignificant. The American Academy of Pediatrics considers enalapril to be compatible with breast feeding (38).

References

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