Imipramine

 Risk Factor: D
 Class: CENTRAL NERVOUS SYSTEM DRUGS / Antidepressants

Contents of this page:

Fetal Risk Summary
Breast Feeding Summary
References
Questions and Answers

Fetal Risk Summary

Six animal reproductive studies using imipramine were reviewed by Shepard in 1989 (1). Some defects were observed in one investigation using rabbits, but other studies with mice, rats, rabbits, and monkeys revealed no evidence of drug-induced teratogenicity.

Bilateral amelia was reported in one child whose mother had ingested imipramine during pregnancy (2). An analysis of 546,505 births, 161 with 1st trimester exposure to imipramine, however, failed to find an association with limb reduction defects (3,4,5,6,7,8,9,10,11,12,13,14 and 15). Reported malformations other than limb reduction include (4,5 and 6): Defective abdominal muscles (1 case) Diaphragmatic hernia (2 cases) Exencephaly, cleft palate, adrenal hypoplasia (1 case) Cleft palate (2 cases) Renal cystic degeneration (1 case) These reports indicate that imipramine is not a major cause of congenital limb deformities (see also below).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 75 newborns had been exposed to imipramine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Six (8.0%) major birth defects were observed (three expected), including (observed/expected) 3/0.8 cardiovascular defects, 1/0.2 spina bifida, and 1/0.2 hypospadias. No anomalies were observed in three other defect categories (oral clefts, polydactyly, and limb reduction defects) for which specific data were available. Only with cardiovascular defects is there a suggestion of an association, but other factors, including the mother's disease, concurrent drug use, and chance, may be involved.

Neonatal withdrawal symptoms have been reported with the use of imipramine during pregnancy (16,17 and 18). Symptoms observed in the infants during the 1st month after birth were colic, cyanosis, rapid breathing, and irritability (16,17 and 18). Urinary retention in the neonate has been associated with maternal use of nortriptyline (chemically related to imipramine) (19).

Breast Feeding Summary

Imipramine and its metabolite, desipramine, enter breast milk in low concentrations (20,21). A milk:plasma ratio of 1 has been suggested (20). Assuming a therapeutic serum level of 200 ng/mL, an infant consuming 1000 mL of breast milk would ingest a daily dose of about 0.2 mg. The clinical significance of this amount is not known. The American Academy of Pediatrics classifies imipramine as an agent whose effect on the nursing infant is unknown but may be of concern (22).

References

1. Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD:Johns Hopkins University Press, 1989:3456.
2. McBride WG. Limb deformities associated with iminodibenzyl hydrochloride. Med J Aust 1972;1:492.
3. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA:Publishing Sciences Group, 1977:3367.
4. Kuenssberg EV, Knox JDE. Imipramine in pregnancy. Br Med J 1972;2:29.
5. Barson AJ. Malformed infant. Br Med J 1972;2:45.
6. Idanpaan-Heikkila J, Saxen L. Possible teratogenicity of imipramine/chloropyramine. Lancet 1973;2:2823.
7. Crombie DL, Pinsent R, Fleming D. Imipramine in pregnancy. Br Med J 1972; 1:745.
8. Sim M. Imipramine and pregnancy. Br Med J 1972; 2:45.
9. Scanlon FJ. Use of antidepressant drugs during the first trimester. Med J Aust 1969;2:1077.
10. Rachelefsky GS, Flynt JW, Eggin AJ, Wilson MG. Possible teratogenicity of tricyclic antidepressants. Lancet 1972;1:838.
11. Banister P, Dafoe C, Smith ESO, Miller J. Possible teratogenicity of tricyclic antidepressants. Lancet 1972; 1:8389.
12. Jacobs D. Imipramine (Tofranil). S Afr Med J 1972;46:1023.
13. Australian Drug Evaluation Committee. Tricyclic antidepressant and limb reduction deformities. Med J Aust 1973;1:7669.
14. Morrow AW. Imipramine and congenital abnormalities. NZ Med J 1972;75:2289.
15. Wilson JG. Present status of drugs as teratogens in man. Teratology 1973;7:315.
16. Hill RM. Will this drug harm the unborn infant? South Med J 1977;67:147680.
17. Eggermont E. Withdrawal symptoms in neonate associated with maternal imipramine therapy. Lancet 1973;2:680.
18. Shrand H. Agoraphobia and imipramine withdrawal? Pediatrics 1982;70:825.
19. Shearer WT, Schreiner RL, Marshall RE. Urinary retention in a neonate secondary to maternal ingestion of nortriptyline. J Pediatr 1972;81:5702.
20. Sovner R, Orsulak PJ. Excretion of imipramine and desipramine in human breast milk. Am J Psychiatry 1979;136:4512.
21. Erickson SH, Smith GH, Heidrich F. Tricyclics and breast feeding. Am J Psychiatry 1979;136:1483.
22. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.