Antidepressant
PREGNANCY RECOMMENDATION: Human Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
Although structural anomalies have been reported following 1st trimester exposure to imipramine, no pattern of defects is evident when all reports are examined. Neonatal withdrawal is a potential complication when the drug is used near birth.
FETAL RISK SUMMARY
Shepard reviewed six animal reproductive studies involving imipramine 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 (3–15). Reported malformations other than limb reduction included: defective abdominal muscles (1 case); diaphragmatic hernia (2 cases); exencephaly, cleft palate, adrenal hypoplasia (1 case); cleft palate (2 cases); and renal cystic degeneration (1 case) (4–6). These reports indicate that imipramine is not a major cause of congenital limb deformities.
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.
In a 1996 descriptive case series, the European Network of the Teratology Information Services (ENTIS) prospectively examined the outcomes of 689 pregnancies exposed to antidepressants (16). Multiple drug therapy occurred in about two-thirds of the mothers. Imipramine exposure occurred in 30 pregnancies (1 set of twins). The outcomes of these pregnancies were 1 elective abortion, 3 spontaneous abortions, 25 normal newborns, and 2 infants with congenital defects. The defects (all exposed in the 1st trimester or longer) were six fingers on right hand, and an omphalocele (16).
Neonatal withdrawal symptoms have been reported with the use of imipramine during pregnancy (17–19). Symptoms observed in the infants during the 1st month after birth were colic, cyanosis, rapid breathing, and irritability. Urinary retention in the neonate has been associated with maternal use of nortriptyline (chemically related to imipramine) (20).
A 2002 prospective study compared two groups of mother–child pairs exposed to antidepressants throughout gestation (46 exposed to tricyclics—12 to imipramine; 40 to fluoxetine) with 36 nonexposed, not depressed controls (21). Offspring between the ages 15 and 71 months were studied for effects of antidepressant exposure in terms of IQ, language, behavior, and temperament. Exposure to antidepressants did not adversely affect the measured parameters, but IQ was significantly and negatively associated with the duration of depression, and language was negatively associated with the number of depression episodes after delivery (21).
BREASTFEEDING SUMMARY
Imipramine and its metabolite, desipramine, enter breast milk in low concentrations (22–24). A milk:plasma ratio of 1 has been suggested (22). 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. Ten nursing infants of mothers taking antidepressants (four with imipramine 75–150 mg/day) were compared with 15 bottle-fed infants of mothers with depression who did not breastfeed (24). Concentrations of imipramine in fore- and hindmilk ranged from 34 to 408 ng/mL and from 48 to 622 ng/mL, respectively. The milk:maternal plasma ratios were 0.7–1.7 and 1.2–2.3, respectively. In two infants, plasma levels were 0.6 ng/mL (mother’s dose 75 mg/day) and 3.3–7.4 ng/mL (mother’s dose 75–100 mg/day). No toxic effects or delays in development were observed in the infants. The estimated daily dose consumed by the infants was about 1% of the mother’s weight-adjusted dose (24).
The clinical significance of these amounts is unknown. The American Academy of Pediatrics classifies imipramine as an agent whose effect on the nursing infant is unknown but may be of concern (25).
References
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20.Shearer WT, Schreiner RL, Marshall RE. Urinary retention in a neonate secondary to maternal ingestion of nortriptyline. J Pediatr 1972;81:570–2.
21.Nulman I, Rovet J, Stewart DE, Wolpin J, Pace-Asciak P, Shuhaiber S, Koren G. Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study. Am J Psychiatry 2002;159:1889–95.
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24.Yoshida K, Smith B, Craggs M, Kumar RC. Investigation of pharmacokinetics and of possible adverse effects in infants exposed to tricyclic antidepressants in breast-milk. J Affect Disord 1997;43:225–37.
25.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.