CLOMIPRAMINE

Fetal Risk Summary

No teratogenic effects were observed after dosing with clomipramine via the oral (mice and rats), subcutaneous (mice and rats), and intravenous (mice and rabbits) routes (1). Toxic symptoms, apparently caused by drug withdrawal, but not congenital malformations, have been reported in human fetuses exposed to this antidepressant (2,3,4,5,6,7 and 8).

A mother took clomipramine 25 mg three times daily throughout a normal pregnancy (2). Twelve hours after birth, the 3140-g male infant became dusky and was hypothermic (rectal temperature 35.4°C). Hypothermia persisted for 4 days and was aggravated by feeding and handling. Jitteriness, attributed to drug withdrawal, developed on the 2nd day and persisted for 48 hours. The symptoms were controlled with phenobarbital. Plasma levels of clomipramine and its metabolite, chlordesipramine, were <20 ng/mL and 116 ng/mL, respectively, at 1 day of age, and <20 ng/mL and 96 ng/mL, respectively, at age 3 days. Recovery was uneventful and normal development was noted at 3 and 6 months of age.

Drug withdrawal was observed in two newborns exposed throughout gestation to clomipramine (3). A 3550-g infant, exposed to 200 mg/day, appeared normal at birth but became lethargic, cyanotic, and tachypneic with moderate respiratory acidosis within a few hours. Oxygen therapy corrected the cyanosis and respiratory acidosis. Jitteriness and tremors developed by the end of the 1st day, followed by intermittent hypertonia and hypotonia, tachypnea, and feeding problems. Phenobarbital was used to control the symptoms, which resolved completely in 1 week. A 4020-g newborn, whose mother had taken 100 mg/day of clomipramine, had symptoms similar to those observed in the first infant. Oxygen and phenobarbital therapy were used, and although the neurologic symptoms had resolved within a few days, tachypnea and feeding difficulties persisted for 16 days (3). Both infants were developing normally at 5 months of age.

Neonatal convulsions were observed in two male infants after in utero exposure to clomipramine (maternal doses not specified) (4). The onset of seizures occurred at 8 and 7 hours. The first infant, a 3420-g newborn whose mother had been treated with clomipramine during the last 7 weeks of gestation, had persistent intermittent convulsions, despite treatment with phenobarbital and paraldehyde, until 53 hours of age, after which he remained hypertonic and jittery with ankle clonus until the 11th day (4). The second infant, exposed throughout gestation to clomipramine and flurazepam (dose not specified), delivered at 33 weeks' gestation with a birth weight of 2360 g, had convulsions that were unresponsive to phenobarbital. At 24 hours of age, 0.4 mg of clomipramine was given intravenously over 2 hours, resulting in complete cessation of the symptoms for 11 hours. Upon their recurrence, a dose of 0.5 mg over 2 hours was given, followed by a continuous tapering infusion until age 12 days when oral therapy was started (doses not given). No additional convulsions were observed, but he remained jittery. All therapy was stopped at age 17 days without adverse effect. No follow-up of either infant was mentioned. The combined concentrations of drug and metabolite in the mothers were 610 ng/mL and 549 ng/mL, respectively, both higher than the suggested therapeutic range of 200–500 ng/mL (4). Although exact values could not be obtained from the graphs used in the Reference, the initial combined serum levels of clomipramine and metabolite in the infants appear to be in the range of 250–400 ng/mL. The authors attributed the convulsions to the initial steep decline in serum drug levels, with clomipramine therapy in the second infant permitting a more gradual decline in concentrations and, thus, control of the infant's symptoms. Neurologic symptoms in the infants did not resolve completely until the concentration of clomipramine fell below 10 ng/mL.

Six cases of fetal exposure to clomipramine were described in a 1991 report (5). One infant, with meconium-stained fluid in the trachea, had mild respiratory distress with acidosis, mild hypotonia, and a tremor at birth. At 12 hours of age, the newborn developed jitteriness that resolved spontaneously, along with the other symptoms, by 6 days of age. At birth, clomipramine concentrations were 474.4 ng/mL in the maternal serum and 266.6 ng/mL in the neonatal plasma (ratio 1.8). Levels of the metabolite were not determined. The mother's dose at this time was 125 mg/day. The elimination half-life of clomipramine in the infant during the first week, when the male infant was not breast feeding, was 92.8 hours (5). Among the other five cases, one woman had a therapeutic abortion at 9 weeks' gestation, one stopped clomipramine therapy when she realized she was pregnant, and the remaining three continued therapy with daily doses between 75 and 250 mg throughout gestation. Mild hypotonia, persisting for several weeks, was observed in one of the four liveborn infants, and transient tachypnea requiring oxygen therapy was observed in another. No other symptoms or signs of toxicity were noted.

Three additional cases of drug withdrawal to clomipramine have been reported (6,7 and 8). A short 1990 case report described symptoms of drug withdrawal in a newborn exposed during the last 8–9 weeks of gestation to daily doses of 125 mg of clomipramine and 3 mg of lorazepam (6). The 3900-g infant was normal until 8 hours of age, when tachypnea, with a respiratory rate of 100–120 breaths/minute, and recessions developed. Other symptoms noted in the infant over the next 10 days were intermittent hypertonia and marked diaphoresis. Treatment consisted of intravenous fluids, oxygen, and empiric antibiotic therapy. No follow-up of the infant was reported.

In the second case, a 33-year-old woman with an obsessive-compulsive disorder was treated with clomipramine, 100–150 mg/day, from the 12th week of gestation through the 32nd week (7). At that time, the mother decided on her own to discontinue the drug and 4 days later, she presented in premature labor and imminent delivery, and a 2.7-kg infant was delivered by cesarean section. Repetitive seizures, rigidity, irritability, and decerebrate-like posturing, which was unresponsive to phenobarbital and phenytoin, occurred 10 minutes after birth. After 3 days of convulsions, 0.5 mg of clomipramine was given via gastric tube with resolution of the seizures within 30 minutes. When the seizures recurred 10 hours later, clomipramine, 0.5 mg three times daily, was started and the phenobarbital discontinued. The clomipramine was gradually tapered over the next 20 days. An EEG shortly after birth showed a left temporal epileptogenic focus, but was normal after 20 days of clomipramine therapy. The infant was discharged home at the age of 1 month with no signs or symptoms of neurological damage (7). The third case involved a term male infant who had been exposed throughout gestation to 100 mg/day (8). Generalized, stimular sensitive, status myoclonus developed at age 2 days (clomipramine serum level <10 ng/mL) that were successfully treated with 0.5 mg clomipramine. Previous treatment with clonazepam and phenobarbital was unsuccessful. At 3 weeks of age, only mild jitteriness in response to touch was noted.

In summary, clomipramine therapy during pregnancy does not appear to be teratogenic in animals or humans, but the number of known exposed human fetuses is too small to determine the actual risk. Significant newborn toxicity may occur, however, that appears to be due to drug withdrawal. In two of the above cases, in utero exposure included a benzodiazepine sedative. Neonatal withdrawal following exposure during pregnancy to benzodiazepines has been reported (see Diazepam) and may have contributed to the symptoms observed in these two infants. Although no long-term effects of in utero exposure and newborn withdrawal to clomipramine have been observed, follow-up has not been reported beyond 6 months of age.

Breast Feeding Summary

Clomipramine is excreted into human milk (5). A woman taking 125 mg/day of the antidepressant had milk and plasma concentrations determined on the 4th and 6th postpartum days. Her infant was not breast feeding during this time. Milk levels were 342.7 and 215.8 ng/mL, respectively, compared to plasma levels of 211.0 and 208.4 ng/mL, respectively. The milk:plasma ratios on the 4th and 6th days were 1.62 and 1.04, respectively. Neonatal plasma concentrations of clomipramine, from drug obtained in utero, declined from 266.6 ng/mL at birth to 94.8 ng/mL on the 6th day. The baby was allowed to breast feed commencing at 7 days of age; at the same time, the mother's dose was increased to 150 mg/day. Repeat determinations of milk and plasma clomipramine concentrations were made between 10–14 hours after the daily dose on the 10th, 14th, and 35th days after delivery. Milk levels ranged from 269.8–624.2 ng/mL compared to plasma concentrations of 355.0–509.8 ng/mL, corresponding to milk:plasma ratios of 0.76–1.22. The highest concentrations for both the milk and the plasma occurred on the 35th day, but neonatal drug levels continued to decline from 45.4 ng/mL on the 10th day to 9.8 ng/mL on the 35th day. No adverse effects were noted in the infant during breast feeding.

Although the American Academy of Pediatrics classifies other antidepressants as agents to be used with caution because of unknown effects on the infant's central nervous system function, it considers clomipramine to be compatible with breast feeding (9). However, because of the potential for toxicity in the infant, especially after long-term exposure, clomipramine should be used cautiously, if at all, during this period.

References

1. Watanabe N, Nakai T, Iwanami K, Fujii T. Toxicological studies of clomipramine hydrochloride. Kiso to Rinsho 1970;4:2105–24. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD:Johns Hopkins University Press, 1989:159–60.
2. Ben Muza A, Smith CS. Neonatal effects of maternal clomipramine therapy. Arch Dis Child 1979;54:405.
3. Ostergaard GZ, Pedersen SE. Neonatal effects of maternal clomipramine treatment. Pediatrics 1982;69:233–4.
4. Cowe L, Lloyd DJ, Dawling S. Neonatal convulsions caused by withdrawal from maternal clomipramine. Br Med J 1982;284:1837–8.
5. Schimmell MS, Katz EZ, Shaag Y, Pastuszak A, Koren G. Toxic neonatal effects following maternal clomipramine therapy. J Toxicol Clin Toxicol 1991;29:479–84.
6. Singh S, Gulati S, Narang A, Bhakoo ON. Non-narcotic withdrawal syndrome in a neonate due to maternal clomipramine therapy. J Pediatr Child Health 1990;26:110.
7. Bromiker R, Kaplan M. Apparent intrauterine fetal withdrawal from clomipramine hydrochloride. JAMA 1994;272:1722–3.
8. Bloem BR, Lammers GJ, Roofthooft DWE, De Beaufort AJ, Brouwer OF. Clomipramine withdrawal in newborns. Arch Dis Child Fetal Neonatal Ed 1999;81:F77.
9. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.