Risk Factor: DM
Class: Central nervous system drugs/ Anticonvulsants
Fetal Risk Summary
Clonazepam is a benzodiazepine anticonvulsant that is chemically and structurally similar to diazepam (1). The drug is used either alone or in combination with other anticonvulsants.
Reproduction studies in mice and rats during organogensis at doses up to 4 and 20 times, respectively, the maximum recommended human dose of 20 mg/day for seizures [MRHD-S], and 20 and 100 times, respectively, the maximum recommended human dose of 4 mg/day for panic disorders [MRHD-P], on a mg/m2 basis, revealed no evidence of embryo or fetal effects (2). In rabbits administered doses that were 0.2 to 10 times the MRHD-S and 1 to 50 times the MRHD-P, a low, non-dose-related incidence of a similar pattern of malformations (cleft palate, open eyelid, fused sternebrae, and limb defects) was observed in all dosage groups (2). At the highest dose (twice the dose that produced reductions in maternal weight gain), intrauterine growth retardation was also observed.
In a small series of patients (N = 150) matched with nonepileptic controls, anticonvulsant therapy, including five women using clonazepam, had no effect on the incidence of pregnancy-induced hypertension, albuminuria, premature contractions, premature labor, bleeding in pregnancy, duration of labor, blood loss at delivery, cesarean sections, and vacuum extractions (3).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 19 newborns had been exposed to clonazepam during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Three (15.8%) major birth defects were observed (one expected), two of which were cardiovascular defects (0.2 expected). No anomalies were observed in five other categories of defects (oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available.
A prospective study published in 1999 described the outcomes of 517 pregnancies of epileptic mothers identified at one Italian center from 1977 (4). Excluding genetic and chromosomal defects, malformations were classified as severe structural defects, mild structural defects, and deformations. Minor anomalies were not considered. Spontaneous (N=38) and early (N=20) voluntary abortions were excluded from the analysis, as were 7 pregnancies that delivered at other hospitals. Of the remaining 452 outcomes, 427 were exposed to anticonvulsants of which 313 involved monotherapy: clonazepam (N=6), carbamazepine (N=113), phenobarbital (N=83), valproate (N=44), primidone (N=35), phenytoin (N=31), and other (N=1). There were no defects in the 25 pregnancies not exposed to anticonvulsants. Of the 42 (9.3%) outcomes with malformations, 24 (5.3%) were severe, 10 (2.2%) were mild, and 8 (1.8%) were deformities. There were no malformations with clonazepam monotherapy. The investigators concluded that the anticonvulsants were the primary risk factor for an increased incidence of congenital malformations (see also Carbamazepine, Phenobarbital, Phenytoin, Primidone, and Valproic Acid) (4).
Toxicity in the newborn, apparently related to clonazepam, has been reported. Apnea, cyanosis, lethargy, and hypotonia developed at 6 hours of age in an infant of 36 weeks’ gestational age exposed throughout pregnancy to an unspecified amount of clonazepam (5). There was no evidence of congenital defects in the 2750 g newborn. Cord and maternal serum levels of clonazepam were 19 and 32 ng/mL, respectively, a ratio of 0.59. Both levels were within the therapeutic range (570 ng/mL). At 18 hours of age, the clonazepam level in the infant’s serum measured 4.4 ng/mL. Five episodes of prolonged apnea (1643 seconds/occurrence) were measured by pneumogram over the next 12 hours. Hypotonia and lethargy resolved within 5 days, but overt clinical apnea persisted for 10 days. Follow-up pneumograms demonstrated apnea spells until 10 weeks of age, but the presence of the drug in breast milk may have contributed to the condition (see Breast Feeding Summary). The authors concluded that apnea due to prematurity was not a significant factor. Neurologic development was normal at 5 months (5).
Breast Feeding Summary
Clonazepam is excreted into breast milk. In a woman treated with an unspecified amount of the anticonvulsant, milk concentrations remained constant between 11 and 13 ng/mL (5). The milk:maternal serum ratio was approximately 0.33. After 7 days of nursing, the infant, described above, had a serum concentration of 2.9 ng/mL. A major portion of this probably resulted from in utero exposure because the elimination half-life of clonazepam in neonates is thought to be prolonged. No evidence of drug accumulation after breast feeding was found. Persistent apneic spells, lasting until 10 weeks of age, were observed, but it was not known whether breast feeding contributed to the condition. Based on this case, the authors recommended that infants exposed in utero or during breast feeding to clonazepam should have serum levels of the drug determined and be closely monitored for central nervous system depression or apnea (5).
- Reith H, Schafer H. Antiepileptic drugs during pregnancy and the lactation period. Pharmacokinetic data. Dtsch Med Wochenschr 1979;104:81823.
- Product information. Klonopin. Roche Laboratories, 2000.
- Hiilesmaa VK, Bardy A, Teramo K. Obstetric outcome in women with epilepsy. Am J Obstet Gynecol 1985;152:499504.
- Canger R, Battino D, Canevini MP, Fumarola C, Guidolin L, Vignoli A, Mamoli D, Palmieri C, Molteni F, Granata T, Hassibi P, Zamperini P, Pardi G, Avanzini G. Malformations in offspring of women with epilepsy: a prospective study. Epilepsia 1999;40:12316.
- Fisher JB, Edgren BE, Mammel MC, Coleman JM. Neonatal apnea associated with maternal clonazepam therapy: a case report. Obstet Gynecol 1985;66(Suppl):34S5S.