Risk Factor: DM
Class: Central nervous system drugs/ Anticonvulsants
Fetal Risk Summary
Carbamazepine, a tricyclic anticonvulsant, has been in clinical use since 1962. The drug is teratogenic in rats at doses 1025 times the maximum human daily dose (MHDD) of 1200 mg/day or 1.54 times the MHDD on a mg/m2 basis (1). Anomalies observed included kinked ribs, cleft palate, talipes, and anophthalmos.
The drug crosses the placenta, with highest concentrations found in fetal liver and kidneys (2,3 and 4). Fetal levels are approximately 50%80% of maternal serum levels (4).
Placental function in women taking carbamazepine has been evaluated (5). No effect was detected from carbamazepine as measured by serum human placental lactogen, 24-hour urinary total estriol excretion, placental weight, and birth weight.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 172 newborns had been exposed to carbamazepine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 13 (7.6%) major birth defects were observed (7 expected), including 4 cardiovascular defects (2 expected) and 1 spina bifida (none expected). No anomalies were observed in four other categories of defects (oral clefts, polydactyly, limb-reduction defects, and hypospadias) for which specific data were available. Although the above data have not yet been analyzed to distinguish between combination vs. monotherapy (F. Rosa, personal communication, FDA, 1993), the total number of malformations suggests an association between the drug and congenital defects (see also discussion of Reference 25 below).
Additional reports to the FDA involved five cases of holoprosencephaly in which carbamazepine was used either alone (two cases) or in combination with valproic acid and phenytoin (one case), phenytoin and primidone (one case), or gabapentin (one case) (6). Because of the lack of family histories, an association with familial holoprosencephaly or maternal neurologic problems could not be excluded (6).
A number of reports have described the use of carbamazepine during the 1st trimester (5,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22 and 23,27,33,34,35,36,37,38,39 and 40). Multiple anomalies were found in one stillborn infant in whom carbamazepine was the only anticonvulsant used by the mother (15). These included closely set eyes, flat nose with single nasopharynx, polydactylia, atrial septal defect, patent ductus arteriosus, absent gallbladder and thyroid, and collapsed fontanel. Individual defects observed in this and other cases include talipes, meningomyelocele, anal atresia, ambiguous genitalia, congenital heart disease, hypertelorism, hypoplasia of the nose, cleft lip, congenital hip dislocation, inguinal hernia, hypoplasia of the nails, and torticollis (7,8,9,10,11,12,13,14,15,16,17 and 18). One infant, also exposed to lithium during the 1st trimester, had hydrocephalus and meningomyelocele (18). Decreased head circumference (7 mm less than controls) has been observed in infants exposed only to carbamazepine during gestation (19). The head size was still small by 18 months of age, with no catch-up growth evident. Dysmorphic facial features, combined with physical and mental retardation, were described in an infant girl exposed during gestation to 5001700 mg/day of carbamazepine monotherapy (23). Maternal carbamazepine serum levels had been monitored frequently during gestation, and all were reported to be in the therapeutic range (23).
In a 1982 review, Janz (24) stated that nearly all possible malformations had been observed in epileptic patients. Minor malformations, such as those seen in the fetal hydantoin syndrome (FHS) (see Phenytoin), have also been observed with carbamazepine monotherapy, causing Janz to conclude that the term FHS was misleading (24). Because carbamazepine was thought to present a lower risk to the fetus, the drug has been recommended as the treatment of choice for women who may become pregnant and who require anticonvulsant therapy for the first time (25). However, a 1989 report has indicated that carbamazepine is also probably a human teratogen (22).
Eight children were identified retrospectively after in utero exposure to carbamazepine either alone (N=4), or in combination with other anticonvulsants (phenobarbital, N=2; primidone, N=1; or phenobarbital and clonazepam, N=1) (22). In six mothers, daily carbamazepine doses ranged from 600 to 1600 mg (dosage unknown in two). The following defects were noted in the children: intrauterine growth retardation (two cases), poor neonatal performance (three cases), postnatal growth deficiency (three cases, not determined in four), developmental delay (three cases, not determined in four), microcephaly (three cases, not determined in four), upslanting palpebral fissures (two cases), short nose with long philtrum (two cases), hypoplastic nails (four cases), and cardiac defect (two cases).
Concurrently with the above evaluations, a prospective study involving 72 women treated with carbamazepine in early pregnancy was conducted (22). Fifty-four liveborn children were evaluated from the 72 mothers, with the remaining 18 excluded for various reasons (7 spontaneous abortions, 5 therapeutic abortions, and 6 lost to follow-up before delivery). A control group of 73 pregnant women was prospectively selected for comparison. Anticonvulsant drug therapy in the study group consisted of carbamazepine either alone (N=50) or in combination with phenobarbital (N=12), phenobarbital and valproic acid (N=4), primidone (N=3), valproic acid (N=1), ethosuximide (N=1), and primidone and ethosuximide (N=1). Carbamazepine dosage varied from 200 to 1200 mg/day. Seizures occurred at least once during pregnancy in 59% of the women, but they did not correlate with either malformations or developmental delay in the offspring (22). Of the 54 liveborn children, 48 were examined by the study investigators. Five (10%) of these children had major anomalies consisting of lumbosacral meningomyelocele (N=1), multiple ventricular septal defects (N=1), indirect inguinal hernia (N=1) (all three exposed to carbamazepine alone), and cleft uvula (N=2) (exposed to carbamazepine and phenobarbital). Five (7%) of the control infants also had major anomalies. The incidence of children with two minor malformations was statistically similar for the study and control groups (23% [11 of 48] vs. 13% [9 of 70], respectively). Those presenting with three or more minor anomalies, however, were more frequent in the exposed group (38%; 18 of 48) than in controls (6%; 4 of 70) (p=0.001). Based on the combined results from the retrospective and prospective studies, the investigators concluded that carbamazepine exposure was associated with a pattern of congenital malformations whose principal features consisted of minor craniofacial defects, fingernail hypoplasia, and developmental delay. Because these defects were similar to those observed with the fetal hydantoin syndrome, and because both carbamazepine and phenytoin are metabolized through the arene oxide pathway, a mechanism was proposed that attributed the teratogenicity to the epoxide intermediates rather than to the specific drugs themselves (22).
In later correspondence concerning the above study, the investigators cited unofficial data obtained from the FDA involving 1,307 pregnancies in which the maternal use of carbamazepine was not confounded by the concomitant use of valproic acid (26). Eight infants with spina bifida were identified in the offspring of these mothers. The incidence of 0.6% (1 in 163) represented a 9-fold relative risk for the neural tube defect (26).
A 1991 report cited data accumulated by the FDA on 237 infants with spina bifida born to women taking antiepileptic drugs during gestation (27). Carbamazepine was part of the anticonvulsant regimen in at least 64 of the women, 36 without valproic acid and 28 with valproic acid. The author noted that substantial underreporting was likely in these data, and an accurate assessment of the risk of spina bifida with carbamazepine could not be determined from voluntarily reported cases (27). To overcome these and other biases, the pregnancy outcomes of all Medicaid recipients in Michigan who gave birth in the period from 1980 through 1988, and who took anticonvulsants during the 1st trimester, were examined. Four cases of spina bifida were identified from 1,490 women, including 107 who had taken carbamazepine. Three of the infants with spina bifida had been exposed to carbamazepine in utero, one of whom was also exposed to valproic acid, and two of whom were also exposed to phenytoin, barbiturates, or primidone alone or in combination. Combined with other published studies, the author concluded that in utero exposure to carbamazepine during the 1st trimester, without concurrent exposure to valproic acid, results in a 1% risk of spina bifida (27). The relative risk (RR) was estimated to be about 13.7 (95% confidence interval [CI], 5.633.7) times the expected rate.
The above study generated several published comments involving the risk of spina bifida after 1st trimester exposure to carbamazepine (28,29,30,31 and 32). The last Reference described an infant with closed spina bifida resulting from a pregnancy in which the mother took 600 mg of carbamazepine alone throughout gestation (32). The 3400-g female infant, delivered at 36 weeks’ gestation, had a lumbosacral myelomeningocele covered with skin and no sensory loss. The authors of this report commented on four other cases of spina bifida after exposure to carbamazepine, either alone or in combination with valproic acid (32).
The effects of exposure (at any time during the 2nd or 3rd month after the last menstrual period) to folic acid antagonists on embryo/fetal development were evaluated in a large, multicenter, case-control surveillance study published in 2000 (33). The report was based on data collected between 1976 and 1998 from 80 maternity or tertiary care hospitals. Mothers were interviewed within 6 months of delivery about their use of drugs during pregnancy. Folic acid antagonists were categorized into two groups: group Idihydrofolate reductase inhibitors (aminopterin, methotrexate, sulfasalazine, pyrimethamine, triamterene, and trimethoprim); and group IIagents that affect other enzymes in folate metabolism, impair the absorption of folate, or increase the metabolic breakdown of folate (carbamazepine, phenytoin, primidone, and phenobarbital). The case subjects were 3,870 infants with cardiovascular defects, 1,962 with oral clefts, and 1,100 with urinary tract malformations. Infants with defects associated with a syndrome were excluded, as were infants with coexisting neural tube defects (NTDs; known to be reduced by maternal folic acid supplementation). Too few infants with limb-reduction defects were identified to be analyzed. Controls (N=8,387) were infants with malformations other than oral clefts and cardiovascular, urinary tract, and limb-reduction defects and NTDs, but included infants with chromosomal and genetic defects. The risk of malformations in control infants would not have been reduced by vitamin supplementation, and none of the controls used folic acid antagonists. For group I cases, the RRs of cardiovascular defects and oral clefts were 3.4 (95% CI 1.86.4) and 2.6 (95% CI 1.16.1), respectively. For group II cases, the RRs of cardiovascular defects, urinary tract defects, and oral clefts were 2.2 (95% CI 1.43.5), 2.5 (95% CI 1.25.0), and 2.5 (95% CI 1.54.2), respectively. Maternal use of multivitamin supplements reduced the risks in group I cases, but not in group II cases (33).
A 1996 study described typical dysmorphic facial features in 6 of 47 children (aged 6 months6 years) who had been exposed to carbamazepine monotherapy during pregnancy (34). Moreover, the average cognitive score for the 47 children was significantly lower than a control group. The authors concluded that the facial features and mild mental retardation were consistent with a carbamazepine syndrome that had been described earlier (see Reference 22) (34).
In a 2000 study, a group of 100 Swedish children who had been exposed to antiepileptic drugs (carbamazepine most frequently) in utero were compared to 100 matched controls at 9 months of age (35). Exposed children had an increase in the number of minor anomalies (31 vs. 18, p=0.02) and, after carbamazepine exposure, an increased number of facial anomalies (11 vs. 6). A blinded assessment of psychomotor development using Griffiths’ test (gross motor function, personal and social behavior, hearing and speech, eye and hand coordination, and performance), however, found that antiepileptic drug exposure did not influence the results (35).
The effect of in utero exposure to antiepileptic drugs on fetal growth was described for 977 newborns in another 2000 Swedish study (36). Birth data were collected from 1973 to 1997, during which time the frequency of antiepileptic monotherapy increased from 46% to 88%. As expected, the most marked effects on body weight, length, and head circumference were found with polytherapy. For monotherapy, however, only carbamazepine had a negative influence on these measurements (36).
A 1997 study, using the General Practice Research Database in the United Kingdom, reported an increased prevalence of major malformations in infants of epileptic mothers treated with antiepiletic drugs (3.4%; 10 of 297) compared with matched controls (1.0%; 6 of 594), with a RR of 3.3 (95% CI 1.29.2) (37). Eight of the 10 congenital anomalies involved carbamazepine (7 with monotherapy): ventricular septal defect; pulmonary stenosis; cleft palate, hare lip; Pierre Robin syndrome with cleft palate (also alcohol abuse); sensorineural deafness; congenital megaureter, hydronephrosis syndrome; vesicoureteric reflux; and Marcus Gunn ptosis (combined with sodium valproate) (37).
A 2000 study, using data from the MADRE (an acronym for MAlformation and DRug Exposure) surveillance project, assessed the human teratogenicity of anticonvulsants (38). Among 8,005 malformed infants, cases were defined as infants with a specific malformation, whereas controls were infants with other anomalies. Of the total group, 299 were exposed in the 1st trimester to anticonvulsants. Among these, exposure to monotherapy occurred in the following numbers: phenobarbital (N=65), methobarbital (N=10), carbamazepine (N=46), valproic acid (N=80), phenytoin (N=24), and other agents (N=16). A statistically significant association (CI not overlapping 1 and p0.05) was found between carbamazepine monotherapy and spina bifida (N=4). When all 1st trimester exposures (mono- and polytherapy) were evaluated, a significant association was found between carbamazepine and hypertelorism with localized skull defects (N=3). Although the study confirmed some previously known associations, several new associations with anticonvulsants were discovered and require independent confirmation (see also Mephobarbital, Phenobarbital, Phenytoin, and Valproic Acid) (38).
A prospective study published in 1999 described the outcomes of 517 pregnancies of epileptic mothers identified at one Italian center from 1977 (39). 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: carbamazepine (N=113), phenobarbital (N=83), valproate (N=44), primidone (N=35), phenytoin (N=31), clonazepam (N=6), 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 12 malformations with carbamazepine monotherapy: 7 (6.2%) were severe (spinia bifida, hydrocephalus, diaphragmatic hernia, esophagus atresia, pyloric stenosis, omphalocele, renal dysplasia, and hydronephrosis), 1 (0.9%) was mild (inguinal hernia and valgus/varus foot), and 4 (3.5%) were deformations (club foot and hip dislocation). The investigators concluded that the anticonvulsants were the primary risk factor for an increased incidence of congenital malformations (see also Clonazepam, Phenobarbital, Phenytoin, Primidone, and Valproic Acid) (39).
A 2001 prospective cohort study, conducted from 1986 to 1993 at five maternity hospitals, was designed to determine if anticonvulsant agents or other factors (e.g., genetic) were responsible for the constellation of abnormalities seen in infants of mothers treated with anticonvulsants during pregnancy (40). A total of 128,049 pregnant women were screened at delivery for exposure to anticonvulsant drugs. Three groups of singleton infants were identified: (a) exposed to anticonvulsant drugs, (b) not exposed to anticonvulsant drugs but with a maternal history of seizures, and (c) not exposed to anticonvulsant drugs and with no maternal history of seizures (control group). After applying exclusion criteria, including exposure to other teratogens, 316, 98, and 508 infants, respectively, were analyzed. Anticonvulsant monotherapy occurred in 223 women: phenytoin (N=87), phenobarbital (N=64), carbamazepine (N=58), and too few cases for analysis with valproic acid, clonazepam, diazepam, and lorazepam. Ninety-three infants were exposed to two or more anticonvulsant drugs. All infants were examined systematically (blinded as to group in 93% of the cases) for embryopathy associated with anticonvulsant exposure (major malformations, hypoplasia of the midface and fingers, microcephaly, and intrauterine growth retardation). Compared to controls, significant (p0.05, CI not overlapping 1) associations between anticonvulsants and anticonvulsant embryopathy were: phenytoin monotherapy, 20.7% (18/87); phenobarbital monotherapy, 26.6% (17/64); any monotherapy, 20.6% (46/223); exposure to two or more anticonvulsants, 28.0% (26/93); and all infants exposed to anticonvulsants (mono- and polytherapy), 22.8% (72/316). Nonsignificant associations were found for carbamazepine monotherapy (13.8%; 8/58), nonexposed infants with a maternal history of seizures (6.1%; 6/98), and controls (8.5%, 43/508). The investigators concluded that the distinctive pattern of physical abnormalities observed in infants exposed to anticonvulsants during gestation was due to the drugs, rather than to epilepsy itself (40).
In a study designed to evaluate the effect of in utero exposure to anticonvulsants on intelligence, 148 Finnish children of epileptic mothers were compared with 105 controls (21). Previous studies had shown either intellectual impairment from this exposure or no effect. Of the 148 children of epileptic mothers, 129 were exposed to anticonvulsant therapy during the first 20 weeks of pregnancy, 2 were only exposed after 20 weeks, and 17 were not exposed. In those mothers treated during pregnancy, 42 received carbamazepine (monotherapy in 9 cases) during the first 20 weeks, and 1 received the drug after 20 weeks. The children were evaluated at 5.5 years of age for both verbal and nonverbal measures of intelligence. A child was considered mentally deficient if the results of both tests were less than 71. Two of the 148 children of epileptic mothers were diagnosed as mentally deficient and 2 others had borderline intelligence (the mother of one of these latter children had not been treated with anticonvulsant medication). None of the controls was considered mentally deficient. One child with profound mental retardation had been exposed in utero to carbamazepine monotherapy, but the condition was compatible with dominant inheritance and was not thought to be caused by drug exposure. Both verbal and nonverbal intelligence scores were significantly lower in the study group children than in controls. In both groups, intelligence scores were significantly lower when seven or more minor anomalies were present (p=0.03). However, the presence of hypertelorism and digital hypoplasia, two minor anomalies considered typical of exposure to some anticonvulsants (e.g., phenytoin), was not predictive of low intelligence (21).
A prospective, controlled, blinded observational 1994 study compared the global IQ and language development of children exposed in utero to either carbamazepine (N=34) or phenytoin (N=36) monotherapy to their respective matched controls (41). The cognitive tests were administered to the children between the ages of 18 and 36 months. The maternal IQ scores and socioeconomic status in the carbamazepine subjects and their controls were similar (96.5 vs. 96.0, and 44.7 vs. 46.1, respectively), as they were in the phenytoin subjects and controls (90.0 vs. 93.9, and 40.8 vs. 40.9, respectively). Compared to controls, no significant differences were measured either in IQ or language development scores between carbamazepine-exposed children and their matched controls. In contrast, phenytoin-exposed children had both lower mean global IQ and language development scores than their matched controls (see Phenytoin). No correlation between the daily dose (mg/kg) of either anticonvulsant and global IQ was found. Major malformations were observed in two carbamazepine-exposed children (missing last joint of right index finger and nail hypoplasia; hypospadias), one carbamazepine control (pulmonary atresia), and two phenytoin-exposed children (see Phenytoin) (41). In subsequent correspondence relating to the above study (42,43), various perceived problems were cited and were addressed in a reply (44).
A possible teratogenic mechanism for carbamazepine in combination with other anticonvulsants was proposed in 1984 to account for the higher than expected adverse pregnancy outcome that is observed with combination therapy (45). Accumulation of the toxic oxidative metabolite carbamazepine-10,11-epoxide was shown when the drug was combined with other antiepileptic agents, such as phenobarbital, valproic acid, and phenytoin. These last two agents are also known to produce toxic epoxide metabolites that can bind covalently to macromolecules and may produce mutagenic or teratogenic effects (see also Phenytoin) (45).
A case of attempted suicide with carbamazepine, possibly resulting in a neural tube defect, has been reported (46). A 44-year-old nonepileptic woman at 34 weeks after conception (i.e., during the period of neural tube closure) ingested approximately 4.8 g of the drug as a single dose. Her serum carbamazepine levels for 2 days after the ingestion were more than twice the recommended maximum therapeutic level. Subsequently, a large thoracolumbar spinal defect was observed on sonographic examination and her pregnancy was terminated at 20 weeks’ gestation. Fetal autopsy of the male infant revealed an open myeloschisis and a hypoplastic left cerebral hemisphere, the latter defect thought to be the result of focal necrosis (46).
A case of neuroblastoma was described in a developmentally normal 2 1/2-year-old male infant who had been exposed throughout gestation to carbamazepine and phenytoin (47). The tumor was attributed to phenytoin exposure.
The effect of carbamazepine on maternal and fetal vitamin D metabolism was examined in a 1984 study (48). In comparison to normal controls, several significant differences were found in the level of various vitamin D compounds and in serum calcium, but the values were still within normal limits. No alterations were found in alkaline phosphatase and phosphate concentrations. The authors doubted if the observed differences were of major clinical significance.
In summary, carbamazepine use in pregnancy is associated with an increased incidence of major and minor malformations, including an estimated 1% risk of spina bifida. A fetal carbamazepine syndrome has been proposed consisting of minor craniofacial defects, fingernail hypoplasia, and developmental delay. The latter abnormality, however, is controversial; some studies have found mild mental retardation and some have not. Although pregnant women should be advised of these potential adverse outcomes, if the drug is required during pregnancy it should not be withheld because the benefits of preventing seizures outweigh the potential fetal harm.
Breast Feeding Summary
Carbamazepine is excreted into breast milk, producing milk:plasma ratios of 0.240.69 (2,4,9,14,49,50 and 51). The amount of carbamazepine measured in infant serum is low, with typical levels around 0.4 mg/mL, but levels may be as high as 0.51.8 mg/mL (2,50). In one case, infant serum levels were 15% and 20% of the maternal total and free carbamazepine concentrations, respectively (50). Accumulation does not seem to occur.
In a 1998 case report, seizures were reported by the mother in a nursing infant (51). The mother had bipolar disorder that was being treated with fluoxetine (20 mg/day), buspirone (45 mg/day), and carbamazepine (600 mg/day) (see also Fluoxetine and Buspirone). Carbamazepine was detected in breast milk and the infant’s serum (both 0.5 ng/mL). A neurologic examination of the infant, which included electroencephalography, was within normal limits. The authors were unable to determine the cause of the seizure-like activity, if indeed it had occurred (none of the episodes had been observed by medical personnel) (51).
The American Academy of Pediatrics considers carbamazepine to be compatible with breast feeding (52).
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