Phenobarbital

Name: PHENOBARBITAL
Class: Sedative/Anticonvulsant
Risk Factor: D

Fetal Risk Summary

Phenobarbital has been used widely in clinical practice as a sedative and anticonvulsant since 1912 (1). The drug crosses the placenta to the fetus at birth (2). Factors significantly influencing placental transfer were duration of maternal treatment, gestational age, and arterial cord pH (2).
The potential teratogenic effects of phenobarbital were recognized in 1964 along with phenytoin (3). Since this report, there have been numerous reviews and studies on the teratogenic effects of phenobarbital either alone or in combination with phenytoin and other anticonvulsants. Based on this literature, the epileptic pregnant woman taking phenobarbital in combination with other antiepileptics has a 2–3 times greater risk for delivering a child with congenital defects over the general population (4,5,6,7,8,9,10 and 11) .
It has not always been known if the increased risk of congenital anomalies was caused by antiepileptic drugs, the disease itself, genetic factors, or a combination of these factors. A 1991 study of epileptic mothers who had been treated with either phenobarbital or carbamazepine, or the two agents in combination during pregnancy concluded that major and minor anomalies appeared to be more related to the mother's disease than to the drugs (11). An exception to this was the smaller head circumference observed in infants exposed in utero to either phenobarbital alone or in combination with carbamazepine. However, an earlier publication thought there was evidence that drugs were the causative factor (12).
A prospective study published in 1999 described the outcomes of 517 pregnancies of epileptic mothers identified at one Italian center from 1977 (13). 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: phenobarbital (N=83), carbamazepine (N=113), 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 4 malformations with phenobarbi- tal monotherapy: 2 (2.4%) were severe (Fallot's tetralogy, hydronephrosis), 1 (1.2%) was mild (umbilical and inguinal hernia), and 1 (1.2%) deformation (hip dislocation). The investigators concluded that the anticonvulsants were the primary risk factor for an increased incidence of congenital malformations (see also Carbamazepine, Clonazepam, Phenytoin, Primidone, and Valproic Acid) (13).
A 2001 prospective study provides further evidence that the congenital defects observed in the offspring of epileptic mothers treated with anticonvulsants are caused by drugs (14). The 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. 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). For a variety of reasons, including exposure to other teratogens, many identified infants were excluded, leaving 316, 98, and 508 infants, respectively, in the three groups for analysis. 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 (pЈ0.05, confidence limits not overlapping 1) associations between anticonvulsants and anticonvulsant embryopathy were: phenobarbital monotherapy 26.6% (17/64), phenytoin monotherapy 20.7% (18/87), all infants exposed to anticonvulsant monotherapy 20.6% (46/223), exposed to two or more anticonvulsants 28.0% (26/93), and all infants exposed to anticonvulsants (mono- and poly-therapy) 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 (14).
A phenotype, as described for phenytoin in the fetal hydantoin syndrome (FHS), apparently does not occur with phenobarbital (see Phenytoin for details of FHS). However, as summarized by Janz (15), some of the minor malformations composing the FHS have been occasionally observed in infants of epileptic mothers treated only with phenobarbital.
The effects of prenatal exposure to phenobarbital on central nervous system development of offspring have been studied in both animals (16,17 and 18) and humans (11,19,20,21 and 22) . The neural development in 90-day-old offspring of female rats given phenobarbital in doses of 0, 20, 40, or 60 mg/kg/day before and throughout gestation were described in a 1992 study (16). The drug produced dose- and sex-dependent changes in the electroencephalograms of the offspring. Lower doses resulted in adverse changes in learning and attentional focus, whereas higher doses also adversely affected neural function related to slow-wave sleep and receptor homeostasis. An earlier study measured the long-term effects on the offspring of rats from exposure to 40 mg/kg/day of phenobarbital from day 12 to day 19 of gestation (17). The effects included delays in the onset of puberty, disorders in the estrous cycle, infertility, and altered concentrations of sex steroids, gonadotropic hormones, and estrogen receptors. The changes represented permanent alterations in sexual maturation. A similar study measured decreases in the concentration of testosterone in the plasma and brain of exposed fetal rats (18). These changes persisted into adult life, indicating that phenobarbital may lead to sexual dysfunction in mature animals.
In a 1991 human study, the cognitive development (as measured by school career, reading, spelling, and arithmetic skills) of children who had been exposed in utero to either phenobarbital alone or in combination with carbamazepine was significantly impaired in comparison with children of nonepileptic mothers (11). A similar finding, but not significant, was suggested when the phenobarbital-exposed children were compared with children exposed only to carbamazepine.
In a 1988 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 (19). Previous studies had either shown 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, 22 received phenobarbital in combination with other anticonvulsants, all during the first 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. Both verbal (110.2 vs. 114.5, p<0.05) and nonverbal (108.7 vs. 113.2, p<0.05) 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 phenytoin, was not predictive of low intelligence (19).
A 1996 study also described the effects of in utero phenobarbital exposure on cognitive performance (20). Intelligence scores of Danish adult men, born between 1959 and 1961, who had been exposed to prenatal phenobarbital were measured. Their mothers had no history of central nervous system disorder and there was no exposure to other psychopharmacological drugs. Two double-blind studies using different measures of general intelligence were conducted on subjects (total=114) and controls (total=153). The test scores of matched controls were used to predict scores for each exposed subject. The exposure effects were then estimated by comparing the predicted to the observed scores. Phenobarbital exposure was associated with significantly lower verbal intelligence scores (about 0.5 SD). Exposure in the 3rd trimester was the most detrimental. The magnitude of the intelligence deficit was increased by lower socioeconomic status and being the offspring of an unwanted pregnancy (20).
A two-part 2000 study evaluated the effects of prenatal phenobarbital and phenytoin exposure on brain development and cognitive functioning in adults (21). Subjects and matched controls, delivered at a mean 40 weeks' gestation, were retrospectively identified from birth records covering the years between 1957 and 1972. Maternal diseases of the subjects included epilepsy (treated with anticonvulsants) and other conditions in which anticonvulsants were used as sedatives (nausea, vomiting, or emotional problems), whereas the control group had no maternal pathologies. Only those exposed prenatally to phenobarbital alone or phenobarbital plus phenytoin had sufficient subjects to analyze. The mean occipitofrontal cir- cumference for phenobarbital-exposed neonates was not different from controls (34.49 vs. 34.50 cm), but it was significantly smaller for phenobarbital plus phenytoin subjects compared to phenobarbital alone or controls (33.82 cm, p=0.003). In the follow-up part of the study, no differences in adult cognitive functioning (intelligence, attention, and memory) were found between the exposed and control groups. More subjects than controls, however, were mentally retarded (4 vs. 2; causes of retardation not known except for one case of autism in controls) and more had persistent learning problems (12% vs. 1%). The investigators concluded that phenobarbital plus phenytoin reduced occipitofrontal circumference but may only affect cognitive capacity in susceptible offspring (21).
The relationship between maternal anticonvulsant therapy, neonatal behavior, and neurological function in children was reported in a 1996 study (22). Among newborns exposed to maternal monotherapy, 18 were exposed to phenobarbital (including primidone), 13 to phenytoin, and 8 to valproic acid. Compared to controls, neonates exposed to phenobarbital had significantly higher mean apathy and optimality scores. Phenytoin-exposed neonates also had a significantly higher mean apathy score. However, the neonatal optimality and apathy scores did not correlate with neurological outcome of the children at 6 years of age. In contrast, those exposed to valproic acid had optimality and apathy scores statistically similar to controls but a significantly higher hyperexcitability score. Moreover, the hyperexcitability score correlated with later minor and major neurological dysfunction at age 6 years (22).
The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 1,415 of which had 1st trimester exposure to phenobarbital (23, pp. 336–339). For use anytime during pregnancy, 8,037 exposures were recorded (23, p. 438). In neither group was evidence found to suggest a relationship to large categories of major or minor malformations, although a possible association with Down's syndrome was shown statistically. However, a relationship between phenobarbital and Down's syndrome is unlikely.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 334 newborns had been exposed to phenobarbital during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 20 (6.0%) major birth defects were observed (14 expected). Specific data were available for six defect categories, including (observed/expected) 8/3 cardiovascular defects, 1/1 oral clefts, 1/0 spina bifida, 1/1 polydactyly, 0/1 limb reduction defects, and 1/1 hypospadias. Only the data for cardiovascular defects is suggestive of a possible association.
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 (24). 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 I–dihydrofolate reductase inhibitors (aminopterin, methotrexate, sulfasalazine, pyrimethamine, triamterene, and trimethoprim); group II–agents 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, limb-reduction, 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 relative risks (RRs) of cardiovascular defects and oral clefts were 3.4 (95% confidence interval [CI] 1.8–6.4) and 2.6 (95% CI 1.1–6.1), respectively. For group II cases, the RRs of cardiovascular and urinary tract defects, and oral clefts were 2.2 (95% CI 1.4–3.5), 2.5 (95% CI 1.2–5.0), and 2.5 (95% CI 1.5–4.2), respectively. Maternal use of multivitamin supplements reduced the risks in group I cases, but not in group II cases (24).
Thanatophoric dwarfism was found in a stillborn infant exposed throughout gestation to phenobarbital (300 mg/day), phenytoin (200 mg/day), and amitriptyline (>150 mg/day) (25). The cause of the malformation could not be determined, but both drug and genetic causes were considered.
A 2000 study, using data from the MADRE (an acronym for MAlformation and DRug Exposure) surveillance project, assessed the human teratogenicity of anticonvulsants (26). Among 8005 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: phenobarbital (N=65), mephobarbital (N=10), carbamazepine (N=46), valproic acid (N=80), phenytoin (N=24), and other agents (N=16). Statistically significant associations (CI do not overlap 1 and pЈ0.05) were found with phenobarbital monotherapy and cardiac defects (N=12), and cleft lip/palate (N=11). When all 1st trimester exposures (mono- and poly-therapy) were evaluated, significant associations were found between phenobarbital and cardiac defects (N=20), cleft lip/palate (N=19), and persistent left superior vena cava/other anomalies of the circulatory system (N=3). Although the study confirmed some previously known associations, several new associations with anticonvulsants were discovered and require independent confirmation (see also Carbamazepine, Mephobarbital, Phenytoin, and Valproic Acid) (26).
Phenobarbital and other anticonvulsants (e.g., phenytoin) may cause early hemorrhagic disease of the newborn (27,28,29,30,31, 32,33,34,35 and 36) . Hemorrhage occurs during the first 24 hours after birth and may be severe or even fatal. The exact mechanism of the defect is unknown but may involve phenobarbital induction of fetal liver microsomal enzymes that deplete the already low reserves of fetal vitamin K (36). This results in suppression of the vitamin K–dependent coagulation factors II, VII, IX, and X. A 1985 review summarized the various prophylactic treatment regimens that have been proposed (see Phenytoin for details) (36).
Barbiturate withdrawal has been observed in newborns exposed to phenobarbital in utero (37). The average onset of symptoms in 15 addicted infants was 6 days (range 3–14 days). These infants had been exposed during gestation to doses varying from 64 to 300 mg/day with unknown amounts in four patients.
Phenobarbital may induce folic acid deficiency in the pregnant woman (38,39 and 40) . A discussion of this effect and the possible consequences for the fetus are presented under Phenytoin (see also Reference 24 above).
High-dose phenobarbital, contained in an antiasthmatic preparation, was reported in a mother giving birth to a stillborn full-term female infant with complete triploidy (41). The authors speculated on the potential for phenobarbital-induced chromosomal damage. However, an earlier in vitro study found no effect of phenobarbital on the incidence of chromosome gaps, breaks, or abnormal forms (42). Any relationship between the drug and the infant's condition is probably coincidental.
Phenobarbital and cholestyramine have been used to treat cholestasis of pregnancy (43,44). Although no drug-induced fetal complications were noted, the ther- apy was ineffective for this condition. An earlier study, however, reported the successful treatment of intrahepatic cholestasis of pregnancy with phenobarbital, resulting in the normalization of serum bilirubin concentrations (45). The drug has also been used in the last few weeks of pregnancy to reduce the incidence and severity of neonatal hyperbilirubinemia (46).
Antenatal phenobarbital, either alone or in combination with vitamin K, has been used to reduce the incidence and severity of intraventricular hemorrhage in very-low-birth-weight infants (47,48,49,50,51,52,53 and 54) . The therapy seems to consistently reduce the frequency of grade 3 and grade 4 hemorrhage, and infant mortality from this condition. A 1991 review of this therapy summarized several proposed mechanisms by which phenobarbital might produce this beneficial effect (55). However, three studies (50,52,54), one involving 668 infants (treated and controls) (54), have concluded that the risk of intraventricular hemorrhage or early death in preterm infants is not decreased by antenatal phenobarbital.
In a study using the same subjects and controls as in Reference 53 above, antenatal phenobarbital (10 mg/kg IV, then 100 mg orally every 24 hours until delivery or until completion of 34 weeks' gestation) had no effect, compared to nonexposed controls, on neurodevelopment as measured serially up to age 3 years (56). In contrast, another study using the same subjects and controls as a previous study (Reference 52) found that antenatal phenobarbital (720-780 mg IV, then 60 mg IV every 6 hours until delivery or 34 weeks' gestation) significantly impaired developmental outcome as measured at age 2 years (57,58).
In summary, phenobarbital therapy in the epileptic pregnant woman presents a risk to the fetus in terms of major and minor congenital defects, hemorrhage at birth, and addiction. Adverse effects on neurobehavioral development have also been reported. The risk to the mother, however, is greater if the drug is withheld and seizure control is lost. The risk:benefit ratio, in this case, favors continued use of the drug during pregnancy at the lowest possible level to control seizures. Use of the drug in nonepileptic patients does not seem to pose a significant risk for structural defects, but hemorrhage and addiction in the newborn are still concerns.

Breast Feeding Summary

Phenobarbital is excreted into breast milk (59,60,61,62,63 and 64) . In two reports, the milk:plasma ratio varied between 0.4 and 0.6 (60,61). The amount of phenobarbital ingested by the nursing infant has been estimated to reach 2–4 mg/day (62). The pharmacokinetics of phenobarbital during lactation have been reviewed (61). Because of slower elimination in the nursing infant, accumulation may occur to the point that blood levels in the infant may actually exceed those of the mother (61). Phenobarbital-induced sedation has been observed in three nursing infants probably caused by this accumulation (59).
A case of withdrawal in a 7-month-old nursing infant after abrupt weaning from a mother taking phenobarbital, primidone, and carbamazepine has been reported (64). The mother had taken the anticonvulsant agents throughout gestation and during lactation. The baby's serum phenobarbital level at approximately 8 weeks of age was 14.8 µmol/L, near the lower level of the therapeutic range. At 7 months of age, the mother abruptly stopped nursing her infant, and shortly thereafter withdrawal symptoms were observed in the infant consisting of episodes of “startle” responses and infantile spasms confirmed by electroencephalography. The infant was treated with phenobarbital with prompt resolution of her symptoms and she was gradually weaned from the drug during a 6-month interval. Her neurologic and mental development were normal during the subsequent 5-year follow-up period (64).
Women consuming phenobarbital during breast feeding, especially those on high doses, should be instructed to observe their infants for sedation. Phenobarbital levels in the infant should also be monitored to avoid toxic concentrations (61,65). The American Academy of Pediatrics classifies phenobarbital as a drug that has caused major adverse effects in some nursing infants, and it should be given to nursing women with caution (65).

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