VALPROIC ACID

Fetal Risk Summary

Valproic acid and its salt form, sodium valproate, are anticonvulsants used in the treatment of seizure disorders. The drugs readily cross the placenta to the fetus. At term, the range of cord blood:maternal serum ratios of total valproic acid (protein bound and unbound) has been reported to be 0.52–4.6 (1,2,3,4,5,6,7,8,9,10,11,12 and 13). More recent studies have reported mean ratios of 1.4–2.4 (4,7,9,10,11,12 and 13). In contrast, the mean cord blood:maternal serum ratio of free (unbound) valproic acid was 0.82 (10). Two mechanisms have been proposed to account for the accumulation of total valproic acid in the fetus: partial displacement of the drug from maternal binding sites by increased free fatty acid concentrations in maternal blood at the time of birth (10) and increased protein binding of valproic acid in fetal serum (11). Increased unbound valproic acid in the maternal serum may also be partially a result of decreased serum albumin (14). Although one study measured a mean serum half-life for valproic acid in the newborn of 28.3 hours (9), other studies have reported values of 43–47 hours, approximately 4 times the adult value (2,4,8,10,13). In agreement with these data, valproic acid has been shown to lack fetal hepatic enzyme induction activity when used alone and will block the enzyme induction activity of primidone when the two anticonvulsants are combined during pregnancy (15).

In published reports, doses of valproic acid in pregnancy have ranged from 300 to 3000 mg (1,2 and 3,8,12,16,17,18,19,20,21,22,23,24,25,26,27 and 28). Although a good correlation between serum levels and seizure control is not always observed, most patients will respond when levels are in the range of 50–100 µg/mL (29). In early pregnancy, high (i.e., >1000 mg) daily doses of valproic acid may produce maternal serum concentrations that are much greater than 100 µg/mL (8). However, as pregnancy progresses and without dosage adjustment, valproic acid levels fall steadily so that in the 3rd trimester, maternal levels are often less than 50 µg/mL (8). One study concluded that the decreased serum concentrations were a result of increased hepatic clearance and an increased apparent volume of distribution (8).

Fetal or newborn consequences resulting from the use of valproic acid and sodium valproate during pregnancy have been reported to include: major and minor congenital abnormalities, intrauterine growth retardation, hyperbilirubinemia, hepatotoxicity (which may be fatal), transient hyperglycinemia, afibrinogenemia (one case), and fetal or neonatal withdrawal.

Before 1981, the maternal use of valproic acid was not thought to present a risk to the fetus. A 1981 editorial recommended sodium valproate or carbamazepine as anticonvulsants of choice in appropriate types of epilepsy for women who may become pregnant (30). Although the drug was known to be a potent animal teratogen (31), more potent than phenytoin and at least as potent as trimethadione (32), only a single unconfirmed case of human teratogenicity (in a fetus exposed to at least two other anticonvulsants) had been published between 1969 and 1976 (33). (An editorial comment in that report noted that subsequent investigation had failed to confirm the defect.) In other published cases, both before and after 1980, healthy term infants resulted after in utero exposure to valproic acid (1,2 and 3,12,19,27,28,32,34,35,36,37 and 38). Moreover, a committee of the American Academy of Pediatrics stated in 1982 that the data for a teratogenic potential in humans for valproic acid were inadequate and that recommendations for or against its use in pregnancy could not be given (39).

The first confirmed report of an infant with congenital defects after valproic acid exposure during pregnancy appeared in 1980 (16). The mother, who took 1000 mg of valproic acid daily throughout gestation, delivered a growth-retarded infant with facial dysmorphism and heart and limb defects. The infant died at 19 days of age. Since this initial report, a number of studies and case reports have described newborns with malformations after in utero exposure to either valproic acid monotherapy or combination therapy (4,17,18,19,20,21,22,23,24,25 and 26,36,40,41,42,43,44,45,46, 47,48,49,50,51,52,53,54,55,56,57,58, 59 and 60).

The most serious abnormalities observed with valproic acid (or sodium valproate) exposure are defects in neural tube closure. The absolute risk of this defect is approximately 1%–2%, about the same risk for a familial occurrence of this anomaly (37,40,61,62). No cases of anencephaly have been associated with valproic acid (21,62,63). Exposure to valproic acid between the 17th and 30th day after fertilization must occur before the drug can be considered a cause of neural tube defects (64). Other predominant defects involve the heart, face, and limbs. A characteristic pattern of minor facial abnormalities has been attributed to valproic acid (61). Cardiac anomalies and cleft lip and palate occur with most anticonvulsants and a causal relationship with valproic acid has not been established (37,46). In addition, almost all types of congenital malformations have been observed after treatment of epilepsy during pregnancy (see Janz 1982, Phenytoin). Consequently, the list below, although abstracting the cited References, is not meant to be inclusive and, at times, reflects multiple anticonvulsant therapy.

  NEURAL TUBE DEFECTS Defects in neural tube closure (17,19,21,22,24,26,40,41 and 42,44,45 and 46,53,54,55,56,57 and 58)   (includes entire spectrum from spina bifida occulta to meningomyelocele) CARDIAC DEFECTS Multiple (not specified) (21,24) (26,37,42,44,51) Levocardia (16) Patent ductus arteriosus (4,26,48,50,52) Anomalies of great vessels (51)   Valvular aortic stenosis (23,48) Ventricular septal defect (4,20,48) Tetralogy of Fallot (18,51) Partial right bundle-branch block (16) FACIAL DEFECTS Facial dysmorphism (4,26,42,46,50,53,59) Small nose (16,20,24,26,50,20,53,59), Depressed nasal bridge (18,20,26,50,59) Flat orbits (26) Protruding eyes (16) Hypertelorism (4,26) Low-set/rotated ears (4,16,24,26,50) Micrognathia/retrognathia (16,23,26) Thin upper vermilion border (24,26,48,50,53) Down-turned angles of mouth (50,59)   High forehead (24,26) Bulging frontal eminences (16,20 Strabismus (50) Nystagmus (50) Epicanthal folds (4,26,50,53,59) Coarsened facies (20) Cleft lip/palate (18,37,42,44,51) Microstomia (24,26,48,50) Esotropia (50) Depigmentation of eyelashes and brow (16,25) Short palpebral fissure (26,48,50) Long upper lip (26,50,59) Agenesis of lacrimal ducts (51) HEAD/NECK DEFECTS Brachycephaly (24,26) Hydrocephaly (19,21,42,46) Wide anterior fontanelle (18) Abnormal or premature stenosis of metopic suture (24,26,50)   Microcephaly (4,21,24,38,50,64,65) Short neck (20) Craniostenosis (26) Aplasia cutis (60) UROGENITAL DEFECTS Bilateral duplication of caliceal collecting systems (25) Bilateral undescended testes (23)   Nonspecified (26) Hypospadias (21,23,26,46,50) Bilateral renal hypoplasia (23) SKELETAL/LIMB DEFECTS Aplasia of radius (23,26) Dislocated hip (16,26,35) Hypoplastic thumb (20) Hemifusion of second and third lumbar vertebrae (25) Abnormal sternum (16,26) Scoliosis (25) Multiple (not specified) (24) Clinodactyly of fingers (26) Tracheomalacia (53)   Rib defects (24,26) Foot deformity (17,23,24,50) Abnormal digits (23,26,37,42) Shortened fingers, and toes (4,20) Arachnodactyly (24,26) Overlapping fingers/toes (24,26) Broad or asymmetric chest (16,26 Talipes equinovarus (53) SKIN/MUSCLE DEFECTS Accessory, wide-spaced, or inverted nipples (20,26) Diastasis recti abdominis (4,25) Syndactyly of toes (16,23,50) Hyperconvex fingernails (24,26) Hypoplastic nails (4,18) Umbilical hernias (4,26) Linea alba hernia (47) Inguinal hernia (4,26,50)   Cutis aplasia of scalp (50) Weak abdominal walls (4) Hirsutism (26) Abnormal palmar creases (16,18,50) Hemangioma (4,25,26,50) Sacral dimple (43) Telangiectasia (4) Omphalocele (59) OTHER DEFECTS Multiple defects (not specified) (24,51) Mental retardation (4,20,50,51,53)   Withdrawal or irritation (4,50) Duodenal atresia (25) Single umbilical artery (50) Although a wide variety of minor anomalies, many of which are similar in nature, occurs in infants of epileptic mothers, three groups of investigators have concluded that the deformities associated with valproic acid are distinctly different from those associated with other anticonvulsants and may constitute a valproic acid syndrome (FVS) (26,50,53). The combined features cited in the three reports were: (a) neural tube defects; (b) craniofacial: brachycephaly, high forehead, epicanthal folds, strabismus, nystagmus, shallow orbits, flat nasal bridge, small up-turned nose, hypertelorism, long upper lip, thin upper vermillion border, microstomia, down-turned angles of mouth, low-set/rotated ears; (c) digits: long, thin, partly overlapping fingers and toes, hyperconvex nails; (d) urogenital: hypospadias (in about 50% of males); and (e) other: retarded psychomotor development, low birth weight. Normal psychomotor development has been observed, however, in follow-up studies of children up to 4 years of age after in utero exposure to either mono- or combination therapy with valproic acid (3,34,65,66).

A 1995 review listed the facial features seen in the FVS as trigonocephaly, tall forehead with bifrontal narrowing, epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root anteverted nares, shallow philtrum, long upper lip with thin vermilion border, thick upper lip, small, downturned mouth (67). The most common major congenital defects observed were neural tube defects, congenital heart disease, cleft lip and palate, genital anomalies, and limb defects. Other, less common abnormalities were tracheomalacia, abdominal wall defects, and strabismus. Dose-related withdrawal symptoms (irritability, jitteriness, hypotonia, and seizures) were considered to be very common, typically occurring 12–48 hours after birth (67).

A correlation between valproic acid dosage and the number of minor anomalies in an infant has been proposed (26). Such a correlation has not been observed with other anticonvulsants (26). The conclusion was based on the high concentrations of valproic acid that occur in the 1st trimester after large doses (i.e., 1500–2000 mg/day).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 26 newborns had been exposed to valproic acid during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Five (19.2%) major birth defects were observed (one expected), one of which was a hypospadias. No anomalies were observed in five other categories of defects (cardiovascular, oral clefts, spina bifida, polydactyly, and limb-reduction defects) for which specific data were available. Hypospadias has been associated with 1st-trimester valproic acid exposure (see above).

A 2000 study, using data from the MADRE (an acronym for MAlformation and DRug Exposure) surveillance project, assessed the human teratogenicity of anticonvulsants (68). Among 8005 malformed infants, cases were 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: valproic acid (N=80), phenobarbital (N=65), methobarbital (N=10), carbamazepine (N=46), phenytoin (N=24), and other agents (N=16). Statistically significant associations (CI not overlapping 1 and p£0.05) were found between valproic acid monotherapy and spina bifida (N=12), hypospadias (N=10), porencephaly/multiple cerebral cysts and other specified anomalies of brain (N=2), microstomia, microcheilia, and other anomalies of face (N=2), coarctation of aorta (N=2), and limb reduction defects (N=5). When all 1st trimester exposures (mono- and polytherapy) were evaluated, significant associations were found between valproic acid and spina bifida (N=14), cardiac defects (N=26), hypospadias (N=14), porencephaly/multiple cerebral cysts and other specific anomalies of brain (N=2), limb reduction defects (N=5), and hypertelorism, localized skull defects (N=2). Although the study confirmed some previously known associations, several new associations with anticonvulsants were discovered and require independent confirmation (see also Carbamazepine, Mephobarbital, Phenobarbital, and Phenytoin) (68).

The risk of valproic acid-induced limb deficiencies was estimated in a 2000 study that used data from the Spanish Collaborative Study of Congenital Malformations (ECEMC) collected between 1976 and 1997 (69). A total of 22,294 consecutive malformed infants (excluding genetic syndromes) were compared to 21,937 control infants. A total of 57 malformed infants and 10 controls were exposed to valproic acid during the 1st trimester (odds ratio [OR] 5.62, 95% confidence interval [CI] 2.78-11.71, p<0.0000001). Among the 57 infants, 21 (36.8%) had congenital limb defects of different types (overlapping digits, talipes, clinodactyly, arachnodactyly, hip dislocation, pre- and postaxial polydactyly, and limb deficiencies). Five of the 21 cases, however, were thought to have resulted from immobility (e.g., talipes equinovarus) caused by spina bifida. After exclusion of these cases and their respective controls, the OR for congenital limb defects was 3.95, 95% CI 1.24-13.94, p=0.01. Three of the malformed infants had limb deficiencies: hypoplasia of the left hand; unilateral forearm defect and hypoplastic first metacarpal bone in the left hand; and short hands with hypoplastic first metacarpal bone, absent and hypoplastic phalanges (this case also had retrognathia, facial asymmetry, hypospadias, teleangiectatic angioma in the skull, and hypotonia). The case-control analysis showed a risk for limb deficiencies of OR 6.17, 95% CI 1.28-29.66, p=0.023. In their population, the prevalence at birth of limb deficiencies was 6.88 per 10,000 live births. Based on this, they estimated that the risk of limb deficiencies after exposure to valproic acid in the 1st trimester would be about 0.42% (69).

A prospective study published in 1999 described the outcomes of 517 pregnancies of epileptic mothers identified at one Italian center from 1977 (70). 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: valproate (N=44), carbamazepine (N=113), phenobarbital (N=83), 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 eight malformations with valproic acid monotherapy: six (13.6%) were severe (spinia bifida, hydrocephalus, pyloric stenosis, and cardiac defect), one (2.3%) was mild (inguinal hernia), and one was a deformation (arthrogryposis). The investigators concluded that the anticonvulsants were the primary risk factor for an increased incidence of congenital malformations (see also Carbamazepine, Clonazepam, Phenobarbital, Phenytoin, and Primidone) (70).

A 1997 case report described autism diagnosed in a 5.5-year-old boy who had typical clinical features of the FVS (71). The mother had taken valproic acid (2000 mg/day) during the first 5 months of pregnancy for the treatment of dizzy spells, possible absence seizures, and an abnormal EEG. Although his gross motor milestones were normal, both his speech and language development were delayed. Based on their review of the literature, the authors concluded that a possible relationship between autism and FVS existed (71).

The relationship between maternal anticonvulsant therapy, neonatal behavior, and neurological function in children was reported in a 1996 study (72). 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 minor and major neurological dysfunction at age 6 years (72).

Intrauterine growth retardation (IUGR) or small-for-gestational-age infants have been noted in several reports (4,16,19,23,24,47,48,50,65,73). Both monotherapy and combination therapy with valproic acid were involved in these cases. However, normal birth weights, heights, and head circumferences have been reported with valproic acid monotherapy (25,50,53,65). Growth impairment is a common problem with some anticonvulsant therapy (e.g., see Phenytoin), but the relationship between this problem and valproic acid needs further clarification.

A 1983 letter proposed that the mechanism for valproic acid–induced teratogenicity involved zinc deficiency (74). From in utero studies, the authors had previously shown that valproic acid readily binds zinc. Low zinc serum levels potentiated the teratogenicity of certain drugs in animals and produced adverse effects similar to valproic acid–induced human toxicity (74). Another proposed mechanism, especially when valproic acid is combined with other anticonvulsants, involves the inhibition of liver microsomal epoxide hydrolase, the enzyme responsible for the biotransformation of reactive epoxide metabolites (75). The inhibition of the detoxifying enzyme could result in enhanced fetal exposure to reactive epoxide metabolites, such as carbamazepine epoxide, by preventing its biotransformation to a trans-dihydrodiol metabolite. Based on these findings, the authors recommended that combination drug therapy with valproic acid be avoided during pregnancy (75).

Three reports have observed hyperbilirubinemia in nine newborns exposed in utero to valproic acid monotherapy and in one infant exposed to combination therapy (4,25,48). A causal relationship is uncertain because other studies have not reported this problem.

Liver toxicity has been observed in three infants after in utero exposure to valproic acid (47,48). In the first report, a growth-retarded female infant, exposed to valproic acid and phenytoin, had a linea alba hernia noted at birth but liver function tests were normal (47). The mother breast-fed the child for the first several weeks. At 2.5 months of age, the infant presented with an enlarged liver, slight icterus, vomiting, and failure to thrive. Liver function tests indicated a cholestatic type of hyperbilirubinemia, and liver biopsy specimen demonstrated fibrosis with ongoing necrosis of liver cells. Although they were unable to determine which anticonvulsant caused the injury, the authors concluded that valproic acid was the more likely offending agent. The second report described two siblings born of a mother treated with valproic acid monotherapy during two pregnancies (48). A male infant, exposed in utero to 300 mg/day, was normal at birth but died at age 5 months of liver failure. Autopsy revealed liver atrophy, necrosis, and cholestasis. The female infant, exposed in utero to 500 mg/day, died at age 6 weeks of liver failure. At birth, the infant was noted to have defects characteristic of valproic acid exposure (defects described in list above), IUGR, hyperbilirubinemia, hypoglycemia, hypocalcemia, and seizures. Liver atrophy and cholestasis were noted at autopsy (48).

Undetectable fibrinogen levels resulting in fatal hemorrhage in a full-term 2-day-old infant were attributed to in utero sodium valproate exposure (76). The mother had taken daily doses of sodium valproate 600 mg, phenytoin 375 mg, and lorazepam 1 mg throughout pregnancy. In a subsequent pregnancy, the measurement of slightly decreased maternal fibrinogen levels in late gestation caused the authors to discontinue the sodium valproate while continuing the other two agents. Oral vitamin K was also administered to the mother. A healthy infant without bleeding problems resulted (76).

Transient hyperglycinemia has been observed in two newborns exposed in utero to sodium valproate combination therapy (combined with phenytoin in one and phenytoin, carbamazepine, and clonazepam in the other) (3). Similar increases of glycine have been observed in epileptic adults treated with valproic acid. No adverse effects in the newborns resulted from the amino acid alteration (3).

Fetal distress during labor (late decelerations, silent or accelerated beat-to-beat variations) was observed in 6 (43%) of 14 cases exposed to valproic acid monotherapy (26). Two of the newborns with fetal distress plus two others had low Apgar scores (0–3 after 1 minute or 0–6 after 5 minutes). Maternal doses were 1500–1800 mg/day in 3 cases and 600 mg/day in 1 case. Low Apgar scores were not observed in 12 infants whose mothers had been treated with valproic acid combination therapy. Other studies and case reports have not mentioned this complication. The fetal and newborn depression was thought to have resulted from a 3-fold increase in the maternal serum of valproic acid free fraction (26). A similar increase had been measured in an earlier study (10).

No decreases in adrenocorticotropic hormone or cortisol levels were measured in a mother or her newborn after the use of valproic acid 3000 mg/day during the last 3 months of pregnancy (28). The mother had received combination anticonvulsant therapy during the first 6 months of gestation.

Valproic acid has been measured in the semen of two healthy males (77). Following oral doses of 500 mg, semen levels ranged from 0.53 to 3.26 µg/mL up to 39 hours after the dose. Simultaneous serum levels were 11–17 times those measured in the semen. No effect on sperm motility was suggested based on animal experiments.

In summary, valproic acid and the salt form, sodium valproate, are human teratogens. The absolute risk of producing a child with neural tube defects when these agents are used between the 17th and 30th days after fertilization is 1%–2%. A characteristic pattern of minor facial defects is apparently also associated with valproic acid. Two studies have suggested that a distinct constellation of defects may exist for infants exposed in utero to the anticonvulsant. These defects involve the head and face, digits, urogenital tract, and mental and physical growth. A correlation between maternal dose and major and minor anomalies has been reported, but additional studies are needed for confirmation. Other problems, such as IUGR, hyperbilirubinemia, hepatotoxicity, and fetal or newborn distress, also need additional investigation. Because of the risk for neural tube defects, women exposed during the critical period of gestation should consult their physicians about prenatal testing (37,78,79).

Breast Feeding Summary

Valproic acid and its salt, sodium valproate, are excreted into human milk in low concentrations (1,2,4,5,8,10,12,80,81,82). Milk concentrations have been measured up to 15% of the corresponding level in the mother's serum. In two infants, serum levels of valproate were 1.5% and 6.0% of maternal values (81).

Only one report of adverse effects in a nursing infant attributable to valproate in breast milk has been located. Thrombocytopenia purpura, anemia, and reticulocytosis were observed in a 3-month-old male breast-fed infant whose mother was taking sodium valproate (monotherapy; 1200 mg/day) for epilepsy (82). The infant had a 2-week history of increasing petechiae and minor hematoma on the lower part of the legs. The infant's serum valproate level was 6.6 µg/mL. Breast feeding was discontinued for 5 days but had no effect on the infant's low platelet count. The mother continued to nurse for another 2 weeks and again stopped. Twelve days later, valproate was undetectable in the infant's serum and 7 days later (19 days after nursing was stopped) the platelet count began to rise, reaching normal values sometime after 35 days. At about this same time, the petechiae had resolved. The blood hemoglobin and the reticulocytes normalized between 12 and 19 days after breast feeding was stopped (82).

The American Academy of Pediatrics considers valproic acid to be compatible with breast feeding (83).

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