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Chiari II anomaly — A structural abnormality of the lower portion of the brain (cerebellum and brain stem) associated with spina bifida. The lower structures of the brain are crowded and may be forced into the foramen magnum, the opening through which the brain and spinal cord are connected.
There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).
a) As valproic acid can be teratogenic and cause congenital malformations such as neural tube defects, consider use of valproic acid or its salt form, sodium divalproex, in women of childbearing potential only after the risks have been thoroughly discussed with the patient and the potential benefits outweigh the risk of injury to the fetus. This is particularly imperative when treating a spontaneously reversible condition which does not bear a risk of permanent injury or risk of death (eg, migraine). In cases where the severity and frequency of the seizure disorder may permit removal of the drug without posing a serious therapy to the patient, clinicians may consider discontinuation of the drug prior to or during pregnancy. Where exposure is unavoidable or unanticipated, the pregnant mother should be advised of possible consequences to the fetus. Screening for neural tube defects is recommended and clotting parameters should be routinely monitored (Prod Info DEPAKOTE(R) ER extended-release oral tablets, 2006; Prod Info DEPAKOTE(R) oral sprinkle capsules, 2006; Prod Info DEPAKOTE(R) delayed-release oral tablets, 2006a; Prod Info DEPACON(R) IV injection, 2006; Prod Info DEPAKENE(R) oral capsules, oral syrup, 2006). As general population studies have shown that folic acid supplementation before and during early pregnancy reduces the risk of neural tube defects, folic acid prescription drugs should be considered in women of childbearing potential who are receiving valproate sodium (US Food and Drug Administration, 2009). Infants born to mothers treated with valproate during pregnancy should have blood glucose levels monitored during the first several hours of life (Ebbesen et al, 2000). Encourage enrollment in the North American Antiepileptic Drug (NAAED) Pregnancy Registry (1-888-233-2334) for any woman who becomes pregnant while on valproic acid therapy (US Food and Drug Administration, 2009).
5) Literature Reports
a) Data collected from the North American Antiepileptic Drug (NAAED) Pregnancy Registry revealed 16 cases of congenital malformations (i.e., neural tube defects, craniofacial defects, cardiovascular malformations, and other body system malformations) to infants born of pregnant women (n=149) exposed valproate monotherapy (average doses of approximately 1000 mg/day [range 500 to 2000 mg/day]) during the first trimester. The prevalence rate of birth defects was 10.7% (95% CI, 6.3% to 16.9%). Neural tube defects occurred in 2% of the infants (n=3/149) while 4% of the infants (n=6/149) had less severe malformations. In women (n=1048) exposed to other NAAED monotherapies, the malformation rate was 2.9% (95% CI, 2% to 4.1%). Congenital malformations in valproic acid-exposed mothers was 4-fold higher compared to those treated with other NAAED monotherapies as a group (odds ratio, 4.0; 95% CI, 2.1% to 7.4%) (US Food and Drug Administration, 2009; Prod Info DEPAKOTE(R) ER extended-release oral tablets, 2006; Prod Info DEPAKOTE(R) oral sprinkle capsules, 2006; Prod Info DEPAKOTE(R) delayed-release oral tablets, 2006a; Prod Info DEPACON(R) IV injection, 2006; Prod Info DEPAKENE(R) oral capsules, oral syrup, 2006).
b) Data collected from the Antiepileptic Drug (AED) Pregnancy Registry for over 3000 pregnant women exposed to AEDs included 123 completed pregnancies exposed to valproate monotherapy (Holmes et al, 2003). The prevalence of birth defects was 8.9% in this subset compared to 2.8% (relative risk (RR) 3.5; 95% CI 2 to 6.2) of women exposed to monotherapy with other AEDs and to 1.6% (RR 6; 95% CI 3.5 to 10.2) of an external comparison group. Anomalies reported in order of frequency were cardiac, neural tube, hypospadias, polydactyly, bilateral inguinal hernia, dysplastic kidneys, and club foot. Similarly, a separate retrospective cohort study (n=1411) showed an increased risk of major congenital abnormalities in the offspring of women treated with either carbamazepine (RR 2.6) or valproate (RR 4.1) monotherapy during the first trimester of pregnancy (Samren et al, 1999). Risk associated with valproate was dose-dependent. Valproate alone and in combination with other AEDs were associated with an increased risk of neural tube defects (RR 4, p=0.03; RR 5.4, p=0.004, respectively). The risk of hypospadia was similarly higher in the monotherapy and combination therapy groups (RR 4.8, p=0.05; RR 4.8, p=0.03, respectively).
c) Numerous cases have been reported of fetal neural tube defects, primarily spina bifida, and/or cardiac defects (eg, tetralogy of Fallot, patent ductus arteriosus, valvular aortic stenosis, and ventricular septal defect). There is an increased incidence of neural tube defects with exposure during the first trimester of pregnancy. Risk of spina bifida in children of women exposed to valproic acid during pregnancy is estimated to be 1% to 2% by the CDC. While the American College of Obstetricians and Gynecologists estimates the general risk for congenital neural tube defects to be 0.14% to 0.2%, data from the Antiepileptic Drug (AED) Pregnancy Registry showed that neural tube defects occurred at a rate of 2% (n=3/149) (Prod Info DEPAKOTE(R) ER extended-release oral tablets, 2006; Prod Info DEPAKOTE(R) oral sprinkle capsules, 2006; Prod Info DEPAKOTE(R) delayed-release oral tablets, 2006a; Prod Info DEPACON(R) IV injection, 2006; Prod Info DEPAKENE(R) oral capsules, oral syrup, 2006; Ardinger et al, 1988; Bertollini et al, 1987; Jager-Roman et al, 1986; Bailey et al, 1983; Jeavons, 1982; Robert & Guibaud, 1982; Thomas & Buchanan, 1981; Clay et al, 1981; Dalens et al, 1980).
d) Various other reports of fetal abnormalities resemble those seen in fetal hydantoin syndrome, including craniofacial and skeletal or limb defects (Prod Info DEPAKOTE(R) ER extended-release oral tablets, 2006; Prod Info DEPAKOTE(R) oral sprinkle capsules, 2006; Prod Info DEPAKOTE(R) delayed-release oral tablets, 2006a; Prod Info DEPACON(R) IV injection, 2006; Prod Info DEPAKENE(R) oral capsules, oral syrup, 2006; DiLiberti et al, 1984; Jager-Roman et al, 1986; Ardinger et al, 1988). It is not clearly established, however, whether these anomalies constitute a fetal valproic acid syndrome or are the result of other factors such as genetic or environmental factors, combination therapy with other anticonvulsants, and/or seizure episodes during gestation. A case-control study in which 57 of 22,294 malformed infants and 10 of 21,937 control infants were exposed to valproic acid estimated a risk for limb deficiencies to be about 0.42% (Rodriguez-Pinilla et al, 2000). The same analysis calculated an odds ratio of 6.17 (CI, 1.28 to 29.66, p=0.023) for limb deficiencies after first trimester prenatal exposure to valproic acid. The types of limb deficiencies reported included overlapping digits, talipes, clubfoot, clinodactyly, arachnodactyly, hip dislocation, and others.
e) The relationship of first-trimester plasma antiepileptic drug (AED) concentrations and pregnancy outcomes in 427 exposed women was assessed, including 44 women on valproic acid monotherapy (Canger et al, 1999). Valproic acid showed a significantly higher rate of malformations (p less than 0.02) compared to monotherapy with other AEDs such as primidone, carbamazepine, phenobarbital, phenytoin, and clonazepam. In addition, the mothers of malformed fetuses used higher doses of valproic acid during their first trimester than did mother of nonmalformed fetuses.
f) Twenty-two infants with in utero exposure to a median daily dose of 1 g valproate in the first trimester and 1.2 g during the third trimester were described in one study. In 13 of the 22 infants, blood glucose dropped below 1.8 mmol/L, with the first hypoglycemic episode occurring within 1 hour of birth in 7 infants and within 2 hours in 3 infants. Ten of the infants exhibited withdrawal symptoms within 12 to 24 hours including irritability, jitteriness, hypertonia, seizures, and feeding problems (Ebbesen et al, 2000).
g) Other reported fetotoxic effects include a case of an infant with afibrinogenemia who died of hemorrhage, and a case of hepatic failure that resulted in the death of a newborn infant.
h) If phenytoin or carbamazepine (or any prodrugs) is used in pregnant women, there is a substantially increased risk of teratogenicity with many combinations of other anticonvulsants. The teratogenicity of these drugs is largely or wholly related to the levels of the reactive epoxide metabolites (Buehler et al, 1990c; Van Dyke et al, 1991c; Finnell et al, 1992c). The epoxide/parent drug ratio is generally increased when phenytoin or carbamazepine is combined with each other, any other drugs that induce cytochrome P450 enzymes, or drugs which inhibit epoxide hydrolase, such as valproic acid, progabide, and lamotrigine. Such combinations increase the risk of major birth defects 3- to 4-fold over monotherapy and about 10-fold over background rates.