The most important adverse effects of valproic acid include hepatotoxicity, pancreatitis, teratogenicity, thrombocytopenia, and hyperammonemia. Valproic acid carries a black-box warning for hepatotoxicity, pancreatitis, and teratogenicity. Serious hepatotoxicity usually occurs in young children rather than adults and occurs within the first 6 months of therapy; however, cases of hepatotoxicity have been reported in the older population. Preceding symptoms of malaise, weakness, anorexia, or vomiting may occur before serious or fatal hepatotoxicity is detected. Pancreatitis occurs rarely and appears to be an idiosyncratic effect. It may occur years after initiation of valproate therapy. Cases of rapidly fatal hemorrhagic pancreatitis have been reported in the literature. In addition, valproic acid has a strong teratogenic effect. Its use in pregnant patients is associated with a 1% to 2% rate of neural tube defects in offspring, which is much higher than the general population. High-dose folic acid supplementation should be given routinely to women of childbearing age who require valproate therapy. Thrombocytopenia may occur with valproate use and appears to be dose related. In a clinical trial of valproate monotherapy for epilepsy, 27% of patients had at least one value below 75×10⁹/L when taking a dose of 50 mg/kg/day average. The incidence of thrombocytopenia
increases significantly when plasma valproic acid levels exceeded about 110 to 135 mcg/mL. Finally, hyperammonemia may occur in patients taking valproate, even in the absence of abnormal liver-function tests. Patients who develop unexplained lethargy, nausea, vomiting, or mental status changes while taking valproate should have plasma ammonia levels checked. Underlying urea cycle disorders should be evaluated in patients found to have hyperammonemia in the setting of valproate use. Asymptomatic elevations of ammonia may occur.