Valproic acid, developmental

Dawson, D.A., Schultz, T.W., Wilke, T.S., and Bryant, S. Developmental toxicity of valproic acid stndies with Xenopus, Teratology, 45(5) 493, 1992. 

Fanconi syndrome (metabolic acidosis secondary to malfunction of proximal renal tubules, resulting in urinary excretion of amino acids, glucose, phosphate, bicarbonate, uric acid, and other substances) secondary to longterm valproic acid has been described in an 8-year-old boy with severe developmental disability (1170). In a review of 10 previous reports of Fanconi syndrome secondary to long-term valproic acid therapy the authors found that all occurred at 4-14 years, all had taken valproic acid for 10 months to 10 years, and symptoms were fully reversible within 2-14 months after withdrawal of valproic acid. Most of the patients (9 of 11) were severely disabled, bedridden, or wheelchair-bound. 

A child with developmental delay and epilepsy developed glycosuria about 16 months after starting to take valproic acid (90). Laboratory evaluation showed global defects in proximal tubule function, consistent with the De Toni-Debre-Fanconi syndrome. The authors reviewed the literature on this rare complication, which is reversible on valproate withdrawal. 

Valproic acid is an in vitro developmental toxicant (rodent whole embryo culture system). 

Wiltse J (2005) Mode of action inhibition of histone deacetylase, altering WNT-dependent gene expression, and regulation of beta-catenin-developmental effects of valproic acid. Crit Rev Toxicol 35(8-9) 727-738... 

Valproic acid is associated with a 2- to 3-fold increase in the frequency of congenital anomalies. A 10- to 20-fold increase in the risk of spina bifida in infants born to women treated with valproic acid compared with the general population has been reported. The absolute risk of spina bifida in exposed infants appears to be 1% to 2%. Other problems associated with use in pregnancy include intrauterine growth retardation, hypoglycemia, and coagulopathy. Some investigators have reported developmental delays in up to 90% of children with prenatal exposure to valproic acid. ... 

As with valproic acid, a 2- to 3-fold increase in the frequency of congenital malformations has been attributed to the use of carbamazepine. A 10-fold increase in the risk of spina bifida compared with the general population or an absolute risk of 1% has been described. Other birth defects reported from either monotherapy or combination therapy with other agents include facial roundness, nasal bridge defects, nail defects, and other head anomalies. Developmental... 

Alessandri JL, Isidor B, David A, Martin-Coignard D, Ghazouani J, Ramful D, I-aville JM, Le Caignec C. Tibial developmental field defect in valproic acid embryopathy report on three cases. Am J Med Genet A 2010 152A(11) 2805-9. 

A 6-year-old girl with ADHD and pervasive developmental disorder and behavioural problems who was treated with Depakote (valproic acid) and had an abnormal electrocardiogram (ECG) with left Centro parietal spikes experienced a convulsion the day after the first administration of a methylphenidate dose. A repeat electroencephalography demonstrated continuous spike and slow wave during sleep [73 ]. 

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