Fetal valproic acid exposure syndrome

Philippe Jeanty, MD, PhD Sandra R Silva, MD

Updated 2006-01-18 by Juliana Leite, MD

Original text 1999-05-18 Philippe Jeanty, MD, PhD & Sandra R Silva, MD

Synonym: Depakene exposure.

Definition: Fetal valproic acid exposure syndrome is syndrome resulting from maternal valproate (anticonvulsant) use during pregnancy and it is characterized by a cluster of minor and major anomalies, including central nervous system dysfunction, spina bifida, development delay, intrauterine growth retardation and cardiac anomalies.

Incidence: Unknown, rare. Any epileptic pregnant mother has two to three times increased risk for congenital anomalies compared with the general population. If the exposure to valproic acid takes place between the 17th and 30th days after fertilization, the incidence of neural tube defects reaches 1% to 2%. In general, the teratogenic risks rises with increasing doses of valproic acid, with a significantly higher malformation risk in doses up to 1000 mg/day.

Etiology: Exposure to valproic acid.

Pathogenesis: Unknown.

Diagnosis: The findings include cardiovascular abnormalities, hypotonia, spina bifida, hypospadias and limb reductions. The facial appearance can be characterized by an oral cleft, small broad nose, small ears, flat philtrum, a long upper lip with shallow philtrum, and micro/retrognathia. Intrauterine growth restriction, micrognathia, microcephaly, generalized hypertrichosis sparing palms and soles, coarse face, gum hypertrophy, club feet and club hands, musculoskeletal abnormalities, genital abnormalities and urogenital defects may also be present. Heart defects has also been reported. In 26% of patients with fetal valproic acid exposure syndrome have cardiovascular abnormalities, most frequently ventricular septal defects, aortic or pulmonary stenosis and persistent ductus arteriosus. Pulmonary hypoplasia is also reported. Epilepsy and mental retardation may happen after birth.

Genetic anomalies: None.

Associated anomalies: Anomalies from different systems have been reported in association with this syndrome, such as omphalocele, inguinal hernia, duodenal atresia, and scoliosis. Hyperbilirubinemia, hepatotoxicity, transient hyperglycinemia, afibrinogenemia, and fetal or neonatal distress may be found.

Differential diagnosis: Other neural tube defects. However, the clinical history in the presence of an association of spina bifida and cardiac anomaly should suggest the diagnosis.

Prognosis: Fetuses that present major anomalies have a poor prognosis. Metabolic disturbances may also complicate the neonatal period. These affected children can die in infancy and the surviving patients can develop mental retardation.

Recurrence risk: If the mother is exposed to valproic acid in a second pregnancy, the teratogenic effect will be the same.

Management: When detected in the second trimester, termination of the pregnancy can be offered. If the pregnancy is allowed to continue, no alteration of the management is needed. Many new antiepileptic drugs have been introduced over the past few years, and switching the mother to one of those is recommended. Because of the increased risk of malformations, pregnant women using valproic acid should be informed about the option of prenatal diagnosis by structural ultrasound examination and alpha-1-fetoprotein analysis of maternal serum.

1: Stoll C, Audeoud F, Gaugler C, Bernardin A, Messer J. Multiple congenital malformations including generalized hypertrichosis with gum hypertrophy in a child exposed to valproic acid in utero. Genet Couns. 2003; 14(3):289-98.
2: Kozma C. Valproic acid embryopathy: report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature. Am J Med Genet. 2001 Jan 15; 98(2):168-75.
3: Janas MS, Arroe M, Hansen SH, Graem N. Lung hypoplasia--a possible teratogenic effect of valproate. Case report. APMIS. 1998 Feb; 106(2):300-4.
4: Complex cardiac defect with hypoplastic right ventricle in a fetus with valproate exposure. Berg K, Open ACC, Nickels PGJ, Got ACG, Voet GB, Brilstra EB, Lindhout D. Prenatal Diagnosis 2005;25(2):156-158

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