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Fetal Valproate Syndrome

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Copyright 1994, 2003

Synonyms of Fetal Valproate Syndrome

Disorder Subdivisions

General Discussion

Fetal Valproate Syndrome is a rare congenital disorder caused by exposure of the fetus to valproic acid (dalpro, depakene, depakote, depakote sprinkle, divalproex, epival, myproic acid) during the first three months of pregnancy. Valproic acid is an anticonvulsant drug used to control certain types of seizures in the treatment of epilepsy. A small percentage of pregnant women who take this medication can have a child with Fetal Valproate Syndrome. The exact prevalence of this condition remains to be established. Symptoms of this disorder may include spina bifida, distinctive facial features, and other musculoskeletal abnormalities.


Infants with Fetal Valproate Syndrome may be born with spina bifida. Spina bifida is the incomplete closure of bony spine. It occurs when the tube of tissue that lies along the center of the early embryo (neural tube) does not completely fuse during fetal growth. Part of the contents of the spinal canal may protrude through this opening (bifida cystica). Depending on the severity of the opening, a variety of neurological and physical symptoms may occur. (For more information on this disorder choose "Spina Bifida as your search term in the Rare Disease Database.)

Distinctive facial features are characteristic of Fetal Valproate Syndrome. Affected infants may have a vertical fold of skin on either side of the nose that forms a groove under the eye (epicanthal folds); a small, upturned nose with a flat bridge; a small mouth (microstomia); a long, thin, upper lip; a downturned mouth; and/or minor abnormalities of the ears.

Other abnormalities that may be found in a few affected individuals include: underdeveloped nails of the fingers and toes; dislocation of the hip; long, thin fingers and toes (arachnodactyly); overlapping fingers and toes; separation of the rectus muscle of the abdominal wall (diastasis recti); absence of the first rib; a condition in which the urinary opening is on the underside of the penis (hypospadias); abnormalities of the heart; softening of the windpipe (tracheomalacia); and/or a club foot.

Growth deficiency and an unusually small head (microcephaly) may also occur when valproic acid is taken in combination with other anticonvulsant drugs during pregnancy.


Fetal Valproate Syndrome is a rare disorder that may occur when a fetus is exposed to valproic acid (depakene, dalpro, myproic acid, depakote, depakote sprinkle, divalproex, epival) during the first three months of pregnancy. It is believed that valproic acid crosses the placenta and interferes with normal development causing developmental abnormalities in the fetus (teratogenesis). Some researchers feel that the severity of the defects caused by valproic acid may be dosage related while others have found no dose-related effect.

Valproic acid in combination with other anticonvulsant drugs may also cause fetal abnormalities.

Affected Populations

Fetal Valproate Syndrome affects males and females in equal numbers. Spina Bifida is found in approximately 1-5% of those exposed to valproic acid during fetal development. Facial abnormalities have been found in almost half of the children exposed to valproic acid in utero. There were approximately 175 cases of Fetal Valproate Syndrome reported internationally between 1974 and 1988.

Related Disorders

Symptoms of the following disorders can be similar to those of Fetal Valproate Syndrome. Comparisons may be useful for a differential diagnosis:

Fetal abnormalities caused by other anticonvulsant drugs may be similar to those of Fetal Valproate Syndrome. The determining factor is the identification of the drugs the mother was taking during the first three months of pregnancy.

Standard Therapies

Valproic acid has been reported to cause Fetal Valproate Syndrome in the unborn fetus when taken by the mother during the first three months of pregnancy. As a result, it is important to advise one's physician when a person taking seizure medications is considering pregnancy.

Mild cases of Spina Bifida may not require treatment. In moderate cases surgery may be considered. Surgery may prevent the worsening of the condition in some cases, but cannot restore the lost muscle function. In those extreme cases where the sac (meningocele) breaks or appears about to break, immediate surgery becomes essential. Individuals with severe Spina Bifida may develop contractures (shortening of the muscles) and abnormalities of posture. This is due to the paralysis of muscles in the legs. A child with Spina Bifida should have the necessary therapy (orthopedic and physical) beginning at an early age to prevent contractures. (For more information on this disorder choose "Spina Bifida" as your search term in the Rare Disease Database).

Surgery may be necessary to correct heart defects as well as other major malformations that may be present. Other treatment is symptomatic and supportive.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:

Fetal Valproate Syndrome Resources



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Buyce ML. Editor-in-Chief. Birth Defects Encyclopedia. Blackwell Scientific Publications. Center for Birth Defects Information Services, Inc., Dover, MA; 1990:730.

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;98:168-75.

Witters I, Van Assche F, Fryns JP. Nuchal edema as the first sign of fetal valproate syndrome. Prenat Diagn. 2002;22:834-35.

Malm H, Kajantie E, Kivirikko S, et al. Valproate embryopathy in three sets of siblings: further proof of hereditary susceptibility. Neurology. 2002;59:630-33.

Glover SJ, Quinn AG, Barter P, et al. Ophthalmic findings in fetal anticonvulsive syndrome(s). Ophthalmology. 2002;109:942-47.

Lajeunie E, Barcik U, Thorne JA, et al. Craniosynostosis and fetal exposure to sodium valproate. J Neurosurg. 2001;95:778-82.

Thisted E, Ebbesen F. Malformations, withdrawal manifestations, and hypoglycaemia after exposure to valproate in utero. Arch Dis Child. 1993;69(3 Spec No):288-91.

Williams G, King J, Cunningham M, et al. Fetal valproate syndrome and autism: additional evidence of an association. Dev Med Child Neurol. 200;43:202-06.

Ardinger HH, Atkin JF, Blackston RD, et al. Verification of the fetal valproate phenotype. Am J Med Genet. 1988;29:171-85.

Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes. nd. 3pp.

CDC. Valproate (valproic acid): A New Cause of Birth Defects. Page converted: 08/05/98:(1983) :2pp.

Turnpenny PD. Fetal Anti-Convulsant Syndrome. Contact a Family. Last Updated: November 2002:2pp.

Chemical Teratogens, Carcinogens, Mutagens. nd.

Pasquier S, Zeilinger G. Fetal valproate syndrome. Swiss Society of Neonatology. nd. 2pp.

Report last updated: 2008/04/25 00:00:00 GMT+0