NORD gratefully acknowledges Mariana Bundra Todosiev, PharmD, RPh, and Hatice Mutlu Albayrak, MD, Division of Pediatric Genetics, Cengiz Gökcek Women's and Children's Hospital, Gaziantep, Turkey for assistance in the preparation of this report.
Fetal valproate syndrome (FVS) is a rare condition that is caused by exposure of the unborn baby to valproic acid or sodium valproate (VPA) during the first three months of pregnancy (the first trimester). VPA is a medication used to treat certain types of seizures (epilepsy), bipolar disorder and migraines. Although many babies exposed to VPA are born healthy, a small percentage of pregnant women who take this medication can have a baby born with FVS. The exact prevalence of this condition remains to be established. Symptoms of this condition may include neural tube defects such as spina bifida, distinctive facial features, congenital heart defects and other musculoskeletal abnormalities.
Anti-seizure medications, also known as antiepileptic or anticonvulsant medications are among the most common teratogens prescribed to women of childbearing age. Prenatal exposure to VPA causes teratogenic effects in the fetus, specifically FVS. A teratogen is a drug that interferes with the development of a fetus. Studies have indicated that FVS is associated with greater risk of neurological and cognitive abnormalities than other anti-seizure medications.
The use of VPA as a single drug (monotherapy) in the first trimester of pregnancy was associated with significantly increased risks of major and minor malformations, including a 20-fold increase in neural tube defects (NTDs) such as spina bifida, cleft lip and palate, cardiovascular abnormalities, genitourinary defects, developmental delay, endocrine disorders, limb defects, and autism as compared with no-use of antiepileptic drugs (AEDs) or with use of other AEDs.
Spina bifida is a birth defect where there 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 FVS. Infants with FVS 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.
Children with FVS have a higher chance of developmental problems such as decreased cognitive function, attention deficit disorder, learning difficulties and often the communication problems of autism spectrum disorder.
Growth deficiency and an unusually small head (microcephaly) may also occur when VPA is taken alone or in combination with other antiepileptic drugs during pregnancy.
FVS is a rare condition that may occur when a baby is exposed to VPA (brand names include Depakene, depakine, convulex, depakote, encorate, valpakine, etc) during the first trimester. It is believed that VPA crosses the placenta and interferes with normal development causing developmental abnormalities in the fetus (teratogenesis).
If a woman with epilepsy wishes to have children, the recommended treatment is to avoid VPA and use a single drug or a newer antiepileptic medication. Although it has been advised to avoid VPA during pregnancy to prevent FVS, there are circumstances when the use of VPA is necessary. Studies have shown that there is a dose-effect relationship between prenatal exposure to VPA and fetal abnormalities. A dose-effect relationship is when there is a link between the effect of the drug and the dose of the drug. The dose-effect relationship between fetal abnormalities and prenatal exposure to VPA is that higher doses of VPA have been associated with a greater risk compared to lower doses of VPA in developing fetal abnormalities. Multiple reports have shown a higher risk of fetal abnormality where the maternal VPA doses during pregnancy were above 1000 mg/day or blood concentrations were above 70 μg/ml. The most common abnormalities are cardiac and NTDs. However, the typical facial dysmorphic features and minor skeletal abnormalities that may occur within the both low and high doses in VPA use. There are several variables that have to be taken into account which include not only the specific antiepileptic drug used but also the dose of the drug used. VPA in combination with other antiepileptic drugs may also increase the risk of developing fetal abnormalities.
FVS affects males and females in equal numbers. There is a 20-fold increase in neural tube defects, cleft lip and palate, cardiovascular abnormalities, genitourinary defects, developmental delay, endocrine disorders, limb defects, and autism, when VPA is used during the 1st trimester of pregnancy compared to no use of antiepileptic drugs.
There is no diagnostic testing that can identify FVS. A diagnosis is made clinically based upon identification of characteristic symptoms in an affected infant in conjunction with a history of VPA exposure during pregnancy.
Because FVS is considered a diagnosis of exclusion (diagnosis made by a process of elimination), other medical conditions that have similar symptoms must be ruled out prior to making this diagnosis.
Prenatal diagnosis may be possible by ultrasound where fetal abnormalities such as neural tube defects and organ abnormalities may be detected.
If possible, VPA should be avoided during pregnancy. If the use of antiepileptic medications during pregnancy cannot be avoided, they should be administered as a single drug. The lowest possible dose of the antiepileptic medication should be used as well as constant monitoring of the amount of the drug (serum concentration) should be performed.
Also, it is recommended that women taking valproate take folic acid supplements, both before conception and during pregnancy to reduce the risk of malformations.
However, most women with epilepsy have healthy children. While some infants exposed to an anticonvulsant drug in utero have abnormalities, others do not. Genetic differences in the fetal response to medications probably play a role. The risk of recurrence of FVS in a subsequent pregnancy exposed to VPA would therefore appear to be high, possibly due to inherent problems with the metabolism of VPA in the mothers concerned. Regular counseling is recommended for women with epilepsy to discuss the risks that seizures present for both the developing fetus and the expectant mother.
The treatment of FVS is directed toward the specific symptoms that are apparent in the child. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, oral surgeons, plastic surgeons, neurologists, psychologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.
Infants with FVS can benefit from early developmental intervention to ensure that affected children reach their potential. Affected children may benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. Additional medical, social and/or vocational services may be necessary. Psychosocial support for the entire family is essential as well.
Some children with mild spina bifida may not require treatment, but surgery may be considered for children with moderate to severe spina bifida. Surgery may help prevent the worsening of the condition in some children, 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 physical abnormalities that may be present.
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Hersh JH. Fetal Valproate Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:192-93.
Buyse ML. Editor-in-Chief.Birth Defects Encyclopedia.Blackwell Scientific Publications. Center for Birth Defects Information Services, Inc., Dover, MA; 1990:730.
Mutlu-Albayrak H, Bulut C, Çaksen H. Fetal Valproate Syndrome. Pediatr Neonatol. June 2016; pii: S1875-9572(16):300072-9. http://www.pediatr-neonatol.com/article/S1875-9572(16)30072-9/pdf
Mawhinney E, Craig J, Morrow J, Russell A, Smithson WH, Parsons L, et al. Levetriacetam in pregnancy: results from the UK and Ireland epilepsy and pregnancy registers. Neurology. 2013;80:400–5. doi: 10.1212/WNL.0b013e31827f0874.
Jentink J, Loane MA, Dolk H, et al. Valproic Acid Monotherapy in Pregnancy and Major Congenital Malformations. N Engl J Med. 2010;362:2185-93.http://www.nejm.org/doi/full/10.1056/NEJMoa0907328#t=article
Witters I, Van Assche F, Fryns JP.Nuchal edema as the first sign of fetal valproate syndrome.PrenatDiagn. 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.
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.
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. 2001;43:202-06.
Kaneko S, Battino D, Andermann E, Wada K, Kan R, Takeda A, et al. Congenital malformations due to antiepileptic drugs. Epilepsy Res. 1999;33:145–58. doi: 10.1016/S0920-1211(98)00084-9.
Ardinger HH, Atkin JF, Blackston RD, et al. Verification of the fetal valproate phenotype.Am J Med Genet. 1988;29:171-85.
Fetal valproate syndrome.Genetic and Rare Diseases Information Center. Last updated: 5/22/2017. Available at: https://rarediseases.info.nih.gov/diseases/5447/fetal-valproate-syndrome. Accessed May 20, 2020.
Valproic Acid and Pregnancy.Organization of Teratology Information Specialists. Jan1, 2018. Available at: https://mothertobaby.org/fact-sheets/valproic-acid-pregnancy/ Accessed May 20, 2020.
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