Fetal Valproate Spectrum Disorder

A rare teratogenic disease due to embryo/fetal exposure to valproic acid (VPA) and subsequently characterized by a distinct facial dysmorphism, congenital anomalies and developmental delay (especially in language and communication).

Epidemiology

Prevalence of fetal valproate syndrome (FVS) is unknown. An incidence of neural tube defects (NTDs) of 1-2% has been associated with the use of VPA during the first trimester of pregnancy (10-20 times the rate seen in the general population) while the incidence of congenital heart disease, neurodevelopmental delay and autism spectrum disorder (ASD) are estimated to be around 4 to 5 times higher than in the general population.

Clinical description

The majority of infants exposed to VPA in utero are born healthy. Intrauterine growth retardation is present in 10% of cases but postnatal growth is usually normal and general health is good. Characteristic facial features of FVS are many of the following: high/broad forehead with bifrontal narrowing, metopic craniosynostosis, epicanthal folds, medial deficiency of eyebrows, infraorbital groove, small/broad upturned nose, long and shallow philtrum, long upper lip with thin vermillion borders, thick lower lip and downturned angles of mouth. Congenital anomalies associated with FVS include neural tube defects (e.g. spina bifida aperta), congenital heart defects (e.g. ventricular septal defect), oral clefts, genital abnormalities (e.g. hypospadias with undescended testicles) and limb defects, and less commonly, inguinal and umbilical hernia, tracheomalacia, supernumerary nipples, bifid ribs and pre-axial defects of the feet. Children exposed to VPA have a higher risk of developmental problems such a decreased cognitive function (especially in verbal intelligence), attention deficit disorder, learning difficulties and often the communication problems of ASD.

Etiology

FVS is caused by the exposure during pregnancy to VPA (valproate), a mood stabilizer and broad-spectrum antiepileptic drug (AED. Primarily metabolized in the liver, VPA readily crosses the placenta, where concentrations are higher than in the mother. Embryos and fetuses exposed to VPA during the 1st trimester (especially to doses exceeding 600 mg/day but lower doses may also be teratogenic) have a higher risk of developing FVS, as this is the principal period of structural development.

Diagnostic methods

Diagnosis is based on the presence of the well-recognized cluster of clinical findings in infants born to mothers who took VPA during pregnancy.

Differential diagnosis

Differential diagnoses include other types of AED-related embryofetopathies (e.g. fetal hydantoin syndrome) and possibly fetal alcohol spectrum disorder.

Antenatal diagnosis

Prenatal diagnosis is possible by the detection of anomalies such as NTDs, cardiac and other organ anomalies by ultrasonographic examination and estimation of maternal serum alpha-fetoprotein (with a history of antenatal valproate intake).

Management and treatment

VPA should be avoided (if possible) during pregnancy and high dose folic acid (4-5 mg/day) should be started 6 weeks before conception and continued through the first trimester. In pregnant women with no effective alternative, VPA should be administered in slow release form at the lowest possible divided dosage and preferably as a monotherapy along with high dose folic acid. Surveillance of the newborn should include searching for dysmorphic facial features, congenital malformations and withdrawal symptoms at birth. Long-term follow-up of the child should include early diagnosis and management of any potential behavioral or neurodevelopmental effect and educational and psychosocial support, whenever needed. Management of congenital anomalies should follow standard treatment protocols. Children with ASD should receive the regular treatment offered to children with communication disorders.

Prognosis

The prognosis of newborns is highly variable and depends on the clinical and behavioral symptoms, timing of exposure and the dosage of VPA taken by the mother. Life expectancy may be decreased in those with multiple congenital anomalies (in particular of the cardiovascular system and NTD) or with significant intellectual disability.