Fetal valproate syndrome

Fetal valproate syndrome occurs when a baby develops signs and symptoms as a result of an exposure to valproic acid during fetal development.  Fetal exposure to valproic acid is associated with 2 to 3 times the general population risk for birth defects.  This results in roughly a 6 to 9% risk of having a child with a birth defect versus the general population risk of 2 to 3%.  Some children with this syndrome share common subtle facial characteristics, including thin arched eyebrows that may be spaced far apart, a wide nasal bridge, short nose with anteverted nostrils, thin upper lip, and smooth long philtrum (space between nose and lip).^[1] These features may become less prominent with time.^[1] Fetal valproate syndrome may also be associated with a wide range of other birth defects, as well as intellectual disability.^{[1][2][3][4][5]} In most cases the risks for a particular symptom or defect is not currently known.

Signs and symptoms of fetal valproate syndrome can vary greatly from person to person. There are certain subtle facial features that are more commonly (but not always) associated with this syndrome.^{[1][2][3][4][5]} These features include thin arched eyebrows that may be spaced far apart, a wide nasal bridge, short nose with anteverted nostrils, thin upper lip, and smooth long philtrum (space between nose and lip).^[1] These features may become less prominent with time.^[1]

Symptom and symptom severity varies from person to person. Risks for harmful effects due to prenatal exposure to valproic acid are likely influenced by a variety of factors, including drug dosage, multiple drug or drug combination, timing of drug exposure, severity of seizure disorder in the mother, predisposing genes, and folic acid intake.^[2][5] In general, children of women with a seizure disorder also are at an increased risk for having a seizure disorder themselves.^[5] Parental factors such as IQ and socio-economic status may also play a role in symptom and symptom severity.^[5]

Signs and symptoms associated with fetal valproate exposure that have been described in medical literature are listed below by body system. Please note that some of these symptoms have been reported in only a few or a single case (these symptoms are marked with an asterisk).^[2]

Heart defects 

    Ventricular septal defect 
    Atrial septal defect 
    Aortic stenosis 
    Patent ductus arteriosus 
    *Anomalous right pulmonary artery

Head and neck

    Cleft lip/palate
    Trigonocephaly (a rare type of craniosynostosis that affects the suture close to the forehead)

Limb anomalies

    Radial ray defects 
    Extra digit (polydactyly) 
    Split hand    
    Overlapping toes 
    Camptodactyly (unusual curvature of the fingers)
    Flat feet in childhood 
    Joint laxity (loose joints)
    *Underdevelopment of the ulna or tibia
    *Absent fingers

Gentiourinary anomalies

    Hypospadias 
    *Renal hypoplasia (underdeveloped kidneys)
    *Hydronephrosis 
    *Duplication of the calyceal system

Central nervous system (brain and spinal cord)

     Neural tube defects 
    *Hydranencephaly
    *Porencephaly
    *Arachnoid cysts
    *Cerebral atrophy
    *Partial agenesis of corpus callosum
    *Abscence of the septum pellucidum
    *Lissencephaly of medial sides of occipital lobes
    *Dandy-Walker anomaly

Developmental 

    Low verbal IQ 
    Autism and autistic spectrum disorder

Eye anomalies

    Nearsightedness (myopia)
    Coloboma of the iris/optic disc
    *Congenital cataract
    *Underdevelopment of the optic nerve 
    *Tear duct anomalies 
    * Very small or poorly developed eyes (microphthalmia)
    *Iris defects 
    *Corneal opacities

Ear/Hearing

    Hearing problems due to recurrent ear infections            

Respiratory tract anomalies 

    *Tracheomalacia 
    *Underdeveloped lung 
    *Severely underdeveloped larynx  
    *Abnormal lobulation of the right lung 
    *Right oligaemic lung

Abdominal wall defects 
    
    * Omphalocele

Skin abnormalities

    Birth mark (capillary haemangioma) 
    *Aplasia cutis congenital of scalp

In addition, newborns who were exposed prenatally to seizure medications may require special care after delivery because of withdrawal symptoms. Withdrawal symptoms include feeding difficulties, low blood sugar (hypoglycemia), jitteriness, irritability, and low body temperature (hypothermia). Other symptoms may include poor muscle tone, and joint laxity.^[2]

Some children with fetal valproate syndrome show delays in development, autistic features, and/or intellectual disability. In general, the most commonly affected developmental aspect is speech and language.^[2]  In addition some children have motor delays which may cause clumsiness and impair daily living skills, such as getting dressed, handwriting, riding a bike and swimming. Toilet-training may also be delayed, however most children do achieve this milestone.^[2] Lastly, some children with fetal valproate syndrome have difficulty with social interaction, which may prompt investigation for autistic spectrum disorder.^[2]

Diagnosis of fetal valproate syndrome requires a pregnancy history that includes exposure to valproic acid. Fetal valproate syndrome is a diagnosis of exclusion. This means that all other syndromes that could account for the symptoms in the infant or child are ruled out prior to making the diagnosis of fetal valproate syndrome.  Fetal valproate syndrome can be difficult to diagnose, particularly when the characteristic facial features are absent.^[2][3]

Currently there are no specific treatments for fetal valproate syndrome. Each symptom or birth defect associated with fetal valproate syndrome are managed individually, and may require a team of specialist.  To read about different types of specialists and what they do, you can visit the following link to Harvard Medical School’s Family Health Guide:
http://www.health.harvard.edu/fhg/specialists.shtml 

In general, children with fetal valproate syndrome who show delays in comprehension and expression of speech, may be benefited by early speech therapy.^[2] Physiotherapy may benefit children with motor delays.^[2] Also some children with fetal valproate syndrome may require extra help in school.^[2] The following resource may be helpful for families with a child with developmental, learning, or behavioral issues.

National Dissemination Center for Children with Disabilities
P.O. Box 1492
Washington, DC 20013
Toll free/TTY: (800) 695-0285
Fax: (202) 884-8441
E-mail: nichcy@aed.org
Web site: http://www.nichcy.org