Fetal valproate syndrome

Title

Other Names:

Valproic acid fetal effects from; Embryofoetal valproic acid syndrome; Valproic acid embryopathy

Categories:

Congenital and Genetic Diseases; Ear, Nose, and Throat Diseases; Mouth Diseases

Summary Summary

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.

Last updated: 3/5/2010

Symptoms Symptoms

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]

Last updated: 3/5/2010

The Human Phenotype Ontology (HPO) provides the following list of features that have been reported in people with this condition. Much of the information in the HPO comes from Orphanet, a European rare disease database. If available, the list includes a rough estimate of how common a feature is (its frequency). Frequencies are based on a specific study and may not be representative of all studies. You can use the MedlinePlus Medical Dictionary for definitions of the terms below.

Signs and Symptoms	Approximate number of patients (when available)
Depressed nasal ridge	90%
Downturned corners of mouth	90%
Epicanthus	90%
Long philtrum	90%
Narrow mouth	90%
Omphalocele	90%
Short nose	90%
Thin vermilion border	90%

Last updated: 9/1/2016

Diagnosis Diagnosis

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]

Last updated: 3/5/2010

Treatment Treatment

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

Last updated: 3/5/2010

Management Guidelines

The National Guideline Clearinghouse (NGC) has information on the use of psychiatric medications during pregnancy and lactation, including guidelines regarding the use of valproic acid. The NGC is a public resource for evidence-based clinical practice guidelines. The NGC was originally created by the Agency for Healthcare Research and Quality (AHRQ) in partnership with the American Medical Association and the American Association of Health Plans.

Research Research

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

The Research Portfolio Online Reporting Tool (RePORT) provides access to reports, data, and analyses of research activities at the National Institutes of Health (NIH), including information on NIH expenditures and the results of NIH-supported research. There is a study titled "Washington obstetric-fetal pharmacology research unit" that may be of interest to you. Click on the link above to learn more about this study.

Organizations Organizations

Nonprofit support and advocacy groups bring together patients, families, medical professionals, and researchers. These groups often raise awareness, provide support, and develop patient-centered information. Many are the driving force behind research for better treatments and possible cures. They can direct people to research, resources, and services. Many groups also have experts who serve as medical advisors. Visit their website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD. Suggest an organization to add.

Organizations Supporting this Disease

Birth Defect Research for Children, Inc.
976 Lake Baldwin Lane, Suite 104
Orlando, FL 32814
Telephone: 407-895-0802
E-mail: staff@birthdefects.org
Website: http://www.birthdefects.org/

Living With Living With

Living with a genetic or rare disease can impact the daily lives of patients and families. These resources can help families navigate various aspects of living with a rare disease.

Healthcare Resources

The Organization of Teratology Information Specialists (OTIS) is a non-profit organization made up of individual services (TIS) throughout North America. We are dedicated to providing accurate evidence-based, clinical information to patients and health care professionals about exposures during pregnancy and lactation.

Organization of Teratology Information Specialists (OTIS)
University of Arizona
Drachman Hall
P.O. Box 210202
1295 N. Martin
Room B308
Tucson, AZ 85721-0202
Toll-free: 866-626-OTIS
E-mail: contactus@otispregnancy.org
Web site: http://www.otispregnancy.org/
Find your local OTIS service: http://www.otispregnancy.org/find-a-tis-p135707

Genetics Resources

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by GeneTests, the American College of Medical Genetics, and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from Genetics Home Reference.

Learn More Learn More

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

MedlinePlus.gov provides more information on valproic acid. MedlinePlus is a Web site designed by the National Library of Medicine to help you research your health questions.
TheFetus.net has an information page on fetal valporate syndrome. Click on TheFetus.net to view the page.
The American Congress of Obstetricians and Gynecologists offers information on seizures disorders and pregnancy. Click on the link above to learn more.
The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine.
Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
PubMed is a searchable database of medical literature and lists journal articles that discuss Fetal valproate syndrome. Click on the link to view a sample search on this topic.

Selected Full-Text Journal Articles

Kini U. Fetal valproate syndrome: A review. Paediatric and Perinatal Drug Therapy. 2006;7(3):123-130.
Kini U, Adab N, Vinten J, Fryer A, Clayton-Smith J. Dysmorphic features: an important clue to the diagnosis and severity of fetal anticonvulsant syndromes. Arch Dis Child Fetal Neonatal Ed. 2006 Mar;91(2):F90-5.

News & Events News & Events

NCATS Co-Sponsored Conferences

Third Conference of the MENA Initiative: Future Directions in Developmental Disabilities: Prevention, Screening, and Treatment Tuesday, April 27, 2010 - Thursday, April 29, 2010
Location: Doha, Qatar
Description: The goals of the meeting were to enhance prevention, screening, and treatment of developmental disabilities in the Middle East and North Africa (MENA) and to develop partnerships for building regional resources that will support patient treatment and research collaboration. This included expanding the conditions that had been addressed in the previous conferences to include neurosensory and neurodevelopmental conditions in addition to metabolic conditions.

Contact: Danuta Krotoski, krotoskd@mail.nih.govkrotoskd@mail.nih.gov

Co-funding Institute(s): National Institute of Child Health and Human Development, Office of Rare Diseases Research
- Agenda ( - 82KB)

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References References

Kini U et al. Dysmorphic features: an important clue to the diagnosis and severity of fetal anticonvulsant syndromes. Arch Dis Child Fetal Neonatal Ed. 2006;
Kini U. Fetal valproate syndrome: a review. Paediatric and Perinatal Drug Therapy. 2006;
Clayton-Smith J, Donnai D. Fetal valproate syndrome. J Med Genet. 1995;
Kozma. Valproic acid embryopathy: Report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature. American Journal of Medical Genetics. 2001;
Nicolai J, Vles JSH, Aldenkamp AP. Neurodevelopmental delay in children exposed to antiepileptic drugs in utero: A critical review directed at structural study-bias. Journal of the Neurological Sciences. 2008;