* Department of Gynecology, Félix Guyon'Hospital, ** Department of Obstetric, Intercommunal Hospital ** Department of Neonatology, Hôpital Félix Guyon, Reunion Island, France

Definition: Fetal valproate syndrome is due to maternal valproic acid exposure during pregnancy. Valproic acid is an anti convulsivant drug used initially to control certain types of psychiatric illness and then seizure in the treatment of epilepsy. Fetal valproate syndrome is characterized by different anomalies:  

• central nervous anomalies
• intrauterine  growth restriction
• cardiac anomalies
• facial anomalies

Synonyms: Acid valproic exposure; Depakine exposure; Dalpro fetal effects; Depakene fetal effects

Case report:  This is a 36-year-old-woman, with an epileptic disease and hemiplegia (caused by neonatal effects). She has been taking valproic acid since the age of six. In 2003, she delivered one girl vaginally. In 2004, she delivered another baby at 26 weeks, who died three days later.

The conception occurred on January 2005. She had been taking pills of valproic acid (500mg) three times per day. The first scan was performed at 13 weeks. The patient refused to perform the triple test. During the second trimester, the patient did not undergo the anomaly scan. The ultrasound examination was performed at 32 weeks. The sonographer detected a discordance of size between the ventricular chambers. The patient was referred to our level III unit. Our scan performed at 33 weeks revealed: 

• Discordance of size between ventricular chambers
• Small ventricular septal defect
• Normal pulmonary artery
• Normal aortic isthmus
• In the right ventricle, just below the tricuspid valve, there was a hyperechoic mass. This mass seemed muscular, hyperechogenic, but avascular
• We could not see the penis, but the scrotum seemed normal
• There was no cleft lip
• The kidneys were normal
• There was a single umbilical artery

The baby born at 37 weeks (3400g).  A hypospadias and a posterior cleft palate were diagnosed. The skeletal radiography was normal and also the kidney scan. An echocardiography was performed at day 5 and 10. The cardio pediatrician confirmed the small ventricular septal defect (membrane type). The atrio-ventricular valves were normal. Below the tricuspid valve, there was a right muscular hypertrophy. The aorta and pulmonary valves were normal. The pulmonary artery seemed normal. At the level of the aorta isthmus, they was a anterior notch but the flux was normal. The femoral pulse was present.

The face was dimorphic.  There were:

• Thick and long superior lip with shallow philtrum
• Cleft palate 
• Small broad nose
• Flat philtrum with coarse face
• Bi-temporal narrowness

During the hospitalization, the baby had several episode of apnea. The oxygen-dependance was present up to October. The electroencephalogram and the cerebral sonography were normal. The kidney scan and the skeletal radiography were also normal. On November, the baby was discharge the neonatal unit. He will be schedule to visit the the pediatric surgeon (for hypospadias surgery), the neonatologist (for neurological follow up), the maxillofacial surgeon (cleft palate) and the neonatal cardiologist. Three months later, a left inguinal hernia and right muscular diastase were diagnosed.

4-chamber view at 33 weeks showing marked echo-reflectivity near the tricuspid valve

Pulmonary artery at 33 weeks

Aorta at 33 weeks

3D view at 33 weeks of the sex showing hypospadias

Cardiac examination at 34 weeks. Note the interventricular septal defect.

Doppler examination at 33 weeks showing interventricular septal defect

Four- chamber view at 34 weeks showing marked echo-reflectivity near the tricuspid valve

Transverse scan of the umbilical cord.

Four chamber view at 34 weeks. Note the echo-reflectivity near the tricuspid valve and right ventricular hypertrophy.

Parasagittal cardiac view showing pulmonary artery and aorta.

2D view of the profile and 3D view of the face at 36 weeks

History: Valproic acid has been on the french market on 1967. Valproic acid is used now essentially to treat epileptic seizures. The first indications of its teratogenic effect on human embryos were observed in an epidemiological study in 1982. This study revealed that embryos exposed to valproic acid during the first trimester of pregnancy had 30% more risk to have spina bifida. Other studies postulated that there was a high risk of hypospadias, bone and cardiac malformation either. In 1984, DiLiberti et al proposed that intrauterine exposure to valproic acid produces a consistent craniofacial phenotype that they called valproate acid syndrome (association of facial dimorphism, cardiac malformation and bones anomalies). By this time, there had been several reports suggesting that in utero exposure to valproic acid could result in an unusual facial phenotype. In 1988, Ardinger et al evaluated 40 childreen who had intra-utero exposure to valproic acid. The first prenatal diagnosis of valproate acid syndrome was described few years latter.

Prevalence: Any epileptic pregnant woman has two or three times increased risk for congenital anomalies compared to the general population. If exposure to valproic acid takes place between the 17th and 30th days after conception, the incidence of neural tube defects reaches 1% to 2% (dose adjusted is 50 to 100 g/ml to be efficacy). Nevertheless the exact prevalence of fetal valproate syndrome remains difficult to establish.

Etiology: Exposure to valproic acid

Pathogenesis: Unknown.

Sonographic findings: Prenatal diagnosis, in particular after maternal serum-fetoprotein screening and targeted ultrasound scan, should be offered to all pregnant women exposed to valproic acid. The couple must be aware of a prenatal diagnosis of valproic acid syndrome. Valproic acid exposure can cause different anomalies as:

• Cardiovascular anomalies (25%)
• Ventricular septal defects
• Persistent ductus arteriosus
• Aortic stenosis
• Coarctation 
• Pulmonary stenosis
• Bone anomalies
• Spina bifida
• Limbs defects reduction
• Club feet and club hand; polydactyly; finger-like thumbs and rudimentary  digits; arachnodactyly; overlapping fingers; radial ray defects
• Sex anomalies: hypospadias
• Facial appearance: cleft lip; thin upper lip with shallow philtrum; thick lower lip; micrognathia; midfacial hypoplasia; small broad nose with a flat bridge; small ears; low-set posteriorly rotated ears with occasionally prominent malformed lobes; narrow forehead; flat philtrum with coarse face; epicanthal folds;
• IUGR
• Epilepsy
• Mental retardation
• Head and neck: trigonocephaly; defect of the calvaria; metopic ridging
• Urogenital system: hypospadias; small scrotum; cryptorchidism; incomplete fusion of Mullerian duct.

Implications for target examinations: If fetal valproate syndrome is suspected, amniocentesis must be proposed.

Differential diagnosis: Other neural tubal defects

Associated anomalies: Inguinal hernia and tracheomalacia with stridor

Prognosis: Fetuses that present major anomalies have a poor diagnosis. In pregnant woman exposed to valproate acid, manifestations of withdrawal include irritability, abdominal tones, feeding difficulties and seizures. Metabolic disturbances may also complicate the neonatal period, such as hyperbilirubinemia, hepatotoxicity (which can be fatal) and transient hyperglycinemia and growth retardation. The surviving patients can develop mental retardation.

Management: If a woman desire to have a pregnancy, it is important to recommend stopping the use of valproic acid. Peri conceptual prophylaxis with high doses of folic acid (5 mg) is recommended for all women on valproic acid and counseling should also emphasize planning pregnancy to optimize folic acid supplementation. 

If the fetal valproate syndrome is discovered during the pregnancy (second or third trimester), termination of pregnancy can be proposed. If the parents refused to interrupt the pregnancy, the management will be as a normal pregnancy, but the neonatologist needs to be informed of the prenatal anomalies. So the better management of this epileptic woman, is to manage and plan the pregnancy. It is important to try to switch the medication. If the mother is exposed to valproic acid in another pregnancy, the teratogenic effects can repeat. Because of the increased risk of malformation with valproic acid, pregnant woman using valproic acid should be informed about the importance to perform the triple test and an anomaly scan.  Finally, in pregnant woman taking valproate acid  and having baby with facial, cardiovascular and skeletical anomalies, fetal valproate syndrome must be suggested.