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
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
- 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;
- 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.