Prenatal sonographic diagnosis of fetal valproate syndrome: a case report
© The Author(s). 2016
Received: 23 January 2016
Accepted: 10 October 2016
Published: 3 November 2016
Prenatal exposure of mother to valproate (VPA) causes teratogenic effects in the fetus, namely fetal valproate syndrome (FVS). We report a case of fetal valproate syndrome rarely diagnosed by prenatal sonographic examination.
Our patient was a female infant who was born to a 27-year-old nulliparous Japanese woman with epilepsy. The mother was diagnosed with infantile epilepsy at 1 year of age and had been using three antiepileptic drugs, including valproate, but preconceptional counseling was not performed. At 25 weeks of gestation, contracture of the fetal right wrist joint suggestive of a radial ray defect was observed by transabdominal ultrasonography. The fetus demonstrated growth retardation starting from 32 weeks of gestation. In addition, saddle nose as a facial anomaly was detected by three-dimensional ultrasound at 37 weeks of gestation. Accordingly, we suspected that the fetus had fetal valproate syndrome. At 39 weeks of gestation, the mother delivered an infant weighing 2056 g. The neonate had characteristic features of fetal valproate syndrome, such as facial configuration, slight muscular hypotonia of the whole body, breathing problems, right-hand articular contracture accompanied by radial ray defect, and cardiovascular malformation.
When obstetricians manage epileptic pregnant women without enough preconceptional counseling or adjustment for antiepileptic drugs, careful sonographic observation of the fetus is mandatory.
KeywordsEpilepsy Fetal valproate syndrome Prenatal diagnosis Ultrasonography Preconceptional counseling
Valproate (VPA) is used for the treatment of epilepsy and mood disorders . Prenatal exposure of the mother to VPA causes teratogenic effects in the fetus, namely fetal valproate syndrome (FVS). FVS is characterized by a number of abnormalities, including neural tube defects; congenital heart defects; limb defects; genitourinary defects; brain, eye, and respiratory anomalies; and abdominal wall defects . Although FVS is well-known as a newborn disease, reports of prenatal ultrasonographic diagnosis are limited, and only two cases have been reported in the English-language literature. We report another case of FVS diagnosed by prenatal ultrasonography. Careful ultrasonographic observation might be useful for predicting FVS in pregnant women using antiepileptic drugs, including high-dose VPA, without enough preconceptional counseling.
Our patient was a female infant who was born to a 27-year-old Japanese nulliparous woman. The mother had been diagnosed with infantile epilepsy at 1 year of age. Her antiepileptic therapy was discontinued at the age of 7 years because she had no symptoms, but she had an epileptic seizure at the age of 17 years, and treatment with the antiepileptic drugs was resumed. She married at the age of 25 years; however, she did not receive preconceptional consultation. Because she had slight mental retardation, she did not report her wish for a pregnancy to her physician. At the age of 27 years, she was referred to our hospital from a primary obstetrical clinic at 13 weeks of gestation. She was obese, with a body mass index of 30 kg/m2. The antiepileptic drugs she was taking included 1400 mg/day of VPA, 140 mg/day of phenobarbital (PB), and 1200 mg/day of carbamazepine (CBZ). The blood concentrations of the drugs were 80 μg/ml VPA (effective blood range is from 40 to 100 μg/ml), 26.1 μg/ml PB (10–30 μg/ml), and 10.5 μg/ml CBZ (4–12 μg/ml). Despite the mother’s use of three antiepileptic drugs, she had convulsions about three times per week. Therefore, reduction or alteration of the drugs was difficult. She was informed of her epileptic status and the teratogenic effects of VPA, but her wish to have a baby was so strong that she continued her pregnancy with oral folic acid of 5 mg/day.
The recommended treatment for a woman with epilepsy who wishes to have children is to use a single drug or newer antiepileptic drugs such as lamotrigine or levetiracetam [3–5]. Although avoidance of VPA is an option to prevent FVS, there are cases where the control of convulsions is impossible without VPA. There is a dose-effect relationship between fetal malformations and VPA exposure during the first trimester of pregnancy; that is, higher VPA doses are associated with a significantly greater risk than lower doses. Several investigators have reported a higher fetal malformation risk with maternal VPA doses above 1000 mg/day or high blood concentrations above 70 μg/ml during pregnancy . Combined use of antiepileptic drugs is also associated with a high risk of fetal malformations. The risk of major congenital malformations is influenced not only by the type of antiepileptic drug used but also by dose and other variables, which should be taken into account in the management of epilepsy in women of childbearing potential . Thus, preconceptional counseling for a woman with epilepsy who is taking antiepileptic drugs is very important.
Reported cases of fetal valproate syndrome detected by prenatal ultrasonography
US findings of fetus (gestational weeks)
Additional postnatal findings
Witters et al. 2002 
VPA; 1000 mg/day
Flat nasal bridge with short nose (21 weeks)
Long philtrum, thin upper lip, long toes
Kennelly and Moran 2007 
VPA; dose N/A
Bilateral radial ray defects (19 weeks)
Termination of pregnancy
Aortic valve stenosis
VPA 1400 mg/day
PB 140 mg/day
CBZ 1200 mg/day
Contracture of right wrist joint suggestive of radial ray defect (25 weeks)
VSD, ASD, PDA; shallow philtrum; euryopia
Saddle nose (37 weeks)
When radial ray defects and facial anomaly are observed by prenatal ultrasonography, differential diagnoses of FVS are trisomy 18, trisomy 13, Cornelia de Lange syndrome, Roberts syndrome, acrofacial dysostosis, Baller-Gerold syndrome, Fanconi anemia, Aase syndrome, thrombocytopenia-absent radius (TAR) syndrome, and Holt-Oram syndrome . The facial anomaly in FVS is usually flat nasal bridge or saddle nose; facial anomalies seen in other syndromic disorders are micrognathia (trisomy 18, Cornelia de Lange syndrome, acrofacial dysostosis, Baller-Gerold syndrome, and TAR (thrombocytopenia with absent radius) syndrome, cleft lip and/or palate (trisomy 13, Roberts syndrome, and Aase syndrome), mandibular protrusion (Cornelia de Lange syndrome), microphthalmus (Fanconi anemia), and hypertelorism (Holt-Oram syndrome) . VACTERL association (vertebral anomalies, anal atresia, cardiovascular anomalies, tracheoesophageal fistula, esophageal atresia, renal (kidney) and/or radial anomalies, limb defects) is associated with radial ray defects, but it is not usually accompanied by facial anomaly . Although Binder syndrome is characterized by a flat midface and nasal hypoplasia, it is not usually accompanied by radial ray defects .
The present case indicated the possibility of prenatal diagnosis of FVS using ultrasonography. Especially, detection of contracture of the fetal wrist joint and saddle nose seemed to have diagnostic value. When obstetricians manage women with epilepsy using epileptic drugs without preconceptional counseling, meticulous ultrasonographic observation should be performed to prevent serious morbidity and mortality in postnatal life. Furthermore, when multiple malformations to an extensive degree exist, early prenatal diagnosis may lead to more appropriate management of FVS, including termination of pregnancy and providing counseling for future pregnancies.
The authors are grateful to Yukihide Miyosawa (Department of Pediatrics, Shinshu University School of Medicine) for examination and treatment of the neonate.
Availability of data and materials
NK, RA, KT, and AT performed fetal ultrasonography during the mother’s pregnancy. SO and TS helped to draft the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. We gave attention to privacy protection in accordance with ethics committee guidelines.
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- Genton P, Semah F, Trinka E. Valproic acid in epilepsy: pregnancy-related issues. Drug Saf. 2006;29:1–21.View ArticlePubMedGoogle Scholar
- Clayton-Smith J, Donnai D. Fetal valproate syndrome. J Med Genet. 1995;32:724–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Juárez-Olguín H, Belmont-Gόmez A, Flores-Pérez J, Barranco-Garduño LM, Flores- Pérez C. Malformations in newborns associated to anticonvulsant consumption during pregnancy: experience in third level hospital of Mexico. Rev Invest Clin. 2008;60:15–20.PubMedGoogle Scholar
- Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Sabers A, et al. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol. 2011;10:609–17.View ArticlePubMedGoogle Scholar
- Mawhinney E, Craig J, Morrow J, Russell A, Smithson WH, Parsons L, et al. Levetriacetam in pregnancy: results from the UK and Ireland epilepsy and pregnancy registers. Neurology. 2013;80:400–5.View ArticlePubMedGoogle Scholar
- Kaneko S, Battino D, Andermann E, Wada K, Kan R, Takeda A, et al. Congenital malformations due to antiepileptic drugs. Epilepsy Res. 1999;33:145–58.View ArticlePubMedGoogle Scholar
- Witters I, Van Assche F, Fryns JP. Nuchal edema as the first sign of fetal valproate syndrome. Prenat Diagn. 2002;22:834–5.View ArticlePubMedGoogle Scholar
- Kennelly MM, Moran P. A clinical algorithm of prenatal diagnosis of radial ray defects with two and three dimensional ultrasound. Prenat Diagn. 2007;27:730–7.View ArticlePubMedGoogle Scholar
- Cook K, Prefumo F, Presti F, Homfray T, Campbell S. The prenatal diagnosis of Binder syndrome before 24 weeks of gestation: case report. Ultrasound Obstet Gynecol. 2000;16:578–81.View ArticlePubMedGoogle Scholar