Severe fetal valproate syndrome: combination of complex cardiac defect, multicystic dysplastic kidney, and trigonocephaly

Abstract

Valproic acid (VPA) is a teratogenic drug used in pregnant women for the treatment of epilepsy and mood disorders. Fetal valproate syndrome (FVS) is characterized by a number of abnormalities associated with VPA exposure in utero including neural tube defects, congenital heart defects, limb defects, genitourinary defects, brain, eye and respiratory anomalies, and abdominal wall defects. Complex cardiac defect and trigonocephaly have rarely been reported and multicystic dysplastic kidney has never been detected in FVS. We here report a female infant who was born to a mother with a history of low-dose VPA monotherapy (250 mg/day) during pregnancy and who had presented with a combination of unilateral multicystic dysplastic kidney, multicomplex cardiac defect including severe coarctation of aorta, Ebstein anomaly, secundum atrial septal defect, mesocardia along with trigonocephaly due to metopic craniosynostosis, typical facial appearance and limb defects. To our knowledge, this is the first case presented with multicystic dysplastic kidney, complex cardiac defect, trigonocephaly and other limb and facial defects because of exposure to very low-dose VPA monotherapy (250 mg/day) in utero. We conclude that VPA must be used very cautiously in pregnant women even as monotherapy and in low doses to prevent major congenital defects.

Valproate fetopathy

“…8 The characteristic facial anomalies include arched eye brows, epicanthal folds, broad nasal bridge, small nose with anterverted nostrils and occasionally cleft palate and trigonencephaly due to premature closure of the metopic suture. 1,5 The most characteristic facial findings are small nose (57%) and epicanthal folds (31%). Limb anomalies are characteristically preaxial in the upper extremity and include absent radius and hypoplastic, bifid or triphalangeal thumbs.…”

“…However, the risk of neural tube defects with intrauterine exposure to valproate is 10 times than that compared with the general population 4 and the risk for facial, cardiac, genitourinary and skeletal anomalies is 2 to 5 times than that compared with the general population. 5 The inhibition of histone deacetylase and changes in gene expression by valproate may explain the teratogenicity of this drug. 6 Valproate taken in the daily dose of 1000 mg or more is associated with a higher teratogenic risk.…”

Epigenetics of psychoactive drugs

“…Recently, it has been shown that VPA induces apoptosis and neural tube defects in postimplantation embryos [100] . A severe foetal valproate syndrome has also been documented [101] . Experimental studies also support the effect of VPA on reprogramming and intrauterine development [102,103] …”

Fingerprinting of neurotoxic compounds using a mouse embryonic stem cell dual luminescence reporter assay

“…Major limitations of presently available studies on neurotoxicity, both developmental and general, include the following aspects:

Relatively few clinical and epidemiological data are available (Smirnova et al 2014). Well-accepted exceptions are tragic events such as the large-scale methylmercury poisoning in Minamata (Ekino et al 2007) or the identification of the fetal valproate syndrome because of the widespread treatment of pregnant epileptic patients with valproic acid (Ozkan et al 2011; Smith and Whitehall 2009);

Neurotoxicity is typically not characterized by cytotoxicity (i.e., neuronal cell death), but rather by impact of toxicants on connectivity, structure, and function of the nervous system during development or at maturity (Giordano and Costa 2012);Extrapolation of data from animal experiments to the human situation may be challenging due to interspecies differences (“humans are no 70 kg mice” (Leist and Hartung 2013);In vitro studies on neurotoxicity usually use transformed or cancer cell lines, which have a response pattern significantly different from normal cells (Kadereit et al 2012; Stiegler et al 2011). …”

“…Well-accepted exceptions are tragic events such as the large-scale methylmercury poisoning in Minamata (Ekino et al 2007) or the identification of the fetal valproate syndrome because of the widespread treatment of pregnant epileptic patients with valproic acid (Ozkan et al 2011; Smith and Whitehall 2009);…”