RESEARCH ARTICLE Effect of In Utero Exposure of Gabapentin and Valproic Acid on Skeletal Anomalies in Rat Fetuses K. P. Singh • Kiran Gupta • M. Singh Received: 9 March 2013 / Revised: 6 July 2013 / Accepted: 22 October 2013 / Published online: 12 March 2014 Ó The National Academy of Sciences, India 2014 Abstract For treatment of epileptic seizures, classical and novel antiepileptic drugs (AEDs) are available for general population and also recommended to pregnant women with caution considering their teratogenic risks. Literature indicates that skeletal teratogenic safety of novel or atypical AEDs has not been well documented so far as established for classical AEDs. Reports on fetal skeletal anomalies caused by in utero exposure of gabapentin (GBP) are less and inconclusive. Therefore, present study has been undertaken to compare the skeletal safety of GBP and valproic acid (VPA, a classical drug) in non-epileptic pregnant rats using equivalent therapeutic doses. The present study concludes that maternal exposure of GBP or VPA may adversely affect the development and growth of skeletal system in rat fetuses but skeletal anomalies were found more intense in VPA than GBP. The involvement of multifactorial inducing mechanisms, from environmental to molecular, are expected for variable skeletal birth defects. Therefore, extrapolation of animal data to clinics should be critically scrutinized before drug (GBP) recom- mendation to pregnant women population. Keywords Antiepileptic drugs Á Gabapentine Á Valproic acid Á Skeletal anomalies Á Prenatal Á Rat Introduction For treatment of epilepsy both second generation (atypical) and first generation (classical) antiepileptic drugs (AEDs) are available in the world market [1]. These drugs are also used by pregnant women with caution considering their teratogenic risks to fetus/neonate [2]. Clinical and non- clinical literature indicate that classical AEDs like VPA are associated with teratogenic risk, both major and minor congenital anomalies including skeletal (axial and appen- dicular) defects [3]. The teratogenic safety of second generation AEDs including GBP has not been well estab- lished so far in general and skeletal teratogenicity in par- ticular if these drugs were administered during different gestation periods in humans and animals. Although some reports are available on this issue but are contradictory and inconclusive [4–6]. Reports on animals have shown that GBP exposure at different gestation period may induce delayed ossification in the skull bones, vertebral column, upper and lower limbs in fetuses and other related skeletal deformities [4, 7, 8]. In these reports prenatal exposure of GBP was variable for drug doses, rodent models, strain differences, exposure period and route of administration etc. Hence, variable results were observed which are summarized in Table 1. GBP is relatively a new agent of atypical antiepileptic class and categorized as ‘C’ considering its possible tera- togenic risk by FDA. Its mechanism of action is to block the GABAergic action in cerebral cortex and basal nuclei [9]. This drug is also used for relief of neuropathic pain and prophylaxis of migraine [10, 11]. Due to low molecular weight (171 Da) and poor binding capacity to plasma protein, it crosses easily the placental membrane and blood–brain barrier (BBB) [12]. Valproic acid is an old or classical drug generally used for generalized seizure K. P. Singh (&) Á K. Gupta Neurobiology Lab, Department of Zoology, University of Allahabad, Allahabad, India e-mail: kps29@rediffmail.com M. Singh Department of Anatomy, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India 123 Natl. Acad. Sci. Lett. (March–April 2014) 37(2):117–121 DOI 10.1007/s40009-013-0206-3