A Comparative Study of the Teratogenic Effects of Antiepileptic Drugs: Lamotrigine and Levetiracetam on Adult Albino Rats

Abstract

Background: Lamotrigine (LTG) and levetiracetam (LEV) are widely and increasingly prescribed second generation antiepileptic drugs for women with epilepsy during childbearing age. However, data pertaining to their congenital malformations are lacking. Aim: This study aimed to investigate and compare the teratogenic effects of LTG and LEV on normal adult female albino rats and their fetuses in order to find out the least teratogenic one of them. Materials and methods: Ninety-six adult albino rats (64 virgin females and 32 males) of almost the same range of weight and age were used. Pregnant rats were divided into 4 groups. The 1 st group (control; received 1 ml of distilled water) and the 2 nd group (vehicle; received 1 ml of 2% Arabic gum), while the 3 rd (LTG-treated) and 4 th (LEV-treated) groups received 50 mg/kg/b.wt. of LTG and 310 mg/kg/b.wt. of LEV, respectively. All substances were administered as single oral dose starting from gestational day (GD) 7 to 15. On GD 20, all dams were weighted then sacrificed and subjected to Cesarean section. The total numbers of ovarian corpora lutea and the status of all implantation sites (the total numbers of resorption sites, live and dead fetuses, and the total implantations) were counted. The gravid uteri were subsequently removed, weighted, and fetuses were delivered. The fetuses' numbers, weights, different body lengths, gross abnormalities, and skeletal malformations were recorded. Results: On GD 20, maternal weight gains and gravid uteri weights were statistically significantly lower in both treated groups than control and these differences were more significant in LTG than LEV. The percentages of pre-implantation and post-implantation losses in LTG and LEV exhibited statistically significant increase and non-significant differences compared with control, respectively, and the latter was more pronounced in LTG than LEV. As regard the numbers, weights, crown-rump lengths, biparietal diameters and head lengths of the fetuses, both treated groups showed significant differences in comparison to the control with higher abnormalities in LTG-treated than LEV-treated groups. Fetuses from treated groups revealed various gross abnormalities in the internal organs. Fetuses' skeletons examination revealed bone defects in both treated groups. Skull, vertebrae, and hind limb skeletal malformations were more prevalent in LTG-treated group, while sternum was more affected in LEV-treated group. Conclusion: Both antiepileptic drugs were teratogenic in variable degrees; however, LEV appears to be less teratogenic than LTG.

Pathological findings in viscera of albino rat’s fetuses of mother treated by lamotrigine

“…Padmanabhan et al (2003) reported that administering lamotrigine as single dose of 50-200 mg/kg body weight can induce intrauterine growth retardation in mice, whereas multiple doses of 25, 50, 75 mg/kg body weight caused a dose dependent increase in embryonic resorption and craniofacial malformations. Mohanty et al (2011) and Elgndy et al (2016) showed an increase in the ventricular size in lamotrigine exposed rat fetus.…”