Comparative Histo-morphological and Histo-stereological Teratogenic Effects of In-utero Exposure to Lamotrigine and Levetiracetam on the Fetal Kidneys in Albino Rats (Rattus novegicus)

Abstract

Lamotrigine and levetiracetam are second-generation antiepileptic medicines that are currently being used widely in the management of maternal epilepsy and other neuralgic disorders during pregnancy. However, their comparative histo- morphological and histo-stereological teratogenic risks on the developing fetal kidneys remains unclear. The broad objective of this study therefore was to comparatively evaluate their histo-morphological and histo-stereological nephron- teratogenic effects on the developing fetal kidney when exposed in varied doses and at different gestational periods. In carrying out this study, a posttest experimental study design with a control group was adopted. All animal experimentation procedures that included breeding of the animals, feeding, drug administration up to harvesting of fetuses was done in Nairobi university (UON) while tissue processing for histology and stereological analysis was done in the department of Human anatomy in JKUAT. A sample size of 30 albino rat dams was used for each of lamotrigine and the levetiracetam treatment groups. These 30 albino rat dams for each of the two study categories were first randomly assigned into two broad study groups of 3 rats control and 27 rats experimental. The 27 rats in each of the experimental category were further randomly assigned into three subgroups of 9 rats each according to the three dose groups of low, medium and high dose as follows, 9 rats low dose lamotrigine/ levetiracetam treatment group, 9 rats for the medium dose lamotrigine/ levetiracetam treatment group and 9 rats for the high dose lamotrigine/ levetiracetam treatment groups. To further evaluate the effects of the time of exposure, the 9 rats in each of the three dose categories were further randomly sub- divided into three sub-groups of 3 rats each as follows; 3 rats for trimester I, the next 3rats for trimester II; and the last 3 rats for Trimester III. The study findings showed that in both lamotrigine and levetiracetam treatment groups, there was a statistical significance increase (p<0.05) in medullary thickness while the cortical thickness reduced in a proportionate manner. Stereologically there was marked reduction in glomerular numbers per field of view as well as in their volume densities resulting to their observed sparse distribution. There was an observed remarkable condensation of glomerular tufts capillaries with significantly hypertrophied bowman spaces. The critical nephron-teratogenic period was noted to be when both the drugs were administered in trimester one and trimester two with critical teratogenic doses being both the high dose of the two medicines. Lamotrigine was established to be more teratogenic compared to levetiracetam across all dose groups and across all the trimesters of exposure. In conclusion, both lamotrigine and levetiracetam are teratogenic to the developing fetal kidney and their teratogenic effects depicted patterns of both time-dose dependency. The study recommends caution when using high doses of both drugs by pregnant mothers particularly during trimester one and trimester two. It also recommends further studies on higher primates with close relations to humans.