Comparative Morphological and Histo-stereological Teratogenic Effects of Phenobarbital and Phenytoin on the Developing Fetal Kidneys in Albino Rats (Rattus norvegicus)

Abstract

The prenatal teratogenicity exposures to phenobarbital and phenytoin on the morphology and the histo-stereological structures of the developing fetal kidneys remains largely unclear. At the same time, it is also not clear whether or not the teratogenic effects of the two medicines are dose and time dependent. In carrying out this study, post-test only control experimental study design was adopted. A resource equation for one-way analysis of variance (ANOVA) was used to arrive at a sample size of 30 albino rats (Rattus norvegicus) for each of the two-treatment groups. The rats were nine weeks old and weighed between 150-250 mg. These 30 albino rats in each of the study categories of phenobarbital and phenytoin were first randomly assigned into two broad study groups of three rats control and the 27 rats treatment category. To first evaluate the intrauterine effects of varied doses, the 27 rats in each of the treatment category were further subdivided in to three sub-groups of nine rats each as follows: nine rats for low dose, nine rats for medium and nine for high dose groups. To further evaluate the effects on the time of exposure, the nine rats in each of the three doses categories of low, medium and high was were further sub-divided into three sub-groups of three rats according to the trimesters of exposures as follows; three rats for Trimester I (TM1); three rats for trimester II (TM2) and three rats for trimester III (TM3). At gestation day 20, all the rats were humanely sacrificed, three fetuses from each rat were selected and their kidneys harvested for histo-morphological and stereological analysis. The data was collected using a structured check list, then coded and entered into the computer using an excel spreadsheet for windows version 10, it was then exported to the Statistical package for the Social Scientist (SPSS) version 25 for statistical analysis. The inferential statistical significance levels were determined by use ANOVA and MANOVA and all values whose P<0.05 were considered significant. This study established that the prenatal exposure of both phenobarbital and phenytoin in all doses had a statistical significant reduction (p<0.05) to all the maternal and fetal growth parameters that included placental weights, maternal weight gain, birth weights, bi-parietal diameters as well as crown lamp lengths, when exposed at TM1 and TM2. At trimester three (TM3), only the high doses were seen to negatively influence the outcomes. The histo-stereological finding revealed that in-utero exposure to either of the two medicine has a deleterious effect on the developing fetal kidneys including significant decrease (p<0.05) in the kidney volumes and volume densities. Widening of the bowman’s spaces, renal tubules and the increase in cellular densities per glomeruli was also observed in a dose and time dependent manner. In conclusion all doses of both phenytoin and phenobarbital are teratogenic to the developing fetal kidneys at TM1 and TM2 and whenever possible the mothers should then be advised not to use these two medicines in their early pregnancy.