Comparative Histomorphological and Histostereological Teratogenic Effects of In-utero Exposure to Varied Doses of Omeprazole and Pantoprazole on Fetal Kidneys in Albino Rats (Rattus norvegicus)

Abstract

Omeprazole and pantoprazole are proton pump inhibitor medicines which are commonly used in management of gastric esophageal reflux disease during pregnancy. However, their teratogenic risk or their safety indexes on the developing fetal kidneys remains unclear. Further, whether their teratogenic effects are dose and time dependent is yet to be elucidated. The broad objective of this study therefore was to comparatively evaluate the histomorphological and the histostereological teratogenic effects of in-utero exposure to varied doses of omeprazole and pantoprazole on the developing kidneys in Albino rats (Rattus norvegicus). In carrying out this study, a post-test-only experimental study design with control was used. All the animal experimentation was carried out in the animal research facility at the University of Nairobi, while tissue processing for histology and stereological analysis was done at JKUAT, main campus. A Sample size of 30 Albino rats weighing between 190 to 230grams were used for each of the two study medicines. This sample size of 30 rats per group was determined by use of the resource equation for one-way Analysis of Variance method (ANOVA). The 30 Albino rats in each of the two study categories of omeprazole and pantoprazole were first randomly divided into two study groups of 3 rats control and 27 rats in treatment category. To evaluate whether the teratogenic effects of both medicines are dose dependent, the 27 rats in the experimental category were subdivided into three study sub groups of 9 rats each as follows; (i) 9 rats for low doses of omeprazole and pantoprazole group (2.07mg/kg/4.13mg/kg, respectively), (ii) 9 rats for medium doses of omeprazole and pantoprazole group (medium19.63mg/kg /13.43mg/kg, respectively), (iii) 9 rats for the high omeprazole and pantoprazole group (37.8mg/kg, /24.8mg/kg). To further evaluate whether the observed teratogenic effects are time dependent, the 9 rats in each of the three dose categories were further sub-divided into three subgroups of 3 rats each according to the trimesters of exposure as follows; (i) 3 rats for trimester one (ii) 3 rats for trimester two and (iii) 3 rats for trimester three. All the rats in both the control and the treatment groups were sacrificed on 20th gestational day. The fetal kidneys were harvested for both histo-morphological and stereological analysis. The quantitative data was collected using structured checklists, stored in excel spreadsheets windows 10, version 2016, then was exported for analysis into SPSS programme for windows version 25 for analysis (Chicago Illinois). The histo-photomicrographs were taken using a swift 3.0 microscope digital camera then uploaded to swift 3.0 software for labelling. Data analysis was done using ANOVA and MANOVA. Results were expressed as mean ±SD, and all results whose P<.05 were considered significant. The study findings were as follows: in the treatment groups, there was a statistical significant reduction in the fetal growth parameters. Additionally, both omeprazole and pantoprazole affected the development of the fetal kidneys in a dose and time dependent manner particularly at TM1 and TM2, with omeprazole having more detrimental effects that included the altered renal histo-cytoarchitecture compared to pantoprazole. Further, both drugs led to a statistical reduction (P<.05) in the kidney volumes more so in the medium and high dose groups. Conclusion was drawn that both omeprazole and pantoprazole affected the development of the fetal kidneys in a dose dependent manner. It is recommended that medium and high dosages of the two drugs should be used with caution during pregnancy particularly in TM1 and TM2. Further studies with non-primates closer to human are recommended to help collaborate these findings to humans.