Cranial neural tube defect after trimethoprim exposure

Area of Science:

• Developmental toxicology
• Pharmacology
• Teratology

Background:

• A case of central nervous system malformation in a newborn was linked to maternal use of a tablet named TELSE.
• The Neural Tube Defects Research Group was tasked with investigating the potential teratogenicity of the TELSE tablet.

Purpose of the Study:

• To identify the active compound in the TELSE tablet.
• To investigate the effects of TELSE tablet exposure on primary neurulation in an animal model.
• To determine if trimethoprim acts as a teratogen causing neural tube defects.

Main Methods:

• Liquid Chromatography Tandem Mass Spectrophotometry (LC-MS/MS) was used to analyze the TELSE tablet's composition.
• Pregnant mice were administered TELSE tablets or varying concentrations of trimethoprim during the peri-conception period.
• Embryo development was assessed for malformations, specifically focusing on neural tube defects like exencephaly.

Main Results:

• LC-MS/MS analysis confirmed trimethoprim as the active compound in the TELSE tablet.
• Exposure to TELSE tablets resulted in a significant incidence of exencephaly (36.4%) in mouse embryos.
• Administration of pure trimethoprim also led to exencephaly, confirming its teratogenic potential.
• Folic acid supplementation did not prevent adverse pregnancy outcomes in TELSE-treated mice.

Conclusions:

• Trimethoprim is identified as the teratogenic agent in the TELSE tablet responsible for exencephaly.
• Peri-conceptional exposure to trimethoprim, a folic acid antagonist, significantly increases the risk of neural tube defects.
• These findings underscore the potential teratogenic risks of trimethoprim during early pregnancy and the critical role of folic acid in preventing such defects.