Cranial neural tube defect after trimethoprim exposure

Abstract

Objectives: The Neural Tube Defects Research Group of University of Malaya was approached to analyze a tablet named TELSE, which may have resulted in a baby born with central nervous system malformation at the University of Malaya Medical Centre. In this animal experimental study, we investigated the content of TELSE and exposure of its contents that resulted in failure of primary neurulation.

Results: Liquid Chromatography Tandem Mass spectrophotometry analysis of the TELSE tablet confirmed the presence of trimethoprim as the active compound. The TELSE tablet-treated females produced significant numbers of embryos with exencephaly (n = 8, 36.4%, *P < 0.0001), in all litters. The TELSE tablet-treated females subsequently given folic acid did not result in pregnancies despite there being evidence of possible resorption. Furthermore, after multiple rounds of mating which did not yield viable pregnancies, eventually, 2 embryos with exencephaly were harvested in a litter of 6 at 0.05% w/v pure trimethoprim once. The use of trimethoprim, a folic acid antagonist, peri-conceptionally increased the risk of exencephaly in the mouse.

Keywords: Acne; Folic acid antagonist; Malaysia; Neural tube defects; Primary neurulation; Trimethoprim.

Fig. 1

Mouse model exhibiting cranial neural tube defect after trimethoprim exposure. a Control mouse embryo (untreated) at E10.5 (24 somites stage) age matched against b mouse embryo with exencephaly at E10.5 (23 somites stage) harvested from TELSE tablet (0.5% w/v containing 0.1% w/v trimethoprim) administered female CD1 mouse. The arrows indicate the open cranial neural tube. c Mouse embryo with cranial neural tube defect at E10.5 (22 somites stage) harvested from pure trimethoprim (containing 0.05% w/v trimethoprim) administered female CD1 mouse. d Transverse section through the cranial region of embryo C showing open hindbrain (Scale bar for A-C represent 0.5 mm and D represent 0.1 mm). e TELSE tablet administered female CD1 mouse showed significantly increased number of exencephalic embryos (n = 8) compared to control embryos (n = 24) (*P < 0.0001) (ANOVA). f, g No significant differences were seen between crown-rump length and number of somites in the E10.5 embryos between affected (n = 8) and not affected embryos of both treated mice (n = 14) and untreated mice (n = 24) (P < 0.0001) (ANOVA) (Value of bars are medians ± standard deviation). h, i Chromatogram of trimethoprim showed a single peak at 1.54 min and mass spectrometry analysis of the TELSE tablet confirmed the presence of trimethoprim as the active compound, with an exact mass of 291 and 230 for parent and daughter ions respectively