A mechanistic perspective on the specificity and extent of COX-2 inhibition in pregnancy

Cyclo-oxygenase (COX)-2-specific inhibitors form one of the most commonly prescribed groups of pain relief drugs. Despite the known reproductive toxicity of NSAIDs, which are nonspecific COX inhibitors, little is known about the differential role between COX-1 and COX-2 inhibition on reproduction. It has been suggested that COX-2 plays a prominent role in animals at all stages of reproduction, from ovulation to implantation to decidualisation and delivery. Both estrogen and progesterone have been shown to be involved in regulation of COX production in tissues of the reproductive tract. Similar to NSAIDs, warnings on reproduction have been included in the product labelling of marketed COX-2-specific inhibitors. Variations in the level of warnings in these labels are noted, with an order of stringency being celecoxib approximate, equals etoricoxib > rofecoxib approximate, equals valdecoxib. The specificity of etoricoxib for COX-2 has been found to be approximately 3-fold greater than that of rofecoxib and valdecoxib and approximately 14-fold more than celecoxib in human whole blood assays. There is growing evidence to suggest that the inducible COX-2, rather than the COX-1, is the main enzyme responsible for reproduction. It was demonstrated that the change in estrogen and progesterone levels during pregnancy contributes to the dramatic increase in COX-2 expression. This further strengthens the earlier findings that COX-2 activities are necessary to support pregnancy. It is also worth mentioning that although a definite correlation between the specificity of a COX-2-specific inhibitor and the level of precaution stated in the drug labels in UK was not obtained, a direct relationship between the specificity and the potential to result in teratogenicity has not been excluded. With growing interest of the pharmaceutical industry in developing more COX-2-specific inhibitors and the fact that reproductive toxicity is not tested in pregnant women before marketing, it is important for drug regulators to raise awareness of the potential reproductive adverse effects and provide guidance on the level of caution when using these drugs in pregnancy.