Analysis of the nonsteroidal anti‐inflammatory drug literature for potential developmental toxicity in rats and rabbits

Abstract

This analysis of the non-clinical NSAID literature demonstrated a possible association between exposure to NSAIDs and developmental anomalies. The anomalies were similar for aspirin and for other NSAIDs, but effects occurred at a much lower incidence with non-aspirin NSAIDs than previously reported with aspirin. Such a finding is consistent with the concept that reversible inhibition of COX-1 and/or COX-2 by other NSAIDs would produce weaker developmental toxicity signals than aspirin. However, there were limitations of the evaluated studies: (1) there were very few robust International Conference on Harmonization-compliant studies conducted with NSAIDs in the published literature; (2) many of the studies were conducted at doses well below the maximum tolerated dose (MTD), where effects are rarely seen; and (3) numerous studies were conducted above the MTD, where reduced numbers of fetuses hampered detection of low-incidence findings. Although weak associations were observed, these limitations prevented us from definitively determining the presence or absence of a developmental toxicity signal from the existing body of NSAID data. Further exploration of this hypothesis will require assessing the potential association in animal models by using dose levels centered around the MTD.

Organ and prenatal toxicity of nonsteroidal anti-inflammatory drugs

“…Cook et al [20] presented similar findings. However, these were restricted to non-selective COX inhibitors.…”

“…Nevertheless, the role of disorders in the function and morphology of the placenta in their etiopathogenesis remains unknown. Briggs et al [20] indicate that xenobiotics can easily cross the placental barrier which separates the mother's circulatory system from the foetal circulation.…”

Micro Hardness of Dental Tissues Influenced by Administration of Aspirin During Pregnancy

“…In the contemporary study, the medicine was administered systemically to evaluate the effect on the dental tissues of the neonates. Review of the literature indicated the potential association of NSAIDs with developmental toxicity of diaphragmatic hernia, midline defect and ventricular septal defects in rats and rabbits Gupta et al, 2003;Cook et al, 2003). The rate of perinatal mortality was reported providing the information of high-risk pregnancies, where aspirin treatment seemed to have a small but significant effect on reducing the rate of preterm deliveries, but did not reduce the rate of perinatal death (Kozer et al, 2003).…”

Pharmacological safety during pregnancy: the principles of teratogenesis and teratogenicity of drugs

“…Позднее были опубликованы свидетельства возрастающего риска орофациальных расщелин и ВПС, в частности аномалий развития сердечной перегородки [78][79][80]. Ацетилсалициловая кислота (Аспирин) является единственным НПВП, который необратимо ингибирует ЦОГ путем ацетилирования, с чем, по-видимому, связана более высокая распространенность ВПР в исследова-ниях на животных [81]. В настоящее время связь между полиморфизмом материнских ферментов ЦОГ-1 и ЦОГ-2 и возросшей частотой врожденных аномалий остается неизученной.…”