Maternal and Early Developmental Effects of Perinatal Exposure to Therapeutically Relevant Doses of Common Nonsteroidal Anti-Inflammatory Drugs in Rats.

BACKGROUND

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used during pregnancy, yet information on their developmental safety during sensitive perinatal windows remains limited. This study evaluated the maternal and early developmental effects of paracetamol/acetaminophen, aspirin, and nimesulide administered at therapeutically relevant doses during late gestation and lactation.

METHODS

Pregnant Wistar rats were treated daily by oral gavage with paracetamol/acetaminophen (APAP; 126 mg/kg/day), aspirin (ASA; 5.6 mg/kg/day), or nimesulide (NIM; 11 mg/kg/day) from gestational day 15 to postnatal day 22. Maternal clinical parameters, body weight, food and water intake, organ weights, hematological and biochemical markers, and maternal behavior were evaluated. In F1 offspring, early developmental indicators, anogenital distance, sexual maturation endpoints, reproductive organ weights, and hematological parameters were assessed.

RESULTS

Exposure to the evaluated NSAIDs produced little evidence of overt maternal toxicity. Maternal body weight, food and water intake, gestational length, and most organ weights remained unchanged. Mild hematological and biochemical alterations were observed, particularly in NIM-treated dams. Maternal behavior was largely preserved, although APAP-treated dams showed reduced latency to initiate pup grooming. In offspring, anogenital distance and female reproductive maturation were unaffected. Male offspring exposed to APAP showed earlier testicular descent, whereas ASA exposure was associated with increased seminal vesicle weight. These findings were isolated and were not associated with a consistent pattern of reproductive alterations.

CONCLUSION

Perinatal exposure to therapeutically relevant doses of paracetamol/acetaminophen, aspirin, and nimesulide produced little evidence of overt maternal or developmental toxicity during the evaluated period. Although a limited number of drug-specific findings were identified, they were isolated and did not indicate a consistent pattern of reproductive toxicity. These results contribute to the preclinical safety assessment of NSAID exposure during pregnancy and lactation and support further studies to determine the functional relevance of these early observations.