Effects of Antibiotics and Anti-Inflammatory Drugs on Enamel Development: A Systematic Review with Quantitative Synthesis

ABSTRACT: Objective: To investigate the effects of commonly prescribed antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs) during early life on enamel development through a systematic review with quantitative synthesis. Methods: PubMed, Web of Science, Embase, CINAHL, and Scopus were searched for English-language studies published between 1995 and 2024. In vitro and in vivo experimental studies evaluating antibiotics and/or NSAIDs during tooth development were included. Quantitative meta-analysis was restricted to in vivo animal studies reporting comparable outcomes for enamel thickness or mineral content, while in vitro studies contributed to qualitative mechanistic synthesis. Studies focusing solely on dentine, using questionnaires, lacking extractable data, or classified as grey literature or reviews were excluded. Results: Experimental exposure to antibiotics and NSAIDs was associated with alterations in ameloblast morphology and function, including changes in tight junction proteins, MMP-20, KLK4, COX-2, and Runx2 expression. Enamel matrix abnormalities such as vacuolar changes and cyst-like lesions were frequently reported. Quantitative synthesis indicated a moderate-to-large pooled effect estimate for reduced enamel thickness associated with amoxicillin exposure (Cohen’s d = 0.79, 95% CI: 0.40-1.36), with a trend toward larger effect sizes at higher experimental doses; these estimates were interpreted cautiously due to substantial heterogeneity. NSAIDs were primarily associated with qualitative disturbances in enamel mineralization. Pooled effect estimates for calcium (Cohen’s d = 0.52, 95% CI: −0.21 to 1.46) and phosphorus (Cohen’s d = 0.46, 95% CI: −0.31 to 1.75) were inconsistent and imprecise. Conclusions: Certain antibiotics and NSAIDs may disrupt ameloblast integrity and enamel biomineralization in experimental animal models. These findings are hypothesis-generating, and further well-designed human observational and mechanistic studies are required before clinical translation. Clinical Relevance: This systematic review synthesizes experimental evidence on the biological vulnerability of developing enamel to pharmacological exposure, highlighting potential mechanisms underlying enamel thinning and hypomineralization while underscoring the need for cautious interpretation when extrapolating animal data to human clinical contexts.PROSPERO Registration No.: CRD42025606606.