ObjectiveThe growth potential of children with short stature in middle and late adolescence may be limited by the effect of estrogen on epiphyseal closure. In recent years, the third generation of non-steroidal aromatase inhibitors (AIs) have been used in the treatment of short stature but with off-label. This study aimed to systematically review the efficacy and safety of the third-generation non-steroidal AIs in the treatment of children with short stature, and to provide evidences for rational drug use in clinical practice. MethodsWe searched PubMed, Embase, Cochrane Library, CNKI, WanFang Data, VIP and CBM from inception to December 28, 2022. Relevant studies on the treatment for children with short stature using the recombinant human growth hormone (rhGH) combined with or without the third-generation non-steroidal AIs were collected. Two reviewers independently screened the literature, extracted data, and evaluated the risk of bias of the included studies. Meta-analysis was performed using RevMan 5.3 software. ResultsA total of 18 articles were finally included, involving 9 randomized controlled trials and 9 cohort studies, with a total of 1 053 patients. The Meta-analysis showed that: (1) in terms of efficacy, the final adult height (MD=2.48, 95%CI 2.02 to 2.94, P<0.01), predicted adult height (MD=4.27, 95%CI 2.71 to 5.83, P<0.01), predicted adult height difference (MD=4.26, 95%CI 3.23 to 5.28, P<0.01), bone age (MD=−0.62, 95%CI −0.89 to −0.36, P<0.01), bone age difference/actual age difference (MD=−0.47, 95%CI −0.56 to −0.37, P<0.01), and growth velocity (MD=1.34, 95%CI 0.89 to 1.78, P<0.01) at the end of treatment in the experimental group were better than those in the control group, but there was no statistical difference in the height at the end of treatment between the two groups (MD=4.03, 95%CI −0.01 to 8.06, P=0.05). (2) in terms of safety, the total incidence of adverse events in the experimental group (RR=2.10, 95%CI 1.48 to 2.99, P<0.01) was higher than that in the control group, among which the incidence of adverse events in the endocrine system and skin and subcutaneous tissue system was statistically different between the two groups (P<0.05), and the incidence of adverse events in the hepatobiliary system, kidney and urinary system, metabolism and nutrition, gastrointestinal system, musculoskeletal system, blood and lymph system, vascular and lymphatic system, and neuropsychiatric system was not statistically different between the two groups (P>0.05). ConclusionCurrent evidence shows that the third-generation non-steroidal AIs combined with rhGH can effectively improve the final height of children with short stature, but it may increase the incidence of adverse drug events. Limited by the quality and the follow-up period of the included studies, high-quality studies are still needed to demonstrate the above conclusions and further evaluate the long-term safety of AIs in children with short stature.