Efficacy of Monotherapy Letrozole Versus Methotrexate for the Management of Ectopic Pregnancy: A Systematic Review and Meta-Analysis of Comparative Studies.

Background

Ectopic pregnancy (EP) is a serious condition often treated with methotrexate. Letrozole, a safer aromatase inhibitor, may offer an effective alternative. This study presents a meta-analysis comparing the efficacy and safety of single-agent letrozole versus methotrexate for EP management.

Methods

A systematic review and meta-analysis were conducted following PRISMA guidelines. Six sources of information underwent screening until 12 June 2025. Risk of bias and evidence certainty of evidence were assessed. Primary outcome was treatment success rate. Results were presented as mean difference (MD) or risk ratio (RR) along with a 95% confidence interval (CI) using a random-effects model.

Results

Six studies (three randomized controlled trials and three nonrandomized prospective cohort studies) comprising seven arms and 260 patients (letrozole = 130, methotrexate = 130) were included. Almost all studies (n = 5) had overall moderate or high risk. Treatment success rates were comparable between groups (n = 7 arms; RR = 1.05; 95% CI: [0.94, 1.17]; p = 0.40). Letrozole was associated with significantly lower β-hCG levels on day 4 (n = 5 arms; MD = -95 mIU/mL; 95% CI: [-189.7, -0.91]; p = 0.048), day 7 (n = 5 arms; MD = -86.24 mIU/mL; 95% CI: [-143.1, -29.36]; p < 0.001), and day 14 (n = 3 arms; MD = -9.15 mIU/mL; 95% CI: [-17.24, -1.06]; p = 0.03); however, the differences were not clinically meaningful. Letrozole showed a better safety profile with higher platelet counts and lower liver enzymes. AMH levels were similar between groups. Most analyses were consistent, though secondary outcomes were less stable. Overall evidence certainty was rated 'very low' due to seriousness of risk of bias and imprecision.

Conclusions

While letrozole shows comparable efficacy to methotrexate and a potentially better safety profile in the management of EP, the certainty of evidence is 'very low' due to risk of bias and imprecision. Therefore, these findings should be interpreted with caution, and further high-quality studies are urgently needed to confirm the results.