Risk of Fetal Harm with Letrozole Use in Fertility Treatment: A Systematic Review and Meta-Analysis

Background: The aromatase inhibitor letrozole is increasingly recommended for ovulation induction, as it is more effective with fewer side-effects than other agents. But many clinicians are reluctant to use the drug for fertility treatment due to a strong-label warning against its use, which warns about congenital malformation risk to the fetus in women seeking pregnancy. Objective: To determine the risks of congenital malformations and pregnancy loss with letrozole compared with clomiphene primarily, and against other fertility drugs and natural conception. Methods: A systematic review and meta-analysis. Findings: We included 45 studies (18 randomised trials; 20 comparative cohorts; 7 non-comparative cohorts). We did not observe a significant increase in congenital malformations with letrozole vs clomiphene in the randomised trials (Risk Difference RD 0.01, 95% CI -0.02, 0.03; I2 = 0%; 14 studies), and found a significant reduction in the cohort studies (RD -0.02, 95% CI -0.03, -0.004; I2 = 0%, 10 studies). The risks of pregnancy loss were not increased with letrozole vs clomiphene in the 14 randomised trials (RD -0.01, 95% CI -0.06, 0.04; I2 = 0%), and the risks were reduced in the six cohort studies (RD -0.09, 95% CI -0.17, -0.00; I2 = 68%). The GRADE quality of evidence was low to moderate for congenital malformations and pregnancy loss. We did not find any increased congenital malformation risk with letrozole vs gonadotrophins, natural conception or natural cycle assisted reproductive technology, but the number of studies was small. Interpretation: There is no evidence that letrozole increases the risk of congenital fetal malformation or pregnancy loss than clomiphene, natural conception or other fertility agents to warrant warning against its use. Given its therapeutic benefits and lack of evidence of harm to the fetus, clinicians should consider letrozole as first-line agent for ovulation induction. Funding Statement: None. Declaration of Interests: None.