Does Letrozole Increase the Risk of Foetal Harm?

Sarfaroj Khan 

Disclosures

January 12, 2021

Takeaway

  • This meta-analysis found no evidence of increased congenital foetal malformations or pregnancy loss with letrozole compared with clomiphene and other fertility agents or with natural conception in women undergoing fertility treatment.

Why this matters

  • Given the therapeutic benefits of letrozole and lack of evidence of foetal harm, findings do not support the concerns raised about the safety of letrozole as a fertility agent and provide crucial evidence to support clinical practice for its routine use.

Study design

  • 46 studies (18 randomised trials; 21 comparative cohorts; 7 non-comparative cohorts) met eligibility criteria after a search across MEDLINE, EMBASE and other databases.

  • Funding: None disclosed.

Key results

  • Overall, 2.15% (101/4697; 95% CI, 1.7-2.5%) of babies conceived on letrozole for fertility treatment had congenital malformations.

  • No significant increase in the risk of congenital malformations was observed with letrozole vs clomiphene in the randomised trials (14 studies; 867 babies; risk difference [RD], 0.01; 95% CI, 0.02-0.03), and a significant reduction was seen in the cohort studies (11 studies; 2453 babies; RD, −0.02; 95% CI, −0.04 to −0.01) (The GRADE quality of evidence was low).

  • No increased risk of pregnancy loss was observed with letrozole vs clomiphene in the randomised trials (14 studies; 1117 pregnancies; RD, −0.01; 95% CI, −0.06 to 0.04) and a significant reduction was seen in the cohort studies (6 studies; 404 pregnancies; RD, −0.09; 95% CI, −0.17 to −0.00; I2=68%) (The GRADE quality of evidence was moderate).

  • No significant increase in the risk of congenital malformations was observed with letrozole compared with gonadotrophins, natural conception or natural cycle-assisted reproductive technology.

Limitations

  • Heterogeneity among studies.

 

Pundir J, Achilli C, Bhide P, Sabatini L, Legro RS, Rombauts L, Teede H, Coomarasamy A, Zamora J, Thangaratinam S. Risk of foetal harm with letrozole use in fertility treatment: a systematic review and meta-analysis. Hum Reprod Update. 2020 Dec 29 [Epub ahead of print]. doi: 10.1093/humupd/dmaa055. PMID: 33374012 View abstract

This clinical summary originally appeared on Univadis, part of the Medscape Professional Network.

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