First Trimester Use of Macrolide Antibiotics and Risk of Congenital Anomaly

Sarfaroj Khan 


February 02, 2021


  • First trimester use of macrolide antibiotics (mainly erythromycin, spiramycin, clarithromycin and azithromycin) was not associated with an increased risk of congenital heart defects (CHDs) as a whole.

  • Erythromycin, clarithromycin and azithromycin were associated with a higher risk of atrioventricular septal defect (AVSD).

  • Erythromycin, clarithromycin, azithromycin and clindamycin were linked to other non-heart defects.

Why this matters

  • Further research is required on the risk of specific congenital anomaly (CA) associated with the use of macrolides and lincosamides (clindamycin) during the first trimester, particularly relevant for the potential use of azithromycin in the treatment of COVID-19.

Study design

  • A case-control study of 143,229 babies with CA diagnosis (livebirths, stillbirths and terminations of pregnancy for CA) from 15 EUROCAT registries in 13 European countries covering an 18-year period (1995-2012).

  • 100,702 cases were babies with CHD, anencephaly, orofacial clefts and genital and limb reduction anomalies associated with antibiotic exposure.

  • Controls were babies with other CA or genetic conditions (23,467 non-genetic controls and 19,060 genetic controls).

  • Funding: None.

Key results

  • Macrolide and lincosamide exposure was recorded for 304 and 28 cases, 72 and 4 non-genetic controls and 57 and 7 genetic controls, respectively.

  • No increased risk of CHD was seen with first trimester macrolides use (adjusted OR [aOR], 0.94; 95% CI, 0.70-1.26 vs non-genetic controls; aOR, 1.01; 95% CI, 0.73-1.41 vs genetic controls).

  • No increased risk of CHD was observed with any specific macrolide.

  • The risk of AVSD was significantly increased with exposure to:

    • any macrolides (aOR, 2.98; 95% CI, 1.48-6.01);

    • erythromycin (aOR, 3.68; 95% CI, 1.28-10.61);

    • clarithromycin (aOR, 6.85; 95% CI, 1.41-33.32); and

    • azithromycin (aOR, 4.50; 95% CI, 1.30-15.58).

  • Exposure to erythromycin, clarithromycin, azithromycin and clindamycin was associated with an increased risk of:

    • diaphragmatic hernia (aOR, 3.19; 95% CI, 1.22-8.32);

    • orofacial clefts (aOR, 2.94; 95% CI, 1.04-8.30);

    • syndactyly (aOR, 3.80; 95% CI, 1.62-8.94); and

    • hydrocephalus (aOR, 6.63; 95% CI, 1.46-30.18), respectively.


  • Antibiotic exposures were under-ascertained.

  • Risk of bias.


Leke AZ, Dolk H, Loane M, Casson K, Nelen V, Barišić I, Garne E, Rissman A, O'Mahony M, Neville AJ, Pierini A, Bergman JEH, Klungsøyr K, Materna-Kiryluk A, Bielenska AL, Carbonell CC, Addor MC, Tucker D. Macrolide and lincosamide antibiotic exposure in the first trimester of pregnancy and risk of congenital anomaly: A European case-control study. Reprod Toxicol. 2021 Jan 14 [Epub ahead of print]. doi: 10.1016/j.reprotox.2021.01.006. PMID: 33454317 View abstract

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


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