Macrolide and lincosamide antibiotic exposure in the first trimester of pregnancy and risk of congenital anomaly: A European case-control study

Aminkeng Leke, Helen Dolk, Maria Loane, K. Casson, Vera Nelen, Ingeborg Barisic, Garne Ester, Anke Rissmann, Mary O'Mahony, Amanda Neville, Anna Pierini, Jorieke E.H Bergman, Kari Klungsoyr, Anna Materna-Kiryluk, Anna Latos-Bielenska , Clara Cavero-Carbonell, Marie-Claude Addor, David Tucker

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This study investigated the risk of congenital heart defects (CHD) and other congenital anomalies (CA) associated with first trimester use of macrolide antibiotics (mainly erythromycin, spiramycin, clarithromycin and azithromycin) and lincosamides (clindamycin) using a case-malformed control design.

Data included 145,936 babies with a CA diagnosis (livebirths, stillbirths and terminations of pregnancy for CA) from 15 population-based EUROCAT registries in 13 European countries, covering 9 million births 1995–2012. Cases were babies with CHD, anencephaly, orofacial clefts, genital and limb reduction anomalies associated with antibiotic exposure in the literature. Controls were babies with other CA or genetic conditions. Main outcomes were odds ratios adjusted (AOR) for maternal age and registry, with 95% Confidence Intervals (95%CI).

Macrolide and lincosamide exposure was recorded for 307 and 28 cases, 72 and 4 non-genetic controls, 57 and 7 genetic controls, respectively. AOR for CHD was not significantly raised (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), nor significantly raised for any specific macrolide. The risk of atrioventricular septal defect was significantly raised with exposure to any macrolide (AOR 2.98; 95%CI: 1.48 – 6.01), erythromycin (AOR 3.68, 95%CI: 1.28 – 10.61), and azithromycin (AOR 4.50, 95%CI: 1.30 – 15.58). Erythromycin, clarithromycin, azithromycin, and clindamycin were associated with an increased risk of at least one other CA.

Further research is needed on the risk of specific CA associated with macrolide and lincosamide use in the first trimester, particularly relevant for the potential use of azithromycin in the treatment of COVID-19.
Original languageEnglish
Pages (from-to)101-108
Number of pages8
JournalReproductive Toxicology
Early online date14 Jan 2021
Publication statusPublished (in print/issue) - 1 Mar 2021

Bibliographical note

Funding Information:
AZL received the Ulster University Vice Chancellor PhD Research Scholarship (2013-2017).

Publisher Copyright:
© 2021 Elsevier Inc.


  • Azithromycin
  • Clarithromycin
  • Clindamycin
  • Congenital anomaly
  • Erythromycin
  • First trimester
  • Macrolides
  • Pregnancy
  • Spiramycin


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