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Macrolide antibiotic exposure in the first trimester of pregnancy and risk of congenital anomaly: A European case-control study
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  • Aminkeng Leke,
  • Helen Dolk,
  • Maria Loane,
  • Karen Casson,
  • Vera Nelen,
  • Ingeborg Barisic,
  • Ester Garne,
  • Anke Rissmann,
  • Mary O'Mahony,
  • Amanda Neville,
  • Anna Pierini,
  • Jorieke Bergman,
  • Kari Klungsoyr,
  • Anna Materna-Kiryluk,
  • Anna Bielenska,
  • Clara Cavero-Carbonell,
  • Marie-Claire Addor,
  • David Tucker
Aminkeng Leke
Ulster University - Jordanstown Campus

Corresponding Author:[email protected]

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Helen Dolk
University of Ulster School of Nursing
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Maria Loane
Ulster University
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Karen Casson
Ulster University - Jordanstown Campus
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Vera Nelen
Provinciaal Instituut voor Hygiene
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Ingeborg Barisic
Medical School University of Zagreb
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Ester Garne
Paediatric Department Hospital
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Anke Rissmann
Otto von Guericke University Medical Faculty
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Mary O'Mahony
St Finbarr’s Hospital
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Amanda Neville
University of Ferrara Faculty of Medicine and Surgery
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Anna Pierini
National Research Council / Fondazione Toscana Gabriele Monasterio
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Jorieke Bergman
University of Groningen, University Medical Center Groningen
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Kari Klungsoyr
University of Bergen
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Anna Materna-Kiryluk
Poznan University of Medical Sciences
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Anna Bielenska
Poznan University of Medical Sciences
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Clara Cavero-Carbonell
Foundation for the Promotion of Health and Biomedical Research in the Valencian Region
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Marie-Claire Addor
University Hospital of Lausanne
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David Tucker
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Objective To investigate the risk of congenital heart defects (CHD) and other congenital anomalies (CA) associated with first trimester use of macrolides. Design Population-based case-malformed control study. Setting Thirteen European countries. Population Data on 145,936 livebirths, stillbirths and terminations of pregnancy for CA from 15 EUROCAT registries, covering 9 million births 1995–2012. Methods 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. A meta-analysis of the literature, including this study, was conducted for CHD. Main outcome Odds ratios adjusted (AOR) for maternal age and registry, with 95% Confidence Intervals (95%CI). Results Macrolide exposure was recorded for 307 cases, 72 non-genetic controls, 57 genetic controls. 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 also associated with an increased risk of at least one other CA. Meta-analysis gave an overall CHD OR 1.14, 95%CI 0.90 –1.49 for macrolides. Conclusions Guidelines for macrolide use in pregnancy should consider the increased risk of specific CA. This is relevant for the potential use of azithromycin in the treatment of COVID-19.