Drug Safety

, Volume 35, Issue 7, pp 589–598 | Cite as

The Outcomes of Pregnancy in Women Exposed to the New Macrolides in the First Trimester

A Prospective, Multicentre, Observational Study
  • Benjamin Bar-Oz
  • Corinna Weber-Schoendorfer
  • Maya Berlin
  • Maurizio Clementi
  • Elena Di Gianantonio
  • Loes de Vries
  • Marco De Santis
  • Paul Merlob
  • Bracha Stahl
  • Giorgio Eleftheriou
  • Eva Maňáková
  • Lucie Hubičková-Heringová
  • Ilan YoungsterEmail author
  • Matitiahu Berkovitch
Original Research Article


Background: Macrolides are a group of commonly prescribed antibiotics. There is some doubt surrounding the use of the newer macrolides in pregnancy.

Objective: The present study aimed to compare outcomes of pregnancies exposed to the new macrolides clarithromycin, azithromycin and roxithromycin with non-teratogenic preparations.

Methods; In this prospective, multinational, multicentre, controlled, observational study, information was obtained either from pregnant women or their healthcare professionals who contacted their local teratogen information services in Italy, Israel, the Czech Republic, the Netherlands and Germany seeking information after exposure to macrolides. The comparison group included women or their healthcare professional who contacted these centreswithquestionsregardingknownnon-teratogenicpreparations. Information on obstetric and other background parameters was collected at enrollment; after delivery, subjects or their healthcare professionals were contacted to ascertain pregnancy outcome parameters and other exposures through the remainder of the pregnancy.

Results: A total of 608 women exposed to macrolides during pregnancy were enrolled; 511 of the exposures occurred during the first trimester. The comparison group comprised 773 women exposed to non-teratogenic preparations during the first trimester of pregnancy. No significant difference in the rate of major congenital malformations was found between the study group and the comparison group (3.4% vs 2.4%; p = 0.36; odds ratio (OR) 1.42; 95% CI 0.70, 2.88) or in the rate of cardiovascular malformations (1.6% vs 0.9%; p = 0.265; OR 1.91; 95% CI 0.63, 5.62).

No significant differences were found between subgroups of macrolides in the rates of major congenital malformations or cardiac malformations, although for azithromycin this was of borderline significance.

Conclusions: This study, in agreement with earlier smaller studies, suggests that the new macrolides do not pose a significantly increased risk of major congenital malformations or cardiac malformations.


Live Birth Clarithromycin Azithromycin Macrolides Ventricular Septal Defect 
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The first two authors have equally contributed to the manuscript. The authors state that no financial support or author involvement with organizations with financial interest in the subject matter exists, and that no actual or potential conflict of interest exists.


  1. 1.
    Czeizel AE, Rockenbauer M, Sorensen HT, et al. Population-based case-control teratologic study of oral erythromycin treatment during pregnancy. Reprod Toxicol 1999; 13: 531–6PubMedCrossRefGoogle Scholar
  2. 2.
    Källén BA, Otterblad Olausson P. Maternal drug use in early pregnancy and infant cardiovascular defect. Reprod Toxicol 2003; 17: 255–61PubMedCrossRefGoogle Scholar
  3. 3.
    Källén BA, Otterblad Olausson P, et al. Is erythromycin therapy teratogenic in humans? Reprod Toxicol 2005; 20: 209–14PubMedCrossRefGoogle Scholar
  4. 4.
    Erythromycin. In: Briggs GG, Freeman RK, Yaffe SJ, editors. Drugs in pregnancy and lactation. 8th ed. Philadelphia (PA): Lippincott Williams and Wilkins, 2008: 657-9Google Scholar
  5. 5.
    Heikkinen T, Laine K, Neuvonen PJ, et al. The transplacental transfer of the macrolide antibiotics erythromycin, roxithromycin and azithromycin. Br J Obstet Gynaecol 2000; 107: 770–5CrossRefGoogle Scholar
  6. 6.
    Wilton LV, Pearce GL, Martin RM, et al. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 1998; 105: 882–9PubMedCrossRefGoogle Scholar
  7. 7.
    Azithromycin. In: Briggs GG, Freeman RK, Yaffe SJ, editors. Drugs in pregnancy and lactation. 8th ed. Philadelphia (PA): Lippincott Williams and Wilkins, 2008: 158-60Google Scholar
  8. 8.
    Clarithromycin. In: Briggs GG, Freeman RK, Yaffe SJ, editors. Drugs in pregnancy and lactation. 8th ed. Philadelphia (PA): Lippincott Williams and Wilkins, 2008: 379-80Google Scholar
  9. 9.
    Sarkar M, Woodland C, Koren G, et al. Pregnancy outcome following gestational exposure to azithromycin. BMC Pregnancy Childbirth 2006; 6: 18PubMedCrossRefGoogle Scholar
  10. 10.
    Drinkard CR, Shatin D, Clouse J. Postmarketing surveillance of medications and pregnancy outcomes: clarithromycin and birth malformations. Pharmacoepidemiol Drug Saf 2000; 9: 549–56PubMedCrossRefGoogle Scholar
  11. 11.
    Einarson A, Phillips E, Mawji F, et al. A prospective controlled multicentre study of clarithromycin in pregnancy. Am JPerinatol 1998; 15: 523–5CrossRefGoogle Scholar
  12. 12.
    Bar-Oz B, Diav-Citrin O, Shechtman S, et al. Pregnancy outcome after gestational exposure to the new macrolides: a prospective multi-center observational study. Eur J Obstet Gynecol Reprod Biol 2008; 141: 31–4PubMedCrossRefGoogle Scholar
  13. 13.
    Chun JY, Han JY, Ahn HK, et al. Fetal outcome following roxithromycin exposure in early pregnancy. J Matern Fetal Neonatal Med 2006; 19: 189–92PubMedCrossRefGoogle Scholar
  14. 14.
    Czeizel AE, Rockenbauer M, Olsen J, et al. A case-control teratological study of spiramycin, roxithromycin, oleandomycin and josamycin. Acta Obstet Gynecol Scand 2000; 79: 234–7PubMedCrossRefGoogle Scholar
  15. 15.
    Paulus W, Karl S, Frank S. Does roxithromycin affect embryo development?. Reprod Toxicol 2005; 20: 477Google Scholar
  16. 16.
    Finer LB, Henshaw SK. Disparities in rates of unintended pregnancy in the United States, 1994 and 2001. Perspect Sex Reprod Health 2006; 38: 90–6PubMedCrossRefGoogle Scholar
  17. 17.
    Martin JA, Hamilton BE, Sutton PD, et al. Births: final data for 2004. Natl Vital Stat Rep 2006; 55: 1–101Google Scholar
  18. 18.
    Centers for Disease Control and Prevention. Metropolitan Atlanta Congenital Defects Program coding manual [online]. Available from URL: [Accessed 2012 May 10]
  19. 19.
    Crider KS, Cleves MA, Reefhuis J, et al. Antibacterial medication use during pregnancy and risk of birth defects: National Birth Defects Prevention Study. Arch Pediatr Adolesc Med 2009; 163: 978–85PubMedCrossRefGoogle Scholar
  20. 20.
    Koren G, Bologa M, Long D, et al. Perception of teratogenic risk by pregnant women exposed to drugs and chemicals during the first trimester. Am J Obstet Gynecol 1989; 160: 1190–4PubMedGoogle Scholar
  21. 21.
    Schaefer C, Ornoy A, Clementi M, et al. Using observational cohort data for studying drug effects on pregnancy outcome: methodological considerations. Reprod Toxicol 2008; 26: 36–41PubMedCrossRefGoogle Scholar
  22. 22.
    Rasmussen SA, Mulinare J, Khoury MJ, et al. Evaluation of birth defect histories obtained through maternal interviews. Am J Hum Genet 1990 Mar; 46(3): 478–85PubMedGoogle Scholar

Copyright information

© Adis Springer International Publishing AG 2012

Authors and Affiliations

  • Benjamin Bar-Oz
    • 1
  • Corinna Weber-Schoendorfer
    • 2
  • Maya Berlin
    • 3
  • Maurizio Clementi
    • 4
  • Elena Di Gianantonio
    • 4
  • Loes de Vries
    • 5
  • Marco De Santis
    • 6
  • Paul Merlob
    • 7
  • Bracha Stahl
    • 7
  • Giorgio Eleftheriou
    • 8
  • Eva Maňáková
    • 9
  • Lucie Hubičková-Heringová
    • 9
  • Ilan Youngster
    • 3
    Email author
  • Matitiahu Berkovitch
    • 3
  1. 1.Department of NeonatologyHadassah and Hebrew University Medical CenterJerusalemIsrael
  2. 2.Pharmakovigilanzzentrum EmbryonaltoxikologieBBGes/Charité Universitätsmedizin BerlinBerlinGermany
  3. 3.Clinical Pharmacology and Toxicology Unit, Teratogen Information Service, Assaf Harofeh Medical Center, Sackler School of MedicineTel Aviv UniversityTel AvivIsrael
  4. 4.Servizio Informazione Teratologica, Genetica, Clinica et EpidemiologicaUniversity of PadovaPadovaItaly
  5. 5.Teratology Information ServiceNational Institute of Public Health and EnvironmentBilthoventhe Netherlands
  6. 6.Department of Obstetrics & GynecologyCatholic University of Sacred HeartRomeItaly
  7. 7.Beilinson Teratology Information Service, Rabin Medical Center, Sackler School of MedicineTel Aviv University, Beilinson CampusTel AvivIsrael
  8. 8.Department of Clinical PharmacologyCentro antiveleni-Tossicologia clinicaBergamoItaly
  9. 9.Division of Histology and EmbryologyCenter of Biomedical Sciences, Faculty of Medicine, Charles UniversityPragueCzech Republic

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