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Drug Safety

pp 1–11 | Cite as

Prenatal Exposure to Macrolides and Risk of Congenital Malformations: A Meta-Analysis

  • Narmeen Mallah
  • Hamid Reza Tohidinik
  • Mahyar Etminan
  • Adolfo Figueiras
  • Bahi TakkoucheEmail author
Systematic Review

Abstract

Introduction

Macrolides are widely used during pregnancy; however, their fetal safety remains uncertain. We performed a meta-analysis to assess the relation between prenatal exposure to macrolides and occurrence of congenital malformations.

Methods

We searched MEDLINE, EMBASE, and other databases until June 12, 2019. We assessed the quality of the studies and checked for heterogeneity and publication bias. We performed three different analyses and compared the effect of macrolides with each of the following unexposed populations: Group 1: babies unexposed to any medicine before birth, Group 2: babies exposed to non-macrolide antibiotics/non-teratogens, and Group 3: mixed population of the first and second comparators.

Results

A weak association between macrolides and congenital malformation of any type was observed when macrolides were compared with the mixed population (ORgroup 3 1.06 [95% CI 1.01–1.10]). Subgroup analysis showed that this weak association is restricted to fetus exposure in the first trimester of pregnancy (OR 1.06 [95% CI 1.01–1.11]) and to cohort studies (OR 1.07 [95% CI 1.02–1.13]). Digestive system malformations were found to be slightly associated with prenatal exposure to macrolides (ORgroup 3 1.14 [95% CI 1.02–1.26]). The musculoskeletal system was also found to be potentially affected (ORgroup 2 1.21 [95% CI 1.08–1.35] and ORgroup 3 1.15 [95% CI 1.05–1.26]). European studies showed a slightly stronger association than American studies in these two comparisons.

Conclusions

Our study suggests a weak association between prenatal use of macrolides and congenital malformations, limited to exposure in early pregnancy, and musculoskeletal and digestive systems. In addition to studies with a larger control of confounding, risk–benefit research is needed to determine the usefulness of macrolides during pregnancy.

Notes

Author Contributions

Conception and design of the study: BT and ME; Conceptualization of the manuscript and review and synthesis of the literature: NM; Data extraction: NM and HT; Coordination and supervision of data extraction and analysis: BT and AF; All authors made substantial contribution to the interpretation of data, critically reviewed the manuscript, and approved its submission for publication.

Compliance with Ethical Standards

Funding Source

No specific funding for this work. Dr. Takkouche’s and Dr. Figueiras’ work is funded by a Grant from the Regional Ministry of Education, Universities and Vocational Training, Santiago de Compostela, Spain, ED431C 2018/20.

Conflict of interest

Narmeen Mallah, Hamid Reza Tohidinik, Mahyar Etminan, Adolfo Figueiras, and Bahi Takkouche declare that they have no conflict of interest.

Data Sharing

All data generated or analyzed during this study are included in this published article and its Supplementary Information File (Online Resource 1, see ESM).

Supplementary material

40264_2019_884_MOESM1_ESM.xlsx (29 kb)
Supplementary material 1 (XLSX 29 kb)
40264_2019_884_MOESM2_ESM.docx (29 kb)
Supplementary material 2 (DOCX 29 kb)
40264_2019_884_MOESM3_ESM.docx (19 kb)
Supplementary material 3 (DOCX 18 kb)

References

  1. 1.
    World Health Organization. Congenital anomalies. World Health Organization. 2016. http://www.who.int/mediacentre/factsheets/fs370/en/. Accessed 19 Feb 2019.
  2. 2.
    Centers for Disease Control and Prevention. Birth Defects 2018. https://www.cdc.gov/ncbddd/birthdefects/facts.html. Accessed 19 Feb 2019.
  3. 3.
    Petrini J, Damus K, Russell R, Poschman K, Davidoff MJ, Mattison D. Contribution of birth defects to infant mortality in the United States. Teratology. 2002;66(Suppl 1):S3–6.  https://doi.org/10.1002/tera.90002.CrossRefPubMedGoogle Scholar
  4. 4.
    Kochanek KD, Murphy SL, Xu JQ, Arias E. Mortality in the United States, 2016. NCHS Data Brief. 2017. Report No.: 293.Google Scholar
  5. 5.
    Janz T, Navaneelan T, Pearson C. Deaths from congenital anomalies in Canada, 1974 to 2012. Health at a Glance. Statistics Canada. 2016. Catalogue No.: 82-624-X.Google Scholar
  6. 6.
    Christianson A, Howson CP, Modell B. Global report on birth defects. The hidden toll of dying and disabled children. White Plains (NY): March of Dimes Birth Defects Foundation. 2006. https://www.marchofdimes.org/global-report-on-birth-defects-the-hidden-toll-of-dying-and-disabled-children-full-report.pdf. Accessed 02 Apr 2019.
  7. 7.
    Adam MP, Polifka JE, Friedman JM. Evolving knowledge of the teratogenicity of medications in human pregnancy. Am J Med Genet C Semin Med Genet. 2011;157C(3):175–82.  https://doi.org/10.1002/ajmg.c.30313.CrossRefPubMedGoogle Scholar
  8. 8.
    Bookstaver PB, Bland CM, Griffin B, Stover KR, Eiland LS, McLaughlin M. A review of antibiotic use in pregnancy. Pharmacotherapy. 2015;35(11):1052–62.  https://doi.org/10.1002/phar.1649.CrossRefPubMedGoogle Scholar
  9. 9.
    Crider KS, Cleves MA, Reefhuis J, Berry RJ, Hobbs CA, Hu DJ. Antibacterial medication use during pregnancy and risk of birth defects: national birth defects prevention study. Arch Pediatr Adolesc Med. 2009;163(11):978–85.  https://doi.org/10.1001/archpediatrics.2009.188.CrossRefPubMedGoogle Scholar
  10. 10.
    Brauer R, Ruigómez A, Downey G, Bate A, Rodriguez LAG, Huerta C, et al. Prevalence of antibiotic use: a comparison across various European health care data sources. Pharmacoepidemiol Drug Saf. 2016;25(sup 1):11–20.  https://doi.org/10.1002/pds.3831.CrossRefPubMedGoogle Scholar
  11. 11.
    Lin KJ, Mitchell AA, Yau WP, Louik C, Hernandez-Diaz S. Safety of macrolides during pregnancy. Am J Obstet Gynecol. 2013;208(3):221.  https://doi.org/10.1016/j.ajog.2012.12.023.CrossRefPubMedGoogle Scholar
  12. 12.
    Santos F, Sheehy O, Perreault S, Ferreira E, Berard A. Trends in anti-infective drugs use in pregnancy. J Popul Ther Clin Pharmacol. 2012;19(3):e460–5.PubMedGoogle Scholar
  13. 13.
    Kallen BA, Otterblad Olausson P, Danielsson BR. Is erythromycin therapy teratogenic in humans? Reprod Toxicol. 2005;20(2):209–14.  https://doi.org/10.1016/j.reprotox.2005.01.010.CrossRefPubMedGoogle Scholar
  14. 14.
    Lund M, Pasternak B, Davidsen RB, Feenstra B, Krogh C, Diaz LJ, et al. Use of macrolides in mother and child and risk of infantile hypertrophic pyloric stenosis: nationwide cohort study. BMJ. 2014;348:g1908.  https://doi.org/10.1136/bmj.g1908.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Dinur AB, Koren G, Matok I, Wiznitzer A, Uziel E, Gorodischer R, et al. Fetal safety of macrolides. Antimicrob Agents Chemother. 2013;57(7):3307–11.  https://doi.org/10.1128/AAC.01691-12.CrossRefGoogle Scholar
  16. 16.
    Andersen JT, Petersen M, Jimenez-Solem E, Broedbaek K, Andersen NL, Torp-Pedersen C, et al. Clarithromycin in early pregnancy and the risk of miscarriage and malformation: a register based nationwide cohort study. PLoS One. 2013;8(1):e53327.  https://doi.org/10.1371/journal.pone.0053327.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Fan H, Li L, Wijlaars L, Gilbert RE. Associations between use of macrolide antibiotics during pregnancy and adverse child outcomes: a systematic review and meta-analysis. PLoS One. 2019;14(2):e0212212.  https://doi.org/10.1371/journal.pone.0212212.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Prospero International Prospective Register of Systematic Reviews. 2017. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=55131.
  19. 19.
    Wells GA, Shea B, O’Connell D, et al. The Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 19 Feb 2019.
  20. 20.
    Rothman KJ, Greenland S, Lash TL. Measure of effect and measures of association. Modern epidemiology. 3rd ed. Philadelphia: Lippincott, Williams and Wilkins; 2008. p. 61.Google Scholar
  21. 21.
    Takkouche B, Cadarso-Suárez C, Spiegelman D. Evaluation of old and new tests of heterogeneity in epidemiologic meta-analysis. Am J Epidemiol. 1999;150(2):206–15.CrossRefGoogle Scholar
  22. 22.
    Kallen B, Danielsson BR. Fetal safety of erythromycin. An update of Swedish data. Eur J Clin Pharmacol. 2014;70(3):355–60.  https://doi.org/10.1007/s00228-013-1624-3.CrossRefPubMedGoogle Scholar
  23. 23.
    Mahon BE, Rosenman MB, Kleiman MB. Maternal and infant use of erythromycin and other macrolide antibiotics as risk factors for infantile hypertrophic pyloric stenosis. J Pediatr. 2001;139(3):380–4.  https://doi.org/10.1067/mpd.2001.117577.CrossRefPubMedGoogle Scholar
  24. 24.
    Wolfgang P, Schloemp S, Sterzik K, Stoz F, editors. Does roxithromycin affect embryo development? 33rd Annual Conference of the European Teratology Society; 3–7 Sep, 2005; Haarlem, The Netherlands: Reproductive Toxicology.Google Scholar
  25. 25.
    Lê Nguyên T, Araujo M, Hurault-Delarue C, Lacroix I, Damase-Michel C, Sommet A. Teratogenic risk of macrolides during the first trimester of pregnancy: a study with two complementary approaches within the EFEMERIS database. Clin Ther. 2017;39(8):e11–2.CrossRefGoogle Scholar
  26. 26.
    Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34.CrossRefGoogle Scholar
  27. 27.
    Costa-Bouzas J, Takkouche B, Cadarso-Suárez C, Spiegelman D. HEpiMA: software for the identification of heterogeneity in meta-analysis. Comput Methods Programs Biomed. 2001;64:101–7.CrossRefGoogle Scholar
  28. 28.
    Bar-Oz B, Weber-Schoendorfer C, Berlin M, Clementi M, Di Gianantonio E, de Vries L, et al. The outcomes of pregnancy in women exposed to the new macrolides in the first trimester: a prospective, multicentre, observational study. Drug Saf. 2012;35(7):589–98.  https://doi.org/10.2165/11630920-000000000-00000.CrossRefPubMedGoogle Scholar
  29. 29.
    Romoren M, Lindbaek M, Nordeng H. Pregnancy outcome after gestational exposure to erythromycin—a population-based register study from Norway. Br J Clin Pharmacol. 2012;74(6):1053–62.  https://doi.org/10.1111/j.1365-2125.2012.04286.x.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer SM, Gideon PS, et al. Antibiotics potentially used in response to bioterrorism and the risk of major congenital malformations. Paediatr Perinat Epidemiol. 2009;23(1):18–28.  https://doi.org/10.1111/j.1365-3016.2008.00978.x.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Bar-Oz B, Diav-Citrin O, Shechtman S, Tellem R, Arnon J, Francetic I, 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(1):31–4.  https://doi.org/10.1016/j.ejogrb.2008.07.008.CrossRefPubMedGoogle Scholar
  32. 32.
    Chun JY, Han JY, Ahn HK, Choi JS, Koong MK, Nava-Ocampo AA, et al. Fetal outcome following roxithromycin exposure in early pregnancy. J Matern Fetal Neonatal Med. 2006;19(3):189–92.  https://doi.org/10.1080/14767050500439657.CrossRefPubMedGoogle Scholar
  33. 33.
    Sarkar M, Woodland C, Koren G, Einarson AR. Pregnancy outcome following gestational exposure to azithromycin. BMC Pregnancy Childbirth. 2006;6:18.  https://doi.org/10.1186/1471-2393-6-18.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Einarson A, Phillips E, Mawji F, D’Alimonte D, Schick B, Addis A, et al. A prospective controlled multicentre study of clarithromycin in pregnancy. Am J Perinatol. 1998;15(9):523–5.  https://doi.org/10.1055/s-2007-994053.CrossRefPubMedGoogle Scholar
  35. 35.
    Cooper WO, Griffin MR, Arbogast P, Hickson GB, Gautam S, Ray WA. Very early exposure to erythromycin and infantile hypertrophic pyloric stenosis. Arch Pediatr Adolesc Med. 2002;156(7):647–50.  https://doi.org/10.1001/archpedi.156.7.647.CrossRefPubMedGoogle Scholar
  36. 36.
    Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol. 1998;105(8):882–9.CrossRefGoogle Scholar
  37. 37.
    Muanda FT, Sheehy O, Berard A. Use of antibiotics during pregnancy and the risk of major congenital malformations: a population based cohort study. Br J Clin Pharmacol. 2017;83(11):2557–71.  https://doi.org/10.1111/bcp.13364.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Czeizel AE, Rockenbauer M, Olsen J, Sorensen HT. A case–control teratological study of spiramycin, roxithromycin, oleandomycin and josamycin. Acta Obstet Gynecol Scand. 2000;79(3):234–7.CrossRefGoogle Scholar
  39. 39.
    Louik C, Werler MM, Mitchell AA. Erythromycin use during pregnancy in relation to pyloric stenosis. Am J Obstet Gynecol. 2002;186(2):288–90.  https://doi.org/10.1067/mob.2002.119718.CrossRefPubMedGoogle Scholar
  40. 40.
    Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. A population-based case–control teratologic study of oral erythromycin treatment during pregnancy. Reprod Toxicol. 1999;13(6):531–6.  https://doi.org/10.1016/s0890-6238(99)00046-5.CrossRefPubMedGoogle Scholar
  41. 41.
    Bulska M, Szcześniak P, Pięta-Dolińska A, Oszukowski P, Orszulak-Michalak D. The placental transfer of erythromycin in human pregnancies with group B streptococcal infection. Ginekol Pol. 2015;86(1):33–9.CrossRefGoogle Scholar
  42. 42.
    Danielsson BR, Skold AC, Azarbayjani F. Class III antiarrhythmics and phenytoin: teratogenicity due to embryonic cardiac dysrhythmia and reoxygenation damage. Curr Pharm Des. 2001;7(9):787–802.CrossRefGoogle Scholar
  43. 43.
    Gorelik E, Masarwa R, Perlman A, Rotshild V, Muszkat M, Matok I. Systematic review, meta-analysis, and network meta-analysis of the cardiovascular safety of macrolides. Antimicrob Agents Chemother. 2018;62(6):89.  https://doi.org/10.1128/AAC.00438-18.CrossRefGoogle Scholar
  44. 44.
    Canfield MA, Mai CT, Wang Y, O’Halloran A, Marengo LK, Olney RS, et al. The association between race/ethnicity and major birth defects in the United States, 1999–2007. Am J Public Health. 2014;104(9):e14–23.  https://doi.org/10.2105/AJPH.2014.302098.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Goossens H. Antibiotic consumption and link to resistance. Clin Microbiol Infect. 2009;15:12–5.  https://doi.org/10.1111/j.1469-0691.2009.02725.x.CrossRefPubMedGoogle Scholar
  46. 46.
    Hollier LM, Leveno KJ, Kelly MA, MCIntire DD, Cunningham FG. Maternal age and malformations in singleton births. Obstet Gynecol. 2000;96(5 Pt 1):701–6.  https://doi.org/10.1016/s0029-7844(00)01019-x.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Preventive MedicineUniversity of Santiago de CompostelaSantiago de CompostelaSpain
  2. 2.Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBER-ESP)MadridSpain
  3. 3.HIV/STI Surveillance Research Center, and WHO Collaborating Center for HIV Surveillance, Institute for Futures Studies in HealthKerman University of Medical SciencesKermanIran
  4. 4.Department of Epidemiology and Biostatistics, School of Public HealthTehran University of Medical SciencesTehranIran
  5. 5.Eye Care CenterUniversity of British ColumbiaVancouverCanada

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