Maternal Use of Antibacterial or Antifungal Drugs for Systemic Use and Infant Congenital Malformations

  • Bengt Källén


Most information in the literature based on prospective exposure information shows that the use of common antibacterial drugs is not associated with a significant risk increase for major congenital malformations in the offspring. Two drugs are associated with problems in the offspring: discolored teeth after maternal use of tetracycline exposure after the first trimester and ototoxicity after maternal use of streptomycin and related drugs. Neither phenomenon represents true congenital malformations. An association between maternal use of macrolides (and notably erythromycin) and infant cardiovascular defects has repeatedly been demonstrated from Swedish data but has not been verified in studies from other countries. Methodological problems may explain the difference in results. A number of other associations which have been observed may have been chance findings in spite of formal statistical significance and more data are needed on little used drugs.

Most data on antifungals exist for fluconazole. In moderate doses this drug seems to have no observable teratogenic effect but in high doses (400 mg/day or more), when used for serious fungal infections, it is likely that a teratogenic effect can occur but the magnitude of the risk is not known. Data on other antifungals are less complete but have not shown any definite teratogenicity.


  1. Ailes EC, Gilboa SM, Broussard CB, Crider KS, Berry RJ, Carter TC, Hobbs CA, Interrante JD, Reefhuis J, the National Birth Defects Prevention Study 1997-2011. Association between antibiotic use among pregnant women with urinary tract infections in the first trimester and birth defects. Birth Defects Res (Part A). 2016;106:940–9.CrossRefGoogle Scholar
  2. Andersen JT, Petersen M, Jiminez-Solem E, Norgaard Rasmussen K, Hjelvang BR, Køber L, Torp-Pedersen C, Poulsen HE. Trimethoprim use prior to pregnancy and the risk of congenital malformation: a register-based nationwide cohort study. Obst Gynecol Int. 2013a;2013:364526. Scholar
  3. Andersen JT, Petersen M, Jimenez-Solem E, Broedbaek K, Andersen NL, Torp-Pedersen C, Kelding N, Poulsen HE. Clarithromycin in early pregnancy and the risk of miscarriage and malformation: a register based nationwide study. PLoS One. 2013b;8:e53327. Scholar
  4. Bar-Oz B, Diav-Citrin O, Shechtman S, Tellem R, Arnon J, Francetic I, Berkovitch M, Ornoy A. Pregnancy outcome after gestational exposure to the new macrolides: a prospective multi-center observational study. Eur J Obst Gynecol Reprod Biol. 2008;141:31–4.CrossRefGoogle Scholar
  5. Bar-Oz B, Moretti ME, Bishai R, Mareels G, Van Tittelboom T, Verspeelt J, Koren G. Pregnancy outcome after in utero exposure to itraconazole: a prospective cohort study. Am J Obstet Gynecol. 2000;183:617–20.CrossRefGoogle Scholar
  6. Bérard A, Sheehy O, Zhap J-P, Nordeng H. Use of macrolides during pregnancy and the risk of birth defects: a population-based study. Pharmacoepidemiol Drug Saf. 2015;24(12):1241–8. Scholar
  7. Berkovitch M, Diav-Citrin O, Greenberg R, Cohen M, Bulkowstein M, Schechtman S, Bortnik O, Arnon J, Ornoy A. First-trimester exposure to amoxicillin/clavulanic acid: a prospective, controlled study. J Clin Pharmacol. 2004;58:298–302.CrossRefGoogle Scholar
  8. Berkovitch M, Pastuszak A, Gazarian M, Lewis M, Koren G. Safety of the new quinolones in pregnancy. Obstet Gynecol. 1994;84:535–8.PubMedGoogle Scholar
  9. Berkovitch M, Segal-Socher I, Greenberg R, Bulkowshtein M, Arnon J, Perlob P, Or-Noy A. First trimester exposure to cefuroxime: a prospective study. Br J Pharmacol. 2000;50:161–5.CrossRefGoogle Scholar
  10. Carey JC, Martinez L, Balken E, Leen-Mitchell M, Robertson J. Determination of human teratogenicity by the astute clinician method: review of illustrative agents and a proposal of guidelines. Birth Def Res (Part A). 2009;85:63–8.CrossRefGoogle Scholar
  11. Carter TC, Druschel C, Romitti PA, Bell EM, Werler MM, Mitchell AA, for the Nationak Birth Defects Prevention Study. Antifungal drugs and the risk of selected birth defects. Am J Obstet Gynecol. 2008;198:191.e1–7.CrossRefGoogle Scholar
  12. Chun JY, Han JY, Ahn HK, Choi JS, Koong MK, Nava-Ocampo AA, Koren G. Fetal outcome following roxithromycin exposure in early pregnancy. J Matern Fetal Neonatal Med. 2006;19:189–92.CrossRefGoogle Scholar
  13. Crider KS, Cleves MA, Reefhuis J, Berry RJ, Hobbs CA, Hu DJ. Antibacterial medication use during pregnancy and risk of birth defects. Arch Paediatr Adolesc Med. 2009;163:978–85.Google Scholar
  14. Cooper WO, Hernandez S, Arbogast PG, Dudley JA, Shannon MD, Gideon PS, Hall KS, Kaltenbach LA, Ray WA. Antibiotics potentially used in response to bioterrorism and the risk of major malformations. Paediatr Perinat Epidemiol. 2008;13:18–28.Google Scholar
  15. Czeizel AE, Kazy Z, Puhó E. Population-based case-control teratologic study of topical miconazole. Congenit Anom (Kyoto). 2004a;44:41–5.CrossRefGoogle Scholar
  16. Czeizel AE, Kazy Z, Vargha P. A population-based case-control teratological study of vaginal econazole treatment during pregnancy. Eur J Obst Gynecol Reprod Biol. 2003;111:135–40.CrossRefGoogle Scholar
  17. Czeizel AE, Métneki J, Kazy Z, Puhó E. A population-based case-control study of oral griseofulvin treatment during pregnancy. Acta Obstet Gynecol Scand. 2004b;83:827–31.CrossRefGoogle Scholar
  18. Czeizel AE, Puhó E, Sørensen HT, Olsen J. Possible association between different congenital abnormalities and use of different sulfonamides during pregnancy. Congenit Anom (Kyoto). 2004c;44:79–86.CrossRefGoogle Scholar
  19. Czeizel AE, Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol. 1997;89:524–8.CrossRefGoogle Scholar
  20. Czeizel AE, Rockenbauer M, Sørensen HT, Olsen J. A population-based case-control teratologic study of oral erythromycin treatment during pregnancy. Reprod Toxicol. 1999;13:531–6.CrossRefGoogle Scholar
  21. Czeizel AE, Rockenbauer M, Olsen J, Sørensen HT. A teratological study of aminoglycoside antibiotic treatment during pregnancy. Scand J Infect Dis. 2000a;32:309–13.CrossRefGoogle Scholar
  22. Czeizel AE, Rockenbauer M, Olsen J, Sørensen HT. A population-based case-control study of the safety of oral anti-tuberculosis drug treatment during pregnancy. Int J Tuberc Lung Dis. 2001c;5:564–8.PubMedGoogle Scholar
  23. Czeizel AE, Rockenbauer M, Sørensen HT, Olsen J. A teratological study of lincosamides. Scand J Infect Dis. 2000b;32:579–80.CrossRefGoogle Scholar
  24. Czeizel AE, Rockenbauer M, Sørensen HT, Olsen J. A population-based case-control teratologic study of ampicillin treatment during pregnancy. Am J Obstet Gynecol. 2001a;185:140–7.CrossRefGoogle Scholar
  25. Czeizel AE, Sørensen HT, Rockenbauer M, Olsen J. A population-based case-control teratologic study of nalidixic acid. Int J Gynaecol Obstet. 2001b;73:221–8.CrossRefGoogle Scholar
  26. Czeizel AE, Rockenbauer M, Sørensen HT, Olsen J. Nitrofurantoin and congenital anomalies. Eur J Obstet Gynecol Reprod Biol. 2001d;95:119–26.CrossRefGoogle Scholar
  27. De Santis M, Di Gianantonio E, Cesari E, Ambrosini G, Straface G, Clementi M. First-trimester itraconazole exposure and pregnancy outcome: a prospective cohort study of women contacting teratology information services in Italy. Drug Saf. 2009;32:239–44.CrossRefGoogle Scholar
  28. Dinur AB, Koren G, Malok I, Wiznitzer A, Uziel E, Gorodischer R, Levy A. Fetal safety of macrolides. Antimicrob Agents Chemother. 2013;57:3307. Scholar
  29. Dudás I, Puhó E, Czeizel AE. Population-based case-control study of oxoline acid use during pregnancy for birth outcomes. Congenit Anom (Kyoto). 2006;46:39–42.CrossRefGoogle Scholar
  30. Einarson A, Phillips E, Mawji F, D’Alimonte D, Schick B, Addis A, Mastroiacovo P, Mazzone T, Matsui D, Koren G. A prospective controlled multicenter study of clarithromycin in pregnancy. Am J Perinatol. 1998;15:523–5.CrossRefGoogle Scholar
  31. Goldberg O, Koren G, Landau D, Lunendfeld E, Matok I, Levy A. Exposure to nitrofurantoin during the first trimester of pregnancy and the risk for major malformations. J Clin Pharmacol. 2013;53:991–5.CrossRefGoogle Scholar
  32. Goldberg O, Moretti M, Levy A, Koren G. Exposure to nitrofurantoin during early pregnancy and congenital malformations: a systematic review and meta-analysis. J Obstet Gynaecol Can. 2015;37:150–6.CrossRefGoogle Scholar
  33. Hansen C, Andrade SE, Freiman H, Dublin S, Haffenreffer K, Cooper WO, Cheetham TC, Toh S, Li D-K, Raebel MA, Kuntz JL, Perrin N, Rosales AG, Carter S, Pawlowski PA, Maloney EM, Graham DJ, Sahin L, Scott PE, Yap J, Davis R. Trimethoprim-sulfonamide use during the first trimester of pregnancy and the risk of congenital anomalies. Pharmacoepidemiol Drug Saf. 2016;25:170–8.CrossRefGoogle Scholar
  34. Heinonen OP, Slone D, Shapiro S. Birth defects and drugs during pregnancy. Littleton, MA: Publishing Sciences Group; 1977.Google Scholar
  35. Howley MM, Carter TC, Browne ML, Romitti PA, Cunniff CM, Druschel CM. Fluconazole use and birth defects in the National Birth Defects Prevention Study. Am J Obstet Gynecol. 2016;214:e1–657.Google Scholar
  36. Jepsen P, Skriver MV, Floyd A, Lipworth L, Schønheyder HC. A population-based study of maternal use of amoxicillin and pregnancy outcome in Denmark. J Clin Pharmacol. 2003;55:216–21.CrossRefGoogle Scholar
  37. Jick SS. Pregnancy after maternal exposure to fluconazole. Pharmacotherapy. 1999;19:221–2.CrossRefGoogle Scholar
  38. Kalayci T, Erener-Ercan T, Buyukkale G, Cetinkaya M. Limb deformity in a newborn. Is rifampicin just an innocent bystander? Eur Rev Med Pharmacol Sci. 2015;19:517–9.PubMedGoogle Scholar
  39. Källén B, Danielsson BR. Fetal safety of erythromycin. An update of Swedish data. Eur J Clin Pharmacol. 2013;70:355–60.CrossRefGoogle Scholar
  40. Källén B, Otterblad Olausson P. Maternal drug use in early pregnancy and infant cardiovascular defect. Reprod Toxicol. 2003;17:255–61.CrossRefGoogle Scholar
  41. Källén B, Otterblad Olausson P, Danielsson BR. Is erythromycin therapy teratogenic in humans? Reprod Toxicol. 2005;20:209–14.CrossRefGoogle Scholar
  42. Kazy Z, Puhó E, Czeizel AE. The possible association between the combination of vaginal metronidazole and miconazole treatment and poly-syndactyly. Population-based case-control teratologic study. Reprod Toxicol. 2005;20:89–94.CrossRefGoogle Scholar
  43. Knudsen LB. No association between griseofulvin and conjoined twinning. Lancet. 1987;ii:1097.CrossRefGoogle Scholar
  44. Larsen H, Nilsson GL, Schønheyder HC, Olesen C, Sørensen HT. Birth outcome following maternal use of fluoroquinolones. Int J Antimicrob Agents. 2001;18:259–62.CrossRefGoogle Scholar
  45. Lee SW, Han JY, Choi JS, Chung JH, Kim MY, Yang JH, Koong MK, Nava-Ocampo AA, Koren G. Pregnancy outcome of women inadvertently exposed to ribostamycin during early pregnancy: a prospective cohort study. Reprod Toxicol. 2009;27:196–8.CrossRefGoogle Scholar
  46. Leroux L. Existe-t-il une surdite congenitale acquise due à la streptomycin? Ann Otolaryngol. 1950;67:194–6.PubMedGoogle Scholar
  47. Lin KJ, Mitchell AA, Yau W-P, Louik C. Hernándes-Díaz. Maternal exposure to amoxicillin and the risk of oral clefts. Epidemiology. 2012;23:699–705.CrossRefGoogle Scholar
  48. Lin KJ, Mitchell AA, Yau W-P, Louk C, Hernándes-Díaz. Safety of macrolides during pregnancy. Am J Obstet Gynecol. 2013;208:221.e1–8.CrossRefGoogle Scholar
  49. Loebstein R, Addis A, Ho E, Andreou R, Sage S, Donnenfeld AE, Schick B, Bonati M, Moretti M, Lalkin A, Pastuszak A, Koren G. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother. 1998;42:1336–9.CrossRefGoogle Scholar
  50. Lopez-Rangel E, Van Allen MI. Prenatal exposure to fluconazole: an identifiable dysmorphic phenotype. Birth Defects Res (Part A). 2005;73:919–23.CrossRefGoogle Scholar
  51. Mastroiacovo P, Mazzone T, Botto LD, Serafini MA, Finardi A, Caramelli L, Fusco D. Prospective assessment of pregnancy outcomes after first.trimester exposure to fluconazole. Am J Obstet Gynecaol. 1996;175:1645–50.CrossRefGoogle Scholar
  52. Métneki J, Czeizel AE. Griseofulvin teratology. Lancet. 1987;i:1042.CrossRefGoogle Scholar
  53. Mickal A, Panzer JD. The safety of lincomycin in pregnancy. Am J Obstet Gynecol. 1975;12:1071–4.CrossRefGoogle Scholar
  54. Mølgaard-Nielsen D, Hviid A. Maternal use of antibiotics and the risk of orofacial clefts: a nationwide cohort study. Pharmacoepidemiol Drug Saf. 2012;21:246–2553.CrossRefGoogle Scholar
  55. Muanda FT, Sheehy O, Bérard 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. Scholar
  56. Nordeng H, Lupatteli A, Romøren M, Koren G. Neonatal outcomes after gestational exposure to nitrofurantoin. Obstet Gynecol. 2013;121:306–13.CrossRefGoogle Scholar
  57. Nørgaard M, Pedersen L, Gislum M, Erichsen R, Kobberø Søgaard K, Schønheider HC, Sørensen HT. Maternal use of fluconazole and risk of congenital malformations: a Danish population-based cohort study. J Anitmicrob Chemother. 2008;62:172–6.CrossRefGoogle Scholar
  58. Padberg S, Wacker E, Meister R, Panse M, Weber-Schoendorfer C, Opperman M, Schaefer C. Observational cohort study of prergnancy outcome after first-trimester exposure to fluoroquinolones. Antimicrob Agents Chemther. 2014;58:4392–8.CrossRefGoogle Scholar
  59. Pursley TJ, Blomquist IK, Abraham J, Andersen HF, Bartley JA. Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis. 1996;22:336–40.CrossRefGoogle Scholar
  60. Romøren M, Lindbæck M, Nordeng H. Pregnancy outcome after gestational exposure to erythromycin—a population-based register study from Norway. Br J Clin Pharmacol. 2012;74:1053–62.CrossRefGoogle Scholar
  61. Rosa FW, Hernandez C, Carlo WA. Griseofulvin teratology including two thoracopagus conjoined twins. Lancet. 1987;i:171.CrossRefGoogle Scholar
  62. Sánchez AB, Rogers RS, Sheridan PJ. Tetracycline and other tetracycline-derivate staining of the teeth and oral cavity. Int J Dermatol. 2004;43:709–16.CrossRefGoogle Scholar
  63. Sarkar M, Woodland C, Koren G, Einarson A. Pregnancy outcome following gestational exposure to azithromycin. BMC Pregnancy Childbirth. 2006;6:18.
  64. Schaefer C, Amoura-Elefant E, Vial T, Ornoy A, Garbis H, Robert E, Rodriguez-Pinilla E, Prapas N, Merlob P. Pregnancy outcome after prenatal quinolone exposure. Evaluation of a case registry of the European Network of Teratology Information Services (ENTIS). Eur J Obstet Gynecol Reprod Biol. 1996;69:83–9.CrossRefGoogle Scholar
  65. Scheinhorn DJ, Angelillo VA. Antituberculous therapy in pregnancy. West J Med. 1977;127:195–8.PubMedPubMedCentralGoogle Scholar
  66. Schwachman H, Schuster A. The tetracyclines: applied pharmacology. Pediatr Clin N Am. 1956;3:295–303.CrossRefGoogle Scholar
  67. Sørensen HT, Nielsen GL, Olesen C, Larsson H, Steffensen FH, Schønheyder HC, Olsen J, Czeizel AE. Risk of malformations and other outcomes in children exposed to fluconazole in utero. Br J Clin Pharmacol. 1999;199(48):234–8.Google Scholar
  68. Sun Y, Wu CS, Olsen J. Trimethoprim use before pregnancy and risk of congenital malformation: reanalyzed using a case-crossover design and a case-time-control design. Pharmacoepidemiol Drug Saf. 2014;23:1076–83.CrossRefGoogle Scholar
  69. Taylor AW, Mosimaneotsile B, Mathebula U, Mathoma A, Moathlodi, Theebetsile I, Samandari T. Pregnancy oucomes in HIV-infected women receiving long-term isoniazid prophylaxis for tuberculosis and antiretroviral therapy. Infect Dis Obstet Gynecol. 2013;2013:195637. Scholar
  70. Vinther Skriver M, Nørgaard M, Pedersen L, Schonheyder H, Sørensen HT. Pivmecillinam and adverse birth and neonatal outcomes: a population-based study. Scand J Infect Dis. 2004;36:733–7.CrossRefGoogle Scholar
  71. Wogelius P, Nørgaars M, Gisium M, Pedersen L, Schønheyder HC, Sørensen HT. Further analysis of the risk of adverse birth outcome after maternal use of fluoroquinolones. Int J Antimicrob Agents. 2005;26:323–6.CrossRefGoogle Scholar
  72. Wolfgang P, Schloemp S, Sterzik K, Stoz F. Does roxithromycin affect embryo development? Reprod Toxicol. 2005;20:477.Google Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Bengt Källén
    • 1
  1. 1.Tornblad Institute for Comparative EmbryologyLund UniversityLundSweden

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