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

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Abstract

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.

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References

  • 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.

    Article  CAS  Google Scholar 

  • 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. https://doi.org/10.1155/2013/364526.

    Article  Google Scholar 

  • 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. https://doi.org/10.1371/journal.pone.0053327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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. https://doi.org/10.1002/pds.3900.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Berkovitch M, Pastuszak A, Gazarian M, Lewis M, Koren G. Safety of the new quinolones in pregnancy. Obstet Gynecol. 1994;84:535–8.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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 

  • 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 

  • Czeizel AE, Kazy Z, Puhó E. Population-based case-control teratologic study of topical miconazole. Congenit Anom (Kyoto). 2004a;44:41–5.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Czeizel AE, Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol. 1997;89:524–8.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Czeizel AE, Rockenbauer M, Sørensen HT, Olsen J. A teratological study of lincosamides. Scand J Infect Dis. 2000b;32:579–80.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Czeizel AE, Rockenbauer M, Sørensen HT, Olsen J. Nitrofurantoin and congenital anomalies. Eur J Obstet Gynecol Reprod Biol. 2001d;95:119–26.

    Article  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Dinur AB, Koren G, Malok I, Wiznitzer A, Uziel E, Gorodischer R, Levy A. Fetal safety of macrolides. Antimicrob Agents Chemother. 2013;57:3307. https://doi.org/10.1128/AAC.01691-12.

    Article  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Heinonen OP, Slone D, Shapiro S. Birth defects and drugs during pregnancy. Littleton, MA: Publishing Sciences Group; 1977.

    Google Scholar 

  • 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 

  • 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.

    Article  Google Scholar 

  • Jick SS. Pregnancy after maternal exposure to fluconazole. Pharmacotherapy. 1999;19:221–2.

    Article  CAS  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Källén B, Danielsson BR. Fetal safety of erythromycin. An update of Swedish data. Eur J Clin Pharmacol. 2013;70:355–60.

    Article  Google Scholar 

  • Källén B, Otterblad Olausson P. Maternal drug use in early pregnancy and infant cardiovascular defect. Reprod Toxicol. 2003;17:255–61.

    Article  Google Scholar 

  • Källén B, Otterblad Olausson P, Danielsson BR. Is erythromycin therapy teratogenic in humans? Reprod Toxicol. 2005;20:209–14.

    Article  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Knudsen LB. No association between griseofulvin and conjoined twinning. Lancet. 1987;ii:1097.

    Article  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Leroux L. Existe-t-il une surdite congenitale acquise due à la streptomycin? Ann Otolaryngol. 1950;67:194–6.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Lopez-Rangel E, Van Allen MI. Prenatal exposure to fluconazole: an identifiable dysmorphic phenotype. Birth Defects Res (Part A). 2005;73:919–23.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Métneki J, Czeizel AE. Griseofulvin teratology. Lancet. 1987;i:1042.

    Article  Google Scholar 

  • Mickal A, Panzer JD. The safety of lincomycin in pregnancy. Am J Obstet Gynecol. 1975;12:1071–4.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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. https://doi.org/10.1111/bcp.13364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nordeng H, Lupatteli A, Romøren M, Koren G. Neonatal outcomes after gestational exposure to nitrofurantoin. Obstet Gynecol. 2013;121:306–13.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Pursley TJ, Blomquist IK, Abraham J, Andersen HF, Bartley JA. Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis. 1996;22:336–40.

    Article  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Rosa FW, Hernandez C, Carlo WA. Griseofulvin teratology including two thoracopagus conjoined twins. Lancet. 1987;i:171.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Sarkar M, Woodland C, Koren G, Einarson A. Pregnancy outcome following gestational exposure to azithromycin. BMC Pregnancy Childbirth. 2006;6:18. https://doi.org/10.1186/1471-2393-6-18.

  • 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.

    Article  CAS  Google Scholar 

  • Scheinhorn DJ, Angelillo VA. Antituberculous therapy in pregnancy. West J Med. 1977;127:195–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schwachman H, Schuster A. The tetracyclines: applied pharmacology. Pediatr Clin N Am. 1956;3:295–303.

    Article  Google Scholar 

  • 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 

  • 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.

    Article  CAS  Google Scholar 

  • 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. https://doi.org/10.1155/2013/195637.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Wolfgang P, Schloemp S, Sterzik K, Stoz F. Does roxithromycin affect embryo development? Reprod Toxicol. 2005;20:477.

    Google Scholar 

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Källén, B. (2019). Maternal Use of Antibacterial or Antifungal Drugs for Systemic Use and Infant Congenital Malformations. In: Maternal Drug Use and Infant Congenital Malformations. Springer, Cham. https://doi.org/10.1007/978-3-030-17898-7_15

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