INTERIM UPDATE
CommitteeOpinion2017
Number 717, September 2017
(Replaces Committee Opinion 494, June 2011)


Committee on Obstetric Practice
This Committee Opinion was developed by the American College of Obstetricians and Gynecologists’ Committee on Obstetric Practice.

This information is designed as an educational resource to aid clinicians in providing obstetric and gynecologic care, and use of this information is voluntary. This information should not be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. It is not intended to substitute for the independent professional judgment of the treating clinician. Variations in practice may be warranted when, in the reasonable judgment of the treating clinician, such course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or technology. The American College of Obstetricians and Gynecologists reviews its publications regularly; however, its publications may not reflect the most recent evidence. Any updates to this document can be found on www.acog.org or by calling the ACOG Resource Center.

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INTERIM UPDATE: This Committee Opinion is updated as highlighted to reflect a limited, focused change in references and regarding glucose-6-phosphate dehydrogenase deficiency.


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Sulfonamides, Nitrofurantoin, and Risk of Birth Defects

ABSTRACT: The evidence regarding an association between the nitrofuran and sulfonamide classes of antibiotics and birth defects is mixed. As with all patients, antibiotics should be prescribed for pregnant women only for appropriate indications and for the shortest effective duration. During the second and third trimesters, sulfonamides and nitrofurantoins may continue to be used as first-line agents for the treatment and prevention of urinary tract infections and other infections caused by susceptible organisms. Prescribing sulfonamides or nitrofurantoin in the first trimester is still considered appropriate when no other suitable alternative antibiotics are available. Pregnant women should not be denied appropriate treatment for infections because untreated infections can commonly lead to serious maternal and fetal complications.


Because antibiotics are commonly prescribed in pregnancy, there is a considerable body of pharmacoepidemiologic data addressing the relationship of antibiotic exposure and birth defects. The debate surrounding this relationship was heightened in November 2009, with a new publication by Crider and colleagues (1). The goal of this Committee Opinion is to assess the current evidence regarding the use of certain specific antibiotics in pregnancy and their association with birth defects (1).

In 2009, Crider and colleagues published a population-based case–control study of the relationship between antibiotics and birth defects that used data from the National Birth Defects Prevention Study. In this study, two classes of antibiotics commonly used to treat urinary tract infections—1) nitrofuran derivatives and 2) sulfonamides—were found to be significantly associated with multiple birth defect categories. Although this was a large study, it had several significant limitations. First, it was subject to recall bias because women were asked about antibiotic use after pregnancy. Second, the prescription of antibiotics was not confirmed by the medical record; approximately 35% of patients could not recall the specific product name. Third, because this was an observational study, it was not possible to determine whether the birth defect was due to the antibiotic itself, the infection for which the antibiotic was prescribed, or some other confounding factor. Additional studies examining the relationship between prenatal exposure to these antibiotics and birth defects have reported potential fetal risks, whereas other studies have not found such risks among other populations or when using different epidemiologic methods (2–8). For example in 2013, a population-based cohort study was published that examined first-trimester nitrofurantoin exposure through linked filled-prescription and birth databases (9). The authors found no association between first-trimester dispensing of nitrofurantoin and risk of major malformations.

It is reassuring that commonly used antibiotics, namely, penicillins, erythromycin, cephalosporins, and a less commonly used group, the quinolones, were not associated with an increased risk of birth defects in the 2009 study (1). These findings are in agreement with many other studies also reporting no increased risk of birth defects associated with prenatal exposure to penicillin (10), ampicillin (11), augmentin (6), pivampicillin (12), cephalosporins (13–14), gentamicin (15), oxacillin (16), erythromycin (17), metronidazole (18), and quinolones (19–20).

Conclusion and Recommendations

Commonly used antibiotics, such as penicillins, erythromycin, and cephalosporins, have not been found to be associated with an increased risk of birth defects. However, the evidence regarding an association between the nitrofuran and sulfonamide classes of antibiotics and birth defects is mixed. As with all patients, antibiotics should be prescribed for pregnant women only for appropriate indications and for the shortest effective duration. In pregnancy, many urine cultures show bacterial contaminants that do not represent true infection. Thus, cultures showing mixed gram-positive bacteria, lactobacilli, and Staphylococcus species (other than S saprophyticus), may be presumed to be contaminants and not treated. When selecting an antibiotic for a true infection during the first trimester of pregnancy (that is, during organogenesis), obstetrician–gynecologists and other health care providers should consider and discuss with patients the benefits as well as the potential unknown risks of teratogenesis and fetal and maternal adverse reactions. Prescribing sulfonamides or nitrofurantoin in the first trimester is still considered appropriate when no other suitable alternative antibiotics are available. During the second and third trimesters, sulfonamides and nitrofurantoins may continue to be used as first-line agents for the treatment and prevention of urinary tract infections and other infections caused by susceptible organisms (8). Obstetrician–gynecologists and other health care providers also should be aware that sulfonamides and nitrofurantoin are contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency, or in pregnant women identified to be at risk of this condition. Pregnant women should not be denied appropriate treatment for infections because untreated infections can commonly lead to serious maternal and fetal complications.

References

  1. 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;163:978–85.
  2. Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 2000;343:1608–14.
  3. Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. The teratogenic risk of trimethoprim-sulfonamides: a population based case-control study. Reprod Toxicol 2001;15:637–46.
  4. Czeizel AE, Puho E, Sorensen HT, Olsen J. Possible association between different congenital abnormalities and use of different sulfonamides during pregnancy. Congenit Anom (Kyoto) 2004;44:79–86.
  5. Norgard B, Czeizel AE, Rockenbauer M, Olsen J, Sorensen HT. Population-based case control study of the safety of sulfasalazine use during pregnancy. Aliment Pharmacol Ther 2001;15:483–6.
  6. Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. Augmentin treatment during pregnancy and the prevalence of congenital abnormalities: a population-based case-control teratologic study. Eur J Obstet Gynecol Reprod Biol 2001;97:188–92.
  7. Czeizel A. A case-control analysis of the teratogenic effects of co-trimoxazole. Reprod Toxicol 1990;4:305–13.
  8. Forna F, McConnell M, Kitabire FN, Homsy J, Brooks JT, Mermin J, et al. Systematic review of the safety of trimethoprim-sulfamethoxazole for prophylaxis in HIV-infected pregnant women: implications for resource-limited settings. AIDS Rev 2006;8:24–36.
  9. Nordeng H, Lupattelli A, Romoren M, Koren G. Neonatal outcomes after gestational exposure to nitrofurantoin. Obstet Gynecol 2013;121:306–13.
  10. Dencker BB, Larsen H, Jensen ES, Schonheyder HC, Nielsen GL, Sorensen HT. Birth outcome of 1886 pregnancies after exposure to phenoxymethylpenicillin in utero. Clin Microbiol Infect 2002;8:196–201.
  11. Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. A population-based case-control teratologic study of ampicillin treatment during pregnancy. Am J Obstet Gynecol 2001;185:140–7.
  12. Larsen H, Nielsen GL, Sorensen HT, Moller M, Olsen J, Schonheyder HC. A follow-up study of birth outcome in users of pivampicillin during pregnancy. Acta Obstet Gynecol Scand 2000;79:379–83.
  13. Berkovitch M, Merlob P. Use of cephalosporins during pregnancy and in the presence of congenital abnormalities [letter]. Am J Obstet Gynecol 2002;187:817;author reply 817.
  14. Czeizel AE, Sorensen HT, Rockenbauer M, Olsen J. A population-based case-control teratologic study of nalidixic acid. Int J Gynaecol Obstet 2001;73:221–8.
  15. Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. A teratological study of lincosamides. Scand J Infect Dis 2000;32:579–80.
  16. Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. Teratogenic evaluation of oxacillin. Scand J Infect Dis 1999;31:311–2.
  17. Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. A population-based case-control teratologic study of oral erythromycin treatment during pregnancy. Reprod Toxicol 1999;13:531–6.
  18. Sorensen HT, Larsen H, Jensen ES, Thulstrup AM, Schonheyder HC, Nielsen GL, et al. Safety of metronidazole during pregnancy: a cohort study of risk of congenital abnormalities, preterm delivery and low birth weight in 124 women. J Antimicrob Chemother 1999;44:854–6.
  19. Schaefer C, Amoura-Elefant E, Vial T, Ornoy A, Garbis H, Robert E, et al. 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.
  20. Larsen H, Nielsen GL, Schonheyder HC, Olesen C, Sorensen HT. Birth outcome following maternal use of fluoroquinolones. Int J Antimicrob Agents 2001;18:259–62.

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Sulfonamides, nitrofurantoin, and risk of birth defects. Committee Opinion No. 717. American College of Obstetricians and Gynecologists. Obstet Gynecol 2017;130:e150–2.

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