Is Macrobid Safe in 1st Trimester Pregnancy?

Background: In 2011, the American College of Obstetricians and Gynecologists (ACOG) released a committee opinion warning against the use of nitrofurantoin (Macrobid) during the first trimester of pregnancy due to the perceived risk of an increased rate of congenital abnormalities with its use (Committee Opinion 2017). While the committee continued to recommend that nitrofurantoin be used as a first-line agent during the second and third trimesters, they stated that it should only be considered appropriate in the first trimester when no other suitable alternative antibiotics were available. While this recommendation seems to have been slow to permeate into the emergency medicine community, growing awareness has led to clinical trepidation in the provision of nitrofurantoin.

Clinical Question: Should nitrofurantoin be used in the empiric treatment of first trimester urinary tract infections?

Literature Review:

Study #1: Crider, Cleves, and Reefuis. Arch Pediatr Adolesc Med, 2009 (Cited in ACOG Committee Opinion)

• U.S.-based case control study using questionnaires.
• Case and control mothers were interviewed by telephone in English or Spanish using a computer‐based questionnaire 6 weeks to 24 months after the delivery.
• Mothers asked whether they had a UTI at any point from 1 month prior to conception until the end of the third month of pregnancy, and which antibiotic they were prescribed.
  • Specific names of antibiotics were read to mothers to help them recall which antibiotics they were prescribed. Mothers then had to recall timing and duration, but not dosage information.
• No verification by study authors of timeline or accuracy of patient recall.
• Mothers who did not know whether they were exposed, or were unsure regarding timing of exposure, were excluded from analysis.
• Participation rate was moderate, with 70.5% of case mothers and 67.2% of control mothers.
• Total of 150 case exposures to nitrofurantoin.
• 66 birth defect associations analyzed.
  • Nitrofurantoin associated with increased risk of 4 birth defects: anophthalmia or microphthalmos (OR 3.7; 95% CI, 1.1-12.2), hypoplastic left heart syndrome (OR 4.2; 95% CI, 1.9-9.1), atrial septal defects (OR 1.9; 95% CI, 1.1-3.4), and cleft lip with cleft palate (OR 2.1; 95% CI, 1.2-3.9)
  • Increased risk of birth defects also identified with penicillins (intercalary limb deficiency) and cephalosporins (atrial septal defects), however no increased rate of birth defects identified with tetracycline use. Note: tetracyclines were classified as category D–positive evidence of human fetal risk.
• Take Home Point: This study was flawed by irreconcilable recall bias, included a relatively small number of total nitrofurantoin case exposures. It lacks face validity, given that tetracyclines (a known teratogen) seemed to be associated with less adverse events than penicillins or cephalosporins.

Study #2: Ailes, Gilboa, Gill et al. Birth Defects Research, 2016 (Cited in CDC bulletin)

• U.S.-based case control study using questionnaires.
• Case and control mothers were interviewed by telephone in English or Spanish using a computer‐based questionnaire 6 weeks to 24 months after the delivery.
• Mothers asked whether they had a UTI at any point from 3 months prior to conception until delivery, and which antibiotic they were prescribed.
• No verification by study authors of timeline or accuracy of patient recall.
• Low participation rate, with 67% of case mothers and 64% of control mothers.
• Total of 60 case exposures to nitrofurantoin.
• 22 birth defect associations analyzed.
  • No significant risk increase except for 1: increased risk of oral clefts (OR 1.97; 95% CI, 1.10-3.53), which occurred in 37 patients.
• No increased risk was noted among 21 other categories, including the oral cleft subsets of cleft palate and cleft lip—only when these subsets were combined did the result meet statistical significance.
• The authors noted that individual birth defects are rare, and absolute risks should drive treatment decisions.
• Take Home Point: This was an extremely small study, similarly flawed by recall bias.

Study #1 and Study #2 are both case-control studies, which are generally a useful study design for rare occurrences or when there is a long latency period between exposure and disease manifestation (e.g. antibiotic exposure in the 1^st trimester and subsequent development of birth defects), however they are by nature subject to selection and observation biases, and are prone to difficult-to-control confounders (other exposures or contributors which may account for the observed birth defects). For example, in these studies patients could not recall details of other over-the-counter medications used—a potentially huge confounder in the case of common OTC medications linked to birth defects, such as NSAIDs. Furthermore, though patients are often control-matched, it is not possible to determine whether birth defects are associated with the exposure (antibiotic) or the underlying disease (urinary tract infection). Finally, case-control studies do not permit determination of incidence rates and cannot determine causal relationships between exposure and outcome (only associations).

Study #3: Nordeng, Lupattelli, Romoren, and Koren. Obstetrics and Gynecology, 2013.

• Norwegian population-based cohort study.
• 180,120 total pregnancies were analyzed, including 5,794 nitrofurantoin exposures (1,334 during the first trimester).
  • Information on exposure to antibiotics was extracted from the Norwegian Prescription Database. It was assumed that any dispensed antibiotic was consumed by the patient, and this was counted as exposure to the antibiotic.
• Patients exposed to nitrofurantoin were “sicker”– more likely to smoke during pregnancy and to not take folic acid before and during pregnancy in comparison with unexposed women in the control group.
• There was no association with major malformations (OR 0.79; 95% CI 0.55–1.13) or with a cardiovascular malformation (OR 0.95; 95% CI 0.55–1.64) among women who had been dispensed nitrofurantoin during the first trimester compared with unexposed women in the control group.
• There was no association between exposure to nitrofurantoin use in the first trimester and the risk for any of the 11 predefined specific malformations.
  • None of the 1,334 first-trimester nitrofurantoin exposures developed an oral cleft.
• Take Home Point: In this large population-level study, not only was nitrofurantoin not associated with an increased risk of congenital malformations, not a single exposed patient developed an oral cleft.

Study #4: Goldberg, Koren, Landau, et al. Clinical Pharmacology, 2013

• Israeli population-based cohort study.
• 105,492 total pregnancies were analyzed, including 1,319 nitrofurantoin exposures during the first trimester.
  • Information on birth defects and nitrofurantoin exposure obtained from four linked databases including HMO records (covering 70% of the district’s population) and the regional hospital (performing 98% of the region’s deliveries).
• There was no association between exposure to nitrofurantoin use in the first trimester and the risk for any congenital malformations.
  • None of the 1,319 nitrofurantoin-exposed patients developed an oral cleft.
• Take Home Point: In yet another large population-level study, nitrofurantoin was again not associated with an increased risk of congenital malformations, and not a single exposed patient developed an oral cleft.

Study #3 and Study #4 are both cohort studies, which are always limited by information available in the records used for review, which may be incomplete or inaccurate. For example, both studies used self-reporting of smoking status (a notoriously under-reported confounder) for control data. Cohort studies are susceptible to significant confounding, as well. In both studies there is no guarantee that the antibiotic prescribed/filled was taken at all, or for the full duration it was prescribed.

Takeaway: All four studies examining the association between nitrofurantoin and birth defects are observational studies. These trials are susceptible to recall bias and uncontrollable confounders, and the true incidence of rare disease is often difficult to examine. Nonetheless, there is no compelling evidence of any significant risk of fetal abnormalities with the use of nitrofurantoin in the first trimester.

Why It Matters: Urinary tract infections complicate up to 10% of pregnancies, and untreated and undertreated infections have been associated with low birth weights, preterm labor, and neonatal sepsis (Delzell 2010). While cephalexin (recommended first line in first trimester UTIs by ACOG) is typically effective in the majority of urinary tract infections, growing resistance of some isolates to cephalosporins, as well as gram-positive organisms on which cephalexin has no activity—such as E. faecalis, which represented up to 12% of cultures in one recent investigation (Huttner 2018)—is concerning. Certainly, in patients with recent antibiotic use or in whom testing indicates lack of urinary nitrites (suggestive of an increased likelihood of E. faecalis infection (Larson 1997) (Weisz 2010)), it seems likely that the risk of undertreated infection outweighs the possibility of congenital malformation.

Recommendation: The ACOG committee opinion recommending withholding nitrofurantoin unless alternative agents are unavailable should be revisited. Emergency physicians should have a low threshold to prescribe nitrofurantoin for patients with urinary tract infections in the first trimester of pregnancy, particularly when there is suspicion for cephalosporin-resistant organisms—that is, patients with recent antibiotic use, previous resistant organisms, or nitrite-negative urinalyses. Shared decision-making and documentation of clinical concern can reconcile this best practice with the ACOG opinion.

References:

1. Committee on Obstetric Practice. “Committee Opinion No. 717: Sulfonamides, Nitrofurantoin, and Risk of Birth Defects.” Obstetrics and gynecology 130.3 (2017): e150. (PMID: 28832488)
2. Crider, Krista S., et al. “Antibacterial medication use during pregnancy and risk of birth defects: National Birth Defects Prevention Study.” Archives of pediatrics & adolescent medicine 163.11 (2009): 978-985. (PMID: 19884587)
3. Ailes, Elizabeth C., et al. “Association between antibiotic use among pregnant women with urinary tract infections in the first trimester and birth defects, National Birth Defects Prevention Study 1997 to 2011.” Birth Defects Research Part A: Clinical and Molecular Teratology 106.11 (2016): 940-949. (PMID: 27891788)
4. Nordeng, Hedvig, et al. “Neonatal outcomes after gestational exposure to nitrofurantoin.” Obstetrics & Gynecology 121.2, PART 1 (2013): 306-313. (PMID: 23344280)
5. Goldberg, Ori, et al. “Exposure to nitrofurantoin during the first trimester of pregnancy and the risk for major malformations.” The Journal of Clinical Pharmacology 53.9 (2013): 991-995. (PMID: 124142)
6. Delzell JE, Lefevre ML. “Urinary tract infections during pregnancy.” Am Fam Physician 61.3 (2000): 713-720. (PMID: 10695584)
7. Huttner, Angela, et al. “Effect of 5-day nitrofurantoin vs single-dose fosfomycin on clinical resolution of uncomplicated lower urinary tract infection in women: A randomized clinical trial.” Jama 319.17 (2018): 1781-1789. (PMID: 29710295)
8. Larson, Michael J., et al. “Can urinary nitrite results be used to guide antimicrobial choice for urinary tract infection?.” The Journal of emergency medicine 15.4 (1997): 435-438. (PMID: 9279691)
9. Weisz, Dany, Jamie A. Seabrook, and Rodrick K. Lim. “The presence of urinary nitrites is a significant predictor of pediatric urinary tract infection susceptibility to first-and third-generation cephalosporins.” Journal of Emergency Medicine39.1 (2010): 6-12. (PMID: 18757159)

Post Peer Reviewed By: Salim R. Rezaie, MD (Twitter: @srrezaie)

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