Which Antibiotics Are Safe in the First Trimester of Pregnancy?

Associate Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI

Dr. Allen reports she is a Nexplanon trainer for Merck.

SYNOPSIS: A total of 7.2% of pregnant women were diagnosed with a urinary tract infection, and of these, 69% filled an antibiotic prescription. The most common antibiotics prescribed in the first trimester were nitrofurantoin, ciprofloxacin, cephalexin, and trimethoprim-sulfamethoxazole.

SOURCE: Ailes EC, Summers AD, Tran EL, et al. Antibiotics dispensed to privately insured pregnant women with urinary tract infections — United States, 2014. MMWR Morb Mortal Wkly Rep 2018;67:18-22.

This cross-sectional study by the Centers for Disease Control and Prevention (CDC) was designed to identify antibiotics prescribed to pregnant women with urinary tract infections (UTIs). The Truven Health MarketScan Commercial Database contains a convenience sample of women with employer-sponsored private health insurance. This database was queried to identify women who were pregnant in 2014 (pregnancies had to include at least one day in 2014). To be included, pregnant women had to be enrolled continuously in insurance with prescription drug coverage, or missing only one month of enrollment from 90 days prior to the last menstrual period to the end of pregnancy. Claims from physician offices, emergency departments, and urgent care centers were searched to identify those with a diagnosis of UTI using ICD-9 diagnosis codes. Inpatient hospitalizations and women who had recurrent UTIs (three or more during the study period) were excluded. Prescription records then were searched to identify antibiotic medications dispensed on the day of and up to seven days after the outpatient UTI claim.

The researchers identified 482,917 pregnant women who met the study criteria. Among these, 34,864 (7.2%) were diagnosed with UTIs, 41% in the first trimester, 22% in the second trimester, and 11.8% in the third trimester. Overall, 69% of women diagnosed with UTIs filled prescriptions within seven days of the outpatient visit. The antibiotics most commonly prescribed in pregnancy were nitrofurantoin, cephalosporins, and penicillins. The most frequently dispensed medications in the first trimester were nitrofurantoin (37.5%), ciprofloxacin (10.5%), cephalexin (10.3%), and trimethoprim-sulfamethoxazole (TMP-SMX; 7.6%).

COMMENTARY

The CDC performed this study to ascertain which antibiotics were being prescribed to pregnant women in the first trimester for UTIs based on a concern for teratogenicity with nitrofurantoin and TMP-SMX. As confirmed in this study, UTI/asymptomatic bacteriuria occurs in about 8% of pregnant women. In pregnant women, untreated UTIs/asymptomatic bacteriuria can lead to pyelonephritis, sepsis, and preterm delivery, resulting in severe maternal and fetal morbidity and possibly mortality.¹ Therefore, pregnant women are screened in the first trimester for bacteriuria and treated if the culture result is positive to prevent pyelonephritis.²

Study limitations included reliance on diagnosis and procedure codes to identify pregnancies and UTIs, which can be subject to misclassification. Last menstrual period dates, delivery dates, and UTI diagnoses were not validated by examining the clinical record. Furthermore, the pregnancy may not yet have been diagnosed in some cases when the provider was prescribing treatment. In addition, the specific and appropriate use of nitrofurantoin or TMP-SMX based on culture sensitivity reports were not ascertained. Finally, the database is not generalizable to the U.S. population, and antibiotic prescriptions paid out of pocket were not captured.

Although penicillins, cephalosporins, metronidazole, and erythromycin/azithromycin are regarded as safe during embryonic organogenesis, questions remain about nitrofurantoin and TMP-SMX. Fluoroquinolones usually are not prescribed during pregnancy because of concerns about toxicity to developing cartilage in animal studies. I suspect that the use of ciprofloxacin documented in this study during the first trimester occurred mostly in cases in which the pregnancy had not yet been diagnosed clinically.

The American College of Obstetricians and Gynecologists (ACOG) published a committee opinion in 2011, updated in 2017, that addressed concerns regarding nitrofurantoin and TMP-SMX.³ In essence, case-control studies using the National Birth Defects Prevention Study database have shown a relationship between nitrofurantoin and TMP-SMX use during pregnancy and birth defects.^4,5 However, these studies have major limitations, such as relying on mothers to recall postpartum if they had even been diagnosed with a UTI during pregnancy and which antibiotic they had been prescribed. The diagnosis and prescription of antibiotics were not confirmed in the medical record, and many mothers could not recall the specific name of the antibiotic prescribed. Other studies have not shown any association.⁶ Therefore, the data are mixed, and ACOG recommended that use of nitrofurantoin and TMP-SMX in the first trimester is still appropriate when no other suitable alternative exists (e.g., a penicillin or cephalosporin cannot be used).

We should all practice antibiotic stewardship when treating patients and select antibiotics carefully. Often, despite the clean-catch technique, urine cultures are contaminated in pregnancy, and we should be sure only to treat women with recognized uropathogens. The urine culture can always be repeated to confirm the diagnosis. Nevertheless, pregnant women should not be denied treatment for UTI/asymptomatic bacteriuria based on theoretical concerns regarding birth defects. Failure to treat can lead to more devastating adverse outcomes for both mother and fetus such as sepsis, preterm delivery, and death.

REFERENCES

1. American College of Obstetricians Gynecologists/American Academy of Pediatrics. Guidelines for Perinatal Care. 8th ed. September 2017.
2. Nicolle LE, Bradley S, Colgan R, et al; Infectious Diseases Society of America; American Society of Nephrology; American Geriatric Society. Infections Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis 2005;40:643-654.
3. ACOG Committee Opinion #717. Sulfonamides, nitrofurantoin, and risk of birth defects. September 2017.
4. Ailes EC, Gilboa SM, Gill SK, et al; The National Birth Defects Prevention Study. 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 Res A Clin Mol Teratol 2016;106:940-949.
5. Crider KS, Cleves MA, Reefhuis J, et al. Antibacterial medication use during pregnancy and risk of birth defects: National Birth Defects Prevention Study. Arch Pediatr Adolesc Med 2009;163:978-985.
6. Nordeng H, Lupattelli A, Romoren M, Koren G. Neonatal outcomes after gestational exposure to nitrofurantoin. Obstet Gynecol 2013;121:306-313.

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