Antibiotic Use during Pregnancy and Risk of Birth Defects
Abstract & Commentary
By Jeffrey T. Jensen, MD, MPH, Editor, Leon Speroff, Professor of Obstetrics and Gynecology, Vice Chair for Research, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: First trimester exposure to nitrofurantoin and sulfonamides was associated with an increase in the risk of several birth defects including cleft lip and palate in the National Birth Defects Prevention Study.
Source: Crider KS, 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.
The purpose of this study was to estimate the association between antibacterial medications and selected birth defects. The authors conducted a population-based, multisite, case-control study of women who had pregnancies affected by 1 of more than 30 eligible major birth defects identified via birth defect surveillance programs. The study population included 13,155 cases of women with affected pregnancies and 4941 control women with unaffected pregnancies randomly selected from the same geographical regions (10 states). The main exposure was reported maternal use of antibacterials (1 month before pregnancy through the end of the first trimester), and odds ratios (ORs) measuring the association between antibacterial use and selected birth defects were constructed and adjusted for potential confounders. The reported use of antibacterials increased during pregnancy, peaking during the third month.
Sulfonamides were associated with anencephaly (adjusted OR [AOR] = 3.4; 95% confidence interval [CI], 1.3-8.8), hypoplastic left heart syndrome (AOR = 3.2; 95% CI, 1.3-7.6), coarctation of the aorta (AOR = 2.7; 95% CI, 1.3-5.6), choanal atresia (AOR = 8.0; 95% CI, 2.7-23.5), transverse limb deficiency (AOR = 2.5; 95% CI, 1.0-5.9), and diaphragmatic hernia (AOR = 2.4; 95% CI, 1.1-5.4).
Nitrofurantoins were associated with anophthalmia or microphthalmos (AOR = 3.7; 95% CI, 1.1-12.2), hypoplastic left heart syndrome (AOR = 4.2; 95% CI, 1.9-9.1), atrial septal defects (AOR = 1.9; 95% CI, 1.1-3.4), and cleft lip with cleft palate (AOR = 2.1; 95% CI, 1.2-3.9).
Other antibacterial agents were not associated with a significant increase in the AOR of these birth defects. The authors concluded that sulfonamides and nitrofurantoins were associated with several birth defects, indicating a need for additional scrutiny. In contrast, penicillins, erythromycins, and cephalosporins appeared to be safer alternatives.
The National Birth Defects Prevention Study (NBPS) is conducted by investigators at the Centers for Disease Control and Prevention. This large representative multistate database is about as good as we get in the current United States health care system to assess exposure and rare outcomes in a large population-based classic case-control study. While case-control studies cannot demonstrate a causal relationship, they can suggest important relationships worthy of additional consideration. For the assessment of rare outcomes where prospective randomized studies are impractical, they provide the best evidence for clinical guidance.
This study published last fall in the Archives of Pediatric and Adolescent Medicine has received little press in the obstetric literature. As I discovered recently that nurses and residents at my institution were not aware of these results, I felt it was important to bring them to the attention of readers of OB/GYN Clinical Alert.
Case-control studies are always subject to confounding. Common events like urinary tract infections (UTIs) will lead to multiple exposures, and common drugs will be widely used. Recall bias further complicates studies of exposure, as those women that experience an abnormal pregnancy may have a greater tendency to report exposure or to recall the drug they were treated with.
More than 2% of women in this study were treated for a UTI in the first trimester. The authors designed their assessment to critical exposure during the period of early fetal development. Still, many of the abnormalities are restricted to an even more limited time of exposure, with most structural anomalies occurring before 6 weeks of gestation.1 The majority of subjects in the NBPS were treated between 8-13 weeks, well after the expected developmental critical windows for the listed anomalies.
However, the most commonly used antibiotics penicillins, erythromycins, and cephalosporins (all FDA pregnancy category B) were not associated with an increased risk of anomalies in this study, while both nitrofurantoin and sulfonamides were associated with significant increased AOR of risk for a variety of anomalies. Sulfonamides (FDA pregnancy category C or D) have been shown to be teratogenic in animal studies, although it is unclear whether sulfonamides without trimethoprim pose a significant risk.2 The two drugs act synergistically to block two steps in the biosynthesis of reduced folates, and other case-control studies have demonstrated an increased risk of anomalies with first trimester exposure.3 These drugs can also affect bilirubin metabolism and should not be used in the third trimester and while breast feeding. The observed increase in risk with nitrofurantoin (Category B) is more surprising. The drug primarily concentrates in the urinary tract and has not previously been associated with fetal harm. It is well tolerated, easy to take, and highly effective against most pathogens.
Taken together, the results from this study are far from conclusive. Still, this information will be available on the internet and your patients will be searching that source as soon as they leave the office with your prescription. To avoid a call from your patient (or maybe from her lawyer), it makes sense to provide counseling on your antibiotic choice. Since there are alternatives to use of nitrofurantoins and sulfa/trimethoprim in the first trimester, it is wise to do so even if the evidence is limited. Avoid sulfonamides in the third trimester to avoid the known association with hyperbilirubinemia.
A more important consideration is the reproductive age non-pregnant patient that presents or calls with UTI symptoms. Is it safe to use nitrofurantoin or sulfa drugs in these women? In contrast to the patient at 8 weeks, these are exactly the individuals in whom an early fetal exposure is possible. Consider carefully the drug resistance patterns in your community, and the contraceptive status of your patient when considering therapy. If she is at high risk for pregnancy, best to avoid these drugs.
- Webster WS, et al. The relationship between cleft lip, maxillary hypoplasia, hypoxia and phenytoin. Curr Pharm Des 2006;12:1431-1448.
- Czeizel AE, et al. The teratogenic risk of trimethoprim-sulfonamides: A population based case-control study. Reprod Toxicol 2001;15:637-646.
- Hernandez-Diaz S, et al. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 2000;343:1608-1614.