Damkier P, Bronniche LMS, Korch-Frandsen JFB, et al. In utero exposure to antibiotics and risk of congenital malformations: a population-based study. Am J Obstet Gynecol. 2019 Dec;221(6):648.e1-648.e15. doi: 10.1016/j.ajog.2019.06.050. Epub 2019 Jun 28. (Original study)

BACKGROUND: Antibiotics are commonly prescribed during pregnancy. Although the safety of most penicillins is well established, some controversy and uncertainty are associated with the use of other commonly prescribed antibiotics.

OBJECTIVE: To determine the risk of congenital malformations following first-trimester in utero exposure to 10 commonly prescribed antibiotics in Denmark.

MATERIALS AND METHODS: This was a cohort study comprising all singleton liveborn children in Denmark between 2000 and 2015. Data on malformations were collected through 2016. Merging validated and comprehensive populationwide Danish healthcare and civic registries, we merged data on pregnancy, prescription drugs purchases during first trimester and congenital malformations. Using logistic regression, we calculated the odds ratio for congenital malformations (any), major congenital malformations, and cardiac congenital malformations for the 10 most commonly prescribed antibiotics (excluding 4 penicillins that served as control). In the primary analysis, the exposed cohort was compared to a cohort exposed to any of 4 penicillins considered safe during pregnancy (ampicillin, pivampicillin, benzylpenicillin, and phenoxymethylpenicillin). In sensitivity analysis, the exposed cohort was compared to an unexposed cohort. Covariate adjustments were made for maternal age at delivery, year of delivery, parity, pre-pregnancy body mass index, smoking, educational status, employment status, and annual personal income.

RESULTS: We found no increased risk of congenital malformations to be related to first-trimester in utero exposure to the 10 most commonly prescribed antibiotics in Denmark compared to a cohort of pregnant women exposed to penicillins that are considered safe during pregnancy. Compared to unexposed pregnancies, small increased risks for major malformations and cardiac malformations were apparent for pivmecillinam (odds ratio, 1.13; confidence interval, 1.06-1.19; and odds ratio, 1.15; confidence interval, 1.04-1.28, respectively), sulfamethizole (odds ratio, 1.15; confidence interval, 1.07-1.24; and odds ratio, 1.22; confidence interval, 1.07-1.39, respectively), and azithromycin (odds ratio, 1.19, confidence interval, 1.03-1.38; and odds ratio, 1.29, confidence interval, 0.99-1.67, respectively).

CONCLUSION: In this large populationwide cohort study, we found, with a high degree of precision, no increased risk of congenital malformations following first-trimester exposure to 10 commonly prescribed systemic antibiotics.

Discipline Area Score
FM/GP/Obstetrics 7 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Infectious Disease 6 / 7
Family Medicine (FM)/General Practice (GP) 6 / 7
Emergency Medicine 6 / 7
Pediatric Neonatology 6 / 7
Obstetrics 5 / 7
Comments from MORE raters

Emergency Medicine rater

Large epidemiolgoic Danish study of 1st-trimester pregnancy exposure to antibiotics and the risk for congenital malformations. No clear increased risk for 10 common antibiotics as compared with penicillin. Clear overall increased risk associated with any antibiotic compared to non-exposure, suggesting confounding by indication. Of the 10 tested with narrow enough CIs and relevance to North America -- TMP-SMX, azithromycin, amoxicillin, dicloxacillin, and nitrofurantoin -- only azithromycin and TMP-SMX had increased congenital malformation risk compared with the non-exposed cohort, although not compared with penicillin. Lower 95% CI was close to 1 in both cases compared with penicillin, however, the upper 95% CI limit was up to 1.2-1.3, which could thus still reasonably contain a small increased risk such that I would probably try to avoid those two classes of antibiotics unless absolutely indicated.

Emergency Medicine rater

Given the frequency of antibiotic prescribing to pregnant patients in the ED and concern for congenital effects, this should serve as a reassurance to EM physicians and patients.

Family Medicine (FM)/General Practice (GP) rater

Antibiotics seem to have no association with congenital malformations. Of course, the decision to use antibiotics is always weighed against the risk for maternal harm and death if not given. As always, be cautious but use if needed.

FM/GP/Obstetrics rater

This helpful registry based study shows that we cannot be complacent about the potential for teratogenesis following the use of antibiotics in pregnancy.

FM/GP/Obstetrics rater

Very interesting especially since no significant risk with quinolones, sulfamethizole, and doxycycline!

Infectious Disease rater

This large study provides some reassurance that most common antibiotics are not associated with increased risk for malformation when given to pregnant women in their first trimester.

Infectious Disease rater

Reassuring data for parents and healthcare workers when antibiotics are indicated during the first trimester of pregnancy. Although the odds ratios for several of the antibiotics were slightly more than one, indicating an increased risk of major congenital and cardiac malformations, when interpreted in the context of a 2-4% risk without antibiotics, this increased risk is very small. Thus, when indicated, the benefit of these antibiotics outweighs the small risk.

Obstetrics rater

Important information about the safety of antibiotics in pregnancy, but does not address the serious problem of overuse of all antibiotics.

Pediatric Neonatology rater

I`m not sure there was ever much concern that antibiotic use in pregnancy caused malformations. This may have answered a question that wasn`t asked but perhaps should have been.
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