Trimethoprim-sulfonamide use during the first trimester of pregnancy and the risk of congenital anomalies

Craig Hansen; Susan E Andrade; Heather Freiman; Sascha Dublin; Katie Haffenreffer; William O Cooper; T Craig Cheetham; Sengwee Toh; De-Kun Li; Marsha A Raebel; Jennifer L Kuntz; Nancy Perrin; A Gabriela Rosales; Shelley Carter; Pamala A Pawloski; Elizabeth M Maloney; David J Graham; Leyla Sahin; Pamela E Scott; John Yap; Robert Davis

doi:10.1002/pds.3919

Trimethoprim-sulfonamide use during the first trimester of pregnancy and the risk of congenital anomalies

Pharmacoepidemiol Drug Saf. 2016 Feb;25(2):170-8. doi: 10.1002/pds.3919. Epub 2015 Nov 24.

Authors

Craig Hansen^{1

2}, Susan E Andrade³, Heather Freiman^{1

4}, Sascha Dublin⁵, Katie Haffenreffer⁶, William O Cooper^{7

8}, T Craig Cheetham⁹, Sengwee Toh⁶, De-Kun Li¹⁰, Marsha A Raebel¹¹, Jennifer L Kuntz¹², Nancy Perrin¹², A Gabriela Rosales¹², Shelley Carter¹³, Pamala A Pawloski¹⁴, Elizabeth M Maloney¹⁵, David J Graham¹⁵, Leyla Sahin¹⁶, Pamela E Scott¹⁷, John Yap¹⁸, Robert Davis^{1

19

20}

Affiliations

¹ Center for Clinical and Outcomes Research, Kaiser Permanente Georgia, Atlanta, GA, USA.
² South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
³ Meyers Primary Care Institute, University of Massachusetts Medical School Worcester, Worcester, MA, USA.
⁴ Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
⁵ Group Health Research Institute, Seattle, WA, USA.
⁶ Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.
⁷ Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁸ Department of Health Policy, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁹ Pharmacy Analytical Services, Kaiser Permanente Southern California, Downey, CA, USA.
¹⁰ Division of Research, Kaiser Foundation Research Institute, Kaiser Permanente, Oakland, CA, USA.
¹¹ Kaiser Permanente Colorado Institute for Health Research, Denver, CO, USA.
¹² Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA.
¹³ LCF Research, Albuquerque, NM, USA.
¹⁴ Health Partners Institute for Education and Research, Minneapolis, MN, USA.
¹⁵ Office of Surveillance and Epidemiology, Food and Drug Administration, Silver Spring, MD, USA.
¹⁶ Office of New Drugs, Food and Drug Administration, Silver Spring, MD, USA.
¹⁷ Office of Women's Health, Food and Drug Administration, Silver Spring, MD, USA.
¹⁸ Office of Biostatistics, Food and Drug Administration, Silver Spring, MD, USA.
¹⁹ Center in Biomedical Informatics, University of Tennessee, Memphis, TN, USA.
²⁰ Department of Pediatrics, University of Tennessee, Memphis, TN, USA.

Abstract

Background: Sulfonamide antibacterials are widely used in pregnancy, but evidence about their safety is mixed. The objective of this study was to assess the association between first-trimester sulfonamide exposure and risk of specific congenital malformations.

Methods: Mother-infant pairs were selected from a cohort of 1.2 million live-born deliveries (2001-2008) at 11 US health plans comprising the Medication Exposure in Pregnancy Risk Evaluation Program. Mothers with first-trimester trimethoprim-sulfonamide (TMP-SUL) exposures were randomly matched 1:1 to (i) a primary comparison group (mothers exposed to penicillins and/or cephalosporins) and (ii) a secondary comparison group (mothers with no dispensing of an antibacterial, antiprotozoal, or antimalarial medication during the same time period). The outcomes were cardiovascular abnormalities, cleft palate/lip, clubfoot, and urinary tract abnormalities.

Results: We first identified 7615 infants in the TMP-SUL exposure group, of which 7595 (99%) were exposed to a combination of TMP-SUL and the remaining 1% to sulfonamides alone. After matching (1:1) to the comparator groups and only including those with complete data on covariates, there were 20 064 (n = 6688 per group) in the primary analyses. Overall, cardiovascular defects (1.52%) were the most common and cleft lip/palate (0.10%) the least common that were evaluated. Compared with penicillin/cephalosporin exposure, and no antibacterial exposure, TMP-SUL exposure was not associated with statistically significant elevated risks for cardiovascular, cleft lip/palate, clubfoot, or urinary system defects.

Conclusions: First-trimester TMP-SUL exposure was not associated with a higher risk of the congenital anomalies studied, compared with exposure to penicillins and/or cephalosporins, or no exposure to antibacterials.

Keywords: antibacterial agents; birth defects; medications; pharmacoepidemiology; pregnancy; sulfonamides.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Abnormalities, Drug-Induced / diagnosis
Abnormalities, Drug-Induced / epidemiology*
Adult
Anti-Bacterial Agents / adverse effects
Cohort Studies
Female
Humans
Infant
Infant, Newborn
Male
Pregnancy
Pregnancy Trimester, First / drug effects*
Prenatal Exposure Delayed Effects / chemically induced*
Prenatal Exposure Delayed Effects / diagnosis
Prenatal Exposure Delayed Effects / epidemiology*
Retrospective Studies
Risk Factors
Sulfonamides / adverse effects*
Trimethoprim / adverse effects*
Young Adult

Substances

Anti-Bacterial Agents
Sulfonamides
Trimethoprim

Abstract

Publication types

MeSH terms

Substances

Grants and funding