title: Trimethoprim-sulfonamide use during the first trimester of pregnancy and the risk of congenital anomalies.
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.
authors.affiliation: Center for Clinical and Outcomes Research, Kaiser Permanente Georgia, Atlanta, GA, USA.|South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
authors.forename: Craig
authors.initials: C
authors.lastname: Hansen
authors.affiliation: Meyers Primary Care Institute, University of Massachusetts Medical School Worcester, Worcester, MA, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Andrade
authors.affiliation: Center for Clinical and Outcomes Research, Kaiser Permanente Georgia, Atlanta, GA, USA.|Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Freiman
authors.affiliation: Group Health Research Institute, Seattle, WA, USA.
authors.forename: Sascha
authors.initials: S
authors.lastname: Dublin
authors.affiliation: Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Haffenreffer
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Health Policy, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: William O
authors.initials: WO
authors.lastname: Cooper
authors.affiliation: Pharmacy Analytical Services, Kaiser Permanente Southern California, Downey, CA, USA.
authors.forename: T Craig
authors.initials: TC
authors.lastname: Cheetham
authors.affiliation: Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.
authors.forename: Sengwee
authors.initials: S
authors.lastname: Toh
authors.affiliation: Division of Research, Kaiser Foundation Research Institute, Kaiser Permanente, Oakland, CA, USA.
authors.forename: De-Kun
authors.initials: DK
authors.lastname: Li
authors.affiliation: Kaiser Permanente Colorado Institute for Health Research, Denver, CO, USA.
authors.forename: Marsha A
authors.initials: MA
authors.lastname: Raebel
authors.affiliation: Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Kuntz
authors.affiliation: Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Perrin
authors.affiliation: Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA.
authors.forename: A Gabriela
authors.initials: AG
authors.lastname: Rosales
authors.affiliation: LCF Research, Albuquerque, NM, USA.
authors.forename: Shelley
authors.initials: S
authors.lastname: Carter
authors.affiliation: Health Partners Institute for Education and Research, Minneapolis, MN, USA.
authors.forename: Pamala A
authors.initials: PA
authors.lastname: Pawloski
authors.affiliation: Office of Surveillance and Epidemiology, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Maloney
authors.affiliation: Office of Surveillance and Epidemiology, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Graham
authors.affiliation: Office of New Drugs, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Leyla
authors.initials: L
authors.lastname: Sahin
authors.affiliation: Office of Women's Health, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Scott
authors.affiliation: Office of Biostatistics, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: John
authors.initials: J
authors.lastname: Yap
authors.affiliation: Center for Clinical and Outcomes Research, Kaiser Permanente Georgia, Atlanta, GA, USA.|Center in Biomedical Informatics, University of Tennessee, Memphis, TN, USA.|Department of Pediatrics, University of Tennessee, Memphis, TN, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Davis
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000175:diagnosis / Q000453:epidemiology*; D000328:Adult; D000900:Anti-Bacterial Agents / Q000009:adverse effects; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000187:drug effects*; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology*; D012189:Retrospective Studies; D012307:Risk Factors; D013449:Sulfonamides / Q000009:adverse effects*; D014295:Trimethoprim / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D013449:Sulfonamides; D014295:Trimethoprim
keywords: antibacterial agents; birth defects; medications; pharmacoepidemiology; pregnancy; sulfonamides