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Trimethoprim use in early pregnancy and the risk of miscarriage: a register-based nationwide cohort study

  • J. T. ANDERSEN (a1) (a2), M. PETERSEN (a1) (a2), E. JIMENEZ-SOLEM (a1) (a2), K. BROEDBAEK (a1) (a2), E. W. ANDERSEN (a3), N. L. ANDERSEN (a4), S. AFZAL (a1) (a2), C. TORP-PEDERSEN (a5) (a6), N. KEIDING (a3) and H. E. POULSEN (a1) (a2) (a6)...

The antibiotic trimethoprim acts as a folate antagonist. Since trophoblasts are very sensitive to drugs that interfere with the folic acid cycle and thereby inhibit DNA synthesis, use of trimethoprim during the first trimester could be associated with miscarriage. A nationwide cohort study including all women in Denmark with a registered pregnancy between 1997 and 2005 was conducted. We used nationwide registers to identify all women giving birth, having a record of miscarriage or induced abortion. Data on exposure to trimethoprim were obtained from the National Prescription Register. Cox proportional hazard regression analysis with exposure to trimethoprim as a time-dependent variable was used to estimate the risk of miscarriage. The adjusted hazard ratio of having a miscarriage after exposure to trimethoprim in the first trimester compared to non-exposure was 2·04 (95% confidence interval 1·43–2·91). Our results indicate that trimethoprim exposure in the first trimester is associated with a doubling of the hazard of miscarriage.

Corresponding author
*Author for correspondence: Dr J. T. Andersen, Laboratory of Clinical Pharmacology, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. (Email:
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1.Schweitzer, BI, Dicker, AP, Bertino, JR. Dihydrofolate-reductase as a therapeutic target. FASEB Journal 1990; 4: 24412452.
2.Baird, DT. Mode of action of medical methods of abortion. Journal of the American Medical Womens Association 2000; 55: 121126.
3.Hernandez-Diaz, S, et al. Folic acid antagonists during pregnancy and the risk of birth defects. New England Journal of Medicine 2000; 343: 16081614.
4.Hernandez-Diaz, S, et al. Neural tube defects in relation to use of folic acid antagonists during pregnancy. American Journal of Epidemiology 2001; 153: 961968.
5.Czeizel, AE, Toth, M, Rockenbauer, M. Population-based case control study of folic acid supplementation during pregnancy. Teratology 1996; 53: 345351.
6.Berry, RJ, et al. Prevention of neural-tube defects with folic acid in China. New England Journal of Medicine 1999; 341: 14851490.
7.Wald, N. Prevention of neural-tube defects – results of the Medical Research Council Vitamin Study. Lancet 1991; 338: 131–7.
8.Werler, MM, et al. Multivitamin supplementation and risk of birth defects. American Journal of Epidemiology 1999; 150: 675682.
9.Yang, QH, et al. Does periconceptional multivitamin use reduce the risk for limb deficiency in offspring? Epidemiology 1997; 8: 157161.
10.Czeizel, AE. Reduction of urinary tract and cardiovascular defects by periconceptional multivitamin supplementation. American Journal of Medical Genetics 1996; 62: 179183.
11.Botto, LD, et al. Periconceptional multivitamin use and the occurrence of conotruncal heart defects: Results from a population-based, case-control study. Pediatrics 1996; 98: 911917.
12.Smulders, YM, et al. Trimethoprim and fasting plasma homocysteine. Lancet 1998; 352: 18271828.
13.Goldberg, AB, Greenberg, MB, Darney, PD. Drug therapy: misoprostol and pregnancy. New England Journal of Medicine 2001; 344: 3847.
14.Grimes, DA, Creinin, MD. Induced abortion: an overview for internists. Annals of Internal Medicine 2004; 140: 620626.
15.UNAIDS. Provisional WHO/UNAIDS secretariat recommendations on the use of cotrimoxazole prophylaxis in adults and children living with HIV/AIDS in Africa. Geneva: UNAIDS; 2000.
16.Andersen, TF, et al. The Danish National Hospital Register – a valuable source of data for modern health sciences. Danish Medical Bulletin 1999; 46: 263268.
17.Knudsen, LB. The Danish Fertility Database. Danish Medical Bulletin 1998; 45: 221225.
18.The Danish National Board of Health. Project regarding data quality in the National Hospital Register [in Danish]. Copenhagen: The Danish National Board of Health; 2004.
19.Gaist, D, Sorensen, HT, Hallas, J. The Danish prescription registries. Danish Medical Bulletin 1997; 44: 445448.
20.von Elm, E, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 2007; 370: 14531457.
21.Sorensen, HT, et al. Identification of patients treated with strong analgesics: an assessment of two Danish information systems with respect to epidemiological research. Journal of Medical Systems 1996; 20: 5765.
22.Kumar, S. Occupational, environmental and lifestyle factors associated with spontaneous abortion. Reproductive Sciences 2011; 18: 915930.
23.Di Prima, FA, et al. Antiphospholipid syndrome during pregnancy: the state of the art. Journal of Prenatal Medicine 2011; 5: 4153.
24.Buss, L, et al. Spontaneous abortion: a prospective cohort study of younger women from the general population in Denmark. Validation, occurrence and risk determinants. Acta Obstetrica et Gynecologia Scandinavica 2006; 85: 467475.
25.Stover, J, Fahnestock, M. Coverage of selected services for HIV/AIDS prevention, Care, and treatment in low- and middle-income countries in 2005. Washington, DC: Constella Futures, POLICY Project, 2006.
26.UNAIDS. Report on the global HIV/AIDS epidemic 2008. Geneva: UNAIDS; 2008.
27.Wiktor, SZ, et al. Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-1-infected patients with tuberculosis in Abidjan, Cote d'Ivoire: a randomised controlled trial. Lancet 1999; 353: 14691475.
28.Nunn, AJ, et al. Role of co-trimoxazole prophylaxis in reducing mortality in HIV infected adults being treated for tuberculosis: randomised clinical trial. British Medical Journal 2008; 337: a257.
29.Mermin, J, et al. Effect of co-trimoxazole prophylaxis on morbidity, mortality, CD4-cell count, and viral load in HIV infection in rural Uganda. Lancet 2004; 364: 14281434.
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Epidemiology & Infection
  • ISSN: 0950-2688
  • EISSN: 1469-4409
  • URL: /core/journals/epidemiology-and-infection
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