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Trimethoprim under graviditet?


Bemærk at indholdet på denne side er mere end ét år gammel. Indholdet afspejler derfor ikke nødvendigvis IRFs nuværende holdning.


Månedens spørgsmål fra en praktiserende læge til Klinisk Farmakologisk Afdeling (KKA) i Odense.

 

Konklusion

 

Trimethoprim bør så vidt muligt ikke anvendes under graviditet. De bedste epidemiologiske studier synes ikke at associere in utero eksposition for trimethoprim med en væsentligt øget risiko for medfødte misdannelser. Et større case-kontrol studie har dog kastet nogen tvivl over dette emne, hvilket begrunder den overordnede konklusion.

 

 

 

 

 

Profylaktisk behandling anbefales ikke ved ønsket graviditet. Såfremt der udvikles ukompliceret førstegangscystitis under graviditeten, kan denne behandles efter urinmikroskopi. Mecillinam/pivmecillinam (Selexid) kan anvendes til gravide, og i dag kan sulfametizol ligeledes bruges frem til og med sidste semester, hvis man blot undlader det lige op til forventet fødsel. Ved udebleven effekt bør der foretages dyrkning. I tvivlstilfælde anbefales det at diskutere valg af lægemiddel med en klinisk mikrobiolog og/eller en klinisk farmakolog.  

 

 

 

Question

Is the use of trimethoprim throughout pregnancy associated with increased risk of congenital malformations?

 

 

 

 

 

Case description

A 30-year-old woman suffers from a chronic urinary infection, that requires long-term prophylactic treatment. She is contemplating pregnancy, and her treating gynecologist intends to start treatment with trimethoprim.

 

 

 

 

 

Background information

Trimethoprim is the subject of some controversy with regard to its safety during pregancy. Trimethoprim is a folic acid antagonist, a fact that is of concern, as some folic acid antagonists have been associated with an increased risk of congenital malformations, including cardiac malformations and neural tube defects. Hence, a caution for its use during pregnancy has been advocated for (1).

 

 

 

A few case-reports on malformations following in utero exposure to trimethoprim exist, though these are hardly indicative of a causal relationship (1).

 

 

 

Most epidemiological evidence seem to argue against a substantial teratogenic effect of trimethoprim. In a surveillance study of 229101 completed pregnancies conducted between 1985 and 1992 in the US, 2296 infants had been exposed to the combination of trimethoprim-sulfamethoxazole during the first trimester. A total of 126 major birth defects were found as opposed to 98 expected from the incidence in the background population (1). For the cardiac malformations the numbers were 37 observed versus 23 expected. These data are suggestive of a slightly increased risk of congenital cardiac malformations, but pertains de facto to the specific drug combination rather than to trimethoprim alone. These data are only available in a form that does not permit a critical evaluation.

 

 

 

In a case-control study of 6228 infants with congenital defects, the overall risk of congenital malformations among children exposed to the drug combination of trimethoprim-sulfamethoxazole was increased as the statistical analysis yielded an odds ratio of 2.5 (95 per cent confidence limits 1.22-4.00) (2). No specific pattern of malformations, including cardiac, were obvious in this study.

 

 

 

Recently, a large case-control study on the possible fetal effects of folic acid antagonists (trimethoprim, triamterene sulfazalazine along with antiepileptic folic acid inhibitors) has generated new fuel into the debate (3). Three groups of congenital malformations: cardiac (3870 cases), oral clefts (1962 cases) and urinary tract defects (1100 cases) were compared to a control group of 8387 infants with malformations believed not to be related to folic acid synthesis. A relative risk of 3.4 (95 per cent confidence limits 1.8 to 3.4) and 2.6 (95 per cent confidence limits 1.1 to 6.1) for cardiovascular and oral cleft defects, respectively, were found for the cases exposed to any dihydrofolate reductase inhibitors, ie trimethoprim, triamterene and sulfazalazine, during the second and third trimester.

 

 

 

Importantly, the design and choice of controls do not allow for a conclusion on the overall teratogenic effect of the drugs involved. Subsequently, it was revealed that the results above were based on 12 trimethoprim-sulfonamide exposures among the 3870 cases of cardivascular malformations against six exposures among the 8387 controls. This study has been the subject of some methodological criticisms (4). It should be kept in mind that case-control studies of this nature are associated with substantial methodological difficulties that tend to bias the result toward an overestimation of the alleged risks involved.

 

 

 

In three minor cohort studies, also on the combination of trimethoprim-sulfamethoxazole, including a total of 342 pregancy exposures, increased congenital malformation rates were not observed (5).

 

 

 

The Swedish Birth Registry, which may basically be viewed as a nation-wide cohort study, lists 765 cases of in utero exposure to trimethoprim among whom only 22 were born with congenital defects though some of which were severe (6).

 

 

 

 

 

Conclusion

Prophylactic treatment is not recommended, if pregnancy is planned for. If cystitis develops during pregnancy, treatment should be based on microscopy. Mecillinam/pivmecillinam (Selexid) can be used during all pregnancy as well as sulfametizol, the latter except for the period just ahead of the birth. In case of no effect a microbiologic diagnosis is recommended. In case of doubt it is recommended to discuss the choice of drugs with a clinical microbiologist and/or a clinical pharmacologist.

 

 

 

 

 

References

  1. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 6th edition 2002: 1393t-7t.
  2. Czeizel A. A case-control analysis of the teratogenic effects of co-trimoxazole. Reproduc Toxicol 1990; 4: 305-13.
  3. Hernandez-Diaz S, Werler MM, Walker AM et al. Folic acid antagonists during pregnancy and the risk of birth defects. N Eng J Med 2000; 343: 1608-14.
  4. Sharfstein JM. Folic acid antagonists during pregnancy and risk of birth defects. N Eng J Med 2001; 344: 933-4.
  5. Trimethoprim. TERIS in REPRORISK(R) System. MICROMEDEX (R), Englewood, Colorado (Edition expires 03/2003).
  6. Janus – Stockholms läns landsting (Cited 21/02/04) http://www.janusinfo.org


References Consulted

  • Speight TM, Holford NHG, editors. Avery´s Drug treatment. 4th ed. (1997)  
  • Laegemiddelinformationscentralen, CeKFO, Odense, Denmark  
  • Dollery C Sir editor. Therapeutic Drugs 2nd ed. (1999)  
  • Laegemiddelkataloget. http://www.lk-online.dk  
  • Danish Medicines Agency. Summary of product characteristics. www.dkma.dk  
  • FASS. www.fass.se  
  • Dukes MNG, et al editor. Meyler´s Side effects of drugs. 14th ed. (2000)  
  • Schardein JL. Chemically induced birth defects. 3rd ed. (2000)  
  • Medline  
  • Drugline  
  • Davies DM et al, editors. Davie´s textbook of adverse drug reactions. 5th ed. (1998)  
  • Goodman & Gillman´s. The Pharmacological Basis of Therapeutics 10th ed. (2001)  
  • Janus. http://www.janusinfo.se  
  • Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 6th ed. (2002)  
  • Micromedex  
  • RELIS database. http:/www.relis.no/database. 

 

 

Institut for Rationel Farmakoterapi, 24. april 2006

 

 

 

 

 

 

 

 

 


 

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