Exposure to trimethoprim during the 12 weeks before conception increases risk of heart and limb defects: Study
The antibiotic trimethoprim is an inhibitor of dihydrofolate reductase (DHFR), which converts folate to more active components. This folate antagonism of trimethoprim has been associated with several types of congenital malformations and miscarriage when given during pregnancy. This effect is almost entirely abolished by concomitant use of vitamin supplements containing folic acids. The use of multivitamins including folic acid has been associated with a reduced risk of having offspring with cardiovascular, urinary tract, oral cleft, limb and neural tube defects. This further strengthens the evidence of a direct association between DHFR inhibition and malformation. Theoretically, DHFR inhibitors can result in folate deficiency that lasts into the pregnancy period. A risk of congenital malformations occasioned by DHFR inhibitor use prior to pregnancy could have serious consequences.
Trimethoprim is widely used throughout the world to treat urinary tract, respiratory tract, and gastrointestinal infections and is used as daily prophylaxis in HIV infection and AIDS treatment in Africa. Due to its common use, large numbers of fertile women are exposed to the drug before becoming pregnant.
Authors tested the hypothesis that trimethoprim use during the months prior to pregnancy increases the risk of congenital malformations. To this end, authors performed a nationwide study in which administrative registers of trimethoprim use were coupled with registrations of birth and congenital malformations. They conducted a nationwide register-based cohort study including all Danish women giving birth from 1997 to 2004. All women with at least one prescription of trimethoprim dispensed during the 12 weeks before conception were identified.
There was a doubling of congenital malformations in offspring to women exposed to trimethoprim in the 12 weeks before conception. The adjusted odds ratio (OR) of major congenital malformation was 1.87, 95% confidence interval (CI) 1.25–2.81. There was a significant increase in major malformations in heart (OR 2.49) and limbs (OR 2.18).
In the present study, authors found a doubling in the prevalence of major congenital malformations in offspring of women exposed to trimethoprim during the 12 weeks before conception. According to the EUROCAT subgrouping, there was an increased prevalence of heart and limb defects.
In conclusion, study found an association of maternal exposure to trimethoprim during the 12 weeks before conception and a doubling of the rate of congenital malformations in the subsequent offspring. This calls for further investigation, both epidemiological and in vivo animal studies.
Source: Hindawi Publishing Corporation Obstetrics and Gynecology International
Volume 2013,ArticleID 364526
http://dx.doi.org/10.1155/2013/364526
