The teratogenic risk of trimethoprim-sulfonamides: a population based case-control study

• Published in: Reproductive toxicology (Elmsford, N.Y.) Vol. 15; no. 6; pp. 637 - 646
• Main Authors: Czeizel, Andrew E., Rockenbauer, Magda, Sørensen, Henrik T., Olsen, Jørn
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-11-2001; Elsevier
• Subjects: Abnormalities, Drug-Induced - epidemiology; Adult; Anti-Infective Agents, Urinary - adverse effects; Biological and medical sciences; Case-Control Studies; Congenital cardiovascular malformations; Cotrimoxazole; Drug Combinations; Drug toxicity and drugs side effects treatment; Female; Gestational Age; Humans; Hungary - epidemiology; Infant, Newborn; Medical sciences; Miscellaneous (drug allergy, mutagens, teratogens...); Multiple congenital abnormalities; Pharmacology. Drug treatments; Population Surveillance; Pregnancy; Pregnancy Outcome; Registries; Risk Assessment; Risk Factors; sulfamethazine; Sulfamethazine - adverse effects; Teratogenic risk; Trimethoprim, Sulfamethoxazole Drug Combination - adverse effects; Trimethoprim-sulfamethazine; Trimethoprim-sulfamethoxazole; Hungary; Europe; Congenital cardiovascular malformations; Trimethoprim-sulfamethoxazole; Cotrimoxazole; Multiple congenital abnormalities; Teratogenic risk; Trimethoprim-sulfamethazine; Human; Drug combination; Sulfonamide; Malformation; Toxicity; Trimethoprim; Case control study; Teratogen; Antibacterial agent; Epidemiology
• ISSN: 0890-6238; 1873-1708
• DOI: 10.1016/S0890-6238(01)00178-2

Objective: To study human teratogenic potential of two trimethoprim-sulfonamide combinations: trimethoprim-sulfamethoxazole (cotrimoxazole) and trimethoprim-sulfamethazine during pregnancy. These agents have antifolate effects and other antifolate agents can induce multiple congenital abnormalities, neural-tube defects, cardiovascular, and other malformations in animal experiments and in humans.
Design: Pair analysis of cases with congenital abnormalities and matched healthy controls in the large population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities between 1980 and 1996.
Participants: 38,151 pregnant women who had newborn infants without any congenital abnormalities (control group) and 22,865 case pregnant women who had newborns or fetuses with congenital abnormalities.
Main Outcome: Prevalence of drug use in matched case-control pairs to study the possible association with congenital abnormalities.
Results: In the case group 351 (1.5%) and in the control group 443 (1.2%) pregnant women were treated with cotrimoxazole (crude OR 1.3 with 95% CI 1.1–1.5). In addition 45 (0.2%) case and 39 (0.1%) control pregnant women had trimethoprim-sulfamethazine treatment (crude OR 1.9 with 95% CI 1.3–3.0). A higher rate of multiple congenital abnormalities (including mainly urinary tract and cardiovascular abnormalities) was found in case infants born to mothers with cotrimoxazole treatment during the second-third months of pregnancy. In addition, a higher rate of cardiovascular malformations occurred in cases born to mothers with cotrimoxazole treatment and trimethoprim-sulfamethazine treatment during the second-third months of pregnancy, respectively.
Conclusion: Treatment with cotrimoxazole during pregnancy may increase the risk of cardiovascular malformations, and particularly multiple congenital abnormalities including defects of the urinary tract and cardiovascular system. A higher rate of cardiovascular malformations was also found after treatment with trimethoprim-sulfamethazine in the second-third months of pregnancy.