A Possible Association between Oral Aminophylline Treatment during Pregnancy and Skeletal Congenital Abnormalities

To study the human teratogenic potential of oral aminophylline treatment during pregnancy.

The analysis of each case and its matched controls, as well as comparison of population or patient controls and cases with 25 groups of congenital abnormalities in the population-based data set of the large Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996.

38 151 pregnant women who had newborn infants without any congenital abnormalities (population control group), 22 843 pregnant women who had newborn infants or fetuses with congenital abnormalities, and 834 patient controls with Down's syndrome.

Prevalence of aminophylline use in cases with the 25 congenital abnormality groups compared with population control and patient control groups.

The prevalence of oral aminophylline treatment during pregnancy was similar in the case group (1374 pregnant women; 6.0%) and the population control group (2284 pregnant women; 6.0%) [crude prevalence odds ratio (POR) 1.0, 95% confidence interval (CI) 0.9-1.1], while it was higher in the patient control group (55 pregnant women; 6.6%). Comparisons of total population or patient control groups and cases with the 25 different congenital abnormality groups, as well as analysis of cases and their matched controls, indicated an association between aminophylline use and congenital abnormalities of the musculoskeletal system (crude POR 5.0, 95% CI 1.4-18.4, adjusted POR 4.7, 95% CI 1.3-17.2 for aminophylline treatment during the second through third months of gestation; crude POR 1.5, 95% CI 1.0-2.2, adjusted POR 1.5, 95% CI 0.9-2.2 for aminophylline treatment during the entire pregnancy), particularly pectus excavatum/carinatum (3.5 times excess). There was a possible association between aminophylline and clubfoot and posterior cleft palate. These findings may be connected with recall bias, although this bias was restricted by the evaluation of maternal drug use only during the critical period of the above congenital abnormalities and by evaluating medically recorded aminophylline treatment, as well as by the use of patient controls.

Our findings and previous animal investigations can only be regarded as a signal for the possible association between oral treatment with aminophylline during pregnancy and some congenital abnormalities of the skeletal system.