Use of phenytoin, phenobarbital, or diazepam during pregnancy and risk of congenital abnormalities: a case-time-control study.
OBJECTIVE
Case-control studies are often used to examine putative teratogenic drug effects during organogenesis but these studies are subject to confounding by indication, recall, and participation bias. The case-time-control approach is less susceptible to these sources of bias. We studied congenital abnormalities following exposure to phenytoin, phenobarbital, and diazepam in early pregnancy, i.e., second and third month, compared to mid-pregnancy, i.e., fifth and sixth month of pregnancy.


METHODS
We analyzed data from the Hungarian Case-Control Surveillance of Congenital Abnormalities (1980-1996) in a case-time-control study.


RESULTS
The study included 22 843 children with congenital abnormalities (cases) and 38 151 children with no abnormalities (controls). Overall, odds ratio (OR) for congenital abnormalities after exposure to one of the three drugs in early pregnancy was 1.2 (95% confidence interval (CI): 1.0-1.4). Among children exposed to phenytoin OR for congenital abnormalities was 3.7 (95%CI: 0.3-49.6), for children exposed to phenobarbital the OR was 1.1 (95%CI 0.7-1.7), and for diazepam, OR for congenital abnormalities was 1.2 (95%CI: 1.0-1.4).


CONCLUSIONS
The associations we found between the drugs examined and congenital abnormalities were either only borderline significant or not statistically significant. The case-time-control study provides an interesting way of using existing case-control data to study rare side effect of drugs taken during pregnancy.
Kjaer
Dorte
D
The Danish Epidemiology Science Centre, Department of Epidemiology, Institute of Public Health, University of Aarhus, Aarhus, Denmark. dkkj@soci.au.dk
Horvath-Puhó
Erzsébet
E
Christensen
Jakob
J
Vestergaard
Mogens
M
Czeizel
Andrew E
AE
Sørensen
Henrik Toft
HT
Olsen
Jørn
J
D000014:Abnormalities, Drug-Induced / Q000453:epidemiology / Q000209:etiology*; D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects*; D016022:Case-Control Studies; D018592:Cross-Over Studies; D003975:Diazepam / Q000009:adverse effects*; D005260:Female; D006801:Humans; D006814:Hungary / Q000453:epidemiology; D016017:Odds Ratio; D010634:Phenobarbital / Q000009:adverse effects*; D010672:Phenytoin / Q000009:adverse effects*; D011159:Population Surveillance; D011247:Pregnancy; D012042:Registries / Q000706:statistics & numerical data; D018570:Risk Assessment; D011795:Surveys and Questionnaires; D013997:Time Factors
D000927:Anticonvulsants; D010672:Phenytoin; D003975:Diazepam; D010634:Phenobarbital