Hindawi Publishing Corporation Obstetrics and Gynecology International Volume 2012, Article ID 148616, 16 pages doi:10.1155/2012/148616 Review Article The Problem of Confounding in Studies of the Effect of Maternal Drug Use on Pregnancy Outcome Bengt Ka¨lle´ n Tornblad Institute, Lund University, 223 62 Lund, Sweden Correspondence should be addressed to Bengt Ka¨lle´n, Bengt.Kallen@med.lu.se Received 12 August 2011; Accepted 29 August 2011 Academic Editor: Gideon Koren Copyright © 2012 Bengt Ka¨lle´n. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In most epidemilogical studies, the problem of confounding adds to the uncertainty in conclusions drawn. This is also true for studies on the eﬀect of maternal drug use on birth defect risks. This paper describes various types of such confounders and discusses methods to identify and adjust for them. Such confounders can be found in maternal characteristics like age, parity, smoking, use of alcohol, and body mass index, subfertility, and previous pregnancies including previous birth of a malformed child, socioeconomy, race/ethnicity, or country of birth. Confounding by concomitant maternal drug use may occur. A geographical or seasonal confounding can exist. In rare instances, infant sex and multiple birth can appear as confounders. The most diﬃcult problem to solve is often confounding by indication. The problem of confounding is less important for congenital malformations than for many other pregnancy outcomes. 1. Introduction The golden standard in medical clinical science is the randomized double-blind study. There are, however, many situations when this method is not applicable for ethical reasons. One such situation refers to use of drugs during pregnancy and pregnancy outcome. It would be unethical to randomize sick or healthy pregnant women or women who plan pregnancy to the use of a speciﬁc drug or a placebo. Conclusions therefore have to be based on nonrandomized epidemiological studies when exposure (use of drugs) occurs spontaneously. Notably when moderate eﬀects occur, such studies are open to criticism for many reasons, for example, bias in exposure or outcome data and diﬃculty in the control of confounding. If one is studying the relationship between maternal use of a speciﬁc drug (e.g., an antidepressant) and the presence of, for instance, congenital malformations in the oﬀspring an observed relationship may not be due to eﬀects of the drug. If a factor directly aﬀects both exposure and outcome, a confounding will exist and adjustment for it is needed. This situation is schematically shown in Figure 1(a) and can be exempliﬁed with maternal age as a confounder in the analysis of maternal smoking and the risk for Down syndrome. In a crude analysis, maternal smoking seems to decrease the risk for Down syndrome with an odds ratio (OR) of 0.77. If, however, one adjusts for the fact that pregnant women smoke less with increasing age at delivery and that the risk for Down syndrome increases with woman’s age, the OR changes to 0.94 and is far from being statistically signiﬁcant. The opposite eﬀect is obtained if the exposure is a drug, the use of which increases with maternal age, and Down syndrome is the outcome. This will result in an increased crude OR. If adjustment is made for maternal age, the eﬀect may disappear. These two examples also show that confounding can result in a too low risk estimate or a too high estimate, depending on whether the eﬀects of the confounder are in the opposite or the same direction on exposure and outcome. Various methods have been used in studies on the eﬀect of maternal drug use on pregnancy outcome. These were discussed by the author in an earlier article [1]. Many diﬀerent pregnancy outcomes can be studied, for example, miscarriage, congenital malformations, preterm birth, low birth weight, intrauterine growth retardation, neonatal mor- bidity, and long-term morbidity including eﬀects on neu- ropsychiatric development and risk of cancer. The problem of confounding will be relevant for all outcomes.