Interpretation of recurring weak associations obtained from epidemiologic studies of suspected human teratogens

Abstract

Epidemiological studies of suspected human teratogens not infrequently lead to recurring weak or moderate associations (relative risks or odds ratios ranging from greater than 1 to 3 for adverse effects and from 1/3 to less than 1 for protective effects) between specific defects and prenatal exposures. Examples of such associations include cigarette smoking and oral clefts (odds ratios between 1 and 2) and periconceptional multivitamin/folic acid supplementation and neural tube defects (odds ratios from 1/3 to 1). In this paper, we illustrate that low relative risk recurring in well-designed studies may reflect underlying biologic mechanisms and should not be readily dismissed. Low relative risks could be the result of a combination of the following factors: 1) unmeasured confounding, 2) exposure misclassification (often related to the inability to pinpoint relevant dose and timing), 3) outcome misclassification (related to the etiologic heterogeneity of birth defects), 4) biologic interactions (related to teratogenic effects in population subgroups defined by genetic susceptibility or the presence of other exposures), and 5) differential prenatal survival (related to the combined impact of the exposure and the defect on prenatal survival). These issues can be addressed in epidemiologic studies by using biological markers of exposure and susceptibility, dysmorphologic evaluation of affected infants, subgroup analysis for etiologic heterogeneity, a search for biologic interactions, and the use of prospective cohort studies. Finally, low relative risks in the face of common exposures can reflect an important public health contribution of the exposure to the occurrence of the defect in the population.

Risk of uterine perforation with levonorgestrel-releasing and copper intrauterine devices in the European Active Surveillance Study on Intrauterine Devices

“…In general, it is very difficult to interpret a relative risk of two or less in such research [14][15][16][17][18].…”

Chemical exposure during pregnancy and oral clefts in newborns

“…Khoury et al (1992) sum up the above comments when they conclude that weak associations may be influenced by five factors: potential confounders that have not been evaluated, exposure classification errors, etiologic heterogeneity of birth defects, effects of biological interactions, and differential prenatal survival. Thus, some immeasurable factors belonging to the causal chain could dilute the effects of association, resulting in smaller measures.…”

Phenotypic discordance in a family with monozygotic twins and non-syndromic cleft lip and palate

“…Case-control and cohort studies have searched for environmental factors that might influence the development of this common malformation, such as maternal cigarette smoking [Saxen, 1974;Evans et al, 1979;Ericson et al, 1979;Shiono et al, 1986;Khoury et al, 1987Khoury et al, , 1989Werler et al, 1990;Hwang et al, 19951, periconceptional supplementation of folic acid and multivitamins [Tolarova and Harris, 1995;Shaw et al, 19951, agricultural chemical use [Gordon and Shy, 1981;Nurminen et al, 19951, and place of residence [Christensen et al, 19951, among others. However, these studies are subject to numerous biases [Khoury et al, 1992;Hemminki et al, 1995;Nurminen, 1995;Lie, 19951, and their results have often been contradictory and inconclusive.…”