Using reproductive effect markers to observe subclinical events, reduce misclassification, and explore mechanism

Biological markers of effect, in general less widely available than exposure markers, do exist in the field of reproduction and increasingly are being used in epidemiological studies. Several such markers, including semen quality, menstrual hormones, early pregnancy loss, and placental abnormalities, are cited as examples. We argue the value of effect markers for detecting subclinical events that are critical for reproductive performance. Such studies can extend knowledge of the true frequency and determinates of reproductive disorders. A second portion of the paper deals with the role of effect markers in reducing disease misclassification. With a hypothetical early pregnancy study as a case in point, we illustrate the degree and direction of bias associated with several different protocols and encourage epidemiologists to weigh these quantitative considerations in deciding on study design. Finally, we discuss uses of biological markers to explore mechanisms, drawing on experience in an ongoing reproductive study that is testing a hypothetical pathway from maternal psychosocial stress to reduced fetal growth using urine catecholamine levels as a physiological marker of exposure and placental vascular abnormalities as a marker of effect.