A Practical Approach, Second Edition=Ronald D. Ho.pdf

HUMAN STUDIES 801I. INTRODUCTIONEpidemiological studies of human reproduction are important sources of information on developmentaltoxicity for the human. Because of species variability in developmental processes and inresponses to different harmful factors, the ultimate answer to questions on risks to humans canonly be obtained by information on humans. Controlled experiments are usually out of the questionfor practical and ethical reasons. The most important source of information will therefore beepidemiology: studies of possible statistical associations between specific exposures and reproductiveoutcome. Such associations do not necessarily prove causality because they may be due tounidentified or uncontrolled confounders, to bias, or to chance.In rare situations, when a very high risk exists, formal epidemiological studies may not benecessary in order to identify a risk. Examples are thalidomide and rubella embryopathy. Both ofthese important human teratogens were detected by alert clinicians. For such effects to be found,however, the risk increase associated with the exposure must be huge, which means that the effectmust be highly unusual. In most instances, however, we are dealing with small or moderate riskincreases (e.g., anticonvulsant drugs, maternal smoking). It is then necessary to make strict epidemiologicalanalyses, but it is easy to draw wrong conclusions because most such studies have someimperfection and are burdened with uncertainty.High risks are cause for concern for the individual — examples are thalidomide, isotretinoin,rubella, and maternal alcoholism. Low risks may be of little concern for any one exposed individual,but if many women are exposed, the number of reproductive failures caused by the factor may belarge anyway. Maternal smoking is an example. It has been shown to cause reproductive anomalies,including an increased risk for perinatal deaths. But the risk increase is moderate and does notnoticeably affect the probability that a specific pregnancy will end with a perinatal death (perhapsan increase from 0.6% to 0.9% in Sweden). Nevertheless, it has been estimated that some 10% ofall perinatal deaths are related to maternal smoking. 1From the individual’s point of view, absence of a demonstrable risk may be enough. Epidemiologicalstudies can never prove a lack of reproductive toxicity; they can only show that the riskis below a certain level. A low risk, perhaps not detectable even with a number of well-performedepidemiological studies, may nevertheless represent a major cause of birth defects or other reproductivefailures in the population. This also means that society’s decision about possible risks fromspecific exposures must sometimes be based not only on epidemiological data (notably when theseare negative), but also on other types of data, including animal toxicological tests.The basic question which the epidemiological study tries to answer is this: Is there an associationbetween a specific exposure (in the widest sense of the word) and an outcome; if so, can thisassociation be explained by chance, by the action of confounding factors (for a discussion, seeSection VIII), or by bias? Such associations can be estimated with different techniques, the twoclassical ones being the case control (or case referent) and cohort approaches. The first comparesexposures in “cases” (the abnormal reproductive outcome under study) and “controls” (lacking thatabnormal reproductive outcome). With this design, many exposures can be studied simultaneouslyin relation to the selected outcome. The cohort approach studies reproductive outcome in parentswho were exposed in a specific way and the outcome is compared with that of unexposed cohortsor the total population; with this approach, many different abnormal outcomes can be studied aftera specific exposure. In both methods, two variables must be defined: reproductive outcome andexposure.In the analysis and interpretation of all epidemiological studies, two main problems exist:confounding and bias. Confounding means that a third factor covaries with both exposure andoutcome, resulting in a statistical association between the two. Bias means that the informationon exposure is influenced by the outcome or vice versa. These problems are discussed later inthe text.© 2006 by Taylor & Francis Group, LLC