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

832 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONA. General ConsiderationsVIII. CONFOUNDINGWe have already mentioned the phenomenon of confounding: a variable that affects both theexposure rate and the outcome rate. An example mentioned was maternal age, which affects bothsmoking rate and the risk of having an infant with Down syndrome. Many possibly importantconfounders can exist in reproductive epidemiology; some thought should be given to the biologicalmeaning of the statistical relationships, otherwise completely misleading results may be drawn. Aclassical example is maternal smoking and perinatal death rate, with birth weight as a confounder.Smoking causes a decrease in birth weight and an increase in perinatal mortality. Low birth weightis an important determinant of perinatal death risk and could therefore be regarded as a confounder.By stratifying for birth weight, not only does the effect of smoking on perinatal death disappear,but also an apparent protective effect appears. This does not mean that maternal smoking does notaffect perinatal death risk, but it means that it does so to a large extent by changing the birth weightdistribution. After birth weight stratification, one will compare small but otherwise healthy infantsof smoking women with small but sick (growth retarded) infants of nonsmoking women. This willnaturally result in a seemingly protective effect of smoking on perinatal death rate. Similar effectswere seen in a study on socioeconomic characteristics and infant mortality. 27B. Maternal Age and Reproductive HistoryBoth of these variables are important confounders in reproductive epidemiology, especially instudies of spontaneous abortion rate, birth weight distribution, and perinatal mortality. They can,however, have a complex effect on outcome, and it is not absolutely clear that a compensation forthem should always be made. Let us look at the group of relatively old primiparous women (say,above 35 years of age). This group contains two main subgroups: women who have had difficultybecoming pregnant and therefore give birth for the first time late in reproductive life, and womenwho have voluntarily postponed pregnancy because of considerations such as education or career.These two groups will have different distributions in, for example, different occupational groups.Differences recorded in reproductive outcome will not be due to actual differences in exposuresrelated to occupation, but to the fact that incomparable groups are compared. If the presence oflong-standing subfertility is recorded in an adequate way, this can be entered into the model, butoften such information is not available.Previous reproductive history, including subfertility, may be an important confounder in studieson occupational exposures, as was pointed out above. It may also affect drug usage, smoking, andother possible exposures. It can be shown that there is a positive association between the use ofantidepressive drugs and the occurrence of hypospadias. This is completely explained by the excessuse of these drugs by subfertile women and an association between subfertility and hypospadias. 65C. Maternal DiseasesMaternal diseases are obvious confounders in the study of the reproductive effects of maternal useof drugs during pregnancy. If the disease directly or indirectly (e.g., by genetic linkage) increasesthe risk for a congenital malformation, any drug used for that disease will appear to be a teratogen.A classical example is insulin and maternal diabetes. It is generally thought that the increased riskfor malformations seen in infants of diabetic mothers 66 is due to the disease and not to insulin;actually, good control of the disease with insulin may reduce the risk. Similarly, epilepsy as suchmay (perhaps mainly because of linked genes) increase the risk for facial clefts, 67 even thoughmaternal anticonvulsant drug use has an effect of its own.© 2006 by Taylor & Francis Group, LLC