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

HUMAN STUDIES 821Table 20.1Maternal smoking and odds ratiosfor different types of facial clefts 60Facial Cleft Category Odds Ratio 95% Confidence IntervalCleft lip and /or palate, isolated 1.11 0.99–1.29Associated 1.41 0.98–2.09Median cleft palate, isolated 1.35 1.12–1.63Associated 0.88 0.51–1.54All facial clefts, isolated 1.18 1.06–1.31Associated 1.19 0.88–1.62B. Selection of CasesIt may seem easy to define a case in studies of reproductive epidemiology, but it sometimes offersdifficulties. If we are interested in the effect of environmental factors, obviously it would be goodto exclude all infants where the malformation has a nonenvironmental cause, e.g., a monogeniccondition or a chromosome anomaly. Even though environment may play a role in the etiology ofa specific malformation (e.g., duodenal atresia) in a Down infant, the major cause of the malformationin that infant is the nondisjunction process leading to trisomy 21. In many conditions, e.g.,cleft lip and palate, a genetic component occurs. It can then be debated whether infants with aknown family history should be excluded. The ideal is to treat them as a separate group, butunfortunately such splitting results in a reduced number of cases available for analysis. It can alsobe argued that the genetic background may act by increasing the susceptibility to environmentalagents, and an exclusion of infants with a known family history may reduce the proportion of“susceptible” cases.Case selection can be more or less strict. Should all neural tube defects be lumped together, orshould anencephaly and spina bifida be kept apart, and should the latter perhaps be divided intohigh and low forms? It is possible that only a subset of the group is associated with the environmentalexposure. If all are analyzed together, the risk is that this subgroup will be drowned among theremaining ones that are not associated with the exposure. Again, the ideal is to subdivide thematerial and look for heterogeneity in it, but the risk is that numbers and statistical power arediminished. A balance must be kept between large enough numbers to permit statistical analysisand groupings specific enough to prevent dilution of possible associations, thereby reducing power.One important distinction that is often made is between infants with isolated congenital malformationsand infants with two or more associated malformations. There is some good evidencethat these may be different etiological and pathogenetic entities that should be analyzed separately.In some circumstances, separating cases into subgroups that make biological sense does notseem to affect the association with an exposure. Table 20.1 exemplifies this from a study on thepossible association between maternal smoking and facial clefts. 60 The material was divided intocleft lip with or without cleft palate and isolated cleft palate; these are regarded as very differententities. Cases involving known chromosomal anomalies were deleted, and those remaining werecategorized as “isolated” and “associated.” The association with maternal smoking was seen inthree of the four subgroups, and the estimated odds ratios did not differ significantly. Statisticalsignificance was not reached in all groups separately but was attained when the groups were totalled.C. Control DefinitionControl definition can also offer problems. It is important to realize the definition of a control. Itis not necessarily a delivery of a normal infant; it is a pregnancy that could have ended as a casebut did not. A spontaneous abortion can never be a control to an infant with a congenital malformation,but an infant with a congenital malformation can be a control to a spontaneous abortion.© 2006 by Taylor & Francis Group, LLC