Additional insights into the etiology of cardiac anomalies.

Abstract

In this issue, two reports by Botto and colleagues shed more light on question of what factors influence development of congenital heart defects (CHDs). One study identified a 1.8-fold increased risk of CHDs for reported maternal fever, using data from At? lanta Birth Defects Case Control Study (ABDCCS).1 The other identified a greater than 9-fold increased risk of transposition of great arteries for retinol intakes of 10,000 IU or more, using data from Baltimore-Washington Infant Study (BWIS).2 CHDs, as a group, are most common structural malfor? mation, occurring among an estimated 4-6 infants per 1,000 live births when prematurity-associated de? fects and spontaneously closing atrial septal defects are excluded.3,4 A continuing challenge among birth defects epidemiologists is classification of CHDs into etiologically meaningful groups. Over 30 specific anatomical defects are included under label CHD, with varying epidemiologic features.5 In consideration of this variability, Botto and colleagues appropriately focused their analyses on defects that were not asso? ciated with a known syndrome. The greater challenge is classifying cases with more than one cardiac defect and/or extra-cardiac defects. The approach used in both studies was to create a diagnostic hierarchy, giving priority to defects with earliest embryologic disturbance, and then to categorize case with one diagnosis that is highest in hierarchy.5 This strategy represents a major advance in studying epidemiology of CHDs, but there are limitations. First, approach ignores issue of complex car? diac defects by combining cases affected by multiple defects (particularly defects that are thought to arise from different pathogenetic mechanisms) with cases affected by only one defect. Second, approach also ignores fact that both single and multiple cardiac defects can occur along with defects of other organs and/or systems, possibly representing different etiologies. Although cases in BWIS and ABDCCS databases have previously been classified according to presence of extra-cardiac defects, these subgroups w re not presented in these reports, presumably owing to small numbers. The list of known risk factors for specific CHDs is short, including only positive family history of CHD and maternal diabetes mellitus, epilepsy and/or anticonvulsant use, rubella, and isotretinoin use.6,7 The paucity of known risk factors cannot be attributed to a lack of studies. Indeed, there are many suspected risk factors?those that have been implicated in some studies, but refuted in others. Both maternal fever and vitamin A intake fall into this category.6,8-18 Many methodologic arguments (e.g., confounding, selection bias, definitions of outcomes, random misclassifica? tion, recall bias) can be invoked here to explain differences in study findings. Because specific CHDs are rare, usual epidemiologic approach is retro? spective, with concomitant challenges in accurate exposure measurement. In an effort to assess validity of reported fever in ABDCCS, Botto et al. compare its reported prevalence of fever with prevalences reported in other studies,6,8,9 acknowledging differences in exposure definition. Such comparisons are further complicated by length of exposure interval because longer interval greater opportunity for exposure to occur. While ABDCCS examined a four-month interval, previous studies examined the first trimester,6,8,9 which tends to be regarded by study subjects as an approximate 3 month interval from time pregnancy is recognized to third month. In addition, infectious diseases that cause fever will vary by geography and time, further obscuring comparisons across studies. Nevertheless, concerns about reporting accuracy are warranted. The ABDCCS collected exposure information by maternal interview two to fourteen years after birth of study child. Fever as an indicator of hyperthermia or infection is extremely difficult to measure accurately in retrospective studies, even when interval between early gestation and data collection is comparatively short. I recently collected data that illustrate this point. Among control mothers who were interviewed within six months of birth, only 60% of those with a reported fever had taken their temperatures, and 80% of documented fevers were reported to be less than 102?F (38.9?C), postulated threshold for teratogenesis in humans.19 It is also likely that some women with infections do not report fever, From Slone Epidemiology Unit, Brookline, MA and Fogarty Senior Inter? national Fellow, Institute for Child Health Research, Perbin, Australia.