The epidemiology of neural tube defects was reviewed, using data from two birth defects surveillance systems: the nationwide Birth Defects Monitoring Program and the Metropolitan Atlanta Congenital Defects Program, for 1970-1978 and 1968-1979, respectively. After excluding cases with recognized causes, neural tube defects were divided into two major groups: "singles" and "multiples," depending on the presence of associated major defects. Only singles, which accounted for the majority of cases, were shown to have the well-known epidemiologic characteristics of neural tube defects: marked predominance of females and whites, geographic variation with an east-to-west gradient, and decreasing rates over time. On the other hand, multiples had no excess of females and occurred less predominantly in whites; moreover, their rates showed no geographic variation and little or no downward trends over time. The presence of associated defects indicates that neural tube defects are epidemiologically and probably etiologically heterogeneous. It is suggested that analytic studies of neural tube defects may be more rewarding if they try to identify different risk factors associated with various subgroups. This approach to the study of birth defects may provide better clues to their etiology and pathogenesis.

Estimates of the Apert syndrome birth prevalence and the mutation rate are reported for Washington State, Nebraska, Denmark, Italy, Spain, Atlanta, and Northern California. Data were pooled to increase the number of Apert births (n = 57) and produce a more stable birth prevalence estimate. Birth prevalence of the Apert syndrome was calculated to be approximately 15.5/1,000,000 births, which is twice the rate determined in earlier studies. The major reason appears to be incomplete ascertainment in the earlier studies. The similarity of the point estimates and the narrow bounds of the confidence limits in the present study suggest that the birth prevalence of the Apert syndrome over different populations is fairly uniform. The mutation rate was calculated to be 7.8 x 10(-6) per gene per generation. Apert syndrome accounts for about 4.5% of all cases of craniosynostosis. The mortality rate appears to be increased compared to that experienced in the general population; however, further study of the problem is necessary.

As part of its epidemiologic studies of congenital malformations, the Centers for Disease Control (CDC) conducts two birth defects surveillance systems in the United States. The Metropolitan Atlanta Congenital Defects Programme (MACDP) is an intensive surveillance system using several methods to identify infants born with birth defects in the Atlanta area. The Birth Defects Monitoring Programme (BDMP) is a nationwide surveillance system that monitors 1 million births per year, about a third of all births in the U.S. It relies on diagnoses from newborn discharge summaries to ascertain affected infants. The systems were originally designed to detect potential 'epidemics' of birth defects that could occur following the widespread dissemination of new teratogens similar to thalidomide. In addition to monitoring, they have also proved to be useful resources for a variety of studies of the epidemiology of birth defects.

The extent of clustering of 2 or more defects in the same infant can be expressed as the ratio of the observed number of infants with the defects (O) over the expected number of such infants (E). The expected is usually derived from the product of population rates of individual defects. Because large O/E ratios are obtained for many defect combinations, it has been suggested that clustering of defects is generalized and nonspecific. To control for the tendency of nonspecific clustering of defects, an alternative method is to perform the same calculations among multimalformed infants only. A main limitation of this method is that it adjusts for the clustering tendency of all defects rather than the ones of interest, often resulting in spuriously low O/E ratios. We present a new method to adjust for the tendency for nonspecific clustering between defects that overcomes this limitation. With this method, adjusted O/E ratios are inversely related to the proportion of infants who are multimalformed and have one or more of the defects being examined. Using data from the Metropolitan Atlanta Congenital Defects Program, we apply this method to the previously described associations among VACTERL defects and midline or "schisis" defects. We show that adjusted O/E ratios obtained are greater than those obtained by using multimalformed infants. For midline defects, many of the adjusted ratios were close to one, indicating nonspecific clustering of these defects. Finally, using the example of isotretinoin embryopathy, we show that O/E ratios depend highly on the frequency of exposure in the population, and thus, they should be interpreted with caution.

A retrospective epidemiological study of cleft lip and palate in King County, Washington, between 1956 and 1965 is reported. Multiple sources of ascertainment were employed, and particular attention was given to obtaining information concerning other associated malformations. Occurrences of cleft lip (CL), cleft lip and palate (CL + P), and cleft palate (CP) were analyzed by separate categories, depending on the presence or absence of associated major or minor malformations. The results strongly indicated that clefts with associated malformations are different epidemiological entities from pure clefts. Sex-ratio reversals occurred for some categories with associated malformations. In contrast to the usual male excess of CL f P, there was a female excess of CL f P with major associated malformations. In contrast to the usual female excess of CP, 49% of children with CP with associated malformations were male. No maternal-age effect was observed for any "pure" cleft category, but significant "U-shaped maternal-age distributions were seen for CL + P with associated major malformations, CP with associated major malformations, and CP with all associated malformations. Increased frequency of low birth weight and infant mortality were confined to categories with associated malformations. No significant birth order, season, secular change, or time-space clustering effects were observed. The incidence rate for all clefts was 1.84/1000 live births.

Recent cytogenetic evidence has shown that trisomy 21 can arise, perphaps even in substantial proportion, from paternal nondisjunction. The statistical association between Down syndrome incidence and maternal age, paternal age and birth order has been studied in a sample of over 4000 cases. The size of this sample made it possible to control for the effect of maternal age by single years of age during the search for a paternal age effect and vice versa, and the importance of such stringent control is emphasized. The maternal age association was confirmed with an extremely high degree of statistical significance while no independent effect of paternal age was found; indeed, the rates at paternal ages over 45 years appear to be nearly constant. After adjusting for the effects of parental age, a significant inverse association of birth order with incidence was noted. It also appears that the incidence among very young mothers may be high: for maternal ages 15 years and less the rates seem to be equivalent to those found at 30 or 35 years. In order to help answer the question of whether the maternal age association is the result of increasing rates of nondisjunction or of some other mechanism (for example, an age related defect in a spontaneous abortion screening mechanism), the proportion of cases due to maternal and paternal nondisjunction at different parental ages must be determined.

Health care workers may be occupationally exposed to known and suspected teratogens including viruses, anesthetic gases, sterilants, mercury, and x-radiation. To assess the risk of congenital defects among offspring of health care workers, we analyzed parental occupational histories for 4,915 case babies with congenital defects, registered during the years 1968-1980 by the Metropolitan Atlanta Congenital Defects Program (MACDP) registry, and for 3,027 control babies born without defects during the same period. Offspring of mothers employed in a nursing occupation during the periconceptional period had a modest excess risk of having at least one congenital defect (relative risk [RR] = 1.42; 95% confidence interval [CI] 1.06-1.88); the offspring were at statistically significant increased risk of having anencephaly or spina bifida (RR = 2.00; 95% CI 1.01-4.30), coarctation of the aorta (RR = 2.06; 95% CI 1.10-3.82), genital system defects (RR = 1.61; 95% CI 1.03-2.53), and urinary system defects (RR = 3.43; 95% CI 1.41-8.34). These associations were not confounded by maternal age, education, or alcohol consumption. Offspring of mothers employed in administrative or clerical jobs in the health care industry also had a modest excess risk of defects (RR = 1.35; 95% CI 0.96-1.90), including a statistically significant excess risk of limb defects. We also found associations between neural tube defects and potential exposure to anesthetic gases and to x-radiation, but each association was based on only three case babies of potentially exposed parents. We found no associations between defects and paternal health care employment, except for a few individual defects, and these were based on small numbers of exposed subjects. Only one of five previous studies reviewed found an increased risk of congenital defects among offspring of nurses, but three of the four negative studies had substantially smaller sample sizes than the present study. Detection bias may be a possible explanation for the apparent excess risk of certain defects among offspring of nurses.

The Atlanta Birth Defects Case-Control Study data comprises information obtained from interviews with parents of 4,900 babies born with major birth defects and with the parents of 3,000 babies born without defects. The source of cases is the Centers for Disease Control's Metropolitan Atlanta Congenital Defects program; the case-control study is population-based. Birth defects are classified into 92 groups and cross-tabulated by 105 exposure/risk factor variables; data from selected cross-tabulations are presented. The associations of each of the 105 exposure variables with all types of defects combined are presented, as are the associations of each of the 92 defect groups with the specific exposure variable, maternal diabetes. These data can be used to evaluate hypotheses arising from other sources, and for the purpose of "generating" hypotheses. The data describing all 92 x 105 cross-tabulations are available to other investigators on floppy disk; write to Chief, Birth Defects and Genetic Diseases Branch, Centers for Disease Control, Atlanta, Georgia 30333.