The National Birth Defects Prevention Study.

The National Birth Defects Prevention Study was designed to identify infants with major birth defects and evaluate genetic and environmental factors associated with the occurrence of birth defects. The ongoing case-control study covers an annual birth population of 482,000 and includes cases identified from birth defect surveillance registries in eight states. Infants used as controls are randomly selected from birth certificates or birth hospital records. Mothers of case and control infants are interviewed and parents are asked to collect buccal cells from themselves and their infants for DNA testing. Information gathered from the interviews and the DNA specimens will be used to study independent genetic and environmental factors and gene-environment interactions for a broad range of birth defects. As of December 2000, 7,470 cases and 3,821 controls had been ascertained in the eight states. Interviews had been completed with 70% of the eligible case and control mothers, buccal cell collection had begun in all of the study sites, and researchers were developing analysis plans for the compiled data. This study is the largest and broadest collaborative effort ever conducted among the nation's leading birth defect researchers. The unprecedented statistical power that will result from this study will enable scientists to study the epidemiology of some rare birth defects for the first time. The compiled interview data and banked DNA of approximately 35 categories of birth defects will facilitate future research as new hypotheses and improved technologies emerge.

Maternal age specific risk rate estimates for Down syndrome among live births in whites and other races from Ohio and metropolitan Atlanta, 1970-1989.

Our primary objective was to estimate, by one year and five year intervals, maternal age specific risk rates for Down syndrome among whites and among other races from two different populations, metropolitan Atlanta and south west Ohio, using live birth and prenatally diagnosed cases ascertained during 1970-1989. The five year estimates were also calculated separately for each of the five four year periods during these 20 years. Additionally, we compared two different methods of estimating these risk rates by using a third population of whites, and compared two different statistical methods of smoothing the risk rates. The results indicate good agreement between the metropolitan Atlanta and south west Ohio estimates within races, but show a statistically significant difference between the two race categories. Because 86% of live births in the "other races" category in the combined population are to blacks, these data may be seen as the first estimates of maternal age specific risk rates for Down syndrome among blacks calculated by one year intervals. We found excellent agreement in the risk rate estimates among the five four year time periods, between the estimates obtained by using the two different methods of estimation, and between the estimates obtained using the two different methods of statistical smoothing. Our estimated risk rates for white women in their 20s strongly reinforce those from previous studies currently being used for genetic counselling purposes. While we did find somewhat higher rates for women under 20, and increasingly higher rates for those over 30 years of age, these differences are not substantial. Thus, this study in general supports the risk rates estimated from data collected mostly during the 1960s and 1970s.

Goldenhar syndrome among infants born in military hospitals to Gulf War veterans.

Reports in the popular press described the occurrence of Goldenhar syndrome among children of Persian Gulf War veterans (GWVs). The objective of this investigation was to compare the birth prevalence of Goldenhar syndrome among infants born in military hospitals to GWVs and to military personnel who were not deployed to the Gulf War (NDVs). Computerized hospital discharge data were reviewed for infants conceived after the war and born prior to the 1st of October, 1993, in medical treatment facilities (MTFs) operated by the U.S. Department of Defense. Medical records were evaluated for infants diagnosed at birth with at least one abnormality that might be related to Goldenhar syndrome. Two pediatricians, blinded to the parental Gulf War status of each infant, reviewed records. An estimated 75,414 infants were conceived after the Gulf War and born in MTFs during the study period (34,069 GWV infants and 41,345 NDV infants). Seven infants fulfilled the case criteria (five GWV infants and two NDV infants). All infants had fathers who served in the military at the time of their conception and birth. The birth prevalence was 14.7 per 100,000 live births among GWV infants (95% confidence interval [CI]: 5.4-36.4) and 4.8 per 100,000 live births (95% CI: 0.8-19.5) among NDV infants (relative risk: 3.03; 95% CI: 0.63-20.57; P values: [2-tailed] = 0.26, [1-tailed] = 0.16). The few affected cases and the broad confidence intervals surrounding the relative risk require that these results be interpreted with caution and do not exclude chance as an explanation for these findings.

Assessment of reproductive disorders and birth defects in communities near hazardous chemical sites. I. Birth defects and developmental disorders.

Members of the workgroup on birth defects and developmental disorders discussed methods to assess structural anomalies, genetic changes and mutations, fetal and infant mortality, functional deficits, and impaired fetal and neonatal growth. Tier 1 assessments for all five adverse reproductive outcomes consist of questionnaires and reviews of medical records rather than laboratory testing of biologic specimens. The work-group members noted a role for neurodevelopmental testing and for limited genetic studies, such as karyotyping in Tier 2 assessments. Emerging methodologies to identify chromosomal aberrations, DNA adducts, and repair inhibition were reserved for Tier 3.

Prevalence of spina bifida at birth--United States, 1983-1990: a comparison of two surveillance systems.

PROBLEM/CONDITION: Spina bifida is a birth defect of the spinal column that is a substantial contributor to serious developmental disabilities in the United States. The risk for spina bifida and other neural tube defects (NTDs) can be reduced if women consume 0.4 mg of folic acid before and during the first trimester of pregnancy. Public health programs are being developed to prevent many NTDs by increasing the consumption of folic acid by women of childbearing age. To assess the national impact of these programs on the prevalence of NTDs at birth, multistate surveillance is needed to monitor secular trends in birth-prevalence rates. This report summarizes a collaborative effort by CDC and state birth defect surveillance programs in 16 states to a) obtain multistate, population-based data concerning the birth prevalence and descriptive epidemiology of spina bifida and b) determine the usefulness of combining state surveillance data to monitor national trends in the birth prevalence of NTDs. REPORTING PERIOD: This report presents data from birth defects surveillance systems in 16 states for the period 1983-1990 (specific periods covered varied by state). These findings are compared with CDC's Birth Defects Monitoring Program (BDMP) for the same period. DESCRIPTION OF SYSTEMS: Population-based data about live-born and stillborn infants who have spina bifida were analyzed from 16 state programs. These 16 programs differed in size and racial/ethnic composition of the populations, surveillance methods, and completeness of case ascertainment. Hospital-based data about live-born and stillborn infants who have spina bifida also were analyzed from BDMP, a passive case ascertainment surveillance system that obtains data from participating hospitals in 50 states. RESULTS AND INTERPRETATION: From 1983 through 1990, the birth-prevalence rate for spina bifida for the 16 states was 4.6 cases per 10,000 births; the BDMP rate was nearly identical (4.4 cases). State-specific rates varied substantially, ranging from 3.0 (Washington) to 7.8 (Arkansas). Both state-based and BDMP rates varied among racial/ethnic groups; in both systems, the rates were highest for Hispanics and lowest for Asians/Pacific Islanders. In both the state-based surveillance systems and BDMP, the annual rate of spina bifida for the total population declined during the period 1983-1990. Much of this decline can be attributed to increased prenatal diagnosis in the 1980s. However, because of decline in the rates of spina bifida and other NTDs in the United States began before the widespread availability of prenatal diagnostic services, an environmental component may have contributed substantially to the etiologies of these defects. The birth-prevalence rate of spina bifida was slightly higher among females than males. The ratio of female-to-male prevalence rates was 1.2 for both the state-based surveillance systems and BDMP. This ratio varied considerably among racial/ethnic groups and among states. The similarities of rates and trends in the birth prevalence of spina bifida between the state-based surveillance data and the BDMP data indicate that both types of surveillance systems can provide reliable information concerning national trends in the birth prevalence of spina bifida. ACTIONS TAKEN: CDC and state birth defects surveillance programs will use results from this analysis to monitor national trends in the birth prevalence of spina bifida in the United States. Aggregated state-based surveillance data about spina bifida, anencephaly, and other NTDs will facilitate the monitoring of changes in NTDs after implementation of programs to increase folic acid consumption by women of childbearing age.

Chorionic villus sampling and transverse digital deficiencies: evidence for anatomic and gestational-age specificity of the digital deficiencies in two studies.

Several but not all studies indicate that chorionic villus sampling (CVS) is associated with an increased risk for transverse limb deficiencies, including digital deficiencies. It has been suggested that variations in results regarding the transverse digital deficiencies (TDDs) may be due to the use of different classification criteria. We present the combined analysis of two case-control studies, the U.S. Multistate CVS (US) study and the Italian Multicentric Birth Defects (IP-IMC) study, using two different definitions of TDDs. We compared the frequency of CVS exposure in control infants with that among those infants with any number of affected digits (any TDD), and those with all five digits of at least one limb affected (extensive TDDs). The estimated relative risk (RR) for any TDD following CVS was 10.6 (IPIMC) and 6.6 (US). For the extensive TDDs, the RR was 30.5 (IPIMC) and 10.7 (US). In both studies, extensive TDDs were less than 25% of all TDDs. Compared to all TDDs, extensive TDDs were more likely to occur after CVS performed earlier in the first trimester (before 10-11 weeks' gestation). These findings suggest a relationship between the timing of CVS and the severity of TDDs; indicate that using a restrictive definition of TDDs (all five digits affected) may limit the ability to evaluate the association between CVS and TDDs in populations in whom CVS is usually performed at or after 10 weeks' gestation; and highlight the necessity to consider gestational age in any evaluation of the relative risk for limb deficiencies associated with CVS.

Surveillance for anencephaly and spina bifida and the impact of prenatal diagnosis--United States, 1985-1994.

PROBLEM/CONDITION: The reported prevalence of anencephaly and spina bifida in the United States has steadily declined since the late 1960s. During this time, the ability to diagnose these defects prenatally has progressed rapidly. Many U.S. birth defects surveillance systems ascertain defects only among live-born infants or among infants and fetuses beyond a certain gestational age, thus excluding defects among pregnancies prenatally diagnosed as being affected by a neural tube defect (NTD) and electively terminated before the gestational age limit. The impact of prenatal diagnosis and subsequent pregnancy termination on the reported prevalence of anencephaly and spina bifida in the United States has not been well established. However, assessment of this impact is crucial to the use of surveillance data to monitor trends in the occurrence of NTDs and the effectiveness of interventions for these defects (e.g., increased consumption of folic acid). REPORTING PERIOD: This report presents data from birth defects surveillance systems in six states over different time periods: Arkansas, 1985-1989; California, 1989-1991; Georgia, 1990-1991; Hawaii, 1988-1994; Iowa, 1985-1990; and South Carolina, 1992-1993. DESCRIPTION OF SYSTEMS: Population-based data about a) live-born and stillborn infants with anencephaly and spina bifida and b) pregnancies electively terminated after prenatal diagnosis of these defects were analyzed from the Arkansas Reproductive Health Monitoring System; the California Birth Defects Monitoring Program; CDC's Metropolitan Atlanta Congenital Defects Program; the Iowa Birth Defects Registry, the University of Iowa, and the Iowa Department of Public Health; and the Greenwood Genetic Center in South Carolina. Data also were analyzed from the Hawaii Birth Defects Monitoring Program, which includes data for some women who were not residents of the state. The systems differed in the size and racial/ethnic composition of the populations studied, the surveillance methods used, the completeness of ascertainment, and the availability and utilization of prenatal testing and pregnancy termination. RESULTS AND INTERPRETATION: Among all pregnancies ascertained in which the infant or fetus had anencephaly or spina bifida, the percentages that were electively terminated ranged from 9% in Arkansas to 42% in Atlanta and Hawaii, with a corresponding increase in the adjusted prevalence of these defects compared with the prevalence at birth. In each system, pregnancies associated with anencephaly were terminated more frequently than were those associated with spina bifida. These data indicate that the impact of prenatal diagnosis and subsequent pregnancy termination on the prevalence at birth of anencephaly and spina bifida differs among geographic areas and populations. Comprehensive surveillance for these defects requires inclusion of pregnancies that are prenatally diagnosed and then terminated. ACTIONS TAKEN: CDC will use these data to promote the inclusion of prenatally diagnosed and terminated pregnancies in estimates of the prevalence of anencephaly and spina bifida generated by birth defects surveillance programs in the United States. Including such pregnancies is crucial to the ability of these programs to monitor trends accurately and to establish the effectiveness of interventions, including the use of folic acid, for these defects.

Evaluating false positives in two hospital discharge data sets of the Birth Defects Monitoring Program.

The principal goal in this study was to quantify false positives in the hospital discharge data of the Birth Defects Monitoring Program conducted by the Centers of Disease Control and Prevention. The two hospital data processing agencies which contribute data to the Birth Defects Monitoring Program, the Commission on Professional and Hospital Activities and the McDonnell Douglas Health Information Systems, had respective levels of false positives of 13.2 percent and 8.5 percent, levels which were statistically different from each other. These false positive levels should be considered minimal because these data bases do not include information on sick babies who may be transferred into or out of member hospitals, and who may have their initial diagnoses significantly modified. Potential correlates of false positives were evaluated, including hospital size, diagnostic certainty, race, sex, and insurance source. Two-thirds of all false positives were due to the miscoding of correctly diagnosed anomalies, and another quarter were clearly contradicted in notes easily available before the patients were discharged. The authors hope that this study of false positives will enhance the interpretation of the Birth Defects Monitoring Program data and lead to improved understanding of data collection and processing.

Evaluating a new algorithm for linking maternal and newborn medical records.

Linking material and newborn medical records is a valuable tool for assessing the relationship between maternal variables and fetal outcome. This study evaluated the Center for Disease Control's newly developed maternal and newborn medical record linkage system, a computer program that uses weighted variables to determine the most likely maternal and newborn pairs. Any newborn record not achieving a set minimum score with a maternal record remains nonmatched. The objectives of the study were to estimate the program's matching accuracy, determine causes of incorrect matches and nonmatches, develop suggestions for program revisions, and evaluate the effects of the revisions. The study sample included 521 matched and 247 nonmatched maternal and newborn medical records from seven Ohio hospitals. Of all available newborn records (10,068), 574 (5.7%) did not match with maternal records; for those in which a match occurred, the authors ascertained a 98% matching accuracy and determined explanations for nonmatched and incorrectly matched records. The authors noted a greater prevalence of birth defects and prematurity among newborns with nonmatched records than among those with matched records. Program revisions, therefore, focused on reducing the prevalence of nonmatched records. The revised program reduced the prevalence of nonmatched records from 5.7% to 3% but reduced matching accuracy.

Increased risk for transverse digital deficiency after chorionic villus sampling: results of the United States Multistate Case-Control Study, 1988-1992.

Although numerous infants have been reported with transverse limb deficiencies after their mothers had undergone chorionic villus sampling (CVS), it has been unclear whether the procedure caused these defects. We report the results of the first multistate case-control study to assess and quantify the risk for specific limb deficiencies associated with CVS. Case subjects were 131 infants with nonsyndromic limb deficiency ascertained from 7 population-based birth defect surveillance programs, and born from 1988-1992 to mothers 34 years of age or older. Control subjects were 131 infants with other birth defects. We ascertained exposure to CVS from medical records and maternal and physician questionnaires. We assessed rates and timing of exposure to CVS, and estimated relative and absolute risks for anatomic subtypes of limb deficiency. The odds ratio for all types of limb deficiency after CVS from 8-12 weeks' gestation was 1.7 (95% confidence interval, 0.4-6.3). For specific anatomic subtypes, the strongest association was for transverse digital deficiency (odds ratio = 6.4; 95% confidence interval, 1.1-38.6). The risk for transverse digital deficiency increased with earlier gestational exposure (P < 0.01 for trend). We estimated that the absolute risk for transverse digital deficiency in infants after CVS was 1 per 2,900 births (0.03%). Exposure to CVS was associated with a sixfold increase in risk for transverse digital deficiency. The causality of this association is supported by its strength, specificity, biologic plausibility, and consistency with the results of previous studies. Although some centers already inform patients about risk for limb deficiency, this study quantifies the magnitude of risk associated with CVS from 8-12 weeks' gestation.

Comparative epidemiology of Down syndrome in two United States population, 1970-1989.

This study compared the epidemiology of Down syndrome over a 20-year period, 1970-1989, in two populations in which livebirths with Down syndrome were believed to be highly ascertained. One population was a 10-county region in southwest Ohio; the second was a five-county region in metropolitan Atlanta, Georgia. The major objectives were to 1) compare observed incidences of Down syndrome over the entire study period; 2) calculate expected incidences of Down syndrome for each population and compare these with observed incidences; 3) determine incidence trends throughout the period; and 4) examine the impact of prenatal diagnosis on the observed incidence of Down syndrome in each population. Excluding aborted fetuses with Down syndrome diagnosed prenatally, the observed incidence of Down syndrome, 0.98, was significantly lower than that expected, 1.27, within the Atlanta white data set. Once the observed data were adjusted to include aborted fetuses with Down syndrome (total incidence = 1.17), no statistically significant differences remained. No differences were found between observed and expected incidences of Down syndrome for whites in southwest Ohio or for other races in either population. Although uncorrected observed incidences were significantly different between the two populations of whites for the entire 20-year period, the differences again disappeared after the data were corrected to include aborted fetuses. No significant effect of prenatal diagnosis on those of other races was found in either population. Expected Down syndrome incidences rose from the late 1970s throughout the 1980s for both racial groups in Ohio and Atlanta, Georgia; however, because the termination of fetuses with Down syndrome increased over the decade, the observed incidence among whites in southwest Ohio remained at earlier levels and actually fell among whites in Atlanta. These results indicate the increasing importance of prenatal diagnosis and selective abortion in the epidemiology of Down syndrome and of correcting for it when comparing incidences between populations, even within the same time period. These data from 2 decades show that differences in both observed and expected incidences of Down syndrome exist between both populations and races, principally because of differences in demographic age structure and maternal age fertility rates and because of differential use of prenatal diagnosis and selective abortion.

Risk of childhood cancer for infants with birth defects. II. A record-linkage study, Iowa, 1983-1989.

To attempt to confirm associations found in a companion study in Atlanta, Georgia between Down's syndrome and acute leukemia and between pyloric stenosis and childhood cancer, the authors used the State Health Registry of Iowa to link the records of infants and children with cancer for 1983 to 1989 with the records of infants with birth defects for 1983 to 1988. During the study period, birth defects were diagnosed in 10,891 infants younger than 1 year of age, and cancer was diagnosed in 396 children younger than 8 years of age. The authors compared the observed number of children with a defect who developed cancer with the number expected on the basis of the cancer registry rates. Of the 10,891 children with birth defects, 16 developed cancer (standardized incidence ratio (SIR) = 2.0, 95% confidence interval (CI) 1.2-3.3). Of 251 children with Down's syndrome (trisomy 21), two developed leukemia (SIR = 32.1, 95% CI 3.9-116.0). None of the infants with cancer had pyloric stenosis (SIR = 0.0, 95% CI 0.0-6.7). The results of this study supported the association found in the Atlanta study between Down's syndrome and leukemia, but did not support the association found there between pyloric stenosis and childhood cancer. This study, however, had a shorter follow-up period and a smaller number of subjects than the Atlanta study.

Surveillance for and comparison of birth defect prevalences in two geographic areas--United States, 1983-88.

PROBLEM/CONDITION: CDC and a number of states have developed surveillance systems to monitor the birth prevalence of major defects. REPORTING PERIOD COVERED: This report covers birth defects surveillance in Metropolitan Atlanta, Georgia and selected jurisdictions in California for the years 1983-1988. DESCRIPTION OF SYSTEM: The California Birth Defects Monitoring Program and the Metropolitan Atlanta Congenital Defects Program are two population based surveillance systems that employ similar data collection methods. The prevalence estimates for 44 diagnostic categories are based on data from 1983 to 1988 for 639,837 births in California and 152,970 births in metropolitan Atlanta. The prevalences in the two areas are compared adjusting for race, sex and maternal age using Poisson regression. RESULTS: Regional differences in the prevalence of aortic stenosis, fetal alcohol syndrome, hip dislocation/dysplasia, microcephalus, obstruction of the kidney/ureter, and scoliosis/lordosis may be attributable to general diagnostic variability. However, differences in the prevalences of arm/hand limb reduction, encephalocele, spina bifida, or trisomy 21 (Down Syndrome) are probably not attributable to differences in ascertainment because these defects are relatively easy to diagnose. INTERPRETATION: Regional differences in prenatal diagnosis and pregnancy termination may affect prevalences of trisomy 21 and spina bifida. However, the reason for differences in arm/hand limb reduction is unknown, but may be related to variability in environmental exposure, heterogeneity in gene pool, or random variation. ACTIONS TAKEN: Because of the similarities of these data bases, several collaborative studies are being implemented. In particular, the differences in the birth prevalence of spina bifida and Down Syndrome will focus attention on the impact of prenatal diagnosis.

Prevalence of birth defects among low-birth-weight infants. A population study.

Major birth defects are diagnosed in about 3% to 4% of infants during their first year of life. Because many infants with birth defects have intrauterine growth retardation, are born prematurely, or both, the rate of birth defects undoubtedly varies according to the infant's birth weight. Nevertheless, the magnitude of such variation has not, to our knowledge, been adequately studied in well-defined populations. We analyzed data from the population-based Metropolitan Atlanta (Ga) Congenital Defects Program for 1978 through 1988. These data included information on 11,398 infants who were diagnosed with serious birth defects among 317,499 singleton live-born infants. Although the overall rate of birth defects was 3.6%, we observed a striking inverse relationship between the birth defects rate and the infants' birth weights. The birth defect rates were 16.2% for newborns weighing less than 1500 g at birth, 13.2% for newborns weighing from 1500 g to 1999 g, 6.2% for newborns weighing from 2000 g to 2499 g, 3.2% for newborns weighing from 2500 g to 3999 g, and 2.8% for newborns weighing 4000 g or more. Analyses by type of defect indicated that most birth defects were significantly associated with low birth weight. The higher risk of birth defects among low-birth-weight infants demonstrates that birth defects contribute to excess morbidity among low-birth-weight infants. Because of the overlap between birth defects and low birth weight, the prevention of low birth weight in the population depends greatly on a better recognition of the complex etiology of low birth weight and, in part, on the delineation of risk factors that influence the occurrence of birth defects.

Epidemiology of Rh hemolytic disease of the newborn in the United States.

Nationwide surveillance of Rh hemolytic disease of the newborn (RhHDN) indicates that, after a substantial decline in incidence, reported rates reached a plateau in the late 1970s. We conducted a study designed to validate RhHDN surveillance data, to obtain corrected incidence estimates, and to identify potential reasons for the reported plateau. We obtained data from the Birth Defects Monitoring Program, a national surveillance system that collects data from public and private hospitals participating voluntarily. We asked hospitals for copies of the medical records for all infants discharged with a code for RhHDN and for a sample of the medical records of infants discharged with a code for other and unspecified hemolytic disease during 1986. The estimated incidence rate of RhHDN was 10.6 per 10,000 total births, with some regional variations. Our findings indicate that, despite the availability of an effective preventive measure, RhHDN continues to contribute significantly to infant morbidity and mortality in the United States.