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Population Study of Congenital Hypothyroidism and Associated Birth Defects, Atlanta, 1979-1992 by Helen E. Roberts, Cynthia A. Moore, Paul M. Fernhoff, Ann L. Brown, and Muin J. Khoury
Very little data are available from population-based studies on congenital hypothyroidism (CH) epidemiology and patterns of associated birth defects. By linking data from two population-based registries, we describe the epidemiology of CH and associated defects in Atlanta from 1979-1992. Cases included all infants with CH born from 1979-1992 to mothers residing in the metropolitan Atlanta area at the time of birth. We ascertained CH cases by reviewing newborn screening records and records of the Metropolitan Atlanta Congenital Defects Program (MACDP), a population-based registry of all serious birth defects diagnosed during a child’s first year of life. We linked CH cases with MACDP records to ascertain the presence of serious birth defects among infants with CH. Of 97 infants identified with CH through newborn screening and/or MACDP (1:5,000 live births), 87 had primary CH, and 10 had secondary. The rate of primary CH was higher among non-hispanic whites than among blacks (1:4,400 vs. 1:10,000) and among females compared with males (1:4,000 vs. 1:7,700). Among infants with primary CH, 77 had isolated CH, 3 had Down syndrome, and 7 had unrelated major structural defects. Based on Atlanta population rates of Down syndrome and major structural anomalies, we infer i) infants with Down syndrome have a 35-fold increased risk for primary CH compared with infants in the general population (P<.0001); ii) infants with primary CH have a 2.2-fold increased risk for major structural anomalies (P<.05). Because this is the first population study of CH in the United States in which data from two population-based registries were linked, the epidemiologic patterns and associated defects are more representative than those found in studies based on newborn screening records only. The incidence of congenital hypothyroidism (CH) in North America is about 1 in 4,000 live births, making it one of the most common preventable causes of mental retardation [Fisher et al., 1979]. Researchers have shown that infants with CH have normal developmental quotients at 6-7 years of age if they are treated promptly after birth and monitored closely during their early years [Glorieux et al., 1985; New England Congenital Hypothyroidism Collaborative, 1985]. Affected infants have few signs or symptoms during their neonatal course, so routine screening is the only means of detection. Newborn screening for CH is now required in every state in the United States, and screening in Georgia for CH began in February 1979 [Fernhoff et al., 1982]. There are several reports of an increased frequency of birth defects associated with primary CH [Fernhoff et al., 1987; New England Congenital Hypothyroidism Collaborative, 1988; Grant et al., 1988; Lazarus et al., 1988; Rosenthal et al., 1988; Siebner et al., 1992; Majeed-Saidan et al., 1993; Cassio et al., 1994], particularly cardiac defects. However, a wide variation exists in these frequencies, ranging from no increased frequency [Chanoine et al., 1986] to 24% [Majeed-Saidan et al., 1993], or eight times the frequency found in the general population. By linking data from two population-based registries, we describe the epidemiology of CH and associated defects in Atlanta from 1979 through 1992. The Georgia Newborn Screening Program In Georgia, blood specimens are collected on filter paper from all neonates between the second and seventh day of life. Details of the program have been described elsewhere [Fernhoff et al., 1982; Brown et al., 1981]. Thyroxine (T4) concentrations measured by radioimmunoassay from filter paper dried blood spots greater than or equal to 2.0 standard deviations below the daily mean for infants of the same age and weight are considered abnormal. Thyroid stimulating hormone (TSH) concentrations are assayed by radioimmunoassay on all specimens within and below the lowest sixth percentile of all T4 values. Infants with low T4 and/or elevated TSH concentrations are immediately traced for confirmatory serum studies. Infants with low T4 values but normal or slightly elevated TSH values are monitored until either T4 values become normal, or a diagnosis of thyroid binding globulin deficiency or secondary CH is established. The Metropolitan Atlanta Congenital Defects Program The Metropolitan Atlanta Congenital Defects Program (MACDP) is an on-going, population-based surveillance system for birth defects with active case ascertainment. Details of the program have been reported elsewhere [Edmonds et al., 1981; Lynberg et al., 1992]. The following criteria must be fulfilled to meet the MACDP case definition of a congenital defect: 1) the mother must be a resident of the five-county metropolitan Atlanta area at the time of birth; 2) the baby must have a gestational age of at least 20 weeks or a birth weight of at least 500 grams; 3) the baby must have a structural or chromosomal defect that can adversely affect health or development; 4) the diagnosis must be made or symptoms must be present in the child’s first year of life; and 5) the case must be abstracted by the child’s sixth birthday. Data sources for MACDP include birth hospitals, pediatric referral hospitals, cytogenetic laboratories, and vital statistics records. The subjects in this study included all infants with confirmed primary CH born from 1979 through 1992 to mothers residing in the five-county metropolitan Atlanta area at the time of birth. The cases of CH were ascertained through the Georgia Newborn Screening Program and/or MACDP records. Infants with transient hypothyroidism were excluded from the study. We linked CH cases with MACDP records to ascertain the presence of serious birth defects among infants with CH. Isolated patent ductus arteriosus (PDA) associated with prematurity, and accessory spleen were not classified as major birth defects. There were three infants with isolated PDA and one infant with an accessory spleen in the study. We used an observed to expected ratio (O/E) analysis based on data collected for MACDP during 1979 through 1992 to compare the incidence of major birth defects in infants with primary CH with infants in the general population of Atlanta. The Poisson distributions (1-sided), O/E, and 90% confidence intervals (CIs) were derived using a statistical analysis package (Statistical Analysis Battery for Epidemiologic Research) available at the Centers for Disease Control and Prevention. We identified 97 infants with CH in Atlanta during the study period using newborn screening records and/or MACDP records. Eleven of the infants did not have a newborn screening test and were identified through MACDP only (five with primary CH and six with secondary). Among the 97 infants, 87 had primary, and 10 had secondary hypothyroidism. Among infants with primary CH, 77 had isolated CH, 3 had Down syndrome, and 7 had the following unrelated major structural defects: ventriculoseptal defect, sagittal synostosis, clubfoot, lipoma of the spermatic cord, cleft lip and palate, posterior urethral valves, and situs inversus totalis. The prevalence of major congenital anomalies associated with primary CH was 11.5%. However, the prevalence of cardiac defects was 1.1%. Table I provides the rates of primary CH by race and sex. Denominator data were based on the number of live births to residents of metropolitan Atlanta during the study period and were obtained from the Georgia vital statistics records. Because of the small number of CH cases, we classified race/ethnicity as white and other. The other group consisted of 18 black, 4 Asian, and 2 hispanic infants. We calculated the risk ratios (RRs) and 95% CIs for each of the groups. The rate of primary CH was higher among non-hispanic whites than among the other group and among females compared with males. The overall incidence of primary CH during the study period was 1:5,000 live births. The higher rate among females was seen only for isolated primary CH. The term "isolated" indicates that no major structural defect was present in the infant, and the term "multiple" indicates that a major structural defect was present, in addition to primary CH. There were only three infants in the study with a known syndrome. Table II lists the rates of primary CH by maternal age. The RRs and 95% CIs were calculated for each of the maternal age groups. There was a statistically significant lower rate of primary CH in the 20-24 age group compared with the other groups. This finding has not been reported in other studies and should be addressed in future investigations. The maternal ages of two of the three infants with Down syndrome in the study were in the 35 years and older age group. Table III provides the O/E ratios, 90% CIs, and Poisson distributions (1-sided) for the major birth defects among the 87 infants with primary CH. The major birth defects were classified as structural anomalies or Down syndrome. The O/E ratios for both of the groups were statistically significant. There was a 2.2-fold increased risk for major structural anomalies and an overall 3.0-fold increased risk for major birth defects. Infants with Down syndrome had a 35-fold increased risk for primary CH compared to the general population. Table IV compares the prevalences of major birth defects and cardiac defects from several published studies. All of the studies except one [Majeed-Saidan et al., 1993] are population-based. The figures in the brackets represent the adjusted prevalences after reanalyzing the data excluding isolated PDA associated with prematurity. Two of the studies listed in the table [Grant et al., 1988; Lazarus et al., 1988] did not specify the types of congenital heart disease, and therefore, could not be reanalyzed. In addition, we reclassified one of the malformations (situs inversus totalis) reported by Fernhoff et al. from a cardiac to a laterality defect. Our results are consistent with other published studies showing an increased prevalence of major congenital anomalies among infants with primary CH (Table IV). Although the studies listed in Table IV involve different populations and methods of classification, all except Chanoine et al. [1986] have shown an increased prevalence of major congenital anomalies among infants with primary CH. We did not find an increased prevalence of cardiac defects or any specific pattern of anomalies in our study. It is well known that infants with Down syndrome have an increased risk for primary CH [New England Congenital Hypothyroidism Collaborative, 1988; Fort et al., 1984]. We found a 35-fold increased risk in our study compared to the general population. Because infants with Down syndrome are also at risk for acquired hypothyroidism, the American Academy of Pediatrics Committee on Genetics recommends additional thyroid screening tests at 4-6 months, again at 12 months, and then annually in children with Down syndrome [Committee on Genetics, 1994]. Brown et al. [1981] reported that the incidence of primary CH in Georgia is less than that in other screening centers in North America because of the larger black population in Georgia. Our results from Atlanta are consistent with their observation with a rate of 1:4,400 among non-hispanic whites compared to 1:10,000 in blacks. We also found an almost 2:1 female:male ratio reported in their study. Several studies have documented delayed newborn screening in infants with CH and additional birth defects [Fernhoff et al., 1987; Cassio et al., 1994]. The 11 infants with CH (5 with primary and 6 with secondary CH) that were ascertained only by MACDP had other congenital anomalies. It is possible that the presence of additional anomalies in these infants may have played a role in their not being screened. Errors in sample collection or delivery to the state laboratory are other possible contributory factors. Our study has two important limitations. The first, incomplete CH case ascertainment, has already been briefly discussed. A small number of infants will not be screened or will have false-negative screening values. These infants should have been ascertained by MACDP if additional birth defects were present. The second limitation of the study is the lack of available clinical information on the majority of affected infants. Therefore, we were unable to classify the infants based on their underlying pathogenesis, such as thyroid dysgenesis or dyshormonogenesis. Despite these limitations, our study has two important strengths. First, since it is the first population study of CH in the U.S. in which data from two population-based registries were linked, the epidemiologic patterns and associated defects will be more representative than those found in studies based on newborn screening records only. Second, multiple sources of case ascertainment were used in the study, and these provide the best potential for complete case finding. The results of this study quantitate the magnitude of the association between primary CH and Down syndrome and between CH and major structural anomalies. The data also show racial and gender differences in the rate of primary CH. All newborn babies, especially those with congenital anomalies, should be screened at the recommended age to avoid delays in the treatment of CH.
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