Adolfo Correa
Larry Edmonds
Oral clefts are among the more frequent and readily diagnosed major congenital anomalies. Accordingly, they have been the subject of many studies that have increased our knowledge of their epidemiology. For instance, studies of the variation in prevalence by race/ethnicity have shown a high rate of oral clefts in Asians, followed by whites and African-Americans (Vanderas, 1987). Etiologic studies have identified possible increases in the risk of oral clefts with a number of factors, including maternal smoking (Khoury et al., 1989; Kallen 1997; Lieff et al., 1999), alcohol consumption (Shaw et al., 1999), use of corticosteroids (Carmichael and Shaw, 1999), occupational factors (Bianchi et al., 1997; Lorente 2000) (see Chapter 16 and Chapter 17). Data for these studies have come from population-based surveillance systems for birth defects. This chapter examines the methods of population-based birth defects surveillance systems, reviews recent prevalence data on oral clefts from state and international monitoring programs, and offers some recommendations for enhancing the use of birth defects surveillance programs for studies of oral clefts.
Methods of Birth Defects Surveillance
Population-based birth defects surveillance programs aim at having a relatively complete or representative sample of affected infants in the population and, as such, can provide more accurate and reliable estimates of rates and risk factors for birth defects than birth defects registries based on a selected sample of hospitals. Therefore, after the epidemic of limb reduction defects associated with thalidomide use in the 1960s, interest was extensive in population-based surveillance systems for identifying increases in the frequency of birth defects possibly associated with maternal exposure to teratogens in the general population. As methodologic issues of this approach became apparent (Khoury and Holtzman, 1987), birth defects surveillance programs expanded their functions; and interest in birth defect surveillance has grown, with population-based programs currently monitoring the occurrence of birth defects in 31 U.S. states and internationally (Centers for Disease Control and Prevention, 2000; International Clearinghouse for Birth Defects Monitoring Systems, 2000).
The fundamental objective in population-based surveillance for birth defects, including oral clefts, is the description of their frequency in the population and how this frequency varies with time, place, and personal characteristics of infants with birth defects and their mothers (e.g., child's sex, maternal age). Accordingly, the general methods in surveillance for birth defects, including oral clefts, are as follows: (1) specification of the population covered; (2) definition and ascertainment of affected infants and children (i.e., cases) in the population; (3) collection of clinical and descriptive data; (4) coding and classification of cases; and (5) data analysis and dissemination. The methods used (e.g., case criteria, case classification) need to be related to the specific objectives of the surveillance program.
Population Covered
The population covered by the surveillance system needs to be specified in terms of the geographic area, number of yearly live births and stillbirths to area residents, and hospitals in the study area where births are delivered and children undergo medical evaluations. Given the variation in the race/ethnicity characteristics in the population of the United States and the known variation in prevalence of oral clefts by race/ethnicity, surveillance systems in the United States collect information on the race/ethnicity characteristics of the yearly births. For example, the population covered by the Metropolitan Atlanta Congenital Defects Program (MACDP), a population-based surveillance system for birth defects in operation since 1967, included about 47,000 births in 1999 in 22 area hospitals, occurring among residents of five counties in metropolitan Atlanta. The percent of nonwhite births has increased over time from about 27% in 1967 to 46% in 1999.
Case Definition
The definition of a case specifies the inclusion criteria, such as (1) births with any major defect (i.e., a defect that can cause death or a major disability in the absence of treatment), infants with any one of a select subgroup of major defects, infants with major or minor defects, or infants with other groups of birth defects; (2) period of detection of birth defects; (3) age by which cases should be ascertained; and (4) inclusion of live-born infants and stillbirths, 20 weeks of gestation or more, or 500 g or more. For example, within MACDP the case definition includes all infants born to residents of five counties in metropolitan Atlanta and who have at least one major birth defect diagnosed in their first year and identified by MACDP within their first 5 years of life.
Case Ascertainment
Affected children can be identified from a variety of routine data sources: (1) vital records (birth certificates, fetal death certificates, and infant death certificates), where health professionals are asked report the presence of structural defects at birth or as a cause of death; (2) newborn hospital discharge summaries and obstetric and nursery logs; (3) hospital records of subsequent hospitalizations; and (4) data from other sources, including specialty clinics (such as medical genetics for syndrome diagnosis), pathology reports for terminations, abortion records, autopsy records, and cytogenetic laboratories. Each of these sources of information affects the quality of the data.
Vital records have several strengths: (1) the complete coverage of the population since they are population-based, (2) availability of some information on the type of defect, (3) availability of some information on characteristics of the parents, (4) availability of data for previous years, (5) low cost, and (6) potential for linkage with other data for the conduct of follow-up studies of children with birth defects. The weaknesses of vital records include (1) underreporting of several birth defects because of diagnostic difficulties (e.g., limited evaluations for defects), (2) inaccurate diagnoses because of limited evaluations, (3) lack of specificity the diagnosis for most birth defects, (4) possible exclusion of case infants born outside of the state, and (5) lack timeliness of the death certificates. That underascertainment of oral clefts may result from the use of birth certificates as the only source of cases is well documented. In a study in Norway, a 14.5% under reporting error was noted for cleft lip and palate patients’ birth records when compared to subsequent surgery records (Abyholm, 1978). Sixteen percent of orofacial clefts and other anomalies were underreported in Pennsylvania's birth certificates (Ivy, 1957), and 35% of facial cleft anomalies were not recorded as such in the birth certificates of affected infants in Arkansas (Green et al., 1979). Furthermore, many cases of oral clefts that are reported on the birth certificates misclassified (Meskin and Pruzansky, 1967). For instance, 52% of all facial clefts in Arkansas were reported incorrectly (Green et al, 1979).
Newborn hospital discharge summaries have several strengths: (1) more complete recording of birth defects than in the birth certificate, (2) more readily available data (usually within 6 months of discharge), (3) data that may be already computerized and in digital form in many hospitals. The weaknesses of newborn hospital discharge summaries include (1) incomplete recording of information on birth defects, (2) possible incomplete or incorrect preliminary diagnosis in the newborn period, (3) lack of access to personal identifiers (making follow-up difficult), (4) difficulties in defining the population base because many infants born at home are not included, (5) difficulties in establishing the representativeness of the case data, and (6) lack of information about maternal characteristics. The potential problem of relying solely on newborn discharge summaries was highlighted by a study of hospital newborn records as the sole source for oral facial clefts in King County, Washington, for the years 1956-1965 (Emanuel et al., 1973). This study showed that hospital newborn records ascertained 98.5% of the total cases of oral clefts found through all sources combined but that only 68.4% of them had been coded correctly on the discharge abstract.
Records from subsequent hospitalizations, specialty clinics, pathology reports, abortion reports, and cytogenetic laboratories are potentially very useful in that they can provide clinical and laboratory data that may help clarify questions about possible diagnoses. However, such records may be collected and maintained only on a select sample of cases, and practical or legal considerations may limit their availability. Consequently, population-based birth defects surveillance programs do not rely on such records as sole sources for case ascertainment. In 1999, none of the 31 operational birth defects surveillance programs in the United States relied solely on medical records for case ascertainment (Centers for Disease Control and Prevention, 2000). Twenty-two of these programs reported use of medical records as one of several sources for case ascertainment.
Use of multiple sources for case ascertainment offers the best potential for complete case finding and for obtaining the best quality data on affected children. The strengths of multiple-source case ascertainment include (1) relative completeness of the recording of cases, (2) more precise and accurate diagnoses, (3) availability of maternal and infant data, and (4) relative ease for researchers to conduct follow-up studies of children with birth defects. The weaknesses of multiple-source case ascertainment include (1) more time and effort required to collect data from multiple sources, (2) higher costs (often limiting the use of this method to small populations), (3) more time and effort to prepare the database, and (4) more time needed to establish the baseline rates. Of the 31 operational birth defects surveillance systems in the United States in 1999, 29 used two or more sources for case ascertainment and two relied on vital records alone (Centers for Disease Control and Prevention, 2000).
Case ascertainment can be characterized also by the intensiveness of the efforts involved. Case ascertainment may be limited to identification of cases from vital records or from reports submitted to the surveillance program by staff from hospitals, clinics, or other facilities. Such reports may be submitted voluntarily or through reporting systems established by law or regulation. More intensive surveillance methods entail the identification of cases by trained staff who actively seek cases in hospitals, clinics, or other facilities by systematically reviewing medical and other records. They may also query personnel who know about the newly diagnosed cases. Program staff record the case information on standard forms designed for the program.
Figure 11.1 shows the geographic distribution birth defects surveillance systems that were operational or in the planning phase in the United States in August of 2000. Among the 31 operational systems, 28 were statewide and 3 were limited to specific counties within a state. Among the operational systems, 10 (Alabama, Arizona, California, Georgia, Hawaii, Iowa, Massachusetts, Oklahoma, South Carolina, and Texas) had intensive surveillance, 7 (Colorado, Illinois, New Mexico, New Jersey, New York, North Carolina, and Utah) had mandatory reporting with follow-up and quality-control procedures, 11 (Arkansas, Connecticut, Delaware, Florida, Kentucky, Maryland, Mississippi, Missouri, Nebraska, Virginia, and West Virginia) had mandatory hospital reporting but no follow-up or quality-control procedures, and 9 (Louisiana, Montana, New Hampshire, Ohio, Pennsylvania, Tennessee, Washington, Wisconsin, and Wyoming) were planning or developing a registry.
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FIG. 11.1. State birth defects surveillance systems in the United States, 2000. (From Centers for Disease Control and Prevention, 2000, with permission.) |
Data Collection
Information collected on infants that meet the case definition may include (1) identifying information on infant and parents, (2) demographic information (such as maternal age, race/ethnicity), (3) pregnancy history and birth outcomes, (4) information on the index pregnancy and outcome, (5) diagnostic information on the types of birth defect, (6) cytogenetic and laboratory data, and (7) information on the hospital and physician to facilitate follow-up procedures. To evaluate the completeness and accuracy of the data, surveillance systems may set up quality-control procedures.
Coding and Classification of Birth Defects
Information may be collected on several defects for each affected infant. These defects may then be reviewed by a clinician/dysmorphologist and coded according to established procedures. For instance, MACDP uses a modified British Paediatric Association (BPA) six-digit code (British Paediatric Association, 1979) that is more detailed than the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM codes) (World Health Organization, 1979). These modified BPA codes for orofacial clefts are as follows: cleft palate without cleft lip, 749.000-749.099; and cleft lip and with and without palate, 749.100-749.299. Based on the clinical reviews, cases can be further classified into patterns of associated defects (isolated, sequences, syndromes with recognized cause, and “multiples”) (Spranger et al., 1982; Stevenson and Hall, 1993).
Data Analysis and Dissemination
Data on major defects are analyzed to monitor the frequency of birth defects and to detect variations by calendar time or any unusual patterns. The frequency of birth defects is usually measured as prevalence at birth, expressed as the number of affected infants per 1000 or 10,000 births. Some systems include late fetal deaths (stillbirths) in the prevalence estimates. In addition, the gestational age at which delivery must occur for a classification of fetal death as late varies, being 20 weeks in some systems and 28 weeks in others. Prevalence data are monitored by statistical evaluation of the difference between observed and expected numbers of specific defects or defect combinations for a specified time in a specified area. Expected numbers are obtained from baseline prevalence data. Such comparisons may lead to the identification of clusters birth defects and to epidemiologic studies to identify possible risk factors.
State and International Monitoring Programs
The objectives of birth defects monitoring programs are to describe the magnitude of the problem by quantifying its prevalence, to serve as a source of cases for studies of risk factors, and to enable follow-up studies of the impact of these conditions on children's health and development and of the need of health and social services. This section describes recent prevalence rates for oral clefts and the extent to which birth defects surveillance systems are being used to address these objectives.
Prevalence Rates
Estimates of the birth prevalence of oral clefts have been published recently for selected state surveillance systems in the United States and for the International Clearinghouse for Birth Defects Monitoring Systems (ICBDMS).
State Birth Defects Surveillance Systems in the United States
Prevalence data are available for cleft lip with or without cleft palate and for cleft palate without cleft lip from 26 state surveillance systems in the United States for calendar year 1996 (except a few states where data are available only for 1991, 1993, 1994, or 1995) by race (white and other) (National Birth Defects Prevention Network, 2000). The state birth defects surveillance programs that provided data on oral clefts vary in several respects: (1) case ascertainment methods, (2) definition of birth defects, (3) coding systems, (4) inclusion of stillbirths and pregnancy terminations in counts of birth defects occurrences, and (5) population coverage. In addition, some states do not include conditions noted in the medical chart as possible birth defects and in need of definitive confirmation or exclusion, while other states do. Because of these differences, state surveillance data on the prevalence of oral clefts cannot be combined to give a reliable overall national rate for the United States or be used to make meaningful comparisons between states. However, it is possible to examine the variation in prevalence of oral clefts by subgroup of oral clefts and race within each state as methods of case ascertainment are likely to vary less within than between states.
For cleft lip with or without cleft palate (Table 11.1), overall prevalence varied from 6 to 16 cases per 10,000 births (median 10/10,000), with rates generally higher for white than for nonwhite infants. Among white infants, the prevalence of cleft lip with or without cleft palate varied from 6 to 26 per 10,000 births (median 13/10,000); among infants of other races, it varied from 1 to 15 per 10,000 births (median 7/10,000).
For cleft palate without cleft lip (Table 11.2), the overall prevalence varied from 1 to 14 cases per 10,000 births (median 6/10,000) with some (but less pronounced) variation by race. Among white infants, the prevalence of cleft palate without cleft lip and varied from 2 to 19 per 10,000 births (median 6/10,000); among infants of other races, it varied from 0 to 15 per 10,000 births (median 4/10,000).
Within each surveillance system, the prevalence for cleft lip with or without palate tended to be higher than that for cleft palate without cleft lip. In addition, the prevalence of oral clefts tended to be higher among white than among nonwhite infants. These observations have been noted before (Edmonds, 1997; Tolarova and Cervenka, 1998; Amidei et al., 1994; Croen et al., 1998; Robert et 1996).
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TABLE 11.1. Prevalence Rates for Cleft Lip with and without Cleft Palate per 10,000 Live Births and Stillbirths by Surveillance System, Reporting Year, and Race |
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TABLE 11.2. Prevalence Rates for Cleft Palate without Cleft Lip per 10,000 Live Births and Stillbirths by Surveillance System, Reporting Year, and Race |
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International Clearinghouse for Birth Defects Monitoring Systems
The ICBDMS, an organization of birth defects monitoring programs around the world, recently published its Annual Report 2000, which includes prevalence data for several birth defects (International Clearinghouse for Birth Defects Monitoring Systems, 2000). These data include prevalence rates for cleft lip with or without cleft palate and for cleft palate without cleft lip for 1974–1998 for 25 systems: Australia, USA Atlanta, Canada National, New Zealand, Canada Alberta, England and Wales, Norway, North Netherlands, Finland, Ireland Dublin, Italy Birth Defects Registry of Campania (BDRCAM), Italy North East, Italy Tuscany, Italy Emilia-Romagna Registry of Congenital Malformations (IMER), Italy Sicilian Registry of Congenital Malformations (ISMAC), France Strasbourg, France Central East, France Paris, Mexico Registry and Epidemiological Surveillance of External Congenital Malformations (RYVEMCE), Spanish Collaborative Study of Congenital Malformations (ECEMC), South America Latin American Collaborative Study of Congenital Malformations (ECLAMC), Czech Republic, Hungary, Israel Birth Defects Monitoring System (IBDMS), and Japan Association of Obstetricians and Gynecologists (JAOG). The clearinghouse programs differ in their methods, so meaningful between-program comparisons are not possible. However, the clearinghouse data do allow for monitoring of temporal trends within each program.
In 1998, the prevalence rate for cleft lip with or without cleft palate varied from 4 to 17 cases per 10,000 live births and stillbirths among the 25 reporting systems (Fig. 11.2). Between 1974 and 1998, the prevalence of cleft lip with or without cleft palate showed a consistent decline in six systems (USA Atlanta, New Zealand, England and Wales, North Netherlands, Italy Northeast, and Hungary), a consistent increase in three systems (Finland, France Strasbourg, and Japan JAOG), and no consistent change for the rest.
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FIG. 11.2. Time trends in prevalence of cleft lip with or without cleft palate [(live births + stillbirths)/10,000] in programs participating in the International Clearinghouse for Birth Defects Monitoring Systems 1974–1998. (From International Clearinghouse for Birth Defects Monitoring Systems, 2000, with permission.) |
In 1998, the prevalence rate for cleft palate without cleft lip varied from 3 to 15 cases per 10,000 live births and stillbirths among the 25 reporting systems (Fig. 11.3). Between 1974 and 1998, the prevalence for cleft palate without cleft lip showed a consistent decline in six systems (USA Atlanta, England and Wales, North Netherlands, Italy Northeast, France Strasbourg, and Japan JAOG), a consistent increase in five systems (Australia, Finland, Norway, France Central East, and France Paris), and no appreciable change for the rest.
Within each ICBDMS surveillance system, the prevalence of cleft lip with or without palate tended to be higher than that for cleft palate without cleft lip, consistent with data from state surveillance systems in the United States. Temporal trends for both subgroups of oral clefts showed no consistent patterns. The reasons for these temporal trends are unclear. Possibilities include changes in methods or changes in risk factors in the population over time. Without additional information on possible changes in case ascertainment, methods of diagnosis, and patterns of prenatal detection pregnancy termination, interpreting these temporal changes in prevalence of oral clefts is difficult.
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FIG. 11.3. Time trends in prevalence of cleft palate without cleft lip [(live births + stillbirths)/10,000] in programs participating in the International Clearinghouse for Birth Defects Monitoring Systems 1974–1998. (From International Clearinghouse for Birth Defects Monitoring Systems, 2000, with permission.) |
Source of Cases for Etiologic and Follow-Up Studies
In addition to monitoring trends in prevalence, population-based surveillance programs have become an important source of cases for etiologic studies. Cases of oral clefts ascertained by population-based surveillance programs have been included in case-control studies of a wide range of risk factors (see Chapter 13 and 14). Examples of such etiologic studies include studies of cigarette smoking (Khoury et al., 1989; Lieff et al.; 1999; Kallen, 1997), alcohol consumption (Shaw and Lammer, 1999), corticosteroid use (Rodriguez-Pinilla and Martinez-Frias, 1998; Carmichael and Shaw, 1999), occupational factors (Bianchi et al., 1997; Lorente et al., 2000), use of multivitamins and folk acid (Shaw et al., 1995; Czeizel 1999), and interactions between genetic factors and cigarette smoking (Hwang et al., 1995; Beaty 1997). Currently, eight population-based birth defects surveillance programs in the United States serve as sources of cases for the National Birth Defects Prevention Study, a multi-center case-control study of birth defects that is evaluating the role of genetic and environmental factors gene-environment interactions in the risk of oral clefts.
Children with oral clefts are at increased risk for several disorders that can impair normal development, including dental problems (Ranta, 1986; Bokhout et al., 1997), hearing disorders (Koempel and Kumar, 1997), speech and hearing problems (Broen et al., 1998), and cognitive and psychomotor deficits (Speltz et al., 2000; Kapp-Simon and Krueckeberg, 2000). Much of this knowledge has been derived from studies of children with oral clefts referred to evaluation or treatment facilities. Studies of children referred for treatment may select for the more severe surviving cleft cases or for the group of cases in the segment of the population served by the treating facility (Oka, 1979). Consequently, such a select group of cases may not reflect the wide spectrum of oral clefts in the population and may result in biased assessment of the natural history, morbidity, and developmental deficits associated with oral clefts.
Concluding Remarks
Many genetic and epidemiologic studies have focused on oral clefts, resulting in increased knowledge about the different types of oral cleft and their differences in genetic and epidemiologic characteristics. However, meaningful characterization of the spatial variation of the prevalence of oral clefts through comparisons of rates across regions, a basic goal of descriptive epidemiology and a useful source of etiologic hypotheses, has not been possible because of differences in methods between surveillance systems. One approach to address this issue is to compare prevalence rates among surveillance programs that use similar methods. With the continued development of birth defects surveillance systems in the United States and efforts to standardize the methods used, analyses of spatial variations will be more feasible.
In recent years, use of sophisticated diagnostic procedures to detect and diagnose birth defects in utero has increased, resulting in a corresponding increase in elective terminations of affected pregnancies. Such practices can result in underestimation of the prevalence of birth defects at birth. A recent study in Hawaii (Forrester et al., 1998) found that the proportion of oral cleft cases diagnosed prenatally was 14% for cleft lip with or without cleft palate and 0% for without cleft lip and that the resulting underestimation of the prevalence rates was not substantial. Whether this limited impact of prenatal diagnosis on the prevalence of oral clefts at birth is similar for other geographic areas and likely to remain in future years is unclear. Further monitoring of the impact of prenatal diagnoses on the prevalence of oral clefts at birth may become increasingly important, particularly in interpreting temporal trends in relation to changes in risk or preventive factors in the population.
Oral clefts represent a heterogeneous group of defects, including cleft lip only, and cleft palate, and cleft palate only. Cleft lip with or without and cleft palate without cleft lip are different entities that can occur as isolated defects, as part of a sequence of primary defects, or as a multiple congenital anomaly (Fogh-Andersen, 1942; Lettieri, 1993). In addition, oral clefts can be part of a known monogenetic syndrome, part of a chromosomal aberration, part of an association, or part of a complex of multiple defects of unknown etiology (Cohen, 1991). Because these different types of oral cleft may have different etiologies, surveillance systems may need to invest more resources in classifying infants with oral clefts into subgroups to account for such heterogeneity in descriptive and risk factor studies.
Because the causes of oral clefts remain unknown, population-based surveillance systems will continue to serve as sources of cases for studies of etiologic hypotheses. Such studies will be instrumental in identifying primary prevention strategies for population-based interventions for oral clefts, as was done for neural tube defects with folic acid interventions. If and when such interventions become available, surveillance systems for birth defects are likely to play a key role in the evaluation of their effectiveness. In addition, population-based surveillance systems of birth defects are likely to play an important role in population-based studies of the long-term effects of oral clefts on children's health and development and of prognostic and risk factors for developmental delays and morbidity associated with oral clefts. These efforts may ultimately help to further control and prevent the morbidity associated with oral clefts and thereby to improve the quality of life of affected children and their families.
Acknowledgements
The authors thank the International Clearinghouse of Birth Defects for permission to print the figures on temporal trends for oral clefts, and Ms. Cara Mai for valuable technical assistance with formatting of the illustrations.
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