ARTICLE. Risk of Mental Retardation Among Children Born With Birth Defects

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1 ARTICLE Risk of Mental Retardation Among Children Born With Birth Defects Laura L. Jelliffe-Pawlowski, PhD; Gary M. Shaw, DrPH; Verne Nelson, MS; John A. Harris, MD, MPH Background: A paucity of epidemiologic research exists concerning the co-occurrence of birth defects and mental retardation (MR). Study of this co-occurrence may yield important clues about the causes of both. Objective: To examine the co-occurrence of birth defects and MR, taking into consideration the type of birth defect, level of MR, co-occurrence of MR with other developmental disabilities, and individual and maternal factors. Design: A retrospective cohort study of infants born in the California Central Valley with and without a structural birth defect by 1 year of age, and with or without MR by 7 to 9 years of age. Setting and Participants: One-year survivors (N=119556) born in nonmilitary hospitals in 8 California counties between January 1, 1992, and December 31, 1993, for whom information about birth defects was recorded within the first year of life. Main Outcome Measure: Diagnosis of MR by age 7 years considered as being mild or severe and as occurring without other developmental disabilities (isolated MR) or as occurring with other developmental disabilities, including cerebral palsy, epilepsy, or a pervasive developmental disorder. Results: Children with birth defects were nearly 27 times more likely to have MR by 7 years of age compared with children without a diagnosed birth defect regardless of type of defect (prevalence ratio, 26.8; 95% confidence interval, ). Among those with birth defects, children with Down syndrome (prevalence ratio, 211.7; 95% confidence interval, ) and children with sex chromosomal defects (prevalence ratio, 57.4; 95% confidence interval, ) were at the highest risk for MR. Children with nonchromosomal defects, including central nervous system defects and all types of organ and system defects, were at substantially increased risk for all levels of MR. Risks of MR among children with Down syndrome and nonchromosomal defects were not substantially altered when adjusted for individual and maternal factors. Conclusions: Children with chromosomal and other structural birth defects are at a substantially increased risk for having MR by 7 years of age compared with children born without a birth defect. Children with birth defects are at an especially increased risk for having severe MR and MR occurring independently of other developmental disabilities. Arch Pediatr Adolesc Med. 2003;157: From the March of Dimes Birth Defects Foundation, California Birth Defects Monitoring Program, Oakland. Dr Jelliffe-Pawlowski is now affiliated with the Childhood Lead Poisoning Prevention Branch, California Department of Health Services, Oakland. MANY EPIDEMIOLOGIC studies 1-6 have investigated structural birth defects and mental retardation (MR) separately. However, few studies have investigated this co-occurrence. Although data suggest that children with structural defects are at increased risk for having MR in childhood, 7,8 limited information is available with respect to defect-specific and MR severity specific risks. Kirby and colleagues 8 found that nearly 70% of children with neural tube defects and nearly 46% of children with chromosomal defects had a developmental disability (DD) (including MR) by 4 years of age. Decoufle and colleagues 7 found an 8-fold risk of MR among children who were aged between 3 and 10 who were born with 1 or more birth defects, compared with children born without birth defects. Therefore, studies 7,8 have focused on birth defects and developmental disabilities in general but have not examined the association between specific birth defects and specific levels of MR. Co-occurrence may indicate an alternative cause compared with the occurrence of these conditions in isolation. By investigating co-occurrence, important clues about the cause of both conditions, particularly about the timing of potential insults, may be revealed. We investigated the relationship between specific birth defects and sever- 545

2 ity of MR in a cohort of California-born children. We determined whether the risk of MR differed by type of chromosomal or structural birth defect and explored whether severity of MR or the occurrence of MR in combination with other developmental disabilities differed by type of birth defect. Several individual and maternal factors were examined to determine effects on observed risks. METHODS The Institutional Review Board of the California Department of Health Services approved the protocol for this study. SUBJECTS AND SOURCES All infants born in nonmilitary hospitals from 8 California Central Valley counties (Fresno, Kern, Kings, Madera, Merced, San Joaquin, Stanislaus, and Tulare) in 1992 and 1993 who survived to 1 year of age were included (N=119556). Information about survival, sex, plurality, gestational age, birth weight, maternal age, maternal race/ethnicity, parity, maternal birthplace, and maternal education was obtained from birth certificate and infant mortality files. Information about birth defects was derived from the California Birth Defects Monitoring Program. 9,10 This populationbased active surveillance system collects diagnostic information from multiple sources of medical records on all stillborn and liveborn infants with structural birth defects diagnosed within 1 year of delivery in a subset of California counties, including the 8 counties targeted for this study. 10 Ascertainment is estimated to be 97% complete. 9,10 Of the infants surviving to 1 year in the specified birth counties and nonmilitary hospitals, 2337 were diagnosed as having 1 or more birth defects. Information about MR was obtained from the California Department of Developmental Services, Sacramento. In California, individuals with developmental disabilities (defined as MR, cerebral palsy, epilepsy, autism, or other condition closely related to MR 11 ) are eligible to receive services from birth until death from this department via a system of independently operated regional centers across the state. A listing of all children born in 1992 and 1993 who were receiving services in March 2001 for a DD was obtained (n=9134). Records for these children were linked to birth certificate and infant mortality files by place of birth (when present) and by child, maternal, and paternal identifiers (including date of birth, first name, middle name, last name, and mother s maiden name). All matches were verified via record review. Using this method, 895 children receiving services in 2001 were identified as born at nonmilitary hospitals in the study counties between January 1, 1992, and December 31, These children were further linked to California Birth Defects Monitoring Program files to identify those with birth defects. Service delivery charts for 893 of the 895 children were found and reviewed. Among these, 635 had MR based on American Association on Mental Deficiency (AAMD) guidelines. 12 Twenty-two had normal intellectual functioning before severe head trauma, near drowning, or stroke and were excluded based on our objective to investigate potentially unknown causes. We categorized the remaining 613 individuals into 2 severity groups consistent with AAMD criteria using IQ or adaptive functioning. The 2 groups were mild MR and severe MR, the latter corresponding to the AAMD criteria for moderate, severe, or profound MR. Included in the mild MR group were 259 children tested as having an IQ between 50 and 70 on their last psychometric testing and an additional 59 children who did not have standardized testing within 3 years but were consistent with AAMD adaptive functioning criteria for mild MR and had a diagnosis of mild MR from a licensed psychologist who had conducted an in-person evaluation of the child. Included in the severe MR group were 213 children who tested as having an IQ less than 50 on their last psychometric testing and an additional 72 children who did not have standardized testing within the past 3 years but were consistent with adaptive functioning criteria for severe MR and had a diagnosis of moderate MR, severe MR, or profound MR from a licensed psychologist who had conducted an in-person evaluation. Ten children who were found to have MR based on reported adaptive functioning did not have a specific diagnosis or enough information present to determine the level of MR and were excluded from all analyses. Therefore, the analytic database used included 318 children with mild MR and 285 children with severe MR. Information about the presence of other developmental disabilities was collected. Children with MR were coded as having (1) cerebral palsy if there was a clear diagnosis made by a physician; (2) epilepsy if there was a clear diagnosis made by a physician; or (3) pervasive developmental disorder (PDD) if diagnosed with autistic disorder, Rett disorder, childhood disintegrative disorder, Asperger disorder, or unspecified PDD. Diagnosis of a PDD was only considered if made by a psychologist or physician using standard criteria. 13 Among children with mild MR, 109 (34.3%) had cerebral palsy (n=30), epilepsy (n=43), or a PDD (n=49) and were therefore classified as having mild MR with another DD (diagnoses not mutually exclusive). The remaining 209 children with mild MR and no other DD were classified as having isolated MR. Among children with severe MR, 173 (60.7%) had cerebral palsy (n=83), epilepsy (n=117), or PDD (n=50) and were classified as having severe MR co-occurring with another DD (diagnoses not mutually exclusive). The 112 remaining children with severe MR and no other diagnosed DD were classified as having isolated MR. STATISTICAL ANALYSIS Prevalences of MR groupings were estimated among infants with (n=2337) or without (n=117219) birth defects. Prevalences of MR groupings were also estimated among infants grouped into 4 mutually exclusive birth defect categories, including Down syndrome (n=155), other autosomal abnormality (n=36), sex chromosomal abnormality (n=26), unspecified chromosomal abnormality (n=2), and nonchromosomal abnormality (n=2118). Mental retardation prevalences were further estimated for specific birth defects among children with nonchromosomal defects. Prevalences of MR (by subgrouping) per 1000 children with birth defects (overall and by subtype) were estimated. The prevalence of MR among children with a specified birth defect was compared with the prevalence of MR among children without any major birth defect. The ratios of these prevalences, along with 95% confidence intervals (CIs), were computed using Poisson regression techniques. The potential contribution of individual and maternal factors was estimated by adjustment using Poisson regression models. All regression modeling was done using Statistical Analysis Software, version Individual factors studied included sex, race/ethnicity (white, Hispanic, black, Asian, or other, which included Native Americans, Pacific Islanders, and Alaskan Natives), plurality (singleton or multiple), gestational age ( 37 or 37 weeks), and birth weight ( 2500 or 2500 g). Maternal factors studied included age at delivery ( 20, 20-24, 25-29, 30-34, or 35 years), years of education ( 12, 12, 13-16, or 17), birthplace (United States, Mexico, or other), and parity (0 or 1). 546

3 Table 1. Prevalence of Mild Mental Retardation (MR) Among 1-Year Survivors Born in the California Central Valley in 1992 and 1993 Without Birth Defects vs Prevalence of Mild MR Among Children With Birth Defects* Isolated Mild MR Mild MR and Other Disability No. No. per 1000 Ratio (95% CI) No. No. per 1000 Ratio (95% CI) No birth defect (n = ) Referent Referent Any birth defect (n = 2337) ( ) ( ) Down syndrome (n = 155) ( ) Other autosomal abnormality (n = 36) ( ) ( ) Sex chromosomal abnormality (n = 26) ( ) Nonchromosomal abnormality (n = 2118) ( ) ( ) *Number per 1000 is by birth defect grouping (survivors to 1 year, nonmilitary births). Ratio is prevalence of mild MR among individuals with the specified birth defect divided by the prevalence of mild MR among individuals without a major birth defect. Prevalence is by birth defect grouping and by co-occurrence with other development disabilities including cerebral palsy, epilepsy, or a pervasive developmental disorder. RESULTS The study cohort included similar numbers of males and females (51% and 49%, respectively) and was predominantly white or Hispanic (38% and 47%, respectively). Most children were born to women with 12 (31%) or fewer (44%) years of education, who were born in the United States (62%). Overall, MR occurred in 5 (mild MR, 2.6; severe MR, 2.4) per 1000 births. Birth defects occurred in 19.5 (Down syndrome, 1.3; other autosomal defects, 0.3; sex chromosomal defects, 0.2; and nonchromosomal defects, 17.7) per 1000 births. Children with birth defects were observed to be at nearly a 27-fold risk of having MR diagnosed by 7 years of age compared with children without birth defects (prevalence ratio [PR], 26.8; 95% CI, ). Children with Down syndrome were at a more than 200-fold risk of MR (PR, 211.7; 95% CI, ), children with sex chromosomal defects were at nearly a 60-fold increased risk (PR, 57.4; 95% CI, ), and children with nonchromosomal defects were at more than an 11-fold increased risk (PR, 11.1; 95% CI, ) of having MR compared with children without birth defects. The risk of MR among children with Down syndrome and nonchromosomal defects did not decrease substantially when adjusted for individual and maternal covariates (PR, 178.4; 95% CI, ; and PR, 8.9; 95% CI, ; respectively). A further evaluation of these large risks by more detailed MR subgroupings revealed that the largest MR risks among children with birth defects tended to be for severe MR and isolated MR (Table 1 and Table 2). Furthermore, analyses of MR risks in children with specific nonchromosomal birth defects revealed that infants with all types of organ- and system-level defects at birth, including those not associated with the central nervous system, were at substantially increased risks for all levels of MR (Table 3 and Table 4). These MR risks tended to be the largest among infants born with central nervous system and heart defects. COMMENT Our findings indicate that being born with a structural birth defect, including birth defects not involving the central nervous system, elevates an infant s risk of developing mild or severe MR by 7 to 9 years of age by as much as several hundred fold. Our findings extend the knowledge base concerning MR risks among children with birth defects. Our findings are consistent with previous investigations that found children with birth defects at greater risk for being diagnosed as having developmental disabilities, including MR, in early childhood 7,8 and for being diagnosed as having isolated MR and severe MR. 7,8 However, we found larger risks than other investigators. Specifically, we found that children with a birth defect were at a 27-fold increased risk for MR, compared with an 8-fold increased risk observed by Decoufle and colleagues. 7 Our larger observed risks may be due to differences in study design, including differences in population and case eligibility criteria. For example, most children in our study cohort were white or Hispanic, whereas most children in the study by Decoufle et al 7 were white or black. We used adaptive evaluations of intellectual functioning, in addition to using IQ, when diagnosing and categorizing children with MR. This inclusion, while reflective of AAMD, 12 American Association on Mental Retardation, 15 and American Psychological Association 13 guidelines, represents a departure from the methods used by Decoufle and colleagues, who used IQ score exclusively. Elevated risks of MR among children with birth defects indicate that the causes of MR may differ between those children who are born with birth defects compared with those born without birth defects. Such observations specifically provide evidence to suggest a prenatal cause for MR when there is co-occurrence. Taken together with the hundreds of studies that have identified specific syndromes that include MR and 1 or more birth defects as phenotypic components (eg, Mowat- Wilson, 16 Hennekam, 17 and Jancar 18 syndromes), elevated risks suggest that MR and birth defects may be pathogenetically related. This relationship may be causal (eg, a specific birth defect causes MR), temporal (eg, a deleterious event or teratogen caused the birth defect and MR), or genetic (eg, a gene or genes caused the birth defect and MR) or may be characterized by multiple causal pathways and mechanisms. This study represents a rigorous first step toward investigating the potential association between specific birth defects and the risk of MR by severity and co- 547

4 Table 2. Prevalence of Severe Mental Retardation (MR) Among Children Without an Identified Birth Defect vs Prevalence of Severe MR Among Children With Birth Defects* Isolated Severe MR Severe MR and Other Disability No. No. per 1000 Ratio (95% CI) No. No. per 1000 Ratio (95% CI) No birth defect (n = ) Referent Referent Any birth defect (n = 2337) ( ) ( ) Down syndrome (n = 155) ( ) ( ) Other autosomal abnormality (n = 36) ( ) ( ) Sex chromosomal abnormality (n = 26) ( ) ( ) Nonchromosomal abnormality (n = 2118) ( ) ( ) *Number per 1000 is by birth defect grouping (survivors to 1 year, nonmilitary births). Ratio is prevalence of severe MR among individuals with the specified birth defect divided by the prevalence of mild MR among individuals without a major birth defect. Prevalence is by birth defect grouping and by co-occurrence with other developmental disabilities including cerebral palsy, epilepsy, or a pervasive developmental disorder. Table 3. Prevalence of Mild Mental Retardation (MR) Among Children With Specific Types of Nonchromosomal Birth Defects vs Prevalence of Mild MR Among Children Without Any Birth Defects* Isolated Mild MR Mild MR and Other Disability No. per 1000 Ratio (95% CI) No. per 1000 Ratio (95% CI) No birth defect (n = ) 1.1 Referent 0.8 Referent Spina bifida (n = 29) ( ) Other nervous system defect (n = 232) ( ) ( ) Other structural defects Eye (n = 204) ( ) ( ) Ear, face, and neck (n = 170) ( ) Bulbus cordis or cardiac septal closure (n = 163) ( ) ( ) Other cardiac (n = 56) ( ) ( ) Circulatory system (n = 29) ( ) ( ) Respiratory system (n = 45) ( ) Cleft palate and cleft lip (n = 105) ( ) ( ) Other upper alimentary tract (n = 203) ( ) ( ) Other digestive system (n = 98) ( ) Genital organs (n = 244) ( ) Urinary system (n = 112) Musculoskeletal (n = 85) ( ) ( ) Limbs (n = 153) ( ) Other musculoskeletal (n = 90) ( ) ( ) Integument (n = 87) ( ) ( ) Other and unspecified anomalies (n = 13) *Children with specific types of nonchromosomal birth defects excludes all children with Down syndrome or other identified chromosomal defects. Number per 1000 is by birth defect grouping (survivors to 1 year, nonmilitary births). Ratio is prevalence of severe MR among individuals with specific birth defect divided by the prevalence of severe MR among individuals without a major birth defect. Excludes children with nervous system defects, not mutually exclusive of other structural birth defects. occurrence with other neurodevelopmental disabilities. These data, however, have associated limitations. Complete ascertainment of children with MR is challenging in the United States. Although we took steps to maximize case finding of children with MR, there is the possibility that children with birth defects were more likely to be identified as having MR because they may have been more likely to be under greater medical scrutiny and therefore more likely to be receiving regional center services. Such a situation, if present, would likely have a greater effect on risk estimation associated with mild MR, owing to the fact that the prevalence of mild MR is lower than reported in some other studies, 3 whereas the prevalence of severe MR in this study is consistent with other studies, as is the prevalence of birth defects. 7,20 To minimize potential biased ascertainment, we focused on children who were diagnosed as having MR by age 7 to 9 and were actively receiving services in March 2001, when medical record review was initiated. By 1992, statewide programs were in place to identify newborns, infants, and children with MR, autism, cerebral palsy, and epilepsy. These regional center based programs work with hospitals, local agencies, and schools to identify and provide case management to children with these disorders. Focusing on children born in 1992 and 1993 ensured that children with MR or another DD had a minimum of 7 years to be identified by 1 or more professionals in this network, including at least 2 years in primary school. Focusing only on children who were actively receiving services meant that children were likely to have up-to-date 548

5 Table 4. Prevalence of Severe Mental Retardation (MR) Among Children With Specific Nonchromosomal Birth Defects vs Prevalence of Severe MR Among Children Without Any Birth Defects* Isolated Severe MR Severe MR and Other Disability No. per 1000 Ratio (95% CI) No. per 1000 Ratio (95% CI) No birth defect (n = ) 1.4 Referent 0.3 Referent Spina bifida (n = 29) ( ) Other nervous system defect (n = 232) ( ) ( ) Other structural defects Eye (n = 204) ( ) ( ) Ear, face, and neck (n = 170) ( ) ( ) Bulbus cordis or cardiac septal closure (n = 163) ( ) ( ) Other cardiac (n = 56) ( ) Circulatory system (n = 29) ( ) ( ) Respiratory system (n = 45) Cleft palate and cleft lip (n = 105) ( ) ( ) Other upper alimentary tract (n = 203) ( ) ( ) Other digestive system (n = 98) ( ) Genital organs (n = 244) ( ) ( ) Urinary system (n = 112) Musculoskeletal (n = 85) ( ) ( ) Limbs (n = 153) ( ) ( ) Other musculoskeletal (n = 90) ( ) ( ) Integument (n = 87) ( ) ( ) Other and unspecified anomalies (n = 13) ( ) ( ) *Children with specific nonchromosomal birth defects excludes all children with Down syndrome or other identified chromosomal defects. Number per 1000 is by birth defect grouping (survivors to 1 year, nonmilitary births). Ratio is the prevalence of severe MR among individuals with specific birth defect divided by the prevalence of severe MR among individuals without a major birth defect. Excludes children with nervous system defects, not mutually exclusive of other structural birth defects. What This Study Adds Although many epidemiologic studies have investigated structural birth defects and MR separately, few studies have investigated co-occurrence. Consequently, limited information is available regarding the risk of MR among children with specific birth defects. This study is unique in that it examined the association between specific birth defects and level of MR. Defect-specific risks are presented, which suggest that having a structural birth defect, including a defect not involving the central nervous system, substantially elevates an infant s risk for developing mental retardation by 7 to 9 years of age. These results suggest a need for ongoing developmental follow-up with infants and children born with 1 or more birth defects, including those with birth defects not typically thought to be associated with long-term cognitive difficulty. diagnostic information. We believe these strategies minimized underascertainment and maximized diagnostic accuracy. Still, the possibility remains that observed results were, at least in part, a reflection of ascertainment source. This approach also meant that children who had died, who had moved, or whose caregivers had refused services before March 2001 were not included. We observed some evidence for underascertainment. For example, we found that 71% of children with Down syndrome at birth had MR at age 7 to 9. This finding was lower than we expected and may be due to underascertainment of mild MR. It is also possible that some children with Down syndrome were functioning in the normal to borderline level of adaptive functioning and were not receiving services for MR. Our study was also limited in its evaluation of MR risk by specific birth defect phenotypes. Our sample size did not allow for risk estimations of finer definitions of birth defect phenotypes than those represented by the organ and system levels. This limitation did not diminish observed results but, rather, restricted our ability to make inferences about birth defect groupings that may have more homogeneous underlying pathogeneses. Despite these limitations, these data offer some insight into the complex causes of MR by narrowing the time frame of potential insult to the prenatal period in a large number of cases. They also argue for the need to consider children with and without structural birth defects as separate analytic groups for the purposes of disentangling the causes of MR. We suggest that future research, particularly in California, include other sources of case ascertainment, especially public and private schools and vital statistics death files. We also suggest that future research more thoroughly investigate the effect of considering adaptive functioning when diagnosing and subsequently studying MR, particularly in populations where MR is common. Accepted for publication January 16, This work was supported in part by the March of Dimes Birth Defects Foundation. We thank Kerri Ormerod for her assistance in all phases of the study and Rebecca Murray, MA, and Shelby Hyvonen, MA, for their assistance with clinical review. 549

6 Corresponding author and reprints: Laura L. Jelliffe- Pawlowski, PhD, Childhood Lead Poisoning Prevention Branch, California Department of Health Services, 1515 Clay St, Suite 1801, Oakland, CA ( REFERENCES 1. Williams LO, Decoufle P. Is maternal age a risk factor for mental retardation among children? Am J Epidemiol. 1999;149: Drews CD, Murphy CC, Yeargin-Allsopp M, Decoufle P. The relationship between idiopathic mental retardation and maternal smoking during pregnancy. Pediatrics. 1996;97: Boyle CA, Yeargin-Allsopp M, Doernberg NS, Holmgreen P, Murphy CC, Schendel DE. Prevalence of selected developmental disabilities in children 3-10 years of age: the Metropolitan Atlanta Developmental Disabilities Surveillance Program, MMWR Morb Mortal Wkly Rep. 1996;45: Rantakallio P, von Wendt L. Risk factors for mental retardation. Arch Dis Child. 1985;60: Shaw GM, Lammer EL. Maternal periconceptional alcohol consumption and risk for orofacial clefts. J Pediatr. 1999;134: Wasserman CR, Shaw GM, O Malley CD, Tolarova MM, Lammer EJ. Parental cigarette smoking and risk for congenital anomalies of the heart, neural tube, or limb. Teratology. 1996;53: Decoufle P, Boyle CA, Paulozzi LJ, Lary JM. Increased risk for developmental disabilities in children who have major birth defects: a population-based study. Pediatrics. 2001;108: Kirby RS, Brewster MA, Canino CU, Pavin M. Early childhood surveillance of developmental disorders by birth defects surveillance system: methods, prevalence comparisons, and mortality patterns. J Dev Behav Pediatr. 1995;16: Schulman J, Hahn JA. Quality control of birth defect registry data: a case study. Public Health Rep. 1993;108: Croen L, Shaw GM, Jensvold NG, Harris JA. Birth defects monitoring in California: a resource for epidemiologic research. Paediatr Perinat Epidemiol. 1991;5: Lanterman Act, California Welfare and Institutions Code 4512(a) (1969). 12. Classification in Mental Retardation. Washington, DC: American Association on Mental Deficiency; American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC: American Psychiatric Association; Statistical Analysis Software (SAS). Version 8.0. Cary, NC: SAS Institute Inc; Mental Retardation: Definition, Classification, and Systems of Support. 10th ed. Washington, DC: American Association on Mental Retardation; Stromme P, Valvatne K. Mental retardation in Norway: prevalence and subclassification in a cohort of children born between 1980 and Acta Paediatr. 1998;87: Katusic SK, Colligan RC, Beard CM, et al. Mental retardation in a birth cohort, , Rochester, Minnesota. Am J Ment Retard. 1996;100: Steffenburg U, Hagberg G, Viggedal G, Kyllerman M. Active epilepsy in mentally retarded children, I: prevalence and additional neuro-impairments. Acta Paediatr. 1995;84: Hagberg G, Lewerth A, Olsson E, Westerberg B. Mild mental retardation in Gothenburg children born between : changes between two points of time. Uppsala J Med Sci Suppl. 1987;44: Schulman J, Edmonds LD, McClearn AB, Jensvold N, Shaw GM. Surveillance for and comparison of birth defect prevalences in two geographic areas United States, MMWR Morb Mortal Wkly Rep. 1993;42: