AMERICAN JOURNAL OF EPIDEMIOLOGY
Copyright © 1976 by The Johns Hopkins University School of Hygiene and Public Health
Vol. 104, Xo. 5 Printed in U.S.A.
SEX, BIRTH ORDER, AND MATERNAL AGE CHARACTERISTICS OF INFANTS WITH CONGENITAL HEART DEFECTS KENNETH J. ROTHMAN AND DONALD C. FYLER Rothman, K. J . and Fyler, D. C. (Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115). Sex, birth order and maternal age characteristics of infants with congenital heart defects. Am J Epidemiol 104:527-534,1976. The records of the New England Regional Infant Cardiac Program, a service program covering all of New England, provide a useful source of information about the characteristics of children born with congenital heart defects. Data were analyzed on more than 2000 children born in New England who were diagnosed with a congenital heart defect before the first birthday. Children with arterio-venous fistula, aortic stenosis, transposition of the great arteries or hypoplastic left ventricle were predominantly male; children with persistent ductus arteriosus and endocardial cushion defect were predominantly female. Positive trends in risk with increasing birth order were present for pulmonic stenosis and transposition of the great arteries, and a negative trend was seen for persistent ductus arteriosus. What evidence there was for associations with maternal age was greatly reduced after controlling for confounding by birth order. aortic diseases; aortic valve stenosis; arterio-venous fistula; heart defects, congenital
The New England Regional Infant Cardiac Program (NERICP) is a service program designed to provide medical care for all infants with serious congenital heart disease born in New England (1). The population coverage and centralized record-keeping provide the equivalent of a regional registry of congenital heart disease. In a previous report (2) we used these data to describe the associations of congenital heart defects with season and with Received for publication January 12, 1976, and in final form March 30, 1976. Abbreviations: NERICP, New England Regional Infant Cardiac Program; TGA, transposition of the great arteries. From the Department of Epidemiology, Harvard School of Public Health, 677 Huntington Ave., Boston, MA 02115 (reprint requests to Dr. Rothman at this address), Department of Cardiology, Children's Hospital Medical Center and Department of Pediatrics, Harvard Medical School, Boston, MA 02115. Supported by project no. 260 and grant MC-R-250197-03 from the Maternal and Child Health Service, Health Service and Mental Health Administration of the US Public Health Service.
population density. In this paper we present the sex, birth order and maternal age characteristics of infants with congenital heart defects. SUBJECTS AND METHODS
Enrollment of patients into the NERICP began July 1, 1968, and 2336 children under one year of age born in New England with serious cardiac defects were enrolled by June 30, 1974. When the program The authors express their gratitude to the many individuals whose cooperative efforts make NERICP successful. Participating centers in NERICP are the pediatric divisions of the following hospitals: Hartford Hospital and St. Francis Hospital, Hartford; YaleNew Haven Hospital, New Haven; Maine Medical Center, Portland; Boston City Hospital, Boston Floating Hospital for Infants and Children, Children's Hospital Medical Center, Massachusetts General Hospital, Boston; Dartmouth-Hitchcock Medical Center, Hanover; Rhode Island Hospital-Brown University, Providence; Medical Center Hospital of Vermont (Mary Fletcher Unit), Burlington.
527
528
ROTHMAN AND FYLER
began, a major effort in professional education was mounted to maximize early referral of infants critically ill with congenital heart disease. A NERICP nurse made periodic visits to outlying newborn nurseries to discuss early recognition of critical heart disease and present educational materials which had been prepared to promote recognition. In addition, movies, editorials, brochures and special symposia were directed at the physicians and nurses who might refer infants. Evidence suggests that the NERICP roster includes a large proportion of the eligible infants: 1) The impact of the professional education campaign was evident during the program's first year with a large increase (about 80 per cent) in the number of infants with congenital heart disease reported from outlying, small hospitals. 2) A search of death records revealed less than 15 per cent additional infants dying of congenital heart disease unknown to the NERICP, a figure which includes those who did not survive long enough for referral. 3) All hospitals which provide definitive care to infants with cardiac problems participate in the program. 4) The ascertainment rate of infants seriously ill with congenital heart disease is greater than would be expected from other reports (1). Diagnosis was determined by cardiac catheterization, surgery or autopsy. For this presentation we include only broad categories containing 10 or more subjects for the analysis of sex and 20 or more for the analysis of birth order and maternal age. This led to 21 separate diagnostic categories comprising 2100 subjects for the sex analysis and 19 categories comprising 1768 subjects for the birth order and maternal age analyses, after excluding from the respective analyses two subjects with unknown sex, 236 with unknown birth order, and 425 with unknown maternal age. Individuals with more than one defect are classified according to the predominant problem; the designations "simple" and "complex" are used to denote single
defects and multiple cardiac defects, respectively. In evaluating the distributions of birth order and maternal age, the remainder of the NERICP experience was used as a comparison group for each diagnostic category. For the derivation of "exact" confidence limits, a modification of the classical solution for "exact" limits was employed (3). RESULTS
Sex The sex distribution for each of the major diagnostic categories is given in table 1, with point and "exact" two-sided 90 per cent confidence interval estimates for the proportion of male subjects. The highest proportion of males was seen for the numerically small group, arteriovenous fistula, with 10 males out of 11 subjects. Even for the small size of the group, the lower bound of the confidence interval for proportion male is greater for arterio-venous fistula than for any other category. Infants with aortic stenosis also were predominantly (78 per cent) male, with a confidence interval extending only as low as 0.66. The categories transposition of the great arteries (66 per cent male) and hypoplastic left ventricle (65 per cent male) both exhibited lower confidence bounds greater than 0.50, and thus also can be characterized as predominantly male. For one other category, coarctation of the aorta, also having a lower confidence bound exceeding 0.50, there is a strong suggestion of an excess of males. Data for the other diagnostic categories with a majority of males indicate only a slight excess of males or are sufficiently sparse to be reasonably consistent with a wide range of sex distributions, including an excess of females. The category with the largest proportion of females was persistent ductus arteriosus (36 per cent male). For this defect the confidence band was relatively narrow, giving strong support to the notion that
529
INFANTS WITH CONGENITAL HEART DEFECTS TABLE 1
Sex distribution for 21 categories of congenital heart disease Proportion male Diagnosis
Aortic stenosis Arterio-venous fistula Atrial septal defect Coarctation of the aorta Double outlet right ventricle Ebstein's anomaly Endocardial cushion defect Hypoplastic left ventricle Malposition Myocardiopathy Persistent ductus arteriosus Pulmonary atresia Pulmonic stenosis Single ventricle Tetralogy of Fallot Total anomalous pulmonary venous drainage Transposition of the great arteries Tricuspid atresia Truncus arteriosus Ventricular septal defect simple complex Other Total
No.*
Males
41 11 64 143 29 19 105 163 81 63 179 117 86 62 160 59 259 62 30
32 10 28 85 17 9 42 106 47 33 64 63 45 36 86 33 170 30 13
0.78 0.91 0.44 0.59 0.59 0.47 0.40 0.65 0.58 0.52 0.36 0.54 0.52 0.58 0.54 0.56 0.66 0.48 0.43
0.66-0.87 0.68-0.99 0.34-0.54 0.53-0.66 0.43-0.73 0.29-0.66 0.32-0.48 0.59-0.71 0.49-0.67 0.42-0.63 0.30-0.42 0.46-0.61 0.43-0.61 0.48-0.68 0.47-0.60 0.45-0.66 0.61-0.70 0.38-0.59 0.29-0.58
253 114 234
140 46 113
0.55 0.40 0.48
0.50-0.61 0.33-0.48 0.43-0.54
2334
1248
0.535
0.518-0.552
Point estimate
9C7 confidence interval
* One subject with tetralogy of Fallot and one with complex ventricular septal defect are excluded because sex was unknown.
persistent ductus arteriosus is predominantly a disease of females. Two other categories gave reasonably strong evidence for an excess of females: endocardial cushion defect and complex ventricular septal defect, both showing a male proportion of 0.40 with an upper bound for the confidence interval of 0.48. Of the 114 individuals with complex ventricular septal defect, 35 also had persistent ductus arteriosus. The proportion of males among the latter group was 29 per cent (10/35), whereas the proportion of males among the remainder of those with complex ventricular septal defect was 46 per cent (36/79). The largest category in table 1, transposition of the great arteries (TGA), with 259 subjects, was originally examined by sub-
categories "simple" and "complex". For simple TGA, the proportion male was 0.67; for complex TGA, the proportion male was 0.64. For both subcategories, the lower bound of the confidence intervals exceeded 0.50 considerably. In view of the similar sex ratio for these subcategories, and particularly in view of recent evidence (2) that other epidemiologic features (seasonal distributions and associations with population density) for these subcategories are nearly identical, the subcategories are merged for this presentation. Birth order For this analysis, 71 subjects with the diagnosis of Down's syndrome were excluded, leaving 2265 subjects, of whom
530
ROTHMAN AND FYLER
1994 had known birth order. Of these, 226 fell into a variety of diagnostic categories with insufficient subjects to obtain reliable inferences about the birth order distribution; these 226 were considered jointly as "other." The remaining 1768 subjects constituted 19 diagnostic categories each with 20 or more subjects; the birth order distributions for these categories and for "other" are given in table 2. For each category, the birth order distribution was compared to that of the remainder of the 1994 subjects with known birth order. Statistical tests for linear trend of risk with birth order, deviations from linearity, and overall heterogeneity of risk with birth order were applied to each category. On
this basis several categories showed strong evidence for an association with birth order. Subjects with transposition of the great arteries experienced a generally increasing risk with increasing birth order, the pvalue (two-sided) for trend being 0.0005. The trend was equally evident for subjects with simple and complex transposition. A consistent decrease in risk with increasing birth order was noted for subjects with persistent ductus arteriosus (p = 0.001). The group with atrial septal defect also demonstrated a higher risk for first born, but no consistent pattern was seen among later born children (p = 0.02). For infants with pulmonic stenosis, those first born
TABLE 2
Birth order distribution for 19 categories of congenital heart disease,* with risk ratio estimates indicated in parentheses for those diagnoses with a two-sided p-value for linear trend less than 0.05. (Risk ratios are relative to a risk of 1.00 for birth order 1.) Birth order Diagnosis
Aortic stenosis Atrial septal defect Coarctation of the aorta Double outlet right ventricle Endocardial cushion defect Hypoplastic left ventricle Malposition Myocardiopathy Persistent ductus arteriosus Pulmonary atresia Pulmonic stenosis Single ventricle Tetralogy of Fallot Total anomalous pulmonary venous drainage Transposition of the great arteries Tricuspid atresia Truncus arteriosus Ventricular septal defect simple complex Other Total
2
l 14
12
8(0.27)
Total
% first birthsf
41 62 143 29 62 163 81
23
7 10 17
176 115 86 61 155
39 59 34 32 38 32 35 28 42 30 20 33 42
5
9
58
39
3
5 4 (0.25) 22 5 5 25
4+
5 11(0.58) 26
Unknown 5 6 15
33 43 8 20 46 25 16 67 30 16 17 58
17 35
8 24 (0.75) 19 18 (2.49) 6 22
19
15
10
63 20 10
67 (1.28)
34(1.17) 7 4
67 (2.07) 13 6
28 4 3
259 62 30
27 34 37
74 34 78
64 31 61
40 41
33 17 46
36 16 35
247 111 261
35 36 35
691
590
323
390
271
2265
35
37 8 13 41 25 17
52 (0.90) 35
27 (2.02)
18 7
11
13
4 14
32 10 16 16 (0.40) 17 18 (2.04) 11
* Excludes 71 subjects with Down's syndrome. + Calculated by excluding those births for which birth order was unknown.
4
10 19 10 6 17 14
63
531
INFANTS WITH CONGENITAL HEART DEFECTS TABLE 3
Maternal age distribution for 19 categories of congenital heart disease,* with risk ratio estimates indicated in parentheses for those diagnoses with a two-sided p-ualue for linear trend less than 0.05 (Risk ratios are relative to a risk of 1.00 for maternal age < 20.) Maternal age (yrs)
Diagnosis
Per cent
Copyright © 1976 by The Johns Hopkins University School of Hygiene and Public Health
Vol. 104, Xo. 5 Printed in U.S.A.
SEX, BIRTH ORDER, AND MATERNAL AGE CHARACTERISTICS OF INFANTS WITH CONGENITAL HEART DEFECTS KENNETH J. ROTHMAN AND DONALD C. FYLER Rothman, K. J . and Fyler, D. C. (Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115). Sex, birth order and maternal age characteristics of infants with congenital heart defects. Am J Epidemiol 104:527-534,1976. The records of the New England Regional Infant Cardiac Program, a service program covering all of New England, provide a useful source of information about the characteristics of children born with congenital heart defects. Data were analyzed on more than 2000 children born in New England who were diagnosed with a congenital heart defect before the first birthday. Children with arterio-venous fistula, aortic stenosis, transposition of the great arteries or hypoplastic left ventricle were predominantly male; children with persistent ductus arteriosus and endocardial cushion defect were predominantly female. Positive trends in risk with increasing birth order were present for pulmonic stenosis and transposition of the great arteries, and a negative trend was seen for persistent ductus arteriosus. What evidence there was for associations with maternal age was greatly reduced after controlling for confounding by birth order. aortic diseases; aortic valve stenosis; arterio-venous fistula; heart defects, congenital
The New England Regional Infant Cardiac Program (NERICP) is a service program designed to provide medical care for all infants with serious congenital heart disease born in New England (1). The population coverage and centralized record-keeping provide the equivalent of a regional registry of congenital heart disease. In a previous report (2) we used these data to describe the associations of congenital heart defects with season and with Received for publication January 12, 1976, and in final form March 30, 1976. Abbreviations: NERICP, New England Regional Infant Cardiac Program; TGA, transposition of the great arteries. From the Department of Epidemiology, Harvard School of Public Health, 677 Huntington Ave., Boston, MA 02115 (reprint requests to Dr. Rothman at this address), Department of Cardiology, Children's Hospital Medical Center and Department of Pediatrics, Harvard Medical School, Boston, MA 02115. Supported by project no. 260 and grant MC-R-250197-03 from the Maternal and Child Health Service, Health Service and Mental Health Administration of the US Public Health Service.
population density. In this paper we present the sex, birth order and maternal age characteristics of infants with congenital heart defects. SUBJECTS AND METHODS
Enrollment of patients into the NERICP began July 1, 1968, and 2336 children under one year of age born in New England with serious cardiac defects were enrolled by June 30, 1974. When the program The authors express their gratitude to the many individuals whose cooperative efforts make NERICP successful. Participating centers in NERICP are the pediatric divisions of the following hospitals: Hartford Hospital and St. Francis Hospital, Hartford; YaleNew Haven Hospital, New Haven; Maine Medical Center, Portland; Boston City Hospital, Boston Floating Hospital for Infants and Children, Children's Hospital Medical Center, Massachusetts General Hospital, Boston; Dartmouth-Hitchcock Medical Center, Hanover; Rhode Island Hospital-Brown University, Providence; Medical Center Hospital of Vermont (Mary Fletcher Unit), Burlington.
527
528
ROTHMAN AND FYLER
began, a major effort in professional education was mounted to maximize early referral of infants critically ill with congenital heart disease. A NERICP nurse made periodic visits to outlying newborn nurseries to discuss early recognition of critical heart disease and present educational materials which had been prepared to promote recognition. In addition, movies, editorials, brochures and special symposia were directed at the physicians and nurses who might refer infants. Evidence suggests that the NERICP roster includes a large proportion of the eligible infants: 1) The impact of the professional education campaign was evident during the program's first year with a large increase (about 80 per cent) in the number of infants with congenital heart disease reported from outlying, small hospitals. 2) A search of death records revealed less than 15 per cent additional infants dying of congenital heart disease unknown to the NERICP, a figure which includes those who did not survive long enough for referral. 3) All hospitals which provide definitive care to infants with cardiac problems participate in the program. 4) The ascertainment rate of infants seriously ill with congenital heart disease is greater than would be expected from other reports (1). Diagnosis was determined by cardiac catheterization, surgery or autopsy. For this presentation we include only broad categories containing 10 or more subjects for the analysis of sex and 20 or more for the analysis of birth order and maternal age. This led to 21 separate diagnostic categories comprising 2100 subjects for the sex analysis and 19 categories comprising 1768 subjects for the birth order and maternal age analyses, after excluding from the respective analyses two subjects with unknown sex, 236 with unknown birth order, and 425 with unknown maternal age. Individuals with more than one defect are classified according to the predominant problem; the designations "simple" and "complex" are used to denote single
defects and multiple cardiac defects, respectively. In evaluating the distributions of birth order and maternal age, the remainder of the NERICP experience was used as a comparison group for each diagnostic category. For the derivation of "exact" confidence limits, a modification of the classical solution for "exact" limits was employed (3). RESULTS
Sex The sex distribution for each of the major diagnostic categories is given in table 1, with point and "exact" two-sided 90 per cent confidence interval estimates for the proportion of male subjects. The highest proportion of males was seen for the numerically small group, arteriovenous fistula, with 10 males out of 11 subjects. Even for the small size of the group, the lower bound of the confidence interval for proportion male is greater for arterio-venous fistula than for any other category. Infants with aortic stenosis also were predominantly (78 per cent) male, with a confidence interval extending only as low as 0.66. The categories transposition of the great arteries (66 per cent male) and hypoplastic left ventricle (65 per cent male) both exhibited lower confidence bounds greater than 0.50, and thus also can be characterized as predominantly male. For one other category, coarctation of the aorta, also having a lower confidence bound exceeding 0.50, there is a strong suggestion of an excess of males. Data for the other diagnostic categories with a majority of males indicate only a slight excess of males or are sufficiently sparse to be reasonably consistent with a wide range of sex distributions, including an excess of females. The category with the largest proportion of females was persistent ductus arteriosus (36 per cent male). For this defect the confidence band was relatively narrow, giving strong support to the notion that
529
INFANTS WITH CONGENITAL HEART DEFECTS TABLE 1
Sex distribution for 21 categories of congenital heart disease Proportion male Diagnosis
Aortic stenosis Arterio-venous fistula Atrial septal defect Coarctation of the aorta Double outlet right ventricle Ebstein's anomaly Endocardial cushion defect Hypoplastic left ventricle Malposition Myocardiopathy Persistent ductus arteriosus Pulmonary atresia Pulmonic stenosis Single ventricle Tetralogy of Fallot Total anomalous pulmonary venous drainage Transposition of the great arteries Tricuspid atresia Truncus arteriosus Ventricular septal defect simple complex Other Total
No.*
Males
41 11 64 143 29 19 105 163 81 63 179 117 86 62 160 59 259 62 30
32 10 28 85 17 9 42 106 47 33 64 63 45 36 86 33 170 30 13
0.78 0.91 0.44 0.59 0.59 0.47 0.40 0.65 0.58 0.52 0.36 0.54 0.52 0.58 0.54 0.56 0.66 0.48 0.43
0.66-0.87 0.68-0.99 0.34-0.54 0.53-0.66 0.43-0.73 0.29-0.66 0.32-0.48 0.59-0.71 0.49-0.67 0.42-0.63 0.30-0.42 0.46-0.61 0.43-0.61 0.48-0.68 0.47-0.60 0.45-0.66 0.61-0.70 0.38-0.59 0.29-0.58
253 114 234
140 46 113
0.55 0.40 0.48
0.50-0.61 0.33-0.48 0.43-0.54
2334
1248
0.535
0.518-0.552
Point estimate
9C7 confidence interval
* One subject with tetralogy of Fallot and one with complex ventricular septal defect are excluded because sex was unknown.
persistent ductus arteriosus is predominantly a disease of females. Two other categories gave reasonably strong evidence for an excess of females: endocardial cushion defect and complex ventricular septal defect, both showing a male proportion of 0.40 with an upper bound for the confidence interval of 0.48. Of the 114 individuals with complex ventricular septal defect, 35 also had persistent ductus arteriosus. The proportion of males among the latter group was 29 per cent (10/35), whereas the proportion of males among the remainder of those with complex ventricular septal defect was 46 per cent (36/79). The largest category in table 1, transposition of the great arteries (TGA), with 259 subjects, was originally examined by sub-
categories "simple" and "complex". For simple TGA, the proportion male was 0.67; for complex TGA, the proportion male was 0.64. For both subcategories, the lower bound of the confidence intervals exceeded 0.50 considerably. In view of the similar sex ratio for these subcategories, and particularly in view of recent evidence (2) that other epidemiologic features (seasonal distributions and associations with population density) for these subcategories are nearly identical, the subcategories are merged for this presentation. Birth order For this analysis, 71 subjects with the diagnosis of Down's syndrome were excluded, leaving 2265 subjects, of whom
530
ROTHMAN AND FYLER
1994 had known birth order. Of these, 226 fell into a variety of diagnostic categories with insufficient subjects to obtain reliable inferences about the birth order distribution; these 226 were considered jointly as "other." The remaining 1768 subjects constituted 19 diagnostic categories each with 20 or more subjects; the birth order distributions for these categories and for "other" are given in table 2. For each category, the birth order distribution was compared to that of the remainder of the 1994 subjects with known birth order. Statistical tests for linear trend of risk with birth order, deviations from linearity, and overall heterogeneity of risk with birth order were applied to each category. On
this basis several categories showed strong evidence for an association with birth order. Subjects with transposition of the great arteries experienced a generally increasing risk with increasing birth order, the pvalue (two-sided) for trend being 0.0005. The trend was equally evident for subjects with simple and complex transposition. A consistent decrease in risk with increasing birth order was noted for subjects with persistent ductus arteriosus (p = 0.001). The group with atrial septal defect also demonstrated a higher risk for first born, but no consistent pattern was seen among later born children (p = 0.02). For infants with pulmonic stenosis, those first born
TABLE 2
Birth order distribution for 19 categories of congenital heart disease,* with risk ratio estimates indicated in parentheses for those diagnoses with a two-sided p-value for linear trend less than 0.05. (Risk ratios are relative to a risk of 1.00 for birth order 1.) Birth order Diagnosis
Aortic stenosis Atrial septal defect Coarctation of the aorta Double outlet right ventricle Endocardial cushion defect Hypoplastic left ventricle Malposition Myocardiopathy Persistent ductus arteriosus Pulmonary atresia Pulmonic stenosis Single ventricle Tetralogy of Fallot Total anomalous pulmonary venous drainage Transposition of the great arteries Tricuspid atresia Truncus arteriosus Ventricular septal defect simple complex Other Total
2
l 14
12
8(0.27)
Total
% first birthsf
41 62 143 29 62 163 81
23
7 10 17
176 115 86 61 155
39 59 34 32 38 32 35 28 42 30 20 33 42
5
9
58
39
3
5 4 (0.25) 22 5 5 25
4+
5 11(0.58) 26
Unknown 5 6 15
33 43 8 20 46 25 16 67 30 16 17 58
17 35
8 24 (0.75) 19 18 (2.49) 6 22
19
15
10
63 20 10
67 (1.28)
34(1.17) 7 4
67 (2.07) 13 6
28 4 3
259 62 30
27 34 37
74 34 78
64 31 61
40 41
33 17 46
36 16 35
247 111 261
35 36 35
691
590
323
390
271
2265
35
37 8 13 41 25 17
52 (0.90) 35
27 (2.02)
18 7
11
13
4 14
32 10 16 16 (0.40) 17 18 (2.04) 11
* Excludes 71 subjects with Down's syndrome. + Calculated by excluding those births for which birth order was unknown.
4
10 19 10 6 17 14
63
531
INFANTS WITH CONGENITAL HEART DEFECTS TABLE 3
Maternal age distribution for 19 categories of congenital heart disease,* with risk ratio estimates indicated in parentheses for those diagnoses with a two-sided p-ualue for linear trend less than 0.05 (Risk ratios are relative to a risk of 1.00 for maternal age < 20.) Maternal age (yrs)
Diagnosis
Per cent
