SEX, BIRTH ORDER, AND MATERNAL AGE CHARACTERISTICS OF INFANTS WITH CONGENITAL HEART DEFECTS

AMERICAN JOURNAL OF EPIDEMIOLOGY Copyright 1 by The Johns Hopkins University School of Hygiene and Public Health Vol., Xo. 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 02). Sex, birth order and maternal age characteristics of infants with congenital heart defects. Am J Epidemiol :2-,1. 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, 1, and in final form March, 1. Abbreviations: NERICP, New England Regional Infant Cardiac Program; TGA, transposition of the great arteries. From the Department of Epidemiology, Harvard School of Public Health, Huntington Ave., Boston, MA 02 (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 02. Supported by project no. 20 and grant MC-R-201-0 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, 1, and 2 children under one year of age born in New England with serious cardiac defects were enrolled by June, 1. 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; Yale- New 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. 2 Downloaded from https://academic.oup.com/aje/article-abstract///2/20

2 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 0 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 1 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. ) All hospitals which provide definitive care to infants with cardiac problems participate in the program. ) 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 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 20 subjects for the sex analysis and 1 categories comprising subjects for the birth order and maternal age analyses, after excluding from the respective analyses two subjects with unknown sex, 2 with unknown birth order, and 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 (). RESULTS Sex The sex distribution for each of the major diagnostic categories is given in table 1, with point and "exact" two-sided 0 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 males out of 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 ( per cent) male, with a confidence interval extending only as low as 0.. The categories transposition of the great arteries ( per cent male) and hypoplastic left ventricle ( per cent male) both exhibited lower confidence bounds greater than 0.0, and thus also can be characterized as predominantly male. For one other category, coarctation of the aorta, also having a lower confidence bound exceeding 0.0, 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 ( per cent male). For this defect the confidence band was relatively narrow, giving strong support to the notion that Downloaded from https://academic.oup.com/aje/article-abstract///2/20

INFANTS WITH CONGENITAL HEART DEFECTS 2 TABLE 1 Sex distribution for 21 categories of congenital heart disease Proportion male Diagnosis No.* Males Point estimate C confidence interval 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 anomalous pulmonary venous drainage Transposition of the great arteries Tricuspid atresia Truncus arteriosus Ventricular septal defect simple complex Other 2 1 1 2 0 2 2 2 2 2 2 0 0 0. 0.1 0. 0. 0. 0. 0.0 0. 0. 0.2 0. 0. 0.2 0. 0. 0. 0. 0. 0. 0. 0.0 0. 0.-0. 0.-0. 0.-0. 0.-0. 0.-0. 0.2-0. 0.2-0. 0.-0.1 0.-0. 0.-0. 0.-0. 0.-0.1 0.-0.1 0.-0. 0.-0.0 0.-0. 0.1-0.0 0.-0. 0.2-0. 0.0-0.1 0.-0. 0.-0. 2 0. 0.1-0.2 * 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 0.0 with an upper bound for the confidence interval of 0.. Of the individuals with complex ventricular septal defect, also had persistent ductus arteriosus. The proportion of males among the latter group was 2 per cent (/), whereas the proportion of males among the remainder of those with complex ventricular septal defect was per cent (/). The largest category in table 1, transposition of the great arteries (TGA), with 2 subjects, was originally examined by subcategories "simple" and "complex". For simple TGA, the proportion male was 0.; for complex TGA, the proportion male was 0.. For both subcategories, the lower bound of the confidence intervals exceeded 0.0 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. For this analysis, 1 subjects with the diagnosis of Down's syndrome were excluded, leaving subjects, of whom Downloaded from https://academic.oup.com/aje/article-abstract///2/20

ROTHMAN AND FYLER 1 had known birth order. Of these, fell into a variety of diagnostic categories with insufficient subjects to obtain reliable inferences about the birth order distribution; these were considered jointly as "other." The remaining subjects constituted 1 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 1 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 p- value (two-sided) for trend being 0.000. 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 distribution for 1 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 0.0. (Risk ratios are relative to a risk of 1.00 for birth order 1.) Diagnosis l 2 + Unknown % first birthsf 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 anomalous pulmonary venous drainage Transposition of the great arteries Tricuspid atresia Truncus arteriosus Ventricular septal defect simple complex Other 20 2 1 20 (0.2) 2 2 (0.0) 2 (2.02) 1 (1.2) 1 1 1 (0.2) 2 2 (0.) 1 1 (2.) (1.) 0 (0.) 2 2 (0.0) 1 (2.0) 2 (2.0) 1 1 2 2 2 2 1 1 1 2 2 2 1 21 2 2 2 20 2 1 0 2 0 21 * Excludes 1 subjects with Down's syndrome. + Calculated by excluding those births for which birth order was unknown. Downloaded from https://academic.oup.com/aje/article-abstract///2/20

INFANTS WITH CONGENITAL HEART DEFECTS 1 TABLE Maternal age distribution for 1 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 0.0 (Risk ratios are relative to a risk of 1.00 for maternal age < 20.) Diagnosis <20 20-2 Maternal age (yrs) 2-2 + Unknown Per cent <20i 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 anomalous pulmonary venous drainage Transposition of the great arteries Tricuspid atresia Truncus arteriosus Ventricular septal defect simple complex Other 2 1 1 1 2 1 2 (0.) 2 (1.) 2 1 2 (0.) 2 (2.) 1 0 2 2 2 (0.0) 2 (2.2) 2 0 2 1 2 1 2 1 2 2 2 1 1 1 2 2 2 1 21 1 20 20 2 0 * Excludes 1 subjects with Down's syndrome. t Calculated by excluding subjects for which maternal age was unknown. experienced a smaller risk than children of higher birth rank, but among the latter there was no consistent trend (p = 0.0). Subjects with tetralogy of Fallot exhibited some small variation in risk with birth order, but this variation was within the bounds that might be reasonably explained by chance alone. The birth order associations for the other categories were all either small or accompanied by a large sampling error. Maternal age The maternal age distributions for the major categories are given in table. As with birth order, the analysis was restricted to subjects without Down's syndrome and diagnostic categories with at least 20 subjects with known maternal age. As expected, the diagnostic groups having strong associations with birth order also exhibited associations with maternal age. For atrial septal defect, the pattern of risk with maternal age mirrored the pattern with birth order, though the changes in risk were not as marked for maternal age. Persistent ductus arteriosus and transposition of the great arteries also displayed a pattern of risk with increasing maternal age which corresponded closely to the respective patterns seen with birth order for each. Complex ventricular septal defect displayed little overall trend, but an erratic pattern of high risk for infants born of Downloaded from https://academic.oup.com/aje/article-abstract///2/20

2 ROTHMAN AND FYLER mothers age 20-2 (2.) and low risk for older mothers (0.1 for age 2-2, 0.2 for +), with mothers < 20 showing intermediate risk (1.00). For single ventricle, there was little evidence for trend, but young mothers (< 20) showed small risk relative to mothers age 20+. Separation of effects For atrial septal defect, persistent ductus arteriosus, and transposition of the great arteries, there were strong and parallel effects for both birth order and maternal age. To separate the effects of these correlated variables, a multiple linear regression analysis was used with birth order and maternal age as independent variables, and a binary indicator of the diagnosis of interest as the dependent variable. (Cross classification by birth order and maternal age, while theoretically more informative, gave unreliable risk estimates due to the large number of categories relative to the number and distribution of subjects.) Subjects with Down's syndrome or unknown information were excluded. The results of the regression analyses are given in table. For each of the three diagnoses, the birth order effect outweighs the maternal age effect, though the difference between the two effects is small for atrial septal defect. The large p-values and small coefficients for atrial septal defect reflect in part the non-linear relationships observed for the crude effects. DISCUSSION There are several possible sources of inaccuracy in the present data. To the extent that the series is not complete, there may be some biases in the referral and ascertainment process which would distort the distribution by sex, birth order or maternal age. Evidence suggests that the NERICP comprises nearly all of its target population (1); nevertheless, for certain smaller diagnostic groups it is possible that the ascertainment is small enough to lead to bias, although there is no particular reason to believe that there would be differential ascertainment by sex, birth order or maternal age. Conceivably, ascertainment is less complete for lower socioeconomic classes, which would lead to underascertainment of infants with high birth rank. However, unless such a bias were of different magnitudes for different diagnoses, the assessment of birth order effects in this analysis would remain unbiased, because the remainder of the NERICP was used as a comparison group. Infants who die from congenital heart disease before they can be referred to a participating NERICP center are not included in the roster. If early death is associated with sex, birth order, or maternal age for some diagnoses, this would lead to inaccuracies in the present analysis. The proportion of infants who die before referral to the NERICP is small (about -1 TABLE Multiuariate analysis of birth order and maternal age effects for three diagnostic groups Dependent variate Independent variate Standardized coefficient p-value (two-tail) Atrial septal defect Maternal age 0.0 0.0 0. 0. Persistent ductus arteriosus Maternal age 0.0-0.02 0.0 0. Transposition of the great arteries Maternal age 0.0 0.0 0.0 0. Downloaded from https://academic.oup.com/aje/article-abstract///2/20

INFANTS WITH CONGENITAL HEART DEFECTS per cent), however, and probably does not result in any material error. The NERICP only enrolls children under one year of age. For many children with congenital heart disease, referral for treatment occurs after the first birthday. For those diagnostic categories in which a substantial proportion of cases are omitted from this series because the disease does not become manifest in the first year of life, there is also the possibility of bias. Such bias would exist if the earlier occurring cases differ from the later occurring ones by sex, birth order or maternal age. Even if there were evidence for such differential occurrence with age, the present series would be of considerable interest, as the early cases are the most serious ones, and the risk factors for serious congenital heart disease are worthy of separate description. Epidemiologic characteristics of congenital heart disease for selected diagnostic categories have been reviewed recently in a report of 1 cases from Liverpool by Kenna, Smithells and Fielding (). These authors reported sex distributions by diagnostic category and compared findings with two smaller series (, ). All three series of cases have sex distributions, for each diagnostic category, similar to the ones given here. The main value of the present series is its greater size it is larger than these three previous series combined. Thus the NERICP data provide more precise information about each diagnostic category, as well as giving an indication of the sex distribution for many diagnoses which were not included in the previous studies due to insufficient numbers. Previous studies on the relation of maternal age and birth order to risk of congenital heart disease have yielded conflicting results. Mitchell et al. () reported a 0 per cent increase in risk for all congenital heart defects combined, excluding subjects with Down's syndrome, when comparing subjects with maternal age or greater to subjects with maternal age or less. The data of Kenna et al. (), with subjects classified by maternal age 2 or less or or greater suggested only a slight increase in risk for congenital heart disease, again after excluding subjects with Down's syndrome. MacMahon () found no association between congenital heart disease and maternal age or birth order except among children with Down's syndrome. With regard to specific defects, Polani and Campbell (), Campbell () and Kenna et al. () all found risk to tetralogy of Fallot to be associated with greater maternal ages, but only Kenna et al. found birth order also to be associated with tetralogy. Kenna et al. also report positive associations of birth order with persistent ductus arteriosus, and maternal age with pulmonic stenosis. For each diagnostic group in the present study, the comparison group for the birth order and maternal age analyses was the remainder of the NERICP series. Thus, a general effect of greater maternal age and/ or birth order in elevating risk for congenital heart disease would result in underestimates of the effect in specific categories. The bulk of evidence from other studies suggests that if any overall effect exists for birth order or maternal age, it is likely to be small enough so that it would not affect the present results to a significant extent. Even strong effects of birth order or maternal age for specific diagnostic groups would not materially affect comparisons for other diagnoses, inasmuch as the largest category constitutes only about per cent of the total, and therefore should not unduly distort the comparison. The relationships of specific defects with maternal age and birth order differ in these data from some previously published reports. For example, the direction of association with persistent ductus arteriosus in the present data is the reverse of what has been reported in Liverpool (), although the data are consistent with what was reported earlier from Birmingham (). Several studies have found an association Downloaded from https://academic.oup.com/aje/article-abstract///2/20

ROTHMAN AND FYLER between advanced maternal age and tetralogy of Fallot (,, ), but in this study the relative risk estimates for the four maternal age categories used were 1.00 (the referent category), 0., 1.01 and 1.02. The discrepancies in birth order and maternal age associations between previous studies and these data may reflect real differences between the populations studied; geographic, secular and ethnic differences exist among these groups, and biologic differences may exist as well. Alternatively, biases in selection or comparison may have distorted the associations in any or all of these reports, though it is unclear what such biases might be to account for some of the large differences in the magnitude of the associations. A third explanation may be the most reasonable: in most studies of congenital heart disease, the small number of subjects in any particular diagnostic group yields estimates of association which are subject to great sampling variability. The larger size of the present series and consequent smaller sampling variability makes the random error component in this study less of a problem than in the previous ones. REFERENCES 1. Fyler DC, Parisi L, Berman MA: The regionalization of infant cardiac care in New England. Cardiovasc Clin :-, 12 2. Rothman KJ, Fyler DC: Association of congenital heart defects with season and population density. Teratology :2-, 1. Miettinen OS: Comment. J Am Stat Assn :-2, 1. Kenna AP, Smithells RW, Fielding DW: Congenital heart disease in Liverpool: 10-1. Q J Med :-, 1. MacMahon B, McKeown T, Record RG: The incidence and life expectation of children with congenital heart disease. Br Heart J 1:1-, 1. Carlgren LE: The incidence of congenital heart disease in Gothenburg 1-10. Br Heart J 21:0-0, 1. Mitchell SC, Sellmann AH, Westphal MC, et al: Etiologic correlates in a study of congenital heart disease in, births. Am J Cardiol 2:-, 11. MacMahon B: Association of congenital malformation of the heart with birth rank and maternal age. Br J Soc Med :-, 12. Polani PE, Campbell M: An aetiological study of congenital heart disease. Ann Hum Genet 1:20-2, 1. Campbell M: Causes of malformations of the heart. Br Med J 2:-0, 1 Downloaded from https://academic.oup.com/aje/article-abstract///2/20