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Asplenia syndrome is characterized by complex congenital heart defects, asplenia and abdominal heterotaxy. Recent interest in the syndrome has been increased by new knowledge arising from animal models and by continuing improvements in surgical outcome in childhood. To further elucidate the embryologic timing and mechanisms of the asplenia syndrome, 32 necropsy cases were reviewed and 487 published autopsy cases were reanalyzed at the hospital. The most common congenital heart defects were atrial septal defects, common atrioventricular canals and conotruncal anomalies. With use of current information on the timing of normal development, it was hypothesized that most defects originate at Streeter Horizon XIII; patients averaged 3.2 Horizon XIII defects, more than at any other stage. Distribution was unimodal. Extracardiac anomalies also exhibited a developmental spectrum. Because the normal spleen develops by Horizon XIII, asplenia, the sine qua non of the syndrome, originates then or earlier. Abnormal pulmonary lobation occurred in 80% of cases, with right isomerism occurring most often; pulmonary branching asymmetry also originates at or before Horizon XIII. Abdominal heterotaxy occurred in 72% of cases, but the timing of origin is unclear. Anomalies of other systems, including genitourinary, musculoskeletal, endocrine, and nervous systems, develop later (typically XV to XXIII); specific anomalies were less frequent, although much more prevalent than in the general population. It is concluded that asplenia syndrome is a focal developmental disturbance in laterality which occurs primarily at Horizon XIII.

Cardiomyopathy (Cm), a rare form of cardiac disease in infancy, is receiving increasing attention stimulated by the availability of endocardial biopsy and new forms of therapy. Population-based information on frequency of occurrence, types, and maternal and infant characteristics of this diverse group of heart muscle disorders has been obtained in the course of an etiologic study on cardiovascular disease in infancy. The Baltimore-Washington Infant Study (BWIS) enrolled 2659 infants with heart disease and 2801 control infants between January 1, 1981 and March 31, 1987, a 6-year prevalence of 4.46/1000 live births. Fifty-six infants had cardiomyopathy, in the absence of a structural defect (prevalence 1/10,000). The cases were classified clinicopathologically as follows: dilated Cm (n = 17), hypertrophic Cm (n = 26), tumor (n = 5), endocardial fibroelastosis (n = 5), glycogen storage (n = 1), mucocutaneous lymph node syndrome (n = 1), and infarction (n = 1). Eleven syndromic associations and six metabolic disturbances indicate genetic risk factors. Some of the same syndromes occurred in other infants who had structural cardiac abnormalities. This overlap suggests that embryonic myocardial disease might sometimes be responsible for altered cardiac structures, possibly secondary to hemodynamic changes. Familial myocardial disease occurred in two infants with hypertrophic Cm. The Cm group did not differ by race and sex from controls, but the mothers were of lower educational and occupational status with less private care and with later registration for pregnancy care. The descriptive epidemiology of this population-based case group provides evidence of greater etiologic heterogeneity than has been shown in clinical reports.

To identify determinants of adverse outcome in this era of early, definitive treatment, retrospective data were analyzed for 1988 on infants aged less than 1 year with congenital cardiac disease hospitalized at The Johns Hopkins Hospital. In this cohort of 108 infants, 34% (37 of 108) had complex cardiac disease, 33% (36 of 108) had major extracardiac anomalies, 88 patients (81%) underwent 116 surgical procedures, 37% (40 of 108) were hospitalized for greater than 28 days and 29% (31 of 108) died during the first year. Univariate analysis showed that complex disease (i.e., severe ventricular hypoplasia, ventricular septal malalignment or outflow atresia), extracardiac anomalies, early initial presentation, and prolonged stay in the intensive care unit were significantly associated with infant death, whereas surgery was associated with a significantly increased rate of survival. The findings for complex disease and surgery persisted in multiple logistic regression analysis. It is concluded that outcome in most infants with congenital cardiac defects is now extremely favorable, and that major research and preventive efforts should focus on complex congenital cardiac defects.

To determine if the pattern of cardiac care is affected by the presence of Down syndrome (DS) we analyzed the records of infants enrolled in the Baltimore-Washington Infant Study, a regional case-control study of congenital cardiovascular malformations. The age at cardiac diagnosis, the timing of cardiac surgery, and the one-year outcome were compared in 160 infants with DS and 540 infants with the same cardiac diagnoses but without chromosomal or other extracardiac anomalies (Isolated cardiovascular malformation [ICM] group). Cardiac referral and diagnosis were accomplished by 13 weeks of age in 78% of infants with DS and 67% of those with ICMs. However, by 26 weeks of age, the proportion of infants in both groups was comparable. Cardiac surgery was performed before 1 year of age in 99 of 160 infants with DS and in 141 of 540 infants with ICMs. The surgical outcome was similar in the two groups. We conclude that for defects of comparable severity, the pattern of cardiac care in the Baltimore-Washington, DC, area for infants with DS is timely and comparable to care for infants with ICMs.

The Baltimore-Washington Infant Study is a regional epidemiologic study of congenital heart disease. Among Infants born in the study area in 1981 and 1982, 664 had a diagnosis of congenital heart disease confirmed in the first year of life by echocardiography, cardiac catheterization, cardiac surgery, or autopsy. The prevalence rate was 3.7/1,000 livebirths for all cases and 2.4/1,000 livebirths for cases confirmed by invasive methods only. Diagnosis-specific prevalence rates of congenital heart disease are compared with those of eight previous case series. Changing diagnostic categorizations in the time span covered and methodological differences resulted in great variation of the data. However, the data of the New England Infant Cardiac Program which used the same case discovery methods showed similar occurrences of major morphologic abnormalities, suggesting that these are stable basic estimates in the eastern United States. For all case series, the rate of confirmed congenital heart disease was approximately 4/1,000 livebirths over the 40-year time span.

The Baltimore-Washington Infant Study is a population-based case-control study that seeks to identify risk factors for cardiovascular malformations. Between 1981 and 1986, a total of 2102 infants with cardiovascular malformations were ascertained, among whom 271 (12.9%) also had a chromosome abnormality. Among 2328 random control subjects, only two had a chromosome abnormality. Down syndrome with cardiovascular malformations had a maternal age-adjusted regional prevalence of 4.33/10,000 for the white population and 3.70/10,000 for the nonwhite population. Endocardial cushion defect, the predominant cardiac abnormality in Down syndrome (60.1%), rarely occurred as an isolated cardiac lesion (2.8%). The absence of transpositions and the rarity of heterotaxias and of right- and left-sided obstructive lesions in trisomies indicate that there may be a genetic influence on specific embryologic mechanisms. Alimentary tract lesions were more common in Down syndrome than among euploid patients with heart disease and more severe than in control subjects. Urinary tract lesions also occurred in excess of the rate in control subjects. The coexistence of these major malformations with heart disease raises the possibility of incomplete expression of the VA(C)TER (vertebral, anal, cardiac, tracheal, esophageal renal) association. The selective association of chromosome abnormalities with certain cardiovascular defects is now beginning to be explained by reported embryologic studies on cellular characteristics. An explanation of the negative association with transposition and obstructive lesions requires further multidisciplinary studies on genetic and epigenetic factors.

A regional case-control study of congenital cardiovascular malformations (CCVMs) searches for all live-born infants in the community in whom the cardiac diagnosis has been confirmed by echocardiography, cardiac catheterization, surgery, or autopsy. Their families are studied in comparison to those of a representative sample of resident live-born infants. Detailed descriptions of noncardiac abnormalities are obtained from physician reports and maternal interviews expanded by medical record and death certificate data. Among 1,494 cases and 1,572 controls, chromosomal abnormalities, syndromes, heritable disorders, and suspect syndromes occurred with an overwhelming excess in cases (chromosomes, P less than 10(-4); syndromes/heritable disorders, P less than .005). Abnormalities affecting chromosomes 13, 18, and 21 constituted 93% of the cytogenetic defects. Syndromes and heritable disorders were of 39 types. Nonsyndromic abnormalities were three times more frequent in cases than in controls (P less than .005). Case excesses occurred for central nervous system malformations, eye disorders, major abdominal wall defects, and abnormalities of the alimentary and urinary tracts. Severe anomalies frequent among cases were those which also occur in certain recognized syndromes, and it is suggested that paired combinations of cardiac and other midline anomalies may represent "formes frustes" of syndromes with similar though variable phenotypic expressions. Cleft lip and palate, inguinal hernia, and lower limb anomalies occurred with equal frequency, suggesting their association with CCVMs by chance alone.

In a population-based study on congenital cardiovascular malformations (CCVM), the occurrence of heritable coagulopathies among case parents and not among controls raised the possibility of an etiologic association of CCVM with blood disorders. The literature was searched for evidence that such an association could be biologically plausible. Reported embryologic and clinical data provided confirmatory findings. The heart and blood arise from common angiogenic cells; endothelial cells, the first components of the primitive heart, synthesize coagulation factors; resultant osmotic alterations of embryonic fluids could alter early cardiac morphogenesis. Bleeding diatheses are common in cyanotic and acyanotic patients with CCVM and hemostatic disorders have been reported in some families. CCVM and blood disorders are joint components of several malformation syndromes. The hypothesis of an etiologic relationship between HBD and CCVM needs to be tested in multiple research areas. Future experimental studies should be based on current theories of cardiac morphogenesis to include investigations of embryonic blood in genetic blood disorders. Clinical studies should clarify hematologic alterations in CCVM probands and their families.

In an ongoing population-based study of congenital cardiovascular malformations in the Baltimore-Washington, DC, area, 1527 affected infants were ascertained from multiple sources during the years 1981 to 1984. Ninety-eight percent were evaluated at a regional pediatric cardiology center. Among the unreferred cases, in which the cardiac defect was diagnosed only at autopsy, most infants died in the first week of life and had associated problems, such as low birth weight, major noncardiac malformations, or other life-threatening illnesses, but a few infants with potentially remediable heart disease escaped clinical detection. Until preventive measures become available, reduction of infant mortality due to congenital cardiovascular malformations will continue to depend on early recognition of signs of serious heart disease in infants and on effective community-wide use of specialized cardiac services.

Exogenous female sex hormone exposure was studied in the mothers of 110 infants with conotruncal malformations of the heart, born in the years 1972-75. Cases were ascertained throughout the referral area of the Maryland State Intensive Care Neonatal Program. For each case, three normal controls were chosen from the birth population: Two matched on eight characteristics related to the likelihood of hormone-taking (race, maternal age, parity, fetal losses, gestational age, delivery mode, time of prenatal registration, private/service), and one also on the infant's sex and birthweight; the third control was chosen at random. In personal interviews, information was obtained on the mother's general health, family history, reproductive characteristics, pregnancy health, and environmental exposures. Identification of hormonal products was aided by a display of pills and packages. Maternal recall was examined in comparison to the responses of a group of mothers of infants with hypoplastic left heart ("disease controls"). Regression analysis on time elapsed since the infant's birth revealed no difference in recall between the mothers of cases and of controls. Multilogistic regression analysis, controlling for confounding variables and for scores constructed for reproductive, malformation, and exposure risks, showed no increase in relative risk for cases when compared with matched controls. When compared to random controls, the analysis suggested a possible increase in relative risk with increased environmental exposure scores; components of the risk score were excess smoking and alcohol intake, exposure to X-ray, drugs, paints, insecticides, and chemicals. The possible significance of this finding needs to be further investigated.

The Baltimore-Washington Infant Study, an epidemiologic investigation of congenital heart disease, searches for genetic and environmental risk factors. Among 2,102 infants with heart disease, 17.5% had a noncardiac abnormality of chromosomal or genetic origin, whereas among 2,328 control infants, only 0.7% had a genetic abnormality. Familial cardiovascular malformations encountered can be grouped into five distinct etiologic mechanisms. Single gene effects may be responsible for the specific histologic and biochemical changes in familial atrial septal defect with conduction disturbance and also in idiopathic ventricular hypertrophy. Left heart lesions showed familial concordance by the presumed morphogenetic mechanism of abnormal embryonic blood flow with phenotypes of varying severity. Pulmonary stenosis appeared with familial heritable disorders, as well as a partially concordant lesion with tetralogy of Fallot. Ventricular septal defect with transposition of the great arteries (one sibling pair) and with truncus arteriosus (two sibling pairs) indicate forme fruste expression of conotruncal defects. Endocardial cushion defect occurred with and without Down's syndrome in members of three families, suggesting inheritance of a defect affecting cellular migration. Heritable blood coagulopathies occurred in case families and not in control families. The associated of hemophilia and transposition, observed also by others, is extremely unlikely by chance and suggests genetic errors of endothelial cell function. The description of specific families from a population-based study emphasizes biologic questions on the nature of the inheritance of cardiovascular malformations.