Congenital cardiovascular malformations: questions on inheritance. Baltimore-Washington Infant Study Group.

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.

Subsequent pregnancy in mothers of infants with congenital heart disease.

Pregnancy rates for mothers of infants with conotruncal cardiac malformations and mothers of healthy control infants were compared for a 3-year period. Mothers of infants who died of congenital heart disease had the highest pregnancy rates, followed by control mothers, and then by mothers of surviving infants with congenital heart disease. Comparison in relation to the number of living children showed similar subsequent pregnancy rates for mothers of deceased infants with congenital heart disease and mothers of control infants, but lower rates for mothers of surviving infants with congenital heart disease. "Replacement" of a deceased infant occurs frequently, apparently in order to achieve a desired family size, whereas decreased reproduction in families of living infants with congenital heart disease may reflect the psychosocial and economic impact of the continuing care of a child with severe heart disease.

Increased prevalence of ventricular septal defect: epidemic or improved diagnosis.

The Baltimore-Washington Infant Study is an ongoing case-control study of congenital cardiovascular malformations in infants in whom the clinical diagnoses have been confirmed by echocardiography, catheterization, surgery, or autopsy. An increase in the prevalence of ventricular septal defects was detected in 1,494 infants with congenital cardiovascular malformations between 1981 and 1984. The prevalence of congenital cardiovascular malformations increased from 3.6 to 4.5 per 1,000 live births (P less than .025) and the prevalence of ventricular septal defect increased from 1.0 to 1.6 per 1,000 live births (P less than .001). The increase in ventricular septal defects accounted for the total increase in congenital cardiovascular malformations. The prevalence of isolated ventricular septal defect increased from 0.67 to 1.17 per 1,000 live births (P less than .001). The prevalence of ventricular septal defect with associated coarctation of the aorta, patent ductus arteriosus, atrial septal defect, and pulmonic stenosis did not change. The prevalence of ventricular septal defect diagnosed by catheterization, surgery, and autopsy did not change; however, defects diagnosed by echocardiography increased from 0.30 to 0.70 per 1,000 live births (P less than .001). It is concluded that the reported increase in prevalence of ventricular septal defect is due to improved detection of small, isolated ventricular septal defects and that there is no evidence of an "epidemic."

Failure to diagnose congenital heart disease in infancy.

OBJECTIVE: To identify factors that predict failure to diagnose congenital heart disease in newborns. DESIGN: All fatal cases in the Baltimore-Washington Infant Study were compiled. The Baltimore-Washington Infant Study includes 4390 cases of infants with congenital cardiovascular malformations identified in a population-based study between 1981 and 1989 in the Baltimore-Washington metropolitan area. Death occurred in 800 such infants in the first year of life. In 76 of these infants, death occurred before diagnosis of heart disease. These cases were identified by community search of autopsy records. Their characteristics are compared with those of infants who died after a cardiac diagnosis was made. RESULTS: Infant characteristics (birth weight, gestational age, intrauterine growth retardation, and chromosomal anomaly) are associated with death of infants with congenital cardiovascular malformations and with death of such infants before diagnosis. Diagnoses of coarctation of the aorta, Ebstein's anomaly, atrial septal defect, and truncus arteriosus are overrepresented in infants found by community search, particularly in those infants without associated malformations. Paternal education is associated with failure to diagnose congenital heart disease in life but other sociodemographic characteristics of the infant's family are not. CONCLUSIONS: Diagnosis of congenital cardiovascular malformations requires close observation in the neonatal period. Analysis of age at death of infants with undiagnosed congenital cardiovascular malformation suggests that such infants may be at risk if discharged within the first 2 days of life.

VACTERL-hydrocephaly, DK-phocomelia, and cerebro-cardio-radio-reno-rectal community.

Phenotypic manifestations of the autosomal recessive form of VACTERL-hydrocephaly syndrome (David-O'Callaghan syndrome) and the X-linked recessive form (Hunter-MacMurray) syndrome are almost identical. The absence of cardiovascular malformations in cases with undoubtedly X-linked inheritance may be the only exception. The comparison of patients with David-O'Callaghan syndrome and nonclassified sporadic cases of VACTERL-hydrocephaly showed two marked differences. First, radial involvement (usually bilateral) occurred in all familial but only in 22 of 36 sporadic cases. Therefore, radial noninvolvement may be evidence against a genetic origin of the complex in a sporadic case. Second, predominantly severe forms of cardiovascular malformations were found in cases of David-O'Callaghan syndrome, whereas in sporadic cases almost all cardiovascular malformations were simple defects with minimal, if any, hemodynamic disturbances. The similarity of the spectrum and frequency of main manifestations of David-O'Callaghan and von Voss-Cherstvoy syndromes allows us to think that both of these syndromes actually might be 2 forms of one genetic entity. There are some syndromes with abnormalities of the brain (different for each syndrome) sharing the same limb defects (mainly preaxial), congenital heart defects, abnormalities of kidneys, and anal atresia/ectopia. Baller-Gerold syndrome, Steinfeld syndrome, XK-aprosencephaly, and DK-phocomelia (von Voss-Cherstvoy) syndrome as well as Mendelian forms of VACTERL-hydrocephaly syndromes fit into this "cerebro-cardio-radio-reno-rectal community."

"Shifted" threshold may explain diversity of cardiovascular malformations in multiple congenital abnormalities syndromes: 3C (Ritscher-Schinzel) syndrome as an example.

The analysis of cardiovascular malformations (CVM) in 3C (Ritscher-Schinzel) syndrome showed at least 9 types of CVM in 24 cases, including 4 cases from the Baltimore-Washington Infant Study. The proportion of different CVM forms was similar to that of the general population. The same is also true for many other syndromes of multiple congenital abnormalities (MCA), due either to aneuploidy or to Mendelian mutation. Such a wide spectrum of very different CVM in patients with the same entity has yet to be explained. According to the hypothesis proposed, the basic mutation (or chromosome imbalance) affects cellular homeostasis and leads to the "shifting" of a threshold to the left. This allows the expression of some genes silent under normal conditions. The principle of the shifted threshold is applicable to the explanation of the origin of many other defects in MCA syndromes.

Endocardial cushion defect: further studies of "isolated" versus "syndromic" occurrence.

The isolated occurrence of endocardial cushion defect (ECD) has been suggested to differ from its occurrence within the context of a syndrome, with regard to the nature (complete or partial) of the defect and the associated cardiovascular malformations. Analysis of data derived from the Baltimore-Washington Infant Study of congenital cardiovascular malformations supports the observation that "syndromic" ECD tends to be of the complete atrioventricular canal type and is less frequently associated with left cardiac anomalies than the isolated form. However, each syndrome has a unique impact on the overall cardiovascular "phenotype", including the ECD. This is especially true for Down and Ivemark syndromes, which are most frequently associated with ECD, but also for other syndromes as well. It is also suggested that isolated ECD is specifically associated with gastrointestinal and urinary tract anomalies. However, in Down syndrome ECD appears to be a specific cardiovascular expression of the trisomic state that is unrelated to other noncardiac malformations. Additional information on the association of ECD with other less common genetic syndromes is needed in order to further investigate the possible genetic basis of this cardiac defect.

Non-cardiac malformations in individuals with outflow tract defects of the heart: the Baltimore-Washington Infant Study (1981-1989).

In the Baltimore-Washington Infant Study, a regional case-control study of 4,390 liveborn infants with cardiovascular malformations (CVM), 642 patients (14.2%) had outflow tract abnormalities, with extracardiac defects in 157 (approximately 25%) of them. Associated defects were found in 1/3 of patients with normal great arteries, but only in 1/10 of patients with transposition of great arteries (TGA). The extracardiac defects were especially rare in the groups "TGA with intact ventricular septum" and "TGA with ventricular septal defect". Patients with multiple associated defects outnumbered patients with isolated associated defects in the ratio 2.5:1. The associated defects were heterogeneous: 46 patients had chromosome abnormalities, 16 had different Mendelian syndromes, and 36 had associations (DiGeorge sequence and VACTERL association were the most frequent). A new syndrome of multiple congenital abnormalities including tetralogy of Fallot, and rare cases of chromosomal and Mendelian syndromes (distal trisomy 1q, tetrasomy 8p, Holzgreve syndrome) are described briefly. Sufficient variability of a spectrum of conotruncal defects in the patients with the same chromosomal or Mendelian syndromes suggests that at least in some cases different conotruncal defects are stages of the same morphologic spectrum. The analysis of conotruncal defects in sibs of patients with Mendelian syndromes may provide new data about the links between different definitive forms of CVM.

Familial risks of congenital heart defect assessed in a population-based epidemiologic study.

Congenital heart defects (CHD) represent a heterogeneous group of disorders caused by chromosome abnormalities, mendelian disorders, teratogenic exposures, and unknown etiologic mechanisms. A large group of various isolated defects is presumably multifactorial in origin. Previous studies of familial risks for specific anatomic defects obtained from clinical series may include significant biases and obscured pathogenic relationships. In this population-based study we analyzed all cases of CHD in infants and a control birth cohort in the Baltimore-Washington area. The rates of CHD were defined for first-degree relatives of cases with isolated defects, grouped by a pathogenic classification scheme. Precurrence risks were found to vary among the groups, and risks for flow lesions were higher than previously reported. The sibling precurrence risk for hypoplastic left heart syndrome (13.5%) was not significantly different from that expected for an autosomal recessive mechanism; the risks for different types of ventricular septal defects (VSD) varied among mechanistic groups. The results indicate that the additive multifactorial model does not adequately account for the risks in all forms of isolated CHD of unknown etiology.

Use of prescription and non-prescription drugs in pregnancy. The Baltimore-Washington Infant Study Group.

We analyzed use of therapeutic drugs during pregnancy by 2752 mothers of infants without major congenital malformations. During pregnancy, 68% of the women used at least one prescription or non-prescription drug. Drug use in pregnancy was significantly more common for women who were white, older, married, better educated, of higher income and occupational status, receiving private prenatal care and not living in urban areas. Number of maternal illnesses, higher socioeconomic status, white race, multiparity and use of recreational drugs explained 26% of reported drug use. The mean number of drugs reported (1.2) underestimates total drug exposure due to exclusion of some drug categories including multivitamins and illicit drugs. Since the majority of women giving birth to normal infants report use of at least one pharmacologic agent during pregnancy, attribution of adverse outcome to drug use in an individual case is rarely justified.

Congenital heart disease in adolescents and adults. Teratology, genetics, and recurrence risks.

This brief review has described historic highlights of etiologic knowledge, current concepts in the categorization of cardiovascular anomalies based upon ongoing advances in teratology, and epidemiologic evaluations of biologic and xenobiotic risk factors with emphasis on the teratogenic roles of maternal diabetes, hyperphenylalaninemia, and parental exposures to alcohol, drugs, solvents, pesticides, lead, and other toxic substances. Evidence is presented for a strong genetic basis of cardiovascular maldevelopment requiring further studies to define at-risk families. Counseling and personal and societal preventive interventions may reduce the occurrence of some forms of CHD.

Paternal exposures and cardiovascular malformations. The Baltimore-Washington Infant Study Group.

Possible associations between paternal exposures and cardiovascular malformations were evaluated in the Baltimore-Washington Infant Study, a population based case-control investigation of congenital heart disease and environmental factors. Home interviews of case and control parents elicited information on parental home and occupational exposures. Analysis focused on twelve cardiac diagnostic groups and paternal exposures incurred during the six months preceding the pregnancy. Associations were identified between jewelry making and atrial septal defect (Odds ratio: 12.6; 95% confidence interval: 2.3-68.6) and membranous ventricular septal defect (8.1; 2.0-33.3), welding and endocardial cushion defect with Down syndrome (1.8; 1.1-3.0), lead soldering and pulmonary atresia (2.3; 1.1-4.9) and ionizing radiation and endocardial cushion defect without Down syndrome (4.7; 1.7-12.6). Ionizing radiation was found to be associated with endocardial cushion defect with Down syndrome only when father was present at interview (5.6; 1.7-17.9); a similar effect of father at interview was noted for paint stripping in relation to coarctation of the aorta (3.5; 1.5-8.0) and muscular ventricular septal defect (3.5; 1.5-8.5). Also, paint stripping was associated with hypoplastic left heart only in the presence of family history of cardiac defects (11.9; 2.4-60.0). This large study on cardiac diagnostic groups and specific preconceptional exposures provides new leads for further assessment of the role of paternal exposures on adverse pregnancy outcome.

Maude E Abbott - physician and scientist of international fame.

Dr Maude E Abbott (1869 to 1940) is the only Canadian and the only woman represented in Diego Rivera's great mural of the History of Cardiology in Mexico City. She gained this place among the world's famous physicians and scientists by her outstanding studies of congenital heart disease. Her atlas of 1000 cases with clinical, pathological and morphological findings is the first systematic study of these anomalies. Dr Abbott developed a pathophysiological classification of cardiovascular defects fundamental for the development of cardiac surgery. She also considered prevention by prenatal care, recognizing possible genetic and environmental risk factors. Maude Abbott was a thoughtful clinician and a brilliant scientist of incomparable industry. She leaves an unfinished legacy to make the prevention of congenital heart disease a reality.

Origin of congenital heart disease: reflections on Maude Abbott's work.

In honour of Dr Harold Segall's 90th birthday an historical review was made of concepts on the etiology of congenital heart disease. The work of Maude Abbott, highlighted in alignment with early results of an ongoing population based study, illustrates her remarkable perception of a kaleidoscope of risk factors which are now gaining acceptance. Abbott's letters to L. Emmett Holt express her belief that prenatal infections cause cardiac maldevelopment, but she also raises relevant questions on the potential role of inheritance. The Baltimore-Washington Infant Study (1981-86) reveals a predominance of genetic factors, evidence of intrauterine infection and of a teratogenic effect of maternal diabetes. Among environmental agents, alcohol and recreational drug intake appear to affect cardiac looping. Harold Segall's historical interests and continued professional activities demonstrate the validity of his scholastic motto: "It is good to know."

'Microgastria--limb reduction' complex with congenital heart disease and twinning.

We report a newborn, the second of male twins, with multiple abnormalities, including microphthalmia, a complex cardiovascular malformation, asplenia, anomalous lobation of the lungs, oesophageal atresia, microgastria, intestinal malrotation, anal atresia, multicystic dysplastic kidneys, and reduction defects of the upper extremities. These defects fit into the so-called 'microgastria-limb reduction' complex. Two of twelve previously reported patients with this complex were from discordant twin pairs. The occurrence of twinning in three out of 13 cases suggests that the origin of the 'microgastria-limb reduction' complex may be related to the process of twinning itself.