Congenital heart defects in Europe: prevalence and perinatal mortality, 2000 to 2005.

BACKGROUND: This study determines the prevalence of Congenital Heart Defects (CHD), diagnosed prenatally or in infancy, and fetal and perinatal mortality associated with CHD in Europe. METHODS AND RESULTS: Data were extracted from the European Surveillance of Congenital Anomalies central database for 29 population-based congenital anomaly registries in 16 European countries covering 3.3 million births during the period 2000 to 2005. CHD cases (n=26 598) comprised live births, fetal deaths from 20 weeks gestation, and terminations of pregnancy for fetal anomaly (TOPFA). The average total prevalence of CHD was 8.0 per 1000 births, and live birth prevalence was 7.2 per 1000 births, varying between countries. The total prevalence of nonchromosomal CHD was 7.0 per 1000 births, of which 3.6% were perinatal deaths, 20% prenatally diagnosed, and 5.6% TOPFA. Severe nonchromosomal CHD (ie, excluding ventricular septal defects, atrial septal defects, and pulmonary valve stenosis) occurred in 2.0 per 1000 births, of which 8.1% were perinatal deaths, 40% were prenatally diagnosed, and 14% were TOPFA (TOPFA range between countries 0% to 32%). Live-born CHD associated with Down syndrome occurred in 0.5 per 1000 births, with > 4-fold variation between countries. CONCLUSION: Annually in the European Union, we estimate 36 000 children are live born with CHD and 3000 who are diagnosed with CHD die as a TOFPA, late fetal death, or early neonatal death. Investing in primary prevention and pathogenetic research is essential to reduce this burden, as well as continuing to improve cardiac services from in utero to adulthood.

Investigation of Copy Number Variation in Children with Conotruncal Heart Defects

Background:Congenital heart defects (CHD) are the most prevalent group of structural abnormalities at birth and one of the main causes of infant morbidity and mortality. Studies have shown a contribution of the copy number variation in the genesis of cardiac malformations.Objectives:Investigate gene copy number variation (CNV) in children with conotruncal heart defect.Methods:Multiplex ligation-dependent probe amplification (MLPA) was performed in 39 patients with conotruncal heart defect. Clinical and laboratory assessments were conducted in all patients. The parents of the probands who presented abnormal findings were also investigated.Results:Gene copy number variation was detected in 7/39 patients: 22q11.2 deletion, 22q11.2 duplication, 15q11.2 duplication, 20p12.2 duplication, 19p deletion, 15q and 8p23.2 duplication with 10p12.31 duplication. The clinical characteristics were consistent with those reported in the literature associated with the encountered microdeletion/microduplication. None of these changes was inherited from the parents.Conclusions:Our results demonstrate that the technique of MLPA is useful in the investigation of microdeletions and microduplications in conotruncal congenital heart defects. Early diagnosis of the copy number variation in patients with congenital heart defect assists in the prevention of morbidity and decreased mortality in these patients.

Epidemiological study of congenital heart defects in children and adolescents: analysis of 4,538 cases

OBJECTIVE: To analyze the frequency and prevalence of congenital heart defects in a tertiary care center for children with heart diseases. METHODS: We carried out an epidemiological assessment of the first medical visit of 4,538 children in a pediatric hospital from January 1995 to December 1997. All patients with congenital heart defects had their diagnoses confirmed at least on echocardiography. The frequency and prevalence of the anomalies were computed according to the classification of sequential analysis. Age, weight, and sex were compared between the groups of healthy individuals and those with congenital heart defects after distribution according to the age group. RESULTS: Of all the children assessed, 2,017 (44.4%) were diagnosed with congenital heart disease, 201 (4.4%) with acquired heart disease, 52 (1.2%) with arrhythmias, and 2,268 (50%) were healthy children. Congenital heart diseases predominated in neonates and infants, corresponding to 71.5% of the cases. Weight and age were significantly lower in children with congenital heart defects. Ventricular septal defect was the most frequent acyanotic anomaly, and tetralogy of Fallot was the most frequent cyanotic anomaly. CONCLUSION: Children with congenital heart defects are mainly referred during the neonatal period and infancy with impairment in gaining weight. Ventricular septal defect is the most frequent heart defect.

Recent decrease in the prevalence of congenital heart defects in europe.

OBJECTIVES: To examine trends in the prevalence of congenital heart defects (CHDs) in Europe and to compare these trends with the recent decrease in the prevalence of CHDs in Canada (Quebec) that was attributed to the policy of mandatory folic acid fortification. STUDY DESIGN: We used data for the period 1990-2007 for 47 508 cases of CHD not associated with a chromosomal anomaly from 29 population-based European Surveillance of Congenital Anomalies registries in 16 countries covering 7.3 million births. We estimated trends for all CHDs combined and separately for 3 severity groups using random-effects Poisson regression models with splines. RESULTS: We found that the total prevalence of CHDs increased during the 1990s and the early 2000s until 2004 and decreased thereafter. We found essentially no trend in total prevalence of the most severe group (group I), whereas the prevalence of severity group II increased until about 2000 and decreased thereafter. Trends for severity group III (the most prevalent group) paralleled those for all CHDs combined. CONCLUSIONS: The prevalence of CHDs decreased in recent years in Europe in the absence of a policy for mandatory folic acid fortification. One possible explanation for this decrease may be an as-yet-undocumented increase in folic acid intake of women in Europe following recommendations for folic acid supplementation and/or voluntary fortification. However, alternative hypotheses, including reductions in risk factors of CHDs (eg, maternal smoking) and improved management of maternal chronic health conditions (eg, diabetes), must also be considered for explaining the observed decrease in the prevalence of CHDs in Europe or elsewhere.

The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome.

Congenital heart defect (CHD) occurs in 40% of Down syndrome (DS) cases. While carrying three copies of chromosome 21 increases the risk for CHD, trisomy 21 itself is not sufficient to cause CHD. Thus, additional genetic variation and/or environmental factors could contribute to the CHD risk. Here we report genomic variations that in concert with trisomy 21, determine the risk for CHD in DS. This case-control GWAS includes 187 DS with CHD (AVSD = 69, ASD = 53, VSD = 65) as cases, and 151 DS without CHD as controls. Chromosome 21-specific association studies revealed rs2832616 and rs1943950 as CHD risk alleles (adjusted genotypic P-values <0.05). These signals were confirmed in a replication cohort of 92 DS-CHD cases and 80 DS-without CHD (nominal P-value 0.0022). Furthermore, CNV analyses using a customized chromosome 21 aCGH of 135K probes in 55 DS-AVSD and 53 DS-without CHD revealed three CNV regions associated with AVSD risk (FDR ≤ 0.05). Two of these regions that are located within the previously identified CHD region on chromosome 21 were further confirmed in a replication study of 49 DS-AVSD and 45 DS- without CHD (FDR ≤ 0.05). One of these CNVs maps near the RIPK4 gene, and the second includes the ZBTB21 (previously ZNF295) gene, highlighting the potential role of these genes in the pathogenesis of CHD in DS. We propose that the genetic architecture of the CHD risk of DS is complex and includes trisomy 21, and SNP and CNV variations in chromosome 21. In addition, a yet-unidentified genetic variation in the rest of the genome may contribute to this complex genetic architecture.

Prenatal diagnosis and treatment planning of congenital heart defects-possibilities and limits

BACKGROUND: Newborns with hypoplastic left heart syndrome (HLHS) or right heart syndrome or other malformations with a single ventricle physiology and associated hypoplasia of the great arteries continue to be a challenge in terms of survival. The vast majority of these forms of congenital heart defects relate to abnormal morphogenesis during early intrauterine development and can be diagnosed accurately by fetal echocardiography. Early knowledge of these conditions not only permits a better understanding of the progression of these malformations but encourages some researchers to explore new minimally invasive therapeutic options with a view to early pre- and postnatal cardiac palliation. DATA SOURCES: PubMed database was searched with terms of "congenital heart defects", "fetal echocardiography" and "neonatal cardiac surgery". RESULTS: At present, early prenatal detection has been applied for monitoring pregnancy to avoid intrauterine cardiac decompensation. In principle, the majority of congenital heart defects can be diagnosed by prenatal echocardiography and the detection rate is 85%-95% at tertiary perinatal centers. The majority, particularly of complex congenital lesions, show a steadily progressive course including subsequent secondary phenomena such as arrhythmias or myocardial insufficiency. So prenatal treatment of an abnormal fetus is an area of perinatal medicine that is undergoing a very dynamic development. Early postnatal treatment is established for some time, and prenatal intervention or palliation is at its best experimental stage in individual cases. CONCLUSION: The upcoming expansion of fetal cardiac intervention to ameliorate critically progressive fetal lesions intensifies the need to address issues about the adequacy of technological assessment and patient selection as well as the morbidity of those who undergo these procedures.

Is low parental education associated with congenital heart defects?

Objective. The purpose of this study was to determine if there are associations between low parental education and congenital heart defects. ^ Methods. This was a cross-sectional study of 281,262 live born singletons, 1765 of whom were identified by the Texas Birth Defects Monitoring Division (TBDMD) as having heart defects without known chromosomal anomalies. Data on the specific diagnoses of these infants were linked to their corresponding birth certificates. Only infants born between January 1, 1995 and December 31, 1997, whose mothers resided in the Texas public health regions under surveillance by the TBDMD were included in the study. The number of years of schooling of the most educated parent was used to calculate crude, stratified and adjusted odds ratios. ^ Results. An increase in the likelihood of having an infant with any type of congenital heart defect was found among parents with less than 16 years of education, compared to those with 16 or more years of schooling. The association became more marked with increasing paternal age, and was found among whites and Hispanics but not among blacks. Statistically significant associations with low parental education were found for ventricular septal defects, transposition of the great vessels and miscellaneous heart and vessel defects. Among whites, there was an inverse association between parental education and likelihood of having an infant with a severe ASD. This association was not found among non-whites. The suggestion of an association between low parental education and tetralogy of Fallot, was also found, but was not statistically significant. Parents with ≥16 years of education had a greater likelihood of having an infant with severe endocardial cushion lesions or total anomalous pulmonary return than less well educated parents. ^ Conclusion. This study suggests that parental education is associated with certain types of heart defects, especially among whites and Hispanics. ^

Pulse oximetry screening for congenital heart defects in newborn infants:an evaluation of acceptability to mothers

Background: Introducing neonatal screening procedures may not be readily accepted by parents and may increase anxiety. The acceptability of pulse oximetry screening to parents has not been previously reported. Objective: To assess maternal acceptability of pulse oximetry screening for congenital heart defects and to identify factors predictive of participation in screening. Design and setting: A questionnaire was completed by a cross-sectional sample of mothers whose babies were recruited into the PulseOx Study which investigated the test accuracy of pulse oximetry screening. Participants: A total of 119 mothers of babies with false-positive (FP) results, 15 with true-positive and 679 with true-negative results following screening. Main outcome measures: Questionnaires included measures of satisfaction with screening, anxiety, depression and perceptions of test results. Results: Participants were predominantly satisfied with screening. The anxiety of mothers given FP results was not significantly higher than that of mothers given true-negative results (median score 32.7 vs 30.0, p=0.09). White British/Irish mothers were more likely to participate in screening, with a decline rate of 5%; other ethnic groups were more likely to decline with the largest increase in declining being for Black African mothers (21%, OR 4.6, 95% CI 3.8 to 5.5). White British mothers were also less anxious (p<0.001) and more satisfied (p<0.001) than those of other ethnicities Conclusions: Pulse oximetry screening was acceptable to mothers and FP results were not found to increase anxiety. Factors leading to differences in participation and satisfaction across ethnic groups need to be identified so that staff can support parents appropriately.

Pulse oximetry as a screening test for congenital heart defects in newborn infants: a test accuracy study with evaluation of acceptability and cost-effectiveness

Background: Screening for congenital heart defects (CHDs) relies on antenatal ultrasound and postnatal clinical examination; however, life-threatening defects often go undetected. Objective: To determine the accuracy, acceptability and cost-effectiveness of pulse oximetry as a screening test for CHDs in newborn infants. Design: A test accuracy study determined the accuracy of pulse oximetry. Acceptability of testing to parents was evaluated through a questionnaire, and to staff through focus groups. A decision-analytic model was constructed to assess cost-effectiveness. Setting: Six UK maternity units. Participants: These were 20,055 asymptomatic newborns at = 35 weeks’ gestation, their mothers and health-care staff. Interventions: Pulse oximetry was performed prior to discharge from hospital and the results of this index test were compared with a composite reference standard (echocardiography, clinical follow-up and follow-up through interrogation of clinical databases). Main outcome measures: Detection of major CHDs – defined as causing death or requiring invasive intervention up to 12 months of age (subdivided into critical CHDs causing death or intervention before 28 days, and serious CHDs causing death or intervention between 1 and 12 months of age); acceptability of testing to parents and staff; and the cost-effectiveness in terms of cost per timely diagnosis. Results: Fifty-three of the 20,055 babies screened had a major CHD (24 critical and 29 serious), a prevalence of 2.6 per 1000 live births. Pulse oximetry had a sensitivity of 75.0% [95% confidence interval (CI) 53.3% to 90.2%] for critical cases and 49.1% (95% CI 35.1% to 63.2%) for all major CHDs. When 23 cases were excluded, in which a CHD was already suspected following antenatal ultrasound, pulse oximetry had a sensitivity of 58.3% (95% CI 27.7% to 84.8%) for critical cases (12 babies) and 28.6% (95% CI 14.6% to 46.3%) for all major CHDs (35 babies). False-positive (FP) results occurred in 1 in 119 babies (0.84%) without major CHDs (specificity 99.2%, 95% CI 99.0% to 99.3%). However, of the 169 FPs, there were six cases of significant but not major CHDs and 40 cases of respiratory or infective illness requiring medical intervention. The prevalence of major CHDs in babies with normal pulse oximetry was 1.4 (95% CI 0.9 to 2.0) per 1000 live births, as 27 babies with major CHDs (6 critical and 21 serious) were missed. Parent and staff participants were predominantly satisfied with screening, perceiving it as an important test to detect ill babies. There was no evidence that mothers given FP results were more anxious after participating than those given true-negative results, although they were less satisfied with the test. White British/Irish mothers were more likely to participate in the study, and were less anxious and more satisfied than those of other ethnicities. The incremental cost-effectiveness ratio of pulse oximetry plus clinical examination compared with examination alone is approximately £24,900 per timely diagnosis in a population in which antenatal screening for CHDs already exists. Conclusions: Pulse oximetry is a simple, safe, feasible test that is acceptable to parents and staff and adds value to existing screening. It is likely to identify cases of critical CHDs that would otherwise go undetected. It is also likely to be cost-effective given current acceptable thresholds. The detection of other pathologies, such as significant CHDs and respiratory and infective illnesses, is an additional advantage. Other pulse oximetry techniques, such as perfusion index, may enhance detection of aortic obstructive lesions.

Investigating 22q11.2 Deletion and Other Chromosomal Aberrations in Fetuses With Heart Defects Detected by Prenatal Echocardiography

Congenital heart disease (CHD) is the most common birth defect and the leading cause of mortality in the first year of life. In fetuses with a heart defect, chromosomal abnormalities are very frequent. Besides aneuploidy, 22q11.2 deletion is one of the most recognizable chromosomal abnormalities causing CHD. The frequency of this abnormality varies in nonselected populations. This study aimed to investigate the incidence of the 22q11.2 deletion and other chromosomal alterations in a Brazilian sample of fetuses with structural cardiac anomalies detected by fetal echocardiography. In a prospective study, 68 fetuses with a heart defect were evaluated. Prenatal detection of cardiac abnormalities led to identification of aneuploidy or structural chromosomal anomaly in 35.3% of these cases. None of the fetuses with apparently normal karyotypes had a 22q11.2 deletion. The heart defects most frequently associated with chromosomal abnormalities were atrioventricular septal defect (AVSD), ventricular septal defect (VSD), and tetralogy of Fallot. Autosomal trisomies 18 and 21 were the most common chromosomal abnormalities. The study results support the strong association of chromosome alterations and cardiac malformation, especially in AVSD and VSD, for which a chromosome investigation is indicated. In fetuses with an isolated conotruncal cardiopathy, fluorescence in situ hybridization (FISH) to investigate a 22q11.2 deletion is not indicated.

A Comparison of Radiation Dose Between Standard and 3D Angiography in Congenital Heart Disease

Background: The use of three-dimensional rotational angiography (3D-RA) to assess patients with congenital heart diseases appears to be a promising technique despite the scarce literature available. Objectives: The objective of this study was to describe our initial experience with 3D-RA and to compare its radiation dose to that of standard two-dimensional angiography (2D-SA). Methods: Between September 2011 and April 2012, 18 patients underwent simultaneous 3D-RA and 2D-SA during diagnostic cardiac catheterization. Radiation dose was assessed using the dose-area-product (DAP). Results: The median patient age and weight were 12.5 years and 47.5 Kg, respectively. The median DAP of each 3D-RA acquisition was 1093µGy.m2 and 190µGy.m2 for each 2D-SA acquisition (p<0.01). In patients weighing more than 45Kg (n=7), this difference was attenuated but still significant (1525 µGy.m2 vs.413µGy.m2, p=0.01). No difference was found between one 3D-RA and three 2D-SA (1525µGy.m2 vs.1238 µGy.m2, p = 0.575) in this population. This difference was significantly higher in patients weighing less than 45Kg (n=9) (713µGy.m2 vs.81µGy.m2, P = 0.008), even when comparing one 3D-RA with three 2D-SA (242µGy.m2, respectively, p<0.008). 3D-RA was extremely useful for the assessment of conduits of univentricular hearts, tortuous branches of the pulmonary artery, and aorta relative to 2D-SA acquisitions. Conclusions: The radiation dose of 3D-RA used in our institution was higher than those previously reported in the literature and this difference was more evident in children. This type of assessment is of paramount importance when starting to perform 3D-RA.

Congenital Heart Disease as a Warning Sign for the Diagnosis of the 22q11.2 Deletion

Background: To alert for the diagnosis of the 22q11.2 deletion syndrome (22q11.2DS) in patients with congenital heart disease (CHD). Objective: To describe the main CHDs, as well as phenotypic, metabolic and immunological findings in a series of 60 patients diagnosed with 22q11.2DS. Methods: The study included 60 patients with 22q11.2DS evaluated between 2007 and 2013 (M:F=1.3, age range 14 days to 20 years and 3 months) at a pediatric reference center for primary immunodeficiencies. The diagnosis was established by detection of the 22q11.2 microdeletion using FISH (n = 18) and/or MLPA (n = 42), in association with clinical and laboratory information. Associated CHDs, progression of phenotypic facial features, hypocalcemia and immunological changes were analyzed. Results: CHDs were detected in 77% of the patients and the most frequent type was tetralogy of Fallot (38.3%). Surgical correction of CHD was performed in 34 patients. Craniofacial dysmorphisms were detected in 41 patients: elongated face (60%) and/or elongated nose (53.3%), narrow palpebral fissure (50%), dysplastic, overfolded ears (48.3%), thin lips (41.6%), elongated fingers (38.3%) and short stature (36.6%). Hypocalcemia was detected in 64.2% and decreased parathyroid hormone (PTH) level in 25.9%. Decrease in total lymphocytes, CD4 and CD8 counts were present in 40%, 53.3% and 33.3%, respectively. Hypogammaglobulinemia was detected in one patient and decreased concentrations of immunoglobulin M (IgM) in two other patients. Conclusion: Suspicion for 22q11.2DS should be raised in all patients with CHD associated with hypocalcemia and/or facial dysmorphisms, considering that many of these changes may evolve with age. The 22q11.2 microdeletion should be confirmed by molecular testing in all patients.

Palliative Senning in the Treatment of Congenital Heart Disease with Severe Pulmonary Hypertension

Background:Transposition of the great arteries (TGA) is the most common cyanotic cardiopathy, with an incidence ranging between 0.2 and 0.4 per 1000 live births. Many patients not treated in the first few months of life may progress with severe pulmonary vascular disease. Treatment of these patients may include palliative surgery to redirect the flow at the atrial level.Objective:Report our institutional experience with the palliative Senning procedure in children diagnosed with TGA and double outlet right ventricle with severe pulmonary vascular disease, and to evaluate the early and late clinical progression of the palliative Senning procedure.Methods:Retrospective study based on the evaluation of medical records in the period of 1991 to 2014. Only patients without an indication for definitive surgical treatment of the cardiopathy due to elevated pulmonary pressure were included.Results:After one year of follow-up there was a mean increase in arterial oxygen saturation from 62.1% to 92.5% and a mean decrease in hematocrit from 49.4% to 36.3%. Lung histological analysis was feasible in 16 patients. In 8 patients, pulmonary biopsy grades 3 and 4 were evidenced.Conclusion:The palliative Senning procedure improved arterial oxygen saturation, reduced polycythemia, and provided a better quality of life for patients with TGA with ventricular septal defect, severe pulmonary hypertension, and poor prognosis.