Insight into the Genetic Relevance of Congenital Heart Defects

Congenital heart disease is the most common type of birth defect in the newborn??occurring in 1?% of neonates. In addition, cardiac defects account for nearly half of the neonatal deaths resulting from congenital malformations. Due to recent advances in spatial resolution of ultrasound machines and improvements in sonographic techniques, the clinician is increasingly able to detect cardiac anomalies in utero. At the same time, advances in cardiovascular surgery have improved the overall survival of the affected neonates. Due to the combination of advances in prenatal diagnosis and postnatal intervention, parents with fetuses affected by congenital cardiac defects have become the largest group who seek prenatal counseling on the risks of associated anomalies, risks for subsequent pregnancies, and the risks to the offspring of a successfully treated patient. Although most congenital heart defects are not familiarly clustered, genetic factors are still involved in most cases. In this review, we summarize recent evidence of chromosomal and genetic defects associated with congenital heart diseases to provide the optimal counseling and management for the parents with affected neonates.     

Routine screening with fetal echocardiography for prenatal diagnosis of congenital heart disease

Congenital cardiac anomalies are the most common congenital anomalies, occurring in approximately eight of 1000 live births. Proper perinatal and neonatal management is dependent upon accurate prenatal diagnosis. Approximately 10% of fetuses with cardiac abnormalities have identified risk factors; hence, most of the anomalies occur in pregnancies without prenatal risk factors. The application of detailed fetal echocardiography for prenatal screening, at present reserved mainly for high-risk cases, requires further evaluation before being recommended for the general population.

This article presents our experience of evaluating the accuracy of fetal echocardiography as a screening method in detecting cardiac anomalies in the general population of Singapore. We reviewed data from 39 808 pregnant women who received antenatal care at the National University Hospital, Singapore, between January 1986 and December 1994, and who underwent routine fetal echocardiography at 21-22 weeks of gestation. We identified 294 cases of congenital heart defects by fetal echocardiography. We obtained a sensitivity of 85.4% for the detection of congenital heart disease, and a specificity of 99.9% to rule out such anomalies. Our positive and negative predictive rates were 87.7% and 99.9%, respectively.

We recommend routine screening by echocardiography of all pregnancies at 21-22 weeks of gestation, irrespective of risk stratifcation, for the prenatal detection of cardiac anomalies, in order to improve perinatal management.     

Terminated pregnancy following prenatal diagnosis of congenital anomalies--a part of register of congenital anomalies

The most of European registries of congenital anomalies (CA) collected information of CA in livebirths, stillbirths and terminated pregnancies following prenatal/ultrasound diagnosis. OBJECTIVES: to assess terminated pregnancies after prenatal/ ultrasound diagnosis of CA as a part of register of CA performed in University Hospital-Pleven. Among 21 202 births monitored during the study period (1996-2005), 679 CA were detected. The total prevalence of CA was 32/ 1000 births. The outcome of pregnancy for all cases of selected CA by register was 620 livebirths (91.3%), 36 stillbirths (5.3%), 23 terminated pregnancies (TP) (3.4%). The percentage of pregnancy termination was higher in the case of isolated anomalies, mainly lethal and CA associated with a low survival rate (61%), than with multiple ones. The most common CA detected after prenatal/ ultrasound diagnosis were neural tube defects (NTD) - the main reason for TP (52% of cases). The low proportion of these CA in TP (1/3) compared to their proportion in livebirths (50%) demonstrated an insufficiency of prenatal diagnosis of NTD as a part of register of CA performed in University Hospital-Pleven. Prenatal diagnosis of CA allows an early genetic counseling of mother presenting information on neonatal prognosis and recurrence risk for subsequent pregnancies. It helps family to take an adequate decision for termination of pregnancy with bad prognosis about heavy fetal CA.     

产前超声诊断前脑无裂畸形

目的 了解产前超声诊断前脑无裂畸形(HPE)的特征,加强对此类畸形的认识. 方法回顾性分析我院2001年5月至2007年11月,产前超声诊断与疑似诊断HPE 30例,超声重点观察颅内结构、颜面部畸形及脑与面部以外的结构畸形,部分病例行染色体和产前MRI检查.结果 30例产前诊断或疑似HPE病倒中经尸检、引产后MRI或CT确诊25例,男10例,女15例;误诊5例,尸检分别为脑积水、孔洞脑和水脑.无叶型HPE 21例(产前超声与生后尸检、引产后MRI或CT一致);半叶型4例(产前MRI与产后尸检诊断).头颅大小径线改变者占83.3 0A(20/24),双顶径小于正常者占62.5%(15/24).面部以中轴部畸形多见,22例(88.0%)有面部畸形,全部有限距的变化,鼻部异常11例、中央性唇、腭裂11例.合并复杂先天性心脏病10例(40.0%).10例行脐血或羊水染色体检查,核型异常5例,其中4例有复杂先天性心脏病. 结论 产前超声检查是诊断HPE的重要方法,诊断准确率高,但对前脑无裂分型有困难,MRI对分型有肯定价值.HPE均有颅内结构异常,常伴有颜面部畸形,少数不伴有颜面部畸形.脑与面部以外的结构畸形中以复杂先天性心脏病为主.HPE与染色体异常高度相关.     

Latest advances in fetal echocardiography

Cardiac anomalies are the most commonly overlooked defects in prenatal ultrasound assessment. The issue of missed prenatal diagnosis is disturbing, particularly when it occurs against a background of tremendous skill and technologic support. New policies to minimize mistakes in this critical aspect need to reach a consensus. Recent new strategies should be put in place in a multidisciplinary manner if they are to have a significant clinical impact. Particularly relevant are the strategies to improve prenatal diagnosis of congenital heart defects, to advance gestational age at diagnosis, to identify new prenatal markers of heart defects and to incorporate new tools in the field of fetal echocardiography. As a result of these advances, the prenatal detection and diagnosis of coronary heart disease has developed an increasing impact on the perinatal outcome of pregnancies complicated by fetal heart disease. We review some of the recent developments in this multidisciplinary area.     

Doppler in fetal heart failure

Fetal echocardiography has progressed to be able to diagnose many forms of congenital heart disease (CHD) and to assess the prognosis of cardiac lesions based on their anatomy and presentation in utero. Fetal echocardiography is for pregnancies at risk of structural, functional, and rhythm-related fetal heart disease. Routine obstetrical ultrasound screening is critical in the prenatal detection of fetal heart disease/CHD. With or without CHD, fetal heart dysfunction defined as inadequate tissue perfusion may occur. Perinatal problems other than CHD can also be assessed, such as the effects of noncardiac malformations that affect hemodynamics, that is, twin-twin transfusion. Cardiac rhythm can affect cardiac function and outcome, and prenatal diagnosis can be lifesaving. A tool for the assessment of cardiac function is the Cardiovascular Profile Score that combines ultrasonic markers of fetal cardiovascular unwellness based on univariate parameters, which have been correlated with perinatal mortality. This "heart failure score" could potentially be used in much the same way as and in combination with the biophysical profile score. This study will present a summary of fetal Doppler and its place in the diagnosis and assessment of prognosis of fetal heart failure.     

Fetal Echocardiography Assists in Determining Optimal Delivery Site

ObjectiveCongenital heart disease is one of the most common types of structural fetal abnormalities and a major cause of perinatal morbidity and mortality. Fetal echocardiography aids in the diagnosis of congenital heart disease, which allows management planning for parents and physicians, including continuation or termination of the pregnancy and triaging for location of delivery. This is a key component of planning, as transport of neonates entails risks, costs, and parental stress. In this study, we examined the outcomes of pregnancies with fetal cardiac anomalies diagnosed at a single tertiary care centre. We aimed to assess whether the system of directing affected pregnancies to either a tertiary and quaternary care centre is effective.MethodsWe identified pregnancies with fetal cardiac anomalies diagnosed on fetal echocardiography between 2005 and 2009. Information about diagnosis, pregnancy outcome, delivery location, and surgical management was collected. This information was analyzed retrospectively.ResultsAnomalies were demonstrated in 120 fetal echocardiography studies. Four of the babies (3.3%) were stillborn, and 27 (22.5%) pregnancies were terminated. There were 89 live born babies, and 74 of these (61.7%) survived the neonatal period. Fifteen babies (12.5%) died as neonates. Thirty-two pregnant women were triaged to deliver at the quaternary centre with pediatric cardiac surgery services, and 20 of these babies underwent surgery. Two of the 89 live born babies (2.2%) required emergency transfer.ConclusionFetal echocardiography is an important contributor to efficient use of pediatric cardiac services and minimizes need for neonatal transfer. Contemporary use of fetal echocardiography is associated with optimized delivery location.     

Evaluation of ultrasound diagnosis of fetal anomalies in women with pregestational diabetes: University of Florida experience

Fetal congenital anomalies have become the major cause of perinatal morbidity and mortality in pregnancies complicated by insulin-dependent diabetes. We evaluated the use of level II ultrasound in predicting congenital anomalies, to determine if the management of pregnant women with insulin-dependent diabetes would be altered by these findings. We examined 43 insulin-dependent diabetic pregnancies. In this group, 10 newborns (23%) were diagnosed either at birth or later to have an abnormality. Of these, four (9%) were diagnosed by ultrasound. Of the seven cases that were undiagnosed, three women did not undergo the level II examination, two women had lesions undetectable by ultrasound, and in two women cardiac abnormalities were missed. Of the four congenital anomalies that were prenatally diagnosed, the findings influenced the management in three cases. The level II ultrasound used as a screening test had a 67% sensitivity and a 100% specificity, with a positive predictive value of 100% and a negative predictive value of 91%. We conclude that high-resolution ultrasound may be used as a screening tool for congenital anomalies in the insulin-dependent diabetic pregnancy. This study also suggests that the use of fetal echocardiography with evaluation of aortic and pulmonary outflow tracts, the arch of the aorta, and ventricular size may be helpful in the diagnosis of fetal cardiac anomalies in the pregnant woman with insulin-dependent diabetes.     

Rate of prenatal detection of congenital right heart defects

Congenital right heart lesions (including tetralogy of Fallot, pulmonary valve stenosis, pulmonary atresia with intact ventricular septum, Ebstein's anomaly and dysplastic tricuspid valve) account for about 19% of congenital cardiac anomalies. We performed a retrospective study in order to assess the percentage of patients with significant right heart lesions (requiring therapy in the first year of life), which is detected prenatally and referred to a centre for perinatal treatment. From 1/1990 until 12/1997 congenital right heart lesions were diagnosed in 21 fetuses and 190 infants (211 patients. The majority of patients had tetralogy of Fallot (64%), less frequently we found critical pulmonary valve stenosis (9%), pulmonary atresia with intact ventricular septum (9%), tricuspid atresia (14%) and Ebstein's anomaly or dysplastic tricuspid valve (4%). Prenatally the cardiac anomaly was diagnosed in all 21 cases who were referred to our center (10%). The highest referral and detection rate was found among fetuses with Ebstein's anomaly or dysplastic tricuspid valve (5/8 patients = 63%) followed by fetuses with pulmonary atresia and intact ventricular septum (5/20 = 25%), critical pulmonary stenosis (4/18 = 22%) or tricuspid atresia (4/29 = 14%). The prenatal referral rate was disappointing in children with tetralogy of Fallot (3/136 = 2.2%). A higher prenatal detection rate of congenital right heart lesions can be achieved only by an improvement of prenatal screening including the 4-chamber view and the origin of the great arteries. A first step would be the inclusion of the fetal 4-chamber view into the routine examination during the 18th-20th week of pregnancy (stage 1 of a multistage concept of prenatal screening) and by assessment of the outflow tracts and the great arteries in pregnancies associated with risk factors or anomalies of the fetus (stage 2 and 3 of a multistage concept).     

Congenital heart disease and extracardiac anomalies: associations and indications for fetal echocardiography

Fetal echocardiography is a well-established technique for the prenatal identification of congenital heart disease. One of the indications for its use is the presence of extracardiac anomalies, as such coexistent defects may have important implications for obstetric and neonatal management. We have reviewed the obstetric and pediatric literature to examine reported associations. If a fetus is suspected to have hydrocephalus, microcephaly, holoprosencephaly, agenesis of the corpus callosum, Meckel-Gruber syndrome, esophageal atresia, duodenal atresia, diaphragmatic hernia, omphalocele, or renal dysplasia, cardiac evaluation should be pursued. Furthermore, echocardiography may be of help in differential diagnosis of some anomalies (for instance, skeletal dysplasias). Maternal diabetes and phenylketonuria, as well as exposure to phenytoin, trimethadione, or isotretinoin, may result in multiple systemic defects, including congenital heart disease.     

Prenatal diagnosis in twin gestations

Twin gestations face an increased risk of structural abnormalities compared with singleton gestations, as well as an increased risk of aneuploidy. Accordingly, there is a need for accurate prenatal diagnosis of fetal genetic disorders and structural anomalies in twin gestations. Given the increased risk of congenital anomalies, a detailed sonographic survey of fetal anatomy is recommended in the early second trimester of twin gestations. In addition, fetal echocardiography should be considered in monochorionic twin gestations and in dichorionic twin pregnancies conceived using assisted reproductive technologies given the increased risk of congenital heart disease in these populations. Although first- and second-trimester aneuploidy screening in twin gestations is available, screening is less accurate than in singleton gestations. Invasive prenatal diagnosis in twin pregnancies is associated with a risk of pregnancy loss that is higher than the baseline risk of loss among twin gestations. Precise procedure-related loss rates in twin gestations undergoing chorionic villus sampling or amniocentesis, however, remain unclear because of methodological differences between published studies investigating diagnostic procedures in twins.     

Chromosomal microarray analysis in fetuses with high-risk prenatal indications: A retrospective study in China

ObjectiveThe present study aimed to determine the diagnostic value of prenatal chromosomal microarray analysis (CMA) for fetuses with several indications of being at high risk for various conditions.Materials and methodsThis retrospective analysis included 1256 pregnancies that were prenatally evaluated due to high-risk indications using invasive CMA. The indications for invasive prenatal diagnosis mainly included ultrasound anomalies, high-risk for maternal serum screening (MSS), high-risk for non-invasive prenatal tests (NIPT), family history of genetic disorders or birth defects, and advanced maternal age (AMA). The rate of clinically significant genomic imbalances between the different groups was compared.ResultsThe overall prenatal diagnostic yield was 98 (7.8%) of 1256 pregnancies. Clinically significant genomic aberrations were identified in 2 (1.5%) of 132 patients with non-structural ultrasound anomalies, 36 (12.7%) of 283 with structural ultrasound anomalies, 2 (4.5%) of 44 at high-risk for MSS, 38 (26.6%) of 143 at high-risk for NIPT, 11 (3.8%) of 288 with a family history, and 7 (2.1%) of 328 with AMA. Submicroscopic findings were identified in 29 fetuses, 19 of whom showed structural ultrasound anomalies.ConclusionThe diagnostic yields of CMA for pregnancies with different indications greatly varied. CMA could serve as a first-tier test for structural anomalies, especially multiple anomalies, craniofacial dysplasia, urinary defects, and cardiac dysplasia. Our results have important implications for genetic counseling.     

Perinatal management of fetal cardiac anomalies in a specialized obstetric-pediatrics center.

Perinatal teams dealing with fetal heart disease frequently wonder which pregnancies might be terminated, and when delivery should take place in a specialized surrounding. We present a retrospective study of 229 fetuses, in which prenatal ultrasound showed a cardiac anomaly not compatible with a standard maternity ward delivery. One hundred nineteen pregnancies were terminated (group I) while 110 pregnancies led to the birth of a live baby (group II). Pathology in group I was discovered earlier than in group II (24 vs. 29.3 weeks' gestation; p <0.01), and associated malformations or chromosomal anomalies were much more frequent in group I (80/119 vs. 9/110; p <0.001). Among live born babies, three infants with transposition of the great arteries underwent Rashkind atrioseptostomy in the delivery room. With a minimum follow-up of 12 months, 69 children (63%) have undergone surgery. Among 92 survivors (1 child is lost to follow-up), 78 (71%) are asymptomatic and 14 symptomatic. Early prenatal diagnosis of fetal heart anomalies significantly facilitates prenatal work-up and perinatal care. We present the types of pathology having led to termination and define the situations in which children are at risk of perinatal hemodynamic compromise.     

Fetal echocardiography: accuracy and limitations in a population at high and low risk for heart defects.

OBJECTIVE: Our objective was to assess the accuracy of prenatal echocardiography in detecting congenital heart defects in patients at high and low risk for structural cardiac anomalies. STUDY DESIGN: Sixty-nine consecutive fetuses with congenital heart defects who had had prenatal ultrasonography at greater than or equal to 18 weeks' gestation were evaluated to determine the accuracy of prenatal ultrasonography in identifying structural cardiac defects. Thirty-nine patients were at high risk and 30 patients were at low risk for cardiac anomalies. All fetuses were scanned with standard four-chamber and outflow tract views. Data concerning extracardiac anomalies and karyotypic abnormalities were tabulated. The accuracy of the four-chamber view alone in identifying congenital heart defects was evaluated. RESULTS: Fifty-seven of 69 fetuses (83%) were prenatally identified ultrasonographically as having a heart defect. There was no difference in the sensitivity of detecting cardiac anomalies between high-risk and low-risk groups. When the four-chamber view was used, only 63% of fetuses were recognized as having an abnormal heart. Extracardiac anomalies were noted in 36% and karyotypic abnormalities in 17% of patients. CONCLUSION: The four-chamber and outflow tract views done routinely in an ultrasonography laboratory seeing a mixed population of patients was successful in detecting 83% of fetuses with structural cardiac malformations. Because 43% of the fetuses with heart defects were referred for low-risk indications, systematic ultrasonographic examination of the fetal heart should not be reserved only for those at high risk.     

Diagnóstico prenatal de masa suprarrenal: secuestro pulmonar intraabdominal,una entidad a tener en cuenta

Congenital lung sequestrations are uncommon but are well recognized. Recently, the incidence of these anomalies has increased due to routine ultrasound scans in pregnant women. Although these anomalies represent only 0,15% to 6,45% of all pulmonary malformations, they constitute between 8% and 23% of the prenatal diagnosis of lung abnormalities. Extralobar pulmonary sequestration is an extremely rare congenital infradiaphragmatic anomaly. Most of these lesions are located in the left abdomen and differential diagnosis with adrenal masses is essential. Pulmonary sequestration should be considered in any infant with an upper abdominal or adrenal mass, especially when diagnosis is prenatal.     

Evaluation of prenatal diagnosis by a registry of congenital anomalies.

Prenatal diagnosis performed by fetal karyotype and ultrasound scan is now a routine part of antenatal care in many countries. How many fetal anomalies are actually detected by these procedures? We have used our registry of congenital malformations to answer this question. In our region, prenatal diagnosis was performed in 23.1 per cent of fetuses with a chromosomal aberration and in 20.1 per cent of fetuses with non-chromosomal anomalies. Only 6.9 per cent of the pregnancies with fetuses with non-chromosomal anomalies were terminated. The sensitivity of prenatal diagnosis by ultrasonographic examination was much lower for isolated malformations (fetuses with only one anomaly) than for multiple malformed children, 15.3 and 48.3 per cent respectively, chromosomal anomalies excluded.     

Suspected fetal anomalies

Assessment of the unborn patient following the initial detection of a fetal structural anomaly involves further detailed ultrasound scanning, usually followed by other investigations to ascertain the extent of the abnormality, and to attempt to identify an underlying cause. Although many congenital fetal anomalies are sporadic, some are associated with maternal infections or medical disorders, such as diabetes, and others are caused by underlying pathological genetic variants. As the understanding of the human genome advances, the proportion of ‘idiopathic’ congenital anomalies will decline. The new molecular technologies of array hybridization and non-invasive prenatal diagnosis will move the specialty of prenatal diagnosis into a new era in the very near future. However, there will always be a place for careful history taking, as one of the cases below illustrates.Diagnosis of maternal disease following clinical assessment of fetal anomalies allows maternal treatment in order to prevent progression of disease, prevent further fetal consequences and may even have implications for the family and other siblings. Similarly, the diagnosis of genetic disorders allows for focused earlier testing in future pregnancies, and may also have wider implications for the family.This journal has published a number of articles previously which use case histories to illustrate the principles of prenatal diagnosis and management. This article adds three further cases. The details of the anomalies are less important than the processes by which the final diagnoses were reached.     

Outcome for fetuses with prenatally detected congenital heart disease and cardiac arrhythmias in Taiwan.

BACKGROUND/PURPOSE: Outcome for fetuses with prenatally detected congenital heart disease (CHD) and/or cardiac arrhythmias is important for prenatal counseling and perinatal management; however, there exists little literature regarding the outcome for CHD diagnosed in utero in Taiwan. Therefore, we attempted to investigate the outcome for fetuses with CHD and/or cardiac arrhythmias diagnosed prenatally at a tertiary care medical center in Taiwan. METHODS: Between January 1995 and December 2000, 339 patients referred to the National Taiwan University Hospital for fetal echocardiography were included in this study. Medical records were reviewed retrospectively to determine the salient clinical characteristics for all fetuses. RESULTS: CHD was found in 103 fetuses. Gestational age at diagnosis ranged from 17 to 40 weeks; in 37 cases (35.9%) the diagnosis was made before 24 weeks. Mean gestational age at diagnosis was 27.8 weeks. Of the 103 cases, 15 fetuses (14.6%) had major extra cardiac malformations and 15 fetuses (14.6%) had chromosomal abnormalities (five had both) and 30 pregnancies (29.1%) were terminated. Of the remaining 73 pregnancies, three (4.1%) of the fetuses died in utero and 28 (38.4%) postnatally, with 42 (57.5%) surviving. The mortality rates were both 60% in cases with extracardiac or chromosomal anomalies. Arrhythmias were identified in 25, and two pregnancies involving hydrops fetalis were terminated. Of the remaining 23 continued pregnancies, two (8.7%) with long QT syndrome expired postnatally. CONCLUSION: Outcome for fetuses with prenatally detected CHD remains poor, with the prognosis negatively influenced by the presence of complex heart defects as well as extracardiac and chromosomal anomalies. However, prognosis is good for fetuses with cardiac arrhythmia, except with long QT syndrome or hydrops fetalis.     

3D ultrasound and Doppler angiography for evaluation of fetal cardiovascular anomalies

ObjectiveTo highlight the value of 3D ultrasound in the prenatal assessment of fetal cardiovascular anomalies through offline diagnosis and/or second opinion (e.g. via internet link).MethodsA retrospective offline analysis of volume datasets of fetuses diagnosed with cardiovascular anomalies by 2D ultrasound was conducted.ResultsThirty-three fetuses with 38 cardiac malformations were evaluated. Mean gestational age at diagnosis was 26 weeks (range, 20–34 weeks). Isolated cardiovascular malformations were detected in 23 fetuses. Extracardiac abnormalities were identified in 8 fetuses, of which 2 had trisomy 21 and 1 had trisomy 18. One fetus exhibited 22q11 microdeletion. Ten pregnancy terminations were performed.ConclusionOffline analysis of cardiovascular anomalies conferred significant diagnostic advantages over 2D ultrasound. 3D ultrasound is invaluable for the prenatal diagnosis and management of congenital heart diseases. It may be used to facilitate scientific cooperation between high- and low-income countries.     

Diagnosing Chromosomal Abnormalities From “Big” to “Small” With Molecular Cytogenetic Technology

We reviewed the available molecular cytogenetic techniques and their potential use in prenatal diagnosis of fetuses with multiple congenital anomalies and a “normal” standard chromosomal karyotype. We searched Medline to identify reports published after 1995 that were related to molecular prenatal diagnosis. After review, we reached the following conclusions:

• 1.In fetuses with a normal standard karyotype result, common chromosomal microdeletion syndromes may be suspected based on the pattern of congenital anomalies seen on prenatal ultrasound.
• 2.When a microdeletion syndrome is suspected based on the pattern of fetal anomalies, FISH testing for the specific molecular locus should be undertaken.
• 3.Routine chromosome analysis, which has been the gold standard for prenatal cytogenetic diagnosis, may in the future be replaced by microarray technology with increased diagnostic capability for smaller, submicroscopic genetic alterations associated with postnatal morbidity.
• 4.Microarray technology has been shown to increase our ability to make a diagnosis of known or new chromosomal deletion syndromes in pediatric populations with developmental delay. The use of this technology for prenatal diagnosis is currently limited but is likely to expand.