**3.1. Prenatal**

on samples from chorionic villus sampling or amniocentesis. It is, however, not possible to predict the severity of the phenotype in an identified fetus [69]. The diagnosis needs to be considered in a baby with a cardiac defect and prolonged jaundice, and with at least three of the recognized features [61]. Alagille syndrome has a mortality rate around 10–20%. The risk of recurrence is low in the absence of a positive family history, but it is 50% if there is an

The phenotype is characterized by the bilateral, asymmetrical upper limb anomalies of variable severity and is estimated to occur in 1 per 100,000 live births. There is a variation in the severity of the phenotype even within a family, and in some the upper limb anomalies may be so mild that X-ray can only diagnose them. A thumb anomaly is usually present [70]. Approximately 75% of the patients diagnosed with Holt-Oram syndrome have CHD. Atrial septal defects (secundum type) are present in 58% of these patients, in addition 28% have VSD. Up to 40% have conduction defects including a long PR interval, sinus bradycardia, atrial fibrillation and complete heart block [71]. Other types of congenital heart diseases in the form of total anomalous pulmonary venous drainage, TOF and truncus arteriosus have been associated with this syndrome [72]. There appears to be a correlation between the severity of

Holt-Oram syndrome is an autosomal dominant condition with 100% penetrance and variable expression. New mutations make up 30–40% of the inheritance pattern. The affected gene is TBX5 on chromosome locus 12q24 [74]. The diagnosis should be considered prenatally when a cardiac lesion occurs in the presence of an upper limb anomaly. The risk to the off-

The most familiar syndrome to cardiologists is Down's syndrome is trisomy 21 in which there is a complete extra copy of chromosome 21 in 94% of cases. Less commonly, partial trisomy of chromosome 21(6% overall), is present owing to a chromosomal translocation or mosaicism. Common findings include: hypotonia, global developmental delays and moderate intellectual disability, microbrachycephaly, small ears, mouth and nose, protruding tongue, up-slanting eyes with epicanthal folds, transverse palmar creases, and sparse hair. Skeletal anomalies include fifth finger clinodactyly, brachydactyly, a gap between first and second toes, atlantoaxial instability, hypoplastic pelvis, and joint laxity. Additional problems involve the visual, auditory, endocrine, hematologic, reproductive, and gastrointestinal systems. Almost half of live born Down's syndrome individuals have a CHD, approximately 40% of whom have a complete atrioventricular septal defect (also known as atrioventricular canal defect or endocardial cushion defect) [75]. The association of Down syndrome and atrioventricular septal defects is underscored by the fact that approximately 75% of patients with a complete atrioventricular septal defect have Down syndrome. Other common CHDs include secundum atrial septal defect, conoventricular and muscular ventricular septal defect, tetralogy of Fallot (with and without atrioventricular septal defect), and hemodynamically significant patent ductus arteriosus [75]. The overall prevalence of Down syndrome is

affected parent [61, 68].

**2.8. Holt-Oram syndrome**

418 Congenital Anomalies - From the Embryo to the Neonate

the upper limb anomaly and the cardiac lesion [73].

spring of an affected individual is 50% [61].

**2.9. Trisomy 21 (Down's syndrome)**

1 in 700 live births [76].

The process of prenatal counseling and its recommendations, should be based on the best available current evidenced-based practice. This process may require more than one consultation due to its emotional nature of the situation and complexity of information being delivered. Any prenatal counseling should include the suspected cardiac diagnosis in detail based on the fetal ultrasound findings. The purpose of this is to give the most accurate and up to date information about the prognosis and outcome of the pregnancy and fetus. This will allow the parents to make the best-informed decision for them and the fetus.

In regards to the screening ultrasound, all relevant information available needs to be given prior to the examination. Ideally, all prescreening information should be made available to the referring hospital. It needs to be emphasized that not all cardiac defects can be detected in the initial ultrasound examination [81, 82]. Whenever a cardiac abnormalities is detected this will require prompt referral for specialist examination. The general screening detection rates for congenital heart disease (CHD) vary between 14–45% [83]. A standard 4-chamber view can detect 40–50% of major CHD [84], while a 4-chamber view and outflow tract detects 70–80% of major CHD [85]. In dedicated fetal cardiac centers the diagnostic accuracy is close to 100% [86, 87]. Thereafter a referral for specialized echocardiography and cardiology consultation should be done. If there are suspected cardiac abnormalities on the screening fetal ultrasound, there should be minimal time delay in referring the mother for a fetal echocardiogram and cardiology consultation. Delays in referral for further evaluation increase parental stress [88], and may prohibit the option of early termination of pregnancy. At the referral center, before the scan, the physician should make sure that the parents have consented to the examination and understand why they have been referred. A detailed review of past maternal history, including health wellbeing, previous pregnancies outcomes and similar conditions in the family need to be determined. In addition, any previous genetic screening has been performed or suspected in the family.

the information to the parent [92]. The parent should be counseled after each scan, and should be given enough time for questions and follow up information [89]. If the amniocentesis detects a chromosomal abnormality, advance cytogenetic testing may be warranted. These testing include FISH, chromosomal microarray and whole exome sequencing [93]. The next step in the counseling, should mention the possibility of chorionic villus sampling or amniocentesis, as this knowledge may help determine prognosis and guide postnatal care. The finding of an associated chromosomal abnormality may also strongly influence decisions about pregnancy termination [94, 95]. Whatever the parental decision is made, the counselor should express full support.

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In the final step, the counselor needs to identify and discuss the prenatal options and parental decision-making. This stage is crucial, because the counselor will be discussing the management options with the parents in regards to the outcome of the pregnancy. The management options include: pregnancy continuation, pregnancy termination (if legally allowed) and pre-

If the decision is to continue with the pregnancy, there will be further decisions to be made as to where the infant will to be delivered, mode of delivery and the need for postnatal care and intervention [97]. Delivery at a tertiary care facility with access to pediatric cardiac care is recommended for ductal-dependent lesions and any heart defect that is expected to require neonatal and surgical interventions. Transfer is usually between 30 and 34 weeks gestation to allow the mother to become familiar with the new obstetrician and hospital in the time of her delivery. At the same time, it can be useful to have parent meet the surgeon. The fetus can be delivered at the local hospital, depending on the nursery's comfort level in dealing with such newborns. However, continued communications between the referral hospitals is vital for optimal outcome [98]. Delivery after 39 weeks is typically recommended because of high morbidity, and mortality has been reported in babies born before 36 weeks. Particularly in those with extracardiac and genetic abnormalities [99]. Parents should be counseled that IUGR is associated with increased morbidity after cardiac surgery [100]. Similarly, lower weight (<2.5 kg) is associated with higher mortality after cardiac surgery [101]. Mode of delivery is not typically altered in the setting of fetal CHD, and high rates of vaginal delivery can be achieved [102]. Cesarean section is almost never indicated for cardiac reasons and should be avoided if possible if the cardiac malformation is associated with a high mortality [103]. When the parents make an informed decision to continue the pregnancy, it may be useful for them to meet and speak with parents who have had a child with similar cardiac abnormalities. This will allow for them to have a better understanding of what is to be expected of the journey ahead. If the decision is to terminate the pregnancy, parents should be counseled and supported fully, as this can cause guilt and emotional stress. Counselor should appreciate the mixed feelings of the parents when it comes to such decisions. It is very important to highlight that termination of pregnancy is never recommended nor absolutely indicated in any circumstances. Termination of pregnancy is a legal option in most of the developed world, but the gestational age limit is variable. In general, it is allowed up to 24 weeks of gestation in most countries all over the world, but late termination, even up to term, can be obtained in some countries like the United States of America for fetal malformations. The counselor must be able to discuss the options of termination of pregnancy and its risks, regardless of their personnel beliefs. The earlier the diagnosis of fetal malformation can be reached (possible from as early as 12 weeks of gestation) the more safely termination of pregnancy can be accomplished. This will create

natal intervention if available [96].

Ideally, the parents should be counseled by a pediatric cardiologist specialized in fetal cardiology, once the fetal echocardiogram is complete. The counselor needs to have full knowledge of the anatomy, physiology, gestational age, and association with extra-cardiac malformations and its natural history. In addition, the discussion should include the short and longterm management and possible outcomes. If possible a multidisciplinary meeting with the parents should be conducted. This conversation should include the most accurate information and include prenatal and postnatal management. Ideally this discussion should include fetal cardiologist, obstetrician, neonatologist, geneticist, pediatric cardiac surgeon and a psychologist or social worker. In addition to the physicians, a fetal nurse coordinator or midwife should be involved from the first counseling visit to delivery of the baby or termination of the pregnancy. This is to provide continuous support and ongoing resources for follow up with the family [89]. There is little research on performing prenatal counseling for CHD or determining the most effective strategies for providing family support. Therefore, it is important that counselors have good communication skills, show empathy, and be perceptive in assessing how the information is being received. The counselor must assess parental understanding and emotional status throughout the discussion.

A structured explanation focused on assessing the parents understanding is very important at this stage. Highlights of the counseling of session needs to repeated and the expected parent should be made to verbalize understanding in their own words. This may need to be repeated to ensure complete understanding of the situation and implication for treatment and intervention. Throughout this process, the counselor needs to assess and give feedback to the treating team on how the information is being received. Particularly at the first visit, the initial shock and grief reactions to an abnormal finding may inhibit the parents' ability to retain information. Therefore, it maybe necessary to repeat information on subsequent encounters and assess understanding. A common issue that complicates counseling in today technological age, is the access and availability of the vast amount of information on the Internet. At time such recourses can be beneficial, but more often than not, this information is misleading, biased and inappropriate for the precise circumstances. Unfortunately, none of this information is subject to review and can be a source of major confusion for the parent [90].

Complications of the cardiac abnormality and its progression in utero, and the results of surgery or any intervention also figure in to the discussion. There is a need to describe possible poor outcomes, so that they have been informed of all possible scenarios, even though unlikely to happen. This information allows the parents to decide how best to proceed with knowledge of the worst-case scenario [91]. One of the most important points which needs to be mentioned during the consultation is that the risk of intrauterine death is low in fetuses with CHD who are in sinus rhythm with good myocardial function [89]. Characterization of the cardiac defect and its association with genetic syndrome or not will guide the counselor on how best to give the information to the parent [92]. The parent should be counseled after each scan, and should be given enough time for questions and follow up information [89]. If the amniocentesis detects a chromosomal abnormality, advance cytogenetic testing may be warranted. These testing include FISH, chromosomal microarray and whole exome sequencing [93]. The next step in the counseling, should mention the possibility of chorionic villus sampling or amniocentesis, as this knowledge may help determine prognosis and guide postnatal care. The finding of an associated chromosomal abnormality may also strongly influence decisions about pregnancy termination [94, 95]. Whatever the parental decision is made, the counselor should express full support.

and cardiology consultation. Delays in referral for further evaluation increase parental stress [88], and may prohibit the option of early termination of pregnancy. At the referral center, before the scan, the physician should make sure that the parents have consented to the examination and understand why they have been referred. A detailed review of past maternal history, including health wellbeing, previous pregnancies outcomes and similar conditions in the family need to be determined. In addition, any previous genetic screening has been

Ideally, the parents should be counseled by a pediatric cardiologist specialized in fetal cardiology, once the fetal echocardiogram is complete. The counselor needs to have full knowledge of the anatomy, physiology, gestational age, and association with extra-cardiac malformations and its natural history. In addition, the discussion should include the short and longterm management and possible outcomes. If possible a multidisciplinary meeting with the parents should be conducted. This conversation should include the most accurate information and include prenatal and postnatal management. Ideally this discussion should include fetal cardiologist, obstetrician, neonatologist, geneticist, pediatric cardiac surgeon and a psychologist or social worker. In addition to the physicians, a fetal nurse coordinator or midwife should be involved from the first counseling visit to delivery of the baby or termination of the pregnancy. This is to provide continuous support and ongoing resources for follow up with the family [89]. There is little research on performing prenatal counseling for CHD or determining the most effective strategies for providing family support. Therefore, it is important that counselors have good communication skills, show empathy, and be perceptive in assessing how the information is being received. The counselor must assess parental understanding

A structured explanation focused on assessing the parents understanding is very important at this stage. Highlights of the counseling of session needs to repeated and the expected parent should be made to verbalize understanding in their own words. This may need to be repeated to ensure complete understanding of the situation and implication for treatment and intervention. Throughout this process, the counselor needs to assess and give feedback to the treating team on how the information is being received. Particularly at the first visit, the initial shock and grief reactions to an abnormal finding may inhibit the parents' ability to retain information. Therefore, it maybe necessary to repeat information on subsequent encounters and assess understanding. A common issue that complicates counseling in today technological age, is the access and availability of the vast amount of information on the Internet. At time such recourses can be beneficial, but more often than not, this information is misleading, biased and inappropriate for the precise circumstances. Unfortunately, none of this informa-

tion is subject to review and can be a source of major confusion for the parent [90].

Complications of the cardiac abnormality and its progression in utero, and the results of surgery or any intervention also figure in to the discussion. There is a need to describe possible poor outcomes, so that they have been informed of all possible scenarios, even though unlikely to happen. This information allows the parents to decide how best to proceed with knowledge of the worst-case scenario [91]. One of the most important points which needs to be mentioned during the consultation is that the risk of intrauterine death is low in fetuses with CHD who are in sinus rhythm with good myocardial function [89]. Characterization of the cardiac defect and its association with genetic syndrome or not will guide the counselor on how best to give

performed or suspected in the family.

420 Congenital Anomalies - From the Embryo to the Neonate

and emotional status throughout the discussion.

In the final step, the counselor needs to identify and discuss the prenatal options and parental decision-making. This stage is crucial, because the counselor will be discussing the management options with the parents in regards to the outcome of the pregnancy. The management options include: pregnancy continuation, pregnancy termination (if legally allowed) and prenatal intervention if available [96].

If the decision is to continue with the pregnancy, there will be further decisions to be made as to where the infant will to be delivered, mode of delivery and the need for postnatal care and intervention [97]. Delivery at a tertiary care facility with access to pediatric cardiac care is recommended for ductal-dependent lesions and any heart defect that is expected to require neonatal and surgical interventions. Transfer is usually between 30 and 34 weeks gestation to allow the mother to become familiar with the new obstetrician and hospital in the time of her delivery. At the same time, it can be useful to have parent meet the surgeon. The fetus can be delivered at the local hospital, depending on the nursery's comfort level in dealing with such newborns. However, continued communications between the referral hospitals is vital for optimal outcome [98]. Delivery after 39 weeks is typically recommended because of high morbidity, and mortality has been reported in babies born before 36 weeks. Particularly in those with extracardiac and genetic abnormalities [99]. Parents should be counseled that IUGR is associated with increased morbidity after cardiac surgery [100]. Similarly, lower weight (<2.5 kg) is associated with higher mortality after cardiac surgery [101]. Mode of delivery is not typically altered in the setting of fetal CHD, and high rates of vaginal delivery can be achieved [102]. Cesarean section is almost never indicated for cardiac reasons and should be avoided if possible if the cardiac malformation is associated with a high mortality [103]. When the parents make an informed decision to continue the pregnancy, it may be useful for them to meet and speak with parents who have had a child with similar cardiac abnormalities. This will allow for them to have a better understanding of what is to be expected of the journey ahead.

If the decision is to terminate the pregnancy, parents should be counseled and supported fully, as this can cause guilt and emotional stress. Counselor should appreciate the mixed feelings of the parents when it comes to such decisions. It is very important to highlight that termination of pregnancy is never recommended nor absolutely indicated in any circumstances. Termination of pregnancy is a legal option in most of the developed world, but the gestational age limit is variable. In general, it is allowed up to 24 weeks of gestation in most countries all over the world, but late termination, even up to term, can be obtained in some countries like the United States of America for fetal malformations. The counselor must be able to discuss the options of termination of pregnancy and its risks, regardless of their personnel beliefs. The earlier the diagnosis of fetal malformation can be reached (possible from as early as 12 weeks of gestation) the more safely termination of pregnancy can be accomplished. This will create the least amount of physical and emotional trauma for the mother and family [90, 96, 104]. In one center experience, over 2000 sets of parents were counseled, half of them chose termination and the other half continued with pregnancy. Those who accepted termination of pregnancy recovered from it and with time ended up as normal healthy family. However, many of those who continued with the pregnancy, eventually lost the affected child, which was associated with increase grief and agony. In addition, break- down of the whole family unit after many years was reported [90].

to reach adult age. For example, infants with simple CHD such as VSD or ASD have survival rate of 95%, whereas moderate severity such as TOF reach 90%, and complex CHD such as single ventricle reach 80%.) [111]. A follow up study of 1000 Fontan patients by d'Udekem et al. showed 97% 10-year survival rate [112]. Although there are relatively good survival many of these patient may manifest other complications, including dysrhythmias, need for pacemaker and thromboembolic events [98]. Parents have to be informed about that there is an increased risk of neurodevelopmental delay in children with cardiac malformations. The severity of cardiac defect correlates with the degree of developmental delay [113]. In a recent meta-analysis, fetuses with severe cardiac malformation showed signs of impaired fetal cerebral development as shown by fetal MRI or ultrasound. However, correlations of fetal brain findings with neurodevelopmental outcome have been inconclusive and more long-term data are needed [114].

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The advancement of cardiac diagnostic and therapeutic techniques in the past decade, with relatively low morbidity and mortality, has led to more and more children with congenital heart disease living to adulthood. Therefore, the role of genetic counseling becomes even more paramount as there is a higher likelihood of these patients living to reproduce and that they may have families of their own [22]. It is very important to help elucidate the genetic basis for patients' congenital cardiac malformation for the reason mentioned, as there may be important reproductive risks that the families need to know about [22, 115, 116]. Recent analysis indicate that adults now constitute roughly two-thirds of the congenital heart disease population, representing a nearly 60% increase in congenital heart disease among adult patients since the year 2000 [115, 116]. The greatest increase in congenital heart disease survival has occurred among the 18-year old to 40-year-old demographic, which has clear implications for heritability [116].

One of the obstacles, in performing genetic testing in patients with congenital heart disease is that there are no standardized recommendations or protocols incorporating, newer genetic testing technologies at present. The literature is sparse with guidelines, and there is evidence that there is under use even of those modalities of testing that are available [22, 115]. However, there has been an emphasis from the American Heart Association in the recent past, in obtain-

Cardiac malformation present at birth are an important component of pediatric cardiovascular disease. Defects can range from simple ventricular septal defects to complicated cyanotic lesions, requiring complex interventions shortly after birth. With the possibility of myriad of presentations, it begets one to ask, what is the percentage of pediatric cardiac defects are a result of a genetic anomaly. CHD is estimated that the prevalence of cardiac malformation at birth ranges from 4 to 10 live born infants per 1000. The true incidence, perhaps maybe higher as there are silent cardiac malformations that are only found later on in life [115]. As most calculations do not include bicuspid aortic valves, mitral valve prolapse and conduction problems, such as prolonged QT syndrome and complete atrioventricular block [115, 116]. The care of the pediatric patient with cardiac malformation is multifaceted, ranging from simple reassurance and observation to advanced surgeries and

**3.2. Postnatal**

ing genetic testing in these patients [117].

*3.2.1. Genetics in congenital heart disease*

Outcomes in terms of rate of termination, after prenatal diagnosis of heart defects vary between countries and even between centers within the same country [105, 106]. The reason for this may be due to differences in social/religious elements and in the local laws and practices. Termination rates are greatly influenced by the gestational age at the time of diagnosis [107], by the presence of the chromosomal abnormalities and other extracardiac malformations [25]. Severity of the cardiac malformation also influences the termination rate like hypoplastic left heart syndrome [81, 105].

Intrauterine interventions may be available for some cardiac malformations like Balloon aortic and pulmonary valvuloplasty. Currently there is a conflict between American College of Obstetricians and Gynecologists and the American Academy of Pediatrics (AAP) regarding the issue of fetal interventions [108]. The AAP favors fetal intervention if available, and puts less weight in maternal decision that is recommended for fetal benefits. This approach may place the mother at greater risks and decrease autonomy [96, 109]. If the intervention considered are questionable and carry a high risks to the mother, it is prudent to respect the mothers autonomy and giving her priority [96], until further research and consensuses are definitive in this regards.

In case of multiple pregnancies with one fetus with a serious congenital anomaly need to be highlighted in this step of the counseling. These risks and benefits of continuing or terminating the pregnancy of affected twin needs to be considered and balanced. The expectant parents need to understand that the death of the normal twin can occur if the twin pregnancy is continued. This is particularly true when there is a monochorionic twin pregnancy [96, 110].

The prenatal counseling should discuss the anticipated postnatal course, intervention and outcome/survival. In most cases, the infant born with cardiac malformation will require immediate medical and/or surgical intervention. Medical intervention to ensure patency of the ductus arteriosus will include starting Prostaglandin for duct-dependent lesions for either pulmonary blood flow (e.g., severe TOF or pulmonary atresia) or systemic blood flow (e.g., HLHS, interrupted aortic arch). Once these patients are stable medically, they may require cardiac catheterization and/or surgical repair. Parents should be counseled on what to expect in the delivery room. Management will vary, depending on the severity of the cardiac defect. Decision such as, where the baby will be admitted and how much time they will have the baby, will be decided prior to the delivery date. Parent should be made aware that the postnatal cardiac diagnosis might be modified after birth. Emphasis on the possibility of modification of the postnatal course, including change in the interventions and length of stay needs to be discussed. Helping the parents understand and deal with changes that may occur and be contrary to what they might have been told [98].

The outcomes and long-term survival (20 years) are profoundly dependent on the type of defect in babies born with CHD. Majority of these babies, approximately 85% are expected to reach adult age. For example, infants with simple CHD such as VSD or ASD have survival rate of 95%, whereas moderate severity such as TOF reach 90%, and complex CHD such as single ventricle reach 80%.) [111]. A follow up study of 1000 Fontan patients by d'Udekem et al. showed 97% 10-year survival rate [112]. Although there are relatively good survival many of these patient may manifest other complications, including dysrhythmias, need for pacemaker and thromboembolic events [98]. Parents have to be informed about that there is an increased risk of neurodevelopmental delay in children with cardiac malformations. The severity of cardiac defect correlates with the degree of developmental delay [113]. In a recent meta-analysis, fetuses with severe cardiac malformation showed signs of impaired fetal cerebral development as shown by fetal MRI or ultrasound. However, correlations of fetal brain findings with neurodevelopmental outcome have been inconclusive and more long-term data are needed [114].
