Prenatal diagnosis: lessons learned and future ...

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Ultrasound Rev Obstet Gynecol 2002;2:195–204

Prenatal diagnosis: lessons learned and future challenges A. Kurjak, F. Stipoljev and M. Stanojevic

The Ultrasound Review of Obstetrics and Gynecology Downloaded from informahealthcare.com by Universitaetsbibliothek Duisburg-Essen on 05/20/14 For personal use only.

Department of Obstetrics and Gynecology, Medical School University of Zagreb, Sveti Duh Hospital, Zagreb, Croatia

Key words: Prenatal diagnosis / Ultrasound / Genetic techniques

INTRODUCTION likely, therefore, that there are many more genetic diseases affecting the fetus that have not yet been recognized, and many that may be incorrectly diagnosed2. It can be shown that technological advances in the fields of both obstetric procedures during pregnancy and laboratory technology have influenced each other, and that laboratory investigators have constantly pushed clinicians and vice versa.

A few months ago the world’s population reached 6 billion. The news is daunting, given that the figure has doubled since 1960. Yet 6 billion actually represents significant progress made in the past 30 years in reducing birth rates, improving health care and giving women greater access to education and economic opportunities1. How do these new data affect perinatal medicine? Having 300 000 births every day is not the only problem. Indeed, we are witness to dramatic changes in population demographics in the developed world, which have far-reaching consequences for health services. This is not only evident from an increasingly aging population, but also from an increase in the number of women who become pregnant at a more advanced maternal age, many of whom are opting to have a single child.

After three decades of amazing scientific and clinical progress in prenatal medicine, it is clear that most advances have been made, and will continue to be made, using ultrasound and genetic laboratory techniques to complement each other. Indeed, the progress and future development of perinatal medicine depend upon the development of prenatal diagnosis and its integration with fetal therapy and fetal pathology. However, for prenatal diagnosis to be appropriate, of good quality and accurate, detailed knowledge of genetic and acquired fetal disease is necessary2.

Hardly any area in medicine has experienced such dramatic advances during the past three decades as the complex field of prenatal diagnosis. We have learned many lessons and we can foresee new, significant challenges. Some of them are reviewed in this article.

WHAT THREE-DIMENSIONAL AND FOUR-DIMENSIONAL SONOGRAPHY ADD TO PRENATAL DIAGNOSIS

In the past 30 years, two principal tools have dramatically changed the methods of acquiring knowledge of fetal disease: amniocentesis and ultrasonography. The former allows for the cytogenetic, biochemical, molecular and immunological analysis of the fetus. The latter allows for a detailed morphological, functional, behavioral and developmental analysis of the fetus.

The more recent technological breakthroughs in diagnostic ultrasound have surpassed all expectations. With these advances, clinicians now have the tools to contend with many significant diagnostic challenges. At the same time, these new technologies are so numerous, and have been introduced in such rapid succession, that considerable confusion surrounds how these technologies work and how they should best be used in prenatal diagnosis.

Prenatal diagnosis has its roots in the hope and desire to improve perinatal outcomes, to reduce perinatal mortality, to reduce the familial suffering and pain caused by fetal and neonatal death, and to reduce the burden of disease that is inherited or begins in utero. We are aware that there are many more abnormal embryos than fetuses, and many more fetuses than children and adults affected by diseases owing to mutations. It is

Indeed, with the advent and evolution of threedimensional (3D) ultrasound technology during the past 10 years, we now stand at a threshold in non-invasive diagnosis. It is clear that the

CORRESPONDENCE: Professor A. Kurjak, Department of Obstetrics and Gynecology, Medical School University of Zagreb, Sveti Duh Hospital, Sveti Duh 64, 10000 Zagreb, Croatia 195

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Challenges for prenatal diagnosis


progression from two to three dimensions has brought with it a variety of new options for storing and processing image data and displaying anatomical structures. This technology gives ultrasound the multiplanar capabilities that previously were reserved for computed tomography and magnetic resonance imaging. In addition, it can generate surface-rendered and transparent views that provide entirely new diagnostic capabilities. Recent literature in relation to the application of new diagnostic modalities in prenatal diagnosis is reviewed below, but first, a novel, promising assessment of the nasal bones in screening for trisomy 21 is described.

Nasal bone assessment in screening for trisomy 21 It is known that skeletal abnormalities in fetuses with Down’s syndrome include brachycephaly: long bones with reduced growth velocity, hypoplasia of the middle phalanx of the fifth digit and absence of ossification of the nasal bones. Ossification of the nasal bones, which can be detected in normal fetuses from 14 weeks of gestation, was absent in one-quarter of trisomic fetuses, regardless of gestational age3. A postmortem radiographic study of the axial skeleton showed malformation or agenesis of the nasal bones in 19/31 (61%) of trisomy 21 and in 8/10 (80%) of trisomy 18 fetuses4,5. The nasal bones are formed by intramembranous ossification of connective tissue of the nasal capsule. Using transvaginal sonography, its ossification is first visualized at a crown–rump length (CRL) of 42 mm and increases linearly with gestation. Ossification centers appear as increased echogenicity of the bones seen from the first trimester6. The normal range of nasal bone length is 4 mm at 14 weeks to 12 mm at 35 weeks of gestation7. Most importantly, the absence of nasal bone is a factor independent of nuchal translucency (NT) thickness. Therefore, its assessment is additional to the classic NT screening program. A recent study showed that the absent nasal bone likelihood ratio for trisomy 21 was 146, and with present nasal bone this ratio was 0.278. To quote the optimistic statement of Cuckle in a Lancet editorial: ‘It is the time for total shift to firsttrimester screening for Down’s syndrome’9.

Advances in three-dimensional sonography Baba and Satoh were the first to use the surfacerendering techniques of 3D ultrasound for clinical application in obstetrics10. Since then, 3D ultrasound has been shown to be especially useful in the evaluation of fetal anomalies. A recent study 196

Kurjak, Stipoljev and Stanojevic

showed that 3D ultrasound images provide, in 51% of cases, additional information, in 45% of cases they are equivalent to two-dimensional (2D) ultrasound and in 4% of cases are disadvantageous in detecting fetal anomalies11. Although there is still no large randomized study, it is clear that 3D ultrasound is more helpful in evaluating fetuses with facial anomalies12–15, hand and foot abnormalities16–18, and axial spine and neural tube defects.

Facial abnormalities Examination of the fetal face with 2D sonography usually requires a long examination period and an experienced ultrasonographer, because multiple cross-sectional images must be reconstructed in the examiner ’s mind. Moreover, according to the Eurofetus Study, the sensitivity of routine 2D sonography for detecting cleft lips and palates is only 18%19. Therefore, in situations in which facial anomalies are suspected on conventional sonographic examination, the additional use of 3D ultrasonography is recommended20–22. This modality has also been shown to be especially useful in detecting and localizing facial clefting. The images of the face obtained in three dimensions can be displayed in two fashions: multiplanar view and surface-rendered pictures. However, a successfully surface-rendered image is obtained in only about 72% of fetuses scanned between 20 and 35 weeks6. Berge and colleagues found a strong relationship between the types of facial cleft, associated malformations, chromosomal abnormalities and fetal outcome23. In screening for aneuploidies, analysis of the fetal head and face can be useful. Nyberg and associates24 proposed criteria to classify fetal cleft lip and palate based on the degree of lesion. They also correlated each class with outcome and found that unilateral or bilateral cleft lip and palate are associated with an approximate 31% aneuploidy rate. Finally, midline facial clefts are often associated with extremely poor outcome, in contrast to a more favorable result with lateral defects.

Ear abnormalities Since Hall25 reported that dysplastic ears are present in 60% of fetuses with Down’s syndrome, prenatal evaluation of the ear seemed to be useful in screening for aneuploidies. Using 2D ultrasound, only the auricular geometry may be visualized. However, volume images with surface rendering provide more helpful detail of the morphology, and spatial information including lying axis, orientation and cranial location of the fetal ears. By using three-dimensional reconstruction, the examiners are able to diagnose a dysplastic ear by morphology analysis, and also to determine whether the ears are low-set.

The Ultrasound Review of Obstetrics and Gynecology






Recognition of this ear malformation can contribute to diagnoses of aneuploidies.

sonography than with 2D or color Doppler ultrasound.

Central nervous system anomalies

Limb deformities

Three-dimensional ultrasound provided additional information in 92% of extracerebral central nervous system (CNS) anomalies including encephalocele and spinal neural tube defects. Simultaneous display of three orthogonal planes makes the determination of topographic relationships much easier11.

In 63% of fetuses with hand or foot anomalies, 3D ultrasound scans are advantageous when compared with 2D ultrasound images. These include cases of clenched and contracted hands, as well as club and rocker-bottom feet11,18. Therefore, 3D ultrasonography is the method of choice for optimal morphological reconstruction of fetal extremities, including even detailed morphology and fingers and toes. Surface-rendering-mode imaging has been accepted as the best technique for the evaluation of topographic relationships between the segments of each limb and morphology of fingers and toes.

According to the Eurofetus Study, the sensitivity of routine 2D sonography for detecting encephalocele is 85.4%. Despite its relatively high sensitivity, 2D ultrasound is inferior, compared with 3D, in evaluating the lesion, in terms of determining the exact location of the extracranial mass and the amount of extracranial tissue in the encephalocele19. According to the Eurofetus Study, the sensitivity of routine 2D sonography for detecting spina bifida without hydrocephalus is 66.3%. However, the location and extent of a lesion cannot be evaluated accurately with 2D sonography. However, localization of spinal defects can be accurately accomplished by using simultaneous multiplanar imaging19. Axial skeletal anomalies (scoliosis or segmentation defects) are better visualized by 3D than by 2D ultrasound in 56% of cases. These anomalies are displayed better using rotation of volume-rendered images.

This new diagnostic tool has the potential to facilitate the depiction of fetal distal extremities. Budorick and co-workers17 reported that the normal features of distal extremities may be demonstrated more often with 3D than with 2D ultrasound (85% vs. 52%). Three-dimensional ultrasound has a better potential to facilitate depiction of the fetal digits. Ploeckinger-Ulm and colleagues33 reported that the antenatal depiction rate of all fetal digits was higher with 3D than with 2D ultrasound (74.3% vs. 52.9%, p < 0.05). Moreover, distinguishing between the thumb and fingers, counting fingers and clear depiction of overlapping fingers on surface-rendered images can be easier than with 2D ultrasound. Therefore, if there is suspicion on 2D ultrasound of polydactyly or overlapping fingers, 3D ultrasonography should be recommended.

Fetal weight estimation by three-dimensional ultrasound For many years, fetal weight has been assessed by determining the abdominal circumference. Among all the possible sections and parameters of the fetal trunk, the abdominal circumference was chosen because it reflects the changes in liver size that occur early in many fetuses with growth abnormalities. This method does not consider soft tissue thickness, despite evidence that abnormal tissue content may be a reliable indicator of fetal growth aberrations26–28. Catalano and colleagues29 showed that, although neonatal fat mass represents only 14% of birth weight, it explains 46% of its variance. Some authors reported that birth weight estimation based on volumetry of the upper arm30 or thigh31 using new formulae is far more accurate than the classical approach.

Four dimensions: the new diagnostic frontier The latest developments of 3D and fourdimensional (4D) sonography enable the precise study of embryonic and fetal activity and behavior.

Nuchal cord

With 4D ultrasound, movements of the head, body and all four limbs and extremities can be seen simultaneously in three dimensions34. Therefore, the earliest phases of human anatomical and motor development can be visualized and studied simultaneously. It is clear that neurological development in terms of early fetal motor activity and behavior, detailed with 2D real-time ultrasonography35,36, needs to be re-evaluated using this new technique.

Three-dimensional surface imaging did not provide more useful diagnostic information, compared with 2D and color Doppler ultrasound, for detecting nuchal cord in utero32. However, the ability to view the nuchal cord (subjective assessment of the ease of visualization of the nuchal cord) was better with three-dimensional

Recently, our group37 studied the development of the complexity of spontaneous embryonic and fetal movements. With advancing gestational age the movements become more and more complex. The increase in the number of axodendritic and axosomatic synapses between 8 and 10 weeks, and again between 12 and 15 weeks38, correlates with



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periods of fetal movement differentiation and the onset of general movements and complex activity patterns such as swallowing, stretching and yawning, seen easily using the 4D technique. At 7–8 weeks of pregnancy, gross body movements begin, consisting of changing the position of the head towards the body. At 9–10 weeks of pregnancy, limb movements begin, consisting of changing the position of extremities towards the body without extension or flexion in the elbow and knee. At 10–12 weeks of pregnancy, complex limb movements are noted, consisting of changes in the positions of limb segments towards each other, such as extension and flexion in the elbow and knee. At 12–15 weeks of pregnancy, swallowing, stretching and yawning activities become evident. In addition to these activities, it is now feasible to study a full range of facial expressions including smiling, crying and eyelid movement. It is hoped that the 4D technique will help in the better understanding of both somatic and motoric development of the early embryo. It might also help in the more precise study of both fetal and parental behavior34.

ADVANCES IN MOLECULAR GENETICS As a result of the increased knowledge of DNA chemistry, and detailed understanding of the cellular mechanisms controlling genetic material, molecular genetics has evolved as a powerful diagnostic technique. The application of this knowledge to the analysis of human disease is probably the most powerful tool ever used in diagnosis. The localization and characterization of human genes has explained the etiology, pathogenesis and prognosis of a large, growing number of conditions, making their diagnosis and prognosis more accurate and, in some cases, possible for the first time. These advances have greatly improved the possibility of detecting gene mutations, which cause many diseases. Prenatal diagnosis was initially restricted to standard cytogenetic techniques, which allowed only the diagnosis of chromosomal diseases. The introduction of fetal ultrasonography in routine practice increased the number of chromosomal and genetic diseases that can be diagnosed in the embryonal and fetal period39. Specific fetal ultrasound markers for different trisomies are now known40. However, some of the most frequently diagnosed genetic diseases have a higher incidence rate, compared to that of common chromosomal diseases such as trisomy 18 and trisomy 13 (Table 1). The diagnostic frequency of specific anomalies varies primarily depending on the availability of imaging technology and on the skills of the sonographer. Correct prenatal diagnosis is of importance, as accurate genetic counselling is fully 198


Table 1 Diagnostic frequency of some chromosomal and genetic disorders Trisomy 21 Structural aberrations Microdeletion syndromes Cystic fibrosis Werdnig–Hoffman disease Trisomy 13 Myotonic dystrophy Trisomy 18 Phenylketonuria Triploidy

dependent on it. Table 2 lists the specific ultrasonographic findings in some genetic disorders indicating the necessity for further prenatal molecular testing41–50. It is well known that the use of invasive procedures, such as amniocentesis, chorionic villus sampling, fetal biopsies or cordocentesis, carries variable risk of fetal loss. Present trends in prenatal diagnosis include the routine use of biochemical parameters in maternal serum, in combination with ultrasonographic markers, to perform risk screening for fetal aneuploidy. Many of the maternal serum markers have been used as diagnostic markers for non-invasive screening of fetal aneuploidies in low-risk populations. Prenatal biochemical screening for trisomy 21 includes the combination of maternal age with maternal serum α-fetoprotein and free β-human chorionic gonadotropin (β-hCG)51; in addition with unconjugated estriol these markers can detect about 65% of aneuploid pregnancies with a 5% false-positive rate52. The use of increased fetal nuchal thickness in combination with maternal serum pregnancyassociated plasma protein-A (PAPP-A) and free β-hCG has significantly increased the sensitivity of the screening program for trisomy 21 in the first trimester of pregnancy. The detection rate increases to 90%, with a false-positive rate of 5%53. Interphase-fluorescence in situ hybridization (FISH), using amniotic fluid with specific probes for chromosomes 13, 18, 21 and sex chromosomes, should be offered in pregnancies of 20 weeks or greater with abnormal ultrasound findings indicating the presence of trisomy 13, 21 or 18. The use of FISH of interphase and metaphase chromosomes is routinely carried out in prenatal diagnosis of microdeletion syndromes (Prader– Willi, Angelman syndrome, Miller–Dieker, Williams syndrome, Smith–Magenis syndrome). However, women of advanced age have an increased risk of carrying a fetus with a chromosomal aberration, and many are reluctant to be exposed to the risks associated with an invasive prenatal diagnostic procedure. A further concern is the high false-positive rate for the detection of



1 : 800 1 : 1000 1 : 1000–2000 1 : 1600–2500 1 : 6000 1 : 10 000 1 : 8000 1 : 8000 1 : 14 000–20 000 1 : 60 000





Table 2 Specific ultrasonographic findings for some genetic disorders that should indicate further molecular testing Genetic disorder

Ultrasound markers

Prenatal diagnosis

Cystic fibrosis (Muller et al., 199341; Stipoljev et al. 199942) Phenylketonuria (Levy et al., 200143)

hyperechogenic bowel

CA DNA analysis of CFRT gene CA DNA analysis of PAH gene

Werdnig–Hoffman disease (Burglen et al. 199644; Stiller et al., 199945) Myotonic dystrophy (Esplin et al., 199846) Pallister–Killian syndrome (Paladini et al., 200047) Roberts syndrome (Paladini et al., 199648)

Miller–Dieker syndrome (Chitayat et al., 199749) Beckwith–Wiedermann syndrome (Ranzini et al., 199750)

IUGR microcephaly heart defect arthrogryposis heart defect (VSD, ASD) polyhydramnios (AFI > 25) plus abnormal position of extremities diaphragmatic hernia polyhydramnios short femur cleft lip and palate early IUGR heart defect phocomelia (most severe cases) polyhydramnios omphalocele ventriculomegaly omphalocele plus polyhydramnios > 25 weeks’ gestation: polyhydramnios plus accelerated fetal growth

CA DNA analysis of SMN and NAIP genes CA DNA analysis of DMPK gene CA (fibroblasts and fetal blood)

CA (C banding: premature chromosome separation)

CA FISH (17p13) CA FISH (11p15.5)

CA, chromosomal analysis; CFRT, cystic fibrosis; IUGR, intrauterine growth restriction; PAH, phenylalanine hydroxylase; VSD, ventricular septal defect; ASD, atrial septal defect; SMN, survival motor neuron; NAIP, neuronal apoptosis inhibiting protein; AFI, amniotic fluid index; DMPK, dystrophia myotonica protein kinase; FISH, fluorescence in situ hybridization

Fetal cells found in maternal blood include erythrocytes, trophoblasts, lymphocytes and granulocytes, with their estimated number ranging from 1/100 000 000 to 1/2765. False-positive results in relation to a Y-specific signal are caused by previous pregnancy with a male fetus; the life span of fetal lymphocytes is more than 2 years in the maternal circulation. This problem could be overcome by using fetal cells with a short life span. Separation procedures include double-density gradient centrifugation, and flow or magnetic sorting of fetal cells. Methods of nucleated red blood cell (NRBC) recognition based on immunocytochemical staining for fetal hemoglobin combined with the FISH technique using chromosome-specific probes have also been described66. Several factors influence an increased number of fetal aneuploid cells in the maternal circulation, including altered hematopoiesis in the early trisomic embryo, disturbed placental function owing to disrupted chorionic villi and prolonged survival of aneuploid NRBCs.

fetal aneuploidies associated with current noninvasive methods. Because amniocentesis or chorionic villus sampling, even when performed by experienced operators using ultrasound guidance, still contain an appreciable risk of complications including fetal loss, there is strong motivation to improve the screening tests for aneuploidies, so that the ultrasound-guided procedures can be offered based on a much more sophisticated risk analysis than just looking at maternal age or ultrasound and biochemical screen markers. This is where the fetal cell isolation efforts and the ultrasound screening programs meet as complementary, not necessarily alternative, methods54–64. Recent advances in prenatal diagnosis have been based on the development of reliable non-invasive methods. Prenatal detection of both chromosomal and genetic disorders has been successfully performed using fetal cells from the maternal circulation. Basel laboratory is a leading pioneer in the enrichment of fetal cells from maternal blood, with the aim of developing a non-invasive, riskfree form of prenatal diagnosis. By using the (then) novel method of magnetic activated cell sorting (MACS), they were among the first to detect fetal aneuploidies55,58,59,61,63,64.

The introduction of new techniques in molecular cytogenetics, especially FISH that identifies specific DNA sequences labelled by fluorescentlabelled probes, and the polymerase chain reaction (PCR) that amplifies a particular gene region, The Ultrasound Review of Obstetrics and Gynecology


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enables us to penetrate the pathogenesis of an investigated genetic disorder67. Many in the field are confident that we are indeed approaching that elusive goal of being able to perform an accurate prenatal diagnosis using non-invasive techniques, such as the enrichment of fetal cells from the blood of a pregnant woman, or the analysis of circulatory fetal DNA in maternal plasma.

FETAL ECHOCARDIOGRAPHY: THE PAST IS PREDICTING THE FUTURE Fetal cardiology gained a tremendous advantage from 2D ultrasonography for postnatal diagnostics and treatment of congenital cardiac defects. About 20 years ago, the significance of prenatal diagnosis of a congenital heart defect (CHD) was considered very important for the prognosis of the fetus, and the outcome of pregnancy, possibility of postnatal correction or life-saving intervention, and prediction of life quality of the newborn and the family. When introduced, 3D and 4D echocardiography was a new and exciting possibility in fetal cardiology. Medications for rhythm disturbances of the fetal heart have been used successfully for many years. Prenatal interventions, very rarely performed on a fetal heart, are becoming more available with the development of new non-surgical methods of cardiac defect repair. What direction will the development of fetal cardiology take? If the diagnosis of CHD is shifted towards earlier gestation, this will result in an increase in the rate of terminations of pregnancy. In those who survive, prenatal interventions will be possible in some cases, while in others prognoses will be improved by early life-saving postnatal intervention in cardiac tertiary centers.

Development of fetal echocardiography In the 1980s, it was revealed that fetal echocardiography could correctly predict structural malformations of the heart, and it was concluded that the technique was sufficiently reliable to give an accurate prognosis in early pregnancy and provide the basis for alterations in obstetric management68. In a series of 1600 pregnancies, 34 cases of CHD were correctly identified by fetal echocardiography, with confirmation of the diagnosis by anatomical study. It was a great success in that 14 pregnancies were terminated electively. Twenty fetuses died subsequently, owing either to the complexity of the congenital heart disease or to associated extracardiac abnormalities. Eight errors were reported in interpretation of the fetal echocardiogram. There were no reports concerning prenatal intervention with regard to the fetal heart at that time. In another study, the authors reported their experience with fetal CHD since 1980, diagnosing the condition in 200


1006 fetuses69. Chromosomal anomalies were more frequent in fetuses with CHD than in live births. The survival rate after diagnosis was poor because of frequent parental choice to interrupt pregnancy, and the complexity of the disease. Much experience with fetal CHD allows good diagnostic accuracy, based on postnatal and pathological evaluation of the prenatal findings. Knowledge of the natural history of heart malformations and their treatment allows accurate counselling of parents. Parental decisions in the above investigation shifted towards termination of pregnancy, meaning that a smaller number of infants and children with complex cardiac malformations would present in postnatal life69. In another study, 1589 infants with CHD were identified in a well-defined population70. The live-birth prevalence of CHD was 8.1/1000, of which only 6.1% were diagnosed prenatally. The percentage of prenatally diagnosed CHD increased from 2.6 to 12.7% using echocardiography, and detection was lowest for atrial septal defect (4.7%) and highest for hypoplastic left heart syndrome (HLHS) (28%). Prenatally diagnosed CHD was associated with a high incidence of infant mortality (30.9%) and fetal wastage (17.5%). Fetal echocardiography has been used increasingly in the prenatal diagnosis of congenital cardiac malformation, and the above study indicated that survival of infants was not improved after prenatal diagnosis with fetal echocardiography70. There is some discussion concerning the responsibility for prenatal screening of CHD: is the pediatric cardiologist or the gynecologist responsible for the screening71–73? There is a large discrepancy in the study results of second-trimester ultrasound screening for fetal malformations, owing to a varying level of experience of the examiners. The reported detection rates of fetal CHD were 0–60%71. Various screening concepts for more effective detection of CHD are available, and the most recent technique of early echocardiography between 13 and 15 weeks of gestation was considered very useful, owing to easier termination of pregnancy if necessary. It is the opinion of our group that the gynecologist is responsible for screening of CHD, and, if CHD is suspected, then the pediatric cardiologist should examine the patient and confirm or make the diagnosis74–77. The gynecologist, pediatric cardiologist, geneticist, psychologist and social-worker should be involved in counselling.

Outcome after prenatal diagnosis of fetal cardiac lesion The prenatal diagnosis of structural CHD is associated with a poor prognosis74. A high mortality rate of 79% has been reported in the study of 222 fetuses, infants and children in whom prenatal diagnosis of CHD was made. Prenatal death







selection of severe cases and technical problems during the procedure84.

occurred in 57 fetuses, 87 died as neonates and 31 died in infancy and childhood. Among 47 survivors only five have survived beyond 4 years. High mortality was associated with the presence of extracardiac anomalies in 32% and prenatal cardiac failure in 13%74. Fetal echocardiography has been a useful tool for prenatal detection of CHD and other heart lesions, and in some cases for the treatment of fetal arrhythmias78. As most forms of heart disease occur in otherwise normal pregnancies with no high-risk features, detection of these cases is dependent on the skill of the ultrasonographer performing general obstetric scanning78. Detection of even major malformations seen in the four-chamber view is still less than perfect78,79. It is expected that CHD will be detected earlier in pregnancy, and that examination will include evaluation of the great artery structure79. There is now evidence that prenatal diagnosis of CHD improves perinatal morbidity or mortality80. New information about the molecular genetic basis of CHD will help in management and counselling. If extracardiac malformations are excluded, then in utero therapy should be considered for some malformations80. It has been available for fetal arrhythmias, fetal heart failure and in some cases for a very few structural CHDs81.

Future of fetal echocardiography: reality or illusion Are improvements in the field of fetal echocardiography possible? The answer should be affirmative, because in the past two decades there have been so many new facts concerning the pathophysiology and management of cardiac diseases. The shift from prenatal diagnosis of structural cardiac anomalies and rhythm disturbances towards fetal cardiac flow dynamics has been possible because of the development of sophisticated ultrasound techniques used by skilled professionals85,86. Improvements from the point of view of public health can be achieved if better screening protocols are set up and widely performed by more skilled professionals at earlier gestational ages87. After the diagnosis of CHD, appropriate multidisciplinary counselling should be offered, and effective treatment developed. Genetic counselling and gene treatment in some CHD cases may be the future challenge of fetal cardiology88. The past, that is the first prenatal diagnoses of CHD, was a glimpse into the future: dynamic growth of the challenging field of fetal cardiology, with a promising perspective.

The outcome after prenatal diagnosis of HLHS in 30 fetuses was as follows. Four of 12 mothers whose fetuses were diagnosed before 24 weeks of gestation chose to terminate the pregnancy82. Intention to treat was present in 24 mothers of the remaining fetuses, of whom five were not offered the Norwood stage 1 procedure because of trisomy 18, unfavorable cardiac anatomy or neurological impairment. Of the 19 patients who were selected for the operation, nine survived, which means that the survival rate was 37.5% from an intentionto-treat position. It was concluded that survival rate of the patient with HLHS is poor and discouraging82.

CONCLUSION Recent advances in prenatal diagnosis have opened many medical, moral, ethical and legal questions that should be addressed and answered appropriately to allow and support the further development of these diagnostic tools. It is clear that new developments will be necessary to meet so many challenges, in particular the process of developing novel, accurate, risk-free prenatal diagnostic techniques using fetal cells isolated from the maternal circulation, or the more recent development of examining cell-free fetal DNA in maternal plasma or serum by PCR.

Survival after fetal aortic balloon valvuloplasty has been reported, and seemed a very encouraging approach to the treatment of fetal CHD83. Discouraging world experience of percutaneous ultrasound-guided balloon valvuloplasty in human fetuses with severe aortic valve obstruction was reported in 12 fetuses between 27 and 33 weeks of gestation84. The range between initial presentation and intervention was 3 days to 9 weeks. Technically successful balloon valvuloplasties were achieved in seven fetuses, none of whom had atretic valve. Only one of these seven fetuses survived, while the remaining six died postnatally owing to cardiac dysfunction, or at surgery in the early postnatal period. The conclusion was that the experience with fetal ultrasound-guided balloon valvuloplasty has been poor as a result of

As a possible new addition to screening, ultrasound investigations would be coupled with looking at the fetal cells or free DNA as predictors for fetal aneuploidies, prematurity and pre-eclampsia. Mankind should use the same creativity and serendipity that has allowed the gathering of amazing knowledge on the human genome to develop the medical, social, ethical, moral and political strategies for the acceptable application of this technology for the benefit of humanity. Undoubtedly, the most important aspect of these efforts is the need for properly trained individuals to use this amazingly powerful technology appropriately. This is exactly what the present issue of our journal is about.



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