Abstract
The Second Philadelphia Conference on Prenatal Diagnosis Update was held on 4 June 2010. This meeting had a larger registration than expected and was larger than the year before, with over 300 attending, including physicians, genetic counselors, nurses, midwives, sonographers and other healthcare professionals. The presentations of the meeting encompassed topics in the field of prenatal diagnosis, the current standards of prenatal diagnosis practice, innovations and new discoveries in the field, and their future implications for clinical practice. We also focused on the role of ultrasound in prenatal diagnosis, and had a full-day course on fetal echocardiography. During the conference, we had sessions that were dedicated to genetic disorders that could be diagnosed prenatally (22q11.2 deletion), in addition to genetic disorders that have an impact on the pregnant mother and her fetus (e.g., thrombophilia). As in our previous conference, we had a reproductive endocrine lecture. This year topics included IVF and congenital anomalies, the teratogenic and implications of fetal exposure to psychotropic medications used in pregnancy. Array comparative genomic hybridization in prenatal diagnosis was presented as part of reviewing current and cutting-edge methods that improve detection of fetal abnormalities. The fetal heart/fetal echocardiography course and the role of ultrasound in prenatal diagnosis were presented by national and international leaders in the field of prenatal fetal heart sonography.
A total of 18 sponsors with a sincere interest, not only in promoting their product, but also in promoting education, participated with impressive displays and are listed in the Acknowledgements of this article. The program was planned and led by Ossie Geifman-Holtzman (Drexel University, PA, USA), Course Director, and the excellent scientific committee members who included Laird Jackson (Drexel University College of Medicine, PA, USA), Deborah Driscoll (University of Pennsylvania Health System, PA, USA), Adele Schneider (Albert Einstein Medical Center, PA, USA) and Stuart Weiner (Thomas Jefferson University Hospital, PA, USA), registered nurse Cheryl Selden Klein (Temple University Hospital, PA, USA) and certified genetic counselors Amanda Carré (Drexel College of Medicine, PA, USA), Janet Berman (Temple University School of Medicine, PA, USA) and Elena Ashkinadze (University of Medicine and Dentistry of New Jersey – Robert Wood Johnson Medical School, NJ, USA).
The meeting began with a greeting and welcome speech by Owen Montgomery, Chairman of the Department of Obstetrics and Gynecology at Drexel College of Medicine, who hosted and sponsored the meeting.
The conference’s first session was dedicated to chromosome 22q11.2 deletion syndrome (22q11.2DS) and its implications for prenatal diagnosis testing and counseling. This session was a tribute to Angelo DiGeorge, who passed away earlier this year. The session was presented by a distinguished team from the University of Pennsylvania Health System and was led by Driscoll, who acted as moderator. The session began with an excellent presentation by Beverly S Emanuel, Chief of the Division of Human Genetics and Molecular Biology at the Children’s Hospital of Philadelphia (PA, USA) and the University of Pennsylvania (PA, USA), and was followed by a presentation by Elaine H Zackai (Director of Clinical Genetics at the Children’s Hospital of Philadelphia and the University of Pennsylvania) and by the certified genetic counselor Donna M McDonald-McGinn (The Children’s Hospital of Philadelphia, PA, USA). The following is a summary of the presentation: 22q11.2DS is considered a genomic disorder. In general, the clinical features are believed to reflect changes in normal copy number or dosage of the genes contained within the genomic interval deleted, one or more of which contribute to the resulting phenotype. Technological improvements, coupled with higher quality sequence and better annotation, have revealed a number of underlying mechanistic etiologies for genomic disorders. Several chromosomal regions, including 22q11, are characterized by the presence of chromosome-specific, low-copy repeats (LCRs) or segmental duplications. Many of these LCRs flank the genomic regions associated with known human deletion and duplication syndromes, and have been regarded as part of the underlying basis for genomic disorders. Segmental duplications share a high level of sequence identity, predisposing the regions they occupy to nonallelic homologous recombination. Segmental duplications appear to allow for mispairing and unequal crossing over between homologous chromosomes. There is significant evidence that such a mechanism is responsible for the 22q11.2 deletion. The 22q11 deletion interval contains at least four large blocks of duplicated DNA sequence, which appear to coincide with the common recurrent deletion end points.
The diagnostic procedure most often used for detection of deletions and duplications at 22q11.2 is chromosomal analysis coupled with FISH using commercially available probes located between LCRs A and B. Recently, we as well as others have shown that the 22q11.2DS multiplex ligation-dependent probe amplification (MLPA) kit (MRC-Holland, Amsterdam, The Netherlands) is a cost effective, rapid and sensitive method for the detection of the typical recurrent deletions and duplications in proximal 22q11 extending to LCR-D. Since copy-number changes at 22q11.2 have been identified that would not have been detected by the current commercially available diagnostic FISH probes, MLPA has become an important adjunct to testing for the deletion. The detection and analysis of these genomic copy-number alterations at 22q11.2 is significant because, to date, little information is available with regard to their prevalence and whether there are consistently associated phenotypic differences. Indeed, identification of these variant cases is of particular interest since it may provide insight into which genes or genomic regions are crucial for specific phenotypic manifestations and are likely to assist in the quest to determine deletion and duplication mechanisms.
Several oligonucleotide-based platforms, including oligonucleotide arrays, have recently been used and they provide proof of principle that the technology can be successfully applied for detection of the hemizygous loss of DNA in the 22q11.2DS. It is clear that the newer higher resolution techniques such as MLPA, bacterial artificial chromosome or oligonucleotide-based microarrays are now capable of providing more sensitive and rapid deletion breakpoint localization without the need for reiterative FISH or PCR-based experiments. Application of these techniques has permitted the identification of numerous distal deletions and interstitial duplications, and has facilitated identification of breakpoint differences in several proximal 22q11.2 deletions as well. The application of these techniques to prenatal diagnosis will certainly be rapidly increasing in the near future.
This session continued with Elizabeth Goldmuntz (University of Pennsylvania) who presented ‘The 22q11.2 Deletion Syndrome and the Heart’. Goldmuntz described that the 22q11.2 syndrome is characterized, in part, by congenital heart defects, particularly conotruncal defects. Approximately 75% of patients with a 22q11.2 deletion have a cardiovascular anomaly. The most common defects include: tetralogy of Fallot, interrupted aortic arch, truncus arteriosus, conoventricular ventricular septal defect and isolated aortic arch anomalies. Studies show that 22q11.2-deleted patients with a cardiac defect commonly have a concurrent aortic arch anomaly, which may cause a vascular ring. Therefore, careful attention must be paid not only to the intracardiac but also to the aortic arch anatomy. Although the aforementioned subset of lesions is the most commonly seen in this disorder, a wide variety of congenital heart defects have been reported in patients with a 22q11.2 deletion. Of note, certain types of conotruncal defects are very rarely seen in association with the deletion syndrome, including dextro-transposition of the great arteries and double outlet right ventricle.
For prenatal counseling purposes, it is important to know the frequency with which a patient with a cardiac defect has a 22q11.2 deletion. Studies demonstrate that a 22q11.2 deletion is relatively commonly detected in patients diagnosed with one of the associated congenital heart defects including tetralogy of Fallot (8–35%), interrupted aortic arch (50–75%), truncus arteriosus (35%), conoventricular ventricular septal defects (10%) and isolated aortic arch anomalies (24%). The presence of an aortic arch anomaly in conjunction with an intracardiac anomaly significantly increases the likelihood of detecting a 22q11.2 deletion in that patient. For example, although 45% of patients with a conoventricular ventricular septal defect and aortic arch anomaly had a 22q11.2 deletion, only 3% with a conoventricular ventricular septal defect and normal aortic arch anatomy (i.e., left-sided aortic arch with a right-sided innominate artery and normal branching pattern) had a 22q11.2 deletion. The same trend holds true for patients with tetralogy of Fallot, where those with a concurrent aortic arch anomaly will much more commonly have a 22q11.2 deletion than those with completely normal aortic arch anatomy. Likewise, Goldmuntz found that nearly 30% of children diagnosed after the age of 6 months with a 22q11.2 deletion who had no apparent heart defect were nonetheless found to have aortic arch anomalies upon detailed imaging, of which one-third formed vascular rings. These findings highlight the importance of detailing the aortic arch anatomy in all patients diagnosed with a 22q11.2 deletion. These findings also highlight the importance of considering testing for a 22q11.2 deletion in any fetus with one of the five cardiac defects (listed earlier) most commonly associated with the 22q11.2 deletion syndrome. The reasons to identify the deletion-bearing patient include anticipatory guidance for the parents regarding the deletion syndrome, early intervention for the newborn and child for noncardiac features, and detection of affected parents. In addition, studies suggest potentially different surgical outcomes for some cardiac patients with a 22q11.2 deletion, such that specific counseling may also be warranted.
The morning session continued with a presentation by Ron Wapner, Professor and Director of Research from the Department of Obstetrics and Gynecology at Columbia University (NY, USA). Wapner discussed current trends in invasive prenatal diagnosis. If prenatal screening is to successfully transition to the first trimester, the invasive testing approach must be as safe and reliable as that used in the second trimester. Amniocentesis has been the gold standard of second-trimester testing. Its complications, risks and safety have been well evaluated, and its use accepted by practitioners and patients. Under 14 weeks gestation chorionic villus sampling is the procedure of choice.
Chorionic villus sampling has been available as a first-trimester diagnostic procedure since the early 1980s, but its acceptance as a replacement for amniocentesis has been slow. Concerns regarding the risks of maternal cell contamination, confined placental mosaicism, pregnancy loss rates and fetal limb-reduction defects all needed to be addressed before the acceptance of chorionic villus sampling as an alternative to amniocentesis could occur. In skilled operator, Wapner data suggested almost equal risks for both procedures.
The following presentation took us to the prepregnancy period and the association between IVF and assisted reproductive technology. This excellent presentation was given by David L Keefe (Department of Obstetrics and Gynecology at the New York University School of Medicine, NY, USA) and Stanley H Kaplan (Professor and Chair, Department of Obstetrics and Gynecology, NYU Langone Medical Center, New York University Fertility Center, NY, USA). Keefe presented that over 1 million babies have been born from IVF worldwide. This represents approximately 1% of all babies born in the USA and 2–3% of babies born in France and Israel. IVF typically involves controlled ovarian stimulation, transvaginal oocyte retrieval, IVF, culture and transcervical uterine transfer of resulting embryos. Theoretically, each of these steps could contribute to birth defects. IVF is successful in 5–50% of attempts, depending on the woman’s age, BMI and smoking history. Women conceiving through IVF tend to have higher rates of congenital anomalies by virtue of who they are and the kind of births they have. They tend be older – 50% are over age 35 years, and 30% of IVF births are twins or triplets. Both advanced maternal age and multiple gestations are known to predispose to congenital anomalies, and therefore provide confounders for the analysis of the effects of IVF on congenital anomalies. Complications of advanced maternal age and multiparity include low birthweight, prematurity, pregnancy-induced hypertension and congenital anomalies. In addition to the increased rate of dizygotic twins, IVF pregnancies have a three- to fivefold increased rate of monozygotic twins, which further increases the risk of birth defects. In addition, many IVF cycles are performed for male-factor infertility, and some male-factor infertility derives from paternal sex chromosome abnormalities, which are transmissible to male offspring. Increased rates of imprinting abnormalities in offspring have also been associated with IVF as well as with infertility.
Whether IVF itself produces increased rates of birth defects remains controversial. Some studies suggest no increase in rates of major and minor birth defects after IVF compared with the general population. Other studies suggest that IVF births do exhibit increased rates of birth defects, even after controlling for advanced age and multiparity. A registry of births, IVF births and major birth defects in Western Australia showed increased major birth defects and chromosomal and musculoskeletal defects even after adjusting for advanced maternal age, parity and the sex of the infant (odds ratio [OR]: 2.0; range: 1.3–3.2; 9.0% IVF vs 4.2% controls). Most over-represented were neural tube defects, omphalocele, alimentary atresia and hypospadias. There was no difference in congenital anomalies between IVF and intracytoplasmic sperm injection. Keefe presented a study of registries of births, IVF births and major birth defects in Israel during two periods, 1986–1994 and 1996–2002. After adjusting for maternal age, parity and sex of the infant they found an increased rate of birth defects among IVF babies (OR: 2.3 and 1.75; 9.0% IVF vs 4.05% controls) with no difference between IVF and intracytoplasmic sperm injection. Cardiac defects were the most common (29.2% of the total).
Interpretation of this data is complicated by the low rate of birth defects overall, which requires large sample sizes to provide adequate power to detect significant effects. Moreover, the retrospective nature of epidemiological studies makes it difficult to discern whether birth defects result from the IVF procedure itself, or from the effects of whatever pathological processes underlie infertility. Indeed, the rate of congenital anomalies in the offspring of infertile couples who conceive spontaneously is also increased, suggesting that untreated infertility is associated with birth defects. Since most infertility is idiopathic, common mechanisms could underlie both infertility and birth defects. The answer to the question of whether IVF itself actually causes birth defects will only be answered definitively by a randomized clinical trial.
The conference continued with the presentation of David Ledbetter (Robert W Woodruff Professor of Human Genetics, Emory University, GA, USA), who discussed commercial interests versus public good in genetic testing and prenatal diagnosis. In this presentation, he pointed out that many human genes have been patented, not just by private companies, but also by many academic institutions. Each institution, and the individual investigators involved in the gene discovery and commercialization process, have a choice of licensing the technology (gene patent) on a nonexclusive or exclusive basis. The latter creates a genetic test monopoly, which may limit access to the genetic test if the monopoly laboratory does not accept particular state Medicaid or private insurance, and does not provide maximum incentive for technology improvement or cost reduction. He made a plea to all investigators and institutions involved in gene discovery to consider nonexclusive licensing of their technology (patent) to maximize access and quality of genetic testing.
Following the plenary session, the conference continued with two breakout sessions – one on prenatal genetics and the other on prenatal ultrasound. In the genetics session, Ledbetter was the first presenter on comparative genomic hybridization array cutting-edge molecular testing and its implications in prenatal diagnosis. This topic was discussed in our prior conference by Jackson – both agreed about the importance and cautious investigation of this method before its use in clinical care. One of the most popular methods is microarrays that quantitatively compare normal genomic DNA to that of a patient. This can be done by direct comparison of an unknown DNA sample to a standard DNA or to a standard contained within the computer software that ‘reads’ and interprets the array. Arrays are constructed of printed sets of short DNA sequences (targets) from 45 to 65 oligonucleotide lengths to smaller single-nucleotide-polymorphism lengths of 20–25 nucleotides. Up to 4 million or more such targets can be printed and subsequently ‘interrogated’ by allowing controlled hybridization of the fragmented DNA sample under study. The readout or report from the array will detect any absence of hybridization or overhybridization by the unknown to any target, thus detecting imbalances such as deletions or duplications. By sensing several contiguous or near-contiguous targets thus involved, one can determine a shorter or longer length of imbalance. Postnatal application of the technology is advancing rapidly but prenatal application requires caution as the technique is capable of finding small imbalances whose clinical significance is not yet clear. Thus, a clinical trial of the prenatal diagnostic application of microarray cytogenetics in direct comparison with standard cytogenetics, is currently in progress, supported by the National Institute of Child Health and Human Development (MD, USA). Concordance between the two techniques for those abnormalities capable of microscopic detection has been complete thus far, indicating that the new technology can replace the old without loss of sensitivity. A greater incidence of submicroscopic imbalances, not seen by conventional cytogenetics, has been found in the early stage of the trial than was anticipated. Completion of the trial is expected within 2–2.5 years and should lead to the clinical use of new prenatal diagnostic methods.
From prenatal diagnosis, the topic moved on to medication use in pregnancy. C Neill Epperson, Associate Professor and Director of the Penn Center for Women’s Behavioral Wellness from the Departments of Psychiatry and Obstetrics and Gynecology at the University of Pennsylvania School of Medicine (PA, USA) presented this topic and discussed that mood and anxiety disorders are extremely common in women during the childbearing years. Thus, clinicians are likely to encounter women who are taking psychotropic medications for the treatment of disorders such as major depression, dysthymia, panic disorder, generalized anxiety disorder, post-traumatic stress disorder, obsessive–compulsive disorder and bipolar affective disorder. Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacologic therapy for many of these disorders. SSRIs are generally safe with respect to first-trimester use as they have minimal-to-low teratogenic potential. The SSRI paroxetine has been linked in some studies with cardiac septal anomalies and is therefore avoided in the first trimester when possible. Up to one-third of newborns exposed to SSRIs at the time of delivery are likely to have minor symptoms of neonatal adjustment syndrome. These symptoms (jitteriness, irritability, mild respiratory distress, difficulty feeding and hypo- or hypertonia) are time limited and not life threatening. Persistent pulmonary hypertension of the newborn has also been linked with second- and third-trimester SSRI use, but the connection remains tentative and is thought to be a rare event in this population. Women with depression and anxiety, whether taking SSRIs or not, may have earlier births. Research is needed to confirm the link between SSRI use and preterm birth. Limited studies suggest that infants exposed to SSRIs during pregnancy have normal cognitive development as toddlers and young school-aged children. A recent consensus statement from perinatal mental health specialists recommends SSRI treatment for women with moderate-to-severe and/or chronic/recurrent depression during pregnancy. A trial of psychotherapy is recommended for women with milder depression. Medications such as benzodiazepines and some mood stabilizers (lithium and lamotrigine) are frequently used in pregnant and postpartum women and appear to have a favorable benefit-to-risk profile for women who cannot remain stable without these medications. However, knowledge regarding their potential for adverse long-term neurodevelopmental sequelae is woefully inadequate. Clinicians working with pregnant women who may require psychotropic medications during gestation are encouraged to refer their patients to a psychopharmacologist with expertise in perinatal mental health.
This session ended with a detailed lecture from James Airoldi (Director of Obstetrics, Director of Perinatal Research, St Luke’s Hospital and Health Network, PA, USA), who gave an excellent and detailed presentation on thrombophilia and its genetic and clinical implications. Thrombophilia can be classified as acquired, such as the antiphospholipid antibody syndrome, or genetic, which includes hereditary conditions such as Factor V Leiden or the prothrombin gene mutation. The incidence of all thromboembolic events averages approximately 1.3 out of 1000 pregnancies. A total of 50% of women who have thrombotic events during pregnancy possess an underlying congenital or acquired thrombophilia. In 50% of patients with a hereditary thrombophilia, the initial thrombotic event occurs in the presence of an additional risk factor, and thus thrombophilia is not the only factor that should be taken into account when assessing a patient’s risk for thrombosis. Other risk factors include obesity, immobilization, recent surgery, a personal history of thrombosis or a family history of a first-degree relative with an episode of venous thromboembolism diagnosed at under 50 years of age.
The prior theory that placental thrombosis was a cause of adverse pregnancy outcomes in women with thrombophilia seems less likely. The most common genetic thrombophilias include Factor V Leiden, prothrombin gene mutation, antithrombin III, protein C, protein S and homocysteine. Generally, they can be divided into low- and high-risk proteins. The high-risk group includes antithrombin III, homozygotes for prothrombin gene and Factor V Leiden, double heterozygotes or patients who have multiple thrombophilias. The association between venous thromboembolism and thrombophilia appears strong, as was demonstrated in a few studies that Airoldi presented.
The association between genetic thrombophilias and adverse pregnancy outcomes is controversial. There is only one randomized controlled trial that showed that women with a prior unexplained pregnancy loss after the 10th week in women who received heparin had a higher live birthweight than women receiving low-dose aspirin alone. Screening for thrombophilia is controversial and should be performed if positive results would change the management. It is clear that universal screening should not be performed. Airoldi suggested that high-quality randomized controlled trials are desperately needed in this area to better counsel our patients.
While genetics were the focus of one breakout session, ultrasound in prenatal diagnosis was the focus of the second breakout session. This session began with a well-known expert on ultrasound, Ilan Timor-Tritsch (Professor in the Ultrasound Unit from the Department of Obstetrics and Gynecology, NYU School of Medicine, NY, USA) who presented ‘Ultrasound Scan of the Fetal Anatomy – Fetal Structural and Anomaly Detection at 9–16 Weeks’. Advances in transducer technology and a broader understanding of fetal anatomy led to the realistic possibility of considering early fetal anatomy scans between 9 and 16 weeks. Such early scans can even be ‘piggybacked’ to the first-trimester screening (nuchal translucency plus biochemistry). In this lecture, a pictorial testimony to this fact was presented through 18 postmenstrual weeks fetal scan. Most of these early scans can and should be performed using a transvaginal ultrasound probe. In the second part of the presentation, a selected number of early-detected fetal anomalies were shown. Anomalies of each system or body part were represented with the adequate explanation of their salient and characteristic features. In spite of the fact that such early and routine anatomy scans are not yet the ‘gold standard’ or standard of care in the USA, they are used in many countries. Before such early anatomy scans are introduced in the USA, one can use it in cases of suspected anomalies or in special high-risk cases.
This was followed by informative and entertaining presentations by Israeli ultrasound expert Israel Shapiro (Unit of Ultrasound in Obstetrics/Gynecology Bnai-Zion Medical Center, Technion, Faculty of Medicine, Haifa, Israel), who presented on ‘Pitfalls and Artifacts in 3D Ultrasound’. Shapiro discussed the popularity of 3D ultrasound, not only because of its prenatal diagnostic importance but also because of its added value as an entertaining modality to view the fetus in 3D. However, the examiner may be misled by pitfalls and artifacts; some are derived from those of 2D ultrasound and some others unique to 3D technique.
Some pitfalls and artifacts seen in 3D ultrasound are ‘imported’ from the 2D ultrasound. This category includes acoustic shadowing, acoustic enhancement and enhanced echoes from surfaces perpendicular to the beam. These artifacts may be more misleading in 3D than in 2D ultrasound since the cause of the artifact seen in the 2D image is usually not seen in the 3D image. A common example is a bone causing an acoustic shadow that may hide a deeper structure, that is, a segment of a limb or portion of the upper lip. In 2D ultrasound, both the origin of the shadow and the missing part are seen on one plane. In addition, the extension of the shadow may be seen as deep as the furthest point in the image. Thus, one can easily interpret the missing part as caused by the shadow. However, the 3D rendered image may be presented without linkage to the original plane and thus does not include the source of the shadow. Furthermore, the source of the shadow (i.e., a hand) may be missing because it was deliberately cut away in order not to hide the deeper structures. Pitfalls and artifacts that are unique to the 3D technique include motion artifacts, superposition of objects located in various depths, sealing of small gaps by interpolation and ‘amputation’ of organs that were located out of the sampled volume. In most cases, 2D ultrasound, if used, could have provided the clue.
3D ultrasound should be used cautiously and the examiner should be aware of potential pitfalls and artifacts that may lead to erroneous results. 2D ultrasound should be used for investigating each abnormal 3D finding.
This breakout session ended with a presentation by the session moderator, Weiner, on the clinical application of obstetric Doppler sonography. After a brief review of Doppler physics, the application of duplex and color Doppler to measure impedance in the umbilical artery and middle cerebral artery was described in the detection of fetal hypoxia to guide management of fetal growth restriction, especially directing antepartum fetal surveillance and delivery timing. With further placental insufficiency, the progression of fetal hypoxia to acidosis and ultimately myocardial failure can be detected with a combination of the biophysical profile and Doppler investigation of the ductus venosus, offering further information to guide management in severe growth restriction, especially when this occurs remote from term.
Shapiro also the final talk; a key note presentation on ‘Three-dimensional ultrasound: is it gimmick or breakthrough?’ Shapiro commented that, although it spread quickly among the ultrasound community, 3D ultrasound is still considered by many to be a gimmick. This issue is frequently raised, not only by the patient but also by the obstetrics/gynecology personnel. During the last 10 years that we have been involved in the use of 3D ultrasound and the development of 3D ultrasound machines, we have experienced many cases where 3D ultrasound played an important role and sometimes was the only clue that led to the diagnosis:
• Early detection of major limb anomalies: during the first trimester (particularly 8–11 weeks), most examiners do not look for more than a heartbeat and crown–rump length measurements. Major limb anomalies will usually be missed using 2D ultrasound, unless properly searched for. However, with a short 3D scan such anomalies are readily demonstrated;
• Diagnosis of skeletal dysplasia: 2D ultrasound is successfully used for measuring bone length but has a limited value in demonstrating the shape of the long bones. This is because, even in the single plane inherent in 2D, only a small portion of the real slice is shown owing to bone acoustic shadowing. There is little information regarding the shape of the bone, which is sometimes the clue for the definition of the specific type of skeletal dysplasia. X-ray is considered the gold standard in this matter but fetal bone demonstration in this modality is quite vague and not possible at all before 20 weeks of gestation. 3D ultrasound is able to demonstrate the bone shape since it can show the bone surface. The fetal skeleton can be elegantly demonstrated as early as the first trimester. Thus, it is superior to 2D ultrasound and x-ray for the correct diagnosis of bone dysplasia;
• Cranial sutures: since the cranial sutures and fontanels are not located on a single plane, the diagnosis of craniosynostosis is not an easy task with 2D ultrasound. 3D ultrasound is an excellent tool for this purpose as early as the first trimester;
• Finger anomalies: in the first half of the pregnancy the fingers are extended most of the time and 2D ultrasound is usually sufficient, but later on the fingers are usually flexed. 3D ultrasound is able to show finger anatomy regardless of finger position. 4D is especially convenient in demonstrating syndactyly, usually evident only with extended fingers, or in ruling out clenched hand. Another advantage is gained when the hand is not surrounded by fluid, where conventional ultrasound has a limited value in demonstrating fingers. 3D ultrasound with x-ray mode eliminates the soft tissues and overcomes this problem;
• Inaccessible planes: multiplanar technique enables the reconstruction of 2D images in orientations that cannot be gained otherwise (i.e., demonstration of corpus callosum and uterine anomalies);
• Minor facial dysmorphism: 3D ultrasound is by far superior at demonstrating minor facial features that may lead to the detection of fetal syndromes. It also enables 3D demonstration of structures not accessible in 2D, such as the posterior palate;
• Cardiovascular demonstration: new 3D modalities such as spatiotemporal image correlation, B-flow and inversion mode open a new fascinating window to the demonstration and evaluation of the cardiovascular system of the fetus.
The following day of the conference was dedicated to a ‘fetal echocardiography (ECHO) course’ and national and international experts reviewed all topics related to the performance and significance of fetal heart sonography. Shapiro did an excellent presentation of the basics of fetal ECHO scanning and Jack Rychik (Professor and Director of the Fetal Heart Program, Children’s Hospital of Philadelphia, PA, USA) presented the subject of fetal arrhythmias. Rychik discussed that fetal arrhythmias can be categorized as extra beats, fast rhythms or slow rhythms. Fetal echocardiographic techniques can help distinguish the various rhythm abnormalities and guide management and therapy. Premature atrial contractions are benign extra beats and can be distinguished from premature ventricular contractions, as the former resets the sinus node and the latter does not. In premature atrial contractions, there is a pause after the premature beat as the sinus node recovers, while in premature ventricular contractions the sinus node may continue to fire in a regular and uninterrupted manner, hence the cadence of atrial activity is unaltered.
The most common fast rhythm in the fetus is supraventricular tachycardia. This arrhythmia is commonly due to abnormal fibers within the atrioventricular node or additional nodal bypass tracts, which allow for a ‘re-entry’ rhythm. There is 1:1 atrioventricular conduction and the rate is over 220 beats per minute (bpm). Atrial flutter is the next most common fast rhythm and is due to atrial re-entry with extremely fast atrial rates as high as 400–500 bpm. Conduction is typically not 1:1, but rather 2:1, 3:1 or 4:1 as the atrial beats are halted at the atrioventricular node. M-mode ECHO of Doppler ECHO can help to identify the degree of synchrony between atrial and ventricular activity, and can help distinguish these tachycardias. Treatment is initiated in a stepwise manner, starting with maternal administration of digoxin to slow nodal conduction. Our second-line drug of choice is sotalol at starting doses of 80 mg twice-daily, but it can be increased to 160 mg three times-daily under careful maternal monitoring. Factors such as presence of hydrops and gestational age will often dictate decisions towards more aggressive care such as direct fetal administration of agents or premature delivery and postnatal care.
Maternal autoimmune-mediated heart block is the most common slow rhythm seen in the fetus. Heart rates of over 55 bpm are well tolerated; however, rates under 55 bpm may impair cardiac output. If SSA/SSB maternal antibodies are present, then we recommend administration of maternal dexamethasone to halt the inflammatory process, and prevent further conduction tissue damage and cardiomyopathy. The development of fetal hydrops is an indication for premature delivery and immediate postnatal pacing.
Rychik continued with a presentation on ‘Complex Heart Disease in the Fetus: its Diagnosis and Management’. Fetal cardiovascular imaging through the use of fetal ECHO has advanced tremendously in the past decade. Improved operator skill and technological advances now allow for the identification and understanding of complex physiological processes. Imaging can be performed as early as 13 weeks gestation, with good information obtainable on heart anatomy and function. Anomalies such as septal defects, atrioventricular canal, left- and right-sided obstruction and conotruncal anomalies such as tetralogy of Fallot and truncus arteriosus can be well characterized in great detail. Appropriate counseling can be offered and an anticipatory plan of action for delivery and postnatal care can be implemented, resulting in improved outcomes.
Some forms of congenital heart disease are still challenging to diagnose before birth. Dextro-transposition of the great arteries remains poorly diagnosed in fetal life, as visualization of the outflow tracts and great vessels is still not uniformly performed. Training and special attention to imaging the origins of the great vessels will increase the yield of diagnosis and will contribute to an improved outcome for this very correctable anomaly.
Hypoplastic left heart syndrome is readily diagnosed before birth. Postnatal management has improved substantially in recent years; however, risk factors for survival through staged surgical reconstruction exist and can be identified in the fetus. Prenatal detection of an intact or highly restrictive atrial septum is a significant risk factor for poor outcome. Pulmonary vascular development is severely affected in the presence of obstruction at the level of the atrial septum. Doppler interrogation of the pulmonary veins will reveal a unique flow pattern or reversal with atrial contraction if the atrial septum is restrictive and there is impediment to left atrial egress. A protocol of maternal hyperoxygenation has been developed that allows for assessment of fetal pulmonary vasoreactivity and is helpful when administered in the third trimester. Fetuses with severe atrial level obstruction are candidates for fetal cardiac intervention and atrial septoplasty using needle and balloon catheter techniques.
Twin–twin transfusion syndrome is a complex disease that affects the fetal cardiovascular system. The recipient twin develops cardiomyoapthy with right-sided outflow tract obstruction, while the donor twin experiences severe hypovolemia and intravascular volume contraction. A disease stratification and cardiovascular scoring system using echocardiographic parameters has been developed, which offers a means to gauge disease severity and response to laser photocoagulation therapy.
Fetal ECHO provides a way to assess a number of complex physiological processes affecting the developing cardiovascular system before birth. Through these techniques, our understanding of complex disease has improved, allowing for the implementation of novel management strategies, all resulting in better outcomes.
Dennis Wood (Thomas Jefferson University, PA, USA) presented ‘Indications for and Genetics Implications of the Targeted Fetal Echocardiogram’ and listed the indications as follows:
• Suspected heart anomaly on routine fetal ultrasound or cardiomegaly;
• Family history of congenital heart disease;
• Previous children born with congenital heart disease;
• Suspected chromosomal abnormalities;
• Other fetal structural anomaly or malformations, or pericardial or pleural effusion;
• Maternal pregestational diabetes;
• Maternal systemic lupus erythematosis or Sjögren syndrome;
• Teratogen exposure;
• Fetal arrhythmias;
• Twin–twin transfusion syndrome and twin reversed arterial perfusion sequence;
• Intrauterine growth restriction;
• Intracardiac tumors;
• Hydrops fetalis.
“The heart could not be well seen on routine anatomy scans”, “Increased nuchal translucency” at the 12–14 gestational week scan. Wood reviewed the timing of fetal ECHO, the approach and the consequences of finding a cardiac anomaly at fetal ECHO. The cardiac teratogenic effect has been documented following exposure to several drugs and medications that were listed. The mode of inheritance and recurrence risks for the different cardiac defects were discussed. Cardiac anomalies are commonly detected as part of a large number of congenital syndromes and these syndromes were listed.
This was followed by presenting the role of first-trimester screening as an early screening method for both aneuploidy and congenital cardiac anomalies. An increased fetal nuchal translucency has been shown to be associated with the presence of such malformations in several studies.
The finding of a structural cardiac anomaly should prompt further evaluation including fetal ECHO, detailed anatomical survey searching for additional anomalies in other systems, genetic counseling, and specific tests looking for an underlying chromosomal aneuploidy or deletion. Conversely, the elucidation of an abnormal karyotype should lead to a thorough, detailed cardiac ultrasound examination looking for associated anomalies. It is well appreciated that, for example, 50% of children with Down’s syndrome have significant cardiac pathology. We need to increase our understanding of the interplay between aneuploid or otherwise genomically derived abnormalities, and cardiac pathology, Wood concluded.
Another excellent presentation by Wood was on the ‘General Concepts in the Interpretation of Fetal Doppler Waveforms’. He discussed the role of Doppler ultrasound and the interpretation of the waveforms enhancing the diagnostic role of Doppler studies. Doppler also helps to identify problematic pregnancies and aid in the management of critical cases. Five vascular structures easily identified by Doppler interrogation have been found to be useful in screening for the diagnoses of pregnancy-induced hypertension, utero–placental insufficiency, intrauterine growth restriction and congestive heart failure. They include the maternal uterine artery and the fetal umbilical and middle cerebral arteries, ductus arteriosus and ductus venosus – all were described in the normal and pathological forms.
The last presentation was open to audience participation, with Wood presenting cases and Rychik and Shapiro presenting management schemes from the maternal–fetal medicine and pediatric cardiology perspectives. A total of 16 unknown cases of fetal congenital heart disease were discussed. Cine loops of diagnostic images were presented so that all of the speakers could offer comments on the information presented, including probable diagnosis, what information was lacking and how often to follow the fetuses in utero. Also discussed with each case were social implications and surgical and medical management, with both the audience and coordinator, Geifman-Holtzman, commenting on their experiences.
Acknowledgements
The author thanks the following exhibitors and sponsors for their support of education, care of the pregnant patient and their generous support of the conference: Alere, Artemis, Athena, CMB Diagnostics, Cord Blood Registry, Counsyl, GeneDx/Bio Reference, General Electric, Genzyme (national and local), Lippincott, Williams & Wilkins, Lab Corp, March of Dimes, Mosby/Saunders/Elsevier Publishers, NTD Labs, PerkinElmer, Philips, Quest Diagnostics, Sequenom and Signature Genomic.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.