Ascertainment and Diagnosis of Birth Defects
October 18-19, 2004
Sheraton Midtown Atlanta at Colony Square
Atlanta, GA

This meeting was held in conjunction with the National Children’s Study, which is led by a consortium of federal agency partners: the U.S. Department of Health and Human Services (including the National Institute of Child Health and Human Development [NICHD] and the National Institute of Environmental Health Sciences [NIEHS], two parts of the National Institutes of Health, and the Centers for Disease Control and Prevention [CDC]) and the U.S. Environmental Protection Agency (EPA).

Introductions, Overview, and Charge of Workshop
Adolfo Correa, M.D., Ph.D., M.P.H., National Center on Birth Defects and Developmental Disabilities, CDC, DHHS

Dr. Correa welcomed the participants and thanked them for participating in the workshop and being part of the National Children’s Study (Study). After the participants introduced themselves, Dr. Correa presented a brief overview of the Study and described the workshop objectives and guidelines.

The Study was mandated by PL 106-310—the Children’s Health Act of 2000. It evolved from the work of the President’s Task Force on Environmental Health Risks and Safety Risks to Children, which concluded:

• Many risks are not clear or quantified.
• There is a need for a longitudinal study of effects of environmental exposures (broadly defined).

Study concepts include:

• Longitudinal study of children, their families, and their environment
• National in scope
• Hypothesis driven
• Environment defined broadly to include chemical, physical, behavioral, social, and cultural factors
• Study common range of "environmental" exposures and less common outcomes (n100,000)
• Exposure period begins in pregnancy
• Environment and genetic expression
• State-of-the-art technology
  • Tracking
  • Measurement
  • Data management
• Consortium of multiple federal agencies
• Extensive public-private partnerships
• National resource for future studies.

Priority outcomes include:

• Pregnancy outcome: preterm birth, birth defects, and fetal influences on adult health
• Neurodevelopment and behavior: cognitive development (IQ), autism, learning disabilities, schizophrenia, depression, adjustment, normal variation, and resilience
• Injury: intentional and unintentional, violence
• Asthma: environmental, genetic, infectious, and immune factors
• Obesity and physical development: diabetes, pubertal/reproductive development, growth, and obesity "epidemic."

Dr. Correa noted that approximately 70 relevant hypotheses have been suggested for the Study. Examples of relevant hypotheses include:

• Undesirable outcomes of pregnancy
  • Impaired glucose tolerance is associated with birth defects.
  • Inflammation and infection increase the risk of preterm birth and fetal growth restriction.
• Obesity and physical development
  • Gestational diabetes increases the risk of childhood obesity.
  • Environmental factors (structural, social, and familial) affect risk of obesity.

Anticipated exposure measures include:

• Environmental samples: air, water, dust, etc.
• Biomarkers for chemicals: blood, breast milk, hair, tissue, etc.
• Interview and history
• Serology and medical data
• Housing and living characteristics
• Family and social experiences
• Neighborhood and community characteristics.

Anticipated outcome measures include:

• Fetal growth and outcome of pregnancy
• Birth defects and newborn exam
• Growth, nutrition, and physical development
• Medical condition and history: illness (for example, asthma, obesity), conditions, and injuries
• Cognitive and emotional development
• Mental, developmental, and behavioral conditions.

Aspects of Study sampling strategy include:

• National probability sample
• Multistage design with clusters to enhance the ability to measure chemical, physical, and social characteristics of communities, as well as those of individual participants
• Regional centers
• Central coordinating center.

The intervals of participant examinations used for initial Study cost projections are:

The projected timeline for the Study is:

• 2000-2005: Pilot study/methods development work
• 2001-2002: Form Advisory Committee and Working Groups
• Periodically: Meetings, peer reviews, consultations
• Mid 2004: Finalize specific hypotheses, develop Study plan
• Late 2005: Select initial centers and pilot test core protocol
• Late 2006: Begin full Study with initial centers
• 2006-2007: Enroll additional centers
• 2009-2010: First preliminary results available from pregnancy
• 2007-2030: Analyze data as collection continues, publish results throughout:
  hypothesis-specific, public-use data sets, requests for applications.

Workshop objectives were to identify methods/protocols for:

• Ascertaining birth defects in utero, in infancy, and in childhood that are feasible to implement in the Study and specifying minimal timing of examinations
• Pilot studies (for example, to assess feasibility, reliability, and validity) and/or for standardization and quality control of such methods/protocols.

Dr. Correa listed the following ascertainment sources:

• Primary sources: prenatal and postnatal examinations
  • Study centers
  • Field
• Other possible sources
  • Records
    • Hospital with obstetric services
    • Pediatric hospitals
    • Specialty health centers
    • Laboratories
  • Vital records.

The workshop guidelines specified that the participants were to:

• Identify methods/protocols for ascertaining birth defects, not for providing clinical services
• Identify feasible methods for:
  • Entire Study cohort
  • Substudies, for example, a step-wise approach for a more comprehensive evaluation
• Develop/outline possible protocols/algorithms for appropriate referral of suspected birth defects.

Day-1 lectures and discussion about lessons learned and new methods included the following:

• Use of prenatal ultrasound to ascertain birth defects
  • Two-dimensional (2D) ultrasound
  • Three-dimensional (3D) ultrasound
• Ascertainment of birth defects in fetal deaths
  • Early fetal deaths
  • Stillbirths
• Prenatal and postnatal ascertainment of cardiac defects
  • Fetal echocardiography
  • Postnatal evaluations
• Evaluation of the face using 3D photographic imaging.

Use of Prenatal Ultrasound to Ascertain Birth Defects: 2D
Lynn L. Simpson, M.D., Columbia University

Dr. Simpson reviewed the findings of several studies on 2D ultrasound for prenatal ascertainment of birth defects:

• RADIUS Study (Crane et al., 1994)
• Fetal anomaly detection (VanDorsten et al., 1998)
• FASTER Trial (Malone et al., 2003)
• Accreditation of ultrasound practice (Abuhamad et al., 2004).

She summarized a brief history of obstetric 2D ultrasound as:

• 1970s-1980s—real-time, 2D ultrasound incorporated into obstetric practice
• 21st century—widespread clinical use to image the developing fetus and diagnose fetal abnormalities
• Approximately 90-95 percent of all pregnancies now get routine ultrasound screening.

Characteristics of the RADIUS Study of anomaly detection include:

• Practice-based, multicenter randomized clinical trial of routine ultrasound screening during pregnancy
• Screened group (7,685) versus control group (7,596)
• Two ultrasound exams, at 15-22 weeks and at 31-35 weeks
• Prevalence of at least one major anomaly: 2.3 percent
• Detection rate as follows:

Comments on routine use of ultrasound in low-risk pregnancy include:

"In a population of women with low-risk pregnancy, neither a reduction in perinatal morbidity and mortality nor a lower rate of unnecessary interventions can be expected from routine diagnostic ultrasound. Thus, ultrasound should be performed for specific indications in low-risk pregnancy." (ACOG Practice Patterns, 1997)

Dr. Simpson summarized the fetal anomaly detection by ultrasound at 15-22 weeks gestation in a tertiary center:

Features of the FASTER Trial include:

• Objective: To describe optimal combinations of tests for population Down syndrome screening
• Pregnancies enrolled: 38,189
• Number of sites: 12
• Number of sonographers: 102
  • Uniform practical training
  • Standard nuchal translucency protocol
  • Periodic review
• Ultrasound for nuchal translucency: 10-13 weeks
• Screening ultrasound: 18-22 weeks
• Pregnancy and pediatric follow-up
  • Standard approach
  • Consistent exam
  • Expert review
• Outcome obtained: 37,002 (97 percent).

Features of the study of accreditation of ultrasound practice by the American Institute of Ultrasound in Medicine (AIUM), Ultrasound Practice Accreditation Commission, include:

• AIUM developed standards and guidelines for the accreditation of ultrasound practices in 1996.
• Standards serve as a benchmark for ultrasound professionals seeking to meet nationally accepted protocols.
• Accreditation is granted for a 3-year period following a voluntary peer-review process.
• Proportion of obstetric practices meeting AIUM performance guidelines improved significantly with reaccreditation (86.6 percent) compared with initial accreditation (57.3 percent).

Findings of 2D ultrasound for prenatal ascertainment of birth defects include:

• Detection of fetal anomalies depends heavily on the examiner’s level of training, expertise, and experience.
• Detection rate varies between indicated versus screening ultrasound.
• Optimal time for screening for fetal structural defects is 18-22 weeks.
• Major internal and external malformations can be detected.
• Approach
  • AIUM accreditated practices
  • Universal consistent screening
  • Complete ascertainment
  • Reliable outcome and follow-up.

Use of Prenatal Ultrasound to Ascertain Birth Defects: 3D
Dolores H. Pretorius, M.D., University of California, San Diego

Dr. Pretorius began her presentation by comparing two images: a photographic image of infant (at 42 weeks) and 3D image of fetus at 31 weeks. She described the use of 3D imaging as still being in the "infancy" of practice. She said that 3D imaging does add information to help detect anomalies and adds confidence in identifying anomalies.

Dr. Pretorius explained that the number of 3D ultrasound publications in Obstetrics & Gynecology increased from 8 in 1994 to a peak of 75 in 2002 (with 63 in 2003). She then presented the results of two studies on detecting fetal malformations using 3D ultrasound:

• Nuchal lucency screening for chromosomal anomalies and anomalies (for example, cardiac)
  • 3D adds little to 2D.
• Congenital anomalies
  • Little data are available.
  • Case reports, primarily of brain lesions, are most common.
  • 3D is not widespread, but there is great potential.

• Cleft lip and palate at 12 weeks
• Acrania versus normal at 12 weeks
• Cleft lip and palate, prenatal and postnatal (prerepair and postrepair images)
• Myelocystocele at 18.5 weeks
• Clubfoot at 28 weeks
• Ribs and spine.

Dr. Pretorius listed the following methods as suitable for a large study:

• 3D should be used as an adjunct to 2D for anomaly detection, targeted to an abnormal area seen on 2D or a clinical history.
• At least two volumes should be acquired, from different planes, of each anomaly detected on 2D ultrasound.
• 3D provides better measurements of organs (for example, lungs, brain, and heart) and has the potential to assist in detection of pulmonary hypoplasia or microcephaly.
• 3D ultrasound is equivalent to 2D ultrasound in linear measurements (for example, femur or abdominal circumference).

Dr. Pretorius listed the following equipment as suitable for a large study:

• All the major manufacturers of ultrasound equipment are developing 3D equipment.
• General Electric, Philips, and Medison currently have an edge, but Siemens is very near in having clinical 3D.
• Specialized acquisition of cardiac information would be helpful but may only be available on certain equipment.

In implementing the use of 3D ultrasound in a large population study, Dr. Pretorius noted the following:

• 3D equipment will be added on to nearly all new equipment being purchased.
• Skills required to perform 3D will be obtained gradually; some images will be easy to learn; other images will be more difficult. Images of the entire fetus could be acquired by sonographers in the field and reviewed by specialists.
• Volumes of the entire fetus can be acquired and reviewed at a later date.
• Artifacts of scanning (for example, shadowing from adjacent structures) and position of the fetus (for example, face adjacent to uterus) affect the data acquired, but many anomalies will be present on review.
• Cardiac imaging may need to be done in a subgroup by specially trained sonographers but would be very helpful.

To archive volume data, Dr. Pretorius suggested the following:

• Archive on CD-ROM.
• Various media have been used over last 10 years (SyQuest disc, magnetico-optical disc, CD-ROM).
• Volume measurement programs will be changing over years
  • Outlining area of interest
  • Segmentation techniques
• There is concern regarding reviewing archives.

With regard to cultural/ethnic/socioeconomic background, Dr. Pretorius noted the following:

• Minimal impact on ultrasound scanning
• No difference from 2D
• Nasal bone is shortened in Asian women.

Features of optimal scanning time include:

• For anomaly detection, 3D can be performed at same time as 2D:
  • Optimally at 18-20 wks
  • Can be performed from 12 weeks to term
• Surface anomalies are better imaged a little later, at 22-26 weeks.

Features of measurement evaluation include:

• Technique changing over years
• Outlining area of interest
• Segmentation techniques
  • Preliminary methods now available on some equipment
  • New automated techniques are expected
• Validation depends on organs desired and development of new technology.

Dr. Pretorius summarized the results of two studies on the potential of using lung volumes to diagnosis pulmonary hypoplasia:

• 32 fetuses
• Compared multiplanar tracing to rotational (VOCAL) technique
• Intermethod variability had correlations of r = 0.93 for left lung and r = 0.96 for right lung.
• Lung volumes with diaphragmatic hernia: 3D ultrasound equivalent to magnetic resonance imaging (MRI).

In a brief question-and-answer session, the participants discussed the following issues:

• Fetal brain MRI versus 3D ultrasound scan
• The need to recognize the potential of MRI
• The relative merit of different imaging modalities
• Automated approaches
• Operator-dependent imaging outcomes
• Operator training and dedication
• Cost of MRI compared with 3D ultrasound.

Ascertainment of Birth Defects in Fetal Deaths: Early Fetal Deaths
Ona M. Faye-Peterson, M.D., University of Alabama, Birmingham

With regard to ascertainment of birth defects in early fetal death, Dr. Faye-Peterson said that three main questions emerge:

• Is the process of ascertainment and diagnosis of structural defects different for cases of previable/early fetal death than for stillbirth later in gestation?
• What is the purpose(s) of the pathologic examination in detection of structural defects in cases of early fetal death, for this study?
• How can the goal(s) of this study best be met given limitations of fetal size and maceration when encountering loss of a previable fetus?

Question 1: Is the process of ascertainment and diagnosis of structural defects different for cases
of previable/early fetal death than for stillbirth later in gestation? No:

• Assuming that examination performed by invested (pediatric/perinatal) pathologist
• Overall, same principles and protocol of examination applied to evaluation of previable fetus
• Placental examination is included.

Protocol for examination of previable fetus:

• Rule out structural anomalies (modified NICHD Stillbirth Study)
• Review clinical record
• Obtain gross color photographs: full body front and back; frontal face; facial profile from both sides; hands and feet; any suspicious appearing features
• Obtain fetogram: anterior-posterior and lateral views, well positioned with minimal overlap of extremities and rotation of head or torso
• Perform external examination to include:
  • Assessment of gestational age (GA), appropriateness of developmental features
    • Compare measurements observed with normal ranges expected for clinically estimated GA; if different, use anatomically determined GA and organ weights, etc., for body habitus
    • Anthropometry: weight; foot length; CHL* (may be overestimated in macerated fetuses); crown-rump length*, head circumference*; CC; abdominal circumference; (Fontanelle size*)
      *questionably reliable in macerated fetuses
  • Correlate developmental maturation with anatomically estimated GA as determined by anthropometry
  • Assess degree of maceration
• Note external anomalies by categories: craniofacial, truncal, limb, vertebral
• Perform internal examination: with photo documentation of organs in situ, anomalies; weigh and describe organs
• Central nervous system examination: inspection of brain in situ and post removal with photos; fixation in situ for central nervous system abnormalities
• Microscopic evaluation of all organs, brain, and spinal cord
• Postmortem cytogenetic analysis: skin or chorionic villous tissue
• Consider tissue culture for cell lines of fibroblasts, cartilage, etc., for research/diagnosis
• Consider microbiologic cultures
• Placental examination.

Is the process of ascertainment and diagnosis different? But:

• Examination more difficult due to small fetal size
• Relative rates of syndromes and anomalies are different in spontaneous abortion versus stillbirths >24 weeks GA
• Anthropometry, correct assessment of GA and of development even more critical
• Manifestations of syndromes and anomalous complexes less overt and therefore more easily overlooked
• Cause of preterm delivery/death less frequently due to intrauterine infection.

External developmental features of previable (10 weeks-23 6/7 weeks) fetus by GA include:

• 10-12 weeks
  • Head about one-half body size and round
  • Intestine herniated <12 weeks
  • Eyelids closed 11-12 weeks
  • Dorsal thoracic flexure replaces cervical flexure
  • Hair follicles in skin
  • Fingernails developing
  • Nose anteverted
• 13-14 weeks
  • External genitalia distinguishable at 13-14 weeks (that is, hypospadius, etc., diagnosable)
  • Head about one-third body size of fetus
  • Eyelids closed
  • Scalp hair pattern discernable
  • "Micrognathia"
• 14-16 weeks
  • Finger nails recognizable
  • Growth of lower limbs catches up with and then surpasses growth of upper limbs
  • Hair follicles well established
  • Head about one-quarter body size
  • Brown fat forming
• 17-18 weeks
  • Legs crossed
  • Ossification of skeleton advanced; all bones identifiable; relative proportions of femur to tibia/fibula achieved
  • Brown fat easily seen to 22 weeks
• 19-20 weeks
  • Lanugo present; vernix starts to form
  • Epidermal ridges for dermatoglyphics in hands
  • Eyebrows well recognizable; scalp hair present
  • Ears normally "low set" until 20 weeks GA; ear configuration well differentiated
  • Nasal septum root ossified
  • Appearance of sternal ossification center in manubrium
  • Fingernails and toenails defined
• 20-24 weeks
  • Weight gain but scant subcutaneous body fat
  • Skin wrinkled, transparent/translucent gelatinous until 23 weeks
  • Eyelids opening 24 weeks
  • Eyelashes present
  • Two sternal ossifications centers present.

Dr. Faye-Peterson described the results of a study by Dimmick and Kalousek (1987) on prevalence of major developmental defects (per 1,000 examined):

PVF <20 weeks GA. PVF = previable fetus, SBF = stillbirth fetus.

Dr. Faye-Peterson presented details from a study on chromosomal anomalies in 271 autopsies at BCCH, Vancouver, British Columbia (1982-1989). The anomalies included:

• Tris 21
• Tris 18
• Tris 13
• Tris 22
• Tris 9
• XXY
• XXX
• XO
• Triploidy.

Dr. Faye-Peterson noted that previable fetuses and stillbirths have 10-50 times higher rates of structural anomalies over live births:

• Of live births, 2-3 percent have major anomaly; 10-15 percent have minor anomaly if term; live birth phenotypically normal has 3 percent chance of anomaly.
• 3.3-8 out of 1,000 live births have major congenital cardiovascular malformation (CCVM) compared with 2.4-18 out of 100 stillbirths.
• 6-12 percent of live births with CCVMs have chromosomal anomaly compared with 20-50 percent of stillbirths.
• Ventricular septal defects (VSD), coarctation of the aorta (coarct), and hypoplastic left heart are the most common autopsy CCVMs of live births compared with VSD, coarct, and CAVL in stillbirths (10-20 weeks GA).
• Tetralogy of Fallot is never an isolated/nonsyndromic lesion in stillbirths.

Dr. Faye-Peterson commented that:

• Persons with the most experience can provide the most information.
• Growth is on a continuum.
• It is difficult to detect many anomalies with ultrasound prenatally.

Question 2: What is the purpose(s) of the pathologic examination in detection of structural defects in cases of early fetal death, for this study? Is an autopsy always necessary?

• What do you want the examination to tell/do for you?
  • Confirm ultrasonographic diagnoses
  • Detect new unsuspected anomalies in fetuses with normal ultrasound exam
  • Determine, as confidently as possible, what kind of syndrome, association, sequence, field defect, etc., is present
  • Determine cause of death
  • Provide tissue for genetics
  • Provide visceral or central nervous system tissue for research
• What are you going to do with the information?
  • Provide explanation of demise for parents
  • Use for genetic counseling for recurrence and precurrence risks
  • Use for quality assurance monitoring
  • Generate database for birth defects study, but what kind of database are you interested in creating?

With regard to specific rates of detection of structural anomaly at autopsy in previable fetuses, Dr. Faye-Peterson listed the following:

• Very few studies where this is studied or extractable
• Rates of findings by perinatal autopsy of anomalies that were significantly different from or added to diagnosis such that genetic counseling affected: 3-6 percent; most 20-26 percent
• If ultrasound is performed and specifically correlated with postmortem findings, major additional findings found in 30-40 percent.

Another study (Johns et al., 2004) found the following:

• 47 of 153 anomalous ultrasound studies had "autopsy correlation"
• Complete agreement 22 of 47 = 46.8 percent; 34 of 47 were 12-24 weeks GA
• Agreement major plus other = 24 of 47 = 51.1 percent
  • 11 of "other findings" minor
  • 13 of "other findings" significant
  • 10 of these 13 were TOP and <22 weeks GA (cloacal dysgenesis, anorectal agenesis, renal abnormalities).

Dr. Faye-Peterson described the "conclusions" of this study as:

• Ultrasound is much more reliable, but autopsy is still the gold standard, especially when a multidisciplinary approach is used (geneticist also evaluates fetus with pathologist).
• Oligohydramnios is associated with the greatest number of significant discrepancies.
• Central nervous system anomalies are most often diagnosed correctly (neural tube defects, especially).
• Radiologic studies alone are nearly diagnostic for bone dysplasias.
• If an autopsy is refused, is fetal MRI an option?

Question 3: How can the goal(s) of this study best be met given limitations of fetal size and maceration when encountering loss of a previable fetus?

Detection of structural defects in cases of early fetal death

• Is an autopsy always necessary?
• If so, what kind, and how will this be determined?
• If so, what skills and equipment will be necessary?
• If so, what will be the cost?

In a brief question-and-answer session, a participant noted that biomarkers for heart disease may offer evolving approaches for detecting birth defects.

Ascertainment of Birth Defects in Fetal Deaths: Stillbirths
J. Frederick Frøën, M.D., University of Oslo

Dr. Frøën explained that there are many challenges in ascertaining birth defects in stillbirths. To address these challenges, the specific problems must be identified, including:

• What is (not) a stillbirth?
• Ascertaining congenital malformations (CMs) in stillbirths
• CMs and/or causes of death
• Classification—of what?
• Ascertaining chromosomal/genetic defects
• Overcoming barriers.

In describing what is (and what is not) a stillbirth, Dr. Frøën began by presenting a graph that listed mortality per 1,000 by year of birth (1965—1995) for:

• Stillborn <28 weeks
• Stillborn >28 weeks
• Neonatal mortality
• Perinatal mortality.

To ascertain CMs in stillbirths—malformations as "causes of death" in stillbirth research—Dr. Frøën listed the following:

• The cause of death not equivalent to prevalence of CMs, but cause of death is crucial in understanding the effects of CMs, their "natural history," and etiology.
• Most classifications are hierarchical with CMs "on top."
• In reality, CMs can be
  • Cause of death
  • An association
  • Found only because of death
• Tools change their sensitivity and specificity after death (for example, ultrasound/Doppler/MRI scan for heart defects and brain).
• Major ultrasound findings will be confirmed in >90 percent of autopsies; but in 26—45 percent of stillbirths, autopsy will alter or add significantly to the clinical diagnosis. Placental pathology will contribute in explaining death in 30-50 percent of stillbirths.

Dr. Frøën presented details of the results from three studies on malformations as "causes of death":

• Sawardeker, 2004—no autopsies but reported as malformed
• Horn, 2003—only autopsies
• Incerpi, 1998—before autopsy.

Dr. Frøën noted that studying "fully explored" stillbirths separately would skew the material if a large proportion remains "partly explored."

Dr. Frøën presented details on the success rate of karyotyping from eight studies that used different source materials to find chromosomal/genetic defects. The four sources and their respective total (combined) success rates were:

• Skin/cartilage (35 percent)
• Placenta (63 percent)
• Amniocentesis (87 percent)
• FISH (100 percent?).

In a discussion of finding/detecting chromosomal/genetic defects, Dr. Frøën explained that the success rate of karyotyping often depends on the quality and source of the genetic material (that is, the tissue types used, "fresh" versus maceration). He then listed the following questions and answers:

• Why amniocentesis?
  • Best, easiest, cheapest for successful karyotyping (without FISH)
  • Reduced time from death to sampling (one-third > 24 hours x 2)
  • Reduced risk for pollution/infection in sample
  • Needed as "control" for placental finding
  • Best material for evaluation of infections, cytokines, erythropoietin, etc.
• Why placenta?
  • Needed to identify isolated placental mosaicism (1—2 percent, 9—17 mortality)
  • Need both placental and fetal tissues
• Why FISH?
  • The last step from 90 percent to 100 percent?
  • Open a new field of research?
  • Skip the amniocentesis?

Dr. Frøën identified the following issues for overcoming barriers:

• Autopsies/MRI
  • Uniform protocols
  • Uniform classification of both cause of death and CM
  • 100 percent(?) autopsy rates (or MRI?)
  • Reduced time from diagnosis to autopsy
• Amniocentesis
  • Institutional review board will want to know
  • Improved diagnostics and care, or only more hardships for a study?

In concluding his presentation, Dr. Frøën described the challenges involved:

• Ascertaining both the malformations and chromosomal/genetic defects and the cause(s) of death
• Classifying it accordingly, including the level of evidence
• OBS! Optimal research tools = optimal tools for improved quality and safety of clinical care.

In a brief question-and-answer session, a participant described general karyotyping as "a crude test." The participants observed that:

• FISH is considered to be a better alternative.
• Developing more efficient approaches to detecting genetic defects is an evolving field of research.

Prenatal and Postnatal Ascertainment of Cardiac Defects: Fetal Echocardiography
Charles S. Kleinman, M.D., Columbia University

Dr. Kleinman described the aims of his presentation:

• Review early development of the field of fetal cardiology
• Describe where the field is now
• Describe where the field is going.

Dr. Kleinman noted the challenges of imaging a dynamic organ/structure, such as the fetal heart. He characterized the cardiovascular flow in the fetus:

• Ventricles in parallel
• Equal pressures
• Ductal and foramenal shunts
  • Vascular "detours"
• Form follows function
• Neutral thermal environment
• "ECMO" circuit.

A.M. Rudolph’s contributions to fetal cardiology include:

• Chronically instrumented fetal lambs
• Radionuclide-labeled microsphere studies of regional flow distribution
• Models of congenital heart disease
• Characterization of the transitional circulation.

Clinical fetal cardiology originated in 1977 with a study by Dr. Kleinman and his associates (Echocardiographic Studies of the Human Fetus: Prenatal Diagnosis of Congenital Heart Disease and Cardiac Dysrhythmias, Kleinman et al., 1980). This study examined:

• nl
• Tricuspid atresia
• Heart block
• Atrial flutter
• Atrioventricular canal defect.

Early comments about fetal echocardiography included:

"The future of fetal echocardiography has not yet been defined. Although identification and precise intrauterine morphological diagnosis of congenital heart disease are a great tour de force, I am not sure of the clinical usefulness." (A.S. Nada, Yearbook of Cardiology, 1981)

Current indications for fetal echocardiography include:

• Atrioventricular canal defect
• Triscuspid atresia
• Hypoplastic right ventricle
• Hypoplastic left heart.

Altered anatomy of the fetal heart’s four chambers reflects abnormal physiology:

• Normally atria and ventricles are symmetrical.
• In abnormal hearts:
  • Large right atrium and large left ventricle
  • Right ventricular hypertrophy
  • Anatomic basis not seen
  • Pulmonary stenosis and tricuspid regurgitation.

In discussing the fetal heart as a space-occupying mass, Dr. Kleinman posed the question: "How Big Is Too Big?" He presented a graph of cardiothoracic ratio versus gestational age from a study by Allan (2000).

In examining the fetal heart beyond the four-chamber view, Dr. Kleinman explained that the aorta and pulmonary artery are at right angles (normal), compared with tetralogy of Fallot and transposition. He presented images from Silverman, 1996.

Dr. Kleinman then asked what following five patient images have in common:

• Tetralogy of Fallot
• Truncus arteriosus
• Normal left ventricular outflow tract
• Double-outlet right ventricle
• Interrupted aortic arch (type B).

According to Dr. Kleinman, the "catch-22" of fetal cardiology involves the following:

• Conotruncal malformations
• Malalignment and deficiency of conal septum
• DiGeorge and velocardiofacial syndromes
• Neural crest migration
• Chromosome 22q11 microdeletions.

Dr. Kleinman reviewed the evolution of fetal heart disease by posing questions and discussing several studies, including:

• Left Heart Obstructive Lesions and Left Ventricular Growth in the Midtrimester Fetus: A Longitudinal Study, Hornberger et al., 1995
• Outcome analysis: Does prenatal diagnosis alter prognosis?—d-transposition of the great arteries (Detection of Transposition of the Great Arteries in Fetuses Reduces Neonatal Morbidity and Mortality, Bonnet et al., 1999)
  • Lower preoperative mortality (0/68 versus 15/250 [p < 0.05])
  • Shorter hospital stay (24 =/- 11 days versus 30 +/- 17 days [p <0.01])
  • Lower postoperative mortality (0/68 versus 20/235 [p < 0.01]).
• Does prenatal diagnosis alter prognosis?: Hypoplastic left heart syndrome (Improved Surgical Outcome After Fetal Diagnosis of Hypoplastic Left Heart Syndrome, Tworetzky et al., 2001)
  • Prenatally diagnosed were less likely to undergo surgery (p = 0.008)
  • Lower mortality (0/14 versus 13/38 [p = 0.009])
  • Less preop acidosis (p = 0.02).
• Does prenatal diagnosis alter prognosis?: Avoidance of metabolic acidosis (Prenatal diagnosis of congenital heart disease affects preoperative acidosis in the newborn patient, Verheijen et al., 2001)
  • Avoids neonatal acidosis
  • More profound impact on ductal dependant lesions, left heart obstruction
  • Survival and neurodevelopmental implications.

Dr. Kleinman summarized recent findings at New York-Presbyterian Hospital:

• 331 fetuses with complex congenital heart disease diagnosed in past 2 years
  •   57 percent of all neonates with coronary heart disease admitted to neonatal intensive care units are prenatally diagnosed
  • 90+ percent survival rate with Norwood operation
  • >98 percent overall survival rate
• Focus changing
  • Quality of survival
  • Neurodevelopmental outcomes
  • Effect of birth hospital on outcome.

Future areas of fetal cardiology may include:

• Aortic balloon valvuloplasty
• Fetal pacemaker placement
• Cardiopulmonary bypass
• Inducing fetal immunotolerance and postnatal transplantation.

Dr. Kleinman provided the following conclusions:

• Fetal cardiology has arrived as a new subspecialty.
• It is based almost completely on ultrasound.
• It offers enormous clinical research opportunities.
• Initial attempts at prenatal intervention are being made.
• The challenge will be to avoid mistakes made by our predecessors.

In a brief question-and-answer session, Dr. Correa asked Dr. Kleinman if he is using 3D ultrasound in research efforts. Dr. Kleinman replied that he is not comfortable using only 3D ultrasound to screen for anomalies. He prefers that examiners use 2D ultrasound to identify anomalies and then use 3D ultrasound to provide additional information on those anomalies.

Prenatal and Postnatal Ascertainment of Cardiac Defects: Postnatal Screening
Catherine L. Webb, M.D., Northwestern University

Dr. Webb explained that an effective screening program depends on:

• Prevalence of the disorder (coronary heart disease = 8/1,000 live births)
• Simple and reliable methods
• Available therapy
• Favorable cost/benefit ratio.

Dr. Webb cited the following reasons to screen for childhood heart disease:

• Serious structural disease may be initially asymptomatic at birth
  • Outcry for pulse oximetry screening
• First symptom may be sudden death
  • Hypertrophic cardiomyopathy
    • Outcry for echocardiographic screening
  • Long QT syndrome
    • Outcry for electrocardiographic screening.

Dr. Webb asked: What heart disease occurs in childhood? Structural malformations include:

• Severe disease presents at birth
  • Right and left heart obstructive disease
  • Transposition of the great arteries
• Mild disease at birth may progress
  • Bicuspid aortic valve.

In discussing appropriate times to screen for childhood heart disease, Dr. Webb listed the following:

• Some conditions do not progress
  • Mild pulmonary stenosis
  • Important to identify for preventive care
• Some conditions resolve over time
  • Newborn arrhythmias
  • Small ventricular septal defects
  • Patent foramen ovale
  • Patent ductus arteriosus
• Some conditions develop over time
  • Hypertrophic cardiomyopathy
  • Heart rhythm disorders.

Dr. Webb asked: What heart disease occurs in childhood? Acquired or progressive diseases include:

• Infectious
  • Myocarditis
  • Kawasaki disease
• Serious disease—not evident at birth
  • Long QT syndrome
  • Progressive arrhythmias
  • Cardiomyopathy—dilated, hypertrophic
  • Unusual coronary artery malformations.

Tools for heart disease screening in children include:

• Prenatal echocardiogram
• History and family history
• Physical exam
• Pulse oximetry
• Chest x-ray
• Electrocardiogram (ECG)
• Echocardiogram
• MRI
• Gene screening—not feasible.

Problems with screening tools include:

• Radiation exposure
• Convenience
• Technical training
  • Errors of lead placement
  • Placement of oximetry probe
  • Echocardiography
  • MRI
• Interpretation
  • Large numbers
  • Missed diagnoses
    • True miss
    • Not screened at right time
• False sense of security.

Dr. Webb then asked: What could be missed?

• Prenatal screening
  • Pulmonary vein anomalies
  • Coarctation of the aorta
• Pulse oximetry
  • Total anomalous pulmonary venous return (TAPVR) and other mixing lesions
  • Left heart obstructive disease.

Dr. Webb cited the results from Koppel et al., 2003:

• Postductal pulse oximetry
• 11,281 asymptomatic newborns in two New York hospitals
  • At time of state metabolic screen (>24hrs)
  • Discharge procedure
• False negatives determined by New York Congenital Malformations Registry
• Prevalence of coronary heart disease in all live births (CMR): 1/564
• Prevalence of coronary heart disease in this study: 1/2,256
  • Two TAPVR
  • One truncus arteriosus
• Sensitivity: 60 percent (one false positive)
• Specificity: 99.95 percent (two false negatives)
• Positive predictive value: 75 percent
• Negative predictive value: 99.98 percent.

In elaborating on congenital heart diseases that could be missed, Dr. Webb explained that some conditions develop over time, including:

• Heart rhythm abnormalities
  • Progressive heart block
  • Long QT syndrome
• Cardiomyopathy
  • Hypertrophic cardiomyopathy.

Dr. Webb provided details on hypertrophic cardiomyopathy:

• Heterogeneity of hypertrophic cardiomyopathy
  • Incidence 0.2 percent (1:500)
  • Prevalence of sudden death 1:200,000
• Naperville, Illinois
  • Screening program
  • 25,000 screening echocardiogram/2 years without positive result.

Dr. Webb presented a graph that depicted results from Bader et al., 2004 (Risk of sudden cardiac death in young athletes: Which screening strategies are appropriate?). This graph showed the prevalence (percentage) of 11 disorders; hypertrophic cardiomyopathy was ranked highest at 36 percent.

In discussing the tools for heart disease screening for children, Dr. Webb listed the following screening charges (hospital plus professional fee):

Logistical problems using echocardiogram to screen for childhood heart disease include:

• Equipment is expensive.
• Large numbers of skilled personnel are needed.
• Personnel need to be trained to:
  • Perform
  • Interpret.

Dr. Webb’s suggestions for heart disease screening included:

• Prenatal—per Dr. Kleinman’s presentation
• Birth
  • Pulse oximetry
    • Right arm and right leg (false positive?)
    • Right leg only
  • Echo per physical exam or if pulse oximetry is:
    • <95 percent at 24 hours
    • >10 percent arm/leg difference.
  • Family and medical history
  • Elementary school entry
    • ECG
    • Echocardiogram per history and family history
  • High school entry
    • ECG
    • Echocardiogram
      • Mini machines
      • Limited views—PLSA, PSSA.

Dr. Webb suggested that heart disease screening include the following aspects of echocardiography:

• Large numbers for echocardiographic screening
  • Difficult to screen all children in study
  • 20-25,000
• Pediatric cardiology techs versus trained adult techs
• Pediatric cardiologists versus other trained interpreter
• Large medical centers compared with local hospital settings
• Random samples from each group with comparisons.

In a question-and-answer session, the participants discussed the following issues:

• Study of isolated congenital defects
• Prenatal and postnatal physical exams for minor malformations
• Screening with physical exams
• Clues from very careful physical exams
• Split second heart sound
• Screening exam with pulse oximetry
• Cost-effective equipment (for example, fetal echocardiography versus pulse oximetry)
• Training
• Charges versus costs of screening tools.

Evaluation of the Face in Infancy and Childhood: 3D Photographic Imaging
Simeon Boyd, M.D., Johns Hopkins University

Dr. Boyd explained that the aims of 3D evaluation of the face are to:

• Objectively document phenotypes
• Identify subgroups within phenotype
• Describe craniofacial growth patterns and anatomical variability
• Determine anthropometric features that correlate with the medical and developmental outcomes and with the underlying genotype.

Methods for facial data collection include:

• Conventional:
  • Tape, caliper measurements (time, no archive)
  • Photography (2D, no landmarks)
  • Computed tomography (CT), MRI (radiation, cost)
• 3D digital surface imaging (validation).

Available 3D soft-tissue imaging systems are:

• Laser based
• Visible-light based.

Features of 3D laser based systems include:

• Require further validation
• Slow (seconds to minutes)
• Time-consuming analysis
• Require computer expertise
• Not portable
• Expensive
• Eye damage.

Cyberware includes:

• Mini 3D scanner
• Desktop 3D scanner
• Whole body color 3D scanner.

Characteristics of the visible-light Genex Rainbow 3D system include:

• Portable
• Less expensive
• Users:
  • Maurice Nahabedian, M.D., John Hopkins University
  • Carroll-Ann Trotman, M.D., UNC School of Dentistry
  • Mary Marazita, Ph.D., University of Pittsburgh
• Partially validated
• <200 degree capture.

Dr. Boyd highlighted the results of a recent Genex validation study (Weinberg et al., 2004):

• Precision—higher than caliper measurements
• Repeatability—adequate as determined by acquiring three sequential captures of a stable anthropomorphic bust
• Accuracy—fairly good as corroborated by caliper measurements (12 of 19 variables).

Types of potential errors for 3D imaging systems include:

• Decomposition of the sources of error
  • Due to the image acquiring system
  • Due to the operator collecting the data
  • Due to biological variability
• Nested analysis of variance.

Dr. Boyd presented images of the 3dMD system, which include 3D images generated by the system. In the 3dMD system, six synchronized digital cameras fire simultaneously (in only 0.002 seconds) from various angles to capture both geometry and texture. Dr. Boyd then cited another recent study (Anthropometric landmarks from 3dMD surface images: A study of accuracy and repeatability. Aldridge et al., Abstract 750, American Society of Human Genetics, Toronto, Canada, Oct. 2004) and presented a 3dMD facial evaluation that included:

• Smooth 3D geometry with texture map
• 3D wireframe geometry
• Smooth 3D geometry.

Dr. Boyd discussed validation of 3dMD, including:

• 3dMD versus 3D-CT.
• 3dMD facial landmarks
• Precision of anthropometric landmark locations.

Dr. Boyd made the following recommendations:

• Select and validate a set of landmarks (for example, eyes, nose, mouth)
• Validate congruence of 3D measurements with those obtained by direct anthropometry
• Prelabel landmarks prior to image acquisition
• Reduce observer’s error by proper training
• Obtain images in a fixed facial expression.

Dr. Boyd offered the following conclusions:

• 3D anthropometry is capable of very high degree of precision.
• There is a good congruence between direct and indirect (3D) anthropometry for most, but not all measurements.
• The compact design and rapid acquisition time of 3D machines makes them good candidates for the goals of the Study.

Other Study considerations include:

• Both GENEX and 3dMD are compact and suitable for evaluation of a large sample in "field" situation without specialized facilities.
• The 3dMD has been validated in male/female, child/adult, African American/Caucasian, and control/disease groups.
• Optimal time periods need to be determined.
• Validation of each 3D machine and a pilot study are recommended.
• 3D technology is likely to remain a permanent part of our repertoire of evaluation tools and will be further optimized.

Dr. Boyd’s presentation included the following definitions:

• Anatomic craniofacial landmarks: Biologically meaningful loci that can be unambiguously defined and repeatedly located with a high degree of accuracy and precision.
• Precision: average absolute difference between repeated measures of the same image.
• Imprecision: within-subject variability caused by inconsistency between repeated measures of the same entity.
• Repeatability: precision of the measure relative to the differences among individuals.
• Inaccuracy: extent of measurement’s deviation from its "true" value.
• Validation: relative contribution of the imaging system to measurement error.

In a brief question-and-answer session, Dr. Boyd said that the cost of a 3D imaging system is approximately $50,000. He noted that these systems are widely used and that their software is improving. Dr. Judith Allanson, M.D., Ch.B., Children’s Hospital of Eastern Ontario, commented that the software is critical for accurate linear measurements. Dr. Boyd noted that all of these 3D imaging systems need further validation.

Breakout Sessions

In the day-1 breakout sessions, the participants were asked to:

• Consider life stages/organ system
  • Prenatal
  • Fetal deaths
  • Cardiac defects
  • Infancy and childhood
• Identify most useful methods
  • When and how often
  • Relative ratings
  • Current problems or barriers
• Identify additional studies (validation, standardization)
• Review and discuss
  • Preliminary recommendations
  • Appropriateness of methods for whole Study or substudies, field versus center, timing of exams.

In the day-2 breakout sessions, the participants were asked to:

• Draft summaries of their findings, including:
  • Draft recommendations for realistic methods for ascertaining birth defects, considering the overall scope of the evaluations across time and centers
  • Draft recommendations for pilot studies
  • Draft recommendations for standard protocols
• Participate in large group review and discussion to address:
  • Potential approaches
  • Further development of methods.

Each group was asked to address the following questions on methods and examinations:

• Which methods should be considered for use for this life stage/organ system for the Study?
• When (at what ages) and how often should evaluations be made? Feasible? Mandatory minimum?
• Which methods do you expect to be most useful (for example, low risk, low burden, reliable, accurate, feasible, low cost) for use for this life stage/organ system for the Study?
• What are the current problems/barriers, if any, with using these methods in the Study? How can these problems/barriers be solved/overcome?

Each group was asked to address the following questions on validation and standardization of methods:

• For those methods that are expected to be most useful, what research, additional validation, or pilot studies would be needed to make these methods a viable option for ascertaining and evaluating birth defects in the Study?
• What approaches should be considered for ascertaining and evaluating birth defects across time and centers in the Study, including standardized protocols and practical algorithms?

Dr. Correa presented the following conceptual framework for the breakout sessions:

• Consideration 1
  • Appropriateness for the Study
  • Evaluations of key structures/organs
  • Safe and minimum subject burden
  • Time and inconvenience
• Consideration 2
  • Feasibility and applicability
  • Assessment in field/center
  • Specialized diagnostic facility
  • Whole Study or part sample (substudies)
  • "Core" information needed on every participant
  • For Study participant with suspected birth defects or with antecedent risk factors: more intensive follow-up and/or evaluations
• Consideration 3
  • Technical issues (within and among centers)
  • Precision and validity
  • Technicians and training
  • Level of expertise
  • Time to train
  • Ongoing reliability
  • Standardization
  • Instrumentation/methods
  • Quality control.

Dr. Correa listed the following types of methods to be considered:

• "Field" methods (home or mobile van)
  • Reliable, widely used, inexpensive (relative to information obtained), and safe
  • Measure all participants ("core")
  • Examples include:
    • History and physical exam
    • 2D ultrasound for fetal organ structure
• Clinic/center facilities
  • More accurate, but more expensive, less safe (for example, radiation exposure), and more burdensome
  • Need for primary data repository
  • Measure all or just in a subsample?
  • Examples include:
    • 3D ultrasound fetal scans
    • Fetal echocardiogram
    • Pulse oximetry
• Specialized center/facilities
  • Extremely accurate, but most expensive, less safe (radiation), and most burdensome; includes need for primary data repository
  • Applicable to subsample only to
    • Address specific diagnostic issues
    • Validate field or other methods
  • Examples include:
    • Autopsy
    • Whole body MRI
    • CT.

Specific information requested for the group reports included:

• Method(s) for life stage/organ
• Timing
• Ratings
• Technical concerns
• Appropriateness for whole Study or substudy
• Pilot/validation studies needed.

Prenatal Examination Group Report
Rapporteur: Dr. Simpson

The most useful examinations ready for the whole Study are:

The most useful examinations ready for the whole Study are summarized as follows:

*Includes Doppler of uterine arteries. WGA = gestational age in weeks, QC = quality control.

The most useful examination ready for substudy is:

The most useful examination ready for substudy is summarized as:

The group suggested the following practical protocols/algorithms for the whole Study:

• Preconception (n25,000) à maternal blood sampling
• Pregnancy (recruitment) à history
• 11-14 WGA à maternal blood sampling, 2D ultrasound (transvaginal)
• 15-20 WGA à maternal blood sampling
• 18-23 WGA à 2D ultrasound (abdominal); 3D ultrasound; if suspected abnormality, then MRI
• 30 ± 2 WGA à 2D ultrasound; if suspected abnormality, then MRI.

The group suggested the following pilot studies for examinations for the whole Study:

• MRI—all in a small subgroup will receive fetal MRI at 30 ± 2 WGA to determine whether this tool will increase ascertainment of birth defects above ultrasound alone
• Must be performed in a tertiary center
• Whole fetal MRI
• Goal is to determine whether fetal MRI is logical and/or achievable for entire Study cohort.

The group offered the following additional comments and/or recommendations:

• All specimens are to be banked, including paternal semen specimens, cord blood, etc.
• Ultrasound must be performed in an accredited practice.
• Maternal blood specimen rationale is to increase sensitivity of targeted ultrasound; it may also indicate intrauterine growth restriction and fetal death.
• Sensitivity of some biochemical markers is better before 11 WGA or after 15 WGA.

In response to a question about using controls for MRIs, Dr. Simpson explained that all suspected anomalies should be further examined using MRIs because there will, most likely, also be additional abnormalities in such cases. MRI controls would include a subset of participants who are screened at a routine time to gather information on "normal." These routine screens should be initiated at the beginning of the third trimester.

Fetal Deaths Group Report
Rapporteur: Carolyn Salafia, M.D., M.S., Columbia University

The most useful examinations ready for the whole Study are:

*Standard postmortem photographs with a ruler in the field.

The most useful examinations ready for the whole Study are summarized as follows:

NA = not applicable.

The group proposed the following practical protocols and/or algorithms for the whole Study:

• Standard postmortem examination to ascertain structural and/or chromosomal anomalies—modifications for GA, condition of fetus, consent, and options for limited exam
• Postmortem exam needs to be part of a comprehensive and standard protocol to determine conditions associated with fetal (spontaneous and induced losses), infant, and child deaths (standard protocols exist that may be modified for the Study).
• Standard protocol for examination of the placenta in all pregnancies.

The group listed the following pilot studies for examinations:

• Feasibility issues and standardization for postmortem exams in 12-20 weeks
• Feasibility imaging techniques (MRI, CT, ultrasound) for refusal of autopsy; use of imaging alone for ascertaining structural anomalies
• Methods to increase autopsy rate
• Use of 3D photography for nonmacerated, intact fetuses
• Prevalence of confined placental mosaicism in normal, growth restricted, and congenital anomalies (sample).

Other considerations include:

• After fetal death
  • Consider inclusion of next pregnancy in the study
  • Assess maternal health postpartum
• Prenatal findings will impact the extent of the postmortem exam for anomalies and possibly for cause of death.
• Minimal standard protocol for all placentas:
  • Standard photograph
  • Weigh and measure
  • Mid-section at cord (full depth)
  • External inspection
  • Uniform collection and storage of placental samples/specimens.

In a brief discussion session, Lawrence D. Platt, M.D., University of California, Los Angeles, commented that, in lieu of an MRI, an alternative postmortem examination technique involves ultrasound with the fetal specimen immersed in a water bath. Dr. Platt cautioned that this technique is effective for about 24 hours after death. He said that brain abnormalities are observable with this technique. The participants mentioned the following issues:

• Spontaneous losses versus terminations
• Prevalence and detection of losses <12 weeks GA
• Life style changes of women who register with the Study prior to conception
• Evaluation of all live births that subsequently die postnatally, not just stillbirths, terminations, and other losses.

Prenatal, Newborn, Infancy, and Childhood—Heart Group Report
Rapporteur: James Huhta, M.D., University of South Florida

The most useful examinations ready for the whole Study are:

MRA = magnetic resonance angiography.

The most useful examinations ready for the whole Study are summarized as follows:

The group offered the following recommendations on standard protocols and/or algorithms for the whole Study:

• Prenatal period (18-22 weeks)
  • Echocardiogram: stick volume or equivalent
  • Referral to center in absence of reassuring scan in the field
• Newborn period (24-36 hours)
  • History and physical exam
  • Echocardiogram
  • Pulse oximetry
• 6 years of age
  • History and physical exam
  • ECG
• 14 years of age
  • History and physical exam
  • Echocardiogram (a restricted one: just get mass and volume, if already gotten coronaries).

The group offered the following recommendations for pilot studies for examinations for the whole Study:

• Neonatal and 14-year-old echocardiogram
  • Coronary artery screening, field versus laboratory
  • Growth restricted versus normal at 14 years of age whether they have cardiac abnormalities (myocardial assessment, wall thickness) using tissue Doppler and M-mode
• Fetal echocardiogram at 18—22 weeks
  • Pilot study: fetal echocardiogram versus fetal screen (extended, heart screening exam)
  • Early first trimester (5—12 weeks) fetal echocardiogram screening complements nuchal translucency
• History, family history, and physical exam at every encounter
  • Prevalence of MTHFR
  • Prevalence of congenital heart disease
• MRI/MRA at 14 years of age
  • Coronary
  • Arrythmogenic right ventricular dysplasia.

Dr. Pretorius suggested that the Study wait for technologies to evolve/advance/develop before beginning the pilot studies with 14-year-olds. A participant asked why pilot studies should focus on 14-year-olds when participation in sports often begins at an earlier age. It was noted that physical exams for sports participation are generally not mandated until a child enters high school.

In a brief discussion session, participants mentioned:

• Screening for/detection of long QT syndrome and arrhythmias in fetuses
• Evolving technologies
• Imaging of soft tissues of the heart
• Correlation of MTHFR, homocysteine levels, and congenital heart disease.

Newborn, Infancy, and Childhood—Other Group Report
Rapporteur: Dr. Allanson

The group offered the following recommendations on standard protocols/algorithms for the whole Study:

• Detailed, structured dysmorphologic exam at
  • 1—3 days of age
  • 1 year of age
  • 5—7 years of age
• Minimum requirement
  • 1—3 days of age
  • Either at 1 year or at 5—7 years of age.

The group offered the following recommendations on standard protocols/algorithms for the whole Study:

• Medical history
  • Focused on issues relevant to birth defects (for example, sei