The Wisconsin Pediatric Cardiac Registry: A Mechanism For

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WISCONSIN MEDICAL JOURNAL
The Wisconsin Pediatric Cardiac
Registry: A Mechanism for Exploring
Etiologies of Congenital Heart Defects
Kathleen A. Hanson-Morris, MS, RN; Andrew N. Pelech, MD
ABSTRACT
On January 1, 2000, the Wisconsin Pediatric Cardiac
Registry began registering families of infants born with
a congenital heart defect (CHD) in Wisconsin. Pediatric
cardiologists across the state developed the Registry as a
database and as a research study exploring potential etiologies of CHDs. Participating pediatric cardiologists identify the infants and refer families to the Registry. Families
are asked to participate by completing a comprehensive
questionnaire that inquires into exposures and illnesses
experienced during the 6 months prior to the pregnancy
and during the pregnancy itself. A subset of families, based
on the infant’s diagnosis (hypoplastic left heart syndrome,
conotruncal abnormalities, and Ebstein’s anomaly) participates in DNA testing. This article describes the development of the Registry, family referral and participation
to date, genetic advances in the etiology of CHDs, and
research initiatives utilizing the data provided by families
for the WPCR.
single genes (Table 1), and about 2% are attributed to
known environmental factors.1 For the remaining 85%90% of cases, gene-environment interaction theory—first
described and investigated by Nora3—continues to be the
subject of considerable interest and research. Past studies
have attributed the development of certain heart defects to
maternal diabetes, obesity, use of cocaine and marijuana,
fever early in pregnancy, smoking, pesticides, exposure to
paints, and maternal exposure to lithium and antiepileptic
medications.1,4,5
In recent years, studies of chick, zebrafish, and mouse
embryos have significantly increased our knowledge of
heart development by identifying pathways that control
early cardiogenesis and by defining the stages of heart development.6 Since the heart is completely developed by
the end of the first trimester of human pregnancy, the critical periods for teratogenic influences is now well defined7
and allows for correlation of reported environmental exposures with the development of certain defects.
INTRODUCTION
Congenital heart defects (CHD), while rare, constitute the
most common birth defect encountered in Wisconsin. The
prevalence of CHD in the literature ranges from 0.3% to
0.8%.1 With Wisconsin’s population now exceeding 5 million and a birth rate of 12/1000, an estimated 400-600 new
cases of congenital heart defects are diagnosed annually,
for an estimated prevalence of 0.5%-0.8%. In developed
societies, CHDs are the leading cause of infant mortality
and continue to contribute to childhood mortality and
morbidity well into adult life.2
The exact cause of most cases of CHD is unknown.
Approximately 5%-10% are associated with a chromosome abnormality, 3%-5% can be linked to defects in
THE WISCONSIN PEDIATRIC CARDIAC
REGISTRY (WPCR)
The concept of a registry of children born in Wisconsin
with a CHD began in the late 1990s when pediatric cardiologists noted a potentially higher than expected number of infants born with hypoplastic left heart syndrome
(HLHS) in various parts of the state. The Baltimore
Washington Infant Study (BWIS) (1981-1989),2 the first
regional population-based study to explore potential environmental etiologies of congenital heart defects, had
demonstrated the utility of registries in defining epidemiological characteristics and trends, population differences, regional variations in incidence, patterns of specific
disease, and etiologic hypotheses.
The Wisconsin Pediatric Cardiac Registry (WPCR),
framed after the BWIS, was developed as an official record
of infants born in Wisconsin with a CHD and a database
of demographic and parental exposure and illness information. The primary aim of both the BWIS and the WPCR
Authors are with the Children’s Hospital of Wisconsin, Milwaukee, Wis,
and the Medical College of Wisconsin, Milwaukee, Wis. Please address correspondence to: Kathleen Hanson-Morris, MS, RN, 9000 W
Wisconsin Ave, PO Box 1997, MS 713, Milwaukee, WI 53201-1997;
phone 414.266.2325; fax 414.266.3979; e-mail [email protected]
Wisconsin Medical Journal 2006 • Volume 105, No. 3
45
WISCONSIN MEDICAL JOURNAL
Table 1. Overview of CHD’s Associated with Select Syndromes and Genetic Advances in Etiology
Gene
Locus
Syndrome
CHD
ZIC3
TFAP-2b
TBX5
Xq26.2
Heterotaxy:8
Char syndrome9
Holt Oram10
Multiple
22q11 deletion11
DiGeorge
Velocraniofacial
Conotruncal facial
JAG1
DSCAM
10q12
21q22.2-21q22.3
Alagille12
Down13
Situs abnormalities8
PDA
ASD-primarily
VSD
Atrioventricular septal defect
Tetrology of Fallot
truncus arteriosus
interrupted arch type B
ASD, VSD, isolated vascular ring-less common
right-sided cardiac defects
AVSD
VSD
ASD
AVSD, pulmonary stenosis, coartation of aorta,
ASD, Tetrology of Fallot
Supravalvular aortic stenosis, pulmonary stenosis,
septal defects
PDA, ASD, VSD, Tetrology of Fallot
ASD, VSD, Tetrology of Fallot, Ebstein’s
12q24.1
Noonan14
Williams
Charge
NKTX2.5
tinman
5q34
ASD=atrial septal defect; VSD=ventricular septal defect; PDA=patent ductus arteriosus; AVSD=atrioventricular septal defect.
Heterotaxy syndrome: autosomal recessive disorder with right sided heart and reversed position of abdominal disorders14
DiGeorge syndrome: characterized by defects of thymus, parathyroid glands, and heart14
Holt-Oram syndrome: autosomal dominant disease with upper extremity and congenital heart abnormalities15
Alagille syndrome: autosomal dominant disorder with facial dysmorphism, vertebral defects, and congenital heart defects15
Velocraniofacial syndrome: autosomal dominant disorder with specific facial charactreristics, some mental retardation, cardiac defects, and cleft palate15
Noonan syndrome: geneticlayy heterogeneic disorder with short stature, mental retardation (not all), specific facial features, and heart defects15
Williams syndrome: autosomal dominant disease with disorder of Vitamin D metabolism, teeth abnormalities, growth deficiencies, heart problems, and mental retardation15
Charge syndrome: associate with coloboma, heart disease, atresia of chonanae, mental retardation, genital hypoplasia, ear abnormalities, deafness15
is to allow for the study of characteristics and exposures
that may contribute to the development of CHDs. The
WPCR began January 1, 2000, and continues to operate.
METHODS
Inclusion Criteria
Any infant with a structural congenital heart defect who is
conceived in Wisconsin and born January 1, 2000 onward
is eligible for inclusion in the WPCR. Diagnosis is made
by clinical exam performed by a pediatric cardiologist, or
by echocardiography, cardiac catheterization, surgical inspection, and occasionally, through autopsy.
Exclusion Criteria
Diagnostic exclusions include infants with an isolated patent foramen ovale or patent ductus arteriosus, electrical
conduction disturbances of the heart without an associated
structural abnormality, and acquired heart diseases, such as
Kawasaki’s, rheumatic fever, or endocarditis.
Referral Process
An explanation of the WPCR along with a printed brochure is provided to each family with an infant newly di46
agnosed with a CHD. If a family agrees to participate, the
infant’s and parents’ names, current address, infant’s date
of birth, gender, race, cardiac and non-cardiac diagnoses
are sent to the WPCR office for input into the central database. All information is encrypted and strict confidentiality is maintained. If a family declines to participate, they
are removed from further contact.
Families participate by completing a self-administered
35-page questionnaire that inquires into maternal and paternal illnesses, drug and toxic exposures prior to and during this pregnancy, as well as family history of congenital
and acquired diseases (Table 2). It can be completed in
either print form or directly on-line, with a unique, computer-generated ID code that allows the family to access
their questionnaire for 30 days. Those completing the print
form are provided with a stamped, addressed return envelope and asked to complete and return the questionnaire
within 30 days. The questionnaire takes approximately 4560 minutes. Follow-up reminders are made by phone or,
when possible, in person.
A subset of families—based on the infant’s diagnosis of
HLHS, Ebstein’s anomaly, or conotruncal abnormalities—
Wisconsin Medical Journal 2006 • Volume 105, No. 3
WISCONSIN MEDICAL JOURNAL
are asked to participate in DNA sampling. DNA testing
includes the infant and first-degree relatives and is accomplished through a blood sample, the preferred method, or
buccal samples using a swab or mouth wash. Each family
member who agrees to participate in DNA testing signs a
separate consent form.
PRELIMINARY RESULTS
Since January 1, 2000, over 2600 families have been referred to the WPCR. Of these, 1950 have agreed to participate, providing 1200 questionnaires and 950 DNA samples. Less than 5% of families have declined for a variety
of reasons: disinterest, confidentiality concerns, or lack of
time. Two other groups of non-participants are those who
do not respond to the introductory letter (6%) and those
who agree to participate but do not return the questionnaire despite follow-up efforts (12%).
We estimate that approximately 75% of infants born
with a CHD in Wisconsin are referred to the WPCR.
Centers across the state that actively refer families include
Children’s Hospital of Wisconsin (CHW) in Milwaukee,
Marshfield Clinic, Prevea Medical Clinic in Green Bay,
Dean Medical Center in Madison, and Gundersen Clinic
in LaCrosse. CHW houses the premier cardiovascular surgical department and interventional catheterization lab in
the state, assuring ascertainment of infants with complex
congenital heart defects. Table 3 provides a breakdown of
referrals by diagnosis, compared to percentages reported
in the literature.
Research
A number of pilot studies utilizing the data from the
WPCR have been completed. Table 4 outlines preliminary
results of these studies. DNA samples are suitable for cluster analysis and for specific gene localization studies.
Several ongoing studies are investigating the incidence
of CHD in eastern Wisconsin, while another is utilizing
subject DNA samples to examine a gene that may be implicated in certain defects. CHW Foundation provides the
primary funding for the WPCR, with money for specific
research projects obtained through various grant sources.
DNA testing is funded by the General Clinical Research
Center Grant M01-RR00058 from the National Institutes
of Health.
CONCLUSIONS
Research into etiologies of congenital heart defects remains
in its infancy. Few large-scale population studies have examined associations between exposures reported by parents and the development of specific congenital heart defects. Laboratory research and analysis of specific genes
and gene pathways, along with data from the WPCR, pro-
Table 2. Data Categories and Variables Investigated for the
WPCR
Infant Factors
Gender, race, birth number, date of birth, and expected DOB
Specific CHD diagnosis and when diagnosed, associated syndromes, and other diagnoses If infant has died, cause of death
Birth Control
Problems with and treatment for menstrual periods, birth control,
fertility treatment, including in vitro fertilization, ultrasound, amniocentesis, chorionic villus sampling
Socioeconomic Factors
Mother/father race, date of birth, place of birth, income, schooling,
occupation, marital status, type of house, heat, and water source,
use of fireplace, pets in home
Maternal Illness
Diabetes, asthma, thyroid disease, epilepsy, lupus, eating disorders, cancer, hypertension, obesity, bladder/kidney infections,
emotional problems, vaginal infections, arthritis, headaches, upper
and lower respiratory infections, fever greater than 101, exposure
to AIDS/HIV, hepatitis, chicken pox, measles, mumps, nausea/
vomiting, bleeding/spotting
Other Maternal Factors
Use of multivitamins, vegetarian, use of protein supplements,
health food/supplements, use of any OTC/prescribed medications,
height/weight and amount of weight gained during pregnancy, conception/birth addresses, and months pregnant when mom moved
Paternal Illness
Diabetes, eating disorder, cancer, asthma, allergies, epilepsy, thyroid disease, lupus
Maternal/Paternal Exposures
X-ray, nuclear scans, anesthesia, cigarettes (smoke and exposure),
alcohol use, cocaine, hashish, marijuana, heroin, barbiturates, caffeine, active duty, carpentry, paint, varnish, turpentine, welding, dry
cleaning solvents, mercury, paper/pulp products, nickel, jewelry
making, art oils and acrylics, hair dyes/perms, plastics, extreme
heat/cold, ionizing radiation, anesthetic gases, fertilizers, pool
cleaning chemicals, exposure to radiation, pesticides
Family History
CHD, acquired heart disease, other birth defects. Includes mother,
father, full and half siblings, grandparents, aunts, uncles, and first
cousins.
vide an exciting future for the study of potential etiologies
and prevention strategies of CHD.
One goal of the Registry is to increase ascertainment of
infants across the state. Alternatively, we welcome referrals
from primary care physicians, with a copy of the echocardiograph report. The WPCR can be reached by phone
(414.266.2325 or 877.809.9727) or e-mail: [email protected]
ACKNOWLEDGMENTS
The authors wish to thank the families who participate
in the WPCR, the pediatric cardiologists who refer families, the staff of the Bioinformatics Research Center at the
Medical College of Wisconsin for designing and maintaining the WPCR database, and Julia Harris, Medical
College of Wisconsin student, for her contributions to
Tables 1 and 3.
Wisconsin Medical Journal 2006 • Volume 105, No. 3
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WISCONSIN MEDICAL JOURNAL
Table 3. Primary Diagnosis of Select Cases of CHD in WPCR,
Compared to Literature16,17
CHD Diagnosis
Coarctation of aorta
Secundum ASD
Bicuspid AV valve*
AV stenosis
Atrioventricular Septal Defects
With Down syndrome
Without Down syndrome
Hypoplastic left heart syndrome
Total anomalous pulmonary veins
Pulmonary valve stenosis*
Double outlet right ventricle
Ebstein’s anomaly
D-transposition of great arteries
Tetrology of Fallot
VSD’s
Muscular*
Membranous
Shone’s syndrome
Pulmonary atresia with VSD
Pulmonary atresia without VSD
% in
WPCR
% Cited in
Literature
4.3
11
3.8
1
6.2
3.6
2.6
3
1
11
1
0.7
3.5
3.5
39
25
14
0.6
1.3
1
5-10
5-10
0.4-2.25
2-6
2
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* Most likely unreported
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Table 4. Preliminary Results from WPCR Research Studies
9.
Comparison of descriptive characteristics and reported exposures
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10.
DS, N=67
Maternal and paternal age >35
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Nausea/vomiting during
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Lead
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Smoking
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56% male
64% diagnosed prenatally
16% twinning
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Total population:
• Total number of cases were increased in 2004 for quarters 1
and 3, but no significant variations noted across the 5 years
• 52.3% female, 47.7% male
• Septal defects were more common in females; more males had
left ventricular outflow tract obstructions (LVOTO)
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Comparison of incidence of CHD in upper and lower Fox River areas
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Milwaukee County had the highest incidence with 0.905%. This
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48
Wisconsin Medical Journal 2006 • Volume 105, No. 3
The mission of the Wisconsin Medical Journall is to provide a vehicle for professional
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