Download Population-based study of congenital heart defects in Down syndrome

American Journal of Medical Genetics 80:213–217 (1998)
Population-Based Study of Congenital Heart
Defects in Down Syndrome
Sallie B. Freeman,1* Lisa F. Taft,1 Kenneth J. Dooley,2 Katherine Allran,1 Stephanie L. Sherman,1
Terry J. Hassold,3 Muin J. Khoury,4 and Denise M. Saker3
1
Department of Genetics, Emory University, Atlanta, Georgia
Children’s Heart Center, Department of Pediatrics, Emory University, Atlanta, Georgia
3
Department of Genetics and the Center for Human Genetics, Case Western Reserve University and University
Hospitals of Cleveland, Cleveland, Ohio
4
Office of Genetics and Disease Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia
2
Mental retardation and hypotonia are found
in virtually all Down syndrome (DS) individuals, whereas congenital heart defects
(CHDs) are only present in a subset of cases.
Although there have been numerous reports
of the frequency of CHDs in DS, few of the
studies have had complete ascertainment of
DS in a defined geographic area. The Atlanta
Down Syndrome Project, a population-based
study of infants born with trisomy 21, provides such a resource. In the first 6.5 years of
the study, 243 trisomy 21 livebirths were identified in the five-county Atlanta area (birth
prevalence: 9.6/10,000). Cardiac diagnoses
were available on 227 (93%) of the cases and
89% of these evaluations were made by echocardiography, cardiac catheterization, surgery, or autopsy. Of the 227 DS infants, 44%
had CHDs including 45% atrioventricular
septal defect (with or without other CHDs),
35% ventricular septal defect (with or without
other CHDs), 8% isolated secundum atrial
septal defect, 7% isolated persistent patent
ductus arteriosus, 4% isolated tetralogy of
Fallot, and 1% other. This report is unique in
that it contains the largest number of trisomy
21 infants ascertained in a population-based
study where modern techniques for diagnosing cardiac abnormalities predominate. Am.
J. Med. Genet. 80:213–217, 1998.
© 1998 Wiley-Liss, Inc.
Contract grant sponsor: Georgia affiliate of the American Heart
Association; Contract grant sponsor: NIH; Contract grant numbers: N01-HD 92907 and PO1-HD 32111; Contract grant sponsor:
American Academy of Pediatrics Section on Cardiology.
*Correspondence to: Sallie B. Freeman, Ph.D., Department of
Genetics, 1462 Clifton Road, NE, Emory University, Atlanta, GA
30322. E-mail: [email protected]
Received 9 January 1998; Accepted 23 June 1998
© 1998 Wiley-Liss, Inc.
KEY WORDS: trisomy 21; Down syndrome;
congenital heart defects; congenital malformations
INTRODUCTION
Aside from mental retardation and hypotonia, which
are present in virtually all Down syndrome (DS) individuals, the frequency of ‘‘typical’’ findings ranges from
about 1% for leukemia [Zipursky et al., 1992] and 12%
for various gastrointestinal defects [Knox and ten
Bensel, 1972; Scola, 1982] to 40% or more for congenital heart disease (CHD; see Discussion).
Pueschel [1982] reviewed the earlier literature in
which prevalence figures for CHD in DS ranged from
16% to 62%. Of more recent studies, the largest survey
of children with CHD and DS was the BaltimoreWashington Infant Study [Ferencz et al., 1989]. It described 218 children with DS ascertained because of
heart defects (Table I). However, despite a wealth of
literature on the subject, there is a surprising lack of
population-based data on the frequency of CHD in DS.
That is, few of the studies have started with complete
ascertainment of all DS newborns in a defined geographic area. In one of the largest studies of this type,
Stoll et al. [1990] reported the incidence of DS with and
without CHD in 118,265 consecutive births in France
(Table I). Pradat [1992] described the spectrum of CHD
in 167 DS individuals ascertained on a population basis
in Sweden. An advantage of these recent studies is that
more accurate diagnostic tools have come into widespread use for the early detection of heart defects.
The Atlanta Down Syndrome Project (ADSP) was
initiated in 1989 to examine correlations between chromosome 21 nondisjunction and environmental, maternal, and other epidemiologic factors. The ADSP works
in conjunction with the Centers for Disease Control
and Prevention (CDC) to screen all prenatal, clinical,
and cytogenetic diagnoses in the five-county metropolitan Atlanta area. Virtually all liveborn and stillborn
infants with DS are identified. Cases ascertained
through the ADSP-CDC collaboration constitute a
valuable resource for determining the incidence of
214
Freeman et al.
TABLE I. Reports of CHDs in DS
Current
study
(Atlanta)
Study period
1989–1995
Population based
Yes
Number of cases
227b
Percentage with CHD
44%
Types of CHD (% of total with CHD)a
AVSD
45.0%
VSD
35.0%
2° ASD
26.0%c
Coarctation of the
aorta
1.0%
TOF
5.0%f
Other
9.0%
Ferencz et
Martin
al., 1989
et al.,
(Baltimore1989
Washington, (Washington,
DC)
DC)
Stoll
et al.,
1990
(France)
Khoury
and
Erickson,
1992
(Atlanta)
1981–1986
No
218
—
Unknown
No
137
47%
60.1%
15.6%
9.6%
49%
22%
14%
41.9%
29.0%
N/Ad
53%
17%
20%
2.3%
7.3%
1.8%
N/Ad
3%
8%d
4.8%
3.2%
14.5%
N/Ad
N/Ad
N/Ad
Pradat,
1992
(Sweden)
Wells
et al.,
1994
(Alabama)
Rowe and
Uchida,
1961
(Canada)
1979–1987 1968–1989 1981–1986 1988–1992 1955–1957
Yes
Yes
Yes
No
No
139
532
167
118b
174b
44.6%
33%
—
48%
40.2%
59%
{ 31.7%
38.8%
30.6%
28.6%
35.7%
32.8%
8.6%
3.6%
N/Ad
N/Ad
4.1%
8.2%
14.3%
N/Ad
1%
11%
e
a
Total may be >100% when more than one defect per infant is present. Total may be <100% because PDAs were omitted from this table.
Number of cases with records available for review (total number of cases may be greater).
8% isolated.
d
N/A, not available or grouped with other cardiac defects.
e
ASD and/or VSD.
f
4% isolated.
b
c
CHD in DS. Moreover, this study is the largest reported to date where modern cardiac diagnostic techniques predominate. Thus it provides a highly accurate
accounting of CHD in DS.
METHODS
Case Ascertainment
The ADSP population was ascertained through the
ongoing Metropolitan Atlanta Congenital Defects Program (MACDP) of the CDC. The MACDP uses multiple
sources to identify infants born with birth defects including DS. MACDP personnel monitor births in the
five-county metropolitan Atlanta area by regularly reviewing records from birth hospitals, pediatricians,
specialty clinics, and cytogenetic laboratories. Details
of the system are described elsewhere [Edmonds et al.,
1981]. Additionally, for the present study, identification of DS infants within the five-county Atlanta area
was facilitated because many were referred to Emory
University for karyotyping, genetic consultation, or
cardiac evaluation. Included in the current report are
all liveborn infants with trisomy 21 born between
January 1, 1989 and June 30, 1995 to women living in
the five-county Atlanta area at the time of the birth.
The number of stillbirths (艌20 weeks gestation) is reported here, but, because no cardiac information was
available, these cases are not included in the tabulation of CHD.
Record Review
MACDP abstractors reviewed records of infants with
trisomy 21 and collected data on phenotypic manifestations. They noted the methods of diagnosis for each
case [e.g., cardiac exam, electrocardiogram (ECG),
chest X-ray, echocardiography]. However, most detailed cardiac information in this study was obtained
by reviewing records of the pediatric cardiologists who
evaluated the children referred to their practice. Furthermore, it was customary for all ECGs and echocar-
diograms to be interpreted by pediatric cardiologists.
Reports of cardiac catheterizations, surgeries, and autopsies were reviewed by ADSP study personnel. The
most definitive diagnostic procedure was used to classify the cases and resolve any discrepancies. For example, a ventricular septal defect (VSD) noted on
physical examination was classified as a partial atrioventricular septal defect (AVSD) if the echocardiogram
showed the VSD to be of an inlet type. Because of referral patterns in the Atlanta area, most cardiac evaluations in this study were done through a single large
university-based pediatric cardiology practice, thus
providing consistency in diagnosis.
Classification
We classified CHD according to standard anatomic
nomenclature, which assigns priority to the morphologically dominant traits. The classification scheme
used in this study is presented in Table II. The total
cases were divided into two groups: those with CHD
and those without. The CHD cases were then classified
by assigning them first to a broad category and then by
refining the categories to include any associated cardiac defects [Park et al., 1977]. The CHD cases were
divided into six groups: AVSD, VSD, secundum atrial
septal defect (2° ASD), tetralogy of Fallot (TOF), patent
ductus arteriosus (PDA), and other. For the purposes of
this study, patent foramen ovale (PFO) versus 2° ASD
and a PDA associated with prematurity or which closed
spontaneously were not considered forms of CHD.
RESULTS
The birth population in the five-county Atlanta area
from January 1, 1989 through June 30, 1995 was
255,401 (252,374 livebirths, 3,027 stillbirths) and 250
infants with trisomy 21 were identified (243 livebirths,
7 stillbirths). This gives a birth prevalence of 9.8 per
10,000 births for trisomy 21 (9.6 per 10,000 livebirths).
Table III indicates the total trisomy 21 livebirths in
the geographic area, the number of cases with and
Congenital Heart Defects in Down Syndrome
TABLE II. CHDs in DS
CHD
AVSD
Complete
Isolated
With 2° ASD
Only
And arch abnormalitya
And TOF
With persistent PDA only
With arch abnormalityb
Partial
1° ASD
Inlet VSD
VSD
Isolated
With 2° ASD (±PDA) only
With 2° ASD and otherc
With persistent PDA only
With otherd
2° ASD (isolated)
TOF (without AVSD)
PDA (persistent)
Other heart defectse
Total
Number (%)
Total 45 (45%)
19
5
1
1
7
2
3
7
Total 35 (35%)
18
7
4
4
2
8 (8%)
4 (4%)
7 (7%)
1 (1%)
100 (100%)
a
Aberrant left subclavian artery.
Right aortic arch, coarctation.
c
Double outlet right ventricle (2), pulmonic stenosis (2).
d
Coarctation, double aortic arch, and pulmonic stenosis.
e
Vascular ring (aberrant left subclavian artery and right aortic arch).
b
without cardiac information, and the methods of diagnosis for cases with and without CHD. Of the 243 cases
ascertained, there were 227 cases (93%) with cardiac
records available for review. Congenital heart disease
was present in 100 cases (44%), and absent in 127 cases
(56%). For those with CHD, all diagnoses were made by
echocardiogram, cardiac catheterization, surgery, or
autopsy. Eighty percent of those without CHD were
evaluated by echocardiography, but, in 17%, CHD was
ruled out by ECG or physical examination. In the three
remaining cases, the method used to exclude CHD was
not documented.
Table II presents the types of heart defects found in
this DS population. AVSD was the most common type,
representing 45% of CHDs. Complete AVSDs were
seen in 35 cases and were usually isolated (19 cases).
Defects associated with a complete AVSD included 2°
ASD, PDA, arch abnormalities (coarctation, right aortic arch, aberrant right subclavian artery), and TOF.
Partial AVSDs included three ostium primum ASDs
and seven inlet VSDs.
VSD was the second most common type of CHD (35%
of CHDs). Isolated VSDs were frequent; however, VSDs
were also commonly associated with a variety of other
defects: 2° ASD, PDA, arch abnormalities, right ventricular outflow tract obstruction (pulmonic stenosis
and pulmonary atresia), and double-outlet right ventricle. Isolated secundum ASD (8%), TOF (4%), persistent PDA (7%), and one case with a vascular ring (aberrant left subclavian artery and right aortic arch)
made up the remainder.
Table IV presents the racial and maternal age distribution of cases with and without CHD. There were
no significant differences in either the mother’s race or
215
age between those cases with and without CHD or
AVSD.
DISCUSSION
Table III demonstrates that, in the present study,
diagnoses were chiefly made on the basis of echocardiography, cardiac catheterization, surgery, or autopsy.
This was true of infants with CHD (100%) and without
CHD (80%). Tubman et al. [1991] compared the accuracy of several types of diagnostic procedures in a study
of DS and CHD. They found that 29% of infants with a
normal ECG were subsequently found by echocardiography to have a significant heart defect. There were 16
infants in our study for whom CHD was ruled out
solely by an ECG plus six with only a physical examination. If 29% of these actually had a CHD, this would
add six cases to our list of those with heart defects, but
the overall rate would not increase appreciably (47%
versus 44%). Little can be said about the 16 for whom
we have no cardiac information. If we assume that
none of them had a heart defect, the prevalence of CHD
would change from 44% to a minimum possible rate of
41%.
In order to obtain an accurate estimate of the prevalence and types of heart defects in DS, it is essential to
have a population-based sample and to use the most
reliable diagnostic methods currently available. The
difficulty has been finding a population where both of
these criteria can be met. Over the past decade there
have been a number of studies reporting the occurrence
of CHD in DS. Table I summarizes several of these
recent reports and indicates whether or not they are
population based. For comparison, the table also includes an earlier study conducted in the 1950s [Rowe
and Uchida, 1961]. Many of the studies have enrolled
only those cases presenting to a cardiologist or to a
geneticist and, therefore, they do not necessarily include all DS infants born in a defined population. For
example, in the Baltimore-Washington Infant Study
[Ferencz et al., 1989], infants were ascertained through
pediatric cardiology clinics; thus, infants without CHD
were not included and an overall assessment of the
prevalence of CHD in DS was not possible. However,
the authors of that study used echocardiography, cardiac catheterization, surgery, and autopsy to obtain an
accurate accounting of the types of heart defects in all
DS infants with CHD who were born in the geographic
area covered by their study. They reported the highest
rate of AVSD of any of the studies (60.1%), but a generally lower rate of non-AVSD VSD (15.6%) and 2° ASD
(9.6%). These differences may reflect the types of cases
most often referred to pediatric cardiologists.
Khoury and Erickson [1992] reported on DS and
CHD using the same geographic area and similar ascertainment methods as in the present study, but their
sample was collected from 1968 to 1989 whereas our
collection began in 1989. Therefore, there is only a oneyear overlap between the two study populations. In
general, over the 22-year period covered in their survey, the rate of reported CHD in DS rose from 20% to
over 50%, an increase they attribute to improved ascertainment of these defects. For those cases with
216
Freeman et al.
TABLE III. Trisomy 21 Case Ascertainment and Method of Cardiac Evaluation
Method of cardiac evaluation
Cases
Trisomy 21 livebirths
No cardiac information
Cardiac information
CHD present
CHD absent
Number (%)
Unknown
Physical exam
ECG
Echocardiogram
(and/or other)b
243
16 (7%)
227 (93%)
100 (44%)
127 (56%)
0
3a
0
6
0
16
100
102
a
CHD ruled out in newborn period but type of cardiac evaluation not recorded on abstracted record.
Echocardiography and/or cardiac catheterization, surgery, or autopsy.
b
CHD, they reported similar rates of AVSDs (53% versus 45% of CHD in our study) and 2° ASD (20% versus
our 26% isolated or with other CHD), but their proportion of VSDs was smaller (17% versus our 35%).
In general, all of the recent reports listed in Table I
confirmed that an AVSD is the most common heart
defect in DS (38.8% to 60.1%). Results from the present
study fell in the midrange (45%). Among the several
reports, non-AVSD VSDs occurred in 15.6% to 35% of
DS infants, the latter proportion being from the present study. Not included in Table I are the rates for
PDA, which ranged widely from 3% to 41.9%. This reflects the difficulty in determining when a PDA is persistent and clinically significant and when it is related
to prematurity or to having a cardiac evaluation in the
first day or two of life. For example, the higher rate of
PDA reported by Khoury and Erickson [1992], 38% versus our 7%, probably reflects the fact that those authors relied predominantly on newborn records
whereas we were able to exclude the transient PDAs
seen in some newborns by reviewing the cardiac reevaluations performed after initial hospital discharge.
Finally, in the majority of studies, coarctation of the
aorta and TOF were found in less than 10% of individuals. Although only the more recent studies of CHD
in DS are discussed here and emphasis is placed on the
importance of modern methods of cardiac diagnosis, it
is remarkable that the four-decade-old study by Rowe
and Uchida [1961] found results very similar to current
studies that use more sophisticated diagnostic methods.
Previous studies on CHD in DS have not always included information on demographic factors such as ma-
ternal age and race. Of the three population-based
studies of DS cited in this article, the French population enrolled by Stoll et al. [1990] was over 90% white
and the authors did not report CHD information separately by race or maternal age. In the study by Pradat
[1992], subjects were ascertained from two Swedish
birth defects registries. The authors did not include
racial or maternal age information, although, presumably, the population was predominantly white. The Atlanta study reported by Khoury and Erickson [1992]
included 346 white and 174 black infants with DS. The
authors reported a significantly greater incidence of
CHD in black infants (38.5% versus 28.6% for whites;
odds ratio (OR) 1.6, 95% confidence interval (CI) ⳱ 1.0
to 2.3). Our cases, from the same geographical area but
a different time period, showed a trend toward increased CHD in black infants with DS (49% in blacks
versus 40% in whites), but the difference was not significant (OR 1.48, 95% CI ⳱ 0.8 to 2.7). Comparing the
proportion of DS infants with CHD between women
<35 years old and 艌35 years old, Khoury and Erickson
[1992] did not find a significant difference. Similarly,
we report no relationship between maternal age and
CHD in our cases. Rowe and Uchida [1961] found no
apparent difference in the maternal age distribution in
cases with and without CHD. Their population was
from Ontario, Canada, and again, presumably, was
predominantly white, although racial and ethnic data
were not included. Since the ADSP was originally designed to investigate the influence of maternal and environmental factors on chromosome nondisjunction, we
have collected extensive epidemiological data on our
population. A detailed analysis of the influence of these
TABLE IV. Mother’s Race and Age in DS Cases With and Without CHD
All cases
Race
Caucasian
Black
Hispanic
Asian
Maternal age
<35
艌35
a
Total
trisomy 21
livebirthsa
CHD (%)
No CHD (%)
AVSD (%)
No cardiac
information
243
100 (44%)
127 (56%)
45 (20%)
16
132
92
6
13
50 (40%)
41 (49%)
4 (67%)
5 (42%)
76 (60%)
42 (51%)
2 (33%)
7 (58%)
24 (19%)
18 (22%)
0
3 (25%)
6
9
0
1
171
72
72 (45%)
28 (42%)
89 (55%)
38 (58%)
33 (20%)
12 (18%)
10
6
In five-county Atlanta area from 1/1/89–6/30/95. Numbers in parentheses are percentages of
all cases with cardiac information. None of the differences in this table reached significance
(i.e., all P > 0.05).
Congenital Heart Defects in Down Syndrome
factors on CHD in DS will be the subject of a later
paper.
It is generally known that both the frequency and the
types of CHD vary between the DS and non-DS population. For example, in the Baltimore-Washington Infant Study, AVSD was found in only 2.8% of non-DS
cases but in 60.1% of DS cases [Ferencz et al., 1989]. As
pointed out by others [Van Praagh et al., 1984; Ferencz
et al., 1989], several cardiac lesions seen in the non-DS
population are rarely if ever found in individuals with
DS. This was true in the present study where there
were no cases of heterotaxy or transposition of the
great arteries. These differences between the DS and
non-DS populations suggest that a variety of spatially
and temporally distinct processes are occurring during
the formation of the heart and the presence of a third
copy of a gene or genes on chromosome 21 has an impact on only specific developmental points. This provides incentive to search chromosome 21 for genes that,
when present in three copies, disrupt specific steps in
the embryological development of the heart [Duff et al.,
1990; Zittergruen et al., 1995; Davies et al., 1995]. Our
laboratory is currently searching for these genes by
identifying areas of disomic homozygosity on chromosome 21 [Feingold et al., 1995] and by studying allelic
variation in candidate genes for CHD.
ACKNOWLEDGMENTS
We acknowledge the cooperation of the Children’s
Heart Center at Emory University and thank the children with Down syndrome and their families for their
participation. The work was supported by a grant from
the Georgia affiliate of the American Heart Association, NIH contract N01-HD 92907, and NIH grant
PO1-HD 32111. D.M.S. was supported by the American
Academy of Pediatrics Section on Cardiology Research
Fellowship Award.
REFERENCES
Davies GE, Howard CM, Farrer MJ, Coleman MM, Bennett LB, Cullen
LM, Wyse RKH, Burn J, Williamson R, Kessling AM (1995): Genetic
variation in the COL6A1 region is associated with congenital heart
defects in trisomy 21 (Down’s syndrome). Ann Hum Genet 59:253–269.
217
Duff K, Williamson R, Richards SJ (1990): Expression of genes encoding
two chains of the collagen type VI molecule during human fetal heart
development. Int J Cardiol 27:128–129.
Edmonds LD, Layde PM, Levy MJ, Flynt JW, Erickson JD, Oakley GP Jr
(1981): Congenital malformations surveillance: Two American systems. Int J Epidemiol 10:257–252.
Feingold E, Lamb NE, Sherman SL (1995): Methods for genetic linkage
analysis using trisomies. Am J Hum Genet 56:475–483.
Ferencz C, Neill CA, Boughman JA, Rubin JD, Brenner JI, Perry LW
(1989): Congenital cardiovascular malformations associated with chromosome abnormalities: An epidemiologic study. J Pediatr 114:79–86.
Khoury MJ, Erickson JD (1992): Improved ascertainment of cardiovascular
malformations in infants with Down’s syndrome, Atlanta, 1968–1989.
Am J Epidemiol 136:1457–1464.
Knox GE, ten Bensel RW (1972): Gastrointestinal malformations in Down’s
syndrome. Minn Med 55:542–544.
Martin GR, Rosenbaum KN, Sardegna KM (1989): Prevalence of heart
disease in trisomy 21: An unbiased population. Pediatr Res 25:77A.
Park SC, Matthews RA, Zuberbuhler JR, Rowe RD, Neches WH, Lenox CC
(1977): Down syndrome with congenital heart malformation. Am J Dis
Child 131:29–33.
Pradat P (1992): Epidemiology of major congenital heart defects in Sweden,
1981–1986. J Epidemiol Community Health 46:211–215.
Pueschel SM (1982): Biomedical aspects in Down syndrome: Cardiology. In
Pueschel S, Rynders J (eds):‘Down Syndrome: Advances in Biomedicine
and the Behavioral Sciences.‘ Cambridge, Massachusetts: Ware Press,
pp 203–206.
Rowe RD, Uchida IA (1961): Cardiac malformation in mongolism. Am J
Med 31:726–735.
Scola PS (1982): Biomedical aspects in Down syndrome: Gastroenterology.
In Pueschel S, Rynders J (eds):‘Down Syndrome: Advances in Biomedicine and the Behavioral Sciences.‘ Cambridge, Massachusetts: Ware
Press, pp 207–210.
Stoll C, Alembik Y, Dott B, Roth M (1990): Epidemiology of Down syndrome in 118,265 consecutive births. Am J Med Genet Suppl 7:79–83.
Tubman TRJ, Shields MD, Craig BG, Mulholland HC, Nevin NC (1991):
Congenital heart disease in Down’s syndrome: Two year prospective
early screening study. BMJ 302:1425–1427.
Van Praagh S, Antoniadis S, Otero-Coto E, Leidenfrost RD, Van Praagh R
(1984): Common atrioventricular canal with and without conotruncal
malformations: An anatomic study of 251 postmortem cases. In Nora
JJ, Takao A (eds): ‘‘Congenital Heart Disease: Causes and Processes.’’
New York: Futura, pp 599–639.
Wells G, Barker SE, Finley SC, Colvin EV, Finley WH (1994): Congenital
heart disease in infants with Down’s syndrome. South Med J 87:724–
727.
Zipursky A, Poon A, Doyle J (1992): Leukemia in Down syndrome: A review. Pediatr Hematol Oncol 9:139–142.
Zittergruen MM, Murray JC, Lauer RM, Burns TL, Sheffield VC (1995):
Molecular analysis of nondisjunction in Down syndrome patients with
and without atrioventricular septal defects. Circulation 92:2803–2810.