Vol 5 No 1 full text edit.indd

Althea Medical Journal. 2018;5(1)

6 AMJ March 2018

Congenital Heart Disease among Down Syndrome Children at Dr.
Hasan Sadikin General Hospital from 2008 to 2013

Thyviyaa Rajamany,¹ Rahmat Budi Kuswiyanto,² Leonardo Lubis3
1Faculty of Medicine Universitas Padjadjaran, 2Department of Internal Medicine Faculty of
Medicine Universitas Padjadjaran/Dr. Hasan Sadikin General Hospital Bandung Indonesia,

3Department of Physiology Faculty of Medicine Universitas Padjadjaran Bandung, Indonesia

Abstract

Background: Children with Down syndrome are more prone to congenital heart disease due to the
consequences of trisomy chromosomal 21 on gene expression. The aim of this study was to determine the
pattern of congenital heart disease in children with Down syndrome.
Methods: This was a retrospective study of reviewed children with Down syndrome from January 2008 to
January 2013 at Dr. Hasan Sadikin General Hospital, Bandung, Indonesia. This study was conducted from
August until October 2014. Patients under the age of 15 years and diagnosed having congenital heart disease
from 2008 to 2013 were enrolled in this study by using the total sampling method. Incomplete medical
records and children who had not performed an echocardiogram were excluded. Sex, age at diagnosis for
congenital heart disease, nutritional status and other comorbidities were also examined.
Results: Congenital heart disease occurred in 28 children with Down Syndrome. Patent ductus arteriosus
(PDA) was the most common and found in 11 patients followed by a combination of congenital heart diseases
in 5 patients. Other 3 patients had Atrioventricular septal defect (AVSD), and Tetralogy of fallot (TOF) was
found in 3 patients, 2 patients had Atrial septal defect (ASD) and 1 patient had miscellaneous cardiac defect.
Conclusions: The most common CHD in Down syndrome is PDA.

Keywords: Children, congenital heart disease, Down syndrome

Correspondence: Thyviyaa Rajamany, Faculty of Medicine, Universitas Padjadjaran, Jalan Raya Bandung-Sumedang
Km.21, Jatinangor, Sumedang, Indonesia, Email: thyviyaarajamany@gmail.com

Introduction

The World Health Organization (WHO)
confirmed that children with Down syndrome
were more prone to get congenital heart disease
and other diseases.1 Incidence of congenital
heart defect is higher among Down syndrome
children, approximately 50% as suggested
by several studies and this is associated with
abnormality in genes of the children with
Down syndrome.2 Previous studies in the
North East of England and Turkey showed that
the most common single defect of congenital
heart disease is an Atrioventricular septal
defect.3,4 Several studies were also conducted
to determine the pattern of congenital heart
disease and they concluded that the most
common types of congenital heart disease
are Atrioventricular septal defect (AVSD),
Ventricular septal defect(VSD), Atrial septal
defect(ASD) and Tetralogy of fallot (TOF).5

Trisomy of Hsa21 which occurs in children
with Down syndrome is associated with
congenital heart defects. However, not one
study has proven yet that chromosome 21 is
the exact chromosome responsible for the
cardiac anomaly in Down syndrome. Thus,
the presence of specific gene variants such as
trisomy 21 can further increase susceptibility
for cardiac defects in Down syndrome.6

The variation in folate pathway genes plays
an important role in forming the congenital heart
disease in Down syndrome. In this metabolic
pathway, the methylenetetrahydrofolate
reductase (MTHFR) undergoes polymorphism
which causes decrease in availability of
5-methylTHF for methylation, and then leads
to reduction of global DNA methylation.
Inhibition of DNA methylation can cause
decrease in S-adenosylmethionine/S-
adenosylhomocysteine ratio which results in
cranial defects.7 The objective of this study was

AMJ. 2017;5(1):6–11

ISSN 2337-4330 || doi: http://dx.doi.org/10.15850/amj.v5n1.1328

Althea Medical Journal. 2018;5(1)

to determine the pattern of congenital heart
disease in children with Down syndrome.

Methods

This study was conducted from August to
October 2014 as a descriptive retrospective
study, and medical records were used as the
source of data. Data collection using medical
records has been approved by the Health
research ethics committee at Dr. Hasan Sadikin
General Hospital. The target population
in this study were all children with Down
syndrome and the samples for this study were
children with Down syndrome who were
diagnosed with congenital heart disease in the
Department of Child Health, Dr. Hasan Sadikin

General Hospital. The total sampling method
was used in this study.

Medical records and echocardiogram
reports were evaluated which included gender,
height, and weight for nutritional assessment,
age at diagnosis, types of congenital heart
disease, and other non-cardiac diseases. Data
of patients were considered eligible if the
patient was under the age of 15 years and had
been diagnosed with congenital heart disease
from 2008 to 2013. Incomplete medical
records and children who had not performed
the echocardiogram were excluded.

In this study, the children’s standard age
was under the age of 15 years, and age was
recorded in months and years. Age at diagnosis
was calculated by deducting the age of children
when first diagnosed having a congenital

Figure 1 Flow chart of data collection

Thyviyaa Rajamany, Rahmat Budi Kuswiyanto, Leonardo Lubis: Congenital Heart Disease among Down
Syndrome Children at Dr. Hasan Sadikin General Hospital from 2008 to 2013

Althea Medical Journal. 2018;5(1)

8 AMJ March 2018

heart disease with date of birth of that child.
Moreover, age group were classified according
to Nelson’s paediatric age classification which
was neonates (less than 1 month), infant (1
month to 2 years), pre-school children (2 to 5
years), middle childhood (6 to 11 years) and
early to middle adolescents (12 to 14 years).8

Types of congenital heart disease were
diagnosed using the echocardiogram and
it was classified according to ICD-10. The
nutritional status was measured according
to WHO child growth assessment. Children
under the age of 6 years were measured for
their weight for length or weight for age. The
nutritional status in children more than 6 years
old was calculated by BMI. This was done to
determine the height and weight appropriate
to children’s age. For the interpretation,
Z-score classification system is used. Children
are considered obese if the Z-score is above 3,
overweight if the Z-score is above 2, possible
risk of overweight if the children have a Z-score
above 1. Z-score 0 to -1 are considered normal
weight and Z-score below -2 indicates that the
children are wasted and Z-score -3 means the
children are severely wasted.9

Results of the study were arranged in
frequency tables and graphics charts to
evaluate the pattern of congenital heart disease

in Down syndrome children according to sex,
age when diagnosed having congenital heart
disease, types of congenital heart disease and
other comorbidities. The results were then
analysed and explained descriptively by using
the Microsoft Office Excel 2011®.

Results

Furthermore, a total of 179 cases of congenital
heart disease among children with Down
syndrome was reported from January 2008
to January 2013. However, about 84 medical
records were lost, and out of the remaining
95 medical records, 57 patients did not have
a congenital heart disease, 10 patients did not
perform the echocardiogram, so 28 samples
(33%) were selected according to the inclusion
criteria.

Moreover, the highest number of cases were
reported in 2013 which were 11 cases among
28 cases. Overall, it showed the distribution
of patients increased about 32.8% from 2008
to 2013, as 2 cases were reported in 2008
and another 2 cases were reported in 2009.
In 2010, 5 Down syndrome patients were
reported having a congenital heart disease and
4 people came in 2011 and 2012.

The number ofemale patient was 18 patients

Table 1 Characteristics of Down Syndrome Patient with Congenital Heart Disease
Data Characteristics Frequency (n=28)

Sex
Male 8
Female 15
Age group
≤ 1 month 1
1 month – 2 years 22
2 – 5 years 4
6 – 11 years 0
12 – 14 years 1
Nutritional status
Obese 0
Overweight 1
Possible risk of overweight 0
Normal 13
Wasted 8
Severly wasted 6

Althea Medical Journal. 2018;5(1)

Table 2 Type of Congenital Heart Disease among Children with Down Syndrome
Type of congenital heart disease Frequency (n=28)

ASD 2
VSD 3
AVSD 3
PDA 11
TOF 3
Combined 5
Unspecific 1

Notes: ASD=Atrial Septal Defect; VSD= Ventricular Septal Defect; AVSD= Atrio Ventricular Septal Defect; PDA= Patent
Ductus Arteriosus; TOF= Tetralogy of Fallot

Thyviyaa Rajamany, Rahmat Budi Kuswiyanto, Leonardo Lubis: Congenital Heart Disease among Down
Syndrome Children at Dr. Hasan Sadikin General Hospital from 2008 to 2013

while male patients were 10. Consequently,
the dominated gender among the patients
was female. The samples for the study were
divided into five categories according to
their age. The majority of patients were one
month until 2 years old. Whereas 13 patients
were found to be in the normal category but
about 50% of patients were in the abnormal
category where 8 patients were wasted, and 6
patients were severely wasted. These provided
indications of malnutrition occurrences in half
of the patients.

The most common type of congenital heart
disease among Down syndrome patients
was PDA which accounted for 11 patients,
followed by multiple type of congenital heart
disease with 5 patients. Among the 5 patients
who had multiple type of congenital heart
disease, 4 patients were diagnosed with
PDA+ASD while the remaining 1 patient had
AVSD+TOF. Moreover, PDA associated lesions
were the most common in combined lesions.
The unspecific lesion or miscellaneous cardiac
defect was found in 1 patient where the
diagnosis was stated as ICD q 24.9.

Furthermore, congenital hypothyroid was
the highest defect in Down syndrome patients
with congenital heart disease followed by
bronchopneumonia.

Discussion

A number of researchers from previous
studies stated that half of the children with
Down syndrome had a congenital heart
disease. In this study, the total frequency of
Down syndrome children with a congenital
heart disease was 33.3% which was less than
previously estimated. Many factors might affect
the results, firstly, it could be due to health care
systems aspects. A huge number of medical
records were missing which could cause big
changes in the data. The use of echocardiogram
and routine screening for congenital heart
disease was not really practiced to all the
children. Approximately 15 samples were
excluded due to this factor. Secondly, the lower
frequency in samples could be due to ethnic
or race factors. Previous studies proved that
less Asian people with Down syndrome had

Table 3 Other Non-cardiac Diseases in Down Syndrome Patient with Congenital Heart
Disease

Other defects Frequency

Total 28
Congenital hypothyroid 10
Bronchopneumonia 8
Pulmonary hypertension 3
Sepsis 3
Failure to thrive 2
Respiratory failure 2

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10 AMJ March 2018

a congenital heart disease. A study that was
carried out by the Atlanta Down Syndrome
Project, showed that only 13 Asian people
with Down syndrome had cardiac defect
among 243 people.2 Another study also stated
that among 487 patients with Down syndrome
only 20 Asian people had congenital heart
disease. Thus, this could be the corresponding
reason for the lower frequency number in the
present study.10

According to this study, the common type
of congenital heart disease in children with
Down syndrome was PDA. From previous
studies, PDA is one of the common congenital
heart disease in Down syndrome. However,
many studies indicated the AVSD and VSD as
the common type of congenital heart disease
among children with Down syndrome. Several
studies suggested that factors like ethnic and
geographic differences such as high altitude
with lower partial pressures of oxygen may
contribute to a higher frequency of PDA. At a
high altitude, arterial oxygen desaturation can
occur. The usual left-to-right shunting of blood
reverses will cause right-sided pressures to
increase.11 However, these hypotheses need to
be tested by further large-scale multinational
collaborative studies.

The congenital heart disease was higher
in female compared to male and this result
corresponds with previous studies. According
to a study carried out by the National Down
Syndrome Project (NDSP), it was proven that
the incidence of Atrioventricular Septal Defect
(AVSD) in Down syndrome are about two times
greater in female than male.2 In this study, the
age group of 1 month until 2 years showed the
highest frequency of congenital heart disease
among Down syndrome children. This might
be due to the improved medical facilities and
interventions in early detection of congenital
heart disease. Based on a study, it stated that
early diagnosis of heart disease in Down’s
syndrome is important in order to initiate a
timely referral to the concerned specialties
and to educate the parents regarding the early
and late complications of Down syndrome.12

The researcher also studied the nutritional
status of children with Down syndrome
with congenital heart disease. Although
characteristics of Down syndrome patients
with congenital heart disease showed the
highest frequency in normal nutritional
status however 50% of children were wasted
and severely wasted (Table 1). Many studies
looked for the relationship of congenital heart
disease with nutritional status; the researchers
found out that it is common for children with

congenital heart disease to have malnutrition
due to multifactorial issues which include
inadequate nutritional intake due to difficulties
in feeding, malabsorption, and increased
energy requirements caused by increased
metabolism.13 Inadequate feeding capabilities
in neonates with congenital heart disease are
usually due to respiratory compromise or
vocal cord paralysis or because of underlying
neurological consequences which lead to
growth failure if untreated.14 However, one
patient was overweight in this study. The
American Heart Association guidelines
indicate that children with CHD are less likely
to meet physical activity recommendations
due to self-esteem and physical self-concept
which may lead to overweight or obesity.15

Moreover, other defects were evaluated
in this study. The congenital hypothyroid
showed the highest frequency which was
35.7% compared to other defects such as
bronchopneumonia, pulmonary hypertension,
sepsis, failure to thrive and respiratory failure.
Based on a previous study, the abnormalities in
thyroid are due to slow maturation of negative
feedback control systems in the hypothalamo-
pituitary axis in Down syndrome which lead to
the production of a less active form of TSH, or
TSH insensitivity in the thyroid gland.16

In a study, it was stated that the thyroid
hormone deficiency may cause abnormalities
in the cardiovascular function such as an
impaired cardiac contractility and diastolic
function, increased systemic vascular
resistance, decreased endothelial derived
relaxation factor, increased serum cholesterol,
increased C-reactive protein, and increased
homocysteine where this conditions will
enhance the severity of the heart disease.17
Additionally, Murine Nkx-2.5, is a gene which
is expressed in the early embryogenesis of
thyroid and myocardium, thus patients with
congenital hypothyroid are associated with
cardiac defects.18 Pulmonary hypertension
which showed remarkable occurrences in
previous studies was less in the present study
because it is more associated with the AVSD
type of congenital heart disease. This is due to
the uncorrected left-to-right shunt increases
the pulmonary pressure that eventually leads
to vascular remodelling and dysfunction. Thus,
the progressive rise in pulmonary vascular
resistance and increased pressures in the right
heart occurred as a result.19

There were certain limitations in this study.
Firstly, it was due to the loss of some medical
records. This factor could influence the results
of the study due to the small sample size. If

Althea Medical Journal. 2018;5(1)

there was a more systematic way and the
number of medical records were complete , the
results would be more accurate. Besides, many
patients did not perform the echocardiogram
test. This could be due to several factors. First,
many children were not followed up until
the echocardiogram results or the patients
wanted to be referred to another hospital
which was nearer. Not many Down syndrome
patients visited or were being referred here.
It was either they did not visit the primary
care physician or the parents’ socioeconomic
status did not allow them to visit the general
hospital in Bandung from their remote
hometown or they died prior to the diagnosis,
since the survival rate of Down syndrome with
congenital heart disease is usually low.

In conclusion, the most common congenital
heart disease in children with Down syndrome
is PDA.

References

1. WHO. Genes and human disease.2013.
[Cited 2014 November 10] Available from:
http://www.who.int/genomics/public/
geneticdiseases/en/index.html.

2. Freeman SB, Bean LH, Allen EG, Tinker
SW, Locke AE, Druschel C, et al. Ethnicity,
sex, and the incidence of congenital
heart defects: a report from the National
Down Syndrome Project. Genet Med.
2008;10(3):173–80.

3. Nisli K, Oner N, Candan S, Kayserili H,
Tansel T, Tireli E, et al. Congenital heart
disease in children with Down’s syndrome:
Turkish experience of 13 years. Acta
Cardiol. 2008;63(5):585–9.

4. Irving CA, Chaudhari MP. Cardiovascular
abnormalities in Down’s syndrome:
spectrum, management and survival over
22 years. Arch Dis Child. 2012;97(4):326–
30.

5. Wiseman FK, Alford KA, Tybulewicz
VL, Fisher EM. Down syndrome–recent
progress and future prospects. Hum Mol
Genet. 2009;18(R1):R75–R83.

6. Joziasse IC, Smith KA, Chocron S, van
Dinther M, Guryev V, van de Smagt JJ, et al.
ALK2 mutation in a patient with Down’s
syndrome and a congenital heart defect.
Eur J Hum Genet. 2011;19(4):389–93.

7. Blom HJ, Smulders Y. Overview of
homocysteine and folate metabolism.
With special references to cardiovascular

disease and neural tube defects. J Inherit
Metab Dis. 2011;34(1):75–81.

8. Stanton B, Berhman K, Stanton J.
Nelson textbook of Pediatrics. 19th ed.
Philadelphia: Elsevier, pg; 2007. p. 29–39.

9. De Onis M, Mercedes, WHO. WHO child
growth standards: length/height–for–
age, weight–for–age, weight–for–length,
weight–for–height and body mass index–
for–age: methods and development.
Geneva: WHO; 2006 [Cited 2014 November
3]. Available from: http://apps.who.int/
iris/handle/10665/43413

10. Mogra R, Zidere V, Allan L. Prenatally
detectable congenital heart defects in
fetuses with Down syndrome. Ultrasound
Obstet Gynecol. 2011;38(3):320–4.

11. Forsey JT, Elmasry OA, Martin RP. Patent
arterial duct. Orphanet J Rare Dis.
2009;4(1):17.

12. Abbag FI. Congenital heart diseases
and other major anomalies in patients
with Down syndrome. Saudi Med J.
2006;27(2):219–22.

13. Okoromah CA, Ekure EN, Lesi FE, Okunowo
WO, Tijani BO, Okeiyi JC. Prevalence,
profile and predictors of malnutrition in
children with congenital heart defects: a
case–control observational study. Arch Dis
Child. 2011; 96(4):354-60

14. Jadcherla S, Vijayapal A, Leuthner S. Feeding
abilities in neonates with congenital heart
disease: a retrospective study. J Perinatol.
2008;29(2):112–8.

15. Pemberton VL, McCrindle BW, Barkin
S, Daniels SR, Barlow SE, Binns HJ, et al.
Report of the National Heart, Lung, and
Blood Institute’s Working Group on obesity
and other cardiovascular risk factors in
congenital heart disease. Circulation.
2010;121(9):1153–9.

16. Gibson P, Newton R, Selby K, Price D,
Leyland K, Addison G. Longitudinal study
of thyroid function in Down’s syndrome
in the first two decades. Arch Dis Child.
2005;90(6):574–8.

17. Klein I, Danzi S. Thyroid disease and the
heart. Circulation. 2007;116(15):1725–35.

18. Park S, Chatterjee V. Genetics of
congenital hypothyroidism. J Med Genet.
2005;42(5):379–89.

19. D’Alto M, Mahadevan VS. Pulmonary
arterial hypertension associated with
congenital heart disease. Eur Respir Rev.
2012;21(126):328–37.

Thyviyaa Rajamany, Rahmat Budi Kuswiyanto, Leonardo Lubis: Congenital Heart Disease among Down
Syndrome Children at Dr. Hasan Sadikin General Hospital from 2008 to 2013