Eur J Pediatr (2010) 169:11951199

DOI 10.1007/s00431-010-1200-0

ORIGINAL PAPER

Prevalence of congenital heart defects and persistent

pulmonary hypertension of the neonate with Down syndrome
Michel Emile Weijerman & A. Marceline van Furth & Maurike D. van der Mooren &
Miriam M. van Weissenbruch & Lukas Rammeloo & Chantal J. M. Broers &
Reinoud J. B. J. Gemke

Received: 12 February 2010 / Accepted: 6 April 2010 / Published online: 23 April 2010
# The Author(s) 2010. This article is published with open access at Springerlink.com

Abstract The aim of this study was to assess the (p=0.008). The presence of CHD in children with DS had
prevalence of congenital heart defects (CHDs) and persis- no influence on their birth weight, mean gestational age and
tent pulmonary hypertension of the neonate (PPHN) in Apgar score. In neonates with DS, we found not only a
children with Down syndrome (DS) and to assess its impact 43% prevalence of CHD, but also a high incidence of
on neonatal factors. It was a prospective study of a birth PPHN at 5.2%. Early recognition of the cardiac condition
cohort of children with DS born between 2003 and 2006 of neonates with DS seems justified.
registered by the Dutch Paediatric Surveillance Unit
(DPSU). A CHD occurred in 43% of 482 children with Keywords Down syndrome . Prevalence . Persistent
trisomy 21. Atrioventricular septal defect was found in pulmonary hypertension of the neonate . Congenital heart
54%, ventricular septal defect in 33.3% and patent ductus defects . Neonate
arteriosus in 5.8%. The incidence of PPHN in DS was
5.2%, which is significantly higher than the general
population (p<0.001). The reported mortality in newborns Introduction
with DS was overall 3.3% and was still significant higher in
children with a CHD versus no CHD (5.8% versus 1.5%) Down syndrome (DS) is the most common autosomal
chromosome anomaly, affecting 16 out of every 10,000 live
births in the Netherlands [19]. DS is frequently associated
M. E. Weijerman : A. M. van Furth : M. D. van der Mooren : with congenital heart defects (CHD). Indeed CHDs are
C. J. M. Broers : R. J. B. J. Gemke considered to be the most important clinical phenomenon of
Department of Paediatrics, DS highly relevant to morbidity and decisive in infant
Subdivision of General Paediatrics and Infectious Diseases,
VU University Medical Center,
mortality [16]. Over recent decades, there has been a
Amsterdam, the Netherlands substantial increase in the life expectancy of children with
DS in general with an improvement in average life
M. M. van Weissenbruch expectancy from 12 years in the 1940s to 60 years
Department of Paediatrics, Subdivision of Neonatology,
VU University Medical Center,
nowadays [16]. This increase in life expectancyhas mainly
Amsterdam, the Netherlands been due to the successful early surgical treatment of CHD
in children with DS [5, 9, 10, 16].
L. Rammeloo Atrio-ventricular septal defect (AVSD), ventricular septal
Department of Paediatrics, Subdivision of Paediatric Cardiology,
VU University Medical Center,
defect (VSD) and atrial septal defect (ASD) are the most
Amsterdam, the Netherlands common forms of CHD and recent reports have shown that
the distribution of CHDs in children with DS may vary with
M. E. Weijerman (*) ethnicity [3, 4, 7, 8, 14, 15, 17, 20].
Department of Paediatrics and Infectious Diseases,
VU University Medical Center,
In addition, Shah et al. have recently identified
P.O. Box 7057, 1007 MB Amsterdam, the Netherlands persistent pulmonary hypertension of the neonate (PPHN)
e-mail: [email protected] in 24 out of 175 children with DS retrospectively; this
1196 Eur J Pediatr (2010) 169:11951199

increased prevalence in children with DS has not previously Statistical analysis

been identified as a specific problem among children with
DS [13]. The binomial test was used to compare the prevalence of
In the present study, we describe the prevalence of CHD and PPHN in children with DS and the Dutch
CHDs in neonates with DS in the Netherlands, determine reference population, respectively. We tabulated the fre-
the incidence of PPHN in this population and analyse the quency of CHD and the combinations of CHDs. Statistical
effect of a CHD on other neonatal factors. comparisons of birth weight and gestational age for
children with DS with and without CHD were made with
independent sample t tests. Because of the influence of the
Patients and methods gestational age on birth weight, we corrected birth weight
for gestational age by using a multiple regression model.
Our study includes all live births of children born between We used the MannWhitney test to compare non-
January 1, 2003 and December 31, 2006 who were parametric variables (e.g. Apgar score) and the Chi-square
diagnosed with DS and were reported to the Dutch test for paired comparison of properties (e.g. asphyxia,
Paediatric Surveillance Unit (DPSU). The DPSU is a ethnicity and mortality). Statistical analysis was performed
national registry used by paediatricians to report various with SPSS 16.0 statistical software. A p value of <0.05 was
paediatric disorders, including DS. For each DS case considered significant.
reported to the DPSU, a questionnaire was sent to the
attending pediatrician. The completed forms were returned
to the Down Syndrome Study Group at the VU University Results
Medical Center, Amsterdam. The method and details of
the data collection have already been described earlier, Study group
and in 2003 the response rate for the DPSU was 96% and
the overall response rate between 2003 and 2006 was The DPSU registered 820 children with DS who were born
93.3% [19]. between January 1, 2003 and December 31, 2006. A total
The diagnosis of DS was made in 91% in the first 7 days of 630 questionnaires were returned by the DPSU, and of
of life in the Netherlands, and most questionnaires were these, 482 included complete data regarding the cardiac
returned within the first 3 months after birth. In the status. A CHD was reported in 207 (43%) of the children
Netherlands, 20% of the population under the age of 18 is with trisomy 21, which is significantly higher than the
from an ethnic minority background [19]. prevalence of CHD in the Dutch reference population
Only children with a karyotype analysis (antenatal or (0.62%, p<0.001) [12] (Fig. 1).
postnatal) were included. To ensure the homogeneity of In 2003, the prevalence in the Netherlands of live and
the children with DS, all children with DS due to still-born children with DS was 26.8 per 10,000 pregnan-
mosaicism or translocation were excluded. Children with cies compared with 16 newborns with DS per 10,000 live
DS for whom information regarding their cardiac status births; there were no exact data on the prevalence of CHD
was absent or incomplete were also excluded. The Dutch in these stillborn children with DS [19].
DS screening program carries out an echocardiogram
within the first 3 months of birth. We used the following Congenital heart defects
items in the questionnaire for the analyses: sex, chromo-
somal analysis, ethnicity, cardiac evaluation, birth weight, The data for CHD in children with DS are summarized in
gestational age of birth, 5-min Apgar score and the Table 1. In 2.4% (n=5) of children, the CHD did not match
presence of PPHN. The diagnosis of PPHN was based any of the categories mentioned and thus these were thus
on a clinical assessment and echocardiogram in the first counted as other. In 28.9% (n=60) of the children, there
week of life performed by neonatologists or paediatric were multiple cardiac defects (i.e. a combination of
cardiologists who answered the questionnaires. PPHN is defects).
defined, if the pulmonary pressure exceeds the systemic
pressure, as being present a right-to-left shunt and is Ethnicity
diagnosed by echocardiography. The use of a high
percentage of oxygen is needed usually without a reaction The ethnic background of children with DS was reported
on 100% oxygen and a difference in oxygen saturation for 404 children and was predominantly Caucasian (77.5%,
measured pre-ductal and post-ductal, when a PDA is n=313). Of these Caucasian children, 127 (40.6%) had a
present [1, 13, 18]. Secundum ASD and persistent foramen CHD. In 22.5% (n=91), one or both of the parents came
ovale (PFO) were excluded as a CHD. from an ethnic minority group most of which were from a
Eur J Pediatr (2010) 169:11951199 1197

Table 1 Children with Down syndrome and a congenital heart defect

DS children
registered (CHD; total n=207)
n=820
Congenital heart defect (CHD) N Percent

Returned Single defect 147 71.0

questionnaires AVSD 92 44.4
n=630(76.8%)
VSD 38 18.4
PDA 12 5.8
Translocation Mosaicism Trisomy21 Other Other
n=15(2.4%) n=10(1.6%) n=604(95.9%) n=1(0.2%)
Hypoplastic pulmonary arteries 1 0.5
COA 1 0.5
PS 2 1.0
Completed
questionnaires AR 1 0.5
n=482(79.8%)
Combination of defects 60 29.0
AVSD + TOF 3 1.5
CHD+ CHD-
AVSD + ASD 6 2.9
n=207(43%) n=275(57%) AVSD + other
Hypoplastic aortic arch 1 0.5
Fig. 1 Children with Down syndrome (DS) in the Netherlands born in IAA-b 1 0.5
the period January 1, 2003 to December 31, 2006 with and without PS 1 0.5
congenital heart defect (CHD). Asterisk (*) one child had a TOF 8 3.9
combination of trisomy 21 and triple X (0.2%)
VSD + ASD 29 14.0
VSD + overriding AO 2 1.0
Moroccan, Turkish or Antillean background. Within this ASD + PS 7 3.4
ethnic group, 42.9% (n=39) of the children with DS had a Other
CHD. There were no differences in the distribution of CAT-II + IAA-a 1 0.5
CHDs neither in the ethnic group compared to the DAA 1 0.5
Caucasian group nor within the ethnic subgroups. The data Total 207 100.0
on ethnicity were missing for 78 children with DS.
ASD secundum atrial septal defect, AVSD atrioventricular septal
Persistent pulmonary hypertension of the neonate defect, VSD ventricular septal defect, PDA patent ductus arteriosus,
TOF Tetralogy of Fallot, IAA-a interruption of the aortic arch type a,
IAA-b interruption of the aortic arch type b, COA coarctation of the
PPHN was reported in 25 children with DS; an incidence aorta, PS pulmonary valve stenosis, AR aortic regurgitation, CAT-II
of 5.2%, which is significant, elevated in comparison with common arterial trunk type II, DAA double aortic arch
the reported 0.1% in the general population (p<0.001)
[18]. Table 2 shows the distribution of CHDs in children Mortality
with DS and PPHN of which 36% (n=9) of the children
had no CHD. The reported mortality among the neonates with DS was16
out of 482 (3.3%). Most of the 16 children with DS died
Neonatal variables within 30 days of birth (n=11), one died on day 39 and

The presence or absence of a CHD had no significant Table 2 Children with Down syndrome and persistent pulmonary
hypertension of the neonate (PPHN) (n=25) and the distribution of a
relationship with birth weight and gestational age. The concomitant congenital heart defect (CHD)
mean birth weights of the children with and without a CHD
were 2,926 and 3,013 g, respectively (95% CI; 27087), Congenital heart defect (CHD)a N Percent
and the mean gestational age of the children with DS
AVSD 7 28
with and without CHD were 38.0 and 38.3 weeks,
VSD 6 24
respectively (95% CI; 0.640.16). The median of the
VSD + ASD 3 12
Apgar score at 5 min was nine in children with DS both
No CHD 9 36
with and without a CHD. Also, the frequency of asphyxia
Total 25 100
(Apgar score <6) in children with DS with a CHD did
not differ from those without a CHD (1.6% versus 2.8%) ASD atrial septal defect, AVSD atrioventricular septal defect, VSD
(p=0.39). ventricular septal defect
1198 Eur J Pediatr (2010) 169:11951199

another on day 318 following birth. The data of the PDA were most common. This study however began at the
remaining three non-survivors are missing. Among the age 13, so the mortality prior to the age of 13 may explain
neonates with DS who died, 12 children had a CHD (12 out their distribution of CHDs [3].
of 207 CHD children (5.8%)) and four children had no Another relevant phenomenon which, to our knowledge,
CHD (4 out of 275 non CHD children, 1.5%). This was a had not previously been appreciated and as such was not
significant difference in mortality among the children with DS included in DS guidelines [2, 6] was the significantly
with and without a CHD, (p=0.008). The causes of death in increased incidence of PPHN in neonates with DS (5.2%)
the 12 children with DS and a CHD were as follows: we found in our study. This corresponds with Cua et al. who
respiratory distress (n=3, all AVSD), neonatal infection (n=2, estimated the incidence of idiopathic PPHN in neonates with
AVSD and aortic regurgitation), asphyxia (n=1, AVSD), post DS between 1.2% and 6.6%, which is much higher than the
cardiac operation (n=1, AVSD) and necrotizing enterocolitis reported overall incidence of 0.1% in the general population
(n=1, VSD). In four children, the cause of death was not [1]. In our study, only seven children (28%) had an AVSD,
documented in the questionnaires (three AVSD and one and in these children, we cannot exclude a relationship with
PDA). The four children without a CHD died as a result of the development of PPHN and nine (36%) children with DS
asphyxia, respiratory distress and infection, respectively, and and PPHN did not have a CHD. In addition Shah et al. found
one cause of death was unknown. no serious structural heart defect in 70% of children with DS
and PPHN [13]. PPHN should be distinguished from another
type of pulmonary hypertension, originating from a cardiac
Discussion defect that permits left-to-right shunting and requires some
period of time to be clinically detected. The newborn
This is the first large-scall study in the Netherlands children with DS, who develop PPHN, are by contrast
regarding CHDs in children with DS. We found a symptomatic just after birth [1, 13, 18].
prevalence of CHDs of 43%, which is concordant with Wren et al. found no clinical signs in the first weeks in
the prevalence presented in the literature of 4458% [3, 4, some children with DS, with major cardiac malformations
7, 8, 14, 15, 17, 20], AVSD (54%) was the most commonly and associated pulmonary hypertension, even in some who
occurring CHD in children with DS in our study. In our progressed to irreversible pulmonary vascular disease [21].
study, early diagnostic echocardiography was performed. A normal neonatal examination in children with DS does
Secundum ASD and persistent foramen ovale (PFO) were not therefore exclude a serious CHD [11]. This corresponds
excluded as a CHD because a small secundum ASD is with our findings and emphasizes the importance of an early
sometimes difficult to differentiate from a persistent echocardiography of neonates with DS to detect any CHD and
foramen ovale, and the study design did not include to determine the possible risk of developing pulmonary
follow-up to provide sufficient clarity about ASD versus hypertension, as supported by the DS health care guidelines
PFO [9, 16]. This could have caused an underestimation of published by the American Academy of Pediatrics and the
the prevalence of CHD in our study. The early diagnostic Down Syndrome Medical Interest Group of the United
procedure was used to make an early assessment of cardiac Kingdom and Ireland [2, 6]. Because of the high incidence
anatomy and in case of a significant defect to perform early of a significant CHD in children with Down syndrome, the
intervention and to prevent pulmonary arterial hypertension early recognition of CHD can lead to the optimal manage-
in defects with a left to right shunt. ment of the defect. The surgical correction of significant
The inclusion of various cardiac defects and the use of defects usually takes place at the age of 24 months, though
different terminology in studies with children with DS made it this happens earlier in certain cases (e.g. TOF) [9, 10].
difficult to compare these studies with our results. For In our study, basic neonatal characteristics, Apgar scores,
instance, Stoll et al. did not report ASD as a CHD as well, birth weight and gestational age were not different in
which may explain why PDA is one of the three most children with DS with and without CHD. This is in concords
prevalent defects in their study [7, 10, 14, 17]. In our study, with Frid et al. who analysed the influence of CHD on these
there was no significant difference in the distribution of CHD neonatal issues in 304 neonates with DS and also found no
according to ethnicity, as the subgroups were too small. difference between those with and without CHD [5].
Freeman et al. reported in their study in the United States In the past decade, research has shown that neonatal
of America that black infants with DS had an AVSD more mortality in DS appears to be becoming less dependent on
frequently than whites and that Hispanic infants with DS CHDs and more often caused by neonatal pathology such
had an AVSD less frequently than whites [4]. In Chinese as asphyxia, low birth weight and prematurity, as in the
children with DS and a CHD, VSD was seen in 38% and general population [5, 19]. With regard to mortality, we
AVSD in 25% [7]. AVSDs accounted for only 9% of the should emphasize that with the exception of one child who
CHDs in Mexican children with DS, while ASD, VSD, and died following a cardiac operation, the presence of a CHD
Eur J Pediatr (2010) 169:11951199 1199

was not responsible for reported mortality in children with 4. Freeman SB, Bean LH, Allen EG et al (2008) Ethnicity, sex, and
the incidence of congenital heart defects: a report from the
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Creative Commons Attribution Noncommercial License which per- syndrome: a cardiovascular perspective. J Intellect Disabil Res
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