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BMJ Paediatrics Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available. When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to. The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript. BMJ Paediatrics Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjpaedsopen.bmj.com). If you have any questions on BMJ Paediatrics Open’s open peer review process please email
Confidential: For Review OnlyGender Differences in CHD in Down Syndrome
Journal: BMJ Paediatrics Open
Manuscript ID bmjpo-2018-000414
Article Type: Original research letter
Date Submitted by the Author: 06-Dec-2018
Complete List of Authors: Takano, Takako; Tokyo Kasei University, Department of Child HealthAkagi, Michio; Kyorin University, Department of Medical EducationTakaki, Haruyoshi; Tokyo Healthcare University, Department of NursingInuzuka, Ryo; University of Tokyo, Department of PediatricsNogimori, Yoshitsugu; Kanagawa Children’s Medical Center, Department of CardiologyOno, Hiroshi; National Center for Child Health and Development, Department of CardiologyKaneko, Masahide; Kanto Central Hospital, Department of PediatricsHagiwara, Norifumi; Teikyo University, Department of Pediatrics
Keywords: Epidemiology, Cardiology, Congenital Abnorm, Mortality
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Arch Dis Child Short report
Title page
Title: Gender Differences in CHD in Down Syndrome
Correspondence to: Takako Takano, MD, PhD, Professor, Department of Child Health, Tokyo Kasei
University, 1-18-1 Kaga, Itabashi-ku, Tokyo 173-8602, Japan
Telephone number: +81-3-3961-5339; Fax number: +81-3-3961-5339;
E-mail: [email protected]
Authors: Takako Takano1, Michio Akagi2, Haruyoshi Takaki3, Ryo Inuzuka4, Yoshitsugu Nogimori5, Hiroshi
Ono6, Masahide Kaneko7, Norifumi Hagiwara8
1. Department of Child Health, Tokyo Kasei University, Tokyo, Japan
2. Department of Medical Education, Kyorin University, Tokyo, Japan
3. Department of Nursing, Tokyo Healthcare University, Tokyo, Japan
4. Department of Pediatrics, The University of Tokyo, Tokyo, Japan
5. Department of Cardiology, Kanagawa Children’s Medical Center, Kanagawa, Japan
6. Department of Cardiovascular Medicine, National Center for Child Health and Development, Tokyo,
Japan
7. Department of Pediatrics, Kanto Central Hospital, Tokyo, Japan
8. Department of Pediatrics, Teikyo University, Tokyo, Japan
Total word count of manuscript: 1118 words
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ABSTRACT
Objective Shorter female compared with male survival among people with Down syndrome (DS) has been
reported in Western Australia (Glasson EJ, 2003), in contrast to female longevity in the general population.
We studied gender differences in congenital heart disease (CHD), which may be related to prognosis and
mortality rates among Japanese patients with DS.
Methods Study cases were ascertained from the medical records of five hospitals and the results of two
questionnaires given to the parents.
Results We investigated the cases of 1,310 (626 females, 684 males) patients with DS. The rate of
complications of CHD in females (354; 57%) was significantly higher than that in males (338; 49%)
(p=0.010). Significantly more females underwent surgery for CHD (199; 32%) than males (175; 26%)
(p=0.018).
Conclusions The higher prevalence and grave degree of severity of CHD in female DS patients in Japan may
contribute to their shorter life expectancy.
Keywords: Down syndrome; Congenital heart disease; Gender difference
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INTRODUCTION
As the mortality rate of people with Down syndrome (DS) has declined, the life expectancy at birth has risen.
Among those registered in a DS database in Western Australia, life expectancy for the time period of 1953 to
2000 was 58.6 years1 compared with 16.2 years for the period of 1948 to 1957.2 The life expectancy at birth
for 1,052 Japanese people with DS who were born between 1966 and 1975 increased to 48.9 years;3 earlier
data are not available. In contrast to female longevity in the general population worldwide, males with DS
were shown to have significantly greater life expectancy than females with DS in a cohort of 1,332 people in
Western Australia.4 These authors proposed possible reasons for the reduced life expectancy of females at the
early and late stages of their lives. In early childhood, it was in part ascribed to the increased prevalence of
congenital heart diseases (CHD) and the need for treatment of atrioventricular septal defects (AVSDs) in
females with DS. As women with DS experience menopause 4–5 years earlier than women in the general
population, and 2–4 years earlier than nulliparous women in most Western societies, early natural menopause
and the accompanying drop in oestrogen levels could be a risk factor in increased early death due to cardiac
disease, particulary in the presence of pre-existing CHD. We make it the first priority that the shorter life
expectancy of females with DS may be attributed to increased prevalence of CHD, especially in those with
severe CHD for whom the prognosis is poor. The aim of this study was to clarify the gender-based prevalence
and severity of CHD in Japanese patients with DS.
METHODS
Our data are based on medical records from five hospitals in Tokyo and two questionnaires given to the
parents of people with DS in Tokyo and Shizuoka prefectures in Japan. The diagnosis of DS was made based
on cytogenetic evaluation of free, mosaic or translocation trisomy 21. Small (≤ 6 mm diameter) defects at the
fossa ovalis were excluded from the diagnosis of atrial septal defect (ASD). Arterial ducts that were closed
before 1 month of age were excluded from the diagnosis of patent ductus arteriosus (PDA). Before starting
this investigation, we obtained approvals from the ethical committees of Tokyo Kasei University and the
cooperation of each hospital. The questionnaires, which were mailed to patients’ parents, instructed the
parents to return the completed questionnaire only if they were agreeable to the contents. The original data
were encrypted to prevent any linking of patients’ personal information (names, addresses and hospital ID
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numbers) and stored in a safe. Data files without personal information were used for analyses. Statistical
analyses were performed using SPSS (ver. 21).
RESULTS
We studied the cases of 1,310 patients with DS, of which 626 were female and 684 male (sex ratio = 1.09).
Chromosome analysis revealed that 94.5% (1,238/1,310) of patients had an extra free-standing chromosome
21; 1.4% (18/1,310) had a translocation involving chromosome 21; 1.2% (16/1310) had a mosaic type mixture
of trisomic and normal cells; and the remaining 2.9% (38/1,310) had no cytogenetic information.
The rate of complications of CHD in females (354; 57%) was significantly higher than that in
males (338; 49%) (p=0.010 by the chi-square test). Moreover, significantly more females (199; 32%) than
males (175; 26%) underwent cardiac surgery (p=0.018 by the chi-square test) (Table 1). The main lesions
involved in the CHD in order of prevalence were ventricular septal defect (VSD), ASD, AVSD, PDA and
tetralogy of Fallot (TOF) (Table 2).
The prevalence of CHD with PDA was significantly higher in females (115; 18%) than males (87;
13%) (p=0.005), while the prevalence of all other types of CHD without PDA was almost equal in females
(239; 38%) and males (251; 37%).
Among the patients born in the 1970s (female, 46.2%; male, 15.8%), 1980s (female, 51.2%; male,
37.7%) and 1990s (female, 59.7%; male, 47.5%), more females had CHD than males, but we found no
significant gender-related difference in the prevalence rate of the patients born after 2000 (female, 57.0%;
male, 58.6%).
DISCUSSION
In our study, females with DS were at a disadvantage compared with males with regard to CHD
complications. The higher prevalence and grave degree of severity of CHD that we observed in females may
contribute to the shorter female life expectancy in DS. Among the people with DS who were registered in
Western Australia until 2000, the median age of survival of DS was 57.8 years for females and 61.1 years for
males,4 whereas females had a significantly longer life expectancy than males in the Australian general
population for the same year, with a median age at death of 82.2 years for females and 76.7 years for males. A
similar advantage in life expectancy for females exists in the Japanese general population, exceeding that for
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males by 6.9 years in 2000 and by 6.2 years in 2016. Although Japan does not have a nationwide registry of
individuals with congenital disabilities that is comparable to the Disability Services Commission of Western
Australia, we suspect that the inverse trend of gender-specific life expectancy for DS patients in Western
Australia also exists in Japan because of the profile of CHD in females.
In our study, the most common cardiac anomalies (main lesions) were VSD, ASD, AVSD, PDA
and TOF; these five anomalies comprise 95.5% of the total CHD in DS. In a EUROCAT (European
Surveillance of Congenital Anomalies) population-based study, these five anomalies accounted for more than
99% of the live births and fetal deaths in DS babies with cardiac anomalies.5 The same anomalies occupied
the top five spots in previous reports, although the order of incidence of each varied in different countries.
In Japan, pregnancy among women aged 35 and older is increasing together with the frequency of
DS at birth, contrary to the stable frequencies of DS at birth in Europe, the USA and Australia, where there is
elective termination of pregnancy subsequent to prenatal diagnosis. We found that significantly more female
DS patients than males born in the 1970s, 1980s and 1990s had CHD, but this gender-related difference in the
prevalence of DS disappeared in the patients born after 2000. This fairly recent change might be attributable
to a gradual increase in the rate of detection of complications of CHD in males that has come with
improvements in diagnostic techniques including cardiac ultrasound, as well as higher success rates in heart
surgery. With the spread of available echocardiographic examination into every corner of Japan in the 1990s,
mild defects are now diagnosed with more accuracy than ever before. These mild defects may have diluted the
gender difference of more severe CHD in DS patients in the era of echocardiography.
REFERENCES
1. Glasson EJ, Sullivan SG, Hussain R, et al. The changing survival profile of people with Down's syndrome:
implications for genetic counselling. Clin Genet 2002; 62: 390-393.
2. Collmann RD and Stroller A. Data on mongolism in Victoria: Prevalence and life expectation. J Ment Def
Res 1963; 7: 60-68.
3. Masaki M, Higurashi M, Iijima K, et al. Mortality and survival for Down syndrome in Japan. Am J Hum
Genet 1981; 33: 629-639.
4. Glasson EJ, Sullivan SG, Hussain R, et al. Comparative survival advantage of males with Down syndrome.
Am J Hum Biol 2003; 15: 192-195.
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5. Morris JK, Garne E, Welleesley D, et al. Major congenital anomalies in babies born with Down syndrome:
A EUROCAT population-based registry study. Am J Med Genet Part A 2014; 164A: 2979-2986.
What is already known?
The survival of children born with Down syndrome (DS) has continued to improve over recent
decades.
Shorter female survival than male in DS has been reported in Western Australia.
What this study adds?
The rate of complications of congenital heart disease (CHD) in females with DS was significantly
higher than that in males.
Significantly more females underwent surgery for CHD than males.
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Table 1. Gender-segregated complication of congenital heart disease (CHD) and operations on patients with
Down syndrome
CHD (+)
GenderOperation
(+)Operation
(-)CHD (-)
Total
Female 199 155 272 626
32% 25% 43% 100%
Male 175 163 346 684
26% 24% 51% 100%
Total 374 318 618 1310
29% 24% 47% 100%
Legend for table 1 χ2=8.05 , d.f.=2 , p=0.018
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Table 2. Gender-segregated main lesion of congenital heart disease (CHD) of the patients with Down
syndrome
Gender
Female MaleTotalMain lesion
Of CHD Number Percent Number Percent Number Percent
VSD 142 40.1% 131 38.8% 273 39.5%
ASD 75 21.2% 70 20.7% 145 21.0%
AVSD 55 15.5% 47 13.9% 102 14.7%
PDA 48 13.6% 40 11.8% 88 12.7%
TOF 23 6.5% 30 8.9% 53 7.7%
PS 1 0.3% 5 1.5% 6 0.9%
DORV 0.0% 3 0.9% 3 0.4%
Ebstein 1 0.3% 1 0.3% 2 0.3%
AR 1 0.3% 0.0% 1 0.1%
CoA 0.0% 1 0.3% 1 0.1%
MR 1 0.3% 0.0% 1 0.1%
TA 0.0% 1 0.3% 1 0.1%
TR 0.0% 1 0.3% 1 0.1%
unkown 7 2.0% 8 2.4% 15 2.1%
Total 354 100.0% 338 100.0% 692 100.0%
Legend for table 2
VSD, ventricular septal defect; ASD, atrial septal defect; AVSD, atrioventricular septal defect; PDA, patent
ductus arteriosus; TOF, tetralogy of Fallot, PS, pulmonary stenosis; DORV, double outlet right ventricle;
Ebstein, Ebstein’s anomaly; AR, aortic regurgitation; CoA, coarctation of aorta; MR, mitral regurgitation; TA,
tricuspid atresia; TR, tricuspid regurgitation.
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Contributors T Takano designed the study, participated in interpretation of the results and drafted the initial
manuscript. M Aakagi participated in data collection and interpretation of the results. H Takaki participated in
data analysis and interpretation of the results. R Inuzuka, Y Nogimori, H Ono, M Kaneko and N Hagiwara
participated in data collection. All authors approved the final manuscript for submission.
Funding JSPS KAKENHI Grant number 23500893, Japan
Acknowledgements We thank Michelle Kahmeyer-Gabbe, PhD, from Edanz Group (www.edanz.com/ac) for
editing a draft of this manuscript.
Competing interests None declared.
Ethics approval Tokyo Kasei University Ethics Committee, Kyorin University Ethics Committee, Teikyo
University Ethics Committee, University of Tokyo Ethics Committee, and the National Center for Child
Health and Development Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
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Confidential: For Review OnlyGender Differences in Congenital Heart Disease in Down Syndrome — Study Data Taken from Medical Records and
Questionnaires in a Part of Japan
Journal: BMJ Paediatrics Open
Manuscript ID bmjpo-2018-000414.R1
Article Type: Original research letter
Date Submitted by the Author: 11-Jan-2019
Complete List of Authors: Takano, Takako; Tokyo Kasei University, Department of Child HealthAkagi, Michio; Kyorin University, Department of Medical EducationTakaki, Haruyoshi; Tokyo Healthcare University, Department of NursingInuzuka, Ryo; University of Tokyo, Department of PediatricsNogimori, Yoshitsugu; Kanagawa Children’s Medical Center, Department of CardiologyOno, Hiroshi; National Center for Child Health and Development, Department of CardiologyKaneko, Masahide; Kanto Central Hospital, Department of PediatricsHagiwara, Norifumi; Teikyo University, Department of Pediatrics
Keywords: Epidemiology, Cardiology, Congenital Abnorm
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BMJ Pediatrics Open Original research letters
Title page
Title: Gender Differences in Congenital Heart Disease in Down Syndrome — Study Data Taken
from Medical Records and Questionnaires in a Part of Japan
Correspondence author: Takako Takano, MD, PhD, Professor, Department of Child Health, Tokyo Kasei
University, 1-18-1 Kaga, Itabashi-ku, Tokyo 173-8602, Japan
Telephone number: +81-3-3961-5339, e-mail: [email protected]
Authors: Takako Takano,1 Michio Akagi,2 Haruyoshi Takaki,3 Ryo Inuzuka,4 Yoshitsugu Nogimori,5 Hiroshi
Ono,6 Masahide Kaneko,7 Norifumi Hagiwara,8
1Department of Child Health, Tokyo Kasei University, Tokyo, Japan 2Department of Medical Education,
Kyorin University, Tokyo, Japan 3Department of Nursing, Tokyo Healthcare University, Tokyo, Japan
4Department of Pediatrics, University of Tokyo, Tokyo, Japan 5 Department of Cardiology, Kanagawa
Children’s Medical Center, Kanagawa, Japan 6Department of Cardiovascular Medicine, National Center for
Child Health and Development, Tokyo, Japan 7Department of Pediatrics, Kanto Central Hospital, Tokyo,
Japan 8Department of Pediatrics, Teikyo University, Tokyo, Japan
Total word count of manuscript: 600 words
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ABSTRACT
Shorter female survival than male in Down syndrome (DS) has been reported in Australia contrary to female
longevity in the general population. We investigated gender differences of congenital heart diseases (CHD) in
Japanese DS patients which may be related to the cause of mortality. The total number of patients through
medical records from five hospitals and questionnaires to patients’ parents was 1,310 (626 females, 684
males). The rate of complication of CHD in females (354; 57%) was significantly higher than that in males
(338; 49%) (p=0.010). Significantly more females underwent surgery for CHD (199; 32%) than males (175;
26%) (p=0.018).
Key Words: Down syndrome; Congenital heart disease; Gender difference
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INTRODUCTION
As there is a decline in the deaths of patients with Down syndrome (DS), the life expectancy at birth in
Western Australia between 1953 and 2000 was 58.6 years1 as compared to 16.2 years between 1948 and
1957.2 The life expectancy at birth for 1,052 Japanese DS who were born between 1966 and 1975 increased to
48.9 years3. Contrary to female longevity in the general population, males with DS had significantly greater
life expectancies than females with DS in Australia.4 We make it the first priority that shorter life expectancy
of female DS may be attributed to increased prevalence of CHD. The aim was to clarify the gender-difference
prevalence and severity of CHD in Japanese DS.
METHODS
Our data are based on medical records from five hospitals in Tokyo and two questionnaires to patients’
parents in Tokyo and Shizuoka prefectures (online supplemnatary file 1). Patients were not directly involved
in the design of this study. Small (less than 6 mm in diameter) defects at fossa ovalis were excluded from the
diagnosis of atrial septal defect (ASD). Arterial ducts that were closed before one month of age were excluded
from the diagnosis of patent ductus arteriosus (PDA). We obtained the approval from the ethical committees
of Tokyo Kasei University and each hospital in cooperation. The questionnaires mailed to patients’ parents
were sent back if parents agreed with the content. Statistical analyses without personal information were
performed using SPSS (ver. 21).
RESULTS
The total number of patients with DS was 1,310, with 626 females and 684 males (sex ratio=1.09). The rate of
complication of CHD in females (354; 57%) was significantly higher than that in males (338; 49%) (p=0.010
at the chi-square test). Moreover, significantly more females underwent cardiac surgery (199; 32%) than
males (175; 26%) (p=0.018 at the chi-square test) (Table 1). The main lesions of CHD were ventricular septal
defect (VSD), ASD, atrioventricular septal defect (AVSD), PDA and tetralogy of Fallot (TOF), in order of
prevalence (Table 2). The prevalence of CHD with PDA was significantly higher in females (115; 18%) than
males (87; 13%) (p=0.005), while the prevalence of other CHD without PDA was almost equal in females
(239; 38%) and males (251; 37%). Among the patients born in the 1970s (female; 46.2%, male; 15.8%),
1980s (female; 51.2%, male; 37.7%) and 1990s (female; 59.7%, male; 47.5%), more females had CHD than
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males, but we found no significant difference by gender in the prevalence of the patients born after 2000
(female; 57.0%, male; 58.6%).
DISCUSSION
In our study, females with DS had disadvantages in regards to CHD complications compared to males. Those
results, higher prevalence and graver severity of CHD in females, may in part attribute to poor prognosis. The
most common cardiac anomalies (main lesions) were VSD, ASD, AVSD, PDA and TOF; these five anomalies
occupy 95.5% of total CHD. In a EUROCAT (a European network of population-based registers for the
epidemiologic surveillance of congenital anomalies) study5, these five anomalies accounted for more than
99% in DS with cardiac anomalies. We found significantly more female DS patients
had CHD than males born in the 1970s, 1980s and 1990s, but no significant
difference by gender in patients born after 2000. Many factors seem to
have contributed to this change, such as improvement of diagnostic
techniques including cardiac ultrasound, and improving heart surgery.
Especially echocardiographic examination has spread into every corner of
Japan in the 1990s, so mild defects have come to be diagnosed with more
accuracy than before. These mild defects may have diluted the gender
difference of more severe CHD with DS patients in the era of
echocardiography.
REFERENCES
1. Glasson EJ, Sullivan SG, Hussain R, et al. The changing survival profile of people with Down's syndrome:
implications for genetic counselling. Clin Genet 2002; 62: 390-393.
2. Collmann RD and Stroller A. Data on mongolism in Victoria: Prevalence and life expectation. J Ment Def
Res 1963; 7: 60-68.
3. Masaki M, Higurashi M, Iijima K, et al. Mortality and survival for Down syndrome in Japan. Am J Hum
Genet 1981; 33: 629-639.
4. Glasson EJ, Sullivan SG, Hussain R, et al. Comparative survival advantage of males with Down syndrome.
Am J Hum Biol 2003; 15: 192-195.
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5. Morris JK, Garne E, Welleesley D, et al. Major congenital anomalies in babies born with Down syndrome:
A EUROCAT population-based registry study. Am J Med Genet Part A 2014; 164A: 2979-2986.
What is already known?
The survival of children born with Down syndrome has continued to improve over recent decades.
Shorter female survival than male in Down syndrome (DS) has been reported in Western Australia.
What this study adds?
The rate of complication of CHD in females was significantly higher than that in males.
Significantly more females underwent surgery for CHD than males.
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Legend for the tables
Table 1 χ2=8.05 , d.f.=2 , p=0.018
Table 2
VSD, ventricular septal defect; ASD, atrial septal defect; AVSD, atrioventricular septal defect; PDA,
patent ductus arteriosus; TOF, tetralogy of Fallot, PS, pulmonary stenosis; DORV, double outlet right
ventricle; Ebstein, Ebstein’s anomaly; AR, aortic regurgitation; CoA, coarctation of aorta; MR, mitral
regurgitation; TA, tricuspid atresia; TR, tricuspid regurgitation.
Table 1. Gender-segregated complication of congenital heart disease (CHD) and operations on patients with
Down syndrome
CHD (+)
GenderOperation
(+)Operation
(-)CHD (-)
Total
199 155 272 626Female
32% 25% 43% 100%
175 163 346 684Male
26% 24% 51% 100%
374 318 618 1310Total
29% 24% 47% 100%
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Table 2. Gender-segregated main lesion of congenital heart disease (CHD) of patients with Down syndrome
Gender
Female MaleTotalMain lesion
Of CHD Number Percent Number Percent Number Percent
VSD 142 40.1% 131 38.8% 273 39.5%
ASD 75 21.2% 70 20.7% 145 21.0%
AVSD 55 15.5% 47 13.9% 102 14.7%
PDA 48 13.6% 40 11.8% 88 12.7%
TOF 23 6.5% 30 8.9% 53 7.7%
PS 1 0.3% 5 1.5% 6 0.9%
DORV 0.0% 3 0.9% 3 0.4%
Ebstein 1 0.3% 1 0.3% 2 0.3%
AR 1 0.3% 0.0% 1 0.1%
CoA 0.0% 1 0.3% 1 0.1%
MR 1 0.3% 0.0% 1 0.1%
TA 0.0% 1 0.3% 1 0.1%
TR 0.0% 1 0.3% 1 0.1%
unkown 7 2.0% 8 2.4% 15 2.1%
Total 354 100.0% 338 100.0% 692 100.0%
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Contributors TT designed the study, participated in interpretation of the results and drafted the initial
manuscript. MA participated in data collection and interpretation of the results. HT participated in data
analysis and interpretation of the results. RI, YN, HO, MK and NH participated in data collection. All authors
approved the final manuscript for submission.
Funding JSPS KAKENHI Grant number 23500893, Japan
Competing interests None declared
Ethics approval Tokyo Kasei University Ethics Committee, Kyorin University Ethics Committee, Teikyo
University Ethics Committee, University of Tokyo Ethics Committee, National Center for Child Health and
Development Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
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Confidential: For Review Only
I translated our Japanese questionnaire about congenital heart disease into English.………………………………………………………………………………………………………………
25 January, 2003Dear All,
I am writing to you regarding the questionnaire about congenital heart disease in your child (if he or she has any). If you are agreeable to the contents, please return the completed questionnaire in the enclosed envelope. Congenital heart diseases are the most frequent complications in Down syndrome. The increased life expectancy may be attributed to improvement of heart surgery. However, we have little data about congenital heart diseases after adolescence. For that reason, we would like to conduct some inquiries about congenital heart diseases, the therapy and the prognosis.
Though we would like to have your child’s name in the questionnaire in order to avoid mistakes or overlapping of the data, we anonymize the data and use only numerical values for statistical work. Thus, there is no possibility of private information being exposed to the public. It is greatly appreciated if you would return the questionnaire by the end of February. I apologize for taking up your valuable time. If you have any questions, please do not hesitate to contact me. Thank you very much for your attention.
Takako Takano MD, PhD, Principal investigatorDepartment of Child HealthTokyo Kasei University1-18-1 Kaga, Itabashi-ku, Tokyo, 173-8602JAPANPhone & FAX: +81-3-3961-5339
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Questionnaire about Congenital Heart Disease
Please fill in the blanks, or choose and circle the mark (*) of the most accurate answer from the list. If you don’t know the answer, please choose "unknown" instead of leaving it unanswered. Please write the details as far as you know in the brackets [ ].
Your child’s Name Sex ( *Male, *Female )Your child’s Birthday (year) (month)(1) Chromosome type of Down syndrome: *trisomy 21 *translocation *mosaic(2) Does your child have congenital heart disease (including cured state)? ( Yes, No )→ If No, please go to (4).(3)-1 Please circle the lesion of congenital heart disease. (Circle all, if multiple.)
* patent ductus arteriosus * fossa ovalis * atrial septal defect * ventricular septal defect* tetralogy of Fallot * atrioventricular septal defect * tricuspid atresia *coarctation of aorta* pulmonary artery stenosis *other [ ] *unkonown
(3)-2 Has your child been diagnosed with “pulmonary hypertension”? ( Yes, No )(3)-3 Did your child undergo cardiac surgery (including catheter-based therapy)? ( Yes, No )(3)-4 Please write the date or age of the cardiac surgery.
First operation: Date (year) (month) or Age (year) (month)old Second operation: Date (year) (month) or Age (year) (month)oldThird operation: Date (year) (month) or Age (year) (month)old
(3)-5 Regarding the status of cardiac diseases in your child at present. Please circle the most accurate choice (*).1) Does your child see a doctor regularly?
*Yes *Not now2) The status of cardiac diseases of your child at present:
* fully healed, no abnormality *minor abnormality, but no limitation of daily activities* limitation of daily activities
3) Does your child have symptoms?*nothing * dyspnea on exercise *dyspnea at rest *cyanosis *edema* other [ ]
4) Is your child taking any treatment?*No *taking medicine [drug name: ]*pacemaker or implantable cardiac defibrillator* waiting for a surgery date [in detail ]
(4) If your child has other complications except cardiac disease, circle all appropriate choices and write in detail.*No*disease of the gastrointestinal tract [disease name: *during therapy, *operated, *cured ]*leukemia [disease name: *during therapy, *operated, *cured ]*other [disease name: *during therapy, *operated, *cured ]
(5) Please use this space if you have any questions about your child’s medical problems.
I am grateful for your cooperation.
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Confidential: For Review OnlySex Differences in Congenital Heart Disease in Down
Syndrome: Study Data from Medical Records and Questionnaires in a Region of Japan
Journal: BMJ Paediatrics Open
Manuscript ID bmjpo-2018-000414.R2
Article Type: Original research letter
Date Submitted by the Author: 05-Mar-2019
Complete List of Authors: Takano, Takako; Tokyo Kasei University, Department of Child HealthAkagi, Michio; Kyorin UniversityTakaki, Haruyoshi; Tokyo Healthcare University - Kokuritsu Byoin Kiko CampusInuzuka, Ryo; University of TokyoNogimori, Yoshitsugu; Kanagawa Childrens Medical CenterOno, Hiroshi; National Center for Child Health and DevelopmentKaneko, Masahide; Kanto Central Hospital, Department of PediatricsHagiwara, Norifumi; Teikyo University
Keywords: Epidemiology, Cardiology, Congenital Abnorm
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BMJ Paediatrics Open, Original Research Letter
Sex Differences in Congenital Heart Disease in Down Syndrome: Study Data from Medical
Records and Questionnaires in a Region of Japan
Corresponding author: Takako Takano, MD, PhD, Professor, Department of Child Health, Tokyo Kasei
University, 1-18-1 Kaga, Itabashi-ku, Tokyo 173-8602, Japan; Telephone
number: +81-3-3961-5339, e-mail: [email protected]
Authors: Takako Takano,1 Michio Akagi,2 Haruyoshi Takaki,3 Ryo Inuzuka,4 Yoshitsugu Nogimori,5 Hiroshi
Ono,6 Masahide Kaneko,7 Norifumi Hagiwara8
1Department of Child Health, Tokyo Kasei University, Tokyo, Japan
2Department of Medical Education, Kyorin University, Tokyo, Japan
3Department of Nursing, Tokyo Healthcare University, Tokyo, Japan
4Department of Pediatrics, University of Tokyo, Tokyo, Japan
5 Department of Cardiology, Kanagawa Children’s Medical Center, Kanagawa, Japan
6Department of Cardiovascular Medicine, National Center for Child Health and Development, Tokyo, Japan
7Department of Pediatrics, Kanto Central Hospital, Tokyo, Japan 8Department of Pediatrics, Teikyo
University, Tokyo, Japan
Total word count of manuscript: 599 words
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ABSTRACT
Reports indicate lower Down syndrome (DS) survival among female patients than among male patients in
Australia, contrasting with female longevity in the general population. Using data on 1,310 (626 female, 684
male) DS patients in Japan from five hospitals’ medical records and questionnaires completed by patients’
parents, we investigated sex differences in congenital heart disease (CHD), which may be related to mortality.
The CHD rate was significantly higher for female patients (354, 57%) than for male patients (338, 49%; p =
0.010). Significantly more female patients (199, 32%) than male patients (175, 26%) underwent surgery for
CHD (p = 0.018).
Key words: Down syndrome; Congenital heart disease; Sex difference
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INTRODUCTION
Life expectancy for patients with Down syndrome (DS) has increased in Australia,1 Japan,2 and other
advanced countries. In Japan, improvements in early survival have been attributed to surgical intervention for
congenital heart disease (CHD).3 In Australia, in contrast to female longevity in the general population, male
patients with DS had significantly longer life expectancies than did their female counterparts.4 The shorter life
expectancy of these female patients may be attributed to their higher prevalence of CHD. This study aimed to
clarify sex differences in the prevalence and severity of CHD among Japanese DS patients.
METHODS
We used data from medical records from five hospitals in Tokyo and two questionnaires completed by
patients’ parents in Tokyo and Shizuoka prefectures (Online Supplementary File 1). Patients were not directly
involved in the design of this study. Small (diameter < 6 mm) fossa ovalis defects were excluded from the
diagnosis of atrial septal defect (ASD). Arterial ducts closed before one month of age were excluded from the
diagnosis of patent ductus arteriosus (PDA). The study was approved by the ethical committees of Tokyo
Kasei University and each participating hospital. Questionnaires were mailed to patients’ parents; completing
and returning the questionnaire was considered to indicate consent to participate. Statistical analyses were
performed using SPSS, Version 21.
RESULTS
In total, there were 1,310 patients with DS (626 female patients and 684 male patients; sex ratio = 1.09).
Prevalence of CHD was significantly higher among female patients (354, 57%) than among male patients
(338, 49%; chi-square test: p = 0.010). Moreover, significantly more female (199, 32%) than male patients
(175, 26%) underwent cardiac surgery (chi-square test: p = 0.018; Table 1). The main CHD lesions (in order
of prevalence) were ventricular septal defect (VSD), ASD, atrioventricular septal defect (AVSD), PDA, and
tetralogy of Fallot (TOF; Table 2). The prevalence of CHD with PDA was significantly higher in female
patients (115, 18%) than in male patients (87, 13%; p = 0.005), whereas the prevalence of CHD without PDA
was almost equal in female (239, 38%) and male (251, 37%) patients. Among patients born before 1970
(female: 34, 43.6%; male: 10, 18.5%), in the 1980s (female: 63, 51.2%; male: 46, 37.7%), or in the 1990s
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(female: 74, 59.7%; male: 85, 47.5%), more female patients than male patients had CHD, but we found no
significant sex difference in CHD prevalence for patients born after 2000 (female: 183, 60.8%; male: 196,
59.8%).
DISCUSSION
In our study, female patients with DS had disadvantages in CHD complication, compared with male patients,
consistent with previous reports in the United States5 and Europe.6 Higher prevalence and greater severity of
CHD in female patients may contribute to poor prognoses. We found that the most common cardiac anomalies
(main lesions) were VSD, ASD, AVSD, PDA, and TOF, which together accounted for 95.5% of all CHD
cases. Likewise, a EUROCAT (a European network of population-based registers for the epidemiologic
surveillance of congenital anomalies) study6 found that these five anomalies accounted for more than 99% of
cardiac anomaly cases in DS patients. Among patients with DS born in the 1970s, 1980s,
or 1990s, we found that significantly more female than male patients had
CHD, but we found no significant sex difference for patients born after
2000. Many factors seem to have contributed to this change, including the
improvement of diagnostic techniques such as cardiac ultrasound and the
improvements in heart surgery. In particular, echocardiographic
examination spread throughout Japan in the 1990s, facilitating the
accurate diagnosis of mild defects. This shift may have attenuated
previously observed sex differences in CHD severity among patients with
DS.
REFERENCES
1. Glasson EJ, Sullivan SG, Hussain R, et al. The changing survival profile of people with Down's syndrome:
implications for genetic counselling. Clin Genet 2002; 62: 390-393.
2. Masaki M, Higurashi M, Iijima K, et al. Mortality and survival for Down syndrome in Japan. Am J Hum
Genet 1981; 33: 629-639.
3. Hijii T, Fukushige J, Igarashi H et al. Life expectancy and social adaptation in individuals with Down
syndrome with and without surgery for congenital heart disease. Clin Pediatr 1997; 36: 327–332.
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4. Glasson EJ, Sullivan SG, Hussain R, et al. Comparative survival advantage of males with Down syndrome.
Am J Hum Biol 2003; 15: 192-195.
5. Freeman SB, Bean LH, Allen EG et al. Ethnicity, sex, and the incidence of congenital heart defects: a report
from the National Cown Syndrome Project. Genet Med 2008; 10: 173-180.
6. Morris JK, Garne E, Welleesley D, et al. Major congenital anomalies in babies born with Down syndrome:
A EUROCAT population-based registry study. Am J Med Genet Part A 2014; 164A: 2979-2986.
What is already known?
The survival of children born with Down syndrome has continued to improve in recent decades.
In Australia, shorter life expectancies have been reported for female patients with Down syndrome than for their male counterparts.
Prevalence of congenital heart disease is higher in female patients with Down syndrome than in their male counterparts in the United States and Europe.
What this study adds?
Prevalence of congenital heart disease was significantly higher among female patients than among male patients in Japan.
Significantly more female patients than male patients underwent surgery for congenital heart disease.
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Table legends
Table 1 χ2 = 8.05 , d.f. = 2 , p = 0.018
Odds female versus male with CHD (95% CI) 1.33 (1.07-1.66)
Odds female versus male with CHD Operation (95% CI) 1.36 (1.07-1.72)
Table 2
VSD: ventricular septal defect; ASD: atrial septal defect; AVSD: atrioventricular septal defect; PDA:
patent ductus arteriosus; TOF: tetralogy of Fallot; PS: pulmonary stenosis; DORV: double outlet right
ventricle; Ebstein: Ebstein’s anomaly; AR: aortic regurgitation; CoA: coarctation of aorta; MR: mitral
regurgitation; TA: tricuspid atresia; TR: tricuspid regurgitation
Table 1. Congenital heart disease (CHD) and operations among patients with Down syndrome by sex
CHD (+)
SexOperation
(+)Operation
(-)CHD (-)
Total
199 155 272 626Female
32% 25% 43% 100%
175 163 346 684Male
26% 24% 51% 100%
374 318 618 1310Total
29% 24% 47% 100%
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Table 2. Main congenital heart disease (CHD) lesion among patients with Down syndrome by sex
Sex
Female MaleTotalMain lesion
Of CHD Number Percent Number Percent Number Percent
VSD 142 40.1% 131 38.8% 273 39.5%
ASD 75 21.2% 70 20.7% 145 21.0%
AVSD 55 15.5% 47 13.9% 102 14.7%
PDA 48 13.6% 40 11.8% 88 12.7%
TOF 23 6.5% 30 8.9% 53 7.7%
PS 1 0.3% 5 1.5% 6 0.9%
DORV 0.0% 3 0.9% 3 0.4%
Ebstein 1 0.3% 1 0.3% 2 0.3%
AR 1 0.3% 0.0% 1 0.1%
CoA 0.0% 1 0.3% 1 0.1%
MR 1 0.3% 0.0% 1 0.1%
TA 0.0% 1 0.3% 1 0.1%
TR 0.0% 1 0.3% 1 0.1%
unkown 7 2.0% 8 2.4% 15 2.1%
Total 354 100.0% 338 100.0% 692 100.0%
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Funding: This work was supported by JSPS KAKENHI grant number 23500893, Japan.
Competing interests: None declared
Contributors: TT designed the study, participated in the interpretation of the results, and drafted the initial
manuscript. MA participated in the data collection and interpretation of the results. HT participated in the data
analysis and interpretation of the results. RI, YN, HO, MK, and NH participated in the data collection. All of
the authors approved the final manuscript for submission.
Ethics approval: Tokyo Kasei University Ethics Committee, Kyorin University Ethics Committee, Teikyo
University Ethics Committee, University of Tokyo Ethics Committee, National Center for Child Health and
Development Ethics Committee
Provenance and peer review: Not commissioned; externally peer reviewed.
Acknowledgment: We thank Jennifer Barrett, PhD, from Edanz Group (www.edanzediting.com/ac) for
editing a draft of this manuscript.
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I translated our Japanese questionnaire about congenital heart disease into English.
………………………………………………………………………………………………………………
25 January, 2013
Dear All,
I am writing to you regarding the questionnaire about congenital heart disease in your child (if he or she has any). If you are
agreeable to the contents, please return the completed questionnaire in the enclosed envelope.
Congenital heart diseases are the most frequent complications in Down syndrome. The increased life expectancy may be
attributed to improvement of heart surgery. However, we have little data about congenital heart diseases after adolescence.
For that reason, we would like to conduct some inquiries about congenital heart diseases, the therapy and the prognosis.
Though we would like to have your child’s name in the questionnaire in order to avoid mistakes or overlapping of the
data, we anonymize the data and use only numerical values for statistical work. Thus, there is no possibility of private
information being exposed to the public.
It is greatly appreciated if you would return the questionnaire by the end of February. I apologize for taking up your
valuable time. If you have any questions, please do not hesitate to contact me.
Thank you very much for your attention.
Takako Takano MD, PhD, Principal investigator
Department of Child Health
Tokyo Kasei University
1-18-1 Kaga, Itabashi-ku, Tokyo, 173-8602
JAPAN
Phone & FAX: +81-3-3961-5339
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Questionnaire about Congenital Heart Disease
Please fill in the blanks, or choose and circle the mark (*) of the most accurate answer from the list. If you don’t know the
answer, please choose "unknown" instead of leaving it unanswered. Please write the details as far as you know in the
brackets [ ].
Your child’s Name Sex ( *Male, *Female )
Your child’s Birthday (year) (month)
(1) Chromosome type of Down syndrome: *trisomy 21 *translocation *mosaic
(2) Does your child have congenital heart disease (including cured state)? ( Yes, No )
→ If No, please go to (4).
(3)-1 Please circle the lesion of congenital heart disease. (Circle all, if multiple.)
* patent ductus arteriosus * fossa ovalis * atrial septal defect * ventricular septal defect
* tetralogy of Fallot * atrioventricular septal defect * tricuspid atresia *coarctation of aorta
* pulmonary artery stenosis *other [ ] *unkonown
(3)-2 Has your child been diagnosed with “pulmonary hypertension”? ( Yes, No )
(3)-3 Did your child undergo cardiac surgery (including catheter-based therapy)? ( Yes, No )
(3)-4 Please write the date or age of the cardiac surgery.
First operation: Date (year) (month) or Age (year) (month)old
Second operation: Date (year) (month) or Age (year) (month)old
Third operation: Date (year) (month) or Age (year) (month)old
(3)-5 Regarding the status of cardiac diseases in your child at present. Please circle the most accurate choice (*).
1) Does your child see a doctor regularly?
*Yes *Not now
2) The status of cardiac diseases of your child at present:
* fully healed, no abnormality *minor abnormality, but no limitation of daily activities
* limitation of daily activities
3) Does your child have symptoms?
*nothing * dyspnea on exercise *dyspnea at rest *cyanosis *edema
* other [ ]
4) Is your child taking any treatment?
*No *taking medicine [drug name: ]
*pacemaker or implantable cardiac defibrillator
* waiting for a surgery date [in detail ]
(4) If your child has other complications except cardiac disease, circle all appropriate choices and write in detail.
*No
*disease of the gastrointestinal tract [disease name: *during therapy, *operated, *cured ]
*leukemia [disease name: *during therapy, *operated, *cured ]
*other [disease name: *during therapy, *operated, *cured ]
(5) Please use this space if you have any questions about your child’s medical problems.
I am grateful for your cooperation.
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123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review OnlySex Differences in Congenital Heart Disease in Down
Syndrome: Study Data from Medical Records and Questionnaires in a Region of Japan
Journal: BMJ Paediatrics Open
Manuscript ID bmjpo-2018-000414.R3
Article Type: Original research letter
Date Submitted by the Author: 30-Mar-2019
Complete List of Authors: Takano, Takako; Tokyo Kasei University, Department of Child HealthAkagi, Michio; Kyorin UniversityTakaki, Haruyoshi; Tokyo Healthcare University - Kokuritsu Byoin Kiko CampusInuzuka, Ryo; University of TokyoNogimori, Yoshitsugu; Kanagawa Childrens Medical CenterOno, Hiroshi; National Center for Child Health and DevelopmentKaneko, Masahide; Kanto Central Hospital, Department of PediatricsHagiwara, Norifumi; Teikyo University
Keywords: Epidemiology, Cardiology, Congenital Abnorm
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BMJPaediatrics Open, Original Research Letter
Sex Differences in Congenital Heart Disease in Down Syndrome: Study Data from Medical
Records and Questionnaires in a Region of Japan
Corresponding author: Takako Takano, MD, PhD, Professor, Department of Child Health, Tokyo Kasei
University, 1-18-1 Kaga, Itabashi-ku, Tokyo 173-8602, Japan; Telephone number: +81-3-3961-5339, e-mail:
Authors: Takako Takano,1 Michio Akagi,2 Haruyoshi Takaki,3 Ryo Inuzuka,4 Yoshitsugu Nogimori,5 Hiroshi
Ono,6 Masahide Kaneko,7 Norifumi Hagiwara8
1Department of Child Health, Tokyo Kasei University, Tokyo, Japan
2Department of Medical Education, Kyorin University, Tokyo, Japan
3Department of Nursing, Tokyo Healthcare University, Tokyo, Japan
4Department of Pediatrics, University of Tokyo, Tokyo, Japan
5 Department of Cardiology, Kanagawa Children’s Medical Center, Kanagawa, Japan
6Department of Cardiovascular Medicine, National Center for Child Health and Development, Tokyo, Japan
7Department of Pediatrics, Kanto Central Hospital, Tokyo, Japan
8Department of Pediatrics, Teikyo University, Tokyo, Japan
Total word count of manuscript: 589 words
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ABSTRACT
Reports indicate lower Down syndrome (DS) survival among females than among males in Australia,
contrasting with female longevity in the general population. Using data on 1,310 people with DS (626 females
and 684 males) in Japan from five hospitals’ medical records and questionnaires completed by parents of
people with DS, we investigated sex differences in congenital heart disease (CHD), which may be related to
mortality. The CHD rate was significantly higher for females (354, 57%) than for males (338, 49%; p =
0.010). Significantly more females (199, 32%) than males (175, 26%) underwent surgery for CHD (p =
0.018).
Key words: Down syndrome; Congenital heart disease; Sex difference
Page 2 of 10
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INTRODUCTION
Life expectancy for people with Down syndrome (DS) has increased in Australia,1 Japan,2 and other advanced
countries. In Japan, improvements in early survival have been attributed to surgical intervention for congenital
heart disease (CHD).3 In Australia, in contrast to female longevity in the general population, males with DS
were found to have significantly longer life expectancies, compared with their female counterparts.4 The
shorter life expectancy of these females may be attributed to their higher prevalence of CHD. This study
aimed to clarify sex differences in the prevalence and severity of CHD among Japanese people with DS.
METHODS
We used data from medical records from five hospitals in Tokyo and two questionnaires completed by parents
of people with DS in Tokyo and Shizuoka prefectures (Online Supplementary File 1). People with DS were
not directly involved in the design of this study. Small (diameter < 6 mm) fossa ovalis defects were excluded
from the diagnosis of atrial septal defect (ASD). Arterial ducts closed before one month of age were excluded
from the diagnosis of patent ductus arteriosus (PDA). The study was approved by the ethical committees of
Tokyo Kasei University and each participating hospital. Questionnaires were mailed to parents of people with
DS; completing and returning the questionnaire was considered to indicate consent to participate. Statistical
analyses were performed using SPSS, Version 21.
RESULTS
In total, there were 1,310 subjects with DS (626 females and 684 males; sex ratio = 1.09). The prevalence of
CHD was significantly higher among females (354, 57%) than among males (338, 49%; chi-square test: p =
0.010). Moreover, significantly more females (199, 32%) than males (175, 26%) underwent cardiac surgery
(chi-square test: p = 0.018; Table 1). The main CHD lesions (in order of prevalence) were ventricular septal
defect (VSD), ASD, atrioventricular septal defect (AVSD), PDA, and tetralogy of Fallot (TOF; Table 2). The
prevalence of CHD with PDA was significantly higher in females (115, 18%) than in males 87, 13%; p =
0.005), whereas the prevalence of CHD without PDA was almost equal in females (239, 38%) and males (251,
37%.) Among subjects born before 1979 (female: 34, 43.6%; male: 10, 18.5%), in the 1980s (female: 63,
51.2%; male: 46, 37.7%), or in the 1990s (female: 74, 59.7%; male: 85, 47.5%), more females than males had
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CHD, but we found no significant sex difference in CHD prevalence for subjects born in 2000 or later
(female: 183, 60.8%; male: 196, 59.8%).
DISCUSSION
In our study, females with DS had a significantly higher prevalence of CHD than did males with DS, as has
previously been reported in the United States5 and Europe.6 Higher prevalence and greater severity of CHD in
females may contribute to poor prognoses. We found that the most common cardiac anomalies (main lesions)
were VSD, ASD, AVSD, PDA, and TOF, which together accounted for 95.5% of all CHD cases. Likewise, a
EUROCAT (a European network of population-based registers for the epidemiologic surveillance of
congenital anomalies) study6 found that these five anomalies accounted for more than 99% of cardiac anomaly
cases in people with DS. Among people with DS born before 1979, in the1980s, or 1990s, we found that
significantly more female than male subjects had CHD, but we found no significant sex difference for subjects
born in 2000 or later. Many factors seem to have contributed to this change, including the improvement of
diagnostic techniques such as echocardiographic examination and improvements in heart surgery. This shift
may be attributed to a great increase in the diagnosis of less severe CHD for both sexes.
REFERENCES
1. Glasson EJ, Sullivan SG, Hussain R, et al. The changing survival profile of people with Down's syndrome:
implications for genetic counselling. Clin Genet 2002; 62: 390-393.
2. Masaki M, Higurashi M, Iijima K, et al. Mortality and survival for Down syndrome in Japan. Am J Hum
Genet 1981; 33: 629-639.
3. Hijii T, Fukushige J, Igarashi H et al. Life expectancy and social adaptation in individuals with Down
syndrome with and without surgery for congenital heart disease. Clin Pediatr 1997; 36: 327–332.
4. Glasson EJ, Sullivan SG, Hussain R, et al. Comparative survival advantage of males with Down syndrome.
Am J Hum Biol 2003; 15: 192-195.
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Confidential: For Review Only
5. Freeman SB, Bean LH, Allen EG et al. Ethnicity, sex, and the incidence of congenital heart defects: a report
from the National Cown Syndrome Project. Genet Med 2008; 10: 173-180.
6. Morris JK, Garne E, Welleesley D, et al. Major congenital anomalies in babies born with Down syndrome:
A EUROCAT population-based registry study. Am J Med Genet Part A 2014; 164A: 2979-2986.
What is already known on this topic?
The survival of children born with Down syndrome has continued to improve in recent decades.
In Australia, shorter life expectancies have been reported for females with Down syndrome than
for their male counterparts.
Prevalence of congenital heart disease is higher in females with Down syndrome than in their male
counterparts in the United States and Europe.
What this study hopes to add?
The prevalence of congenital heart disease was significantly higher among females than among
males with Down syndrome in Japan.
Significantly more females than males underwent surgery for congenital heart disease with Down
syndrome in Japan.
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Table legends
Table 1 χ2 = 8.05 , d.f. = 2 , p = 0.018
Odds: female versus male with CHD (95% confidence interval) 1.33 (1.07–1.66)
Odds: female versus male with CHD operation (95% confidence interval) 1.36 (1.07–1.72)
Table 2
VSD: ventricular septal defect; ASD: atrial septal defect; AVSD: atrioventricular septal defect; PDA:
patent ductus arteriosus; TOF: tetralogy of Fallot; PS: pulmonary stenosis; DORV: double outlet right
ventricle; Ebstein: Ebstein’s anomaly; AR: aortic regurgitation; CoA: coarctation of aorta; MR: mitral
regurgitation; TA: tricuspid atresia; TR: tricuspid regurgitation
Table 1. Congenital heart disease (CHD) and operations among people with Down syndrome by sex
CHD (+)
SexOperation
(+)Operation
(-)CHD (-)
Total
199 155 272 626Female
32% 25% 43% 100%
175 163 346 684Male
26% 24% 51% 100%
374 318 618 1310Total
29% 24% 47% 100%
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Table 2. Main congenital heart disease (CHD) lesion among people with Down syndrome by sex
Sex
Female MaleTotalMain lesion
Of CHD Number Percent Number Percent Number Percent
VSD 142 40.1% 131 38.8% 273 39.5%
ASD 75 21.2% 70 20.7% 145 21.0%
AVSD 55 15.5% 47 13.9% 102 14.7%
PDA 48 13.6% 40 11.8% 88 12.7%
TOF 23 6.5% 30 8.9% 53 7.7%
PS 1 0.3% 5 1.5% 6 0.9%
DORV 0.0% 3 0.9% 3 0.4%
Ebstein 1 0.3% 1 0.3% 2 0.3%
AR 1 0.3% 0.0% 1 0.1%
CoA 0.0% 1 0.3% 1 0.1%
MR 1 0.3% 0.0% 1 0.1%
TA 0.0% 1 0.3% 1 0.1%
TR 0.0% 1 0.3% 1 0.1%
unkown 7 2.0% 8 2.4% 15 2.1%
Total 354 100.0% 338 100.0% 692 100.0%
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Funding: This work was supported by JSPS KAKENHI grant number 23500893, Japan.
Competing interests: None declared
Contributors: TT designed the study, participated in the interpretation of the results, and drafted the initial
manuscript. MA participated in the data collection and interpretation of the results. HT participated in the data
analysis and interpretation of the results. RI, YN, HO, MK, and NH participated in the data collection. All of
the authors approved the final manuscript for submission.
Ethics approval: Tokyo Kasei University Ethics Committee, Kyorin University Ethics Committee, Teikyo
University Ethics Committee, University of Tokyo Ethics Committee, National Center for Child Health and
Development Ethics Committee
Provenance and peer review: Not commissioned; externally peer reviewed.
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I translated our Japanese questionnaire about congenital heart disease into English.
………………………………………………………………………………………………………………
25 January, 2013
Dear All,
I am writing to you regarding the questionnaire about congenital heart disease in your child (if he or she has any). If you are
agreeable to the contents, please return the completed questionnaire in the enclosed envelope.
Congenital heart diseases are the most frequent complications in Down syndrome. The increased life expectancy may be
attributed to improvement of heart surgery. However, we have little data about congenital heart diseases after adolescence.
For that reason, we would like to conduct some inquiries about congenital heart diseases, the therapy and the prognosis.
Though we would like to have your child’s name in the questionnaire in order to avoid mistakes or overlapping of the
data, we anonymize the data and use only numerical values for statistical work. Thus, there is no possibility of private
information being exposed to the public.
It is greatly appreciated if you would return the questionnaire by the end of February. I apologize for taking up your
valuable time. If you have any questions, please do not hesitate to contact me.
Thank you very much for your attention.
Takako Takano MD, PhD, Principal investigator
Department of Child Health
Tokyo Kasei University
1-18-1 Kaga, Itabashi-ku, Tokyo, 173-8602
JAPAN
Phone & FAX: +81-3-3961-5339
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Questionnaire about Congenital Heart Disease
Please fill in the blanks, or choose and circle the mark (*) of the most accurate answer from the list. If you don’t know the
answer, please choose "unknown" instead of leaving it unanswered. Please write the details as far as you know in the
brackets [ ].
Your child’s Name Sex ( *Male, *Female )
Your child’s Birthday (year) (month)
(1) Chromosome type of Down syndrome: *trisomy 21 *translocation *mosaic
(2) Does your child have congenital heart disease (including cured state)? ( Yes, No )
→ If No, please go to (4).
(3)-1 Please circle the lesion of congenital heart disease. (Circle all, if multiple.)
* patent ductus arteriosus * fossa ovalis * atrial septal defect * ventricular septal defect
* tetralogy of Fallot * atrioventricular septal defect * tricuspid atresia *coarctation of aorta
* pulmonary artery stenosis *other [ ] *unkonown
(3)-2 Has your child been diagnosed with “pulmonary hypertension”? ( Yes, No )
(3)-3 Did your child undergo cardiac surgery (including catheter-based therapy)? ( Yes, No )
(3)-4 Please write the date or age of the cardiac surgery.
First operation: Date (year) (month) or Age (year) (month)old
Second operation: Date (year) (month) or Age (year) (month)old
Third operation: Date (year) (month) or Age (year) (month)old
(3)-5 Regarding the status of cardiac diseases in your child at present. Please circle the most accurate choice (*).
1) Does your child see a doctor regularly?
*Yes *Not now
2) The status of cardiac diseases of your child at present:
* fully healed, no abnormality *minor abnormality, but no limitation of daily activities
* limitation of daily activities
3) Does your child have symptoms?
*nothing * dyspnea on exercise *dyspnea at rest *cyanosis *edema
* other [ ]
4) Is your child taking any treatment?
*No *taking medicine [drug name: ]
*pacemaker or implantable cardiac defibrillator
* waiting for a surgery date [in detail ]
(4) If your child has other complications except cardiac disease, circle all appropriate choices and write in detail.
*No
*disease of the gastrointestinal tract [disease name: *during therapy, *operated, *cured ]
*leukemia [disease name: *during therapy, *operated, *cured ]
*other [disease name: *during therapy, *operated, *cured ]
(5) Please use this space if you have any questions about your child’s medical problems.
I am grateful for your cooperation.
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