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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

https://mc.manuscriptcentral.com/bmjpo

BMJ Paediatrics Open

Confidential: For Review Only

1

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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https://www.ncbi.nlm.nih.gov/pubmed/12431254


https://www.ncbi.nlm.nih.gov/pubmed/?term=Masaki%2520M%255BAuthor%255D&cauthor=true&cauthor_uid=6455063

https://www.ncbi.nlm.nih.gov/pubmed/?term=Higurashi%2520M%255BAuthor%255D&cauthor=true&cauthor_uid=6455063

https://www.ncbi.nlm.nih.gov/pubmed/?term=Iijima%2520K%255BAuthor%255D&cauthor=true&cauthor_uid=6455063



6

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


Manuscript ID bmjpo-2018-000414.R1


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




1

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


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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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4

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



2. Collmann RD and Stroller A. Data on mongolism in Victoria: Prevalence and life expectation. J Ment Def

Res 1963; 7: 60-68.


Genet 1981; 33: 629-639.


Am J Hum Biol 2003; 15: 192-195.

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5




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.


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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7

Table 2. Gender-segregated main lesion of congenital heart disease (CHD) of patients with Down syndrome

Gender



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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8

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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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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https://eow.alc.co.jp/search?q=make&ref=awlj

https://eow.alc.co.jp/search?q=inquiries&ref=awlj

https://eow.alc.co.jp/search?q=appreciated&ref=awlj


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




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





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]


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


Page 1 of 10



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



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

Page 2 of 10



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


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

Page 3 of 10



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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




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.

Page 4 of 10



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960








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.




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.


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.

Page 5 of 10



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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



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%

Page 7 of 10



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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


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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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 ]



Page 10 of 10



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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




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





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:

[email protected]


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


Page 1 of 10



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



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



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


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

Page 3 of 10



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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




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.


Am J Hum Biol 2003; 15: 192-195.

Page 4 of 10



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960








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.



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.

Page 5 of 10



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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%

Page 6 of 10



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Table 2. Main congenital heart disease (CHD) lesion among people with Down syndrome by sex

Sex



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%

Page 7 of 10



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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


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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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 ]



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