Prevalence of HemoPHilia in cHina

Vol 45 No. 2 March 2014 455

Correspondence: Siyan Zhan, Department of epidemiology and biostatistics, School of Public Health, Peking University Health Science Cen-ter, 38 Xueyan Road, Haidian District, Beijing, PR China 100191.Tel: 86 10 82805162; Fax: 86-10-82077775E-mail: siyan-zhan@bjmu.edu.cn

THE PREVALENCE OF HEMOPHILIA IN MAINLAND CHINA: A SYSTEMATIC REVIEW AND META-ANALYSIS

Yanji Qu1, Xiaolu Nie1, Zhirong Yang1, Huan Yin1, Yuanjie Pang1, Peng Dong2 and Siyan Zhan1

1Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Haidian, Beijing; 2Phizer China,

Dongcheng, Beijing, PR China

Abstract. The prevalence of hemophilia in mainland China was unclear; therefore, we can conducted a meta-analysis using existing data to evaluate the prevalence of hemophilia and its subtypes hemophilia A (HA), hemophilia B (HB), hemophilia C (HC) and Von Willebrand disease (VWD) in mainland China. We conducted a systematic literature review during August, 2011 using PubMed, EMBASE, and Cochrane Library in English and CBMDISK, CNKI, VIP and Wanfang Database in Chinese. We also carried out a search of general and specific hemophilia related websites. Reference lists of key reviews were hand-searched for further relevant research. Studies providing data of the prevalence of hemophilia or its subtypes were included. Meta-analysis was done using the generic inverse variance model. Twenty-two studies were included in the meta-analysis. The overall weighted prevalence of hemophilia was 3.6 per 100,000 and the prevalence among males was 5.5 per 100,000. The prevalence based on community studies was 2.9 per 100,000. The proportions of HA, HB, HC and VWD were 70.97%,16.13%,6.45% and 2.90%, respectively. The prevalences calculated in our study were higher than any previous studies in mainland China, but lower than the world-wide prevalences. The registration rate of hemophiliacs was extremely low. HA and HB were the major subtypes of hemophilia.

Keywords: hemophilia, prevalence, registration, systematic review, meta-analysis

INTRODUCTION

Hemophilia is a group of X-linked, recessive, hereditary clotting diseases (Ding et al, 2010). Hemophilia A (blood coagulation factor VIII deficiency, HA)

and hemophilia B (blood coagulation factor IX deficiency, HB) are common sub-types of hemophilia. Hemophilia C (blood coagulation factor XI deficiency, HC) and Von Willibrand disease (Von Willibrand factor deficiency, VWD) are sometimes included in surveys of the prevalence of these diseases (Ding et al, 2010). Due to the low prevalence of hemophilia it is challenging to carry out epidemiological studies regarding hemophilia. There has been only one nationwide survey of he-mophilia in mainland China (Chinese Col-

SoutHeaSt aSian J troP med Public HealtH

456 Vol 45 No. 2 March 2014

laboration Group of Hemophilia, 1992). It was carried out by a Chinese hemophilia collaboration group in 24 provinces and cities and 37 districts in China between 1986 and 1989. The results published in 1992 showed a prevalence of hemophilia in mainland China of 2.73 per 100,000 with 80% being HA (Chinese Collabora-tion Group of Hemophilia, 1992). The aim of the current study was to estimate the prevalence of hemophilia in mainland China using existing data and compare it with the list of registered hemophilia patients.

MATERIALS AND METHODS

Search strategySearches were conducted in English

and Chinese using PubMed, EMBASE, Cochrane library, CBM, CNKI, VIP and Wanfang database during August, 2011 using the terms “Hemophilia”, “Epide-miology or prevalence” and “China or Chinese”. We excluded studies carried out in Hong Kong, Macao and Taiwan because this data were not easily accessible. No retrieval limitations were set. Reference lists of key reviews and grey literature were hand-searched for further relevant studies. We also searched general and hemophilia related websites to capture all possible data. Study inclusion criteria

For analysis and to reduce skewed data, selected studies had to fulfill the fol-lowing criteria: 1. study objects needed to be Chinese patients with HA, HB, HC or VWD living in mainland China; 2. study content was comprised of reported data used to calculate the prevalence of hemo-philia or the proportions of the subtypes; 3. study types needed to be observational studies with no controls to minimize the impact of patient selection criteria from

the original study or disease surveillance studies.

Studies not matching the above inclu-sion criteria were excluded along with studies having the following criteria: 1) duplicate studies using the same litera-ture, or having results already introduced in other literature from the same project; 2) Animal studies, in vitro studies and other basic medical studies; 3. lectures, reviews, commentaries and news.

The bibliographies, abstracts and full texts of the reviewed studies were examined in parallel by two researchers to determine whether to include the study. Disagreements were resolved by discus-sion or consulting experts.Information extraction

Data were entered in duplicate by 2 researchers into Epidata 3.1. Data were entered. Extracted information included the study field (community or hospital), district, type of research, basic characteris-tics of study subjects, diagnostic methods used to detect hemophilia, the prevalence of hemophilia (numerator and denomina-tor) and the proportions of subtypes of hemophilia.Quality of the studies

The quality of the studies was as-sessed using criteria revised from Prins et al (2002). A score was given to each study based on the following criteria: ex-ternal validity, internal validity, informa-tion, and other. The quality of the study was based on the score.Statistical analysis

Classification of hemophilia subtypes varied by study. Most studies included HA and HB, and some included HC and VWD. The overall prevalence and proportions of subtypes were combined using the generic inverse variance model

Prevalence of HemoPHilia in cHina

Vol 45 No. 2 March 2014 457

recommended by Sutton et al (2000) and Higgins et al (2003):

Y = ∑WiYi ÷ ∑Wi

95%CI of Y = Y ± 1.96SQRT (1/∑Wi)where Yi is the natural logarithm of

the rate or proportion reported by the ith study, Yi = ln (di/qi).di and qi are the nu-merator and denominator, respectively, of the rate or proportion. Wi is the weight factor of the ith study, Wi = 1/Vari = 1/(1/di + 1/qi), Vari is the variance of the ith study. I2 is the indicator of heterogeneity among the studies; is ranges from 0% to 100% and the larger it is, the greater the heterogeneity. A strength of this method is that it can endow different weights to the different studies based on their sample sizes. META-ANALYST was used to com-bine the prevalences and proportions. Subgroup analyses of the prevalences of hemophilia were carried out based on the study field, district, time of publication and subtype of hemophilia. Analysis and

graphing were done using EXCEL2007, META-ANALYST or RevMan-5.

RESULTS

Basic informationIn total, 868 articles were found in our

study, of which 22 were used for the analy-sis: 20 were published in Chinese and 2 were published in English (Fig 1). The 22 studies were published during 1985-2010 and 16/22 were published during 1987-1992 (Fig 2). The reason for this clustering of studies is because a nationwide census of hemophilia was carried out between 1986 and 1989. General information re-garding the 22 studies is shown in Table 1.Quality of the studies

The mean quality assessment score of the included studies was 8.9/18 (2-13). The mean scores for external validity, internal validity and information were 2.3/6 (1-5), 3.7/6 (0-6) and 1.9/3 (0-3), respectively.

Total studies identified (N=868)

Chinese: CNKI-413 Wanfang-160 VIP-80 CBM-74

English: PubMed-66 EMBASE-69 Cochran Library-6

Potentially relevant studies

(N=552)

Studies that met inclusion criteria

(N =38)

Duplications (316)

Based on titles and abstracts:

1. No patients with HA\HB\HC\VWD (219).

2. No prevalence/proportion data nor could it be calculated (194).

3. Animal studies, in vitro studies or other basic medical studies (27).

4. Lectures, reviews, commentaries, news (58).

5. Not carried out in mainland China or subjects not Chinese (16).

Included studies

(N =22)

Chinese: 20; English: 2

Based on full texts:

1. Duplications (2).

2. No prevalence/proportion data nor could it be calculated (6).

3. Animal studies, in vitro studies or other basic medical studies (2).

4. Lectures, reviews, commentaries, news (5).

5. Not carried out in mainland China or subjects not Chinese (1).

Fig 1–Flow diagram of studies chosen for this evaluation.

SoutHeaSt aSian J troP med Public HealtH

458 Vol 45 No. 2 March 2014

Tabl

e 1

Basi

c ch

arac

teri

stic

of i

nclu

ded

stud

ies.

Num

ber

Stud

y D

istr

ict

Stud

y

Stud

y

Age

s D

iagn

ostic

met

hods

D

iagn

ostic

N

umer

ator

D

enom

inat

or

fie

ld

type

st

udie

d

crite

rion

of p

reva

lenc

e of

pre

vale

nce

1 2 3 4 5 6 7 8 9 10

Liu,

198

5

Wan

g, 1

985

Yuan

, 198

7

CC

GH

et al

, 19

87

CG

HL

et a

l, 19

88C

hen

and

Lui,

1988

Hu

et al

, 19

88

Wei

et al

, 19

89a

Sun

et a

l, 19

89

Zhan

g et

al,

1989

East

ern

Chi

na

East

ern

Chi

na

Nor

thea

ster

n C

hina

Nat

ionw

ide

Nor

thea

ster

n C

hina

East

ern

Chi

na

East

ern

Chi

na

Sout

hern

C

hina

Cen

tral

Chi

na

Nor

thw

este

rn

Chi

na

Com

mun

ity

Com

mun

ity

Com

mun

ity

Hos

pita

l

Com

mun

ity

Hos

pita

l

Com

mun

ity

Com

mun

ity

Com

mun

ity

Com

mun

ity

Cen

sus

Cen

sus

Sam

plin

g su

rvey

Cas

e se

ries

Cen

sus

Cen

sus

Cen

sus

Cen

sus

Cro

ss-s

ec-

tiona

l stu

dy

Cen

sus

24.7

/27.

5 (2

.5-4

4)

20.8

9/19

.5

(1.1

7-66

)

24.4

4/23

(1

5-40

)

18/1

6

(1.5

-61)

(10-

25)

26.7

8/25

.5

(3-6

5) 0

5.33

/5.5

(2

-9)

24 (0

.33-

55)

38.7

1/35

(9

-78)

His

tory

-taki

ng, p

hysi

cal e

xam

inat

ion,

fam

ily

stud

y,cl

inic

al e

xam

inat

ion,

scre

enin

g te

st(P

TT,A

PTT,

PT,B

T,PL

T,C

T),c

linic

al d

iagn

ostic

test

(TG

T,S-

TGT,

FVIII

:C/F

VIII

:Ag,

FIX:

C/F

IX:A

g), t

ourn

ique

t te

st.

His

tory

-taki

ng,p

hysi

cal e

xam

inat

ion,

fam

ily

stud

y,cl

inic

al e

xam

inat

ion,

scre

enin

g te

st

(PTT

,APT

T,PT

), cl

inic

al d

iagn

ostic

test

(TG

T,S-

TGT,

FVIII

:C/F

VIII

:Ag)

. H

isto

ry-ta

king

,fam

ily st

udy,

clin

ical

ex

amin

atio

n,sc

reen

ing

test

(PT,

CT,

PCT)

, clin

ical

di

agno

stic

test

(TG

T,FV

III:C

/FV

III:A

g).

0 0 His

tory

-taki

ng,p

hysi

cal e

xam

inat

ion,

fam

ily

stud

y,cl

inic

al e

xam

inat

ion,

scre

enin

g te

st

(PTT

,APT

T,PT

,BT,

PLT,

CT)

, clin

ical

dia

gnos

-tic

test

(TG

T,S-

TGT,

FVIII

:C/F

VIII

:Ag,

FIX:

C/

FIX:

Ag)

,smea

r,tou

rniq

uet t

est.

His

tory

-taki

ng,p

hysi

cal e

xam

inat

ion,

fam

ily

stud

y,cl

inic

al e

xam

inat

ion,

scre

enin

g te

st

(PTT

,APT

T,PT

,BT,

PLT,

CT,

CRT

), cl

inic

al d

iagn

ostic

te

st (T

GT,

S-TG

T,FV

III:C

/FV

III:A

g,V

WF:

Ag)

. H

isto

ry-ta

king

,fam

ily st

udy,

clin

ical

ex

amin

atio

n,sc

reen

ing

test

(PTT

,APT

T,PT

,CT)

, cl

inic

al d

iagn

ostic

test

(TG

T,FV

III:C

/FV

III:A

g,FI

X:C

/FIX

:Ag)

. H

isto

ry-ta

king

,phy

sica

l exa

min

atio

n,fa

mily

st

udy,

clin

ical

exa

min

atio

n,sc

reen

ing

test

(P

TT,A

PTT,

PT,B

T,C

T,C

RT),

clin

ical

dia

gnos

tic te

st

(TG

T,FV

III:C

/FV

III:A

g).

His

tory

-taki

ng,fa

mily

stud

y,cl

inic

al

exam

inat

ion,

scre

enin

g te

st

(PTT

,APT

T,PT

,BT,

PLT,

CT)

, clin

ical

dia

gnos

tic te

st

(TG

T,S-

TGT,

FVIII

:C/F

VIII

:Ag)

.

Unc

lear

Unc

lear

Unc

lear

The

diag

nosi

s sta

ndar

d of

hr

ombo

sis a

nd h

emos

tasi

s ac

adem

ic m

eetin

g in

198

2U

ncle

ar

Unc

lear

Unc

lear

Unc

lear

The

coag

ulat

ion

diso

rder

s di

agno

stic

crit

eria

of t

he

Firs

t Chi

nese

Hem

atol

ogy

Soci

ety

Nat

iona

l Con

fer-

ence

on

thro

mbo

sis a

nd

hem

osta

sis,1

987

The

coag

ulat

ion

diso

rder

s di

agno

stic

crit

eria

of t

he

Firs

t Chi

nese

Hem

atol

ogy

Soci

ety

Nat

iona

l Con

fer-

ence

on

thro

mbo

sis a

nd

hem

osta

sis,1

987

8

350,

000

16

55

9,24

1

9

318,

575

91

1

3

149,

584

19

70

0,00

0

10

14

2,76

6

6

2,86

6,78

5

36

1,

440,

000

7

150,

777

Prevalence of HemoPHilia in cHina

Vol 45 No. 2 March 2014 459

His

tory

-taki

ng,p

hysi

cal e

xam

inat

ion,

fam

ily

stud

y,cl

inic

al e

xam

inat

ion,

scre

enin

g te

st

(PTT

,APT

T,PT

,BT,

PLT)

,clin

ical

dia

gnos

tic te

st)

TGT,

FVIII

:C/F

VIII

:Ag)

His

tory

-taki

ng,fa

mily

stud

y, c

lini-

cal e

xam

inat

ion,

scre

enin

g te

st

(PTT

,APT

T,PT

,BT,

PLT,

CT)

, clin

ical

dia

gnos

tic

test

(TG

T,B-

TGT,

FVIII

:C/F

VIII

:Ag,

FIX:

C/

FIX:

Ag)

, Gen

e di

agno

stic

test

)DO

H)

His

tory

-taki

ng,p

hysi

cal e

xam

inat

ion,

fam

ily

stud

y,cl

inic

al e

xam

inat

ion,

scre

enin

g te

st

(PTT

,APT

T,PT

,BT,

PLT)

, clin

ical

dia

gnos

tic te

st

(TG

T,B-

TGT,

FVIII

:C/F

VIII

:Ag,

FIX:

C/F

IX:A

g)H

isto

ry-ta

king

,fam

ily st

udy,

clin

ical

ex

amin

atio

n,sc

reen

ing

test

(BT,

CT)

, clin

ical

di

agno

stic

test

(TG

T,FV

III:C

/FV

III:A

g)

His

tory

-taki

ng,p

hysi

cal e

xam

inat

ion,

fam

ily

stud

y,cl

inic

al e

xam

inat

ion,

scre

enin

g te

st

(PTT

,APT

T,PT

,BT,

CT)

, clin

ical

dia

gnos

tic te

st

(TG

T,B-

TGT,

FVIII

:C/F

VIII

:Ag,

VW

F:A

g)

Fam

ily st

udy,

clin

ical

exa

min

atio

n,sc

reen

ing

test

(P

T), c

linic

al d

iagn

ostic

test

(TG

T)

His

tory

-taki

ng,p

hysi

cal e

xam

inat

ion,

fam

ily

stud

y,cl

inic

al e

xam

inat

ion,

scre

enin

g te

st

(PTT

,APT

T,PT

,CT,

PCT)

, Clin

ical

dia

gnos

tic te

st

(TG

T)

His

tory

-taki

ng,c

linic

al e

xam

inat

ion,

scre

enin

g te

st (P

TT,A

PTT,

PT,B

T,PL

T,C

T), c

linic

al d

i-ag

nost

ic te

st (T

GT,

FVIII

:C/F

VIII

:Ag,

FIX:

C/

FIX:

Ag,

VW

F:A

g), R

isto

w a

mph

oter

icin

cof

acto

r m

easu

rem

ent

His

tory

-taki

ng,p

hysi

cal e

xam

inat

ion,

fam

ily

stud

y,cl

inic

al e

xam

inat

ion,

scre

enin

g te

st

(PTT

,APT

T,PT

,BT,

PLT,

CT)

, clin

ical

dia

gnos

tic

test

(TG

T,S-

TGT,

FVIII

:C/F

VIII

:Ag,

FIX:

C/

FIX:

Ag)

0 Clin

ical

exa

min

atio

n,C

linic

al d

iagn

ostic

test

(F

VIII

:C/F

VIII

:Ag,

FIX:

C/F

IX:A

g,V

WF:

Ag)

0

The

coag

ulat

ion

diso

rder

s di

agno

stic

crit

eria

of t

he F

irst

Chi

nese

Hem

atol

ogy

Soci

ety

Nat

iona

l Con

fere

nce

on

thro

mbo

sis a

nd h

emos

ta-

sis,1

987

The

coag

ulat

ion

diso

rder

s di

agno

stic

crit

eria

of t

he F

irst

Chi

nese

Hem

atol

ogy

Soci

ety

Nat

iona

l Con

fere

nce

on

thro

mbo

sis a

nd h

emos

ta-

sis,1

987

The

diag

nost

ic st

anda

rd fo

r he

mop

hilia

A a

nd h

emop

hilia

B

of C

hang

zhou

mee

ting,

1982

Unc

lear

The

coag

ulat

ion

diso

rder

s di

agno

stic

crit

eria

of t

he F

irst

Chi

nese

Hem

atol

ogy

Soci

ety

Nat

iona

l Con

fere

nce

on

thro

mbo

sis a

nd h

emos

ta-

sis,1

987

Unc

lear

Unc

lear

The

coag

ulat

ion

diso

rder

s di

agno

stic

crit

eria

of t

he F

irst

Chi

nese

Hem

atol

ogy

Soci

ety

Nat

iona

l Con

fere

nce o

n th

rom

-bo

sis a

nd h

emos

tasi

s,198

7Th

e co

agul

atio

n di

sord

ers

diag

nost

ic c

riter

ia o

f the

Firs

t C

hine

se H

emat

olog

y So

ciet

y N

atio

nal C

onfe

renc

e on

th

rom

bosi

s and

hem

osta

-si

s,198

7U

ncle

ar

Unc

lear

Unc

lear

11 12 13 14 15 16 17 18 19 20 21 22

Wei

et a

l, 19

89b

Anh

ui,

1991

Lu et

al,

1991

Wan

g et

al,

1991

Wei

et a

l, 19

91

Zhao

et a

l, 19

91Ya

n et

al,

1991

CC

GH

et a

l, 19

92

Jing

et a

l, 19

93

Wei

, 199

6

Zhan

g et

al,

2003

Wan

g et

al,

2010

Nat

ionw

ide

East

ern

Chi

na

Cen

tral

Chi

na

East

ern

Chi

na

Nor

thea

ster

n C

hina

Cen

tral

Chi

na

Sout

hwes

tern

C

hina

Nat

ionw

ide

Sout

hwes

tern

C

hina

Sout

hern

C

hina

Nat

ionw

ide

Nat

ionw

ide

Unc

lear

Both

Com

mun

ity

Com

mun

ity

Com

mun

ity

Com

mun

ity

Com

mun

ity

Both

Com

mun

ity

Hos

pita

l

Hos

pita

l

Unc

lear

Roun

d-up

s

Sam

plin

g su

rvey

Cen

sus

Cro

ss-s

ectio

nal

stud

y

Cro

ss-s

ectio

nal

stud

y

Cro

ss-s

ectio

nal

stud

yC

ross

-sec

tiona

l st

udy

Cro

ss-s

ectio

nal

stud

y

Cen

sus

Cas

e se

ries

Cas

e se

ries

Scre

enin

g

(2-7

8)

22.0

8/22

(3

-40)

23.8

8/20

.5

(3-6

5)

14.2

(0

.92-

41)

(2-3

7)

(14-

48)

0 0

19.5

8/21

.5

(2.5

-43)

0 0 0

24

1,

052,

063

12

20

3,28

0

8

189,

591

18

51

0,48

7

7

203,

938

14

49

7,71

5

5

238,

150

46

0 16

,866

,654

18

80

8,76

2

8

18,2

83

11

90

-

15

95

-

Tabl

e 1

(Con

tinue

d).

Num

ber

Stud

y D

istr

ict

Stud

y

Stud

y

Age

s D

iagn

ostic

met

hods

D

iagn

ostic

N

umer

ator

D

enom

inat

or

fie

ld

type

st

udie

d

crite

rion

of p

reva

lenc

e of

pre

vale

nce

CC

GH

, Chi

nese

Col

labo

ratio

n G

roup

of H

emop

hilli

a; C

GH

L, C

olla

bora

tion

Gro

up o

f Hem

ophi

lia o

f Lia

oyua

n.

SoutHeaSt aSian J troP med Public HealtH

460 Vol 45 No. 2 March 2014

4.5

4

3.5

3

2.5

2

1.5

1

0.5

0

1985 1987 1988 1989 1990 1991

Year published

1992 1993 1996 2003 2010

Nu

mb

er

of

stu

die

s in

clu

de

d

Fig 2–Distribution of included studies by publication year.

Low risk of bias Unclear risk of bias High risk of bias

0% 25% 50% 75% 100%

Source population (External validity)

Description of eligibility criteria (External validity)

Participants and non-responders (External validity)

Description of study period (External validity)

Description of study population (External validity)

Data collection (Internal validity)

Measurement instrument (Internal validity)

Definition of diseases (Internal validity)

Reported prevalence (Internal validity)

Method of data collection properly described (Informativity)

Questions and answer possibilities stated (Informativity)

Reported prevalence rates reproducible (Informativity)

Epidemiology method adaptable (Others)

Quality control strategy (Others)

Limitations clear (Others)

Fig 3–Quality of included studies.

Thus, the quality of the included studies was not good. This could be related to when the studies were published. The main factors affecting quality were de-scription of study population, statement of questions and answer possibilities, quality control and limitations clarity (Fig 3).

Prevalence of hemo-philiaTo t a l p r e v a l e n c e . Nineteen s tudies were used to estimate the prevalence of he-mophilia in main-land China (Liu, 1985; Wang, 1985; Chen and Liu, 1988; Hu et al, 1988; Sun et al, 1989; Lu et al, 1991; Wang et al, 1991; Zhao et al, 1991; Chinese Collaboration Group of Hemophilia, 1992; Jing et al, 1993; Wei, 1996; Yuan et al, 1987; The Collaboration Group of Hemophil-ia of Liaoyuan et al, 1988; Wei et al, 1989a; Zhang et al, 1989; Wei et al, 1989b; The In-vestigation Group of Hemophilia of Anhui, 1991; Wei et al, 1991; Yan et al, 1991). Eight of these included the census results report-ed in 1992 (Yuan et al, 1987; The Collabora-tion Group of Hemo-philia of Liaoyuan et al, 1988; Wei et al, 1989a; Zhang et al, 1989; Wei et al, 1989b;

The Investigation Group of Hemophilia of Anhui, 1991; Wei et al, 1991; Yan et al, 1991). The remaining 11 studies gave a weighted prevalence of hemophilia in mainland China of 3.6 per 100,000 (95%CI: 2.7-4.9 per 100,0000). Sensi-tivity analysis was done by combin-ing all the studies except the national

Prevalence of HemoPHilia in cHina

Vol 45 No. 2 March 2014 461

5

4.5

4

3.5

3

2.5

2

1.5

1

0.5

0

Eastern

China

Central

China

Southern

China

Northeastern

China

Northwestern

China

Southwestern

China

6No. of studies 3 2 3 1 2

2,465,774Sample size 2,127,306 2,885,068 672,097 150,777 1,046,912

Pre

vale

nce o

f hem

ophili

n (

per

100,0

00)

8

7

6

5

4

3

2

1

01985 1987 1988 1989 1990 1991 1993

2No. of studiesSample size

1 3 3 2 4 1909,241 318,575 992,350 4,457,562 442,088 1,401,073 808,762

Pre

va

len

ce

of

he

mo

ph

ilin

(p

er

10

0,0

00

)

Fig 4–District–distributions of included studies.

Fig 5–Time trends of hemophilia prevalence.

census which gave a pooled preva-lence of hemophilia of 3.1 per 100,000 (Table 2).Prevalence of hemophilia in the commu-nity and in hospitals

Subgroup analysis was done by study location. The weighted prevalence of he-mophilia in the community was 2.9 per 100,000 (95%CI: 2.5-3.3 per 100,000) in 10

related studies. Two hospital-based study found the prevalence of hemophilia was 43.8 per 100,000 in pediatric patients or 2.7 per 100,000 popu-lation (Table 2). Prevalence of hemo-philia in males

Seventeen stud-ies repor ted the prevalence of hemo-philia in males (Liu, 1985; Wang, 1985; Chen and Liu, 1988; Hu et al, 1988; Sun et al, 1989; Lu et al, 1991; Zhao et al, 1991; Chinese Collabora-tion Group of Hemo-philia et al, 1992; Jing et al, 1993; Yuan et al, 1987; The Collabora-tion Group of Hemo-philia of Liaoyuan et al, 1988; Wei et al, 1989a; Zhang et al, 1989; Wei et al, 1989b; The Investi-gation Group of He-mophilia of Anhui et al, 1991; Wei et al, 1991; Yan et al, 1991). Of these, 8 included

the nation-wide census (Yuan et al, 1987; The Collaboration Group of Hemophilia of Liaoyuan et al, 1988; Wei et al, 1989a; Zhang et al, 1989; Wei et al, 1989b; The Investigation Group of Hemophilia of Anhui et al, 1991; Wei et al, 1991; Yan et al, 1991). The weighted prevalence of he-mophilia in males was 5.5 per 100,000 (95%CI: 4.6-6.5 per 100,000) based on the

SoutHeaSt aSian J troP med Public HealtH

462 Vol 45 No. 2 March 2014

Items No. of Prevalence Results of Prevalence Results of studies (95%CI) sensitivity (95%CI) sensitivity (per 100,000) analysis (per 100,000) analysis

Total prevalence 11 3.6 (2.7-4.9) 3.1 (2.4-4.0) 2.7 (2.3-3.0) 2.8 (2.4-3.0)Study field Community 10 2.9 (2.5-3.3) - 2.7 (2.3-3.0) - Hospital 1 43.8 - 2.7 -Male 9 5.5 (4.6-6.5) 5.2 (4.2-6.5) 5.0 (4.4-5.7) 5.0 (3.6-6.8)

Table 2Prevalence of hemophilia.

CI, Confidence interval.

Hemophilias A,B,C and Hemophilias A and B Only Von Willibrand disease

Subtypes of No. of Prevalence (95%CI) No. of Prevalence (95%CI) hemophilia studies (per 100 000) studies (per 100,000)

A 10 2.2 (1.9-2.6) 9 4.2 (3.5-5.0)B 10 0.5 (0.4-0.7) 9 1.0 (0.7-1.5)C 4 0.3 (0.1-1.4) 4 0.6 (0.1-2.8)VWD 1 0.09 1 0.17

Table 3Prevalence of different subtypes of hemophilia.

CI, Confidence interval; VWD, Von Willibrand’s disease.

Total population as denominator Male population as denominator

remaining 9 studies. Sensitivity analysis was done and the pooled prevalence of he-mophilia among males was 5.2 per 100,000 (Table 2). Prevalence of hemophilia by districts

Excluding the reports of the nation-wide census, subgroup analysis was done by district for the remaining 17 studies (Fig 4). The pooled prevalences of hemo-philia in eastern China, central China, southern China, northeastern China, northwestern China and southeastern China were: 3.7 per 100,000 (95%CI: 2.6-5.1 per 100,000), 2.8 per 100,000 (95%CI: 2.1-

3.6 per 100,000), 3.9 per 100,000 (95%CI: 0-9.3 per 100,000), 2.9 per 100,000 (95%CI: 1.8-4.5 per 100,000), 4.6 per 100,000 and 2.2 per 100,000 (95%CI: 1.5-3.3 per 100,000), respectively.Chronological prevalence of hemophilia

Subgroup analysis was done by year of study publication (Fig 5). The preva-lence of hemophilia remained about the same between 1985 and 1993. A study published in 1996 was not included in Fig 5; it studied children in the hospital and the prevalence of hemophilia was 43.8 per 100,000.

Prevalence of HemoPHilia in cHina

Vol 45 No. 2 March 2014 463

Anhui, 1991

Chen and Liu, 1988

Hu et al, 1988

Jing et al, 1993

Lu et al, 1991

CCGH et al, 1987

CCGH et al, 1992

Sun et al, 1989

Wang et al, 1991

Wang et al, 2010

Wang, 1985

Wei, 1996

Wei, 1991

Wei et al, 1989a

Wei et al, 1989b

Liu, 1991

Yan, 1990

CGHL et al, 1988

Yuan et al, 1987

Zhang et al, 2003

Zhang et al, 1989

Zhao et al, 1991

Sourc

e p

opula

tion (

Exte

rnal valid

ity)

Description o

f elig

ibili

ty c

rite

ria (

Exte

rnal valid

ity)

Part

icip

ants

and n

on-r

esponders

(E

xte

rnal valid

ity)

Description o

f stu

dy p

eriod (

Exte

rnal valid

ity)

Description o

f stu

dy p

opula

tion (

Exte

rnal valid

ity)

Data

colle

ction (

Inte

rnal valid

ity)

Measure

ment in

str

um

ent (I

nte

rnal valid

ity)

Definitio

n o

f dis

eases (

Inte

rnal valid

ity)

Report

ed p

revale

nce (

Inte

rnal valid

ity)

Meth

od o

f data

colle

ction p

roperly d

escribed (

Info

rmativity)

Questions a

nd a

nsw

er

possib

ilities s

tate

d

Report

ed p

revale

nce r

ate

s r

epro

ducib

le

Epid

em

iolo

gy m

eth

od a

dapta

ble

(O

thers

)

Qualit

y c

ontr

ol str

ate

gy

Lim

itations c

lear

Fig 6–Quality of included studies. CCGH, Chinese Collaboration Group of Hemophillia; CGHL, Collaboration Group of Hemophilia of Liaoyuan.

SoutHeaSt aSian J troP med Public HealtH

464 Vol 45 No. 2 March 2014

Prevalence of different subtypes of he-mophilia

The results of the studies that re-ported the prevalence of HA, HB, HC and VWD were combined (Table 3). The pooled prevalences of HA, HB, HC and VWD were 2.2, 0.5, 0.3 and 0.09 per 100,000 respectively. The prevalences of HA, HB, HC and VWD in males were 4.2, 1.0, 0.6 and 0.17 per 100,000, respectively.Proportions of different subtypes of he-mophiliaOnly HA and HB included. Data from 9 studies included only subtypes HA and HB, giving a total sample of 1701 (Liu, 1985; Wang, 1985; Chen and Liu, 1988; Lu et al, 1991; Wang et al, 1991; Jing et al, 1993; Zhang et al, 1989; The Investiga-tion Group of Hemophilia of Anhui et al, 1991; Wang et al, 1991). The pooled proportions of HA and HB were 80.9% (95%CI: 68.7-89.2) and 19.1% (95%CI: 10.8-31.3), respectively.HA, HB, HC and VWD included. Data from 3 studies included all 4 subtypes (HA, HB, HC and VWD), giving a total sample of 2561 (Chinese Collaboration Group of Hemophilia, 1992; Zhang et al, 2003; Chinese Collaboration Group of hemophilia, 1997). The pooled propor-tions of HA, HB, HC and VWD were 76.5% (95%CI: 72.7-79.9), 13.3% (95%CI: 12-14.7), 1.8% (95%CI: 1.2-2.8) and 4.3% (95%CI: 3-6.1), respectively; 4.1% of he-mophiliacs were not classified.

DISCUSSION

The prevalences of hemophilia in the USA, England, Switzerland, France, Finland and Japan in 2003 were: 10 per 100,000, 6.9 per 100,000, 6.6 per 100,000, 6.3 per 100,000, 5.0 per 100,000 and 2.3-2.6 per 100,000, respectively (Higgins et al, 2003). The overall weighted prevalence

of hemophilia in our study was 3.6 per 100,000 and was 2.9 per 100,000 in the community. Our results are lower than in western countries and higher than in Japan. There are no regional or ethnic differences in hemophilia prevalence and the prevalence of hemophilia has been recognized to be between 10 per 100,000 and 15 per 100,000 (Yang, 2008). The re-sults of our study indicate the prevalence of hemophilia in East Asia may be lower than in Europe and America. Another pos-sibility is that many hemophiliacs remain undetected or unreported in mainland China. There may be 2 reasons for this: 1). health care professionals in China are not familiar with hemophilia and its clinical manifestations; 2). the laboratory investi-gations required to diagnose hemophilia may not be adequate.

The results of the nationwide census carried out by the Chinese collaboration Group of Hemophilia in 24 provinces and cities and 37 districts of China be-tween 1986 and 1989 found a prevalence of hemophilia of 2.73 per 100,000, with HA comprising 80% (Chinese Collabora-tion Group of Hemophilia, 1992). The combined prevalence in our study was higher than that of nationwide census, but the prevalence in the community in our study was close to their census. The reason for the higher prevalence in our study could be that it included hospital based studies. Future prevalence studies need to include hospital-based data to avoid underestimation of the prevalence. In our study, HA and HB were the main subtypes of hemophilia found compris-ing 70%-80% and 10%-20% of the total, respectively. The proportions of HC and VWD combined comprised less than 10% of the total. These proportions are similar to other studies (Ding et al, 2010).

We excluded the results of studies in-

Prevalence of HemoPHilia in cHina

Vol 45 No. 2 March 2014 465

cluded in the nation-wide census from our meta-anaysis. The results of these studies when combined gave a pooled preva-lence of 2.2 per 100,000 (95%CI: 0.9-4.7 per 100,000). The excluded studies were mainly from eastern and central China. If these were included, the prevalence of hemophilia in the community in eastern and Central China would be higher than the national average. The district distribu-tion of hemophilia prevalence confirms this (Fig 4). The chronological prevalence of hemophilia did not change much over time.

During the sixth nationwide popula-tion census in 2010-2011, the total popula-tion of mainland China was 1,370,536,875. Using the prevalence of hemophilia in mainland China found in our study, the number of hemophiliacs in mainland China is estimated to be 49,339. The Na-tional Information Management Center for Hemophilia covers 31 medical units in different provinces and municipali-ties and is the only official registration institution for hemophilia authorized by the Chinese Ministry of Health. On July 4, 2012, the total number of registered hemophiliacs was 10,652. The registration rate for hemophilia in mainland China is low. To improve management, it is neces-sary to improve the registration of hemo-philiacs. One way to improve registration is to include more hospitals, then more hemophiliacs would be detected in time to avoid becoming disabled.

Due to its low prevalence, it is dif-ficult to collect epidemiological data regarding hemophilia. There has been only nationwide census of hemophilia in mainland China and similar surveys are scarce. Knowledge of the prevalence of hemophilia in mainland China is limited. Under this circumstance, a systematic re-view and meta-analysis is a feasible and

credible way to evaluate the prevalence of hemophilia. The quality of this study was affected by several limitations: most of the included studies were conducted before 1993 and were of inadequate quality, but those have the best data available. When we studied the prevalence using only high quality studies, the results were similar (Fig 6).

ACKNOWLEDGEMENTS

This study was supported by Pfizer China.

REFERENCESChen YX, Liu XH. [Investigation of the preva-

lence of hemophilia in 700 000 population of Nanjing]. J Nanjing Med Uni 1988; 8: 164-5.

Chinese Collaboration Group of Hemophilia, Shao ZH, Yang TY. [Investigation of the prevalence and survival rates of hemo-philia in eight regions of China]. Chin J Hematol 1992; 13: 461-3.

Chinese Collaboration Group of Hemophilia, Shao ZH, Yang TY, Ji LX. [Clinical analysis of 911 cases of hemophilia]. Chin J Hematol 1987; 8: 649-51.

Ding QL, Wang XF, Wang HL, et al. Expert con-sensus on the diagnosis and treatment of hemophilia. J Clin Hematol 2010; 23: 49-53.

Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557-60.

Hu LM, Gu MZ, Ye LL, et al. [Investigation of the prevalence of hemophilia in Yongqiang district, Ouhai county, Wenzhou]. Zhejiang Med 1988; 10: 90-1.

Jing BN, Li ZJ, Hui X, Liao RN, Yang AY, Wei LY. [Investigation of the prevalence and pedigree of hemophilia in Guiyang]. Gui-zhou Med 1993; 17: 114-7.

Liu XH. [Investigation of the prevalence of hemophilia in Gulou district, Nanjing]. Chin J Hematol 1985; 10: 617-8.

SoutHeaSt aSian J troP med Public HealtH

466 Vol 45 No. 2 March 2014

Lu HB, Liu AH, Xu M, Chen JW, Ling ZS, The Group of 1985’s Census of Hemophilia. [Investigation of the prevalence of he-mophilia in the east district, Changsha]. J Hunan Med Univ 1991; 16: 352-4.

Prins J, Blanker MH, Bohnen AM, Thomas S, Bosch JLHR. Prevalence of erectile dysfunction: a systematic review of population-based studies. Int J Impot Res 2002; 14: 422-32.

Sun HY, Xu HZ, Yang SH, Zhang JL, Tang JZ. [Hemophilia in Hankou, Wuhan]. J Hua-Zhong Univ Sci Technol 1989; S2: 139-41.

Sutton AJ, Abrams KR, Jones DR, et al. Methods for meta-analysis in medical research. John Wiley & Sons, 2000.

The Coagulation Disorders Diagnostic Criteria of the First Chinese Hematology Society National Conference on thrombosis and hemostasis. Chin J Hematol 1987: 3.

The Collaboration Group of Hemophilia of Li-aoyuan, Ye YG, Jiang W. [Sampling survey report of the prevalence of hemophilia in Liaoyuan]. Jilin Med 1988; 9: 378-9.

The Investigation Group of Hemophilia of An-hui. [Sampling survey of the prevalence of hemophilia in Hefei district, Anhui]. Anhui Med 1991; 12: 6-7.

Wang JL, Lin H, Li JH, et al. [Epidemiological survey of hemophilia in Weicheng dis-trict, Weifang]. J Weifang Med Univ 1991; 13: 120-2.

Wang X, Zhao Y, Yang R, Wu J, Sun J, Zhang X. Hemophilia Care China: A giant step in development by a first phase China/Novo Nordisk Foundation project. Haemophilia 2010; 16: 63.

Wang YJ. [Investigation of the prevalence of he-

mophilia in Jurong county]. Chin J Hematol 1985; 10: 618-9.

Wei LG. [Investigation of the genetic diseases of children based on hospital in Duan district, Guangxi]. Chin J Children Health Care 1996; 02: 109-10.

Wei QZ, Liu RZ, Wang JP, et al. [Epidemiological survey of hemophilia]. J Harbin Med Univ 1991; 25: 215-8.

Wei SF, Tan GX, Li JX, Fan SF. [Investigation of the prevalence of hemophilia in Tianhe district, Guangzhou]. J Jinan Univ 1989a; 04: 97-9.

Wei SF, Tan GX, Li JX, et al. [The integrated report of the prevalence survey of hemo-philia]. Chin J Hematol 1989b; 10: 643.

Yang RC. [New advances in bleeding disorders: try to improve the level of diagnosis and treatment for hemophilia in China]. Chin J Pract Intern Med 2008; 28: 811-3.

Yan WR, Chen CY, Gao D, et al. [Investigation of the prevalence of hemophilia in Chongq-ing]. Chin J Hematol 1991; 12: 485.

Yuan YX, Hou P, Zhang HM, et al. [Sampling survey of the prevalence of hemophilia in Shenyang]. Chin J Hematol 1987; 734-5.

Zhang GH, Zhou WH, Ren XM, et al. [Investi-gation of the prevalence of hemophilia in the old district, Yinchuan]. J Ningxia Med 1989; 11: 282-3.

Zhang L, Li H, Zhao H, Zhang X, Ji L, Yang R. Retrospective analysis of 1312 patients with haemophilia and related disorders in a single Chinese institute. Haemophilia 2003; 9: 696-702.

Zhao WJ, Li JT, Chen ZY, et al. [Sampling survey of the prevalence of hemophilia in Zheng-zhou]. Chin J Hematol 1991; 12: 468.