Awareness of folic acid use increases its consumption, and reduces the risk of spina bifida

Abstract

The majority of neural tube defects were believed to be folic acid (FA)-preventable in the 1990s. The Japanese government recommended women planning pregnancy to take FA supplements of 400 μg/d in 2000, but the incidence of spina bifida has not decreased. We aimed to evaluate the OR of having an infant with spina bifida for women who periconceptionally took FA supplements and the association between an increase in supplement use and possible promoters for the increase. This is a case-control study which used 360 case women who gave birth to newborns afflicted with spina bifida, and 2333 control women who gave birth to healthy newborns during the first 12 years of this century. They were divided into two 6-year periods; from 2001 to 2006 and from 2007 to 2012. Logistic regression analyses were conducted to compute OR between cases and controls. The adjusted OR of having an infant with spina bifida for supplement users was 0·48 in the first period, and 0·53 in the second period. The proportion of women who periconceptionally consumed supplements significantly increased from 10 % in the first period to 30 % in the second period. Awareness of the preventive role of FA was a promoter for an increase in supplement use, and thus an FA campaign in high school seems rational and effective. The failure of the current public health policy is responsible for an epidemic of spina bifida. Mandatory food fortification with FA is urgent and long overdue in Japan.

Full text

Awareness of folic acid use increases its consumption, and reduces the
risk of spina bifida
Atsuo Kondo
1
*, Nobuhito Morota
2
, Hiroaki Date
3
, Kazuhisa Yoshifuji
4
, Toshibumi Morishima
5
,
Minoru Miyazato
6
, Reizo Shirane
7
, Hideki Sakai
8
, Kyong Hon Pooh
9
and Tomoyuki Watanabe
10
1
Department of Urology, Tsushima Rehabilitation Hospital, Minami-Shinkai 1-114, Tsushima 496-0072, Japan
2
Division of Neurosurgery, National Center for Child Health and Development, Okura 2-10-1, Setagayaku,
Tokyo 157-8535, Japan
3
Department of Neurosurgery, Chiba Children’s Hospital, Heta 579-1, Midoriku, Chiba 266-0007, Japan
4
Department of Neurosurgery, Children’s Medical Center, Ichijo 1-240, Kanayama, Teineku, Sapporo 006-0041, Japan
5
Department of Orthopedics, Hamanasu Rehabilitation Center for Children with Disabilities, Otsuka 17-729, Okubo,
Hachinohe 031-0833, Japan
6
Department of Urology, Graduate School of Medicine, University of the Ryukyu, Chihara 1, Nishihara, Nakagami-gun,
Okinawa 903-0213, Japan
7
Department of Neurosurgery, Miyagi Children’s Hospital, Ochiai 4-3-17, Aoba-ku, Sendai 989-3126, Japan
8
Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto 1-7-1,
Nagasaki 852-8501, Japan
9
Department of Neurosurgery, National Shikoku Medical Center for Children and Adults, Zentsuji 2603,
Zentsuji 765-8501, Japan
10
Department of Nutritional Science, Faculty of Psychological and Physical Science, Aichi Gakuin University, Araike 12,
Iwasaki, Nisshin 470-0195, Japan
(Submitted 1 December 2014 – Final revision received 30 March 2015 – Accepted 4 February 2015)
Abstract
The majority of neural tube defects were believed to be folic acid (FA)-preventable in the 1990s. The Japanese government recommended
women planning pregnancy to take FA supplements of 400 mg/d in 2000, but the incidence of spina bifida has not decreased. We aimed to
evaluate the OR of having an infant with spina bifida for women who periconceptionally took FA supplements and the association between
an increase in supplement use and possible promoters for the increase. This is a case – control study which used 360 case women who gave
birth to newborns afflicted with spina bifida, and 2333 control women who gave birth to healthy newborns during the first 12 years of this
century. They were divided into two 6-year periods; from 2001 to 2006 and from 2007 to 2012. Logistic regression analyses were conducted
to compute OR between cases and controls. The adjusted OR of having an infant with spina bifida for supplement users was 0·48 in the first
period, and 0·53 in the second period. The proportion of women who periconceptionally consumed supplements significantly increased
from 10 % in the first period to 30 % in the second period. Awareness of the preventive role of FA was a promoter for an increase in
supplement use, and thus an FA campaign in high school seems rational and effective. The failure of the current public health policy is
responsible for an epidemic of spina bifida. Mandatory food fortification with FA is urgent and long overdue in Japan.
Key words: Folic acid: Knowledge: Mandatory food fortification: Neural tube defects: Spina bifida
An important randomised controlled trial was reported from
the UK
(1)
in 1991. The periconceptional administration of
folic acid (FA) 4mg/d to women who had previously had
pregnancies that were affected with a neural tube defect
(NTD) demonstrated a 72 % risk reduction of recurrence.
An intervention study from China
(2)
in 1999 giving FA
supplements 400 mg/d demonstrated that the first occurrence
of NTD was prevented by 41 % in the southern and 79 % in
the northern regions. These studies have confirmed that FA
can be effectively used to prevent NTD, although not all
the cases could be prevented.
In 1992 the United States Public Health Service
(3)
recommended that all women of childbearing age who are
capable of becoming pregnant should consume 400 mgof
*Corresponding author: Dr A. Kondo, fax: þ81 561 73 2155, email akondo@fj8.so-net.ne.jp
Abbreviations: FA, folic acid; NTD, neural tube defect.
British Journal of Nutrition, page 1 of 7 doi:10.1017/S0007114515001439
qThe Authors 2015
British Journal of Nutrition

FA/d for the purpose of reducing their risk of having a
pregnancy affected by NTD. The US Food and Drug
Administration
(4)
mandated in 1996 that food fortification
must involve fortification with 140 mg of FA/100 g of enriched
cereal-grain products by January 1998 to further decrease the
incidence of NTD.
The Ministry of Health and Welfare of Japan
(5)
in 2000 rec-
ommended that those women planning pregnancy should
take a well-balanced diet and FA supplements of 400 mg
daily from 1 month before to the first 3 months of pregnancy.
According to the Japan Association of Obstetricians and
Gynaecologists
(6)
, the incidence of spina bifida, encephalocele
and anencephaly was 5·2, 0·8 and 0·4 per 10 000 total births
(live births and stillbirths) in 2012, respectively. They were
ranked as the 16th, 42nd and 61st most frequent anomalies
in the Japanese population, respectively, while an unknown
number of foetuses affected with NTD were aborted. If
the number of terminations were counted, they would be
ranked in much higher positions. Based on domestic
(6)
and
international
(7)
data (Fig. 1), the mean prevalence of spina
bifida in Japan for each 5-year period over the past three dec-
ades has not shown any declining tendency, whereas that of
encephalocele plus anencephaly declined steeply in accord-
ance with clinical application of ultrasonography followed
by induced abortions. Since efficacy of FA supplements for
the prevention of spina bifida has not been ascertained in
Japan, we aimed to evaluate the OR of having a pregnancy
affected by spina bifida for women who periconceptionally
took supplements and examine the association between an
increase in supplement use and possible promoting factors
for the increase.
Subjects and methods
Data were gathered from a case–control study which ident-
ified four risk factors for spina bifida among Japanese
women
(8)
. Recruitment of subjects was conducted during the
period between June 2011 and January 2013. Women who
were considered eligible for the study were those who
gave birth to live-born offspring afflicted with spina bifida
(case women), and those who gave birth to healthy live-
born offspring (control women) during the period from 2001
to 2012. Judging by the recent prevalence of spina bifida
(Fig. 1), we estimate that approximately 500 to 600 neonates
are born every year with this anomaly. Recruitment of these
patients, however, was not easy because the patients have
not been officially registered in Japan. We had to rely on a
membership list of the Spina Bifida Society of Japan which
comprised approximately 1400 patients together with their
family members. The Society sent questionnaires to 402 eli-
gible case women, and twenty medical colleagues handed
at their outpatient clinic a questionnaire over to sixty case
women who were not members of the Spina Bifida Society
of Japan. A total of 177 obstetricians and gynaecologists
residing in various parts of Japan sent the questionnaire to
4200 women who, based on the birth record, had delivered
live-born babies without spina bifida at their hospitals. The
questionnaire consists of fourteen questions regarding FA sup-
plement use, awareness of the role of FA, diet and so forth.
Initially 364 case women and 2337 control women com-
pleted the questionnaire and were later compensated with a
¥500 coupon. Of the 364 women, four were excluded – one
because of lipomyelomeningocele and three for providing
incomplete data. Of the 2337 controls, four were similarly
excluded – two because of stillbirth and two for providing
incomplete data. Subsequently 360 case women and 2333 con-
trol women were divided into two 6-year periods, i.e., the first
period from 2001 to 2006 and the second period from 2007
to 2012. Birth places were grouped into two regions: the
northern region comprising the Hokkaido, Tohoku, Kanto
and Chubu areas, and the southern region comprising the
Kansai, Chugoku, Shikoku and Kyushu areas. The frequencies
of demographic characteristics among women and their new-
borns are depicted in Table 1. Distributions of women’s BMI
and age, and sex of offspring were not significantly different
between cases and controls. Body weight of neonates, the
year of birth, place of birth and the rate of FA supplement
use were significantly different between the groups (P,0·01).
We chose six of fourteen parameters (Table 2) as possible
promoters which seemed to be closely associated with
an increase in the rate of maternal supplement use, and
deserved to be statistically assessed, namely (1) knowledge
about the preventive role of FA before pregnancy in relation
to the occurrence of spina bifida; (2) planned pregnancy;
2·3
2·9 3·3 3·7
4·6
5·1 5·7
10·5
9·5
6·4
3·6
2·3 1·8 1·5
0
2
4
6
8
10
12
1978–82 83–87 88–92 93–97 98–2002 03–07 08–12
Recommendation in 2000
Mean prevalence per 10 000 births
Fig. 1. The mean prevalence of spina bifida ( –B– ) and encephalocele plus anencephaly ( –X– ) per 10 000 births (live births þstillbirths) is illustrated for each
5-year period since 1978.
A. Kondo et al2
British Journal of Nutrition

(3) well-balanced diet consuming any amount of fruits,
green-yellow vegetables, or consuming any amount of
cooked poultry/animal liver during the period between 0
and 15 weeks’ gestation; (4) daily smoking during a period
between 0 and 15 weeks’ gestation; (5) treatment of infertility
with assisted reproductive technologies such as fertility drugs,
in vitro fertilisation, or intracytoplasmic sperm injection prior
to pregnancy; (6) family history of spina bifida in first-,
second-, or third-degree relatives. If any parameters of both
groups were found increased or decreased simultaneously in
Table 1. Demographic data of 360 cases and 2333 controls are depicted and compared with
x
2
tests*
(Number of subjects and percentages)
Cases (n360) Controls (n2333)
n%n%P
Women
BMI (kg/m
2
)
,18·5 60 17 476 20
.18·5–25 265 74 1690 72
.25–30 25 7 121 5
.30 10 3 46 2 0·17
Age at birth (years)
,20 0 0 12 1
.20–30 137 38 758 32
.30–40 210 58 1492 64
.40 13 4 71 3 0·08
Offspring
Sex
Male 177 49 1210 52
Female 183 51 1123 48 0·15
Body weight (g)
,2500 98 27 190 8
$2500 262 73 2143 92 ,0·0001
Birth year
1st period (2001–6) 205 57 988 42
2nd period (2007–12) 155 43 1345 58 ,0·0001
Birth place
1st period – northern region 125 35 741 32
1st period – southern region 80 22 247 11
2nd period – northern region 101 28 859 37
2nd period – southern region 54 15 486 21 ,0·0001
The rate of FA supplement use
2001– 6 9/205 4 110/988 11 0·003
2007– 12 26/155 17 428/1345 32 ,0·0001
FA, folic acid.
* The rate of FA supplement use, when all women of both groups were put together, significantly increased from 10 %
(119/1193) to 30 % (454/1500) in the 2nd period (P,0·0001).
Table 2. Six parameters were evaluated to find out possible promoters which increased the
rate of maternal folic acid (FA) supplement use†
(Number of subjects and percentages)
Cases Control
Parameters Period of time n/N%n/N%
Knowledge of FA 2001 – 6 24/205 12 156/988 16
2007–12 36/155 23** 481/1345 36***
Planned pregnancy 2001–6 127/205 62 652/988 66
2007–12 96/155 62 930/1345 69
Well-balanced diet 2001–6 62/205 30 326/988 33
2007–12 40/155 26 456/1345 34
Smoking 2001–6 25/205 12 97/988 10
2007–12 19/155 12 111/1345 8
Infertility treatments 2001–6 22/205 11 70/988 7
2007–12 8/155 5 100/1345 7
Family history of spina bifida 2001 – 6 2/205 1 3/988 0·3
2007–12 2/155 1 4/1345 0·3
** P¼0·0037.
*** P,0·0001
† Knowledge of FA of both groups significantly increased in the 2nd period relative to the 1st period (
x
2
test),
which was suggested to be a possible promoter for an increase in supplement use.
Awareness of folic acid use and spina bifida 3
British Journal of Nutrition

the second period with regard to those in the first period, they
were determined as promoting factors for an increase in sup-
plement use. Seven other parameters which were not evalu-
ated as they had nothing to do with an increase in maternal
supplement use were: (1) intakes of antiepileptic drugs with-
out FA; (2) treatment of diabetes mellitus before pregnancy;
(3) febrile episodes above 398C lasting more than 24 h
during the period between 0 and 15 weeks’ gestation; (4)
very hot bathing/sauna bathing for 15 min or more during the
period between 0 and 15 weeks’ gestation; (5) pre-pregnancy
BMI of the mother; (6) maternal age at birth; (7) birth
weight of the baby. The last parameter, namely intake of FA
supplements, was an independent variable (Table 3).
Ethical approval and statistical analyses
The study was conducted according to the guidelines laid
down in the Declaration of Helsinki and all procedures
involving human subjects were approved by the ethical com-
mittee of Tsushima Rehabilitation Hospital. Our clinical trial
was registered as ‘Recommendation on prevention of spina
bifida: Investigation of risk factors related to spina bifida and
studies to transmit important information of a role of folic
acid’ at the Japan Pharmaceutical Information Center with
the registration identification number of 1011 1850 9739
(http://www.japic.or.jp/index.html). Statistical difference of
distributions of Table 1 was assessed with
x
2
tests. Changes
in the values of six parameters were evaluated by
x
2
or Fisher’s
exact tests (Table 2). OR with 95 % CI were estimated (Table 3)
using logistic regression analyses (IBM SPSS Statistics 20)
where an independent variable of FA supplement use was
adjusted for the year and place of birth.
Results
The proportion of case and control women who periconcep-
tionally took FA supplements significantly increased in the
second period, i.e., the rate increased fourfold in the
cases from 4 to 17 % and threefold in the controls, from 11
to 32 % (P,0·001) (Table 1). When all women of both
the groups were put together, the rate of supplement use
significantly increased from 10 % (119/1193) to 30 % (454/
1500) (P,0·0001). Of the six possible promoting parameters
(Table 2), knowledge about the preventive role of FA
significantly increased in the second period, from 12 to 23 %
in the cases (P¼0·0037) and from 16 to 36 % in the controls
(P,0·0001), suggesting that this parameter was associated
with an increase in maternal supplement use. The estimated
adjusted OR of having a baby with spina bifida for pericon-
ceptional FA users relative to non-users was 0·48 (95% CI
0·23, 0·96) in the first period and 0·53 (95 % CI 0·34, 0·84) in
the second period, respectively (Table 3). Periconceptional
supplement use reduced the risk of having an infant afflicted
with spina bifida by approximately 50 %.
Discussion
The recommendation of the Ministry of Health and Labour of
Japan in 2000 significantly increased the proportion of women
who periconceptionally took FA supplements (Table 1) and
who were aware of the important role of FA (Table 2). The
real problem, however, is that the prevalence of spina bifida
has not decreased over the past 30 years (Fig. 1). It can be
said, therefore, that the recommendation is a public health
failure, and mandatory food fortification with FA is urgently
required and long overdue in Japan.
Folic acid use in the era of food fortification
Mosley et al.
(9)
reported a case–control study from the US in
2009 with 285 case women who gave birth to newborns
with spina bifida and 2743 control women during a period
from 1998 through 2003; their study background was different
from that of ours because mandatory food fortification with FA
in the former had been implemented
(4)
. It is not surprising that
these authors failed to confirm any risk reduction due to FA
supplementation with an adjusted OR of 1·4 (95 % CI 1·0, 1·8),
because food fortification had significantly improved
blood constituents. For instance, serum folate concentration
significantly increased from 12·6 to 18·7 ng/ml
(10)
, and the pro-
portion of people with either low serum folate (,3 ng/ml) or
with high homocysteine concentration (.13 mmol/l) declined
from 22·0 to 1·7 % in the for mer (P,0·001), and from 18·7 to
9·8 % in the latter (P,0·001)
(11)
, respectively. It is possible that
the higher serum folate and lower homocysteine concen-
trations decreased the occurrence of FA-preventable NTD;
thus, an add-on effect of FA supplements was not obtainable.
It is possible that the risk reduction of supplement use was
considerably influenced by the presence of mandatory food
fortification.
Table 3. Supplement use* in case and control women
(Number of subjects and percentages; odds ratios and 95 % confidence intervals)
Cases (n360) Controls (n2333) Crude Adjusted
Periods of study and supplement use n/N%n/N% OR† 95 % CI POR† 95 % CI P
2001–6 0·005 0·039
Supplements use (þ) 9/205 4 110/988 11 0·37 0·18, 0·74 0·48 0·23, 0·96
Supplements use (2) 196/205 96 878/988 89 Referent Referent
2007–12 ,0·001 0·006
Supplements use (þ) 26/155 17 428/1345 32 0·43 0·28, 0·67 0·53 0·34, 0·84
Supplements use (2) 129/155 83 917/1345 68 Referent Referent
* Supplement use significantly increased in the 2nd period in both groups (P,0·0001;
x
2
test).
† The adjusted OR was 0·48 and 0·53 in the 1st and 2nd periods, respectively. OR were adjusted for the year and place of birth.
A. Kondo et al4
British Journal of Nutrition

Knowledge promotes supplement use
Among the six possible parameters (Table 2), knowledge of
the preventive role of FA was considered the sole promoting
factor for an increase in supplement use, whereas the rest of
the parameters had neither increased nor decreased in either
group between periods 1 and 2, and had no relationship
with supplement use. Matsuo
(12)
evaluated awareness of FA
use among 836 young female college students in Japan. He
observed that although 42 % of them had some knowledge
of FA, only 9% had a detailed understanding of the preventive
role of FA. The data suggest that women of reproductive
age or women planning to conceive in Japan are mostly una-
ware of the preventive role of FA and this crucial awareness
should be systematically disseminated by the government,
mass media and medical societies. If we take advantage of
the high rate of students’ enrolment to junior high school,
99·9 %, or to the senior high school, 98·1 %
(13)
, transmitting
this information to female students as a part of health edu-
cation or sex education components of school curricula
would seem to be quite rational and effective. In 2005,
Botto et al.
(14)
studied the efficacy of transmitting information
by exploring thirteen birth defect registries in European
countries from 1988 to 1998. They concluded that governmen-
tal recommendations alone were followed by no detectable
improvement in the trend of incidence of NTD. We fully
agree with their emphasis on the great importance of FA
supplement and prompt implementation of food fortification
and guidelines.
Planned pregnancy and supplement use
Although the rate of planned pregnancy among our subjects
was fairly high – 62 % in case women and 68 % in control
women (Table 2), the proportion of women who periconcep-
tionally took FA supplements was surprisingly low – 10 % (35/
360) in the former and 23 % (538/2333) in the latter (Table 3).
In order to establish an association between the two par-
ameters, we searched for articles published after 1991, when
the classic Medical Research Council study
(1)
was reported.
Figures available in other reports are: Werler et al.
(15)
,60%
of planned pregnancies v. 8 % of supplement use in case
mothers and 13 % in control mothers from the US and
Canada; Knudsen et al.
(16)
, 76 % of planned pregnancies v.
14 % supplement use from Denmark; Inskip et al.
(17)
,77v.
3 % from the UK; Nilsen et al.
(18)
,80v. 31 % from Norway.
On the other hand, among 212 women serving as US military
soldiers
(19)
, the rate of planned pregnancy was considerably
lower, 35 %. These data obtained from women living in the
conventional environment of developed countries suggest
that planned pregnancy is prevalent in a range of 60 to
80 %; however, it appears not to be necessarily associated
with an increased use of FA supplements, as its actual range
of use is 3 to 31 %. Consequently, providing information on
FA effectiveness to women planning pregnancy and the care-
ful inclusive designing of health education programs are very
effective strategies to encourage greater use of FA sup-
plements and to decrease the prevalence of NTD.
How far is mandatory food fortification effective?
Youngblood et al.
(20)
estimated that 328 300 infants are born
with NTD globally each year, and 75% of them, 246 200, are
FA-preventable. They reported that sixty-nine countries forti-
fied wheat or maize flour with FA to varying extents in 2012,
which prevented an estimated 38 400 (15·6 %) to 62 800
(25·5 %) cases of the potential 246 200 FA-preventable NTD
cases every year, based on their own models. These authors
stressed that world-wide FA fortification is necessary for
global prevention of FA-preventable spina bifida and
anencephaly.
Heseker et al.
(21)
based on their systematic review observed
that (1) food fortification or supplement use decreased the
prevalence of NTD at birth or abortions by five to eight
cases per 10 000, irrespective of countries, ethnicities, and
the amount of FA administered, suggesting the presence of a
floor effect which restricts the effect of food fortification (the
lower threshold); they observed further that (2) the magnitude
of decline of the NTD prevalence depends on the initial NTD
rate. These authors also mentioned that counting NTD cases
among foetuses at birth and from abortions will avoid under-
estimating the preventive effect of fortification and provide
a more realistic analysis. The mean prevalence of NTD in
Japan was reported to be 7·2 (5·7 þ1·5) per 10 000 total
births (live births and stillbirths) for a 5-year period from
2008 to 2012 (Fig. 1), while there is no information on the
number of induced abortions due to NTD. Based on a predic-
tion of our clinically active colleagues (obstetricians and
gynaecologists), the proportions of induced abortions were
deemed to be 30 % for fetuses afflicted with spina bifida and
90 % with encephalocele or anencephaly. When using these
figures, the baseline incidence of current NTD would increase
from 7·2 to 23·1 (i.e. 8·1 þ15·0) per 10 000 total births and
abortions. If we then let the value 23·1 equal Xin the formula
(Y¼0·77X24·6) reported by De Wals et al.
(22)
, we would get
Y¼13·2 as the difference in prevalence rates before and after
fortification. In other words, the post-fortification prevalence
of NTD would decrease from 23·1 to 9·9 (i.e. 23·1 213·2),
which is a 57 % reduction. We believe that our case –control
study together with the epidemiological analysis of De Wals
et al.
(22)
suggest that the present prevalence of spina bifida
will be halved by a food fortification policy in Japan, and
that the floor effect theory
(21)
will not be applicable to the
Japanese prevalence. It should be noted that three times as
many NTD have occurred in Japan as have been officially
reported
(6)
, and that two-thirds have been insidiously aborted,
creating a health hazard for the pregnant women involved and
increasing healthcare expenditure.
Study limitations
First, we had difficulty in collecting responses to question-
naires from the control women because of selection bias.
Initially, we planned to recruit six control women matched
for age, sex, place and calendar year of birth for each case
woman. However, very few control women responded to
the questionnaire, because the number of women who had
Awareness of folic acid use and spina bifida 5
British Journal of Nutrition

delivered were not enough in the majority of hospitals to
obtain a sufficient number of controls, and because the
women chosen as controls shifted residence and hence we
could not contact them. Subsequently we changed the study
plan and sent a questionnaire to two random control
women who had delivered a healthy baby for each year
between 2001 and 2012. This is the reason why place and
year of birth were different between the groups (Table 1).
Second, the bearing of recall bias on data collected needs to
be considered: we expected more than half of the case and
control women to recall anthropometric variables and life
style factors for 6 to 12 years after delivery. It is likely that
intakes of supplements, knowledge of FA, diet and other
information were difficult to recall accurately as time went
by; analysis of inherently weak data could lead to inherently
weak interpretation and weak findings. Despite these limi-
tations we believe that the present analysis offers valuable
information for clinicians and policy makers to prevent the
occurrence of NTD.
In conclusion, our case–control study evidenced that
knowledge about the preventive role of FA was a promoter
of increased FA supplement use, which was found to be
associated with a reduction in the risk of spina bifida births
by 50 % approximately. We strongly urge the Japanese
Government to introduce a mandatory FA food fortification
programme for Japanese women, and launch a sustained
awareness campaign on the preventive role of FA at the
earliest. This will surely reduce the number of neonates
born with avoidable serious birth defects, which in turn will
lead to considerable economic benefits
(23)
, and significant
reduction in the cost burden on the healthcare system and
healthcare payers
(24)
.
Acknowledgements
We thank K. Jonin, S. Matsumoto, T. Morioka, A. Usui and
K. Yoshino who cooperated with us in recruiting case
women. We are grateful to Godfrey P. Oakley, Jr for his
helpful comments.
The study was supported by a grant from the Ministry of
Health, Labour and Welfare of Japan, 2011: H23 Nanchi-
Japan 050.
The authors declare no conflict of interest.
The authors’ contributions are as follows: A. K. and N. M.
designed the study, collected literature, wrote the manuscript
and had primary responsibility for the final content. All
authors except T. W. formulated the questionnaire, interpreted
raw data, and discussed the study outcome. T. W. did all stat-
istical analyses and interpreted the study outcome. All authors
read and approved the final version of the report.
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