Review
Night Shift Work Increases the Risks of MultiplePrimary Cancers in Women: A Systematic Reviewand Meta-analysis of 61 ArticlesXia Yuan, Chenjing Zhu, Manni Wang, Fei Mo,Wei Du, and Xuelei Ma
Abstract
A growing number of studies have examined associationsbetween night shift work and the risks of common cancersamong women, with varying conclusions. We did a meta-analysis to identify whether long-term night shift workincreased the risks of common cancers in women. We enrolled61 articles involving 114,628 cases and 3,909,152 participantsfrom Europe, North America, Asia, and Australia. Risk estimateswere performed with a random-effect model or a fixed-effectmodel. Subgroup analyses and meta-regression analyses aboutbreast cancer were conducted to explore possible sources ofheterogeneity. In addition, we carried out a dose–responseanalysis to quantitatively estimate the accumulative effect ofnight shift work on the risk of breast cancer. A positive rela-tionship was revealed between long-term night shift work andthe risks of breast [OR ¼ 1.316; 95% confidence interval (CI),
1.196–1.448], digestive system (OR ¼ 1.177; 95% CI, 1.065–1.301), and skin cancer (OR ¼ 1.408; 95% CI, 1.024–1.934).For every 5 years of night shift work, the risk of breast cancer inwomen was increased by 3.3% (OR ¼ 1.033; 95% CI, 1.012–1.056). Concerning the group of nurses, long-term night shiftwork presented potential carcinogenic effect in breastcancer (OR ¼ 1.577; 95% CI, 1.235–2.014), digestive systemcancer (OR ¼ 1.350; 95% CI, 1.030–1.770), and lung cancer(OR ¼ 1.280; 95% CI, 1.070–1.531). This systematic reviewconfirmed the positive association between night shift workand the risks of several common cancers in women. We iden-tified that cancer risk of women increased with accumulatingyears of night shift work, which might help establish andimplement effective measures to protect female night shifters.Cancer Epidemiol Biomarkers Prev; 27(1); 25–40. �2018 AACR.
IntroductionIn modern society, the fast-growing productivity demands
for working across time zones and night shift work is increas-ingly prevalent in different industries such as food production,entertainment, health care, and transportation (1). Circadiandisruption from electric lighting poses huge challenges onpublic health, including cardiovascular diseases, neuropsychi-atric and endocrine system disorders, and even cancers, inparticular breast cancer (2–4). Cancer incidence in industrial-ized regions is noticeably higher than that in developingcountries, suggesting that environmental factors of modernsociety play an role in cancer etiology. In 2007, the Interna-tional Agency for Research on Cancer (IARC) has identified"shift work that involves circadian disruption" to be probablycarcinogenic (Group 2A), based on "limited evidence in
humans for the carcinogenicity of shift work that involves nightwork," and "sufficient evidence in experimental animals forthe carcinogenicity of light during the daily dark period (bio-logical night)" (5). Among night shift workers, female employ-ees account for a large proportion, and the number of womenin nursing is always overwhelming more than male. During2004–2005, night shift workers accounted for 12.4% of thefemale working population and 17.4% for European countries(6). Long-term night shift work serves as a potential risk factorfor the common cancers in female population.
Much of the research has examined that nocturnal melatoninsuppression and circadian rhythm disruption caused by nightshift work function as carcinogens that increase tumor inci-dence (5). Melatonin, primarily produced by pineal gland, wasreported to play an important role in inhibiting tumor growththrough antioxidation, antiangiogenesis, and regulation ofimmunity (7). Unnatural light at night reduced melatoninrelease, which contributed to tumor development. However,melatonin suppression had a negative feedback effect onhypothalamic-pituitary-gonadal axis, promoting gonadotro-pins secretion (8). Previous studies stated that night shift workincreased the risk of hormone-dependent cancers includingprostate cancer in men, breast cancer and ovarian cancer inwomen (9). In addition, another mechanism was related toclock genes expression which played an important role inseveral cellular processes such as DNA repair and cell apopto-sis. Circadian rhythm disturbance among shift workers resultedin changes of clock genes expression, ultimately increasedcancer susceptibility (10, 11).
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital,West China Medical School, Sichuan University, Chengdu, P.R. China.
Note: Supplementary data for this article are available at Cancer Epidemiology,Biomarkers & Prevention Online (http://cebp.aacrjournals.org/).
X. Yuan, C. Zhu, and X. Ma contributed equally to this article.
Corresponding Author: Xuelei Ma, West China Medical School, Sichuan Uni-versity, No. 37, Guoxue Alley, Chengdu 610041, P.R. China. Phone: 8113-4084-10416; Fax: 8628-8547-5576; E-mail: [email protected]
doi: 10.1158/1055-9965.EPI-17-0221
�2018 American Association for Cancer Research.
CancerEpidemiology,Biomarkers& Prevention
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Animal models focused on light at night to study the effect ofcircadian disruption on cancer incidence (12), whereas epidemi-ological evidence is limited with differing results. A growingnumber of females are being exposed to night shift work andemployments in different working fields vary in exposure statussuch as frequency and period time. Nursing group are generallyexposed to long-term and high-intensity night shift work. Theassociation between night shift work and cancer risk of femalenurses was not covered by published reviews. Breast cancer is themost common cancer in women worldwide. Most of previousmeta-analyses emphasized, in particular, the association betweennight shift work and breast cancer and had controversial conclu-sions (13–17). Some of them concluded that night shift work wassignificantly associated with higher risk of breast cancer (13, 14,17) whereas another study provided limited evidence (16) andalso one study reported a small nonsignificant effect of long-termnight shiftwork (15). Thus it still remains unknownwhether nightshift work elevates the risk of common cancers such as breastcancer, ovarian cancer and lung cancer. Here we performed ameta-analysis to demonstrate the effect of night shift work on therisk of common cancers among women. Meanwhile, the group offemale nurses was evaluated for the separate risk estimation ofmultiple common cancers. By systematically integrating a multi-tude of previous data, we expected to arrive at a convincingconclusion which would help propose health protection pro-grams for long-term female night shift workers.
Materials and MethodsLiterature search
We conducted the meta-analysis following the quality stan-dards of a meta-analysis. An extensive systematic literature searchupdated to October, 2016 was performed. We searched thekeywords "night shift" "shift work" "shift-work" "cancer risk""cancer mortality" in PubMed, Embase, Medline, and Web ofScience databases. Only English articles were enrolled, and noother limitations were restricted. Also, we manually searchedciting and reference lists to identify other relevant studies.
Inclusion and exclusion criteriaStudies were identified according to inclusion and exclusion
criteria. Studieswere included if theymet the following criteria: (i)cohort study, case–control study, or nested case–control studywithin cohort study; (ii) study evaluating cancer risk amongwomen that were �18 years old and were exposed to night shiftwork; (iii) study involving OR, RR, HR, or standardized incidenceratio (SIR) with 95% confidence intervals (CIs) or providingsufficient data to calculate the above parameters. Studies wereexcluded if they met the following criteria: (i) study involvingfemale cancer risks that could not be separated from that of male;(ii) study providing overlapping or insufficient data; (iii) studyinvolving recurrent cancer.
Data extractionExtracted information from enrolled studies included first
author, published year, number of cases and subjects, OR andcorresponding 95%CI, study design, quality score, region, type ofcancer, range of night shift work, occupation, variables of adjust-ment, and exposure assessment. We adopted the shortest andlongest exposure time for preceding analysis. Data extraction was
performed independently by two investigators and a third authorresolved the differences by face-to-face discussion.
Quality evaluationWe used the Newcastle-Ottawa Quality Assessment Scale
(NOS; ref. 18) for quality evaluation of eligible studies. NOSadopted the star system with a maximum of nine stars scoringfrom 0 to 9, which was divided into four parts: participantselection, comparability of study group, exposure assessment,outcome evaluation, and scoring <7 indicated a low quality. NOSquality evaluation was conducted by two investigators indepen-dently and a third author settled all disagreements.
Statistical analysisWe evaluated the association between night shift work and
female cancer risk using statistical software STATA Version 11.0(StataCorp). ORs with their corresponding 95% CIs were usedas effect measure. Statistical heterogeneity was evaluated by Qand I2 statistics. P < 0.10 and I2 > 50% indicated an existence ofstatistical heterogeneity and a random-effect model was thencarried out, otherwise a fixed-effect model was used (19). Toexplore the possible sources of heterogeneity regarding breastcancer, meta-regression analyses were performed. Moreover, weconducted subgroup analyses stratified by region, study design,occupation, exposure assessment, number of variables, andquality score.
For dose–response meta-analysis, we retrieved studies whichinvolved at least three levels of exposure categories and informa-tion of cases, number of total subjects, person-year, years ofexposure in each category were extracted. The midpoint of lowerand high boundary was used as average time of night shiftexposure. The range of highest category was supposed to be thesame as the adjacent category if the upper boundary was notprovided (20). Two-stage random-effect model was adopted toestimate the overall dose–response trend.
Begg funnel plot was performed to evaluate the publicationbias of enrolled studies and P < 0.05 suggested the evidence ofpublication bias (15). In the Begg funnel plot, the standard errorof logarithm (Log) for ORwas plotted against its OR, and Log ORwas plotted versus standard error of Log OR for each enrolledstudy (21).
ResultsLiterature search and selection of studies
The initial search yielded 368 articles, and 98 articles wereretrieved after checking titles and abstracts. Then, we reviewed fulltexts of these articles and 56 were included according to eligibilitycriteria. Also, 5 relevant studies were identified by manuallysearching citing and reference lists. Finally, 61 articles (22–82)were eligible for a comprehensive analysis. The selectionflowchartis shown in Fig. 1.
Study characteristicsSixty-one articles were enrolled in the meta-analysis includ-
ing 26 cohort studies, 24 case–control studies, and 11 nestedcase–control studies. Several articles investigated whether thecarcinogenic effect of night shift was related to breast cancerestrogen-receptor status (ERþ and ER� breast cancer; ref. 38) ormenopausal status (premenopausal and postmenopausal;ref. 46) or different years in employment (60). In addition,
Yuan et al.
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several articles reported the risks for a number of cancersincluding breast cancer, cervical cancer, and colon cancer, andso on (57, 61, 62, 71, 77). One study (82) evaluated associa-tions between night shift work and the risk of breast cancer intwo cohorts, respectively [Nurses' Health Study (NHS) andNurses' Health Study II (NHS2)]. Thus, 67 studies from 61articles comprising 114,628 cases and 3,909,152 participantswere analyzed for the association between night shift work andcommon cancers at 11 sites of women including breast cancer,digestive system cancer, skin cancer, reproductive system can-cer, hematologic system cancer, endocrine system cancer, ner-vous system cancer, urinary system cancer, lung cancer, boneand soft tissue cancer. Most studies reached a standard of highfollow-up rate or favorable response rate. Seventeen out of 67studies were conducted among nurses, and 49 out of 67 studiesevaluated the association between night shift work and the riskof breast cancer. Questionnaire, interview, and databases wereadopted for exposure assessment, and we extracted the shortestversus longest history of night shift work as exposure indicator.Forty-nine studies were adjusted for >3 confounders and 18studies for �3 confounders. The main characteristics of theincluded studies were summarized in Table 1.
Risk assessment and heterogeneityWe integrated multivariable-adjusted ORs of longest versus
shortest exposure duration to identify the correlation betweennight shift work and the risk of common cancers. Long-termnight shift work increased the risk of female cancer (OR ¼1.190; 1.122–1.262) and OR forest plots (with 95% CIs) ofcancer for long-term night shift female workers were shown inSupplementary Fig. S1. A positive association was observedregarding breast cancer (OR ¼ 1.316; 95% CI, 1.196–1.448),
digestive system cancer (OR ¼ 1.177; 95% CI, 1.065–1.301)and skin cancer (OR ¼ 1.408; 95% CI, 1.024–1.934). OR forestplots (with 95% CIs) of breast cancer, reproductive systemcancers, digestive system cancers, lung cancer, and skin cancerwere shown in Fig. 2. ORs of association between night shiftwork and the risk of common cancers in women were sum-marized in Supplementary Table S1. With regard to nurses, therisk of six common cancers were estimated and as a result nightshift work was associated with increased risk of breast cancer(OR ¼ 1.577; 95% CI, 1.235–2.014), digestive system cancer(OR ¼ 1.350; 95% CI, 1.030–1.770), and lung cancer (OR ¼1.280; 95% CI, 1.070–1.531). ORs of the common cancers innurses were shown in Supplementary Table S2.
Significant heterogeneity was observed in the groups of breastcancer (P ¼ 0.000, I2 ¼ 80.4%), skin cancer (P ¼ 0.009, I2 ¼64.7%), and uterine cancer (P ¼ 0.042, I2 ¼ 59.6%), and riskestimates were conducted with a random-effect model. No evi-dence of heterogeneity existed among the other groups.
Subgroup analysis and meta-regression analysisSubgroup analyses about breast cancer were conducted strat-
ified by geographic location, study design, number of variables,study quality, exposure assessment, and occupation. When strat-ified by geographical location, Europe (OR ¼ 1.416; 95% CI,1.246–1.610) and North America (OR ¼ 1.236; 95% CI, 1.048–1.459) shared higher OR estimates, whereas positive correlationdid not exist in Asia (OR ¼ 1.236; 95% CI, 0.865–1.767) andAustralia (OR¼ 1.040; 95%CI, 0.852–1.271). When stratified bydesign, the highest pooled OR estimate was obtained amongnested case–control studies (OR ¼ 1.555; 95% CI, 1.115–2.169)and the lowest was among cohort studies (OR ¼ 1.193; 95% CI,1.030–1.382). In terms of occupation, it was revealed that the
Studies identified by initial searchin PubMed, Embase, Medline andWeb of Science (n = 368)
Studies reviewed for full texts (n = 98)
Potential eligible studies (n = 56)
Eligible studies (n = 61)
Articles retrieved by manualsearch from reference list (n = 5)
Animal researches (n = 6)Meeting abstracts, reviews, and letters (n = 8)Insufficient data (n = 14)Other language (n = 5)Irrelevant to our topic (n = 9)
Studies excluded based on title andabstract (n = 270)
Not related to the topic
Studies excluded (n = 42)Figure 1.
Flow chart of eligible studies selectionprocess. An extensive systematicliterature search updated to October,2016 was performed in PubMed,Embase, Medline, and Web of Sciencedatabases, yielding 368 articles, andfinally 61 articles were includedaccording to eligibility criteria.
Night Shift Work Increases Cancer Risk of Women
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Table
1.Maincharacteristicsofinclud
edstud
iesontherelationshipbetwee
nnight
shiftwork
andtherisksofco
mmoncancersin
femalepopulations
Stud
yPub
lishe
dye
arNo.ofcases/
No.ofsubjects
OR(95%
CI)
Stud
ydesign
Qua
lity
score
Reg
ion
Typeof
canc
erRan
geofnight
shiftwork
Occup
ation
Variablesofad
justmen
tExp
osure
assessmen
tmetho
d
Knu
tssonA
2012
94/4,036
2.02(1.03–
3.95)
Coho
rtstud
y7
Swed
enBreastcancer
Day
vs.n
ight
shift
NA
Num
ber
ofchild
ren,
alco
hol
consum
ption,
BMI,he
ight,w
eight,
waist,h
ipcircum
ference,
educationa
llev
el,smoking
men
opau
salstatus,status
oforal
contraceptive
use,
andho
rmone
sother
than
contraceptive
s
Que
stionn
aire
CarterBD
2014
1,289/16,10
04
1.27(1.03–
1.56)
Coho
rtstud
y8
USA
Ovarian
cancer
Day
vs.rotating
shifts
NA
Oralco
ntraceptive
use,
ageat
men
archean
dmen
opau
se,tub
allig
ation,
parity,
postmen
opau
sal
estrogen
use,race,fam
ilyhistory
of
breast/ovarian
cancers,exercise,
BMI,an
dhe
ight
Que
stionn
aire
Poole
EM
2011
718/181,5
48
0.8
(0.51–1.2
3)Coho
rtstud
y7
USA
Ovarian
cancer
Nev
ervs.2
0þ
yearsrotating
shiftwork
Nurses
Age,
durationoforalcontraceptive
use,
parity,
BMI,sm
oking
status,
tubal
ligationhistory,m
enopau
sal
status,fam
ilyhistory
ofovarian
cancer,d
urationofbreas
tfee
ding,
andco
hort
Que
stionn
aire
Viswan
atha
nAN
2007
515/53
,487
1.47(1.03–
2.1)
Coho
rtstud
y7
USA
End
ometrial
cancer
Nev
ervs.2
0þ
yearsrotating
shiftwork
Nurses
Age,
ageat
men
arche,
ageat
men
opau
se,p
arity,BMId
urationof
oralcontraceptive
use,
usean
ddurationofpostmen
opau
sal
horm
one
s,hy
pertension,
diabetes,
pack-ye
arsofsm
oking
Que
stionn
aire
AkerstedtT
2015
463/1,3
656
1.77(1.03–
3.04)
Coho
rtstud
y8
Swed
enBreastcancer
Nev
ervs.2
1–45
years
NA
Age,
educationleve
l,tobacco
consum
ption,
BMI,ha
ving
child
ren,
coffee
consum
ption,
previous
cancer,u
seofho
rmone
sinclud
ing
oralcontraceptive
s
Telep
hone
interview
Koppes
LLJ
2014
2,53
1/28
5,72
30.87(0.72–1.0
5)Coho
rtstud
y8
Nethe
rlan
dBreastcancer
Nev
ervs.reg
ular
night
work
NA
Age,
origin,childrenin
househ
old
education,
occup
ation,
jobtenu
re(yea
rs)
Persona
linterview
NattiJ
2012
48/1,649
2.82(1.19
6–6
.645)
Coho
rtstud
y8
Finland
Unclassified
cancer
Day
vs.w
eekly
night
shift
NA
Age,
andsm
oking
status,
dem
ographics
andhe
alth-an
dwork-related
factors
Face-to-faceinterview
Schernh
ammer
ES
2006
1,352
/115,022
1.79(1.06–3
.01)
Coho
rtstud
y7
USA
Breastcancer
Nev
ervs.2
0þ
yearsrotating
shiftwork
Nurses
Age,
ageat
men
arche,
men
opau
sal
status,a
geat
men
opau
se,a
geat
firstbirth
andparityco
mbined
,age
atfirstbirth,B
MI,curren
talco
hol
consum
ption,
oralcontraceptive
use,postmen
opau
salhorm
one
use,
smoking
status,b
enignbreast
disea
se,fam
ilyhistory
ofbreast
cancer,a
ndphy
sicala
ctivity
Que
stionn
aire
Pronk
A20
1034
9/69,472
0.8
(0.5–1.2)
Coho
rtstud
y8
China
Breastcancer
Nev
ervs.17þ
years
NA
Age,
education,
family
history
of
breastcancer,n
umber
of
pregna
ncies,ag
eat
firstbirth,a
ndoccup
ationa
lphy
sicala
ctivity
Interview
(Con
tinu
edon
thefollowingpag
e)
Yuan et al.
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Table
1.Maincharacteristicsofinclud
edstud
iesontherelationshipbetwee
nnight
shiftwork
andtherisksofco
mmoncancersin
femalepopulations
(Cont'd)
Stud
yPub
lishe
dye
arNo.ofcases/
No.ofsubjects
OR(95%
CI)
Stud
ydesign
Qua
lity
score
Reg
ion
Typeof
canc
erRan
geofnight
shiftwork
Occup
ation
Variablesofad
justmen
tExp
osure
assessmen
tmetho
d
Schernh
ammer
ES
2003
602/78
,586
1.35(1.03–
1.77)
Coho
rtstud
y8
USA
Colorectal
cancer
Nev
ervs.15þ
yearsrotating
shiftwork
Nurses
Agein
years;pack-ye
arsofsm
oking
before
age30
inquintiles;BMIin
five
categories;p
hysicala
ctivityin
quintiles;regular
aspirin
use;
colorectal
cancer
inparen
tor
sibling;scree
ning
endoscopy
duringthestud
yperiod;
consum
ptionofbee
f,pork,orlamb
asamaindish;alco
holconsum
ption
status;totalcaloricintake
inquintiles;useofpostmen
opau
sal
horm
one
s;men
opau
salstatus;an
dhe
ight
inseve
ncategories
Que
stionn
aire
VistisenHT
2014
1,281/169,011
1.68(1.28–2.2)
Coho
rtstud
y5
Den
mark
Breastcancer
Nev
ervs.e
ver
NA
Shiftwork
Datab
ase
Schernh
ammer
ES
2013
1,455
/78,612
1.28(1.07–1.5
3)Coho
rtstud
y7
USA
Lung
cancer
Nev
ervs.15þ
yearsrotating
shiftwork
Nurses
Age,
ageat
startsm
oking
,cigarettes
smokedper
day
,fruitintake,
vegetab
leintake,B
MI,mea
suredas
weight
inkilogramsdivided
by
height
inmeterssqua
red,
men
opau
salstatus,ho
rmone
use
among
postmen
opau
salw
omen
,an
doralcontraceptive
use,
aswell
asen
vironm
entalsmoking
exposures:paren
tssm
oking
while
livingwiththem
,yea
rslivingwith
someo
newho
smoked,exp
osure
tosm
oking
atwork,a
ndexposure
tosm
oking
atho
me
Que
stionn
aire
GuF
2015
5,413/74,862
1.08(0.98–1.08)
Coho
rtstud
y7
USA
Unclassified
cancer
Nev
ervs.15þ
yearsrotating
shiftwork
Nurses
Age,
alco
holconsum
ption,
phy
sical
exercise,m
ultivitamin
use,
men
opau
salstatusan
dpostmen
opau
salh
orm
one
use,
phy
sicale
xam
inthepast2ye
ars,
healthyea
ting
score
(quintiles),
smoking
status,p
ack-ye
ars;BMI,
andhu
sban
d'sed
ucation
Que
stionn
aire
Ren
Z20
14712/1,4
541.3
4(1.04–1.71)
Case–co
ntrol
6China
Breastcancer
Nev
ervs.e
ver
NA
Age,
education,
BMI,marital
status,
ageat
men
arche,
men
opau
sal
status,p
arity,
activity,
breastfee
ding,fam
ilyhistory
of
breastcancer,a
ndother
slee
pfactors
Datab
ase
San
tiSA
2015
743/1,5
181.7
(1.04–2
.79)
Case–co
ntrol
7Can
ada
Breastcancer
Nev
ervs.10þ
yearsrotating
shiftwork
Nurses
Age,family
history,lev
elofe
ducation,
oralcontraceptionuse,
alco
hol
consum
ption,nu
mber
ofb
irths,an
dag
eoffirstmen
struation
Que
stionn
aire
Datta
K20
1450
/150
1.509(0.267–8.516)
Case–co
ntrol
6SouthAsia
Breastcancer
Nev
ervs.e
ver
NA
Workingin
night
shift
Directinterview
LieJS
2013
172/646
1.8(1–3
.1)Case–co
ntrol
7Norw
ayERþbreast
cancer
Nev
ervs.5þ
years
night
shiftwork
Nurses
Ageat
diagno
sis,periodofdiagno
sis,
parity,
family
history
ofbreast
cancer
inmother
orsister,
horm
ona
ltreatmen
tintheprevious
2ye
arsbefore
diagno
sis,an
dfreq
uencyofalco
holconsum
ption
atthetimeofdiagno
sis
Telep
hone
interview
(Con
tinu
edon
thefollowingpag
e)
Night Shift Work Increases Cancer Risk of Women
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Table
1.Maincharacteristicsofinclud
edstud
iesontherelationshipbetwee
nnight
shiftwork
andtherisksofco
mmoncancersin
femalepopulations
(Cont'd)
Stud
yPub
lishe
dye
arNo.ofcases/
No.ofsubjects
OR(95%
CI)
Stud
ydesign
Qua
lity
score
Reg
ion
Typeof
canc
erRan
geofnight
shiftwork
Occup
ation
Variablesofad
justmen
tExp
osure
assessmen
tmetho
d
LieJS
2013
22/346
2.8(0.8–9
.2)
Case–co
ntrol
7Norw
ayER�breast
cancer
Nev
ervs.5þ
years
night
shiftwork
Nurses
Ageat
diagno
sis,periodofdiagno
sis,
parity,
family
history
ofbreast
cancer
inmother
orsister,
horm
ona
ltreatmen
tintheprevious
2ye
arsbefore
diagno
sis,an
dfreq
uencyofalco
holconsum
ption
atthetimeofdiagno
sis
Telep
hone
interview
LieJS
2006
537/2,680
2.21
(1.1–
4.45)
Nestedcase–
control
6Norw
ayBreastcancer
Nev
ervs.3
0þ
yearsnight
shift
work
Nurses
Totale
mploym
enttimeas
anu
rses
andparity
Datab
ase
Pap
antoniouK
2015
1,708/3,486
1.22(0.82–1.8
1)Case–co
ntrol
8Spain
Breastcancer
Nev
ervs.15þ
yearsnight
shift
work
NA
Age,
center,e
ducationa
llev
el,p
arity,
men
opau
salstatus,family
history
ofbreastcancer,B
MI,sm
oking
status,o
ralcontraceptive
use,
leisuretimephy
sicala
ctivity,
alco
holconsum
ption,
slee
pduration
Face-to-faceinterview
Truong
T20
141,126
/2,300
1.32(1.02–1.7
2)Case–co
ntrol
8France
Breastcancer
Nev
ervs.e
ver
NA
Age,stud
yarea
,parity,ag
eat
firstfull-
term
pregna
ncy,
ageat
men
arche,
family
history
ofbreastcancer,
curren
tuseofho
rmona
lreplacemen
ttherap
y,BMI,an
dtobacco
andalco
holconsum
ption
In-personinterview
Han
senJ
2012
267/1,3
02
2.1(1.3–3
.2)
Nestedcase–
control
7Den
mark
Breastcancer
Nev
ervs.2
0þ
yearsnight
shift
work
Nurses
Age,
weight
regularity,
useof
horm
one
replacemen
ttherap
y,ag
eat
men
arche,
men
strual
regularity,
men
opau
salstatus,ag
eat
birth
of
firstchild
,breastcancer
inmother
orsister,totald
urationoflactation
Interview
KloogI
2011
794/1,679
1.359
(1.12
1–1.6
47)
Case–co
ntrol
6Northe
rnIsrael
Breastcancer
Nolig
htvs.light
atnight
NA
Light
atnight
Interview
Han
senJ
2001
5,964/11,7
501.7
(1.3–1.7)
Case–co
ntrol
8Den
mark
Breastcancer
Nev
ervs.6
þye
ars
night
shiftwork
NA
Age,
social
class,ag
eat
birth
offirst
child
,ageat
birth
oflast
child
,and
number
ofchild
ren
Interview
Grund
yA
2013
1,134
/2,313
2.21
(1.14
–4.31)
Case–co
ntrol
7Can
ada
Breastcancer
Nev
ervs.3
0þ
yearsnight
shift
work
NA
Yea
rsofnight
shifthistory
Que
stionn
aire
LiQ
2010
74/201
0.9
(0.2–3
.9)
Case–co
ntrol
8USA
Breastcancer
Nev
ervs.e
ver
NA
Agegroup
,race,
BMI,ag
eat
first
men
strual
period,fam
ilyhistory
of
breastcancer,ageat
firstfull-term
birth,m
onths
oflifetim
ebreast
feed
ing,cigarette
smoking
,alco
hold
rink
ing,a
ndpremen
opau
sal
Interview
LiQ
2010
289/518
1.4(0.5–4
.3)
Case–co
ntrol
8USA
Breastcancer
Nev
ervs.e
ver
NA
Agegroup
,race,
BMI,ag
eat
first
men
strual
period,fam
ilyhistory
of
breastcancer,ageat
firstfull-term
birth,m
onths
oflifetim
ebreast
feed
ing,cigarette
smoking
,alco
hold
rink
ing,a
ndpostmen
opau
sal
Interview
Han
senJ
2012
218/1,117
2.1(1–4
.5)
Nestedcase–
control
7Den
mark
Breastcancer
Nev
ervs.15þ
yearsnight
shift
work
Military
women
Age,
horm
one
replacemen
ttherap
y,nu
mber
ofchild
births,ag
eat
men
arche,
yearsofed
ucation,
occasiona
lsun
bathing
freq
uency,
andtobacco
smoking
status
Que
stionn
aire
(Con
tinu
edon
thefollowingpag
e)
Yuan et al.
Cancer Epidemiol Biomarkers Prev; 27(1) January 2018 Cancer Epidemiology, Biomarkers & Prevention30
Retrac
ted Feb
ruary
4, 20
19
on July 3, 2020. © 2018 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from
Table
1.Maincharacteristicsofinclud
edstud
iesontherelationshipbetwee
nnight
shiftwork
andtherisksofco
mmoncancersin
femalepopulations
(Cont'd)
Stud
yPub
lishe
dye
arNo.ofcases/
No.ofsubjects
OR(95%
CI)
Stud
ydesign
Qua
lity
score
Reg
ion
Typeof
canc
erRan
geofnight
shiftwork
Occup
ation
Variablesofad
justmen
tExp
osure
assessmen
tmetho
d
KwonP
2015
1,451/4,491
0.88(0.69–1.12
)Nestedcase–
control
7China
Breastcancer
Nev
ervs.3
0.6þ
yearsnight
shift
work
Textile
workers
Age,
smoking
,parity,
anden
dotoxin
Factory
personn
elreco
rdreview
(80%),
supervisor
interviews(12%
),an
din-personem
ploye
eorclose
relative
interviews(8%).
DavisS
2001
813/1,606
2.3(1.2–4
.2)
Case–co
ntrol
8USA
Breastcancer
Nev
ervs.4
.6þ
yearsnight
shift
work
NA
Parity,family
history
ofbreastcancer,
oralcontraceptive
use,
andrecent
disco
ntinue
duseofho
rmone
replacemen
ttherap
y
In-personinterview
Rab
steinS
2013
857
/1,749
1.01(0.68–
1.5)
Case–co
ntrol
8German
yBreastcancer
Nev
ervs.e
ver
NA
Fam
ilyhistory
ofbreastcancer,
horm
one
replacemen
tuse,nu
mber
ofmam
mograms,an
destrogen
receptorstatus
Telep
hone
interview
Men
egau
xF
2013
1,232
/2,549
1.4(1.01–1.9
2)Case–co
ntrol
8France
Breastcancer
Nev
ervs.4
.5þ
yearsnight
shift
work
NA
Age,stud
yarea
,parity,ag
eat
firstfull-
term
pregna
ncy,
ageat
men
arche,
family
history
ofbreastcancer,
curren
tho
rmona
lrep
lacemen
ttherap
y,BMI,tobacco
andalco
hol
In-personinterview
Bha
ttiP
2013
1,101/2,933
1.02(0.74–1.42)
Case–co
ntrol
8USA
Invasive
epithe
lial
ovarian
cancer
Nev
ervs.7þ
years
night
shiftwork
NA
Ageat
reference,
coun
ty,referen
ceye
ar,durationofo
ralcontraceptive
use,
number
offull-term
pregna
ncies,an
dBMIat
age30
In-personinterview
Wan
gP
2015
712/1,4
541.3
4(1.05–
1.72)
Case–co
ntrol
8China
Breastcancer
Nev
ervs.e
ver
NA
Age,ed
ucation,BMI,ag
eat
men
arche,
men
opau
salstatus,parity,phy
sical
activity,b
reast-feed
ing,fam
ilyhistory
ofbreastcancer,a
ndother
slee
pfactors
Face-to-faceinterview
LiW
2015
1,709/6,489
0.73(0.66–0
.82)
Nestedcase–
control
6China
Breastcancer
Nev
ervs.e
ver
Textile
workers
Ageat
thebeg
inning
offollo
w-up
Rev
iew
offactory
personn
elreco
rds
(80%),interviewsof
factory
supervisors
(12%
),an
din-person
interviewsofw
omen
ortheirrelative
sO'Lea
ryES
2006
486/1,444
0.32(0.12
–0.83)
Case–co
ntrol
8USA
Breastcancer
Nev
ervs.8þ
years
night
shiftwork
NA
Ageat
referencedate,
parity,
family
history,e
ducation,
andhistory
of
ben
ignbreastdisea
se
30-m
inutein-home
interview
FritschiL
2013
1,202/2,987
1.02(0.71–1.4
5)Case–co
ntrol
7Australia
Breastcancer
Nev
ervs.2
0þ
yearsnight
shift
work
NA
Night
shiftwork
Que
stionn
aire
anda
follo
w-uptelepho
neinterview
Schwartzbau
mJ
2007
236/1148,661
1(0.89–1.13
)Coho
rtstud
y8
Swed
enbCan
cer
Eve
rvs.n
ever
NA
Age,
socioecono
micstatus,
occup
ationa
lposition,
andco
unty
ofresiden
ce
Interview
Bau
erSE
2013
34,053
/48,511
1.12(1.04–1.2)
Case–co
ntrol
7USA
Breastcancer
Low
light
atnight
vs.h
igh
NA
Race,
tumorgradean
dstag
e,ye
arof
diagno
sis,ag
eat
cancer
diagno
sis,
Metropolitan
StatisticalArea(M
SA)
status,b
irthsper
1,000women
ages
15–5
0,M
SApopulation
mobility,p
opulationove
r16
inthe
laborforce,
andprevalenceof
cigarette
smoking
Infrared
light
detection
byanighttime
satellite
(Con
tinu
edon
thefollowingpag
e)
Night Shift Work Increases Cancer Risk of Women
www.aacrjournals.org Cancer Epidemiol Biomarkers Prev; 27(1) January 2018 31
Retrac
ted Feb
ruary
4, 20
19
on July 3, 2020. © 2018 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from
Table
1.Maincharacteristicsofinclud
edstud
iesontherelationshipbetwee
nnight
shiftwork
andtherisksofco
mmoncancersin
femalepopulations
(Cont'd)
Stud
yPub
lishe
dye
arNo.ofcases/
No.ofsubjects
OR(95%
CI)
Stud
ydesign
Qua
lity
score
Reg
ion
Typeof
canc
erRan
geofnight
shiftwork
Occup
ation
Variablesofad
justmen
tExp
osure
assessmen
tmetho
d
Kojo
K20
05
27/544
1.52(0.49–4
.74)
Nestedcase–
control
7Finland
Breastcancer
Nev
ervs.o
ften
Cab
in attend
ants
Cum
ulativeradiationdose,num
ber
of
fertile
years,parity,family
historyof
breastcancer,a
lcoho
lco
nsum
ption,
disruptionofslee
prhythm
,and
men
strual
cycle
Que
stionn
aire
RafnssonV
2003
35/175
5.24
(1.58–17.38
)Nestedcase–
control
6Icelan
dBreastcancer
<5ye
arsvs.�
5ye
ars
Cab
in attend
ants
Ageat
firstchild
birth
andleng
thof
employm
ent,nu
mber
ofchild
ren
Employm
enthistory
RafnssonV
2003
35/175
0.82(0.34–1.97)
Nestedcase–
control
6Icelan
dBreastcancer
<5ye
arsvs.�
5ye
ars
Cab
in attend
ants
Ageat
firstchild
birth
andleng
thof
employm
ent,nu
mber
ofchild
ren
Employm
enthistory
Puk
kala
E20
1255
9/8,244
1.16(1.06–1.25)
Nestedcase–
control
5Finland
,Iceland
,Norw
ayan
dSwed
en
bCan
cer
Cab
increw
vs.
gen
eral
population
Airlinecabin
crew
Leng
thofem
ploym
ent
Employm
enthistory
Linn
ersj€ oA
2003
71/2,324
1.01(0.78–1.24)
Nestedcase–
control
5Swed
enbCan
cer
Cab
increw
vs.
gen
eral
population
Airlinecabin
crew
Agean
dcalend
arperiod
Employm
enthistory
Rey
noldsP
2002
104/44,021
1.05(0.86–1.27)
Coho
rtstud
y5
USA
Unclassified
cancer
Flig
htattend
ants
versus
gen
eral
population
Flig
ht attend
ants
None
HistoricalA
FAflight
reco
rdsextrap
olated
toCalifornia
coho
rt
McE
lroyJA
2006
4,033
/9,347
0.94(0.62–
1.44)
Case–co
ntrol
8USA
Breastcancer
Sho
rtdurationof
slee
pper
night
vs.n
orm
al
NA
Referen
ceag
e,state,
parity,
ageat
firstfull-term
pregna
ncy,
family
history
ofbreastcancer,a
lcoho
lco
nsum
ption,
BMI,men
opau
sal
status,a
geat
men
opau
se,
postmen
opau
salh
orm
one
use,
education,
andmarital
status
Interviews
Schernh
ammer
E20
149,14
0/193,39
60.95(0.77–1.17
Coho
rtstud
y5
USA
Breastcancer
Nev
ervs.3
0þ
yearsrotating
shiftwork
Nurses
Multivariab
lead
justmen
tLa
rgeprospective
data
sets
MarinoJL
2008
812/2,12
51.2
(1–1.5)
Case–co
ntrol
5USA
Epithe
lial
ovarian
cancer
Nev
erns
ever
NA
Multivariab
lead
justmen
tIn-personinterviews
LieJS
2011
699/1,594
1.3(0.9–1.8)
Nestedcase–
controlstudy
8Norw
ayBreastcancer
Nev
ervs.12þ
yearsrotating
shiftwork
Nurses
Age,periodofd
iagno
sis,parity,family
history
ofbreastcancer
inmother
orsister
(no/yes),an
dfreq
uencyof
alco
holconsum
ptionat
timeof
diagno
sis
Telep
hone
interviews
LieS
2013
513/1,2
702.4(1.3–4
.3)
Case–co
ntrol
5Norw
ayBreastcancer
Nev
ervs.5þ
years
night
shiftwork
Nurses
None
Datab
ase
LahtiT
A20
08
2,494/N
Aa
1.02(0.94–1.12
)Coho
rtstud
y6
Finland
Non-Hodgkin
lympho
ma
Nev
ervs.e
ver
NA
Age,
social
class,an
dco
hortperiod
Finnish
Job-Exp
osure
Matrix(FINJE
M)
GirschikJ
2013
624
/1,543
1.05(0.82–1.3
3)Case–co
ntrol
8Australia
Breastcancer
Sho
rtdurationof
slee
ptvs.
norm
al
NA
Age,
number
ofchild
ren,
ageat
first
birth,b
reastfee
ding,m
enopau
sal
status,u
seofho
rmone
replacemen
ttherap
y,durationof
useofho
rmone
replacemen
ttherap
y,alco
holconsum
ption,
comparativeweight
atag
e30
years,ev
eruseofmelatonin,
and
phy
sicala
ctivity
Que
stionn
aire
TsaiR
J20
14839
/2,457
1.34(1.06–1.68)
Case–co
ntrol
8USA
Breastcancer
Day
timework
vs.
regular
rotating
shiftwork
NA
Obesity,
smoking
status,a
lcoho
lco
nsum
ption,
race,income,
education,
health
insurance
cove
rage,
andmarital
status
Interview
TsaiR
J20
141,2
53/6,238
0.98(0.78–1.21)
Case–co
ntrol
8USA
Cervical
cancer
Day
timework
vs.
regular
rotating
shiftwork
NA
Obesity,
smoking
status,a
lcoho
lco
nsum
ption,
race,income,
education,
health
insurance
cove
rage,
andmarital
status
Interview
(Con
tinu
edon
thefollowingpag
e)
Yuan et al.
Cancer Epidemiol Biomarkers Prev; 27(1) January 2018 Cancer Epidemiology, Biomarkers & Prevention32
Retrac
ted Feb
ruary
4, 20
19
on July 3, 2020. © 2018 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from
Table
1.Maincharacteristicsofinclud
edstud
iesontherelationshipbetwee
nnight
shiftwork
andtherisksofco
mmoncancersin
femalepopulations
(Cont'd)
Stud
yPub
lishe
dye
arNo.ofcases/
No.ofsubjects
OR(95%
CI)
Stud
ydesign
Qua
lity
score
Reg
ion
Typeof
canc
erRan
geofnight
shiftwork
Occup
ation
Variablesofad
justmen
tExp
osure
assessmen
tmetho
d
TsaiR
J20
141,4
12/2,17
61.17(1.01–1.3
6)
Case–co
ntrol
8USA
Coloncancer
Day
timework
vs.
regular
rotating
shiftwork
NA
Obesity,
smoking
status,a
lcoho
lco
nsum
ption,
race,income,
education,
health
insurance
cove
rage,
andmarital
status
Interview
Chu
CH
2010
408/2,023
2.54
(1.37–
4.7)
Nestedcase–
controlstudy
5China
Breastcancer
Nev
ervs.e
ver
NA
Potentialconfoun
ders
Interview
LuoJ
2012
295/14,2933
0.79(0.61–1.0
2)Coho
rtstud
y8
USA
Thy
roid
cancer
Sho
rtslee
pdurationvs.
norm
al
NA
Ageat
enrollm
ent,ethn
icity,
educationa
llev
el,smoking
,BMI
(weight
(kg)/he
ight
(m)2),
recrea
tiona
lphy
sicala
ctivity,
alco
holintake,
family
history
of
cancer,p
revious
thyroid
disea
se,
history
ofho
rmone
therap
yuse,
dep
ressionscore,a
nddifferent
trea
tmen
tassignm
ents
for
Women
'sHea
lthInitiative
clinical
trials
Que
stionn
aire
Verkasalo
PK
2005
242/12,222
0.88(0.11–6
.91)
Coho
rtstud
y8
Finland
Breastcancer
Sho
rtslee
pdurationvs.
norm
al
NA
Age,
zygosity,social
class,nu
mber
of
child
ren,useofo
ralcontraceptive
s,BMI,alco
holu
se,smoking
,and
phy
sicala
ctivity
Que
stionn
aire
Jiao
L20
13851/7,5828
1.36(1.06–1.74)
Coho
rtstud
y8
USA
Colorectal
cancer
Sho
rtslee
pdurationvs.
norm
al
NA
Age,
ethn
icity,
fatigue
,horm
one
replacemen
ttherap
y,waist-to-hip
ratio,a
ndphy
sicala
ctivity
Que
stionn
aire
KakizakiM
2008
143/23
,995
1.67(1.002–2.78
)Coho
rtstud
y8
Japan
Breastcancer
Sho
rtslee
pdurationvs.
norm
al
NA
Age,
BMI,history
ofdisea
ses,family
history
ofcancer,job,m
arital
status,e
ducation,
cigarette
smoking
,alcoho
lconsum
ption,
timespen
twalking
,totalcaloric
intake,m
enopau
salstatus,ag
eat
men
arche,
ageat
firstdelivery,
number
ofdeliveries,useoforal
contraceptive
drugs,useof
horm
one
drugsexceptfororal
contraceptive
drugs(yes
orno
)
Que
stionn
aire
Tyn
esT
1996
140/2,16
91.2
(1–1.4)
Coho
rtstud
y6
Norw
aybCan
cer
Nev
ervs.e
ver
Rad
ioan
dtelegraph
operators
Shiftwork
anddurationof
employm
ent
Datab
ase
Pesch
B20
1074
9/1,542
2.48(0.62–9.99)
Case–co
ntrol
8German
yBreastcancer
Nev
ervs.2
0þ
yearsnight
shift
work
NA
Apotentialselectionbiasusing
bootstrap
ping,fam
ilyhistory
of
breastcancer,h
orm
one
replacemen
tuse,
andnu
mber
of
mam
mograms
Interview
Bai
Y20
16613/14004
0.90(0.66–1.23)
Coho
rtstud
y8
China
Unclassified
cancer
Nev
ervs.2
0þ
yearsnight
shift
work
NA
Age,
BMI,family
history
ofcancer,
alco
hold
rink
ingan
dsm
oking
status,n
umber
ofchild
ren,
men
opau
salstatus,ho
rmone
replacemen
ttherap
y,an
dco
ntraceptionstatus
Que
stionn
aire
Cohe
nJM
2015
415/10,2484
0.90(0.67–1.2
0)
Coho
rtstud
y8
USA
Melan
oma
Sho
rtslee
pdurationvs.
norm
al
Nurses
Age,
number
ofsunb
urns,m
oles,ha
irco
lor,family
history
ofmelan
oma
(yes,n
o),reactionto
thesun,
tann
ing,C
aucasian
ethn
icity,
ultravioletflux
(quintiles),sno
ring
Que
stionn
aire
(Con
tinu
edon
thefollowingpag
e)
Night Shift Work Increases Cancer Risk of Women
www.aacrjournals.org Cancer Epidemiol Biomarkers Prev; 27(1) January 2018 33
Retrac
ted Feb
ruary
4, 20
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Table
1.Maincharacteristicsofinclud
edstud
iesontherelationshipbetwee
nnight
shiftwork
andtherisksofco
mmoncancersin
femalepopulations
(Cont'd)
Stud
yPub
lishe
dye
arNo.ofcases/
No.ofsubjects
OR(95%
CI)
Stud
ydesign
Qua
lity
score
Reg
ion
Typeof
canc
erRan
geofnight
shiftwork
Occup
ation
Variablesofad
justmen
tExp
osure
assessmen
tmetho
d
TravisRC
2016
4,809/522
,246
1.00(0.92–1.0
8)
Coho
rtstud
y8
UK
Breastcancer
Nev
ervs.e
ver
NA
Socioecono
micstatus,p
arityan
dag
eat
firstbirth,B
MI,alco
holintake,
strenu
ous
phy
sicala
ctivity,
family
history
ofbreastcancer,a
geat
men
arche,
oralcontraceptive
use,
smoking
,living,w
ithapartner,and
useofmen
opau
salh
orm
one
therap
y
Que
stionn
aire
Weg
rzyn
LR(N
HS)c
2017
5,971/7,8516
0.95(0.77–1.17)
Coho
rtstud
y8
USA
Breastcancer
Nev
ervs.3
0þ
yearsnight
shift
work
Nurses
Age,
height,B
MI,BMIat
age18,
adolescen
tbodysize,a
geat
men
arche,
ageat
firstbirth
and
parityco
mbined
,breastfee
ding,
typeofmen
opau
sean
dag
eat
men
opau
seco
mbined
,men
opau
salh
orm
one
therap
y,durationofestrogen
alone
men
opau
salh
orm
one
therap
y,durationofestrogen
and
progesterone
men
opau
sal
horm
one
therap
y,first-deg
ree
family
history
ofbreastcancer,
history
ofben
ignbreastdisea
se,
alco
holconsum
ption,
phy
sical
activity,a
ndcurren
tmam
mography
use
Que
stionn
aire
Weg
rzyn
LR(N
HS2)
c20
173,57
0/114,559
2.15
(1.23–
3.73
)Coho
rtstud
y8
USA
Breastcancer
Nev
ervs.2
0þ
yearsnight
shift
work
Nurses
Age,
height,B
MI,BMIat
age18,
adolescen
tbodysize,a
geat
men
arche,
ageat
firstbirth
and
parityco
mbined
,breastfee
ding,
typeofmen
opau
sean
dag
eat
men
opau
seco
mbined
,men
opau
salh
orm
one
therap
y,durationofestrogen
alone
men
opau
salh
orm
one
therap
y,durationofestrogen
and
progesterone
men
opau
sal
horm
one
therap
y,first-deg
ree
family
history
ofbreastcancer,
history
ofben
ignbreastdisea
se,
alco
holconsum
ption,
phy
sical
activity,a
ndcurren
tmam
mography
use
Que
stionn
aire
Abbreviations:NA,n
otavailable;BMI,bodymassindex.
aFrom
theen
rolledarticle,
weco
uldno
tobtain
theaccurate
number
ofparticipan
ts.T
hus,in
theprecedingcalculation,
wemissedthedata.
ORan
dco
rrespond
ing95%
CIwereextracteddirectlyfrom
thearticle.
bThe
sefour
stud
iesreported
theSIR
forcancer
ove
rallam
ong
femalenight
shiftersan
dalso
reported
onanu
mber
ofd
ifferent
cancers,includ
ing,forexam
ple,b
reastcancer,coloncancer,cervix/uterus
cancer,and
other
cancers.
cThisstud
yexam
ined
associations
betwee
nrotating
night
shiftwork
andbreastcancer
intw
oprospective
coho
rts(N
HSan
dNHS2).
Yuan et al.
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strongest OR existed in the nursing group (OR ¼ 1.577; 1.235–2.014). In the analysis stratified by quality score, both groups ofhigh score (OR ¼ 1.273; 95% CI, 1.152–1.407) and low score(OR ¼ 1.434; 95% CI, 1.133–1.814) presented a positive asso-ciation but the latter tended to have significant heterogeneity (P¼0.000, I2 ¼ 89.7%). As for the number of adjusted confounders,both groups indicated that night shift work was associatedwith increased risk of breast cancer and significant heterogeneity(P ¼ 0.000, I2 ¼ 89.1%) existed in the group adjusted for �3confounders. When stratified by exposure assessment method,
the questionnaire group presented a stronger correlation andlower heterogeneity compared with interview and databasegroup, whereas negative association was observed among studiesadopting other assessment methods (OR ¼ 0.906; 95% CI,0.596–1.378).
Furthermore, meta-regression analysis was carried out toexplore the possible heterogeneity sources among stratified fac-tors andnone of the variables was considered as a potential sourceof heterogeneity. The results of subgroup analyses and meta-regression were summarized in Table 2.
Figure 2.
Forest plots of the association between night shift work and the risks of common cancers. I2, measure to quantify the degree of heterogeneity inmeta-analyses. The squares and horizontal lines correspond to the study-specific OR and 95% CI. The area of the squares reflects the study-specificweight. The diamond represents the pooled OR and 95% CI.
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Dose–response meta-analysisDose–response meta-analysis was performed among stud-
ies that involved at least 3 levels of exposure categories.The number of studies on breast cancer accounted for anoverwhelming proportion and sixteen studies were includedto quantitatively assess the cumulative effect of exposure tonight shift work on breast cancer incidence. As for othertypes of cancers, the number of relevant literature was notenough for dose–response meta-analysis. For every 5 years ofnight shift work, the risk of breast cancer in women increasedby 3.3% (OR ¼ 1.033; 95% CI, 1.012–1.056) as shownin Fig. 3.
Study qualityThe NOS was employed for quality evaluation of eligible
studies. Their scores ranged from 5 to 8 and the mean value was7.1, indicating a favorable overall quality. Among the includedstudies, 43 articles were considered to be of high quality withscores �7 and 8 studies got 5 scores because of lack of completeresearch records and variables of adjustment.
Publication biasWe performed Begg funnel plot to assess the publication bias
of included studies. Potential publication bias was identified(P ¼ 0.006) among all retrieved studies probably due to thevariety of involved cancers, whereas no publication bias wasobserved among studies on breast cancer (P ¼ 0.208; Supple-mentary Fig. S2).
DiscussionSome people in contemporary society work in a 24-hour
mode, disrupting the 8-hour day routine (83). With the pro-ductive and economic development, night shift work is stronglyrequired in the fields of industry, commerce, and entertainment.Shift workers suffer from disturbance of circadian rhythm andsuppression of nocturnal melatonin. Short-term effects of nightshift work were summarized as "jet-lag" syndrome, includingsleep disorders, digestive troubles, fatigue, emotional fluctua-tion, and reduced physical activity. Long-term night shift workwas reported to be associated with increased risks of cardiovas-cular disease, neuropsychiatric disorder, endocrine system dis-orders, and cancer (84–87). Data from the third EU Survey(2000) showed that 76% employee worked beyond normalworking time (88). Up to 21.9% of men and 10.7% of womenwere exposed to shift work, with 7% population working per-manently at night (89). Large numbers of people are beingexposed to night shift work, which brings huge detrimentalimpact on health; it is therefore of much significance to conductthe study to illustrate the relationship between night shift workand the risks of frequently-occurred cancers in women.
Sixty-one studies were enrolled in the meta-analysis including26 cohort studies, 24 case–control studies, and 11 nested case–control studies with 114,628 cases and 3,909,152 participantsfromEurope, North America, Asia, and Australia. A positive dose–response relationship was present between night shift work andthe risks of breast cancer (OR ¼ 1.316; 95% CI, 1.196–1.448),
Table 2. Results of subgroup analyses and meta-regression analyses on the correlation between night shift work and the risk of breast cancer in women
Risk estimates HeterogeneitySubgroup Number of studiesa Weight (%) OR (95% CI) P P I2 PinteractionGeographic location 0.472Europe 27 (22, 26–27, 32, 38–44, 47, 50–51, 57, 59–62,
67–68, 74, 77–78, 81)54.42 1.416 (1.246–1.610) 0.000 0.000 77.4%
North America 13 (29, 36, 45–46, 49, 55, 58, 64–65, 71, 82) 25 1.236 (1.048–1.459) 0.012 0.001 65.3%Asia 7 (30, 35, 37, 53–54, 72, 76) 15.13 1.236 (0.865–1.767) 0.245 0.000 88.3%Australia 2 (56, 70) 5.45 1.040 (0.852–1.271) 0.698 0.895 0.0%Study design 0.584Cohort study 14 (22, 26, 27, 29, 30, 32, 57, 65, 74, 76–77, 81, 82) 32.32 1.193 (1.030–1.382) 0.019 0.000 72.5%Case–control 24 (35–38, 40–41, 43–46, 49–51, 53, 55–56, 58,
64, 68, 70–71, 78)47.79 1.329 (1.189–1.486) 0.000 0.000 63.1%
Nested case–control 11 (39, 42, 47, 54, 59–62, 67, 72) 19.89 1.555 (1.115–2.169) 0.009 0.000 90.0%Number of variables 0.592�3 15 (32, 37, 39, 43, 45, 54, 56, 60–62, 65, 68, 72,
77)31.18 1.440 (1.139–1.820) 0.002 0.000 89.1%
>3 34 (22, 26–27, 29–30, 35–36, 38, 40–42, 44, 46–47, 49–51, 53, 55, 57–59, 64, 67, 70–71, 74, 76,78, 81, 82)
68.82 1.273 (1.152–1.405) 0.000 0.000 71.4%
Study score 0.658Low 14 (32, 35, 37, 39, 43, 54, 60–62, 65, 68, 72, 77) 30.37 1.434 (1.133–1.814) 0.003 0.000 89.7%High 35 (22, 26–27, 29–30, 36, 38, 40–42, 44–47, 49–
51, 53, 55–59, 64, 67, 70–71, 74, 76, 78, 81, 82)69.63 1.273 (1.152–1.407) 0.000 0.000 71.3%
Exposure assessment 0.077Database 10 (32, 35, 39, 60–62, 65, 68, 77) 21.85 1.452 (1.211–1.741) 0.000 0.001 67.2%Questionnaire 12 (22, 29, 36, 45, 47, 59, 70, 74, 76, 81, 82) 21.42 1.380 (1.137–1.676) 0.001 0.001 65.2%Interview 25 (26–27, 30, 37–38, 40–44, 46, 49–51, 53, 55–
57, 64, 67, 71–72, 78)49.54 1.287 (1.126–1.471) 0.000 0.000 68.6%
Other 2 (54, 58) 7.19 0.906 (0.596–1.378) 0.645 0.000 97.6%Occupation 0.350Nurses 11 (29, 36, 38, 39, 42, 65, 67, 68, 82) 21.02 1.577 (1.235–2.014) 0.000 0.000 72.0%Unclassified occupation 30 (22, 26–27, 30, 32, 35, 37, 40–41, 43–46, 49–
51, 53, 55–58, 64, 70–72, 74, 76, 78, 81)63.60 1.250 (1.130–1.383) 0.000 0.000 73.3%
Flight attendants 5 (59–62) 7.98 1.454 (1.100–1.922) 0.009 0.161 39.0%Military women 1 (47) 1.13 2.100 (0.990–4.455) 0.053 — —
Textile workers 1 (54) 3.55 0.730 (0.655–0.814) 0.000 — —
Radio and telegraph operators 1 (77) 2.73 1.500 (1.112–2.023) 0.008 — —
aSome enrolled articles discussed more than one type of cancer separately, when calculating the number of studies; we took different cancers into consideration inone article.
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digestive system cancer (OR¼ 1.177; 95% CI, 1.065–1.301), andskin cancer (OR ¼ 1.408; 95% CI, 1.024–1.934). Among thegroup of nurses, long-term night shift work increased the risks ofbreast cancer (OR ¼ 1.577; 95% CI, 1.235–2.014), digestivesystem cancer (OR ¼ 1.350; 95% CI, 1.030–1.770), and lungcancer (OR ¼ 1.280; 95% CI, 1.070–1.531). A nonsignificanteffect was observed for ovarian cancer (OR¼1.135; 0.970–1.328)and no effect was seen for cervical cancer (OR ¼ 0.980; 95% CI,0.787–1.221). Night shift work elevated the risk of breast cancerin a dose–response way which was consistent with previousstudies (6, 20, 90). For every 5 years of night shift work, the riskof breast cancer in women increased by 3.3% (OR ¼ 1.033; 95%CI, 1.012–1.056).
Night shift work causes an increase in sex hormones, which isspeculated to be relevant for hormone-dependent cancers (91).Strong epidemiologic evidence supports the associationbetween night shift work and increased risk of breast cancer,and also there is limited evidence on prostate cancer (92, 93)and endometrial cancer (25). In our analysis, the risks ofhormone-sensitive cancers including breast cancer, ovariancancer, and uterine cancer among night shift workers wereshown in Table 2. Night shift work was strongly associatedwith higher risk of breast cancer in females whereas no effectwas observed for ovarian cancer and uterine cancer.
The underlying biological mechanisms of the associationbetween night shift work and increased cancer risks are complex.One of the possible hypotheses is that exposure to light at nightaccompanying night shift work results in the disruption of circa-dian rhythm and the reduction of melatonin production (5).Melatonin is characterized with oncostatic effect which worksthrough antioxidation, antiangiogenesis, regulation of immunity,andmetabolism (7). Melatonin reduction stimulates the produc-tion of pituitary gonadotropins by negative feedback, henceincreasing the risk of sensitive cancers such as breast cancer,ovarian cancer, and endometrial cancer (8). Animal experimentshave demonstrated that long-term oral melatonin supplementoffered aprotective effect against breast cancer (94). Several in vitroresearches showed that melatonin administration of even bio-logical dose had a significant growth inhibition effect on breast
cancer cells (95–98) and other tumor cells (99–103). Sun expo-sure is sharply decreased among night shift workers, leading toreduced vitaminD level. Some experimental and epidemiologicalresearches supported the inverse correlation between circulatingvitamin D and the risk of breast cancer (104, 105) or colorectalcancer (106, 107). However, night shift work was often accom-panied with irregular eating habits, which somewhat contributedto digestive system tumors. Results in our study were inconsistentwith the above theories that night shift work increased the risk ofhormone-sensitive cancers and digestive system cancers.
Q and I2 statistics were used to evaluate heterogeneity. As aresult, significant heterogeneity was observed in the groups ofbreast cancer (P ¼ 0.000, I2 ¼ 80.4%), skin cancer (P ¼ 0.009,I2 ¼ 64.7%), and uterine cancer (P ¼ 0.042, I2 ¼ 59.6%).Random-effect model was adopted in an attempt to eliminateall sources of heterogeneity. Furthermore, subgroup analysesabout breast cancer were conducted and less heterogeneityexisted among cohort studies, high-score studies and studiesadjusted for >3 confounders, suggesting that these studieswould provide more reliable evidence. Moreover, we carriedout meta-regression analysis and no explanation was found forpossible heterogeneity sources from variables due to low sta-tistical power, therefore the results of risk estimates should beinterpreted with caution. When stratified by region, positivecorrelation existed in Europe and North America, but not inAsia and Australia. One possible reason might be that Asianpopulation was less sensitive to nightshift exposure. Anotherwas partly attributed to the difference of sleeping habits,economic development, and medical service across differentgeographical areas. Short sleep duration, light at night, andairline cabin crew servings involved potential circadian rhythmdisturbances just like nightshift; therefore, relevant articles wereincluded in this meta-analysis to reduce selection bias. Flightattendants were simultaneously exposed to cosmic radiationwhich was a potential cancer-related unmeasurable factor, thusthe odds risk might be overestimated. Among nurses, remark-able elevation of cancer risk was observed regarding breastcancer (OR ¼ 1.577; 95% CI, 1.235–2.014), digestive systemcancer (OR ¼ 1.350; 95% CI, 1.030–1.770), and lung cancer(OR ¼ 1.280; 95% CI, 1.070–1.531). In the future, large-sample and multiregion researches are needed to update andconfirm the association.
The present meta-analysis involved 3,909,152 participants and114,628 female patients with cancers at 11 sites. To the best of ourknowledge, this is the first meta-analysis to comprehensivelyassess the association between night shift work and the risk ofcommon cancers among female population. Compared withprevious meta-analyses, the study has the following merits. First,in the methodological aspect we systematically conducted riskestimates, subgroup analyses, meta-regression analysis, anddose–response meta-analysis. Random effect model was used toeliminate the source of heterogeneity to some extent. In addition,subgroup analyses and meta-regression were performed toexplore potential sources of heterogeneity from confoundingfactors. Second, according to inclusion and exclusion criteria,61 studieswere enrolled in themeta-analysis and the accumulatedevidence with enlarged sample size enhanced statistical power toderive a more precise and reliable risk estimation. Beyond that,longest versus shortest duration was taken as exposure indicatorand each individual article was involved in the pooled riskestimate, increasing the generalizability of results. Third, the
Figure 3.
OR of breast cancer in women by years of night shift work based on dose-response meta-analysis. Solid line represents the estimated OR and the dottedlines represent the low limit and upper limit of 95% CIs.
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majority of included studies (40 out of 67) were carried outamong general population, therefore the estimation of associa-tion between night shift work and cancer risk of women could beextended, not limited to some particular working groups. Acertain amount of studies (17 out of 67) were based on nursinggroup which was an important part of female shift workers and astratified analysis revealed that night shift work increased the riskof breast cancer, lung cancer and digestive system cancer in femalenurses. Fourth, cohort study is less susceptible to confoundingfactors and less affected by recall bias, thus result from cohortstudy is considered more credible and valuable compared withcase–control study. In this meta-analysis, 26 cohort studies withenough follow-up period were included and a positive relation-ship was found in the cohort group.
Nevertheless, some shortcomings in the study have to bementioned. First, the period time of night shift across allenrolled studies was not defined uniformly, for example onedefinition was "working at least three nights per month" (29)and another was "working during the night (23:00–06:00 h)"(28). Included studies used very different definitions of periodtime regarding night shift and the lack of consistent definitionmight result in a certain degree of misclassification, consequent-ly leading to a dilution of pooled estimates when doing datasynthesis. Second, a significant between-study heterogeneityandpublicationbiaswas observed. Significant variability existedin different individual studies regarding study population, geo-graphical location, adjustment confounders, study design andexposure definition, and each of these factors may contribute toheterogeneity. Disappointingly, we failed to find out the possi-ble sources of heterogeneity from a meta-regression due to thelow statistical power. Given substantial heterogeneity observedamong included studies, the evidence supporting the associa-
tion might be weakened and additional well-designedresearches are needed. Third, case–control study are vulnerableto varying levels of bias, and in general patients in case grouptend to recall past exposure history of night shift. Twenty-fourcase–control studies were included in our analysis which couldprobably bring about selection and recall bias. Also, unstan-dardized questionnaires might produce information bias andinadequate control of adjustment factors could lead to eitherunderestimation or exaggeration of the pooled risk. Finally, onlya small number of enrolled studies were involved in dose-response meta-analysis, hence limiting the reliability of theresult.
In conclusion, this meta-analysis updated previous studies andidentified that cancer risk in female populationwas increasedwithaccumulating years of night shift work. Given the expandingprevalence of shift work worldwide and heavy public burden ofcancers, further researches, particularly large-size, high-scorecohort studies are of great necessity to confirm the relationshipbetweennight shiftwork and cancer risk. Also, in-depth biologicalresearches should be done to explore the mechanisms by whichnight shift work affects cancer risk. Knowing how night shift workserves as a risk factor for cancers might help establish andimplement effective measures to protect female night shifters.Moreover, it is important that long-termnight shift workers acceptregular physical examination and cancer screening for potentialmalignancies, particularly breast cancer.
Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed.
Received March 22, 2017; revised July 27, 2017; accepted October 11, 2017;published online January 8, 2018.
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Retraction
Retraction: Night Shift Work Increases theRisks of Multiple Primary Cancers in Women:A Systematic Review and Meta-analysis of61 ArticlesXia Yuan, Chenjing Zhu, Manni Wang, Fei Mo,Wei Du, andXuelei Ma
This article (1) has been retracted at the request of the authors. The journal receivedLetters to the Editor from Boyle and Fritschi (2), and from Labr�eche and collea-gues (3), pointing out a number of misclassifications and methodologic flaws in themeta-analysis. Misclassification of exposure led to the questionable eligibility ofarticles included in the study and methodologic flaws led to the inclusion ofinappropriate studies and the inclusion of articles providing overlapping data. Theauthors made efforts to correct the errors. After excluding inappropriate and over-lapping articles, 47 of the original 61 articles remained and, although some resultswere similar, conclusions were changed. The authors regret any inconveniences orchallenges resulting from the publication and subsequent retraction of this article.
A copy of this retraction notice was sent to the last known e-mail addresses of theauthors. Two authors (Xia Yuan and Xuelei Ma) agreed to the retraction; theremaining authors (Chenjing Zhu, Manni Wang, Fei Mo, and Wei Du) did notrespond.
References1. Yuan X, Zhu C,WangM,Mo F, DuW,Ma X. Night shift work increases the risks of multiple primary
cancers in women: a systematic review and meta-analysis of 61 articles. Cancer EpidemiolBiomarkers Prev 2018;27:25–40.
2. Boyle T, Fritschi L. Night shift work increases cancer risk of women—letter. Cancer EpidemiolBiomarkers Prev 2019;28:421.
3. Labreche F, Guenel P, Levi F, Dore J-F, Costa G, Lasfargues G, et al. Night shift work increases cancerrisk of women—letter. Cancer Epidemiol Biomarkers Prev 2019;28:422.
Published online February 4, 2019.doi: 10.1158/1055-9965.EPI-18-1085�2019 American Association for Cancer Research.
CancerEpidemiology,Biomarkers& Prevention
www.aacrjournals.org 423
2018;27:25-40. Cancer Epidemiol Biomarkers Prev Xia Yuan, Chenjing Zhu, Manni Wang, et al. in Women: A Systematic Review and Meta-analysis of 61 ArticlesNight Shift Work Increases the Risks of Multiple Primary Cancers
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