Cancer Night Shift Work Increases the Risks of Multiple ... · shift work function as carcinogens that increase tumor inci-dence (5). Melatonin, primarily produced by pineal gland,

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.

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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


edstud


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)



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ruary

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Table


edstud


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


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.


Retrac

ted Feb

ruary

4, 20

19



Table


edstud


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


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)



Retrac

ted Feb

ruary

4, 20

19



Table


edstud


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.


Retrac

ted Feb

ruary

4, 20

19



Table


edstud


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

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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)



Retrac

ted Feb

ruary

4, 20

19



Table


edstud


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

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Occup

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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)

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Abbreviations:NA,n

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dNHS2).

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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

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http://crossmark.crossref.org/dialog/?doi=10.1158/1055-9965.EPI-18-1085&domain=pdf&date_stamp=2019-1-25

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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