The association between psychological stress and miscarriage: A systematic review and meta-analysis

Abstract

This systematic review and meta-analysis was designed to investigate whether maternal psychological stress and recent life events are associated with an increased risk of miscarriage. A literature search was conducted to identify studies reporting miscarriage in women with and without history of exposure to psychological stress (the only exposure considered). The search produced 1978 studies; 8 studies were suitable for analysis. A meta-analysis was performed using a random-effects model with effect sizes weighted by the sampling variance. The risk of miscarriage was significantly higher in women with a history of exposure to psychological stress (OR 1.42, 95% CI 1.19–1.70). These findings remained after controlling for study type (cohort and nested case-control study OR 1.33 95% CI 1.14–1.54), exposure types (work stress OR 1.27, 95% CI 1.10–1.47), types of controls included (live birth OR 2.82 95% CI: 1.64–4.86). We found no evidence that publication bias or study heterogeneity significantly influenced the results. Our finding provides the most robust evidence to date, that prior psychological stress is harmful to women in early pregnancy.

Full text

Qu, F., Wu, Y., Zhu, Y., Barry, J.A., Ding, T., Baio, G., Muscat, R., Todd, B., Wang, F. & Hardiman,
P. J. (2017). The association between psychological stress and miscarriage: A systematic review
and meta-analysis. Scientific Reports, 7(1), p. 1731. doi: 10.1038/s41598-017-01792-3
City Research Online
Original citation: Qu, F., Wu, Y., Zhu, Y., Barry, J.A., Ding, T., Baio, G., Muscat, R., Todd, B.,
Wang, F. & Hardiman, P. J. (2017). The association between psychological stress and miscarriage:
A systematic review and meta-analysis. Scientific Reports, 7(1), p. 1731. doi: 10.1038/s41598-017-
01792-3
Permanent City Research Online URL: http://openaccess.city.ac.uk/17473/
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Scientific RepoRts | 7: 1731 | DOI:10.1038/s41598-017-01792-3
www.nature.com/scientificreports
The association between
psychological stress and
miscarriage: A systematic review
and meta-analysis
Fan Qu1, Yan Wu1, Yu-Hang Zhu1, John Barry2, Tao Ding3, Gianluca Baio3, Ruth Muscat4,6,
Brenda K. Todd5, Fang-Fang Wang1 & Paul J Hardiman
2
This systematic review and meta-analysis was designed to investigate whether maternal psychological
stress and recent life events are associated with an increased risk of miscarriage. A literature search was
conducted to identify studies reporting miscarriage in women with and without history of exposure to
psychological stress (the only exposure considered). The search produced 1978 studies; 8 studies were
suitable for analysis. A meta-analysis was performed using a random-eects model with eect sizes
weighted by the sampling variance. The risk of miscarriage was signicantly higher in women with a
history of exposure to psychological stress (OR 1.42, 95% CI 1.19–1.70). These ndings remained after
controlling for study type (cohort and nested case-control study OR 1.33 95% CI 1.14–1.54), exposure
types (work stress OR 1.27, 95% CI 1.10–1.47), types of controls included (live birth OR 2.82 95% CI:
1.64–4.86). We found no evidence that publication bias or study heterogeneity signicantly inuenced
the results. Our nding provides the most robust evidence to date, that prior psychological stress is
harmful to women in early pregnancy.
Spontaneous pregnancy loss is the most common complication of pregnancy1, 2; it occurs before 24 weeks of ges-
tation in around 20% of pregnancies3–5 and in 12–15% of clinically recognized pregnancies6. However, many cases
of miscarriage are unreported; especially those involving early fetal loss, so the incidence may be even higher7.
Only a small proportion (<10%) of women who experience miscarriage report recurrent pregnancy loss7 and as
many as a third of pregnancy losses are not linked to chromosomal abnormalities5. Miscarriage is oen associated
with high levels of distress for women, their partners and families; therefore, every potential cause of miscarriage
should be investigated. e evidence relating stress to spontaneous miscarriage is conicting. Women reporting
one or more recent negative life events prior to miscarriage were twice as likely to have a chromosomally normal
spontaneous abortion8, even aer adjusting for life-style factors9 and a similar two-fold increase in miscarriage
was found in women with a history of exposure to psychological stress1. Stress (e.g. nancial or marital problems,
death, divorce, physical and nonphysical abuse inicted on a woman by her partner and loss of social support)
was also associated with the likelihood of miscarriage among women reporting to an emergency department
or admission to hospital10, 11.Psychological challenges can include the experience of emotional trauma, social
problems, concerns about money, marital/partnership disharmony, work pressure, signicant change in personal
circumstances as well as prior pregnancy loss12. In addition, retrospective studies link increase in workplace
demands with adverse pregnancy outcomes including miscarriage7, 13.
On the other hand, possibly because of a desire not to exacerbate women’s concerns, many doctors discount
any association between stress and miscarriage. In the UK for example, an NHS website (http://www.nhs.uk/
1Women’s Hospital, School of Medicine, Zhejiang University, No.1 Xueshi Road, Hangzhou, 310006, Zhejiang,
P. R. China. 2Institute of Women’s Health, University College London, Rowland Hill Street, London, NW3 2PF, UK.
3Department of Statistical Science, University College London, Gower Street, London, WC1E 6BT, UK. 4Library
Services, University College London, Gower Street, London, WC1E 6BT, UK. 5Psychology Department, School of
Social Sciences, City University London, Northampton Square, London, EC1V 0HB, UK. 6Present address: EBSCO
Health for UK North & Ireland at EBSCO Information Services, 4th Floor Kingmaker House, Station Road, New
Barnet, EN5 1NZ, UK. Fan Qu, Yan Wu and Yu-Hang Zhu contributed equally to this work. Correspondence and
requests for materials should be addressed to P.J.H. (email: p.hardiman@ucl.ac.uk)
Received: 5 August 2016
Accepted: 31 March 2017
Published: xx xx xxxx
OPEN

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Conditions/Miscarriage/Pages/Causes.aspx) advises mothers that the risk of miscarriage being related to a moth-
er’s emotional state is a “common misconception”. Perhaps because of a lack of evidence, opposing opinions
regarding stress as a cause of miscarriage are widely held.
Further evidence of a link between stress and adverse reproductive outcomes comes from animal studies; for
example, among non-domesticated animals, re-location and exposure to unfamiliar conspecics can lead to suf-
cient stress to cause miscarriage14. e negative eect of stress on the nervous, endocrine and immune systems
of mice is also associated with abortion15.
e belief that stress at the time of conception or during pregnancy can harm their baby, causing problems
such as miscarriage, is widely held amongst women. For example, 76% of women attending an antenatal clinic in
the USA, thought that a mother’s stress can negatively aect pregnancy outcome, with 35% believing that preg-
nant women should avoid upsetting things like violent programs or funerals16. Women in that study were inter-
preting the term “stress” in its psychological form i.e. they experience negative emotionality when their physical
or psychological well-being is threatened. Some doctors and midwives share this view although they know that
fetal chromosomal abnormality is present in around two thirds of cases of early pregnancy failure5. Other risk
factors for miscarriage include increased maternal age, obesity, caeine17, alcohol7, 18, 19, cigarette smoke20, 21 and
exercise22.
e diverse views held by women and healthcare professionals demonstrate the need for evidence in this vital
area of human wellbeing. Awareness of the eects of psychosocial stress could lead to improved strategies for
screening psychological support and changes in employment practices. is systematic review and meta-analysis
as therefore designed to investigate whether maternal psychological stress is associated with an increased risk of
miscarriage.
Results
Characteristics of included studies. e search strategy produced 1978 studies; of which, 1896 studies
with irrelevant title and/or abstract were excluded. Full text papers were retrieved for 82 studies and 74 studies
were further excluded in compliance with the criteria dened in methods section. A nal number of 8 studies
were included for the meta-analysis. Details of the study selection process were presented in Fig.1.
Characteristics of all studies included in the systematic review were shown as Table1. Of the 8 included stud-
ies, 4 are case-control studies, 3 are cohort studies, and 1 is a nested case-control study. e sample size in these
studies ranged from 96 to 6945. All of the 8 included studies reported odds ratio (OR) with 95% condence inter-
val (CI) as the outcome measure of the association between psychological stress and miscarriage1, 2, 7, 8, 10, 11, 13, 23.
Quality assessment and publication bias. Results from Newcastle-Ottawa Scale (NOS) indicated that
six of our included studies were rated7–9 stars whereas two studies were rated 6 stars (shown as Supplementary
TableS1). Seven studies achieved high comparability by adjusting for or matching on at least one of the following
confounders: maternal age, gestational age, pregnancy history, caeine and tobacco consumption, and social sup-
port. Begg’s rank correlation test (p = 0.536), Egger’s linear regression test (p = 0.170) and the funnel plot (shown
as Supplementary FigureS1) suggested that there was no signicant publication bias.
Eect size analysis. We evaluated for the outliers before starting the analysis, and found no extreme val-
ues. As presented in Fig.2, the overall pooled OR was 1.42 (95% CI 1.19 to 1.70) with moderate heterogeneity
(I2 = 35.6%), indicating that maternal psychological stress is signicantly associated with an increased risk of
miscarriage.
Figure 1. Flow diagram illustrating the selection procedure of relevant articles reporting on the association
between psychological stress and miscarriage.

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First
author, year
published Country Ye a r Design
Total
sample
size
Sample size
related to our
meta-analysis Exposures Reference
group Stress
measurement Eect
estimates
Matched
or adjusted
confounders NOS score
Bashour H1Syria 1999 Case-control 1098 1098 Psychological
stress
Women
delivered
normal
babies at
term
Questionnaires
(the cases and
controls were
interviewed by
trained midwives,
using a structured
questionnaire).
OR No 6
Boyles SH8USA 1995–1997 Nested case-
control 970 970 Life events
Women
maintained
their
pregnancy
A modied life
event inventory
(the participants
were questioned
about dierent
categories
of major life
events, including
death,debt burden,
legal problems,
and personal
relationships).
OR
Tobacco use,
cocaine use,
alcohol use,
prenatal care,
living with
the father
9
Brandt L,
199212 Denmark 1983–1985 Cohort 6945 4500 Work stress ND
A questionnaire
about stress-related
job characteristics
(a questionnaire
about the
information on
occupational
status, job title,
stress-related job
characteristics,
ergonomic work
load, exposure to
organic solvents,
exposure to video
display terminals,
lifestyle factors,
and health factors
during pregnancy).
OR Previous
pregnancies 6
Fenster L,
199522 USA 1990–1991 Cohort 3953 3953 Work stress
Women
maintained
their
pregnancy
An abbreviated
version of
instrument (the
instrument is
based on the
concepts that job
stress results from
high psychological
demands in
combination with
low control over
those demands
and that social
support at work
can ameliorate the
eects of stressful
work).
OR
Maternal
age, race,
pregnancy
history,
marital
status,
alcohol,
cigarette,
and caeine
consumption
9
Maconochie
N7UK 2001 Case-control 6719 5272 Work stress
Women
maintained
their
pregnancy
Questionnaires
(Stage1:a short
“screening”
questionnaire;
Stage2:a
more lengthy
questionnaire;
Stage3:a
shortened version
of the stage2
questionnaire,
containing only
the questions
relating to
biological, socio-
demographic and
behavioral details
of last pregnancy
which in relation
to the most recent
miscarriage).
OR
Year of
conception,
maternal
age, previous
miscarriage
and previous
live birth,
nausea
7
Continued

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Subgroup analysis was conducted to explore the sources of the heterogeneity (presented in Table2). ere was
positive association between psychological stress and miscarriage for the type of study (OR: 1.69 for case-control
studies; 1.33 for cohort and nested case-control study).However, the OR was statistically signicant only for
cohort and nested case-control studies (OR, 1.33; 95% CI, 1.14–1.54; P < 0.001). Moreover, substantial heter-
ogeneity (I2 = 62.1%) was reported for case-control studies, whereas for cohort and nested case-control study,
heterogeneity was low (I2 = 0.0%).
Exposures in the included studies were divided into three types: psychological stress, life events and work
stress. In terms of subgroup analysis based on exposure factors, we found that there was no heterogeneity
(I2 = 0.0%) between studies concerning work stress7, 13, 23. We found that work stress was signicantly associated
with an increased risk of miscarriage (OR, 1.27; 95% CI, 1.10–1.47; P = 0.001).
In subgroup analysis according to the types of controls, psychological stress was observed to have the greatest
impact on miscarriage when the comparison group consisted of women who had a live birth (OR, 2.82; 95% CI,
1.64–4.86; P < 0.001)1, 11.
We further categorized the eight included studies by NOS scores; heterogeneity decreased (I2 = 21.7%) when
the two lower quality studies were excluded1, 13. Aer removing the study not controlling for potential confound-
ing factors1, the pooled OR slightly decreased to 1.34 (95% CI 1.16 to 1.54; I2 = 9.2%). Results from sensitivity
analysis (i.e. excluding one study at a time) demonstrated that none of the studies caused signicant heterogeneity
compared with the rest, or strongly inuenced the results (shown as Supplementary FigureS2).
Discussion
e results of this meta-analysis support the belief that psychological stress before and during pregnancy is
associated with miscarriage. A view held by some medical practitioners and around three quarters of pregnant
women, but most oen dismissed by doctors and other health care professionals. Whilst chromosomal abnor-
malities underlie many cases of early pregnancy loss, the present results show that these psychological factors can
increase the risk by approximately 42%.
Psychological stress can inuence well-being through associated health-impairing behaviors and through
physiological responses which aect vascular, immune, metabolic or neuroendocrine functions24. e experience
of stress can originate in a wide range of circumstances and is dened as “any situation that overwhelms our abil-
ity to cope”25. erefore, the experience of stress varies, not only by an individual’s internal resources but also by
the social and material support which is available to them. Eects are dicult to assess as physiological responses
First
author, year
published Country Ye a r Design
Total
sample
size
Sample size
related to our
meta-analysis Exposures Reference
group Stress
measurement Eect
estimates
Matched
or adjusted
confounders NOS score
Meaney S2Ireland 2012 Cohort 417 417 Psychological
stress
Women
maintained
their
pregnancy
Questionnaires
and psychometric
tests (detailed
lifestyle
questionnaires,
including common
risk factors for
miscarriage, and
psychometric
tests, including
the 36-Item
Health Survey, the
Maternity Social
Support Scale,
the Revised Life
Orientation Test
and the Perceived
Stress Scale).
OR
ND (without
detailed
description
of the
adjusted
confounders)
7
Nelson DB10 USA 1999–2000 Case-control 326 326 Psychological
stress
Women
maintained
their
pregnancy
Perceived
Stress Scale;
Prenatal Social
Environment
Inventory; Index of
Spousal Abuse.
OR
Maternal age,
gestational
age, cigarette
and cocaine
use, prior
spontane ous
abortion
8
O’Hare T11 UK ND Case-control 96 96 Life events Women
giving birth
in hospital
Life Events and
Diculties
Schedule (the
women were
interviewed in
hospital).
OR
Age, marital
status,
social class
distribution,
woman’s or
partner’s
employment
status,
numbers
of children
or adults in
household,
obstetric
history
8
Table 1. Characteristics of all studies included in the systematic review. Note: NOS: Newcastle-Ottawa Scale;
OR: Odds Ratio; CI: condence interval; ND: Not Described; BMI: Body Mass Index.

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to stress vary with its intensity and duration, and are contingent on the genetic vulnerability and life history of
the aected individual26. For example, the degree of stress experienced in infancy and childhood have implica-
tions for the individual’s subsequent physiological response to stress25. Persistent stressors, which are perceived as
Figure 2. Meta-analysis of eight studies about the eect of maternal psychological stress on miscarriage. (note:
OR, odds ratio; CI, condence interval).
Factor Number of
studies OR (95% CI) P Va lu e I2(%), p Value*
Study type
Case-control 4 1.69 (0.99 to
2.88) 0.054 < 0.001 62.1, 0.048
Cohort + Nested case-control 41.33 (1.14 to
1.54) <0.001 0.0, 0.464
Exposures
Psychological stress 31.80 (1.01 to
3.19) 0.045 49.5, 0.138
Life events 21.85 (0.86 to
3.97) 0.116 58.1, 0.123
Work stress 31.27 (1.10 to
1.47) 0.001 0.0, 0.911
Control (Miscarriage vs)
Live birth 22.82 (1.64 to
4.86) <0.001 0.0, 0.765
Ongoing pregnancy 51.33 (1.12 to
1.57) 0.001 0.0, 0.485
Undened 1 1.28 (1.05 to
1.57) 0.016 —
Quality of studies
Low 21.73 (0.85 to
3.51) 0.130 77.6, 0.034
High 61.38 (1.13 to
1.70) 0.002 21.7, 0.270
With/without adjusted confounders
With 71.34 (1.16 to
1.54) <0.001 9.2, 0.358
Without 12.67 (1.39 to
5.12) 0.003 —
Table 2. Results of subgroup analyses. Note: OR: Odds Ratio; CI: condence interval; *p Value for
heterogeneity.

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uncontrollable, are the most damaging to physical and mental health25. However, as far as the authors are aware,
dierent classes of stress do not systematically elicit dierential physiological responses.
Because of the complexity of the mechanisms and the degree of individual variation in the response to stress-
ors, accurate measurement and comparisons of the experience of stress between individuals or groups of indi-
viduals is challenging. Psychological stress is also likely to co-occur with other psychological factors such as
anxiety and depression27 and may be chronic, acute or transient. A variety of relevant scales have been applied
in specic studies, for example, the Perceived Stress Scale28, the Pre-natal Social Environment Inventory29 and
Index of Spousal Abuse30 and others pertaining more generally to life events and stress symptoms, thus making
simple comparisons between studies dicult. Retrospective reports, both from focal groups and controls, may be
especially vulnerable to recall bias. Even a small indicator of prospective miscarriage, or history of previous mis-
carriage, is likely to produce stress, therefore confounding the direction of eects. In addition, many miscarriages
are managed at home and never reported7. Estimating miscarriage risk is further complicated by the diculty in
distinguishing the eect of stress from the eects of substances like alcohol, tobacco and caeine which are taken
to relieve stress.
Based on the considerations described above, interpretation of the ndings from this meta-analysis is subject
to some caution; the included studies also vary by the types of stress under focus and their prospective or retro-
spective design. e measures of stress vary between studies and do not always assess symptoms directly8, 13 and
some scales do not specify cut-o points between high and low stress (e.g. Perceived Stress Scale). Participant
self-reports are oen retrospective with an associated risk of recall bias, as authors generally acknowledge11, 13.
Whilst the NOS assessment provided a means to assess non-randomized studies, the scoring system itself is not
without its drawbacks and criticisms31. Study quality is also variable: some oer limited detail on assessment1, 7, 23,
on case selection procedures1 and on timing of assessment in relation to outcome1. erefore we propose the
need for high quality research into an association between the experience of stress in a variety of contexts and
miscarriage risk.
In the present meta-analysis, on sub analysis, six studies with higher quality showed a signicantly increased
miscarriage risk in women suering from psychological stress, but this was not found in the two studies with
lower NOS scores. An increased miscarriage risk was found on analysis of cohort and nested case-control but not
in case-control studies. For case-controls, the variability is also much larger (leading to an interval including 0).
e explanation for this possibly relates to the smaller number of studies (hence larger variability), or perhaps
the increased level of heterogeneity intrinsic in case-controls. However inclusion or exclusion of confounders did
not aect the results.
The association between psychological stress and miscarriage could result, at least in part, from activa-
tion of the hypothalamic-pituitary-adrenal axis by recruitment of hypothalamic neurones which secrete
corticotrophin-releasing hormone, increasing pituitary secretion of adrenocorticotrophic hormone secretion
and hence of adrenal cortisol32. is hormone has direct eects on decidual and placental metabolism but also
interacts with progesterone signalling32. Stress-related early pregnancy failure could also result from suppres-
sion of the hypothalamic-pituitary-gonadal axis32–35. Although generally considered a “stress hormone”, prolactin
production is decreased by stress in early pregnancy14, 32, 36. Since prolactin stimulates progesterone secretion, the
reduced levels will decrease progesterone synthesis37, 38. Stress also inhibits pituitary human chorionic gonadotro-
pin secretion compounding the eect of prolactin on progesterone release from the corpus luteum32, 39, 40. ese
mechanisms are relevant because progesterone activity is crucial for the maintenance of pregnancy; low levels in
early of gestation predicting miscarriage32. Among its multiple eects, this hormone contributes to the suppres-
sion of maternal immune response to the conceptus32.
In summary, the result of this systematic review and meta-analysis support the belief that psychological stress,
including life events and occupational stress, in pregnancy is associated with an increased risk of miscarriage and
indicates a critical need for further high quality research into the relationship between miscarriage and stress
experienced prior to pregnancy and in the early gestational period. Taken together with the serious morbidi-
ties already known to be associated with stress (pregnancy induced hypertension, preterm birth and low birth
weight), this nding also highlights the need to include a structured psychological assessment in early pregnancy
into routine antenatal care. is demonstration that stress contributes to early pregnancy failure could provide the
basis for novel and eective interventions in this eld. As far as we are aware there have been no randomized trials
of psychological therapy to prevent miscarriage, however Liddell, Pattison and Zanderigo41 reported a live birth
rate of 86% in women with recurrent (≥3) miscarriages who were enrolled into a program of emotional support,
compared to 33% in similar women who had no formal supportive care. Twenty-ve years later, the results of
our meta-analysis, highlight the potential to identify and treat psychological factors which contribute to adverse
pregnancy outcomes in the human.
Methods
Literature search. We searched the following databases for published articles and conference abstracts and
proceedings in consultation with a search methodologist, using the Medline search strategy below (with minor
modications to account for dierent controlled vocabularies and syntax): MEDLINE (Ovid, 1946 – June, 2016),
EMBASE (Ovid, 1980 – June, 2016), PsycINFO (Ovid, 1806 – June, 2016), CINAHL plus (EBSCO, 1937 – June,
2016), Maternity & Infant Care (Ovid, 1971 – June, 2016), and Conference Proceedings Citation Index - Science
(CPCI-S, 1990 – June, 2016). No language or date restrictions were applied.
Search strategy: (1) exp abortion, spontaneous/; (2) ((tubal or threatened or missed or spontaneous or recur-
rent or incomplete or inevitable or habitual or septic) adj abortion*).mp;(3) miscarr*.ti,ab;(4) ((pregnancy or
embryo) adj3 (loss or failure)).mp; (5) blighted ovum.mp;(6)misbirth.mp; (7) exp fetal death/; (8) ((fetal or foetal
or fetus or foetus or intrauterine or antepartum or prenatal) adj (death or resorption or mummication)).ti,ab;
(9)or/1–8; (10) exp stress, psychological/;(11)anxiety/; (12)exp stress disorders, traumatic/; (13) panic disorder/;

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(14)((stress* or distress* or anxiety or PTSD or panic) not oxidative).ti,ab;(15)life change events/; (16) (life adj2
event*).ti,ab;(17)or/10–16; (18) exp risk factors/or exp risk/; (19) risk*.ti,ab;(20) 18 or 19; (21) 9 and 17 and 20.
We only included case-control, cohort (retrospective or prospective) and nested case-control studies for this
review and for studies that reported similar or overlapping data, only the latest or those with a larger sample size
were considered.
Only studies that included women who had miscarriage (cases) and women with ongoing pregnancy or live
birth (controls) were considered for eligibility. Miscarriage or pregnancy loss occurring before the rst 22 weeks
gestation is dened as the natural death of an embryo or fetus before it is able to survive independently. e
following exclusion criteria were applied: (i) psychological stress was induced by miscarriage; (ii) psychological
stress and/or miscarriage-related data could not be retrieved; (iii) women had mental or psychological disorders
before pregnancy; (iv) no relevant comparison or available control were present; (v) psychological stress before
miscarriage (including anxiety, depression, life event, work/job stress, etc.) was not the only exposure factor.
ree authors(F.Q., Y.W., and Y.Z) independently reviewed and selected the articles in compliance with the
inclusion/exclusion criteria. Disagreement was resolved by consensus or arbitration.
Study coding. e following information was recorded or coded for each article: country, year, study design,
study population characteristics, total sample size, stress measurement methods of the studies, sample size related
to our meta-analysis and outcome data. All the reviewers cross-checked the extracted data repeatedly and any
disagreements were resolved by consensus. Authors were contacted for further details if necessary.
e quality of the included studies was assessed independently by three authors (F.Q., Y.W. and Y.Z.) using
NOS42. Dierent assessment items were applied to case-control and cohort studies, respectively. For each type of
study, eight criteria were used in the assessment, namely (1) for cohort studies: representativeness of exposed cohort,
selection of non-exposed cohort, ascertainment of exposure, outcome not present at baseline, comparability of
cohorts, assessment of outcome, sucient follow-up duration, and adequate follow-up; (2) for case-control studies:
adequate denition of cases, representativeness of cases, selection of controls, denition of controls, comparabil-
ity of cases and controls, ascertainment of exposure, same method of ascertainment for cases and controls, and
non-response rate. e total score for each study was obtained by summing up stars from each item. More than six
stars indicate good quality, whereas 5–6 stars indicate acceptable quality. Disagreements were resolved by consensus.
Meta-analysis procedures. Data were all presented as OR with 95% condence interval CI. We rstly eval-
uated for the outliers, dening as that the individual ORs were more than 2 standard deviations from the mean
of all the eect sizes, to see if replacement of extreme values is necessary. e statistical analysis was performed
in STATA 12.0 soware (StataCorp, College Station, USA). is provided eect sizes weighted by the sampling
variance, with a 95% condence interval and a measure of heterogeneity. DerSimonian and Laird random-eects
model was employed, as our eect sizes were assumed to be sampled from a large number of possible sample sizes.
Heterogeneity between studies was evaluated using homogeneity statistic (Q), which follows a Chi-square dis-
tribution with a degree of freedom of (n-1) where n is the total number of studies included43. I2 statistic was also
used to evaluate the heterogeneity, and results were deemed signicance in correspondence of a Chi-squared test
with p < 0.10 or I2 > 50%43, 44. Subgroup analysis was conducted to explore the sources of the heterogeneity, and
sensitivity analysis was performed to examine the eect of excluding each study. Publication bias was examined
through visual inspection of a funnel plot, and further evaluated by Begg’s and Egger’s tests45 (p < 0.05 indicated
a signicant publication bias).
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Author Contributions
P.H. conceived and designed the study. F.Q., J.B., R.M. and P.H. developed the search strategy for the identication
of articles and identied the articles. F.Q., Y.W., Y.Z., T.D. and G.B. acquired and analysed the data. F.Q., Y.W.,
Y.Z., J.B., B.T. and P.H. draed the manuscript. F.W. helped to revise the manuscript with all the other authors. All
authors approved the nal version of the manuscript.
Additional Information
Supplementary information accompanies this paper at doi:10.1038/s41598-017-01792-3
Competing Interests: e authors declare that they have no competing interests.
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