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com/ on March 20, 2020 at Western Sydney University. Protected
►► Additional material is
published online only. To view,
please visit the journal online
(http://d​ x.​doi.o​ rg/​10.​1136/​
archdischild-​2019-​318412).
1
Institute of Clinical Physiology
National Research Council,
Pisa, Italy
2
Fondazione Toscana Gabriele
Monasterio, Pisa, Italy
Correspondence to
Dr Silvia Baldacci, Institute of
Clinical Physiology National
Research Council, Pisa 56124,
Italy; ​silviab@​ifc.​cnr.​it
Received 18 October 2019
Revised 24 January 2020
Accepted 24 January 2020
© Author(s) (or their
employer(s)) 2020. No
commercial re-­use. See rights
and permissions. Published
by BMJ.
To cite: Baldacci S,
Santoro M, Coi A, et al.
Arch Dis Child Epub ahead of
print: [please include Day
Month Year]. doi:10.1136/
archdischild-2019-318412
Lifestyle and sociodemographic risk factors for
gastroschisis: a systematic review and meta-­analysis
Silvia Baldacci,1 Michele Santoro,1 Alessio Coi,1 Lorena Mezzasalma,1
Fabrizio Bianchi,1,2 Anna Pierini1,2
ABSTRACT
Background  Gastroschisis is strongly associated with
young maternal age. This association suggests the need
for further investigations on non-­genetic risk factors.
Identifying these risk factors is a public health priority in
order to develop prevention strategies aimed at reducing
the prevalence and health consequences in offspring.
Objective  To systematically assess and quantitatively
synthesise the available epidemiological studies to
evaluate the association between non-­genetic risk
factors and gastroschisis.
Methods  Literature from PubMed, EMBASE and Scopus
was searched for the period 1990–2018. Epidemiological
studies reporting risk estimates between lifestyle and
sociodemographic risk factors and gastroschisis were
included. Two pairs of reviewers independently extracted
information on study characteristics following Preferred
Reporting Items for Systematic Reviews and Meta-­
Analyses and MOOSE (Meta-­analysis Of Oservational
Studies in Epidemiology) guidelines. Relative risk (RR)
estimates were calculated across the studies and meta-­
analysis was performed using random-­effects model.
Results  We identified 58 studies. Meta-­analyses were
conducted on 29 studies. Maternal smoking (RR 1.56,
95% CI 1.40 to 1.74), illicit drug use (RR 2.14, 95% CI
1.48 to 3.07) and alcohol consumption (RR 1.40, 95% CI
1.13 to 1.70) were associated with an increased risk
of gastroschisis. A decreased risk among black mothers
compared with non-­Hispanic white mothers (RR 0.49,
95% CI 0.38 to 0.63) was found. For Hispanic mothers
no association was observed.
Conclusions  Exposure to smoking, illicit drugs and
alcohol during pregnancy is associated with an increased
risk of gastroschisis. A significantly decreased risk for
black mothers was observed. Further epidemiological
studies to assess the potential role of other
environmental factors are strongly recommended.
PROSPERO registration number  CRD42018104284.
Introduction
Gastroschisis is a rare congenital anomaly. The
International Clearinghouse for Birth Defects
Research and Surveillance defines gastroschisis as ‘a
congenital malformation characterised by visceral
herniation, usually through a right side abdom-
inal wall defect to an intact umbilical cord and not
covered by a membrane. It excludes aplasia or hypo-
plasia of abdominal muscles, skin-­covered umbilical
hernia, omphalocele’.1 This anomaly mainly occurs
as isolated (simplex); more rarely it is associated
with other intestinal pathologies (complex) or with
chromosomal syndromes.2 3
Baldacci S, et al. Arch Dis Child 2020;0:1–9. doi:10.1136/archdischild-2019-318412
Original research
What is already known on this topic?
►► Gastroschisis is a rare congenital anomaly
characterised by serious neonatal medical
complications and infant morbidity and
mortality, with an increasing prevalence
worldwide.
►► The aetiology of gastroschisis is still unknown
but the cause is likely to be multifactorial.
►► Several studies have previously demonstrated a
strong association between young maternal age
and gastroschisis.
What this study adds?
►► This study showed that maternal smoking,
illicit drug use and alcohol consumption during
pregnancy were associated with an increased
by copyright.
risk of gastroschisis.
►► For African-­American mothers, a lower risk
was observed while for Hispanic mothers no
association was found.
►► A healthy diet may reduce the risk of
gastroschisis while younger fathers and
socioeconomically disadvantaged mothers may
be at higher risk, but further studies are needed
to verify it.
Gastroschisis requires specialised surgical repair
at birth and it is characterised by serious neonatal
medical complications and infant morbidity and
mortality. Thus, gastroschisis represents a major
healthcare burden.4–6
The prevalence of gastroschisis ranges from 2 to 3
cases per 10 000 live births and several studies indi-
cate an increasing prevalence worldwide in the last
two decades.4 7–10 The prevalence of gastroschisis
also varies across geographic regions and between
race/ethnicity; recent studies estimate its current
prevalence up to 4–5 cases per 10 000 pregnancies
in high-­income countries.10–12
The aetiology of gastroschisis is still largely
unknown but the major hypothesis relies on multi-
factorial genesis involving gene-­ environment
interactions.
Several studies have previously identified a strong
association between young maternal age and gastro-
schisis.4 8–12 This consistentassociation suggests
that gastroschisis could be caused by the exposure
to environmental factors more frequent among
adolescent mothers.
   1

Original research
Three reviews reported several studies investigating the associ-
ation between several non-­genetic risk factors and gastroschisis,
but no factor, other than young maternal age, has been identi-
fied as steadily associated with gastroschisis.13–15 Moreover, the
interpretation of these findings is difficult, as they summarised
the available studies without providing a quantitative synthesis
of estimates. To date, only a meta-­ analysis by Hackshaw et
al reported a significant association between smoking and
gastroschisis.16
Identifying potential risk factors for gastroschisis is a public
health priority in order to develop prevention strategies aimed
at reducing the prevalence and health consequences in offspring.
Thus, we conducted a systematic review to summarise the
available epidemiological studies and meta-­ analysis to deter-
mine the associations of selected non-­genetic risk factors with
gastroschisis.
As 123 studies were found eligible, in this current study we
focused only on lifestyle (ie, cigarette smoking, illicit drugs use,
coffee and alcohol consumption, diet) and sociodemographic
factors (ie, race/ethnicity, paternal age, socioeconomic status).
Studies on exposure to environmental contaminants, medica-
tions use and physiological risk factors were included in another
article, currently in progress.
Methods
This systematic review followed the Preferred Reporting Items
for Systematic Reviews and Meta-­ Analyses17 and MOOSE
guidelines.18
Search strategy
We conducted literature search on PubMed, EMBASE and Scopus
electronic databases from 1 January 1990 to 18 July 2018 (date
of the last search). For databases search we used combinations of
the relevant medical subject heading and keywords related to the
exposure and the outcome of interest: [smoking OR “maternal
infection” OR “maternal illness” OR maternal age OR medica-
tion OR “body mass index” OR diet OR race OR alcohol OR
drug OR risk OR waste OR environment* OR occupation* OR
socioeconomic OR exposure] AND gastroschisis. The search
was restricted to English language. Reference lists of reviews and
relevant papers were hand-­searched to identify additional rele-
vant studies. Since all eligible studies were available, it was not
necessary to contact the authors.
Details of the search strategy are presented in the online
supplementary appendix 1.
Eligibility criteria
We included studies if they met the following criteria: a) were
population-­ based studies with case-­ control, cohort or cross-­
sectional design; b) assessed exposure to lifestyle, physiological,
sociodemographic and environmental risk factors; c) assessed
risk factors exposure at individual level; d) reported risk esti-
mates on the association between gastroschisis and at least one
risk factor.
We excluded in vitro experimental studies, in vivo and ex vivo
studies, letters, reviews, editorials, reports, comments, docu-
ments issued by regulatory bodies and book chapters. We also
excluded ecological studies, since they assessed risk factor expo-
sure at aggregate level rather than at individual level. Moreover,
as maternal age has been demonstrated consistently associated
with gastroschisis, studies which investigated only maternal age
were not included.
2 Baldacci S, et al. Arch Dis Child 2020;0:1–9. doi:10.1136/archdischild-2019-318412
Arch Dis Child: first published as 10.1136/archdischild-2019-318412 on 12 February 2020. Downloaded from http://adc.bmj.com/ on March 20, 2020 at Western Sydney University. Protected
Study selection
Two pairs of reviewers independently (SB and AC; MS and
LM) screened each study by title and abstract to assess confor-
mity with selection criteria and identify potentially relevant
studies. Agreement regarding potential relevance was reached
by consensus. The articles potentially eligible were examined
in full-­text against the selection criteria, independently by the
reviewers, to reach a final list of studies to be included in the
review. Disagreements were resolved by discussion between
reviewers.
Data extraction
Data on the following characteristics were extracted from
eligible studies independently by each reviewer using a stan-
dardised extraction form: first author, year of publication,
country of study, study design, study duration, sample size, data
collection methods, description of exposure, risk factors under
study, description of participants, estimates of risk (ie, OR, risk
ratio, HR, prevalence ratio) and associated 95% CI and p value
(when available), adjusted or unadjusted effect measures, details
of the variables/confounders that were adjusted for, study limita-
tions and quality assessment score.
Quality assessment
Methodological quality assessment of cohort and case-­control
studies was performed independently by each reviewer using
the Newcastle-­Ottawa Scale (NOS)19 illustrated in the online
supplementary appendix 2. An adapted NOS was used to eval-
uate the quality of cross-­sectional studies (online supplementary
appendix 2).20
by copyright.
Studies scored from 7 to 9 stars (up to 10 stars in the case
of cross-­sectional studies) were considered as of good quality,
studies that scored 6 or 5 stars as medium quality and studies
that scored <5 as poor quality.
Statistical analyses
Meta-­analysis was conducted only if more than five studies inves-
tigating the same risk factor were available. Furthermore, only
studies adjusted at least for maternal age and with a NOS score
>4 were included. After applying these criteria, meta-­analyses
were feasible only for studies investigating the association of
gastroschisis with maternal smoking, illicit drug use, alcohol
consumption and race/ethnicity.
Since gastroschisis is a rare event, the OR is a commonly
applied measure to approximate relative risk (RR). The OR and
95% CI of the included studies were pooled and summary effect
estimates were calculated using a random-­effects model. The
95% prediction interval (PI) was computed in addition to the CI.
An I2 test was used to measure heterogeneity between studies.21
The possible publication bias was evaluated by Egger’s test and
Peters’ test (significance level was set at p<0.05).22 23
In order to assess the robustness of the results, sensitivity anal-
yses were performed including/excluding studies on the basis of
the following criteria: study design, publication year, NOS score
and study weight (ie, excluding cross-­sectional studies or the
study with the highest weight, selecting only high-­quality studies
with NOS >6 or studies published after 1999).
Statistical meta-­analyses were performed using STATA V.13.0
(StataCorp, College Station, Texas, USA).
Results
Of 3005 citations identified, a total of 256 articles were selected
for full-­text reading. Of these, 123 studies met the inclusion

Figure 1  Literature search using Preferred Reporting Items for
Systematic Reviews and Meta-­Analyses flow diagram.
criteria (figure 1). Fifty-­ eight studies11 24–80 concerning life-
style and sociodemographic risk factors were included in the
systematic review (online supplementary tables S1-­S2). Twenty-­
nine studies11 29 32 34 37 38 40 41 46 48–51 53–55 59 60 62–66 69 73–75 79 80
were available for meta-­analyses comprising 21 994 cases of
gastroschisis. Among them, four studies were adjusted only for
maternal age or for maternal age and body mass index (BMI).
In nine studies, adjustment variables included at least one life-
style habits or sociodemographic factors. Sixteen studies were
also adjusted for other additional factors (eg, medications use
and maternal physiological conditions). A detailed description of
the included studies is provided in online supplementary tables
S1-­S2.
In 28 studies, cases were ascertained in live births infants;
in 24 studies cases included live births, stillbirths and elective
terminations of pregnancy. In five studies, cases were ascertained
in live births and stillbirths, and one study included live births
and elective terminations of pregnancy only.
Based on NOS quality assessment score, 40 studies were classi-
fied as good, 16 studies as medium and 2 as poor quality (online
supplementary tables S3-­S4 a, b).
Studies on lifestyle risk factors11 24–67 mainly investigated
maternal smoking, illicit drug use, maternal alcohol consump-
tion and maternal nutrition. Few studies investigated other
maternal lifestyle habits (online supplementary table S1).
Studies on sociodemographic risk
factors27 29 30 32 34 40 42 44 48 50 52 53 55 56 60 66 68–80 were mainly
focused on maternal race/ethnicity, education level and
paternal age. Maternal marital status, place of residence,
family income, change in paternity and maternal or paternal
occupation were also investigated (online supplementary table
S2).
Baldacci S, et al. Arch Dis Child 2020;0:1–9. doi:10.1136/archdischild-2019-318412
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Original research
Lifestyle risk factors
Maternal gestational smoking
Twenty-­one studies11 29 32 34 37 38 40 41 46 48–50 53–55 60 62–66 were
included in the meta-­analysis providing data on 13 483 cases
(figure 2). Pooled data showed that maternal smoking was
significantly associated with the risk of gastroschisis (random-­
effects RR 1.56, 95% CI 1.40 to 1.74, 95% PI 1.10 to 2.21).
Heterogeneity among the studies was observed (I2=56.0%) with
no evidence of publication bias (online supplementary table S5).
Sensitivity analyses did not change our pooled estimates.
Among the studies not included in the meta-­ analysis, six
studies reported unadjusted data.30 43 45 52 56 58 Three studies
showed an increased risk among exposed mothers27 42 44 (online
supplementary table S1).
Maternal gestational illicit drug use
Seven studies were included in the meta-­analysis, providing data
for 2366 cases (figure 3A).11 32 34 53 59 60 63 Pooled data showed
that maternal gestational illicit drug use was significantly asso-
ciated with the risk of gastroschisis (random-­effects RR 2.14,
95% CI 1.48 to 3.07, 95% PI 0.77 to 5.99). Heterogeneity
among the studies was observed (I2=60.6%) with no evidence
for publication bias (online supplementary table S5). Sensitivity
analyses did not change our pooled estimates.
Among the studies not included in the meta-­analysis, one study
presented unadjusted data.31 One study showed an increased
risk among exposed mothers,27 three studies39 46 48 reported no
significant association except for marijuana smoking (online
supplementary table S1).
by copyright.
Maternal gestational alcohol consumption
Eight studies were included in the meta-­analysis, providing data
for 3429 cases (figure 3B).11 34 48 50 51 53 63 66 Pooled data showed
that maternal alcohol consumption was significantly associated
with the risk of gastroschisis (random-­effects RR 1.39, 95% CI
1.13 to 1.70, 95% PI 0.82 to 2.35). Heterogeneity among the
studies was observed (I2=57.3%) with no evidence for publi-
cation bias (online supplementary table S5). Sensitivity analyses
did not change our pooled estimates.
Three studies that were not included in the meta-­ analysis
presented unadjusted data30 52 56 (online supplementary table
S1).
Maternal nutrition
Two studies suggested that a better diet quality during pregnancy
or an increased fruit or vegetable intake were associated with a
statistically significant decreased risk of gastroschisis.35 50 In one
study, no significant association was observed.36 Three studies
reported an increased risk of gastroschisis with low levels of
protein, zinc, BMI, α-carotene and total glutathione, and with
high levels of nitrosamines.46 47 59 One study showed a mild asso-
ciation with higher maternal intake of total energy and fat.57 One
study suggested a weak association with a lower phytoestrogen
intake.61 In one study, the exposed group was not large enough
for consistent risk estimation67 (online supplementary table S1).
Other maternal lifestyle habits
Three studies28 50 66 showed inconclusive evidence of an associa-
tion between maternal caffeine intake and gastroschisis.
Two studies25 33 found an increased risk in mothers having a
shower for >15 min or taking hot baths. One study observed no
significant association between swimming pool use and the risk
of gastroschisis.24 One study showed a decreased risk associated
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Original research
Figure 2  Forest plot (random-­effects analysis) showing association between maternal smoking during pregnancy and risk of gastroschisis.
with increased water consumption26 (online supplementary table
S1).
Demographic risk factors
Maternal race/ethnicity
Eleven studies were included in the meta-­ analysis, providing
data for 8636 cases (figure 4A).29 34 48 54 55 69 73–75 79 80 Pooled
data showed that black mothers have a lower risk to have a child
with gastroschisis (random-­ effects RR 0.49, 95% CI 0.38 to
0.63, 95% PI 0.21 to 1.15). Heterogeneity among the studies
was observed (I2=81.1%) with no evidence for publication
bias (online supplementary table S5). Sensitivity analyses did
not change our pooled estimates. For Hispanic white mothers,
pooled data revealed no significant association (random-­effects
RR 1.00, 95% CI 0.85 to 1.18, 95% PI 0.59 to 1.72, figure 4B).
Among studies not included in the meta-­analysis, three studies
reported unadjusted data.40 44 56 One study showed a lower risk
among the offspring of black and Hispanic teenager mothers.27
One study reported a significantly higher risk among the
offspring of non-­Hispanic white and Hispanic young mothers
compared with blacks42 (online supplementary table S2).
4 Baldacci S, et al. Arch Dis Child 2020;0:1–9. doi:10.1136/archdischild-2019-318412
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by copyright.
Paternal age
Seven studies found that younger fathers were at a higher risk
of gastroschisis.29 53 68 70 71 76 80 Conversely, one study42 showed
a decreased risk. One study reported unadjusted data52 (online
supplementary table S2).
Socioeconomic status risk factors
Education
Two studies suggested that a high level of education is associated
with gastroschisis.27 42 Eight studies showed no significant asso-
ciation between maternal or parental education level and the risk
of gastroschisis.34 53 55 60 66 69 72 80 Three studies reported unad-
justed data44 52 56 (online supplementary table S2).
Maternal marital status
Two studies reported an increased risk of gastroschisis for unmar-
ried women.32 55 One study showed a significantly decreased risk
compared with unmarried young mothers.42 Conversely, one
study60 observed a higher risk for married mothers. One study
did not adjust for maternal age40 (online supplementary table
S2).
 Arch Dis Child: first published as 10.1136/archdischild-2019-318412 on 12 February 2020. Downloaded from http://adc.bmj.com/ on March 20, 2020 at Western Sydney University. Protected
Original research

by copyright.

Figure 3  (A) Forest plot (random-­effects analysis) showing association between maternal illicit drug use during pregnancy and risk of gastroschisis.
(B) Forest plot (random-­effects analysis) for maternal alcohol consumption during pregnancy and risk of gastroschisis.

Baldacci S, et al. Arch Dis Child 2020;0:1–9. doi:10.1136/archdischild-2019-318412 5

 Arch Dis Child: first published as 10.1136/archdischild-2019-318412 on 12 February 2020. Downloaded from http://adc.bmj.com/ on March 20, 2020 at Western Sydney University. Protected
Original research

by copyright.

Figure 4  (A) Forest plot (random-­effects analysis) showing association between black mothers and risk of gastroschisis. (B) Forest plot (random-­
effects analysis) showing association between Hispanic mothers and risk of gastroschisis.

6 Baldacci S, et al. Arch Dis Child 2020;0:1–9. doi:10.1136/archdischild-2019-318412


Maternal residence
Two studies29 55 reported no significant association, one study
showed a higher risk for infants of mothers with non-­urban
residence.79 One study did not adjust for maternal age40 (online
supplementary table S2).
Income
One study found a decreased risk among women living in
households with an annual income >US$50 000.48 Two studies
observed a higher risk of gastroschisis among offspring of
mothers living in a more disadvantaged neighbourhood.54 60 One
study34 reported no significant association. Two studies reported
unadjusted data52 56 (online supplementary table S2).
Occupation
One study showed no significant association between parental
occupation status and the risk of gastroschisis.50 Two studies
reported unadjusted data40 52 (online supplementary table S2).
Change in paternity
One study showed that change in paternity is associated with
increased risk for gastroschisis.30 In two studies, no significant
association was observed.50 78 One study reported unadjusted
data52 (online supplementary table S2).
Discussion
Our systematic review included 58 studies. Our meta-­analyses,
conducted on 29 studies and over 21 994 gastroschisis cases,
showed that maternal smoking, illicit drug use and alcohol
consumption during pregnancy are associated with the risk of
gastroschisis in the offspring. Furthermore, meta-­analysis results
indicated a decreased risk of gastroschisis among black mothers
compared with white, non-­Hispanic mothers. Among Hispanic
mothers, no significant association was detected. Sensitivity
analyses supported the robustness of these results.
Our systematic review suggested that maternal healthy diet
and being married may be protective factors for gastroschisis.
Conversely, younger fathers and socioeconomically disadvan-
taged mothers may be at higher risk of having a newborn with
gastroschisis. Although current literature is not sufficient to
draw conclusions on the relationship between maternal nutri-
tion, paternal age and socioeconomic status and the risk of
gastroschisis, some studies supported their role as confounding
or interaction factors. To date, few studies have evaluated if
socioeconomic disparities may be associated with the risk of
gastroschisis, thus the epidemiological evidence is still limited.
An important consideration is that lower socioeconomic status
is associated with health-­damaging behavioural habits such as
heavy smoking, increased alcohol consumption and poor health-
care. Overall, these results support the role of socioeconomic
factors as determinants of health and have implications for a
health programme and policy.
To the best of our knowledge, this is the first meta-­analysis
of several potential risk factors for gastroschisis. The greater
number and the increased quality of included studies, compared
with a previous meta-­analysis16 on smoking, is the main strength
of our results.
Previous epidemiological and experimental studies have
suggested that tobacco can have a teratogenic and carcino-
genic effect on germ cells.81 82 Thus, tobacco toxin may lead to
abnormal development of the ventral body wall during the fetal
growth. Moreover, nicotine produces vasoconstriction, so it may
be implied in the gastroschisis pathogenic process.64
Baldacci S, et al. Arch Dis Child 2020;0:1–9. doi:10.1136/archdischild-2019-318412
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Original research
Our meta-­analysis shows that recreational drug use is asso-
ciated with gastroschisis. Animal studies have demonstrated
the teratogenic effects of carbon monoxide, one of the most
important components of marijuana.83 84 The most psychoactive
agent in marijuana interferes with cellular growth, morphology,
in exchange pathways, leading to the apoptosis in placental
development.85 Human and animal studies have suggested that
prenatal cocaine use might affect embryonic and fetal devel-
opment through vasoconstriction in maternal and fetal tissues,
leading to hypoperfusion and hypoxia.86 87
Our meta-­analysis shows that maternal alcohol consumption
is associated with gastroschisis. It is well known that prenatal
alcohol exposure may be harmful to the fetus leading to a wide
range of lifelong adverse birth outcomes known as fetal alcohol
spectrum disorders.88–90 WHO has recently published an over-
view of the literature on interventions to prevent alcohol expo-
sure during pregnancy addressed to pregnant and non-­pregnant
women.91
Our meta-­ analysis shows a decreased risk among black
mothers compared with white non-­Hispanic mothers. Among
Hispanic mothers, no association was evidenced. The observed
prevalence variations might account for different genetic suscep-
tibility to specific environmental factors across ethnic groups,
even if the relationship between race and ethnicity and the risk
of gastroschisis is still largely debated.4 8 10
Our meta-­ analyses were performed on several multistate
studies with large sample size and expansive geographic scale that
allow ample statistical power to investigate several risk factors
and provide the opportunity to identify variations between
surveillance areas. Moreover, most of the studies included in the
by copyright.
meta-­analyses are based on cases identified from registries with
an active surveillance system and the inclusion of live births,
fetal deaths and elective terminations of pregnancy provided a
more complete case ascertainment. Additionally, we conducted
sensitivity analyses, which suggested that our results were not
influenced by differences in study design, weight or period of
study publication.
Our study hasfew limitations. Our review was limited to
studies that were published in English and the studies included
in our meta-­analyses varied in terms of adjustment variables,
study design, time and geography. Furthermore, all the included
studies are observational and their findings may still be influ-
enced by problems of residual confounding. Another limitation
with case-­control studies is the potential for recall bias. More-
over, exposure misclassification may occur in self-­ reported
exposure assessment. Finally, the majority of the studies included
in our meta-­analyses was conducted in the USA and may reflect
country-­specific maternal lifestyle habits as well as specific socio-
demographic characteristics.
Conclusion
Meta-­ analyses findings indicate that maternal smoking, illicit
drug use and alcohol consumption during early pregnancy are
associated with an increased risk of gastroschisis in offspring.
These findings strengthen the importance that prevention strat-
egies are focused primarily on tackling behavioural risk factors.
Moreover, our systematic review highlights that beyond the
effects of conventional behavioural risk factors, further investi-
gations of potential associations between gastroschisis and other
environmental factors and gene-­ environment interactions are
needed.
Contributors  SB, MS, AC, LM and AP contributed to the writing of the study
protocol. SB conceived the study, conducted the literature search, screened and
7

Original research
reviewed the studies, extracted the data, carried out a quality assessment of the
studies and prepared the first draft of the manuscript. MS and AC carried out the
statistical analyses, screened and reviewed the studies, extracted the data, carried
out a quality assessment of the studies. LM screened and reviewed the studies,
extracted the data and carried out a quality assessment of the studies. FB and AP
supervised data collection. All authors were involved in revising the manuscript and
approved the final version.
Funding  The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-­for-­profit sectors.
Competing interests  None declared.
Patient consent for publication  Not required.
Provenance and peer review  Not commissioned; internally peer reviewed.
Data availability statement  Data sharing not applicable as no datasets
generated and/or analysed for this study. The study is a systematic review, thus data
sharing is not applicable.
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