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Physical activity and the risk of preterm birth: a systematic
review and meta-analysis of epidemiological studies
Dagfinn Aune1,2, Sabrina Schlesinger2, Tore Henriksen3, Ola Didrik Saugstad4, Serena
Tonstad5
Affiliations
1 Department of Public Health and General Practice, Faculty of Medicine, Norwegian
University of Science and Technology, Trondheim, Norway
2 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College
London, London, United Kingdom
3 Section of obstetrics, Division of Obstetrics and Gynaecology, Rikshospitalet, Oslo
University Hospital, Oslo, Norway
4 Department of Pediatric Research, Rikshospitalet, Oslo University Hospital, University of
Oslo, Oslo, Norway
5 Department of Preventive Cardiology, Oslo University Hospital, University of Oslo, Oslo,
Norway
Correspondence to: Dagfinn Aune, Department of Epidemiology and Biostatistics,
School of Public Health, Imperial College London, St. Mary's Campus, Norfolk Place,
Paddington, London W2 1PG, UK.
Telephone: +44 20 7594 8478
Fax: +44 20 7594 0768
E-mail: [email protected]
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Short title: Physical activity and preterm birth – a meta-analysis23
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Abstract
Background: Physical activity has been inconsistently associated with risk of preterm birth,
and the strength of the association and the shape of the dose-response relationship needs
clarification.
Objectives: To conduct a systematic review and dose-response meta-analysis to clarify the
association between physical activity and risk of preterm birth.
Search strategy: PubMed, Embase and Ovid databases were searched for relevant studies up
to February 9th 2017.
Selection criteria: Studies with a prospective cohort, case-cohort, nested case-control, or
randomized study design were included.
Data collection and Analysis: Data were extracted by one reviewer and checked for
accuracy by a second reviewer. Summary relative risks (RRs) were estimated using a random
effects model.
Main Results: Fourty one studies (43 publications) including twenty randomized trials, and
21 cohort studies were included. The summary RR for high vs. low activity was 0.87 (95%
CI: 0.70-1.06, I2=17%, n=5) for physical activity before pregnancy, and it was 0.86 (95% CI:
0.78-0.95, I2=0%, n=30) for early pregnancy physical activity. The summary RR for a 3 hour
per week increment in leisure-time activity was 0.90 (95% CI: 0.85-0.95, I2=0%, n=5). There
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was evidence of a nonlinear association between physical activity and preterm birth,
pnonlinearity<0.0001, with the lowest risk observed at 2-4 hours per week of activity.
Conclusion: This meta-analysis suggests that higher leisure-time activity is associated with
reduced risk of preterm birth. Further randomized controlled trials with sufficient frequency
and duration of activity to reduce the risk and with larger sample sizes are needed to
conclusively demonstrate an association.
Keywords: Physical activity, preterm birth, meta-analysis
Word count abstract: 250
Word count text: 3408
Tweetable abstract: Physically active compared to inactive women have an 18-22%
reduction in the risk of preterm birth.
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Introduction
In 2012 an estimated 15 million preterm births (defined as birth before 37 completed weeks
of gestation) occurred worldwide 1. Preterm births account for approximately 29% of the 3.6
million neonatal deaths worldwide 2 and is an important risk factor for neonatal morbidity
including breathing problems, infections and jaundice 2. Babies born preterm have also been
found to have a greater risk of cognitive and developmental disabilities, and chronic diseases
in adulthood. Apart from tobacco smoking which is an established risk factor, maternal
obesity has also been associated with increased risk of preterm birth, particularly very
preterm births in several studies 3;4, and this was confirmed in a recent meta-analysis also
found an increased risk of preterm births among overweight and obese pregnant women 5.
Physical activity is an important determinant of overweight and obesity 6 and reduces
the risk of excess gestational weight gain 7-10, and has been associated with reduced risk of
other obesity-related pregnancy complications including gestational diabetes 11, and
preeclampsia 12. Several randomized trials 13-31, cohort studies 32-54and case-control studies 55-63
have investigated the association between physical activity and preterm births, but the results
have been inconsistent, with some studies showing significant inverse associations 32-34;55;56;59,
while other studies reported no significant associations 13-19;21;23;24;26-31;35;37-39;41-43;45;57;58;63-65.
Several of the studies showed non-significant inverse associations 19;24;30;35;38;39;41;42, but may
have been limited by low statistical power. However, even among the studies that reported
inverse associations there was considerable variability in the strength of the associations
reported with some studies reporting a 15-20% reduction in risk with high physical activity
35;36;38;42, while other studies reported up to a 40-80% reduction in risk 19;32-34;41;46;55;56;59. It is
possible that differences in the timing, amount, type and intensity of physical activity or
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different degrees of adjustments for confounders or other study characteristics could explain
some of this variation in the results. To clarify whether physical activity before or during
pregnancy is associated with the risk of preterm birth we conducted a systematic review and
meta-analysis of epidemiological studies on the subject. We were particularly interested in
clarifying the dose-response relationship between physical activity, including total, leisure-
time and occupational physical activity, and preterm birth, potential confounding, and other
study characteristics that could explain the observed heterogeneity in the results.
Methods
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Search strategy
We searched the PubMed and Embase databases up to 15th of December 2014 for cohort
studies (including prospective cohorts, case-cohorts and nested case-control studies within
cohort studies), and randomized trials of physical activity (including total, leisure-time, and
occupational physical activity) and risk of preterm birth (defined as birth before 37 completed
weeks of gestation) and the searches were later updated to the 9th of February 2017. We used
the following search terms: (“physical activity” OR “leisure activity” OR exercise OR sports
OR walking OR biking OR running OR fitness OR “exercise test” OR inactivity OR
sedentary) AND (“preterm birth” OR preterm OR “premature birth” OR prematurity OR
“preterm labor” OR “premature labor” OR “preterm delivery” OR “premature delivery” OR
“premature labor” OR “birth outcomes” OR “birth outcome” OR “pregnancy outcomes” OR
“pregnancy outcome”) AND (“case-control” OR retrospective OR cohort OR cohorts OR
prospective OR longitudinal OR “follow-up” OR “cross-sectional” OR trial OR “relative
risk” OR “hazard ratio” OR “odds ratio” OR odds OR regression). We also searched the
reference lists of previous reviews of the subject and of the studies included in the analysis
for any further studies. DA conducted the initial screening of all the records, and DA and SS
conducted the screening of the potentially relevant records in duplicate. Any discrepancies
between the reviewers were resolved by discussion.
Study selection and assessment of study quality and risk of bias
To be included, the study had to have a prospective cohort, case-cohort, nested case-control
(within a cohort), or randomized study design and to investigate the association between
physical activity and risk of preterm birth and be published in English language. Abstracts,
grey literature and unpublished studies were not included. Estimates of the relative risk
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(hazard ratio, risk ratio, odds ratio) had to be available with the 95% confidence intervals and
for the dose-response analysis, a quantitative measure of activity level and the total number
of cases and person-years or participants had to be available in the publication or on request
from the authors. For cohort studies we included only studies that provided risk estimates that
were adjusted for at least one confounder, while we included all randomized trials as they are
considered adjusted due to the randomization process. We calculated the relative risks and
95% confidence intervals for the randomized trials based on the distribution of cases and non-
cases when risk estimates were not provided in the paper using standard formula 66. We
included studies on total and all subtypes of leisure-time physical activity, but for
occupational activity we only included studies of total occupational activity and walking.
Studies of physically demanding work, such as prolonged standing, heavy lifting, physical
exertion, occupational fatigue and demanding posture were excluded as they have been
summarized in a recent meta-analysis 67. A list of excluded studies and the reason for
exclusion is provided in Table S1.
Data extraction
The following data were extracted from each study in duplicate by DA and SS: The first
author’s last name, publication year, country where the study was conducted, the study name,
follow-up period, sample size, gender, age, number of cases, exposure, physical activity
level, RRs and 95% CIs for the each physical activity level and variables adjusted for in the
analysis.
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Risk of bias and study quality assessment
We used the Cochrane Collaboration's tool to assess the risk of bias of the randomized trials
68. The risk of bias assessment was based on random sequence generation, allocation
concealment, blinding of participants and personnel, blinding of outcome assessment,
incomplete outcome data, selective reporting, and other biases. The quality of the cohort
studies was assessed using the Newcastle-Ottawa scale 69 which ranks studies based on the
selection (representativeness of the exposed cohort, selection of the non-exposed cohort,
ascertainment of exposure, demonstration that the outcome was not present at the start of the
study), comparability (adjustment for confounding factors), and the outcome (outcome
assessment, long enough follow-up, adequacy of follow-up of cohorts).
Statistical methods
We used random effects models 70 to calculate summary RRs and 95% CIs for the highest vs.
the lowest level of physical activity and for the dose-response analysis. The average of the
natural logarithm of the RRs was estimated and the RR from each study was weighted by the
inverse of its variance and was then un-weighted by a variance component which corresponds
to the amount of heterogeneity in the analysis. A two-tailed p<0.05 was considered
statistically significant.
We used the method described by Greenland and Longnecker 71 for the linear dose–
response analysis and computed study-specific slopes (linear trends) and 95% CIs from the
natural logs of the RRs and CIs across categories of physical activity. The method requires
that the distribution of cases and person-years or non-cases and the RRs with the variance
estimates for at least three quantitative exposure categories are known. We estimated the
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distribution of cases or person-years in studies that did not report these, but reported the total
number of cases/person-years 72. The median or mean physical activity level in each category
was assigned to the corresponding relative risk for each study. For studies that reported the
physical activity by ranges of activity we estimated the midpoint for each category by
calculating the average of the lower and upper bound. When the highest or lowest category
was open-ended we assumed the open-ended interval length to be the same as the adjacent
interval. We examined a potential nonlinear dose-response relationship between physical
activity and preterm birth by using restricted cubic splines with 3 knots at 10, 50 and 90%
percentiles of the distribution which was combined using multivariate meta-analysis 73;74. A p-
value for nonlinearity was obtained by testing that the coefficient of the second spline term
was equal to zero 75.
Heterogeneity between studies was assessed by the Q test and I2 76. A p-value for the
Q test <0.05 indicated statistically significant heterogeneity. I2 is the amount of total variation
that is explained by between study variation. I2 values of approximately 25%, 50% and 75%
are considered to indicate low, moderate and high heterogeneity, respectively. Sources of
heterogeneity was explored in subgroup analyses stratified by study design, geographic
location, study quality (cohorts), risk of bias (randomized trials), number of cases as an
indicator of study size, and adjustment for confounding factors (including age, education,
income, drug use, smoking, alcohol, parity, hypertension, diabetes and BMI) and meta-
regression analyses were used to test for heterogeneity between subgroups.
Publication bias was assessed with Egger’s test 77 and the results were considered to
indicate publication bias when p<0.10. We conducted sensitivity analyses excluding one
study at a time to ensure that the results were not simply due to one large study or a study
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with an extreme result. The statistical analyses were conducted using Stata, version 12.0
software (StataCorp, College Station, TX, USA).
Results
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Out of a total of 2053 records identified by the search 41 studies (43 publications) were
included in the meta-analysis of physical activity and preterm birth, including twenty
randomized trials 13-21;23-31;64;65, and twenty one cohort studies (23 publications) 32-54 (Table S2-
S3, Figure 1). Fourteen studies were from Europe, fifteen studies were from North America,
5 from South America, 4 from Asia, and 4 from Australia and New Zealand (Table S2-S3).
The definition of preterm birth was consistent across studies (<37 weeks) (Table S2-S3).
Leisure-time physical activity before pregnancy
Five cohort studies 36;41;46;47;78 were included in the analysis of prepregnancy leisure-time
physical activity and the risk of preterm birth including 633 cases and 12 723 participants.
The summary RR for high vs. low prepregnancy physical activity was 0.87 (95% CI: 0.70-
1.06, I2=16.5%, pheterogeneity=0.31, n=5) (Figure 2a). Because of differences in the way the data
were reported, it was not possible to conduct dose-response analyses.
Leisure-time physical activity during pregnancy
Twenty randomized trials 13-20;23-31;64;65;79, and ten cohort studies 33;34;37-39;41;42;44;45;47 were
included in the analysis of leisure-time physical activity during pregnancy and the risk of
preterm birth and included >8 621 cases among 171 595 participants. The summary RR for
high vs. low physical activity in early pregnancy was 0.86 (95% CI: 0.78-0.95, I2=28%,
pheterogeneity=0.12) (Figure 3). The summary RR was significant for cohort studies (summary
RR=0.84, 95% CI: 0.73-0.96, I2=21.7%, pheterogeneity=0.24), but not for randomized clinical
trials (summary RR=0.91, 95% CI: 0.72-1.15, I2=0%, pheterogeneity=0.76), however, there was no
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between subgroup heterogeneity, p=0.61. There was no evidence of publication bias with
Egger’s test, p=0.89 and Begg’s test, p=0.63 (Figure S1). The summary RR ranged from 0.84
(95% CI:0.75-0.94) when the study by Bird et al 47 was excluded to 0.87 (95% CI: 0.79-0.97)
when the study by Mishra et al 80 was excluded (Figure S2). Five studies 38;41;42;45;81 were
included in the dose-response analysis, and the summary RR was 0.90 (95% CI: 0.85-0.95,
I2=0%, pheterogeneity=0.67) per 3 hours per week increase in leisure-time activity (Figure 2b) and
0.84 (95% CI: 0.76-0.91, I2=0%, pheterogeneity=0.67) for a 5 hour per week increase in leisure-
time activity during pregnancy. There was evidence of a nonlinear association between
physical activity during pregnancy and preterm birth, pnonlinearity<0.0001, with a reduction in
risk up to 2-4 hours per week of activity, but no further reductions in risk with higher levels
of activity (Figure 2c, Table S4).
Moderate physical activity during pregnancy
Two cohort studies 39;44 were included in the analysis of moderate physical activity during
pregnancy and preterm birth and included 349 cases and 6 581 participants. The summary RR
for high vs. low moderate intensity physical activity was 0.78 (95% CI: 0.49-1.23, I2=73.9%,
pheterogeneity=0.009) (Figure 4a).
Vigorous physical activity during pregnancy
Two cohort studies 35;41 were included in the analysis of vigorous physical activity during
pregnancy and preterm birth and included 301 cases and 3 346 participants. The summary RR
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for high vs. low vigorous intensity activity was 0.36 (95% CI: 0.04-3.09, I2=66.6%,
pheterogeneity=0.08) (Figure 4b).
Total physical activity during pregnancy
Four cohort studies 32;41;54;82 were included in the analysis of total physical activity (including
leisure-time and occupational physical activity) during pregnancy and preterm birth and
included >466 cases and 7 519 participants. The summary RR was for high vs. low total
physical activity was 0.95 (95% CI: 0.63-1.42, I2=56.8%, pheterogeneity=0.07) (Figure 4c).
Occupational physical activity during pregnancy
Two cohort studies 41;48 were included in the analysis of occupational physical activity and
preterm birth and included 349 cases and 6 581 participants. The summary RR for high vs.
low occupational activity was RR=0.67 (95% CI: 0.33-1.34, I2=0%, pheterogeneity=0.82) (Figure
4d).
Walking during pregnancy
Five cohort studies 34;39;44;49;51 and two randomized trials 64;65 were included in the analysis of
walking during pregnancy and preterm birth and included 1 065 cases and 26 903
participants. The summary RR for high vs. low walking was 1.09 (95% CI: 0.68-1.75,
I2=72.3%, pheterogeneity<0.0001) (Figure 4e).
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Bicycling during pregnancy
Five randomized trials 19;23;26;28;31 and one cohort study 40 investigated the association between
bicycling during pregnancy and the risk of preterm birth and included 3 706 cases and 74 682
participants. The summary RR for high vs. low bicycling was 0.84 (95% CI: 0.69-1.04,
I2=0%, pheterogeneity=0.44) (Figure 4f).
Subgroup, sensitivity and meta-regression analyses
In subgroup and meta-regression analyses we found no significant heterogeneity between
subgroups when studies were stratified by study type, geographic location, number of cases,
physical activity assessment, risk of bias (RCTs), study quality (cohorts) or adjustment for
confounding factors including age, education, income, drug use, smoking, alcohol, parity,
hypertension, diabetes or BMI (Table S5). In general there was low or moderate
heterogeneity in most of the subgroup analyses. The inverse association between physical
activity and preterm birth was significant only among the cohort studies with a high study
quality, although there was no between-subgroup heterogeneity (Table S5). The risk of bias
assessment showed that 8 studies had low, 8 studies had unclear and 4 studies had high risk
of bias (Table S6). The mean (median) study quality score for the modified Newcastle-
Ottawa score was 6.7 (7.0) out of 8 possible points (Table S7).
Because few studies could be included in the dose-response analysis of leisure-time physical
activity during pregnancy and the risk of preterm birth we conducted a sensitivity analysis
restricting the high vs. low analysis to the five studies included in the dose-response analysis
to see if these studies differed greatly from the overall result among cohort studies. The
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summary RR was 0.84 (95% CI: 0.73-0.96) for these five cohort studies, which was similar
to the summary estimate 0.86 (95% CI: 0.78-0.95) for all the cohort studies.
Discussion
Main findings
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This is to our knowledge the first dose-response meta-analysis of physical activity and risk of
preterm birth and we found that higher leisure-time physical activity during pregnancy was
associated with a statistically significant 14% decrease in the relative risk of preterm birth,
and for each 3 hour per week increase in leisure-time physical activity during pregnancy there
was a 10% reduction in the relative risk of preterm birth. There was evidence of a nonlinear
association between physical activity during pregnancy and preterm birth with the lowest risk
(15-16% reduction in relative risk) observed at a physical activity level of approximately 2-4
hours per week, however, some caution is needed in the interpretation of the nonlinear
analysis as the number of data points at higher physical activity levels was limited. The
inverse association was significant in cohort studies, but not in the randomized controlled
trials, however, there was no heterogeneity by study design, and the small study sizes and low
number of cases may have contributed to the lack of a significant association among the
randomized trials. Other measures of physical activity including leisure-time physical activity
before pregnancy and total, moderate or vigorous physical activity, bicycling, walking, and
occupational physical activity during pregnancy showed non-significant associations in the
direction of reduced risk, most likely also due to low statistical power.
Strengths
Our meta-analysis also has several strengths. Because we only included cohort studies and
randomized trials the possibility that recall bias and selection bias explains the results is
reduced. The study quality of the cohort studies was high and approximately half of the
randomized trials were at low risk of bias. Among the cohort studies the inverse association
was only significant among studies with a high study quality, although there was no between-
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subgroup heterogeneity. We conducted dose-response analyses and found evidence of a dose-
response relationship up to 2-4 hours per week, but no further reductions in risk with higher
levels of activity, however, because of few data points at higher levels of physical activity
further studies are needed to clarify the dose-response relationship at higher levels of activity.
In contrast, we have previously reported further benefits of higher levels of physical activity
(up to 5-7 hours per week) in relation to preeclampsia 12, gestational diabetes 11, and type 2
diabetes 83 and any recommendations regarding physical activity need to take into
consideration overall health, not just the risk of preterm birth.
Limitations
Our meta-analysis may have some limitations that could have affected the results.
Unmeasured or residual confounding could have influence the results. Higher physical
activity is associated with other healthy behaviors and risk factors including lower prevalence
of smoking and overweight/obesity. However, many of the studies included in this meta-
analysis adjusted for known confounding factors such as age, BMI, smoking, and the
associations persisted in subgroup analyses with adjustment for these variables and there was
no evidence of between subgroup heterogeneity with meta-regression analyses. The
possibility of confounding by less established risk factors including diet cannot be ruled out,
but needs clarification in future studies. We found no evidence of publication bias with the
statistical tests or by inspection of the funnel plot.
Although the result from the twenty randomized clinical trials was not statistically
significant, most of the trials were very small (14 of the trials had <10 cases, 5 trials had
between 17 and 39 cases and the largest trial had 66 cases) and had therefore too low
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statistical power to detect an association. Some of them may have had a physical activity
level that may have been too low to reduce risk, and there may also be issues with low
compliance and contamination of the control groups, which could have biased the estimates
toward the null. The percentage of withdrawals was similar in the intervention and control
groups in most of the clinical trials, thus attrition bias is less likely to have affected the
results.
Another limitation was that few of the studies reported results in such a way that they
could be included in dose-response analyses (for example in 3-4 or more categories by hours
or MET-hours per month or week), and therefore the dose-response analyses may not have
been representative for all the studies. This problem has also been observed in our previous
meta-analyses of physical activity and preeclampsia 12, gestational diabetes 11, and type 2
diabetes 83 and point to a need for more standardized reporting of physical activity data in
epidemiological studies. Based on the nonlinear dose-response analysis the data suggest that
2-4 hours per week of physical activity will be needed to reduce the risk of preterm birth by
15-16%, although for other pregnancy complications further benefits are observed for higher
levels of activity 11;12.
Since most of the morbidity and mortality associated with preterm births occurs in
infants born very premature, a further limitation of the present study is that most of the
studies included in this meta-analysis reported results for preterm birth overall and did not
present results according to clinical subtype or severity. One study reported similar inverse
associations for very premature births (<33 weeks) as for premature births (33-35 weeks) 62,
while another study which found no association found no differences by subtypes of severity
84. Any further studies could try to clarify if the association differs by clinical subtypes or
severity.
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Interpretation
Several potential mechanisms may explain the inverse association we observed between
physical activity and preterm birth. Physical activity is essential for weight control and
reduces the risk of adiposity and excess gestational weight gain 7-9, which has been associated
with increased risk of preterm birth 5. Although the association was slightly stronger among
studies that did not adjust for BMI and reduced adiposity partly may explain the association,
there was still a significant 19% reduction in the relative risk among studies that adjusted for
BMI, suggesting a clinically relevant reduction in risk independent of BMI. Physical activity
also reduces the risk of type 2 diabetes 83, gestational diabetes 11, and preeclampsia 12, obesity-
related conditions that have been associated with increased risk of preterm birth in several
studies 85-89. Physical activity improves insulin sensitivity 90-92 and may decrease the
inflammatory response that is suggested as a risk factor for preterm birth 93. Higher levels of
tumor necrosis factor-α (TNF- α) has been related to the onset of labor and preterm birth 94;95,
and physically active women have lower levels of TNF- α than inactive women 96;97.
Conclusion
In conclusion, these results suggest that higher physical activity is associated with reduced
risk of preterm birth. Any additional studies should try to further clarify the dose-response
relationship, joint effects between physical activity before and during pregnancy and risk of
preterm births, and associations between specific subtypes and intensities of physical activity
and risk of preterm birth, as well as clinical subtypes and severity of preterm births. Further
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well-designed large randomized controlled trials with a sufficient level of activity to reduce
the risk are also needed to conclusively demonstrate an association. However, considering
benefits of physical activity for the prevention of obesity and other pregnancy outcomes, our
results support previous recommendations for pregnant women to be active on most if not all
days of the week.
Acknowledgements: We thank Dr. Darren C. Greenwood (Biostatistics Unit, Centre for
Epidemiology and Biostatistics, University of Leeds, Leeds, United Kingdom) for providing
the Stata code for the nonlinear dose-response analyses.
Disclosure of interest: The authors declare that there is no duality of interest associated with
this manuscript.
Contribution to authorship: DA designed the project, conducted the literature search and
analyses and wrote the first draft of the paper. SS contributed to the study screening and data
extraction. DA, SS, TH, ODS, ST interpreted the data, revised the subsequent drafts for
important intellectual content and approved the final version of the paper to be published.
Details of ethics approval: Ethical approval was not needed as the study uses already
published data.
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Funding: This project has been funded by Liaison Committee between the Central Norway
Regional Health Authority (RHA) and the Norwegian University of Science and Technology
(NTNU) and the Imperial College National Institute of Health Research (NIHR) Biomedical
Research Centre (BRC).
Reference List
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Figure 1. Flow-chart of study selection
732733734735736737738739740741
31
2053 records identified in total:715 records identified in the PubMed database889 records identified in the Embase database447 records identified in the Ovid database
2 records identified from other searches
183 given detailed assessment
1870 excluded based on information in title or abstract
142 studies excluded48 not relevant data,
outcome or exposure15 abstracts14 case-control studies10 reviews9 protocols9 combined diet and
activity interventions7 no risk estimates7 not relevant activity6 meta-analyses4 duplicates4 cross-sectional studies3 yoga /stretching3 unadjusted risk estimates 3 comment
41 studies included (43 publications)20 randomized trials (20 publications)21 cohort studies (23 publications)
Figure 2. Leisure-time physical activity before and during pregnancy and preterm birth
742743744745746747748749
32
B
C Leisure-time physical activity during pregnancy and preterm birth, nonlinear dose-response analysis
0.6
0.8
1.0
RR
0 1 2 3 4 5 6 7Physical activity during pregnancy (hours/wk)
Best fi tting cubic spline95% confidence interval
Relative Risk .2 .5 .75 1 1.5 2 3
Study
Relative Risk
(95% CI)
Tinloy, 2014 1.11 ( 0.69, 1.77)
Jukic, 2012 0.97 ( 0.76, 1.24)
Owe, 2012 0.90 ( 0.84, 0.98)
Hegaard, 2008 0.71 ( 0.45, 1.13)
Juhl, 2008 0.88 ( 0.81, 0.96)
Overall 0.90 ( 0.85, 0.95)
A
Relative Risk .2 .5 .75 1 1.5 2 3
Study
Relative Risk
(95% CI)
Bird, 2016 0.99 ( 0.79, 1.24)
Vamos, 2015 0.55 ( 0.33, 0.91)
Jukic, 2012 0.60 ( 0.10, 2.80)
Orr, 2006 0.95 ( 0.62, 1.46)
Haas, 2005 0.81 ( 0.52, 1.27)
Overall 0.87 ( 0.70, 1.06)
Leisure-time physical activity during pregnancy and preterm birth, per 3 hours per week
Leisure-time physical activity before pregnancy and preterm birth, high vs. low analysis
750
33
Figure 3. Leisure-time physical activity during pregnancy and preterm birth
Relative Risk
.01 .1 .25 .5 .75 1 1.5 2 3 5
Study Relative Risk (95% CI)
Randomized controlled trials
Wang, 2017 0.60 ( 0.14, 2.57)
Barakat, 2016 0.76 ( 0.46, 1.28)
Garnæs, 2016 0.98 ( 0.14, 6.80)
Seneviratne, 2016 2.30 ( 0.20, 29.60)
Taniguchi, 2016 0.19 ( 0.02, 2.10)
Halse, 2015 1.50 ( 0.33, 7.00)
Nobles, 2015 1.03 ( 0.47, 2.25)
Barakat, 2014 0.55 ( 0.21, 1.39)
Barakat, 2014 0.87 ( 0.24, 3.10)
Ghodsi, 2014 3.00 ( 0.45, 20.51)
Kong, 2014 0.35 ( 0.03, 4.03)
Renault, 2014 1.32 ( 0.49, 3.57)
Salvesen, 2014 1.05 ( 0.57, 1.92)
Kasawara, 2013 0.53 ( 0.26, 1.06)
Tomic, 2013 1.57 ( 0.72, 3.47)
Price, 2012 3.34 ( 0.28, 40.27)
Haakstad, 2011 2.04 ( 0.38, 10.89)
Cavalcante, 2009 0.84 ( 0.28, 2.53)
Barakat, 2008 0.65 ( 0.13, 3.16)
Santos, 2005 1.89 ( 0.26, 14.12)
Subtotal 0.91 ( 0.72, 1.15)
Cohort studies
Bird, 2016 0.98 ( 0.76, 1.24)
Sealy-Jefferson, 2014 0.77 ( 0.44, 1.36)
Tinloy, 2014 1.12 ( 0.67, 1.86)
Jukic, 2012 0.60 ( 0.30, 1.20)
Owe, 2012 0.86 ( 0.73, 1.07)
Hegaard, 2008 0.70 ( 0.38, 1.28)
Juhl, 2008 0.81 ( 0.64, 1.04)
Orr, 2006 0.93 ( 0.63, 1.38)
Hatch, 1998 0.11 ( 0.02, 0.81)
Misra, 1998 0.51 ( 0.27, 0.95)
Subtotal 0.84 ( 0.73, 0.96)
Overall 0.86 ( 0.78, 0.95)
751
752
34
Figure 4. Moderate, vigorous, total, and occupational physical activity, and walking and bicycling during pregnancy and preterm birth
B
A
Vigorous physical activity during pregnancy and preterm birth, high vs. low analysis
Moderate physical activity during pregnancy and preterm birth, high vs. low analysis
Relative Risk
.01 .1 .25 .5 .75 1 1.5 2 3 5
Study
Relative Risk
(95% CI)
Sealy-Jefferson, 2014 1.01 ( 0.71, 1.44)
Hegaard, 2008 0.34 ( 0.14, 0.85)
Overall 0.64 ( 0.22, 1.83)
Relative Risk
.01 .1 .25 .5 .75 1 1.5 2 3 5
Study
Relative Risk
(95% CI)
Jukic, 2012 0.08 ( 0.01, 1.00)
Evenson, 2002 0.80 ( 0.48, 1.35)
Overall 0.36 ( 0.04, 3.09)
D
C
Occupational physical activity during pregnancy and preterm birth, high vs. low analysis
Total physical activity during pregnancy and preterm birth, high vs. low analysis
Relative Risk
.01 .1 .25 .5 .75 1 1.5 2 3 5
Study
Relative Risk
(95% CI)
Jukic, 2012 0.60 ( 0.20, 2.00)
Teitelman, 1990 0.71 ( 0.35, 2.04)
Overall 0.67 ( 0.33, 1.34)
Relative Risk .01 .1 .25 .5 .75 1 1.5 2 3 5
Study
Relative Risk
(95% CI)
Rego, 2016 1.35 ( 0.74, 2.49)
Currie, 2014 1.06 ( 0.67, 1.69)
Jukic, 2012 1.20 ( 0.50, 3.10)
Magann, 1996 0.62 ( 0.44, 0.87)
Overall 0.95 ( 0.63, 1.42)
F
E
Bicycling during pregnancy and preterm birth, high vs. low analysis
Walking during pregnancy and preterm birth, high vs. low analysis
Relative Risk .01 .1 .25 .5 .75 1 1.5 2 3 5
Study Relative Risk (95% CI)
Randomized controlled trials
Ghodzi, 2014 3.00 ( 0.45, 20.51) Kasawara, 2013 0.53 ( 0.26, 1.06) Wang, 2017 0.60 ( 0.14, 2.57) Seneviratne, 2016 2.30 ( 0.20, 29.60)
Halse, 2015 1.50 ( 0.33, 7.00) Subtotal 0.83 ( 0.44, 1.58)
Cohort study Juhl, 2010 0.86 ( 0.69, 1.08)
Subtotal 0.86 ( 0.69, 1.08)
Overall 0.84 ( 0.69, 1.04)
Relative Risk .01 .1 .25 .5 .75 1 1.5 2 3 5
Study Relative Risk (95% CI)
Randomized controlled trials Taniguchi, 2016 0.19 ( 0.02, 2.10) Kong, 2014 0.35 ( 0.03, 4.03)
Subtotal 0.25 ( 0.05, 1.37)
Cohort studies Sealy-Jefferson, 2014 0.64 ( 0.43, 0.94) Hegaard, 2008 1.01 ( 0.51, 2.01) Misra, 1998 2.18 ( 1.38, 3.20) Henriksen, 1995 1.40 ( 0.70, 2.50) Launer, 1990 1.33 ( 0.85, 2.08)
Subtotal 1.21 ( 0.75, 1.95)
Overall 1.09 ( 0.68, 1.75)
753754
755
35
Figure S1. Funnel plot of leisure-time physical activity during pregnancy and preterm birth0
.51
1.5
s.e.
of l
ogrr
-3 -2 -1 0 1 2logrr
Funnel plot with pseudo 95% confidence limits
756757
758759760761762763764765766767768769770771772773774775776777778779780781782
36
Figure S2. Influence analysis of leisure-time physical activity during pregnancy and preterm birth
0.75 0.86 0.78 0.95 0.97
Wang, 2017 Barakat, 2016 Garnæs, 2016
Seneviratne, 2016 Taniguchi, 2016
Halse, 2015 Nobles, 2015
Barakat, 2014 Barakat, 2014 Ghodsi, 2014
Kong, 2014 Renault, 2014
Salvesen, 2014 Kasawara, 2013
Tomic, 2013 Price, 2012
Haakstad, 2011 Cavalcante, 2009
Barakat, 2008 Santos, 2005
Bird, 2016 Sealy-Jefferson, 2014
Tinloy, 2014 Jukic, 2012 Owe, 2012
Hegaard, 2008 Juhl, 2008 Orr, 2006
Hatch, 1998 Misra, 1998
Study ommited Meta-analysis random-effects estimates (exponential form)
------------------------------------------------------------------------------ Study omitted | Estimate [95% Conf. Interval]-------------------+---------------------------------------------------------- Wang, 2017 | .86279517 .7807495 .95346272 Barakat, 2016 | .86558867 .781937 .95818937 Garnæs, 2016 | .86103141 .77923381 .95141548 Seneviratne, 2016 | .85997754 .77832067 .95020133 Taniguchi, 2016 | .86372221 .78170031 .95435053 Halse, 2015 | .85928327 .77758849 .94956112 Nobles, 2015 | .85882252 .77670252 .94962502 Barakat, 2014 | .86585605 .78325611 .95716679 Barakat, 2014 | .86127698 .77931851 .95185477 Ghodsi, 2014 | .85839516 .77684456 .94850659 Kong, 2014 | .86259913 .78069127 .9531005 Renault, 2014 | .85755265 .77579379 .94792789 Salvesen, 2014 | .85661268 .77427453 .94770682 Kasawara, 2013 | .86995947 .78661567 .96213371 Tomic, 2013 | .8529371 .77138841 .94310683 Price, 2012 | .85943884 .77783233 .94960713 Haakstad, 2011 | .85869789 .77708721 .94887954 Cavalcante, 2009 | .8615039 .77944326 .95220393 Barakat, 2008 | .86229628 .78032726 .95287561 Santos, 2005 | .85964197 .77798241 .94987273 Bird, 2016 | .83949864 .75269067 .93631822 Sealy-Jefferson, 2014| .86444151 .78117728 .9565807 Tinloy, 2014 | .85240543 .77002078 .94360447 Jukic, 2012 | .86792761 .784756 .95991409 Owe, 2012 | .86182064 .76679558 .96862167
783784785
786787788789790791792793794795796797798799800801802803804805806807808809810811812813814815
37
Hegaard, 2008 | .86628735 .78301924 .95841038 Juhl, 2008 | .87212658 .78180259 .97288603 Orr, 2006 | .85677022 .77285683 .94979453 Hatch, 1998 | .86649907 .78417164 .95746982 Misra, 1998 | .87303346 .78919202 .96578193-------------------+---------------------------------------------------------- Combined | .86132526 .77960237 .95161486------------------------------------------------------------------------------
816817818819820821822823824825826827828829830831832833834835836837838839840841842843844845846847848849850851852853854855856857858859860861862863864
38
Table S1. List of excluded studies and exclusion reason
Exclusion reason Reference number
Abstract [1-15]
Case-control study [16-29]
Combined diet and activity intervention [30-38]
Comment [39-41]
Cross-sectional study [42-45]
Duplicate [46-49]
Meta-analysis [50-55]
No risk estimates [56-62]
Not relevant activity [63-69]
Not relevant data [70-85]
Not relevant exposure [86-88]
Not relevant outcome [89-117]
Protocol [118-126]
Review [127-136]
Unadjusted risk estimates [137-139]
Yoga or stretching as intervention [140-142]
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Table S2: Randomized controlled trials of physical activity and preterm birth risk
Author, publication year, country
Study period
Study size, gender, age, number of cases
Preterm birth definition (weeks of completed gestation)
Assessment of gestational age
Exposure Quantity RR (95% CI)1 Adjustment for confounders
Santos IA et al, 2005, Brazil
2000-2002
46 women randomized (37 analyzed) to exercise group: 2 cases46 women randomized (35 analyzed) to control group: 1 case
<37 weeks Ultra-sonography
Physical activity during pregnancy:Supervised physical exercise, 60 minutes three times per week
3 x 60 min sessions per week 1.89 (0.26-14.12) No
Barakat R et al, 2008, Spain
NA 80 women randomized (72 analysed) training group: 2 cases80 women randomized (70 analysed) control group: 3 cases
<37 weeks Hospital perinatal records
Physical activity during pregnancy:Physical exercise with three 35 minute sessions per week, from gestational weeks 12-13 to weeks 38-39
3 x 35 min sessions per week 0.65 (0.13-3.16) No
Cavalcante SR et al, 2009, Brazil
2002-2004
34 women randomized to water aerobics: 2 cases37 women randomized to control group: 3 cases
<37 weeks Not available Physical activity during pregnancy:Water aerobics exercise Not available? 0.84 (0.28-2.53) No
Haakstad LAH et al, 2011, Norway
2007-2008
52 women randomized (33 analysed): 2 cases
<37 weeks Labor records Physical activity during pregnancy:Physical exercise with aerobic 2 x 50 min sessions per week 2.04 (0.38-10.89) No
12901291
51
53 women randomized (36 analysed): 1 case
dance classes
Price BB et al, 2012, USA
2006-2010
43 women randomized to exercise group, 31 analyzed: 1 case48 women randomized to control group, 31 analyzed: 0 cases
<37 weeks Not available Physical activity during pregnancy:Supervised aerobic training of 45-60 min, four times/week at moderate intensity
45-60 min x 4/week 3.35 (0.28-40.31) No
Tomic V et al, 2013, Croatia
2008-2009
180 women randomized (166 women analysed), exercise group: 14 cases180 women randomized (168 women analysed), control group standard antenatal care: 9 cases
<37 weeks Not available Physical activity during pregnancy:Physical exercise (aerobic exercise) three 30 minute sessions per week from gestational weeks 6-8
Aerobic exercise 3 x 30 min per week
1.57 (0.72-3.47) No
Kasawara KT et al, 2013, Brazil
2008-2011
116 women with chronic hypertension and/or previous preeclampsia: 58 women randomized (56 analysed), exercise group 11 cases58 women randomized (53 analysed), control group: 18 cases
<37 weeks Ultrasound Physical activity during pregnancy:Physical exercise (stationary bicycle) from 12-20 weeks gestation
1 x 30 minutes/wk vs control (no activity)
0.53 (0.26-1.06) BMI, race/color, number of gestation, chronic hypertension, previous preeclampsia
52
Barakat R et al, 2014, Spain
NA 160 women randomized (138 analysed), exercise group: 6 cases160 women randomized (152 analysed), control group: 11 cases
<37 weeks Ultrasound Physical activity during pregnancy:Physical activity program with three 55-60 min sessions per week from 9-13 weeks gestation to weeks 39-40
55-60 min x 3 /week 0.55 (0.21-1.39) No
Barakat R et al, 2014, Spain
NA 107 women, exercise group: 4 cases93 women, control group: 4 cases
<259 days Not available Physical activity during pregnancy:Physical activity program with three 55-60 min sessions per week from 8-10 weeks gestation to weeks 38-39
55-60 min x 3 /week 0.87 (0.24-3.10) No
Ghodsi Z et al, 2014, Iran
2011 40 women, exercise group: 3 cases40 women, control group: 1 case
Not available Not available Physical activity during pregnancy:Physical activity from 20-26 weeks gestation, 15 minutes ergometer bicycling 3 times/week
15 min x 3/week 3.00 (0.45-20.51) No
Renault KM et al, 2014, Denmark
2009-2012
125 women, physical activity group: 2 cases134 women, control group: 7 cases
<37 weeks Not available Physical activity during pregnancyPhysical activity intervention to increase daily step count to 11000 (monitored by pedometer)
11000 steps/day 1.32 (0.49-3.57) No
Salvesen KA et al, 2014, Norway
2007-2009
429 women randomized to exercise group (427 analyzed): 20 cases426 women randomized to control group (426 analyzed): 19 cases
<37 weeks Ultrasound Physical activity during pregnancyPhysical activity intervention with low impact aerobics, strength exercises and light stretching
30-35 min low impact aerobics, 20-25 min strength training and 5-10 min light stretching x 1/week and were encouraged to train home x 2/week (45 min)
1.05 (0.57-1.92) No
Kong KL et al, 2014, USA
Not available
19 women randomized to walking intervention (18 analyzed): 0
<37 weeks Last normal menstrual cycle or medical provider
Physical activity during pregnancyUnsupervised walking program 5 x 30 min walking (at least
150 min/week in total)0.35 (0.03-4.03) No
53
cases23 women randomized to control group (19 analyzed): 1 case
ultrasound
Nobles C et al, 2015, USA
2007-2012
124 women, exercise group: 12 cases127 women, control group: 19 cases
<37 weeks Medical records
Physical activity during pregnancyIntervention to increase activity level to moderate-intensity physical activity of 30 min on most days of the week
30 min most days of the week 1.03 (0.47-2.25) No
Halse RE et al, 2015, Australia
20 women randomized to exercise group: 3 cases20 women randomized to control group: 2 cases
<37 weeks Not available Physical activity during pregnancyHome-based exercise program (stationary bicycle), 3 sessions/week
25-30 min increasing to 45 min sessions x 1/week + 2/week x 30 min unsupervised aerobic activity
1.50 (0.33-7.00) No
Taniguchi C et al, 2016, Japan
2000-2001
60 women, walking group: 0 cases58 women, control group: 2 cases
Not available Not available Physical activity during pregnancyIntervention to increase brisk walking to 30 min/d three or more times per week
30 min x ≥3/week 0.19 (0.02-2.10) No
Seneviratne SN et al, 2016, New Zealand
2013-2014
38 women, exercise group: 2 cases37 women, control group: 1 case
<37 weeks Not available Physical activity during pregnancyHome based exercise intervention using stationary bicycles, 3-5 times/week 15-30 min per session
15-30 min x 3-5/week 2.3 (0.2-29.6) No
Garnæs KK et al, 2016, Norway
2011-2013
46 women, exercise training group: 1 case45 women, control group: 1 case
<37 weeks Not available Physical activity during pregnancyThree weekly supervised sessions of 35 min moderate intensity endurance exercise and 25 min of strength training
60 min x 3/week 0.98 (0.14-6.80) No
Barakat R et 2011- 420 women <37 weeks Not available Physical activity during
54
al, 2016, Spain 2015 randomized to exercise intervention, 382 analyzed: 29 cases420 women randomized to control group, 383 analyzed: 37 cases
pregnancyExercise intervention of 50-55 min, 3 days/week from week 9-11 to the end of the third trimester (aerobic exercise, dance, muscular strength, flexibility)
50-55 min x 3/week 0.76 (0.46-1.28) Maternal age, parity, smoking status, occupational physical activity during pregnancy, prepregnancy exercise habits, prepregnancy BMI
Wang C et al, 2017, China
2014-2016
150 women randomized to exercise group: 3 cases150 women randomized to control group: 5 cases
<37 weeks Not available Physical activity during pregnancyThree sessions of stationary cycling per week, 30 min/session
30 min x 3/week 0.60 (0.14-2.57) No
1 All relative risk estimates apart from the studies by Kasawara et al, 2013 and Barakat et al, 2016 were estimated based on the distribution of cases and participants in the intervention and control group.
Table S3: Prospective cohort studies of physical activity and preterm birth risk
Author, Follow- Study size, Preterm birth Assessment of Physical Exposure Quantity RR (95% CI) Adjustment for
129212931294129512961297129812991300130113021303130413051306
55
publication year, country
up period gender, age, number of cases
definition gestational age activity assessment
confounders
Teitelman AM et al, 1990, USA
1980-1982
1206 women: 51 preterm births
<37 weeks Last menstrual period
Based on job classification
Physical activity during pregnancy:Occupational activity (based on job types)
Active vs. sedentary 0.71 (0.35-2.04)1 Parity, cigarettes per day, education, marijuana, race, time of interview, marital status
Launer LJ et al, 1990, Guatemala
1984-1986
15786 women: 368 preterm births
<37 weeks Clinical examination, last menstrual period
Questionnaire Physical activity during pregnancy:Occupational activity Sitting
Walking1.001.33 (0.85-2.08)
Maternal age, height, income, birthweight of previous infant
Klebanoff MA et al, 1990, USA
1984-1987
7101 women: 808 preterm births
<37 weeks Last menstrual period, sonograms, uterine measurements, detection of fetal heart tones
Interview Physical activity during pregnancy: Heavy work or exercise
Light work or exercise
0 hrs/d1-3≥40 hrs/d1-34-7≥8
1.000.94 (0.75-1.18)1.04 (0.76-1.42)1.000.74 (0.48-1.14)0.69 (0.44-1.17)0.59 (0.38-0.93)
Age, study site, ethnicity, education, parity, marital status, income, smoking, alcohol, insurance status, current employment
Henriksen TB et al, 1995, Denmark
1989-1991
4259 women: 147 preterm births
<37 weeks Ultrasonographically determined fetal biparietal diameter, last menstrual period, birth certificate
Questionnaire Physical activity during pregnancy:Walking 0-2 hrs/d
>2-5>5Per 1 hr/d
1.01.2 (0.8-1.7)1.4 (0.7-2.5)1.1 (1.0-1.2)
Parity, maternal height, smoking, leisure-time activity, partner’s social class
Magann EF et al, 1996, Australia
1989-1991
2743 pregnant women: 241 preterm births
<37 weeks Last menstrual period and ultra-sonographic
Validated questionnaire
Physical activity during pregnancy:Total physical activity <2500 vs. ≥2501 kcal/d 1.61 (1.15-2.26) Socioeconomic score,
parity, weight gain
56
examinationHatch M et al, 1998, USA
1987-1989
557, age ≥18 years: NA
<37 weeks Sonograms and last menstrual period
Telephone interview, questionnaire
Physical activity during pregnancy:Exercise level, preterm week 32
Exercise level, preterm week 34
Exercise level, preterm week 36
None≤1000 kcal/wk>1000None≤1000 kcal/wk>1000None≤1000 kcal/wk>1000
1.000.53 (0.07-4.17)0.01 (0.00-0.52)1.000.62 (0.13-2.97)0.04 (0.00-0.65)1.000.72 (0.45-2.15)0.11 (0.02-0.81)
Maternal age, parity, prepregnancy weight, first-trimester bleeding, study site, per capita income
Misra DP et al, 1998, USA
1988-1990
1117: 198 preterm births
<37 weeks Clinical assessment
Interview Physical activity during pregnancy:Climbing stairs
Walking
Leisure-time exercise
10 times/d>10<4 days/wk≥4<60 days≥60
1.001.60 (1.05-2.46)1.002.10 (1.38-3.20)1.000.51 (0.27-0.95)
Maternal age, race, use of illicit drugs, prenatal care, mother’s height, smoking, insurance/aid to families with dependent children, prior fetal losses, prior low birth weight delivery, bleeding, hypertension, antepartum hospitalization, febrile/ antibiotic administration
Tuntiseranee P et al, 1998, Thailand
1994-1995
1797: 57 preterm births
<37 weeks Dubowitz's fetal maturing score
Interview and questionnaire
Occupational activity during pregnancy:Fast walk None
SometimesOften
1.02.4 (1.0-5.7)1.4 (0.3-6.1)
Maternal age, parity, height, obstetrical complication, sex of the baby, number of
57
antenatal care visits, maternal weight at delivery day, number of working hours, squatting, standing, commuting, lifting, lifting level, carrying more than 12 kilograms, physical job demand, psychological job demand, work control
Evenson KR et al, 2002, USA
1995-1998,
1699 women: 193 preterm births113 spontaneous preterm births
<37 weeks Last menstrual period and ultrasound dating
Telephone interview
Physical activity before pregnancy: Vigorous leisure activity, before pregnancy, preterm birth Vigorous leisure activity, before pregnancy, spontaneous preterm birthPhysical activity during pregnancy:Vigorous leisure activity, 1st trimester, preterm birthVigorous leisure activity, 1st trimester, spontaneous preterm birthVigorous leisure activity, 2nd trimester, preterm birthVigorous leisure activity, 2nd trimester, spontaneous preterm birth
Any vs. none
Any vs. none
Any vs. none
Any vs. none
Any vs. none
Any vs. none
1.06 (0.71-1.57)
0.99 (0.59-1.65)
0.80 (0.48-1.35)
0.62 (0.30-1.30)
0.52 (0.24-1.11)
0.45 (0.16-1.29)
Maternal age, smoking, BMI, marital status, education, race, parity, energy intake, bedrest
Haas JS et al, 2005, USA
2000-2001
1619 women: 129 cases
<37 weeks Not available Telephone surveys
Physical activity before pregnancy: Exercise during the month before pregnancy
No vs. yes 1.24 (0.79-1.92) Age, country of birth, race/ethnicity, level of education, parity,
58
site of care, body mass index, physical function prior to pregnancy, depressive symptoms prior to pregnancy, chronic health conditions prior to pregnancy, smoking status prior to pregnancy, smoking status during pregnancy, physical function during pregnancy, depressive symptoms during pregnancy, eclampsia or preeclampsia during pregnancy, gestational diabetes, other pregnancy complications, use of illicit drugs during pregnancy, and inadequate prenatal care
Orr ST et al, 2006, USA
1993-1995
922 women: 126 preterm births
<37 weeks Last menstrual period, fundal height, sonogram, and date at first fetal heartbeat
Questionnaire Physical activity before pregnancy: Exercise Physical activity during pregnancy: Exercise
Yes vs. no
Yes vs. no
0.95 (0.62-1.46)
0.93 (0.63-1.38)
Alcohol use, drug use, first or second trimester bleeding, chronic diseases, previous poor pregnancy outcome, smoking
59
Hegaard HK et al, 2008, Denmark
1989-1991
5749 women: 210 preterm births
<37 weeks Ultrasound and last menstrual period
Questionnaire Physical exercise during pregnancy:Participation in sports
Time spent on sports
Type of sports activity
Leisure time physical activities
NoYes0 h/wk1-2≥3NoneOne non-weight carrying activityOne weight carrying activity>1 activityOther types of sport incl. walkingSedentaryLightModerate
1.000.77 (0.53-1.11)1.000.80 (0.53-1.23)0.70 (0.38-1.28)1.000.75 (0.40-1.40)
0.94 (0.54-1.61)
0.09 (0.01-0.66)1.01 (0.51-2.01)
1.000.76 (0.60-1.02)0.34 (0.14-0.85)
Maternal age, years in school, maternal prepregnancy BMI, maternal smoking during pregnancy
Juhl M et al, 2008, Denmark
1996-2002
87232 singleton pregnancies: 4279 preterm births
<37 weeks Not available Interview Physical exercise during pregnancy:Physical exercise during pregnancyPhysical exercise during pregnancy
Physical exercise during pregnancy
Changes in physical activity during pregnancy(<22/22+ weeks)
NoneAny0 hrs/wk>0-1>1-2>2-3>3-5>50 MET-hrs/wk>0-5>5-10>10-15>15No/noYes/noNo/yes
1.000.82 (0.76-0.88)1.000.80 (0.72-0.87)0.81 (0.72-0.92)0.89 (0.76-1.05)0.89 (0.75-1.06)0.81 (0.64-1.04)1.000.77 (0.68-0.87)0.82 (0.74-0.91)0.83 (0.71-0.96)0.88 (0.78-1.00)1.001.06 (0.96-1.18)0.83 (0.73-0.95)
Age, gravidity, parity, previous spontaneous abortions, uterine fibroids/ malformations/ cone biopsy, subfecundity, coffee, alcohol, smoking, BMI, job status, working hours, working position, job strain
60
Yes/yes 0.81 (0.72-0.91)Juhl M et al, 2010, Denmark
1996-2002
74486 singleton pregnancies: 3673 preterm births
<37 weeks Not available Interview Physical exercise during pregnancy: Leisure-time physical activity
Swimming
Bicycling
No exerciseBicyclingSwimmingNo<90 min/week≥90No<90 min/week≥90
1.000.95 (0.83-1.08)0.80 (0.72-0.88)1.000.80 (0.72-0.89)0.78 (0.61-1.00)1.000.99 (0.85-1.15)0.86 (0.69-1.08)
Maternal age, parity, occupational status, smoking during pregnancy, gravidity, previous spontaneous abortions, illnesses overall, abdominal diseases, subfecundity, bleeding early in pregnancy, coffee, alcohol, pre-pregnancy BMI, working hours, working position, physically strenuous work, psycho-social jobstrain
Snijder CA et al, 2012, Netherlands
2002-2006
4680 pregnant women: 231 preterm births
<37 weeks Crown-rump length and pibarietal diameter
Questionnaire Occupational activity during pregnancy: Long periods of walking No
OccasionallyOften
1.001.07 (0.78-1.46)0.85 (0.54-1.33)
Maternal age, height, weight before pregnancy, education, ethnicity, parity, smoking, alcohol, folic acid supplement use, self-perceived health, fetal gender
Owe KM et al, 2012, Norway
2000-2006
61098 singleton pregnancies: 3181 preterm births
<37 weeks Ultrasound and last menstrual date
Validated questionnaire
Physical exercise during pregnancy:Exercise frequency, week 17 Never
1-3/mo1-2/wk
1.000.91 (0.82-1.02)0.89 (0.80-0.98)
Maternal age, prepregnancy BMI, education, smoking,
61
Exercise frequency, week 30
3-5/wk≥6/wkNever1-3/mo1-2/wk3-5/wk≥6/wk
0.84 (0.75-0.93)0.86 (0.73-1.07)1.000.90 (0.81-1.01)0.81 (0.73-0.89)0.76 (0.68-0.86)0.81 (0.62-1.05)
parity, working hours, spontaneous abortions, assisted reproduction, vaginal bleeding before the 20th week, preexisting high blood pressure, vaginal bleeding after the 20th week, predominantly standing/walking at work
Jukic AM et al, 2012, USA
2004-2007
1647 births, age 25-34 years: 108 preterm births
<37 weeks Last menstrual period and ultrasound
Validatd telephone interview (7 day recall)
Physical exercise during pregnancy:Total activity
Recreational activity
Frequency of vigorous recreational activity sessions
Duration of vigorous recreational activity sessions
Occupational activity
Outdoor/indoor household activity
Child/adult care activity
None1-30 min/wk31-6061-435>435NoneNon-vigorous≥1 min/wkvigor.0-1 sessions/wk2-3≥40-9 min10-50>50NoneNon-vigorous OPA≥1 min/wk OPANoneNon-vigorous≥1 min/wk vigor.NoneNon-vigorous
1.01.0 (0.4-2.3)0.2 (0.05-1.0)0.6 (0.3-1.2)1.2 (0.5-3.1)1.01.2 (0.7-2.0)0.6 (0.3-1.2)1.01.0 (0.2-5.4)0.08 (0.006-1.0)1.00.4 (0.07-2.6)0.5 (0.07-4.1)1.00.6 (0.2-1.5)0.6 (0.2-2.0)1.00.5 (0.3-0.9)0.5 (0.2-1.3)1.00.7 (0.4-1.3)
Maternal age, race/ ethnicity, education, income, marital status, alcohol, BMI, cigarette smoking, illicit drug use, history of miscarriage, history of preterm birth, parity, vaginal bleeding, nausea/vomiting, diabetes, starting to exercise in preparation for getting pregnant, change in vigorous activity compared to before pregnancy, all modes of physical activityFrequency of
62
Started exercising in preparation for getting pregnantChange in vigorous activity compared to before pregnancy
≥1 min/wk vigor.Not reportedReportedStayed the sameDecreasedIncreased
0.9 (0.4-2.2)1.00.6 (0.1-2.8)1.00.7 (0.5-1.2)1.3 (0.5-3.6)
recreational activity and duration of activity are adjusted for vigorous recreational activity
Currie LM et al, 2014, Canada
2002-2005
1749 women: 117 preterm births
<37 weeks Ultrasound and last menstrual period
Validated Kaiser Physical Activity Survey
Physical activity during pregnancy: Total physical activity <6.44 KPAS score
6.44-<7.97≥7.97
1.000.84 (0.52-1.35)1.06 (0.67-1.69)
Maternal age, prepregnancy BMI, education, parity
Sealy-Jefferson S et al, 2014, USA
2001-2004
832 women: 139 preterm births
<37 weeks Last menstrual period and ultrasound
Questionnaire Physical activity during pregnancy:Leisure-time physical activity
Leisure-time physical activity
Intensity of leisure-time physical activity
Stair climbing
Walking
NoYes0 min/wk1-60>60NoneLight/moderateHigh≤10 times/d>10≤30 min/d>30
1.000.86 (0.61-1.23)1.000.91 (0.61-1.36)0.77 (0.44-1.36)1.001.01 (0.71-1.44)0.35 (0.11-1.01)1.000.82 (0.57-1.16)1.000.64 (0.43-0.94)
Drug use, cigarette smoking, locus of control, family resource scaleLocus of control, family resource scaleLocus of control, family resource scale, depression, cigarette smoking, drug use Locus of control, family resource scale, cigarette smoking, drug use Drug use, locus of control, family resource scale
Tinloy J et al, 2014, USA
2009-2011
2370 women, age 18-35 years: 118 late preterm births
<37 weeks Not available Validated questionnaire
Physical activity during pregnancy:Prenatal leisure-time physical activity (exercise)
<60 min/wk60-149≥150
1.001.14 (0.71-1.84)1.12 (0.67-1.86)
Age, race/ethnicity, marital status, education, poverty
63
status, prepregnancy weight, gestational weight gain, prepregnancy diabetes or hypertension
Vamos CA et al, 2015, USA
1994-2008
1713 women: 270 preterm births
<37 weeks Not available Questionnaire Physical activity before pregnancy:Pre-pregnancy leisure-time physical activity
Not activeShort-term physically activeLong-term physically active
1.000.80 (0.55-1.14)
0.55 (0.33-0.91)
Age, race, family income, smoking during pregnancy, prenatal care, months between birth and wave 4 interview
Rego AS et al, 2016, Brazil
2009-2010
1380 women: not available
<37 weeks Last menstruation and ultrasound
Validated questionnaire
Physical activity during pregnancy:Total physical activity 1
2345
1.001.13 (0.62-2.08)1.09 (0.58-2.07)0.82 (0.41-1.63)1.35 (0.74-2.49)
Maternal schooling, economic class, living with a partner, living with children
Bird AL et al, 2016, New Zealand
2009-2010
6822 women: not available
<37 weeks Not available Interview Physical activity before pregnancy:Moderate or vigorous activity
Physical activity during first trimester:Moderate or vigorous activity
Physical activity during the rest of pregnancy:Moderate or vigorous activity
≥5 x 30/≥2 x 30 min/week (mod./vig.)
≥5 x 30/≥2 x 30 min/week (mod./vig.)
≥5 x 30/≥2 x 30 min/week (mod./vig.)
0.99 (0.79-1.24)
0.98 (0.76-1.24)
0.81 (0.61-1.06)
Maternal age, ethnicity, area deprivation, maternal education, labour force participation, parity, pregnancy planning
1 Odds ratio was inverted to have the least active as comparison group. 1307
64
Table S4. Leisure-time physical activity during pregnancy and preterm birth, risk estimates from the nonlinear dose-response analysis
Hours per week Relative risk (95% CI)0 1.001 0.90 (0.89-0.92)2 0.85 (0.83-0.87)3 0.84 (0.81-0.86)4 0.85 (0.83-0.88)5 0.89 (0.85-0.93)6 0.93 (0.88-0.99)7 0.97 (0.90-1.05)
1308130913101311
13121313131413151316131713181319132013211322132313241325132613271328132913301331133213331334133513361337133813391340134113421343134413451346
65
Table S5: Subgroup analyses of leisure-time physical activity and preterm birth risk, dose-response analysis
Leisure-time physical activity
n RR (95% CI) I2 (%) Ph1 Ph
2
All studies 30 0.86 (0.78-0.95) 0 0.62
Study design
Randomized controlled trials 20 0.91 (0.72-1.15) 0 0.76 0.61
Cohort studies 10 0.84 (0.73-0.96) 21.7 0.24
Geographic location
Europe 11 0.85 (0.74-0.97) 0 0.82 0.36
North-America 10 0.82 (0.63-1.06) 24.8 0.22
South-America 3 0.66 (0.38-1.17) 0 0.45
Australia, New Zealand 2 1.68 (0.46-6.20) 0 0.78
Asia 4 0.92 (0.53-1.61) 17.9 0.30
Number of cases
Cases <200 24 0.86 (0.73-1.02) 0 0.72 0.82
Cases 200-<1000 1 0.70 (0.38-1.28)
Cases ≥1000 2 0.84 (0.72-0.98) 0 0.70
Not available 2 0.40 (0.05-3.30) 81.0 0.02
Physical activity assessment (cohorts)
Questionnaire 3 0.83 (0.63-1.11) 0 0.71 0.85
Validated questionnaire 2 0.89 (0.74-1.06) 0 0.34
Questionnaire and interview 1 0.11 (0.02-0.70)
Interview 4 0.80 (0.63-1.02) 39.2 0.18
Risk of bias (RCTs)
High 4 1.26 (0.76-2.09) 0 0.57 0.32
Unclear 8 0.80 (0.54-1.20) 0 0.69
Low 8 0.86 (0.61-1.21) 0 0.60
13471348
66
Study quality (cohorts)
0-3 0 0.88
4-6 3 0.84 (0.68-1.03) 0 0.44
7-8 7 0.81 (0.66-0.99) 38.9 0.13
Adjustment for confounding factors3
Age Yes 8 0.82 (0.69-0.98) 37.3 0.13 0.89
No 2 0.87 (0.63-1.21) 0 0.59
Education Yes 5 0.89 (0.78-1.02) 0 0.50 0.36
No 5 0.74 (0.55-0.99) 42.2 0.14
Income Yes 2 0.32 (0.06-1.60) 64.7 0.09 0.14
No 8 0.86 (0.77-0.97) 0 0.57
Drug use Yes 3 0.71 (0.48-1.05) 33.3 0.22 0.45
No 7 0.86 (0.75-1.00) 21.7 0.26
Smoking Yes 6 0.81 (0.71-0.93) 0 0.57 0.32
No 4 0.88 (0.60-1.29) 51.6 0.10
Alcohol Yes 3 0.82 (0.67-1.00) 0 0.55 0.71
No 7 0.83 (0.67-1.02) 40.6 0.12
Parity Yes 6 0.81 (0.66-0.99) 43.5 0.12 0.91
No 5 0.82 (0.65-1.05) 7.4 0.36
Hypertension Yes 4 0.78 (0.57-1.06) 43.7 0.15 0.86
No 7 0.83 (0.69-1.00) 23.3 0.25
Diabetes Yes 2 0.86 (0.47-1.57) 50.5 0.16 0.82
No 8 0.83 (0.72-0.96) 25.5 0.23
BMI Yes 7 0.79 (0.65-0.96) 31.2 0.19 0.54
No 4 0.86 (0.68-1.09) 23.2 0.27
ndenotes the number of studies.
1 P for heterogeneity within each subgroup,
2 P for heterogeneity between subgroups with meta-regression analysis,
1349
1350
1351
67
3 Subgroup analyses by adjustment for confounding factors excluded the randomized trials except for Kasawara et al, 2013 which adjusted for some confounding factors and for this reason the number of studies does not add up to the total.
135213531354
1355
1356
1357
1358
1359
1360
1361
1362
1363
1364
1365
1366
1367
1368
1369
1370
1371
1372
1373
1374
1375
1376
1377
68
Table S6: Risk of bias assessments for the included randomised control trials Random sequence
generation
Allocation concealment
Blinding of participants &
personnel
Blinding of outcome
assessments
Incomplete outcome data
Selective Reporting
Other Bias Overall
Wang, 2017 Low Unclear High Unclear Low Low Low Unclear
Barakat, 2016 Low Unclear High Low Low Low Low Unclear
Garnas, 2016 Low Low High Low Low Low Low Low
Seneviratne, 2015 Low Low High Low Low Low Low Low
Taniguchi, 2015 Unclear Low High Unclear Low Low Low Unclear
Halse, 2015 Unclear Low High Low Low Low Low Unclear
Nobles, 2015 Low High High Low Low Low Low High
Kong, 2014 Low Unclear High Unclear Low Low Low Unclear
Renault, 2014 Low Low High Low Low Low Low Low
Ghodsi, 2014 High High High Low High Low Low High
Barakat, 2014 (107) Low Low High Low Low Low Low Low
Barakat, 2014 (160)Low
Low High Low Low Low Low Low
Salvesen, 2014 Low Low High Low Low Low Low Low
Kasawara, 2013 Low Low High Low Low Low Low Low
Tomic, 2013 High High High Unclear Low Low Low High
1378
69
Price, 2012 Unclear Unclear High Unclear Low Low Low Unclear
Haakstad, 2011 Low Low High Low Low Low Low Low
Cavalcante, 2009 Low Low High Unclear Low Low Low Unclear
Barakat, 2008 Low Low High Low Low Low Low High
Santos, 2005 Low Unclear High Unclear Low Low Low Unclear
1379
1380
1381
1382
1383
1384
1385
1386
1387
1388
1389
1390
70
Table S7: Study quality (Newcastle-Ottawa scale) for cohort studies of leisure-time physical activity during pregnancy and preterm birth
Criteria
Author, year
Representativeness Selection of non-exposed cohort
Exposure assessment
Adjustment for one confounding factor
Adjustment for at least one additional confounder
Assessment of the outcome
Long enough follow-up for cases to accrue
Adequacy of follow-up
SUM
Bird, 2016 1 1 1 1 1 1 1 0 7
Sealy-Jefferson, 2014 1 1 0 1 1 1 1 1 7
Tinloy, 2014 1 1 1 1 1 0 1 0 6
Jukic, 2012 1 1 1 1 1 1 1 0 7
Owe, 2012 1 1 1 1 1 1 1 0 7
Hegaard, 2008 1 1 0 1 1 1 1 0 6
Juhl, 2008 1 1 1 1 1 0 1 0 6
Orr, 2006 1 1 0 1 1 1 1 1 7
Hatch, 1998 1 1 1 1 1 1 1 0 7
Misra, 1998 1 1 1 1 1 1 1 0 7
The Newcastle-Ottawa scale was modified because one of the criteria "demonstration that the outcome was not present at the start" could not be applied to the current type of pregnancy studies so the maximum total score was 8 instead of 9 points.
1391
1392
13931394
