Risks of Venous Thromboembolism After Cesarean Sections: A Meta-Analysis

Accepted Manuscript Risks of venous thromboembolism after cesarean sections: A meta-analysis Marc Blondon, MD MS, Alessandro Casini, MD, Kara K. Hoppe, DO, Françoise Boehlen, MD, Marc Righini, MD, Nicholas L. Smith, PhD PII:

S0012-3692(16)49108-7

DOI:

10.1016/j.chest.2016.05.021

Reference:

CHEST 490

To appear in:

CHEST

Received Date: 23 March 2016 Revised Date:

17 May 2016

Accepted Date: 23 May 2016

Please cite this article as: Blondon M, Casini A, Hoppe KK, Boehlen F, Righini M, Smith NL, Risks of venous thromboembolism after cesarean sections: A meta-analysis, CHEST (2016), doi: 10.1016/ j.chest.2016.05.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Risks of venous thromboembolism after cesarean sections: A meta-analysis.

Short title: cesarean deliveries and venous thrombosis

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Authors: Marc Blondon, MD MS 1,4 Alessandro Casini, MD 1 Kara K Hoppe, DO 2,3

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Françoise Boehlen, MD 1 Marc Righini, MD 1

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Nicholas L Smith, PhD 4,5

Affiliations: 1 Division of Angiology and Hemostasis, Department of Specialties of Medicine, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland. 2 Department of Obstetrics and Gynecology and of Maternal Fetal Medicine, University of Wisconsin, Madison, USA ; 3 Department of Obstetrics and Gynecology, University of Washington,

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Seattle, USA; 4 Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, USA; 5 Department of Epidemiology, University of Washington, Seattle, USA; Corresponding author’s contact information: Marc Blondon, Geneva University Hospitals, Gabrielle-

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Perret-Gentil 4, 1205 Geneva, Switzerland; email: [email protected]; telephone +41-22-372-

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92-92; fax +41.22.372.92.99

Keywords: deep venous thrombosis, pulmonary embolism, pregnancy, metaanalysis Word count: abstract 250 / text 3680 Figures/tables: 4 / 4

Conflicts of interest: none

Funding: M Blondon was supported by a fellowship for prospective researchers from the Swiss National Science Foundation. This sponsor had no role in the development of the research or the manuscript. th

Disclaimers: part of this work has been presented as a poster at the 5 International Symposium on Women’s Health Issues in Thrombosis and Haemostasis (Vienna, February 1-3, 2013).

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ASH = American Society of Hematology BMI = body-mass index CS = cesarean sections DVT = deep vein thrombosis FIGO = International Federation of Gynecology and Obstetrics ISTH = International Society on Thrombosis & Haemostasis LMWH = low-molecular-weight heparin OR = odds ratio PE = pulmonary embolism RCOG = Royal College of Obstetricians and Gynaecologists SGI = Society for Gynecologic Investigation SMGM = Society for Maternal-Fetal Medicine VD = vaginal deliveries VTE = venous thromboembolism WHITH = Women’s Health Issues in Thrombosis & Haemostasis

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Abbreviations list

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Abstract Background: Cesarean sections (CS) are believed to be associated with greater risks of postpartum venous thromboembolism (VTE). Our objective was to systematically review the

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evidence on this association and on the absolute risk of VTE after CS. Methods: We searched Pubmed, Embase and conference proceedings from 1980 to

11/2015 for reports on the associations of delivery methods with postpartum VTE and on the incidence of VTE after CS. We excluded studies on thrombophilia or recurrent VTE and

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restricted to prospective studies when assessing the incidence of VTE. Pooled relative and absolute risks were estimated with random-effects models.

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Results: Our search retrieved 28 mostly retrospective observational studies comparing risks of VTE after CS and after vaginal deliveries (VD) (n>53000 VTE events), and 32 prospective studies reporting risks of VTE after CS (n=218 VTE events). Compared with VD, the relative risk of VTE after CS ranged from 1-22, with a meta-analytic odds ratio (OR) of 3.7 (95%CI

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3.0-4.6). Adjustment for age and BMI had a marginal influence on the estimated pooled OR. Associations were observed for both elective and emergency CS, with stronger estimates of associations for emergency CS. The pooled incidence was 2.6VTE/1000 CS (95%CI 1.7-

(4.3/1000 CS).

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3.5), and was greater in studies with a longer and better follow-up in the postpartum

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Conclusion: The risk of VTE is 4-fold greater after CS than VD, appears independent of other VTE risk factors, and is greater after emergency than elective CS. On average, 3 in 1000 women will develop a VTE after CS.

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Introduction For hormonal and mechanical reasons, pregnant women suffer from increased risks of venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary

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embolism (PE).1 Because the risk is highest in the two weeks after delivery, preventing VTE in the early postpartum period likely represents the best opportunity to reduce the burden of morbidity and mortality associated with pregnancy-related VTE. Obstetrical DVT leads to

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long-term post-thrombotic syndrome and decreased quality of life in a substantial proportion of women 2 and PE is potentially fatal with also a long-term risk of disability through chronic

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pulmonary hypertension.

About a third of all women deliver by cesarean section (CS) in Europe and North American today.3 CS are associated with more VTE than vaginal deliveries (VD) in many but not all studies, and whether elective CS are associated with increased VTE risk remains debated.4

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A better estimation of the associations of CS with VTE and the absolute risk of VTE after CS may help inform obstetricians and their patients, as well as the development of future guidelines on thromboprophylaxis during the postpartum period.

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In this systematic review and meta-analysis, our first aim was to refine the estimates of the relative risk of postpartum VTE after CS, compared with after VD, in both unadjusted and

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multi-adjusted analyses. The second aim was to provide a meta-analytic summary estimate of the incidence of postpartum VTE after CS.

Methods

We conducted this meta-analysis following the MOOSE and PRISMA recommendations for reporting meta-analyses of observational studies .5 No review protocol had been published

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Eligibility criteria

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For the meta-analysis of the relative risk of VTE (CS compared with VD), inclusion criteria were observational or interventional studies reporting the association of CS (planned

[elective] or/and emergency [acute]) with the risk of VTE (DVT and/or PE), compared with VD, in the postpartum (at most 3 months after delivery), or reporting the crude data

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necessary to estimate this association. For the meta-analysis of the absolute risk, we

included observational or interventional studies reporting the incidence of VTE after CS,

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without restriction on minimal follow-up after delivery but with restriction to prospective study designs to maximize the validity of VTE diagnoses. Studies focused on women with history of VTE or with thrombophilia, family studies, or studies entirely conducted before 1980, prior to the implementation of valid non-invasive tests for VTE, were excluded. Studies published

details.

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in abstract form were only included if their authors could be contacted to provide further

Search strategy and study selection

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We electronically searched Pubmed and Embase using relevant subject headings, from 01/1980 through 11/24/2015. As an example, the Pubmed search query was (Cesarean

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Section[Mesh] OR "Postpartum Period"[Mesh] OR "Pregnancy"[Mesh]) AND ("Venous Thrombosis"[Mesh] OR "Venous Thromboembolism"[Mesh] OR "Thrombosis"[Mesh] OR "Pulmonary Embolism"[Mesh]). Search results were limited to articles related to humans, in English or French, with original data and excluding case reports. A Pubmed search without subject headings (Mesh) was conducted from 05/01/2015 through 11/23/2015, for recent publications not yet indexed. We also screened available proceedings of conferences for unpublished material from the following conferences, since 2003 : WHITH (International Symposium on Women’s Health Issues in Thrombosis and Haemostasis, from 2005 to

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ACCEPTED MANUSCRIPT 2015), ISTH (International Society on Thrombosis and Haemostasis, from 2003 to 2015), ASH (American Society of Hematology, from 2004 to 2015), FIGO (International Federation of Gynecology and Obstetrics, from 2009 to 2015), RCOG (Royal College of Obstetricians and Gynaecologists, from 2011 to 2012), SMFM (Society for Maternal-Fetal Medicine, from

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2005 to 2015) and SGI (Society for Gynecologic Investigation, 2012). Bibliographies of all retrieved full-texts were manually screened and potential relevant citations retrieved. Authors were contacted by email if data were partly missing to estimate relative risks or absolute

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risks of VTE after CS, or for precisions regarding study design or results.

The review of titles, abstracts and full-texts for inclusion was done independently by 2

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medical researchers (MB and AC or KKH). Disagreements were resolved by discussion between them.

Data extraction and quality assessment

Data from all included reports were extracted independently by two authors (MB and AC),

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with disagreement resolved by discussion. Variables of interest included study sampling design and characteristics, identification, characteristics and validation of VTE events, definition of the postpartum period and assessment of the regression models. The quality

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assessment of the reports was based on usual criteria for observational studies and adapted from items of the Newcastle-Ottawa Scale,6 with the following relevant variables:

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representativeness of the sample, potential for selection bias for the comparator group, potential for outcome misclassification (VTE), potential of VTE capture (duration of follow-up in the postpartum, outpatient capture).

Statistical methods

The comparison of the risk of VTE after CS with that after VD, estimated as relative risks (or odds ratios (OR) for case-control studies), was summarized as a meta-analytic OR using a random-effect model with 95% confidence intervals (95%CI), by the method of DerSimonian and Laird. This model was chosen a priori, at the time of study design, as we expected

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ACCEPTED MANUSCRIPT substantial heterogeneity due to differences in sample characteristics. Heterogeneity itself was measured by the I2, describing the percentage of the observed between-studies variation not due to chance. Small-study effects were explored graphically with funnel plots and statistically with Egger’s test. Secondary analyses included subgroups of studies defined

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by the use of objective tests for the diagnosis of VTE and by sampling design (populationbased vs. not). We evaluated the influence of covariate adjustment on the association

between CS and VTE by including estimates that were at least adjusted for maternal age and BMI. We also planned to compare the proportion of PE among all postpartum VTE after

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CS vs. after VD.

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For absolute risks of VTE after CS, the risk was summarized as the proportion of VTE within 3 months per 1000 CS. The meta-analytic estimate was pooled using random-effect models, for similar reasons as before. Study estimates were transformed with the Freeman-Tukey double arcsin method to remove the dependence of the variance on the mean of the transformed proportion and correct for overdispersion of estimates.7

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All analyses were conducted with Microsoft Excel 2010 (Washington, USA), Stata 11 (Stata

Australia).

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Results

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Corporation, College Station, Texas, USA) and MetaXL 4.0 (Epigear International Pty Ltd,

Our search criteria retrieved 4873 references, after excluding duplicates (Figure 1). We evaluated 628 abstracts and 198 full-texts, of which 28 reports were kept for the metaanalysis of relative risks and 32 for the meta-analysis of absolute risks.

Systematic review and meta-analysis of relative risks Study selection, characteristics and quality

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ACCEPTED MANUSCRIPT Fourteen case-controls studies and 19 cohort studies (1 reporting risk estimates separately for PE and DVT) were initially found, set in Europe, North America, Asia and Australia (Table 1). Five studies were then excluded because of the following reasons: data reported in more recent studies using the same source (data duplicate) 8-10 ; estimates of relative risks only

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presented in strata of other risk factors 4 ; one study published in 1983 but capturing suspected VTE cases well before 1980 (1952 to 1979) .11 The final study sample was 28. The two main study designs were retrospective hospital-based studies using chart reviews with validated VTE events, and retrospective population/large registry-based studies using

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administrative data, with potential for outcome misclassification but a greater

representativeness of participants to the general population. However, 5 studies had

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population or large registry-based design and included only validated VTE events.12-16 Further, 4 studies had some validation of VTE events, using an algorithm requiring the prescription of an anticoagulant or by specific selection and position of ICD-9 codes.17-20 The postpartum period was defined as the first 4-12 weeks after delivery for most studies.

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Outpatient diagnoses of VTE were only captured in six studies.12,17,20-24 Investigators ascertained the exposure (CD) from chart review, ICD codes or birth records in retrospective studies. The representativeness of the study samples was considered

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excellent in population-based studies, good in hospital-based studies, moderate in a study restricting to beneficiaries of Medicaid 23 and low in a Japanese survey of hospital VTE

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cases with a response rate of 55%.25 Two studies had a significant risk of selection bias for women without VTE, who did not emanate from the same population as women with VTE.13,25

Relative risk of VTE

Twenty-eight studies reported >53,000 VTE events in the postpartum, of which about 900 were objectively diagnosed (Table 2). Mean age of included women was around 25-30 years, with a minority >35 years and reports of body-mass index (BMI) were often lacking. While most studies focused on White women, 10 studies included other race/ethnicity or had

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ACCEPTED MANUSCRIPT racially diverse samples.15,17,18,23,25-30 Data on postpartum thromboprophylaxis were rarely available. In unadjusted analyses of individual studies, the risk of postpartum VTE in women after CS was 1-22 times that of women after VD. The pooled random-effect OR was 3.7 (95%CI 3.0-

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4.6) and was not different between case-control and cohort studies (Figure 2A). Heterogeneity was substantial, with an estimated I2 of 89%. Estimates were almost identical between studies with follow-up of less and more than 6 weeks or with or without capture of

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outpatient VTE diagnoses. However, population-based studies and hospital/registry-based studies yielded different OR: 3.0 (95%CI 2.4-3.7) and 6.4 (95%CI 4.1-10.1), respectively

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Also, the OR associated with CS was greater in studies with objective VTE diagnoses (OR 5.9, 95%CI 3.9-9.1) than in studies without objective VTE diagnoses (OR 3.0, 95%CI 2.43.7), but objective diagnoses were mainly assessed in hospital-based studies. We were not able to explore the heterogeneity by differential use of thromboprophylaxis or by women’s characteristics due to lack of data or heterogeneous reporting. In multiple meta-

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regression evaluating study design characteristics, study setting (population-based vs. not) was associated with a 50% decrease in the estimated OR (p=0.04) but objective VTE diagnosis, follow-up or outpatient capture were not.

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The Egger’s test for small-study effect was borderline significant (p=0.06) and the funnel plot was asymmetric, suggesting a publication bias: studies with spuriously inflated risk ratios in

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the 3 studies reporting OR>10 appeared as outliers.25,27,28 Biased estimates may have aroused from 2 of these 3 studies, which were at risk of selection bias 25 and ascertainment bias (due to the occurrence of a fatal PE after CS during the study period).27 Exclusion of these two studies yielded a meta-analytic OR of 3.4 (95%CI 2.8-4.1). The influence of adjustment for at least maternal age was marginal in the 7 studies reporting both an univariate and multivariate estimate multivariate analyses.18,20,23,29,31-33 The unadjusted OR comparing CS to VD was 3.3 (95%CI 2.4-4.4) in univariate analyses and 2.8 (95%CI 2.1-3.8) in adjusted analyses (Figure 3). Further, the combination of age and BMI

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ACCEPTED MANUSCRIPT did not appear to mediate much of the increased risk of VTE after CS in the 4 studies adjusting for at least these covariates: pooled OR 2.8 (95%CI 2.1-3.7) in crude analyses and OR 2.5 (95%CI 1.8-3.1) in adjusted analyses.18,20,29,32 Combining all 7 studies reporting adjusted risk estimates yielded a meta-analytic OR of 2.7 (95% 2.2-3.3).18,20,23,29,31-33

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Elective vs. emergency CS In 10 studies reporting risks separately by type of CS, all relative risk point estimates were higher for emergency procedures than elective procedures (Figure 4) 14-17,19,23,26,34-36. The

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pooled OR, compared with VD, were 2.3 (95%CI 1.7-3.1) and 3.6 (95%CI 2.8-4.7) for

elective and emergency CS. After adjustment in 6 studies, elective CS and emergency CS

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appeared still associated with greater risk of postpartum VTE than VD (pooled OR 2.1, 95%CI 1.5-2.9 & OR 2.8, 95%CI 2.1-3.6, respectively) 14,16,17,19,34,35. Another study (not included in the meta-analysis because of results for CS presented in strata of infection) reported a lack of increased risk for women with elective CS and no infection, but this study

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was at risk of spuriously low risk for CS due to selection bias of hospital controls 4.

Proportion of DVT and PE

Among 5 studies 18,26,28,37 (including a study initially excluded because of data duplication 10),

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the random-effect meta-analytic proportion of PE among all VTE was greater after CS (49%, 95%CI 44-55) than after VD (31%, 95%CI 21-43). However, this observation arose mainly

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from non-validated VT events (administrative codes).

Systematic review and meta-analysis of absolute risk (incidence) Study characteristics and quality Our literature search retrieved 32 prospective observational cohorts or subsamples from prospective cohorts or randomized trials with reports of incidence of postpartum VTE after CS. Several publications were excluded because they reported the same sample of women,

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ACCEPTED MANUSCRIPT at least partially (for example within the MFMU Cesarean registry) 15,38. Sample sizes ranged from small in pilot studies to very large in registries (n=15 to 54184). Studies were based mainly in Europe or in North America, but some were conducted in Australia, China, Japan, Pakistan and Israel.

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Most studies were hospital-based cohorts with objectively diagnosed VTE (Table 3). The follow-up during the postpartum period was often limited to the period of hospitalization for delivery, without data on VTE diagnosed in the outpatient setting. Nine cohorts were

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considered to have an excellent potential for capture of VTE in the postpartum period, with a follow-up of at least 6 weeks, including both inpatient and outpatient VTE events and a

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negligible loss to follow-up 17,39-46. Four had a population-based unselected sampling 45,47,48, with excellent generalizability of the sample, and most were unselected or somewhat selected samples within large maternities. In 6 cohorts and 1 trial, screening for asymptomatic DVT was performed with a compression ultrasound of the lower limb before discharge, around day 2-5 after CS 43,49-54.

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Incidence of VTE after CS

Among 32 prospective studies, there were altogether 120,603 women after CS with 218 VTE

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events in the postpartum. Mean age and BMI were ~ 30 years and ~ 25kg/m2. Data on the use of thromboprophylaxis were rarely reported. The random-effect pooled incidence was

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2.6/1000 deliveries (95%CI 1.7 to 3.5). In sensitivity analyses, we restricted to the 9 studies with an excellent potential capture of VTE events in the postpartum (n=60,125 CS and 92 VTE) 39-46. The pooled incidence was somewhat greater, at 4.3/1000 deliveries (95%CI 1.4-8.4). When excluding 11 studies without clear diagnoses with objective tests, we estimated a pooled incidence of 3.2/1000 deliveries (95%CI 1.7-5.1). When restricting to the 4 studies with the most representativeness of the general population, we found an incidence of 2.4/1000 CS (95%CI 1.0-4.3) 45. The lack of data on use of thromboprophylaxis did not allow us to estimate its influence on VTE incidence. 11

ACCEPTED MANUSCRIPT Incidence of VTE after elective vs. emergency CS Thirteen studies reported VTE events separately for both elective and emergency CS (2 VTE after 1990 elective CS and 6 VTE after 2296 emergency CS) 17,26,39,40,43,44,49,50,55-59. Pooled

0.8-4.5), respectively.

Incidence of VTE in low-risk women after CS

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incidences were 1.6/1000 pregnancies (95%CI 1.2-2.2) and 2.4/1000 pregnancies (95%CI

Eight studies focused on women at lower risk of VTE, by excluding women with pregnancy

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incidence was 2.0/1000 deliveries (95%CI 0.2-5.2).

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complications or other risk factors for VTE (N=1336 CS, 2 VTE) 26,42,44,46,49,51,60,61. Pooled

Utility of screening

Seven studies evaluated the utility of DVT screening with a compression ultrasound in 697 women before discharge, around day 2-5 after CS, among whom 1 proximal DVT and 1 PE were diagnosed 43,49-54. Samples were heterogenous, ranging from women considered at

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high risk of postpartum DVT 50 to asymptomatic healthy women at low risk of postpartum DVT 49,52. The pooled incidence of VTE was 4.5/1000 deliveries (95%CI 0.6-11.2) and was not different from the pooled incidence of VTE without screening (2.7/1000 deliveries, 95%CI

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1.7-4.4). The only proximal DVT that was diagnosed was symptomatic, meaning that screening achieved no diagnosis of asymptomatic proximal DVT. Among 102 women

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deemed at high risk of postpartum VTE in 1 study, whole-leg US diagnosed 4 distal DVT, which were unilateral soleus vein thrombosis of uncertain clinical significance 54. Among 11 studies which reported DVT (n=25) and PE (n=36) separately, the proportion of PE was 41%.

Discussion In this comprehensive systematic review, we pooled >50 reports documenting risks of VTE after CS and found a 4-fold increased risk of VTE, compared with VD. This increased risk

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ACCEPTED MANUSCRIPT appeared mostly independent of maternal age and BMI and was present after both emergency and elective CS, although associations were greater for the former. These relative risks translated into a pooled incidence of 2.6 VTE per 1000 CS for all studies, 4.3 VTE per 1000 CS in studies with the best postpartum capture and 2.0 VTE per 1000 CS

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when restricting to low-risk women. Most of the reports included in this review were of good quality, as assessed by a good

representativeness of samples and low potential for selection bias when comparing CS to

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VD. However, there remained possible misclassifications of VTE events in retrospective studies and often a low potential for VTE capture in the postpartum, due to short follow-ups

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and the absence of outpatient diagnoses, which may lead to an underestimation of the incidence of VTE after CS. Most strikingly, there were very few data on the use of thromboprophylaxis, which may be common in some countries (United Kingdom for example) and is expected to reduce the risk of VTE. This may also have influenced our results.

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To our knowledge, this is the first systematic review to assess risks of VTE after CS. Recently, a systematic review and a meta-analysis reported risks of VTE in the postpartum, regardless of the method of delivery, with estimates varying from 0.5-0.6 per 1000

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pregnancies in retrospective national databases to 0.3-3.0 per 1000 pregnancies in hospitalbased studies, and a pooled incidence rate of 486 per 100,000 person-years (or about 0.6

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per 1000 deliveries) 62,63. Our estimate of 2.6 VTE per 1000 CS (95%CI 1.7-3.5) appears somewhat greater than expected from these risks for VTE after all deliveries. The inclusion of retrospective studies may lead to either an overestimation or an underestimation of the true absolute risk, through misclassification of VTE events identified by administrative coding (by including non VTE events or by non capturing all VTE events). Our restriction to prospective studies, while limiting the power, reduces potential biases due to VTE misclassification.

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ACCEPTED MANUSCRIPT That women with CS may suffer from greater risk of VTE than women with VD has biological plausibility. Pregnancy induces important hemostatic modifications, with major increases in some coagulation factors (fibrinogen, factor VIII, factor von Willebrand), decreases of inhibitors such as protein S and the appearance of a hypofibrinolytic state. In the postpartum

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specifically, women after CS show greater activation of coagulation than women after VD, as reflected by greater D-dimer levels, compared with women after VD 64. This may result from the conditions leading to the CS or to the procedure itself, similar to the increased VTE risk after non-obstetrical surgery. Further, physical activity is reduced after CS compared with

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after VD, with delayed recovery of mobility occurring in the first 2 days after delivery 59.

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We found that screening with compression US at the time of discharge (usually around 2-5 days after delivery) was not useful, as it led to no diagnosis of asymptomatic proximal DVT among 700 women. Research investigators should therefore not consider such screening when designing future randomized trials for thromboprophylaxis in the postpartum. Today, thromboprophylaxis in the postpartum period still represents a unique opportunity to

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reduce maternal morbidity and perhaps mortality. In Europe and North America, about 30% of all women deliver with CS 3. We can estimate, in the United States, that the annual ~ 1.2 million CS would lead to about 3000-4000 postpartum VTE every year. However,

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thromboprophylaxis appears widely under-utilized in the US: it is prescribed in 25% of women after CS, mainly by compression stockings with <3% of heparin prescription. It is

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estimated that 75% of women after CS do not receive any prophylaxis in the postpartum 65. This may arise from a lack of recognition by care providers of the risk of VTE after CS, or a low recognition of the usefulness of preventive thromboprophylaxis methods. There is however strong evidence supporting the efficiency of chemoprophylaxis with heparin in medical and surgical patients, and emerging evidence in the obstetrical setting 66. Mechanical thromboprophylaxis, while less studied, appears useful in surgical patients and is not associated with an accrued bleeding risk.

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ACCEPTED MANUSCRIPT However, at an absolute risk of VTE of 2.6/1000 and 4.3/1000, assuming a reduction of 70% of VTE with thromboprophylaxis, about 550 and 330 or women would need to receive prophylaxis after CS to prevent 1 VTE event. In view of these relatively high numbers needed to prevent 1 VTE event, national guidelines differ somewhat but suggest a relatively

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wide use of thromboprophylaxis after CS. The American College of Obstetricians and Gynecologists suggests the use of pneumatic compression devices for all patients

undergoing CS, and to consider adding heparin in case of additional risk factors 67. The

American College of Chest Physicians recommends no thromboprophylaxis following CS in

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women without additional risk factors, and heparin in case of additional risk factors 68. The Royal College of Obstetricians and Gynecologists in the UK suggests the use of low-

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molecular-weight heparin (LMWH) for 10 days after all CS except elective CS without additional risk factors 69. Taken together, these recommendations appear in line with the results of a previous decision analysis model from our group: some (marginal) benefit of the use of LMWH was suggested if the risk of VTE after CS was greater than 1.5-2.2 /1000 CS,

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but appeared clinically more relevant at a greater risk of VTE 70. Further, the threshold of VTE risk for thromboprophylaxis should also depend on the cost-effectiveness balance, which remains undetermined, and on personal preferences given the burden of injections

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and the associated, although likely very low, bleeding risks. The limitations of this systematic review lie mainly in the limitations of the primary data.

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While we gathered numerous studies evaluating VTE risks after delivery, their designs were mostly non population-based, with short follow-ups, possible VTE misclassification, and the wide lack of reports on the use of thromboprophylaxis. Specifically, one could postulate that the meta-analytic incidence of 2.6 VTE per 1000 CS may represent an underestimate of the true risk, because of the short follow-up periods and the unknown use of thromboprophylaxis. The strengths of our review include the search of multiple databases and of conference abstracts, the contact to authors to gather the most comprehensive data on the topic, and

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ACCEPTED MANUSCRIPT the restriction to prospective studies to best estimate the absolute risk of VTE after CS. The validity of our results is also strengthened by the consistency of the findings across the studies. In conclusion, we found that CS is an important independent risk factor for the development

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of VTE in the postpartum, and that about 3 VTE will occur for every 1000 CS performed, with greater risks for emergency CS. Preventing postpartum VTE after CS may lead to an important reduction of its associated morbidity and mortality from a public health’s

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perspective. In this setting, further observational studies and randomized trials are needed, in order to better appreciate risks of VTE in specific groups after CS and to define the

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efficacy and safety of thromboprophylaxis.

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Acknowledgements

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M Blondon takes responsibility for the content of this manuscript, including the data and analysis. Author contributions:

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Acquisition of data: MB, AC and KKH.

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Study conception and design: MB, FB, MR and NLS.




Analysis and interpretation of the data: MB, AC, KKH, FB, MR and NLS.




Drafting of the manuscript: MB




Critical revision of the manuscript: AC, KKH, FB, MR and NLS.

We are thankful to all authors who provided information or data on original studies following

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our requests. We are also thanksful to Prof. P. Fontana and Dr. H. Robert-Ebadi for their thoughtful comments on the manuscript.

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M Blondon was supported by a fellowship for prospective researchers from the Swiss National Science Foundation. This sponsor had no role in the development of the research

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or the manuscript.

The authors have nothing to disclose.

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Table 1. Design and quality of 28 studies included in the meta-analysis of the relative risk of VTE after cesarean section, compared with vaginal deliveries.

Country

Period

Prospective (P) / retrospective (R)

Setting

Inclusion criteria

Exclusion of women with a history of VT

Outcomes

Representativeness of VT cases to the average population

Selection of controls

Duration of postpartum follow-up

Capture of outpatient VT diagnoses

Adjustment variables in multivariate model

Waldman 2015

Israel

19881998

R

Hospitalbased

deliveries at Soroka University Medical Center

no

DVT, PE and other

unclear

+++

+++

6 weeks

no

-

USA

19872011

R

Populationbased

all deliveries in Washington State

yes

DVT and PE

Admin. algorithm

++++

+++

3 months

no

age, BMI, race, parity, smoking, preeclampsia, diabetes, preterm, SGA, education

Korea

20022008

R

Hospitalbased

deliveries at Cheil General Hospital

no

DVT and PE

with objective tests

+++

+++

4 weeks (unclear)

no

-

DVT and PE

with objective tests

++++

+++

6 weeks

yes

-

++++

+++

14 weeks

no

parity, preeclampsia, placenta praevia / abruptio, ART

+++

+++

6 weeks

yes

-

++++

+

10 weeks

no

-

30

deliveries of Population- primigravidae with no based antithrombotic treatment deliveries in 18 Populationhospitals in 11 based Norwegian counties

Galanaud 1999France 12 2010 2009

P

Jacobsen 1990Norway 14 2008 2003

R

Lindqvist 1990Sweden 24 2005 2008

R

Hospitalbased

Hiltunen 13 2007

R

Populationbased

Finland

19971998

yes

SC

M AN U

TE D

Won 2011

EP

Blondon 18 2014

yes

DVT and PE

deliveries at Malmö University Hospital

no

DVT and PE

deliveries in Finland from national pregnancy registry

no

DVT, PE and cerebral thrombosis

AC C

71

Assessment of VTE

Study

RI PT

CASE-CONTROL STUDIES

with objective tests with objective tests with objective tests

24

ACCEPTED MANUSCRIPT

with objective tests

Populationbased

all deliveries in Sweden

yes

+++

+++

6 weeks

unclear

-

++++

+++

6 weeks

no

age, parity, smoking, multiple pregnancy, preeclampsia

DVT, PE, cerebral and none portal thrombosis COHORT STUDIES

DVT, PE and With cerebral anticoagulant thrombosis treatment

Adjustment variables in multivariate model

-

Capture of outpatient VT diagnoses

yes

yes

Duration of postpartum follow-up

Population- hospital deliveries in based Northern Denmark

RI PT

DVT and PE

3 months

SC

no

+++

Selection of women with VD

R

deliveries of Chinese women at a tertiary hospital

no

blood group; BMI; cardiac disease; gestation at delivery; maternal age; method of delivery; feeding method at discharge

Representativeness of women with CS to the average population

Period

Country

Study

Colmorn Denmar 200019 2014 k 2010

Hospitalbased

+++

In-hospital only (unclear)

++++

Adjudication of outcome

R

Lindqvist 1990Sweden 31 1999 1993

DVT and PE

++++

M AN U

R

yes

TE D

19982000

Population- deliveries in Olmsted based County

27% with objective tests & 73% clinical diagnosis

VT outcomes

Hong Kong

none

EP

R

DVT, PE, cerebral and splanchnic thrombosis

Exclusion of women with a history of VT

19661990

no

AC C

27

USA

deliveries in North Thames region

Inclusion criteria

Chan 2001

R

Populationbased

Setting

DanilenkoDixon 21 2001

UK

19881997

Prospective (P) / retrospective (R)

Simpson 29 2001

++++

+++

3 months

No

BMI or maternal age

25

ACCEPTED MANUSCRIPT

20

USA

19942009

UK

19952009

Kane 198034 Scotland 2013 2005

O'Connor 72 2011

USA

20032008

Morris 200135 Australia 2006 2010

R

Populationbased

Deliveries of women in the Nationwide Inpatient Sample (community hospitals)

R

Populationbased

deliveries of women in network of GP and medical practices

R

Population- deliveries in Scottish based maternity hospitals

R

R

Hospitalbased

deliveries in 2 urban tertiary hospitals

DVT, PE and cerebral thrombosis

no

yes

no

deliveries >20wks Populationgestation in New based South Wales hospitals

no

no

With objective tests or anticoagulati on

None

Admin. Code+ DVT and PE Anticoagulant prescription DVT, PE, cerebral and superficial none venous 2 thrombosis DVT and PE

Only PE

+++

RI PT

yes

DVT, PE, cerebral, ovarian and portal thrombosis

++++

++++

+++

SC

R

deliveries of pregnant Populationwomen without prior based VTE, CVD or cancer

yes

M AN U

Sultan 2013

Denmar 1995k 2009

R

TE D

Ghaji 33 2013

19972010

EP

Virkus 16 2014

UK

Admin. Code + DVT and PE anticoagulant prescription

AC C

Abdul Sultan 17 2014

deliveries of pregnant Population- women in England based within the CPRD network

with objective tests

None

12 weeks

yes

Age, BMI, smoking, varicose vein, cardiac disease, IBD, preeclampsia, gestational hypertension, pregnancy length, stillbirth, postpartum bleeding and infection

12 weeks

No

age, calendar yr, education, thrombophilia, anticoagulation, medical diseases, ART, parity

++++

+++

Birth hospitalizati on only

no

++++

+++

12 weeks

yes

calendar year, age, insurance, region, urban/rural, anemia, diabetes, heart disease, hypertension, obesity, transfusion, bleeding, multiple gestation, preeclampsia, postnatal infection age, parity, BMI, smoking, duration of pregnancy, hemorrhage, varicose veins, IBD, cardiac disease

++++

+++

6 weeks

no

age, year of delivery, deprivation status, parity, hypertension, history of VTE, hemorrhage, preeclampsia

+++

+++

3 months

no

-

no

Age, parity, twins, hypertension, diabetes, lupus, smoking, prior fetal loss, prior VTE, stillbirth, preterm birth, SGA and LGA, transfusion

++++

+++

6 weeks

26

ACCEPTED MANUSCRIPT

no

P

Hospitalbased

deliveries of consecutive pregnant women with follow-up at University hospital

no

Kobayashi 1991Japan 25 2008 2000

R

Hospitalbased

survey of deliveries in 68 university and 34 general hospitals

1997 and 2002

R

P

Chauleur 2002France 37 2008 2003

Pallasmaa Finland 36 2008 Landon 15 2004

PE

1

none

++++

Birth hospitalizati on only

no

+++

6 weeks

no

-

+

Birth hospitalizati on only (8 days)

no

-

+++

DVT and PE

with objective tests

no

PE only

with objective tests

singleton deliveries of Populationsingleton of >22wks & based >500g in Finland

no

DVT and PE

none

++++

+++

6 weeks

no

-

singleton deliveries of Registrywomen with prior based cesarean section at 19 university hospitals

no

DVT and PE

with objective tests

+++

+++

Birth hospitalizati on ony

no

-

none

++

+++

2 months

yes

no

DVT and PE

none

+++

+++

Birth hospitalizati on only

no

prolonged second stage of labour

no

DVT and PE

with objective 4 tests

+++

+++

6 weeks

no

-

no

Burrows 26 2004

USA

19952000

R

term singleton Hospital- deliveries at University based hospital (MageeWomens Hospital)

Gherman 28 1999

USA

19781996

R

Hospitalbased

EP

USA

+

3

DVT, PE and cerebrovascul ar disorders

R

singleton deliveries of PopulationOhio Medicaid based beneficiaries without disabling conditions

19911996

+++

age, race, medical risk factors, dabetes, hypertension, premature rupture, abruptio placentae, dysfunctional labor, breech, fetal distress, other medical risk factors, complications of labor and delivery

AC C

Koroukian 23 2004

USA

19992002

R

SC

19912006

M AN U

Canada

TE D

32

RI PT

deliveries in Canada Population(except Quebec and based Manitoba)

Liu 2009

adjusted for 40 variables, including age, smoking, obesity, diabetes, hx of circulatory disease, hypertension, transfusion, hemorrhage, preterm labour, breech, infection

deliveries in a tertiary center

27

ACCEPTED MANUSCRIPT

R

Hospitalbased

deliveries in Boras Central Hospital

no

DVT

with objective tests

+++

+++

4 weeks

yes

-

RI PT

Kierkegaa 197522 Sweden rd 1983 1980

1

reports of DVT and PE but restriction to peripartum hospitalization for PE only. PE was excluded from analyses because of non-stratification by antenatal or postnatal 3 survey response rate of 55.1% 4 including impedance plethysmography

SC

2

M AN U

Representativeness of women with CS: ++++ population-based with high rate of participation +++ population-based with low rate of participation (<80%) or hospital-based with high rate of participation (>80%) ++ hospital-based with low or unknown rate of participation (<80%) + selected group of women and other

AC C

EP

TE D

Selection of women with VD: +++ low risk of selection bias ++ moderate risk of selection bias + high risk of selection bias Abbreviations: DVT= deep vein thrombosis ; PE= pulmonary embolism ; BMI = body mass index; SGA= small for gestational age; LGA= large for gestational age; ART= assisted reproduction therapy; IBD= inflammatory bowel disease.

28

ACCEPTED MANUSCRIPT

Table 2. Results from 28 studies included in the meta-analysis of the relative risk of VTE after cesarean section, compared with vaginal deliveries.

Age [years]1

BMI (kg/m2)1

Postpartum thromboprophylax is

Cases with CS

Waldman 2015 71

31y

1% obesity

N/A

26

Blondon 2014 18

27.6y

26.3

N/A

358

Won 2011 30

32

NA

NA

20

Galanaud 2010 12

28

36% overweight (controls)

NA

Jacobsen 2008 14

14.8% >35y

N/A

Routine after CS

Lindqvist 2008 24

N/A

N/A

N/A

Hiltunen 2007 13

28.8

23.1

Simpson 2001 29

12.5% >35y

Danilenko-Dixon 2001 21 Chan 2001 27 Lindqvist 1999 31

Controls with CS

Controls with VD

55

~918

~7062

329

2,332

7,912

2

22,075

34,907

4

16

1061

4243

129

185

77,493

535,739

15

22

6,265

45,703

N/A

5

12

79

562

N/A

N/A

256 (CS+VD)

256 (CS+VD)

20,090 (CS+VD)

20,090 (CS+VD)

N/A

9.4% obesity

2%

10

46

9

47

29.6

26.7 2

" not routine"

20

4

3,291

13,018

12.4% >35y

N/A

123

177

12,759

102,181

all CS

all VD

EP

TE D

M AN U

SC

Cases with VD

AC C

Studies

RI PT

CASE-CONTROL STUDIES

N/A

COHORT STUDIES

Studies

Age (years)

BMI (kg/m2)

Postpartum thromboprophylax is

VTE among CS

VTE among VD

29

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16% >35y

5% >35

N/A

23

56

43,391

186,846

Abdul Sultan 2014 17

15% >35y

11% >30

N/A

83

85

54,184

141,207

Virkus 2014 16

15.2% >35y

11.8% obese

N/A

105

188

~156,906

~744,852

Ghaji 2013 33

20% >35y

5% obese

N/A

46756 (CS+VD)

46756 (CS+VD)

~64 million(CS+VD)

~64 million(CS+VD)

Sultan 2013 20

range of 1544y

13.6% obese

N/A

83

186

58,109

294,426

Kane 2013 34

27.2

N/A

N/A

140

358

242,165

1,233,136

O'Connor 2011 72

33y 3

5% obese

100%

26

12

9,558

23,753

19.8% >35y

N/A

N/A

~134

~96

~135,331

~375,692

Liu 2009 32

N/A

N/A

N/A

2857 (CS+VD)

2857 (CS+VD)

3,852,569 (CS+VD)

3,852,569 (CS+VD)

Chauleur 2008 37

29y

N/A

<10%

5

4

500

2,236

Kobayashi 2008 25

NA

NA

NA

50

9

87,382

348,702

Pallasmaa 2008 36

N/A

N/A

N/A

18

37

17,412

93,306

Landon 2004 15

29.3

32.72

N/A

14

3

20,560

13,139

3% >35y

N/A

N/A

~125

~110

31,034

137,702

Burrows 2004 26

28.9y

N/A

14

19

5,656

27,178

Gherman 1999 28

28.3

15.5% >91kg 68.6 kg

N/A

31

19

36,489

232,036

30.3 3

N/A

dextran after CS

3

6

2,622

12,247

Kierkegaard 1983 22

1

SC

M AN U

TE D

EP

Koroukian 2004 23

AC C

Morris 2010 35

RI PT

Colmorn 2014 19

mean (median if mean not reported)

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2

at delivery among VTE cases or hospitalizations Abbreviations: CS = cesarean section ; VD = vaginal delivery ; BMI = body-mass index ; VTE = venous thromboembolism.

AC C

EP

TE D

M AN U

SC

RI PT

3

31

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Intern ational

20032011

Multicenter RCT

CS in women within a primary care research database (CPRD) in England

Singleton term CS of healthy women >35y without pregnancy complications CS in RCT of planned CS vs. planned vaginal in twin pregnancies after 32w of gestation

RI PT

US at day 6 (in 71%)

6 days

No

+

+

Yes

DVT and PE

Administr ative algorithm (ICD-10 + anticoag ulation)

No

12 weeks

Yes

+++

++++

yes

DVT and PE

With objective tests

No

6 weeks

Yes

+++

+

no

DVT, thrombo phlebitis or PE

Requiring anticoag ulation

No

4 weeks

Likely

+

+

Estimate of capture of all VT events during the postpartum (6w-3m) Representativeness of women with CS to the average population

With objective tests

SC

Capture of outpatient VT diagnoses

Barrett 2013 73

Follow-up in the postpartum

Hospitalbased cohort

Screening for VT

Gizzo 2014 42

Adjudication of outcome

Italy

20112012

17

VT outcomes

Populationbased cohort

DVT and PE

EP

UK

19972010

no

M AN U

CS in women at high risk of VTE (hx of VTE, BMI>25, age >35, twin, etc.)

Exclusion of women with a history of VT

Hospitalbased cohort

TE D

Inclusion criteria

Japan

20112012

AC C

Abdul Sultan 2014

Design

50

Period

Goto 2015

Country

Study

Table 3. Design and quality of 32 studies included in the meta-analysis of the incidence of VTE after CS.

32

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Pakist an

20062007

Hospitalbased cohort

CS at Lady Reading Hospital in Peshawar

no

DVT

Sharma 2012 59

Engla nd

~ 2010

hospitalbased cohort

CS at Charlotte's and Chelsea Hospital, London

no

Likely DVT and PE

Cavazza 2012 40

Italy

20072009

hospitalbased cohort

no

Larsson 2011 44

Swede n

20032005

Hospitalbased cohort

Hutton 2011 74

interna tional

20042008

Multicenter RCT

Pallasmaa 2010 48

Finlan d

2005

Populationbased cohort

CS in 12 large delivery units in Finland

20002003

Hospitalbased cohort

Singleton CS of primiparous healthy with no VT family hx with antenatal care at 2 tertiary hospitals

2002

Hospitalbased cohort

random sample from all CS deliveries at Rhode Island hospital

Sia 2009 54

USA

No

1 month

Likely

+

++

no

7 days

N/A

+

++

DVT and PE

with objective tests

no

3 months

yes

+++

++

N/A

DVT and PE

likely with objective tests

no

3 months

yes

+++

+

no

DVT, thrombo phlebitis and PE

Required anticoag ulation

no

4 weeks

yes

+

+

no

DVT and PE

Likely with objective tests

no

hospital stay only

no

+

++++

yes

Likely DVT and PE

Likely with objective tests

no

hospital stay only

no

+

+

yes

DVT and PE

with objective tests

US at discharge & at 2-4 weeks

3 months

yes

++

++

M AN U

SC

N/A

TE D

EP

58

Austra lia

AC C

Said 2010

CS of women without bleeding disorder in a tertiary hospitals planned CS of healthy primiparous non-obese women for breech or maternal request at tertiary hospital CS of women with singleton breech fetus >33 weeks without contraindication to external cephalic version

N/A

RI PT

Raees 2013 57

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with objective tests with objective tests likely With compress ion US 1 with objective tests

Compressi on US at discharge Compressi on US at day 3-7

DVT

with objective tests

no

DVT and PE

N/A

CS with uncertain indication for LMWH

likel y yes

DVT and PE

CS deliveries in 19 hospitals (MFMU network)

no

DVT and PE

no

DVT and PE

no

Likely DVT and PE

20022003

Hospitalbased cohort

consecutive CS in tertiary hospital

no

DVT and PE

Clark 2007 55

Scotla nd

19972000

Hospitalbased cohort

CS of unselected consecutive women attending antenatal care at tertiary hospital

no

DVT and PE

Rodger 2006 53

Canad a

~ 2004

Hospitalbased RCT

CS of women at moderate to high VTE risk

yes

DVT

Chan 2005 49

China

20002001

Hospitalbased cohort

no

DVT

51

Norwa y

20022003

Hospitalbased cohort

likel y yes

Häger 2004 47

Norwa y

19981999

Populationbased cohort

CS of singletons in 24/26 large obstetrics hospitals

Gates 2004 41

UK

19982000

Multicenter pilot RCT

Hauth 2003 75

USA

19992000

Multicenter prospective cohort

Salomon 2004 46

Israel

20002002

Hospitalbased

Murphy 2001 76

USA

19992000

Hospitalbased cohort

M AN U

TE D

EP

AC C

Jacobsen

CS of women with no suspicion of DVT in tertiary hospital Elective singleton CS deliveries of healthy pregnant women without pregnancy complications in tertiary hospital

CS in healthy nulliparous women, with no history of pregnancy complications. CS of cephalic term singletons in women at full cervical dilation

no

6 weeks

no

++

+++

hospital stay only

no

+

+++

Hospitalstay only

No

+

+

hospital stay only

no

+

+

Compressi on US at day 2-5

6 weeks

yes

+

+++

no

hospital stay only

no

+

++++

no

6 months

yes

+++

++

no

6 weeks 2

no 2

++

++

no

2 months

yes

+++

+

no

hospital stay only

no

+

+

RI PT

Franc e

SC

Chauleur 2008 37

with objective tests with objective tests likely with objective tests N/A

no

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(emergency CS)

Hospitalbased RCT

Austra lia

1999

Hannah 2000 56

Intern ational

19972000

Multicenter RCT

CS of women without clear indication for heparin, contra-indication to LMWH or increased bleeding risk CS of non-macrosomic term singletons in breech presentation, without contra-indication to VD

no

DVT and PE

yes

DVT and PE

N/A

no

Hospital stay only (~5 d)

no

+

+

with objective tests

no

6 weeks

yes

+++

+

yes

+

+

no

DVT and PE

Requiring anticoag ulation

no

6 weeks (wheneve r possible)

no

“thromb oemboli c complic ations”

N/A

no

hospital stay only

no

+

+

no

DVT and PE

with objective tests

no

3 months

yes

+++

++++

Switze rland

19831996

Prospective registry

Lindqvist 1999 45

Swede n

19941995

Populationbased cohort

CS of women in Malmo

Kalro 1999 43

Scotla nd

~ 1998

Hospitalbased cohort

CS of women at tertiary hospital

N/A

DVT and PE

with objective tests

Compressi on US at day 2-5

3 months

yes

+++

++

Macklon 1995 52

Scotla nd

~ 1994

Hospitalbased cohort

no

DVT

with objective tests

Compressi on US at day 4

hospital stay only

no

+

+

UK

~ 1987

Hospitalbased RCT

yes

Likely DVT and PE

N/A

no

hospital stay only

no

+

+

Hill 1988 60

EP

TE D

Rageth 1999 78

Elective singleton CS deliveries of women with previous CS

AC C

Burrows 2001 39

Hospitalbased pilot RCT

CS in women with at least 1 additional VTE risk factor

RI PT

~200 0

SC

UK

M AN U

Ellison 2001 77

Asymptomatic women after CS at tertiary hospital CS deliveries in women with no pregnancy complication or coagulation disorders

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Franc e

~198 2

Hospitalbased RCT

CS deliveries in women without VTE risk factors (cardiac disease, varicose veins, obesity)

yes

DVT and PE

clinical diagnosis

Nielsen 1983 79

Swede n

19781980

Hospitalbased

CS deliveries at Boras central hospital

no

thrombo sis

with objective tests

no

RI PT

MasliahPlanchon 1983 61

no

~ 12 days

N/A

+

+

hospital stay only

no

+

+++

M AN U

SC

Estimate of capture: +++ min. 6 weeks of follow-up with negligeable loss to follow-up (<10%) and outpatient capture ++ min. 6 weeks of follow-up with loss to follow-up (>10%) or no outpatient capture + other

Representativeness of sample: ++++ population-based with high rate of participation +++ population-based with low rate of participation (<80%) or hospital-based with high rate of participation (>80%) ++ hospital-based with low or unknown rate of participation (<80%) + selected group of women and other 2

Magnetic Resonance Venogram results not taken into account. based on other MFMU publications

TE D

1

AC C

EP

Abbreviations: DVT= deep vein thrombosis ; PE= pulmonary embolism ; BMI = body mass index; VTE= venous thromboembolism; RCT= randomized controlled trial; LMWH= low-molecular-weight heparin

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Table 4. Results of 31 studies included in the meta-analysis of the incidence of VTE after CS. n VTE (DVT/PE)

143 54184 529 1873 100 30 499 292 828 2496 491 164 3 500 1016 15 93 59 2751 141 117 39285 209 30 76 1392 11433

04 88 0 7 1 (0/1) 0 1 (1/0) 1 (0/1) 1 (1/0) 7 (3/4) 0 1 (1/0) 5 (3/2) 3 (N/A) 0 0 0 6 (NA) 1 (0/1) 1 (1/0) 40 (24/16) 0 0 1 (1/0) 0 49 (NA)

RI PT

n CS

SC

25 11% obese 27 N/A N/A 24 75kg N/A 73kg 17% obese 24.8 32.2 2 N/A N/A N/A 22.3 26 25 30% >80kg N/A N/A 15% >30 28 81kg N/A N/A

M AN U

36y 20% >35y 38y 45% >30y 31y ~ 33y 34y 32y 30y 31y 29.2y 30y 29y 28y 33y 32y 32y 30y 31y 28 y N/A 9% >35y 27y 31y 68% <30y 54% >30y

Postpartum thromboprophyla xis 100% N/A 66% N/A N/A 100% 50% 0% N/A 4% N/A N/A ~8% 64-93% ~50% low 0% N/A 50% 0% vs. N/A N/A N/A 100% 50% N/A N/A

TE D

BMI (kg/m2)1

EP

Goto 2015 50 Abdul Sultan 2014 17 Gizzo 2014 42 Barrett 2013 73 Raees 2013 57 Sharma 2012 59 Cavazza 2012 40 Larsson 2011 44 Hutton 2011 74 Pallasmaa 2010 48 Said 2010 58 Sia 2009 54 Chauleur 2008 37 Clark 2007 55 Rodger 2006 53 Chan 2005 49 Jacobsen 2004 51 Häger 2004 47 Gates 2004 41 Salomon 2004 46 Hauth 2003 75 Murphy 2001 76 Ellison 2001 77 Burrows 2001 39 Hannah 2000 56 Rageth 1999 78

age (years)1

AC C

Study

Incidence per 1000 pregnancies 0.0 1.6 0.0 3.7 10.0 0.0 2.0 3.4 1.2 2.8 0.0 6.1 10.0 3.0 0.0 0.0 0.0 2.2 7.1 8.5 1.0 0.0 0.0 13.2 0.0 4.3

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29y 11% >35y N/A N/A N/A

65kg 8% >80kg N/A N/A N/A

N/A N/A N/A 50% 52%

17.9% >35y

38.3% obese

0%

61

Nielsen 1983 79

mean (median if mean not reported) at time of delivery 3 with complete data 4 four distal asymptomatic soleal DVT not taken into account.

3 (NA) 1 (0/1) 0 0 0

12.9 7.8 0.0 0.0 0.0

1319

1 (1/0)

0.8

SC

1

233 129 94 50 196

RI PT

Lindqvist 1999 45 Kalro 1999 43 Macklon 1995 52 Hill 1988 60 Masliah-Planchon 1983

AC C

EP

TE D

M AN U

2

38

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AC C

EP

TE D

M AN U

SC

RI PT

Figure 1. Flow diagram

39

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RI PT

Figure 2. Forrest plot (A) and funnel plot (B) of the unadjusted relative risk of venous thromboembolism after cesarean deliveries, compared with after vaginal deliveries

M AN U

SC

A

AC C

EP

TE D

B

40

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AC C

EP

TE D

M AN U

SC

unadjusted analyses and analyses adjusted at least for maternal age.

RI PT

Figure 3. Forrest plots of relative risk of venous thromboembolism after cesarean delivery, compared with after vaginal delivery, stratified into

41

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RI PT

Figure 4. Forrest plot of the unadjusted relative risk of venous thromboembolism after cesarean delivery, compared with after vaginal

AC C

EP

TE D

M AN U

SC

deliveries, stratified for elective and emergency cesarean delivery.

42

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AC C

EP

TE D

M AN U

SC

RI PT

Figure 5. Forrest plot of the absolute risk of postpartum VTE in prospective cohort studies

43

AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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EP

TE D

M AN U

SC

RI PT

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EP

TE D

M AN U

SC

RI PT

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EP

TE D

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SC

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EP

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