http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–9 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.913130
REVIEW ARTICLE
Incidence of venous thromboembolism during pregnancy and the puerperium: a systematic review and meta-analysis J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 12/20/14 For personal use only.
Kaikai Meng1, Xiaolan Hu2, Xiaoxia Peng2, and Zhenyu Zhang1 1
Department of Obstetrics and Gynecology, Beijing Chaoyang Hospital, and 2Department of Epidemiology and Biostatistics, School of Public Health, Capital Medical University, Beijing, China Abstract
Keywords
Objective: Women during pregnancy or puerperium have a higher risk of venous thromboembolism (VTE). The reported incidence of pregnancy-associated VTE from literature varied considerably. To summarize the overall incidence of the disease, we conducted this meta-analysis. Methods: We searched PubMed, EMBase and CNKI (China National Knowledge Infrastructure) for studies that reported the incidence of VTE during pregnancy or puerperium. The quality of included studies was assessed using the Newcastle–Ottawa scale and the meta-analysis was conducted using R software and Meta analyst Beta 3.13. Sensitivity analyses were performed to analyze the robustness of the results and publication bias was assessed using Egger’s test. Results: Twenty-seven articles met the inclusion criteria. The pooled incidence rate was 1.4% (1.0–1.8%) for VTE, 1.1% (1.0–1.3%) for deep vein thrombosis (DVT) and 0.3% (0.2–0.4%) for pulmonary embolism (PE). The weighted proportion of VTE postpartum was 57.5% and the pooled proportion of right-sided DVT was 27.9%. We noted substantial heterogeneity among individual studies. Conclusions: Women during pregnancy or puerperium are associated with a higher morbidity of VTE. Physicians should be of high vigilance to pregnancy-associated VTE, especially for women postpartum.
Incidence, meta-analysis, pregnancy, puerperium, venous thromboembolism
Introduction Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a serious and possibly life-threatening condition. Pregnant women are 4 to 5 times more likely to develop VTE than non-pregnant women of similar age [1]. Moreover, VTE is the leading cause of maternal death in developed countries [2]. Besides death, women who experience VTE during pregnancy are more likely to develop sequelae such as edema, pain, varicosities, discoloration of skin, recurrent thrombosis and sometimes even ulceration [3]. The components of Virchow’s triad (hypercoagulability, venous stasis and vascular damage) all occur during pregnancy and continue to the postpartum period [4]. Increases in coagulation factors and decreases in coagulation inhibitors during pregnancy lead to a hypercoagulable state, which
Address for correspondence: Zhenyu Zhang, MD, Department of Obstetrics and Gynecology, Beijing Chaoyang Hospital, Capital Medical University, No. 8, Baijiazhuang Rd, Chaoyang District, Beijing 100020, China. Tel: +86 10 85231765. E-mail: mengkaikaide@ hotmail.com Xiaoxia Peng, PhD, Department of Epidemiology and Biostatistics, School of Public Health, Capital Medical University, Beijing, China. Tel: +86 10 83911360. E-mail: [email protected]
History Received 17 January 2014 Accepted 5 April 2014 Published online 7 May 2014
represent the physiological preparation to protect women from the bleeding challenge during miscarriage or childbirth; venous stasis occurs as a result of diminution in venous return caused by the pressure from the gravid uterus on the iliac veins and vena cava [5]; and trauma to the venous system could occur in the course of vaginal delivery and can be exacerbated by cesarean section (CS). All these factors lead to an increased risk of venous thromboembolism. The incidence of VTE during pregnancy and puerperium have been reported in a number of studies, and the reported incidence varies considerably (ranging from 0.08 to 7.13 per 1000 pregnancies) [6,7]. The actual incidence is difficult to define for its rare frequency, differences in study design, lack of objective diagnosis in retrospective studies, different populations that studied in individual articles and variable usage of thromboprophylaxis. Inconsistencies also surround both the period when a pregnant woman is at a higher risk of VTE and the leg in which there is a higher risk of DVT. There has been a meta-analysis of the period of risk and the leg of presentation of DVT during pregnancy and the puerperium using all relevant studies published between 1966 and 1998; however, it is too old to reflect the situation of pregnancyassociated VTE nowadays [8]. A synthesis of relevant data would provide important evidence for physicians to develop effective strategies for
2
K. Meng et al.
diagnosis and prevention of pregnancy-associated VTE. We thus conducted this systematic review and meta-analysis with the primary aim to estimate the overall incidence of pregnancy-associated VTE, and to summarize the period of risk and the leg of presentation of DVT during pregnancy and the postpartum period as the secondary aim.
Methods
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 12/20/14 For personal use only.
Search strategy We systematically searched PubMed, Embase and China National Knowledge Infrastructure (CNKI) for studies (published before December 2013) of the incidence of VTE during pregnancy or puerperium. The following search terms were used: (‘‘venous thromboembolism’’ OR ‘‘deep vein thrombosis’’ OR ‘‘pulmonary embolism’’) AND (‘‘postpartum’’ OR ‘‘puerperium’’ OR ‘‘pregnancy’’ OR ‘‘peripartum’’ OR ‘‘perinatal’’ OR ‘‘Obstetric*’’). Additionally, the references of included articles and key review papers were handsearched to implement the search. Inclusion criteria and study selection Articles that met the following criteria were included: (1) studies that reported the incidence of VTE during pregnancy or puerperium; (2) studies that presented sufficient data to calculate the incidence of VTE; (3) articles published in English or Chinese language. Reviews, studies with the sample size less than 1000, studies in a population with risk factors wholly (e.g. an article with women after CS as the study population [9]) or studies without mentioning diagnostic criteria were excluded. When both the population and the study period in different articles overlapped, we chose the latest publication and supplemented it from the earlier studies if possible. The articles identified were selected based on the inclusion criteria described above by two authors (Meng and Hu) independently. First, an assessment of the identified records by reading the title/abstract was performed. The records which were not relevant to the topic or duplicates were excluded. Second, the studies remained after the first step were promoted to further screening by reading the full-text, and the studies that met the inclusion criteria were finally selected in the meta-analysis. Disagreements were resolved by discussion and consultation with the experts (Peng and Zhang). Data extraction For each selected article in this review, the following information were extracted: first author and publication year, study design, data source, study period, diagnostic criteria, sample size, numbers of cases with VTE, DVT or PE, reported incidence, the period of risk and the leg of presentation. Four studies investigated DVT, PE and other kind of thromboembolic diseases [10–13], we extracted only the number of DVT and PE in our analysis. Ros et al. [11] study reported the number of venous thrombosis which included both DVT and superficial vein thrombosis (SVT), and the number of DVT were not available separately, therefore, only the number of PE was extracted. Data
J Matern Fetal Neonatal Med, Early Online: 1–9
extraction was performed independently and then aggregated. Disagreements were resolved through discussion and consensus. Quality assessment Two reviewers (Meng and Hu) independently assessed the quality of eligible articles using pre-developed checklist based on the NEWCASTLE – OTTAWA Quality Assessment Scale [Available from: http://www.lri.ca/progras/ceu/oxford.htm in 26 May 2011]. There were six criteria in the checklist: defined inclusion criteria, diagnostic criteria, quality control, statistics analysis, sample size and its representativeness. The risk of bias was considered as ‘‘low’’ if a study fulfilled five or more of the criteria, ‘‘moderate’’ if a study fulfilled three or four, and ‘‘high’’ if a study fulfilled only two or less. Disagreements were resolved by discussion. Statistical analysis A variance-stabilizing double arcsine transformation was performed to estimate the incidence of VTE for the inverse variance weight in the meta-analyses is considered as suboptimal when dealing with binary data with low incidences [14], and the data used to estimate the case fatality rate of PE was log transformed. The meta-analysis of the incidence of VTE and the case fatality rate of PE were pooled in R software (R Development Core Team 2010), and the proportion of postpartum VTE and proportion of rightsided DVT were calculated using Meta analyst Beta 3.13 (Tufts Medical Center). The heterogeneity among included studies was estimated using the Cochran Q-test (p50.10 represents significant heterogeneity) and the I2 statistic (I2 ¼ 25, 50 and 75 represents low, medium and high heterogeneity, respectively). When the heterogeneity among individual studies was observed, the pooled prevalence and its 95% CI were calculated by Random Effect Model (REM); otherwise, the Fixed Effect Model was chosen. To analyze the robustness of the results, two sensitivity analyses were conducted with the studies which reported the incidence of VTE: one by removing the studies with high-risk bias to determine whether the quality of the included studies would influence the meta-analytic results and the other by removing the studies which reported the highest and lowest incidences. Publication bias was measured using Egger’s test (p50.05 represents statistically significant publication bias).
Results Characteristics of the included studies Of the 4437 articles identified, 27 were finally eligible for the meta-analysis after the title/abstract screening and the fulltext screening (Supplementary Figure S1). Main characteristics and primary data of the eligible studies are presented in Tables 1 and 2 [5–7,10–13,15–34]. The majority of these studies (n ¼ 24) were retrospective cohort studies, and three were prospective studies. The enrolled studies included data from 14 countries, of which six studies were from the USA [5,7,13,16,24,26], three each from China [10,25,29] and Sweden [11,32,33], two each from Sudan [19,27], England [15,30], Denmark [18,31], and Australia [17,23] and one each
retrospective cohort study
Retrospective study
Retrospective study
Retrospective study
Retrospective study
Retrospective study
Retrospective study
Prospective cohort study
Retrospective study Retrospective study
Retrospective study
Retrospective study
Retrospective study Prospective cohort study
Retrospective study Retrospective study
Retrospective study Retrospective cohort Study
Retrospective cohort study
Retrospective study Retrospective study
Retrospective study
Prospective cohort study Retrospective study
Retrospective study
Jang 2011 [6]
David 2010 [16]
Morris 2010 [17]
Virkus 2010 [18]
Gader 2009 [19]
Liu 2009 [20]
Jacobsen 2008 [21]
Kobayashi 2008 [22]
Sharma 2008 [23] James 2006 [24]
Liu 2006 [25]
Heit 2005 [26]
Haggaz 2003 [27] Soomro 2002 [28]
Armour 2001 [7] Chan 2001 [29]
Ros 2001 [11] Simpson 2001 [30]
Gherman 1999 [5]
Olson 1998 [12] Andersen 1997 [31]
James 1996 [13]
Bergqvist 1983 [32] Kierkegaard 1983 [33]
Treffers 1983 [34]
University Hospital Wilhelmina Gasthuis, the Netherlands
Wad Medani Hospital, Sudan King Fahad Hospital, Al Baha, Saudi Arabia a university hospital in inner-city, USA a tertiary university teaching hospital in Hong Kong, China The Birth Register, Sweden the St Mary’s Maternity Information System database, England Los Angeles and University of Southern California Women’s hospital, America St John’s Mercy Medical Center, Belgium The Regional Hospital, North Jutland, Denmark Good Samaritan Hospital, Cincinnati, Ohio, USA Karnsjukhuset, Skovde, Sweden the Central Hospital, BorAs, Sweden
13 tertiary hospitals in Guangdong, China A large prospective primary care database, UK Korean Health Insurance Review and Assessment Service (HIRA) database, Korea Two affiliated urban tertiary care facilities, USA New South Wales (NSW) hospitals, Australia The National Registry of Patients, Denmark Khartoum and Khartoum North Teaching hospitals, Sudan Hospital admission collated by the Canadian Institute, Canada 18 hospitals in 11 Norwegian counties, Norway 68 university hospitals and 34 general hospitals, Japan Ballarat Health Services, Australia Healthcare Cost and Utilization Project of the Agency, USA Obstetrical patients in 18 hospitals in Guangzhou, china Olmsted County, Minnesota, USA
Resource
1952–1979
1974–1980 1975.1–1980.12
1989.5–1994.10
1985–1995 1984.1–1994.12
1978.1–1996.12
1987.1–1995.9 1988–1997
1992–1997 1998.1–2000.12
1999.1–2000.12 1986.1–1998.12
1966–1995
1992.1–2001.12
1999.3–2006.6 2000–2001
1991–2000
1990.1–2003.12
1991–2006
2007.4–2008.3
1995.1–2005.12
2001–2006
All deliveries
women of antepartum All deliveries
All deliveries
All deliveries All deliveries
All deliveries
All deliveries All deliveries
All deliveries All deliveries
All deliveries All deliveries
All deliveries
All deliveries
All deliveries All deliveries
All deliveries
All deliveries
All deliveries
All deliveries
All deliveries
All deliveries
All deliveries
All deliveries
2006–2010 2003.6–2008.6
All deliveries All deliveries
Study participants
2005.1–2010.6 1987.4–2004.11
Study period
VTE
DVT DVT
VTE
DVT VTE
VTE
PE VTE
VTE VTE
VTE VTE
VTE
VTE
VTE VTE
PE
VTE
VTE
DVT
VTE
PE
VTE
VTE
VTE VTE
Outcome
Phlebography or plethysmography Phlebography for DVT; lung scanning for PE Cases with anticoagulant therapy
Ultrasound or ventilation perfusion scan
Doppler ultrasound, venography, pulmonary angiography CPT codes 671.3 Ultrasound or lung scan
ICD-9 ICD9 (1988–1995); ICD10 (1995–1997)
Ultrasound or Ventilation perfusion scan Ultrasound or ventilation perfusion scan
Objectively or according to clinical symptoms Doppler for VTE Ultrasound or pulmonary scintigraphy
Ultrasound or ventilation perfusion scan
Ultrasound or pulmonary angiogram ICD-9
Pulmonary angiography
Ultrasound for DVT; lung scan for PE
ICD-9 and ICD-10
Doppler ultrasound for DVT
ICD-10
ICD-10
Ultrasound for DVT; angiography for PE.
The Korean Classification of Disease codes
ICD-9 Anticoagulant therapy in records
Diagnostic methods
3.00
7.00 0.74
0.50
0.77 0.85
0.61
0.25 0.85
7.13 1.88
3.80 1.26
1.99
0.52
1.14 1.72
0.17
1.00
1.76
4.49
1.21
0.73
2.22
0.08
0.79 1.01
Incidence (%)
Pregnancy-associated venous thromboembolism
DVT ¼ deep venous thrombosis; PE ¼ pulmonary embolism; VTE ¼ venous thromboembolism; ICD ¼ international classification of diseases; CPT ¼ current procedural terminology.
Retrospective study Prospective cohort study
Study design
Huang 2012 [10] Alyshah 2011 [15]
Study ID
Table 1. Studies included in the meta-analysis.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 12/20/14 For personal use only.
DOI: 10.3109/14767058.2014.913130
3
4
K. Meng et al.
J Matern Fetal Neonatal Med, Early Online: 1–9
Table 2. Primary data of included studies.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 12/20/14 For personal use only.
Study ID
Participants
VTE
DVT
PE
Death
Antepartum*
Postpartumy
Left sidez
Right sideô
Both sidesx
169 218 20 7327 1 795 064 33 311 510 889 584 990 14 490 3 852 569 613 232 436 084 6987 8 330 927 93 651 50 080 14 210 39 757 4910 16 993 654 957 395 335 268 525 65 912 63 319 30 040 2429 14 869 56 022
133 210 147 74 / 709 / 6791 615 / 8 14335 49 100 54 50 35 32 / 336 165 / 54 15 / / 168
128 / / 37 / / 65 4677 449 / 7 11326 46 76 52 23 30 30 / / 127 51 52 12 17 11 /
5 / / 37 375 / / 2114 166 76 1 3009 3 24 2 27 5 2 161 / 38 / 2 3 / / /
/ / / 0 7 / / 47 3 11 / 89 2 / / 1 / 1 / / / / 0 0 / / 3
24 94 44 36 135 491 4 / 301 17 7 7177 11 36 8 17 29 8 63 109 109 / 33 9 / 2 40
109 116 103 38 240 218 61 / 314 59 1 7158 38 64 46 33 6 24 98 227 56 / 21 6 / 9 128
/ / / 23 / / 51 / / / 2 / 35 / 43 26 29 15 / / 104 29 / 10 14 6 /
/ / / 14 / / 13 / / / 6 / 0 / 9 6 1 13 / / 23 20 / 3 3 5 /
/ / / 3 / / 1 / / / 0 / 14 / 2 1 0 4 / / 0 2 / 0 0 0 /
Huang 2012 Alyshah 2011 Jang 2011 David 2010 Morris 2010 Virkus 2010 Gader 2009 Liu 2009 Jacobsen 2008 Kobayashi 2008 Sharma 2008 James 2006 Liu 2006 Heit 2005 Haggaz 2003 Soomro 2002 Armour 2001 Chan 2001 Ros 2001 Simpson 2001 Gherman 1999 Olson 1998 Andersen 1997 James 1996 Bergqvist 1983 Kierkegaard 1983 Treffers 1983
*Number of cases of VTE occurred during pregnancy. yNumber of cases of VTE occurred postpartum. zNumber of cases of DVT presented in left leg only. ôNumber of cases of DVT presented in right leg only. xNumber of cases of DVT presented in both legs.
from Korea [6], the Netherlands [34], Saudi Arabia [28], Norway [21], Canada [20], Japan [22] and Belgium [12]. Sixteen studies used objective methods (e.g. duplex ultrasound, venography or perfusion lung scan) to diagnose VTE, two [15,34] relied on anticoagulant therapy in medical records, seven studies [10,11,17,18,20,24,30] identified VTE according to International Classification of Diseases (ICD) codes, one [12] by Current Procedural Terminology (CPT) codes and one [6] by the Korean Classification of Disease codes. Twenty studies reported the incidence of VTE during pregnancy and the postpartum period, three studies [12,19,33] reported information of pregnancy-associated DVT, three [11,17,22] reported pregnancy-associated PE and one [32] reported antepartum DVT. The reported incidence of VTE during pregnancy or puerperium varies from 0.08 [6] to 7.13 [7] per 1000 pregnancies. Incidence of VTE Twenty articles were identified with sufficient data to estimate the incidence of VTE during pregnancy and puerperium (Figure 1). The sample size varied from 4910 to 8 330 927, and the reported incidence varied from 0.08 to 7.13%. Heterogeneity was significant (I2 ¼ 99.7%; p50.0001) among studies included and the pooled incidence of REM was 1.4% (95% CI: 1.0–1.8%). Incidence of DVT Eighteen articles were available to assess the incidence of pregnancy-associated DVT (Figure 2). The sample size varied
from 4910 to 8 330 927, and the incidence calculated from individual articles ranged from 0.4 to 6.1%. Heterogeneity was statistically significant (I2 ¼ 97.8%; p50.0001); therefore, we chose the REM with a pooled incidence of 1.1% (95% CI: 1.0–1.3%). Incidence and case fatality rate of PE Eighteen articles provided sufficient data to assess the incidence of PE (Figure 3). The sample size varied from 4910 to 8 330 927, and the calculated incidence ranged from 0.0 to 1.1%. Heterogeneity among the individual studies was observed (I2 ¼ 98%; p50.0001), and the pooled incidence based on REM was 0.3% (95% CI: 0.2–0.4%). There were 11 articles available to assess the case fatality rate of PE (Supplementary Figure S2). The number of cases with PE varied from 2 to 3009, and the calculated case fatality rate ranged from 0.00 to 66.67%. Heterogeneity was significant (I2 ¼ 91.1%; p50.0001), and the random-effects pooled event rate was 6.58% (95% CI: 3.30–13.09%). Distribution of VTE in different periods There were 23 articles that compared the incidence rate in the antepartum period versus the puerperium, of which 19 studies compared antepartum VTE with postpartum VTE, two reported the distribution of DVT in pregnancy versus puerperium and two compared antepartum PE with postpartum PE. We therefore conducted a subgroup analysis (Figure 4). The pooled proportions of postpartum VTE, DVT
Pregnancy-associated venous thromboembolism
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 12/20/14 For personal use only.
DOI: 10.3109/14767058.2014.913130
5
Figure 1. Combined incidence of pregnancy-associated VTE from 20 studies.
Figure 2. Combined incidence of pregnancy-associated DVT from 18 studies.
and PE were 57.5% (95% CI: 50.9–63.9%), 90.5% (95% CI: 74.9–96.8%) and 70.3% (95% CI: 55.3–81.9%), respectively. Heterogeneity was found among individual studies (I2 ¼ 0.486, Q ¼ 0.998, p ¼ 0.000). Additionally, number of VTE by trimesters were available in eight articles and were presented in Table 3. The extracted data were consolidated to calculate the proportion of VTE in three trimesters. The proportions of VTE during the first, second and third trimester were 21.36, 22.69 and 55.95%, respectively.
Distribution of DVT in legs Thirteen studies reported the side in which leg DVT was presented (Figure 5). Twelve studies reported DVT in pregnancy and puerperium and one reported DVT only during pregnancy. 530 cases of DVT were documented in total with 387 left-sided DVT, 116 right-sided DVT and 27 bilateral DVT. The weighted event rate for right-sided DVT was 27.9% (95% CI: 20.7–36.4%). Heterogeneity among the studies was observed (I2 ¼ 0.410; Q ¼ 0.998; p ¼ 0.000).
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 12/20/14 For personal use only.
6
K. Meng et al.
J Matern Fetal Neonatal Med, Early Online: 1–9
Figure 3. Combined incidence of pregnancy-associated PE from 18 studies.
Quality assessment and sensitivity analysis 11 articles [5,7,12,13,16,19,23,27,32–34] were found to have high-risk of bias according to the quality assessment of eligible studies (Supplementary S3). We excluded the studies with high risk bias from studies that reported the incidence of VTE to evaluate the robustness of the results (Supplementary Figure S4), and the incidence of VTE decreased by 0.3% (from 1.4 to 1.1%). When the studies which reported the highest and lowest incidence were excluded, the pooled incidence was 1.3% (I2 ¼ 98.6%, p50.0001, 95% CI: 1.1–1.5%). Publication bias The publication bias was assessed using Egger’s test, and the result did not reveal any evidence of publication bias (p ¼ 0.4309).
Discussion The present systematic review and meta-analysis examined the incidence of VTE in pregnancy and puerperium with 27 eligible studies. The pooled incidence of pregnancyassociated VTE was 1.4%, which was significantly higher than non-pregnant women of similar age. The reported incidence from individual studies varied widely (0.08– 7.13%), which might be due to different populations investigated, different diagnostic criteria and validity of data; moreover, the different definition of the postpartum period could also contribute to the variation of the reported incidence, for instance, the Morris et al. [17] study defined the postpartum period as 12 weeks after delivery, whereas puerperium was defined as the first two months after delivery in a study from Denmark [31]. The true incidence could be higher still for that thromboprophylaxis was initiated in cases with suspicion of VTE in some studies. The case fatality rate of PE calculated in individual studies varied widely which may be caused mostly by varied
intervention. The study with the highest rate did not describe any anticoagulant measure to the cases with VTE [25]; in contrast, the O’Connor et al.’s [16] study undertook sufficient intervention to the patients which included thromboprophylaxis to women with a prior history of venous thrombosis, anticoagulant therapy to patients with confirmed VTE, and inferior vena cava filters to patients with bleeding complications. Obviously, prophylaxis and treatment with anticoagulants can significantly reduce the morbidity and mortality of VTE, whereas, only women with additional risk factors could receive thromboprophylaxis for the side-effects of anticoagulants such as thrombocytopenia and bleeding. A comprehensive guideline has been published and recently updated which supply management guidelines of VTE-based on risk assessment [35]. Consistent with the findings from an earlier meta-analysis [8], the present analysis also confirmed the striking predisposition to left-sided DVT which might result from compression of the left iliac vein by the right iliac and ovarian arteries at their crossing [36]. However, the proportion of right-sided DVT reported in the earlier analysis (21.5%) was lower than that in the present review (27.9%). Our explanation was that, unlike the approach of using the number of cases with DVT as the denominator and cases with isolated right-sided DVT as the numerator (which would underestimate the proportion of right-sided DVT), we took account of the number of legs that suffered DVT as the denominator and the number of right legs with DVT as the numerator which would adjust the cases with bilateral DVT. If the same algorithms were conducted, the results would be more comparable. There are several limitations in our study. First, the literature search was limited to articles published in English or Chinese; nevertheless, no evidence of publication bias was found. Second, articles with VTE diagnosed without objective methods were also included; for instance, we
Pregnancy-associated venous thromboembolism
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 12/20/14 For personal use only.
DOI: 10.3109/14767058.2014.913130
7
Figure 4. Proportion of postpartum VTE combined from 23 studies.
Table 3. Distribution of VTE in three trimesters. Study ID Treffers 1983 James 1996 Chan 2001 Soomro 2002 Heit 2005 Jacobsen 2008 Sharma 2008 David 2010 Total Proportion (%)
First trimester
Second trimester
Third trimester
3 3 3 7 4 62 5 10 97 21.36
5 3 3 5 14 64 0 9 103 22.69
32 3 2 5 18 175 2 17 254 55.95
adopted an article with the study period 1952–1979 when non-invasive diagnostic tests were unavailable [34]. VTE was diagnosed on the basis of clinical symptoms which could potentially lead to an overestimation of the morbidity since many of the classic signs and symptoms, including leg swelling, tachycardia, tachypnea and dyspnea, can be present in a normal pregnancy. Third, there was substantial heterogeneity among the studies which might come from differences presented in the study population, study design or diagnostic criteria; hence, the results of the meta-analysis should be interpreted with caution. Finally, we conducted the sensitivity analysis only with the studies used to estimate
8
K. Meng et al.
J Matern Fetal Neonatal Med, Early Online: 1–9
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 12/20/14 For personal use only.
Figure 5. Proportion of right-sided DVT combined from 13 studies.
the incidence of VTE to get a broad idea of robustness of our results, the results of incidence of DVT or PE were not evaluated with sensitivity analysis separately. Although the overall incidence of VTE in pregnancy and puerperium is low, clinicians should be highly vigilant to the development of this disease because of the severe consequences and high mortality. Our findings provide guidance to physicians who are considering diagnosis of VTE. For instance, more than one in five of VTE during pregnancy were detected in the first trimester, which could imply that diagnostic suspicion should start early in the first trimester. Furthermore, the incidence of postpartum VTE was significantly higher; therefore, prophylaxis against pregnancy-associated VTE should be particularly targeted to postpartum women, especially to women with additional risk factors (such as CS in labor, previous VTE or asymptomatic thrombophilic). Moreover, VTE is difficult to diagnose in pregnant women because its associated signs and symptoms (such as dyspnea, edema and pains in the lower extremities) can exist in normal pregnancy, we found that three in four of DVT presented in the left side; therefore, women with edema and pain in left leg should be highly suspected of DVT. Our study highlights the urgent need for large-scale, multicenter and prospective studies on epidemiology of pregnancy-associated VTE. Although meta-analyses are useful tools to synthesize the existing data, it cannot substitute findings from well-conducted primary document [37]. Furthermore, an improvement of the methodology is required to produce comparable data and reduce heterogeneity among studies. In conclusion, women during pregnancy and puerperium are associated with a higher morbidity of VTE. Physicians should be of high vigilance to pregnancy-associated VTE, especially for women postpartum.
Declaration of interest This study was supported by a grant from the Beijing Training Plan of Top-notch Personnel (CIT&TCD201304189), and the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors report no declarations of interest.
References 1. Heit JA, Kobbervig CE, James AH, et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005;143: 697–706. 2. Chang J, Elam-Evans LD, Berg CJ, et al. Pregnancy-related mortality surveillance – United States, 1991–1999. MMWR Surveill Summ 2003;52:1–8. 3. Bergqvist A, Bergqvist D, Lindhagen A, Matzsch T. Late symptoms after pregnancy-related deep vein thrombosis. Brit J Obstet Gynaec 1990;97:338–41. 4. Gray G, Nelson-Piercy C. Thromboembolic disorders in obstetrics. Best Pract Res Cl Ob 2012;26:53–64. 5. Gherman RB, Goodwin TM, Leung B, et al. Incidence, clinical characteristics, and timing of objectively diagnosed venous thromboembolism during pregnancy. Obstet Gynecol 1999;94: 730–4. 6. Jang MJ, Bang SM, Oh D. Incidence of pregnancy-associated venous thromboembolism in Korea: from the Health Insurance Review and Assessment Service database. J Thromb Haemost 2011;9:2519–21. 7. Armour R, Schwedler M, Kerstein MD. Current assessment of thromboembolic disease and pregnancy. Am Surg 2001;67:641–4. 8. Ray JG, Chan WS. Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis of the period of risk and the leg of presentation. Obstet Gynecol Surv 1999;54:265–71. 9. Zhang XX, He QW, Zhang SC. Experience on management of 15 cases with deep venous thrombosis after cesarean section. Shanxi Med J 2007;36:243–4. 10. Huang QT, Zhong M, Wang CH, et al. Prevalence and major risk factors of peripartum thromboembolic disease in different regions of Guangdong province. Chin J Epidemiol 2012;33:413–17.
Pregnancy-associated venous thromboembolism
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 12/20/14 For personal use only.
DOI: 10.3109/14767058.2014.913130
11. Ros HS, Lichtenstein P, Bellocco R, et al. Increased risks of circulatory diseases in late pregnancy and puerperium. Epidemiology 2001;12:456–60. 12. Olson HF, Nunnelee JD. Incidence of thrombosis in pregnancy and postpartum: a retrospective review in a large private hospital. J Vasc Nurs 1998;16:84–6. 13. James KV, Lohr JM, Deshmukh RM, Cranley JJ. Venous thrombotic complications of pregnancy. Cardiovasc Surg 1996;4:777–82. 14. Freeman MF, Tukey JW. Transformations related to the angular and the square root. Ann Math Stats 1950;21:607–11. 15. Sultan AA, West J, Tata LJ, et al. Risk of first venous thromboembolism in and around pregnancy: a population-based cohort study. Br J Haematol 2011;156:366–73. 16. O’Connor DJ, Scher LA, Gargiulo III NJ, et al. Incidence and characteristics of venous thromboembolic disease during pregnancy and the postnatal period: a contemporary series. Ann Vasc Surg 2011;25:9–14. 17. Morris JM, Algert CS, Roberts CL. Incidence and risk factors for pulmonary embolism in the postpartum period. J Thromb Haemost 2010;8:998–1003. 18. Virkus RA, Løkkegaard ECL, Bergholt T, et al. Venous thromboembolism in pregnant and puerperal women in Denmark 1995– 2005: a national cohort study. Thromb Haemost 2011;106:304–9. 19. Gader AA, Haggaz AED, Adam I. Epidemiology of deep venous thrombosis during pregnancy and puerperium in Sudanese women. Vasc Health Risk Manag 2009;5:85–7. 20. Liu S, Rouleau J, Joseph KS, et al. Epidemiology of pregnancyassociated venous thromboembolism: a population-based study in Canada. J Obstet Gynaecol Can 2009;31:611–20. 21. Jacobsen AF, Skjeldestad FE, Sandset PM. Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium – a register-based case-control study. Am J Obstet Gynecol 2008; 198:233.e1–7. 22. Kobayashi T, Nakabayashi M, Ishikawa M, et al. Pulmonary thromboembolism in obstetrics and gynecology increased by 6.5-fold over the past decade in Japan. Circ J 2008;72:753–6. 23. Sharma S, Monga D. Venous thromboembolism during pregnancy and the postpartum period: incidence and risk factors in a large Victorian health service. Aust N Z J Obstet Gynaecol 2008;48: 44–9. 24. James AH, Jamison MG, Brancazio LR, Myers ER. Venous thromboembolism during pregnancy and the postpartum
25. 26. 27. 28. 29. 30.
31. 32. 33. 34.
35.
36. 37.
9
period: incidence, risk factors, and mortality. Am J Obstet Gynecol 2006;194:1311–15. Liu B, Zhong M, Xu Y, et al. An epidemiological study on incidence and risk factors of deep venous thrombosis during perinatal period. Guangdong Med J 2006;27:266–7. Heit JA, Kobbervig CE, James AH, et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30year population-based study. Ann Intern Med 2005;143:697–706. Haggaz AA, Mirghani OA, Adam I. Venous thromboembolism in pregnancy and the puerperium in Sudanese women. Int J Gynecol Obstet 2003;83:309–10. Soomro RM, Bucur IJ, Noorani S. Cumulative incidence of venous thromboembolism during pregnancy and puerperium: a hospitalbased study. Angiology 2002;53:429–34. Chan LY, Tam WH, Lau TK. Venous thromboembolism in pregnant Chinese women. Obstet Gynecol 2001;98:471–5. Simpson EL, Lawrenson RA, Nightingale AL, Farmer RDT. Venous thromboembolism in pregnancy and the puerperium: incidence and additional risk factors from a London perinatal database. Br J Obstet Gynaecol 2001;108:56–60. Andersen BS, Steffensen FH, Sørensen HT, et al. The cumulative incidence of venous thromboembolism during pregnancy and puerperium. Acta Obstet Gynecol Scand 1998;77:170–3. Bergqvist A, Bergqvist D, Hallbook T. Deep vein thrombosis during pregnancy: a prospective study. Acta Obstet Gynecol Scand 1983;62:443–8. Kierkegaard A. Incidence and diagnosis of deep vein thrombosis associated with pregnancy. Acta Obstet Gynecol Scand 1983;62: 239–43. Treffers PE, Huidekoper BL, Weenink GH, Kloosterman GJ. Epidemiological observations of thrombo-embolic disease during pregnancy and in the puerperium in 56,022 women. Int J Gynaecol Obstet 1983;21:327–31. Royal College of Obstetricians and Gynaecologists. Reducing the risk of thrombosis and embolism during pregnancy and the puerperium. Green-top Guideline No.37a 2009. Available from: http://www.rcog.org.uk/files/rcog-corp/GTG37aReducingRisk Thrombosis.pdf [last accessed 28 Apr 2014]. Ginsberg JS, Brill-Edwards P, Burrows RF, et al. Venous thrombosis during pregnancy: leg and trimester of presentation. Thromb Haemost 1992;67:519–20. Moher D, Pham B. Meta-analysis: an adolescent in need of evidence and a watchful eye. Ann Med 1999;31:153–5.
Supplementary material available online Supplementary Figures S1–S4
REVIEW ARTICLE
Incidence of venous thromboembolism during pregnancy and the puerperium: a systematic review and meta-analysis J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 12/20/14 For personal use only.
Kaikai Meng1, Xiaolan Hu2, Xiaoxia Peng2, and Zhenyu Zhang1 1
Department of Obstetrics and Gynecology, Beijing Chaoyang Hospital, and 2Department of Epidemiology and Biostatistics, School of Public Health, Capital Medical University, Beijing, China Abstract
Keywords
Objective: Women during pregnancy or puerperium have a higher risk of venous thromboembolism (VTE). The reported incidence of pregnancy-associated VTE from literature varied considerably. To summarize the overall incidence of the disease, we conducted this meta-analysis. Methods: We searched PubMed, EMBase and CNKI (China National Knowledge Infrastructure) for studies that reported the incidence of VTE during pregnancy or puerperium. The quality of included studies was assessed using the Newcastle–Ottawa scale and the meta-analysis was conducted using R software and Meta analyst Beta 3.13. Sensitivity analyses were performed to analyze the robustness of the results and publication bias was assessed using Egger’s test. Results: Twenty-seven articles met the inclusion criteria. The pooled incidence rate was 1.4% (1.0–1.8%) for VTE, 1.1% (1.0–1.3%) for deep vein thrombosis (DVT) and 0.3% (0.2–0.4%) for pulmonary embolism (PE). The weighted proportion of VTE postpartum was 57.5% and the pooled proportion of right-sided DVT was 27.9%. We noted substantial heterogeneity among individual studies. Conclusions: Women during pregnancy or puerperium are associated with a higher morbidity of VTE. Physicians should be of high vigilance to pregnancy-associated VTE, especially for women postpartum.
Incidence, meta-analysis, pregnancy, puerperium, venous thromboembolism
Introduction Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a serious and possibly life-threatening condition. Pregnant women are 4 to 5 times more likely to develop VTE than non-pregnant women of similar age [1]. Moreover, VTE is the leading cause of maternal death in developed countries [2]. Besides death, women who experience VTE during pregnancy are more likely to develop sequelae such as edema, pain, varicosities, discoloration of skin, recurrent thrombosis and sometimes even ulceration [3]. The components of Virchow’s triad (hypercoagulability, venous stasis and vascular damage) all occur during pregnancy and continue to the postpartum period [4]. Increases in coagulation factors and decreases in coagulation inhibitors during pregnancy lead to a hypercoagulable state, which
Address for correspondence: Zhenyu Zhang, MD, Department of Obstetrics and Gynecology, Beijing Chaoyang Hospital, Capital Medical University, No. 8, Baijiazhuang Rd, Chaoyang District, Beijing 100020, China. Tel: +86 10 85231765. E-mail: mengkaikaide@ hotmail.com Xiaoxia Peng, PhD, Department of Epidemiology and Biostatistics, School of Public Health, Capital Medical University, Beijing, China. Tel: +86 10 83911360. E-mail: [email protected]
History Received 17 January 2014 Accepted 5 April 2014 Published online 7 May 2014
represent the physiological preparation to protect women from the bleeding challenge during miscarriage or childbirth; venous stasis occurs as a result of diminution in venous return caused by the pressure from the gravid uterus on the iliac veins and vena cava [5]; and trauma to the venous system could occur in the course of vaginal delivery and can be exacerbated by cesarean section (CS). All these factors lead to an increased risk of venous thromboembolism. The incidence of VTE during pregnancy and puerperium have been reported in a number of studies, and the reported incidence varies considerably (ranging from 0.08 to 7.13 per 1000 pregnancies) [6,7]. The actual incidence is difficult to define for its rare frequency, differences in study design, lack of objective diagnosis in retrospective studies, different populations that studied in individual articles and variable usage of thromboprophylaxis. Inconsistencies also surround both the period when a pregnant woman is at a higher risk of VTE and the leg in which there is a higher risk of DVT. There has been a meta-analysis of the period of risk and the leg of presentation of DVT during pregnancy and the puerperium using all relevant studies published between 1966 and 1998; however, it is too old to reflect the situation of pregnancyassociated VTE nowadays [8]. A synthesis of relevant data would provide important evidence for physicians to develop effective strategies for
2
K. Meng et al.
diagnosis and prevention of pregnancy-associated VTE. We thus conducted this systematic review and meta-analysis with the primary aim to estimate the overall incidence of pregnancy-associated VTE, and to summarize the period of risk and the leg of presentation of DVT during pregnancy and the postpartum period as the secondary aim.
Methods
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 12/20/14 For personal use only.
Search strategy We systematically searched PubMed, Embase and China National Knowledge Infrastructure (CNKI) for studies (published before December 2013) of the incidence of VTE during pregnancy or puerperium. The following search terms were used: (‘‘venous thromboembolism’’ OR ‘‘deep vein thrombosis’’ OR ‘‘pulmonary embolism’’) AND (‘‘postpartum’’ OR ‘‘puerperium’’ OR ‘‘pregnancy’’ OR ‘‘peripartum’’ OR ‘‘perinatal’’ OR ‘‘Obstetric*’’). Additionally, the references of included articles and key review papers were handsearched to implement the search. Inclusion criteria and study selection Articles that met the following criteria were included: (1) studies that reported the incidence of VTE during pregnancy or puerperium; (2) studies that presented sufficient data to calculate the incidence of VTE; (3) articles published in English or Chinese language. Reviews, studies with the sample size less than 1000, studies in a population with risk factors wholly (e.g. an article with women after CS as the study population [9]) or studies without mentioning diagnostic criteria were excluded. When both the population and the study period in different articles overlapped, we chose the latest publication and supplemented it from the earlier studies if possible. The articles identified were selected based on the inclusion criteria described above by two authors (Meng and Hu) independently. First, an assessment of the identified records by reading the title/abstract was performed. The records which were not relevant to the topic or duplicates were excluded. Second, the studies remained after the first step were promoted to further screening by reading the full-text, and the studies that met the inclusion criteria were finally selected in the meta-analysis. Disagreements were resolved by discussion and consultation with the experts (Peng and Zhang). Data extraction For each selected article in this review, the following information were extracted: first author and publication year, study design, data source, study period, diagnostic criteria, sample size, numbers of cases with VTE, DVT or PE, reported incidence, the period of risk and the leg of presentation. Four studies investigated DVT, PE and other kind of thromboembolic diseases [10–13], we extracted only the number of DVT and PE in our analysis. Ros et al. [11] study reported the number of venous thrombosis which included both DVT and superficial vein thrombosis (SVT), and the number of DVT were not available separately, therefore, only the number of PE was extracted. Data
J Matern Fetal Neonatal Med, Early Online: 1–9
extraction was performed independently and then aggregated. Disagreements were resolved through discussion and consensus. Quality assessment Two reviewers (Meng and Hu) independently assessed the quality of eligible articles using pre-developed checklist based on the NEWCASTLE – OTTAWA Quality Assessment Scale [Available from: http://www.lri.ca/progras/ceu/oxford.htm in 26 May 2011]. There were six criteria in the checklist: defined inclusion criteria, diagnostic criteria, quality control, statistics analysis, sample size and its representativeness. The risk of bias was considered as ‘‘low’’ if a study fulfilled five or more of the criteria, ‘‘moderate’’ if a study fulfilled three or four, and ‘‘high’’ if a study fulfilled only two or less. Disagreements were resolved by discussion. Statistical analysis A variance-stabilizing double arcsine transformation was performed to estimate the incidence of VTE for the inverse variance weight in the meta-analyses is considered as suboptimal when dealing with binary data with low incidences [14], and the data used to estimate the case fatality rate of PE was log transformed. The meta-analysis of the incidence of VTE and the case fatality rate of PE were pooled in R software (R Development Core Team 2010), and the proportion of postpartum VTE and proportion of rightsided DVT were calculated using Meta analyst Beta 3.13 (Tufts Medical Center). The heterogeneity among included studies was estimated using the Cochran Q-test (p50.10 represents significant heterogeneity) and the I2 statistic (I2 ¼ 25, 50 and 75 represents low, medium and high heterogeneity, respectively). When the heterogeneity among individual studies was observed, the pooled prevalence and its 95% CI were calculated by Random Effect Model (REM); otherwise, the Fixed Effect Model was chosen. To analyze the robustness of the results, two sensitivity analyses were conducted with the studies which reported the incidence of VTE: one by removing the studies with high-risk bias to determine whether the quality of the included studies would influence the meta-analytic results and the other by removing the studies which reported the highest and lowest incidences. Publication bias was measured using Egger’s test (p50.05 represents statistically significant publication bias).
Results Characteristics of the included studies Of the 4437 articles identified, 27 were finally eligible for the meta-analysis after the title/abstract screening and the fulltext screening (Supplementary Figure S1). Main characteristics and primary data of the eligible studies are presented in Tables 1 and 2 [5–7,10–13,15–34]. The majority of these studies (n ¼ 24) were retrospective cohort studies, and three were prospective studies. The enrolled studies included data from 14 countries, of which six studies were from the USA [5,7,13,16,24,26], three each from China [10,25,29] and Sweden [11,32,33], two each from Sudan [19,27], England [15,30], Denmark [18,31], and Australia [17,23] and one each
retrospective cohort study
Retrospective study
Retrospective study
Retrospective study
Retrospective study
Retrospective study
Retrospective study
Prospective cohort study
Retrospective study Retrospective study
Retrospective study
Retrospective study
Retrospective study Prospective cohort study
Retrospective study Retrospective study
Retrospective study Retrospective cohort Study
Retrospective cohort study
Retrospective study Retrospective study
Retrospective study
Prospective cohort study Retrospective study
Retrospective study
Jang 2011 [6]
David 2010 [16]
Morris 2010 [17]
Virkus 2010 [18]
Gader 2009 [19]
Liu 2009 [20]
Jacobsen 2008 [21]
Kobayashi 2008 [22]
Sharma 2008 [23] James 2006 [24]
Liu 2006 [25]
Heit 2005 [26]
Haggaz 2003 [27] Soomro 2002 [28]
Armour 2001 [7] Chan 2001 [29]
Ros 2001 [11] Simpson 2001 [30]
Gherman 1999 [5]
Olson 1998 [12] Andersen 1997 [31]
James 1996 [13]
Bergqvist 1983 [32] Kierkegaard 1983 [33]
Treffers 1983 [34]
University Hospital Wilhelmina Gasthuis, the Netherlands
Wad Medani Hospital, Sudan King Fahad Hospital, Al Baha, Saudi Arabia a university hospital in inner-city, USA a tertiary university teaching hospital in Hong Kong, China The Birth Register, Sweden the St Mary’s Maternity Information System database, England Los Angeles and University of Southern California Women’s hospital, America St John’s Mercy Medical Center, Belgium The Regional Hospital, North Jutland, Denmark Good Samaritan Hospital, Cincinnati, Ohio, USA Karnsjukhuset, Skovde, Sweden the Central Hospital, BorAs, Sweden
13 tertiary hospitals in Guangdong, China A large prospective primary care database, UK Korean Health Insurance Review and Assessment Service (HIRA) database, Korea Two affiliated urban tertiary care facilities, USA New South Wales (NSW) hospitals, Australia The National Registry of Patients, Denmark Khartoum and Khartoum North Teaching hospitals, Sudan Hospital admission collated by the Canadian Institute, Canada 18 hospitals in 11 Norwegian counties, Norway 68 university hospitals and 34 general hospitals, Japan Ballarat Health Services, Australia Healthcare Cost and Utilization Project of the Agency, USA Obstetrical patients in 18 hospitals in Guangzhou, china Olmsted County, Minnesota, USA
Resource
1952–1979
1974–1980 1975.1–1980.12
1989.5–1994.10
1985–1995 1984.1–1994.12
1978.1–1996.12
1987.1–1995.9 1988–1997
1992–1997 1998.1–2000.12
1999.1–2000.12 1986.1–1998.12
1966–1995
1992.1–2001.12
1999.3–2006.6 2000–2001
1991–2000
1990.1–2003.12
1991–2006
2007.4–2008.3
1995.1–2005.12
2001–2006
All deliveries
women of antepartum All deliveries
All deliveries
All deliveries All deliveries
All deliveries
All deliveries All deliveries
All deliveries All deliveries
All deliveries All deliveries
All deliveries
All deliveries
All deliveries All deliveries
All deliveries
All deliveries
All deliveries
All deliveries
All deliveries
All deliveries
All deliveries
All deliveries
2006–2010 2003.6–2008.6
All deliveries All deliveries
Study participants
2005.1–2010.6 1987.4–2004.11
Study period
VTE
DVT DVT
VTE
DVT VTE
VTE
PE VTE
VTE VTE
VTE VTE
VTE
VTE
VTE VTE
PE
VTE
VTE
DVT
VTE
PE
VTE
VTE
VTE VTE
Outcome
Phlebography or plethysmography Phlebography for DVT; lung scanning for PE Cases with anticoagulant therapy
Ultrasound or ventilation perfusion scan
Doppler ultrasound, venography, pulmonary angiography CPT codes 671.3 Ultrasound or lung scan
ICD-9 ICD9 (1988–1995); ICD10 (1995–1997)
Ultrasound or Ventilation perfusion scan Ultrasound or ventilation perfusion scan
Objectively or according to clinical symptoms Doppler for VTE Ultrasound or pulmonary scintigraphy
Ultrasound or ventilation perfusion scan
Ultrasound or pulmonary angiogram ICD-9
Pulmonary angiography
Ultrasound for DVT; lung scan for PE
ICD-9 and ICD-10
Doppler ultrasound for DVT
ICD-10
ICD-10
Ultrasound for DVT; angiography for PE.
The Korean Classification of Disease codes
ICD-9 Anticoagulant therapy in records
Diagnostic methods
3.00
7.00 0.74
0.50
0.77 0.85
0.61
0.25 0.85
7.13 1.88
3.80 1.26
1.99
0.52
1.14 1.72
0.17
1.00
1.76
4.49
1.21
0.73
2.22
0.08
0.79 1.01
Incidence (%)
Pregnancy-associated venous thromboembolism
DVT ¼ deep venous thrombosis; PE ¼ pulmonary embolism; VTE ¼ venous thromboembolism; ICD ¼ international classification of diseases; CPT ¼ current procedural terminology.
Retrospective study Prospective cohort study
Study design
Huang 2012 [10] Alyshah 2011 [15]
Study ID
Table 1. Studies included in the meta-analysis.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 12/20/14 For personal use only.
DOI: 10.3109/14767058.2014.913130
3
4
K. Meng et al.
J Matern Fetal Neonatal Med, Early Online: 1–9
Table 2. Primary data of included studies.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 12/20/14 For personal use only.
Study ID
Participants
VTE
DVT
PE
Death
Antepartum*
Postpartumy
Left sidez
Right sideô
Both sidesx
169 218 20 7327 1 795 064 33 311 510 889 584 990 14 490 3 852 569 613 232 436 084 6987 8 330 927 93 651 50 080 14 210 39 757 4910 16 993 654 957 395 335 268 525 65 912 63 319 30 040 2429 14 869 56 022
133 210 147 74 / 709 / 6791 615 / 8 14335 49 100 54 50 35 32 / 336 165 / 54 15 / / 168
128 / / 37 / / 65 4677 449 / 7 11326 46 76 52 23 30 30 / / 127 51 52 12 17 11 /
5 / / 37 375 / / 2114 166 76 1 3009 3 24 2 27 5 2 161 / 38 / 2 3 / / /
/ / / 0 7 / / 47 3 11 / 89 2 / / 1 / 1 / / / / 0 0 / / 3
24 94 44 36 135 491 4 / 301 17 7 7177 11 36 8 17 29 8 63 109 109 / 33 9 / 2 40
109 116 103 38 240 218 61 / 314 59 1 7158 38 64 46 33 6 24 98 227 56 / 21 6 / 9 128
/ / / 23 / / 51 / / / 2 / 35 / 43 26 29 15 / / 104 29 / 10 14 6 /
/ / / 14 / / 13 / / / 6 / 0 / 9 6 1 13 / / 23 20 / 3 3 5 /
/ / / 3 / / 1 / / / 0 / 14 / 2 1 0 4 / / 0 2 / 0 0 0 /
Huang 2012 Alyshah 2011 Jang 2011 David 2010 Morris 2010 Virkus 2010 Gader 2009 Liu 2009 Jacobsen 2008 Kobayashi 2008 Sharma 2008 James 2006 Liu 2006 Heit 2005 Haggaz 2003 Soomro 2002 Armour 2001 Chan 2001 Ros 2001 Simpson 2001 Gherman 1999 Olson 1998 Andersen 1997 James 1996 Bergqvist 1983 Kierkegaard 1983 Treffers 1983
*Number of cases of VTE occurred during pregnancy. yNumber of cases of VTE occurred postpartum. zNumber of cases of DVT presented in left leg only. ôNumber of cases of DVT presented in right leg only. xNumber of cases of DVT presented in both legs.
from Korea [6], the Netherlands [34], Saudi Arabia [28], Norway [21], Canada [20], Japan [22] and Belgium [12]. Sixteen studies used objective methods (e.g. duplex ultrasound, venography or perfusion lung scan) to diagnose VTE, two [15,34] relied on anticoagulant therapy in medical records, seven studies [10,11,17,18,20,24,30] identified VTE according to International Classification of Diseases (ICD) codes, one [12] by Current Procedural Terminology (CPT) codes and one [6] by the Korean Classification of Disease codes. Twenty studies reported the incidence of VTE during pregnancy and the postpartum period, three studies [12,19,33] reported information of pregnancy-associated DVT, three [11,17,22] reported pregnancy-associated PE and one [32] reported antepartum DVT. The reported incidence of VTE during pregnancy or puerperium varies from 0.08 [6] to 7.13 [7] per 1000 pregnancies. Incidence of VTE Twenty articles were identified with sufficient data to estimate the incidence of VTE during pregnancy and puerperium (Figure 1). The sample size varied from 4910 to 8 330 927, and the reported incidence varied from 0.08 to 7.13%. Heterogeneity was significant (I2 ¼ 99.7%; p50.0001) among studies included and the pooled incidence of REM was 1.4% (95% CI: 1.0–1.8%). Incidence of DVT Eighteen articles were available to assess the incidence of pregnancy-associated DVT (Figure 2). The sample size varied
from 4910 to 8 330 927, and the incidence calculated from individual articles ranged from 0.4 to 6.1%. Heterogeneity was statistically significant (I2 ¼ 97.8%; p50.0001); therefore, we chose the REM with a pooled incidence of 1.1% (95% CI: 1.0–1.3%). Incidence and case fatality rate of PE Eighteen articles provided sufficient data to assess the incidence of PE (Figure 3). The sample size varied from 4910 to 8 330 927, and the calculated incidence ranged from 0.0 to 1.1%. Heterogeneity among the individual studies was observed (I2 ¼ 98%; p50.0001), and the pooled incidence based on REM was 0.3% (95% CI: 0.2–0.4%). There were 11 articles available to assess the case fatality rate of PE (Supplementary Figure S2). The number of cases with PE varied from 2 to 3009, and the calculated case fatality rate ranged from 0.00 to 66.67%. Heterogeneity was significant (I2 ¼ 91.1%; p50.0001), and the random-effects pooled event rate was 6.58% (95% CI: 3.30–13.09%). Distribution of VTE in different periods There were 23 articles that compared the incidence rate in the antepartum period versus the puerperium, of which 19 studies compared antepartum VTE with postpartum VTE, two reported the distribution of DVT in pregnancy versus puerperium and two compared antepartum PE with postpartum PE. We therefore conducted a subgroup analysis (Figure 4). The pooled proportions of postpartum VTE, DVT
Pregnancy-associated venous thromboembolism
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 12/20/14 For personal use only.
DOI: 10.3109/14767058.2014.913130
5
Figure 1. Combined incidence of pregnancy-associated VTE from 20 studies.
Figure 2. Combined incidence of pregnancy-associated DVT from 18 studies.
and PE were 57.5% (95% CI: 50.9–63.9%), 90.5% (95% CI: 74.9–96.8%) and 70.3% (95% CI: 55.3–81.9%), respectively. Heterogeneity was found among individual studies (I2 ¼ 0.486, Q ¼ 0.998, p ¼ 0.000). Additionally, number of VTE by trimesters were available in eight articles and were presented in Table 3. The extracted data were consolidated to calculate the proportion of VTE in three trimesters. The proportions of VTE during the first, second and third trimester were 21.36, 22.69 and 55.95%, respectively.
Distribution of DVT in legs Thirteen studies reported the side in which leg DVT was presented (Figure 5). Twelve studies reported DVT in pregnancy and puerperium and one reported DVT only during pregnancy. 530 cases of DVT were documented in total with 387 left-sided DVT, 116 right-sided DVT and 27 bilateral DVT. The weighted event rate for right-sided DVT was 27.9% (95% CI: 20.7–36.4%). Heterogeneity among the studies was observed (I2 ¼ 0.410; Q ¼ 0.998; p ¼ 0.000).
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 12/20/14 For personal use only.
6
K. Meng et al.
J Matern Fetal Neonatal Med, Early Online: 1–9
Figure 3. Combined incidence of pregnancy-associated PE from 18 studies.
Quality assessment and sensitivity analysis 11 articles [5,7,12,13,16,19,23,27,32–34] were found to have high-risk of bias according to the quality assessment of eligible studies (Supplementary S3). We excluded the studies with high risk bias from studies that reported the incidence of VTE to evaluate the robustness of the results (Supplementary Figure S4), and the incidence of VTE decreased by 0.3% (from 1.4 to 1.1%). When the studies which reported the highest and lowest incidence were excluded, the pooled incidence was 1.3% (I2 ¼ 98.6%, p50.0001, 95% CI: 1.1–1.5%). Publication bias The publication bias was assessed using Egger’s test, and the result did not reveal any evidence of publication bias (p ¼ 0.4309).
Discussion The present systematic review and meta-analysis examined the incidence of VTE in pregnancy and puerperium with 27 eligible studies. The pooled incidence of pregnancyassociated VTE was 1.4%, which was significantly higher than non-pregnant women of similar age. The reported incidence from individual studies varied widely (0.08– 7.13%), which might be due to different populations investigated, different diagnostic criteria and validity of data; moreover, the different definition of the postpartum period could also contribute to the variation of the reported incidence, for instance, the Morris et al. [17] study defined the postpartum period as 12 weeks after delivery, whereas puerperium was defined as the first two months after delivery in a study from Denmark [31]. The true incidence could be higher still for that thromboprophylaxis was initiated in cases with suspicion of VTE in some studies. The case fatality rate of PE calculated in individual studies varied widely which may be caused mostly by varied
intervention. The study with the highest rate did not describe any anticoagulant measure to the cases with VTE [25]; in contrast, the O’Connor et al.’s [16] study undertook sufficient intervention to the patients which included thromboprophylaxis to women with a prior history of venous thrombosis, anticoagulant therapy to patients with confirmed VTE, and inferior vena cava filters to patients with bleeding complications. Obviously, prophylaxis and treatment with anticoagulants can significantly reduce the morbidity and mortality of VTE, whereas, only women with additional risk factors could receive thromboprophylaxis for the side-effects of anticoagulants such as thrombocytopenia and bleeding. A comprehensive guideline has been published and recently updated which supply management guidelines of VTE-based on risk assessment [35]. Consistent with the findings from an earlier meta-analysis [8], the present analysis also confirmed the striking predisposition to left-sided DVT which might result from compression of the left iliac vein by the right iliac and ovarian arteries at their crossing [36]. However, the proportion of right-sided DVT reported in the earlier analysis (21.5%) was lower than that in the present review (27.9%). Our explanation was that, unlike the approach of using the number of cases with DVT as the denominator and cases with isolated right-sided DVT as the numerator (which would underestimate the proportion of right-sided DVT), we took account of the number of legs that suffered DVT as the denominator and the number of right legs with DVT as the numerator which would adjust the cases with bilateral DVT. If the same algorithms were conducted, the results would be more comparable. There are several limitations in our study. First, the literature search was limited to articles published in English or Chinese; nevertheless, no evidence of publication bias was found. Second, articles with VTE diagnosed without objective methods were also included; for instance, we
Pregnancy-associated venous thromboembolism
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 12/20/14 For personal use only.
DOI: 10.3109/14767058.2014.913130
7
Figure 4. Proportion of postpartum VTE combined from 23 studies.
Table 3. Distribution of VTE in three trimesters. Study ID Treffers 1983 James 1996 Chan 2001 Soomro 2002 Heit 2005 Jacobsen 2008 Sharma 2008 David 2010 Total Proportion (%)
First trimester
Second trimester
Third trimester
3 3 3 7 4 62 5 10 97 21.36
5 3 3 5 14 64 0 9 103 22.69
32 3 2 5 18 175 2 17 254 55.95
adopted an article with the study period 1952–1979 when non-invasive diagnostic tests were unavailable [34]. VTE was diagnosed on the basis of clinical symptoms which could potentially lead to an overestimation of the morbidity since many of the classic signs and symptoms, including leg swelling, tachycardia, tachypnea and dyspnea, can be present in a normal pregnancy. Third, there was substantial heterogeneity among the studies which might come from differences presented in the study population, study design or diagnostic criteria; hence, the results of the meta-analysis should be interpreted with caution. Finally, we conducted the sensitivity analysis only with the studies used to estimate
8
K. Meng et al.
J Matern Fetal Neonatal Med, Early Online: 1–9
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 12/20/14 For personal use only.
Figure 5. Proportion of right-sided DVT combined from 13 studies.
the incidence of VTE to get a broad idea of robustness of our results, the results of incidence of DVT or PE were not evaluated with sensitivity analysis separately. Although the overall incidence of VTE in pregnancy and puerperium is low, clinicians should be highly vigilant to the development of this disease because of the severe consequences and high mortality. Our findings provide guidance to physicians who are considering diagnosis of VTE. For instance, more than one in five of VTE during pregnancy were detected in the first trimester, which could imply that diagnostic suspicion should start early in the first trimester. Furthermore, the incidence of postpartum VTE was significantly higher; therefore, prophylaxis against pregnancy-associated VTE should be particularly targeted to postpartum women, especially to women with additional risk factors (such as CS in labor, previous VTE or asymptomatic thrombophilic). Moreover, VTE is difficult to diagnose in pregnant women because its associated signs and symptoms (such as dyspnea, edema and pains in the lower extremities) can exist in normal pregnancy, we found that three in four of DVT presented in the left side; therefore, women with edema and pain in left leg should be highly suspected of DVT. Our study highlights the urgent need for large-scale, multicenter and prospective studies on epidemiology of pregnancy-associated VTE. Although meta-analyses are useful tools to synthesize the existing data, it cannot substitute findings from well-conducted primary document [37]. Furthermore, an improvement of the methodology is required to produce comparable data and reduce heterogeneity among studies. In conclusion, women during pregnancy and puerperium are associated with a higher morbidity of VTE. Physicians should be of high vigilance to pregnancy-associated VTE, especially for women postpartum.
Declaration of interest This study was supported by a grant from the Beijing Training Plan of Top-notch Personnel (CIT&TCD201304189), and the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors report no declarations of interest.
References 1. Heit JA, Kobbervig CE, James AH, et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005;143: 697–706. 2. Chang J, Elam-Evans LD, Berg CJ, et al. Pregnancy-related mortality surveillance – United States, 1991–1999. MMWR Surveill Summ 2003;52:1–8. 3. Bergqvist A, Bergqvist D, Lindhagen A, Matzsch T. Late symptoms after pregnancy-related deep vein thrombosis. Brit J Obstet Gynaec 1990;97:338–41. 4. Gray G, Nelson-Piercy C. Thromboembolic disorders in obstetrics. Best Pract Res Cl Ob 2012;26:53–64. 5. Gherman RB, Goodwin TM, Leung B, et al. Incidence, clinical characteristics, and timing of objectively diagnosed venous thromboembolism during pregnancy. Obstet Gynecol 1999;94: 730–4. 6. Jang MJ, Bang SM, Oh D. Incidence of pregnancy-associated venous thromboembolism in Korea: from the Health Insurance Review and Assessment Service database. J Thromb Haemost 2011;9:2519–21. 7. Armour R, Schwedler M, Kerstein MD. Current assessment of thromboembolic disease and pregnancy. Am Surg 2001;67:641–4. 8. Ray JG, Chan WS. Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis of the period of risk and the leg of presentation. Obstet Gynecol Surv 1999;54:265–71. 9. Zhang XX, He QW, Zhang SC. Experience on management of 15 cases with deep venous thrombosis after cesarean section. Shanxi Med J 2007;36:243–4. 10. Huang QT, Zhong M, Wang CH, et al. Prevalence and major risk factors of peripartum thromboembolic disease in different regions of Guangdong province. Chin J Epidemiol 2012;33:413–17.
Pregnancy-associated venous thromboembolism
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 12/20/14 For personal use only.
DOI: 10.3109/14767058.2014.913130
11. Ros HS, Lichtenstein P, Bellocco R, et al. Increased risks of circulatory diseases in late pregnancy and puerperium. Epidemiology 2001;12:456–60. 12. Olson HF, Nunnelee JD. Incidence of thrombosis in pregnancy and postpartum: a retrospective review in a large private hospital. J Vasc Nurs 1998;16:84–6. 13. James KV, Lohr JM, Deshmukh RM, Cranley JJ. Venous thrombotic complications of pregnancy. Cardiovasc Surg 1996;4:777–82. 14. Freeman MF, Tukey JW. Transformations related to the angular and the square root. Ann Math Stats 1950;21:607–11. 15. Sultan AA, West J, Tata LJ, et al. Risk of first venous thromboembolism in and around pregnancy: a population-based cohort study. Br J Haematol 2011;156:366–73. 16. O’Connor DJ, Scher LA, Gargiulo III NJ, et al. Incidence and characteristics of venous thromboembolic disease during pregnancy and the postnatal period: a contemporary series. Ann Vasc Surg 2011;25:9–14. 17. Morris JM, Algert CS, Roberts CL. Incidence and risk factors for pulmonary embolism in the postpartum period. J Thromb Haemost 2010;8:998–1003. 18. Virkus RA, Løkkegaard ECL, Bergholt T, et al. Venous thromboembolism in pregnant and puerperal women in Denmark 1995– 2005: a national cohort study. Thromb Haemost 2011;106:304–9. 19. Gader AA, Haggaz AED, Adam I. Epidemiology of deep venous thrombosis during pregnancy and puerperium in Sudanese women. Vasc Health Risk Manag 2009;5:85–7. 20. Liu S, Rouleau J, Joseph KS, et al. Epidemiology of pregnancyassociated venous thromboembolism: a population-based study in Canada. J Obstet Gynaecol Can 2009;31:611–20. 21. Jacobsen AF, Skjeldestad FE, Sandset PM. Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium – a register-based case-control study. Am J Obstet Gynecol 2008; 198:233.e1–7. 22. Kobayashi T, Nakabayashi M, Ishikawa M, et al. Pulmonary thromboembolism in obstetrics and gynecology increased by 6.5-fold over the past decade in Japan. Circ J 2008;72:753–6. 23. Sharma S, Monga D. Venous thromboembolism during pregnancy and the postpartum period: incidence and risk factors in a large Victorian health service. Aust N Z J Obstet Gynaecol 2008;48: 44–9. 24. James AH, Jamison MG, Brancazio LR, Myers ER. Venous thromboembolism during pregnancy and the postpartum
25. 26. 27. 28. 29. 30.
31. 32. 33. 34.
35.
36. 37.
9
period: incidence, risk factors, and mortality. Am J Obstet Gynecol 2006;194:1311–15. Liu B, Zhong M, Xu Y, et al. An epidemiological study on incidence and risk factors of deep venous thrombosis during perinatal period. Guangdong Med J 2006;27:266–7. Heit JA, Kobbervig CE, James AH, et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30year population-based study. Ann Intern Med 2005;143:697–706. Haggaz AA, Mirghani OA, Adam I. Venous thromboembolism in pregnancy and the puerperium in Sudanese women. Int J Gynecol Obstet 2003;83:309–10. Soomro RM, Bucur IJ, Noorani S. Cumulative incidence of venous thromboembolism during pregnancy and puerperium: a hospitalbased study. Angiology 2002;53:429–34. Chan LY, Tam WH, Lau TK. Venous thromboembolism in pregnant Chinese women. Obstet Gynecol 2001;98:471–5. Simpson EL, Lawrenson RA, Nightingale AL, Farmer RDT. Venous thromboembolism in pregnancy and the puerperium: incidence and additional risk factors from a London perinatal database. Br J Obstet Gynaecol 2001;108:56–60. Andersen BS, Steffensen FH, Sørensen HT, et al. The cumulative incidence of venous thromboembolism during pregnancy and puerperium. Acta Obstet Gynecol Scand 1998;77:170–3. Bergqvist A, Bergqvist D, Hallbook T. Deep vein thrombosis during pregnancy: a prospective study. Acta Obstet Gynecol Scand 1983;62:443–8. Kierkegaard A. Incidence and diagnosis of deep vein thrombosis associated with pregnancy. Acta Obstet Gynecol Scand 1983;62: 239–43. Treffers PE, Huidekoper BL, Weenink GH, Kloosterman GJ. Epidemiological observations of thrombo-embolic disease during pregnancy and in the puerperium in 56,022 women. Int J Gynaecol Obstet 1983;21:327–31. Royal College of Obstetricians and Gynaecologists. Reducing the risk of thrombosis and embolism during pregnancy and the puerperium. Green-top Guideline No.37a 2009. Available from: http://www.rcog.org.uk/files/rcog-corp/GTG37aReducingRisk Thrombosis.pdf [last accessed 28 Apr 2014]. Ginsberg JS, Brill-Edwards P, Burrows RF, et al. Venous thrombosis during pregnancy: leg and trimester of presentation. Thromb Haemost 1992;67:519–20. Moher D, Pham B. Meta-analysis: an adolescent in need of evidence and a watchful eye. Ann Med 1999;31:153–5.
Supplementary material available online Supplementary Figures S1–S4
