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Keywords:

  • anticoagulation;
  • pregnancy;
  • treatment;
  • venous thromboembolism

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

Summary.  Venous thromboembolism (VTE) is one of the most relevant causes of maternal death in industrialized countries. Low molecular weight heparin (LMWH), continued throughout the entire pregnancy and puerperium, is currently the preferred treatment for patients with acute VTE occurring during pregnancy. However, information on the efficacy and safety of anticoagulant drugs in this setting is extremely limited. We carried out a systematic review and a meta-analysis of the literature to provide an estimate of the risk of bleeding complications and VTE recurrence in patients with acute VTE during pregnancy treated with antithrombotic therapy. The weight mean incidence (WMI) of bleeding and thromboembolic events and the corresponding 95% confidence interval (CI) were calculated. Eighteen studies, giving a total of 981 pregnant patients with acute VTE, were included. LMWH was prescribed to 822 patients; the remainder were treated with unfractionated heparin. Anticoagulant therapy was associated with WMIs of major bleeding of 1.41% (95% CI 0.60–2.41%; I) antenatally and 1.90% (95% CI 0.80–3.60%) during the first 24 h after delivery. The estimated WMI of recurrent VTE during pregnancy was 1.97% (95% CI 0.88–3.49%; I2 39.5%). Anticoagulant therapy appears to be safe and effective for the treatment of pregnancy-related VTE, but the optimal dosing regimens remain uncertain.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is one of the most relevant causes of maternal death in developed countries, with a reported mortality rate of 1.56 per 100 000 maternities in the UK [1,2]. Symptomatic VTE is estimated to occur in 5–12 women per 10 000 pregnancies antepartum, and in 3–7 women per 10 000 deliveries postpartum [3,4]. During pregnancy and puerperium, the risk of developing VTE is five times higher than in the general female population of childbearing age [5].

Treatment of VTE in pregnant women poses some particular challenges, because it requires taking into account the safety of the selected drugs not only for the mother, but also for the fetus. Vitamin K antagonists cross the placenta and have the potential to cause fetal bleeding and teratogenicity [6]. Unfractionated heparin (UFH) does not cross the placenta and does not cause fetal teratogenicity, but its use may be associated with additional maternal safety issues, including the risk of heparin-induced thrombocytopenia (HIT) and heparin-associated osteoporosis [6]. Furthermore, the use of therapeutic doses of UFH requires regular laboratory monitoring of the activated partial thromboplastin time (APTT). Like UFH, low molecular weight heparin (LMWH) does not cross the placenta, and there is no evidence of teratogenicity or risk of fetal bleeding [6,7]. In addition, LMWH offers a number of advantages over UFH, thanks to its better bioavailability, longer plasma half-life, more predictable dose response, and improved safety profile with respect to osteoporosis and HIT [6]. For these reasons, LMWH is currently recommended as the treatment of choice for patients with acute VTE occurring during pregnancy [2–4,6–10]. However, evidence to support this recommendation is largely based on case reports or case series of pregnant patients, or on data derived from studies carried out in non-pregnant patients. Consequently, limited data exist on the incidence rate of recurrent VTE or bleeding during treatment with LMWH or UFH in pregnancy and puerperium, and little is known about their optimal therapeutic dosage. Thus, different therapeutic strategies are proposed and used in clinical practice. [3,6,8,9]. Although a few systematic and narrative reviews have tried to assess the risk–benefit profile of anticoagulant treatment of VTE in pregnancy [3,9–11], these studies have often mixed together data from patients receiving anticoagulant therapy for different indications, such as VTE treatment or prophylaxis, prevention of obstetric complications, and prevention of arterial thrombosis in patients with mechanical cardiac valves, or, conversely, have focused on only a single therapeutic agent.

We therefore decided to carry out a systematic review of the literature and a meta-analysis of the studies that have reported on recurrent VTE or bleeding events in patients receiving anticoagulant drugs for the treatment of pregnancy-related VTE, with the aim of providing an estimate of the incidence rates of these complications.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

A protocol was prospectively developed. Specific objectives, criteria for study selection, the approach used to assess study quality, outcomes and statistical methods were defined a priori.

Study identification

Studies were identified with the MEDLINE (1966 to April, week 2, 2012) and EMBASE (1980 to April, week 2, 2012) electronic databases. The search strategy was developed with the following keywords: ‘Venous Thrombosis’, ‘Pulmonary Embolism’, ‘Pregnancy’, ‘Therapy’, and ‘Treatment’.

The electronic search was supplemented by a manual search of reference lists and recent reviews, and by reviewing abstract books from the congress abstracts from the ISTH annual meetings, from the European Society of Human Reproduction and Embryology annual meetings and from the American Society of Hematology (ASH) meetings from 2003 to 2011.

Studies were selected if they reported data about recurrent VTE (any PE or DVT) and/or about any hemorrhagic event that occurred during pregnancy or the postpartum periods.

Study selection

Study selection was performed independently by two reviewers (E.Ro. and E.Ra.), with disagreements being resolved through discussion and by the opinion of a third reviewer (F.D.), if necessary. Any randomized controlled trials or cohort studies were included if they met the following criteria: (i) DVT or PE was objectively confirmed (with Doppler ultrasound, computer tomography, angiography, and lung scan) and occurred during pregnancy; and (ii) patients were treated with one or more anticoagulant drugs.

We excluded studies that considered VTE occurring before pregnancy, studies in which pregnant women were treated for reasons other than the treatment of acute VTE, and when it was impossible to obtain separate data about patients treated for acute VTE only.

To reduce the risk of biased results, we decided to include only studies that enrolled >10 patients. When there were multiple publications for a single study, we decided to use the latest publication and to supplement it, if necessary, with data from the earlier publications.

To assess the agreement between reviewers for study selection, we used the k statistic, which measures agreement beyond chance [12]. Values >0.6 were considered to represent substantial agreement, and values >0.8 almost perfect agreement.

Data extraction

Two reviewers (E.Ro. and E.Ra.) independently completed data extraction with a standardized form. Disagreement was resolved by consensus and by the opinion of a third reviewer (F.D.), if necessary.

The following data were extracted: study characteristics (year of publication, design, and study center), patient characteristics (number of subjects studied, mean age, and mean gestational age at diagnosis of VTE), number of DVT and PE events, drugs and regimens used for the acute treatment, drugs and regimens used for the long-term treatment, hemorrhagic events occurring both antepartum and postpartum, and recurrent VTE events occurring both antepartum and postpartum. The acute treatment phase was defined as the first week of anticoagulant therapy, and the long-term treatment period was defined as the remaining treatment period.

To define the severity of bleeding events, we aimed to use the ISTH classification for hemorrhages occurring antepartum [13]. Postpartum hemorrhage (PPH) was defined as those bleeding events occurring within the first 24 h after delivery, and we aimed to use the classification proposed by the Royal College of Obstetricians and Gynaecologists (RCOG) [14]. According to this definition, major PPH is defined as the loss of ≥ 1000 mL of blood from the genital tract, clinically relevant, non-major bleeding as the loss of ≥ 500 mL of blood, and minor bleeding as any other blood loss being reported. If the quantity of blood loss was not specified, we took into account the definition of bleeding given by the authors, and considered wound hematomas as minor bleeds and atonic postpartum bleeds as clinically relevant, non-major bleeds. In addition, we aimed to collect information about bleeds that occurred after the first 24 h from the delivery, and to classify them again according to the ISTH definitions in the absence of other available classifications.

We considered recurrent VTE as any new thromboembolic event occurring during anticoagulant therapy and after the index VTE, as adjudicated by the authors. In addition, information was collected on the occurrence of HIT during treatment. When necessary, we contacted the authors for additional information.

Study validity assessment

A protocol was prospectively developed. Specific objectives, criteria for study selection, the approach used to assess study quality, outcomes and statistical methods were defined a priori, and reported according to the proposal for reporting of the Meta-analysis of Observational Studies in Epidemiology group [15].

The same two unmasked investigators independently completed the assessment of study validity. We assessed the methodological quality of each study with the Newcastle-Ottawa scale, which was developed to assess the quality of non-randomized studies, with its design, content and ease of use directed to the task of incorporating the quality assessments in the interpretation of meta-analytic results [16]. A ‘star system’ was developed for this scale, in which a study is judged on three broad perspectives: the selection of the study groups; the comparability of the groups; and the ascertainment of either the exposure or outcome of interest for case–control or cohort studies, respectively [16]. We awarded studies a maximum of 3 points for selection, 2 points for comparability, and 2 points for outcome assessment, with more points indicating better quality. The maximum possible score was 7: studies that obtained 6 or 7 points were considered to be of high quality, studies that obtained ≤ 3 points were considered to be of low quality, and the other studies were considered to be of medium quality.

The quality scale was supplemented with other quality criteria that were specific for this study: a description of the methods used for the diagnosis of VTE (how the diagnosis was made in each study), the definition of recurrence, and the use of standardized methods for determining hemorrhage.

Statistical analysis

The weighted mean incidence (WMI) of bleeding complications and of VTE recurrence were calculated with the random effect model [17]. Events occurring antepartum and postpartum were analyzed separately. Statistical heterogeneity was evaluated with Cochran’s Q and the I2 statistic [18]. Analysis was performed with statsdirect software (Version 2.7; StatsDirect, United Kingdom).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

A total of 5011 (2831 MEDLINE and 2180 EMBASE) citations, six abstracts from ISTH meetings and two abstracts from ASH meetings were identified by our systematic search. A total of 4988 studies, three ISTH abstracts and two ASH abstracts were excluded after review of the study titles or abstracts. We subsequently retrieved the full text of 31 potentially eligible articles and three ISTH abstracts. Among the studies published as full articles, we further excluded one article because no antithrombotic therapy was used, seven because they included ≤ 10 patients, two because no data on follow-up were provided, and six because data on patients treated for acute VTE were not distinguishable from data on women receiving antithrombotic prophylaxis. Thus, a total of 15 full articles [19–33] and three abstracts [34–36] were eligible for inclusion in our systematic review (Fig. 1).

image

Figure 1.  Study selection. ASH, American Society of Hematology; DVT, deep vein thrombosis.

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The interobserver agreement for the study selection was optimal (k = 0.91). According to the Newcastle-Ottawa scale, no studies were of high quality and four studies were of medium quality [25,27,30,33]. Eight studies specified that the diagnosis of VTE was made with imaging techniques [20,21,23,25,26,28,32,33], two studies defined the diagnosis of recurrent VTE [20,32], and only one study used the classical definition of PPH to describe postpartum hemorrhages [30].

Among the selected studies, 17 were written in English [19,21–36] and one in German [20]. The corresponding authors of 11 of the selected studies were contacted, with the aim of obtaining missing information, and six authors kindly provided the requested data.

A total of 981 pregnant women with acute VTE were included, with their age ranging from a minimum of 17 years to a maximum of 43 years. Only 13 of the selected studies, including a total of 632 patients, provided separate data on the number of DVTs and PEs (in total: 506 DVTs and 127 PEs) [19–21,23–26,29,30,32,33,35,36] (Table 1). The timing of VTE onset during pregnancy was not reported in all studies. Where available, this ranged from the 7th gestational week to the 38th gestational week.

Table 1. Baseline characteristics of the study populations
AuthorType of studyPatients (no.)Age (years)Gestational ageBMIDVTPE
  1. BMI, body mass index; DVT, deep vein thrombosis; NR, not reported; PE, pulmonary embolism. *Data regarding 252 patients treated with therapeutic tinzaparin.

Aburahma and Boland [19]Case–control24Mean 24 (17–39)1 first trimester 5 second trimester 18 third trimesterNR24NR
Bahlmann et al. [20]Cohort12NR26.1 ± 6.2 weeksNR120
Barillari et al. [34]Cohort38NRNRNRNRNR
Blanco-Molina et al. [21]Cohort173Mean 31 ± 6NRNR13538
Clark et al. [22]Cohort17NRMedian 19 weeks (7–34 weeks)NRNRNR
Daskalakis et al. [23]Case series1827–437–38 weeksNR180
Donnelly et al. [24]Cohort25NRNRNR214
Jacobsen et al. [25]Cohort20Mean 31.8 ± 5.194 first trimester 6 second trimester 11 third trimesterNR192
Mitic et al. [35]Cohort87Mean 29.7 ± 4.86Mean 22 ± 10.2 weeksNR825
Narin et al. [26]Case–control35 (18, group I 17, group II)Mean 28.4 ± 3.5, group I Mean 30.0 ± 5.2, group IIMean 29.3 ± 4.4 weeks, group I Mean 26.5 ± 6.5 weeks, group IINR350
Nelson-Piercy et al. [27]Cohort247Mean 30.1*NRMean 27.7*NRNR
O’Connor et al. [28]Case series34NRNRNRNRNR
Parent et al. [36]Cohort39Mean 32.5NRNR2019
Rodie et al. [29]Case series29NRNRNR236
Roshani et al. [30]Cohort13Mean 32NRNR85
Rowan et al. [31]Cohort13NRNRNRNRNR
Ulander et al. [32]Case–control31 (10, group I 21, group II)31.0 ± 5.7, group I 31.6 ± 4.3, group II27 ± 8.5 weeks, group I 21 ± 9.8 weeks, group II23.4 ± 4.7, group I 25 ± 4.6, group II310
Voke et al. [33]Cohort126Median 32 (16–42)31 first trimester 37 second trimester 58 third trimesterMedian 26 (19–43)7848
All 18 studies 981   506127

Overall, 822 patients received LMWH and 155 UFH for the acute-phase treatment of VTE. None of the studies reporting on patients treated with fondaparinux met our selection criteria. Dosing regimens of LMWH were heterogeneous among studies, and are summarized in Table 2. Only in two studies, during the acute phase, were the dosages adjusted according to the measurement of anti-factor Xa levels [25,32]. UFH was administered both intravenously and subcutaneously, in most cases, but not always, according to APTT values (Table 2).

Table 2. Treatment regimens for the acute phase of venous thromboembolism
AuthorLMWHDose of LMWHUFHDose of UFHWarfarin
  1. APTT, activated partial thromboplastin time; i.v, intravenous; IU, International Units; LMWH, low molecular weight heparin; NR, not reported; s.c., subcutaneous; UFH, unfractionated heparin. *Data reported only for 170 patients. †One patient was treated with danaparoid for a previous heparin-induced thrombocytopenia. ‡Data regarding 252 patients treated with therapeutic tinzaparin.

Aburahma and Boland [19]02411 patients i.v. according to APTT (target 1.5–2.5 times normal); 13 patients i.v. bolus then 5000–10 000 U s.c. every 8–12 h0
Bahlmann et al. [20]1 dalteparin5000 IU s.c. three times daily11According to APTT (target 1.5–2.0 times normal)0
Barillari et al. [34]38 nadroparin100 IU kg−1 twice daily00
Blanco-Molina et al. [21]*154Mean 187 ± 51 IU kg−1 daily16NR0
Clark et al. [22]2 enoxaparin100–110 mg kg−1 twice daily156 patients s.c.0
Daskalakis et al. [23]018According to APTT (target 2.0 times normal)0
Donnelly et al. [24]25NR00
Jacobsen et al. [25]20 dalteparinInitially 100 IU kg−1 twice daily, then according to anti-FXa levels (0.5–1.0 U mL−1)00
Mitic et al. [35]84 (83 nadroparin, 1 dalteparin)100 IU kg−1 twice daily3NR0
Narin et al. [26]035According to APTT (target 1.5–2.5 times normal)0
Nelson-Piercy et al. [27]247 tinzaparinMedian 13 000 IU (3500–28 000)‡00
O’Connor et al. [28]23NR11NR0
Parent et al. [36]39 tinzaparin18 119 UI kg−1 daily00
Rodie et al. [29]29 enoxaparin1 mg kg−1 twice daily00
Roshani et al. [30]†9 nadroparin, 2 dalteparin100 IU kg−1 twice daily or 200 IU kg−1 once daily1NR0
Rowan et al. [31]13 enoxaparin1 mg kg−1 twice daily00
Ulander et al. [32]21 dalteparinBased on anti-FXa (target: 1–1.5 U mL−1)10According to APTT (70–100 s)0
Voke et al. [33]11583 patients once daily, 39 patients twice daily11NR0
Total822 155 0

Treatment regimens during the long-term treatment period are summarized in Table 3. The majority of patients initially treated with UFH were switched to LMWH, others were continued on UFH, in most cases administered subcutaneously, and a few (36 from a single study [21]) were switched to warfarin. In one study, four patients initially treated with LMWH were switched to UFH during the late phase of pregnancy [33]. Six studies reported on dose changes to LMWH during the long-term treatment period according to anti-FXa levels in some patients [25,29,31–33,36].

Table 3. Treatment regimens for the long-term treatment period
AuthorLMWHDoseUFHDoseWarfarinDuration of therapy
  1. IU, International Units; i.v., intravenous; LMWH, low molecular weight heparin; NR, not reported; s.c., subcutaneous; UFH, unfractionated heparin. *Data reported only for 169 patients. †Data regarding 252 patients treated with therapeutic tinzaparin.

Aburahma and Boland [19]0245000–10 000 U s.c. every 8–12 h06–8 weeks after delivery
Bahlmann et al. [20]2500–600 IU h−1 i.v.108 pt s.c., 2 pt i.v.5000–7000 U × 3 s.c.0NR
Barillari et al. [34]3880–100 IU kg−1 once0 03 months after delivery
Blanco-Molina et al. [21]*133Mean 173 ± 59 IU kg−1 daily036NR
Clark et al. [22]370 mg Kg−1 twice daily, 17 000 IU once daily14 s.c.9000–13 000 IU every 8–12 h0NR
Daskalakis et al. [23]186150 anti-FXa IU once daily001 month after delivery
Donnelly et al. [24]25NR00NR
Jacobsen et al. [25]20According to anti-FXa levels (0.5–1.0 U mL−1)00NR
Mitic et al. [35]85Intermediate dosage2NR0NR
Narin et al. [26]351 mg kg−1 twice daily, group I 1.5 mg kg−1 once daily, group II00nr
Nelson-Piercy et al. [27]247Median 13 000 IU (3500–23 100)†00NR
O’Connor et al. [28]23NR11NRNRNR
Parent et al. [36]39According to anti-FXa levels0 02210 weeks
Rodie et al. [29]29According to anti-FXa levels (0.4–1.0 U mL−1)00Median 6 weeks (1–33 weeks)
Roshani et al. [30]9 nadroparin, 2 dalteparin100 IU kg−1 twice daily or 200 IU kg−1 once daily1NR0NR
Rowan et al. [31]13Some patients according to anti-FXa levels00NR
Ulander et al. [32]31100 UI kg−1 twice daily for 2 weeks, then once daily according to anti-FXa levels (0.7 U mL−1 and 0.5–0.6 U mL-1 at the end of pregnancy)00NR
Voke et al. [33]118Some patients according to anti-FXa levels4NR0NR
Total874 66 36 

The duration of the follow-up period was heterogeneous among studies, and in some cases it was not reported. In one study, follow-up was limited to the first 3 months after the diagnosis of VTE [21]. From the information provided, we could not estimate the total duration of the treatment period.

Bleeding complications in the antepartum period

During the antepartum period, a total of 28 bleeding events were reported in 16 studies in a total of 944 patients [19,21–23,25–36]. Regrettably, the available data were not sufficient to enable us to apply the ISTH classification of bleeding severity, so we could only use the definitions given by the authors in each study. Overall, five events were defined by the authors as major, one was defined as clinically relevant non-major, 16 were defined as minor, and six were not classified [27,28]. In one patient, major bleeding developed after severe eclampsia complicated by thrombocytopenia [36]. Four of the five major bleeds occurred during the acute-phase treatment [19,21], and the only clinically relevant non-major bleed occurred after 2 weeks of treatment [26]. Of the four major bleeds that occurred during the acute-phase treatment, two occurred in patients treated with LMWH and two in patients treated with UFH.

The use of anticoagulant therapy was therefore associated with an antepartum incidence of hemorrhagic complications of 3.28% (95% confidence interval [CI] 2.10–4.72; I2 14.6%). The antepartum incidence of major bleeding was 1.41% (95% CI 0.60–2.41%; I2 0%); the incidence of major bleeding during the acute treatment phase only was 1.00% (95% CI 0.4–2.0%; I2 0%) (Fig. 2 A-B). From the available data, it was not possible to separately estimate the incidence of bleeding complications for UFH and LMWH.

image

Figure 2.  (A) All antepartum bleeds (WMD 3.28% [95% confidence interval (CI) 2.10–4.72; I2 14.6%]). (B) Major antepartum bleeds (WMD 1.41% [95% CI 0.60–2.41; I2 0%]). (C) Major bleeds in the first 24 h postpartum (WMD 1.00% [95% CI 0.4–2.0%; I2 0%]). (D) Major postpartum bleeds after 24 h (WMD 1.2% [95% CI 0.30–2.50%; I2 0%]).

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Bleeding complications in the postpartum period

A total of 260 PPHs were reported in 13 studies [22–27,29,30,32–36], in a total of 725 patients. In most studies, information on blood losses was sufficient to enable us to use the classification of the RCOG. In total, 14 PPHs were defined as major, 41 were defined as clinically relevant non-major (four of these were atonic postpartum bleeds), and 205 were defined as minor (Table 4).

Table 4. Adverse events
AuthorAntepartum bleedingAntepartum recurrent VTEOther antepartum adverse eventsPeripartum bleeding (first 24 h after delivery)Other postpartum bleedingOther postpartum adverse eventsFollow-up
  1. DVT, deep vein thrombosis; LMWH, low molecular weight heparin; NR, not reported; PE, pulmonary embolism; UFH, unfractionated heparin; VTE, venous thromboembolism. *Acute phase: the first week after the diagnosis of VTE. †Data regarding 254 patients treated with therapeutic tinzaparin. ‡In two cases, recurrent VTE occurred after tinzaparin cessation. §Data regarding 229 patients treated with therapeutic tinzaparin. ¶Data regarding 262 patients in the therapeutic group.

Aburahma and Boland [19]1 retroperitoneal bleed in acute phase*2 PEs, one fatal, in acute phase on UFH*NRNRNRNR61 months (18–102)
Bahlmann et al. [20]NR4 (2 PEs): 3 in acute phase on UFHNRNRNRNRNR
Barillari et al. [34]00001 epistaxisNR1 year after delivery
Blanco-Molina et al. [21]3 major bleeds in acute phase: 2 on UFH; 1 on LMWH*2 PEs during LMWH after acute phase*NRNRNRNR3 months after VTE
Clark et al. [22]01 PE in acute phase on LMWH*NR1 wound hematoma 1 minor bleed1 clinically relevant non-major bleed 1 major bleedNRNR
Daskalakis et al. [23]001 abortion (at 10 weeks‡)0NR0NR
Donnelly et al. [24]NRNRNR0 bleeds > 1500 mLNRNRNR
Jacobsen et al. [25]001 intrauterine death (at 37 weeks‡)1 atonic postpartum bleed 1 wound hematomaNR0NR
Mitic et al. [35]3 minor bleeds1 DVT in acute phase on LMWH*4 skin reactions on nadroparin 1 fetal loss (at 8 weeks‡)2 clinically relevant non-major bleeds 2 minor bleeds 1 wound hematoma00NR
Narin et al. [26]1 vaginal bleed, 1 hematuria and 1 clinically relevant vaginal bleed on LMWH01 abortion (at 9 weeks)0004–8 weeks after delivery in 57% of patients
Nelson-Piercy et al. [27]4 unspecified†5 (4 PEs)‡NR196 bleeds < 500 mL 31 bleeds > 500 mL and < 1000 mL 3 bleeds > 1000 mL§NR2 stillbirths 1 termination¶NR
O’Connor et al. [28]2 unspecifiedNRNRNR4 unspecifiedNRNR
Parent et al. [36]1 hematuria 2 vaginal bleeds 1 major bleed on LMWH01 fetal death 1 abortion 1 eclampsia with thrombocytopenia (gestational age not specified)1 wound hematomaNRNRNR
Rodie et al. [29]002 skin reactions (on enoxaparin)3 atonic postpartum bleeds 1 wound hematomaNR0NR
Roshani et al. [30]00NR2 major bleeds 2 bleeds < 1000 mL1NRNR
Rowan et al. [31]00NRNRNRNRNR
Ulander et al. [32]1 hematuria1 during LMWH after the acute phase*1 premature delivery (at 23 weeks‡)3 abnormal bleeds > 1000 mL 1 wound hematomaNRNRNR
Voke et al. [33]7 minor bleeds02 intrauterine deaths (at 38 and 23 weeks‡) 1 miscarriage (at 12 weeks) 1 abortion (at 12 weeks‡)6 bleeds > 1000 mL 2 bleeds > 500 mL and < 1000 mL2 major bleeds 4 clinically relevant non-major bleeds1 neonatal deathNR
Total28: 5 major bleeds; 1 clinically relevant non-major bleed; 16 minor bleeds; 6 unspecified16: 11 PEs; 1 fatal‡17: 6 skin reactions; 4 abortions; 1 miscarriage; 4 intrauterine deaths; 1 premature delivery; 1 eclampsia260: 205 minor bleeds; 41 clinically relevant non-major bleeds; 14 major bleeds14: 3 major bleeds; 5 clinically relevant bleeds; 5 unspecified; 1 minor bleed1 neonatal death 2 stillbirths¶ 1 termination ¶ 

The incidence of major PPH was 1.90% (95% CI 0.80–3.60%; I2 36.8%) (Table 5; Fig. 2 C-D). Only seven studies, with a total of 350 patients, provided information on bleeding events occurring after the first 24 h from delivery. The information provided on bleeding events was insufficient for the application of any classification, and the definition of severity provided by the authors was used. Information on the duration of follow-up was not available. A total of 14 hemorrhagic events were reported: three were defined as major (1.2%, 95% CI 0.30–2.50%; I2 0%).

Table 5. Bleeding complication rates
 Incidence (%)95% CI
  1. CI, confidence interval. *Occurred during the first week after the introduction of anticoagulant therapy. †Occurred after the first 24 h from delivery.

All antepartum bleeding complications3.282.10–4.72
Antepartum major bleeding1.410.60–2.41
Acute antepartum major bleeding*1.000.40–2.00
Postpartum major bleeding (< 24 h)1.900.80–3.60
Puerperium major bleeding†1.20.30–2.5

Thromboembolic complications

Information on recurrent VTEs occurring during the antepartum period was available in 16 studies including a total of 922 patients. There were 16 recurrent VTEs: 11 were PEs (one fatal) and five were DVTs (Table 4).

The estimated WMI of antepartum recurrent VTE was 1.97% (95% CI 0.88–3.49%; I2 39.5%) (Fig. 3). The estimated WMI of recurrent PE was 1.30% (95% CI 0.6–2.3%; I2 13.3%). Seven VTE recurrences occurred in the first 7 days after the start of treatment, and five of these occurred while patients were receiving UFH treatment [19,20,22,35].

image

Figure 3.  Antepartum recurrent venous thromboembolism (VTE) (WMD 1.97% [95% CI  0.88–3.49%; I2 39.5%]).

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The incidence rate of recurrent VTE during the acute-phase treatment period was 1.41% (95% CI 0.44–2.90%; I2 38%); during the long-term treatment period, this incidence was 0.95% (95% CI 0.37–1.82%; I2 0%). Once again, from the available data, we could not separately estimate the incidence of bleeding complications for UFH and LMWH.

Two studies [19,22], including 41 patients, reported on four cases of recurrent VTE that occurred during the postpartum period. Finally, we found no reported cases of HIT in the 13 studies that addressed this complication, in a total of 860 patients [21–23,25–27,29,31–36]. The occurrence of HIT was prospectively assessed in only two studies [21,33].

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

The results of this systematic review of the literature substantially support the efficacy and safety of currently used therapeutic strategies for the treatment of pregnancy-related VTE, but suggest that some work is needed to improve their efficacy and safety profile, in particular during the highest-risk periods. In fact, the estimated incidence of recurrent events during pregnancy remains substantial during the first week of treatment, as do the rates of major bleeding complications, again during the first week of treatment and in the first 24 h after delivery.

We observed substantial heterogeneity in the reported treatment regimens: although most patients received LMWH, various dosing regimens for the acute-phase treatment and, in particular, for long-term secondary prevention were prescribed in the studies, and no direct comparisons are currently available. There was also heterogeneity among definitions of major bleeding events before and after delivery in individual studies. Because the application of a single, more widely accepted definition was not always feasible, given the limited information provided in some studies, the observed rates of bleeding should be interpreted cautiously.

The 2012 version of the guidelines of the American College of Chest Physicians (ACCP) recommends the use of adjusted-dose LMWH for the treatment of VTE during pregnancy [6]. LMWH is considered to be the best option, because of its greater bioavailability and its favorable safety profile. It is also recommended that anticoagulant therapy should be continued with the same dose throughout pregnancy, and until at least 6 weeks after delivery [6]. Clear-cut indications about the need for dose adjustments over the course of pregnancy or the usefulness of routine measurement of anti-FXa activity were not provided [6]. In the RCOG guidelines published in February 2007 [2], the authors suggested treating VTE with LMWH given twice daily throughout pregnancy, and discouraged physicians from the routine measurement of peak anti-FXa activity, with the exception of women at extremes of body weight or with other complicating factors, such as renal insufficiency. In our search, we found six studies in which, in some patients, the LMWH dosages were modified according to anti-FXa levels. Unfortunately, a separate assessment of clinical outcomes in this subgroup of patients was not feasible. During the acute-phase treatment period, most patients received weight-adjusted, full-dose LMWH, with an acceptable incidence of major bleeding events; during the long-term treatment period, doses were empirically reduced for most patients, and a minority of patients received dose adjustments based on the measurement of anti-FXa levels.

It is of note that the rates of major bleeding events in our study are consistent with the rates of major bleeding events reported in studies carried out in non-pregnant patients treated for acute VTE with standard anticoagulant therapy [4,37]. Conversely, the estimated incidences of bleeding and recurrent VTE events in our study differ somewhat from the results of a previous systematic review published in 2005 by Greer et al. [9]. In this study, the authors assessed the safety and efficacy of LMWH during pregnancy, and included both patients treated for pregnancy-related DVT or PE (n = 146) and patients receiving antithombotic prophylaxis. The overall rates of what the authors defined as significant bleeding were 1.98% (95% CI 1.50–2.57%) in the antepartum and the postpartum periods combined, and 0.43% (95% CI 0.22–0.75%) in the antenatal period only. The rate of bleeding in the postpartum period in patients receiving LMWH for the treatment of acute VTE was 1.72%. These rates are lower than the rates reported in our study, probably because we included only patients receiving therapeutic doses of anticoagulants and patients receiving UFH, and possibly because of a different definition of bleeding events. Finally, the rates of recurrent VTE in our study were also higher than those reported in the review by Greer et al. (1.15%).

Our meta-analysis has a number of limitations. First, only case–control and cohort studies have been published, and the application of formal meta-analytic methods to observational studies is controversial, as the bias implicit in the study design may misrepresent the strength of associations within the data [12]. In addition, we considered studies with different end-points and with different durations of follow-up. Moreover, the therapeutic strategies were highly heterogeneous among studies, and different compounds with different dosing regimens were used. Unfortunately, separate analysis of these therapeutic regimens was not feasible, owing to insufficient information being provided in the selected studies. Another limitation is the lack of standardized definitions of bleeding severity among selected studies, which mandates some caution when the reported figures are interpreted. This applies in particular to the definition of PPH. PPH is traditionally defined as any blood loss >500 mL from the genital tract during delivery [13,14,38], but other definitions also required the presence of clinical signs of blood loss [39]. Furthermore, we could not obtain data related to the entire duration of the puerperium: first, because of the wide variability in follow-up duration among the selected studies; and second, because, in most studies, data on anticoagulant treatment and on related complications after the delivery were not provided. Similarly, the criteria used to diagnose recurrent VTE were not reported in most studies, and it is possible that some heterogeneity exists in the adjudication criteria that were applied. Moreover, we had insufficient information to identify early recurrences that may have been caused by thrombosis extension or inadequate anticoagulation. Finally, we acknowledge the existence of studies conducted with other anticoagulant agents, including danaparoid [40] and fondaparinux. However, treatment with a heparinoid is not standard practice, and is not listed in the recommended strategies in the most important guidelines (ACCP and RCOG); in addition, in our search, we identified one study on the use of danaparoid in pregnant patients who were intolerant to heparin (also in the case of previous HIT), but in this article we could not distinguish data from patients treated for an acute episode of VTE or data from patients treated for the prophylaxis of VTE, so we decided to not include the study in the meta-analysis; none of the studies with fondaparinux was eligible for inclusion in our study, because none had >10 included patients.

In conclusion, this is, to our knowledge, the first systematic review and meta-analysis specifically aimed at estimating the incidence of recurrent VTE and bleeding during anticoagulant treatment for pregnancy-related VTE. The results of this study suggest that anticoagulant drugs during pregnancy are effective in the prevention of recurrent VTE, with an acceptable safety profile. Most events, both bleeding and recurrences, occurred during the first week of treatment. We could not identify the optimal therapeutic regimen among the different approaches used in the selected studies.

Addendum

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

E. Romualdi: conception and design of the study, acquisition of data, analysis and interpretation of data, drafting of the manuscript, and statistical analysis; F. Dentali: conception and design of the study, analysis and interpretation of data, critical revision of the manuscript, and supervision and statistical analysis; A. Squizzato: conception and design of the study, analysis and interpretation of data, critical revision of the manuscript, and supervision; E. Rancan: acquisition of data; L. Steidl: acquisition of data and critical revision of the manuscript; S. Middeldorp: critical revision of the manuscript; W. Ageno: conception and design of the study, analysis and interpretation of data, critical revision of the manuscript, and supervision.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

We would like to thank G. Barillari, N. Clark, B. Hunt, G. Mitic, C. Narin and J. Voke for the additional data provided to allow completion of this work.

Disclosure of Conflict of Interests

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

The authors state that they have no confict of interests.

References

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  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
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