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Early Use of Fibrinogen Replacement Therapy in Postpartum Hemorrhage—A Systematic Review
YTMRV-50604; No of Pages 7 Transfusion Medicine Reviews xxx (xxxx) xxx
Contents lists available at ScienceDirect
Transfusion Medicine Reviews journal homepage: https://www.journals.elsevier.com/transfusion-medicinereviews/
Early Use of Fibrinogen Replacement Therapy in Postpartum Hemorrhage —A Systematic Review Abbas Zaidi a,b, Ruchika Kohli b,c, Jan Daru a, Lise Estcourt d,e,f, Khalid S. Khan a, Shakila Thangaratinam a,b, Laura Green b,d,e,f,⁎ a
Barts Research Centre for Women’s Health, Queen Mary University of London, UK Barts Health, NHS Trust, London, UK Wolfson Institute, Queen Mary University of London, UK d NHS Blood and Transplant, UK e Radcliffe Department of Medicine, University of Oxford, UK f Blizard Institute, Queen Mary University of London, UK b c
a r t i c l e
i n f o
Available online xxxx Keywords: Postpartum hemorrhage Fibrinogen therapy Cryoprecipitate systematic review Outcomes
a b s t r a c t Fibrinogen levels drop early in postpartum hemorrhage (PPH), and low fibrinogen levels predict outcomes. There is increasing interest in replacing fibrinogen early in severe PPH and this systematic review’s aim was to assess if early fibrinogen replacement therapy improves outcomes in severe PPH. We searched the following databases from inception to June 2019: CDSR and CENTRAL (The Cochrane Library), MEDLINE, Embase, CINAHL, PubMed, Transfusion Evidence Library, LILACS, Web of Science Conference Proceedings Citation Index-Science, ClinicalTrials.gov and the WHO International Clinical Trials Registry Portal. We included randomized (RCT) and well-designed controlled observational studies where fibrinogen replacement therapy was given early (within 90 minutes of bleeding) compared with standard protocol in pregnant women N 24 weeks’ gestation who developed PPH, defined as estimated blood loss ≥500 mL up to 24 hours post-delivery. Two independent reviewers extracted and reviewed the data on the primary outcome of allogeneic blood transfusion at 24 hours after intervention and secondary outcomes including all-cause mortality, rate of thrombosis, and the need for surgical and non-surgical interventions. We identified 5 eligible studies: 2 completed (total of 299 women) RCTs comparing fibrinogen concentrate with placebo, and 3 ongoing RCTs. There was no completed study assessing cryoprecipitate transfusion. There was variation of: timings of intervention administration; severity of PPH; fibrinogen doses and use of tranexamic acid. There was insufficient evidence that early administration of fibrinogen in PPH reduces the need for allogeneic blood transfusion at 24 hours (risk ratio 0.83 (95% CI 0.54–1.26), P = 0.38) (2 trials, 299 participants) or improves other outcomes. Both studies were underpowered to answer our outcomes. There is a lack of evidence that early fibrinogen replacement therapy improves outcomes in PPH. Future studies are needed to address this, underpinned by data on the optimal fibrinogen dose, protocol-driven approaches versus targeted therapy, and cost-effectiveness of cryoprecipitate versus fibrinogen concentrate therapy in PPH. © 2020 Elsevier Inc. All rights reserved.
Contents Methods . . . . . . . . . . . . . . . . . . . . . Search Strategy and Study Selection . . . Outcomes . . . . . . . . . . . . . . . Data Extraction and Quality Assessment . Data Synthesis . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . Study Selection . . . . . . . . . . . . Study Characteristics . . . . . . . . .
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⁎ Corresponding author at: Dr Laura Green, Centre for Neuroscience, Surgery and Trauma Blizard Institute Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark St, London, E1 2AT, UK. E-mail address: [email protected] (L. Green). https://doi.org/10.1016/j.tmrv.2019.12.002 0887-7963/© 2020 Elsevier Inc. All rights reserved.
Please cite this article as: A. Zaidi, R. Kohli, J. Daru, et al., Early Use of Fibrinogen Replacement Therapy in Postpartum Hemorrhage—A Systematic Review, Transfusion Medicine Reviews, https://doi.org/10.1016/j.tmrv.2019.12.002
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A. Zaidi et al. / Transfusion Medicine Reviews xxx (xxxx) xxx
. Risk of Bias of Included Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Data Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Primary Outcome: Mean Difference in Overall Transfusion Requirements at 24 hours from Administration of Fibrinogen Replacement Treatment . Ongoing Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Main Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Strengths and Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Interpretation of Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion and Implication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Postpartum hemorrhage (PPH) remains a major cause of maternal mortality and morbidity worldwide [1-3]. The management of severe PPH includes administration of pharmacological, radiological, and surgical interventions as well as blood transfusion to replace essential coagulation factors that are crucial to achieving hemostasis and thus controlling bleeding. Several studies have demonstrated that fibrinogen (an important clotting factor) levels drop early and significantly in PPH, and that a level of b2g/L is predictive of requirement for hysterectomy, the need for high dependency care and the need for RBC transfusion [4-6]. There is increasing interest in using early fibrinogen replacement therapy for management of severe PPH, but current guidelines only recommend replacing fibrinogen when levels drop to b2 g/L or if the woman has received a massive blood transfusion [7, 8]. Fibrinogen replacement therapy is available in two forms, cryoprecipitate and fibrinogen concentrate, both of which are plasma derived products. Cryoprecipitate is the concentrated precipitate produced after thawing and centrifugation of fresh frozen plasma, and it contains fibrinogen and other coagulation proteins such as factor VIII, von Willebrand factor fibronectin, factor XIII and fibronectin. Cryoprecipitate is stored at b−25°C and requires thawing prior to administration [9]. Advantages of cryoprecipitate include its widespread availability and reduced cost in comparison to fibrinogen concentrate, while disadvantages include the time required to thaw the component resulting in delay in issuing it quickly, and other blood-borne related complications such as transmission of infections (viral or bacterial), immune-mediated conditions (like transfusion related lung injury) and allergic reactions [9]. Fibrinogen concentrate undergoes further treatment to reduce the risk of viral transmission, and hence its main advantages over cryoprecipitate include the reduced risk of viral transmission, standardized fibrinogen concentration in the vials, and the long shelf life. One of the perceived advantages of fibrinogen concentrate is the rapid administration—however, a pilot randomized control trial in trauma setting showed that its early delivery within 45 minutes of admission to hospital was not feasible [10]. For correcting low levels of fibrinogen early outside PPH, there is one large randomized control trial (RCT) currently ongoing in trauma patients who are bleeding (ICRCTN: CRYOSTAT-2). Given that fibrinogen levels drop early in PPH and that its low levels predict outcome, its early replacement in obstetric bleeding would seem logical and could indeed improve outcomes for women. Previous systematic reviews have assessed fibrinogen concentrates in all causes of bleeding [11-14], with only one examining studies in PPH. The latter had insufficient data to draw conclusions regarding clinical effectiveness such as mortality [14]. Further, this review pooled all studies of fibrinogen concentrate across a wide range of acquired bleeding disorders (recognized by its authors as a limitation), and it did not assess other forms of fibrinogen replacement therapy (like cryoprecipitate), and nor did it evaluate if the timing of fibrinogen therapy improved outcomes. Thus, there is a need to synthesize the literature on this topic and assess if early fibrinogen replacement therapy
0 0 0 0 0 0 0 0 0 0 0
improves maternal outcomes in and all-cause mortality in women who develop severe PPH, which is the aim of this systematic review. Methods The protocol for this review was prospectively registered (PROSPERO CRD42018085167) and has been reported in accordance with PRISMA [15] guidelines. Search Strategy and Study Selection Searches of the following databases: CDSR & CENTRAL (The Cochrane Library), MEDLINE, Embase, CINAHL, PubMed (for electronic publications ahead of print only), Transfusion Evidence Library, LILACS, Web of Science Conference Proceedings Citation Index- Science, ClinicalTrials.gov and the WHO International Clinical Trials Registry Portal (ICTRP) were performed from inception to June 2019. There were no restrictions on publication date, language or publication status or study design applied (see Supplement; Search Strategy). Two review authors (A.Z and R.K) screened titles and abstracts identified by the search and assessed citations with reference to a priori criteria independently. Full texts articles of potentially relevant trials were then assessed for eligibility by the two review authors (A.Z. and R.K.) independently. Any disagreements were resolved by consensus or after discussion with a third author (J.D). Studies were included if they were RCTs (including cluster-RCTs with at least two intervention sites in each arm), non-randomized trials, repeated measures studies, interrupted time series studies and controlled before-and-after studies where fibrinogen replacement therapy was administered in the context of PPH. There is no universally accepted definition for PPH, however the most widely used definition is blood loss of at least 500 mL within 24 hours of delivery [7, 16]. Hence for this review, studies were eligible if they included pregnant women of any age, at greater than 24 weeks gestation who had a diagnosis of PPH defined as estimated blood loss ≥500 mL up to 24 hours postdelivery. The intervention evaluated was the early infusion of fibrinogen replacement therapy (within 90 minutes of bleeding started) plus standard care. The comparator was management using a standard major hemorrhage protocol with correction of fibrinogen level based on clotting assays, or if women had received a massive transfusion. We excluded studies that compared fibrinogen replacement therapy with another hemostatic intervention, e.g. early fibrinogen replacement + standard of care versus tranexamic acid + standard of care or any other hemostatic agent that was not fibrinogen replacement therapy. Outcomes The primary outcome of this review was the standardized mean difference in overall transfusion requirements (i.e. red blood cell units,
Please cite this article as: A. Zaidi, R. Kohli, J. Daru, et al., Early Use of Fibrinogen Replacement Therapy in Postpartum Hemorrhage—A Systematic Review, Transfusion Medicine Reviews, https://doi.org/10.1016/j.tmrv.2019.12.002
A. Zaidi et al. / Transfusion Medicine Reviews xxx (xxxx) xxx
platelet, fresh frozen plasma, and cryoprecipitate or fibrinogen concentrate) at 24 hours from administration of fibrinogen replacement treatment. If the data obtained did not allow for direct comparison, we described different blood components separately and reported a 99% confidence interval (CI). Neither included study reported this outcome and therefore, post-hoc it was decided that the requirement for transfusion at 24 hours would also be reported. Secondary outcomes were: all-cause mortality at 24 hours, 7 days and 30 days from onset of PPH; mortality due to bleeding at 24 hours, 7 days, and 30 days from onset of PPH; rate of thrombosis at three months (arterial and/or venous); overall blood transfusion requirement (i.e. red blood cell units, platelet units, fresh frozen plasma, and cryoprecipitate or fibrinogen concentrate) up to 7 days from onset of PPH; length of stay in intensive care/high dependency units; length of hospital stay; surgical intervention (defined as any physical intervention including but not limited to intra-uterine balloon tamponade, uterine arterial ligation/embolization, internal iliac artery ligation, brace uterine sutures, laparotomy or any physical intervention to achieve hemostasis); fibrinogen level pre and post fibrinogen replacement therapy; any non-surgical hemostatic intervention (e.g. use of recombinant activated factor VII or prothrombin complex concentrate);
3
and transfer to another hospital with additional facilities for management of ongoing bleeding (e.g. radiological procedures). Data Extraction and Quality Assessment Data from selected eligible and included studies were independently extracted by two reviewers (AZ and RK) using a standardized data extraction form. The following parameters were collected: study ID, date of publication, study characteristics/design, whether the population studied met our inclusion criteria. We also collected data on clinical outcomes as defined under outcomes. For missing data we contacted the authors directly to clarify the data that was presented. The risk of bias for included studies was assessed by 2 authors (AZ and RK) using the Cochrane Risk of bias tool [17]. The risk of bias was classified as low, high or unclear. Grades of evidence were assessed in terms of certainty as: High: very confident that the true effect lies close to that of the estimate of the effect; Moderate: moderately confident in the effect estimate or the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; Low: confidence in the effect estimate is limited or the true effect may be substantially different from the estimate of the effect; and Very low: very little
Fig. 1. Studies included in systematic review of early fibrinogen replacement therapy in postpartum hemorrhage. *Search run on 12th June 2019.
Please cite this article as: A. Zaidi, R. Kohli, J. Daru, et al., Early Use of Fibrinogen Replacement Therapy in Postpartum Hemorrhage—A Systematic Review, Transfusion Medicine Reviews, https://doi.org/10.1016/j.tmrv.2019.12.002
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A. Zaidi et al. / Transfusion Medicine Reviews xxx (xxxx) xxx
confidence in the effect estimate or the true effect is likely to be substantially different from the estimate of effect Data Synthesis If studies were sufficiently homogenous in their design, we planned to conduct meta-analyses according to the recommendations of Cochrane (42). Separate analyses for pooling results from randomized and non-randomized studies were planned. However, there were no non-randomized studies. We recorded the number of patients lost to follow-up for each study.
in FIB-PPH study received tranexamic acid (40% 49/123 in the fibrinogen arm and 36% 43/121 in the placebo arm). In the OBS2 study, the dose of fibrinogen concentrate was 1 gram guided by the rotational thromboelastometry (ROTEM), FIBTEM parameter [25]. The median time from obtaining ROTEM results to the administration of the study interventions was 24 minutes (IQR 20 to 33 minutes); however, the timing from the start of bleeding to administration of interventions was not reported. (Table 1). Only women who had ongoing major PPH (1000–1500 mL blood loss) were screened with ROTEM. Of the 3894 women with at least 1 L blood loss, 663 were screened and only 57 participants (1.5%) were included in the trial. All participants in OBS2 were given tranexamic acid.
Results Risk of Bias of Included Studies Study Selection We identified a total of 2,038 citations (including 77 trial registrations) (Fig. 1, Prisma Flow Chart). There were 1,595 citations after duplicates were removed. Two review authors (AZ, RK) excluded 1,581 citations on the basis of the abstract, leaving 14 full text articles which were reviewed for eligibility. Of the 14 studies a further 9 studies were excluded (see Supplement; Table S1) because: 6 were retrospective studies [18-22], one was a single arm study with no comparator [23] and the other two were randomized trials that had been withdrawn prior to recruiting any participants [24, 17]. Of the five eligible studies, two were completed randomized control trials (RCTs) [25, 26] (Table 1) and three were ongoing trials (Table 2) [27-29]. In the final analysis only the two completed RCT were included. We identified no good quality ongoing or completed non-randomized studies. Study Characteristics The two completed trials involved a total of 299 participants, of which 244 participants were recruited from FIB-PPH trial by Wikkelso et al [26], and 55 from OBS2 trial by Collins et al [25]. Both trials were multicenter, double-blind, placebo controlled, trials comparing a single dose of fibrinogen concentrate as the intervention with placebo (normal saline) as a comparator (Table 1). In the FIB-PPH trial the dose of fibrinogen concentrate was 2 grams and the median time for delivery of the intervention was 81 minutes (interquartile range (IQR) 59 to 130 minutes) [26]. The inclusion criteria for PPH were Caesarean section with an estimated perioperative blood loss N1 L or vaginal delivery with either estimated blood loss N0.5 L and intended manual removal of placenta or estimated blood loss N1 L and intended manual exploration of the uterus because of continuous bleeding after delivery of the placenta. Approximately 40% of women
The OBS2 Study was classified as having an overall low risk’ of bias and the FIB-PPH was rated ‘unclear. The main sources of potential bias were attrition bias due to incomplete outcome data reporting in the FIB-PPH (there was no clear documentation for reasons for missing data on adverse events) [26]. Further, the OBS2 study [25] was funded by CSL Behring, which is the manufacturer of the fibrinogen concentrate. The supporting evidence for the risk of bias judgments in all domains is presented in Table 3. Data Synthesis Primary Outcome: Mean Difference in Overall Transfusion Requirements at 24 hours from Administration of Fibrinogen Replacement Treatment Neither study reported the review’s primary outcome. However, the need for a red cell transfusion at 24 hours was reported [26] or data were provided by the study authors [25]. There was no evidence of a difference in the need for a red cell transfusion between participants who received fibrinogen and those that did not (risk ratio 0.83 [95% CI 0.54 to 1.26], 2 studies, 299 participants, GRADE low quality evidence). The GRADE level of evidence was downgraded by two, one for imprecision (wide confidence intervals that include clinically significant benefit as well as no effect) and one for generalizability (only patients with severe post-partum hemorrhage were included in either study). Regarding other secondary outcomes, both studies were underpowered to answer any of the outcomes. In summary, there were no reported deaths relating to PPH in either study [25, 26] up to 30 days, however 5/53 participants were lost to follow-up in the OBS2 study. There was one case of pulmonary embolism in the fibrinogen group and one case of right ovarian vein thrombosis in the placebo group in
Table 1 Study Characteristics of trials included in systematic review of early fibrinogen replacement therapy in postpartum hemorrhage Study Title/ Citation
Study Type
n
FIB-PPH
Multicenter, randomized, double blinded, placebo controlled RCT Denmark
244
Multicenter, randomized, double blinded, placebo controlled RCT
55
Wikkelso et al [26]
OBS2 Collins et al [25]
Intervention and dose
Fibrinogen Concentrate, (123 int 2g vs 121 control)
(28 in. vs 27 control)
Control Group Treatment
Timing of intervention
Primary Outcome / Significant finding
P
100 mL Normal Saline
‘Pre-emptive’ infusion
Need for RBC transfusion b6 weeks post PPH
.88 No evidence of benefit for pre-emptive fibrinogen concentrate in PPH
Median time = 81 minutes (IQR 59-130 mins) ‘Early’ infusion
Intervention n=25, (20.3%) Control n=26 (21.5%)
50 mL Fibrinogen Concentrate,1g Normal Saline Guided by viscoelastic testing
Total number of allogeneic blood products up to point of hospital discharge
Overall Conclusion
.45 No improvement in outcome in PPH
⁎Median time = 24 minutes (IQR 20-33 Mean transfusion Rate: mins) Intervention: 2.07 Control: 2.78
RCT, randomized control trial; PPH, postpartum hemorrhage. ⁎ Time from FIBTEM triggering randomization to administration of study medication.
Please cite this article as: A. Zaidi, R. Kohli, J. Daru, et al., Early Use of Fibrinogen Replacement Therapy in Postpartum Hemorrhage—A Systematic Review, Transfusion Medicine Reviews, https://doi.org/10.1016/j.tmrv.2019.12.002
A. Zaidi et al. / Transfusion Medicine Reviews xxx (xxxx) xxx
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Table 2 Characteristics of ongoing studies in systematic review of early fibrinogen replacement therapy in postpartum hemorrhage Title of study
Trial number
Fibrinogen in Hemorrhage of Delivery (FIDEL)
NCT02155725
Administering cryoprecipitate in obstetric bleeding at an earlier time (ACROBAT)
A Program to Evaluate Riastap® and FIBTEM® for the Early Control and Treatment of Postpartum Hemorrhage (PERFECT PPH)
Summary
Early fibrinogen replacement vs Placebo in patients treated with IV prostaglandins following vaginal delivery ISRCTN12146519 The effect of early cryoprecipitate transfusion (within 90 minutes) versus standard care in women who develop severe postpartum hemorrhage NCT02528708 Evaluates early detection and treatment of fibrinogen depletion in PPH.
Study design
Funding
Intervention
Primary outcome
Enrolment Recruitment status
PI/ Country
Randomized, double-blinded, multicenter, placebo-controlled study
Industry
Fibrinogen concentrate 3g IV vs saline placebo
Reduction of Hb N4 g/dL or requirement of 2 U RBC within 48 h of IMP
447
Ducloy-Bouthors
2 U of early cryoprecipitate in addition to standard major hemorrhage protocol vs standard major hemorrhage protocol
Proportion of women administered cryoprecipitate within 90 minutes of major hemorrhage protocol activation
Target 200
ROTEM guided fibrinogen replacement if only FIBTEM A10 b18 mm with IV fibrinogen concentrate 3g vs saline placebo
MCF via FIBTEM A10 taken 15 minutes, 1 hour, 6 h 24 h post IMP
Target 40
(Laboratoire Français de Fractionnement et de Biotechnologie)
Non commercial Cluster randomized trial; A pilot feasibility (Barts Health study charity)
Randomized, double blind, placebo controlled trial
Industry (CSL Behring)
Completed (Dec 2018)
France
Recruiting
L Green UK
Paidas M Currently Suspended (study never USA began, pending review to be reopened)
the OBS2 trial [25], and none in the FIB-PPH trial, however both studies only followed-up participants for a maximum of 6 weeks rather than 3 months (see Table 4).
Discussion
Ongoing Studies
This systematic review identified only two published RCTs that assessed the early use of fibrinogen replacement therapy in PPH. Both trials compared fibrinogen concentrate with placebo, with no studies identified assessing cryoprecipitate transfusion. There were three ongoing RCTs, 2 assessing fibrinogen concentrate and one cryoprecipitate. For completed studies there was variation on timings of intervention administration, severity of PPH, fibrinogen doses, and tranexamic use. All of the evidence was of low or very low quality according to GRADE criteria due to imprecision of estimates and lack of generalizability to all women with a PPH of at least 500 mL.
We identified three ongoing randomized trials (details described in Table 2) assessing upfront use of fibrinogen replacement therapy. Two of these studies are randomized, double-blind, placebo control trials assessing fibrinogen concentrate [28, 29] and one is a pilot cluster randomized trial evaluating early cryoprecipitate transfusion [27]. The NCT02155725 is a French trial of Fibrinogen in Hemorrhage of Delivery (FIDEL) randomizing women who are treated with intravenous prostaglandins following surgery to either 4 grams of intravenous fibrinogen concentrate or saline placebo. Recruitment of 447 patients was completed in December 2018, however the results were not available for review [29]. The NCT02528708, is American trial (PERFECT-PPH) evaluating the early detection and treatment of fibrinogen depletion in PPH using fibrinogen concentrate guided by viscoelastic testing. If FIBTEM A10 measurement is b18 mm, women are randomized to 3g of intravenous fibrinogen concentrate versus saline placebo. The primary outcome is a measure of hemostasis using maximal clot firmness (MCF) via ROTEM measured at different time points after administration of IV fibrinogen. This trial was stopped early during the set-up phase and is pending review to be re-opened [28]. Finally, the UK trial (Administering CRyoprecipitate in Obstetric bleeding At an earlier Time – ACROBAT) (ISRCTN12146519) is the only study assessing early cryoprecipitate as a fibrinogen replacement therapy. This is a pilot study that is evaluating the early use of cryoprecipitate (within 90 minutes) in addition to standard major hemorrhage protocol versus standard care in women who develop PPH that requires blood transfusion [27].
Main Findings
Strengths and Limitations We prospectively registered the review and performed a comprehensive search without language, time, or study design restrictions. We followed the recommended guidelines on review conduct, with two reviewers working independently. We also dealt with missing data by contacting the authors to obtain results for outcomes and had a very good response from authors. We searched for grey literature using the Transfusion Evidence Library and study registration data. Interpretation of Findings We looked for good quality studies, but only found 2 completed RCTs, and no non-randomized studies. Both studies were underpowered to detect differences in any of the outcomes defined in this review. In the FIB-PPH study this was because the expected number of participants who required a transfusion in the placebo arm was much lower than expected (21.5% versus 57%). Using approximate transfusion
Please cite this article as: A. Zaidi, R. Kohli, J. Daru, et al., Early Use of Fibrinogen Replacement Therapy in Postpartum Hemorrhage—A Systematic Review, Transfusion Medicine Reviews, https://doi.org/10.1016/j.tmrv.2019.12.002
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A. Zaidi et al. / Transfusion Medicine Reviews xxx (xxxx) xxx
Table 3 Risk of Bias and Quality Assessment in systematic review of early fibrinogen replacement therapy in postpartum hemorrhage.
Bias Random Sequence Generation (Selection bias)
Wikkelso et al [26] FIB-PPH
Collins et al [25] OBS2
Judgement Support for Judgement
Judgement Support for Judgement
Low risk
Computer generated allocation ‘Used computer-generated allocation and blocks-of-four randomization’ Assignment by concealed envelopes, but no further details given. Placebo was dyed to match color of fibrinogen concentrate and both were in opaque syringes. Blinding incomplete (4% of anesthetists aware of intervention) but unlikely to affect outcome Double blinded study design
Low risk
Computer generated allocation
Low risk
Fibrinogen concentrate, in consecutively labelled concealed packs Syringes were concealed to prevent identification. But does not specify whether blinding complete.
Low risk
Double blinded study design
148 Missing data values for adverse events, no reason supplied Outcomes are reported as pre-specified in the available protocol Most severe bleeding episodes potentially not included due to inability to consent
Low risk
Complete outcome data
Low risk
Outcomes are reported as pre-specified in the available protocol Full protocol available for review
Allocation Concealment (Selection bias) Blinding of participants and personnel (performance bias)
Unclear
Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Other bias
Low risk
Overall Risk of Bias
Unclear
Low risk
High risk Low risk Unclear
Low Risk
Low risk Low risk
rates from the FIB-PPH study, 1368 patients would be required to have an 80% chance of detecting, as significant at the 5% level, a decrease in the need for transfusion at 24 hours from 15% in the control group to 10% in the experimental group. Results of this review highlight the need for further studies to answer the question of whether early replacement of fibrinogen in PPH is clinically beneficial in addition to tranexamic acid. We also found considerable variation in the primary and secondary outcomes used in included and ongoing studies. Although mortality is considered an ideal choice to use as primary outcome, this would require a sample size of over 20,000 women, as seen in the WOMAN trial [30]. Further, in this review we identified two trials that were
suspended due to failure to recruit [17, 24], highlighting some of the challenges around performing trials in obstetric bleeding. Thus, it is important that core outcome sets are agreed for studies assessing interventions for treatment of PPH, in order to obtain meaningful results. This was recently achieved by an international group of experts [31], and this review captured all outcomes agreed in the consensus. Fibrinogen replacement therapy is available in two forms; cryoprecipitate and fibrinogen concentrate, both of which are plasma derived products. However, in this review we did not identify any studies that have assessed the use of cryoprecipitate transfusion in PPH, even though this component has been around for a lot longer than fibrinogen concentrate and it remains the standard fibrinogen
Table 4 Summary of results concerning secondary outcomes of the systematic review of early fibrinogen replacement therapy in postpartum hemorrhage Study
OBS2, Collins et al [25]
FIB-PPH, Wikkelso et al [26]
Intervention
Fibrinogen Control n = 28 n = 27
Difference (95% Confidence interval, P value)
Fibrinogen Control n = 123 n = 121
Difference (95% Confidence interval, p- value)
All-cause mortality up to 30 days#⁎, ⁎⁎
0
0
-
0
0
-
Thrombosis (arterial and venous) (incidence) up to 6 weeks Overall transfusion requirement (total units per patient at 7 days) Hemostatic Intervention
1 (3.6%)
1 (3.7%)
-
0
0
-
2.07
2.78 0
not reported 0
not reported 0
-
0
Adjusted rate ratio 0.72 (95% CI 0.30–1.70, P = 0.45) -
Length of Hospital Stay Median days (IQR)
3 (IQR 2.0-5.0) 5 (17.9%)
3 (IQR 2-4)
P = 0.13
not recorded*
not recorded*
not reported 0
not reported 0
5.5
5.3
0**
0**
Surgical Intervention -until discharge, number of patients Transfer Mean Fibrinogen Level g/L (SD) by Clauss method at 24 h post intervention Duration in High dependency unit median no. of days (IQR) Admission to Level 3 care
5 (18.5%)
0
0
P = 0.95 -
4.1 SD (0.8)
4.0 SD (0.9)
Adjusted difference - 0.02 (95% CI - 0.5 to 0.5, P = 0.95
16 (IQR 12-25) 2 (7.1%)
20.5 (IQR 0.90 10.5-28.5) 2 (7.4%) 0.97
0
0
-
-
Certainty of evidence (GRADE) +--VERY LOW1,2 ++-LOW1,3 ++-LOW1,3 +--VERY LOW1,2 ++-LOW1,3
Mean difference 0.20 g/L (95% CI –0.06 – 0.46, P = 0.13)
++-LOW1,3 ++-VERY LOW1,2 ++-LOW1,3
-
++-LOW1,3
-
-
++-LOW1,3
# Other mortality outcomes were not reported separately because no deaths occurred at up to 30 days. ⁎ author confirmed that it was not collected after personal correspondence with review authors ⁎⁎ author confirmed that there were no admissions to higher level care after personal correspondence with review authors 1 Downgraded by 1 for lack of generalizability. Only participants with severe PPH were included in the studies 2 Downgraded by 2 for imprecision (no events in either arm, rare event) 3 Downgraded by 1 for imprecision
Please cite this article as: A. Zaidi, R. Kohli, J. Daru, et al., Early Use of Fibrinogen Replacement Therapy in Postpartum Hemorrhage—A Systematic Review, Transfusion Medicine Reviews, https://doi.org/10.1016/j.tmrv.2019.12.002
A. Zaidi et al. / Transfusion Medicine Reviews xxx (xxxx) xxx
replacement therapy in most countries. Of the three ongoing studies, only one pilot cluster RCT is evaluating the feasibility of administering early cryoprecipitate transfusion [27] in PPH, underscoring the importance for further studies in this field. Conclusion and Implication This review has demonstrated the paucity of evidence on the early use of fibrinogen replacement therapies in postpartum hemorrhage. The small sample size of included studies and their heterogeneity warrants us to interpret these results with extreme caution until further evidence become available. Therefore, future trials are urgently needed to assess the clinical efficacy and safety of early fibrinogen replacement therapy (particularly cryoprecipitate) in PPH. Evidence is required to determine the optimal dose of fibrinogen replacement therapy in PHH as well as compare the cost-effectiveness of cryoprecipitate transfusion with fibrinogen concentrate, and protocol-driven approaches with targeted-therapy for fibrinogen replacement therapy. Supplementary data to this article can be found online at https://doi. org/10.1016/j.tmrv.2019.12.002. Acknowledgments We would like to acknowledge the following authors for providing the following information: Professor Collins for providing additional data from the OBS-2 trial on the total number of transfusion units required after 24 hours, the number of cases requiring hemostatic intervention and the number of cases requiring transfer to another center. Professor Wikkelso for providing additional data from FIB-PPH trial on the number of cases requiring admission to intensive care or high dependency and Dr Westhuizen for providing data on the completion and recruitment status of the FIB-UPFRONT-PPH study (ANZCTR12614000691640). Funding The study was funded by Barts Charity. The funders had no role in the study design, data collection/analysis or preparation of this article. The views expressed in this article are those of the authors and not necessarily of the funders. Contribution to Authorship AZ and RK extracted/analyzed the data and assessed the risk of bias. LG, KK, ST, LE and JD designed the study. All authors contributed to the writing of the article. Disclosure of Interests LG, ST, JD, and KK are investigators of the ongoing ACROBAT trial reported in this review. JD has received fees from Pharmacosmos for advisory work. References [1] Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PF. WHO analysis of causes of maternal death: a systematic review. Lancet 2006;367:1066–74. [2] Say L, Chou D, Gemmill A, Tuncalp O, Moller AB, Daniels J, et al. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health 2014;2:e323–33. [3] Green L, Knight M, Seeney FM, Hopkinson C, Collins PW, Collis RE, et al. The epidemiology and outcomes of women with postpartum haemorrhage requiring massive transfusion with eight or more units of red cells: a national cross-sectional study. BJOG 2016;123:2164–70. https://doi.org/10.1111/1471-0528.13831. [4] Gayat E, Resche-Rigon M, Morel O, Rossignol M, Mantz J, Nicolas-Robin A, et al. Predictive factors of advanced interventional procedures in a multicentre severe postpartum haemorrhage study. Intensive Care Med 2011;37:1816–25.
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[5] Charbit B, Mandelbrot L, Samain E, Baron G, Haddaoui B, Keita H, et al. P.D. de. The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage. J Thromb Haemost 2007;5:266–73. [6] Cortet M, Deneux-Tharaux C, Dupont C, Colin C, Rudigoz RC, Bouvier-Colle MH, et al. Association between fibrinogen level and severity of postpartum haemorrhage: secondary analysis of a prospective trial. Br J Anaesth 2012;108:984–9. [7] Mavrides E, Allard S, Chandraharan E, Collins PG, Hunt B L, Riris S, et al. o.b.t.R.C.o.O. a.a. Gynaecologists. Prevention and management of postpartum haemorrhage. BJOG 2016. https://doi.org/10.1111/1471-0528.14178. [8] Sentilhes L, Merlot B, Madar H, Sztark F, Brun S, Deneux-Tharaux C. Postpartum haemorrhage: prevention and treatment. Expert Rev Hematol 2016;9:1043–61. [9] Green L, Bolton-Maggs P, Beattie C, Cardigan R, Kallis Y, Stanworth SJ, et al. British Society of Haematology Guidelines on the spectrum of fresh frozen plasma and cryoprecipitate products: their handling and use in various patient groups in the absence of major bleeding. Br J Haematol 2018;181:54–67. [10] Curry N, Foley C, Wong H, Mora A, Curnow E, Zarankaite A, et al. Early fibrinogen concentrate therapy for major haemorrhage in trauma (E-FIT 1): results from a UK multicentre, randomised, double blind, placebo-controlled pilot trial. Crit Care 2018;22:164. [11] Wikkelso A, Lunde J, Johansen M, Stensballe J, Wetterslev J, Moller AM, et al. Fibrinogen concentrate in bleeding patients. Cochrane Database Syst Rev 2013(8):Cd008864. [12] Warmuth M, Mad P, Wild C. Systematic review of the efficacy and safety of fibrinogen concentrate substitution in adults. Acta Anaesthesiol Scand 2012;56:539–48. [13] Lunde J, Stensballe J, Wikkelso A, Johansen M, Afshari A. Fibrinogen concentrate for bleeding—a systematic review. Acta Anaesthesiol Scand 2014;58:1061–74. [14] Fabes J, Brunskill SJ, Curry N, Doree C, Stanworth SJ. Pro-coagulant haemostatic factors for the prevention and treatment of bleeding in people without haemophilia. Cochrane Database Syst Rev 2018;12:CD010649. [15] Moher D, Liberati A, Tetzlaff J, Altman DG, P. Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 2009;62:1006–12. [16] Dahlke JD, Mendez-Figueroa H, Maggio L, Hauspurg AK, Sperling JD, Chauhan SP, et al. Prevention and management of postpartum hemorrhage: a comparison of 4 national guidelines. Am J Obstet Gynecol 2015;213 76 e71-76 e10. [17] J.v.d. Westhuizen. The effect of Upfront Administration of Fibrinogen concentrate on total blood volume loss in Obstetric Haemorrhage – A Pilot study. Australian New Zealand Clinical Trials Registry; 2014. [18] Ahmed S, Harrity C, Johnson S, Varadkar S, McMorrow S, Fanning R, et al. O.R. J.M, B.M. Byrne. The efficacy of fibrinogen concentrate compared with cryoprecipitate in major obstetric haemorrhage—an observational study. Transfus Med 2012;22:344–9. [19] Bell SF, Rayment R, Collins PW, Collis RE. The use of fibrinogen concentrate to correct hypofibrinogenaemia rapidly during obstetric haemorrhage. Int J Obstet Anesth 2010;19:218–23. [20] Deleu F, Deneux-Tharaux C, Seco A, Chiesa-Dubruille C, Bonnet MP. Effect of fibrinogen concentrate administration on maternal morbidity in the treatment of severe postpartum haemorrhage. Int J Obstet Anesth 2017;31(Supplement 1):S51. [21] McQuilten ZK, Bailey M, Cameron PA, Stanworth SJ, Venardos K, Wood EM, et al. Fibrinogen concentration and use of fibrinogen supplementation with cryoprecipitate in patients with critical bleeding receiving massive transfusion: a bi-national cohort study. Br J Haematol 2017;179:131–41. [22] Wen H, Aiping L. Analysis of influence of clinical outcomes of cryoprecipitate infusion in patients with early postpartum hemorrhagic shock. Vox Sang 2017;112(Supplement 2):166. [23] I. Akira. Invasive intervention study of the safety of fibrinogen concentrate used in obstetric hemorrhage (SFOH study). 2019. https://upload.umin.ac.jp/cgi-open-bin/ ctr_e/ctr_view.cgi?recptno=R000025568 [24] Ahonen JV. Use of Prothrombin Complex Concentrate and Fibrinogen Compared With Fresh Frozen Plasma (and Fibrinogen if Needed) in the Treatment of Postpartum Haemorrhage ClinicalTrials.gov ; 2013. [25] Collins PW, Cannings-John R, Bruynseels D, Mallaiah S, Dick J, Elton C, et al. Viscoelastometric-guided early fibrinogen concentrate replacement during postpartum haemorrhage: OBS2, a double-blind randomized controlled trial. Br J Anaesth 2017;119:411–21. [26] Wikkelso AJ, Edwards HM, Afshari A, Stensballe J, Langhoff-Roos J, Albrechtsen C, et al. F.-P.t. group. Pre-emptive treatment with fibrinogen concentrate for postpartum haemorrhage: randomized controlled trial. Br J Anaesth 2015;114:623–33. [27] Green L. Administering cryoprecipitate in obstetric bleeding at an earlier time (ACROBAT) ISRCTN registry ; 2019. [28] Paidas MJ. A Program to Evaluate Riastap® and FIBTEM® for the Early Control and Treatment of Postpartum Hemorrhage (PERFECT PPH) ClinicalTrials.gov ; 2015. [29] Ducloy-Bouthors AS, Mignon A, Huissoud C, Grouin JM, Mercier FJ. Fibrinogen concentrate as a treatment for postpartum haemorrhage-induced coagulopathy: A study protocol for a randomised multicentre controlled trial. The fibrinogen in haemorrhage of DELivery (FIDEL) trial. Anaesth Crit Care Pain Med 2016;35:293–8. [30] Collaborators WT. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet 2017;389:2105–16. [31] Meher S, Cuthbert A, Kirkham JJ, Williamson P, Abalos E, Aflaifel N, et al. Core outcome sets for prevention and treatment of postpartum haemorrhage: an international Delphi consensus study. BJOG 2019;126:83–93.
Please cite this article as: A. Zaidi, R. Kohli, J. Daru, et al., Early Use of Fibrinogen Replacement Therapy in Postpartum Hemorrhage—A Systematic Review, Transfusion Medicine Reviews, https://doi.org/10.1016/j.tmrv.2019.12.002
Contents lists available at ScienceDirect
Transfusion Medicine Reviews journal homepage: https://www.journals.elsevier.com/transfusion-medicinereviews/
Early Use of Fibrinogen Replacement Therapy in Postpartum Hemorrhage —A Systematic Review Abbas Zaidi a,b, Ruchika Kohli b,c, Jan Daru a, Lise Estcourt d,e,f, Khalid S. Khan a, Shakila Thangaratinam a,b, Laura Green b,d,e,f,⁎ a
Barts Research Centre for Women’s Health, Queen Mary University of London, UK Barts Health, NHS Trust, London, UK Wolfson Institute, Queen Mary University of London, UK d NHS Blood and Transplant, UK e Radcliffe Department of Medicine, University of Oxford, UK f Blizard Institute, Queen Mary University of London, UK b c
a r t i c l e
i n f o
Available online xxxx Keywords: Postpartum hemorrhage Fibrinogen therapy Cryoprecipitate systematic review Outcomes
a b s t r a c t Fibrinogen levels drop early in postpartum hemorrhage (PPH), and low fibrinogen levels predict outcomes. There is increasing interest in replacing fibrinogen early in severe PPH and this systematic review’s aim was to assess if early fibrinogen replacement therapy improves outcomes in severe PPH. We searched the following databases from inception to June 2019: CDSR and CENTRAL (The Cochrane Library), MEDLINE, Embase, CINAHL, PubMed, Transfusion Evidence Library, LILACS, Web of Science Conference Proceedings Citation Index-Science, ClinicalTrials.gov and the WHO International Clinical Trials Registry Portal. We included randomized (RCT) and well-designed controlled observational studies where fibrinogen replacement therapy was given early (within 90 minutes of bleeding) compared with standard protocol in pregnant women N 24 weeks’ gestation who developed PPH, defined as estimated blood loss ≥500 mL up to 24 hours post-delivery. Two independent reviewers extracted and reviewed the data on the primary outcome of allogeneic blood transfusion at 24 hours after intervention and secondary outcomes including all-cause mortality, rate of thrombosis, and the need for surgical and non-surgical interventions. We identified 5 eligible studies: 2 completed (total of 299 women) RCTs comparing fibrinogen concentrate with placebo, and 3 ongoing RCTs. There was no completed study assessing cryoprecipitate transfusion. There was variation of: timings of intervention administration; severity of PPH; fibrinogen doses and use of tranexamic acid. There was insufficient evidence that early administration of fibrinogen in PPH reduces the need for allogeneic blood transfusion at 24 hours (risk ratio 0.83 (95% CI 0.54–1.26), P = 0.38) (2 trials, 299 participants) or improves other outcomes. Both studies were underpowered to answer our outcomes. There is a lack of evidence that early fibrinogen replacement therapy improves outcomes in PPH. Future studies are needed to address this, underpinned by data on the optimal fibrinogen dose, protocol-driven approaches versus targeted therapy, and cost-effectiveness of cryoprecipitate versus fibrinogen concentrate therapy in PPH. © 2020 Elsevier Inc. All rights reserved.
Contents Methods . . . . . . . . . . . . . . . . . . . . . Search Strategy and Study Selection . . . Outcomes . . . . . . . . . . . . . . . Data Extraction and Quality Assessment . Data Synthesis . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . Study Selection . . . . . . . . . . . . Study Characteristics . . . . . . . . .
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⁎ Corresponding author at: Dr Laura Green, Centre for Neuroscience, Surgery and Trauma Blizard Institute Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark St, London, E1 2AT, UK. E-mail address: [email protected] (L. Green). https://doi.org/10.1016/j.tmrv.2019.12.002 0887-7963/© 2020 Elsevier Inc. All rights reserved.
Please cite this article as: A. Zaidi, R. Kohli, J. Daru, et al., Early Use of Fibrinogen Replacement Therapy in Postpartum Hemorrhage—A Systematic Review, Transfusion Medicine Reviews, https://doi.org/10.1016/j.tmrv.2019.12.002
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A. Zaidi et al. / Transfusion Medicine Reviews xxx (xxxx) xxx
. Risk of Bias of Included Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Data Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Primary Outcome: Mean Difference in Overall Transfusion Requirements at 24 hours from Administration of Fibrinogen Replacement Treatment . Ongoing Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Main Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Strengths and Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Interpretation of Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion and Implication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Postpartum hemorrhage (PPH) remains a major cause of maternal mortality and morbidity worldwide [1-3]. The management of severe PPH includes administration of pharmacological, radiological, and surgical interventions as well as blood transfusion to replace essential coagulation factors that are crucial to achieving hemostasis and thus controlling bleeding. Several studies have demonstrated that fibrinogen (an important clotting factor) levels drop early and significantly in PPH, and that a level of b2g/L is predictive of requirement for hysterectomy, the need for high dependency care and the need for RBC transfusion [4-6]. There is increasing interest in using early fibrinogen replacement therapy for management of severe PPH, but current guidelines only recommend replacing fibrinogen when levels drop to b2 g/L or if the woman has received a massive blood transfusion [7, 8]. Fibrinogen replacement therapy is available in two forms, cryoprecipitate and fibrinogen concentrate, both of which are plasma derived products. Cryoprecipitate is the concentrated precipitate produced after thawing and centrifugation of fresh frozen plasma, and it contains fibrinogen and other coagulation proteins such as factor VIII, von Willebrand factor fibronectin, factor XIII and fibronectin. Cryoprecipitate is stored at b−25°C and requires thawing prior to administration [9]. Advantages of cryoprecipitate include its widespread availability and reduced cost in comparison to fibrinogen concentrate, while disadvantages include the time required to thaw the component resulting in delay in issuing it quickly, and other blood-borne related complications such as transmission of infections (viral or bacterial), immune-mediated conditions (like transfusion related lung injury) and allergic reactions [9]. Fibrinogen concentrate undergoes further treatment to reduce the risk of viral transmission, and hence its main advantages over cryoprecipitate include the reduced risk of viral transmission, standardized fibrinogen concentration in the vials, and the long shelf life. One of the perceived advantages of fibrinogen concentrate is the rapid administration—however, a pilot randomized control trial in trauma setting showed that its early delivery within 45 minutes of admission to hospital was not feasible [10]. For correcting low levels of fibrinogen early outside PPH, there is one large randomized control trial (RCT) currently ongoing in trauma patients who are bleeding (ICRCTN: CRYOSTAT-2). Given that fibrinogen levels drop early in PPH and that its low levels predict outcome, its early replacement in obstetric bleeding would seem logical and could indeed improve outcomes for women. Previous systematic reviews have assessed fibrinogen concentrates in all causes of bleeding [11-14], with only one examining studies in PPH. The latter had insufficient data to draw conclusions regarding clinical effectiveness such as mortality [14]. Further, this review pooled all studies of fibrinogen concentrate across a wide range of acquired bleeding disorders (recognized by its authors as a limitation), and it did not assess other forms of fibrinogen replacement therapy (like cryoprecipitate), and nor did it evaluate if the timing of fibrinogen therapy improved outcomes. Thus, there is a need to synthesize the literature on this topic and assess if early fibrinogen replacement therapy
0 0 0 0 0 0 0 0 0 0 0
improves maternal outcomes in and all-cause mortality in women who develop severe PPH, which is the aim of this systematic review. Methods The protocol for this review was prospectively registered (PROSPERO CRD42018085167) and has been reported in accordance with PRISMA [15] guidelines. Search Strategy and Study Selection Searches of the following databases: CDSR & CENTRAL (The Cochrane Library), MEDLINE, Embase, CINAHL, PubMed (for electronic publications ahead of print only), Transfusion Evidence Library, LILACS, Web of Science Conference Proceedings Citation Index- Science, ClinicalTrials.gov and the WHO International Clinical Trials Registry Portal (ICTRP) were performed from inception to June 2019. There were no restrictions on publication date, language or publication status or study design applied (see Supplement; Search Strategy). Two review authors (A.Z and R.K) screened titles and abstracts identified by the search and assessed citations with reference to a priori criteria independently. Full texts articles of potentially relevant trials were then assessed for eligibility by the two review authors (A.Z. and R.K.) independently. Any disagreements were resolved by consensus or after discussion with a third author (J.D). Studies were included if they were RCTs (including cluster-RCTs with at least two intervention sites in each arm), non-randomized trials, repeated measures studies, interrupted time series studies and controlled before-and-after studies where fibrinogen replacement therapy was administered in the context of PPH. There is no universally accepted definition for PPH, however the most widely used definition is blood loss of at least 500 mL within 24 hours of delivery [7, 16]. Hence for this review, studies were eligible if they included pregnant women of any age, at greater than 24 weeks gestation who had a diagnosis of PPH defined as estimated blood loss ≥500 mL up to 24 hours postdelivery. The intervention evaluated was the early infusion of fibrinogen replacement therapy (within 90 minutes of bleeding started) plus standard care. The comparator was management using a standard major hemorrhage protocol with correction of fibrinogen level based on clotting assays, or if women had received a massive transfusion. We excluded studies that compared fibrinogen replacement therapy with another hemostatic intervention, e.g. early fibrinogen replacement + standard of care versus tranexamic acid + standard of care or any other hemostatic agent that was not fibrinogen replacement therapy. Outcomes The primary outcome of this review was the standardized mean difference in overall transfusion requirements (i.e. red blood cell units,
Please cite this article as: A. Zaidi, R. Kohli, J. Daru, et al., Early Use of Fibrinogen Replacement Therapy in Postpartum Hemorrhage—A Systematic Review, Transfusion Medicine Reviews, https://doi.org/10.1016/j.tmrv.2019.12.002
A. Zaidi et al. / Transfusion Medicine Reviews xxx (xxxx) xxx
platelet, fresh frozen plasma, and cryoprecipitate or fibrinogen concentrate) at 24 hours from administration of fibrinogen replacement treatment. If the data obtained did not allow for direct comparison, we described different blood components separately and reported a 99% confidence interval (CI). Neither included study reported this outcome and therefore, post-hoc it was decided that the requirement for transfusion at 24 hours would also be reported. Secondary outcomes were: all-cause mortality at 24 hours, 7 days and 30 days from onset of PPH; mortality due to bleeding at 24 hours, 7 days, and 30 days from onset of PPH; rate of thrombosis at three months (arterial and/or venous); overall blood transfusion requirement (i.e. red blood cell units, platelet units, fresh frozen plasma, and cryoprecipitate or fibrinogen concentrate) up to 7 days from onset of PPH; length of stay in intensive care/high dependency units; length of hospital stay; surgical intervention (defined as any physical intervention including but not limited to intra-uterine balloon tamponade, uterine arterial ligation/embolization, internal iliac artery ligation, brace uterine sutures, laparotomy or any physical intervention to achieve hemostasis); fibrinogen level pre and post fibrinogen replacement therapy; any non-surgical hemostatic intervention (e.g. use of recombinant activated factor VII or prothrombin complex concentrate);
3
and transfer to another hospital with additional facilities for management of ongoing bleeding (e.g. radiological procedures). Data Extraction and Quality Assessment Data from selected eligible and included studies were independently extracted by two reviewers (AZ and RK) using a standardized data extraction form. The following parameters were collected: study ID, date of publication, study characteristics/design, whether the population studied met our inclusion criteria. We also collected data on clinical outcomes as defined under outcomes. For missing data we contacted the authors directly to clarify the data that was presented. The risk of bias for included studies was assessed by 2 authors (AZ and RK) using the Cochrane Risk of bias tool [17]. The risk of bias was classified as low, high or unclear. Grades of evidence were assessed in terms of certainty as: High: very confident that the true effect lies close to that of the estimate of the effect; Moderate: moderately confident in the effect estimate or the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; Low: confidence in the effect estimate is limited or the true effect may be substantially different from the estimate of the effect; and Very low: very little
Fig. 1. Studies included in systematic review of early fibrinogen replacement therapy in postpartum hemorrhage. *Search run on 12th June 2019.
Please cite this article as: A. Zaidi, R. Kohli, J. Daru, et al., Early Use of Fibrinogen Replacement Therapy in Postpartum Hemorrhage—A Systematic Review, Transfusion Medicine Reviews, https://doi.org/10.1016/j.tmrv.2019.12.002
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A. Zaidi et al. / Transfusion Medicine Reviews xxx (xxxx) xxx
confidence in the effect estimate or the true effect is likely to be substantially different from the estimate of effect Data Synthesis If studies were sufficiently homogenous in their design, we planned to conduct meta-analyses according to the recommendations of Cochrane (42). Separate analyses for pooling results from randomized and non-randomized studies were planned. However, there were no non-randomized studies. We recorded the number of patients lost to follow-up for each study.
in FIB-PPH study received tranexamic acid (40% 49/123 in the fibrinogen arm and 36% 43/121 in the placebo arm). In the OBS2 study, the dose of fibrinogen concentrate was 1 gram guided by the rotational thromboelastometry (ROTEM), FIBTEM parameter [25]. The median time from obtaining ROTEM results to the administration of the study interventions was 24 minutes (IQR 20 to 33 minutes); however, the timing from the start of bleeding to administration of interventions was not reported. (Table 1). Only women who had ongoing major PPH (1000–1500 mL blood loss) were screened with ROTEM. Of the 3894 women with at least 1 L blood loss, 663 were screened and only 57 participants (1.5%) were included in the trial. All participants in OBS2 were given tranexamic acid.
Results Risk of Bias of Included Studies Study Selection We identified a total of 2,038 citations (including 77 trial registrations) (Fig. 1, Prisma Flow Chart). There were 1,595 citations after duplicates were removed. Two review authors (AZ, RK) excluded 1,581 citations on the basis of the abstract, leaving 14 full text articles which were reviewed for eligibility. Of the 14 studies a further 9 studies were excluded (see Supplement; Table S1) because: 6 were retrospective studies [18-22], one was a single arm study with no comparator [23] and the other two were randomized trials that had been withdrawn prior to recruiting any participants [24, 17]. Of the five eligible studies, two were completed randomized control trials (RCTs) [25, 26] (Table 1) and three were ongoing trials (Table 2) [27-29]. In the final analysis only the two completed RCT were included. We identified no good quality ongoing or completed non-randomized studies. Study Characteristics The two completed trials involved a total of 299 participants, of which 244 participants were recruited from FIB-PPH trial by Wikkelso et al [26], and 55 from OBS2 trial by Collins et al [25]. Both trials were multicenter, double-blind, placebo controlled, trials comparing a single dose of fibrinogen concentrate as the intervention with placebo (normal saline) as a comparator (Table 1). In the FIB-PPH trial the dose of fibrinogen concentrate was 2 grams and the median time for delivery of the intervention was 81 minutes (interquartile range (IQR) 59 to 130 minutes) [26]. The inclusion criteria for PPH were Caesarean section with an estimated perioperative blood loss N1 L or vaginal delivery with either estimated blood loss N0.5 L and intended manual removal of placenta or estimated blood loss N1 L and intended manual exploration of the uterus because of continuous bleeding after delivery of the placenta. Approximately 40% of women
The OBS2 Study was classified as having an overall low risk’ of bias and the FIB-PPH was rated ‘unclear. The main sources of potential bias were attrition bias due to incomplete outcome data reporting in the FIB-PPH (there was no clear documentation for reasons for missing data on adverse events) [26]. Further, the OBS2 study [25] was funded by CSL Behring, which is the manufacturer of the fibrinogen concentrate. The supporting evidence for the risk of bias judgments in all domains is presented in Table 3. Data Synthesis Primary Outcome: Mean Difference in Overall Transfusion Requirements at 24 hours from Administration of Fibrinogen Replacement Treatment Neither study reported the review’s primary outcome. However, the need for a red cell transfusion at 24 hours was reported [26] or data were provided by the study authors [25]. There was no evidence of a difference in the need for a red cell transfusion between participants who received fibrinogen and those that did not (risk ratio 0.83 [95% CI 0.54 to 1.26], 2 studies, 299 participants, GRADE low quality evidence). The GRADE level of evidence was downgraded by two, one for imprecision (wide confidence intervals that include clinically significant benefit as well as no effect) and one for generalizability (only patients with severe post-partum hemorrhage were included in either study). Regarding other secondary outcomes, both studies were underpowered to answer any of the outcomes. In summary, there were no reported deaths relating to PPH in either study [25, 26] up to 30 days, however 5/53 participants were lost to follow-up in the OBS2 study. There was one case of pulmonary embolism in the fibrinogen group and one case of right ovarian vein thrombosis in the placebo group in
Table 1 Study Characteristics of trials included in systematic review of early fibrinogen replacement therapy in postpartum hemorrhage Study Title/ Citation
Study Type
n
FIB-PPH
Multicenter, randomized, double blinded, placebo controlled RCT Denmark
244
Multicenter, randomized, double blinded, placebo controlled RCT
55
Wikkelso et al [26]
OBS2 Collins et al [25]
Intervention and dose
Fibrinogen Concentrate, (123 int 2g vs 121 control)
(28 in. vs 27 control)
Control Group Treatment
Timing of intervention
Primary Outcome / Significant finding
P
100 mL Normal Saline
‘Pre-emptive’ infusion
Need for RBC transfusion b6 weeks post PPH
.88 No evidence of benefit for pre-emptive fibrinogen concentrate in PPH
Median time = 81 minutes (IQR 59-130 mins) ‘Early’ infusion
Intervention n=25, (20.3%) Control n=26 (21.5%)
50 mL Fibrinogen Concentrate,1g Normal Saline Guided by viscoelastic testing
Total number of allogeneic blood products up to point of hospital discharge
Overall Conclusion
.45 No improvement in outcome in PPH
⁎Median time = 24 minutes (IQR 20-33 Mean transfusion Rate: mins) Intervention: 2.07 Control: 2.78
RCT, randomized control trial; PPH, postpartum hemorrhage. ⁎ Time from FIBTEM triggering randomization to administration of study medication.
Please cite this article as: A. Zaidi, R. Kohli, J. Daru, et al., Early Use of Fibrinogen Replacement Therapy in Postpartum Hemorrhage—A Systematic Review, Transfusion Medicine Reviews, https://doi.org/10.1016/j.tmrv.2019.12.002
A. Zaidi et al. / Transfusion Medicine Reviews xxx (xxxx) xxx
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Table 2 Characteristics of ongoing studies in systematic review of early fibrinogen replacement therapy in postpartum hemorrhage Title of study
Trial number
Fibrinogen in Hemorrhage of Delivery (FIDEL)
NCT02155725
Administering cryoprecipitate in obstetric bleeding at an earlier time (ACROBAT)
A Program to Evaluate Riastap® and FIBTEM® for the Early Control and Treatment of Postpartum Hemorrhage (PERFECT PPH)
Summary
Early fibrinogen replacement vs Placebo in patients treated with IV prostaglandins following vaginal delivery ISRCTN12146519 The effect of early cryoprecipitate transfusion (within 90 minutes) versus standard care in women who develop severe postpartum hemorrhage NCT02528708 Evaluates early detection and treatment of fibrinogen depletion in PPH.
Study design
Funding
Intervention
Primary outcome
Enrolment Recruitment status
PI/ Country
Randomized, double-blinded, multicenter, placebo-controlled study
Industry
Fibrinogen concentrate 3g IV vs saline placebo
Reduction of Hb N4 g/dL or requirement of 2 U RBC within 48 h of IMP
447
Ducloy-Bouthors
2 U of early cryoprecipitate in addition to standard major hemorrhage protocol vs standard major hemorrhage protocol
Proportion of women administered cryoprecipitate within 90 minutes of major hemorrhage protocol activation
Target 200
ROTEM guided fibrinogen replacement if only FIBTEM A10 b18 mm with IV fibrinogen concentrate 3g vs saline placebo
MCF via FIBTEM A10 taken 15 minutes, 1 hour, 6 h 24 h post IMP
Target 40
(Laboratoire Français de Fractionnement et de Biotechnologie)
Non commercial Cluster randomized trial; A pilot feasibility (Barts Health study charity)
Randomized, double blind, placebo controlled trial
Industry (CSL Behring)
Completed (Dec 2018)
France
Recruiting
L Green UK
Paidas M Currently Suspended (study never USA began, pending review to be reopened)
the OBS2 trial [25], and none in the FIB-PPH trial, however both studies only followed-up participants for a maximum of 6 weeks rather than 3 months (see Table 4).
Discussion
Ongoing Studies
This systematic review identified only two published RCTs that assessed the early use of fibrinogen replacement therapy in PPH. Both trials compared fibrinogen concentrate with placebo, with no studies identified assessing cryoprecipitate transfusion. There were three ongoing RCTs, 2 assessing fibrinogen concentrate and one cryoprecipitate. For completed studies there was variation on timings of intervention administration, severity of PPH, fibrinogen doses, and tranexamic use. All of the evidence was of low or very low quality according to GRADE criteria due to imprecision of estimates and lack of generalizability to all women with a PPH of at least 500 mL.
We identified three ongoing randomized trials (details described in Table 2) assessing upfront use of fibrinogen replacement therapy. Two of these studies are randomized, double-blind, placebo control trials assessing fibrinogen concentrate [28, 29] and one is a pilot cluster randomized trial evaluating early cryoprecipitate transfusion [27]. The NCT02155725 is a French trial of Fibrinogen in Hemorrhage of Delivery (FIDEL) randomizing women who are treated with intravenous prostaglandins following surgery to either 4 grams of intravenous fibrinogen concentrate or saline placebo. Recruitment of 447 patients was completed in December 2018, however the results were not available for review [29]. The NCT02528708, is American trial (PERFECT-PPH) evaluating the early detection and treatment of fibrinogen depletion in PPH using fibrinogen concentrate guided by viscoelastic testing. If FIBTEM A10 measurement is b18 mm, women are randomized to 3g of intravenous fibrinogen concentrate versus saline placebo. The primary outcome is a measure of hemostasis using maximal clot firmness (MCF) via ROTEM measured at different time points after administration of IV fibrinogen. This trial was stopped early during the set-up phase and is pending review to be re-opened [28]. Finally, the UK trial (Administering CRyoprecipitate in Obstetric bleeding At an earlier Time – ACROBAT) (ISRCTN12146519) is the only study assessing early cryoprecipitate as a fibrinogen replacement therapy. This is a pilot study that is evaluating the early use of cryoprecipitate (within 90 minutes) in addition to standard major hemorrhage protocol versus standard care in women who develop PPH that requires blood transfusion [27].
Main Findings
Strengths and Limitations We prospectively registered the review and performed a comprehensive search without language, time, or study design restrictions. We followed the recommended guidelines on review conduct, with two reviewers working independently. We also dealt with missing data by contacting the authors to obtain results for outcomes and had a very good response from authors. We searched for grey literature using the Transfusion Evidence Library and study registration data. Interpretation of Findings We looked for good quality studies, but only found 2 completed RCTs, and no non-randomized studies. Both studies were underpowered to detect differences in any of the outcomes defined in this review. In the FIB-PPH study this was because the expected number of participants who required a transfusion in the placebo arm was much lower than expected (21.5% versus 57%). Using approximate transfusion
Please cite this article as: A. Zaidi, R. Kohli, J. Daru, et al., Early Use of Fibrinogen Replacement Therapy in Postpartum Hemorrhage—A Systematic Review, Transfusion Medicine Reviews, https://doi.org/10.1016/j.tmrv.2019.12.002
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A. Zaidi et al. / Transfusion Medicine Reviews xxx (xxxx) xxx
Table 3 Risk of Bias and Quality Assessment in systematic review of early fibrinogen replacement therapy in postpartum hemorrhage.
Bias Random Sequence Generation (Selection bias)
Wikkelso et al [26] FIB-PPH
Collins et al [25] OBS2
Judgement Support for Judgement
Judgement Support for Judgement
Low risk
Computer generated allocation ‘Used computer-generated allocation and blocks-of-four randomization’ Assignment by concealed envelopes, but no further details given. Placebo was dyed to match color of fibrinogen concentrate and both were in opaque syringes. Blinding incomplete (4% of anesthetists aware of intervention) but unlikely to affect outcome Double blinded study design
Low risk
Computer generated allocation
Low risk
Fibrinogen concentrate, in consecutively labelled concealed packs Syringes were concealed to prevent identification. But does not specify whether blinding complete.
Low risk
Double blinded study design
148 Missing data values for adverse events, no reason supplied Outcomes are reported as pre-specified in the available protocol Most severe bleeding episodes potentially not included due to inability to consent
Low risk
Complete outcome data
Low risk
Outcomes are reported as pre-specified in the available protocol Full protocol available for review
Allocation Concealment (Selection bias) Blinding of participants and personnel (performance bias)
Unclear
Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Other bias
Low risk
Overall Risk of Bias
Unclear
Low risk
High risk Low risk Unclear
Low Risk
Low risk Low risk
rates from the FIB-PPH study, 1368 patients would be required to have an 80% chance of detecting, as significant at the 5% level, a decrease in the need for transfusion at 24 hours from 15% in the control group to 10% in the experimental group. Results of this review highlight the need for further studies to answer the question of whether early replacement of fibrinogen in PPH is clinically beneficial in addition to tranexamic acid. We also found considerable variation in the primary and secondary outcomes used in included and ongoing studies. Although mortality is considered an ideal choice to use as primary outcome, this would require a sample size of over 20,000 women, as seen in the WOMAN trial [30]. Further, in this review we identified two trials that were
suspended due to failure to recruit [17, 24], highlighting some of the challenges around performing trials in obstetric bleeding. Thus, it is important that core outcome sets are agreed for studies assessing interventions for treatment of PPH, in order to obtain meaningful results. This was recently achieved by an international group of experts [31], and this review captured all outcomes agreed in the consensus. Fibrinogen replacement therapy is available in two forms; cryoprecipitate and fibrinogen concentrate, both of which are plasma derived products. However, in this review we did not identify any studies that have assessed the use of cryoprecipitate transfusion in PPH, even though this component has been around for a lot longer than fibrinogen concentrate and it remains the standard fibrinogen
Table 4 Summary of results concerning secondary outcomes of the systematic review of early fibrinogen replacement therapy in postpartum hemorrhage Study
OBS2, Collins et al [25]
FIB-PPH, Wikkelso et al [26]
Intervention
Fibrinogen Control n = 28 n = 27
Difference (95% Confidence interval, P value)
Fibrinogen Control n = 123 n = 121
Difference (95% Confidence interval, p- value)
All-cause mortality up to 30 days#⁎, ⁎⁎
0
0
-
0
0
-
Thrombosis (arterial and venous) (incidence) up to 6 weeks Overall transfusion requirement (total units per patient at 7 days) Hemostatic Intervention
1 (3.6%)
1 (3.7%)
-
0
0
-
2.07
2.78 0
not reported 0
not reported 0
-
0
Adjusted rate ratio 0.72 (95% CI 0.30–1.70, P = 0.45) -
Length of Hospital Stay Median days (IQR)
3 (IQR 2.0-5.0) 5 (17.9%)
3 (IQR 2-4)
P = 0.13
not recorded*
not recorded*
not reported 0
not reported 0
5.5
5.3
0**
0**
Surgical Intervention -until discharge, number of patients Transfer Mean Fibrinogen Level g/L (SD) by Clauss method at 24 h post intervention Duration in High dependency unit median no. of days (IQR) Admission to Level 3 care
5 (18.5%)
0
0
P = 0.95 -
4.1 SD (0.8)
4.0 SD (0.9)
Adjusted difference - 0.02 (95% CI - 0.5 to 0.5, P = 0.95
16 (IQR 12-25) 2 (7.1%)
20.5 (IQR 0.90 10.5-28.5) 2 (7.4%) 0.97
0
0
-
-
Certainty of evidence (GRADE) +--VERY LOW1,2 ++-LOW1,3 ++-LOW1,3 +--VERY LOW1,2 ++-LOW1,3
Mean difference 0.20 g/L (95% CI –0.06 – 0.46, P = 0.13)
++-LOW1,3 ++-VERY LOW1,2 ++-LOW1,3
-
++-LOW1,3
-
-
++-LOW1,3
# Other mortality outcomes were not reported separately because no deaths occurred at up to 30 days. ⁎ author confirmed that it was not collected after personal correspondence with review authors ⁎⁎ author confirmed that there were no admissions to higher level care after personal correspondence with review authors 1 Downgraded by 1 for lack of generalizability. Only participants with severe PPH were included in the studies 2 Downgraded by 2 for imprecision (no events in either arm, rare event) 3 Downgraded by 1 for imprecision
Please cite this article as: A. Zaidi, R. Kohli, J. Daru, et al., Early Use of Fibrinogen Replacement Therapy in Postpartum Hemorrhage—A Systematic Review, Transfusion Medicine Reviews, https://doi.org/10.1016/j.tmrv.2019.12.002
A. Zaidi et al. / Transfusion Medicine Reviews xxx (xxxx) xxx
replacement therapy in most countries. Of the three ongoing studies, only one pilot cluster RCT is evaluating the feasibility of administering early cryoprecipitate transfusion [27] in PPH, underscoring the importance for further studies in this field. Conclusion and Implication This review has demonstrated the paucity of evidence on the early use of fibrinogen replacement therapies in postpartum hemorrhage. The small sample size of included studies and their heterogeneity warrants us to interpret these results with extreme caution until further evidence become available. Therefore, future trials are urgently needed to assess the clinical efficacy and safety of early fibrinogen replacement therapy (particularly cryoprecipitate) in PPH. Evidence is required to determine the optimal dose of fibrinogen replacement therapy in PHH as well as compare the cost-effectiveness of cryoprecipitate transfusion with fibrinogen concentrate, and protocol-driven approaches with targeted-therapy for fibrinogen replacement therapy. Supplementary data to this article can be found online at https://doi. org/10.1016/j.tmrv.2019.12.002. Acknowledgments We would like to acknowledge the following authors for providing the following information: Professor Collins for providing additional data from the OBS-2 trial on the total number of transfusion units required after 24 hours, the number of cases requiring hemostatic intervention and the number of cases requiring transfer to another center. Professor Wikkelso for providing additional data from FIB-PPH trial on the number of cases requiring admission to intensive care or high dependency and Dr Westhuizen for providing data on the completion and recruitment status of the FIB-UPFRONT-PPH study (ANZCTR12614000691640). Funding The study was funded by Barts Charity. The funders had no role in the study design, data collection/analysis or preparation of this article. The views expressed in this article are those of the authors and not necessarily of the funders. Contribution to Authorship AZ and RK extracted/analyzed the data and assessed the risk of bias. LG, KK, ST, LE and JD designed the study. All authors contributed to the writing of the article. Disclosure of Interests LG, ST, JD, and KK are investigators of the ongoing ACROBAT trial reported in this review. JD has received fees from Pharmacosmos for advisory work. References [1] Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PF. WHO analysis of causes of maternal death: a systematic review. Lancet 2006;367:1066–74. [2] Say L, Chou D, Gemmill A, Tuncalp O, Moller AB, Daniels J, et al. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health 2014;2:e323–33. [3] Green L, Knight M, Seeney FM, Hopkinson C, Collins PW, Collis RE, et al. The epidemiology and outcomes of women with postpartum haemorrhage requiring massive transfusion with eight or more units of red cells: a national cross-sectional study. BJOG 2016;123:2164–70. https://doi.org/10.1111/1471-0528.13831. [4] Gayat E, Resche-Rigon M, Morel O, Rossignol M, Mantz J, Nicolas-Robin A, et al. Predictive factors of advanced interventional procedures in a multicentre severe postpartum haemorrhage study. Intensive Care Med 2011;37:1816–25.
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Please cite this article as: A. Zaidi, R. Kohli, J. Daru, et al., Early Use of Fibrinogen Replacement Therapy in Postpartum Hemorrhage—A Systematic Review, Transfusion Medicine Reviews, https://doi.org/10.1016/j.tmrv.2019.12.002