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Management of postpartum haemorrhage: from research into practice, a narrative review of the literature and the Cardiff experience

Published:August 24, 2018DOI:https://doi.org/10.1016/j.ijoa.2018.08.008

      Highlights

      • Fibrinogen falls before other coagulation factors during postpartum haemorrhage (PPH).
      • Laboratory Clauss fibrinogen and point-of-care FIBTEM A5 predict progression of PPH.
      • Haemostatic impairment is uncommon during PPH and can be assessed by FIBTEM.
      • A fibrinogen of 2 g/L or FIBTEM A5 12 mm and above is adequate for haemostasis during PPH.
      • A national quality improvement programme has been initiated integrating these results.

      Abstract

      Postpartum haemorrhage (PPH) is caused by obstetric complications but may be exacerbated by haemostatic impairment. In a 10-year programme of research we have established that haemostatic impairment is uncommon in moderate PPH and that fibrinogen falls earlier than other coagulation factors. Laboratory Clauss fibrinogen and the point-of-care surrogate measure of fibrinogen (FIBTEM A5 measured on the ROTEM® machine) are predictive biomarkers for progression from early to severe PPH, the need for blood transfusion and invasive procedures to control haemorrhage. Fibrinogen replacement is not required in PPH unless the plasma level falls below 2 g/L or the FIBTEM A5 is below 12 mm. Deficiencies of coagulation factors other than fibrinogen are uncommon even during severe PPH, and ROTEM® monitoring can inform withholding FFP safely in most women. In the absence of placental abruption, clinically significant thrombocytopenia is uncommon unless the platelet count is low before the bleed started, or very large bleeds (>5000 mL) occur. Measuring blood loss is feasible in routine practice during PPH and is more accurate than estimation. These research findings have been collated to design an ongoing quality improvement programme for all maternity units in Wales called OBS Cymru (Wales) (The Obstetric Bleeding Strategy for Wales).

      Keywords

      Aims

      The aims of this review are to: summarise the literature relating to the coagulation profile of women with PPH, describe how point-of-care (POC) based algorithms can provide timely information for clinicians with the potential to reduce blood product use and describe how protocols used during research can have a positive impact on all patients, with fewer major complications and massive blood transfusions.

      Background

      The incidence of postpartum haemorrhage (PPH) is increasing in many countries and is the most common cause of death for women of child-bearing age worldwide.
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      Incidence, risk factors, and temporal trends in severe postpartum hemorrhage.

      Lennox C, Marr L. Scottish confidential audit of severe maternal morbidity. 9th annual report (data from 2011). Available at: http://healthcareimprovementscotland.org/his/idoc.ashx?docid=5fb640e2-d079-48cc-ad49-a58f6929b685&version=-1; 2013.

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      Bleeding is caused by obstetric complications but may be exacerbated by haemostatic impairment.
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      Haemostatic management of obstetric haemorrhage.
      It is widely assumed that haemostatic impairment often complicates PPH and consequently, when coagulation test results are unavailable, guidelines endorse the use of formulaic infusion of fresh frozen plasma (FFP) or cryoprecipitate in fixed ratios with red blood cells (RBC),
      • Mavrides E.
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      Prevention and management of postpartum haemorrhage.
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      based on evidence extrapolated from non-pregnant adult major trauma. It is questionable whether these data should be applied to the management of PPH, given the very different baseline coagulation status of the groups.
      High-quality studies describing coagulopathies associated with PPH are limited, however it is probable that they result from complex interactions between dilution, local consumption, disseminated consumption and increased fibrinolysis.
      • Collis R.E.
      • Collins P.W.
      Haemostatic management of obstetric haemorrhage.
      The nature of haemostatic impairment varies according to the cause of the bleed and is affected by complications of pregnancy such as preeclampsia, sepsis and impaired liver function. The physiological adaptations of pregnancy result in a pro-thrombotic state at term with increased levels of pro-coagulants and decreased anti-coagulants. In particular, at term the fibrinogen level is 4–6 g/L, compared to 2–4 g/L in healthy non-pregnant women.
      • Allard S.
      • Green L.
      • Hunt B.J.
      How we manage the haematological aspects of major obstetric haemorrhage.
      • Solomon C.
      • Collis R.E.
      • Collins P.W.
      Haemostatic monitoring during postpartum haemorrhage and implications for management.
      Until recently it was not known whether fibrinogen replacement during severe PPH should target ‘normal for term’ (>4 g/L), ‘normal for non-pregnancy’ (>2 g/L), or somewhere in between. This is important when considering the role of FFP in treating coagulopathy in PPH.
      • McDonnell N.J.
      • Browning R.
      How to replace fibrinogen in postpartum haemorrhage situations? (Hint: Don't use FFP!).
      Fresh frozen plasma contains about 2 g/L of fibrinogen, whereas the average fibrinogen level in a woman with 1000–2000 mL blood loss due to atony or trauma is about 4 g/L.
      • Collins P.W.
      • Lilley G.
      • Bruynseels D.
      • et al.
      Fibrin-based clot formation as an early and rapid biomarker for progression of postpartum hemorrhage: a prospective study.
      This means that in most cases, infusion of FFP during PPH would reduce fibrinogen by dilution.
      • Collins P.W.
      • Solomon C.
      • Sutor K.
      • et al.
      Theoretical modelling of fibrinogen supplementation with therapeutic plasma, cryoprecipitate, or fibrinogen concentrate.
      This implies that unmonitored fixed-ratio infusions of FFP would expose many women to FFP without any prospect of improving haemostasis. Studies exploring the use of fixed-ratio infusions of FFP:RBC during PPH report fewer women developing laboratory evidence of coagulopathy, however, some of these studies describe multiple interventions including early involvement of senior staff.
      • James A.H.
      • Paglia M.J.
      • Gernsheimer T.
      • Grotegut C.
      • Thames B.
      Blood component therapy in postpartum hemorrhage.
      • Pasquier P.
      • Gayat E.
      • Rackelboom T.
      • et al.
      An observational study of the fresh frozen plasma: red blood cell ratio in postpartum hemorrhage.
      • Saule I.
      • Hawkins N.
      Transfusion practice in major obstetric haemorrhage: lessons from trauma.
      • Shields L.E.
      • Smalarz K.
      • Reffigee L.
      • et al.
      Comprehensive maternal hemorrhage protocols improve patient safety and reduce utilization of blood products.
      • Shields L.E.
      • Wiesner S.
      • Fulton J.
      • Pelletreau B.
      Comprehensive maternal hemorrhage protocols reduce the use of blood products and improve patient safety.
      When guided by viscoelastometric POC testing (VE-POCT), we have shown that FFP can be withheld safely in women experiencing moderate to severe PPH, without development of clinically significant haemostatic impairment.
      • Collins P.W.
      • Cannings-John R.
      • Bruynseels D.
      • et al.
      Viscoelastometry guided fresh frozen plasma infusion for postpartum haemorrhage: OBS2, an observational study.
      A recent review suggested that FFP was not the optimal way to replace fibrinogen during PPH.
      • McDonnell N.J.
      • Browning R.
      How to replace fibrinogen in postpartum haemorrhage situations? (Hint: Don't use FFP!).

      Postpartum haemorrhage observations and research advancements in Cardiff, Wales

      Using fibrinogen concentrate to treat PPH with hypofibrinogenemia

      We observed that some women experiencing severe PPH had laboratory fibrinogen levels <1 g/L associated with clinical haemostatic impairment. At this time the Royal College of Obstetrics and Gynaecology (RCOG) guidance was to maintain fibrinogen >1 g/L using cryoprecipitate.

      Royal College of Obstetricians and Gynaecologists. Prevention and management of postpartum haemorrhage. Green-top guideline No. 52, 2009. Available at: http://www.rcog.org.uk/files/rcog-corp/GT52PostpartumHaemorrhage0411.pdf; 2013.

      Thawing and infusing cryoprecipitate takes time, delaying correction of the coagulopathy. At our centre and others, we addressed this issue by infusing fibrinogen concentrate which rapidly increased the fibrinogen level and was associated with the clinical impression of improvement in haemostasis.
      • Ahmed S.
      • Harrity C.
      • Johnson S.
      • et al.
      The efficacy of fibrinogen concentrate compared with cryoprecipitate in major obstetric haemorrhage –an observational study.
      • Bell S.F.
      • Rayment R.
      • Collins P.W.
      • Collis R.E.
      The use of fibrinogen concentrate to correct hypofibrinogenaemia rapidly during obstetric haemorrhage.
      • Gollop N.D.
      • Chilcott J.
      • Benton A.
      • et al.
      National audit of the use of fibrinogen concentrate to correct hypofibrinogenaemia.
      • Weinkove R.
      • Rangarajan S.
      Fibrinogen concentrate for acquired hypofibrinogenaemic states.
      We infused between 2 and 4 g fibrinogen concentrate to six women over a two-year period (approximately 12 000 deliveries) with clinical improvement, although the data on all women with low fibrinogen was not collected at this time.
      • Bell S.F.
      • Rayment R.
      • Collins P.W.
      • Collis R.E.
      The use of fibrinogen concentrate to correct hypofibrinogenaemia rapidly during obstetric haemorrhage.
      These early reports reflected a reactive rather than preventative strategy to haemostatic impairment. More recent studies from other groups have reported improvements in haemostasis with the use of fibrinogen concentrate to treat hypofibrinogenaemia.
      • Matsunaga S.
      • Takai Y.
      • Nakamura E.
      • et al.
      The clinical efficacy of fibrinogen concentrate in massive obstetric haemorrhage with hypofibrinogenaemia.
      • Seto S.
      • Itakura A.
      • Okagaki R.
      • Suzuki M.
      • Ishihara O.
      An algorithm for the management of coagulopathy from postpartum hemorrhage, using fibrinogen concentrate as first-line therapy.
      These case reports are selective and prone to reporting bias, but were sufficiently encouraging to promote further investigation.

      The role of standard coagulation tests and Clauss fibrinogen for detection of coagulopathy in PPH

      To investigate the effect of severity of bleeding on standard coagulation tests, we evaluated a consecutive cohort of 18 501 women who delivered at our unit over three years. Blood test results of women with PPH >1500 mL (n=456, 2.5%) were reviewed. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) usually remained within the normal range until blood loss reached 4000–5000 mL.
      • De Lloyd L.
      • Bovington R.
      • Kaye A.
      • et al.
      Standard haemostatic tests following major obstetric haemorrhage.
      This reflected sufficient coagulation factors for haemostasis until the bleed volume reached 4000–5000 mL, and infusion of FFP up to that time was unlikely to have improved haemostasis. In contrast, fibrinogen fell rapidly as blood volume loss increased, such that by 2000 mL the majority of cases had a fibrinogen below the normal range for term (4 g/L), and at 4000 mL most women had a fibrinogen <2 g/L.
      • De Lloyd L.
      • Bovington R.
      • Kaye A.
      • et al.
      Standard haemostatic tests following major obstetric haemorrhage.
      A UK Obstetric Surveillance System (UKOSS) survey of women transfused ≥8 units of RBCs (average blood loss 6000 mL) also found that many more women had a fibrinogen <2 g/L than an abnormal PT or aPTT, both at first presentation and when coagulation was at its worst.
      • Green L.
      • Knight M.
      • Seeney F.
      • et al.
      The haematological management and transfusion requirements of women who required massive transfusion for major obstetric haemorrhage in the UK: a population based descriptive study.
      The likelihood of hypofibrinogenaemia depended on the cause of bleeding and was most often associated with placental abruption.
      • Collins P.W.
      • Lilley G.
      • Bruynseels D.
      • et al.
      Fibrin-based clot formation as an early and rapid biomarker for progression of postpartum hemorrhage: a prospective study.
      • Green L.
      • Knight M.
      • Seeney F.
      • et al.
      The haematological management and transfusion requirements of women who required massive transfusion for major obstetric haemorrhage in the UK: a population based descriptive study.
      Taken together, these studies indicate that the standard coagulation tests PT and aPTT show that early depletion of coagulation factors is uncommon in obstetric haemorrhage, and that plasma fibrinogen level may be a more important therapeutic target.

      Fibrinogen and FIBTEM as biomarkers to predict severity of progression of postpartum haemorrhage

      In an influential paper, Charbit et al. measured multiple coagulation factors in women experiencing PPH. Fibrinogen level was the only independent predictor of progression to severe PPH and a fibrinogen <2 g/L had a 100% positive predictive value for progression from moderate to severe PPH.
      • Charbit B.
      • Mandelbrot L.
      • Samain E.
      • et al.
      The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage.
      This finding was confirmed by us in retrospective and prospective studies and by other groups investigating PPH in multiple cohorts using diverse methodologies (Table 1).
      • Collins P.W.
      • Lilley G.
      • Bruynseels D.
      • et al.
      Fibrin-based clot formation as an early and rapid biomarker for progression of postpartum hemorrhage: a prospective study.
      • Charbit B.
      • Mandelbrot L.
      • Samain E.
      • et al.
      The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage.
      • Cortet M.
      • Deneux-Tharaux C.
      • Dupont C.
      • et al.
      Association between fibrinogen level and severity of postpartum haemorrhage: secondary analysis of a prospective trial.
      • De Lloyd L.
      • Collins P.W.
      • Kaye A.
      • Collis R.E.
      Early fibrinogen as a predictor of red cell requirements during postpartum haemorrhage.
      • Gayat E.
      • Resche-Rigon M.
      • Morel O.
      • et al.
      Predictive factors of advanced interventional procedures in a multicentre severe postpartum haemorrhage study.
      • Simon L.
      • Santi T.M.
      • Sacquin P.
      • Hamza J.
      Pre-anaesthetic assessment of coagulation abnormalities in obstetric patients: usefulness, timing and clinical implications.
      These studies now show convincingly that plasma Clauss fibrinogen, measured early during PPH, is a biomarker for predicting progression to severe PPH.
      Table 1Studies investigating the association between fibrinogen and progression of postpartum haemorrhage
      StudyNStudy designFibrinogen g/L
      Time of fibrinogen assayOutcome defining progression of PPHDescriptive statistic reportedNo progression of PPHProgression of PPHROC

      AUC

      (95% CI)
      Charbit
      • Charbit B.
      • Mandelbrot L.
      • Samain E.
      • et al.
      The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage.
      129Infusion of uterotonic after manual exploration of uterusInvasive procedure to control bleeding, fall in Hb ≥4 g/L or ≥4 units RBCMedian (IQR)4.4 (3.7–5.1)3.3 (2.5–4.2)0.75 (CI NR) p <0.0001
      Cortet
      • Cortet M.
      • Deneux-Tharaux C.
      • Dupont C.
      • et al.
      Association between fibrinogen level and severity of postpartum haemorrhage: secondary analysis of a prospective trial.
      738Diagnosis of PPHInvasive procedure to control bleeding, fall in Hb ≥4 g/L, ≥4 units RBC or admission to ITUMean (SD)4.2 (1.2)3.4 (0.9)0.66 (0.64–0.68)
      Poujade
      • Poujade O.
      • Zappa M.
      • Latendre J.
      • Ceccaldi P.F.
      • Vilgrain V.
      • Luton D.
      Predictive factors for failure of pelvic arterial embolization for PPH.
      98Variable time before embolisationSuccess of radiological embolisationMean (SD)2.9 (1.3)1.8 (0.9)NR
      Gayat
      • Gayat E.
      • Resche-Rigon M.
      • Morel O.
      • et al.
      Predictive factors of advanced interventional procedures in a multicentre severe postpartum haemorrhage study.
      257Variable time before procedureInvasive procedure to control bleedingMedian (IQR)2.7 (2.1–3.5)1.8 (1.1–2.5)0.83 (±0.03)
      In this study the ROC refers to a composite predictive tool combining fibrinogen <2 g/L, abnormal placental implantation, prothrombin ratio <50%, heart rate >115 beats per minute, troponin raised.
      de Lloyd
      • De Lloyd L.
      • Collins P.W.
      • Kaye A.
      • Collis R.E.
      Early fibrinogen as a predictor of red cell requirements during postpartum haemorrhage.
      240First clinical concern during PPH≥2500 mL blood lossMean (SD)4.4 (1.1)3.1 (1.0)0.85 (0.78–0.93)
      Collins
      • Collins P.W.
      • Lilley G.
      • Bruynseels D.
      • et al.
      Fibrin-based clot formation as an early and rapid biomarker for progression of postpartum hemorrhage: a prospective study.
      3461000–1500 mL blood lossTransfusion of ≥8 units allogeneic blood productsMedian (IQR)3.9 (3.2–4.5)2.1 (1.8–3.4)0.82 (0.72–0.92)
      Simon
      • Simon L.
      • Santi T.M.
      • Sacquin P.
      • Hamza J.
      Pre-anaesthetic assessment of coagulation abnormalities in obstetric patients: usefulness, timing and clinical implications.
      797Before bleeding startedPPH requiring manual uterine exploration, RBC transfusion or fall in Hb ≥2 g/LMean (SD)4.9 (1.0)4.3 (1.3)NR
      Studies are shown which investigated the association of Clauss fibrinogen, taken early during a postpartum haemorrhage or before bleeding started, with progression of bleeding. Variable study designs were employed but in all cases a low Clauss fibrinogen was associated with a statistically significantly increased risk of progression. This demonstrates that fibrinogen level is a useful biomarker for predicting progression of postpartum haemorrhage, however, due to the time required to obtain a result, its clinical utility is limited. PPH: postpartum haemorrhage; Hb: haemoglobin concentration; RBC: red blood cells; NR: not reported; ITU: Intensive Care Unit; CI: confidence interval; ROC: receiver operating characteristics; IQR: inter-quartile range; SD: standard deviation; AUC: area-under-the-curve.
      * In this study the ROC refers to a composite predictive tool combining fibrinogen <2 g/L, abnormal placental implantation, prothrombin ratio <50%, heart rate >115 beats per minute, troponin raised.
      Although plasma Clauss fibrinogen levels yield useful information, it takes at least an hour for a result to be available, limiting its utility to direct practice during PPH. Visco-elastomeric POC tests generate a surrogate measure of fibrinogen with results available within 10 minutes of venepuncture.
      • Hill J.S.
      • Devenie G.
      • Powell M.
      Point-of-care testing of coagulation and fibrinolytic status during postpartum haemorrhage: developing a thrombelastography®-guided transfusion algorithm.
      • Huissoud C.
      • Carrabin N.
      • Audibert F.
      • et al.
      Bedside assessment of fibrinogen level in postpartum haemorrhage by thrombelastometry.
      • Pavord S.
      • Maybury H.
      How I treat postpartum hemorrhage.
      We initiated the Obstetric Bleeding Study 1 (OBS-1) to investigate whether a FIBTEM assay, performed on the ROTEM® machine (Werfen, Barcelona, Spain), could predict progression from early to severe PPH. A consecutive cohort of 346 women with PPH >1000 mL was enrolled. At recruitment baseline FIBTEM was performed concurrently with a plasma Clauss fibrinogen, whilst all other routine PPH management was provided. Clinicians were blinded to the FIBTEM result but did know the laboratory fibrinogen when it became available (Fig. 1).
      • Collins P.W.
      • Lilley G.
      • Bruynseels D.
      • et al.
      Fibrin-based clot formation as an early and rapid biomarker for progression of postpartum hemorrhage: a prospective study.
      Figure thumbnail gr1
      Fig. 1Study design for OBS-1. PPH: postpartum haemorrhage. APTT: activated partial thromboplastin time. PT: prothrombin time. Hb: haemoglobin
      Despite only a moderate correlation between Clauss fibrinogen and FIBTEM (r=0.59) the two parameters had an almost identical value for predicting progression. As the Clauss fibrinogen or FIBTEM fell the need for any RBC transfusion, ≥4 units RBC, ≥8 units of blood products (RBC + FFP + platelets), use of an invasive procedure or a bleed >2500 mL increased. The lower the fibrinogen or FIBTEM A5 the higher the proportion of women with poor outcomes (Fig. 2). For example, the median (IQR) fibrinogen and FIBTEM A5 of women who received ≥8 units of blood products was 2.1 (1.8–3.4) g/L and 12 (7–17) mm, respectively, compared with 3.9 (3.2–4.5) and 19 (17–23) in those who did not. FIBTEM A5 <10 mm was associated with more prolonged bleeding (median 127 versus 65 min, P=0.02), longer in level 2 care patients needing extended postoperative care with enhanced interventions and monitoring (median 24 versus 11 hours, P <0.001) and shorter time to first RBC transfusion (P <0.001). In addition, the combination of a low fibrinogen/FIBTEM, with the clinical observation that there was on-going PPH at recruitment, was a stronger predictor of these poor outcomes than either alone.
      • Collins P.W.
      • Lilley G.
      • Bruynseels D.
      • et al.
      Fibrin-based clot formation as an early and rapid biomarker for progression of postpartum hemorrhage: a prospective study.
      Figure thumbnail gr2
      Fig. 2The proportion of women progressing to >2500 mL blood loss (red), red blood cell transfusion (dark blue), at least 4 units red blood cell transfusion (light blue) or an invasive procedure to control the bleed (green) dependent on Clauss fibrinogen (a) or FIBTEM A5 (b) taken at 1000–1500 mL blood loss is shown. Data are derived from the Obstetric Bleeding Study-1 study. RBC: red blood cells. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
      The OBS-1 study confirmed that a low fibrinogen or FIBTEM A5, measured early during a PPH, was associated with progression of PPH, however it remained unknown whether correction of these parameters would improve outcome. Furthermore, the appropriate clinical target for fibrinogen or FIBTEM A5 to maintain haemostasis, and therefore when fibrinogen-containing products should be infused, was unknown.

      Appropriate triggers for fibrinogen replacement during PPH

      In an audit report comparing a ROTEM®-based algorithm (that infused 3 g of fibrinogen concentrate if the FIBTEM was <7 mm, or <12 mm with severe bleeding, and FFP if the Extem CT was >100 s) with the unit’s previous practice of treating major PPH with shock packs (consisting of 4 RBC, 4 FFP and 1 pool of platelets), the ROTEM®-based algorithm was associated with a large reduction in FFP, cryoprecipitate and platelet usage: and fewer women needed >5 units RBCs or had transfusion associated circulatory overload or admission to ITU.
      • Mallaiah S.
      • Barclay P.
      • Harrod I.
      • Chevannes C.
      • Bhalla A.
      Introduction of an algorithm for ROTEM-guided fibrinogen concentrate administration in major obstetric haemorrhage.
      • Mallaiah S.
      • Chevannes C.
      • McNamara H.
      • Barclay P.
      A reply.
      While these data were retrospective and non-randomised, the outcomes indicate that ROTEM®-guided transfusion management may be superior to an empiric massive transfusion approach for PPH. There is no information in the paper about response times to administration of blood products after adoption of fibrinogen concentrate infusions, although immediate availability of fibrinogen concentrate stored on their delivery suite may have reduced response time and therefore improved clinical outcomes.
      A prospective, double-blind, randomised controlled trial led by Wikkelsoe investigated whether infusing 2 g of fibrinogen concentrate after 500–1000 mL blood loss, irrespective of plasma fibrinogen level, reduced the need for RBC transfusion and blood loss. No difference in outcomes was achieved with the empiric administration 2 g of fibrinogen concentrate for PPH showing that early pre-emptive, formulaic fibrinogen replacement was not indicated. Analysis found that the average fibrinogen level when fibrinogen concentrate had been infused was about 4.5 g/L in both arms of the study, demonstrating that this level is adequate for haemostasis during PPH.
      • Wikkelsoe A.J.
      • Edwards H.M.
      • Afshari A.
      • et al.
      Pre-emptive treatment with fibrinogen concentrate for postpartum haemorrhage: randomized controlled trial.
      The results provide good evidence against the use of empiric fibrinogen replacement during PPH in the absence of a monitored low plasma fibrinogen level, exposing many women to plasma-derived blood products unnecessarily.
      In the Obstetric Bleeding Study 2 (OBS-2) we used FIBTEM A5 and observation of ongoing bleeding to guide fibrinogen and FFP replacement. In OBS-1, a FIBTEM A5 <16 mm (fibrinogen about 3 g/L), in a woman with ongoing bleeding, had been associated with progression to multiple poor outomes
      • Collins P.W.
      • Lilley G.
      • Bruynseels D.
      • et al.
      Fibrin-based clot formation as an early and rapid biomarker for progression of postpartum hemorrhage: a prospective study.
      and this was supported by other observational studies (Table 1). The OBS-2 was a double-blind, placebo controlled RCT which enrolled women with PPH >1000–1500 mL. The study investigated whether infusing fibrinogen concentrate
      • Bruynseels D.
      • Solomon C.
      • Hallam A.
      • et al.
      Commentary on reconstituting fibrinogen concentrate to maintain blinding in a double-blind randomized trial in an emergency setting.
      if FIBTEM A5 was <16 mm, and bleeding was ongoing, reduced blood product usage. The OBS-2 also investigated whether it was safe to withhold FFP if FIBTEM A5
      • Aawar N.
      • Alikhan R.
      • Bruynseels D.
      • et al.
      Fibrinogen concentrate versus placebo for treatment of postpartum haemorrhage: study protocol for a randomised controlled trial.
      was ≥15 mm on the assumption that a normal fibrinogen was a surrogate for adequate levels of other coagulation factors (Fig. 3a).
      • Collins P.W.
      • Lilley G.
      • Bruynseels D.
      • et al.
      Fibrin-based clot formation as an early and rapid biomarker for progression of postpartum hemorrhage: a prospective study.
      • De Lloyd L.
      • Bovington R.
      • Kaye A.
      • et al.
      Standard haemostatic tests following major obstetric haemorrhage.
      • Charbit B.
      • Mandelbrot L.
      • Samain E.
      • et al.
      The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage.
      Figure thumbnail gr3
      Fig. 3ROTEM® guided blood product algorithms. a shows the study design and blood product algorithm used for women recruited into the Obstetric Bleeding Study-2. b shows the blood product algorithm used for women who were not enrolled. FFP: fresh frozen plasma.
      There was no statistically significant difference in any outcome between the fibrinogen and placebo (Normal saline) groups, demonstrating that a fibrinogen of around 3 g/L is adequate for haemostasis during PPH.
      • Collins P.W.
      • Cannings-John R.
      • Bruynseels D.
      • et al.
      Viscoelastometric-guided early fibrinogen concentrate replacement during postpartum haemorrhage: OBS2, a double–blind randomized controlled trial.
      Pre-specified subgroup analyses
      • Aawar N.
      • Alikhan R.
      • Bruynseels D.
      • et al.
      Fibrinogen concentrate versus placebo for treatment of postpartum haemorrhage: study protocol for a randomised controlled trial.
      showed that fibrinogen >2 g/L or FIBTEM A5 >12 mm were adequate for haemostasis despite severe PPH. However, if FIBTEM A5 or fibrinogen was <12 mm or <2 g/L at the time of randomisation, women in the fibrinogen group received fewer blood products and had lower blood loss after study medication compared to placebo.
      • Collins P.W.
      • Cannings-John R.
      • Bruynseels D.
      • et al.
      Viscoelastometric-guided early fibrinogen concentrate replacement during postpartum haemorrhage: OBS2, a double–blind randomized controlled trial.
      These exploratory subgroup analyses did not reach statistical significance possibly due to the small number of women randomised with a fibrinogen <2 g/L. However these results, in conjunction with the data from Mallaiah,
      • Mallaiah S.
      • Barclay P.
      • Harrod I.
      • Chevannes C.
      • Bhalla A.
      Introduction of an algorithm for ROTEM-guided fibrinogen concentrate administration in major obstetric haemorrhage.
      suggest that an appropriate intervention point for infusion of fibrinogen is a FIBTEM A5 <12 mm or fibrinogen <2 g/L, and a study investigating this is warranted.
      In our experience a fibrinogen level below 2 g/L is uncommon during obstetric haemorrhage. Combining data from consecutive studies and observation from our institution over the last eight years shows a rate of 1–2/1000 deliveries and a similar incidence has been observed across all units in Wales. In OBS-2, irrespective of blood loss, women with a FIBTEM A5 >15 mm or who had stopped bleeding, had FFP withheld (n=605). Median (IQR) blood loss was 1500 mL (1300–2000 mL) and none of the women developed haemostatic impairment,
      • Collins P.W.
      • Cannings-John R.
      • Bruynseels D.
      • et al.
      Viscoelastometry guided fresh frozen plasma infusion for postpartum haemorrhage: OBS2, an observational study.
      suggesting that haemostatic impairment during PPH can be assessed accurately using VE-POCTs.

      Thrombocytopenia and platelet transfusion during postpartum haemorrhage

      It has been suggested that a massive transfusion protocol used for PPH should include platelets.
      • Saule I.
      • Hawkins N.
      Transfusion practice in major obstetric haemorrhage: lessons from trauma.
      • Shields L.E.
      • Wiesner S.
      • Fulton J.
      • Pelletreau B.
      Comprehensive maternal hemorrhage protocols reduce the use of blood products and improve patient safety.
      • Onwuemene O.
      • Green D.
      • Keith L.
      Postpartum hemorrhage management in 2012: predicting the future.
      • Pacheco L.D.
      • Saade G.R.
      • Costantine M.M.
      • Clark S.L.
      • Hankins G.D.V.
      The role of massive transfusion protocols in obstetrics.
      Guidelines recommend maintaining the platelet count above 75 × 109/L during PPH.
      • Mavrides E.
      • Allard S.
      • Chandraharan E.
      • et al.
      Prevention and management of postpartum haemorrhage.
      • Collins P.W.
      • Kadir R.
      • Thachil J.
      Management of coagulopathy associated with postpartum haemorrhage: guidance from the SSC of ISTH.
      There are limited data on the incidence and causes of thrombocytopenia during PPH, therefore we analysed the women recruited to the OBS-1 study. In moderate to severe PPH, thrombocytopenia was uncommon, with 8/347 (2.3%) women having a platelet count <75 × 109/L. Twelve women (3.4%) received a platelet transfusion and these fell into two groups. Firstly, women who were thrombocytopenic before delivery due to preeclampsia or pre-existing diseases such as immune or inherited thrombocytopenia and secondly, women with initially normal platelet counts who either had a placental abruption or bleeds >5000 mL.
      • Jones R.M.
      • De Lloyd L.
      • Kealaher E.J.
      • et al.
      Platelet count and transfusion requirements during moderate or severe postpartum haemorrhage.
      These findings were supported by the UKOSS survey of women who received ≥8 units of RBC (median blood loss 6000 mL) where the median first platelet count taken during the bleed was 131 × 109/L and lowest was 68 × 109/L; 77% of these women received a platelet transfusion. Placental abruption was associated with the largest fall in platelet count (137 to 54 × 109/L).
      • Green L.
      • Knight M.
      • Seeney F.
      • et al.
      The haematological management and transfusion requirements of women who required massive transfusion for major obstetric haemorrhage in the UK: a population based descriptive study.
      These reports suggest that the platelet count is adequate during PPH in the vast majority of cases, and inclusion of platelets in shock packs would result in many women receiving unnecessary platelet infusions.

      Measurement of blood loss after delivery and during PPH

      Early recognition of PPH with measured rather than estimated blood loss is critical because clinicians often underestimate the volume of bleeding.
      • Bose P.
      • Regan F.
      • Paterson-Brown S.
      Improving the accuracy of estimated blood loss at obstetric haemorrhage using clinical reconstructions.
      Measurement of blood loss is more accurate and is feasible in routine practice, should be started after every delivery even if the initial loss seems normal
      • Lilley G.
      • Collis R.E.
      Gravimetric measurement of blood loss versus visual estimation in simulated postpartum haemorrhage.
      and is a key recommendation in RCOG guidance.
      • Mavrides E.
      • Allard S.
      • Chandraharan E.
      • et al.
      Prevention and management of postpartum haemorrhage.
      We adopted the practice of gravimetric measurement of blood loss on swabs and pads with the addition of measured blood loss in conical under-buttock drapes and suction bottles during our studies to standardise patient recruitment and ensure timely escalation of care. Measurement of blood loss alone does not lead to improved outcomes during PPH,
      • Hancock A.
      • Weeks A.D.
      • Lavender D.T.
      Is accurate and reliable blood loss estimation the ‘crucial step’ in early detection of postpartum haemorrhage: an integrative review of the literature.
      but when integrated into a pathway can aid escalation of care.
      • Shields L.E.
      • Wiesner S.
      • Fulton J.
      • Pelletreau B.
      Comprehensive maternal hemorrhage protocols reduce the use of blood products and improve patient safety.
      In addition, escalation of care also needs to take into account other factors such as maternal vital signs, as bleeding can be concealed and the apparent rate of blood loss misleading, although specific guidance is not available.

      Impact of obstetric bleeding studies on practice and evolving quality improvement

      Between 2013 and 2015 women recruited to OBS-2 followed the study blood product algorithm (Fig. 3a) and those not recruited were treated using the local major obstetric haemorrhage ROTEM® algorithm (Fig. 3b). Since 2010 PPH outcome data has been collected at our institution as part of a quality improvement initiative. During OBS-2, RBC usage decreased by 32%, FFP usage by 86% and the number of women receiving five or more units RBC fell by 86% (Fig. 4). In addition, bleeds ≥2500 mL fell by 83% and level 3 ITU admissions (women requiring advanced respiratory support) due to PPH decreased from about four per year to none in three years. Although temporally related, it is unlikely that the intervention of fibrinogen administration was solely responsible for these improved outcomes as only seven women treated in the interventional arm had a fibrinogen <2 g/L. This implies that other factors associated with running the study and complying with protocols were influencing maternal outcomes. In order to standardise recruitment to the study, women were risk assessed, blood loss was measured rather than estimated and obstetricians and anaesthetists attended the mother’s bedside to obtain consent and take study bloods as specified in the study protocol.
      Figure thumbnail gr4
      Fig. 4Changes in transfusion practice across time in Cardiff. a shows the number of units of red blood cells (RBC) (grey) and fresh frozen plasma (FFP) (black) transfused for each year between 2010 and 2017. The Obstetric Bleeding Study-2 study was associated with a reduction in RBC and FFP transfusion which increased after the study finished and fell again once the Obstetric Bleeding Study for Wales Cymru was initiated. b shows data for the number of women who received at least 5 units of RBC, representing a subgroup of very severe postpartum haemorrhage. A similar temporal trend was observed
      When OBS-2 ended in November 2015, it was expected that improved outcomes would continue. However, it rapidly became apparent that this was not the case and the end of the study coincided with an increase in large haemorrhages to rates similar to before the study (Fig. 4). A systematic review of 16 large bleeds over a six-month period identified common themes including a return to estimating blood loss, the multidisciplinary team not attending the mother’s bedside in a timely fashion and POCTs not being performed early in the course of the haemorrhage. This resulted in delayed recognition of a deteriorating patient and delayed escalation of obstetric intervention.

      Quality improvement initiatives in postpartum haemorrhage

      In 2011 Shields described a quality improvement programme that standardised care during PPH. This included risk assessment followed by an escalating three-stage approach based on 500, 1000 and 1500 mL blood loss and/or clinical signs. This stepwise, prescriptive approach required accurate contemporaneous measurement rather than estimation of blood loss and was initiated after every delivery. The protocol stipulated that a senior midwife, obstetrician and anaesthetist should attend the mother’s bedside when blood loss reached 1000 mL. At 1500 mL blood loss, empirical fixed-ratio blood product transfusion was started based on data derived from trauma studies. The group noted that PPH progressed in fewer women, the number of blood products used fell and fewer women developed coagulopathy.
      • Shields L.E.
      • Smalarz K.
      • Reffigee L.
      • et al.
      Comprehensive maternal hemorrhage protocols improve patient safety and reduce utilization of blood products.
      The protocol was rolled out across a region by the California Maternal Quality Care Collaborative (CMQCC) with similar results.
      • Shields L.E.
      • Wiesner S.
      • Fulton J.
      • Pelletreau B.
      Comprehensive maternal hemorrhage protocols reduce the use of blood products and improve patient safety.
      A similar quality improvement programme was initiated by The Association of Women’s Health, Obstetric and Neonatal Nurses (AWHONN). Both CMQCC and AWHONN have extensive information available on their websites (http://www.awhonn.org/?page=PPH and https://www.cmqcc.org/resources-tool-kits/toolkits/ob-hemorrhage-toolkit).
      These initiatives overlapped with our experiences in terms of risk assessment, measured blood loss and early escalation of obstetric care by senior clinicians. The main difference was the approach to blood product replacement, liberal fixed-ratio infusion of blood products based on data derived from trauma
      • Shields L.E.
      • Smalarz K.
      • Reffigee L.
      • et al.
      Comprehensive maternal hemorrhage protocols improve patient safety and reduce utilization of blood products.
      • Shields L.E.
      • Wiesner S.
      • Fulton J.
      • Pelletreau B.
      Comprehensive maternal hemorrhage protocols reduce the use of blood products and improve patient safety.
      versus VE-POCTs to target haemostatic therapy based on our programme of research. It is not known which of these approaches results in better outcomes and clinical trials specifically addressing the value of VE-POCTs are required to address this.

      Understanding the impact of point-of-care tests of coagulation in postpartum haemorrhage

      During OBS-2 ROTEM®-guided blood product replacement was introduced into routine practice at our centre for all patients. As experience increased and clinicians accepted the results as clinically reliable, management of PPH changed. If early in the bleed the ROTEM® results were normal, the bleeding must be due to a physical cause (atony, trauma or retained placental tissue) and not coagulopathy. This knowledge facilitated early targeted escalation of obstetric care and, if necessary, involvement of a more experienced colleague. If coagulation was abnormal early in the bleed the mother was immediately identified as high risk. Early coagulopathy in such cases raises suspicion of delayed resuscitation, placental abruption or amniotic fluid embolus. The mother required urgent treatment for coagulopathy, almost always with fibrinogen replacement, and escalation of obstetric management to address the underlying cause of bleeding. This binary classification helped the team focus on the most important clinical problem and our impression was that VE-POCTs facilitated behavioural change of the multidisciplinary team.
      A National Institute for Health and Care Excellence review of VE-POCT during PPH focused only on blood and blood product usage (https://www.nice.org.uk/guidance/dg13). Our experience is that VE-POCTs can act as a trigger around which care can be structured by encouraging clinicians to attend the bedside early. The VE-POCT results influence decision making and, if normal, allow the obstetrician to focus on managing the obstetric cause of bleeding while the anaesthetist concentrates on appropriate resuscitation and blood product replacement. Our observation, supported by the findings from OBS-2 and other retrospective observational studies,
      • Matsunaga S.
      • Takai Y.
      • Nakamura E.
      • et al.
      The clinical efficacy of fibrinogen concentrate in massive obstetric haemorrhage with hypofibrinogenaemia.
      • Seto S.
      • Itakura A.
      • Okagaki R.
      • Suzuki M.
      • Ishihara O.
      An algorithm for the management of coagulopathy from postpartum hemorrhage, using fibrinogen concentrate as first-line therapy.
      • Mallaiah S.
      • Barclay P.
      • Harrod I.
      • Chevannes C.
      • Bhalla A.
      Introduction of an algorithm for ROTEM-guided fibrinogen concentrate administration in major obstetric haemorrhage.
      • Mallaiah S.
      • Chevannes C.
      • McNamara H.
      • Barclay P.
      A reply.
      • Collins P.W.
      • Cannings-John R.
      • Bruynseels D.
      • et al.
      Viscoelastometric-guided early fibrinogen concentrate replacement during postpartum haemorrhage: OBS2, a double–blind randomized controlled trial.
      is that in the small number of women who are identified as having a fibrinogen <2 g/L or FIBTEM A5 <12 mm, rapid correction of hypofibrinogenaemia with fibrinogen concentrate improves haemostasis and is advantageous, although large prospective trials are needed to verify these findings.

      Local quality improvement initiatives

      Improved local clinical outcomes may be a consequence of multiple inter-related factors. These included risk assessment of all women, cumulative measurement of blood loss and ensuring that an experienced midwife, obstetrician and anaesthetist attend the mother at 1000 mL blood loss with ROTEM® assessment of coagulation for all women whether they were enrolled into the OBS-2 study or not. We do not know which one of these interventions improves outcomes and it is likely to be a combination of all of these factors. Over a one year period (2017, 18 months after finishing the OBS-2 trial) in our tertiary referral centre, 2.8/1000 women had a PPH >2500 mL, a blood transfusion of ≥5 units RBC or received FFP. When compared with the published data from Healthcare Improvement Scotland, where an overall rate of 6/1000 was reported, our results fall below three standard deviations from the mean.

      Lennox C, Marr L. Scottish confidential audit of severe maternal morbidity. 9th annual report (data from 2011). Available at: http://healthcareimprovementscotland.org/his/idoc.ashx?docid=5fb640e2-d079-48cc-ad49-a58f6929b685&version=-1; 2013.

      We are currently seeking to replicate these improvements across Wales.

      All Wales quality improvement programme: OBS Cymru (Obstetric Bleeding Strategy for Wales (Cymru))

      The OBS Cymru (http://www.1000livesplus.wales.nhs.uk/OBS-cymru) is a registered quality improvement initiative that aims to reduce maternal morbidity due to PPH across Wales. Wales has a population of 3.1 million and delivers 30 000 women per year in 12 consultant led units (CLU), with between 500 and 6000 deliveries per annum in each CLU. The project aims to reduce rates of major PPH and blood transfusion, level 3 ICU care and hysterectomy due to PPH.

      The OBS Cymru intervention

      The key to OBS Cymru is to limit the number of moderate bleeds that progress to severe haemorrhage and so reduce maternal morbidity. The project focused on four key elements which draw on the quality improvement work from other groups
      • Shields L.E.
      • Smalarz K.
      • Reffigee L.
      • et al.
      Comprehensive maternal hemorrhage protocols improve patient safety and reduce utilization of blood products.
      • Shields L.E.
      • Wiesner S.
      • Fulton J.
      • Pelletreau B.
      Comprehensive maternal hemorrhage protocols reduce the use of blood products and improve patient safety.
      and the lessons learnt from our research programme.
      • 1.
        Risk assessment of all women: potential risk factors for PPH are flagged on admission to delivery suite and with on-going risk assessment during labour.
      • 2.
        Cumulative gravimetric measurement of blood loss after every delivery: to facilitate escalation of care with specific actions required at 500, 1000 and 1500 mL blood loss.
      • 3.
        Multidisciplinary care with a senior midwife, obstetrician and anaesthetist attending the bedside at 1000 mL blood loss.
      • 4.
        ROTEM®-guided blood product replacement using an algorithm derived from the results of OBS-2.
      These themes are embedded into clinical practice using a number of interventions and tools (available at http://www.1000livesplus.wales.nhs.uk/OBS-cymru). A PPH proforma describing an escalating four-stage approach was developed and is placed in all mothers’ notes on admission to delivery suite. (Specific paperwork which describes all actions and interventions which should occur as PPH progresses and also acts as a template for scribing the events).
      • Stage 0: risk assessment for all women in labour (on admission and as labour progresses).
      • Stage 1: at >500 mL after a vaginal birth a senior midwife is informed, the cause of bleeding assessed and initial treatment instituted.
      • Stage 2: at >1000 mL a senior midwife, obstetrician and anaesthetist attend the bedside to assess and escalate management as appropriate. Samples for ROTEM®, bedside lactate and haemoglobin, FBC and coagulation screen are taken and tranexamic acid is given.
      • Stage 3: at >1500 mL with on-going bleeding the consultant obstetrician and anaesthetist are informed. The major obstetric haemorrhage protocol is activated and ROTEM®-guided blood product replacement instituted whilst medical and surgical treatments are continued.
      This is a complex intervention and so its impact is being assessed according to Medical Research Council guidance.
      • Moore G.F.
      • Audrey S.
      • Barker M.
      • et al.
      Process evaluation of complex interventions: Medical Research Council guidance.
      The step-wise interventions have been incorporated into an all Wales PPH guideline (http://www.wisdom.wales.nhs.uk/sitesplus/documents/1183/Post%20Partum%20Haemorrhage_Maternity%20Network%20Wales%20All%20Wales%20Guidelines_2017.pdf) and are based on the Royal College of Obstetrics and Gynaecology (RCOG) green-top guidance
      • Mavrides E.
      • Allard S.
      • Chandraharan E.
      • et al.
      Prevention and management of postpartum haemorrhage.
      and incorporate the OBS Cymru approach.
      Data are collected prospectively on all PPHs >1000 mL in Wales, to be compared with retrospective data collected from the units. It is too early to assess whether key markers of severe PPH are changing; this information will be reported at the completion of the project in 2019.

      OBS Cymru ROTEM® guided algorithm

      The OBS Cymru ROTEM®-guided blood product algorithm is shown in Fig. 5 (http://www.oaa-anaes.ac.uk/assets/_managed/cms/files/Guidelines/ROTEM%20Protocol.pdf). At 1000 mL blood loss with ongoing bleeding FIBTEM A5 and EXTEM CT, bedside venous lactate and haemoglobin are performed and FBC and coagulation sent to the laboratory. Intravenous tranexamic acid is given. The WOMAN trial showed that tranexamic acid, given within three hours of delivery, reduced death due to bleeding without an increase in thrombotic or other adverse events,
      • Shakur H.
      • Roberts I.
      • Fawole B.
      • et al.
      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.
      so our algorithm infuses tranexamic acid as soon as PPH is recognised or at the latest 1000 mL. The rationale for early ROTEM® testing is not only to rapidly identify the small number of women who need haemostatic support, but to reassure the obstetrician that coagulation is normal and focus treatment on obstetric causes of bleeding. Haemostatic blood product replacement initially focuses on fibrinogen. If FIBTEM A5 is ≤12 mm or Clauss fibrinogen <2 g/L, fibrinogen concentrate is given. Fibrinogen concentrate is not licensed for this indication in the UK and an alternative, as recommended by RCOG, is to infuse cryoprecipitate.
      • Mavrides E.
      • Allard S.
      • Chandraharan E.
      • et al.
      Prevention and management of postpartum haemorrhage.
      The recommendations on fibrinogen replacement are based on data from OBS-2 and the Liverpool PPH algorithm.
      • Mallaiah S.
      • Barclay P.
      • Harrod I.
      • Chevannes C.
      • Bhalla A.
      Introduction of an algorithm for ROTEM-guided fibrinogen concentrate administration in major obstetric haemorrhage.
      • Mallaiah S.
      • Chevannes C.
      • McNamara H.
      • Barclay P.
      A reply.
      • Collins P.W.
      • Cannings-John R.
      • Bruynseels D.
      • et al.
      Viscoelastometric-guided early fibrinogen concentrate replacement during postpartum haemorrhage: OBS2, a double–blind randomized controlled trial.
      The target is to maintain the fibrinogen >2 g/L which is supported in the 2016 RCOG guideline.
      • Mavrides E.
      • Allard S.
      • Chandraharan E.
      • et al.
      Prevention and management of postpartum haemorrhage.
      • Collins P.W.
      • Kadir R.
      • Thachil J.
      Management of coagulopathy associated with postpartum haemorrhage: guidance from the SSC of ISTH.
      If the EXTEM CT is prolonged above the normal range (75 s based on local validation) or the PT/aPTT is above the normal range, after fibrinogen replacement, 15 mL/kg FFP is infused based on RCOG guidance and OBS-2 data.
      • Mavrides E.
      • Allard S.
      • Chandraharan E.
      • et al.
      Prevention and management of postpartum haemorrhage.
      • Collins P.W.
      • Cannings-John R.
      • Bruynseels D.
      • et al.
      Viscoelastometric-guided early fibrinogen concentrate replacement during postpartum haemorrhage: OBS2, a double–blind randomized controlled trial.
      Platelets are transfused if <75 × 109/L based on RCOG guidance.
      • Mavrides E.
      • Allard S.
      • Chandraharan E.
      • et al.
      Prevention and management of postpartum haemorrhage.
      Because coagulopathy can evolve rapidly during PPH we repeat ROTEM® and laboratory testing every 500 mL or every 30 min during ongoing bleeding, or at any time for clinical concern. Tests are repeated after blood products are given to assess response.

      The future – questions to be addressed

      The role of VE-POCTs in the management of PPH remains debated
      • Bamber J.H.
      Point-of-care testing on the labour ward should be mandatory.
      • Collis R.
      Coagulation point-of-care testing on the labour ward should be mandatory.
      and definitive evidence is lacking. We hypothesise that it is the combined effect of the early recognition of bleeding, triggering timely interventions incorporating VE-POCTs and a management strategy involving the whole multidisciplinary team, that is the key to preventing progression of PPH and minimising morbidity. A study comparing such an approach utilising early VE-POCT, with accepted standard care based on laboratory tests of coagulation, is now necessary although this would necessitate large multi-centre studies. It may also be possible to partially address some of these questions by specifically studying high risk surgical procedures such as women having a caesarean section for placenta previa or women who present with abruption.
      Data on the cost effectiveness of such an approach is important if this is to be used more generally within a variety of health care settings. We suggest that qualitative assessment of the impact of the intervention on team dynamics and behaviour should also be studied. A multinational group of interested researchers may be required to address these issues.

      Acknowledgements

      The authors thank the women who have agreed to take part in the studies described and the midwives, anaesthetists and obstetricians who have helped to enrol the subjects. The role of everyone involved in OBS Cymru is gratefully acknowledged.

      Declarations of interest

      PWC has received research support from CSL Behring, Werfen/Tem International and Haemonetics. He has acted as a paid consultant to CSL Behring and Werfen/Tem International.
      SFB has received support for quality improvement initiatives from Werfen/Tem International and Welsh Government.
      L de L has received research support from Werfen/Tem International and Haemonetics.
      REC has received research support from CSL Behring, Werfen/Tem International and Haemonetics. She has received support for quality improvement initiatives from Werfen/Tem International and Welsh Government. She has acted as a paid consultant to CSL Behring and Werfen/Tem International.

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