state of the art review

How we manage the haematological aspects of major obstetric haemorrhage Shubha Allard,1 Laura Green1 and Beverley J. Hunt2 1

Barts Health NHS Trust & NHS Blood and Transplant, and 2Guy’s & St Thomas’ NHS Foundation Trust & King’s College University, London, UK

Summary Major obstetric haemorrhage (MOH) remains an important medical challenge worldwide, contributing to significant maternal morbidity and mortality. Prompt and appropriate management is essential if we are to improve outcomes and reduce substandard care that may result in adverse consequences. This review describes the current understanding of the pathophysiological aspects of MOH together with the principles of transfusion and haemostatic therapy, with emphasis on a coordinated multidisciplinary approach. We also highlight the current lack of evidence available from randomized controlled trials to inform best practice and the need to prioritize research in this key clinical area. Keywords: pregnancy, haemorrhage, transfusion.

Despite major advances in healthcare, it remains an unpalatable fact that worldwide, about 530 000 women die annually during pregnancy and childbirth, with 99% of the deaths in low and middle-income countries. Major obstetric haemorrhage (MOH) is the leading cause of this maternal mortality, occurring mostly in the postpartum period (McLintock & James, 2011) and may contribute to up to 50% of the annual worldwide maternal deaths. One of the Millennium Development Goals set by the United Nations in 2000 is to reduce maternal mortality by three-quarters before 2015 (http://www.un.org/millenniumgoals/maternal. shtml). In the UK, MOH is the sixth most common cause of maternal mortality with an ongoing focus on improving suboptimal care (Cantwell et al, 2011). It is important to note that haemorrhage is the major cause of severe maternal morbidity in almost all reported ‘near miss’ audits (Brace et al, 2007; Penney & Brace, 2007).

A moderate loss of blood after delivery is physiologically tolerated by the majority of mothers, unless there is significant pre-existing anaemia. It is essential to have a clear approach to the management of those mothers with more severe haemorrhage needing transfusion support, for substandard care results in morbidity and mortality (Lewis, 2007). While there are similarities in the management of transfusion in MOH to that of major bleeding in other clinical situations, such as trauma, the pathophysiological processes contributing to MOH require specific focus. This review aims to characterize the haematological aspects of MOH after the usual uterotonic measures have failed, and covers current understanding of the optimum use of transfusion and haemostatic therapy with emphasis on a coordinated multidisciplinary approach. The current lack of evidence of randomized controlled trials (RCTs) to inform best practice is also emphasized.

Definition of MOH Antepartum haemorrhage (APH), defined as bleeding occurring from 24 weeks of pregnancy and prior to delivery, may complicate 3–5% of pregnancies (Royal College of Obstetricians and Gynaecologists (RCOG) 2011a). The RCOG suggests a classification of postpartum haemorrhage (PPH) either as minor (500–1000 ml) or major (>1000 ml) with further sub-division of major to moderate (1000–2000 ml) or severe (>2000 ml; RCOG, 2009). PPH > 500 ml occurs in up to an estimated 18% of births (Elbourne et al, 2001) with approximately 4% of births having a PPH > 1000 ml (Bais et al, 2004). Brace et al (2004) defined a more severe category of MOH for 3
7 in 1000 pregnancies in a Scottish population with estimated blood loss > 2500 ml or needing transfusion of > 5 units of blood or needing treatment for coagulopathy during the acute event.

Risk factors for MOH Correspondence: Dr Shubha Allard, NHS Blood & Transplant, Colindale Blood Centre, Charcot Road, London, NW9 5BG, UK. E-mails: [email protected]; [email protected]

ª 2013 John Wiley & Sons Ltd British Journal of Haematology, 2014, 164, 177–188

While APH commonly occurs without an identifiable cause, there are some known risk factors, namely placenta praevia and placental abruption (Odibo et al, 2007; Yang et al, 2009; Healy et al, 2010; Onwere et al, 2011). Women with risk

First published online 28 October 2013 doi:10.1111/bjh.12605

Review factors identified antenatally may have a subsequent increased incidence of PPH whereas other high risk features may become apparent during labour and delivery, e.g., prolonged labour, and emergency caesarian section (Al-Zirqi et al, 2008). A recent study (Cook et al, 2013) has highlighted that women with multiple repeat caesarian section are at a significantly greater risk of MOH >1500 ml) [adjusted odds ratio (aOR), 18
6; 95% confidence interval (CI), 3
89–88
8]. Primary PPH may result from genital tract trauma, retained placental tissue and inherited or acquired maternal bleeding disorders but uterine atony is recognized as being the most common cause and consequently the leading cause of maternal mortality worldwide (World Health Organization (WHO) 2009). It is important to emphasize that APH and PPH cannot, in the main, be predicted, highlighting the need for ongoing vigilance to ensure prompt recognition and appropriate management.

Optimization haemoglobin levels in early pregnancy The WHO highlights iron deficiency anaemia (IDA) in pregnancy as a significant global problem, with estimates of 25% in industrialized countries to an average of 56% in the developing world (WHO, 2008). While further research is needed on the effect of iron deficiency and on the effectiveness of implementation strategies to reduce maternal anaemia (Reveiz et al, 2011; Haider et al, 2013), iron supplementation should be given to mothers who are deficient, to optimize the haemoglobin concentration (Hb) during pregnancy and before delivery (RCOG, 2009; Pavord et al, 2012).

Identification of high risk cases and multidisciplinary planning Placenta accreta and its more severe forms, increta or percreta, are associated with catastrophic haemorrhage and carry a high mortality (RCOG, 2011b). Some of these cases may be diagnosed antenatally with scope for multidisciplinary planning for delivery. Various case series highlight the potential benefit of interventional radiology including balloon occlusion or embolization of pelvic arteries (Ojala et al, 2005; Bodner et al, 2006) but randomized studies are required to support the use of these techniques. A study by the United Kingdom Obstetric Surveillance System (Knight, 2007) between 2005 and 2006 found the estimated incidence of peripartum hysterectomy to control haemorrhage was 40
6 per 100 000 maternities (95% CI 36
3–45
4 per 100 000 maternities); of these, 39% had a morbidly adherent placenta and the main documented risk factor was previous caesarean delivery (aOR 3
52, 95% CI 2
35–5
26). In recognition of the severe morbidity associated with placenta praevia and previous caesarian section, multidisciplinary planning and management is recommended (RCOG, 2011b), 178

with key elements including consultant obstetrician and anaesthetist input, availability of blood and components together with access to cell salvage and interventional radiology.

Diagnosis of MOH Various parameters, such as estimation of blood loss, maternal vital signs, transfusion of red blood cell (RBC) and laboratory assays, all play a role in the diagnosis of MOH but the prompt recognition of significant bleeding remains challenging. Unfortunately, visual assessment notoriously underestimates large blood loss volumes (>1000 ml) and significantly overestimates low volumes ( 75 9 109/l; Stainsby et al, 2006; RCOG, 2009). These recommendations were based on expert opinion in the absence of RCTs. Recognize blood loss & trigger multidisciplinary MOH protocol

Take baseline blood samples prior to transfusion for: • •

Full blood count, Group & Save, clotting screen including Clauss fibrinogen Near-patient haemostatic testing if available

Consider giving tranexamic acid (if not participating in any tranexamic acid trial)

TEAM LEADER to further co-ordinate management & nominate a member of team to liaise with transfusion laboratory • • •

Use emergency O NEG red cells immediately if severe bleeding Use group specific blood as soon as available Request pre-agreed ratio of blood components, e.g., 6 units RBC & 4 units FFP; Send porter to laboratory to collect urgently

IF BLEEDING CONTINUES

If laboratory results are available: Until laboratory results are available: • Give further FFP at 1 litre (4 units) per 6 units RBC • Consider Cryoprecipitate (2 pools) • Consider platelets (1 ATD) K

Fig 1. Suggested algorithm for haemostatic and transfusion management in major obstetric haemorrhage. MOH, major obstetric haemorrhage; RBC, red blood cell concentrate; FFP, fresh frozen plasma; ATD, adult therapeutic dose. ª 2013 John Wiley & Sons Ltd British Journal of Haematology, 2014, 164, 177–188

IF :

G IV E :

Falling Hb

Red cells

PT ratio >1·5

FFP 15–20 ml/kg

Fibrinogen < 1·5–2 g/l

Cryoprecipitate (2 pools)

Platelet count < 75 x 109/l

Platelets 1 ATD

Continue cycle of monitoring & giving appropriate blood components until bleeding ceases

181

Review Observational and retrospective studies in military combat casualties suggest that early administration of FFP and fibrinogen in bleeding patients improved clinical outcomes (Borgman et al, 2007; Spinella et al, 2008; Stinger et al, 2008). While these studies promoted the use of a 1:1 FFP: RBC ratio for management of traumatic bleeding, there are concerns about the increased rate of multiple organ failure and acute respiratory distress syndrome in patients transfused with the high FFP volumes given (Watson et al, 2009; Johnson et al, 2010; Sambasivan et al, 2011). Several systematic reviews (Phan & Wisner, 2010; Curry et al, 2011; Kozek-Langenecker et al, 2011; Rajasekhar et al, 2011) and one meta-analysis (Murad et al, 2010) have highlighted the challenges in defining an optimal FFP:RBC ratio, including the lack of randomized control studies, the observational and retrospective nature of most studies, survivorship bias, heterogeneous patient population between studies and the lack of standard massive haemorrhage protocols. This has promoted a more cautious approach, with perhaps the use of 1:3 or 1:2 FFP:RBC ratios for the management of major bleeding (Roback et al, 2010; Spahn et al, 2013). Further, guidelines now recommend early administration of FFP for management of major bleeding (Roback et al, 2010; Spahn et al, 2013) but the outcomes of USA randomized control studies to address the optimal FFP:RBC ratio are awaited. The ‘high-ratio’ protocols have been adapted and applied to other patient groups with MOH without supporting evidence. Given the diversity of coagulopathies underlying different types of massive haemorrhage, and that blood transfusion is not without risks; it is important that clinical studies are performed to address this. For now, a pragmatic approach on the management of MOH is suggested with initial coagulation and full blood count assays and the empirical issue of four units FFP with six units of RBC (see Fig 1). Further use of blood components should be guided by regular coagulation screening and a full blood count. A local massive haemorrhage protocol (MHP) for the management of MOH is required. A systematic review compared the use of MHP in trauma bleeding patients with no MHP; the review concluded that having a MHP significantly reduces mortality (RR 0
69, 95% CI 0
55, 0
87), reduces the number of FFP transfusions, while the number of RBC transfusions remained largely unchanged (Vogt et al, 2012). Nevertheless, the availability of MHP has raised concerns about the collateral damage of such protocols resulting in unnecessary transfusion of plasma for patients who do not need it and thus leading to an increased rate of complications, such as fluid overload, adult respiratory distress syndrome and multiple organ failure (Inaba et al, 2010). Until better and faster diagnostic tests become available to guide blood transfusion during MOH, MHP must be regularly audited and monitored to avoid inappropriate blood use. 182

Cryoprecipitate and fibrinogen concentrates The transfusion of cryoprecipitate during major haemorrhage is aimed at correcting acquired fibrinogen deficiency. The previous British Society for Haematology and current RCOG guidelines recommended that fibrinogen replacement should be considered when its levels drop to 75 9 109/l for patients who have ongoing bleeding (Spahn et al, 2013).

Tranexamic acid Tranexamic acid (TXA) is an antifibrinolytic drug that is a competitive inhibitor of the activation of plasminogen. It has been widely used to reduce surgical bleeding (Ker et al, 2012; Perel et al, 2013) and the CRASH-2 (Clinical Randomization of an Antifibrinolytic in Significant Haemorrhage) study (Shakur et al, 2010a) showed that it reduced mortality in bleeding trauma patients. Moreover, it appears to be safe because there was no increased rate of venous thromboembolism in those receiving TXA in CRASH-2. A recent Cochrane review (Novikova & Hofmeyr, 2010) concluded that TXA decreased postpartum blood loss after vaginal birth and after caesarean section but, because there were only two RCTs which were small and of unclear quality, further studies were needed and details of safety were also required. In a subsequent study, Xu et al (2013) conducted a randomized, double-blind, case-controlled study of TXA 10 ml/kg versus placebo in 174 primipara undergoing caesarean section. Blood loss up to 2 h postpartum was significantly lower (P < 0
01) in the TXA group (46
6  42
7) than in the control group (84
7  80
2) but the amount of blood loss in the period from placental delivery to the end of caesarean section did not differ between the TXA and control groups (P = 0
17). No significant abnormal vital signs were observed after TXA administration. DucloyBouthors et al (2011) studied the use of high dose TXA in a randomized, controlled, multi-centre, open-label trial. Women with PPH >800 ml following vaginal delivery were ª 2013 John Wiley & Sons Ltd British Journal of Haematology, 2014, 164, 177–188

randomly assigned to receive TXA (loading dose 4 g over 1 h, then infusion of 1 g/h over 6 h) or not. Blood loss between enrolment and 6 h later was significantly lower in the TXA group (median, 173 ml; first to third quartiles, 59–377 ml) than in controls (221 ml; first to third quartiles 105–564 ml; P = 0
041). In the TXA group, bleeding duration was shorter and progression to severe PPH was less frequent than in controls (P < 0
03). Packed RBC transfusion was needed in 93% of women in the TXA group versus 79% of controls (P = 0
016). This study is the first to demonstrate that high-dose TXA can reduce blood loss and maternal morbidity in women with PPH. Although the study was not adequately powered to address safety issues, the observed side effects were mild and transient. However there is concern about the risk of seizures after high-dose TXA, which can inhibit cerebral glycine receptors (Lecker et al, 2012); moreover the original studies of TXA (Horrow et al, 1995) showed no additional benefit with higher doses. The World Maternal Antifibrinolytic Trial (WOMAN) (Clinicaltrials.gov ID: NCT00872469), a large, pragmatic, randomized, double blind, placebo controlled trial, aims to determine the effect of early administration of TXA on mortality, hysterectomy and other morbidities (surgical interventions, blood transfusion, risk of non-fatal vascular events) in women with clinically diagnosed PPH. The use of health services and safety, especially thromboembolic effect will also be assessed. Treatment entails a dose of TXA (1 g by intravenous injection) or placebo (sodium chloride 0
9%) given as soon as possible after randomization. A second dose may be given if, after 30 min, bleeding continues or if it stops and restarts within 24 h after the first dose. The main analyses will be on an ‘intention to treat’ basis, irrespective of whether the allocated treatment was received or not. The study aims to recruit 15 000 women (and has recruited over 8000 at time of writing) will have over 90% power to detect a 25% reduction from 4% to 3% in the primary endpoint of mortality or hysterectomy and is due to report in 2015 (Shakur et al, 2010b).

Recombinant FVIIa and other factor concentrates in MOH Recombinant FVIIa (rFVIIa), while licensed for use in several inherited bleeding disorders, has been used widely off-label to treat massive bleeding. However enthusiasm for its use ‘off –license’ has waned in recent years due to the lack of high quality RCTs to assess its benefit (unlike TXA, it has never been shown to reduce mortality) and recognition that it has a significant rate of harm – notably arterial thrombosis – as reported by Levi et al (2010). The largest reported series of off-label use of rFVIIa in obstetrics is from the Australian and New Zealand Haemostasis Registry (Phillips et al, 2009). Between January 2002 and July 2008, the use of rFVIIa was recorded in 105 women with PPH in 90 participating hospitals. The majority of 183

Review women (78%) received a single dose with a median dose of 92 u/kg). A decrease in bleeding was seen in 94 patients, in 64% after the first dose with a reduction in transfusion of blood and blood products. Forty-three patients (41%) had a hysterectomy before administration of rFVIIa. A hysterectomy was necessary after administration of rFVIIa in 13 (21%) of the remaining women. Two (1
9%) non-fatal thromboembolic complications were reported considered likely to be linked to rFVIIa (Phillips et al, 2009). The Northern Europe FVIIa in Obstetric Haemorrhage (NEFOH) reported use in 92 women with obstetric haemorrhage from 531 maternity units in nine countries (Alfirevic et al, 2007). Again the majority of women (82%) received a single dose of rFVIIa and it was reported to improve bleeding in 77 women (83%; Alfirevic et al, 2007). What can be derived from this data? Given the limitations of registries and the potential for biased reporting of positive outcomes, one can only conclude there is inadequate data to guide the use of rVIIa in obstetric haemorrhage. We feel there is a need for a trial of rFVIIa versus placebo to be given in a final attempt to avoid a hysterectomy or in a lifethreatening situation. Currently, an early hysterectomy is recommended for severe bleeding as a result of placenta accreta or uterine rupture. In women with uterine atony who have ongoing bleeding in spite of correction of coagulopathy, hypothermia, acidosis and hypocalcaemia, it seems reasonable to consider a trial of rFVIIa vs. placebo before a hysterectomy. When rVIIa has been described as effective, an improvement in bleeding was seen within 10–15 min after the dose of rFVIIa, a short enough time to wait except in women with rapid ongoing blood loss. Adequate thromboprophylaxis should be given to surviving women who have received rVIIa. The use of other factor concentrates, such as prothrombin complex concentrates and FXIII, have been used anecdotally in the management of major haemorrhage in other settings. Their use in obstetric haemorrhage cannot be recommended outside of a RCT in view of their potential prothrombotic effects in mothers who already are thrombophilic.

Cell salvage Intraoperative cell salvage (IOCS) is commonly being used in cardiac, orthopaedic and vascular surgery with reduction of allogeneic blood transfusion (Ashworth & Klein, 2010; Vonk et al, 2013) with increasing use in obstetrics (Liumbruno et al, 2012). A survey of UK maternity units in 2005–2006 showed that around 40% of centres were using cell salvage, with lack of training and availability of equipment being barriers to its use (Teig et al, 2007; RCOG, 2009). Facilities for IOCS should be made available for mothers who refuse blood or blood components (such as Jehovah’s Witnesses) or those where massive blood loss is anticipated (placenta percreta or accreta; RCOG, 2011b). 184

The National Institute of Clinical Excellence (NICE) recommends IOCS for massive blood loss in an emergency, but has called for evidence from RCTs to support its routine use (NICE, 2005). A systematic review of IOCS in caesarean section (Geoghegan et al, 2009) identified only one small, randomized trial on which to base recommendations for practice. A multi-centre trial of cell salvage in caesarean section in women at risk of haemorrhage (ISRCTN66118656; SALVO) is examining the clinical and cost effectiveness of this intervention.

Management of women refusing blood There are additional challenges in the management of mothers refusing blood transfusion, including for religious reasons, i.e., Jehovah’s Witnesses, with a higher risk of morbidity and mortality (Singla et al, 2001; Massiah et al, 2007; van Wolfswinkel et al, 2009). All women declining blood transfusion require careful multidisciplinary planning with senior clinician input during pregnancy to minimize anaemia and to manage bleeding. Early use of iron replacement is indicated with, if needed, use of intravenous iron, which may replenish iron stores faster and more effectively than oral iron (Al et al, 2005; Van Wyck et al, 2007; Breymann et al, 2008; Khalafallah et al, 2012; Froessler et al, 2013). Techniques, such as interventional radiology and IOCS in particular for high-risk caesarean section, e.g. abnormal placentation (RCOG, 2011b) should be made available. An advance decision document should include which blood components are not acceptable even in life-threatening bleeding and, in particular, which haemostatic products or pharmacological agents may be acceptable. An example of a suggested care plan for managing women refusing blood transfusion is available at http://www. transfusionguidelines.org.uk/docs/pdfs/bbt-04_care-plan-v2. pdf.

Drills, audit, adverse events and other aspects of governance The difficulties in clinically detecting early MOH are well recognized and may contribute to substandard care. Accordingly, clinical staff managing delivery need to be aware of these challenges with appropriate training given (RCOG, 2009). The UK Royal Colleges have recommended annual ‘skill drills’ (RCOG, 2009), including maternal collapse and these drills are also now one of the requirements in Maternity Clinical Negligence Scheme for Trusts standards. Such drills should promote a multidisciplinary approach involving relevant teams that include the hospital blood transfusion laboratory. A prospective randomized trial in the UK demonstrated that practical, multi-professional training in the management of obstetric emergencies increases knowledge amongst midwives and doctors (Crofts et al, 2007; Maslovitz et al, 2007). ª 2013 John Wiley & Sons Ltd British Journal of Haematology, 2014, 164, 177–188

Review Accurate documentation is essential and this may be supported by the use of a structured pro forma to aid accurate record keeping (Penney & Brace, 2007); Multidisciplinary audit and case review should be undertaken to assess that effective systems are in place for management of MOH. Any serious adverse reactions (SAR), serious adverse events (SAE) or patient harm due to delay in using blood components in the UK should be reported to the Serious Hazards of Transfusion (SHOT) scheme (www.shotuk.org) with SAE and SAR also reported to the Medicines and Healthcare Products Regulatory Agency (MHRA; www.shotuk. org/sabre).

Suggested areas for future research After years of neglect, there is at last a significant research interest in obstetric haemorrhage with a major RCT of TXA (the WOMAN study) and early studies in the use of fibrinogen supplementation underway. However this is a patchy approach and the seemingly more prosaic questions of how to use red cells and blood components, which have been available for decades, remain poorly studied. There is also an opportunity to address the utility of rFVIIa as rescue

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therapy in those contemplating hysterectomy or radiological intervention. Perhaps, more fundamentally, we need to understand the haemostatic changes of MOH and their drivers, as is starting to happen in traumatic coagulopathy. Lastly, the best tools for monitoring the haemostatic changes remain to be defined.

Conclusion MOH remains a major medical challenge around the world. Best practice is yet to be defined and many research questions remain unanswered. The prompt and appropriate management of obstetric haemorrhage is a fundamental component of obstetric care and essential if we are to achieve the overall target of reducing maternal mortality. While the literature on better understanding of bleeding to guide goal directed therapy in clinical settings, such as trauma, is rapidly expanding, there is a staggering paucity of evidence on the management of MOH. In this modern age, we really do need to concentrate our energies in resolving this common problem, which frequently has tragic outcomes.

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