“The position of women in any civilisation is an index of the advancement of that civilisation: The position of women is best gauged by the care given at the birth of her child” Haggard 1929
INTRODUCTION
PPH remains a major cause of both maternal mortality and morbidity worldwide more so in developing countries with an estimated mortality rate of 140,000 per year or one maternal death every four minutes. 1 PPH occur in 5% of all deliveries, majorities of death occur within four hours of delivery indicating that it is a consequence of third stage of labour2.
Death from PPH occurs in about 1 per 1000 deliveries in low-resource countries compared with 1 in 100,000 deliveries in higher-resource countries3. In 2014, the American College of Obstetricians and Gynecologists (ACOG) updated the definition of PPH. Postpartum hemorrhage is now defined as “a blood loss of 1000 ml or greater, or a blood loss with associated signs or symptoms of hypovolemia, that occurs within 24 h of delivery, regardless of the mode of delivery”4.
PATHOPHYSIOLOGY OF COAGULOPATHY
In the normal hemostatic response to tissue injury, thrombin generation, mediated by tissue factor and activated factor VII, is localized to the site of injury. This localization of thrombin to the site of injury leads to formation of a hemostatic plug composed of platelets and cross-linked fibrin5. In massive uterine hemorrhage, however, bleeding is associated with extensive clot formation and consumption of fibrinogen. As bleeding continues, these newly formed clots are fibrinogen-poor, and thrombin is able to leak from them and gain access to the systemic circulation where it binds to and depletes antithrombin. The decrease in antithrombin is exacerbated by infusions of crystalloids5.6. The direct consequence of circulating thrombin, unopposed by antithrombin, is disseminated intravascular coagulation (DIC).
DIC is characterized by the intravascular deposition of fibrin. Plasminogen, the precursor molecule of the fibrinolytic system, is bound to fibrin and converted to plasmin, the principle fibrinolytic enzyme. Plasmin attacks circulating fibrinogen as well as fibrin, resulting in hypofibrinogenemia. In addition, the ongoing fibrinolysis generates fibrin and fibrinogen degradation products, which inhibit platelet aggregation as well as fibrin formation. The resulting consumptive coagulopathy is manifest by the depletion of fibrinogen, prothrombin, factors V and VIII, and platelets6 which invariably results in worsening of bleeding.
WHO RECOMMENDATIONS ON UTEROTONICS FOR POSTPARTUM HAEMORRHAGE PREVENTION
The use of an effective uterotonic for the prevention of PPH during the third stage of labour is recommended for all births. To effectively prevent PPH, only one of the following uterotonics should be used:7
1.1 The use of oxytocin (10 IU, IM/IV) is recommended for the prevention of PPH for all births.
1.2 The use of carbetocin (100 μg, IM/IV) is recommended for the prevention of PPH for all births in contexts where its cost is comparable to other effective uterotonics.
1.3 The use of misoprostol (either 400 μg or 600 μg, PO) is recommended for the prevention of PPH for all births.
1.4 The use of ergometrine/methylergometrine (200 μg, IM/IV) is recommended for the prevention of PPH in contexts where hypertensive disorders can be safely excluded prior to its use.
1.5 The use of oxytocin and ergometrine fixed-dose combination (5 IU/500 μg, IM) is recommended for the prevention of PPH in contexts where hypertensive disorders can be safely excluded prior to its use.
1.6 Injectable prostaglandins (carboprost or sulprostone) are not recommended for the prevention of PPH.
LABORATORY DIAGNOSIS OF COAGULOPATHY
The role of standard coagulation tests and Clauss fibrinogen for detection of coagulopathy in PPH:
Lioyd et8 al 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. 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/L8. 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 worst9.
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:
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 PPH10. These studies now show convincingly that plasma Clauss fibrinogen, measured early during PPH, is a biomarker for predicting progression to severe PPH.
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 venipuncture.
In Obstetric Bleeding Study 1 (OBS-1)11 investigated whether a FIBTEM assay, performed on the ROTEM machine, could predict progression from early to severe PPH. 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.
TRANSFUSION STRATEGIES
The management of PPH has traditionally been limited to pharmacological agents that target uterine atony as a cause of bleeding. Although uterotonics remain first-line drugs, antifibrinolytics like tranexamic acid, and agents that act on the coagulation cascade, such as fibrinogen concentrate, recombinant activated factor VII, and prothrombin complex concentrates are likely to play increasingly relevant roles in PPH management.
Fibrinogen concentrate:
Hypofibrinogenemia is an early sign of severe PPH10 and typically treated with cryoprecipitate.
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 ITU12,13.
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 PPH14.
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) they used FIBTEM A5 and observation of ongoing bleeding to guide fibrinogen and FFP replacement. The OBS-2 was a double-blind, placebo controlled RCT which enrolled women with PPH >1000–1500 mL. The study investigated whether infusing fibrinogen concentrate15 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 A516 was ≥15 mm on the assumption that a normal fibrinogen was a surrogate for adequate levels of other coagulation factors.
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 PPH17. Pre-specified subgroup analyses16 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 placebo17.
these results, in conjunction with the data from Mallaiah12, 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 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 impairment17, 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. Guidelines recommend maintaining the platelet count above 75 × 109/L during PPH.8,9 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 mL18
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. 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 and is a key recommendation in RCOG guidance. The best practice is gravimetric measurement of blood loss on swabs and pads with the addition of measured blood loss in conical under-buttock drapes and suction bottles. Measurement of blood loss alone does not lead to improved outcomes during PPH but when integrated into a pathway can aid escalation of care.
ROTEM GUIDED ALGORITHM:
The OBS Cymru19 ROTEM-guided blood product algorithm, 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. Haemostatic blood product replacement initially focuses on fibrinogen. If FIBTEM A5 is 12 mm or Clauss fibrinogen <2 g/L, fibrinogen concentrate is given. The target is to maintain the fibrinogen >2 g/L which is supported in the 2016 RCOG guideline. 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. Platelets are transfused if <75 × 109/L based on RCOG guidance.
NEW GUIDANCE AND TARGETED RESEARCH:
At present the guidelines for the haemostatic management of obstetric haemorrhage are largely extrapolated from major trauma and the underpinning research has been lacking.
Compared with formula-driven strategies (such as fixed ratios of blood products), the use of goal directed resuscitation has been advocated for managing coagulopathy following trauma. Goal directed resuscitation can incorporate a point-of care strategy, which can incorporate TEG or ROTEM for the diagnosis of altered hemostasis and treatment efficacy for correcting coagulopathy20,21.
Although formula-driven vs. goal-directed transfusion approaches for PPH have not been compared, several prospective studies in trauma have investigated fixed-ratio transfusion approaches.
Further studies are needed to examine whether initial resuscitation during major PPH with an integrated approach comprising hemostatic agents (such as fibrinogen concentrate) and transfusion therapy is more effective than an only transfusion-based approach.
CONCLUSION
If hypofibrinogenemia is identified during PPH, fibrinogen supplementation may be an important early intervention. However, the precise indications for fibrinogen supplementation still need to be properly investigated. With hypofibrinogenemia and PPH receiving attention in the literature, one should not overlook the fact that fibrinogen supplementation may not necessarily result in complete correction of coagulopathy as other coagulation factors are also essential for achieving a critical rate of thrombin generation.
References:
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