Anomalous insertion of the placenta
Hypertensive diseases of pregnancy
Pathological adherent placenta/retained placenta
Macrosomy/large for gestational age baby
History of surgery of the uterus, including caesarean section
Uterine overdistension (poly-hydramnios, multiple gestations, non-cephalic presentation)
Trauma of the birth channel
(uterine rupture, cervical laceration, vaginal trauma)
Innate or acquired coagulopathy, including HELLP syndrome and pregnancy-associated thrombocytopenia
Amniotic fluid embolism
History of PPH/retained placenta
Elective caesarean section
Emergency caesarean section
Major risk factors associated with PPH. Conditions are classified according to pathophysiology. DIC disseminated intravascular coagulation; vWD von Willebrand’s disease; PPH postpartum haemorrhage
PPH will thus continue to occur in contexts with less than optimal facilities. The aim should be to develop and validate protocols for preventing PPH morbidity and mortality that can be used in clinical contexts outside the big medical centres (and possibly also in low-resource countries), such as the AMTSL (active management of the third stage of labour), a bundle of low-cost measures easily applicable for the management of a parturient after birth and until the placenta is expelled:
Administration of an uterotonic agent (oxytocin is mostly preferred) within a minute of the baby’s birth
Controlled traction of the umbilical cord and massage of the uterus after expulsion of the placenta
9.6 Random Treatment of PPH and Resuscitation in PPH
As in many medical situations, the Pareto principle (the majority of the results is due to the contributions of a minority of factors or agents) also applies for the reduction of PPH mortality and morbidity: a small percentage of measures and interventions will have a greater impact on the outcome and the failure to initiate these interventions in time cannot be compensated by other and more sophisticated measures. The single most important factor in preventing an adverse maternal outcome is the early recognition of an imminent or ongoing PPH , something that the anaesthetist cannot influence. In this case the underestimation of blood loss is a key factor in delaying therapy [13, 19, 26]. The second most important factor is the need for an early resuscitation, largely dependent on the hospital facilities, the organisation of the medical emergency teams, the activation of procedures and finally by the staff training .
In a single institution, PPH is a relatively rare complication that affects 1 out of 1,000 live births , and births are such a frequent event that they often cause a high workload. Hence, it is simply impossible for the staff to develop routine skills for treating severe PPH, especially in small delivery rooms.
Nonetheless, in European countries, PPH often occurs in contexts where virtually all the necessary resources for an initial resuscitation are available, including an expert staff (e.g. MET medical emergency team or outreach team), a laboratory for blood analyses and a transfusion centre for obtaining blood. What must be avoided is an ineffective resuscitation after hypothermia, acidosis and coagulopathy, dubbed the lethal triad .
Panels of international experts emphasise that it is necessary to have standard procedures and protocols for massive transfusions as well as realistic field drills, instrumental simulations that are immensely valuable if not essential [13, 30, 56–59]. After each case of severe PPH, a multidisciplinary debriefing session must be promptly organised to identify and discuss any problems that could have emerged in the local management of the PPH .
9.7 Medical and Surgical Treatment
9.7.1 Uterotonics and Volaemic and Haemostatic Resuscitation
184.108.40.206 Uterotonic Drugs
The majority of PPH cases will be primary PPH caused by uterine atony, in which the uterus does not contract sufficiently to clamp the vascular bed of the decidua. Atony can occur in some 5 % of births but is more often found in births with complications. It usually occurs with painless vaginal bleeding that develops slowly at the beginning. A flaccid uterus can easily contain more than a litre of blood, to be added to an underestimation or a non-recognition of PPH. Table 9.2 shows which uterotonic drugs are mainly used.
Vasodilatation, tachycardia, hypotension (especially with hypovolaemia), antidiuresis (fluid overload), caution in preeclampsia, nausea, vomiting
Bolus: 3–10 UIi.v./10 UI i.m.; continuous: 10 UI/h titrated
100 mcg i.v.
0,25 mg i.m./i.v; can be repeated every 5 min
Maximum 5 doses
Potent vasoconstrictor: contraindicated in hypertensive disease of pregnancy, extreme caution for use in combination with other uterotonics, myocardial ischaemia, pulmonary arterial hypertension, nausea /vomiting/dizziness
0.20 mg i.m; every 5 min; maximum 5 doses
8.3 mcg/min (≤500 mcg/h)
Maximum 1,500 mcg/24 h, de-escalation of dosing necessary
Careful in hypertensive/hypovolemic patients, gastrointestinal disturbance, shivering, pyrexia, hypotension with PGF2α
Bronchospasm (extreme caution in patients with asthma), pulmonary arterial hypertension
0.25 mg im/intramyometrically every 15 min, maximum 2 mg
2 mg per rectum every 2 h
0.5–1mg intramyometrically or 20 mg + 500 ml NaCl 0.9 % infused into uterine cavity
1–2 mg intra uterus/1 mg per rectum
600–1,000 mcg per rectum/intra uterus/sublingually
It is important for all members of the team to be familiar with these important drugs and their properties. In the case of acute PPH, obstetricians can rely on anaesthetists for medical treatment while they operate on the patient. WHO recommends the preventive administration of uterotonics during the third labour stage with oxytocin (IM/IV, 10UI), and this is supported by strong evidence (type A). When oxytocin is not available, WHO recommends the use of other injectable uterotonics (ergometrine/methylergometrine or oxytocin/ergometrine) or oral misoprostol (600 micrograms) (World Health Organisation. WHO recommendations for the prevention and treatment of postpartum haemorrhage 2012).
The current evidence for other components of the active management of the third stage of labour (AMTSL) has prompted WHO to change its recommendations on the controlled traction of the umbilical cord (CCT). It is now considered optional when a well-trained and expert staff is present, otherwise is not recommended. NICE and the International Federation of Gynaecology and Obstetrics (FIGO) support AMTSL, albeit the individual components vary from institution to institution . NICE advises early clamping and early cutting of the cord, whereas massage of the uterine fundus followed by expulsion of the placenta is recommended by FIGO. WHO recent recommendations suggest clamping the cord later (1–3 min after birth) and an intermittent assessment of the uterine tone. AMTSL also requires well-trained health practitioners for this management; the risks of an AMTSL performed by inexpert practitioners, and particularly the CCT, have not yet been studied.
At the moment, oxytocin is the preferred uterotonic for preventing and initially treating PPH caused by uterine atony . However, its efficacy can be limited, and repeated doses might not produce a further effect, probably explained by the desensitisation of the uterine receptors .
The most important side effects of oxytocin are vasodilatation and reflex tachycardia through the calcium-dependent activation of the NO (nitric oxide) pathway. This increases the cardiac output in healthy subjects, but decreases it if the physiological cardiac response is affected as it does in the PPH situation . It must also be remembered that oxytocin has a similar action to ADH and has almost the same chemical structure. Oxytocin must be used with extreme caution in the PPH patient who has not been resuscitated. The German Society of Anaesthesiology and Intensive Care strongly warns against a bolus administration of oxytocin ; the Confidential Enquiry into Maternal and Child Health (CEMACH) recorded a maternal death following the administration of an oxytocin bolus in a hypovolaemic patient . In women with preeclampsia, the cardiovascular effects can be more intense and less predictable, so that oxytocin must be used with specific precautions in these patients .
Some years ago carbetocin, analogous to oxytocin, started to be used in clinical practice. Its main advantage is that its action lasts longer than that of oxytocin (plasma half-life of approximately 40 min vs. under 180 s for oxytocin) [68, 69].
The use of 100 micrograms of carbetocin is the equivalent of oxytocin for PPH prevention with less need for a uterine massage . However, there is no data for the treatment of manifested PH, meaning that this new drug cannot be recommended for it, especially as from a purely mechanistic point of view it shares the ceiling- effect problems and possible haemodynamic side effects of oxytocin.
It should be recalled that this is the only drug with a specific indication for PPH in caesarean sections. If the oxytocin agonists fail as front-line treatment, alternative uterotonics should not be delayed, such as the prostaglandin derivatives now used extensively, especially PGE1 (misoprostol) that can be given in the dose of 800/1,000 mg through the vagina, rectum or sublingual route, which seems to be the most rapid, although not always practicable, route. It is usually the preferred drug in low-resource countries and has limited cardiovascular effects. But it is also extensively used in the majority of protocols in Italy, with few side effects and excellent results. When administered singularly, misoprostol is associated with a higher blood loss than oxytocin [71, 72], but when associated to oxytocin, it seems to have less side effects than other combinations, albeit there is no conclusive data as yet. It has to be remembered that this is an off-label drug, but several regions, including Tuscany, have given specific indications for its use in PPH and medical abortion. Sulprostone, prostaglandin PgE2, has long been used in PPH and can still be considered as an alternative to misoprostol, although with greater side effects and risk (one maternal death by myocardial infarction). Ergot derivatives with less efficacy and greater side effects are also used as second-line uterotonic drugs.
All these drugs can cause side effects and should not be administrated as a bolus. Their combination can cause unpredictable cardiovascular effects, especially if there is continuous bleeding. In many obstetrics departments, the combination of two uterotonic drugs, with the exception of oxytocin-misoprostol, is discouraged. Nevertheless, the fixed combination of oxytocin and ergometrine is available today.
9.7.2 Aetiological Diagnosis of the Haemorrhage and Management of Non-atonic PPH
The treatment of PPH is specific for every cause of bleeding, and an appropriate aetiological management must be developed. The identification of the bleeding source and its subsequent repair can control bleeding from lacerations of the genital tract. If the bleeding is so severe, the formation of the haematoma so rapid or the vaginal tissue so friable that it is impossible to repair, then conservative and mechanical surgery can be entirely justified. The manual removal of the retained placenta is the definitive treatment and should be effected after a gentle attempt on umbilical cord traction compressing the uterus upwards (a manoeuvre only to be carried out by very expert staff), at the same time administering oxytocin IM or IV, but not ergometrine and prostaglandin E2 alpha.
The Cochrane critical review of nine trials suggests that the injection of prostaglandin or plasma expander in the umbilical vein can reduce the need for a manual removal of the placenta, but further research is needed to determine better the effect on the demand for transfusion or uterotonics . Abnormal placentation (placenta accreta, increta and percreta) must be suspected if the manual extraction of the retained placenta is unsuccessful. An antenatal ultrasound scan supplemented by magnetic resonance imaging will minimise maternal and neonatal mortality and morbidity, and it is particularly important for women who have had a previous caesarean delivery. There are less blood losses and minor complications in planned caesarean hysterectomies than in urgent ones, even if overall the risk of PPH is greater in caesarean section compared to the vaginal delivery. Programmed caesareans at 34–35 weeks balance out the increased risks associated with an emergency caesarean at an advanced gestational age, albeit maximising foetal maturity .
An optimal management of the delivery includes antenatal optimisation of the mother’s haemoglobin level, an early anaesthesiologic assessment, the use of graduated compression stockings, the administration of shared prophylactic antibiotics, the execution of preoperative cystoscopy, warning the transfusion centre about a possible massive haemorrhage and the guarantee of having blood products available in the delivery room. When women strongly desire a future fertility, conservative approaches to the management of the placenta accreta must be attempted, such as ligature, suture or embolisation of the uterine artery and the use of methotrexate to accelerate the placental regression. But concrete evidence is lacking for all these methods [75–77].
The rupture of the uterus and uterine inversion are rare, albeit very serious, complications that can lead to a postpartum haemorrhage. The most common aetiology of the uterine rupture is scarring from a caesarean section or other uterine surgery , although it is often caused by a prolonged obstructed labour or the use of herb-based preparations to induce or accelerate delivery in low-resource countries . The rupture can extend upwards towards the uterine fundus, downward towards the bladder or vagina or sideways towards the broad ligaments, thus increasing the risk of substantial haemorrhage and consequent maternal morbidity and mortality. Induced labour is also implicated in the rupture of the uterus, with greater evidence for prostaglandin than for oxytocin .
The American College of Obstetricians and Gynaecologists (ACOG) and the Society of Obstetricians and Gynaecologists of Canada (SOGC) recognise the potential greater risk of the uterus rupturing with induction but recommend its rational use together with appropriate patient counselling. ACOG and RCOG recommend always performing a vaginal delivery after a caesarean (VBAC) in a well-equipped delivery room with a trained staff to guarantee all possible emergency care and assistance. SOGC indicates that laparotomy must be available within 30 min. Signs and symptoms of rupture include abdominal pain and abdominal guarding, vaginal or intra-abdominal bleeding, thoracic pain, foetal deoxygenation, cessation of uterine contractions and palpation of the foetus outside the uterus. But the diagnosis is mainly carried out with cardiotocography, the reason why a continuous CTG is necessary in the event of VBAC. An early detection or the simple suspicion of rupture allows a prompt surgical assessment, foetal delivery and surgical repair of the uterus. Delays in the diagnosis and treatment can result in the death of the foetus and/or the mother.
Uterine inversion can be the result of either an overly forceful traction of the placental cord when the placenta is being expelled, especially when the uterus is not well contracted or spontaneously with a Valsalva manoeuvre . Manually returning the uterus to its proper anatomic position will correct the inversion and the resulting PPH. Tocolytics, halogenated anaesthetics or nitroglycerin can be administered with the purpose of relaxing the uterus and helping it to return to its normal situation. If the inversion resists manual efforts, then surgery can be requested.
Bleeding caused by an inherited or acquired coagulopathy is an uncommon cause of PPH; nevertheless, it should be considered when there is a family history of coagulation defects or a personal history of menorrhagia . More common is the development of DIC, a consumption coagulopathy, caused by a severe PPH. In DIC, the coagulation cascade is activated, and fibrin thrombi are deposited at intravascular level. This process leads to a rapid depletion of the platelets and coagulation factors, and this develops a severe bleeding caused by the body’s incapacity to continue to form coagulates because factors V and VII, the platelets, the prothrombin and the fibrinogen are rapidly consumed. The haemorrhage caused by the depletion of these factors is treated by replacing them and by transfusion of blood products [83, 84].
Treatment of the obstetric population with a fibrinogen concentrate suggests a rapid and efficient treatment of hypofibrinogenaemia without serious side effects. Clinical trials on fibrinogen concentrate conducted on elective and cardiac surgery patients have demonstrated an improvement in the haemostasis and less need for other blood products, although the first randomised controlled trial specifically focussed on PPH is still underway [85–88].
9.7.3 Mechanical Procedures for the Treatment of PPH
The mechanical procedures used to treat PPH from atonic and non-atonic uterus include massage, uterine packing and tamponade. WHO and FIGO strongly recommend the use of uterine massage for the treatment of PPH immediately after diagnosis. WHO no longer recommends uterine packing because of the potential damage it could cause but instead recommends a tamponade with intrauterine balloon (IUB) for atonic PPH that does not respond to uterotonics or when they are not available. The use of the IUB can reduce the need for invasive procedures; however, to date there is no real evidence but only case reports . Uterine balloons such as the Sengstaken tube or Bakri and Rush balloons are available in countries with high economic resources, but their cost is prohibitive (a Foley or a catheter for prostate can also be used) in lower-resource countries.
Any problems that could arise from increased infection rates following the use of the IUB are not today supported in literature but are certainly presumably less than with a vaginal tamponade. The intravaginal tamponade has been suggested for treating vaginal lacerations, but has not yet been adequately explored. The IUB can also be used as a diagnostic instrument to indicate if a laparotomy is necessary. Finally, the use of the IUB with the B-Lynch or other compression sutures is called a “uterine sandwich”; this technique has been successful in avoiding a hysterectomy in all the cases reported with no postpartum morbidity, and it needs further investigation. Chemical agents have also been studied for the PPH tamponade [90–94].
9.7.4 Measures for Gaining Time and Other Procedures for PPH
The recommended measures for gaining time in intractable PPH from atonic or non-atonic uterus include:
External aortic pressure
Double-handed uterine compression
NASG (non pneumatic antishock garment)
External aortic pressure significantly reduces the blood flow to the pelvic organs while the supply of oxygenated blood to the surrounding organs is preserved . It is traditionally performed manually by applying pressure with a closed fist on the abdominal aorta slightly on the patient’s left and immediately above the umbilicus. A recent invention is an external aortic compression device (EACD), comprising a spring compression kept in place by leather belts. The use of EACD has proved useful in significantly reducing the time for the uterine bleeding to cease, although further studies are needed to determine the efficacy of this instrument.
The NASG is a low-technology instrument for the primary resuscitation to be used to stabilise women suffering from hypovolaemic shock secondary to obstetric haemorrhage (OH) . It is a light, reusable garment made of neoprene and Velcro for compressing the lower part of the body. The NASG plays a unique role in haemorrhagic shock treatment by controlling the shock and reducing blood loss, stabilising a woman until definitive care is available. The NASG increases blood pressure by decreasing the vascular volume and raising vascular resistance in the areas of the body submitted to compression, but does not exercise enough pressure to generate tissue ischaemia as in previous instruments. It can be used for obstetric haemorrhages of every aetiology, can be applied by health practitioners with minimum training and does not compete with other PPH treatments. Some experimental studies have shown a significant reduction in blood loss, a quicker recovery from shock and a lower mortality rate [97, 98]. The NASG is recommended as a measure for gaining time in PPH both by WHO and FIGO, and RCOG indicates that the NASG can be useful during transfer to more specialised units and also while waiting for procedures or surgery.
Arterial occlusion and embolisation of the uterine artery are procedures that can prevent a greater loss of blood, avoiding the need for massive blood transfusions and hysterectomy. It is recommended trying them before deciding on surgery, although these procedures can only be performed by a team of expert interventional radiologists. Occlusion is often a prophylaxis for a known placenta accrete, performed by positioning occlusive balloons in the internal iliac and uterine arteries, balloons that are inflated in the case of PPH . If the bleeding continues even after the balloons are inflated, then an embolisation can be performed through the same catheters, positioning microparticles, polyvinyl alcohol, gel foam or spirals that occlude the blood flow to the uterine arteries .
UAE is recommended as an alternative conservative treatment for haemorrhages with multiple aetiologies when the resources to perform it are available. It is not widely used, albeit clinical case studies show high success rates (95 %) and low complication rates (4.5 %) and the evidence, albeit preliminary, of fertility conservation [101, 102]. Some complications have been reported such as uterine necrosis, thromboembolic events or fistula, indicating that these techniques require great experience .
9.7.5 Surgical Treatment of PPH
Should the medical and mechanical treatments of PPH fail, then a surgical exploration is needed . The surgical approach differs according to the method used for delivery, the suspected aetiology and the patient’s clinical state [105, 106].
The surgeon has to decide rapidly if an intervention is necessary. A curettage can be useful in the case of suspected placental residues, the use of a balloon up to a laparotomy (or re-laparotomy after a caesarean section) with exploration and conservative treatments; if these fail, a hysterectomy could be necessary.
The B-Lynch suture is a compression suture, used like braces between the front and rear of the uterus with the aim of promoting its contractibility. It can be an initial attempt to stop the bleeding while trying to preserve fertility. Alternatively, the uterine and internal iliac arteries can be tied bilaterally to diminish temporally the blood flow to the uterus. Whereas the internal iliac artery legation was once more common, the uterine artery legation is now preferred because it is easier to identify and it has higher success rates (80–96 %) [107, 108]. Also to be considered, where possible, is the embolisation of the uterine arteries that can also be used as a prophylaxis, for example, in central placenta previa.
9.7.6 Resuscitation with Fluids and Haemostatic Interventions
There is no doubt that massive transfusion protocols can improve the outcome of patients with massive bleeding [109, 110]. Although these protocols were derived from military medicine and their adoption for PPH ignores some important differences, they are frequently performed for this specific indication and can certainly be useful in severe PPH [83, 101, 111].
A key factor in the protocols of massive transfusions is the fixed ratio of blood products administered, with the aim of avoiding delays in haemostatic resuscitation while waiting for laboratory results. Another factor is that massive transfusion protocols are constructed around local circumstances and local resources. They are usually developed by multidisciplinary teams involving obstetricians, anaesthetists, haematologists, blood bank and transport staff available locally. However, it must be borne in mind that PPH occurs in a context where resuscitation can begin immediately after diagnosis; this is not the case for trauma victims, who could arrive in the emergency room having already lost a great amount of blood and after having had a prolonged resuscitation with crystalloids and colloids.
These events are exactly those which can and must be avoided in PPH , since doubts have arisen about the over triage of massive transfusion protocols . It would be desirable to develop, validate, adopt and strengthen specific transfusion protocols in PPH, because they can help to avoid the most common reason for inadequate care that is an insufficient and delayed administration of blood products . Vigorous, strengthened protocols for PPH emergencies could be defined, with continuous staff training, drills and a scrupulous management of quality that could save many more lives at a lower cost than any other pharmacological intervention.
The main difference between traumatic bleeding and PPH lies in the pregnant woman’s haematological profile compared to that of a trauma victim. PPH occurs in an already activated coagulation system: the coagulation factors have increased in action, fibrinolysis has been activated and the antifibrinolysis damaged; in addition the cross-link between the fibrin monomers has weakened, rendering the fibrin less stable and less resistant to fibrinolysis. The resulting hypercoagulable state followed by hyperfibrinolysis has been interpreted as a chronic low degree of disseminated intravascular coagulation . Other authors have used the term pelvic consumption coagulopathy , suggesting that this latent disorder can rapidly evolve towards a massive DIC and consequently consumption coagulopathy, a frequent early characteristic of PPH. Otherwise, the coagulopathy of trauma victims has been typically described as a dilutional coagulopathy. Early changes in the coagulative state of trauma victims and the significance of these changes have only recently been the subject of specific studies [117, 118]. It is still not clear if acute coagulopathy from trauma can be considered similar to early PPH.
9.7.7 Tranexamic Acid
The D-dimer and fibrinogen degradation product levels are regularly raised during pregnancy and are further increased postpartum because of placental derived PAI-2 (plasminogen activator inhibitor) as a sign of activated fibrinolysis [119, 120]. All this makes therapy with antifibrinolytics, such as tranexamic acid, attractive in PPH situations. There is also convincing clinical evidence for the use of tranexamic acid in bleeding trauma patients and in surgical patients [121, 122].
Current guidelines recommend antifibrinolytic agents for treating trauma . In obstetrics, tranexamic acid is shown to reduce blood loss after a caesarean section in a Cochrane review and in two recent randomised trials [124–126]. But there is little clinical evidence for tranexamic acid as a treatment for manifest PPH . An initial randomised trial on 144 women diagnosed with a blood loss of >di 800 ml has demonstrated that a high dose of tranexamic acid (4 g) can significantly reduce this loss, albeit by only 50 ml . Many other surrogate parameters, such as treatment with first-line uterotonics, were considerably improved. However, the study has not demonstrated significant differences on some major outcomes such as the hysterectomy rate or that of recovery in intensive care.
One problem in using antifibrinolytic agents is the risk of vascular occlusive events, a complication encountered by pregnant women. Aprotinin, another antifibrinolytic, has been withdrawn from sale after a large trial was prematurely halted . A meta-analysis of the data available on thrombotic side effects after the prophylactic use of tranexamic acid has not shown any increase in these effects (no effect is observed in 461 patients included in the meta-analysis) . Another meta-analysis, which included case reports and nonrandomised trials, identified two cases of pulmonary embolism but also established that a causal relationship was not clear .
Ducloy-Bouthors et al.’s study report many vascular occlusive events after the administration of 4 g of tranexamic acid compared to the control group  but always far from statistic significance, although the study did not have the necessary power to evaluate this parameter. In bleeding trauma patients, however, tranexamic acid was found to reduce the risk of vascular occlusive events . The results of a great randomised controlled international trial which enrolled 15,000 parturients, initiated by the CRASH trial collaborative group, will be of great interest but are not available before 2015. Until then, the potential benefits must be weighed against the risk of individual continuous bleeding. Bearing in mind that parturients regularly have an increased fibrinolysis, that the effect of tranexamic acid on blood loss after delivery without PPH has been documented and that there is the strong evidence for using tranexamic acid in bleeding trauma patients and in surgical patients, then it could be appropriate to administer 1 or 2 g of this agent in severe bleeding cases that endanger life even without laboratory evidence of hyperfibrinolysis. A further administration can be decided on the basis of more specific laboratory analyses.
Many authors and WHO’s current guidelines have considered the use of tranexamic acid in severe PPH [65, 131–133], although it is pointed out that there is limited evidence. This endorsement does not mean that tranexamic acid should be used as a routine prevention. In uncomplicated vaginal or caesarean deliveries, such a small blood-saving effect (around 50 ml) and the risk of adverse events encouraged by the induced hypercoagulability of pregnancy have not yet been adequately evaluated .
Fibrinogen levels are usually high in pregnancy at term (average 4.8 g/l vs. 1.8–4 g/l of non-pregnant women) [134, 135] and can decrease with the onset of PPH. During a massive haemorrhage, fibrinogen is one of the first factors to drop under critical values, mainly following the blood loss that depletes the coagulation factors and consumes factors associated with the activation of the coagulation . Laboratory tests show that the clotting process needs an adequate presence of the substrate, i.e. fibrinogen, generally guaranteed by its higher than 1 g/L levels . The progression of PPH is associated with fibrinogenaemia values (<2 g/L) that fall within the normal range in non-pregnant women . In particular, a hypofibrinogenaemia value higher than 4 g/L has a 79 % negative predictive value, while the positive predictive value of a less than 2 g/l concentration is 100 % .
These findings have recently been confirmed  and have ignited an interesting debate about whether this decrease in plasmatic fibrinogen levels plays a pathophysiological role in the development of severe PPH or if it is instead an epiphenomenon of continuous bleeding.
The 2013 guidelines of the European Society of Anaesthesiology for severe postoperative bleeding recommend using a fibrinogen concentrate for significant haemorrhages and for hypofibrinogenaemia (assessed by conventional laboratory tests such as the Clauss test or by thromboelastometry/graphy) .
An indisputable advantage of the fibrinogen concentrate currently on the market is that:
It has undergone a viral inactivation process by pasteurisation.
It has a standard fibrinogen content.
It can be stored at room temperature in delivery rooms as an immediately available resuscitation agent.
Small volumes are sufficient, to be administrated as a bolus to restore fibrinogen levels.
To achieve plasmatic fibrinogen concentrations of 1.5 g/L starting with a 1.3 g/L fibrinogenaemia, 1 g of concentrated fibrinogen in a volume of 50 ml can be used, as well as around 1,250 mL of fresh frozen plasma . But when the fibrinogenaemia target exceeds 1.8 g/L, the quantity of fresh frozen plasma needed grows exponentially until it is impossible to reach this target .
Cryoprecipitate is another potential source of fibrinogen even though the effective fibrinogen content is rather variable and other clotting factors such as VWF, FVIII and FXIII are also present . However, cryoprecipitate is not available in most European countries for the well-known risk of viral transmission . As in the case of tranexamic acid, we have to wait for the results of randomised trials on the use of fibrinogen in PPH. A medium-sized study on women with criteria for “mild” PPH is currently enrolling patients and should be completed in 2013 (clinical trial.gov NCT 1359878). Until the trial data are available, the reasonable approach to fibrinogen and cryoprecipitate would be to keep it available in life-threatening PPH cases, to bypass the logistic constraints of fresh frozen plasma, i.e. its transport and thawing and in case of hypofibrinogenaemia as demonstrated by laboratory tests [86, 114, 138, 139].
In patients with ongoing ascertained hyperfibrinolysis, it is appropriate to administer the antifibrinolysis agent before undertaking a substitute therapy with fibrinogen to avoid the early consumption of this latter. The infusion of HES solutions can also influence fibrinogen laboratory tests. If patients have been treated with HES, it is advisable to raise to 1.5–2 g/l the threshold of the fibrinogen plasmatic concentration under which to supplement with the concentrate .
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9.7.9 Recombinant Activated Human Factor VII
Recombinant activated human factor VII (rhFVIIa) was originally developed for patients with classic haemophilia and haemophiliacs with inhibitor antibodies. Physiologically, factor VII is activated by tissue factor and in turn activates factors IX and X to IX activated. The link of factor VIIa to TF starts the cascade, prompting the activation of the prothrombin to form thrombin and then this latter from fibrinogen to fibrin, thus constructing the clot. In high doses, FVIIa or rhFVIIa directly activates factor X on the surface of the activated platelets, bypassing factors VIII and IX and creating what has been called a “thrombin burst”, generating great quantities of fibrin at the lesion site. The potential of rhFVIIa to reduce blood loss in off-label use for controlling an otherwise uncontrollable bleeding because of its unique action mechanism has generated great expectations . Nonetheless, the recent Cochrane meta-analysis on the therapeutic use of FVIIa, with 11 studies on 2,732 patients suffering continuous bleeding, has not demonstrated any effect on mortality and on control of the bleeding .
In the clinical condition of PPH, some case series and some reports have been encouraging [142–144]. For this type of publication, a substantial bias must always be taken into account, and moreover no controlled trial has yet been published. A randomised trial has been completed in France, but the results are not yet available (NCT 00370877). Many institutions have raised the problem of the increase in thromboembolic complications, but a Cochrane analysis  has not demonstrated any increase in these events in the therapeutic or prophylactic use of rhFVIIa. Despite this, an increase in thromboembolic complications has been observed in over 65-year-old patients. It is unclear how this safety data can apply to PPH because the procoagulant state of a parturient should lead to an increased risk of thromboembolic complications.
At the moment, the majority of specialists, including a panel of experts set up by rhFVIIa manufacturers, only recommend the use of rhFVIIa in some very specific situations [114, 138, 146–148]:
rhFVIIa cannot substitute the proper medical and surgical treatment. In any case, before using it, there must be a definitive diagnosis of the causes of PPH. Practically all cases except for uterine atony without retained foetal tissue must be treated surgically, and rhFVIIa cannot be used. For PPH from uterine atony, after uterotonic agents and properly performed uterine massage, interventions such as balloon tamponade, B-Lynch suture or radiological embolisation of the uterine arteries must be considered (this latter procedure is not however suitable for massive and continuous PPH) .
Before considering rhFVIIa, acidosis and hypothermia must be corrected, and the plasmatic levels of calcium, fibrinogen and platelets must be recovered since not doing so would damage or prevent the effectiveness of rhFVIIa. rhFVIIa is also prone to failure in the presence of continuous arterial bleeding. If these points are addressed promptly and vigorously, the bleeding will stop in the majority of cases before using rhFVIIa; otherwise, rhFVIIa can be used off-label in the attempt to avoid a hysterectomy.
The recommended dose is 90 mcg/kg body weight. If the bleeding continues after 10–20 min, a second dose can be administered. If the bleeding continues even after two doses of rhFVIIa and despite the fact that sufficient levels of calcium, fibrinogen and platelets have been reached, then a hysterectomy cannot be further delayed.
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