Advances in the treatment of postpartum hemorrhage

Postpartum hemorrhage (PPH) is the largest contributor to maternal mortality, occurring in between 1 and 5% of deliveries. Prophylactic uterotonics are widely recommended to prevent atonic hemorrhage. Rapid recognition of PPH and identification of hemorrhage etiology is essential to reduce mortality and morbidity. Treatment is etiology-specific and comprises a range of medical, mechanical, temporizing and surgical procedures. Important developments from trauma and emergency medicine around massive hemorrhage protocols are newly implemented for PPH, and the evidence base for PPH medical management is expanding, with clinical trials ongoing. Improving the management of PPH in limited-resource settings will require continued attention to ensure the availability of low-cost accessible prevention and treatment options, in addition to a focus on skilled care providers. KEYWORDS: emergency obstetric care • hemostatic resuscitation • hypovolemic shock • postpartum hemorrhage Epidemiology Postpartum hemorrhage (PPH) is the leading contributor to maternal mortality globally, responsible for approximately 25% of the nearly 300,000 maternal deaths estimated to occur each year [1, PPH is estimated to occur in between 1 and 5% of deliveries Diagnosis of PPH The majority of PPH occurs without warning; thus, consistent implementation of prevention measures, rapid PPH recognition and prompt identification and treatment of hemorrhage etiology are essential to reduce maternal mortality and morbidity Clinical track and trigger systems including defined threshold values for hemodynamic instability are used to indicate patients at impending risk of an adverse event. The California Maternity Quality Care Collaborative (CMQCC) has proposed designated values for alert and action lines (e.g., heart rate ‡110 bpm, blood pressure (BP) 85/45 mmHg and oxygen saturation <95%), and the UK Confidential Enquiry into Maternal and Child Health (CEMACH) developed an 'Obstetric Early Warning Chart' to alert providers to numeric and visual cues for action, used in the National Health System Timely recognition of PPH through accurate monitoring of blood loss at delivery and postpartum is critical in resourcepoor settings, in particular, but is also useful in the developed world. The gold standard for blood loss estimation, photospectrometry or colorimetric measurement of alkaline hematin, is impractical for many clinical settings Prevention of atonic PPH As uterine atony is the leading cause of PPH, agents that improve uterine tone and increase uterine smooth muscle contractility are most beneficial for overall prevention and treatment of PPH. The WHO recommends prophylactic uterotonic administration during the third stage of labor, with oxytocin (IM/IV, 10 IU) the preferred drug A number of other pharmacologic agents have been evaluated for PPH prophylaxis. Recent literature suggests carbetocin may soon play a greater role in PPH prevention given demonstrated equal efficacy as oxytocin and decreased need for Review El Ayadi, Robinson, Geller & Miller 526 Expert Rev. Obstet. Gynecol. 8(6), (2013) subsequent uterotonic administration at cesarean section, less blood loss and fewer adverse effects than Syntometrine for vaginal deliveries and greater cost-effectiveness over oxytocin among cesarean deliveries Medical management of atonic PPH Pharmacologic management of atonic PPH includes the use of oxytocin, ergometrine and prostaglandins. Intravenous oxytocin is the preferred initial agent in PPH treatment, regardless of whether a prophylactic dose was administered If bleeding proves unresponsive to uterotonics, consideration may be given to tranexamic acid (TXA), a synthetic derivative of lysine with antifibrinolytic properties, or recombinant activated factor VII (rvFIIa), the latter of which is discussed later. A 2010 Cochrane Review of TXA reported decreased blood loss after vaginal and cesarean birth but called for further investigation around efficacy and safety Diagnosis of hemorrhage etiology & management of non-atonic PPH Treatment of PPH is specific to cause of bleeding, and appropriate etiologic management must be implemented. Identification of bleeding source and subsequent repair can rectify bleeding attributable to genital tract lacerations Manual removal of retained placenta is the definitive treatment, and should be performed after attempting gentle CCT with counter pressure upwards on the uterus (skilled provider only), and administration of IM or IV oxytocin but avoidance of ergometrine and prostaglandin E2 alpha (dinoprostone or sulprostone) Abnormal placentation (i.e., placenta accreta, increta, and percreta) should be suspected if manual extraction of retained placenta is unsuccessful. Antenatal diagnosis via ultrasonography, supplemented by magnetic resonance imagery (MRI), will minimize maternal and neonatal mortality and morbidity and is particularly important among women with prior cesarean section Uterine rupture and uterine inversion are rare yet serious obstetrical complications, which may result in PPH. The most common etiology of uterine rupture is a prior uterine scar from a cesarean section or other uterine surgery Bleeding due to inherited or acquired coagulopathy is an uncommon cause of PPH; however, it should be considered with a family history of bleeding defects or personal history of menorrhagia Mechanical procedures for PPH management Mechanical procedures used to treat atonic and non-atonic PPH include uterine massage, uterine packing and tamponade Temporizing measures & other procedures for PPH Temporizing measures recommended for intractable atonic and non-atonic PPH include external aortic compression, bimanual uterine compression and the non-pneumatic anti-shock garment (NASG) The NASG El Ayadi, Robinson, Geller & Miller 528 Expert Rev. Obstet. Gynecol. 8(6), Arterial balloon occlusion and UAE are procedures that can prevent major blood loss, obviating the need for blood transfusion and hysterectomy, and are recommended for trial prior to surgical intervention Surgical management of PPH Failed medical and mechanical approaches to management of PPH warrant surgical exploration Placement of uterine compression sutures in a suspender fashion to promote uterine contractility may be a useful initial attempt at bleeding cessation while preserving fertility. Similar to manual compression and balloon tamponade, compression sutures should be used as a first step in surgical management when hemorrhage is a result of atony. This technique, referred to as a B-Lynch procedure or Cho suture if a hysterotomy has been performed (delivery via cesarean section) and Hayman suture in the absence of a hysterotomy (vaginal delivery), is technically less challenging than vessel ligation and results in less morbidity than a hysterectomy While the aforementioned surgical procedures are often attempted in succession, combining surgical techniques may maximize hemostasis while maintaining fertility. Shahin et al. combined compression sutures and uterine artery ligation on patients with atonic PPH secondary to adherent placenta accreta Transfusion protocols for PPH The WHO recommends that health facilities have a formal protocol in place for PPH management Treatment of postpartum hemorrhage Review www.expert-reviews.com 529 algorithms of PPH are modeled after trauma, and massive transfusion protocols demonstrate improved patient outcomes The fibrinogen decrease seen in severe PPH is of great concern and considered an early predictor of hemorrhage severity Rapid blood product selection may benefit from the use of a thromboelastograph, a point-of-care device that examines clot formation and dissolution in whole blood, and provides faster results than laboratory testing In obstetrical practice, as in other surgical specialties, patients may refuse transfusion of blood products. Worldwide, members of the Jehovah's Witness faith most commonly decline blood transfusions, even for life-saving purposes, posing unique challenges rFVIIa is an effective, yet expensive, synthetic agent initially FDA-approved to control bleeding among patients with hemophilia and factor VII deficiency and is now used for trauma, surgical and severe PPH patients Staying prepared Ensuring that obstetric care providers are adequately prepared for handling hemorrhagic emergencies should be accomplished through high quality medical, nursing and midwifery education, with ample opportunities to practice managing rare events and by verifying that all tools and materials required for PPH intervention are readily available. It is also important that standardized protocols and/or guidelines be adopted and monitored to ensure that facility-level practices are evidence-based. The California Maternal Quality Care Collaborative (CMQCC) established evidence-based guidelines in 2010 to improve the treatment of OH by both identifying women who may be at higher risk of developing OH and producing a set of best practice steps to guide clinicians through OH management, beginning with prenatal assessment and planning through severe OH presentation Review El Ayadi, Robinson, Geller & Miller 530 Expert Rev. Obstet. Gynecol. 8(6), Simulation-based team training (drills) to ensure preparedness for obstetric emergencies can be used to train providers to be prepared for clinical situations, which are infrequent but that have a high potential for morbidity or mortality, such as PPH. Obstetric emergencies are characterized by significant time challenges and the need to manage both mother and child simultaneously. Drills allow for the identification of system weaknesses and strengths, provide the opportunity to test policies and procedures for hemorrhage management and help improve teamwork among staff. RCTs of teamwork training via simulation for acute obstetric situations report increases in knowledge, practical skills, communication and team performance; but have not adequately assessed effectiveness on maternal and neonatal outcomes A number of international and national organizations such as WHO, FIGO, CMQCC, RCOG and ACOG have developed and distributed updated guidelines for the management of PPH over the past few years Particular concerns in the developing world A major challenge to reducing the global burden of PPH is the failure to prevent PPH or rapidly connect patients to treatment in low-resource settings. A series of delays in receiving definitive PPH treatment is associated with much higher mortality rates in such settings. Long transport times from communities or primary healthcare facilities, lack of transport or fuel, shortage of skilled providers and lack of basic medical supplies (e.g., medications, intravenous fluids, safe blood) contribute to these delays. Strategies to reduce PPH in low-resource areas must emphasize communitylevel prevention and first-aid while broadly improving healthcare capacity and access, and will benefit from novel methods designed to overcome the specific challenges of this clinical context Prenatal evaluation of anemia is important globally; however, diagnosis and treatment of nutritional factors, hemoglobinopathy, malaria and helminth infection is even more important in low-resource countries due to the higher burden of anemia among this population Despite the fact that oxytocin is the recommended uterotonic for prevention and treatment of PPH, its availability in the developing world is limited due to the requirement for temperatureregulated storage and administration by skilled health provider. The WHO supports oral misoprostol (600 mg) for PPH prevention by community and lay health workers in resource-limited settings where oxytocin use is not feasible Development of oxytocin in modes that can surmount lowresource delivery challenges in underway. Oxytocin in a Uniject system, an easy-to-use single-dose injection format, was considered safe and feasible for active management of the third stage of labor in Guatemala and Mali pilot evaluations Community mobilization and engagement strategies play an important role in improving the success of PPH-prevention programs. Greater community ownership and support of projects has been achieved by establishing rapport with key opinion leaders, and involving community members in the design and implementation of project activities Several low-cost strategies have been devised to improve accurate blood loss estimation in low-resource settings Given the long delays women in low-resource settings often face obtaining transport, during transport and awaiting definitive treatment, the NASG described previously is particularly suited to these settings (FIGURE 4). A cluster randomized trial of the NASG applied at the primary healthcare level prior to transfer to the RH was recently completed and suggested a promising trend for mortality reduction. The NASG has been recommended as a temporizing measure for PPH by the WHO and FIGO, and is cost effective While the IUB devices currently available are prohibitively expensive for use in low-resource areas, PATH is working to develop an affordable dedicated balloon tamponade Finally, one of the largest contributors to PPH and other causes of maternal mortality and morbidity in low-resource settings is the lack of skilled healthcare providers Conclusion Broad global access to oxytocin, other uterotonics and oral misoprostol for PPH prevention and treatment is an important strategy to reduce PPH-related mortality. Continued institutionalization of PPH management protocols, and simulation efforts will help ensure preparedness for obstetric emergencies when they occur. Higher FFP to RBC ratios are suggested within resuscitation guidelines for better patient outcomes. Research in progress will inform optimal transfusion protocols, and use of TXA and fibrinogen concentrate for the PPH patient. Low-resource areas must focus on development of health workers and task-shifting. Expert commentary The evidence base around PPH prevention and treatment has rapidly expanded over the past decade. Randomized trials evaluating the effectiveness of TXA and fibrinogen concentrate are underway and should provide strengthened treatment guidance over the next few years. The field has benefited from focused efforts on the development of lower cost methods to improve blood loss estimation and temporizing measures targeted for use in low-resource settings such as anti-shock garments. Hemorrhage preparedness through drills and standardized hemorrhage management guidelines are among the most promising measures for PPH. Algorithms for hypovolemic shock resuscitation have benefited from trauma research, and massive transfusion protocols are now being implemented on obstetric wards. These steps improve patient care and prevent severe anemia and coagulopathy. Broader implementation of higher FFP to RBC transfusion ratios (1:1 or Review El Ayadi, Robinson, Geller & Miller 532 Expert Rev. Obstet. Gynecol. 8(6), While adequate therapeutic options are available for PPH in developed countries, reducing the global burden of PPH requires focused attention on prevention, early identification and access to care. However, delays in making the decision to seek medical care, reaching a facility where care is available and in obtaining quality care at the facility are all significant contributors to preventable maternal death in low-resource settings. Five-year view Contemporary resuscitation approaches for PPH are not evidencebased, and recent research suggests that while volume resuscitation followed by RBC transfusion corrects hypovolemia, this approach worsens dilutional coagulopathy and enhances fibrinolysis, leading to poor patient outcomes. Trauma literature reports improved outcomes with increased FFP to RBC ratios, and research is underway to improve the evidence base for defining optimal blood transfusion protocols, particularly among the obstetric population. Mass transfusion protocols are beginning to be developed in the community hospital setting, which will improve treatment capacity and patient outcomes in these settings. Similarly, more rapid selection of blood products, normally a multi-hour process, is enabled by a greater capacity of point-of-care monitoring via thromboelastometry-based machines housed in the labor ward. Randomized trials are currently ongoing around the administration and timing of fibrinogen concentrate, and the role of TXA for PPH. Results will be available within the next few years and will provide valuable guidance for including these agents in broad recommendations for treatment of PPH. Greater attention is being paid to the development and implementation of low-cost health technologies to improve access to medical and first-aid devices in low-resource areas such as an IUB and the NASG, and low-technology blood pressure devices designed to trigger the process for referral by community health workers. Medical education focusing on improving obstetrics and gynecology trainee knowledge and incorporating PPH teaching and drills into residency, nursing and midwifery curricula will improve provider and team preparedness for managing PPH. Greater use of obstetric warning systems and more precise identification of warning thresholds such as the shock index to trigger focused medical attention should expand across facilities. Similarly, evidence-based algorithms have recently been developed for risk prediction of PPH; there may be a future role for individualized medicine, including risk assessment and practice of anticipatory medicine in this field, though the evidence base is undeveloped. Globally, task shifting for maternal health functions is necessary to improve broad access to lifesaving technologies. Emphasis on training to improve the capacity and effectiveness of non-clinicians and non-physician clinicians is crucial

Beyond too little, too late and too much, too soon: a pathway towards evidence-based, respectful maternity care worldwide.

On the continuum of maternal health care, two extreme situations exist: too little, too late (TLTL) and too much, too soon (TMTS). TLTL describes care with inadequate resources, below evidence-based standards, or care withheld or unavailable until too late to help. TLTL is an underlying problem associated with high maternal mortality and morbidity. TMTS describes the routine over-medicalisation of normal pregnancy and birth. TMTS includes unnecessary use of non-evidence-based interventions, as well as use of interventions that can be life saving when used appropriately, but harmful when applied routinely or overused. As facility births increase, so does the recognition that TMTS causes harm and increases health costs, and often concentrates disrespect and abuse. Although TMTS is typically ascribed to high-income countries and TLTL to low-income and middle-income ones, social and health inequities mean these extremes coexist in many countries. A global approach to quality and equitable maternal health, supporting the implementation of respectful, evidence-based care for all, is urgently needed. We present a systematic review of evidence-based clinical practice guidelines for routine antenatal, intrapartum, and postnatal care, categorising them as recommended, recommended only for clinical indications, and not recommended. We also present prevalence data from middle-income countries for specific clinical practices, which demonstrate TLTL and increasing TMTS. Health-care providers and health systems need to ensure that all women receive high-quality, evidence-based, equitable and respectful care. The right amount of care needs to be offered at the right time, and delivered in a manner that respects, protects, and promotes human rights