- Email: [email protected]
Patient blood management in obstetrics – Review
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Review
Patient blood management in obstetrics – Review Jarmila A. Zdanowicz, Daniel Surbek
⁎
Department of Obstetrics and Gynecology, Bern University Hospital, University of Bern, Bern, Switzerland
A R T I C LE I N FO
A B S T R A C T
Keywords: Obstetrics Patient blood management Postpartum hemorrhage Red blood cell transfusion
Patient blood management (PBM) aims to reduce red blood cell transfusion, minimize preoperative anemia, reduce intraoperative blood loss as well as optimize hemostasis, and individually manage postoperative anemia. Benefits include improved clinical outcome with a reduction in patient morbidity and mortality, but also lower hospital costs and shorter hospital length of stay. To date, it has been successfully implemented in several medical specialties, such as cardiac, trauma and orthopedic surgery. In obstetrics, postpartum hemorrhage (PPH) is one of the leading causes of maternal mortality. PBM has the potential to improve outcome of mother and child. However, pregnancy and childbirth pose a special challenge to PBM, and several adaptations compared to PBM in elective surgery are necessary. To date, awareness of the clinical advantages of PBM among obstetricians and midwifes regarding PBM and its concept in PPH is limited. In the following review, we therefore aim to present the current status quo in PBM in obstetrics and its challenges in the clinical routine.
1. Definition of patient blood management (PBM) While allogenic blood transfusion has been viewed as a valid treatment for blood loss for a long time, adequate and prepared pre-, peri- and postoperative management is now emerging for uncomplicated elective surgeries in several medical specialties, summarized as patient blood management [1]. In general, PBM aims to minimize blood loss by maintaining adequate hemoglobin levels, reduce allogenic blood transfusion while at the same time optimizing patient care and outcome [1]. To this end, PBM is based on a so-called three pillar matrix for successful implementation: First, identification and treatment of anemia and low hemoglobin levels, furthermore, reducing (perioperative) blood loss and optimizing hemostasis, and finally, avoiding red blood cell (RBC) transfusions by tolerating individual anemia to a certain justifiable extent [1,2]. Successful PBM has been shown to reduce perioperative blood loss, lower transfusion rates, reduce perioperative morbidity and mortality, and cut hospital length of stay and costs [3–5]. A trigger for PBM has been the realization that RBC transfusions are associated with an increased morbidity and mortality, longer hospital length of stay as well as higher risk for admission to the intensive care unit [1]. In addition, transfusion risks include but are not limited to transmission of infections, hemolytic transfusion reactions, transfusionassociated circulatory overload, transfusion associated acute lung
injury and transfusion-related immunomodulation [6,7]. Furthermore, studies have shown that patients with restrictive RBC administration, such as Jehovah’s witnesses, have better clinical outcomes [1]. In other medical specialties, where elective surgeries are common, PBM has been already successfully established, including in cardiac surgery, trauma surgery and orthopedic surgery [5,8,9]. 2. Current approach to PBM in obstetrics In obstetrics, postpartum hemorrhage (PPH) is defined as a blood loss of 500 ml or more after vaginal birth, and 1000 ml or more after cesarean section within 24 h postpartum [10]. PPH is one of the main causes for 75% of maternal mortality according to the World Health Organization (WHO) [11,12]. Hence, implementing PBM in obstetrics potentially benefits mother and child. However, data on PBM in obstetrics has not been researched as well as in other medical specialties. Risk factors that lead to PPH have been studied extensively, the most common ones being uterine atony, anemia, trauma, placental pathologies and coagulopathies [13]. Yet, most women experiencing a PPH have no known risk factors. Risk factors and causes for PPH are summarized in Table 1. Guidelines have been established in several countries dealing with prevention and treatment of PPH, yet these recommendations across national guidelines are not always consistent [14]. To date, Australia has been one of the few countries that has
⁎ Corresponding author at: Department of Obstetrics and Gynecology, Bern University Hospital, Theodor-Kocher-Haus, Friedbühlstrasse 19, 3010 Bern, Switzerland. E-mail address: [email protected] (D. Surbek).
https://doi.org/10.1016/j.transci.2019.06.017
1473-0502/ © 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: Jarmila A. Zdanowicz and Daniel Surbek, Transfusion and Apheresis Science, https://doi.org/10.1016/j.transci.2019.06.017
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
J.A. Zdanowicz and D. Surbek
successfully and extensively implemented a program for PBM in obstetrics, while elsewhere new guidelines are slowly being established [7,15]. In obstetrics, a three pillar matrix for PBM includes identification of women at risk during pregnancy, minimizing acute peripartal blood loss and tolerating postpartum anemia.
the UK National Institute for Health Care and Excellence (NICE) recommend a cutoff hemoglobin value below 110 g/l in the first trimester and below 105 g/l in in the second trimester to define anemia [19–22]. The main cause for anemia in pregnancy is iron deficiency [23]. Due to the changes in blood circulation, the iron need for pregnant women is also different from that of non-pregnant women, while a majority of women already have an iron deficiency going into the pregnancy [24]. It has been estimated that the additional iron need of a pregnant woman is approximately 1 g [24]. NICE guidelines recommend hemoglobin screening in early pregnancy as well as at 28 weeks of gestation [22]. Current guidelines in Switzerland recommend testing the hemoglobin level at least once per trimester, while additionally analyzing the ferritin level in the first trimester [19]. Here, a cutoff level below 30 ng/ml for serum ferritin has been recommended in pregnancy for diagnosis of iron deficiency [21]. As ferritin is an acute phase protein, CRP (C-reactive protein) should always be analyzed at the same time to exclude an elevated ferritin level due to infection. It is important to diagnose if an existing anemia is caused by iron deficiency and can be treated as such. Iron deficiency anemia can lead to preterm birth, reduce neonatal birth weight, and lead to neonatal iron deficiency as well [7,19]. In women at risk for hemoglobinopathies (such as thalassemia or sickle cell anemia), further blood tests should be performed [7]. This might include a full blood count, mean red cell volume (MCV) as well as additional parameters to detect vitamin B12 or folate deficiency or reticulocyte count [7]. To prevent anemia, treatment with 30–60 mg of elemental iron per day is advised. Oral iron substitution is recommended for anemia with a hemoglobin level above 80 g/l, with a dose of 80–100 mg per day [7]. In case of normal hemoglobin with ferritin levels below 30 ng/ml treatment is also recommended, with a dose of 30–60 mg per day [19,21]. As oral substitution can have some unwanted side effects, most commonly gastrointestinal toxicity, intravenous iron administration is a valid alternative [7]. Further indications for intravenous iron administration might be inadequate increase in hemoglobin after oral substitution, advanced gestational age combined with low hemoglobin levels as well advanced anemia with a hemoglobin level below 80 g/l [18,19]. In addition to RBC and blood volume, there are several changes in clotting mechanisms during pregnancy. Levels of clotting factors VII, VIII, IX, X and XII are increased, as well as fibrinogen levels and von Willebrand factor, leading to a hypercoagulability in pregnancy [17]. At the same time, factor XI and protein S decreases, while prothrombin, protein C and factor V levels stay the same. With plasminogen activator inhibitor levels of PAI-1 and PAI-2 increased, overall fibrinolysis is decreased in pregnancy. While this provides the advantage of minimizing blood loss during delivery, it also leads to a higher risk for thromboembolic events during pregnancy and in the puerperal period [25].
3. Blood circulation and anemia in pregnancy
4. Peripartum management
In pregnancy, blood circulation is adapted for mother and fetus in order to provide an optimized uteroplacental circulation and aims to minimize the effects of blood loss during delivery. The circulating blood volume is increased by 40–45%, while erythropoiesis is enhanced as well [16]. Consequently, plasma volume and red blood cell mass are increased, effectively leading to a hemodilution and physiological anemia. An anemia plateau is reached around 30–32 weeks of gestation [17]. Hence, classification of anemia during pregnancy differs from non-pregnant women, however, a consensus on an exact definition is lacking. According to the WHO, anemia during pregnancy is defined as a hemoglobin level below 110 g/l [18], irrespective of how advanced the pregnancy is. Anemia is further classified into mild (100–109 g/l), moderate (70–99 g/l) and severe (< 70 g/l) [18]. Swiss guidelines, the American College of Obstetricians and Gynecologists (ACOG) as well as
During excessive active bleeding (as defined above) within 24 h of giving birth, several strategies exist to deal with PPH and its underlying causes. Actual blood loss during delivery is often underestimated, particular in vaginal delivery. Treatment is based on birth mode as well on bleeding causes, categorized into “four T’s”: tone (uterine atony), trauma (vaginal laceration, uterine rupture or inversion), tissue (retained placental tissue, clots) and thrombin (coagulopathy). Guidelines for peripartum management vary across national societies [14,26–29]. There is a general agreement that women with placental pathologies such as placenta previa or placenta increta are at a much higher risk for PPH and should be advised to deliver in a tertiary center. First-line treatment includes all mechanical and medicinal treatment. Mechanical interventions include uterine massages to stimulate
Table 1 Risk factors for postpartum hemorrhage (PPH) [13,52]. Uterine Atony (Tone) - Multiparity - Multiple pregnancy - Previous postpartum hemorrhage - Age > 40 years, BMI> 35 kg/ m2 - Asian ethnicity - Placenta previa - Prolonged labor Trauma/Surgery (Trauma) - Perineal or vaginal trauma - Cesarean delivery - Instrumental vaginal delivery - Uterine rupture
Coagulopathy (Thrombin) - Congenital bleeding disorders - Acquired coagulopathies - Anticoagulants - Placental abruption - Pre-eclampsia - Sepsis - Amniotic fluid embolism
Placenta (Tissue) - Retained placenta - Morbidly adherent placenta accreta, increta, percreta - Placental abruption - Placenta previa
Other - Anemia - Antepartum bleeding - Chorioamnionitis - Nicotine and cocaine abuse - Macrosomia - Laceration of birth canal - Preexisting chronic disease - Dead fetus - Uterine fibroma - Medically induced abortion
Table 2 Specific patient blood management in obstetrics. PBM Antepartum
Peripartum
Postpartum
-
Periodic check of hemoglobin and ferritin levels Anemia and iron deficiency treatment Identification of risk factors for postpartum hemorrhage Planned birth for women at risk Evaluation of hemostasis Administration of oxytocin and tranexamic acid Mechanical and surgical treatment Uterine artery embolization Use of cell saver Transfusion of blood and blood products Individual evaluation Hemoglobin levels after acute phase Iron administration Restrictive transfusion of blood products
2
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4.7. Recombinant activated factor VIII (rhFVIIa)
uterine contractions in cases of uterine atony, which is the most frequent cause of PPH [30]. Medicinal treatment includes uterotonics (such as oxytocin and prostaglandins) and pro-coagulants (like fibrinogen, tranexamic acid or fresh frozen plasma).
RhFVIIa (Novo Seven®) should only be administered in cases of severe bleeding if surgical treatment fails and is not considered routine use in PPH [34].
4.1. Oxytocin and prostaglandins
5. Surgical management
Oxytocin, or alternatively carbetocin, is recommended across guidelines as the first-line medication of choice to prevent PPH. It can be administered intravenously (usually 5–10 IU) as well as intramuscularly, with the effect setting in after only a few minutes [30]. Additionally, a continuous intravenous infusion (20–40 IU in 500–1000 L at a rate of 125–150 ml/h) can be applied [14,30]. If bleeding persists, further treatment with prostaglandins or its derivatives are recommended, for example, misoprostol administered at 800 μg vaginally or rectally [26,30]. If this fails, sulprostone intravenously (a maximum of 1500 μg/24 h) can be given [26].
Especially for PPH caused by an atony of the lower uterine segment, balloon tamponades are available as a second-line therapy [13]. There are several different balloon systems available, including Bakri balloon, Foley catheter, or Sengstaken tube [39]. For example, the Bakri balloon is slowly filled with liquid, hence applying pressure to the uterine wall to stop bleeding [40,41]. Further surgical interventions include uterine compression sutures that are placed throughout the uterus for compression of the atony site. The most commonly used are B-Lynch sutures, as well as suture techniques by Hayman and Cho [42–44]. Possible complications include uterine adhesions (synechiae), necrosis and pyometra [45]. Vascular ligation of arteries, usually of uterine, ovarian, or internal iliac arteries, aims to reduce blood flow to the uterus and can be also used as a supporting measure when bleeding persists following a hysterectomy [46]. In addition, pelvic artery embolization of uterine or internal iliac arteries can be performed, which is usually done in the interventional radiology unit and can also effectively stop PPH [47]. If all previously described measures fail, peripartum hysterectomy is the last resort for treatment [46]. As it is associated with a high morbidity and mortality, it should only be performed by an experienced surgeon [48].
4.2. Tranexamic acid Tranexamic acid is an anti-fibrinolytic drug that has been shown to prevent blood loss in surgery by approximately one third. When administered within three hours after onset of bleeding, it also reduces death from bleeding [31,32]. Currently, in obstetrics, the administration of tranexamic acid has not been among the first-line treatment options [26]. However, recently, the early and prophylactic use of tranexamic acid (1–2 g) along with administration of uterotonics has been shown to benefit women with PPH as soon as more than a normal peripartum bleeding occurs [33,34].
6. Postpartum management 4.3. RBC administration After delivery, detection and treatment of anemia is equally important. Swiss guidelines recommend determination of hemoglobin levels at 48 h postpartum, unless other reasons for an earlier blood analysis are present. Postpartum anemia is defined as a hemoglobin level < 120 g/l, while a significant anemia is defined at a level below 110 g/l [19]. Another definition is a hemoglobin level below 110 g/l one week after delivery and below 120 g/l at eight weeks after delivery [7]. Postpartum anemia might lead to several health constraints, such as an increased risk for infections, reduced lactation, reduced cognitive ability and emotional stability as well as fatigue and dyspnea [49]. Low iron concentration in the postpartum period seems to be associated with an increased risk for postpartum depression and fatigue [50,51]. Treatment for postpartum anemia with a hemoglobin level of 90–110 g/l should occur with oral elemental iron at 80–100 mg per day for at least three months. Intravenous iron should be administered with severe anemia below 90 g/l with relevant clinical symptoms [36]. The threshold for RBC transfusion is between 65–70 g/l, however, this also depends on the clinical outcome of the patient and should be administered restrictively [36].
Administration of RBC should be carried out cautiously and restrictively and there is no clear hemoglobin cut-off value as to when RBC transfusion is required. A hemoglobin level below 60 g/l seems a reasonable cutoff below which RBC administration should be performed, provided that there is no active bleeding [35]. However, in the case of active and severe bleeding, a hemodynamically instable patient will clearly benefit from a RBC transfusion, irrespective of hemoglobin level [36]. 4.4. Cell saver Cell saver, that is intraoperative blood salvage or homologous blood transfusion, has been described as an alternative treatment to RBC administration. However, it is not routinely used in obstetrics and few studies exist, although no major complications have been described to date [37]. 4.5. Fibrinogen Fibrinogen is crucial for coagulation and its level is the most sensitive indicator for hemostasis imbalance and severity of PPH. Hypofibrinogenemia (< 1 g/L) can be treated with administration of fresh frozen platelets (FFP) as well as fibrinogen concentrate [34]. Administration of fibrinogen has been shown to reduce bleeding and the need for RBC transfusions [38].
7. Conclusion PPH is one of the leading causes for maternal mortality. There are several strategies and different national guidelines for dealing with PPH in the obstetric field. However, successful PBM strategies aimed at systematically reducing peripartum blood loss are still lacking. In order to reach this goal, a multidisciplinary approach is needed involving obstetricians, anesthesiologists, transfusion medicine specialists and radiologists. As pregnancy is a physiologically different entity regarding hemostasis and its management, particular attention should be paid to this patient cohort. Furthermore, since pregnant women are consistently cared for throughout their pregnancy, this provides an unique
4.6. Fresh frozen plasma (FFP) The Royal College of Obstetricians and Gynaecologists (RCOG) recommends administration of FFP for persistent PPH combined with prolonged prothrombin time or activated partial thromboplastin time. Four units of FFP are recommended for every four units of RBC [35]. 3
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opportunity to successfully implement the three pillars of PBM, as presented in Table 2. Identification of women at risk for PPH and treating anemia during pregnancy, early treatment of peripartum blood loss with tranexamic acid, for example, and iron supplementation in the postpartum period are possible steps for a systematic and effective PBM. This will ultimately lead to an improved clinical outcome and increased patient safety, while at the same time reducing health care costs – a benefit for everyone.
[25] ACOG practice bulletin No. 196: thromboembolism in pregnancy. Obstet Gynecol 2018;132:e1–17. [26] Schlembach D, Mortl MG, Girard T, Arzt W, Beinder E, Brezinka C, et al. [Management of postpartum hemorrhage (PPH): algorithm of the interdisciplinary D-A-CH consensus group PPH (Germany - Austria - Switzerland)]. Der Anaesthesist 2014;63:234–42. [27] ACOG Practice Bulletin: Clinical Management Guidelines for ObstetricianGynecologists Number 76, October 2006: postpartum hemorrhage. Obstet Gynecol 2006;108:1039–47. [28] Active management of the third stage of labour: prevention and treatment of postpartum hemorrhage: No. 235 October 2009 (replaces No. 88, April 2000). Int J Gynaecol Obstet 2010;108:258–67. [29] Management of postpartum hemorrhage. Royal Australian and New Zealand College of Obstetricians and Gynaecologists; 2016. [30] Mousa HA, Blum J, Abou El Senoun G, Shakur H, Alfirevic Z. Treatment for primary postpartum haemorrhage. Cochrane Database Syst Rev 2014:Cd003249. [31] Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. BMJ (Clinical research ed) 2012;344:e3054. [32] Roberts I, Shakur H, Afolabi A, Brohi K, Coats T, Dewan Y, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet (London, England) 2011;377. 1096-101, 101.e1-2. [33] Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet (London, England) 2017;389:2105–16. [34] Ekelund K, Hanke G, Stensballe J, Wikkelsoe A, Albrechtsen CK, Afshari A. Hemostatic resuscitation in postpartum hemorrhage - a supplement to surgery. Acta Obstet Gynecol Scand 2015;94:680–92. [35] Prevention and management of postpartum haemorrhage: green-top guideline No. 52. BJOG 2017;124:e106–49. [36] Milman N. Postpartum anemia II: prevention and treatment. Ann Hematol 2012;91:143–54. [37] Practice bulletin No. 183: postpartum hemorrhage. Obstet Gynecol 2017;130:e168–86. [38] Rahe-Meyer N, Hanke A, Schmidt DS, Hagl C, Pichlmaier M. Fibrinogen concentrate reduces intraoperative bleeding when used as first-line hemostatic therapy during major aortic replacement surgery: results from a randomized, placebo-controlled trial. J Thorac Cardiovasc Surg 2013;145:S178–85. [39] Johanson R, Kumar M, Obhrai M, Young P. Management of massive postpartum haemorrhage: use of a hydrostatic balloon catheter to avoid laparotomy. BJOG 2001;108:420–2. [40] Bakri YN, Amri A, Abdul Jabbar F. Tamponade-balloon for obstetrical bleeding. Int J Gynaecol Obstet 2001;74:139–42. [41] Maher MA, Abdelaziz A. Comparison between two management protocols for postpartum hemorrhage during cesarean section in placenta previa: balloon protocol versus non-balloon protocol. J Obstet Gynaecol Res 2017;43:447–55. [42] Allam MS, C BL. The B-Lynch and other uterine compression suture techniques. Int J Gynaecol Obstet 2005;89:236–41. [43] Hayman RG, Arulkumaran S, Steer PJ. Uterine compression sutures: surgical management of postpartum hemorrhage. Obstet Gynecol 2002;99:502–6. [44] Cho JH, Jun HS, Lee CN. Hemostatic suturing technique for uterine bleeding during cesarean delivery. Obstet Gynecol 2000;96:129–31. [45] Matsubara S, Yano H, Ohkuchi A, Kuwata T, Usui R, Suzuki M. Uterine compression sutures for postpartum hemorrhage: an overview. Acta Obstet Gynecol Scand 2013;92:378–85. [46] Rani PR, Begum J. Recent advances in the management of major postpartum haemorrhage - a review. J Clin Diagn Res 2017;11. Qe01-qe5. [47] Spreu A, Abgottspon F, Baumann MU, Kettenbach J, Surbek D. Efficacy of pelvic artery embolisation for severe postpartum hemorrhage. Arch Gynecol Obstet 2017;296:1117–24. [48] van den Akker T, Brobbel C, Dekkers OM, Bloemenkamp KW. Prevalence, indications, risk indicators, and outcomes of emergency peripartum hysterectomy worldwide: a systematic review and meta-analysis. Obstet Gynecol 2016;128:1281–94. [49] Bergmann RL, Richter R, Bergmann KE, Dudenhausen JW. Prevalence and risk factors for early postpartum anemia. Eur J Obstet Gynecol Reprod Biol 2010;150:126–31. [50] Albacar G, Sans T, Martin-Santos R, Garcia-Esteve L, Guillamat R, Sanjuan J, et al. An association between plasma ferritin concentrations measured 48 h after delivery and postpartum depression. J Affect Disord 2011;131:136–42. [51] Holm C. Intravenous iron treatment in the puerperium. Dan Med J 2018;65. [52] Hofmeyr GJ, Qureshi Z. Preventing deaths due to haemorrhage. Best Pract Res Clin Obstet Gynaecol 2016;36:68–82.
References [1] Isbister JP. The three-pillar matrix of patient blood management–an overview. Best Pract Res Clin Anaesthesiol 2013;27:69–84. [2] Gombotz H. Patient blood management: a patient-orientated approach to blood replacement with the goal of reducing Anemia, blood loss and the need for blood transfusion in elective surgery. Transfus Med Hemother 2012;39:67–72. [3] Goodnough LT, Maggio P, Hadhazy E, Shieh L, Hernandez-Boussard T, Khari P, et al. Restrictive blood transfusion practices are associated with improved patient outcomes. Transfusion 2014;54:2753–9. [4] Moskowitz DM, McCullough JN, Shander A, Klein JJ, Bodian CA, Goldweit RS, et al. The impact of blood conservation on outcomes in cardiac surgery: is it safe and effective? Ann Thorac Surg 2010;90:451–8. [5] Gross I, Seifert B, Hofmann A, Spahn DR. Patient blood management in cardiac surgery results in fewer transfusions and better outcome. Transfusion 2015;55:1075–81. [6] Waters JH. Patient blood management in obstetrics. Int Anesthesiol Clin 2014;52:85–100. [7] Munoz M, Pena-Rosas JP, Robinson S, Milman N, Holzgreve W, Breymann C, et al. Patient blood management in obstetrics: management of anaemia and haematinic deficiencies in pregnancy and in the post-partum period: NATA consensus statement. Transfus Med (Oxford, England) 2018;28:22–39. [8] Rineau E, Chaudet A, Chassier C, Bizot P, Lasocki S. Implementing a blood management protocol during the entire perioperative period allows a reduction in transfusion rate in major orthopedic surgery: a before-after study. Transfusion 2016;56:673–81. [9] Fullenbach C, Zacharowski K, Meybohm P. Improving outcome of trauma patients by implementing patient blood management. Curr Opin Anaesthesiol 2017;30:243–9. [10] Tuncalp O, Souza JP, Gulmezoglu M. New WHO recommendations on prevention and treatment of postpartum hemorrhage. Int J Gynaecol Obstet 2013;123:254–6. [11] Maternal mortality - key facts. World Health Organization; 2018. [12] Say L, Chou D, Gemmill A, Tuncalp O, Moller AB, Daniels J, et al. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health 2014;2:e323–33. [13] Henrich W, Surbek D, Kainer F, Grottke O, Hopp H, Kiesewetter H, et al. Diagnosis and treatment of peripartum bleeding. J Perinat Med 2008;36:467–78. [14] Dahlke JD, Mendez-Figueroa H, Maggio L, Hauspurg AK, Sperling JD, Chauhan SP, et al. Prevention and management of postpartum hemorrhage: a comparison of 4 national guidelines. Am J Obstet Gynecol 2015;213(76):e1–10. [15] Patient blood management guidelines: module 5 obstetrics and maternity. National Blood Authority Australia; 2015. [16] Sanghavi M, Rutherford JD. Cardiovascular physiology of pregnancy. Circulation 2014;130:1003–8. [17] Costantine MM. Physiologic and pharmacokinetic changes in pregnancy. Front Pharmacol 2014;5:65. [18] Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. World Health Organization. [19] Breymann C, Honegger C, Hosli I, Surbek D. Diagnosis and treatment of iron-deficiency anaemia in pregnancy and postpartum. Arch Gynecol Obstet 2017;296:1229–34. [20] ACOG practice bulletin No. 95: anemia in pregnancy. Obstet Gynecol 2008;112:201–7. [21] Pavord S, Myers B, Robinson S, Allard S, Strong J, Oppenheimer C. UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol 2012;156:588–600. [22] Antenatal care for uncomplicated pregnancies. National Institute for Health Care and Excellence (NICE); 2008. [23] Stevens GA, Finucane MM, De-Regil LM, Paciorek CJ, Flaxman SR, Branca F, et al. Global, regional, and national trends in haemoglobin concentration and prevalence of total and severe anaemia in children and pregnant and non-pregnant women for 1995-2011: a systematic analysis of population-representative data. Lancet Glob Health 2013;1:e16–25. [24] Fisher AL, Nemeth E. Iron homeostasis during pregnancy. Am J Clin Nutr 2017;106:1567s–74s.
4
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Review
Patient blood management in obstetrics – Review Jarmila A. Zdanowicz, Daniel Surbek
⁎
Department of Obstetrics and Gynecology, Bern University Hospital, University of Bern, Bern, Switzerland
A R T I C LE I N FO
A B S T R A C T
Keywords: Obstetrics Patient blood management Postpartum hemorrhage Red blood cell transfusion
Patient blood management (PBM) aims to reduce red blood cell transfusion, minimize preoperative anemia, reduce intraoperative blood loss as well as optimize hemostasis, and individually manage postoperative anemia. Benefits include improved clinical outcome with a reduction in patient morbidity and mortality, but also lower hospital costs and shorter hospital length of stay. To date, it has been successfully implemented in several medical specialties, such as cardiac, trauma and orthopedic surgery. In obstetrics, postpartum hemorrhage (PPH) is one of the leading causes of maternal mortality. PBM has the potential to improve outcome of mother and child. However, pregnancy and childbirth pose a special challenge to PBM, and several adaptations compared to PBM in elective surgery are necessary. To date, awareness of the clinical advantages of PBM among obstetricians and midwifes regarding PBM and its concept in PPH is limited. In the following review, we therefore aim to present the current status quo in PBM in obstetrics and its challenges in the clinical routine.
1. Definition of patient blood management (PBM) While allogenic blood transfusion has been viewed as a valid treatment for blood loss for a long time, adequate and prepared pre-, peri- and postoperative management is now emerging for uncomplicated elective surgeries in several medical specialties, summarized as patient blood management [1]. In general, PBM aims to minimize blood loss by maintaining adequate hemoglobin levels, reduce allogenic blood transfusion while at the same time optimizing patient care and outcome [1]. To this end, PBM is based on a so-called three pillar matrix for successful implementation: First, identification and treatment of anemia and low hemoglobin levels, furthermore, reducing (perioperative) blood loss and optimizing hemostasis, and finally, avoiding red blood cell (RBC) transfusions by tolerating individual anemia to a certain justifiable extent [1,2]. Successful PBM has been shown to reduce perioperative blood loss, lower transfusion rates, reduce perioperative morbidity and mortality, and cut hospital length of stay and costs [3–5]. A trigger for PBM has been the realization that RBC transfusions are associated with an increased morbidity and mortality, longer hospital length of stay as well as higher risk for admission to the intensive care unit [1]. In addition, transfusion risks include but are not limited to transmission of infections, hemolytic transfusion reactions, transfusionassociated circulatory overload, transfusion associated acute lung
injury and transfusion-related immunomodulation [6,7]. Furthermore, studies have shown that patients with restrictive RBC administration, such as Jehovah’s witnesses, have better clinical outcomes [1]. In other medical specialties, where elective surgeries are common, PBM has been already successfully established, including in cardiac surgery, trauma surgery and orthopedic surgery [5,8,9]. 2. Current approach to PBM in obstetrics In obstetrics, postpartum hemorrhage (PPH) is defined as a blood loss of 500 ml or more after vaginal birth, and 1000 ml or more after cesarean section within 24 h postpartum [10]. PPH is one of the main causes for 75% of maternal mortality according to the World Health Organization (WHO) [11,12]. Hence, implementing PBM in obstetrics potentially benefits mother and child. However, data on PBM in obstetrics has not been researched as well as in other medical specialties. Risk factors that lead to PPH have been studied extensively, the most common ones being uterine atony, anemia, trauma, placental pathologies and coagulopathies [13]. Yet, most women experiencing a PPH have no known risk factors. Risk factors and causes for PPH are summarized in Table 1. Guidelines have been established in several countries dealing with prevention and treatment of PPH, yet these recommendations across national guidelines are not always consistent [14]. To date, Australia has been one of the few countries that has
⁎ Corresponding author at: Department of Obstetrics and Gynecology, Bern University Hospital, Theodor-Kocher-Haus, Friedbühlstrasse 19, 3010 Bern, Switzerland. E-mail address: [email protected] (D. Surbek).
https://doi.org/10.1016/j.transci.2019.06.017
1473-0502/ © 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: Jarmila A. Zdanowicz and Daniel Surbek, Transfusion and Apheresis Science, https://doi.org/10.1016/j.transci.2019.06.017
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
J.A. Zdanowicz and D. Surbek
successfully and extensively implemented a program for PBM in obstetrics, while elsewhere new guidelines are slowly being established [7,15]. In obstetrics, a three pillar matrix for PBM includes identification of women at risk during pregnancy, minimizing acute peripartal blood loss and tolerating postpartum anemia.
the UK National Institute for Health Care and Excellence (NICE) recommend a cutoff hemoglobin value below 110 g/l in the first trimester and below 105 g/l in in the second trimester to define anemia [19–22]. The main cause for anemia in pregnancy is iron deficiency [23]. Due to the changes in blood circulation, the iron need for pregnant women is also different from that of non-pregnant women, while a majority of women already have an iron deficiency going into the pregnancy [24]. It has been estimated that the additional iron need of a pregnant woman is approximately 1 g [24]. NICE guidelines recommend hemoglobin screening in early pregnancy as well as at 28 weeks of gestation [22]. Current guidelines in Switzerland recommend testing the hemoglobin level at least once per trimester, while additionally analyzing the ferritin level in the first trimester [19]. Here, a cutoff level below 30 ng/ml for serum ferritin has been recommended in pregnancy for diagnosis of iron deficiency [21]. As ferritin is an acute phase protein, CRP (C-reactive protein) should always be analyzed at the same time to exclude an elevated ferritin level due to infection. It is important to diagnose if an existing anemia is caused by iron deficiency and can be treated as such. Iron deficiency anemia can lead to preterm birth, reduce neonatal birth weight, and lead to neonatal iron deficiency as well [7,19]. In women at risk for hemoglobinopathies (such as thalassemia or sickle cell anemia), further blood tests should be performed [7]. This might include a full blood count, mean red cell volume (MCV) as well as additional parameters to detect vitamin B12 or folate deficiency or reticulocyte count [7]. To prevent anemia, treatment with 30–60 mg of elemental iron per day is advised. Oral iron substitution is recommended for anemia with a hemoglobin level above 80 g/l, with a dose of 80–100 mg per day [7]. In case of normal hemoglobin with ferritin levels below 30 ng/ml treatment is also recommended, with a dose of 30–60 mg per day [19,21]. As oral substitution can have some unwanted side effects, most commonly gastrointestinal toxicity, intravenous iron administration is a valid alternative [7]. Further indications for intravenous iron administration might be inadequate increase in hemoglobin after oral substitution, advanced gestational age combined with low hemoglobin levels as well advanced anemia with a hemoglobin level below 80 g/l [18,19]. In addition to RBC and blood volume, there are several changes in clotting mechanisms during pregnancy. Levels of clotting factors VII, VIII, IX, X and XII are increased, as well as fibrinogen levels and von Willebrand factor, leading to a hypercoagulability in pregnancy [17]. At the same time, factor XI and protein S decreases, while prothrombin, protein C and factor V levels stay the same. With plasminogen activator inhibitor levels of PAI-1 and PAI-2 increased, overall fibrinolysis is decreased in pregnancy. While this provides the advantage of minimizing blood loss during delivery, it also leads to a higher risk for thromboembolic events during pregnancy and in the puerperal period [25].
3. Blood circulation and anemia in pregnancy
4. Peripartum management
In pregnancy, blood circulation is adapted for mother and fetus in order to provide an optimized uteroplacental circulation and aims to minimize the effects of blood loss during delivery. The circulating blood volume is increased by 40–45%, while erythropoiesis is enhanced as well [16]. Consequently, plasma volume and red blood cell mass are increased, effectively leading to a hemodilution and physiological anemia. An anemia plateau is reached around 30–32 weeks of gestation [17]. Hence, classification of anemia during pregnancy differs from non-pregnant women, however, a consensus on an exact definition is lacking. According to the WHO, anemia during pregnancy is defined as a hemoglobin level below 110 g/l [18], irrespective of how advanced the pregnancy is. Anemia is further classified into mild (100–109 g/l), moderate (70–99 g/l) and severe (< 70 g/l) [18]. Swiss guidelines, the American College of Obstetricians and Gynecologists (ACOG) as well as
During excessive active bleeding (as defined above) within 24 h of giving birth, several strategies exist to deal with PPH and its underlying causes. Actual blood loss during delivery is often underestimated, particular in vaginal delivery. Treatment is based on birth mode as well on bleeding causes, categorized into “four T’s”: tone (uterine atony), trauma (vaginal laceration, uterine rupture or inversion), tissue (retained placental tissue, clots) and thrombin (coagulopathy). Guidelines for peripartum management vary across national societies [14,26–29]. There is a general agreement that women with placental pathologies such as placenta previa or placenta increta are at a much higher risk for PPH and should be advised to deliver in a tertiary center. First-line treatment includes all mechanical and medicinal treatment. Mechanical interventions include uterine massages to stimulate
Table 1 Risk factors for postpartum hemorrhage (PPH) [13,52]. Uterine Atony (Tone) - Multiparity - Multiple pregnancy - Previous postpartum hemorrhage - Age > 40 years, BMI> 35 kg/ m2 - Asian ethnicity - Placenta previa - Prolonged labor Trauma/Surgery (Trauma) - Perineal or vaginal trauma - Cesarean delivery - Instrumental vaginal delivery - Uterine rupture
Coagulopathy (Thrombin) - Congenital bleeding disorders - Acquired coagulopathies - Anticoagulants - Placental abruption - Pre-eclampsia - Sepsis - Amniotic fluid embolism
Placenta (Tissue) - Retained placenta - Morbidly adherent placenta accreta, increta, percreta - Placental abruption - Placenta previa
Other - Anemia - Antepartum bleeding - Chorioamnionitis - Nicotine and cocaine abuse - Macrosomia - Laceration of birth canal - Preexisting chronic disease - Dead fetus - Uterine fibroma - Medically induced abortion
Table 2 Specific patient blood management in obstetrics. PBM Antepartum
Peripartum
Postpartum
-
Periodic check of hemoglobin and ferritin levels Anemia and iron deficiency treatment Identification of risk factors for postpartum hemorrhage Planned birth for women at risk Evaluation of hemostasis Administration of oxytocin and tranexamic acid Mechanical and surgical treatment Uterine artery embolization Use of cell saver Transfusion of blood and blood products Individual evaluation Hemoglobin levels after acute phase Iron administration Restrictive transfusion of blood products
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4.7. Recombinant activated factor VIII (rhFVIIa)
uterine contractions in cases of uterine atony, which is the most frequent cause of PPH [30]. Medicinal treatment includes uterotonics (such as oxytocin and prostaglandins) and pro-coagulants (like fibrinogen, tranexamic acid or fresh frozen plasma).
RhFVIIa (Novo Seven®) should only be administered in cases of severe bleeding if surgical treatment fails and is not considered routine use in PPH [34].
4.1. Oxytocin and prostaglandins
5. Surgical management
Oxytocin, or alternatively carbetocin, is recommended across guidelines as the first-line medication of choice to prevent PPH. It can be administered intravenously (usually 5–10 IU) as well as intramuscularly, with the effect setting in after only a few minutes [30]. Additionally, a continuous intravenous infusion (20–40 IU in 500–1000 L at a rate of 125–150 ml/h) can be applied [14,30]. If bleeding persists, further treatment with prostaglandins or its derivatives are recommended, for example, misoprostol administered at 800 μg vaginally or rectally [26,30]. If this fails, sulprostone intravenously (a maximum of 1500 μg/24 h) can be given [26].
Especially for PPH caused by an atony of the lower uterine segment, balloon tamponades are available as a second-line therapy [13]. There are several different balloon systems available, including Bakri balloon, Foley catheter, or Sengstaken tube [39]. For example, the Bakri balloon is slowly filled with liquid, hence applying pressure to the uterine wall to stop bleeding [40,41]. Further surgical interventions include uterine compression sutures that are placed throughout the uterus for compression of the atony site. The most commonly used are B-Lynch sutures, as well as suture techniques by Hayman and Cho [42–44]. Possible complications include uterine adhesions (synechiae), necrosis and pyometra [45]. Vascular ligation of arteries, usually of uterine, ovarian, or internal iliac arteries, aims to reduce blood flow to the uterus and can be also used as a supporting measure when bleeding persists following a hysterectomy [46]. In addition, pelvic artery embolization of uterine or internal iliac arteries can be performed, which is usually done in the interventional radiology unit and can also effectively stop PPH [47]. If all previously described measures fail, peripartum hysterectomy is the last resort for treatment [46]. As it is associated with a high morbidity and mortality, it should only be performed by an experienced surgeon [48].
4.2. Tranexamic acid Tranexamic acid is an anti-fibrinolytic drug that has been shown to prevent blood loss in surgery by approximately one third. When administered within three hours after onset of bleeding, it also reduces death from bleeding [31,32]. Currently, in obstetrics, the administration of tranexamic acid has not been among the first-line treatment options [26]. However, recently, the early and prophylactic use of tranexamic acid (1–2 g) along with administration of uterotonics has been shown to benefit women with PPH as soon as more than a normal peripartum bleeding occurs [33,34].
6. Postpartum management 4.3. RBC administration After delivery, detection and treatment of anemia is equally important. Swiss guidelines recommend determination of hemoglobin levels at 48 h postpartum, unless other reasons for an earlier blood analysis are present. Postpartum anemia is defined as a hemoglobin level < 120 g/l, while a significant anemia is defined at a level below 110 g/l [19]. Another definition is a hemoglobin level below 110 g/l one week after delivery and below 120 g/l at eight weeks after delivery [7]. Postpartum anemia might lead to several health constraints, such as an increased risk for infections, reduced lactation, reduced cognitive ability and emotional stability as well as fatigue and dyspnea [49]. Low iron concentration in the postpartum period seems to be associated with an increased risk for postpartum depression and fatigue [50,51]. Treatment for postpartum anemia with a hemoglobin level of 90–110 g/l should occur with oral elemental iron at 80–100 mg per day for at least three months. Intravenous iron should be administered with severe anemia below 90 g/l with relevant clinical symptoms [36]. The threshold for RBC transfusion is between 65–70 g/l, however, this also depends on the clinical outcome of the patient and should be administered restrictively [36].
Administration of RBC should be carried out cautiously and restrictively and there is no clear hemoglobin cut-off value as to when RBC transfusion is required. A hemoglobin level below 60 g/l seems a reasonable cutoff below which RBC administration should be performed, provided that there is no active bleeding [35]. However, in the case of active and severe bleeding, a hemodynamically instable patient will clearly benefit from a RBC transfusion, irrespective of hemoglobin level [36]. 4.4. Cell saver Cell saver, that is intraoperative blood salvage or homologous blood transfusion, has been described as an alternative treatment to RBC administration. However, it is not routinely used in obstetrics and few studies exist, although no major complications have been described to date [37]. 4.5. Fibrinogen Fibrinogen is crucial for coagulation and its level is the most sensitive indicator for hemostasis imbalance and severity of PPH. Hypofibrinogenemia (< 1 g/L) can be treated with administration of fresh frozen platelets (FFP) as well as fibrinogen concentrate [34]. Administration of fibrinogen has been shown to reduce bleeding and the need for RBC transfusions [38].
7. Conclusion PPH is one of the leading causes for maternal mortality. There are several strategies and different national guidelines for dealing with PPH in the obstetric field. However, successful PBM strategies aimed at systematically reducing peripartum blood loss are still lacking. In order to reach this goal, a multidisciplinary approach is needed involving obstetricians, anesthesiologists, transfusion medicine specialists and radiologists. As pregnancy is a physiologically different entity regarding hemostasis and its management, particular attention should be paid to this patient cohort. Furthermore, since pregnant women are consistently cared for throughout their pregnancy, this provides an unique
4.6. Fresh frozen plasma (FFP) The Royal College of Obstetricians and Gynaecologists (RCOG) recommends administration of FFP for persistent PPH combined with prolonged prothrombin time or activated partial thromboplastin time. Four units of FFP are recommended for every four units of RBC [35]. 3
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opportunity to successfully implement the three pillars of PBM, as presented in Table 2. Identification of women at risk for PPH and treating anemia during pregnancy, early treatment of peripartum blood loss with tranexamic acid, for example, and iron supplementation in the postpartum period are possible steps for a systematic and effective PBM. This will ultimately lead to an improved clinical outcome and increased patient safety, while at the same time reducing health care costs – a benefit for everyone.
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