Bleeding Complications During

Keith McCrae, M.D. Cleveland Clinic 4/13/2016 Disclosure

I have no relevant personal financial relationship and I have not presented any promotional talks for any pharmaceutical companies within the past 12 months. Outline

• Epidemiology and causes of maternal mortality

• Placental structure and relation to in pregnancy

• Maternal mortality/morbidity due to

• Life threatening bleeding disorders

• in pregnancy

Maternal Mortality: WHO Analysis

Khan et al, Lancet 2006 Pregnancy-Related Death in the United States

http://www.cdc.gov/reproductivehealth/MaternalInfantHealth/PMSS.html Placentation and the Maternofetal Circulation

Kingdom and Drewlo, 118:4780, 2011 Defective Placentation in Preeclampsia

Normal Preeclampsia

Kingdom and Drewlo, Blood 118:4780, 2011 Q1: Postpartum Hemorrhage

You are called to see a 24 year old woman who has developed severe postpartum hemorrhage following an extended labor and delivery. Her pregnancy had been previously uncomplicated. On further questioning she has had mild epistaxis about once every year or two, usually in the winter. She had previously undergone tonsillectomy as a child and said she bled afterwards but does not recall needing transfusions. She also underwent a laparoscopic appendectomy without excessive bleeding. Her obstetricians want to know whether she has an underlying .

Definitions and Causes of Postpartum Hemorrhage

Abdul-Kadir et al: Transfusion, 2014

Bateman et al: Anesth Analg, 2010 Risk Factors for Postpartum Hemorrhage

Abdul-Kadir et al: Transfusion, 2014 Massive Obstetric Hemorrhage/Disseminated Intravascular Coagulation

• • • Placenta previa • Placenta accreta • Retained products of conception Causes and Pathogenesis of DIC in Pregnancy

Montagna Sem Thromb Hemost 36:404, 2010 ISTH Scoring System for DIC: Relevance to Pregnancy

Réger et al; Thromb Res 2013

Taylor FB et al: JTH, 2001 Charbit G; JTH, 2007

Amniotic Fluid Embolism • Misnomer—“anaphylactoid syndrome of pregnancy” • Incidence: 1/40,000 • Risk factors--controversial – No risk factor identified that justifies prospective alterations of clinical practice • Early clinical signs and symptoms – Hypotension – Dyspnea – Cyanosis – Loss of consciousness – Cardiac arrest • Fulminant coagulopathy (DIC)-diffuse bleeding from uterus, incisions, intravenous sites • Consequences – Maternal mortality in 60% if all classic signs and symptoms are present – If cardiac arrest, mortality increases to 90% – Severe fetal morbidity/mortality if not delivered urgently

Kanayama and Tamura J Obstet Gynec Res 40: 1507, 2014

https://www.studyblue.com/notes/note/n/vascular-disorders-_atlas-images/deck/8094977 Amniotic Fluid Procoagulant Activity/DIC

Sarig et al; Thromb Res, 2011 Clark SL; Obstet Gynec, 2014 Placental Abruption • Partial or complete separation of normally implanted placenta before delivery • Incidence: 0.4-1.0% of – Highest incidence at 24-26 weeks • Risk factors – Advanced maternal age (>35 years) – Smoking – Chronic hypertension – during pregnancy http://umm.edu/health/medical/pregnancy/labor-and- – PROM/ delivery/placenta-abruptio – Obstetrical history (preeclampsia, C-section, , abruption) – Thrombophilia? • Clinical manifestations – Hypovolemic shock, renal failure – Fulminant DIC in severe cases – Neonatal compromise – Maternal mortality < 1% MRI Placental Abruption

Masselli et al. Radiology 259:222, 2011 Ananth et al. AJOG 272e2, 2016 Algorithm for Management After Dx of Amniotic Fluid Embolism

Balinger et al. Curr Opin Obstet Gynec 27:398, 2015 PPH: French Guidelines

Sentilhes et al; EJOG 198:12, 2016 Treatment Algorithm for DIC Management in Obstetric Syndromes

Cunningham and Nelson Obstet Gynec 126:999, 2015 Prevention and Management of PPH

Abdul-Kadir et al: Transfusion, 2014 Management of Severe Postpartum Hemorrhage • Uterine massage/uterotonics – Syntocinon – Ergometrine/Syntometrine – PGF2 alpha/Misoprostol • Interventional approaches – Uterine tamponade – B-lynch suture – Uterine artery/internal iliac artery embolization – Hysterectomy Su et al: Best Prac Clin Res Obstet Gyn, 2012 • Aggressive transfusion, platelet, coagulation factor replacement • Recombinant factor VIIa (rVIIa) Massive Transfusion in Obstetrical Bleeding

Pacheco LD et al: Am J Perinatol, 2013

Burtelow M et al: Transfusion, 2007 rVIIa in Obstetrical Hemorrhage

Leighton et al: Anesthesiology, 2011

Kobayashi et al: Int J Hematolol, 2012 Tranexamic Acid in Postpartum Hemorrhage

TXA: 4 gm over 1 hour, then 1 gm/hr infusion, IV Ducloy-Bouthors et al: Crit Care, 2011 Tranexamic Acid in Pregnancies at High Risk for PPH

Sujata et al IJOG, 2016 Effect of TA on Postpartum Blood Loss: Systematic Analysis

Alam and Choi, Transf Med Rev 29:231-241, 2015 Case 2: VWD in Pregnancy • 32 yo woman with VWD • Menorrhagia • Epistaxis, once per year, usually in winter • Lab • PTT 36 sec (< 32 sec) • RCOF 31% (>35%) • CBA 42% (>41%) • VWF ag 44% (>50%) • All multimers reduced • Presents in week 28 of uncomplicated pregnancy

Prophylaxis of Women with Inherited Bleeding Disorders

Abdul-Kadir et al: Transfusion, 2014 Hemostatic Disorders in Pregnancy:vWD

Sadler JE: JTH, 2006

Huq et al: , 2012 Castaman G: Med J Hematol Inf Dis, 2013 Treatment of VWD in Pregnancy

James A. Hemophilia 21:81, 2015 Levels of VWF, Rcof and FVIII Postpartum

James A, Hemophilia 21:81, 2015 Effect of Treatment on Levels of VWF, RCof and FVIII

James A. Hemophilia 21:81, 2015 Management of Type I VWD at Delivery • Most patients achieve normal levels of VWF by mid second trimester • Vaginal or C-section is safe if RCof and FVIII levels are > 50% • DDAVP can be used in pregnancy if invasive procedures needed before increase in VWF • VWF levels begin to drop by day 3 and return to baseline by day 14— mean time at presentation for hemorrhage in VWF patients is 15.7 days • Patient should be counseled to consult physician at any sign of increased bleeding: treatment options include DDAVP, factor concentrates, tranexamic acid Neff and Sidonio. Am Soc Hematol Educ Prog 2014(1): 536-41 Summary • With respect to coagulation, pregnancy is a closely regulated state, disruption of which can cause profound derangement of hemostasis • The most common cause of post-partum bleeding is • Placental abruption is a cytokine/SIRS driven process, in which profound DIC follows the initial insult and may lead to life- threatening hemorrhage • The normal increases in VWF during pregnancy in patients with Type I VWD are usually sufficient to enable safe delivery, but bleeding can occur in the post-partum period.