Definition and Prevalence

Postpartum hemorrhage (PPH) is commonly defined as blood loss exceeding 500 milliliters (mL) following vaginal birth and 1000 mL following cesarean.¹ Definitions vary, however, and diagnosis of PPH is subjective and often based on inaccurate estimates of blood loss.^1-4 Moreover, average blood loss at birth frequently exceeds 500 or 1000 mL,⁴ and symptoms of hemorrhage or shock from blood loss may be hidden by the normal plasma volume increases that occur during pregnancy. Proposed alternate metrics for defining and diagnosing PPH include change in hematocrit, need for transfusion, rapidity of blood loss, and changes in vital signs, all of which are complicated by the urgent nature of the condition.¹ PPH is often classified as primary/immediate/early, occurring within 24 hours of birth, or secondary/delayed/late, occurring more than 24 hours post-birth to up to 12 weeks postpartum. In addition, PPH may be described as third or fourth stage depending on whether it occurs before or after delivery of the placenta, respectively.

The overall prevalence of PPH worldwide is estimated to be 6 to 11 percent of births with substantial variation across regions.^{5, 6} Prevalence differs by assessment method and ranges from 10.6 percent when measured by objective appraisal of blood loss to 7.2 percent when assessed with subjective techniques to 5.4 percent when assessment is unspecified.⁵ Multiple studies have noted an increase in PPH in high-resource countries, including the United States, Canada, Australia, Ireland, and Norway, since the 1990s.^7-11 In the United States, one study found that the incidence of PPH increased 26% from 1994 to 2006 (2.3% vs. 2.9%, respectively, p < 0.001).¹² Another U.S. study reported the incidence of severe PPH doubled from 1.9 percent in 1999 to 4.2 percent in 2008 (p < 0.0001).¹³ Factors underlying the increase remain unclear, and both recent U.S. studies found rising PPH rates were not explained by changes in risk factors (e.g., maternal age, cesarean birth, multiple gestation).^{12, 13}

Adverse Outcomes Associated With Postpartum Hemorrhage

PPH is a leading cause of maternal mortality and morbidity worldwide and accounts for nearly one-quarter of all maternal pregnancy-related deaths.¹⁴ Multiple studies have suggested that many deaths associated with PPH could be prevented with prompt recognition and more timely and aggressive treatment.^15-17 Morbidity from PPH can be severe with sequelae including organ failure, shock, edema, compartment syndrome, transfusion complications, thrombosis, acute respiratory distress syndrome, sepsis, anemia, intensive care, and prolonged hospitalization.^18-20

The most common etiology of PPH is uterine atony (impaired uterine contraction after birth), which occurs in about 80 percent of cases. Atony may be related to overdistention of the uterus, infection, placental abnormalities, or bladder distention.²¹ Though the majority of women who develop PPH have no identifiable risk factors, clinical factors associated with uterine atony, such as multiple gestation, polyhydramnios, high parity, and prolonged labor, may lead to a higher index of suspicion.^{18, 19, 21, 22} Other causes of PPH include retained placenta or clots, lacerations, uterine rupture or inversion, and inherited or acquired coagulation abnormalities.^{21, 22}

Interventions

Organizations and associations including the World Health Organization, International Confederation of Midwives, International Federation of Gynecologists and Obstetricians, American College of Obstetricians and Gynecologists, Royal College of Obstetricians and Gynaecologists, and the California Maternity Quality Care Collaborative have released guidelines for PPH prevention and management.^{14, 19, 21-25} Initial management includes identifying PPH, determining the cause, and implementing appropriate interventions based on the etiology. A variety of medical, procedure, and surgical interventions are available (see Table 1).

Table 1

Brief descriptions of interventions used in PPH management.

Interventions to treat PPH generally proceed from less to more invasive and include compression techniques, medications, procedures, and surgeries. PPH management may also involve adjunctive therapies, such as blood and fluid replacement and/or an anti-shock garment,^{26, 27} to treat the blood loss and other sequelae that result from PPH. Conservative management techniques such as uterotonic medications, which cause the uterus to contract, external uterine massage, and bimanual compression are generally used as “first-line” treatments.²⁸ These compression techniques encourage uterine contractions that counteract atony and assist with expulsion of retained placenta or clots. Aortic compression is another compression technique that has been used for severe PPH.^{29, 30}

The medications most commonly used in PPH management are uterotonic agents. These medications include oxytocin (Pitocin^®), misoprostol (Cytotec^®), methylergonovine maleate (Methergine^®,), carboprost tromethamine (Hemabate^®), and dinoprostone (Prostin E2^®).^{14, 19, 21, 22, 31} All of these medications are available in the United States. Only oxytocin, methylergonovine maleate, and carboprost tromethamine are approved by the U.S. Food and Drug Administration (FDA) specifically for PPH management; use of these other medications is off label. Typically, oxytocin is used as the initial medication for PPH management then other uterotonics are administered if oxytocin fails to stop bleeding. A recent U.S. study found wide variation in the use of these other uterotonics, which was not attributable to patient or hospital characteristics.³² In cases of severe blood loss from PPH, the hemostatic recombinant activated factor VIIa (NovoSeven^®) and the antifibrinolytic tranexamic acid (Cyklokapron^®) have been used.³³

Procedures used in PPH management include manual removal of the placenta, manual removal of clots, uterine balloon tamponade, and uterine artery embolization.^{14, 19, 21, 22} Laceration repair is indicated when PPH is a result of genital tract trauma. Surgical options when other measures fail to control bleeding include curettage, uterine and other pelvic artery ligation, uterine compression sutures, and hysterectomy.^{14, 19, 21, 22} More invasive procedures (e.g., uterine balloon tamponade and uterine artery embolization) and surgical techniques are generally used after “first-line” conservative management (e.g., uterotonics, uterine massage, bimanual compression, manual placenta and clot removal, and laceration repair) has failed to control bleeding and can be considered “second-line” interventions.²⁸ Procedures and surgeries can increase the risk of infection and other complications, and they may eliminate or adversely affect future fertility and pregnancy.

After PPH has been controlled, followup management varies and may include laboratory testing (e.g., hemoglobin and hematocrit), iron replacement therapy, and other interventions to assess and treat sequelae of PPH. The immediate postpartum period is a unique physiologic state with relative intravascular volume expansion with a reduction in cardiovascular demand compared to pregnancy. The physiologic anemia of pregnancy may be exacerbated by acute blood loss anemia from PPH. These physiologic realities may allow women with low hematocrits to be asymptomatic. Interventions for acute blood loss anemia include red blood cell transfusion and iron supplementation. Erythropoietin-stimulating agents (Aranesp^®, Epogen^®, Procrit^®) have also been used for anemia following stabilization of PPH, but they are not approved by the FDA for this use.¹⁹

At a systems level, PPH has been the focus of perinatal care safety initiatives that attempt to improve patient outcomes by incorporating a variety of strategies, such as practice guidelines or protocols, simulation drills, and teamwork training.^34-38 These systems-level interventions may influence management of PPH.

A variety of outcomes related to PPH management are reported.^39-44 Blood loss itself is measured, although often inaccurately as previously noted. Transfusion and anemia are sometimes used as markers for the amount of blood loss. The outcomes of intensive care unit (ICU) admission and extended hospitalization are used as indicators of maternal morbidity. Severe hemorrhage can lead to hysterectomy and death.

PPH can occur in any birth setting: hospital, birth center, or home. In home birth and birth center settings, severe or recalcitrant PPH can necessitate transfer for inpatient care. In considering setting, it is important to note that PPH management varies significantly according to available resources. All U.S. hospitals do not have immediate access to all interventions for PPH, and hospital volume appears to influence maternal morbidity and mortality from PPH.⁴⁵ In addition, many studies conducted in low-resource countries have limited to no applicability for higher-resource countries such as the United States.

Scope and Key Questions

Key Questions

We have synthesized evidence in the published literature to address the following Key Questions (KQs):

KQ1.What is the evidence for the comparative effectiveness of interventions for management of postpartum hemorrhage?

e.

What is the effectiveness of interventions intended to treat postpartum hemorrhage likely due to atony?

f.

What is the effectiveness of interventions intended to treat postpartum hemorrhage likely due to retained placenta?

g.

What is the effectiveness of interventions intended to treat postpartum hemorrhage likely due to genital tract trauma?

h.

What is the effectiveness of interventions intended to treat postpartum hemorrhage likely due to uncommon causes (e.g., coagulopathies, uterine inversion, subinvolution, abnormal placentation)?

KQ2. What is the evidence for choosing one intervention over another and when to proceed to subsequent interventions for management of postpartum hemorrhage?

KQ3.What are the harms, including adverse events, associated with interventions for management of postpartum hemorrhage?

KQ4. What is the effectiveness of interventions to treat acute blood loss anemia after stabilization of postpartum hemorrhage?

KQ5.What systems-level interventions are effective in improving management of postpartum hemorrhage?

Table 2 outlines the population, intervention, comparator, outcomes, timing, and setting (PICOTS) characteristics for the KQs.

Table 2

PICOTS.

Analytic Framework

The analytic framework illustrates the population, interventions, and outcomes that guided the literature search and synthesis (Figure 1). The framework for management of PPH includes women with PPH immediately post-birth to 12 weeks postpartum following pregnancy of > 24 weeks' gestation. The figure depicts the KQs within the context of the PICOTS described in the document. In general, the figure illustrates how interventions such as compression techniques, medications, procedures, surgeries, blood and fluid products, anti-shock garments or systems-level interventions may result in intermediate outcomes such as blood loss, transfusion, ICU admission, anemia, or length of stay and/or in final health outcomes such as mortality, uterine preservation, future fertility, breastfeeding, or psychological impact. Also, adverse events may occur at any point after the intervention is received.

Figure 1

Analytic framework. Abbreviations: ICU = intensive care unit; KQ = Key Question.

Organization of This Report

The Methods section describes the review processes including search strategy, inclusion and exclusion criteria, approach to review of abstracts and full publications, methods for extraction of data into evidence tables, and compiling evidence. We also describe our approach to grading the quality of the literature and to describing the strength of the body of evidence.

The Results section presents the findings of the literature search and the review of the evidence by KQ, synthesizing the findings across strategies. We present findings by intervention and outcome area where possible under each KQ and focus on comparative studies of higher quality. Cohort and case-control studies, pre-post studies, case series of procedural or surgical approaches, and randomized trials are also described in more detail in summary tables for each KQ. We integrate discussion of sub-questions within that for each KQ because there was not adequate distinction in the literature to address them separately. We also report harms data from case series and note that harms reported in all studies of interventions for PPH are described under KQ3.

The Discussion section of the report discusses the results and expands on methodologic considerations relevant to each KQ. We also outline the current state of the literature and challenges for future research in the field.

The report includes a number of appendixes to provide further detail on our methods and the studies assessed. The appendices are as follows:

• Appendix A. Search Strategies
• Appendix B. Screening and Quality Assessment Forms
• Appendix C. Excluded Studies
• Appendix D. Evidence Tables
• Appendix E. Quality/Risk of Bias Ratings
• Appendix F. Applicability Tables
• Appendix G. Study Design Classification Algorithm

We also provide a list of abbreviations and acronyms at the end of the report.

Uses of This Evidence Report

We anticipate this report will be of primary value to organizations that develop guidelines for managing PPH and to clinicians who provide intrapartum and postpartum care for women. Interested organizations would include the American Congress of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, the American College of Nurse-Midwives, the American Academy of Family Physicians, the Association of Women's Health, Obstetric, and Neonatal Nurses, the Society of Interventional Radiology, and the Society for Obstetric Anesthesia and Perinatology.

PPH is diagnosed and treated by clinicians including obstetricians, maternal-fetal medicine physicians, midwives, family physicians, nurses, interventional radiologists, and anesthesiologists. This report supplies practitioners and researchers up-to-date information about the current state of evidence, and assesses the quality of studies that aim to determine the outcomes of treatments for PPH.

Researchers, including perinatal safety researchers, can obtain a concise analysis of the current state of knowledge of interventions in this field. They will be poised to pursue further investigations that are needed to advance research methods, develop new treatment strategies, and optimize the effectiveness and safety of clinical care for women with this potentially life-threatening condition.

This report is unlikely to be used by women and their families given that PPH is often unanticipated and requires rapid intervention.