US Pharm. 2019;44(9)HS-2-HS-10.
ABSTRACT: The incidence of postpartum hemorrhage (PPH) has increased over the past three decades and accounts for 11% of pregnancy-related deaths in the United States alone. Risk stratification and active management in the third stage of labor are key prevention strategies. An interdisciplinary approach to care of the PPH patient is necessary to prevent adverse outcomes. Uterotonic agents such as oxytocin are employed in conjunction with manipulative techniques such as uterine massage and balloon tamponade to treat atony of the uterus. Antifibrinolytic agents such as tranexamic acid have also been used. Surgical techniques, such as embolization of the pelvic artery or, ultimately, hysterectomy, are more invasive approaches. Pharmacists in the institutional setting have the opportunity to assist in risk stratification and prevention strategies, emergency management of the PPH patient, and provider and staff education, as well as clinical assessment of pharmacotherapy choice, sterile product preparation, and prevention of medication errors.
Between 2011 and 2015, postpartum hemorrhage (PPH) accounted for 11.2% of pregnancy-related deaths in the United States.1,2 PPH prevalence was found to increase from 2.3% to 2.9% between 1994 and 2006, with further increases from 2.9% to 3.2% from 2010 to 2014.3,4 Risk factors for PPH have also increased during this time period. Uterine atony, a primary cause of PPH, accounted for up to 79% of cases and increased in prevalence by 0.8% from 1994 to 2006 and by 0.4% from 2010 to 2014.3,4
PPH has been categorized as primary or secondary based on the timing of occurrence and the likely cause of bleeding. Prior to 2014, primary PPH was commonly defined as blood loss of more than 500 mL after vaginal birth and more than 1,000 mL after a cesarean birth.5 The 2014 reVITALize program by the American College of Obstetricians and Gynecologists (ACOG) defines primary PPH as cumulative blood loss of 1,000 mL or more with presence of hypovolemic signs/symptoms within 24 hours of the birth process.5-7 Hypovolemic signs/symptoms include tachycardia, hypotension, tachypnea, oliguria, pallor, or altered mental status. Increased observation and interventions may be clinically indicated for blood loss of 500 to 999 mL.6,7 Secondary PPH has been defined as hemorrhage that may occur between 24 hours post-birth and up to 12 weeks later.5
Risk factors for developing PPH include contractility abnormalities (e.g., uterine atony, uterine distention due to multiple gestations, fibroids, uterine inversion); trauma (e.g., episiotomy); retained placenta; and coagulation abnormalities (e.g., clotting factor deficiency, infection, preeclampsia). Assessment tools may assist clinicians in identifying patients prior to delivery who are at higher risk of developing PPH. Use of these assessment tools has been shown to identify 60% to 85% of women who will experience significant PPH.5,8-11 Clinicians should evaluate for tone, trauma, tissue, and thrombin—known as the Four T’s mnemonic—during assessment of the actively bleeding patient.5,12
Active Versus Expectant Management
In expectant management of PPH, clinicians wait for signs of placental separation and spontaneous placental delivery.5,12,13 In contrast, active management (active management in the third stage of labor [AMTSL]) involves early administration of uterotonic drug therapy, massage of the uterus, and placental delivery via controlled umbilical cord traction. Active management of PPH is recommended.5,12-15 While more research is needed, active management reduces the risk of additional uterotonic drug therapy, severe maternal hemorrhage >1,000 mL, maternal blood transfusions, postpartum maternal hemoglobin <9 g/dL, and mean maternal blood loss at birth.5,12-17
Oxytocin has long been the drug of choice for AMTSL and is administered no sooner than upon delivery of the anterior shoulder.5,12-16, Should PPH due to uterine tone develop despite active management with oxytocin, then methylergonovine, misoprostol, or carboprost may be used. Choice of secondary agent is based on clinician discretion and drug availability; no agent has shown superiority over the other.5,18 If uterotonic medications do not stop bleeding or if bleeding is the result of trauma, tranexamic acid may be used.5
Additional measures for management beyond the use of pharmacotherapeutic agents are dependent on the cause of PPH and the amount of blood loss (Table 1). A multidisciplinary approach is key to successful management of severe PPH. It is recommended to consult with anesthesia, surgery, intensivists, and pharmacy.5,12 Transfusions of red blood cells, platelets, and/or clotting factors and vasopressors for blood-pressure support should be used as needed. Additional measures include vessel embolization or ligation, use of recombinant factor VIIa, and hysterectomy. Many hospitals, especially those in critical-access areas, have algorithms and checklists in place for management of PPH.5,8,13 An example of a patient-safety checklist is available through ACOG.19
Pharmacotherapeutic options for PPH management are summarized in Table 2. Oxytocin, methylergonovine, and carboprost are approved by the FDA for PPH management, while misoprostol and tranexamic acid are not.20-25
Oxytocin is released from the posterior pituitary and increases uterine contractions by stimulating prostaglandin production and increasing intracellular calcium ion levels in myometrial cells.20,21 Rhythmic contractions of the upper myometrial segment occur, which then constrict spiral arteries and reduce uterine blood flow. Because the number of myometrial oxytocin receptors varies by individual, uterine sensitivity and response to oxytocin administration also varies. To reduce the risk of contamination by vasopressin and by other biologically active peptides, oxytocin is prepared synthetically.12,20,21
Oxytocin is administered no sooner than upon delivery of the anterior shoulder.5,14-16,26 The plasma half-life of oxytocin ranges from 1 to 6 minutes. Patients receiving IV oxytocin have an immediate uterine response lasting about 60 minutes. Patients receiving IM oxytocin achieve uterine response in 3 to 5 minutes, lasting 2 to 3 hours.20,21 Currently, no specific dosing schedule has been shown to have better outcomes than another.26 Oxytocin may be given IM or by IV infusion but should not be given by IV push.16 Infusion rates of up to 6 mU/minute appear to result in the same oxytocin levels that are found during spontaneous labor. According to manufacturer prescribing information, infusion rates of more than 9 to 10 mU/minute are rarely required and should be used very cautiously, but ideally not at all.22 The maximum recommended cumulative dose of oxytocin is 40 units.20,21 It should be noted that oxytocin administration to induce or stimulate labor has not been found to increase the risk of developing PPH or influence PPH outcomes when administered as part of AMTSL.27
During oxytocin administration, contractile tone, frequency, and amplitude should be monitored in conjunction with fetal heart rate. If maternal or fetal distress occurs, contractions are too powerful, or the uterus is too reactive, oxytocin should be immediately discontinued.5,20,21
Fewer drug interactions are noted with oxytocin use compared with other uterotonic agents.20-24 When a vasoconstrictor is given with caudal-block anesthesia and then oxytocin is administered up to 4 hours later, severe hypertension has occurred. Concomitant use with cyclopropane anesthesia has resulted in maternal bradycardia, hypotension, and abnormal heart rhythm. Carboprost and misoprostol prescribing information recommends against use of these agents in combination with other oxytocic drug therapy due to additive prostaglandin activity leading to augmentation of uterine contractility and increased risk of severe adverse events.20-22, 24 Oxytocin is available in single-dose 1-mL vials and multidose 10-mL vials, each containing 10 units/mL. Vials should be stored at room temperature.21
Carboprost is a methylated analogue of naturally occurring prostaglandin F2 that stimulates myometrial contractions and vasoconstriction by increasing the number of oxytocin receptors in the myometrium.12,20,22 Carboprost is recommended for use in PPH after oxytocin, uterine massage, alternative manipulative techniques of the uterus, and IM ergotamine preparations (unless contraindicated) have failed.22 It is considered third- or fourth-line therapy in several guidelines.5,13 Use of carboprost in PPH has been shown to be successful in up to 88% of cases if used as monotherapy and in 95% if used concomitantly with other uterotonic agents.28
Carboprost should not be used for more than 48 hours continuously and is indicated for IM administration only, as IV administration may result in hypertension, vomiting, bronchospasm, or anaphylaxis. Onset of action is 30 minutes. Most patients, a reported 73% of cases, required only one injection for response to occur.22
Carboprost is the tromethamine salt of (15S)-15-methyl prostaglandin F2. Therefore, each 1 mL of carboprost solution contains 250 mcg of carboprost, 83 mcg tromethamine, 9 mg sodium chloride, and 9.45 mg benzyl alcohol preservative. Because it contains benzyl alcohol, fetal “gasping syndrome” has been identified in infants born prematurely, so it should be used cautiously. Carboprost must be refrigerated (2o to 8oC) and is supplied as 1 mL ampules.22
A black box warning states that carboprost should be used only in hospital settings by trained personnel and strict adherence to dosage guidelines is necessary. No specific drug interactions have been identified.20, 22
An ergot alkaloid, methylergonovine stimulates uterine contraction by acting directly on uterine smooth-muscle tissue to increase tone, rate, and amplitude of rhythmic contractions. Blood loss is reduced and the third stage of labor is shortened due to the rapid and sustained tetanic effects.20,23 Methylergonovine is primarily recommended for use in management of PPH. However, the World Health Organization identifies methylergonovine as an alternative option in prevention of PPH, if oxytocin is not available.5,14,15
Methylergonovine is available in oral and injectable formulations. For PPH, IM administration is preferred with an onset of action of 12 to 37 minutes, lasting 3 to 4 hours. IV administration is not recommended due to increased risk of sudden severe hypertension and potential for cerebral vascular accident. IV methylergonovine should be used only in the event that life-saving measures are required. If administered IV, it should be given slowly over not less than 60 seconds, avoiding periarterial and intra-arterial injections. Monitor blood pressure closely.20,23
Methylergonovine is a substrate of cytochrome P450 (CYP) 3A4. Therefore, if given concurrently with strong CYP3A4 inhibitors, vasospasm, cerebral ischemia, and/or ischemia of the lower extremities can occur. Avoid use with CYP3A4 inhibitors such as macrolide antibiotics, ketoconazole and other azole antifungals, or protease inhibitors. Inhibitors such as fluoxetine and grapefruit juice are not as potent but should still be evaluated prior to ergot alkaloid use. Cautious use in the presence of CYP3A4 inducers (e.g., rifampin, nevirapine) is recommended, owing to the potential for reduced effectiveness of methylergonovine.20,23 Vasoconstrictive properties of ergot alkaloids may also be enhanced by beta-blockers. Cautious use should be exercised in renal/hepatic impairment.20,23
Methylergonovine is available in 1 mL single-dose vials that must be refrigerated (2o to 8oC) and protected from light. A combination product of ergot alkaloid (ergometrine) and oxytocin is identified in certain PPH guidelines but is not available in the U.S.13-15
A synthetic analogue of E1 prostaglandin, misoprostol stimulates uterine smooth-muscle contraction.20,24 Misoprostol is recommended primarily for management of PPH, but it may also be used for prevention if other options are not available.5,12-15 Studies have shown that misoprostol use is as effective as oxytocin in treatment of PPH when blood loss is <1,000 mL, but less effective in severe blood loss.28 Use of misoprostol in PPH is an off-label indication. However, prescribing information identifies hospital use of misoprostol for serious PPH.24 It may be administered orally, rectally, or sublingually.20,24
The primary administration method for PPH management is rectally in doses of 800 to 1,000 mcg, although oral or sublingual doses of 600 to 800 mcg may be used. For prevention, 600 mcg is administered orally.5,12,20,24 Onset of action is 9 to 15 minutes; half-life is 20 to 40 minutes; and duration of action is about 3 hours. Drug interactions are few, primarily specific to concomitant oral administration with antacids containing aluminum and magnesium. Hepatic and renal dose adjustments are not required.20,24
A black box warning regarding increased risk of uterine rupture exists regarding use of misoprostol in patients with a history of uterine surgery, cesarean delivery, increasing gestational age, and grand multiparity. Uterine tetany, impaired blood flow between uterus and placenta, amniotic fluid embolism, and fetal heart changes are also potential complications.20,24
Misoprostol is available in 100 mcg and 200 mcg tablets and should be stored at room temperature.24
Tranexamic acid decreases blood loss via fibrinolysis inhibition. In general, tranexamic acid competitively inhibits plasminogen activation, and it becomes a noncompetitive inhibitor of plasmin at higher doses.20,25 Tranexamic acid is recommended for PPH management when uterotonic agents fail and bleeding continues or is due to trauma. It is not recommended for prevention of PPH, due to lack of sufficient studies.5 Currently, use of tranexamic acid in PPH management is not approved by the FDA and is considered off-label.25
The 2017 WOMAN trial found a significant reduction in death (P <.045) resulting from bleeding in patients receiving tranexamic acid (1.5%) compared with placebo (1.9%) with no increase in adverse events when 1 g of tranexamic acid was administered IV within 3 hours of delivery.29 Studies indicate that if used early, tranexamic acid may reduce blood loss of at least 500 mL, but it does not reduce risk of hysterectomy or receipt of blood transfusions.30
Onset of action of IV tranexamic acid is 5 minutes, half-life is 120 minutes, and duration of action is 8 hours in the serum and 17 hours in tissue. Drug interactions are minimal. Tranexamic acid may be mixed with most IV solutions but should not be mixed with blood products or solutions containing penicillins. Risk of thrombosis increases if tranexamic acid is given with anti-inhibitor coagulant or factor IX complex concentrates. No dose adjustments are required in hepatic dysfunction, but an increased interval between doses is recommended in moderate-to-severe renal dysfunction. Tranexamic acid should be stored at room temperature and is available as 10-mL single-dose vials in concentration of 100 mg/mL.20,25
Role of the Pharmacist
While dependent on practice scope and collaborative-practice protocol and algorithm status, opportunities exist for pharmacists in the institutional setting to assist with management of PPH. Pharmacists could assist providers in risk stratification of patients who may develop PPH and could assist in the emergency management of the PPH patient. Provider and clinical staff education opportunities include education regarding hospital formulary status, drug cost, dosing, administration, medication ordering and documentation in the electronic health record, use of patient screening tools and management algorithms, and prevention of medication errors. Pharmacists may manage medication preparation, dose adjustments, and identification and management of potential or actual drug-drug or drug-disease state interactions.
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