Preventing postpartum hemorrhage with combined therapy rather than oxytocin alone pharmacologic therapy

Abstract

Postpartum hemorrhage is the leading cause of maternal morbidity and mortality worldwide, with uterine atony estimated to account for 70% to 80% of cases, thereby remaining the single most common cause. Pharmacotherapy remains the first-line preventative therapy for postpartum hemorrhage. These therapies may be single (oxytocin, carbetocin, methylergonovine, ergometrine, misoprostol, prostaglandin analogs, or tranexamic acid) or combination therapies, acting in an additive, infra-additive, or synergistic fashion to prevent postpartum hemorrhage. Evidence is strong for the use of oxytocin, the first-line uterotonic agent in the United States for prevention of postpartum hemorrhage. Although carbetocin, a long-acting analog of oxytocin, is not yet available for use in the United States, it is likely the most effective single pharmacologic therapy for prevention of postpartum hemorrhage and need for additional uterotonics. Use of second-line uterotonics such as methylergonovine, misoprostol, and carboprost in combination with oxytocin has an additive or synergistic effect and a greater risk reduction for postpartum hemorrhage prevention compared with oxytocin alone. Therefore, combined therapy rather than oxytocin alone should be advised for preventing postpartum hemorrhage. Tranexamic acid has been found to be both effective and safe for decreasing maternal mortality in women with postpartum hemorrhage, and prophylactic use of tranexamic acid may decrease the need for packed red blood cell transfusions and/or uterotonics. The WOMAN-2 Trial, designed to assess if tranexamic acid prevents postpartum hemorrhage in women with moderate to severe anemia undergoing vaginal delivery, is currently recruiting participants. The additive, infra-additive, or synergistic action of oxytocin in combination with other second-line therapies deserves further study.

Introduction

Postpartum hemorrhage (PPH), defined by the American College of Obstetricians and Gynecologists’ (ACOG) reVITALize initiative as cumulative blood loss of >1000 mL (irrespective of route of delivery) or blood loss accompanied by signs or symptoms of hypovolemia within 24 hours after the birth process, is the leading cause of maternal morbidity and mortality worldwide.^1,2 Population-based surveillance of trends demonstrated that in the United States, PPH increased in prevalence by 26% between 1994 and 2006 (from 2.3% to 2.9%). The increase was primarily attributed to uterine atony (from 1.6% to 2.4%).³ Globally, PPH affects 5% of all women giving birth, and nearly one-quarter of all maternal deaths are associated with PPH.^2,4

With the increasing prevalence of PPH, use of systematic and comprehensive maternal hemorrhage protocols by multidisciplinary teams is crucial to successful prevention of PPH. This approach has been shown to lead to significant reduction in blood product use per 1000 births (−25.9%; P<.01) relative to baseline.⁵ Ideally, all hospital labor and delivery units should have a comprehensive PPH protocol, and provide ongoing training to multidisciplinary staff regarding its use. Massive transfusion protocols should be part of each institution’s comprehensive management plan for the prevention and treatment of PPH.¹

Active management of the third stage of labor, including giving a prophylactic uterotonic and applying controlled cord traction to deliver the placenta, has been found to reduce mean maternal blood loss, reduce the need for maternal blood transfusion, and prevent PPH.⁶ However, prevention of PPH ideally should start before pregnancy by optimization of prepregnancy hemoglobin concentration and identification of women at high risk for PPH, including women who have contraindications to pharmacologic agents used to prevent PPH. In addition, screening pregnant women during pregnancy and in labor for risk factors that can predispose to PPH can be critical in preparation for delivery and preventing PPH.⁷ When PPH occurs, management involves inspection of the placenta after delivery to rule out retained placental tissue; inspection of the genital tract for cervical, vaginal, perineal, or rectovaginal lacerations; and management of uterine atony.⁷ A stepwise approach to detection and management is critical for prevention of PPH.

Pharmacologic therapy is most useful for the prevention of PPH caused by uterine atony and/or clotting factor deficiency. These therapies may be used as single agents (oxytocin, carbetocin, methylergonovine, ergometrine, prostaglandin analogs, or tranexamic acid [TXA]) (Table 1) or in combination. When used in combination, agents may act in an additive, infra-additive (ie, less than additive), or synergistic (ie, more than additive) fashion (Table 2). Pharmacologic therapy with oxytocin for PPH prevention is associated with a reduced risk of PPH when compared with no uterotonics.¹² Thus, the World Health Organization (WHO) and ACOG recommend oxytocin as first-line after all births for the prevention of PPH^1,13 with the addition of second-line uterotonic agents such as methylergonovine, ergometrine, misoprostol, prostaglandin analogs, or TXA if hemorrhage occurs or continues after oxytocin use.¹ This review discusses single and combined pharmacologic therapy for the prevention of PPH.

TABLE 1.

Medical therapy for prevention of postpartum hemorrhage

Medication	Mechanism of action	Route of administration and dose	Pharmacokinetics	Absolute and relative contraindications
Oxytocin	Stimulates oxytocin receptors in the uterus	IV: 10–40 units per 500–1000 mL, continuous infusion IM: 5–10 units; 4 dose maximum	Onset of action: 1–6 min (IV); 3–5 min (IM) Half-life: 4 min Peak plasma concentration: 30–60 min	Rare; SIADH, hypotension, hypersensitivity to drug.
Carbetocin	Stimulates oxytocin receptors in the uterus	IV: 100 μg/mL in 1 dose injected over 1 min	Onset of action of 1–6 min Half-life: 40 min Peak plasma concentration: 20–30 min	Hypersensitivity to drug, hypertension, cardiac disease.
Methylergonovine maleate (ergot alkaloid)	Serotoninergic agonist, dopaminergic weak antagonist, and α1-adrenergic partial agonist at receptors in the uterus	IM: 200 μg every 2–4 h; 5 doses maximum PO: 200 μg every 6–8 h for 2–7 d	Onset of action: 1–3 min Half-life: 30–120 min Peak plasma concentration: 40 min	Hypertension, preeclampsia, cardiovascular disease, hypersensitivity to drug.
Misoprostol	PGE1 agonist in the uterine myometrium	Sublingual, oral, or rectal (sublingual preferred): 600–1000 μg in 1-time dose; repeated doses not recommended	Onset of action: 8–11 min (PO, sublingual); 100 min (rectal) Half-life: 20–40 min Peak plasma concentration: 20–60 min	Rare; hypersensitivity to drug, concurrent anticoagulant therapy; efficacy is disputed.
Carboprost tromethamine (PGF2α)	PGF2α agonist in the uterine myometrium	IM or IMM: 250 μg every 15–90 min; 8 doses maximum	Onset of action: 5–10 min Half-life: 8 min Peak plasma concentration: 15–60 min	Asthma; relative contraindication for hypertension, cardiac disease, or active hepatic, pulmonary, or renal disease.
Tranexamic acid	Diminishes the dissolution of hemostatic fibrin by plasmin, stabilizing clots in uterine vessels	IV: 1 g (100 mg/mL) over a 10-min period Second dose may be administered if bleeding persists after 30 min or stops and restarts within 24 h after the first dose	Onset of action: within 5 min Half-life: 120 min Peak plasma concentration: 6–8 min	Hypersensitivity to drug, history of hypercoagulopathy, thromboembolic events during pregnancy.

IM, intramuscular; IMM, intramyometrial; IV, intravascular; PGE₁, prostaglandin E₁; PGF_2α, 15-methyl prostaglandin F_2α; PO, by mouth; SIADH, syndrome of inappropriate antidiuretic hormone secretion.

TABLE 2.

Combination drug therapeutic efficacy for prevention of postpartum hemorrhage

Drug combination	Study	RR of PPH vs placebo or no treatment (95% CI)	RR of PPH vs oxytocin alone (95% CI)	RR of need for additional uterotonics vs oxytocin alone (95% CI)
Oxytocin–carbetocin	Fahmy et al,8 2015	Not quantitatively evaluated
Oxytocin–ergometrine	Gallos et al,9 2018 Jaffer et al,10 2022	0.41 (0.33–0.51) Not evaluated	0.70 (0.59–0.84) Not evaluated	Not evaluated 0.87 (0.11–6.39)
Oxytocin–misoprostol	Gallos et al,9 2018 Jaffer et al,10 2022 Parry Smith et al,11 2020	0.41 (0.31–0.53) Not evaluated Not evaluated	0.70 (0.58–0.86) Not evaluated 0.84 (0.66–1.06)	Not evaluated 0.57 (0.09–3.55) 0.99 (0.94–1.05)
Oxytocin–carboprost	No studies to date evaluating this drug–drug combination vs placebo or other therapies
Oxytocin–tranexamic acid	No studies to date evaluating this drug–drug combination vs placebo or other therapies

CI, confidence interval; PPH, postpartum hemorrhage; RR, relative risk.

Single therapies for prevention of postpartum hemorrhage

Oxytocin

Oxytocin, a cyclic nanopeptide that binds to myometrial receptors to produce uterine contractions, remains the mainstay first-line pharmacologic agent for preventing PPH.¹⁴ It may be administered either intravascularly or intramuscularly, with onset of action within 1 to 6 minutes and 3 to 5 minutes, respectively, reaching maximum plasma concentration within 30 to 60 minutes, depending on the route of administration.¹⁵ Elimination typically follows pseudo–first-order kinetics. Oxytocin is usually dosed as a continuous infusion in lactated Ringer’s solution for PPH prevention. Continuous intravenous administration of oxytocin is preferred to the intramuscular route because of evidence of greater efficacy, greater precision in dosing, and more rapid onset of action when compared with intramuscular injection.^1,16 When administered as a single intravenous dose, oxytocin can lead to profound hypotension. Thus, an intravenous oxytocin push should be avoided.¹ Injection of oxytocin into the umbilical vein does not seem to be effective for PPH prevention.¹⁷

Evidence for the use of oxytocin for prevention of PPH is strong. A 2018 Cochrane systematic review and network meta-analysis of randomized controlled trials (RCTs)⁹ compared several uterotonics with placebo or no treatment. The study included 196 RCTs involving over 135,000 women across 53 countries, and single agents and combination agents were evaluated with placebo. In this network meta-analysis of RCTs, oxytocin was more effective than placebo or no treatment, with a 41% reduction in the risk of PPH ≥1000 mL when compared with placebo (relative risk [RR], 0.59; 95% confidence interval [CI], 0.50–0.70).⁹ Other subsequent meta-analyses have demonstrated similar effects: a 2019 Cochrane systematic review of 23 trials involving over 10,000 women found that oxytocin was more effective than placebo or no treatment, with a 49% reduction in the risk of PPH when compared with placebo or no treatment (RR, 0.51; 95% CI, 0.37–0.72).¹⁸

Carbetocin

Carbetocin, a newer long-acting analog of oxytocin, has similar pharmacologic properties but also the advantage of heat stability and a 4 to 10 times longer half-life than oxytocin. A single dose of carbetocin, when compared with oxytocin, does not show variation in dose-response, is devoid of oxytocin receptor desensitization, and may be more effective than oxytocin without an increase in adverse effects.⁹ Carbetocin is typically administered intravascularly as 100 μg of active drug injected over 1 minute, with an onset of action of 1 to 6 minutes. As with oxytocin, elimination of carbetocin follows first-order kinetics.¹⁹ Currently, carbetocin is not available in the United States.

Data from the Carbetocin Haemorrhage Prevention (CHAMPION) trial demonstrated that carbetocin was noninferior to oxytocin for the prevention of PPH after vaginal delivery.²⁰ In the 2018 Cochrane network meta-analysis, carbetocin was found to be more effective than placebo/no treatment, with a 48% reduction in PPH risk ≥1000 mL (RR, 0.52; 95% CI, 0.37–0.73).⁹ This network meta-analysis also demonstrated carbetocin to be more effective than oxytocin alone, with a 28% reduction in risk of PPH ≥500 mL (RR, 0.72; 95% CI, 0.56–0.93).⁹ A 2020 meta-analysis of RCTs showed that compared with oxytocin, carbetocin administration reduced the need for additional uterotonics (odds ratio, 0.30; 95% CI, 0.11–0.86).²¹ A 2021 meta-analysis of 30 RCTs found that compared with oxytocin, carbetocin was associated with a reduced need for additional uterotonics in women undergoing cesarean delivery (RR, 0.43; 95% CI, 0.30–0.59) and in women at high risk for PPH who underwent vaginal delivery (RR, 0.56; 95% CI, 0.34–0.94).²² In a 2022 network meta-analysis of 46 studies with 7368 participants analyzing medical interventions for the prevention of PPH after cesarean delivery, carbetocin was demonstrated to be the most effective agent in reducing blood loss and the need for additional uterotonics.¹⁰

Ergot alkaloids (ergometrine, ergonovine, methylergonovine)

Ergot alkaloids are serotonergic receptor agonists, partial agonists of alpha-adrenergic receptors, and weak antagonists of dopaminergic receptors in the uterus, thereby inducing sustained uterine contraction.²³ Methylergonovine maleate (methergine) is the ergot alkaloid used primarily in the United States, whereas ergometrine is more commonly used in other parts of the world. Methylergonovine maleate is available as 200 μg of active drug per vial for PPH prevention. Methylergonovine and ergometrine have similar pharmacologic properties. Their onset of action is typically within 1 to 3 minutes, and they have long half-lives of 30 to 120 minutes, reaching maximum plasma concentrations in approximately 40 minutes.²⁴ Elimination typically follows first-order kinetics. Methylergonovine maleate and ergometrine are considered to be relatively contraindicated in patients with hypertensive disorders of pregnancy.¹

In the 2018 Cochrane network meta-analysis of RCTs, ergometrine alone was more effective than placebo or no treatment for prevention of PPH ≥500 mL, with a 37% reduction in the risk of PPH (RR, 0.63; 95% CI, 0.48–0.84) when compared with oxytocin alone.⁹ There was no difference in efficacy between ergometrine and oxytocin for prevention of PPH ≥1000 mL (RR, 0.94; 95% CI, 0.48–1.84).⁹ In the 2022 network meta-analysis analyzing medical interventions for the prevention of PPH after cesarean delivery, ergometrine alone was found to be inferior to oxytocin in reducing both estimated blood loss and need for additional uterotonic therapy.¹⁰

Misoprostol

Misoprostol (Cytotec), a prostaglandin E1 analog, may be administered via the oral, sublingual, rectal, or buccal routes for prevention of PPH. Its onset of action is dependent on the route of administration. Misoprostol is rapidly absorbed after oral or sublingual administration, and reaches maximum plasma concentration within 60 minutes.²⁵ When administered rectally, misoprostol achieves maximum plasma concentration within 20 minutes. Unfortunately, rectal administration has the lowest bioavailability (approximately 33%), despite being the most commonly used route of administration for prevention of PPH.²⁶

In the 2018 Cochrane network meta-analysis, misoprostol was more effective than placebo/no treatment, with a 29% reduction in the risk of PPH ≥1000 mL (RR, 0.71; 95% CI, 0.59–0.85).⁹ However, there was no difference in effect when compared with oxytocin for prevention of PPH ≥1000 mL (RR, 1.19; 95% CI, 1.01–1.42).⁹ In a 2020 Cochrane systematic review, misoprostol alone used as first-line treatment of PPH was found to be less effective than oxytocin for blood loss ≥1000 mL (RR, 2.57; 95% CI, 1.00–6.64), with more adverse effects.¹¹ In the 2022 network meta-analysis analyzing medical interventions for the prevention of PPH after cesarean delivery, misoprostol alone was found to be inferior to oxytocin in reducing both estimated blood loss and need for additional uterotonic therapy.¹⁰ When injectable uterotonics are not available, the WHO and the International Federation of Gynecology and Obstetrics (FIGO) recommend administration of 600-μg misoprostol orally for PPH prevention.^4,27

Carboprost

Carboprost tromethamine (Hemabate), an analog of 15-methyl prostaglandin F2-alpha, acts on prostaglandin receptors to stimulate uterine contractions.²⁸ Carboprost is available as 250 μg of active drug per vial for PPH prevention. After intramuscular injection, the time to peak plasma concentration is between 15 and 60 minutes, and the half-life is 8 minutes.²⁵

In the 2018 Cochrane meta-analysis of RCTs, carboprost alone was more effective than placebo or no treatment, with a 39% reduction in the risk of PPH ≥500 mL compared with placebo/no treatment (RR, 0.61; 95% CI, 0.42–0.90).⁹ However, there was no difference in effect when compared with oxytocin alone for prevention of PPH ≥1000 mL (RR, 0.88; 95% CI, 0.41–1.89).⁹ In the 2022 network meta-analysis analyzing medical interventions for the prevention of PPH after cesarean delivery, carboprost alone was found to be inferior to oxytocin in reducing the need for additional uterotonic therapy for PPH prevention.¹⁰

Carboprost should only be used intramuscularly or intramyometrially because intravenous administration can result in severe complications including severe hypertension and anaphylaxis²⁹. Carboprost is contraindicated in patients with asthma because of the potential risk of life-threatening bronchospasm and airway hyperreactivity from prostaglandin F2-alpha stimulation.^2,30 Of importance, the benzyl alcohol present in carboprost has been reported to be associated with a fatal “gasping syndrome,” a rare complication that can present in premature infants.³¹

Tranexamic acid

TXA, an inhibitor of plasminogen activation, prevents the conversion of plasminogen to plasmin and thereby inhibits fibrinolysis. TXA is typically administered intravenously at 1 g (10 mL of a 100 mg/mL solution) over 10 to 20 minutes. TXA’s onset of action is typically within 5 minutes when administered intravenously, and it has a half-life of 2 hours. The antifibrinolytic action of TXA persists in tissues for up to 17 hours postadministration. Elimination follows first-order kinetics.³² Because of its mechanism of action, TXA is used with caution in patients with a history of hypercoagulability or thromboembolic events during pregnancy.

The 2017 World Maternal Antifibrinolytic (WOMAN) RCT for the treatment of PPH, published in the Lancet, was the first major study to demonstrate the safety and efficacy of TXA for decreasing maternal mortality in women with PPH.³³ Since then, several other RCTs have demonstrated the efficacy of TXA not only for PPH treatment, but also for PPH prevention. A 2018 double-blinded RCT (TRAAP-1 trial) demonstrated that prophylactic use of TXA after vaginal delivery in women receiving oxytocin or carbetocin resulted in similar rates of PPH in both groups, and that the use of TXA did not result in a significantly decreased rate of PPH compared with placebo.³⁴ However, the trial did find that women in the TXA group received additional uterotonics less often (7.2% vs 9.7%; RR, 0.75; 95% CI, 0.61–0.92; P=.04). In a 2020 meta-analysis of RCTs, prophylactic use of TXA after vaginal delivery was found to result in a 39% reduction in risk of PPH when compared with placebo (RR, 0.61; 95% CI, 0.41–0.91), without a reduction in the rate of transfusion or increase in the risk of thrombotic events.³⁵

In a 2021 double-blind RCT of over 4600 participants (TRAAP-2 trial), prophylactic use of TXA after cesarean delivery resulted in a 16% reduction in the composite primary outcome of PPH >1000 mL or receipt of a packed red blood cell (RBC) transfusion within 2 days after delivery when compared with placebo (RR, 0.84; 95% CI, 0.75–0.94),³⁶ but the secondary outcome measures were not statistically significantly different between the TXA and placebo groups. A 2022 RCT by the Maternal-Fetal Medicine Units Network demonstrated that prophylactic administration of TXA during cesarean delivery did not reduce the need for packed RBC transfusion but did modestly decrease the need for uterotonics.³⁷ The WOMAN-2 Trial, designed to assess if TXA prevents PPH in women with moderate to severe anemia undergoing vaginal delivery, is currently recruiting participants (ClinicalTrials.gov Identifier: NCT03475342).

Combined therapies for prevention of postpartum hemorrhage

A second uterotonic is typically required in addition to oxytocin in 3% to 25% of cases of postpartum bleeding.³⁸ There are several combinations of uterotonic medications used for the prevention of PPH, but there is still need for more evidence regarding which specific combinations of additional uterotonics are the most effective. The efficacy of these drug combinations (Table 2) is a function of the pharmacodynamic drug–drug interactions they produce. Drug–drug interactions may be synergistic, in which the effect of one drug is enhanced by the other (typically acting via different drug receptors); additive, in which the interacting drugs have similar actions (usually acting via similar drug receptors), and the resultant effect is an approximate sum total of individual drug responses; and infra-additive, in which the combined effect of 2 drugs is smaller than the sum of the individual drug effects (primarily because of increased adverse effects produced by one or both drugs). These pharmacodynamic drug–drug interactions can be represented generally by dose–response curves, with increasing drug effects demonstrated when the combined dose–response curve is shifted to the left³⁹; by isobolograms, in which synergistic and additive drug–drug interactions are represented simultaneously on a curve⁴⁰; and by response surfaces, which are complex 3-dimensional graphs of dose–response relationships that demonstrate the association between ≥2 medications.⁴¹ For the prevention of PPH, a synergistic (preferred) or additive drug–drug interaction is optimal.

Ergometrine–oxytocin (Syntometrine) drug–drug interaction

The combination of ergometrine and oxytocin (Syntometrine) is an example of a synergistic drug–drug interaction given that these drugs act on different uterine receptors to produce an enhanced synergistic effect. Syntometrine is available as 5 units of oxytocin and 500 μg of ergometrine of active drug per vial. The ergometrine portion of the drug combination promotes rapid onset of action and a sustained uterine contraction pattern, whereas the oxytocin portion prolongs the uterotonic effect of Syntometrine. The onset of action of Syntometrine is typically within 2 to 3 minutes, and it has a prolonged half-life of 120 minutes, reaching maximum plasma concentration in approximately 3 hours.⁴² In the 2018 Cochrane network meta-analysis, the combination of ergometrine and oxytocin resulted in a 51% reduction in the risk of PPH ≥1000 mL when compared with placebo (RR, 0.49; 95% CI, 0.38–0.63), and a 30% reduction in the risk of PPH ≥500 mL when compared with oxytocin alone (RR, 0.70; 95% CI, 0.59–0.84).⁹ In a cumulative rankogram comparing each uterotonic drug’s probability of success (as either single agent or in combination) for the prevention of maternal death, combination therapy with ergometrine plus oxytocin ranked highest for the prevention of PPH >500 mL and >1000 mL for vaginal births and cesarean deliveries, respectively.⁹

Carbetocin–oxytocin drug–drug interaction

The combination of carbetocin and oxytocin has not been extensively studied, and was not evaluated in Cochrane network meta-analyses.^9,11,18 One study by Fahmy et al⁸ that evaluated a combination of carbetocin and oxytocin found evidence of an additive effect. From a pharmacodynamic standpoint, the additive effect of 2 oxytocin receptor agonists would be important if the dose (potency), onset, and duration of action of both agents differ. Acting on oxytocin receptors, oxytocin gives rise to a rapid onset of action to produce uterotonic effects, whereas carbetocin acts on similar receptors to produce a strong and prolonged additive pharmacodynamic effect (sustained uterine contractions).

Misoprostol–oxytocin drug–drug interaction

Although there are no fixed-dose drug combinations of oxytocin and misoprostol, the drug–drug interaction between misoprostol and oxytocin is considered infra-additive in nature because the combination of misoprostol and oxytocin most likely produces negligible to no additive uterotonic activity, and is associated with increased adverse effects when compared with oxytocin alone. In the 2018 Cochrane network meta-analysis, the combination of misoprostol and oxytocin resulted in a 48% reduction in the risk of PPH ≥1000 mL when compared with placebo/no treatment (RR, 0.52; 95% CI, 0.39–0.69). There were no differences in effect when compared with oxytocin alone for the prevention of PPH ≥1000 mL (RR, 0.88; 95% CI, 0.70–1.11).⁹ In a double-blind RCT in India, the use of lower doses of misoprostol–oxytocin was found to significantly reduce the amount of blood loss during and after lower-segment cesarean delivery compared with higher doses of oxytocin or misoprostol alone.^3,43

Conclusions

Pharmacotherapy remains the first-line therapy for PPH prevention. Although it is not yet available in the United States, carbetocin is likely the most effective single pharmacologic agent for prevention of PPH and the need for additional uterotonics. This is true in the setting of prevention of PPH from both vaginal and cesarean deliveries. The synergistic drug–drug interaction of oxytocin and ergometrine seems to be the most effective combination therapy for prevention of PPH and the need for additional uterotonics according to data from RCTs. According to current evidence, oxytocin therapy combined with other uterotonics (carbetocin, methylergonovine, ergometrine, misoprostol, prostaglandin analogs, and TXA) is more beneficial than oxytocin therapy alone for the prevention of PPH, but this merits additional research. The additive drug–drug interactions of carbetocin and oxytocin are not yet well-understood, and further studies are needed.