HHS Public Access

Author manuscript
Am J Obstet Gynecol MFM. Author manuscript; available in PMC 2023 February 21.
Author Manuscript

Published in final edited form as:

Am J Obstet Gynecol MFM. 2023 February ; 5(2 Suppl): 100731. doi:10.1016/j.ajogmf.2022.100731.

Preventing postpartum hemorrhage with combined therapy

rather than oxytocin alone pharmacologic therapy
Amanda J. Jones, MD,
Johns Hopkins Department of Gynecology & Obstetrics, Johns Hopkins University School of
Medicine, Baltimore, MD

Jerome J. Federspiel, MD, PhD,

Author Manuscript

Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Duke University

School of Medicine, Durham, NC

Ahizechukwu C. Eke, MD, PhD

Division of Maternal-Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins
University School of Medicine, Baltimore, MD; Division of Clinical Pharmacology, Department of
Medicine, Johns Hopkins University School of Medicine, Baltimore, MD

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
Author Manuscript

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,
Author Manuscript

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.

Corresponding author: Ahizechukwu C. Eke, MD, PhD. ahizeeke2nd@yahoo.ca.

The authors report no conflict of interest.
 Jones et al. Page 2

Keywords
Author Manuscript

drug–drug interactions; pharmacotherapy; postpartum hemorrhage; prevention; uterotonics

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
Author Manuscript

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
Author Manuscript

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.
Author Manuscript

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

Am J Obstet Gynecol MFM. Author manuscript; available in PMC 2023 February 21.
 Jones et al. Page 3

for the prevention of PPH1,13 with the addition of second-line uterotonic agents such as
Author Manuscript

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.

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
Author Manuscript

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
Author Manuscript

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
Author Manuscript

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.

Am J Obstet Gynecol MFM. Author manuscript; available in PMC 2023 February 21.
 Jones et al. Page 4

Data from the Carbetocin Haemorrhage Prevention (CHAMPION) trial demonstrated that
carbetocin was noninferior to oxytocin for the prevention of PPH after vaginal delivery.20
Author Manuscript

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
Author Manuscript

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
Author Manuscript

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
Author Manuscript

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

Am J Obstet Gynecol MFM. Author manuscript; available in PMC 2023 February 21.
 Jones et al. Page 5

33%), despite being the most commonly used route of administration for prevention of
PPH.26
Author Manuscript

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
Author Manuscript

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;
Author Manuscript

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
Author Manuscript

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

Am J Obstet Gynecol MFM. Author manuscript; available in PMC 2023 February 21.
 Jones et al. Page 6

with caution in patients with a history of hypercoagulability or thromboembolic events

Author Manuscript

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
Author Manuscript

(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
Author Manuscript

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),
Author Manuscript

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

Am J Obstet Gynecol MFM. Author manuscript; available in PMC 2023 February 21.
 Jones et al. Page 7

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
Author Manuscript

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
Author Manuscript

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
Author Manuscript

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
Author Manuscript

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

Am J Obstet Gynecol MFM. Author manuscript; available in PMC 2023 February 21.
 Jones et al. Page 8

Conclusions
Author Manuscript

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.
Author Manuscript

Acknowledgments
Support for this work was provided by the Eunice Kennedy Shriver National Institute of Child Health and Human
Development of the National Institutes of Health (NIH) (award number 1K23HD104517) and the National Center
for Advancing Translational Sciences (award number TL1TR002555). The content is solely the responsibility of the
authors and does not necessarily represent the official views of the NIH.

REFERENCES
1. Committee on Practice Bulletins-Obstetrics. Practice Bulletin No. 183: postpartum hemorrhage.
Obstet Gynecol 2017;130:e168–86. [PubMed: 28937571]
2. Say L, Chou D, Gemmill A, et al. Global causes of maternal death: a WHO systematic analysis.
Lancet Glob Health 2014;2:e323–33. [PubMed: 25103301]
3. Callaghan WM, Kuklina EV, Berg CJ. Trends in postpartum hemorrhage: United States, 1994-2006.
Am J Obstet Gynecol 2010;202. 353.e1–6.
Author Manuscript

4. World Health Organization. WHO recommendations uterotonics for the prevention of postpartum
haemorrhage. Geneva, Switzerland: World Health Organization; 2018.
5. Shields LE, Wiesner S, Fulton J, Pelletreau B. Comprehensive maternal hemorrhage protocols
reduce the use of blood products and improve patient safety. Am J Obstet Gynecol 2015;212:272–
80. [PubMed: 25025944]
6. Begley CM, Gyte GM, Devane D, McGuire W, Weeks A, Biesty LM. Active versus
expectant management for women in the third stage of labour. Cochrane Database Syst Rev
2019;2:CD007412. [PubMed: 30754073]
7. Bienstock JL, Eke AC, Hueppchen NA. Postpartum hemorrhage. N Engl J Med 2021;384:1635–45.
[PubMed: 33913640]
8. Fahmy AA, Fawzy M. Oxytocin infusion after oxytocin bolus and carbetocin bolus to reduce blood
loss during and after cesarean section-a randomized clinical trial. Med J Cairo Univ 2015;83:79–83.
9. Gallos ID, Papadopoulou A, Man R, et al. Uterotonic agents for preventing postpartum
haemorrhage: a network meta-analysis. Cochrane Database Syst Rev 2018;12:CD011689. [PubMed:
Author Manuscript

30569545]
10. Jaffer D, Singh PM, Aslam A, Cahill AG, Palanisamy A, Monks DT. Preventing postpartum
hemorrhage after cesarean delivery: a network meta-analysis of available pharmacologic agents.
Am J Obstet Gynecol 2022;226:347–65. [PubMed: 34534498]
11. Parry Smith WR, Papadopoulou A, Thomas E, et al. Uterotonic agents for first-line
treatment of postpartum haemorrhage: a network meta-analysis. Cochrane Database Syst Rev
2020;11:CD012754. [PubMed: 33232518]
12. Westhoff G, Cotter AM, Tolosa JE. Prophylactic oxytocin for the third stage of labour to prevent
postpartum haemorrhage. Cochrane Database Syst Rev 2013:CD001808. [PubMed: 24173606]

Am J Obstet Gynecol MFM. Author manuscript; available in PMC 2023 February 21.
 Jones et al. Page 9

13. World Health Organization. WHO recommendations for the prevention and treatment of
postpartum haemorrhage. Geneva, Switzerland: World Health Organization; 2012.
Author Manuscript

14. Weeks AD. Oxytocin: still the optimal prophylactic despite soaring rates of haemorrhage at birth.
BJOG 2021;128:1247. [PubMed: 33386665]
15. De Groot AN, Vree TB, Hekster YA, et al. Bioavailability and pharmacokinetics of sublingual
oxytocin in male volunteers. J Pharm Pharmacol 1995;47:571–5. [PubMed: 8568623]
16. Oladapo OT, Okusanya BO, Abalos E, Gallos ID, Papadopoulou A. Intravenous versus
intramuscular prophylactic oxytocin for the third stage of labour. Cochrane Database Syst Rev
2020;11:CD009332. [PubMed: 33169839]
17. Nankali A, Keshavarzi F, Fakheri T, Zare S, Rezaei M, Daeichin S. Effect of intraumbilical vein
oxytocin injection on third stage of labor. Taiwan J Obstet Gynecol 2013;52:57–60. [PubMed:
23548219]
18. Salati JA, Leathersich SJ, Williams MJ, Cuthbert A, Tolosa JE. Prophylactic oxytocin for
the third stage of labour to prevent postpartum haemorrhage. Cochrane Database Syst Rev
2019;4:CD001808. [PubMed: 31032882]
19. Sweeney G, Holbrook AM, Levine M, et al. Pharmacokinetics of carbetocin, a long acting
Author Manuscript

oxytocin analogue, in nonpregnant women. Curr Ther Res 1990;47:528–40.

20. Widmer M, Piaggio G, Nguyen TMH, et al. Heat-stable carbetocin versus oxytocin to prevent
hemorrhage after vaginal birth. N Engl J Med 2018;379:743–52. [PubMed: 29949473]
21. Onwochei DN, Owolabi A, Singh PM, Monks DT. Carbetocin compared with oxytocin in non-
elective cesarean delivery: a systematic review, meta-analysis, and trial sequential analysis of
randomized-controlled trials. Can J Anaesth 2020;67:1524–34. [PubMed: 32748189]
22. Kalafat E, Gokce A, O’Brien P, et al. Efficacy of carbetocin in the prevention of postpartum
hemorrhage: a systematic review and Bayesian meta-analysis of randomized trials. J Matern Fetal
Neonatal Med 2021;34:2303–16. [PubMed: 31537134]
23. Tran MA, Montastruc JL, Montastruc P. [Pharmacological basis for the therapeutic use of ergot
alkaloids]. Presse Med 1983;12:517–20. [PubMed: 6131414]
24. Mäntylä R, Kanto J. Clinical pharmacokinetics of methylergometrine (methylergonovine). Int J
Clin Pharmacol Ther Toxicol 1981;19:386–91. [PubMed: 7298246]
25. Bygdeman M. Pharmacokinetics of prostaglandins. Best Pract Res Clin Obstet Gynaecol
Author Manuscript

2003;17:707–16. [PubMed: 12972009]

26. Tang OS, Gemzell-Danielsson K, Ho PC. Misoprostol: pharmacokinetic profiles, effects on the
uterus and side-effects. Int J Gynaecol Obstet 2007;99:S160–7. [PubMed: 17963768]
27. Escobar MF, Nassar AH, Theron G, et al. FIGO recommendations on the management of
postpartum hemorrhage 2022. Int J Gynaecol Obstet 2022;157:3–50. [PubMed: 35297039]
28. Chen Y, Jiang W, Zhao Y, et al. Prostaglandins for postpartum hemorrhage: pharmacology,
application, and current opinion. Pharmacology 2021;106:477–87. [PubMed: 34237742]
29. Cooley DM, Glosten B, Roberts JR, Eppes PD, Barnes RB. Bronchospasm after intramuscular
15-methyl prostaglandin F2 alpha and endotracheal intubation in a nonasthmatic patient. Anesth
Analg 1991;73:87–9. [PubMed: 1858995]
30. Harber CR, Levy DM, Chidambaram S, Macpherson MB. Life-threatening bronchospasm
after intramuscular carboprost for postpartum haemorrhage. BJOG 2007;114:366–8. [PubMed:
17261125]
31. Hemabate. Carboprost tromethamine. 2013. Available at: https://www.accessdata.fda.gov/
drugsatfda_docs/label/2013/017989s019lbl.pdf. Accessed April 21, 2022.
Author Manuscript

32. Cyklokapron. Tranexamic acid injection. 2013. Available at: https://www.accessdata.fda.gov/

drugsatfda_docs/label/2017/019281s041lbl.pdf. Accessed April 21, 2022.
33. WOMAN Trial Collaborators. 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 2017;389:2105–16.
[PubMed: 28456509]
34. Sentilhes L, Winer N, Azria E, et al. Tranexamic acid for the prevention of blood loss after vaginal
delivery. N Engl J Med 2018;379:731–42. [PubMed: 30134136]

Am J Obstet Gynecol MFM. Author manuscript; available in PMC 2023 February 21.
 Jones et al. Page 10

35. Saccone G, Della Corte L, D’Alessandro P, et al. Prophylactic use of tranexamic acid after
vaginal delivery reduces the risk of primary postpartum hemorrhage. J Matern Fetal Neonatal Med
Author Manuscript

2020;33:3368–76. [PubMed: 30704334]

36. Sentilhes L, Sénat MV, Le Lous M, et al. Tranexamic acid for the prevention of blood loss after
cesarean delivery. N Engl J Med 2021;384:1623–34. [PubMed: 33913639]
37. Pacheco LD. LB 3: Tranexamic acid for the prevention of obstetrical hemorrhage after cesarean
delivery: a randomized controlled trial. Am J Obstet Gynecol 2022;226:S779–80.
38. Bateman BT, Tsen LC, Liu J, Butwick AJ, Huybrechts KF. Patterns of second-line uterotonic use
in a large sample of hospitalizations for childbirth in the United States: 2007-2011. Anesth Analg
2014;119:1344–9. [PubMed: 25166464]
39. Gu J, Zhang X, Ma Y, et al. Quantitative modeling of dose-response and drug combination based
on pathway network. J Cheminform 2015;7:19. [PubMed: 26101547]
40. Huang RY, Pei L, Liu Q, et al. Isobologram analysis: a comprehensive review of methodology and
current research. Front Pharmacol 2019;10:1222. [PubMed: 31736746]
41. Lee SI. Drug interaction: focusing on response surface models. Korean J Anesthesiol 2010;58:421–
34. [PubMed: 20532049]
Author Manuscript

42. Alliance Pharmaceuticals. Syntometrine 500 micrograms/5 IU solution for injection (ampoules).
2016. Available at: https://www.medicines.org.uk/emc/product/865/smpc. Accessed April 28,
2022.
43. Pakniat H, Khezri MB. The effect of combined oxytocin-misoprostol versus oxytocin and
misoprostol alone in reducing blood loss at cesarean delivery: a prospective randomized double-
blind study. J Obstet Gynaecol India 2015;65:376–81. [PubMed: 26663995]
Author Manuscript
Author Manuscript

Am J Obstet Gynecol MFM. Author manuscript; available in PMC 2023 February 21.
 Author Manuscript Author Manuscript Author Manuscript Author Manuscript

TABLE 1

Medical therapy for prevention of postpartum hemorrhage

Absolute and relative

Jones et al.

Medication Mechanism of action Route of administration and dose Pharmacokinetics contraindications

Oxytocin Stimulates oxytocin receptors IV: 10–40 units per 500–1000 mL, continuous Onset of action: 1–6 min (IV); 3–5 min (IM) Rare; SIADH, hypotension,
in the uterus infusion Half-life: 4 min hypersensitivity to drug.
IM: 5–10 units; 4 dose maximum Peak plasma concentration: 30–60 min

Carbetocin Stimulates oxytocin receptors IV: 100 μg/mL in 1 dose injected over 1 min Onset of action of 1–6 min Hypersensitivity to drug,
in the uterus Half-life: 40 min hypertension, cardiac disease.
Peak plasma concentration: 20–30 min

Methylergonovine Serotoninergic agonist, IM: 200 μg every 2–4 h; 5 doses maximum Onset of action: 1–3 min Hypertension, preeclampsia,
maleate (ergot dopaminergic weak antagonist, PO: 200 μg every 6–8 h for 2–7 d Half-life: 30–120 min cardiovascular disease,
alkaloid) and α1-adrenergic partial Peak plasma concentration: 40 min hypersensitivity to drug.
agonist at receptors in the
uterus
Misoprostol PGE1 agonist in the uterine Sublingual, oral, or rectal (sublingual preferred): Onset of action: 8–11 min (PO, sublingual); 100 Rare; hypersensitivity to drug,
myometrium 600–1000 μg in 1-time dose; repeated doses not min (rectal) concurrent anticoagulant therapy;
recommended Half-life: 20–40 min efficacy is disputed.
Peak plasma concentration: 20–60 min

Carboprost PGF2α agonist in the uterine IM or IMM: 250 μg every 15–90 min; 8 doses Onset of action: 5–10 min Asthma; relative contraindication
tromethamine myometrium maximum Half-life: 8 min for hypertension, cardiac disease,
(PGF2α) Peak plasma concentration: 15–60 min or active hepatic, pulmonary, or
renal disease.

Tranexamic acid Diminishes the dissolution of IV: 1 g (100 mg/mL) over a 10-min period Onset of action: within 5 min Hypersensitivity to drug,
hemostatic fibrin by plasmin, Second dose may be administered if bleeding Half-life: 120 min history of hypercoagulopathy,
stabilizing clots in uterine persists after 30 min or stops and restarts within Peak plasma concentration: 6–8 min thromboembolic events during
vessels 24 h after the first dose pregnancy.

IM, intramuscular; IMM, intramyometrial; IV, intravascular; PGE1, prostaglandin E1; PGF2α, 15-methyl prostaglandin F2α; PO, by mouth; SIADH, syndrome of inappropriate antidiuretic hormone
secretion.

Am J Obstet Gynecol MFM. Author manuscript; available in PMC 2023 February 21.
Page 11
 Author Manuscript Author Manuscript Author Manuscript Author Manuscript

TABLE 2

Combination drug therapeutic efficacy for prevention of postpartum hemorrhage

RR of PPH vs placebo or no treatment (95% RR of need for additional uterotonics vs

Jones et al.

Drug combination Study CI) RR of PPH vs oxytocin alone (95% CI) oxytocin alone (95% CI)
Oxytocin–carbetocin Fahmy et al,8 2015 Not quantitatively evaluated

Oxytocin– Gallos et al,9 2018 0.41 (0.33–0.51) 0.70 (0.59–0.84) Not evaluated
ergometrine Jaffer et al,10 2022 Not evaluated Not evaluated 0.87 (0.11–6.39)

Oxytocin–misoprostol Gallos et al,9 2018 0.41 (0.31–0.53) 0.70 (0.58–0.86) Not evaluated
Jaffer et al,10 2022 Not evaluated Not evaluated 0.57 (0.09–3.55)
Parry Smith et al,11 2020 Not evaluated 0.84 (0.66–1.06) 0.99 (0.94–1.05)

Oxytocin–carboprost No studies to date evaluating this drug–drug combination vs placebo or other therapies

Oxytocin–tranexamic No studies to date evaluating this drug–drug combination vs placebo or other therapies
acid

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

Am J Obstet Gynecol MFM. Author manuscript; available in PMC 2023 February 21.
Page 12