Background: Postpartum hemorrhage (PPH) remains a common cause of maternal mortality worldwide. Medical intervention plays an important role in the prevention and treatment of PPH. Prostaglandins (PGs) are currently recommended as second-line uterotonics, which are applied in cases of persistent bleeding despite oxytocin treatment. Summary: PG agents that are constantly used in clinical practice include carboprost, sulprostone, and misoprostol, representing the analogs of PGF, PGE2, and PGE1, respectively. Injectable PGs, when used to treat PPH, are effective in reducing blood loss but probably induce cardiovascular or respiratory side effects. Misoprostol is characterized by oral administration, low cost, stability in storage, broad availability, and minimal side effects. It remains a treatment option for uterine atony in low-resource settings, but its effectiveness as a uterotonic for independent application may be limited. Key Messages: The present review article discusses the physiological roles of various natural PGs, evaluates the existing evidence of PG analogs in the prevention and treatment of PPH, and finally provides a reference to assist obstetricians in selecting appropriate uterotonics.

Postpartum hemorrhage (PPH) is a leading cause of maternal morbidity and mortality. It accounts for approximately 25% of all deaths of pregnant women worldwide, with an estimated 127,000 deaths per year [1-4]. PPH has an overall incidence of about 6% and is associated with serious morbidity. Occasionally, blood transfusions are required with this condition. Moreover, PPH may lead to renal failure, coagulation deficiencies, anemia, and surgical procedures that can result in loss of fertility. Epidemiologic studies have indicated that the incidence of PPH has been steadily increasing even in many well-resourced countries, for unknown reasons [5]. Between 1994 and 2014, rates of PPH have increased by 26%, and there has been a 50% rise in PPH caused by uterine atony [6, 7].

PPH is usually defined as a blood loss >500 mL following a vaginal birth or a loss of >1,000 mL after a cesarean birth [8]. The increased rates of atonic PPH have emphasized the importance of active management in the third stage of labor [9]. Data from several large randomized trials have demonstrated that the prevalence rate of PPH of >500 mL was approximately 5% when active management was applied compared with 13% when expectant management was used [10]. The evidence appeared to show that active management reduced the average risk of severe primary PPH (>1,000 mL) at birth. Therefore, it is essential to perform close monitoring, implement additional measures as necessary, and check for the cause of bleeding, especially for women with possible high-risk factors. One such measure is the administration of uterotonics, which is routinely performed postdelivery to prevent excessive postpartum bleeding due to uterine atony [11].

Traditionally, oxytocin has been the treatment of choice for the prevention and treatment of PPH. Compared to no uterotonics [12, 13], oxytocin prophylaxis is associated with a reduced risk of PPH, but refractory uterine atony can occur when the uterus fails to adequately contract after oxytocin administration. Owing to the saturation of oxytocin receptors, oxytocin confers the disadvantage of receptor desensitization with repeated injections. In addition, it requires refrigerated conditions for storage and professional personnel for its administration, making it difficult to access in remote, low-resource settings. In the setting of refractory uterine atony, approximately 3–25% of patients require other uterotonics to promote uterine contraction after oxytocin injection [8].

Prostaglandin (PG) agents, as second-line uterotonics, are widely used in contemporary obstetric practice [14]. PGs have strong uterotonic properties, and such agents may be used within obstetrics and gynecology for the purpose of cervical ripening, termination of pregnancy, induction of labor, and PPH [15, 16]. In the process of labor, maternal concentrations of endogenous PGs increase gradually in the first stage and steeply in the second stage, and then peak immediately after delivery of the placenta. Noort et al. [17] showed the concentrations of plasma prostaglandin F (PGF) metabolite at placental separation were markedly higher than those at full cervical dilatation, and the concentrations were highest 5 min after placental separation. Their study showed that one of the possible reasons for uterine atony could be insufficient increase in PG concentration in the third stage of labor. Furthermore, according to the same study, PGs also stimulate the production of oxytocin receptors [18]. Therefore, the application of PGs for the prevention and management of PPH was a logical extension of their critical pharmacological effects in labor. The properties of PGs leading to sustained myometrial contractility are well suited to the management of PPH and its complications.

PGs are a series of metabolites formed from arachidonic acid, which are mainly produced by cyclooxygenase (shown in Fig. 1). PGs were originally thought to activate membrane receptors near their formation site. Their different biological activities and generation of second messengers (cyclic AMP [cAMP], inositol phosphates, and Ca2+[IP3/Ca2+]) suggested that PGs interact with distinct receptors, and different receptors correspond with different PGs [19]. It was determined that prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), prostaglandin F (PGF), prostacyclin I2 (PGI2), and thromboxane A2 (TXA2) exert their biological function by interactions with their respective receptors – the DP, EP, FP, IP, and TP receptors [20]. Four subtypes of EP receptor have been identified (EP1–EP4) (Fig. 1). PG receptors are located in the myometrium, trophoblast cells, amnion, and cervix, and all belong to the G-protein-coupled superfamily, incorporating 7 transmembrane domains [21].

Fig. 1.

Metabolism of arachidonic acid. Membrane-bound PG receptors are shown in blue boxes. Cyclooxygenase and related enzymes are shown in red. PG, prostaglandin.

Fig. 1.

Metabolism of arachidonic acid. Membrane-bound PG receptors are shown in blue boxes. Cyclooxygenase and related enzymes are shown in red. PG, prostaglandin.

Close modal

The PGs produced in the human endometrium are mainly those of the E and F series, while PGD2, PGI2, and TXA2 occur less frequently [22]. PGF action is mediated by the FP receptor, increasing the intracellular calcium concentration ([Ca2+]i) via the PLC-IP3-Ca2+ pathway. PGE2 acts differently through 4 subtypes (EP1–EP4) in human myometrium: its interaction with EP1 receptors elevates [Ca2+]i via the PLC-IP3-Ca2+ pathway, while EP2 and EP4 receptor signals stimulate the production of adenylyl cyclase. Overall, differences in biological functions of the PG receptors reveal 3 subclusters (shown in Fig. 2). The first of these subclusters consists of receptors TP, FP, and EP1, which increase [Ca2+]i and constitute a group of “contractile” receptors because they cause smooth muscle contraction. The second group consists of receptors IP, DP, EP2, and EP4, which increase the concentration of intracellular cAMP via Gs protein and are defined as “relaxant” receptors because they induce smooth muscle relaxation. Finally, the third group consists only of EP3 and is generally associated with a decline in cAMP. The “inhibitory” receptor generally causes smooth muscle contraction, depending on the cell type; however, the EP3 receptor can also increase intracellular cAMP and induce [Ca2+]i [23].

Fig. 2.

Prostanoid receptors and their primary signaling pathways. Prostanoid receptors are members of the G-protein-coupled receptor superfamily. The terms “relaxant,” “contractile,” and “inhibitory” refer to the phylogenetic characterization of their primary effects.

Fig. 2.

Prostanoid receptors and their primary signaling pathways. Prostanoid receptors are members of the G-protein-coupled receptor superfamily. The terms “relaxant,” “contractile,” and “inhibitory” refer to the phylogenetic characterization of their primary effects.

Close modal

Interestingly, the nonpregnant human uterus contracts in the presence of PGF and TXA2 but relaxes in the presence of PGE [24]. Uterine strips isolated from pregnant women contract with PGF and low concentrations of PGE2, while PGI2 and high concentrations of PGE2 induce relaxation [24]. One possible explanation for this is that PG receptor expression varies considerably from the nonpregnant state through pregnancy to birth, and the relative level or type of receptors may dictate the degree of uterine quiescence or contractility [25]. For example, the uterine FP mRNA expression level has been found to decline significantly with gestational age in patients not in labor and then at term increase significantly with labor [26]. Thus, in the initiation of parturition, myometrial active quiescence may change to an active contractile state due to an upregulation of contractile receptors and downregulation of relaxatory receptors [27, 28]. Moreover, the additional control for the onset of labor is built into the increased synthesis of endogenous PGs of the E and F series in the uterine compartment [29, 30]. The intra-amniotic, intravenous, or vaginal administration of exogenous PGs can initiate labor at any stage of gestation and in all mammalian species. For pregnant women in labor and placental delivery, PGE or PGF produces a dose-dependent increase in the frequency and intensity of uterine contractions [24]. Additionally, PGE2 appears to play a more important role in cervical ripening and rupture of the fetal membranes than in uterine contractility [31].

However, natural PGs may be associated with rapid metabolism, unstable chemical properties, and a number of adverse reactions that limit their clinical applications. Numerous PG analogs have therefore been developed for appropriate clinical use. The preparations are available in the form of injections, tablets, or suppositories based on their intended application. The objective of this review was to evaluate the existing evidence on the roles of various PG analogs in preventing and treating PPH and to consider their differences in adverse reactions in clinical use.

In the prevention and treatment of PPH, the PG agents that are frequently used in clinical practice include carboprost, sulprostone, and misoprostol, representing the analogs of PGF, PGE2, and PGE1, respectively [32].

Side Effects

Smooth Muscle

Endogenous and synthetic PGs also contract or relax smooth muscles in tissues outside the uterus. In general, TXA2, PGF, and PGD2 contract, while PGE2 and PGI2 relax the bronchial and tracheal smooth muscles. Numerous case reports have been documented of life-threatening bronchospasm associated with carboprost (a synthetic PGF analog) [33]. PGEs and PGFs also induce contraction of the main longitudinal muscle in the gastrointestinal tract and increase the movement of water as well as electrolytes into the intestinal lumen. Such physiological effects could explain the watery diarrhea that follows oral or parenteral administration. Generally, diarrhea, cramps, and reflux of bile have been caused by PG agents as well as endogenous PG release such as labor (nausea and hyperthermia), which are common side effects in patients administered PG analogs (including carboprost, sulprostone, and misoprostol) for clinical use.

Cardiovascular System

Generally, PGs do not directly affect systemic vascular performance. They may, however, modulate local vascular tone at the site of their formation and ultimately affect systemic blood pressure [34]. In most blood vessels, PGE2 elicits vasodilation and a slight drop in blood pressure. PGF is a potent constrictor of both pulmonary arteries and veins. Blood pressure is increased by PGF in humans. However, the observed influence of PG analogs on blood pressure is clinically insignificant, although carboprost should be used with caution in hypertensive patients. Direct inotropic effects have been noted with sulprostone (a synthetic PGE2 analog) [35, 36], especially when administered directly into the uterine wall. However, there is a contradiction between the role of sulprostone as a coronary artery dilator and the coronary vasospastic hypothesis that causes serious cardiovascular side effects related to sulprostone. Experimental studies [37, 38] analyzed the role of endogenous PGE2 in regulating coronary artery resistance and pointed out its vasodilatory effect on arterioles and inhibition of endothelium-myeloid cell interactions; especially in the presence of ischemic factors, it can limit the infarct size. It is considered the treatment with some clinically available PGE analogs, such as misoprostol, could reduce the injury of ischemic cardiomyopathy [38]. Furthermore, we noticed the cases of severe cardiovascular or respiratory side effects reported with the use of injectable PGs to control atonic PPH were associated with the route of administration that is not recommended, high combined doses of both sulprostone and carboprost, or hemorrhagic shock [39-41]. Therefore, in terms of drug labels and clinical management guidelines [42], direct intramyometrial injections are not approved for sulprostone.

CNS

The fever caused by a variety of endogenous and exogenous pyrogens is mediated by PGE2 [24]. PGE2 crosses the blood-brain barrier and acts on EP3 or EP1 in thermosensitive neurons. This stimulates the hypothalamus to elevate the body temperature by promoting increased heat production and reduced heat loss. PGF induces fever but does not participate in the pyretic response. The PG analogs in clinical applications, especially misoprostol, have been shown to be associated with a significantly higher rate of shivering and a body temperature >38°C [43]. A large multicenter study [44] reported an unusually high rate of fever >40°C (36%) in Ecuadorian women who received 800 μg of misoprostol sublingually compared with other participants (0–9%) who received the same regimen. Since the incidence of fever varies greatly in different populations, there is hypothesis that genetic factors may play a role in misoprostol-induced fever [45]. Some studies [46] suggest that genetic variability in ABCC4 and the resultant higher level of misoprostol acid in the brain lead to hyperpyrexia in pregnant women. But after treatments, such effects were related, transient, self-limiting, and do not result in additional health complications [47].

Eye

Prior to the 1970s, studies had demonstrated that the effect of PGF on the eye was to elevate intraocular pressure. Consequently, glaucoma has been a contraindication to the administration of PGF analogs. Until 1977, studies [48] had confirmed that PGF-induced constriction of the iris sphincter muscle and its overall role on the eyes was to reduce intraocular pressure by increasing the outflow of aqueous humor. This represented a dramatic reversal, in our understanding, of the role of PGs in relation to the eye. Since then, a range of FP receptor agonists have proved effective in the treatment of glaucoma [49]. However, in China, the domestic instructions pertaining to PGF agents have not been updated in regard to glaucoma as a contraindication. Pharmaceutical companies and national drug administrations have now been informed about the contraindication on the use of PGF agents in this context.

Injectable PGs

Injectable PG analogs such as sulprostone and carboprost are generally regarded as second-line uterotonics in PPH treatment. They induce strong and sustained myometrial contractions and have a reported efficacy of 87–92% [50]. Injectable PGs are unequivocally considered as suitable medications for PPH treatment, but not for its prevention. For women at low risk of PPH, injectable PGs are related to more frequent cardiovascular or respiratory side effects [51]. In addition, injectable PGs are currently not available in all medical facilities, and where they are available, the drug cost is high [46]. Therefore, in many clinical management guidelines, injectable PGs are not recommended for the prevention of PPH [52-54]; only if oxytocin or other first-line uterotonics do not provide adequate uterine tone, injectable PGs should be considered. Administration of injectable PGs should be guided by the clinical context and presence of contraindications and follow local hospital policies and availability.

Carboprost

Carboprost is an analog of PGF. The rapid metabolism of natural PGs limits their clinical application and promotes the development of analogs with longer durations of action. Carboprost tromethamine is a mixture of 15-methyl PGF and tromethamine (shown in Fig. 3). The oxidation of carboprost, with the hydrogen being replaced by a methyl group, is completely restricted [55]. It has the same pharmacological action as PGF, the contraction intensity of the uterus being 20–100 times stronger than that of PGF. In clinical practice, 80% of patients with uterine atony exhibited a response below 250 μg, and 95% of patients showed a response below 500 μg [56]. Dildy’s statistics on 1,237 cases of carboprost application in 12 medical institutions showed that the effective percentage was 94.19% [57].

Fig. 3.

Structural formula of PGF and carboprost. PG, prostaglandin.

Fig. 3.

Structural formula of PGF and carboprost. PG, prostaglandin.

Close modal

In cases of continuous bleeding that is refractory to the administration of oxytocin or ergot alkaloids, injectable PGs are considered the second therapeutic step. Compared to conventional uterotonics, carboprost results in less blood loss and shorter duration of the third stage of labor, but vomiting, abdominal pain, and diarrhea were more common with carboprost administration [15].

Carboprost can, however, cause bronchospasm. Increases in pulmonary and systemic vascular resistance together with intrapulmonary shunting can trigger desaturation of arterial hemoglobin oxygen. Asthma patients are particularly susceptible to these complications, but there are some reported cases of bronchospasm in patients without asthma [58]. It is worth noting that PGF is an endogenous compound involved both in physiology and in pathology. Many preclinical and clinical studies [59] have revealed PGF to be associated with severe acute or chronic inflammatory diseases such as rheumatic diseases and is a risk factor for atherosclerosis, diabetes, ischemia-reperfusion, septic shock, and many other conditions. For patients with the above diseases, carboprost should be used with caution, especially when repeated injections are necessary.

Sulprostone

The Dutch, German, and French guidelines [42, 60, 61] recommend the application of sulprostone, a PGE2 analog, in cases of persistent bleeding despite oxytocin treatment. It is usually administrated by intravenous infusion; intramuscular and intramyometrial injections are contraindicated for sulprostone. A comparative study on the clinical use of sulprostone and carboprost revealed significantly fewer side effects for sulprostone [62]. However, as case reports [35, 36] found it to be associated with cardiac arrest in 3 women, manufacturers – with the exception of certain European countries – later withdrew the drug. While obstetricians may be reluctant to use sulprostone on account of its reported side effects, this issue is controversial because no causal relationship has been documented and the actual frequency of these events remains unknown.

The current French guidelines recommend the use of a continuous intravenous infusion of sulprostone within 30 min after PPH diagnosis if bleeding persists after oxytocin administration, and also that the dose should not exceed 500 μg in the first hour and 1,500 μg in total. In some population-based studies, with close medication monitoring, sulprostone is thought to be a safe and effective choice for patients with placental retention [63] or for patients with PPH. Severe cardiovascular or respiratory side effects have been found to be uncommon (i.e., a prevalence of 0.1–1% according to the World Health Organization) [64].

Misoprostol

Misoprostol, a PGE1 analog registered for the prevention and treatment of peptic ulcer and upper gastrointestinal hemorrhage caused by nonsteroidal anti-inflammatory drugs, has attracted widespread attention because of its strong uterotonic effects and ease of administration. El-Refaey [65] reported the first use of oral misoprostol for the management of the third stage of labor in an observational study. Compared with naturally occurring PGE1, misoprostol exhibits superiority in many aspects. It transforms the chemical structure of natural PGE1 into a more stable form. These modifications (shown in Fig. 4) increase oral activity, duration of action, and safety [66].

Fig. 4.

Structural formula of PGE1 and misoprostol. PG, prostaglandin.

Fig. 4.

Structural formula of PGE1 and misoprostol. PG, prostaglandin.

Close modal

Misoprostol is not registered for use during pregnancy, but in most countries, physicians may conduct off-label drug use with appropriate informed patient consent [67]. The clinical applications of misoprostol in gynecology and obstetrics include medically induced abortion, induction of labor, cervical ripening, and treatment of uterine atony. The oral preparation offers stability at room temperature and is significantly cheaper than PGE2 and other analogs. Although misoprostol is administered orally, there are also vaginal, sublingual, buccal, and rectal routes. Rectal administration has been used for the prevention and treatment of PPH [68]. Pharmacokinetic evaluations of misoprostol absorption when administered by various routes have been performed [69-72]. In these studies (shown in Table 1), following an administration dose of 400 μg, misoprostol demonstrates a route-dependent pharmacokinetic profile.

Table 1.

Pharmacokinetic parameters of oral, vaginal, sublingual, and rectal misoprostol

Pharmacokinetic parameters of oral, vaginal, sublingual, and rectal misoprostol
Pharmacokinetic parameters of oral, vaginal, sublingual, and rectal misoprostol

In terms of drug peak time, the oral and sublingual administrations seem to be superior. Sublingual misoprostol achieved the highest peak plasma concentrations (Cmax) (574 ± 250.7 pg/mL), and this was significantly higher than those in oral and vaginal routes, which was 287.6 ± 144.3 and 125.2 ± 53.8 pg/mL, respectively. The time to peak concentration (Tmax) was similar in both the sublingual (26.0 ± 11.5 min) and oral routes (27.5 ± 14.8 min), which was significantly shorter than those in the vaginal route [72]. Vaginal administrations of misoprostol show a slower pattern and a longer time (Tmax = 72.0 ± 34.5 min) to peak plasma concentrations (Cmax = 125.2 ± 53.8 pg/mL) [72], but the reduction in plasma concentration is also much slower, with corresponding advantages in bioavailability generally. In another pharmacokinetic study of misoprostol [71], the bioavailability of vaginal route as shown by AUC[240] was 446.0 ± 172.1 (pg·h/mL), greater than either oral or rectal misoprostol. In addition, rectally administered misoprostol is similar in terms of its absorption curve to that of vaginal misoprostol, but is lower in bioavailability, which was expressed by AUC[240] (188.9 ± 126.1 pg h/mL) [71]. The change in plasma concentrations corresponds to the effect on uterine contractility. Taken together, it is considered that the period from the start of treatment to an obvious effect is notably shorter following sublingual and oral administration, and the duration of effect is significantly longer by vaginal and rectal administration. These conclusions will help optimize existing regimens and identify the ideal routes of administration for different clinical indications. In the treatment of PPH, prompt myometrial contractility should be induced by misoprostol, according to pharmacokinetic studies, and oral or sublingual route is preferred with the shortest interval to peak concentrations. In many clinical management guidelines, a single oral/sublingual/rectal dosage of 600–1,000 μg is advocated on PPH in uterine atony (shown in Table 2). Furthermore, a variety of doses and routes of administration [73-75] have been tested using control regimens that have included conventional and nonconventional uterotonics, as well as placebo. It is considered that 400–600 μg misoprostol administered orally is optimal for PPH prevention and 800 μg sublingual misoprostol has the most evidence supporting its safety and efficacy for PPH treatment [76, 77]. It is worth noting that rectal administration has also been proposed for application in the third stage of labor. There may be 2 reasons for this application. First, rectal misoprostol likely has a higher degree of bioavailability because the rectal mucosa is moister in the third stage of labor and thus enhances absorption. Second, there are advantages in considering combined dosage regimens that utilize the absorption speed of oral administration, as well as the higher level of bioavailability, and the longer duration of effect, regarding the rectal route in the third stage of labor and postpartum. Vaginal administration may not be practical in active PPH with massive vaginal bleeding.

Table 2.

Recommendations on the use of misoprostol in the management of PPH

Recommendations on the use of misoprostol in the management of PPH
Recommendations on the use of misoprostol in the management of PPH

As a second-line agent for the prevention and treatment of uterine atony, misoprostol has been suggested as an alternative for the routine management of the third stage of labor. In a meta-analysis [15] of numerous large RCTs comparing misoprostol versus placebo administration, oral or sublingual misoprostol has been shown to be effective in reducing severe PPH and blood transfusion. Compared with conventional injectable uterotonics, oral misoprostol was associated with higher risk of severe PPH, but with a trend toward fewer blood transfusions. Another network meta-analysis [78] comprising 140 randomized trials with data from 88,947 postpartum women indicated the 3 most effective drugs for the prevention of PPH ≥500 mL were ergometrine plus oxytocin, carbetocin, and misoprostol plus oxytocin combined. It has been suggested that misoprostol, as an adjuvant to oxytocin, can also be applied for earlier interventions when uterine atony is refractory. Overall, when considering areas with poor medical services, the supply and storage of expensive or light-sensitive or temperature-sensitive medications are limited, and misoprostol offers an uterotonic alternative that is inexpensive and easy to store [79]. In 2011, the WHO added misoprostol for the prevention of PPH to the Model List of Essential Medicines, thus solidifying recommendations for its use, including dose and route of administration.

Misoprostol appears to have no serious side effects, in appropriate doses and durations, for the treatment of uterine atony. However, it is associated with higher rates of shivering and fever, along with other PG-related side effects such as nausea, vomiting, and diarrhea. Following misoprostol administration, few women have been shown to have a body temperature >40°C during the first hour after delivery. For every 7–9 women given 600 μg of misoprostol, 1 additional woman will have “shivering”; for every 17–21 women, 1 additional woman will have a body temperature >38°C [43]. Taken together, the incidence of fever for misoprostol reportedly varies from 10 up to 50% [44, 80, 81], which is related to both its dosage and route with the highest incidences found in the high-dose sublingual routes, owing to its pharmacokinetics [82]. However, this is not the only influence on postnatal fever. There appear also to be other effects that could be genetic or cultural [44, 45]. Clinically, it is worth noting that fever as the side effect of misoprostol and fever caused by postpartum infection need to be distinguished more carefully [83]. There are no contraindications to using misoprostol in postpartum women except in those with a history of an allergic reaction. Asthma is not a contraindication as misoprostol is a weak bronchodilator. These tablets do not cause hypertension, which enables them to be used for hypertensive patients.

Both injectable PGs and misoprostol are preferable as part of the management in the third stage of labor when the first-line treatments for uterine atony have proved ineffective. The choice of which medication to apply should be based on the patients’ specific details and the clinical diagnosis of the obstetrician in charge of the case. Therefore, it is important for practitioners to understand both the risks and benefits of commonly used PG agents. Optimizing their use might help mitigate progression to severe PPH and reduce the need for invasive procedures. As side effects are dose related, optimal effective dose and route of administration during PPH remain an area of active research. We look forward to further advances in preventing and treating PPH in the future.

The authors have no conflicts of interest to disclose.

This study received funding from Zhejiang Provincial Natural Science Foundation of China (No. LYY21H300006) and the Research funding project of Zhejiang Pharmaceutical Association (No. 2016ZYY06).

Y.C. drafted the manuscript. C.H.Z. carried out conceptualization. W.J. assisted in reviewing literature. Y.C. designed and drew the figures in the manuscript. The manuscript was modified by Y.C.Z. and D.L.S. F.W. and X.Z. helped in reviewing the first draft of the manuscript. All authors approved the final manuscript and agreed to be accountable for all aspects of the work.

1.
Say
L
,
Chou
D
,
Gemmill
A
,
Tunçalp
Ö
,
Moller
AB
,
Daniels
J
,
Global causes of maternal death: a WHO systematic analysis
.
Lancet Glob Health
.
2014
;
2
(
6
):
e323
33
. .
2.
GBD 2015 Maternal Mortality Collaborators
.
Global, regional, and national levels of maternal mortality, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015
.
Lancet
.
2016
;
388
(
10053
):
1775
812
. .
3.
Souza
JP
,
Gülmezoglu
AM
,
Vogel
J
,
Carroli
G
,
Lumbiganon
P
,
Qureshi
Z
,
Moving beyond essential interventions for reduction of maternal mortality (the WHO Multicountry Survey on Maternal and Newborn Health): a cross-sectional study
.
Lancet
.
2013
;
381
(
9879
):
1747
55
. .
4.
Nathan
LM
.
An overview of obstetric hemorrhage
.
Semin Perinatol
.
2019
;
43
(
1
):
2
4
. .
5.
Kramer
MS
,
Berg
C
,
Abenhaim
H
,
Dahhou
M
,
Rouleau
J
,
Mehrabadi
A
,
Incidence, risk factors, and temporal trends in severe postpartum hemorrhage
.
Am J Obstet Gynecol
.
2013
;
209
(
5
):
449
7
. .
6.
Mehrabadi
A
,
Hutcheon
JA
,
Lee
L
,
Liston
RM
,
Joseph
KS
.
Trends in postpartum hemorrhage from 2000 to 2009: a population-based study
.
BMC Pregnancy Childbirth
.
2012
;
12
:
108
. .
7.
Ford
JB
,
Patterson
JA
,
Seeho
SK
,
Roberts
CL
.
Trends and outcomes of postpartum haemorrhage, 2003–2011
.
BMC Pregnancy Childbirth
.
2015
;
15
:
334
. .
8.
Committee on Practice Bulletins-Obstetrics
.
Practice bulletin No. 183: postpartum hemorrhage
.
Obstet Gynecol
.
2017
;
130
(
4
):
e168
e86
.
9.
Weeks
AD
,
Fawcus
S
.
Management of the third stage of labour: (for the Optimal Intrapartum Care series edited by Mercedes Bonet, Femi Oladapo and Metin Gülmezoglu)
.
Best Pract Res Clin Obstet Gynaecol
.
2020
;
67
:
65
79
.
10.
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
(
2
):
Cd007412
. .
11.
Parry Smith
WR
,
Papadopoulou
A
,
Thomas
E
,
Tobias
A
,
Price
MJ
,
Meher
S
,
Uterotonic agents for first-line treatment of postpartum haemorrhage: a network meta-analysis
.
Cochrane Database Syst Rev
.
2020
;
11
:
Cd012754
. .
12.
Govind
N
.
Prophylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage: a Cochrane review summary
.
Int J Nurs Stud
.
2020
:
103712
. .
13.
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
(
4
):
Cd001808
. .
14.
Butwick
AJ
,
Carvalho
B
,
Blumenfeld
YJ
,
El-Sayed
YY
,
Nelson
LM
,
Bateman
BT
.
Second-line uterotonics and the risk of hemorrhage-related morbidity
.
Am J Obstet Gynecol
.
2015
;
212
(
5
):
642
7
. e1.
15.
Tunçalp
Ö
,
Hofmeyr
GJ
,
Gülmezoglu
AM
.
Prostaglandins for preventing postpartum haemorrhage
.
Cochrane Database Syst Rev
.
2012
;
2012
(
8
):
Cd000494
. .
16.
Soon
JA
,
Costescu
D
,
Guilbert
E
.
Medications used in evidence-based regimens for medical abortion: an overview
.
J Obstet Gynaecol Can
.
2016
;
38
(
7
):
636
45
. .
17.
Noort
WA
,
van Bulck
B
,
Vereecken
A
,
de Zwart
FA
,
Keirse
MJ
.
Changes in plasma levels of PGF2 alpha and PGI2 metabolites at and after delivery at term
.
Prostaglandins
.
1989
;
37
(
1
):
3
12
. .
18.
Ravanos
K
,
Dagklis
T
,
Petousis
S
,
Margioula-Siarkou
C
,
Prapas
Y
,
Prapas
N
.
Factors implicated in the initiation of human parturition in term and preterm labor: a review
.
Gynecol Endocrinol
.
2015
;
31
(
9
):
679
83
. .
19.
Kennedy
I
,
Coleman
RA
,
Humphrey
PP
,
Levy
GP
,
Lumley
P
.
Studies on the characterisation of prostanoid receptors: a proposed classification
.
Prostaglandins
.
1982
;
24
(
5
):
667
89
. .
20.
Coleman
RA
,
Smith
WL
,
Narumiya
S
.
International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes
.
Pharmacol Rev
.
1994
;
46
(
2
):
205
29
.
21.
Narumiya
S
,
Sugimoto
Y
,
Ushikubi
F
.
Prostanoid receptors: structures, properties, and functions
.
Physiol Rev
.
1999
;
79
(
4
):
1193
226
. .
22.
Jabbour
HN
,
Sales
KJ
.
Prostaglandin receptor signalling and function in human endometrial pathology
.
Trends Endocrinol Metab
.
2004
;
15
(
8
):
398
404
. .
23.
Tsuboi
K
,
Sugimoto
Y
,
Ichikawa
A
.
Prostanoid receptor subtypes
.
Prostaglandins Other Lipid Mediat
.
2002
;
68–69
:
535
56
. .
24.
Brunton
L
,
Chabner
B
,
Goodman
L
,
Knollmann
B
.
Goodman & Gilman’S The pharmacological basis of therapeutics
;
2011
.
25.
Olson
DM
,
Zaragoza
DB
,
Shallow
MC
,
Cook
JL
,
Mitchell
BF
,
Grigsby
P
,
Myometrial activation and preterm labour: evidence supporting a role for the prostaglandin F receptor: a review
.
Placenta
.
2003
;
24
(
Suppl A
):
S47
54
. .
26.
Brodt-Eppley
J
,
Myatt
L
.
Prostaglandin receptors in lower segment myometrium during gestation and labor
.
Obstet Gynecol
.
1999
;
93
(
1
):
89
93
. .
27.
Konopka
CK
,
Glanzner
WG
,
Rigo
ML
,
Rovani
MT
,
Comim
FV
,
Gonçalves
PB
,
Responsivity to PGE2 labor induction involves concomitant differential prostaglandin E receptor gene expression in cervix and myometrium
.
Genet Mol Res
.
2015
;
14
(
3
):
10877
87
. .
28.
Unlugedik
E
,
Alfaidy
N
,
Holloway
A
,
Lye
S
,
Bocking
A
,
Challis
J
,
Expression and regulation of prostaglandin receptors in the human placenta and fetal membranes at term and preterm
.
Reprod Fertil Dev
.
2010
;
22
(
5
):
796
807
. .
29.
Gibb
W
.
The role of prostaglandins in human parturition
.
Ann Med
.
1998
;
30
(
3
):
235
41
. .
30.
Lee
SE
,
Romero
R
,
Park
IS
,
Seong
HS
,
Park
CW
,
Yoon
BH
.
Amniotic fluid prostaglandin concentrations increase before the onset of spontaneous labor at term
.
J Matern Fetal Neonatal Med
.
2008
;
21
(
2
):
89
94
. .
31.
Bakker
R
,
Pierce
S
,
Myers
D
.
The role of prostaglandins E1 and E2, dinoprostone, and misoprostol in cervical ripening and the induction of labor: a mechanistic approach
.
Arch Gynecol Obstet
.
2017
;
296
(
2
):
167
79
. .
32.
Sharma
S
,
El-Refaey
H
.
Prostaglandins in the prevention and management of postpartum haemorrhage
.
Best Pract Res Clin Obstet Gynaecol
.
2003
;
17
(
5
):
811
23
. .
33.
Booker
WA
,
Siddiq
Z
,
Huang
Y
,
Ananth
CV
,
Wright
JD
,
Cleary
KL
,
Use of antihypertensive medications and uterotonics during delivery hospitalizations in women with asthma
.
Obstet Gynecol
.
2018
;
132
(
1
):
185
92
. .
34.
Fitzgerald
GA
.
Chapter 150: prostaglandin mediators
.
Elsevier Inc.
;
2010
.
35.
Beerendonk
CC
,
Massuger
LF
,
Lucassen
AM
,
Lerou
JG
,
van den Berg
PP
.
[Circulatory arrest following sulprostone administration in postpartum hemorrhage]
.
Ned Tijdschr Geneeskd
.
1998
;
142
(
4
):
195
7
.
36.
Sorbette
F
,
Delay
M
,
Genestal
M
,
Jorda
MF
,
Carrie
D
,
Montastruc
JL
,
[Cardio-circulatory arrest with mifepristone sulprostone combination for pregnancy interruption]
.
Therapie
.
1991
;
46
(
5
):
387
9
.
37.
Zhu
L
,
Xu
C
,
Huo
X
,
Hao
H
,
Wan
Q
,
Chen
H
,
The cyclooxygenase-1/mPGES-1/endothelial prostaglandin EP4 receptor pathway constrains myocardial ischemia-reperfusion injury
.
Nat Commun
.
2019
;
10
(
1
):
1888
. .
38.
Zhu
L
,
Zhang
Y
,
Guo
Z
,
Wang
M
.
Cardiovascular biology of prostanoids and drug discovery
.
Arterioscler Thromb Vasc Biol
.
2020
;
40
(
6
):
1454
63
. .
39.
Hagenaars
M
,
Knape
JT
,
Backus
EM
.
Pulmonary oedema after high infusion rate of sulprostone
.
Br J Anaesth
.
2009
;
102
(
2
):
281
2
. .
40.
Chen
FG
,
Koh
KF
,
Chong
YS
.
Cardiac arrest associated with sulprostone use during caesarean section
.
Anaesth Intensive Care
.
1998
;
26
(
3
):
298
301
. .
41.
Krumnikl
JJ
,
Böttiger
BW
,
Strittmatter
HJ
,
Motsch
J
.
Complete recovery after 2 h of cardiopulmonary resuscitation following high-dose prostaglandin treatment for atonic uterine haemorrhage
.
Acta Anaesthesiol Scand
.
2002
;
46
(
9
):
1168
70
. .
42.
Bohlmann
MK
,
Rath
W
.
Medical prevention and treatment of postpartum hemorrhage: a comparison of different guidelines
.
Arch Gynecol Obstet
.
2014
;
289
(
3
):
555
67
. .
43.
Gülmezoglu
AM
,
Villar
J
,
Ngoc
NT
,
Piaggio
G
,
Carroli
G
,
Adetoro
L
,
WHO multicentre randomised trial of misoprostol in the management of the third stage of labour
.
Lancet
.
2001
;
358
(
9283
):
689
95
. .
44.
Durocher
J
,
Bynum
J
,
León
W
,
Barrera
G
,
Winikoff
B
.
High fever following postpartum administration of sublingual misoprostol
.
BJOG
.
2010
;
117
(
7
):
845
52
. .
45.
Durocher
J
,
Aguirre
JD
,
Dzuba
IG
,
Mirta Morales
E
,
Carroli
G
,
Esquivel
J
,
High fever after sublingual administration of misoprostol for treatment of post-partum haemorrhage: a hospital-based, prospective observational study in Argentina
.
Trop Med Int Health
.
2020
;
25
(
6
):
714
22
. .
46.
Alfirevic
A
,
Durocher
J
,
Elati
A
,
León
W
,
Dickens
D
,
Rädisch
S
,
Misoprostol-induced fever and genetic polymorphisms in drug transporters SLCO1B1 and ABCC4 in women of Latin American and European ancestry
.
Pharmacogenomics
.
2015
;
16
(
9
):
919
28
. .
47.
Goldberg
AB
,
Greenberg
MB
,
Darney
PD
.
Misoprostol and pregnancy
.
N Engl J Med
.
2001
;
344
(
1
):
38
47
. .
48.
Camras
CB
,
Bito
LZ
,
Eakins
KE
.
Reduction of intraocular pressure by prostaglandins applied topically to the eyes of conscious rabbits
.
Invest Ophthalmol Vis Sci
.
1977
;
16
(
12
):
1125
34
.
49.
Klimko
PG
,
Sharif
NA
.
Discovery, characterization and clinical utility of prostaglandin agonists for the treatment of glaucoma
.
Br J Pharmacol
.
2019
;
176
(
8
):
1051
8
. .
50.
Rajan
PV
,
Wing
DA
.
Postpartum hemorrhage: evidence-based medical interventions for prevention and treatment
.
Clin Obstet Gynecol
.
2010
;
53
(
1
):
165
81
. .
51.
Gallos
ID
,
Williams
HM
,
Price
MJ
,
Merriel
A
,
Gee
H
,
Lissauer
D
,
Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis
.
Cochrane Database Syst Rev
.
2018
;
4
(
4
):
CD011689
CD
. .
52.
WHO recommendations: uterotonics for the prevention of postpartum haemorrhage. World Health Organization. Licence: CC BY-NC-SA 30 IGO. 2018.
53.
Heesen
M
,
Carvalho
B
,
Carvalho
JCA
,
Duvekot
JJ
,
Dyer
RA
,
Lucas
DN
,
International consensus statement on the use of uterotonic agents during caesarean section
.
Anaesthesia
.
2019
;
74
(
10
):
1305
19
. .
54.
Queensland Clinical Guidelines. Postpartum haemorrhage Guideline No. MN18.1-V9-R23. Queensland Health. 2020.
55.
Bygdeman
M
.
Pharmacokinetics of prostaglandins
.
Best Pract Res Clin Obstet Gynaecol
.
2003
;
17
(
5
):
707
16
. .
56.
O’Leary
AM
.
Severe bronchospasm and hypotension after 15-methyl prostaglandin F(2alpha) in atonic post partum haemorrhage
.
Int J Obstet Anesth
.
1994
;
3
(
1
):
42
4
. .
57.
Dildy
GA
 3rd
.
Postpartum hemorrhage: new management options
.
Clin Obstet Gynecol
.
2002
;
45
(
2
):
330
44
. .
58.
Harber
CR
,
Levy
DM
,
Chidambaram
S
,
Macpherson
MB
.
Life-threatening bronchospasm after intramuscular carboprost for postpartum haemorrhage
.
BJOG
.
2007
;
114
(
3
):
366
8
. .
59.
Basu
S
.
Bioactive eicosanoids: role of prostaglandin F(2α) and F₂-isoprostanes in inflammation and oxidative stress related pathology
.
Mol Cells
.
2010
;
30
(
5
):
383
91
.
60.
Sentilhes
L
,
Vayssière
C
,
Deneux-Tharaux
C
,
Aya
AG
,
Bayoumeu
F
,
Bonnet
MP
,
Postpartum hemorrhage: guidelines for clinical practice from the French College of Gynaecologists and Obstetricians (CNGOF): in collaboration with the French Society of Anesthesiology and Intensive Care (SFAR)
.
Eur J Obstet Gynecol Reprod Biol
.
2016
;
198
:
12
21
. .
61.
Schmitz
T
,
Tararbit
K
,
Dupont
C
,
Rudigoz
RC
,
Bouvier-Colle
MH
,
Deneux-Tharaux
C
.
Prostaglandin E2 analogue sulprostone for treatment of atonic postpartum hemorrhage
.
Obstet Gynecol
.
2011
;
118
(
2 Pt 1
):
257
65
. .
62.
Biswas
A
,
Roy
S
.
A comparative study of the efficacy and safety of synthetic prostaglandin E2 derivative and 15-methyl prostaglandin F2 alpha in the termination of midtrimester pregnancy
.
J Indian Med Assoc
.
1996
;
94
(
8
):
292
3
.
63.
Stefanovic
V
,
Paavonen
J
,
Loukovaara
M
,
Halmesmäki
E
,
Ahonen
J
,
Tikkanen
M
.
Intravenous sulprostone infusion in the treatment of retained placenta
.
Acta Obstet Gynecol Scand
.
2013
;
92
(
4
):
426
32
. .
64.
Masuzawa
Y
,
Kataoka
Y
,
Fujii
K
,
Inoue
S
.
Prophylactic management of postpartum haemorrhage in the third stage of labour: an overview of systematic reviews
.
Syst Rev
.
2018
;
7
(
1
):
156
. .
65.
El-Refaey
H
,
O’Brien
P
,
Morafa
W
,
Walder
J
,
Rodeck
C
.
Misoprostol for third stage of labour
.
Lancet
.
1996
;
347
(
9010
):
1257
. .
66.
Tang
OS
,
Gemzell-Danielsson
K
,
Ho
PC
.
Misoprostol: pharmacokinetic profiles, effects on the uterus and side-effects
.
Int J Gynaecol Obstet
.
2007
;
99
(
Suppl 2
):
S160
7
. .
67.
Garrigue
A
,
Pierre
F
.
Misoprostol: off-label use in the treatment of post-partum hemorrhage
.
J Gynecol Obstet Biol Reprod
.
2014
;
43
(
2
):
179
89
.
68.
Nasr
A
,
Shahin
AY
,
Elsamman
AM
,
Zakherah
MS
,
Shaaban
OM
.
Rectal misoprostol versus intravenous oxytocin for prevention of postpartum hemorrhage
.
Int J Gynaecol Obstet
.
2009
;
105
(
3
):
244
7
. .
69.
Schaff
EA
,
DiCenzo
R
,
Fielding
SL
.
Comparison of misoprostol plasma concentrations following buccal and sublingual administration
.
Contraception
.
2005
;
71
(
1
):
22
5
. .
70.
Meckstroth
KR
,
Whitaker
AK
,
Bertisch
S
,
Goldberg
AB
,
Darney
PD
.
Misoprostol administered by epithelial routes: drug absorption and uterine response
.
Obstet Gynecol
.
2006
;
108
(
3 Pt 1
):
582
90
. .
71.
Khan
RU
,
El-Refaey
H
,
Sharma
S
,
Sooranna
D
,
Stafford
M
.
Oral, rectal, and vaginal pharmacokinetics of misoprostol
.
Obstet Gynecol
.
2004
;
103
(
5 Pt 1
):
866
70
. .
72.
Tang
OS
,
Schweer
H
,
Seyberth
HW
,
Lee
SW
,
Ho
PC
.
Pharmacokinetics of different routes of administration of misoprostol
.
Hum Reprod
.
2002
;
17
(
2
):
332
6
. .
73.
Walraven
G
,
Blum
J
,
Dampha
Y
,
Sowe
M
,
Morison
L
,
Winikoff
B
,
Misoprostol in the management of the third stage of labour in the home delivery setting in rural Gambia: a randomised controlled trial
.
BJOG
.
2005
;
112
(
9
):
1277
83
. .
74.
Soltan
MH
,
El-Gendi
E
,
Imam
HH
,
Fathi
O
.
Different doses of sublingual misoprostol versus methylergometrine for the prevention of atonic postpartum haemorrhage
.
Int J Health Sci
.
2007
;
1
(
2
):
229
36
.
75.
Chandhiok
N
,
Dhillon
BS
,
Datey
S
,
Mathur
A
,
Saxena
NC
.
Oral misoprostol for prevention of postpartum hemorrhage by paramedical workers in India
.
Int J Gynaecol Obstet
.
2006
;
92
(
2
):
170
5
. .
76.
Sheldon
WR
,
Blum
J
,
Durocher
J
,
Winikoff
B
.
Misoprostol for the prevention and treatment of postpartum hemorrhage
.
Expert Opin Investig Drugs
.
2012
;
21
(
2
):
235
50
. .
77.
Mousa
HA
,
Blum
J
,
Abou El Senoun
G
,
Shakur
H
,
Alfirevic
Z
.
Treatment for primary postpartum haemorrhage
.
Cochrane Database Syst Rev
.
2014
;
2014
(
2
):
Cd003249
. .
78.
Gallos
ID
,
Williams
HM
,
Price
MJ
,
Merriel
A
,
Gee
H
,
Lissauer
D
,
Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis
.
Cochrane Database Syst Rev
.
2018
;
4
(
4
):
Cd011689
. .
79.
Lawrie
TA
,
Rogozińska
E
,
Sobiesuo
P
,
Vogel
JP
,
Ternent
L
,
Oladapo
OT
.
A systematic review of the cost-effectiveness of uterotonic agents for the prevention of postpartum hemorrhage
.
Int J Gynaecol Obstet
.
2019
;
146
(
1
):
56
64
. .
80.
Pongsatha
S
,
Tongsong
T
.
Outcomes of pregnancy termination by misoprostol at 14–32 weeks of gestation: a 10-year-experience
.
J Med Assoc Thai
.
2011
;
94
(
8
):
897
901
.
81.
Wong
KS
,
Ngai
CS
,
Yeo
EL
,
Tang
LC
,
Ho
PC
.
A comparison of two regimens of intravaginal misoprostol for termination of second trimester pregnancy: a randomized comparative trial
.
Hum Reprod
.
2000
;
15
(
3
):
709
12
. .
82.
Chong
YS
,
Chua
S
,
Arulkumaran
S
.
Sublingual misoprostol for first trimester termination of pregnancy: safety concerns
.
Hum Reprod
.
2002
;
17
(
10
):
2777
, author reply 8.
83.
Nijman
TA
,
Voogdt
KG
,
Teunissen
PW
,
van der Voorn
PJ
,
de Groot
CJ
,
Bakker
PC
.
Association between infection and fever in terminations of pregnancy using misoprostol: a retrospective cohort study
.
BMC Pregnancy Childbirth
.
2017
;
17
(
1
):
7
. .
Open Access License / Drug Dosage / Disclaimer
This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC). Usage and distribution for commercial purposes requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.