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Expert Review of Hematology

ISSN: 1747-4086 (Print) 1747-4094 (Online) Journal homepage: http://www.tandfonline.com/loi/ierr20

Postpartum haemorrhage: prevention


and treatment

Loïc Sentilhes, Benjamin Merlot, Hugo Madar, François


Sztark, Stéphanie Brun & Catherine Deneux-Tharaux

To cite this article: Loïc Sentilhes, Benjamin Merlot, Hugo Madar, François Sztark, Stéphanie
Brun & Catherine Deneux-Tharaux (2016): Postpartum haemorrhage: prevention and
treatment, Expert Review of Hematology, DOI: 10.1080/17474086.2016.1245135

To link to this article: http://dx.doi.org/10.1080/17474086.2016.1245135

Accepted author version posted online: 05


Oct 2016.

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Download by: [Cornell University Library] Date: 09 October 2016, At: 13:58
Publisher: Taylor & Francis

Journal: Expert Review of Hematology

DOI: 10.1080/17474086.2016.1245135

Postpartum haemorrhage: prevention and treatment

Loïc Sentilhes1, Benjamin Merlot1, Hugo Madar1, François Sztark2, Stéphanie Brun1,

Catherine Deneux-Tharaux3.

1. Department of Obstetrics and Gynecology, Bordeaux University Hospital, University

of Bordeaux, Bordeaux, France.

2. Department of Anesthesiology, Bordeaux University Hospital, University of

Bordeaux, Bordeaux, France.

3. INSERM U1153, Obstetrical, Perinatal and Pediatric Epidemiology Research Team,

Center for Epidemiology and Statistics Sorbonne Paris Cité, Paris Descartes

University, Paris.

Corresponding author:

Loïc Sentilhes

Department of Obstetrics and Gynecology

Bordeaux University Hospital,


1
Place Amélie Raba Léon, 33076 Bordeaux, France.

Tel: (33) 2 41 35 77 44 Fax: (33) 2 41 35 57 89 E-Mail: loicsentilhes@hotmail.com

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Abstract

Introduction: Postpartum hemorrhage (PPH) is one of the leading causes of maternal death

and severe maternal morbidity worldwide and strategies to prevent and treat PPH vary

among international authorities.

Areas covered: This review seeks to provide a global overview of PPH (incidence, causes,

risk factors), prevention (active management of the third stage of labor and prohemostatic

agents), treatment (first, second and third-line measures to control PPH), by also

underlining recommendations elaborated by international authorities and using algorithms.

Expert Commentary: When available, oxytocin is considered the drug of first choice for

both prevention and treatment of PPH, while peripartum hysterectomy remains the ultimate

life-saving procedure if pharmacological and resuscitation measures fail. Nevertheless, the

level of evidence for preventing and treating PPH is globally low. The emergency nature of

PPH makes randomized controlled trials (RCT) logistically difficult. Population-based

observational studies should be encouraged as they can usefully strengthen the evidence base,

particularly for components of PPH treatment that are difficult or impossible to assess through

RCT.

Key words: postpartum hemorrhage, prevention, treatment, guidelines, oxytocin, active

management of third stage of labor, sulprostone, tranexamic acid, transfusion, hysterectomy.

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1. Introduction

Postpartum hemorrhage (PPH) is the most common complication of childbirth and thus a

relatively common situation in obstetrics. As one of the principal causes of severe maternal

morbidity, it has serious consequences and is responsible today for the deaths of 150,000

women a year, that is, 25% of the 600,000 annual maternal deaths worldwide [1]. PPH

remains the leading cause of maternal mortality in developing countries. In developed

countries, it has fallen to second or third place for direct maternal deaths behind

hypertensive and thromboembolic complications [1-2]. In high-income countries, 80 to 90%

of maternal deaths from PPH may be avoidable, for they appear to follow inadequate

treatment or delays in diagnosis or management [2]. PPH is also the principal cause of acute

severe maternal morbidity and resuscitation procedures of women during pregnancy or in the

postpartum period in these countries. Beyond the direct consequences of acute hypovolemia,

PPH exposes women to the complications of transfusion, resuscitation, infertility when

treated by hysterectomy (1 case per 2000-3500 deliveries in developed countries), increased

risks of thromboembolic complications, and greater psychological fragility [3-4]. The risk of

recurrence triples in a subsequent pregnancy and increases still more with each PPH [3,5] and

maternal genetic predisposition to PPH has been recently reported [6].

Numerous authorities have developed guidelines for the prevention and treatment of PPH to

help professionals (obstetricians, anesthesiologists, hemostasis specialists, midwives, and nurses)

care for the many women who bleed after giving birth and to try to reduce the maternal morbidity

and mortality associated with it [7-15]. The discrepancies among those sets of guidelines [16-18]

underline our lack of knowledge and the globally very low level of scientific evidence available

about the prevention and treatment of PPH. Some argue that PPH treatment today is much more

of an art based on local culture than an evidence-based science. This review seeks to provide a

global overview of PPH prevention and treatment. We first

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highlighted variation in how PPH is defined, difficulties in determining its incidence, causes

and risk factors and addressed the physiology of the third stage of labor and pathophysiology

of PPH. Then, we specifically pointed out on, by underlining recommendations elaborated by

international authorities, (i) the active management of the third stage of labor and

prohemostatic agents to prevent PPH, (ii) the first, second and third-line measures to control

PPH, and (iii) measures required after PPH has resolved. Finally we emphasized the key

research priorities for the future.

2. Definitions

Table 1 summarizes the various definitions of PPH, methods for assessing blood loss, and

thresholds for intervention applied in the guidelines issued by the principal professional

societies.

PPH is generally defined as blood loss from the genital tract ≥ 500 mL after giving birth,

and severe PPH as ≥ 1000 mL (Table 1) [8-13]. Immediate or primary PPH, which occurs in

the 24 hours after delivery, is the most frequent form and the most likely to produce an acute,

serious clinical state. Most of the scientific literature and the management guidelines concern

primary PPH. Secondary PPH, occurring from 24 hours to 6 weeks after delivery, is rarer and

more specific in its causes [13, 19].

Although this definition of PPH, based on a blood loss threshold, initially appears simple,

it presents two principal problems: first, the threshold values are not chosen for any solid

scientific basis; second, precise quantification of blood loss is difficult in practice, and the

method used to assess it influences this volume. The traditional threshold of 500 mL dates

back more than half a century [20-22]. It is an arbitrary cutoff point, apparently based on

percentiles of distribution rather than on clinical considerations of the associated morbidity or

tolerance of bleeding [3]. The threshold of 1000 mL for severe PPH is less arbitrary because

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clinical signs of poor tolerance for bleeding and hemodynamic instability generally appear at

this stage in these healthy young women [23].

The other pitfall of the standard definition of PPH is that the method used to assess blood

loss largely determines the result and therefore the reported incidence, and these methods vary

[3, 13]. Several studies have shown that visual estimates of postpartum blood loss are not

reliable; they lead to overestimation of low volumes and underestimation of high ones, an

underestimation that increases with the quantity of bleeding, even for experienced clinicians

[24-26]. Objective methods to measure blood loss directly have been proposed, including a

collection bag and the weighing of compresses (Table 1) [3, 7, 9, 12-13]. Although these

methods may enable better assessment of the blood volume actually lost, their practical

implementation remains far from consistent. Moreover, their routine use for all deliveries is

not associated with a diminution in the incidence of severe PPH [27].

The clinical assessment of blood loss in cesarean deliveries presents an additional

problem: the difficulty of reliably subtracting the volume of amniotic fluid from the total

volume of fluid aspirated during the surgical procedure [3, 13].

Because of these difficulties in standardizing blood loss measurements, authors have

proposed other criteria to define PPH, based on biomarkers of blood loss, independent of

human judgment: peripartum hematocrit decline of 10% [28] or hemoglobin drop of 2 g/dL

[29] or inclusion of these laboratory indicators in a more complex formula that also considers

the woman's morphology [30]. Although these alternative definitions are useful for research

purposes, they cannot be used in real time to guide management. Direct measurement of

blood loss remains the most appropriate method to assess blood loss [3, 13].

Another controversial aspect of the definition of PPH concerns the utility of different blood

loss thresholds for different modes of delivery. The studies describing the distribution

of blood loss mostly concern vaginal deliveries. Some older [31] and newer [32] studies have
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reported that postpartum blood loss is on average higher after cesarean than vaginal delivery.

Based on these old and undetailed data, some studies and practice guidelines have long

defined PPH after a cesarean by a blood loss ≥ 1000 mL [8, 10, 12] (Table 1); this arbitrary

cutoff point is expected to be around the 90th or 95th percentile of the distribution of blood

loss in this context [3]. Nonetheless, several authors have questioned this differential

threshold, both because it leads to the failure to take the role of cesarean delivery into account

as a risk factor for PPH [13] and because it is hard to see how the same volume of blood loss

could have different consequences for maternal morbidity according to mode of delivery [3].

Accordingly, as Table 1 shows, the most recent United Kingdom guidelines for PPH

management [7], like the most recent updates of the WHO (World Health Organization) 11]

and CNGOF (French college of obstetricians and gynecologists) [13] guidelines, do not apply

different cutoff points for blood loss for vaginal and cesarean deliveries because no solid

evidence justifies this difference. Nonetheless, the threshold for clinical intervention must

take the blood flow rate and clinical context into account. Thus, it is reasonable to begin

active management before the threshold of 500 mL is reached when blood loss is rapid or

clinical tolerance poor. Inversely, for cesarean deliveries, in view of the blood loss inherent in

the surgical procedure, the threshold of action can be set at a level of blood loss higher than

500 mL if clinical tolerance allows [3, 13] (Table 1).

However, one most important question is whether blood loss quantification is a crucial

step in the early detection of PPH. An excellent review of the literature evaluating the

accuracy of visual estimation shows that caregivers were highly inaccurate at estimating

blood loss as a volume and training resulted in short term improvements in skills but these did

not improve clinical outcomes, as well as multi-faceted interventions, suggesting that PPH

diagnosis may rely on factors other than volume, such as speed of blood flow and nature of

loss [33], as recommended by SOGC and FIGO [10,12]

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3. Incidence

The literature contains numerous and very heterogeneous estimates of PPH incidence.

Beyond the variations linked to study population characteristics and PPH prevention

practices, this diversity reflects in part the variety in the definitions and methods of

measurement of PPH (see above), but also that of the data sources.

On the whole, the literature shows a PPH incidence around 5% of deliveries when blood

loss measurement is imprecise or when the data come from routine databases and around 10%

when blood loss is measured precisely and the data come from ad hoc or prospective studies

[3, 13]. The incidence of severe PPH (blood loss > 1000 mL) is around 2%, and that of PPH

requiring transfusion around 0.4% [34-35].

Several studies from high-resource countries report a recent rise in PPH incidence, in the

United States [36-37], Canada [38], and Ireland [39]. This increase primarily involves PPH

due to uterine atony. Interestingly, simultaneous increases in the prevalence of some risk

factors for PPH (obesity, age, multiple pregnancy, induction, and cesarean delivery) [37, 40]

do not appear to explain this finding. Factors either not yet identified or unavailable in the

databases analyzed are thus likely to be involved. However, all of these studies are based on

routine hospital databases, and the increased incidence may be explained by improvements in

the clinical diagnosis of PPH and its coding in hospitals. Nevertheless, additional data suggest

that the increase of PPH incidence is not merely due to increased recognition or reporting of

PPH based on changes in threshold for diagnosing subjectively clinically relevant estimated

blood loss [37]. As highlighted by Kramer et al, an increase rate of procedures likely related

to postpartum blood loss but without ICD-9 code, such as labor augmentation and duration

involved in desensitization of myometrial oxytocin receptors, might be possible explanatory

factors [37].

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4. Causes of PPH

Uterine atony is the predominant cause of PPH, responsible for 50-80% of cases [3]. A defect

in uterine contractility after delivery prevents the uterus from its normal postbirth contraction,

which ensures mechanical hemostasis by causing occlusion of the gaping arteries and drying

up the bleeding. This mechanical hemostasis is flawed or does not occur at all in women with

uterine atony, and abundant bleeding ensues which secondarily can cause loss of coagulation

factors resulting in altered hemostasis, with hemodilution if intravenous fluid resuscitation

occurs concomitantly [3].

Placental retention is generally the second most common cause of PPH, involved in

around 10-30% of cases, but its distinction from or coexistence with uterine atony is not

always clear [3].

Lacerations and wounds are responsible for 15-20% of PPH; after vaginal delivery, these

may be perineal, vaginal, or cervical tears or lacerations (including episiotomy) for PPH

and, in cesareans, bleeding associated with the incision or the injury of a uterine pedicle [3].

Other causes, each responsible for < 1% of PPH cases, include constitutional or

acquired coagulopathy (especially with an amniotic fluid embolism or HELLP syndrome),

abruptio placentae, uterine rupture, and placental insertion abnormalities (placenta previa,

accreta/percreta) [3].

One PPH can be due to several causes, the distribution of which varies as a function of

PPH severity [29]. The most frequent cause of PPH and severe PPH, regardless of mode of

delivery, is uterine atony. But the proportion of PPH due to lacerations and wounds is higher

among the severe PPH (29% after vaginal deliveries, 22% after cesareans) [29].

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5. Risk factors for PPH

Table 2 summarizes the principal risk factors of PPH described consistently in recent

observational studies, distinguishing those linked to mothers' prepregnancy characteristics

from those related to the characteristics of pregnancy, labor, and delivery [29, 37, 41-43]. On

the whole, these factors and their various combinations do not predict PPH, either because

they are very prevalent but only slightly discriminant, or because they are rare [44-45].

Moreover, prediction models poorly discriminate between women with versus without PPH.

Thus, Bateman et al found that only 39% of women with PPH had any identified independent

risk factor for PPH [43]. The impossibility of accurately identifying the women at risk of PPH

justifies the application of prevention strategies to all parturients [7-18].

The risk factors for PPH most often reported are those for uterine atony, which is the

dominant cause of PPH. They include grand multiparity, uterine overdistension in cases of

multiple pregnancy, hydramnios, and fetal macrosomia, labor induction with misoprostol,

prolonged labor, and chorioamnionitis [3]. Among patients with uterine atony after cesarean

delivery, the risk of haemorrhage-related morbidity is increased in African-Americans,

Hispanics, patients with multiple gestation, induced or augmented labor for >18 hours, infant

birth weight >4500 g, clinically diagnosed chorioamnionitis, ASA class III or IV, ≥2 prior

caesarean deliveries and those undergoing general anesthesia [46-48]

A history of PPH is one of the risk factors most closely associated with PPH, but its

prevalence is low. Two recent studies reported an association between the administration of

oxytocin during labor and the onset of PPH [48-49]. Effect of oxytocin appears to be

independent of other risk factors, in particular the mode of labor onset and its duration; the

excess risk appears significant for doses used in current practice, and the relation is dose-

dependent [48]. This result must be taken into account in evaluating the benefit-risk balance of

oxytocin, which is intended to avoid recourse to cesarean delivery for labor dystocia.

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A Norwegian study based on the national birth registry specifically examined the

association between type of delivery and PPH [49]. A cesarean before labor was associated

with an increased risk of severe PPH compared with spontaneous vaginal delivery (aOR

2.33; 95% CI 1.08-2.56). An emergency cesarean during labor increased this risk still further,

by 55% compared with cesarean delivery before labor. The risk was highest for cesarean

deliveries during labor after induction [50]. Operative vaginal deliveries are too associated

with a marked increase in the risk of PPH compared with spontaneous vaginal delivery; this

excess risk is independent of the episiotomy, which is also is a significant risk factor for PPH

[29].

Finally, the risk of PPH does not increase at all for women receiving preventive

anticoagulant treatment and only moderately for those receiving it at a curative dose [13, 51-

52]. Women with coagulation disorders must be monitored in close collaboration with a

specialist in hemostasis, who will plan the specific management for delivery with the

obstetrician and the anesthesiologist [13].

6. Physiology of the third stage of labor and pathophysiology of PPH

The third phase of labor begins with the birth of the child and ends with expulsion of the

placenta. As described above, after the child is born, the uterus normally contracts to promote

closure of uterine venous sinuses. In addition, following delivery, the uterine surface becomes

covered with fibrin and blood clot [53]. In cases of PPH, it is thought that this mechanical

hemostasis does not occur, or is defective, leading to plentiful and possibly fatal bleeding

[54]. It is has also been suggested, however, that coagulation at the placental site represents an

important hemostatic mechanism. Before and after delivery, subtle changes occur in both

coagulation factors and fibrinolytic agents [55]. The increased plasma concentrations of

clotting factors both during pregnancy and after delivery suggest a hypercoagulable state [51].
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After placental separation, however, the fibrinolytic capability of the mother’s blood

increases, reducing its clotting potential [56]. Nevertheless, it is unclear whether fibrinolysis

per se increases and/or whether plasminogen activator inhibitor 1 (PAI-1) drops off to explain

why lytic capacity increases [57-61]

These conflicting changes, which are difficult to reconcile, are further complicated by

changes in platelet activity before and after delivery [62]. Moreover, an inflammatory
response appears to arise in the placental bed after placental delivery [64], which would
promote local coagulation. Some authors have speculated that these activities could stave off
hemorrhaging at the placental site, while elsewhere (particularly in deep pelvic and leg veins)
increased fibrinolysis is likely to prevent thrombi persistence [54-55].

In summary, normal hemostatic mechanisms during and after placental separation

probably involve the contraction of muscle fasciae around the spiral arteries, leading in turn to

platelet plug formation and retraction of the uterus, which cause mechanical occlusion of the

arterioles, further facilitate platelet plug formation, and activate both the clotting cascade and

fibrinolysis [27].

7. PPH prevention

Because prediction models for PPH are not discriminatory, its prevention should be directed

to all women giving birth [7-18]. Because placental expulsion is a critical window for this

prevention, various management strategies have been proposed for this stage of delivery.

These can be schematically divided in two categories: those involving a mechanical

mechanism, and those involving prohemostatic agents.

7.1 Mechanical hemostatic tools to promoting uterine contractility after delivery

Active management of the third stage of labor (AMTSL), first described in the United

Kingdom and in Ireland, comprises a combination of three principal actions: prophylactic


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administration of a uterotonic immediately after delivery of the child, early cord clamping and

cutting, and controlled cord traction (CCT). Some authors also include uterine massage [7-

13]. The underlying principle is to stimulate uterine contraction after birth by uterotonic use

and uterine massage and to promote rapid placental expulsion with CCT. These mechanical

tools should quickly produce the uterine retraction necessary for good local hemostasis [7-13].

According to the Cochrane review, active management for women at mixed levels of

hemorrhage risk compared to expectant management (i.e., signs of placental separation are

awaited and the placenta is delivered spontaneously) reduces the rate of PPH > 1000 mL

(average risk ratio (RR) 0.34, 95% confidence interval (CI) 0.14 to 0.87) and hemoglobin

(Hb) < 9 g/dL (average RR 0.50, 95%CI: 0.30 to 0.83) [64]. It is also associated with a

significant decrease in primary blood loss > 500 mL, mean maternal blood loss at birth,

maternal blood transfusion, and therapeutic uterotonics during the third stage or within the

first 24 hours, or both. Findings were similar for the subgroup of women at low risk of

excessive bleeding, except that the groups did not differ significantly for either severe

hemorrhage or maternal Hb < 9 g/dL (at 24 to 72 hours) [64].

A good level of evidence supports the specific and independent efficacy of preventive

uterotonics, especially oxytocin [65-70]. The meta-analysis of the trials testing the efficacy of

prophylactic oxytocin administration concluded that it reduces the risk of blood loss > 500 mL

by 50% and the risk of blood loss > 1000 mL by 40% [71]. The situation is very different for

CCT, even though it was inseparable from oxytocin administration in the initial concept of

AMTSL. Two large randomized controlled trials recently showed that CCT for the

management of placental expulsion has no significant effect on the incidence of PPH in either

high- or low-resource settings [72-73]. Moreover, early cord clamping is generally no longer

included in AMTSL [10-13], as evidence now suggests that delayed clamping (performed

approximately 1 to 3 minutes after birth) benefits the child [74-75]. The risks and benefits for

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the mother have not yet been assessed, however [13]. Finally, blood loss does not differ in

women with vaginal deliveries receiving oxytocin as well as transabdominal uterine massage

after placental delivery compared with those receiving oxytocin alone [76-77].

In conclusion, based on the results of numerous studies, the active management of the

third stage of labor reduces the risk of PPH compared to expectant management.

7.1.1 What uterotonics? What dose? What route of administration and for

what mode of delivery?

The principal uterotonics evaluated in PPH prevention are oxytocin, ergot derivatives,

misoprostol, and carbetocin [7-18]. The uterotonic that has been evaluated most thoroughly for

this purpose is oxytocin. Its principal disadvantage is that it must be refrigerated for storage (2–

8°C). The prevalence of poor-quality oxytocin samples in low- and middle-income countries is

thus high [78]. Compared with placebo, oxytocin reduces the risk of PPH > 500 mL (10% vs

23.9%, RR 0.53; 95%CI: 0.38-0.74), of severe PPH (> 1000 mL) (2.2% vs

10.9%, RR 0.62; 95%CI: 0.44-0.87), and of the need for supplementary uterotonics (5.1% vs

11.4%, RR 0.56; 95%CI: 0.36-0.87) [71]. The reduction of the risk of PPH > 500 mL was

observed in all subgroups, whether administered intravenously (IV) or intramuscularly

(IM) and regardless of dose (which ranged from 3 to 10 IU) [71].

If oxytocin administration is not possible immediately after delivery of the child, in

particular after delivery of the anterior shoulder and before placental expulsion, it should

nonetheless be administered afterwards. In fact, whether it is administered before or after

placental expulsion does not significantly influence the incidence of PPH, severe PPH,

placental retention, transfusion, or need for additional uterotonics [79].

Administration of ergot derivatives reduces the incidence of PPH compared with placebo

for PPH > 500 mL (RR 0.49; 95%CI: 0.26-0.90) and for severe PPH (RR 0.32; 95%CI: 0.04-

2.59) but at the cost of frequent adverse effects, most especially hypertension (RR 2.60;

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95%CI: 1.03-6.57) [69]. In addition, reports of strokes, hypertensive encephalopathy, and

myocardial infarction associated with methylergometrine call for extreme prudence in its use,

especially among women with a predisposition for vascular disorders [80-81]. Finally,

oxytocin is more effective than methylergometrine for reducing the risk of PPH > 500 mL

(RR 0.76; 95%CI: 0.61-0.94) and better tolerated, inducing less nausea (RR 0.18; 95%CI:

0.06-0.53) and less vomiting (RR 0.07; 95%CI: 0.02-0.25) [68]. Syntometrine is a

combination of ergometrine and oxytocin. It is not more effective than methylergometrine in

preventing PPH > 500 mL (4.6% vs 3.6%, RR 0.90; 95%CI: 0.34-2.41) or severe PPH (0.89%

vs 0.54%, RR 1.67 95%CI: 0.40-6.94) [79]. Compared with oxytocin, syntometrine reduced

the rate of PPH > 500 mL (RR 0.82; 95%CI: 0.71-0.95) but had no effect on the incidence of

severe PPH (RR 0.78; 95%CI: 0.58-1.03), regardless of the oxytocin dose administered (5 or

10 IU) [82]. This benefit is counterbalanced, however, by the frequent adverse effects

associated with ergot derivatives, which raise serious questions about the routine use of

syntometrine (elevated diastolic blood pressure, 1.7% vs 0.7%, RR 2.4; 95%CI: 1.6-3.6, and

vomiting and nausea, 23.4% vs 5.3%, RR 5.71; 95%CI: 5-6.5) [82].

Misoprostol is a powerful uterotonic prostaglandin commonly used in obstetrics,

especially to induce labor after in utero fetal deaths and in elective or medically indicated

abortions. Its current formulation — as tablets only — allows only oral, vaginal, or rectal

administration but has the advantage of facilitating storage. Oral or sublingual misoprostol

compared with placebo is effective in reducing severe PPH (RR 0.66; 95%CI: 0.45-0.98) and

blood transfusions (RR 0.31; 95%CI: 0.10-0.94) [83]. Compared with other uterotonics (oxytocin

IV or IM, methylergometrine, and syntometrine), oral misoprostol administration is associated

with an increased risk of severe PPH (RR 1.33; 95%CI: 1.16-1.52) [83]. These results are due

principally to the weight of the WHO study included in this meta-analysis [70]. That study

compared 600 µg of misoprostol to 10 IU of oxytocin, IV or IM, in two arms, each

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including more than 9000 patients. The rate of severe PPH (the principal endpoint) was higher

in the misoprostol than the oxytocin group (4% vs 3%, RR 1.39; 95%CI: 1.19-1.63), as was

the rate of PPH > 500 mL (20% vs 14%, RR 1.44; 95%CI: 1.35-1.54). Misoprostol was also

associated with more frequent side effects, including nausea (0.8% vs 0.4%; RR 2.27, 95%CI:

1.52–3.39), vomiting (0.7% vs 0.3%, RR 2.64; 95%CI: 1.67–4.18), diarrhea (0.4% vs 0.1%,

RR 4.38; 95%CI: 2.03-9.43) and fever> 38°C (6% vs 0.8%, RR 7.17; 95%CI: 5.67-9.07)

[70]. There is some evidence that a lower dose of oral misoprostol (400µg rather than 600µg)

may be as effective and associated with less side-effects [83]. Besides, misoprostol

administered with prophylactic routine oxytocin did not reduce the rate of postpartum

hemorrhage and increased the rate of adverse events [84]. Finally, although some countries

have embarked on community-level programs to distribute misoprostol where oxytocin is not

available, there is insufficient evidence to recommend its antenatal distribution to pregnant

women for self-administration for the prevention of PPH [85].

Finally, carbetocin is a synthetic analog of oxytocin with a prolonged duration of action.

The recommended dosage is 100µg even if some studies suggest that 20µg or less may be

sufficient [86].

Few trials have compared carbetocin to other uterotonics after vaginal delivery [87]. Two

randomized trials with low levels of evidence compared carbetocin (100 µg) to various doses

of syntometrine after vaginal delivery and found no difference between the two groups for

either PPH rate or need for additional uterotonics [88-89]. A Canadian study that compared

carbetocin (n=83) to an IV oxytocin infusion (n=77) for two hours after vaginal delivery in

women with at least one risk factor for PPH found no difference between the two groups

except for a reduction in the use of additional uterotonics (44.6% vs 63.6%; P=0.02) [90].

After cesarean delivery, carbetocin and oxytocin result in similar rates of PPH > 500 mL (RR

0.66; 95%CI: 0.42-1.06) and PPH > 1000 mL (RR 0.91; 95%CI: 0.39-2.15), but
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complementary uterotonics and uterine massage were used less after carbetocin treatment

(respectively, RR 0.64; 95%CI: 0.51-0.81 and RR 0.54; 95%CI: 0.31-0.96) [87].

There is thus a general consensus that oxytocin is the uterotonic of choice for all women

after vaginal delivery, especially in light of the side effects associated with ergot alkaloids

(Table 3). Most authorities recommend 10 IU IM, because indirect comparisons suggest that

10 UI may be more effective than 5 IU, an IV line is not required, and oxytocin-related

hemodynamic adverse are less frequent with IM than IV administration [71]. Oxytocin has a

prominent vasodilation effect; IV oxytocin, like IV carbetocin [91], decreases systolic arterial

pressure and systemic vascular resistance, and increases heart rate, stroke volume, and cardiac

output. It can therefore cause myocardial ischemia [92]; at a dose of 10 IU it has probably

contributed to maternal deaths [93]. Moreover, recent oxytocin dose-finding studies suggest

that lower doses of 5-IU bolus may be equally as effective and appear to be associated with

fewer and less severe maternal side-effects [91, 94-95]. Thus, investigation of low bolus doses

of oxytocin for vaginal delivery should be encouraged. Nevertheless, no randomized

controlled trials (RCTs) have compared the route and dosage of oxytocin for preventing PPH;

indirect comparisons suggest that IV may be more effective than IM [71]. Consequently, the

RCOG (UK Royal College of Obstetricians and Gynaecologists) and CNGOF suggest doses

of either 5 or 10 IU (not only 10 IU), and CNGOF recommends slow IV rather than IM

administration (Table 3). If the IV route is chosen, however, providers must be aware that

bolus administration is dangerous and that slow IV administration should be over about 1

minute, and in women with cardiac diseases to minimize the oxytocin-related hemodynamic

adverse effects [7, 10, 13] (Table 3).

RCTs about cesarean deliveries have principally compared oxytocin and carbetocin [87].

Evidence supporting the recommendation of oxytocin over ergot alkaloids or misoprostol in

cesarean deliveries is mainly extrapolated from the literature on vaginal delivery [13].

17
Nonetheless, two important trials have examined the effect of an oxytocin bolus alone with

the same bolus combined with an oxytocin infusion to control blood loss during elective

cesarean deliveries. An Australian trial of 720 elective cesareans showed that after an IV

bolus of 5 IU of oxytocin, a slow IV infusion of 30 IU (compared with a slow IV infusion of

placebo) reduced the risks of severe PPH (RR 0.35; 95%CI: 0.2-0.63), additional uterotonic

treatment (RR 0.35; 95%CI: 0.22-0.56), and transfusion (RR 0.12; 95%CI: 0.01-0.98) [96].

Another RCT of 2069 elective cesareans tested an IV 5-IU bolus injection of oxytocin for one

minute followed by either a 40-IU dose (diluted in 500 mL) by infusion for 4 hours or a 500-

mL placebo infusion for 4 h. The incidence of severe PPH was similar in both groups (15.7%

vs 16%, P = 0.86) but additional uterotonics were used less frequently in the bolus + infusion

group (12.2% vs18.4%, adjusted OR 0.61; 95%CI: 0.48-0.78, P<0.001) [30]. Moreover,

women were less likely to have severe PPH in the bolus + infusion group than in the bolus-

only group when the obstetrician was less, compared with more, experienced (OR 0.57;

95%CI: 0.35-0.92, P=0.02). An infusion of oxytocin after the slow IV administration of 5 or

10 IU, especially in university hospitals, thus appears useful [13].

7.2.Prohemostatic agents

The principle prohemostatic agent assessed for PPH prevention is tranexamic acid (TXA), an

antifibrinolytic agent that reduces transfusion rates in elective surgery patients, mortality in

bleeding trauma patients, and menstrual blood loss in women with menorrhagia [97]. It appears

promising for the prevention and treatment of PPH, especially in view of the close relation

demonstrated between reduced fibrinogen levels and PPH outcome [98-99]. Ten published RCTs

have evaluated the efficacy of TXA in preventing PPH after cesareans, and 2 after vaginal

deliveries [97]. All found decreased blood loss in the TXA group, and all the meta-analyses

showed a significant reduction in postpartum blood loss, PPH, severe PPH, and transfusions in

the TXA group compared with the control group [100-103]. Nevertheless, the

18
quality of the RCT data was low to moderate, and the risk of bias high [82]. Because meta-

analyses are only as good as their source data, these results should be interpreted cautiously

[104-105]. Moreover, they lacked the statistical power to assess such adverse effects as

thrombotic events [105-106]. But, due to the poor quality of trial research, the main concern

is related to data quality and reliability and consequently some authors do recommend to not

conduct metaanalysis in this area [107-108]. Thus, the evidence currently available is too

limited to justify the widespread use of TXA for PPH prevention in view of the number of

eligible women. Large, adequately powered multicenter RCTs are required to determine if the

risk-benefit ratio favors the routine use of TXA to prevent PPH after cesarean or vaginal

deliveries or both [109]. No professional guidelines currently recommend TXA for the

prevention of PPH [18, 97].

7.3 Other

7.3.1 Management of retained placenta without bleeding

If bleeding occurs before placental delivery, immediate manual exploration and removal of

the placenta is recommended (see below). A policy of CCT reduces the risk of manual removal of

placenta (4.2% versus 6.1% (RR 0.69; 95%CI 0.53-0.90) [73]. When no bleeding occurs, there is

no consensus about how long to await spontaneous detachment of placenta from the uterus before

taking any action. Some authorities recommend action after 30 minutes [13], and others after 60

minutes [7, 12]. Injection of oxytocin solution into the umbilical vein did not reduce the need for

manual removal compared with expectant management (RR 0.87; 95%CI: 0.74-1.03) or

compared with simple saline solution (RR 0.91; 95%CI: 0.82-1.00)

[110]. Similarly, limiting the analysis to high-quality studies showed no statistically significant

difference (RR 0.92; 95%CI: 0.83-1.01) [110]. Umbilical vein injection thus appears ineffective

in treating retained placenta. Given the absence of an effective alternative,

placental retention should be treated by manual removal.


19
7.3.2 Cord drainage

Cord drainage compared to no placental cord drainage does not reduce the rate of PPH or

of manual removal of the placenta [111].

7.3.3 Early suckling after birth

In an old randomized trial (n=4227), early suckling after birth was not associated with a

reduction in either the PPH rate (7.9% vs 8.4%) or the volume of blood loss (mean difference

2.00 mL, 95%CI: -7.39;11.39) [112]. Because no study has shown an association between

early suckling (i.e., putting the baby's mouth to the mother's nipple) and reduction in PPH, its

routine use for that purpose seems not relevant [13].

7.3.4 Methods of delivering the placenta after cesarean birth.

Manual removal of the placenta, compared with its spontaneous delivery, is associated

with more blood loss, more severe blood loss (> 1000 mL), lower hematocrit after delivery,

greater fall in hematocrit, more endometritis, and longer hospitalization [113]. Consequently,

in our opinion, manual removal of the placenta during cesarean delivery should be avoided in

absence of hemorrhage [13].

7.3.5 Techniques for cesarean delivery

In a meta-analysis including only two studies of low level evidence, the Joel-Cohen incision

technique and its variants (e.g., Misgav-Ladach technique) were found to be associated with less

blood loss than the Pfannenstiel abdominal incision (variants) (RR 0.35, 95% CI: 0.14 to 0.87)

[114]. However the mean difference of estimated blood loss, reported in only one study, was not

clinically relevant (-58 mL, 95% CI: -108;5 mL to -7.5 mL) [104].

7.3.6 Monitoring

Early recognition of PPH is likely crucial for PPH management. All women should be

ideally monitored every 15 minutes for two hours after childbirth, with abdominal palpation to

check uterine tonus for early identification of atony, estimated blood loss, vital signs such

20
as blood pressure, heart rate, respiration (using an oximeter, electrocardiogram, and

automated blood pressure recording), as well as general condition (i.e., color, level of

consciousness, anxiety) [7, 10, 12-13].

8. Treatment of PPH

Evidence to guide the management of PPH is sparse, but there is a global consensus

among the various authorities about the major principles that should guide it [18].

The RCOG has summarized the main measures that must be taken simultaneously:

communication, resuscitation, monitoring, investigation, and treatment [7]. The steps for both

management and monitoring must be recorded on a special monitoring form [13].

8.1 First-line measures

All relevant staff (midwife, obstetrician, and anesthesiology/critical care team) must be

called simultaneously. The medical team must immediately begin resuscitation appropriate to

the results of noninvasive monitoring (heart rate, blood pressure, and pulse oximetry) and

estimated blood loss (CNGOF recommends the use of a collector bag [13] while RCOG

recommends blood-collection drapes and weighing swabs rather than clinical estimation [7]).

Staff must then establish or secure venous access (two peripheral cannulae), take initial blood

samples if none are available (blood group and coagulation screen, both of which should

normally be available before delivery, together with irregular antibody screening, complete

blood count, platelets, and hemostasis including fibrinogen), initiate plasma expansion by

crystalloids, oxygen therapy, and protection against hypothermia (active skin warming and if

needed heating of infusion solutions and of blood products). Urinary output should also be

assessed in all cases [18].

After adequate analgesia, the placenta/retained products of conception (retained placenta,


cotyledon, or membranes) should rapidly be removed manually, and the genital tract should
21
be assessed visually, as the perineum, vagina, and cervix are all potential sources of bleeding.

Any areas of bleeding (that is, episiotomy, vaginal or cervical lacerations) must be repaired

[18]. Some authorities recommend antibiotic prophylaxis after manual exploration of

the uterus [13]. Uterine massage should also follow this exploration [18].

Uterotonic should be administered to strengthen uterine tone, constrict blood vessels, and

decrease blood flow through the uterus. Of the available uterotonics, only misoprostol and

oxytocin have undergone rigorous comparative study and oxytocin is superior [115-117]. In

situations in which prophylactic oxytocin has already been utilized, additional oxytocin is as

effective as or better than misoprostol in stopping hemorrhage, while avoiding the high rate of

fever (22-58%) associated with misoprostol [115-116]. In particular, there is no benefit of

misoprostol in addition to standard injectable uterotonics for the treatment of post-partum

haemorrhage [115]. Consequently, there is a wide consensus that oxytocin, if available, is the

agent of choice for first-line PPH treatment, either IM or, preferably IV, by a short infusion

and then a continuing dose (Table 4). CNGOF, for example, suggests a slow IV injection of

5–10 IU oxytocin followed by maintenance infusion of 5–10 IU/h for 2 h [13] (Table 4). No

evidence indicates that any given regimen is most effective or preferred.

8.2 If bleeding persists, second-line measures should be applied.

These second-line measures consist of intensifying resuscitation, by using mainly

blood products or uterotonic treatment, adding an additional or alternative uterotonic.

FIGO (the international federation of gynecology and obstetrics), WHO, RCOG, and

CNGOF have all chosen to recommend uterotonic administration in two steps: oxytocin first

and then, only if oxytocin fails, other uterotonics (not in combination) (Table 4) [7, 11-13].

The aim of this 2-step procedure is to help healthcare providers to prioritize or rank the

uterotonic agents for bleeding women. Other authorities generally describe the drugs (ergot

alkaloids, carboprost, sulprostone, misoprostol, all with similar dosages and route of

22
administration in each set of guidelines) that may be used to treat PPH, alone or together if

appropriate; they do not, however, define a temporal sequence of administration [8-10] (Table

4). No evidence that this sequence is effective for the prompt management of early PPH is

available. Moreover, there is no evidence for prioritizing one drug over the other if oxytocin

fails [18]. Contrary to most other guidelines, which recommend carboprost [13], CNGOF

recommends only sulprostone as an injectable prostaglandin for PPH (Table 4). This choice is

partly because the French treatment algorithm for PPH has called for sulprostone since 2004

[118] so that French obstetricians and anesthesiologists are familiar with its use [119].

Moreover, only the French guidelines recommend against the use of both ergot alkaloids and

misoprostol for treating PPH, even in the absence of contraindication, as oxytocin and

sulprostone are available in all maternity units and because of the adverse effects associated

with the ergot alkaloids (see above). Nevertheless, methylergonovine is the most commonly

used second line uterotonic in United States [120] and reassuringly Bateman et al did not find

a significant increase in the risk of methylergonovine acute coronary syndrome (ACS) and

acute myocardial infarction (AMI) in women who received methylergonovine compared with

those who did not; estimates were increased only modestly or not at all [121]. They have

estimated that treatment with methylergonovine would result in no more than 5 additional

cases of ACS and 3 additional cases of AMI per 100,000 exposed patients [121]. Lastly,

although no prospective study has compared ergot alkaloids versus carboprost for the

treatment of refractory uterine atony, Butwick et al observed that the risk of hemorrhage-

related morbidity was greater among those receiving carboprost versus methergine [122].

Thus, FIGO and WHO recommend if the bleeding does not respond to oxytocin ergometrine,

an oxytocin-ergometrine fixed dose combination, carbetocin, or misoprostol should be offered

as second-line treatment (Table 4) [11-12].

23
Invasive monitoring of arterial blood pressure or central venous pressure may be

necessary, depending upon the clinical situation. Urinary output should be monitored in all

cases.

There is no data identifying optimal transfusion strategies for postpartum hemorrhage. Given

these gaps in the evidence, obstetric societies therefore base their recommendations on expert

opinion. They underline, however, that blood product use depends principally on clinical signs of

PPH severity, without necessarily awaiting blood test results [7, 9, 13]. The CNGOF guidelines,

for example, state that the objective of RBC transfusion is to maintain a hemoglobin

concentration (Hb) > 8 g/dL. However, when severe PPH occurs, a massive transfusion protocol

has attracted interest as a key therapeutic resource by ensuring sustained availability of blood

products to the labor and delivery unit [123]. Guidelines also recommend maintaining a

fibrinogen level >1-2 g/L [7,9, 13], as fibrinogen < 2 g/L is a strong marker of severe PPH and.

knowing that a RCT found no evidence supporting the use fibrinogen concentrate as preemptive

treatment for severe PPH in patients with normal fibrinogen levels

[124]. Bedside hemoglobin monitoring may be useful for resuscitation, but there is not

currently enough evidence to recommend routine thromboelastometry coagulation

assessment for managing severe PPH [11] even if thromboelastometry can provide earlier

data on the fibrinogen contribution to clot formation compared to clauss-based fibrinogen

tests [125], while it has been never demonstrated that its use was associated with an outcome

improvement.

Finally, RCOG, WHO, and CNGOF all state that TXA administration may be considered

in selected cases of severe PPH [7, 11, 13], based on the extrapolation of its impact in other

clinical bleeding contexts (see above) [104]. To date, only one small open RCT (the

EXADELI trial) has shown that high-dose TXA (10 g) (n=72) compared to controls (n=72)

reduces the median blood loss (173 mL versus 221 mL; p=0.04) [99] but the clinical
24
relevance of this effect is questionable. Moreover, a controlled single-center trial did not find

a significant reduction in blood loss with high-dose TXA according to either the EXADELI

protocol [127] or a high-dose TXA policy [128] for PPH after vaginal delivery. The World

Maternal Antifibrinolytic (WOMAN) Trial, an ongoing pragmatic, randomized, double-

blinded, placebo-controlled trial among 20,000 women [129] should soon provide a reliable

scientific basis for recommendations about the use of TXA in PPH treatment, especially in

middle- and low-income countries.

Awaiting these results, CNGOF has stated that “tranexamic acid may be useful in the

management of PPH, although its clinical value has not yet been demonstrated in obstetrics; but

its use is left to the clinician’s discretion […] and should be limited to cases of sulprostone-

resistant PPH, at a dose of 1 g, renewable once if ineffective the first time” [13].

8.3 If bleeding persists, third-line measures should be applied promptly

All guidelines propose the potentially life-saving procedures described below to stop

bleeding. Their low level of evidence of efficacy results mainly from the lack of control

groups.

Uterine balloon tamponade is the least invasive and swiftest approach in the PPH life-

saving therapeutic arsenal. These balloons appear to have a triple mode of action:

compression of the placental bed, reactive uterine contraction, and reduction of the uterine

vascular flow. The reported effectiveness of this method, defined by the absence of need for

surgical management or interventional radiology, ranges from 60% to 100% [130]. The

introduction of intrauterine balloon use in teams in high-income countries appears to be

associated with a reduction in the rates of such management for severe or persistent PPH

[131]. Even when it is incompletely or not successful, intrauterine balloon tamponade can at

least provide time for inter-hospital transfer to continue resuscitation at a more appropriate

facility or for arterial embolization when unavailable at the initial maternity ward [13].
25
Recently, a vacuum-induced uterine tamponade has been proposed as a possible alternative to

balloon devices [132] but due to possible bias indication in favor of its use, additional data

are required before recommending it to control severe bleeding instead of uterine balloon

tamponade [133]. Finally, some authors have suggested transvaginal uterine artery clamping,

i.e. a novel minimally invasive management of PPH. This method has been developed

initially for the non-surgical management of uterine fibroids and data in the context of PPH is

currently extremely scarce [134].

Pelvic arterial embolization has become a reliable and safe alternative procedure for PPH.

It is recommended especially in high-income countries, but only when the woman is

hemodynamically stable and the embolization unit is located close to the delivery room. Its

availability is limited by the specialized instrumentation and expertise required. Success rate

is estimated to about 90% and the serious complication rate attributable to embolization is

approximately 5% [135]. Some authorities authorize inter-hospital transfer of women with

PPH for embolization but only after hemoperitoneum, a condition for which laparotomy is

preferred, has been ruled out and if the hemodynamic condition allows [13]. Embolization

for PPH, whether or not associated with a uterine-sparing surgical procedure, does not appear

to compromise the woman’s subsequent fertility and obstetric outcome [136].

Uterine-sparing surgical procedures are likely the ideal procedures for persistent severe PPH

th
during cesarean delivery. The first pelvic artery ligation reported, at the end of the 19 century,

involved the internal iliac arteries. However, many practitioners are only slightly familiar with

this technique, which is associated with rare but severe complications, such as vascular or ureteral

injury, transient buttock numbness, and ischemic nerve injury. Finally, the procedure has been

found to be considerably less successful than previously thought (about 69%) [137]. Bilateral

uterine ligation accomplishes the same goal and appears faster and

26
easier to perform [138], with a success rate > 70% and a low risk of serious immediate

complications [139].

Uterine compression sutures, such as B-Lynch and Cho sutures, are another innovation

developed in recent decades and promptly adopted throughout the world for PPH; their

estimated success rate is 75% [140]. Pyometra and ischemic necrosis have been reported after

uterine compression sutures [141]. Neither they nor uterine and/or iliac artery ligation seem to

impair subsequent fertility and obstetric outcome [13, 138, 141]. The methodologic quality of

the studies assessing uterine-sparing procedures nonetheless remains limited, with no

comparative studies. Accordingly, no evidence suggests that any one of these methods is

better than any other for the management of severe PPH and no technique for conservative

surgery should be favored over any other [13].

In case of massive PPH, very unstable hemodynamics, or failure of uterine-sparing

procedures, peripartum hysterectomy should be promptly performed — sooner rather than

later [7, 9]. Temporising measure for massive PPH, whereby bleeding can be controlled very

rapidly while preparing for definitive surgery, particularly when there is a delay due to the

need to call in a more experienced surgeon are obviously the aortic compression but also the

uterine tourniquet technique, often quoted in the context of myomectomy surgery, using an

elastic Foley catheter placed tightly around the lower uterine segment at laparotomy [134].

Because total, compared with subtotal, hysterectomy is not associated with a significantly

higher urinary tract injury rate, this choice is left to the operator’s discretion [13].

Recombinant human activated factor VII (rFVIIa) activates coagulation to generate a

thrombin burst and stabilize blood clots. It is considered a life-saving drug and recommended by

many authorities in cases of life-threatening hemorrhage [7-9, 13] (Table 4). It is also, however,

associated with life-threatening side effects, which is why WHO was reluctant to recommend it

[11]. The only open RCT in women with severe PPH refractory to uterotonics

27
showed that rFVIIa reduces the need for specific second-line treatment (embolization,

uterine-sparing procedures, or hysterectomy) in about one in three patients and that non-fatal

venous thrombotic events occur in one in 20 patients [142]. These results confirm that rFVIIa

should be limited to life-threatening hemorrhages. Before use, fibrinogen should ideally be >

3
1 g/L and platelets > 50,000/mm [13].

In a United Kingdom population-based descriptive study, second-line treatment was used

in about 2.2 cases per 10 000 women delivering whom 25% were managed with intrauterine

tamponade to treat PPH prior to the use of one of the specific second-line therapies. As the

first second-line therapy, 73% had a uterine compression suture, 7% had a pelvic vessel

ligation, 8% had an interventional radiological technique (embolisation or intra-arterial

balloon), and 11% received rFVIIa. Finally, 26% women had a hysterectomy [143]. In a

French population-based observational study, second-line therapies were used in about 20

cases per 10 000 women delivering, i.e. between six and eight times higher than in the UK.

Among women who had a conservative procedure, 70% underwent arterial embolization and

30% had conservative surgery (about 4 arterial ligations for one uterine compression suture)

and finally 14.5% had a hysterectomy [144]. These discrepancies between two countries in

Europe regarding the use of second line therapy reflect indirectly huge differences in

management of PPH as well as in the content or organisation of initial care.

9 After postpartum hemorrhage

Once the bleeding has been controlled and initial resuscitation completed, continuous

close observation in either an intensive care or high-dependency unit on the labor ward is

required. Staff should be aware that thromboembolic events may be considered PPH-related

maternal morbidity in cases of massive transfusion and/or surgery. There is a global

consensus that thrombophylaxis should be recommended for blood loss > 1000 mL or after

28
transfusion and surgery, once the acute situation is under control [7, 10, 13]. Finally,

psychological assessment of the mother and her partner should be considered after severe

PPH in either the immediate or late postpartum period [13], because of its potential long-

term psychological impact [6].

The essential elements of a system ensuring the speed and effectiveness essential to

controlling PPH are a department protocol that is regularly updated and trained staff members

who communicate correctly. In particular, it has been demonstrated that instituting a

comprehensive protocol for the treatment of maternal hemorrhage within a large health care

system reduces the use of blood products and improve patient safety [145-146]. Consequently,

system-wide approaches are recommended to standardize care for improving outcomes in the

form of bundles. For example, the National Partnership for Maternal Safety recommends the

following for all U.S. birthing facilities: a standard obstetric hemorrhage protocol and event

checklist, a hemorrhage kit or cart with appropriate medication and equipment, partnership

with the local blood bank for rapid and sustained availability of blood products, and universal

use of active management of the third stage of labor [147]. Each department is responsible for

training all professionals likely to deal with patients with PPH to manage this situation.

Critical retrospective study of PPH files should be encouraged [13].

In conclusion, the level of evidence about preventing and managing PPH is globally low.

Several key research questions about both prevention and treatment remain unanswered in

low-, middle-, and high-income countries. Professionals should be aware that 80-90% of

PPH-related maternal morbidity follow suboptimal care due to late recognition of PPH or

late or insufficiently aggressive management.

29
10. Expert commentary

While PPH remains one of the leading causes of severe maternal morbidity and mortality

associated with childbearing, the level of evidence about its prevention and particularly its

treatment is globally low. A consensus does exist that prophylactic oxytocin should be

administered to all women after delivery and therapeutic oxytocin for PPH, but their optimal

dosage and mode of administration remain uncertain. There is no consensus about the second-

line drug of choice when therapeutic oxytocin fails or about the optimal resuscitation strategy,

although this situation occurs in 1.5-2% of all deliveries. Obviously, the emergency nature of

PPH makes RCTs logistically difficult. Moreover, such trials may systematically exclude

women at high risk of PPH morbidity and thus create both selection bias and ungeneralizable

results. These trials generally exclude women at the greatest risk — those with placenta

previa or multiple pregnancies, for example. Nor is there a consensus about pertinent, reliable,

and objective primary outcomes that should be used in such trials. Understandably, the more

objective the primary outcome and the greater its association with clinically meaningful

maternal morbidity, the lower its prevalence, and the less feasible the trial.

Peripartum hysterectomy and maternal death should be rare in middle- and high-income

countries and consequently cannot be used as primary endpoints. Although they could be

primary outcome measures in RCTs in developing countries, such as the WOMAN trial [129],

the generalizability of such trials’ results to developed countries is debatable, given the huge

differences in the organization of care and resources. All of the other main PPH outcomes are

at least partially subjective: estimated blood loss, especially during cesareans, but also blood

product use and second-line medical or invasive procedures, the choice and timing of which

can vary substantially between professionals [13]. Therefore, population-based observational

studies, such as those conducted in the UK through the UKOSS system or in France on PPH

or, more broadly, internationally through the INOSS network, including comparative studies

30
between countries [18], should be encouraged as they can usefully strengthen the evidence

base, particularly for components of PPH treatment that are difficult or impossible to assess

through RCTs.

11. Five-year view

The issues differ substantially between low and middle-high income countries. In the

latter, obstetricians should be aware of the disquieting increase in PPH incidence. Particular

attention must be paid to the risk factors corresponding to components of the management of

labor and delivery, that is, induction, oxytocin, episiotomy, and operative vaginal delivery,

because they are potentially modifiable; the examination of their benefit-risk ratio must

consider the associated risk of PPH. In low-income countries, WHO is encouraging the

assessment of community-level programs to distribute misoprostol to pregnant women for

self-administration at delivery for PPH prophylaxis [11], because this strategy may be life-

saving in deliveries in settings where skilled birth or healthcare workers and lay health

workers or attendants are not present. Moreover, non-inferiority trials comparing 600µg

versus 400µg oral misoprostol to prevent PPH are required to attempt to decrease postpartum

side effects in settings where oxytocin is not available.

In any case, the level of evidence for the use of TXA for both prevention and treatment of

PPH, after vaginal and cesarean delivery and in all countries, should increase dramatically

over the next five years [100-109]. If TXA is effective and its benefit-risk ratio acceptable, its

routine use should reduce the incidence of PPH and its related morbidity among women after

they give birth; if it is ineffective, this result will prevent the diffusion into general practice of

an ineffective medication associated with potential adverse effects.

Finally, the best tools to assess the optimal timing to apply various measures to stop
bleeding remain to be determined. Today, they are mainly based on visual blood loss
31
estimation, despite its low accuracy. In future, we hope that the role of other potentially useful

tools, such as clinical signs including the shock index (heart rate/systolic blood pressure) and

bedside hemostasis monitoring by thrombelastometry or point-of-care coagulation systems

[13], can be resolved so that they can help professionals to care for women whose deliveries

are complicated by hemorrhage.

12. Key issues

• Postpartum hemorrhage is one of the leading causes of maternal death and severe

maternal morbidity worldwide.

• Because individual risk factors are poor predictors of postpartum hemorrhage, its

prevention should be directed to all women giving birth.

• Uterine atony is the main cause of postpartum hemorrhage.

• Oxytocin, where available, is the first-line prophylactic drug that should be

administered to all women after vaginal or cesarean delivery.

• First-line measures to treat PPH should include calling in all relevant staff, noninvasive

monitoring, estimating blood loss, securing venous access, taking initial blood samples,

and performing plasma expansion by crystalloids, oxygen therapy, active skin warming,

manual removal of the placenta, visual assessment of the genital tract, uterine massage,

and uterotonic administration.

• If available, the first-line agent for treating PPH is oxytocin, for example by a slow IV

injection of 5–10 IU, followed by a maintenance infusion of 5–10 IU/h for 2 h.

• If oxytocin fails to control bleeding, other uterotonics should be considered as well

as transfusion of blood products including the use of massive transfusion protocol.

32
• If pharmacological treatment fails, balloon intrauterine tamponade, then vessel ligation

or embolization, and peripartum hysterectomy — sooner rather than later — should be

performed concomitantly with resuscitation.

• The essential elements of a system that ensures the speed and effectiveness necessary to

controlling PPH are a written up-to-date department protocol and trained staff who

communicate correctly.

• Critical retrospective study of the records of women with severe PPH should

be encouraged.

Funding

This paper was not funded.

Declaration of Interest

L Sentilhes has been a board member of and has carried out consultancy work for Ferring.

The authors have no other relevant affiliations or financial involvement with any organization

or entity with a financial interest in or financial conflict with the subject matter or materials

discussed in the manuscript apart from those disclosed.

33
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50
Figure 1. Algorithm for PPH management after vaginal delivery, from the French College

of Gynecologists and Obstetricians (CNGOF)

PPH, postpartum hemorrhage; Min, minute; slow IV, Slow intravenous; IM, Intramuscular;

IU, International unit; IAS, Irregular antibody screening; BLUA, Bilateral ligation of the

uterine arteries; BLIIA, Bilateral ligation of the internal iliac arteries; CBC, complete blood

51
count; PT, prothrombin time; ACT, activated clotting time; rFVIIa, recombinant activated

Factor VII

Reprinted from Eur J Obstet Gynecol Reprod Biol 2016 Mar;198:12-21, Sentilhes L,

Vayssière C, Deneux-Tharaux C, Aya AG, Bayoumeu F, Bonnet MP, Djoudi R, Dolley P,

Dreyfus M, Ducroux-Schouwey C, Dupont C, François A, Gallot D, Haumonté JB, Huissoud

C, Kayem G, Keita H, Langer B, Mignon A, Morel O, Parant O, Pelage JP, Phan E, Rossignol

M, Tessier V, Mercier FJ, Goffinet F. 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). Copyright 2016, with

permission from Elsevier.

Table 1. Different definitions of postpartum hemorrhage, methods for assessing blood

loss, and thresholds of intervention recommended by the principal learned societies

(modified from Sentilhes et al [16]).

52
Variables WHO (2012) [11] FIGO (2012) [12] RCOG (2011) [7] ACOG SOGC (2009) RANZCO CNGOF
(reaffirmed [10] G (2016) [9] (2015) [13]
2013) [8]
Definition
Vaginal delivery >500 mL >500 mL Minor (500 mL-1000 >500 >500 mL >500 mL >500 mL
Severe: >1000 mL Any blood loss that has the mL). mL Any blood during Severe:
potential to produce Major >1000 mL loss that has the puerperium >1000 mL
hemodynamic instability potential to produce Severe:
hemodynamic >1000 mL
instability during
puerperium

Cesarean delivery >500 mL >1000 mL Not specified >1000 >1000 mL >500 mL >500 mL
Severe: >1000 mL Any blood loss that has the mL Any blood during Severe:
potential to produce loss that has the puerperium >1000 mL
hemodynamic instability potential to produce Severe:
hemodynamic >1000 mL
instability during
puerperium
Prevention
Tools for assessment of Not mentioned Not mentioned Blood collection Not Not Not Left to the
blood loss drapes for vaginal discussed mentioned mentioned clinician’s
deliveries, weighing swabs. discretion
Visual aids may help
estimate blood loss.
Treatment
Blood Vagi Not specified 500 mL or 2 cups 500–1000 mL Excessiv Not specified 500–1000 500 mL*
loss volume nal Any volume of blood loss for e blood loss mL
threshold to delivery unstable woman
treat PPH
Cesa 1000 mL 500–1000 mL Excessiv Not specified 500–1000 1000 mL*
rean Any volume of blood loss for e blood loss mL
delivery unstable woman

Tools for assessment of Insufficient evidence to Sanitary napkin or other clean Blood collection Not Clinical Weighing Use of
blood loss recommend the measurementmaterial put under the woman's drapes for vaginal mentioned markers rather than drapes, pads, collector bag
of blood loss over clinical
buttocks. Collector bags are a deliveries and weighing a visual estimation and swabs recommended
estimation of blood loss.promising tool for low-resource swabs
settings
PPH, postpartum hemorrhage; WHO, World Health Organization; FIGO, International Federation of Gynaecology and Obstetrics; RCOG, Royal College of Obstetricians and Gynaecologists; ACOG, American

College of Obstetricians and Gynecologists; SOGC, Society of Obstetricians and Gynaecologists of Canada; RANZOG, Royal Australian and New Zealand College of Obstetricians and Gynaecologists; CNGOF,

French College of Gynecologists and Obstetricians

*Beginning active management before the threshold (of 500 mL for vaginal deliveries and 1000 mL for caesarean deliveries) is reached is justified when the bleeding rate is high or clinical tolerance poor.
53
Table 2. Principal risk factors for PPH in the most recent population-based studies (modified

from Deneux-Tharaux et al [3])

Al-Zirqi [42] Sosa [41] Bateman [43] Kramer [37] Dupont [29]

National birth Multicenter Hospital Hospital Population based


Design databases databases
registry cluster RCT Cluster RCT
(NIS) (NIS)
Inclusion period 1999-2004 2003-2004 2004 1999-2008 2004-2006
Geographic zone Norway Argentina and USA USA 3 French regions
Uruguay
All deliveries Vaginal All deliveries All deliveries Vaginal deliveries:
Study population deliveries With severe PPH n=2139
(n=307,415) (n=876,641) (n=8,571,209)
(n=11,323) Controls n=2148
Blood loss Blood loss PPH due to PPH + PPH+ transfusion and/or
uterine transfusion surgery and/or
Definition of PPH >1500 mL
≥500 mL atony + and/or embolization and/or
or transfusion
transfusion surgery ICU and/or Hb loss ≥ 4 g/dL

Risk factors for PPH OR for Adjusted OR (95%CI) in the multivariate analysis Range of reported
main risk factors

Mothers' characteristics
before pregnancy
Maternal age
15-19 years 0.8 (0.6-1.1) 1.3 (1.1-1.5) 1.8 (1.5-2.2) 1.2 (1.2-1.3) NA
20-34 1 1 1 1 1*
35-39 1.1 (1.0-1.2) 0.7 (0.6-0.9) 1.2 (1.0-1.4) 1.5 (1.5-1.6) 0.9 (0.7-1.1)
≥40 years 1.4 (1.1-1.7) 1.7 (1.3-2.2) Between 1 and 2
Primiparas 1.1 (1.0-1.2) 1.3 (1.1-1.7) NA 1.3 (1.2-1.4) 1.7 (1.4-2.0) Between 1 and 2
Grand multiparas 1.2 (0.8-1.9) NA NA 1.4 (1.2-1.7) NA Between 1 and
1.5
Previous cesarean 1.5 (1.0-1.3) NA NA 1.3 (1.2-1.3) 1.9 (1.4-2.6) Between 1 and 2
Characteristics of
the pregnancy
Multiple pregnancy 2.3 (2.0-2.7) 4.7 (2.4- 9.1) 4.3 (1.5-12.9) 2.8 (2.2-3.6) 3.8 (2.2-6.5) Between 2 and 5
Polyhydramnios NA NA NA 1.9 (1.2-3.1) NA
Chorioamnionitis NA NA NA 2.5 (1.9-3.3) NA
Pregnancy-related 1.9 (1.2-2.8) NA NA 2.5 (2.1-2.8) NA Between 1 and
hypertensive disease 2.5
Characteristics of
labor and delivery
Induction 1.9 (1.2-2.8) 1.3 (1.0-1.5) 2.0 (1.3-3.1) NA 1.2 (1.0-1.5) Between 1 and 2
Prolonged labor 1.1 (1.0-1.3) NA NA NA 1.7 (1.4-2.0) Between 1 and 2
Episiotomy NA 1.7 (1.2-2.5) 1.4 (0.9-2.3) NA 2.2 (1.8-2.6) Between 1 and 2
Operative vaginal 1.9 (1.4-2.4) 1.4 (1.1-2.5) 1.2 (0.5-2.9) NA 2.3 (1.5-3.4) Between 1 and
delivery£ 2.5
Cesarean before 2.3 (2.1-2.6) NA NA 1.3 (1.1-1.5) NA Between 1 and
labor£ 2.5
Cesarean during 3.6 (3.3-4.0) NA NA 1.7 (1.5-2.0) 3.2 (2.4-4.2) Between 1 and
labor£ 2.5
Macrosomia 1.9 (1.7-2.3) 2.4 (1.9-2.9) 3.5 (2.3-5.4) NA 1.7 (1.3-2.2) Between 1 and
3.5

54
*: reference category: < 35 years
£: reference category for mode of delivery: spontaneous vaginal delivery
OR: Odds Ratio NIS: Nationwide Inpatient Sample NA: not assessed
RCT: randomized controlled trial

Table 3. Clinical and pharmacological measures for PPH prevention according to various
international guidelines (modified from Sentilhes et al [16]).

55
Prevention WHO (2012) [11] FIGO (2012) [12] RCOG (2011) ACOG SOGC (2009) [10] RANZCO CNGOF (2015)
[7] (reaffirmed G (2016) [9] [13]
2013) [8]
Uter Agent Oxytocin, 10 IU, IV, or IM. Oxytocin, 10 IU IM. Oxytocin, 5 IU Not Oxytocin in low-risk Oxytocin, Oxytocin, slow IV
otonic of choice or 10 IU IM after discussed vaginal deliveries, 10 IU dose not or IM of 5 or 10 IU for

vaginal delivery and IM. specified. both vaginal and

slow IV 5 IU after Oxytocin, 5 to 10 IU cesarean deliveries

cesarean. (given over 1 to 2

minutes), can be used for

PPH prevention only after

vaginal birth.

Carbetocin, 100 µg

over 1 minute IV for

cesarean delivery or

vaginal delivery in women

with at least one risk factor

If Ergometrine or Ergometrine or Ergometrine Not Ergonovine, 0.2 mg Misoprost Not specified


agent of methylergometrine 0.2 mg IM or methylergometrine 0.2 mg 0.5 mg/oxytocin 5 IU discussed IM, or misoprostol, 600- ol, dose not

choice is ergometrine 0.5 mg/oxytocin 5 IU IM or ergometrine IM 800 µg by oral, sublingual, specified.

not IM or misoprostol 600 µg orally. 0.5 mg/oxytocin 5 IU IM or or rectal route in vaginal

available misoprostol 600 µg orally. deliveries

Controlled cord Recommended Recommended AMTSL is Not Recommended Recomme Not recommended
traction recommended with discussed nded

no details of

56
components

Cord clamping Late cord clamping is Late cord clamping is AMTSL is Not Late cord clamping Early cord No specific timing
recommended recommended if the newborn recommended with discussed recommended for clamping recommended for PPH

does not require resuscitation no details of premature newborns. prevention

components Otherwise, left to the

professionals’ discretion.

Uterine massage Not recommended Recommended after Not mentioned Not Not mentioned Not Not recommended
delivery of the placenta discussed mentioned

Management of Use of additional oxytocin Manual removal of Not mentioned Not Manual removal of Not Manual removal
retained placenta in (10 IU, IV/IM) in combination placenta 60 min after discussed placenta between 30 to 45 mentioned of placenta between 30-

absence of bleeding with controlled cord traction is delivery if controlled cord min after delivery. 60 min after delivery

recommended before attempted traction was not applied. Intraumbilical cord Intraumbilical

removal. The timing of the use of Intraumbilical cord injection of misoprostol cord injection of any

these two procedures is left to the injection of misoprostol (800 (800 µg) or oxytocin (10 to uterotonic is not

clinician’s judgment µg) can be considered as an 30 IU) can be considered recommended as an

alternative intervention as an alternative alternative intervention

before manual removal of intervention before manual before manual removal

the placenta. removal of the placenta. of the placenta.

Surveillance and Not specified except “uterine Every 5–10 minutes Not mentioned Not Not mentioned Not Every 15 minutes
reporting of blood loss and tonus assessment” and that women during the first 30 minutes, discussed mentioned for two hours
then every 15 minutes for the
vital signs after delivery should not be left alone during the next 30 minutes, and then
every 30 minutes for the next
2 hours.
57
first hours after delivery of the

baby and the placenta

PPH, postpartum hemorrhage; AMTSL, Active management of the third stage of labor, including the use of a uterotonic, early cord clamping, and controlled cord traction for delivery of the placenta; IM,

intramuscular; IV, intravenous; IU, International Unit; WHO, World Health Organization; FIGO, International Federation of Gynaecology and Obstetrics; RCOG, Royal College of Obstetricians and Gynaecologists;

ACOG, American College of Obstetricians and Gynecologists; SOGC, Society of Obstetricians and Gynaecologists of Canada; RANZOG, Royal Australian and New Zealand College of Obstetricians and

Gynaecologists; CNGOF, French College of Gynecologists and Obstetricians

Table 4. Pharmacological measures for PPH treatment according to various international guidelines (modified from Sentilhes et al [16]).

Pharmacolo WHO (2012) [11] FIGO (2012) [12] RCOG (2011) [7] ACOG SOGC (2009) RANZCOG (2016) CNGOF
gical PPH (reaffirmed 2013) [8] [10] [9] (2015) [13]

treatment

Temporal 2-step Oxytocin should be The following Not mentioned Not mentioned Uterotonics are 2-step
sequence of administration of preferred first. If oxytocin is not
available, or if the bleeding does mechanical and commonly given in administration of
administration uterotonics, oxytocin not respond to oxytocin or
ergometrine, an oxytocin- pharmacological combination and, in the uterotonics, oxytocin
first and then ergometrine fixed dose measures should be absence of individual first and then
combination, carbetocin, or
intravenous misoprostol should be offered as instituted, in turn, until contraindications, a patient sulprostone if
second-line treatment;
ergometrine, oxytocin- carboprost should be offered as
the third-line treatment the bleeding stops: may be given all four in oxytocin fails
ergometrine fixed dose, the event of severe

or a prostaglandin drug ongoing atonic bleeding.

(including sublingual

misoprostol, 800 μg) if

oxytocin fails .

58
Oxytocin Intravenous Oxytocin 10 IU IM or 5 IU Slow IV 5 IU 10–40 IU in Oxytocin 10 IU Oxytocin by slow IV Slow IV or IM
oxytocin is the slow IV push, or 20–40 IU/L IV oxytocin (may have 1000-mL infusion IM or 5 IU IV or 20 or infusion, dose not injection of 5–10 IU

recommended fluid infusion repeat dose) or (IV) or 10 IU IM to 40 IU at 500-1000 specified oxytocin followed

uterotonic drug maintenance infusion of mL/h by a maintenance

40 IU in 500 mL infusion of 5–10

Hartmann’s solution at IU/h for 2 h.

125 mL/hour) unless fluid Cumulative dose

restriction is necessary must not exceed 40

IU.

Carbetocin Not mentioned 100 μg IM or IV over 1 Not mentioned Not mentioned 100 µg IM or IV Not mentioned Not mentioned
minute over 1 min

Ergot See above Ergometrine or Slow IV or IM Methylergonovin Ergonovine Ergometrine by slow Not
alkaloids methylergometrine 0.2 mg IM, injection of ergometrine e 0.2 mg IM every 2-4 0.25 mg IV or IM, IV, in the absence of recommended

every 2–4 h with a maximum of 0.5 mg (contraindicated in hours (contraindicated can be repeated every contraindications

5 doses (1 mg) per 24-h period women with in women with 2 h (contraindicated

or ergometrine 0.5 mg/oxytocin hypertension). hypertension). in women with

5 IU IM (contraindicated in hypertension).

women with hypertension).

Injectable See above Carboprost 0.25 mg IM Carboprost 0.25 mg Carboprost Carboprost Prostaglandin F2α Sulprostone is
prostaglandins repeated at intervals of not less IM repeated at intervals 0.25 mg IM every 15- 0.25 mg IM repeated (500 µg increments up to recommended and

than 15 minutes to a maximum of not less than 15 90 min with a at intervals of not less 3 mg) IM or intra- must be

of 8 doses (contraindicated in minutes to a maximum of maximum of 8 doses than 15 minutes to a myometrially. The most administered within

women with asthma). 8 doses or 0.5 mg (contraindicated in maximum of 8 doses potent uterotonic but also 30 min of the PPH

59
intramyometrially women with asthma). (contraindicated in the most serious adverse diagnosis, should
(contraindicated in women with asthma). effect profile oxytocin be

women with asthma). (contraindicated in women ineffective.

with hypertension or

asthma).

Misoprostol See above 800 μg sublingually (4 × 1000 µg rectally 800-1000 μg 400 to 800 μg 1000 µg rectally Not
200 μg tablets) rectally sublingually or orally recommended if

or 800-1000 μg oxytocin available

rectally

Tranexamic The use of Not mentioned Although evidence Not mentioned Not mentioned Not mentioned Use left to the
acid tranexamic acid is is conflicting, there is a clinician’s discretion

recommended for the consensus view that but any use should

treatment of PPH if fibrinolytic inhibitors be limited to cases

oxytocin and other (such as tranexamic acid) of sulprostone-

uterotonics fail to stop seldom, if ever, have a resistant PPH, at a

the bleeding or if it is place in the management dose of 1 g,

thought that the of obstetric hemorrhage. renewable once if

bleeding may be partly ineffective

due to trauma.

rFVIIa Not Not mentioned For life-threatening For life- Potential role. For life-threatening For life-
recommended because hemorrhage. Fibrinogen threatening Not recommended as hemorrhage. threatening

although potentially should be above 1 g/L hemorrhage. part of a routine hemorrhage.

life-saving, it is and platelets > practice Fibrinogen should

60
associated with life- 20,000/mm3. be above 1 g/L and
threatening side effects platelets >

50,000/mm3.

PPH, postpartum hemorrhage; rFVIIa, recombinant activated factor VII; IM, intramuscular; IV, intravenous; IU, International Unit; WHO, World Health Organization; FIGO, International Federation of

Gynaecology and Obstetrics; RCOG, Royal College of Obstetricians and Gynaecologists; ACOG, American College of Obstetricians and Gynecologists; SOGC, Society of Obstetricians and Gynaecologists of Canada;

RANZOG, Royal Australian and New Zealand College of Obstetricians and Gynaecologists; CNGOF, French College of Gynecologists and Obstetricians

61