Choice of uterotonic agents

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WHO recommendations: Uterotonics for the prevention of postpartum haemorrhage. Geneva: World Health Organization; 2018.

WHO recommendations: Uterotonics for the prevention of postpartum haemorrhage.

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Web annex 7Choice of uterotonic agents

Evidence to Decision framework

1. Background

Characteristics	Oxytocin	Carbetocin	Misoprostol	Injectable prostaglandins	Ergometrine	Oxytocin plus ergometrine	Misoprostol plus oxytocin
Brief description (1,2)	Synthetic cyclic peptide form of the naturally occurring posterior pituitary hormone Binds to oxytocin receptors in the myometrium, stimulating contraction of this uterine smooth muscle by increasing the sodium permeability of its myofibrils	Long-acting synthetic analogue of oxytocin with agonist properties Binds to oxytocin receptors in the uterine smooth muscle, resulting in rhythmic contractions, increased frequency of existing contractions, and increased uterine tone	Synthetic analogue of natural prostaglandin E1 Has oxytocic properties, inhibits gastric acid and pepsin secretion, and enhances gastric mucosal resistance to injury	Injectable prostaglandins (systemic) trialled for PPH prevention include prostaglandin F2α analogues (carboprost), prostaglandin E2 (dinoprostone) and prostaglandin E2 analogues (sulprostone)	Ergometrine and methylergometrine are ergot alkaloids that increase uterine muscle tone by causing sustained uterine contractions	Fixed drug combination – oxytocin (5 IU) plus ergometrine (500 μg)	See misoprostol and oxytocin. Combination agents not in synthetic (fixed-dose) or naturally occurring forms
Pharmacokinetics (1,2)	IV: almost immediate action with peak concentration after 30 minutes IM: slower onset of action, taking 3–7 minutes, but produces a longerlasting clinical effect of up to 1 hour Half-life: 1–6 minutes.	IV: sustained uterine contractions within 2 minutes, lasting for about 6 minutes and followed by rhythmic contractions for 60 minutes IM: sustained uterine contractions last for about 11 minutes and rhythmic contractions for 120 minutes Half-life: 40 minutes.	Absorbed 9–15 minutes after sublingual, oral, vaginal or rectal use Oral and sublingual routes have the advantage of rapid onset of action, while the vaginal and rectal routes result in prolonged activity and greater bioavailability Half-life: 20–40 minutes	IM: 15–60 minutes to peak plasma concentration Half-life: 8 minutes	IM: onset of action within 2–3 minutes, lasting for about 3 hours IV: onset of action within 1 minute, lasting 45 minutes (although rhythmic contractions may persist for up to 3 hours) Half-life: 30–120 minutes	See oxytocin and ergometrine IM: latent period for uterine response is about 2.5 minutes; uterotonic effects last for around 3 hours (3) Half-life: 1–6 minutes (oxytocin) and 30–120 minutes (ergometrine)	See misoprostol and oxytocin
Storage and transport (4)	Requires protection from light, and storage at 2–8 °C^a to prolong shelf life	A heat-stable formulation of carbetocin^b is available.	Does not have any special storage requirements. Tablets should be kept in tightly closed containers and protected from humidity.	Requires storage at a temperature between 2 ° and 8 °C^a to prolong shelf life	Requires protection from light, and storage at a temperature between 2 ° and 8 °C^a to prolong shelf life	See oxytocin and ergometrine	See misoprostol and oxytocin
WHO Model List of Essential Medicines (5)	Listed: 10 IU in 1 ml ampoule for injection	Not listed	Listed: 200 μg tablets^c and 25 μg tablets	Not listed	Listed: Ergometrine (hydrogen maleate) 200 μg in 1 ml ampoule for injection	Oxytocin and ergometrine are listed separately The fixed-drug combination of oxytocin plus ergometrine (5 IU/500 μg) is not listed.	See misoprostol and oxytocin

: IM: intramuscular; IV: intravenous; PPH: postpartum haemorrhage
a: Due consideration should be given to the manufacturer’s instructions on storage and transport.
b: The heat-stable formulation of carbetocin differs only in its excipients from the existing non-heat-stable formulation.
c: For the prevention and treatment of PPH where oxytocin is not available or cannot be safely used, and for the management of incomplete abortion and miscarriage.

2. Question

The following is the question of interest in PICO (population, intervention, comparator, outcome) format:

For women in the third stage of labour (P), is the use of any uterotonic agent(s) (oxytocin, carbetocin, misoprostol, ergometrine/methylergometrine, injectable prostaglandins, oxytocin plus ergometrine, misoprostol plus oxytocin) for prevention of PPH (I) compared with other uterotonic agents (oxytocin, carbetocin, misoprostol, ergometrine/methylergometrine, injectable prostaglandins, oxytocin plus ergometrine, misoprostol plus oxytocin) (C), safer and more effective for improving maternal and perinatal outcomes?

If so, what route of administration and dosing regimen of such uterotonic agent(s) should be used?

Problem: Preventing the onset of postpartum haemorrhage (PPH)

Perspective: Clinical practice recommendation – population perspective

Population (P): Women in the third stage of labour

Intervention (I): Uterotonic agent (single agent: oxytocin, carbetocin, misoprostol, injectable prostaglandins, ergometrine; or combination agents: oxytocin plus ergometrine, misoprostol plus oxytocin)

Comparator (C): Any uterotonic agent (as above)

Setting: Hospital or community setting¹

Subgroups: Women undergoing vaginal birth; women undergoing caesarean section

Priority outcomes (O):²

Maternal death
PPH ≥ 1000 ml
Blood transfusion
Severe maternal morbidity: intensive care unit (ICU) admission
Severe maternal morbidity: shock
PPH ≥ 500 ml
Use of additional uterotonics
Blood loss (ml)
Postpartum anaemia
Breastfeeding
Side-effects³
Maternal well-being
Maternal satisfaction

3. Assessment

3.1. Effects of interventions

What is the effect of uterotonics for PPH prevention on the priority outcomes?

Research evidence

Summary of evidence

Source and characteristics of studies

Evidence on the efficacy and safety of uterotonics for the prevention of postpartum haemorrhage (PPH) was derived from an updated Cochrane systematic review with a network meta-analysis (6). The network meta-analysis included 196 trials (135 559 women) that were conducted across 53 countries (including high-, middle- and low-income countries). Most trials (187/196, 95.4%) were performed in a hospital setting, seven in a community setting (3.6%), one in a mixed setting (0.5%), and in one trial the setting was unclear.

The majority of the trials included women undergoing a vaginal birth (140/196, 71.5%), while 53 trials (27.0%) involved women undergoing caesarean section, two trials (1.0%) included women undergoing either a vaginal birth or caesarean section, and one trial (0.5%) did not specify the mode of birth. A total of 124 trials (63.3%) included women with a singleton pregnancy, 36 trials (18.4%) included women with either singleton or multiple pregnancies, one trial (0.5%) included women with twin pregnancies only and the remaining 35 trials (17.9%) did not specify. A total of 108 trials (55.1%) included both nulliparous and multiparous women, six trials (3.1%) included only nulliparous or primigravida women, one trial included only multiparous women (0.5%), and 81 trials (41.3%) did not specify parity.

Across all 196 trials (412 trial arms) in the network meta-analysis, the following agents were used either as intervention or comparator:

137 trial arms (33.3%) used oxytocin
96 trial arms (23.3%) used misoprostol
39 trial arms (9.5%) used ergometrine
35 trial arms (8.5%) used oxytocin plus ergometrine
33 trial arms (8%) used carbetocin
29 trial arms (7%) used placebo or no treatment
26 trial arms (6.3%) used misoprostol plus oxytocin
17 trial arms (4.1%) used injectable prostaglandins.

Oxytocin was the reference uterotonic in one third of the trials in the network meta-analysis, and was the most frequently investigated agent across all outcomes. The comparative effects of different uterotonics have therefore been presented using oxytocin as the reference agent.

Effects of uterotonics agents (carbetocin, misoprostol, injectable prostaglandins, ergometrine, oxytocin plus ergometrine, misoprostol plus oxytocin) compared with oxytocin (as reference agent)

The results below report the findings of the network meta-analysis for the priority outcomes (which generated effect estimates from both direct and indirect evidence). The findings are summarized in Table 1 below.

Maternal death: See Summary of Findings table 1. Pooled effect estimates from the network meta-analysis suggested that there were no meaningful differences between any of the uterotonic agents versus placebo for maternal death, as this outcome was generally rare. When compared with oxytocin, moderate-certainty evidence suggests that carbetocin (relative risk [RR] 2.00, 95% confidence interval [CI] 0.37–10.92) and misoprostol (RR 0.62, 95% CI 0.14–2.74) probably make little or no difference to the risk of maternal death. Network relative effects were not estimable for the comparisons of other uterotonics with oxytocin.

PPH ≥ 1000 ml: See Summary of Findings table 2. None of the agents was found to be more effective when compared with the reference uterotonic agent oxytocin for PPH ≥ 1000 ml. High-certainty evidence suggests that misoprostol plus oxytocin (RR 0.88, 95% CI 0.70–1.11) and oxytocin plus ergometrine (RR 0.83, 95% CI 0.66–1.03) make little or no difference to risk of PPH ≥ 1000 ml when compared with oxytocin. Low-certainty evidence suggests that ergometrine (RR 0.94, 95% CI 0.48–1.84) may make little or no difference to the risk of this outcome when compared with oxytocin. The evidence for carbetocin and injectable prostaglandins was uncertain. The network evidence shows that misoprostol has less protective effect against PPH ≥ 1000 ml when compared with oxytocin (high-certainty evidence, RR 1.19, 95% CI 1.01–1.42).

Blood transfusion: See Summary of Findings table 3. Misoprostol plus oxytocin was the only agent found to be more effective when compared with the reference uterotonic agent oxytocin (moderate-certainty evidence, RR 0.52, 95% CI 0.38–0.70).

Severe maternal morbidity – ICU admission: See Summary of Findings table 4. Pooled effect estimates for the various comparisons suggested that there were no detectable differences among the uterotonic agents for intensive care unit admission as this outcome was generally rare. When compared with oxytocin, moderate-certainty evidence suggests that carbetocin (RR 1.16, 95% CI 0.67–2.02) and misoprostol (RR 1.16, 95% CI 0.55 to 2.43) probably make little or no difference to the risk of this outcome, while effects are uncertain for ergometrine, oxytocin plus ergometrine and misoprostol plus oxytocin because the certainty of the evidence is very low. This outcome was not reported for any trial involving injectable prostaglandins.

PPH ≥ 500 ml: See Summary of Findings table 5. When compared with oxytocin, moderate-certainty evidence suggests that carbetocin (RR 0.72, 95% CI 0.56–0.93) and oxytocin plus ergometrine (RR 0.70, 95% CI 0.59–0.84) probably reduce PPH ≥ 500 ml, while low-certainty evidence suggests that misoprostol plus oxytocin (RR 0.70, 95% CI 0.58–0.86) may reduce PPH ≥ 500 ml. Low-certainty evidence suggests that misoprostol, injectable prostaglandins and ergometrine may make little or no difference to the risk of this outcome.

Use of additional uterotonics: See Summary of Findings table 6. High-certainty evidence suggests that misoprostol plus oxytocin (RR 0.57, 95% CI 0.44–0.74) reduces the use of additional uterotonics when compared with oxytocin. There is low-certainty evidence that carbetocin (RR 0.45, 95% CI 0.34–0.59), injectable prostaglandins (RR 0.55, 95% CI 0.31–0.96) and oxytocin plus ergometrine (RR 0.66, 95% CI 0.51–0.85) may also reduce the use of additional uterotonics. It is uncertain whether ergometrine reduces use of additional uterotonics because the certainty of this evidence is very low.

Mean blood loss: See Summary of Findings table 7. When compared with oxytocin, moderate-certainty evidence suggests that blood loss is probably on average reduced among women receiving misoprostol plus oxytocin (mean difference [MD] 88.31 ml lower, 95% CI 127.08–49.54 ml lower), and that it may be reduced among women receiving carbetocin (MD 81.93 ml lower, 95% CI 119.91–42.87 ml lower). Low-certainty evidence suggests that there may be little or no difference between ergometrine (MD 4.82 ml higher, 95% CI 28.00 ml lower to 37.64 ml higher) and oxytocin for this outcome. The effects of misoprostol, injectable prostaglandins and oxytocin plus ergometrine is unclear because the certainty of the evidence is very low.

Postpartum anaemia: See Summary of Findings table 8. Postpartum anaemia was not directly reported in the review, but there was evidence relating to mean change in haemoglobin level before versus after birth. Low-certainty evidence suggests that the mean change in haemoglobin level may be lower among women receiving misoprostol plus oxytocin (MD 2.53 g/L lower, 95% CI 3.80 g/L lower to 1.26 g/L lower) and carbetocin (MD 2.18 g/L lower, 95% CI from 3.57 g/L lower to 0.79 g/L lower) compared with those receiving oxytocin. Low-certainty evidence suggests that there may be little or no difference between ergometrine (MD 0.98 g/L higher, 95% CI from 0.74 g/L lower to 2.69 g/L higher) or oxytocin plus ergometrine (MD 1.07 g/L lower, 95% CI 2.38 g/L lower to 0.25 g/L higher) and oxytocin for this outcome. The effects of misoprostol and injectable prostaglandins is unclear because the certainty of the evidence is very low.

Breastfeeding: See Summary of Findings table 9. High-certainty evidence suggests that oxytocin plus ergometrine makes little or no difference to the proportion of women who are breastfeeding at the time of discharge from hospital (RR 0.99, 95% CI 0.96–1.03) when compared with oxytocin. There were no clear findings relating to any other uterotonics, either because the evidence was of very low certainty (for carbetocin) or the outcome was not reported in any of the included trials (misoprostol, injectable prostaglandins, ergometrine, misoprostol plus oxytocin).

Side-effect – nausea: See Summary of Findings table 10. Low-certainty evidence suggests that carbetocin may make little or no difference to the risk of experiencing of nausea among women when compared with oxytocin (RR 1.00, 95% CI 0.71–1.41). However, high-certainty evidence suggests that oxytocin plus ergometrine (RR 2.03, 95% CI 1.47–2.79) and misoprostol plus oxytocin (RR 1.88, 95% CI 1.14–3.09) combinations increase the risk of nausea compared with oxytocin. Moderate-certainty evidence suggests that misoprostol (RR 1.41, 95% CI 1.10–1.81), injectable prostaglandins (RR 2.25, 95% CI 1.16–4.39), and ergometrine (RR 2.40, 95% CI 1.65–3.49) probably increase the risk of nausea compared with oxytocin.

Side-effect – vomiting: See Summary of Findings table 11. Moderate-certainty evidence suggests that carbetocin probably makes little or no difference to the risk of women experiencing vomiting compared with oxytocin (RR 0.93, 95% CI 0.64–1.35). When compared with oxytocin, high-certainty evidence suggests misoprostol plus oxytocin combination (RR 2.11, 95% CI 1.39–3.18) increases the likelihood of vomiting. Moderate-certainty evidence suggests that oxytocin plus ergometrine (RR 2.93, 95% CI 2.08–4.13), misoprostol (RR 1.63, 95% CI 1.25–2.14) and ergometrine (RR 2.36, 95% CI 1.56–3.55) probably increase the likelihood of vomiting, whereas low-certainty evidence suggests that injectable prostaglandins (RR 3.76, 95% CI 1.90–7.42) may increase the risk of women experiencing vomiting.

Side-effect – headache: See Summary of Findings table 12. When compared with oxytocin, low-certainty evidence suggests that women receiving ergometrine (RR 1.89, 95% CI 1.02–3.50) may be more likely to experience headache. Low-certainty evidence also suggests that carbetocin (RR 0.94, 95% CI 0.66-1.33), misoprostol (RR 0.98, 95% CI 0.69-1.40), and misoprostol plus oxytocin (RR 1.48, 95% CI 0.42-5.81) may make little or no difference to the risk of headache when compared with oxytocin. It is uncertain whether injectable prostaglandins impact on the risk of women experiencing headache because the certainty of the evidence is very low.

Side-effect – abdominal pain: See Summary of Findings table 13. High-certainty evidence suggests that misoprostol (RR 1.02, 95% CI 0.80-1.31) and misoprostol plus oxytocin (RR 1.93, 95% CI 0.89-4.20) make little or no difference to of the risk of women experiencing abdominal pain when compared with oxytocin. Low-certainty evidence suggests that oxytocin plus ergometrine (RR 1.39, 95% CI 0.91-2.13) probably make little or no difference to the likelihood of abdominal pain compared with oxytocin. The effects of injectable prostaglandins and ergometrine are uncertain as the certainty of the evidence is very low.

Side-effect – hypertension: See Summary of Findings table 14. Low-certainty evidence suggests that ergometrine (RR 8.54, 95% CI 2.12–34.48) may increase the risk of hypertension when compared with oxytocin, whereas misoprostol (RR 1.50, 95% 0.49–4.61) and oxytocin plus ergometrine (RR 2.48, 95% CI 0.89–6.88) may make little or no difference to the risk of this outcome. It is uncertain whether carbetocin or injectable prostaglandins increase the risk of hypertension because the certainty of the evidence is very low.

Side-effect – shivering: See Summary of Findings table 15. Moderate-certainty evidence suggests that misoprostol plus oxytocin (RR 3.62, 95% CI 2.59–5.05) is probably more likely to cause shivering when compared with oxytocin. Low-certainty evidence also suggests that misoprostol (RR 4.18, 95% CI 3.34–5.23) may increase the likelihood of shivering when compared with oxytocin. Moderate-certainty evidence suggests that oxytocin plus ergometrine (RR 1.38, 95% CI 0.86–2.22) probably makes little or no difference to the likelihood of shivering when compared with oxytocin. Low- certainty evidence suggests that carbetocin (RR 0.77, 95% CI 0.46-1.29) and injectable prostaglandins (RR 0.50, 95% 0.19-1.31) may make little or no difference to the risk of this outcome when compared with oxytocin.

Side-effect – fever: See Summary of Findings table 16. Moderate-certainty evidence suggests that misoprostol (RR 3.87, 95% CI 2.90–5.16) and misoprostol plus oxytocin (RR 3.14, 95% CI 2.20–4.49) probably increase the occurrence of fever when compared with oxytocin. Moderate-certainty evidence suggests that carbetocin (RR 1.07, 95% CI 0.43–2.69) probably makes little or no difference to the likelihood of fever. Low-certainty evidence suggests that injectable prostaglandins (RR 1.12, 95% CI 0.33–3.86) and oxytocin plus ergometrine (RR 0.70, 95% CI 0.35–1.42) may make little or no difference to the risk of this outcome when compared with oxytocin. The comparative effect of ergometrine on this outcome is uncertain because the certainty of the evidence is very low.

Side-effect – diarrhoea: See Summary of Findings table 17. High-certainty evidence shows that misoprostol (RR 2.24, 95% CI 1.64–3.05) and misoprostol plus oxytocin (RR 1.82, 95% CI 1.12–2.98) increase the likelihood of diarrhoea when compared with oxytocin. Moderate-certainty evidence suggests that oxytocin plus ergometrine (RR 1.80, 95% CI 1.18–2.75) and injectable prostaglandins (RR 23.41, 95% CI 11.03–49.70) probably increase the likelihood of diarrhoea when compared with oxytocin. Low-certainty evidence suggests that women receiving ergometrine (RR 2.51, 95% CI 1.20–5.26) may experience diarrhoea more frequently compared with women receiving oxytocin.

Table 1Summary of treatment effects of uterotonic agents versus reference agent (oxytocin) on beneficial outcomes

Desirable outcomes	Oxytocin (absolute risk)	Carbetocin	Misoprostol	Injectable prosta-glandins	Ergometrine	Oxytocin plus ergometrine	Misoprostol plus oxytocin
Maternal death	1 per 1000	Probably similar effect	Probably similar effect	Don’t know	Don’t know	Don’t know	Don’t know
PPH ≥ 1000 ml	37 per 1000	Uncertain	Inferior	Uncertain	Possibly similar effect	Similar effect	Similar effect
Blood transfusion	22 per 1000	Probably similar effect	Probably similar effect	Uncertain	Possibly similar effect	Possibly similar effect	Probably superior
ICU admissions	2 per 1000	Probably similar effect	Probably similar effect	Don’t know	Uncertain	Uncertain	Uncertain
PPH ≥ 500 ml	145 per 1000	Probably superior	Possibly similar effect	Possibly similar effect	Possibly similar effect	Probably superior	Possibly superior
Additional uterotonics	135 per 1000	Possibly superior	Possibly similar effect	Possibly superior	Uncertain	Possibly superior	Probably superior
Blood loss	301.5 ml (98– 1299 ml)	Possibly superior	Uncertain	Uncertain	Possibly similar effect	Uncertain	Probably superior
Change in haemoglobin	11.37 g/L (2.30–27.9 g/L)	Possibly superior	Uncertain	Uncertain	Possibly similar effect	Possibly similar effect	Possibly superior
Breastfeeding	849 per 1000	Uncertain	Don’t know	Don’t know	Don’t know	Similar effect	Don’t know

: ICU: intensive care unit; PPH: postpartum haemorrhage
: Superior, inferior or similar effect: high-certainty evidence of different effect or no effect
: Probably superior, probably inferior or probably similar effect: moderate-certainty evidence of different effect or no effect
: Possibly superior, possibly inferior or possibly similar effect: low-certainty evidence of different effect or no effect
: Uncertain: very low-certainty evidence (regardless of effect)
: Don’t know: outcome not reported/not estimable.

Additional considerations

Subgroup analyses did not reveal a substantial difference by mode of birth (vaginal versus caesarean section) or setting (community versus hospital) in the effects of uterotonic agents on the above outcomes when compared with oxytocin as the reference uterotonic agent.

Desirable effects

How substantial are the desirable anticipated effects of different uterotonics (carbetocin, misoprostol, injectable prostaglandins, ergometrine, oxytocin plus ergometrine, and misoprostol plus oxytocin) compared with oxytocin (as the reference agent)?

Judgement

Carbetocin	— Don’t know	— None	— Trivial	✓ Small	— Moderate	— Large
Misoprostol	— Don’t know	✓ None	— Trivial	— Small	— Moderate	— Large
Injectable prostaglandins	— Don’t know	✓ None	— Trivial	— Small	— Moderate	— Large
Ergometrine	— Don’t know	✓ None	— Trivial	— Small	— Moderate	— Large
Oxytocin plus ergometrine	— Don’t know	— None	— Trivial	✓ Small	— Moderate	— Large
Misoprostol plus oxytocin	— Don’t know	— None	— Trivial	— Small	✓ Moderate	— Large

Undesirable effects

How substantial are the undesirable anticipated effects of different uterotonics (carbetocin, misoprostol, injectable prostaglandins, ergometrine, oxytocin plus ergometrine, and misoprostol plus oxytocin) compared with oxytocin (as the reference agent)?

Judgement

Carbetocin	— Don’t know	— Large	— Moderate	— Small	— Trivial	✓ None
Misoprostol	— Don’t know	— Large	✓ Moderate	— Small	— Trivial	— None
Injectable prostaglandins	— Don’t know	— Large	✓ Moderate	— Small	— Trivial	— None
Ergometrine	— Don’t know	— Large	✓ Moderate	— Small	— Trivial	— None
Oxytocin plus ergometrine	— Don’t know	— Large	✓ Moderate	— Small	— Trivial	— None
Misoprostol plus oxytocin	— Don’t know	✓ Large	— Moderate	— Small	— Trivial	— None

Certainty of the evidence

What is the overall certainty of the evidence of effects of different uterotonics (carbetocin, misoprostol, injectable prostaglandins, ergometrine, oxytocin plus ergometrine, and misoprostol plus oxytocin) compared with oxytocin (as the reference agent)?

Carbetocin	— No included studies	— Very low	— Low	✓ Moderate	— High
Misoprostol	— No included studies	— Very low	— Low	✓ Moderate	— High
Injectable prostaglandins	— No included studies	✓ Very low	— Low	— Moderate	— High
Ergometrine	— No included studies	— Very low	✓ Low	— Moderate	— High
Oxytocin plus ergometrine	— No included studies	— Very low	— Low	✓ Moderate	— High
Misoprostol plus oxytocin	— No included studies	— Very low	— Low	✓ Moderate	— High

Additional considerations

None.

3.2. Values

Is there important uncertainty about, or variability in, how much women (and their families) value the main outcomes associated with different uterotonics (oxytocin, carbetocin, misoprostol, injectable prostaglandins, ergometrine, ergometrine plus oxytocin and misoprostol plus oxytocin) for PPH prevention?

Research evidence

In a review of qualitative studies looking at “what women want” from intrapartum care, findings indicate that most women want a normal birth (with good outcomes for mother and baby), but acknowledge that medical intervention may sometimes be necessary (high confidence) (8). Most women, especially those giving birth for the first time, are apprehensive about labour and birth (high confidence) and wary of medical interventions, although in certain contexts and/or situations women welcome interventions to address recognized complications (low confidence). Where interventions are introduced, women would like to receive relevant information from technically competent health care providers who are sensitive to their needs (high confidence).

Findings from another qualitative systematic review exploring perceptions of PPH prevention and treatment among women and providers suggest that women do not recognize the clinical definitions of blood loss or what might be considered “normal” blood loss (moderate confidence) (9). Furthermore, in some low- and middle-income countries (LMICs), women place a greater value on the expulsion of so-called “dirty blood”, which they perceive as a normal cleansing process and something that should not be prevented (moderate confidence).

The same review highlighted women’s need for information about PPH, ideally given during antenatal care (moderate confidence), and the importance of kind, clinically competent staff with a willingness to engage in shared decision-making around PPH management (moderate/low confidence). In addition, it was found that women are concerned about feelings of exhaustion and anxiety (at being separated from their baby) following PPH, as well as the long-term psychological effects of experiencing PPH and the negative impact this may have on their ability to breastfeed (moderate/low confidence).

Additional considerations

Women typically place a higher value on avoiding severe adverse effects resulting from PPH (death, severe blood loss, blood transfusion) compared with avoiding side-effects of uterotonics, which in some instances are self-limiting. There is probably no important variability in how much value women place on avoiding the severe complications across settings, irrespective of the uterotonic agents being considered.

Judgement

—
Important uncertainty or variability

—
Possibly important uncertainty or variability

✓
Probably no important uncertainty or variability

—
No important uncertainty or variability

Balance of effects

Does the balance between desirable and undesirable effects favour different uterotonics (carbetocin, misoprostol, injectable prostaglandins, ergometrine, oxytocin plus ergometrine, and misoprostol plus oxytocin) or oxytocin (the reference agent)?

Judgement

Carbetocin	— Don’t know	— Varies	— Favours oxytocin	— Probably favours oxytocin	— Does not favour either	✓ Probably favours carbetocin	— Favours carbetocin
Misoprostol	— Don’t know	— Varies	✓ Favours oxytocin	— Probably favours oxytocin	— Does not favour either	— Probably favours misoprostol	— Favours misoprostol
Injectable prostaglandins	— Don’t know	— Varies	✓ Favours oxytocin	— Probably favours oxytocin	— Does not favour either	— Probably favours injectable prostaglandins	— Favours injectable prostaglandins
Ergometrine	— Don’t know	— Varies	— Favours oxytocin	✓ Probably favours oxytocin	— Does not favour either	— Probably favours ergometrine	— Favours ergometrine
Oxytocin plus ergometrine	— Don’t know	— Varies	✓ Favours oxytocin	— Probably favours oxytocin	— Does not favour either	— Probably favours ergometrine plus oxytocin	— Favours ergometrine plus oxytocin
Misoprostol plus oxytocin	— Don’t know	— Varies	✓ Favours oxytocin	— Probably favours oxytocin	— Does not favour either	— Probably favours misoprostol plus oxytocin	— Favours misoprostol plus oxytocin

3.3. Resources

How large are the resource requirements (costs) of different uterotonics (carbetocin, misoprostol, injectable prostaglandins, ergometrine, ergometrine plus oxytocin and misoprostol plus oxytocin) compared with oxytocin (the reference agent) for PPH prevention?

Research evidence

An economic assessment was conducted to assess the cost consequences of various single or combination uterotonic agents compared with oxytocin, with consideration of differences between their effects (benefits and harms), supply costs and other resource requirements (staffing and training, equipment and infrastructure, staff time, supplies, and supervision and monitoring) (10). The period of interest was the immediate postpartum period. Table 2 summarizes:

network evidence on the effects (benefits and harms) of uterotonic agents relative to oxytocin (superior, inferior, similar, uncertain), derived from an update of a Cochrane systematic review and network meta-analysis on uterotonics for PPH prevention (as presented above) (11);
supply costs of uterotonic agents in one high-income country were obtained as an example of relative costs from a setting (the United Kingdom of Great Britain and Northern Ireland) where all of the uterotonic agents under consideration were available (12);
implications of the different uterotonic agents on resource requirements relative to oxytocin (10 IU intramuscular injection).

Carbetocin versus oxytocin: The supply cost of carbetocin is approximately 20 times more than that of oxytocin. Evidence on effects suggests that for most priority outcomes, its effects are similar or possibly superior to those of oxytocin. However, due to evidence suggesting a reduction in the use of additional uterotonics with carbetocin by about half, there might be cost savings related to that outcome. Unlike oxytocin, carbetocin does not require cold chain storage although this translates to negligible cost saving as the cost of maintaining cold chain is almost equivalent to oxytocin supply cost. However, if the supply cost of carbetocin becomes comparable to that of oxytocin (as indicated in the memorandum of understanding signed between WHO and manufacturer of a heat-stable formulation of carbetocin [13]), then moderate to large cost savings can be expected in the longer term given that other resource requirements (e.g. staff and supplies) are similar between carbetocin and oxytocin.
Misoprostol versus oxytocin: The supply cost of misoprostol is approximately 0.56 times that of oxytocin. Evidence on relative effects suggests that it is less effective than oxytocin at reducing severe PPH and use of additional uterotonics but it is probably similar for other priority outcomes. There might be costs associated with managing side-effects of misoprostol (shivering, fever, vomiting and diarrhoea), which are likely to vary according to the setting depending on factors such as bed costs and approach to managing these side-effects. Unlike oxytocin, misoprostol does not require cold chain storage, which might represent a cost saving, and it also has the potential for other cost-savings due to its oral route of administration (easier administration, no additional supplies necessary, and can be task shifted).
Injectable prostaglandins (carboprost) versus oxytocin: The supply cost of carboprost is approximately 20 times more than that of oxytocin. There is insufficient evidence of its effectiveness compared with oxytocin and resource requirements would depend on the extent to which it is necessary for staff to manage the associated side-effects (vomiting and diarrhoea).
Ergometrine versus oxytocin: The supply cost of ergometrine is approximately 1.7 times that of oxytocin. Ergometrine is possibly inferior to oxytocin for several priority outcomes, and there are likely to be higher resource requirements associated with a need for staff to monitor for and manage its side-effects (vomiting, diarrhoea, hypertension and headache).
Oxytocin plus ergometrine versus oxytocin: The supply cost of oxytocin plus ergometrine is approximately 1.7 times that of oxytocin. Evidence on effects suggests that for most priority outcomes its effects are similar to oxytocin. However, due to evidence suggesting a reduction in the use of additional uterotonics by about a third, there might be cost savings, depending on the extent to which it is necessary for staff to manage its side-effects (vomiting, diarrhoea and, possibly, hypertension).
Misoprostol plus oxytocin versus oxytocin: The supply cost of misoprostol plus oxytocin is approximately 1.4 times that of oxytocin. Evidence on effects suggests that, compared with oxytocin, the combination of misoprostol plus oxytocin might be associated with cost savings due to a reduced need for blood transfusions and additional uterotonic agents. However, there might be costs associated with managing side-effects of misoprostol (shivering, fever, vomiting and diarrhoea), which are likely to vary according to the setting depending on factors such as bed costs and approach to managing these side-effects.

Additional considerations

None.

Table 2Relative effects and resource implications of different uterotonic agents compared with oxytocin

	Oxytocin (10 IU)	Carbetocin (100 μg)	Misoprostol (600 μg)	Injectable prostaglandin: carboprost (250 μg)	Ergometrine (500 μg)	Oxytocin (5 IU) plus ergometrine (500μg)	Misoprostol (400 μg) plus oxytocin (10 IU)
Indicative uterotonic agent costs (12)
£	0.90	17.64	0.50	18.20	1.50	1.51	1.22
US$ equivalent^a	1.18	23.11^b	0.66	23.84	1.97	1.98	1.60
Relative cost compared with oxytocin (10 IU)^c	1	19.60^d	0.56	20.22	1.67	1.68	1.36
Relative risks of desirable effects (in terms of reduction)
PPH ≥ 1000 ml	1	0.87 (0.62–1.21)	1.19 (1.01–1.42)	0.88 (0.41–1.89)	0.94 (0.48–1.84)	0.83 (0.66–1.03)	0.88 (0.70–1.11)
Blood transfusion	1	0.81 (0.49–1.32)	0.88 (0.68–1.13)	0.66 (0.25–1.72)	1.11 (0.54–2.28)	0.78 (0.59–1.03)	0.52 (0.38–0.70)
Additional uterotonics	1	0.45 (0.34–0.59)	1.04 (0.88–1.24)	0.55 (0.31–0.96)	0.97 (0.69–1.36)	0.66 (0.51–0.85)	0.57 (0.44–0.74)
PPH ≥ 500 ml	1	0.72 (0.56–0.93)	1.08 (0.97–1.22)	1.05 (0.73–1.51)	1.09 (0.85 –1.39)	0.70 (0.59–0.84)	0.70 (0.58–0.86)
Maternal death	1	2.00 (0.37 – 10.92)	0.62 (0.14–2.74)	No estimate	No estimate	No estimate	No estimate
ICU admissions	1	1.16 (0.67–2.02)	1.16 (0.55–2.43)	No estimate	0.39 (0.01–10.27)	2.99 (0.12–73.32)	0.50 (0.05–5.47)
Relative risks of undesirable effects
Shivering	1	0.77 (0.46–1.29)	4.18 (3.34–5.23)	0.50 (0.19–1.31)	1.31 (0.86–1.99)	1.38 (0.86–2.22)	3.62 (2.59–5.05)
Fever	1	1.07 (0.43–2.69)	3.87 (2.90–5.16)	1.12 (0.33–3.86)	0.77 (0.44–1.35)	0.70 (0.35–1.42)	3.14 (2.20–4.49)
Nausea	1	1.00 (0.71 – 1.41)	1.41 (1.10 – 1.81)	2.25 (1.16 – 4.39)	2.40 (1.65 – 3.49)	2.03 (1.47 – 2.79)	1.88 (1.14 – 3.09)
Vomiting	1	0.93 (0.64–1.35)	1.63 (1.25–2.14)	3.76 (1.90–7.41)	2.36 (1.56–3.55)	2.93 (2.08–4.13)	2.11 (1.39–3.18)
Diarrhoea	1	No estimate	2.24 (1.64–3.05)	23.41 (11.03–49.7)	2.51 (1.20–5.26)	1.80 (1.18–2.75)	1.82 (1.12–2.98)
Hypertension	1	1.24 (0.28–5.56)	1.50 (0.49–4.61)	1.40 (0.09–20.66)	8.54 (2.12–34.48)	2.48 (0.89–6.88)	No estimate
Abdominal pain	1	1.13 (0.90–1.44)	1.02 (0.80–1.31)	1.41 (0.39–5.09)	2.13 (0.98–4.62)	1.39 (0.91–2.13)	1.93 (0.89–4.20)
Headache	1	0.94 (0.66–1.33)	0.98 (0.69–1.40)	1.76 (0.33–9.31)	1.89 (1.02–3.50)	1.08 (0.73–1.61)	1.48 (0.42–5.81)
Other resource requirements relative to oxytocin
Staff and training	Trained maternity staff	Same as for oxytocin	Trained lay health workers can also administer	Same as for oxytocin	Same as for oxytocin	Same as for oxytocin	Same as for oxytocin^e
Supplies	Needle, syringe and swab US$0.07 (14)	Same as for oxytocin	No needle, syringe and swab needed	Same as for oxytocin	Same as for oxytocin	Same as for oxytocin	Same as for oxytocin
Equipment and infrastructure	Cold chain storage^f (15); hazardous waste disposal	Heat stable; also requires hazardous waste disposal	Heat stable	Same as for oxytocin	Same as for oxytocin	Same as for oxytocin	Same as for oxytocin
Staff time	2 minutes to administer (16); time needed for managing side-effects is minimal	Same as for oxytocin	Less time to administer, but possibly more staff time managing side-effects	Possibly more staff time to manage side-effects	More staff time to manage sideeffects	Possibly more staff time to manage side-effects	Same as for oxytocin
Supervision and monitoring	Cold chain requires monitoring of stock quality	Possibly more staff time (if not used previously)	Possibly more staff time to manage side-effects	Possibly more staff time to manage side-effects	More staff time to manage side-effects	Possibly more staff time to manage side-effects	Possibly more staff time to manage side-effects

: ICU: intensive care unit
: Relative risks are given with their 95 per cent confidence intervals in brackets
: Green: superior effect or fewer resource requirements
: Red: inferior effect or more resource requirements
: Grey: similar effect (or slightly better or slightly worse point estimate, defined as a confidence interval (CI) range of less than or equal to 100 points) or comparable resource requirements
: White: unknown, uncertain or any effect possible due to wide CI that includes the point estimate of 1, or resource requirements are not known or vary.
a: Converted using a ratio of US$ 1.31: £1 (rate on 22 August 2018).
b: The manufacturer of heat-stable carbetocin has committed to seeking registration and to manufacture heat-stable carbetocin for the public sector in low- and lower-middle income countries at an affordable and sustainable price (13), which is a subsidized price of US$ 0.31 +/–10% per ampoule of 100 μg. The price set by the United Nations Population Fund (UNFPA) (12 September 2018) of oxytocin is US$ 0.27 per unit (10 IU).
c: The cost of the drug divided by the cost of oxytocin (10 IU) (both in £).
d: Relative cost of carbetocin (at the subsidized price of US$ 0.31 +/- 10%) compared with oxytocin (USD $ 0.27) is 1.03 to 1.26.
e: Oxytocin administered from a Uniject device could be administered by trained lay health workers. This form of oxytocin might have required fewer staff resources than other injectable uterotonics. This device has been discontinued.
f: The cost of this resource has been estimated in one study as US$ 0.84 per birth in a low-resource setting (17).

Resources required

Judgement

Carbetocin	— Varies	— Large costs	✓ Moderate costs	— Negligible costs or savings	— Moderate savings	— Large savings
Misoprostol	✓ Varies	— Large costs	— Moderate costs	— Negligible costs or savings	— Moderate savings	— Large savings
Injectable prostaglandins	— Varies	✓ Large costs	— Moderate costs	— Negligible costs or savings	— Moderate savings	— Large savings
Ergometrine	— Varies	— Large costs	✓ Moderate costs	— Negligible costs or savings	— Moderate savings	— Large savings
Oxytocin plus ergometrine	— Varies	— Large costs	— Moderate costs	✓ Negligible costs or savings	— Moderate savings	— Large savings
Misoprostol plus oxytocin	✓ Varies	— Large costs	— Moderate costs	— Negligible costs or savings	— Moderate savings	— Large savings

Certainty of the evidence on required resources

What is the certainty of the evidence on costs?

Carbetocin	— No included studies	— Very low	✓ Low	— Moderate	— High
Misoprostol	— No included studies	— Very low	✓ Low	— Moderate	— High
Injectable prostaglandins	— No included studies	— Very low	✓ Low	— Moderate	— High
Ergometrine	— No included studies	— Very low	✓ Low	— Moderate	— High
Oxytocin plus ergometrine	— No included studies	— Very low	✓ Low	— Moderate	— High
Misoprostol plus oxytocin	— No included studies	— Very low	✓ Low	— Moderate	— High
Oxytocin	— No included studies	— Very low	✓ Low	— Moderate	— High

Cost–effectiveness

Does the cost–effectiveness of the following uterotonics favour the uterotonic or oxytocin?

Judgement

Carbetocin	— Don’t know	— Varies	— Favours oxytocin	✓ Probably favours oxytocin	— Does not favour either	— Probably favours carbetocin	— Favours carbetocin
Misoprostol	— Don’t know	✓ Varies	— Favours oxytocin	— Probably favours oxytocin	— Does not favour either	— Probably favours misoprostol	— Favours misoprostol
Injectable prostaglandins	— Don’t know	— Varies	✓ Favours oxytocin	— Probably favours oxytocin	— Does not favour either	— Probably favours injectable prostaglandins	— Favours injectable prostaglandins
Ergometrine	— Don’t know	— Varies	✓ Favours oxytocin	— Probably favours oxytocin	— Does not favour either	— Probably favours ergometrine	— Favours ergometrine
Oxytocin plus ergometrine	— Don’t know	— Varies	— Favours oxytocin	✓ Probably favours oxytocin	— Does not favour either	— Probably favours ergometrine plus oxytocin	— Favours ergometrine plus oxytocin
Misoprostol plus oxytocin	— Don’t know	✓ Varies	— Favours oxytocin	— Probably favours oxytocin	— Does not favour either	— Probably favours misoprostol plus oxytocin	— Favours misoprostol plus oxytocin

3.4. Equity

What would be the impact of the use of the uterotonics carbetocin, misoprostol, injectable prostaglandins, ergometrine, oxytocin plus ergometrine and misoprostol plus oxytocin compared with oxytocin for PPH prevention on health equity?

Research evidence

No direct evidence regarding impacts on health equity for comparisons of different uterotonics was identified.

Findings from a qualitative systematic review exploring perceptions of PPH prevention and treatment by women and health care providers showed that some uterotonics (such as oxytocin, misoprostol and ergometrine) are relatively inexpensive and already widely available in a range of resource settings (9). However, inconsistent stock levels and/or heat sensitivity of some uterotonics (such as for oxytocin, ergometrine or any combination that included either oxytocin or ergometrine) may limit their use in low-resource settings in LMICs, particularly in isolated rural areas where the need is arguably greatest (moderate confidence). In some contexts (India and Sierra Leone), supply issues have resulted in women and health care professionals turning to private suppliers to purchase uterotonics, at additional cost to themselves, in order to fulfil guideline recommendations. Advanced distribution of misoprostol to women in low-resource rural communities may be a useful approach in reducing maternal mortality (as a consequence of PPH) for women who may not routinely present to a health care facility to give birth (moderate confidence). There was no direct evidence on the differential impact of introducing carbetocin, injectable prostaglandins or ergometrine compared with oxytocin or other uterotonics for PPH prevention on health equity.

Additional considerations

The 2015 WHO State of inequality report indicates that women who are poor, least educated, and who reside in rural areas have lower health intervention coverage and worse health outcomes than more advantaged women (18). Reducing priority outcomes related to blood loss (such as the effects identified for oxytocin, carbetocin, misoprostol, ergometrine, oxytocin plus ergometrine and misoprostol plus oxytocin) could have a positive impact on health equity and improve outcomes among disadvantaged women. However, there is insufficient evidence on the effects of injectable prostaglandins (carboprost and sulprostone) for most priority outcomes, and they cause undesirable side-effects (especially diarrhoea), and thus may not have an impact on health equity. There was a reduced need for additional interventions to treat PPH (such as reduced use of additional uterotonics and reduced blood transfusion) for oxytocin, carbetocin, misoprostol, oxytocin plus ergometrine and misoprostol plus oxytocin. These benefits would probably reduce health inequities, especially in contexts where health services are covered through out-of-pocket means.

The price of carbetocin and injectable prostaglandins (specifically carboprost) may make these options unaffordable for health services where resources are limited (e.g. where maintenance of cold storage for oxytocin is a challenge), and/or where women are required to pay for health services out of pocket. However, the heat stability potential of carbetocin eliminates the need to cold chain storage and transport and reduces wastage that could be associated with temperature-unstable uterotonics.

In low-resource settings where the incidence of pre-eclampsia/eclampsia is relatively high, the routine administration of ergometrine or oxytocin plus ergometrine may present difficulties given the limited capacity and capability to routinely screening for hypertensive disorders of pregnancy before their administration.

Judgement¹

Carbetocin	— Don’t know	✓ Varies	— Reduced	— Probably reduced	— Probably no impact	— Probably increased	— Increased
Misoprostol	— Don’t know	— Varies	— Reduced	— Probably reduced	— Probably no impact	✓ Probably increased	— Increased
Injectable prostaglandins	— Don’t know	— Varies	✓ Reduced	— Probably reduced	— Probably no impact	— Probably increased	— Increased
Ergometrine	— Don’t know	— Varies	— Reduced	✓ Probably reduced	— Probably no impact	— Probably increased	— Increased
Oxytocin plus ergometrine	— Don’t know	— Varies	— Reduced	✓ Probably reduced	— Probably no impact	— Probably increased	— Increased
Misoprostol plus oxytocin	— Don’t know	— Varies	— Reduced	— Probably reduced	— Probably no impact	✓ Probably increased	— Increased
Oxytocin	— Don’t know	— Varies	— Reduced	— Probably reduced	— Probably no impact	✓ Probably increased	— Increased

3.5. Acceptability

Are different uterotonics (carbetocin, misoprostol, injectable prostaglandins, ergometrine, oxytocin plus ergometrine, misoprostol plus oxytocin, and oxytocin) for PPH prevention acceptable to key stakeholders?

Research evidence

Findings from a qualitative systematic review exploring perceptions of PPH prevention and treatment by women and health care providers suggest that providers would use a uterotonic to prevent PPH if it was shown to be effective (moderate confidence) (9). In certain LMIC settings, traditional birth attendants (TBAs) prefer to use herbal medicines with uterotonic properties (moderate confidence), while in several high-income countries, experienced midwives use expectant management techniques and make selective use of guideline recommendations (ignoring uterotonics use), especially if the birth is perceived to be normal (moderate confidence) (9).

The qualitative review identified that providers recognize the benefits of using oxytocin to prevent PPH and hasten the delivery of the placenta (moderate confidence) (9). However, in some LMIC settings, providers hold the perception that oxytocin may cause retained placenta when administered preventatively or even contribute to PPH when given to induce labour (moderate confidence) (9).

Providers also recognized the benefits of using misoprostol to prevent PPH, especially in rural areas of LMICs where community-based distribution programmes are in place. In these contexts, misoprostol was perceived to be safe, effective and more practical to use compared with oxytocin (low confidence). However, government officials and regional health care managers in some LMICs had concerns about the influence of civil society organizations (CSOs), nongovernmental organizations (NGOs) and private providers in “pushing” misoprostol for other conditions (treatment of PPH) contrary to national guidelines (moderate confidence). In some LMICs, providers (including government officials, health care managers and health care professionals) had concerns about the potential mis-use of misoprostol in community contexts where it might be used to induce abortion or act as a deterrent to facility-based deliveries (moderate confidence). In addition, a number of providers, largely based in LMICs, felt they needed more information on the effectiveness of misoprostol and further guidance on successful implementation strategies for community distribution in LMICs (moderate confidence). One study in Indonesia highlighted shivering as a potential concern for some women taking misoprostol tablets (moderate confidence). No direct evidence was found regarding acceptability of carbetocin and injectable prostaglandins, which are generally not available in lower-resource settings.

There were no direct findings from studies of women’s perspectives relating to the acceptability of uterotonic options.

Additional considerations

In a survey-based evaluation of Uniject devices prefilled with 10 IU of oxytocin, conducted in Mali, a variety of providers found the device easier to use compared with oxytocin delivered via a standard syringe (99.3%; 139/140), with similar reductions in PPH and retained placenta (19). The authors concluded that “the evaluation demonstrated high levels of acceptability of the oxytocin-Uniject device and relative ease of training health care providers in its use, meaning that its introduction for use by most cadres should be relatively easy”.

A number of survey-based studies were identified that looked at the potential benefits of advanced misoprostol distribution in rural settings of LMICs where the maternal mortality ratio was relatively high (20–34). The studies were conducted in Afghanistan, Bangladesh, Ethiopia (two studies), Ghana, Liberia, Madagascar, Mozambique, Nepal, Nigeria (three studies), Pakistan (two studies), South Sudan and the United Republic of Tanzania. In most instances, misoprostol tablets were given to trained community health workers, community health volunteers or traditional birth attendants who then supplied the tablets (usually 3 × 200 mg tablets) to pregnant women in community settings via a home visit or at an antenatal appointment during the eighth month of pregnancy. During the home visit or appointment women were also given information on PPH, the nature of the misoprostol tablets and how/when to take them, as well as details of potential side-effects. Nearly all of the studies reported high levels of usage, acceptability and coverage, with very few safety concerns. One study from Liberia found that 87/265 (32.8%) of women took the misoprostol tablets after the delivery of the placenta but experienced few or no ill effects from doing so (31).

A recent qualitative study was undertaken in Ethiopia, India and Myanmar with 158 health care providers (pharmacists, midwives, nurses, doctors and obstetricians) and 40 key informants (supply chain experts, programme managers and policy-makers) (35). It included direct observations of oxytocin storage practices and cold chain resources in 51 health care facilities. Many respondents in Ethiopia were aware of oxytocin’s heat sensitivity and the requirement for cold storage, but this was less common among participants in India and Myanmar. Maintaining a consistent cold chain was hampered by lack of refrigeration facilities and unreliability of electricity. Poor-quality oxytocin supply was evident in a study undertaken in the Democratic Republic of the Congo where some stakeholders believed that the quality of available oxytocin was compromised (36). Oxytocin ampoules were sampled from 15 facilities (public and private, urban and rural) in five Democratic Republic of the Congo provinces: 80% of ampoules contained less than 90% of the specified content. The authors concluded that “there is evidence of a high prevalence of poor quality oxytocin ampoules in health facilities in the DRC likely resulting from both manufacturing quality issues and uncontrolled storage”.

Judgement¹

Carbetocin	— Don’t know	✓ Varies	— No	— Probably No	— Probably Yes	— Yes
Misoprostol	— Don’t know	— Varies	— No	— Probably No	✓ Probably Yes	— Yes
Injectable uterotonics	✓ Don’t know	— Varies	— No	— Probably No	— Probably Yes	— Yes
Ergometrine	— Don’t know	— Varies	— No	— Probably No	✓ Probably Yes	— Yes
Oxytocin plus ergometrine	— Don’t know	— Varies	— No	— Probably No	✓ Probably Yes	— Yes
Misoprostol plus oxytocin	— Don’t know	— Varies	— No	— Probably No	✓ Probably Yes	— Yes
Oxytocin	— Don’t know	✓ Varies	— No	— Probably No	— Probably Yes	— Yes

3.6. Feasibility

Are different uterotonics (oxytocin, carbetocin, misoprostol, injectable prostaglandins, ergometrine, oxytocin plus ergometrine, misoprostol plus oxytocin and oxytocin) feasible to implement for PPH prevention?

Research evidence

Findings from a qualitative systematic review exploring perceptions of PPH prevention and treatment by women and providers indicate that resource constraints may influence the use of a uterotonic for PPH prevention, particularly in LMICs (high confidence) (9). In a wide variety of settings, health care providers feel they do not have sufficient staff with experience of using uterotonics (high confidence) and need more training in PPH management (high confidence). Inconsistent supplies and reservations about oxytocin storage in areas with limited/inconsistent electricity hinder utilization, and a lack of experienced staff to administer the injection limits use in certain contexts (high confidence).

In some areas where task shifting had been introduced to address staff shortages, health care professionals were occasionally suspicious about the ability of TBAs or community health workers to administer oxytocin correctly. There was a perception in some settings that TBAs and community health workers were poorly trained and untrustworthy (moderate confidence), though TBAs felt they were competent enough and rarely had to deal with a PPH (moderate confidence).

There were no findings from the reviewed studies on women’s perceptions relating to the feasibility of any of the uterotonic options.

Additional considerations

The feasibility of using a uterotonic is directly affected by its local availability. Oxytocin (10 IU in 1 ml for injection), misoprostol (200 mg tablet) and ergometrine (200 mg in 1 ml ampoule for injection) are listed on the WHO Model List of Essential Medicines (5), are widely available in a range of resource settings, and have multiple applications in reproductive health. Other uterotonics (including the fixed-dose oxytocin plus ergometrine combination) are not listed. Ergometrine is contraindicated in severe hypertension and eclampsia, as there is a risk of hypertension associated with its use. The need to exclude hypertensive disorders of pregnancy may affect feasibility, particularly where trained health care providers are scarce.

The qualitative systematic review found that oxytocin storage in areas with limited/inconsistent electricity may hinder utilization (high confidence). A recent qualitative study undertaken in Ethiopia, India and Myanmar with 158 health care providers (pharmacists, midwives, nurses, doctors and obstetricians) and 40 key informants (supply chain experts, programme managers and policy-makers) (35). It included direct observations of oxytocin storage practices and cold chain resources in 51 health care facilities. Many respondents in Ethiopia were aware of oxytocin’s heat sensitivity and the requirement for cold storage, but this was less common among participants in Myanmar and India. Maintaining a consistent cold chain was hampered by lack of refrigeration facilities and unreliability of electricity. A study undertaken in the Democratic Republic of the Congo sampled oxytocin injection ampoules from 15 facilities (public and private, urban and rural) across five provinces, using overt sampling and “mystery shopper” approaches. Eighty percent of ampoules collected contained less than 90% of the specified content. The authors concluded that “there is evidence of a high prevalence of poor quality oxytocin ampoules in health facilities in the DRC likely resulting from both manufacturing quality issues and uncontrolled storage” (37).

The heat-stable formulation of carbetocin does not require cold chain transport and refrigerated storage, and thus may be more feasible. In a survey-based evaluation of Uniject devices prefilled with 10 IU of oxytocin, conducted in Mali, the authors noted that the devices came with a “TempTime Indicator” (TTI) which changed colour following prolonged exposure to heat (19). Of 15 000 devices distributed in rural Mali, only 1 of the 30 health centres visited had 10 devices or more that were heat expired. Most devices were stored in refrigerators or portable cool boxes – 19.0% of health centre directors (8/42) cited storage problems as a disadvantage and 7.7% of pharmacy managers (1/13) felt that the devices created a storage problem.

A number of survey-based studies were identified that looked at the potential benefits of advanced misoprostol distribution in rural settings of LMICs where the maternal mortality ratio was relatively high (20–34). The studies were conducted in Afghanistan, Bangladesh, Ethiopia (two studies), Ghana, Liberia, Madagascar, Mozambique, Nepal, Nigeria (three studies), Pakistan, South Sudan and the United Republic of Tanzania (two studies). In most instances, misoprostol tablets were given to trained community health workers, community health volunteers or traditional birth attendants who then supplied the tablets (usually 3 × 200 mg tablets) to pregnant women in community settings via a home visit or at an antenatal appointment during the eighth month of pregnancy. During the home visit or appointment women were also given information on PPH, the nature of the misoprostol tablets and how/when to take them, as well as details of potential side-effects. In most of the studies the authors concluded that the programmes were effective and feasible, although inconsistent stock supplies and the delivery of inadequate information by community health volunteers were highlighted as concerns in Nepal (29).

Given the issues outlined above relating to the inconsistent supply of oxytocin and the additional training required to administer the drug (particularly in LMICs), it seems likely that the use of combination uterotonics (such as oxytocin plus ergometrine or misoprostol plus oxytocin) would exacerbate these issues. Misoprostol plus oxytocin is not a natural or synthetic drug combination, and practical considerations regarding dosing regimens (oral versus parenteral), transport and storage issues could complicate implementation in non-trial settings.

Judgement

Carbetocin	— Don’t know	— Varies	— No	— Probably No	✓ Probably Yes	— Yes
Misoprostol	— Don’t know	— Varies	— No	— Probably No	✓ Probably Yes	— Yes
Injectable prostaglandins	— Don’t know	✓ Varies	— No	— Probably No	— Probably Yes	— Yes
Ergometrine	— Don’t know	— Varies	— No	— Probably No	✓ Probably Yes	— Yes
Oxytocin plus ergometrine	— Don’t know	✓ Varies	— No	— Probably No	— Probably Yes	— Yes
Misoprostol plus oxytocin	— Don’t know	— Varies	— No	✓ Probably No	— Probably Yes	— Yes
Oxytocin	— Don’t know	— Varies	— No	— Probably No	✓ Probably Yes	— Yes

4. Summary of judgements table

Uterotonics	Carbetocin	Misoprostol	Injectable prostaglandins	Ergometrine	Oxytocin plus ergometrine	Misoprostol plus oxytocin	Oxytocin
Desirable effects	Small	None	None	None	Small	Moderate	Reference
Undesirable effects	None	Moderate	Moderate	Moderate	Moderate	Large	Reference
Certainty of the evidence	Moderate	Moderate	Very low	Low	Moderate	Moderate	Reference
Values	Probably no important uncertainty or variability	Probably no important uncertainty or variability	Probably no important uncertainty or variability	Probably no important uncertainty or variability	Probably no important uncertainty or variability	Probably no important uncertainty or variability	Probably no important uncertainty or variability
Balance of effects	Probably favours carbetocin	Favours oxytocin	Favours oxytocin	Probably favours oxytocin	Favours oxytocin	Favours oxytocin	Reference
Resources required	Moderate costs	Varies	Large costs	Moderate costs	Negligible costs or savings	Varies	Reference
Certainty of the evidence	Low	Low	Low	Low	Low	Low	Reference
Cost-effectiveness	Probably favours oxytocin	Varies	Favours oxytocin	Favours oxytocin	Probably favours oxytocin	Varies	Reference
Equity	Varies	Probably increased	Reduced	Probably reduced	Probably reduced	Probably increased	Probably increased
Acceptability	Varies	Probably Yes	Don’t know	Probably Yes	Probably Yes	Probably Yes	Varies
Feasibility	Probably Yes	Probably Yes	Varies	Probably Yes	Varies	Probably No	Probably Yes

5. Summary of Findings tables

Summary of Findings table 1 (PDF, 219K)

Summary of Findings table 2 (PDF, 151K)

Summary of Findings table 3 (PDF, 145K)

Summary of Findings table 4 (PDF, 114K)

Summary of Findings table 5 (PDF, 155K)

Summary of Findings table 6 (PDF, 155K)

Summary of Findings table 7 (PDF, 149K)

Summary of Findings table 8 (PDF, 144K)

Summary of Findings table 9 (PDF, 92K)

Summary of Findings table 10 (PDF, 148K)

Summary of Findings table 11 (PDF, 151K)

Summary of Findings table 12 (PDF, 139K)

Summary of Findings table 13 (PDF, 132K)

Summary of Findings table 14 (PDF, 108K)

Summary of Findings table 15 (PDF, 140K)

Summary of Findings table 16 (PDF, 132K)

Summary of Findings table 17 (PDF, 126K)

Footnotes

1: For the purposes of the network meta-analysis (6), “community” was defined to include primary health care and home settings or self-administration of a uterotonic by women.
2: These outcomes reflect the prioritized outcomes used in the development of this recommendation, in the WHO recommendations for prevention and treatment of postpartum haemorrhage (2012) (7). The outcomes “shock”, “maternal well-being” and “maternal satisfaction” have been added as part of this update.
3: This includes nausea, vomiting, headache, abdominal pain, hypertension, shivering, fever and diarrhoea.
1: These judgements reflect the judgements from Evidence to Decision frameworks comparing each uterotonic to placebo/no treatment for effects on health equity.
1: These judgements reflect the judgements from Evidence to Decision frameworks comparing each uterotonic to placebo/no treatment for acceptability to stakeholders.
1: Further information available at http://www.gradeworkinggroup.org

6. References

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11.: Gallos ID, Williams H, Price MJ, Pickering K, Merriel A, Tobias A, et al. Uterotonic drugs for preventing postpartum haemorrhage: a network meta-analysis and cost-effectiveness analysis. Health Technol Assessment; 2018 (in press). [PMC free article: PMC6533349] [PubMed: 30506157]
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15.: Voon HY, Shafie AA, Bujang MA, Suharjono HN. Cost effectiveness analysis of carbetocin during cesarean section in a high volume maternity unit. J Obstet Gynaecol Res. 2018;44(1):109–16. doi:10.1111/jog.13486. [PMC free article: PMC5813149] [PubMed: 29027315] [CrossRef]
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17.: Vlassoff M, Diallo A, Philbin J, Kost K, Bankole A. Cost-effectiveness of two interventions for the prevention of postpartum hemorrhage in Senegal. Int J Gynaecol Obstet. 2016;133(3):307–11. doi:10.1016/j.ijgo.2015.10.015. [PMC free article: PMC5010421] [PubMed: 26952348] [CrossRef]
18.: State of inequality: reproductive, maternal, newborn and child health. Geneva: World Health Organization; 2015 (http://apps.who.int/iris/bitstream/handle/10665/164590/9789241564908_eng.pdf?sequence=1, accessed 9 November 2018).
19.: Prevention of Postpartum Hemorrhage Initiative (POPPHI). Pilot use of oxytocin in a Uniject™ device for AMTSL in Mali: evaluation of the safety and feasibility of a new delivery technology. Seattle (WA): Program for Appropriate Technology in Health (PATH); 2008 (https://path.azureedge.net/media/documents/MCHN_popphi_oxy_uniject_mali.pdf, accessed 9 November 2018).
20.: Ejembi C, Shittu O, Moran M, Adiri F, Oguntunde O, Saadatu B, et al. Community-level distribution of misoprostol to prevent postpartum hemorrhage at home births in northern Nigeria. Afr J Reprod Health. 2014;18(2):166–75. [PubMed: 25022154]
21.: Geller S, Carnahan L, Akosah E, Asare G, Agyemang R, Dickson R, et al. Community-based distribution of misoprostol to prevent postpartum haemorrhage at home births: results from operations research in rural Ghana. BJOG. 2014;121(3):319–25. doi:10.1111/1471-0528.12447. [PubMed: 24283350] [CrossRef]
22.: Haver J, Ansari N, Zainullah P, Kim YM, Tappis H. Misoprostol for prevention of postpartum hemorrhage at home birth in Afghanistan: program expansion experience. J Midwifery Womens Health. 2016;61(2):196–202. doi:10.1111/jmwh.12413. [PMC free article: PMC5067583] [PubMed: 26849472] [CrossRef]
23.: Mayer Hashi Project: Preventing postpartum hemorrhage: community-based distribution of misoprostol in Tangail District, Bangladesh (Project brief). EngenderHealth; 2010 (http://www.respond-project.org/pages/files/6_pubs/project_briefs/Project-Brief-2-Bangladesh-PPH-final.pdf, accessed 9 November 2018).
24.: Mir AM, Wajid A, Gull S. Helping rural women in Pakistan to prevent postpartum hemorrhage: a quasi experimental study. BMC Pregnancy Childbirth. 2012;12:120. doi:10.1186/1471-2393-12-120. [PMC free article: PMC3514273] [PubMed: 23110458] [CrossRef]
25.: Orobaton N, Abdulazeez J, Abegunde D, Shoretire K, Maishanu A, Ikoro N, et al. Implementing at-scale, community-based distribution of misoprostol tablets to mothers in the third stage of labor for the prevention of postpartum haemorrhage in Sokoto State, Nigeria: early results and lessons learned. PLoS One. 2017;12(2):e0170739. doi:10.1371/journal.pone.0170739. [PMC free article: PMC5325195] [PubMed: 28234894] [CrossRef]
26.: Prata N, Mbaruku G, Grossman AA, Holston M, Hsieh K. Community-based availability of misoprostol: is it safe? Afr J Reprod Health. 2009;13(2):117–28. [PubMed: 20690255]
27.: Prata N, Gessessew A, Abraha AK, Holston M, Potts M. Prevention of postpartum hemorrhage: options for home births in rural Ethiopia. Afr J Reprod Health. 2009;13(2):87–95. [PubMed: 20690252]
28.: Prata N, Ejembi C, Fraser A, Shittu O, Minkler M. Community mobilization to reduce postpartum hemorrhage in home births in northern Nigeria. Soc Sci Med. 2012;74(8):1288–96. doi:10.1016/j.socscimed.2011.11.035. [PubMed: 22377106] [CrossRef]
29.: Rajbhandari SP, Aryal K, Sheldon WR, Ban B, Upreti SR, Regmi K, et al. Postpartum hemorrhage prevention in Nepal: a program assessment. BMC Pregnancy Childbirth. 2017;17(1):169. doi:10.1186/s12884-017-1347-z. [PMC free article: PMC5460329] [PubMed: 28583092] [CrossRef]
30.: Sibley LM, Spangler SA, Barry D, Tesfaye S, Desta BF, Gobezayehu AG. A regional comparison of distribution strategies and women’s awareness, receipt, and use of misoprostol to prevent postpartum hemorrhage in rural Amhara and Oromiya regions of Ethiopia. J Midwifery Womens Health. 2014;59: Suppl 1:S73–82. doi:10.1111/jmwh.12136. [PubMed: 24588919] [CrossRef]
31.: Smith JM, Baawo SD, Subah M, Sirtor-Gbassie V, Howe CJ, Ishola G, et al. Advance distribution of misoprostol for prevention of postpartum hemorrhage (PPH) at home births in two districts of Liberia. BMC Pregnancy Childbirth. 2014;14:189. doi:10.1186/1471-2393-14-189. [PMC free article: PMC4055371] [PubMed: 24894566] [CrossRef]
32.: Smith JM, Dimiti A, Dwivedi V, Ochieng I, Dalaka M, Currie S, et al. Advance distribution of misoprostol for the prevention of postpartum hemorrhage in South Sudan. Int J Gynaecol Obstet. 2014;127(2):183–8. doi:10.1016/j.ijgo.2014.05.016. [PubMed: 25051905] [CrossRef]
33.: Misoprostol policy and scale-up for the prevention of postpartum hemorrhage in Madagascar. Country report. Arlington (VA): United States Agency for International Development; 2016 (http://www.africanstrategies4health.org/uploads/1/3/5/3/13538666/misoprostol_policy_and_scale_up_in_madagascar_aug_2016.pdf, accessed 9 November 2018).
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36.: Lambert P, Nguyen TH, McEvoy C, Minhas RS, Wright P, Deadman K, et al. Quality of oxytocin ampoules available in health care facilities in the Democratic Republic of Congo: an exploratory study in five provinces. J Glob Health. 2018;8(2):020415. doi:10.7189/jogh.08.020415. [PMC free article: PMC6126516] [PubMed: 30202518] [CrossRef]

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WHO recommendations: Uterotonics for the prevention of postpartum haemorrhage.

Web annex 7Choice of uterotonic agents

1. Background

2. Question

Priority outcomes (O):2

3. Assessment

3.1. Effects of interventions

Research evidence

Summary of evidence

Source and characteristics of studies

Effects of uterotonics agents (carbetocin, misoprostol, injectable prostaglandins, ergometrine, oxytocin plus ergometrine, misoprostol plus oxytocin) compared with oxytocin (as reference agent)

Table 1Summary of treatment effects of uterotonic agents versus reference agent (oxytocin) on beneficial outcomes

Additional considerations

Desirable effects

Judgement

Undesirable effects

Judgement

Certainty of the evidence

Additional considerations

3.2. Values

Research evidence

Additional considerations

Judgement

Balance of effects

Judgement

3.3. Resources

Research evidence

Additional considerations

Table 2Relative effects and resource implications of different uterotonic agents compared with oxytocin

Resources required

Judgement

Certainty of the evidence on required resources

Cost–effectiveness

Judgement

3.4. Equity

Research evidence

Additional considerations

Judgement1

3.5. Acceptability

Research evidence

Additional considerations

Judgement1

3.6. Feasibility

Research evidence

Additional considerations

Judgement

4. Summary of judgements table

5. Summary of Findings tables

Footnotes

6. References

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Priority outcomes (O):²

Judgement¹

Judgement¹