Relevant BNF section: BNF 7.1.1
In 2003-2005, around 9 in every 100,000 women who gave birth in the UK died through subsequent postpartum haemorrhage.1 In Africa and Asia, this complication is the commonest cause of maternal mortality, accounting for over 30% of such deaths in 1997-2002.2 These outcomes highlight the need for effective preventive and treatment strategies for postpartum haemorrhage. One possible option in this setting is the off-label use of misoprostol, a synthetic prostaglandin E1 analogue licensed for prevention and treatment of gastrointestinal ulcers. This drug is used in obstetric and gynaecological practice because of its uterotonic and cervical priming actions.3,4 Here we consider misoprostol as prevention of and treatment for postpartum haemorrhage.
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Relevant BNF section: BNF 7.1.1
About postpartum haemorrhage
Primary postpartum haemorrhage is traditionally defined as blood loss of 500mL or more in the first 24 hours after delivery.5 Secondary postpartum haemorrhage is bleeding between 24 hours and 12 weeks postnatally.5 The World Health Organization (WHO) defines severe postpartum haemorrhage as blood loss of at least 1,000mL6 while the Royal College of Obstetricians and Gynaecologists (RCOG) defines it as over 2,000mL5. In a UK observational study involving 315 women who had postpartum hysterectomy to control postpartum haemorrhage, over half had uterine atony, and other causes included adherent placenta and uterine rupture.7 Risk factors for postpartum haemorrhage include multiple pregnancy, pre-eclampsia, prolonged labour and retained placenta.5
Traditional preventive and treatment options
‘Active management of the third stage of labour’ reduces the likelihood and severity of postpartum haemorrhage.8 It includes administration of oxytocin or another uterotonic drug within 1 minute of the baby's birth, controlled cord traction, and uterine massage after delivery of the placenta as appropriate. The WHO and a joint guideline from the International Confederation of Midwives (ICM) and the International Federation of Gynaecology and Obstetrics (FIGO) advise that such practice must be offered by skilled attendants to all women.8,9 Oxytocin stimulates uterine muscle contraction, so reducing blood loss.10 The RCOG recommends oxytocin 5–10units intramuscularly (an unlicensed route) at the time of vaginal delivery for women without risk factors for postpartum haemorrhage.5 It also states that oxytocin/ergometrine (Syntometrine) can be used instead in women without hypertension but warns that it increases vomiting.5
A guideline from the National Collaborating Centre for Women's and Children's Health does not recommend any particular uterotonic agent over another as treatment for postpartum haemorrhage.11 However, the RCOG recommends intravenous oxytocin 5units (with the option of repeated doses) as first-line drug treatment to control bleeding, followed by intravenous or intramuscular ergometrine, and then oxytocin infusion if necessary.5 Next it recommends carboprost, a synthetic analogue of prostaglandin F2 alpha licensed as intramuscular treatment for postpartum haemorrhage due to uterine atony and refractory to conventional treatment methods.12
Misoprostol is available as 200μg oral tablets and protects the gastro-duodenal mucosa by inhibiting acid secretion and increasing bicarbonate and mucus secretions.4,13 It is also active when administered vaginally, rectally, sublingually or via the buccal route; the rate and extent of absorption varies between routes.4 The tablets have a long shelf-life (3 years) at room temperature but should not be stored above 30oC.13,14 By contrast, alternative uterotonics (e.g. oxytocin, ergometrine), require refrigeration and parenteral administration.15
Prevention of postpartum haemorrhage
Misoprostol versus placebo
A Cochrane review identified 46 randomised trials comparing a prostaglandin with either another uterotonic or no uterotonic in prevention of postpartum haemorrhage in a total of 42,621 women, from “all continents from both low-to middle-income countries and industrialised countries”.16 Twenty-eight trials involved active management of the third stage of labour. There was significant heterogeneity between the seven trials that compared oral misoprostol to placebo and so no meta-analysis was done. However, the authors stated that the earlier trials did not show any reduction in severe postpartum haemorrhage with misporostol whereas the more recent trials suggest some protective effects. Rectal, sublingual and buccal misoprostol were compared to placebo in one trial each16 and only in the trial assessing sublingual misoprostol 600μg17 (involving 661 women) did the drug reduce the occurrence of severe postpartum haemorrhage (blood loss of at least 1,000mL; 11% vs. 17%, relative risk [RR] 0.66, 95% CI 0.45 to 0.98). Of note, the women in this trial gave birth in a resource-poor, primary healthcare centre in Guinea-Bissau.17
Misoprostol versus uterotonics
In the Cochrane review described above, a meta-analysis of 16 trials, involving a total of 29,042 women, found that severe postpartum haemorrhage was more likely with oral misoprostol 400-800μg than with a conventional injectable uterotonic ([3.3% vs. 2.4%] stated RR 1.32, 95% CI 1.16 to 1.51).16 In another meta-analysis, the proportion of women experiencing severe postpartum haemorrhage did not differ between rectal misoprostol 400μg and injectable uterotonics (three trials involving a total of 1,784 women); but more women who received misoprostol required additional uterotonics ([12% vs. 7.3%] stated RR 1.64, 95% CI 1.16 to 2.31).16 The review identified four small trials using sublingual misoprostol but the meta-analysis was “too small to give any meaningful results”.16
Misoprostol plus oxytocin versus injectable uterotonics
The Cochrane review identified two trials comparing the combination of injectable oxytocin plus misoprostol (one using rectal, the other oral treatment) against injectable uterotonics.16 Only in the trial that used misoprostol orally (involving 788 women) did the drug add to the benefit of injectable uterotonics (in this case oxytocin) in preventing severe postpartum haemorrhage (RR 0.38, 95% CI 0.15 to 0.97).
Treatment for postpartum haemorrhage
Misoprostol versus placebo
Another Cochrane review identified three randomised controlled trials that assessed misoprostol as treatment for primary postpartum haemorrhage.19 Compared with placebo, misoprostol reduced the likelihood of blood loss of at least 500mL after enrolment when bleeding had persisted despite routine use of conventional uterotonics (two trials, a total of 397 women, RR 0.57, 95% CI 0.34 to 0.96). However, a more recently published randomised placebo-controlled trial (conducted in hospitals in Argentina, Egypt, South Africa, Thailand and Vietnam), involving 1,422 women with postpartum haemorrhage treated with standard injectable uterotonics (mainly oxytocin), found that additional use of misoprostol 600 g sublingually did not reduce the proportion of participants with blood loss of 500mL or more within 60 minutes of randomisation.20 Meta-analysis of this trial and three earlier studies of misoprostol as adjunctive treatment (including the two in the Cochrane review) also showed no benefit on the same outcome measure.20
Misoprostol versus oxytocin
Two parallel multicentre double-blind randomised non-inferiority* trials in hospitals compared sublingual misoprostol 800μg and intravenous oxytocin 40units as first-line treatments for postpartum haemorrhage.21,22 In one of the trials (conducted in Ecuador, Egypt and Vietnam), none of the women had been exposed to oxytocin either in the second stage or third stage of labour.21 In the other study, (in Burkina Faso, Egypt, Turkey and Vietnam), all the women received prophylactic oxytocin during the third stage.22 The primary outcome measures in both studies were the cessation of active bleeding within 20 minutes after treatment and additional blood loss of 300mL or more after treatment. The trial design allowed the number of women who stopped bleeding within 20 minutes with misoprostol to be up to 6% fewer than with oxytocin, without misoprostol being judged inferior.
Of 9,348 women recruited in hospitals that did not use oxytocin routinely during the second and third stages of labour, 978 experienced postpartum haemorrhage and were randomised.21 Compared with oxytocin, fewer women given misoprostol had active bleeding controlled within 20 minutes (90% vs. 96%; RR 0.94, 95% CI 0.91 to 0.98) and more had additional blood loss of at least 300mL (30% vs. 17%; RR 1.78, 95% CI 1.40 to 2.26). In hospitals that used prophylactic oxytocin, only 809 of the 31,055 women recruited developed postpartum haemorrhage and were randomised.22 The groups did not differ in how many women had active bleeding controlled within 20 minutes after treatment (89% with misoprostol vs. 90%) or who had additional blood loss of at least 300mL (34% with misoprostol vs. 31%). The results indicated that sublingual misoprostol could not be claimed to be non-inferior, and might even be inferior, to oxytocin if a prophylactic uterotonic was not given; however, misoprostol was non-inferior to oxytocin in women who had such prophylaxis.
The third trial identified in the Cochrane review, involving 64 women in South Africa, found that rectal misoprostol 800μg was more likely than intramuscular oxytocin/ergometrine plus subsequent intravenous infusion of oxytocin to produce subjective cessation of haemorrhage within 20 minutes (the primary outcome measure; RR 0.18, 95% 0.04 to 0.76).19
Cautions and unwanted effects
Misoprostol should only be used after the delivery of the baby and after abdominal palpation that confirms there is no other baby still in the uterus.15
Misoprostol can cause unwanted gastrointestinal effects such as diarrhoea, abdominal pain, nausea and vomiting.13 In the largest trial of misoprostol for prevention of postpartum haemorrhage, 18% of women receiving oral misoprostol 600μg had shivering (vs. 5% with oxytocin, numbers needed to harm [NNH] 8) and 6% had a temperature above 38°C (vs. 0.8%, NNH 19).18 When used in hospitals as treatment for postpartum haemorrhage, sublingual misoprostol (800μg) was more likely than oxytocin to cause shivering;21,22 it was also more likely to cause pyrexia in women not given prophylactic oxytocin (14% vs. 0)21 but not in those given such prophylaxis (1% vs. <1%).22
What guidelines say
The joint ICM and FIGO guideline advises that where oxytocin is not available or birth attendants' skills are limited, oral or sublingual misoprostol 600μg taken soon after the baby's birth reduces the likelihood of haemorrhage.8 In this situation, it recommends that controlled cord traction should be applied only when a skilled attendant is present at the birth, and that the women should be offered “uterine massage after the delivery of the placenta as appropriate”. The RCOG offers similar advice and states that misoprostol is not as effective as oxytocin, but that it may be used when oxytocin is unavailable, such as in the home birth setting.5
The joint ICM and FIGO guideline states that, while less is known about the effect of misoprostol as treatment (as opposed to prophylaxis) for postpartum haemorrhage, it may be appropriate for use in low-resource settings.8 It states that in home births without a skilled attendant, misoprostol may be the only technology available to control postpartum haemorrhage. The RCOG guideline states that when uterine atony is perceived to be a cause of the bleeding, mechanical and drug measures should be instituted, in turn, until bleeding stops.5 Rectal misoprostol (1,000μg) is included at the end of this list of options, after carboprost.
An expert group, convened by the WHO in 2006 to recommend optimal misoprostol dosages for postpartum haemorrhage,3 advised giving a single oral or sublingual 600μg dose for both prevention (only where injectable “conventional” uterotonics are not available, and as part of the active management of the third stage of labour)15 and treatment (“only after the provider has exhausted all standard PPH [postpartum haemorrhage] treatments”).23 The group also stated misoprostol (for prevention or treatment), should not be readministered within 2 hours of the initial dose or 6 hours if the initial dose was associated with pyrexia or marked shivering.23 In contrast, the RCOG recommends 1,000μg rectally as treatment for postpartum haemorrhage and many African countries also use a rectal dose of 1,000μg24 despite evidence that serum concentrations are low following such administration.4
Each misoprostol 200μg tablet costs around £0.17. An ampoule of oxytocin 10units costs £0.86; oxytocin 5units plus ergometrine 0.5mg £1.35; ergometrine 0.5mg £0.60; and carboprost 250mg £18.20.
Implications for practice
In the UK, injectable uterotonics are the drugs of choice as prevention and treatment for postpartum haemorrhage. In terms of cost and ease of storage, misoprostol is economically beneficial for developing countries, and can be administered easily by unskilled birth attendants or the women themselves.14,25,26 In rural Afghanistan, some midwives supply misoprostol antenatally to women giving birth at home, or in isolated areas, for self-administration at delivery.25 However, the WHO has recently advised against this approach.27 One suggestion for why misoprostol could help in low-resource community settings relates to the duration of the normal third stage of labour.14,16 In hospitals, there has been a tradition to use early controlled cord traction to coincide with the peak oxytocin concentration; however, such traction in those given misoprostol may result in placental detachment (and haemorrhage) before effective serum levels of the drug are reached.14 In community settings, controlled cord traction is usually done later and is likely to coincide with the peak serum misoprostol concentration at 20 minutes after the dose.14
Misoprostol is a synthetic prostaglandin analogue with uterotonic action that has been used, but is not licensed, for primary postpartum haemorrhage. The drug is less effective than injectable uterotonics as prevention for this problem. Evidence suggests that, when combined with oxytocin, misoprostol may be better than oxytocin alone as prophylaxis. As treatment for postpartum haemorrhage, misoprostol does not offer benefit if bleeding has persisted despite treatment with conventional uterotonics. Also, the drug may be less effective than oxytocin if the woman has not already received prophylactic oxytocin. If she has ready received such prophylaxis, misoprostol appears no less effective than oxytocin. Misoprostol should not replace oxytocin as prophylaxis or treatment for postpartum haemorrhage. However, at a dose of 600μg orally or sublingually, it may be useful for prevention in settings where oxytocin is unavailable (e.g. rural low-resource areas). With such use, early controlled cord traction should not be done, to reduce the likelihood of placental detachment (and resulting bleeding) before an effective serum misoprostol concentration has been reached.
[R=randomised controlled trial; M=meta-analysis]
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