Choice of uterotonic agents in the active management of the third stage of labour
Oxytocin halves the risk of postpartum haemorrhage with blood loss ≥ 500 ml and reduces the risk of severe postpartum haemorrhage (blood loss ≥ 1000 ml). Addition of ergometrine to oxytocin increases the incidence of high blood pressure and vomiting. The rate of severe postpartum haemorrhage and use of additional uterotonics were statistically significantly higher with oral misoprostol compared with conventional injectable uterotonics (e.g. oxytocin and oxytocin–ergometrine combination).
RHL Commentary by Abalos E
More than half of all maternal deaths occur within 24 hours of delivery, most commonly from excessive blood loss. It is estimated that some 140 000 women die each year from postpartum haemorrhage (PPH) (1, 2). PPH also causes serious morbidity in many women. In many developing countries, only a small proportion of women, living in mostly urban areas, have access to health-care facilities for delivering their babies. Most of the deliveries in rural areas take place at home and a relatively low percentage of them are assisted by a skilled birth attendant. However, institutional deliveries can also be risky, owing either to the lack of emergency drugs, blood, and appropriate equipment, or to insufficiently trained or under-skilled staff. Consequently, PPH contributes to maternal mortality in part due to poor maternal health status and also to the lack of adequately equipped delivery facilities and inappropriate management of the third stage of labour.
The primary purpose of active management of the third stage of labour is to reduce the risk of PPH. Active management includes administration of a prophylactic uterotonic at or after delivery of the baby, early cord clamping and cutting (although more recently this component has been removed from international guidelines), controlled cord traction to deliver the placenta, and uterine massage. The present commentary evaluates evidence presented in three Cochrane reviews related to the choice of uterotonics in the active management of the third stage of labour. Prophylactic use of oxytocin, regardless of other aspects of active management of the third stage of labour, was evaluated in a Cochrane review entitled "Prophylactic oxytocin in the third stage of labour" (3). This review includes comparisons of: (i) oxytocin versus placebo or no uterotonic; (ii) oxytocin versus ergot alkaloids (ergometrine); and (iii) oxytocin plus ergometrine (Syntometrine®) versus ergometrine alone in the management of the third stage of labour. Syntometrine® has also been compared with oxytocin alone in another Cochrane review entitled "Prophylactic ergometrine–oxytocin versus oxytocin for the third stage of labour" (4). Prostaglandins compared either with placebo or no treatment or with another uterotonic were evaluated in the review entitled "Prostaglandins for prevention of postpartum haemorrhage" (5).
In the three reviews covered by this commentary, all adequately controlled trials that could be identified have been included. Trials were evaluated for methodological quality and appropriateness of inclusion. The methods employed in the three reviews are overall sound.
Most trials were hospital-based. Only five prostaglandin trials evaluated the intervention in the community or at the primary care level. One trial of oral misoprostol versus oral ergometrine included only home deliveries in Gambia, while in another trial of oral misoprostol versus placebo conducted in India women delivered either at home or at a primary care centre. In two trials in India and in one in Guinea-Bissau the interventions were compared in women delivering at primary care centres. The populations may differ in terms of the incidence of the problem but there are no biological reasons to expect a different effect of the drugs to be administered
3.1. PROPHYLACTIC OXYTOCIN IN THE THIRD STAGE OF LABOUR
In six trials involving ~3200 women, oxytocin use was found to halve the risk of PPH with blood loss ≥ 500 ml [Relative Risk (RR) 0.50; 95% confidence interval (CI) 0.43–0.59]. In four trials (involving 2243 women), compared with placebo or no uterotonics, oxytocin decreased the risk of severe PPH with blood loss ≥ 1000 ml (RR 0.61; 95% CI 0.44–0.87). These findings were consistent regardless of whether oxytocin was used as part of the active management approach or on its own, or whether it was given after or before delivery of the placenta. A significant reduction in the use of additional uterotonics was also found in five trials involving 2327 women (RR 0.50; 95% CI 0.39–0.64). However, confidence intervals were wide to allow detection of differences in the risk of blood transfusion or manual removal of the placenta in pre-specified subgroups.
There was little evidence of differential effects for oxytocin versus ergot alkaloids (six trials, ~2800 women, RR 0.90; 95% CI 0.70–1.16). However, oxytocin was associated with fewer manual removals of the placenta (RR 0.57; 95% CI 0.41–0.79). One small trial suggested that there was less raised blood pressure with oxytocin compared with ergot alkaloids. Five trials (~2800 women) had compared oxytocin plus ergometrine versus ergometrine alone. These trials showed little evidence of a synergistic effect of oxytocin plus ergometrine (RR 1.29; 95%CI 0.90–1.84). Sufficient information was not available to evaluate other outcomes and side-effects of such a combination, including the combination's effects on the baby.
3.2 PROPHYLACTIC ERGOMETRINE–OXYTOCIN VERSUS OXYTOCIN FOR THE THIRD STAGE OF LABOUR
This review includes six trials involving 9332 women. It evaluated the prophylactic use of intravenous and intramuscular ergot alkaloids during the third stage of labour. Although ergot alkaloids are effective in reducing blood loss and preventing postpartum haemorrhage, their adverse effects include vomiting, elevation of blood pressure and pain after birth requiring analgesia, particularly with the intravenous route of administration.
In the six trials included in the review, use of ergometrine plus oxytocin was associated with a small but significant reduction in the incidence of PPH (blood loss ≥ 500 ml) compared with oxytocin alone [odds ratio (OR) 0.82; 95% CI 0.71–0.95], irrespective of the dose (5 IU or 10 IU). Five trials (~8000 women) reported no difference in severe PPH (blood loss ≥ 1000 ml) (OR 0.78; 95% CI 0.58 –1.03) with the ergometrine plus oxytocin combination. However, addition of ergometrine to oxytocin increased the incidence of high blood pressure (four trials, ~7500 women, OR 2.40; 95% CI 1.58–3.64) and vomiting (three trials, ~5500 women, OR 4.92; 95%CI 4.03–6.00), and these harmful effects should be taken into account in determining the best therapy. A useful tool to assess the practical clinical benefits of a therapy is the "number-needed-to-treat" (NNT) (7). The main results of this review can be summarized as follows: when 100 women are treated with oxytocin plus ergometrine, rather than oxytocin alone, three additional episodes of blood loss ≥ 500 ml will be prevented, but at the same time, one additional case of high blood pressure and 10 additional cases of vomiting will be observed.
3.3 PROSTAGLANDINS FOR PREVENTING POSTPARTUM HAEMORRHAGE
In this review, prophylactic use of prostaglandins was compared with either no uterotonics or placebo or with other uterotonics for the management of the third stage of labour. Thirty-seven misoprostol and nine intramuscular prostaglandin trials (involving 42 621 women) were included in this review. Prostaglandins included misoprostol administered via buccal, sublingual, oral, and rectal routes and intramuscular prostaglandins (PGF2alpha and PGE2). All of these drugs were analysed separately according to their dosages and routes of administration, while oxytocin, ergometrine and Syntometrine® were grouped as “conventional injectable uterotonics”. The authors identified severe PPH (blood loss ≥ 1000 ml) and the use of additional uterotonics as the primary outcomes.
Results of studies comparing buccal, sublingual, oral, or rectal misoprostol with no uterotonic/placebo are equivocal and come from small trials showing effects in different directions. Across the trials, side-effects were more common and consistent in those receiving misoprostol.
The rate of severe PPH (RR 1.36; 95% CI 1.17–1.58) and the use of additional uterotonics were statistically significantly higher with 600 µg of oral misoprostol compared with conventional injectable uterotonics. These results are dominated by the large WHO trial (8) but other trials showed the same trend. There were no significant differences between the 600 µg dose and lower doses (i.e. 500 µg or 400 µg) in terms of the rate of severe PPH, although trials using the lower doses had smaller sample sizes compared with the trials with the 600 µg dose. The use of additional uterotonics was also significantly higher with the 400 µg dose of misoprostol compared with conventional injectable uterotonics.
When compared with conventional uterotonics, intramuscular prostaglandins resulted in less blood loss [one trial, 46 women, weighted mean difference (WMD) –224.00 ml; 95% CI -420.35 ml –27.65 ml) and shorter duration of the third stage (WMD –3.60 minutes; 95%CI –7.65 minutes –0.45 minutes). Other outcomes occurred infrequently for any reliable conclusions to be drawn. The concerns related to safety, costs and side-effects are important limitations of intramuscular prostaglandins. Prostaglandin-related side-effects – especially shivering, pyrexia, nausea, vomiting and diarrhoea – were more frequent and consistent across trials.
In addition to the above three reviews, an oxytocin agonist (i.e. carbetocin) was compared with placebo (one trial) or oxytocin (three trials) for preventing postpartum haemorrhage in this recently published systematic review (6). Three studies were conducted in women undergoing elective caesarean deliveries and one in women at high risk of PPH delivering vaginally. Limited evidence suggests that there is little difference in the effectiveness between carbetocin and oxytocin, and adverse effects like headache, nausea and vomiting were also similar. Three of the included trials were known to be have been supported by grants from a pharmaceutical company.
4.1. APPLICABILITY OF THE RESULTS
The trials included in the three reviews were performed in Argentina, Australia, Belgium, Canada, China, Colombia, Egypt, Finland, France, Gambia, Ghana, Guinea-Bissau, Hong Kong, India, Mozambique, Netherlands, Nigeria, Singapore, South Africa, Sweden, Switzerland, Thailand, Turkey, the United Arab Emirates, United Kingdom, USA, Viet Nam and Zimbabwe. This strengthens the case for universal applicability of the interventions.
4.2. IMPLEMENTATION OF THE INTERVENTION
In settings where active management of the third stage of labour using oxytocin is the norm, there is no evidence from these reviews to recommend a change in practice. In health-care facilities considering the introduction of active management of the third stage of labour, education and training of health-care staff would be necessary to ensure that they have the skills to implement the policy. The capacity to use injectable uterotonics needs to be available for emergencies related to haemorrhage. However, in settings where these conditions cannot be met, misoprostol could be considered as the drug of last resort based on current evidence. Misoprostol has undesirable side-effects that are dose-related. It may be prudent to use the lowest effective dose to avoid these side-effects, but this will need to be determined with further research.
The feasibility of using an injectable uterotonic must take into account the availability of trained health-care personnel and health-care facilities for delivery. The cost of oxytocin and syringes is relatively low. However, staff should be trained in the parenteral administration of medications. The latter is necessary for the administration of antibiotics and anticonvulsants in emergency situations and should be regarded as a prerequisite for any health-care facility handling deliveries. Recent WHO guidelines on the prevention of postpartum haemorrhage recommend that oxytocin should be used by skilled attendants, but this should not prevent attendants who are skilled in administering uterotonics (but not skilled in active management) from administering the drug (9).
4.3. IMPLICATIONS FOR RESEARCH
There is a need to conduct randomized controlled trials of active versus expectant management of the third stage of labour for women delivering at home, irrespective of the development status of the country. Results of recent trials of misoprostol in rural and primary care settings should be replicated for dose adjustments and safety assessment.
No further trials comparing oral misoprostol with other uterotonics are needed in routine management of the third stage of labour at the secondary care level in settings where active management is the norm.
Future research should also be aimed at economic evaluations of uterotonic agents and women's views related to uterotonic drug choices.
Sources of support: Centro Rosarino de Estudios Perinatales. Rosario. Argentina.
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- McDonald SJ, Abbott JM, Higgins SP. Prophylactic ergometrine-oxytocin versus oxytocin for the third stage of labour. Cochrane Database of Systematic Reviews 2004;Issue 1. Art. No.: CD000201; DOI: 10.1002/14651858.CD000201.pub2.
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- WHO recommendations for the prevention of postpartum haemorrhage. Geneva: World Health Organization; 2007. http://whqlibdoc.who.int/hq/2007/WHO_MPS_07.06_eng.pdf
This document should be cited as: Abalos E. Choice of uterotonic agents in the active management of the third stage of labour: RHL commentary (last revised: 2 March 2009). The WHO Reproductive Health Library; Geneva: World Health Organization.