The WHO recommends oxytocin as the uterotonic of choice for PPH prevention, and that oxytocin or misoprostol be offered by a health worker trained in its use in the absence of oxytocin and other components of AMTSL, e.g. provision of a uterotonic, uterine massage and controlled cord traction.8
These recommendations are currently based upon a body of studies that do not distinguish between visual and measured blood loss, and are influenced by the sample for which blood loss was visually assessed. Similarly, analyses upon which policy recommendations are based do not separate studies for other factors that influence bleeding. The American College of Obstetricians and Gynecologists has suggested functional definitions of severe blood loss, including a 10% decline from ante- to post-partum haematocrit, or the need for red blood cell transfusion;55
however, too few studies measuring blood loss exist to support such functional definitions.
By reviewing only articles of measured postpartum blood loss, this article provides comparisons unbiased by the proportion of studies using visual compared with measured blood loss. Most of the presented analyses show similar effects to those published in meta-analyses that pool visually estimated and measured blood loss; however, our analyses clarify some important discrepancies.17
Comparing oxytocin with no uterotonic, our analyses of all studies show a slightly stronger and still significant effect for PPH and mean blood loss (PPH, OR 0.43, 95% CI 0.23–0.81 versus Cochrane OR 0.50, 95% CI 0.43–0.59; mean blood loss of −140 ml, 95% CI from −229 to −52 ml versus Cochrane blood loss of −102 ml, 95% CI from −135 to −69 ml), with the same effect on severe PPH (OR 0.61, 95% CI 0.29−1.29 versus Cochrane 95% CI 0.44–0.87). As a smaller subgroup, our analyses of severe PPH do not reach statistical significance.17
Our analyses of studies of adequate quality compared with the Cochrane subgroup of RCTs demonstrate a significant and much stronger reduction of PPH with oxytocin compared with no uterotonic (OR 0.45, 95% CI 0.34–0.60 versus Cochrane OR 0.61, 95% CI 0.51–0.72), and a reduction in mean blood loss (−118 ml, 95% CI from −165 to −71 ml versus Cochrane mean blood loss of −109 ml, 95% CI from −152 to −66 ml), whereas the effect on severe PPH was similar, and was still marginally significant (OR 0.76, 95% CI 0.52−1.09 versus Cochrane OR 0.72, 95% CI 0.49–1.05).
The Cochrane comparisons of misoprostol with no or other uterotonics are less methodologically similar to our analyses.8
The Cochrane review of prostaglandins for PPH prevention does not provide estimates summarising the overall effect comparing misoprostol with no uterotonic; however, the estimate we calculate from the data they present for this comparison, excluding the Gambian study53
(as the comparison group received oral ergometrine) and the Turkish study36
(which compared a combination of oxytocin and misoprostol with no uterotonic), was Cochrane OR 0.75 (95% CI 0.49–1.14) for severe PPH, very similar to our results from all studies (OR 0.74, 95% CI 0.52–1.04), although our adequate-quality studies showed a stronger and highly significant effect (OR 0.67, 95% CI 0.51–0.89). The Cochrane review found that compared with sublingual misoprostol, any injectable uterotonic had a similar yet marginally significant effect on PPH (Cochrane OR 0.93, 95% CI 0.79–1.11), and was inferior to sublingual misoprostol for severe PPH (Cochrane OR 1.85, 95% CI 0.79–4.35). In contrast, the Cochrane review found any injectable uterotonic to be superior to oral misoprostol for severe PPH (Cochrane OR 0.76, 95% CI 0.66–0.86).8
The effects of uterotonics on severe PPH are particularly important, as maternal death as a result of PPH usually occurs when blood loss is >1000 ml.19
Distinct from existing reviews, we found that prophylactic oxytocin significantly reduces PPH, but is only marginally associated with lower severe PPH compared with expectant management. This might be attributable to insufficient statistical power, as severe PPH is a relatively rare condition. In addition, a small portion of PPH and severe PPH would not be responsive to uterotonics (for example, if caused by trauma), thereby minimising the incidence of potentially responsive severe bleeding. However, compared with no uterotonic, misoprostol significantly lowered severe PPH in adequate-quality studies with a much smaller total sample size than that of all studies evaluating the effects of oxytocin on severe PPH. The data from adequate-quality studies or developing country data are too scant to draw conclusions about the effects of oxytocin compared with no uterotonic, or misoprostol, in these contexts.
Prophylactic misoprostol significantly reduces PPH and severe PPH, compared with expectant management, only when analyses are limited to adequate-quality studies, or in studies solely conducted in developing countries. In the WHO multicentre study comparing oxytocin with misoprostol in hospital settings, oxytocin reduces PPH and severe PPH significantly more than misoprostol, but does not differentially affect maternal death.45
Four studies of misoprostol have been conducted in rural, developing country settings: two compared with ergometrine and two with no uterotonic. There is only one quasi-experimental study of oxytocin in a rural developing country setting. No studies compare oxytocin with misoprostol in home birth or primary care centre settings, or in rural areas of developing countries, where misoprostol being simpler, and therefore more feasible to administer and study, may be relatively more effective because of greater coverage.
Distinct from other reviews, this review of measured blood loss, complementing meta-analyses with broader epidemiologic data, and providing sufficient stratification of information, demonstrates that women experience a large range of postpartum blood loss, even when bleeding was carefully measured. The median of reported average blood loss in women receiving any prophylactic uterotonics was similar, and was approximately 40% lower than that of women not receiving prophylactic uterotonics. However, the range of average blood loss, PPH and severe PPH was large, and fairly consistent, across women receiving and not receiving prophylactic uterotonics. The difference between the lowest and highest mean blood loss, incidence of PPH and severe PPH, and the ratio of severe PPH to PPH within each regimen for managing the third stage of labour is greater than the discrepancy in these ranges across the regimens. Variation in blood loss was only slightly larger in study arms with ≤200 women compared with larger study arms.
Women’s characteristics, obstetric practices and other factors associated with setting could account for some of the blood loss variation, and for the differences in the relative effectiveness of uterotonics on blood loss and haemorrhage.10
Eligible studies generally excluded high-risk or complicated pregnancies. Labour augmentation and/or induction were permitted in about half of the reviewed studies with 2–47% (median 27%) of women having augmentation or induction. In women otherwise managed without uterotonic prophylaxis, study arms that permitted augmentation or induction had lower levels of blood loss than those without. Measuring blood loss is more difficult than visual estimation, and thus has been implemented less frequently. Although blood loss measurement could in theory influence observed blood loss, few studies used the drape, and both the bedpan/linens and drape methods are direct measurements that are found to be quite accurate and similar.56,57
Exclusion of studies where the incidence of PPH was extremely high, or limiting analyses to studies measuring blood loss for 1 hour, only slightly modified the incidence of severe PPH for all regimens.