Reviewer's commentary on ‘Should oral misoprostol be used to prevent postpartum haemorrhage in home-birth settings in low-resource countries? A systematic review of the evidence’
We disagree with Hundley et al's conclusion that there is ‘quality evidence’ to support misoprostol use. In an otherwise thorough review of misoprostol for prevention of postpartum haemorrhage (PPH) among women in low resource countries, the authors pay insufficient attention to design weaknesses and lack of generalisability of findings, overemphasizing tests of statistical significance and study type. Furthermore, the SIGN-GRADE criteria expose critical limitations in all of the studies included, both randomised and non-randomised. These are such that there are no good grounds, on this evidence, to support misoprostol use.
The authors assigned a quality score to the studies, adapted from SIGN-GRADE criteria for levels of confidence (see the footnote to Table 2 and SIGN methodology, www.sign.ac.uk/methodology/index.html). SIGN criteria for assessing the strength of evidence include: quantity, quality, and consistency of evidence; external validity (generalisability) of studies and directness of application to the target population for the guideline. The authors rated papers according to whether there was confidence that the analysis was assessing causal association as follows: ‘++’ (high level of confidence), ‘+’ (moderate level of confidence), ‘−’ (low level of confidence), and ‘−−’ (very low level of confidence).
Two randomised controlled trials (RCTs) were graded ‘++’ (Table 2), i.e. high level of confidence of causal association, but insufficient attention was paid to study design and confounding factors. Both RCTs exhibit temporal trends (noted in Table 2) in the intervention and control arms, suggesting effects from factors other than misoprostol. Moreover, the findings are not generalisable because both RCTs excluded women with or at high risk of complications. Indeed, the authors of the RCTs themselves highlight the non-generalisability of their findings. Had Hundley et al. followed the SIGN criteria, the grading would be ‘−’, i.e. low level of confidence.
Similarly, the authors graded three of the four non-randomised studies as ‘+’ (moderate probability the relationship is causal), but failed to consider confounding factors in study design. In the non-randomised studies included in the review, differences existed between the intervention and control arms in birth attendant training and active management of third stage of labour (AMTSL) practices. Blood loss was not measured at all in one study, was reported subjectively by recall in one, and was just estimated in two studies. Once again if the SIGN criteria had been correctly applied the appropriate grading would be ‘−−’, i.e. very low level of confidence.
National Institute for Health and Clinical Excellence (NICE) guidance on the use of SIGN-GRADE criteria for practice recommendations is that ‘Usually, studies rated as ‘−’ should not be used as a basis for making a recommendation’ (NICE, Feb 2004, updated 2005, Guideline Development Methods, UK, www.nice.org.uk/niceMedia/pdf/GDM_Chapter7_0305.pdf, p. 7–7).
This review highlights the difficulties in conducting high-quality studies on PPH in low-resource countries, and, as a consequence, the paucity of evidence supporting oral misoprostol use in home-birth settings, findings confirmed in another recent review co-authored by two of us (Chu CS, et al. Journal of the Royal Society of Medicine 2012;105:336–347). Drawing the wrong conclusions from research that, however unavoidably, is not of high quality, has serious implications for healthcare expenditure, maternal health priorities, and women's health. The conclusion that the ‘distribution of oral misoprostol through frontline health workers is effective in reducing the incidence of PPH’ is not supported by evidence either in this review or an earlier review of trials (Chu CS, et al. Journal of the Royal Society of Medicine 2012;105:336-347). The World Health Organisation should rescind its decision to add misoprostol for the prevention of PPH in low-resource community settings to the Essential Medicines List [WHO (2011), Unedited report of the 18th expert committee on the selection and use of essential medicines, Ghana www.who.int].
AM Pollock,a P Brhlikova,a P McGettiganb
aCentre for Primary Care and Public Health,
bClinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and DentistryLondon, UK