Misoprostol has been arguably the most dis- cussed and researched drug in sexual and re- productive health since the early 1990s. The uterotonic effects of misoprostol to termi- nate pregnancy were first reported in Brazil. Since then, misoprostol has been researched in many areas of sexual and reproductive health in numerous randomized trials and systematic reviews. WHO currently includes misoprostol in its evidence-based guidelines and Model List of Essential Medicines for early pregnancy termination together with mifepristone, medical management of mis- carriage and labour induction. An application to include misoprostol for postpartum haem- orrhage (PPH) prevention has been deferred until the publication of a large trial in Pakistan and review of its dose-related safety in the immediate postpartum period. The most controversial use of misoprostol has been its use in PPH prevention and treat- ment. In a commentary in The Lancet, Potts et al. recommend community distribution of misoprostol to pregnant women as the key intervention to achieve Millennium Develop- ment Goal 5 ��� improve maternal health ��� and further state that rigorous evaluation of bene- fits and harms of this approach is logistically, ethically and financially impossible.1 These authors also allege that WHO has changed its position regarding its recommendations on misoprostol use after childbirth. WHO disa- grees on both. This technical brief reiterates the WHO position on the use of misoprostol for PPH prevention and management and the issues highlighted by Potts et al. WHO���s work on misoprostol follows the principles of evidence-based decision- making and includes randomized controlled trials,2 systematic reviews3 and development of evidence-based guidelines on PPH prevention4 and management.5 For PPH prevention, WHO recommends that ���in the absence of active management of the third stage of labour, a uterotonic drug (oxy- tocin or misoprostol) should be offered by a health worker trained in its use for prevention of PPH. For misoprostol, this recommendation places a high value on the potential benefits of avoiding PPH and ease of administration of an oral drug in settings where other care is not available, but notes there is only one study. The only trial relevant to this recommendation used 600 ��g of misoprostol.6 The efficacy of lower doses has not been evaluated. There is still uncertainty about the lowest effective dose and optimal route of administration.��� 4 The supporting evidence comes from a trial in India where auxiliary nurse-midwives at- tending births at home or in primary health centres used misoprostol without any other component of active management of the third stage of labour.6 This recommendation for mi- soprostol administration after birth appears to have been misinterpreted as a recommen- dation for community distribution during preg- nancy (i.e. advance provision) for use when the need arises after birth. In July 2009, at the request of Member States for clear guidance in the presence of conflict- ing information on the use of misoprostol for PPH prevention and management, WHO published a statement, clarifying its posi- tion.7 Potts et al. refer to this publication to claim that WHO has changed its position from what was published in the guidelines. This is incorrect. While WHO does not condemn the community distribution of misoprostol during pregnancy, WHO does not recommend such practice because its potential benefits and harms are currently unknown and recom- mends proper research to evaluate its role in reducing maternal deaths. Potts et al. ask the question of whether the deaths are going unregistered or whether mi- soprostol is highly effective and remarkably safe. This is the most important question and the answer is not yet known. There are clearly potential benefits but also potential harms of misoprostol use, especially with ad- vance distribution during pregnancy. Among 52 mostly facility-based randomized control- led trials with more than 40 000 participants, 15 maternal deaths were reported in seven trials with 24 609 participants.8 Eleven deaths occurred among women receiving misopros- tol compared with 4 women receiving other uterotonics or placebo. All deaths occurred in Department of Reproductive Health and Research WHO/RHR/10.11 Statement Clarifying WHO position on misoprostol use in the community to reduce maternal death including Clarifying WHO position on misoprostol use in the community to reduce maternal death

For more information, please contact: Department of Reproductive Health and Research World Health Organization Avenue Appia 20, CH-1211 Geneva 27 Switzerland Fax: +41 22 791 4171 E-mail: reproductivehealth@who.int www.who.int/reproductivehealth References 1 Potts M, Prata N, Sahin-Hodoglugil NN. Maternal mortality: one death every 7 min. Lancet 2010 375: 1762���63. 2 G��lmezoglu AM, Villar J, Ngoc NTN, et al., for the WHO Collaborative Group To Evaluate Misoprostol in the Management of the Third Stage of Labour. WHO multicentre randomised trial of misoprostol in the management of the third stage of labour. Lancet 2001 358: 689���95. 3 G��lmezoglu AM, Forna F, Villar J, Hofmeyr GJ. Prostaglandins for preventing postpartum haemorrhage. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD000494. DOI: 10.1002/14651858.CD000494.pub3 4 WHO recommendations for the prevention of postpartum haemorrhage. Geneva, World Health Organization, 2007. http://www.who. int/reproductivehealth/publications/maternal_ perinatal_health/MPS_07_06_/en/index.html 5 WHO guidelines for the management of postpartum haemorrhage and retained placenta. Geneva, World Health Organization, 2009. http://www.who.int/reproductivehealth/ publications/maternal_perinatal_ health/9789241598514/en/index.html 6 Derman RJ, Kodkany BS, Goudar SS, et al. Oral misoprostol in preventing postpartum haemorrhage in resource-poor communities: a randomised controlled trial. Lancet 2006 368: 1248���53. 7 WHO Statement regarding the use of misoprostol for postpartum haemorrhage prevention and treatment. Geneva, World Health Organization, 2009. http:// www.who.int/reproductivehealth/publications/ maternal_perinatal_health/misoprostol/en 8 Novikova N, Hofmeyr GJ, G��lmezoglu AM. Letter to the editor, Lancet submitted. 9 Baskett TF. The development of oxytocic drugs in the management of postpartum haemorrhage. Ulster Med J 2004 May Suppl:2���6. 10 Flandermeyer D, Stanton C, Armbruster D. Uterotonic use at home births in low-income countries: a literature review. Int J Gynaecol Obstet 2010 108(3): 269���75. Epub 2010 Jan 6. 11 Winikoff B, Dabash R, Durocher J, Darwish E, Nguyen TN, Le��n W, Raghavan S, Medhat I, Huynh TK, Barrera G, Blum J. Treatment of post-partum haemorrhage with sublingual misoprostol versus oxytocin in women not exposed to oxytocin during labour: a double-blind, randomised, non-inferiority trial. Lancet 2010 375(9710): 210���16. Epub 2010 Jan 6. 12 Chalmers I. Trying to do more good than harm in policy and practice: the role of rigorous, transparent, up-to-date evaluations. Ann Am Acad Pol Soc Sci 2003 589: 22���40. women receiving 600 ��g or more. It is coun- terintuitive but plausible that misoprostol at high doses could have adverse effects that may overshadow its benefits. As a prostag- landin 1 (PGE1) analogue, misoprostol in- duces various systemic effects which have been observed in numerous research studies. Furthermore, advance provision may lead to inappropriate use for labour induction at very high doses with catastrophic results (doses for PPH are about 20 times those needed for labour induction). It is well documented that both oxytocin and ergometrine have been used in inappropriate doses and routes be- fore delivery when they were first introduced causing many unnecessary deaths.9 Such practices are still believed to be prevalent in some parts of the world.10 The studies Potts et al. refer to as evidence of safe and effective misoprostol use are all nonrandomized studies with significant risks of bias. All of these studies have been con- ducted by groups who firmly believe that mi- soprostol works and that rigorous research in those contexts is a luxury. Most have indicated only appropriate timing of the ad- ministration as a safety endpoint. In addition, Potts et al. are incorrect in claiming that mi- soprostol 800 ��g was as effective as oxytocin in women without previous oxytocin prophy- laxis according to the trial published in Janu- ary 2010.11 In this trial, additional blood loss ���500 mL after treatment was experienced by 53 (11%) women given misoprostol versus 20 (4%) women given oxytocin (RR: 2.84 (1.63��� 5.01)) and the drop in Hb���30 g/L or blood transfusion was observed in 199 (41%) wom- en given misoprostol and 148 (30%) women given oxytocin (RR: 1.35 (1.14���1.60)). These outcomes strongly suggest that for women with no prophylaxis, oxytocin is clearly more effective than misoprostol in the doses used. Finally, as Sir Iain Chalmers stated ���Because professionals sometimes do more harm than good when they intervene in the lives of other people, their policies and practices should be informed by rigorous, transparent, up-to-date evaluations.���12 It is with this line of thought that WHO has taken a cautious approach re- garding the advance community distribution of misoprostol during pregnancy and recom- mends rigorous research. WHO monitors re- search in this area very closely and as new evidence becomes available will review the evidence critically and update its guidance to its Member States. WHO/RHR/10.11 �� World Health Organization 2010 The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers��� products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. Department of Reproductive Health and Research