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Rapid Responses: Rapid Responses published:
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Inadequate reporting of safety issues from clinical trials in academic journals
- Susan C Morgan (14 October 2005)
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Misoprostol: An essential drug to save mothers' lives
- Godfrey Mbaruku, Friday E. Okonofua, Khama Rogo, Harshad Sanghvi, Ndola Prata, Anke Hemmerling, Farnaz Vahidnia, and Malcolm Potts (18 October 2005)
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Re: Inadequate reporting of safety issues from clinical trials in academic journals
- Lars Høj (19 October 2005)
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Figure error?
- Andrew D Weeks (21 October 2005)
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Questions for authors regarding the effect of sublingual misoprostol on postpartum haemorrhage
- Nancy L. Sloan, Beverly Winikoff, Jennifer Blum (4 November 2005)
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Was active management of the third stage of labor used in the research study?
- Deborah A. Armbruster (12 November 2005)
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Misoprostol in the third stage of labour and maternal mortality: a review
- A. Metin Gülmezoglu, G. Justus Hofmeyr, Effective Care Research Unit, East London Hospitals Complex, East London, South Africa (4 January 2006)
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Susan C Morgan, Associate Specialist Mayday Hospital CR7 7YE
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The pragmatic double-blind study of sub-lingual misoprostol versus placebo in a primary health care setting where it is not possible to give the standard treatment of intravenous oxytocin is to be commended. However, despite some efficacy being shown (reduction of the incidence of the severer haemorrhages but not in the primary endpoint of all post- partum haemorrhages) the safety message from the trial was lost. It is recognised that safety issues are inadequately reported on in published trials (refs 1-3) and although mortality was reported under side effects this issue was then not evaluated any further. In this trial report no safety issues were mentioned in the abstract and only the minor symptoms of shivering and mild fever were noted in the conclusion. It is only on closer reading of the safety section that it comes to light that the 1 death occurred in the active arm of the study. A clear cause of death was not obtained which is regrettable. It was a sudden death only 90 minutes post-partum and it was noted that the woman had lost 1417ml of blood. In these circumstances it would appear reasonable to include adverse event to misoprostol as a possible cause for the death. It is known that misoprostol can cause hypotension which could be particularly hazardous in the context of blood loss and undiagnosed cardiovascular or cerebrovascular disease. Use of any therapy is dependent on assessing that the risk/benefit of treatment is favourable when undue emphasis is put on borderline efficacy without balancing comments in the conclusions of the safety issues may give false reassurance that a treatment is appropriate for off-label use. In this trial it was not the complete absence of safety reporting but a complete dismissal of any relationship to the active intervention. Competing interests: None declared |
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Godfrey Mbaruku, Regional Medical Officer Regional Hospital, Maweni PO Box 125 Kigoma, Tanzania, Friday E. Okonofua, Khama Rogo, Harshad Sanghvi, Ndola Prata, Anke Hemmerling, Farnaz Vahidnia, and Malcolm Potts
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We welcome the work of Høj et al. and their careful randomised controlled trial on the use of sublingual misoprostol to prevent post partum haemorrhage (PPH) in a health centre in Guinea Bissau (BMJ 2005; 331; 723). As the authors point out, most women in Africa do not deliver in a health facility and the challenge is to transfer this encouraging data to the village level. We would like to draw attention to a culturally appropriate way to measure blood loss at the village level (1) and to demonstrations in Tanzania and the Gambia where traditional birth attendants (TBAs) used misoprostol responsibly and effectively during home births (2, 3). Moreover, evidence shows that when appropriately counseled, women can correctly use misoprostol in home births even in the absence of a trained TBA (4). Ethically, we felt it was not possible to conduct a placebo control for treatment of PPH when TBAs have no alternative way of stopping haemorrhage. In addition to the Tanzanian study similar intervention trials are ongoing in Nigeria, Bangladesh and soon to start in Afghanistan and Ethiopia. Senior government officials in Uganda and Kenya have endorsed the use of misoprostol to control PPH and the government of India is encouraging the use of sublingual or oral misoprostol for the prevention of PPH at home births, recently having added misoprostol to the official guidelines for skilled attendance (5). We hope that with the additional important work of Høj et al. that use of this life-saving technology will spread. Sincerely, Godfrey Mbaruku MD, PhD
Friday E. Okonofua MD, PhD
Khama Rogo MD, PhD
Dr. Harshad Sanghvi
Ndola Prata MD, MSc;
References 1. Prata N., Mbaruku G., Campbell M. Using the kanga to measure postpartum blood loss. International Journal of Gynaecology and Obstetrics 2005; 89(1):49-50. 2. Prata N., Mbaruku G., Campbell M., Potts M., Vahidnia F. Controlling postpartum hemorrhage after home births in Tanzania Int J Gyn and Obs 2005 90(1):51-5. 3. Walraven G, Blum J, Dampha Y, Sowe M, Morison L, Winikoff B, et al. Misoprostol in the management of the third stage of labour in the home delivery setting in rural Gambia: a randomised controlled trial. BJOG 2005; 112(9):1277-83. 4. Sanghvi HCG, Gulardi, W., Chanpong G., Fishel J, Ahmed S, Zulkarnain M. Prevention of postpartum hemorrhage study, West Java, Indonesia, JPHIEGO, 2004. 5. Maternal Health Division, Department of Family Welfare, Ministry of Health & Family Welfare, (Government of India) Guidelines for antenatal care and skilled attendance at birth by ANMs and LHVs. MOH; 2005. Competing interests: None declared |
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Lars Høj, Staff Specialist Dept. of Obst. Gyn. Aarhus University Hospital, 8200 Aarhus N, Denmark
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Dear Susan C Morgan. Misoprostol has been on the market since 1985 and is approved for prevention of gastroduodenal ulcers in doses of up to 800 µg daily in a group of patients in whom cardiovascular and cerebrovascular diseases are common. No one has questioned the risk/benefit ratio in this relatively mild condition. Delivery under circumstances described in our trial is an extremely unsafe event and 2-4 deaths in 661 deliveries are to be expected. The best possible method to obtain a cause of death – verbal autopsy - was carried out for the single death in our trial, but - as in the majorities of deaths in settings without post-mortems, para-clinical tests and experienced doctors - a clear cause of death was not found. Profound analysis concerning one event in a randomised trial of 661 participants is not possible; instead the event was appropriately reported for inclusion in meta-analyses to come. With one table and one paragraph dedicated to side effects we do not understand the argument ‘complete absence of safety reporting’, and the allegation ‘complete dismissal of any relationship to the active intervention’ is simply not true. We maintain our conclusion: IF the drug is found to be consistently beneficial and safe, sublingual misoprostol should be offered to labouring women at the start of the third stage of labour if injectable uterotonics are not available. Safe motherhood in rural Africa is not accomplished without innovative research. Competing interests: None declared |
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Andrew D Weeks, Clinical Lecturer in O&G Liverpool Women's Hospital, Liverpool, UK L8 7SS
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The histograms in both figure 1 and 2 seem to suggest that the blood loss was greater in the misoprostol group than in the placebo group. I wonder if there has been an error and the labels for the 2 groups accidentally reversed. Could the authors please check this so that a correction can be published if necessary? Competing interests: None declared |
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Nancy L. Sloan, Perinatal and nutritional epidemiologist Columbia University, 10032, Beverly Winikoff, Jennifer Blum
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We are delighted to see a growing interest in misoprostol to prevent postpartum haemorrhage (PPH). Indeed, the relative risk observed by Høj and colleagues (1) for severe PPH of misoprostol v. non-misoprostol treated women is very similar to that which we observed in our community based trial of oral misoprostol v. ergometrine for prevention of PPH (2). However, the incidence of PPH in our study was much closer to that normally expected. Most studies measuring postpartum blood loss describe rates of PPH (>=500 ml) ranging from 10%-20% and severe PPH (>=1000 ml) from 1%-4%. We wonder if Høj et al can tell why their primary care centre incidence of PPH (45% in the misoprostol and 51% in the control group) and severe PPH (8% in the misoprostol and 17% control group) is so much higher. In trying to understand this, could the authors tell us what percent of women (with and without PPH and severe PPH) in each study group received oxytocin in the second and the third stage of labour? Did any women receive oxytocin for treatment of PPH? And what percent of women in each group with and without PPH and severe PPH had episiotomies? Also, we would like to understand why Figure 1 indicates higher incidence of heavy blood loss in the misoprostol than control group, whereas the categorical data in Table 3 reflect the opposite? Finally, as with our study, the one maternal death occurred in the misoprostol group. Perhaps it is time to conduct a specific trial that measures the impact of administering misoprostol in the third stage of labour on maternal death as a primary endpoint. We thank the authors in advance for their response. 1 Høj L., Cardoso P., Nielsen B.B., Hvidman L., Nielsen J., Aaby P. Effect of sublingual misoprostol on severe postpartum haemorhhage in a primary health centre in Guinea-Bissau: randomized double blind controlled trial. BMJ 2005;331;723-7. 2 Walraven G, Blum J, Dampha Y, Sowe M, Morison L, Winikoff B, Sloan N. Misoprostol in the management of the third stage of labour in the home delivery setting in rural Gambia; a randomised controlled trial. British Journal of Obstetrics and Gyneacology 2005;112:1277-1283. Competing interests: None declared |
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Deborah A. Armbruster, Director, Prevention of Postpartum Hemorrhage Initiative (POPPHI) Project PATH Washington, DC 20006
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I read your article with great interest and am pleased to see additional research on misoprostol for prevention of postpartum hemorrhage. Under the section, Treatment protocol and consent, you state that the staff at the health centre where the study was conducted included four midwives and one physician. An expatriate midwife joined them and trained them in controlled cord traction. Controlled cord traction is a component of the very effective intervention: active management of the third stage of labor. However, active management of the third stage of labor includes three components: 1)administration of a uterotonic drug (oxytocin 10 IU IM is the drug of choice) after the birth of the baby followed by the 2) use of controlled cord traction; and 3) massage of the uterus after the delivery of the placenta.)1 Were the four midwives and physician trained in and did they use all three components of active management of the third stage of labor during the study? If your staff were trained and did use active management of the third stage of labor (with controlled cord traction as one component) then the amount of blood loss (45% in the misoprostol group and 51% in the control group with blood loss of >500 mL) is a very unusual finding and differs significantly from previous studies using active management of the third stage of labor. (Bristol(2)and Hinchingbrooke(3)trials found 5.9% and 6.8% PPH in the group using active management and 17.9% and 16.5% PPH without the use of active management, respectively.) However, if controlled cord traction was used without prior use of an uterotonic drug then your study may exemplify a concern raised by New Zealand midwives at the recent International Confederation of Midwives Congress held in Brisbane, Australia in July 2005. Their experience suggested that the use of controlled cord traction without the uterotonic drug could increase bleeding and cause additional problems. Thank you. 1. Joint Statement Management of the Third Stage of Labour to Prevent Post-Partum Haemorrhage, International Confederation of Midwives & International Federation of Gynaecologists and Obstetricians. Managing Complications in Pregnancy and Childbirth: A guide for midwives and doctors, WHO/RHR/00.7, 2000 2. Prendiville et al. 1988. The Bristol third stage trial: active versus physiological management of the third stage of labor. BMJ 297:1295–1300. 3. Rogers J et al. 1998. Active versus expectant management of third stage of labour: The Hinchingbrooke randomised controlled trial. Lancet 351(9104): 693–699. Competing interests: None declared |
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A. Metin Gülmezoglu, Scientist HRP/Department of Reproductive Health and Research, WHO, Geneva CH-1211, G. Justus Hofmeyr, Effective Care Research Unit, East London Hospitals Complex, East London, South Africa
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Misoprostol in the third stage of labour and maternal mortality: a review (G. Justus Hofmeyr and A. Metin Gülmezoglu) Introduction We followed the responses following the paper by Høj et al with interest. Misoprostol has strong uterotonic and known pharmacologic effects on several organ systems. Pharmacologic effects other than on the uterus might explain certain inconsistencies, such as the observation that misoprostol labour induction is associated with an increased rate of postpartum haemorrhage(1). Pharmacologic effects include inhibition of platelet-activating factor, gastrointestinal protection against nonsteroidal drug effects, irradiation injury, experimental gastric cancer, enteropathy and constipation; inhibition of leukocyte adherence and modulation of adhesion molecule expression; improved nutrient absorption in cystic fibrosis; reduced cholesterol and severity of peripheral vascular diseases; prolonged survival of cardiac and kidney transplantation; cyclosporine synergy; effectiveness in acetaminophen and ethanol hepatotoxicity, hepatitis and fibrosis, drug-induced renal damage, interstitial cystitis, lupus nephritis, hepatorenal syndrome, periodontal disease and dental repair; enhanced glycosaminoglycan synthesis in cartilage after injury; prevention of ultraviolet-induced cataracts; reduced intraocular pressure in glaucoma and ocular hypertension; synergism with the anti-inflammatory and analgesic effects of diclofenac or colchicines; reduced chemotherapy-induced hair loss; reduced recovery time from burn injury; and effectiveness in treating sepsis, multiple sclerosis and pancreatitis (2). It is plausible that a drug with ubiquitous pharmacologic effects might have unexpected adverse effects when used in the third stage of labour. For the above reasons, we reviewed maternal mortality in randomised trials of misoprostol used in the third stage of labour. We searched The Cochrane Controlled Trials Register and the electronic data base Pubmed/Medline were searched on the word ‘misoprostol’ in December 2005 for randomised comparisons of misoprostol used for the prevention or treatment of postpartum haemorrhage, with placebo or alternative methods (usually injectable uterotonics). We identified 32 prevention and three treatment trials of postpartum haemorrhage where misoprostol was used as one of the interventions. Of the 32 prevention trials 24 made no reference to maternal deaths. While it is unlikely that maternal deaths would not have been reported had they occurred, we have included only those trials in which the presence or absence of maternal deaths was explicit, or has been confirmed by communication with trial authors in the meta-analysis. Differences were expressed as relative risks, with 95% confidence intervals. Results Of 10 deaths reported in 11 trials (23 803 women), 8 occurred in women receiving misoprostol (relative risk 2.71, 95% confidence interval 0.80 to 9.2). In 24 trials no mention of maternal deaths was made. Discussion The primary motivation for the use of misoprostol in the third stage of labour is to reduce maternal mortality. Because mortality is such a rare outcome, no trials to date have been designed to assess the effect on mortality. However, the occurrence of several deaths in trials in women receiving misoprostol has raised concern. The limitations of this quick review must be emphasised. Firstly, the numbers are small with wide confidence limits, and are consistent, at the 95% confidence level, with anything between a modest reduction and a large increase in maternal mortality with misoprostol. Secondly, this was a post -hoc analysis in response to an observed clustering of maternal deaths, and the statistical calculations need to be interpreted with circumspection. These results should not be construed as evidence of an adverse effect of misoprostol on maternal mortality. On the basis of the results we propose, for further investigation, the hypothesis that misoprostol may have an as yet unexplained adverse effect on maternal homoeostatic functions in the third stage of labour. Conclusions Because of the enormous potential benefits of an effective, orally active third stage uterotonic, and the likelihood that misoprostol will be used on a large scale worldwide, further research is essential to measure the possible beneficial and harmful effects of misoprostol more accurately. Enthusiasm for the use of misoprostol should not detract from international efforts to ensure access for all childbearing women to established, effective and safe uterotonics such as oxytocin. References 1. Hofmeyr GJ. Induction of labour with misoprostol. Curr Opin Obstet Gynecol. 2001;13:577-81 2. Davies NM, Longstreth J, Jamali F. Misoprostol therapeutics revisited. Pharmacotherapy 2001; 21: 60-73. Competing interests: None declared |
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