Jump to navigation. In low- and middle-income countries, postpartum haemorrhage is a major cause of maternal deaths and ill health. In high-income countries, the problems are much less but there is still a small risk of major bleeding problems for women after giving birth. Active management of the third stage of labour, which is generally used to reduce blood loss at birth, consists of giving the mother a drug that helps the uterus to contract, early cord clamping and controlled cord traction to deliver the placenta. Different drugs have been tried and generally either intramuscular oxytocin or intramuscular syntometrine is given.
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Metrics details. Postpartum haemorrhage PPH is the leading cause of maternal mortality in low-income countries and is a significant contributor to severe maternal morbidity and long-term disability. Carbetocin may be an underused uterotonic for prevention of PPH.
A number of studies are being conducted that may challenge the place of oxytocin as the first choice of uterotonics for prevention of PPH.
This paper describes the current research into carbetocin and ranking of effectiveness of uterotonics that may provide important new information to assist healthcare decision makers to ensure that women receive an effective uterotonic for prevention of PPH.
We searched the WHO International Clinical Trials Registry Platform for current studies on effectiveness of carbetocin for prevention of PPH following vaginal delivery with sample sizes large enough to provide quality evidence to support potential changes to international guidelines.
We also searched the Cochrane Library for current systematic reviews including carbetocin used in prevention of PPH. Susceptibility to degradation from exposure to heat is one of the key causes of reduced effectiveness of oxytocin in preventing PPH from uterine atony.
Although heat stable and effective in preventing PPH, misoprostol is also subject to degradation due to exposure to moisture and produces some side-effects. Other uterotonics including ergometrine and combinations of oxytocin, ergometrine and misoprostol are also available and used with varying safety and effectiveness profiles and quality issues. Efforts to reduce maternal mortality from PPH include research studies seeking to identify safe, stable, effective uterotonics.
Heat stable carbetocin is the subject of two major clinical studies into its effectiveness in preventing PPH following vaginal deliveries, information that could expand its application for prevention of PPH. Heat stable carbetocin is being investigated as a potential alternative to oxytocin.
This paper describes two current clinical trials on carbetocin and a network meta-analysis ranking of all uterotonic agents, including carbetocin, which combined may provide evidence supporting expansion of the use of the heat stable formulation of carbetocin in PPH prevention. Postpartum haemorrhage PPH is the leading cause of maternal mortality in low-income countries [ 1 ] and is a significant contributor to severe maternal morbidity and long-term disability, as well as to a number of other severe maternal conditions, generally associated with more substantial blood loss, including severe anaemia, cardiac failure and sepsis.
AMTSL as a prophylactic intervention is composed of a package of three components or steps: 1 administration of a uterotonic, preferably oxytocin, immediately after birth of the baby; 2 controlled cord traction CCT to deliver the placenta; and 3 massage of the uterine fundus after the placenta is delivered [ 2 ]. The administration of a uterotonic to the mother immediately after the birth of the baby is identified as the most important step [ 2 ]. Oxytocin is the recommended uterotonic where its efficacy can be assured.
The effectiveness of uterotonics in generating the uterine contractions necessary to prevent haemorrhage can be impaired through exposure to conditions that cause the uterotonic to degrade. In many low- and middle-income countries where access to sustained cold-chain is unavailable, the efficacy of oxytocin cannot be assured because it is susceptible to heat degradation [ 3 , 4 ].
Ergometrine degrades when exposed to heat or light [ 3 ]. Misoprostol degrades rapidly when exposed to moisture [ 5 ]. When degraded, the level of active ingredient is decreased, resulting in reduced effectiveness. Carbetocin has been widely used for prevention of PPH since [ 6 ]. In countries where cold chain is unreliable or not available, a safe and stable uterotonic could contribute to reduction of maternal mortality from PPH.
This is due primarily to the lack of evidence on its effectiveness in prevention of PPH following vaginal deliveries. The global health community has long sought an effective uterotonic for prevention of PPH that withstands degradation. The objective of this research paper is to highlight studies into heat stable carbetocin, a molecule which may be sufficiently clinically effective and structurally stable to be included in the list of recommended uterotonics for prevention of PPH.
In , results of two major clinical trials on the effectiveness of carbetocin in prevention of PPH following vaginal deliveries will be published:. Sample size 30, women [ 7 ]. Sample size women [ 8 ]. We also identified a systematic review ranking all uterotonics on the basis of effectiveness and side-effects:.
Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis — Cochrane Review [ 9 ]. These three studies will provide the evidence needed to include heat stable carbetocin in global recommendations and respond to the need for additional options for the prevention of PPH.
Globally, access to effective uterotonics remains a key barrier to reducing maternal mortality. In , the UN Commission on Life Saving Medicines [ 10 ] reported on the quality of 13 reproductive and maternal health medicines, highlighting serious quality problems in uterotonics across low and middle-income countries.
In , the Quality of oxytocin available in low- and middle-income countries: a systematic review of the literature , published in BJOG found that across the literature reviewed, on average In this study, titled Quality medicines in maternal health: results of oxytocin, misoprostol, magnesium sulfate and calcium gluconate quality audits, the researchers found that Additional activities focussed on highlighting the need for action on improving the quality and effectiveness of uterotonics for prevention of postpartum haemorrhage include the October Technical Consultation on Messaging for Management of Oxytocin organised by the USAID Global Health Supply Chain Program in collaboration with the Reproductive Health Supplies Coalition.
The meeting report, A Current Review of Evidence will be available online in March and will be followed by an in-depth review of the evidence on oxytocin quality. While effort is going into improving the quality of oxytocin including advocacy, manufacturing quality improvements, regulatory strengthening and supply chain and storage improvements, research is being conducted into whether heat stable carbetocin is an underutilized option for prevention of PPH.
Following are summaries of the current major research activities on effectiveness of carbetocin for prevention of PPH and how they could influence guidelines and practices. Uterine atony is the principle cause of PPH. Administration of an effective uterotonic after delivery of the baby has been demonstrated to reduce PPH caused by uterine atony.
The majority of deaths due to PPH could be avoided through the use of prophylactic uterotonics during the third stage of labour [ 7 ]. Carbetocin, widely used for the prevention of PPH following caesarean section, is a more stable molecule [ 6 ] and induces a prolonged uterine response, when administered postpartum [ 15 ].
A manufacturer of carbetocin has developed a stable formulation heat stable carbetocin, previously referred to as carbetocin RTS which makes it a potential option for countries where maintaining the cold chain is problematic [ 6 , 16 ].
A total of 29, participants were enrolled globally. The blinding of the trial required that both products were refrigerated, although the heat stable carbetocin compound was used. This trial was conducted by the WHO, who completed enrolment at the end of January and who are currently analysing data and preparing the results. The trial is part of a broader collaboration involving regulatory, advocacy and manufacturing activities between Merck for Mothers MSD for Mothers outside the USA and Canada , Ferring Pharmaceuticals and the World Health Organization WHO to make heat stable carbetocin accessible, pending trial results, in the public sector of low and lower-middle income countries at an affordable and sustainable price.
All products were refrigerated for this trial to preserve blinding. Studies in the use of carbetocin following caesarean section have demonstrated effectiveness in prevention of PPH and a safety and side-effects profile similar to oxytocin [ 17 ]. No studies have directly compared all three medicines or compared their overall cost.
The investigators planned to recruit women, in four maternity units in the United Kingdom, with recruitment ending in Investigators will perform an analysis of cost effectiveness once all results are available.
The results of this trial will provide additional support for any changes to international guidelines. The objective of the Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis is to assess the clinical effectiveness and side-effect profile of uterotonic drugs to prevent PPH and to generate a clinically useful ranking of available uterotonics according to their effectiveness and side-effects [ 9 ].
A scientifically rigorous ranking could reduce uncertainty about which is the most effective drug for preventing PPH. All uterotonic drugs used for prevention of PPH have been compared with each other including oxytocin, misoprostol, ergometrine, carbetocin, oxytocin plus misoprostol, oxytocin plus ergometrine and placebo or no-treatment.
The interventions considered were uterotonics administered by healthcare providers during the third stage of labour for preventing PPH compared with a control uterotonic or with placebo or no treatment. The targeted population was women having a vaginal birth or a caesarean section in hospitals or community settings. Carbetocin had the most favourable side-effect profile amongst the top three options. The carbetocin evidence came from small studies.
The authors plan to update the study when the two major carbetocin study results are published. The network meta-analysis and the forthcoming update are of particular value in providing information on the relative effectiveness and side-effects of uterotonics whether they have been directly compared in a clinical trial or not, and will therefore assist decision makers and clinicians in determining the best option for particular patient populations.
Heat Stable Carbetocin is being investigated as a potential alternative to oxytocin and is the subject of two large clinical trials for use in prevention of PPH in vaginal deliveries. In this discussion, we provided an overview of the two clinical trials on heat stable carbetocin and the meta-analysis ranking of all uterotonic agents, including carbetocin.
The WHO trial Heat stable carbetocin for prevention of PPH is the largest trial ever conducted on uterotonics for prevention of PPH and is clearly designed to support guideline changes.
Governments and clinicians may have an option to assist in the prevention of maternal mortality resulting from preventable PPH that is heat stable and therefore more effective at the time of use in setting where cold chain is not reliable. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health.
WHO recommendations for the prevention and treatment of postpartum haemorrhage. Geneva: World Health Organization; Google Scholar. Stability of injectable oxytocics in tropical climates: WHO report; Cumulative effects of heat exposure and storage conditions of oxytocin-in-Uniject in rural Ghana: implications for scale up.
Global Health Sci Pract. Quality of misoprostol products. WHO Drug Inf. Development and stability of a heat-stable formulation of carbetocin for the prevention of postpartum haemorrhage for use in low and middle-income countries. J Pep Sci. Room temperature stable carbetocin for the prevention of postpartum haemorrhage during the third stage of labour in women delivering vaginally: study protocol for a randomized controlled trial.
Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis. Cochrane Database Syst Rev. Survey of the quality of medicines identified by the United Nations Commission on life-saving Commodities for Women and Children. Quality of oxytocin available in low- and middle-income countries: a systematic review of the literature. Quality medicines in maternal health: results of oxytocin, misoprostol, magnesium sulfate and calcium gluconate quality audits.
BMC Pregnancy Childbirth. Oxytocin: adopted text for the international pharmacopoeia: final text for addition to the international pharmacopoeia June Effect of carbetocin, a long-acting oxytocin analog on the postpartum uterus. Clin Pharmacol Ther. Carbetocin for preventing postpartum haemorrhage. Download references. FJT and LC drafted the original manuscript. All authors reviewed, provided feedback, and approved the final manuscript. Correspondence to Fiona J. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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WHO updates guidance to help healthcare workers prevent postpartum haemorrhage
Metrics details. Postpartum haemorrhage PPH is the leading cause of maternal mortality in low-income countries and is a significant contributor to severe maternal morbidity and long-term disability. Carbetocin may be an underused uterotonic for prevention of PPH. A number of studies are being conducted that may challenge the place of oxytocin as the first choice of uterotonics for prevention of PPH.
Carbetocin for preventing postpartum haemorrhage
Postpartum hemorrhage PPH is defined as blood loss of at least ml or more after vaginal delivery and ml or more after abdominal delivery. PPH can be prevented by doing routine use of uterotonic agents in active management of third stage of labour. Uterotonic agents that currently available are oxytocin, carbetocin, methylergometrine, syntometrine, misoprostol and carboprost. Carbetocin a long-acting synthetic analogue of oxytocin is a new drug which has stronger ability to induce uterine contraction than oxytocin. It does not induce hypertension like methylergometrine and syntometrine.