Which type of medication is used to decrease excessive bleeding and uterine atony

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Gallos I, Williams H, Price M, et al. Uterotonic drugs to prevent postpartum haemorrhage: a network meta-analysis. Southampton (UK): NIHR Journals Library; 2019 Feb. (Health Technology Assessment, No. 23.9.)

Chapter 1Background

Existing knowledge

Postpartum haemorrhage

An estimated 289,000 women worldwide died during childbirth in 2013.1 Postpartum haemorrhage (PPH) is the leading direct cause of maternal death worldwide, accounting for up to one-third of all maternal deaths.2 PPH is very common, affecting 1 in 10 women at childbirth in Europe and 67,000 women in England alone every year.3,4 In the UK, death from PPH is usually averted, but it remains an important cause of severe morbidity (e.g. when receiving a blood transfusion) and surgery, including hysterectomy.5

The third stage of labour, defined as the period of time from birth until the birth of the placenta, and the immediate postpartum period are the most hazardous phases of childbirth because of the risk of PPH. The World Health Organization (WHO) defines PPH as blood loss exceeding 500 ml in the first 24 hours after birth.6 Though healthy women can physiologically adapt to this amount of blood loss, for women with a coexisting disease, such as anaemia, it can cause considerable morbidity and mortality. The primary cause of PPH, as defined by WHO, is uterine atony, which accounts for 75% of cases.7 Even though risk factors for adverse maternal outcomes from severe haemorrhage have been identified,8 PPH is often unpredictable because it occurs in the absence of identifiable clinical or historical risk factors.9 Therefore, effective prevention of PPH is advocated for all women during childbirth.6 The routine administration of uterotonic drugs during the third stage of labour is a key intervention that prevents PPH, although there is uncertainty about which drug may be the most effective.

Uterotonic drugs

The active management of the third stage of labour refers to a package of interventions. The administration of uterotonic drugs to prevent PPH is the main intervention within this package and can prevent two-thirds of PPH.6,10 Uterotonics are also essential for the treatment of PPH, but treatment is not the focus of this review.

Several different uterotonic drugs have been used for preventing PPH. These drugs include ergometrine, misoprostol (Cytotec®; Pfizer Inc., New York, NY, USA), misoprostol plus oxytocin (Syntocinon®; Novartis International AG, Basel, Switzerland), carbetocin (Pabal®; Ferring Pharmaceuticals, Saint-Prex, Switzerland), ergometrine plus oxytocin and oxytocin when used alone.

Oxytocin

Oxytocin is the most widely used uterotonic drug. At low doses, it produces rhythmic uterine contractions that are indistinguishable in frequency, force and duration from those observed during spontaneous labour; however, at higher dosages, it causes sustained tetanic uterine contractions.11 It has a short half-life, approximately 3–5 minutes, and can be used as an infusion to maintain uterine contraction. When used intramuscularly, the latent phase lasts 2–5 minutes, but the uterine activity can last 2–3 hours.11 However, oxytocin cannot be used orally. Oxytocin is unstable at room temperature and it requires cold storage and transport. It cannot be given intravenously as a large bolus, because it can cause severe hypotension.12 Owing to its antidiuretic effect, water intoxication can occur with prolonged infusion of oxytocin.11 Oxytocin has a favourable side-effect profile for common side effects, such as nausea and vomiting, but the evidence is scarce.13

Ergometrine

Ergometrine and methylergometrine are ergot alkaloids that increase the uterine muscle tone by causing continuous tetanic contractions. It takes 2–5 minutes after intramuscular injection for the drug to become effective and the plasma half-life is 30–120 minutes.14 However, ergometrine and methylergometrine are unstable in heat and cannot be used orally.15 They are vasoconstrictive and increase the risk of hypertension post partum.16 Other side effects with ergot alkaloids are pain after birth, nausea and vomiting.16

Misoprostol

Misoprostol is a prostaglandin E1 analogue that is licensed for the prevention and treatment of gastric ulcers. It is widely used off-label as a uterotonic agent.17 It is water soluble and heat stable.18 It takes 9–15 minutes after sublingual, oral, vaginal and rectal use for the drug to be effective. The half-life is about 20–40 minutes. Oral and sublingual routes have the advantage of rapid onset of action, whereas the vaginal and rectal routes result in prolonged activity and greater bioavailability.19 However, misoprostol is associated with side effects, such as diarrhoea, abdominal pain, nausea and vomiting, shivering and pyrexia.17

Carbetocin

Carbetocin is a newer long-acting synthetic analogue of oxytocin with agonist properties. After intravenous injection, it produces tetanic uterine contractions within 2 minutes, lasting for approximately 6 minutes followed by rhythmic contractions for 60 minutes.20 When carbetocin is administered by an intramuscular injection the tetanic contractions last for approximately 11 minutes and the rhythmic contractions for 120 minutes.20 Carbetocin is heat stable and the side-effect profile appears to be similar to oxytocin.21

Combinations of uterotonic drugs

The use of combinations of uterotonic drugs is also popular and the most commonly used preparation is oxytocin plus ergometrine. This combination is suggested to be associated with a statistically significant reduction of PPH blood loss of ≥ 500 ml when compared with oxytocin alone, attributable to the additive ergometrine effect.22 Another combination is oxytocin plus misoprostol, which is also found to be associated with a small reduction in PPH blood loss of ≥ 500 ml.17 However, both these combinations are associated with significant side effects and, despite the small difference in PPH, there is no difference found for severe PPH when compared with oxytocin. This has led the WHO to recommend oxytocin over these combinations.6

The WHO recommends that all women giving birth should be offered uterotonics during the third stage of labour for the prevention of PPH; oxytocin [given intramuscularly/intravenously at a dose of 10 international units (IU)] is the uterotonic drug of choice.6 Other injectable uterotonics and misoprostol are recommended as alternatives for the prevention of PPH in settings where oxytocin is not available.

Costs to the National Health Service

Treatment of PPH costs the NHS £32–180M per year. The National Institute for Health and Care Excellence (NICE) recently estimated the costs of treating PPH to be between £488 and £2700 for each woman, depending on the severity of PPH.23 Treating PPH also has societal implications, as it can reduce economic productivity by causing physical disability or a psychological burden to parents and families. A relative risk reduction of 34% in PPH occurrence can represent a saving of £10–60M per year for the NHS, with important benefits for public health.

Existing research

Before conducting the search through Cochrane, a scoping literature search was conducted for trials and reviews of the use of uterotonics for preventing PPH. The databases MEDLINE, EMBASE, Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, ISI Proceedings, ISRCTN Register and metaRegister of Current Controlled Trials were searched from the respective database inception to July 2014. The search terms aimed to capture trials assessing the effectiveness of uterotonic drugs to prevent PPH include ‘post-partum period of haemorrhage’, ‘third stage of labour’, ‘caesarean section’ and ‘obstetric delivery’ AND (‘Oxytocin’, ‘misoprostol’, ‘ergometrine’, ‘syntometrine’, ‘carbetocin’ and ‘prostaglandins’). The scoping literature search had identified 445 randomised trials that could be eligible for inclusion in the network meta-analysis (NMA). There were five separate Cochrane reviews,13,16,17,21,22 including an aggregate total of 115 trials and 77,447 participants, that have compared a uterotonic drug against another or with a placebo or no treatment. These meta-analyses were suggesting that oxytocin plus ergometrine [odds ratio (OR) 0.82, 95% confidence interval (CI) 0.71 to 0.95], oxytocin plus misoprostol [risk ratio (RR) 0.71, 95% CI 0.53 to 0.95] and carbetocin (RR 0.66, 95% CI 0.42 to 1.06) may be more effective than oxytocin in preventing PPH. The Cochrane reviews were pairwise meta-analyses and, therefore, could only compare two drugs that have been compared directly in head-to-head trials (direct evidence), did not make use of the large amount of indirect evidence available and could not always be used for drawing inferences across all the possible comparisons. In the absence of a single randomised controlled trial comparing all uterotonic drugs, uncertainty remained over their relative effectiveness and ranking.

The existing Cochrane reviews were also becoming out of date. In total, 58 new trials (n = 22,071 participants) were identified that could be eligible for inclusion in these reviews and 43 active randomised trials (n = 63,326 participants) due for completion before the end of 2015 (Table 1). These were assessed for inclusion in the NMA in addition to the existing evidence (see Figure 1).

TABLE 1

Cochrane reviews comparing uterotonic drugs for preventing PPH

A systematic review and a NMA were performed synthesising all available, up-to-date direct and indirect evidence of relative treatment effects in a single coherent analysis for all uterotonic drugs. Indirect evidence is obtained when the relative effectiveness of two competing drugs is inferred through a common comparator, even though this pair may not have been compared directly.24 The NMA aimed to provide robust estimates or relative effectiveness, side-effect profile and the relative ranking for each uterotonic drug with a model-based economic evaluation.

Objectives

Primary

To identify the most effective and cost-effective uterotonic drug(s) to prevent PPH, and to generate a clinically useful ranking of available uterotonics according to their effectiveness.

Secondary

1. To provide the relative effectiveness and side-effect profile of each drug for the primary outcomes within (1) treatment subgroups (different dosages and regimens and routes of administration of each uterotonic drug), and (2) population subgroups (prior risk of PPH, mode of birth and health-care setting).

2. To produce effectiveness and side-effect hierarchies of all uterotonic drugs considered, and to estimate the probability that each drug is the best for each outcome.

3. To evaluate the cost-effectiveness for each drug for preventing PPH overall and in the subgroups defined earlier in the UK.

Copyright © Queen’s Printer and Controller of HMSO 2019. This work was produced by Gallos et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

Bookshelf ID: NBK537857

Which type of medication is used to decrease excessive bleeding and uterine atony in the postpartum client?

Which of the following medications are used during postpartum hemorrhage due to uterine atony?

How is uterine atony treated?

Which medication is used to treat a patient with atonic uterus?