Despite the debate about the best dose, oxytocin still has its place in childbirth
In our latest article on landmark drugs, Jenny Bryan looks at the history of oxytocin and finds out why this drug will not be disappearing from practice anytime soon
Most British women who have given birth in the UK in the past 50 years will have had this month’s landmark drug — oxytocin — during labour or after delivery. Yet, despite the fact that oxytocin has been available since the late 1950s, there is continuing debate over the best dose for women who have delivered by caesarean section.
“Oxytocin has been vital in preventing post-partum haemorrhage (PPH) all over the world and in reducing maternal mortality following childbirth. But there is still a need for clinical trials to find out whether it is safe to use lower doses following caesarean section in order to reduce side effects, without jeopardising the benefits of oxytocin on PPH,” explains Nicola Weale, from the North Bristol NHS Trust, Southmead Hospital, Bristol.
Oxytocin was not the first agent to be used to help speed up labour. Doctors and midwives used a liquid preparation of fungus ergot found on the ears of rye to help speed up labour or cause miscarriage from medieval times, and ergot alkaloids were extensively investigated in the early part of the 20th century.1
But the discovery and development of oxytocin permanently changed obstetric practice.
From pituitary extract to synthesis
The stimulatory effects of pituitary extract on uterine contraction were described by Sir Henry Dale at the Wellcome Physiological Research Laboratories in south east London in 1909.2
The substance, which came to be known as oxytocin (from the Greek for “quick birth”), was separated from other pituitary fractions in 1919.3 But it was not until the early 1950s that US biochemist Vincent du Vigneaud and colleagues established the structure of oxytocin and then synthesised it in the laboratory.4 Du Vigneaud was rewarded with the Nobel Prize for Chemistry in 1955.
Oxytocin was the first polypeptide hormone to be synthesised,5 and subsequent studies showed that a synthetic formulation (Syntocinon) developed by Sandoz (now part of Novartis) had the same effects as the natural hormone on the uterus of women undergoing therapeutic abortion or childbirth.6,7
Oxytocin proves its worth
Before the synthesis of oxytocin, doctors wanting to speed up labour used pituitary extract or ergometrine, an ergot alkaloid, discovered in 1935. But it was still common practice for women to deliver the placenta without therapeutic intervention in the 1950s.
This changed when it became clear that using an oxytocic agent during the third stage of labour (delivery of the placenta) could reduce PPH, and intramuscular ergometrine was advocated until synthetic oxytocin became widely available.8
However, since oxytocin is short acting, obstetricians were concerned at the potential for delayed PPH, and so investigated the benefits of combining oxytocin with ergometrine. An early clinical trial, published in 1963, showed that the risk of PPH with this combination (Syntometrine) was half that seen with ergometrine alone (2.9 per cent versus 6.6 per cent), with a trend towards a shorter third stage, and no difference in the need for manual extraction of the placenta.8
“Intramuscular Syntometrine is used in most vaginal deliveries to contract the uterus and deliver the placenta, except where women have requested passive management of the third stage or have medical contraindications. Its use in developing countries has helped enormously in reducing maternal mortality after childbirth,” says Dr Weale. In the last “Confidential enquiry into maternal deaths in the UK”, five deaths due to PPH were reported for 2006–08.9
But oxytocin is not without drawbacks and it can cause peripheral vasodilation and hypotension, with an accompanying increase in heart rate.
“Most women tolerate it well, but those with underlying cardiovascular disease or who become dehydrated can get into difficulties and two deaths were attributed to oxytocin in the confidential enquiry report of 1997–99,” points out Dr Weale.
It is the dose of oxytocin (without ergometrine) following caesarean delivery that has caused considerable debate. Dr Weale explains that it was the 10IU dose of oxytocin administered in a rapid bolus which was linked to the deaths in the late 1990s and, within 12 months of the data being published, few obstetric anaesthetists were still using the high dose in a rapid bolus.
Guidelines from the Royal College of Obstetricians and Gynaecologists now recommend a 5IU dose administered in a slow bolus, and a recent survey has shown no one using the 10IU dose, and about 5 per cent of respondents using doses under 5IU.10
The move towards low doses follows the results of studies mainly in Canada suggesting that doses, as low as 0.3–3IU of oxytocin, may be sufficient to prevent PPH following caesarean section.11 However, as Dr Weale points out, obstetric practice is different in North America from that in the UK.
“The studies only assessed the effects of the low doses on haemorrhage in theatre, not later in the recovery room, so we don’t know if the doses were high enough to prevent delayed haemorrhage.
In North America, women receive a prophylactic oxytocin infusion after their initial bolus in theatre, but this isn’t routine practice in the UK and is only used in high-risk women,” she says. “Most postnatal wards don’t run oxytocin infusions, so the need to do this routinely would have a significant impact on delivery units in the UK,” she adds.
In a recent editorial, she and colleague Christina Laxton advised that, if oxytocin is used in doses less than 5IU it should be followed by a prophylactic infusion which, in the UK, is generally given over four hours.11
Carbetocin: the newer kid on the block
In recent years, the longer-acting oxytocic carbetocin has been used increasingly as an alternative to oxytocin. With a half-life of around 40 minutes, compared with four to 10 minutes for oxytocin,11 it is a practical alternative in cases where there are concerns about delayed PPH.
A Cochrane review of data from 2,635 women in 11 studies showed that, following caesarean section, there was no difference in PPH rates between carbetocin and oxytocin but a statistically significant reduction in the need for therapeutic uterotonics (an agent used to induce contraction or greater tonicity of the uterus) with carbetocin.12 Following vaginal delivery, carbetocin was associated with less blood loss compared with Syntometrine and with significantly fewer adverse effects.
Dr Weale explains that carbetocin is more expensive than oxytocin but, if it removes the need for prophylactic infusions following low doses of oxytocin, there may be a cost saving. She adds that there is also some evidence that lower doses of carbetocin may be possible.
She concludes: “Oxytocin still has the advantage over carbetocin in that we have 40 years of experience with it and we know that it reduces PPH and saves lives. Oxytocin is also still our first-line agent for labour augmentation and after vaginal delivery, and so it will not be disappearing from our practice.”
Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2014.11134250
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