View from over the drapes: oxytocin at caesarean section and the COPE study

Tuesday 1 September (this article will appear in the November issue of Anaesthesia News)

The dose of oxytocin required for prophylaxis and treatment of postpartum haemorrhage (PPH) at caesarean section has been a recent topic of debate. The Summary of Product Characteristics recommends administering 5 IU oxytocin over 5 min by infusion. While a 5 IU dose given by i.v. bolus is commonly used in the UK, a smaller dose may be adequate. Clinical and laboratory studies conducted by the anaesthetic team in Toronto (largely published in anaesthetic journals) suggest that a dose of 3 IU is adequate, even for those who have already received oxytocin infusions during labour [1, 2]. Furthermore, most anaesthetists will have watched with horror as the blood pressure falls in response to an overenthusiastic oxytocin bolus, and will also know of the maternal deaths thought to be caused by intravenous oxytocin [3]. This has recently led experts to call for a reduction to a 1-3 IU i.v. bolus followed by an infusion of 5-10 IU.h-1 [4].

The obstetrician operating on the other side of the drape, however, often sees things differently. They are brought up to know the terrible history of maternal deaths from PPH, and that, even today, somewhere around the world a woman dies from haemorrhage every 10 min. The use of oxytocin to prevent PPH deaths as part of the active management of the third stage of labour has become a mantra for the safe motherhood movement – obstetricians have spent so many years promoting this to save women’s lives globally that to question it seems almost sacrilegious. Oxytocin is administered by midwives at virtually every birth in the world. Obstetricians rarely see a blood pressure decrease in response to oxytocin, but they do see the obstetric literature reporting the benefit of oxytocin for both prevention and treatment of PPH, and randomised trials showing rates of hypotension equivalent to that of placebo [5, 6]. There is immediate biofeedback after oxytocin injection, with rapid uterine contraction and cessation of bleeding. Obstetricians further point to the questionable validity of obstetrician-reported contractions as an outcome for dosage studies [1], as spontaneous rhythmic postpartum contractions occur with or without prophylaxis. Guidelines from NICE and the WHO both recommend 10 IU intravenous oxytocin for PPH, and give little indication as to the speed at which it should be given [7, 8].

So how can the two sides, separated by just a thin piece of paper drape, have evolved such different strategies for PPH treatment? Most would accept that the two specialities attract different types of people; the contrasting stereotypes of agricultural obstetricians and cautious, risk averse anaesthetists are not completely without basis. But are not our interests both focused on safety and care for the woman? Do we never meet in coffee rooms, or discuss these issues in committees? 

The COPE study (ISRCTN16416766) is a randomised trial comparing the effectiveness of carboprost or oxytocin for the first line treatment of PPH. The aim is to recruit 4000 women in 40 UK maternity units with active bleeding for any reason after birth, whether placenta praevia, emergency caesarean, retained placenta or forceps/ vacuum – in fact, any woman in whom oxytocin would normally be given as part of treatment for PPH. The primary outcome is the need for blood transfusion. After long delays in obtaining a placebo match for the carboprost, the study is finally ready to start in September 2020. With the initial study protocol largely developed by obstetricians, we had planned to administer oxytocin as a 10 IU i.v. bolus at both vaginal deliveries and caesarean section. 

However, during site initiation visits, it became clear that there was considerable disquiet amongst the anaesthetic community about this relatively large dose. Those of us writing the protocol pointed to the safety literature, and argued that a high dose was necessary to reflect standard obstetric practice; furthermore, if the study showed oxytocin to be less effective than expected, we wanted to protect the study results against an accusation that we had used too low a dose. Conversely, anaesthetic colleagues argued that not only was a 10 IU bolus unnecessary and unsafe, but was also completely out of line with anaesthetic practice, making it meaningless as a pragmatic control.

The final solution for COPE was to protocolise two separate doses according to ‘usual practice’: the obstetricians would use 10 IU i.v. over 2 min for vaginal births, whilst the anaesthetists would give 5 IU to those having caesarean section. The argument is that those having a caesarean are more likely to have excessive blood loss and to have spinal anaesthesia-related hypotension. In both circumstances, the study training in all 40 maternity recruitment sites would stress the need for injection over at least 2 min, and dilution in 10 ml saline to facilitate this. This would aim to sensitise obstetricians and midwives to the hypotensive effects of oxytocin, whilst retaining ‘normal practice’ control arms.

So, if you are running COPE in your maternity unit, give some thought to the way in which the protocol has been adjusted to reflect normal practice. And if you’re not (and why not?), then this story provides lessons on how working in silos can lead to the evolution of markedly different care pathways for the same problem. Drug safety and efficacy are both critical features of clinical pharmacology, and a focus on either in isolation is unhelpful: real progress is best achieved when we consider both of these to achieve the optimum final outcome. 

Professor Andrew D. Weeks on behalf of the COPE Study Team

Professor of International Maternal Health

University of Liverpool

Twitter: @adweeks

References

1. Balki M, Ronayne M, Davies S, et al. Minimum oxytocin dose requirement after cesarean delivery for labor arrest. Obstetrics and Gynecology 2006; 107: 45-50. 

2. Drew T, Balki M. What does basic science tell us about the use of uterotonics? Best Practice and Research Clinical Obstetrics and Gynaecology 2019; 61: 3-14. 

3. Why Mothers Die 1997–99. Report on Confidential Enquiries into Maternal Deaths in the United Kingdom. London: Royal College of Obstetricians & Gynaecologists, 2001.

4. Heesen M, Carvalho B, Carvalho JCA, et al. International consensus statement on the use of uterotonic agents during caesarean section. Anaesthesia 2019; 74: 1305-19. 

5. Adnan N, Conlan-Trant R, McCormick C, Boland F, Murphy DJ. Intramuscular versus intravenous oxytocin to prevent postpartum haemorrhage at vaginal delivery: randomised controlled trial. British Medical Journal 2018; 362: k3546.

6. Charles D, Anger H, Dabash R, et al. Intramuscular injection, intravenous infusion, and intravenous bolus of oxytocin in the third stage of labor for prevention of postpartum hemorrhage: a three-arm randomized control trial. BMC Pregnancy and Childbirth 2019; 19: 38. 

7. National Institute for Health and Care Excellence. Intrapartum care for healthy women and babies. Clinical guideline [CG190], 2017 https://www.nice.org.uk/guidance/cg190 (accessed 30/7/2020). 

8. Vogel JP, Williams M, Gallos I, Althabe F, Oladapo OT. WHO recommendations on uterotonics for postpartum haemorrhage prevention: what works, and which one? BMJ Global Health 2019; 4: e001466.