Dr Andrew D Weeks
It used to be so simple. Every student knew that active management of the third stage consisted of an oxytocic, controlled cord traction, and early clamping of the umbilical cord. But the times they are a’changing.
Umbilical cord clamping
First it was the cord. We realised that the concerns about oxytocin transfer to the neonate were ill founded and that early cord clamping in fact leads to increased rates of anaemia and low iron stores in the neonate. Protocols started to change. The final nail in the coffin came earlier this year with the publication of two well conducted randomised trials showed that in premature infants early cord clamping increased all-cause mortality in the neonate by some 30% (Tarnow-Mordi 2017, Duley 2018).
This makes delaying cord clamping one of the most effective interventions anywhere in health care and those who persist in immediate clamping are at risk of complaints, litigation and censure. Let no-one say that they haven’t been warned!
Controlled cord traction
This aspect also came under scrutiny with a large WHO randomised trial (Gulmezoglu 2012). This found that the effect of controlled called traction (CCT) was minimal. It shortened the duration of the third stage but had no effect on rates of postpartum haemorrhage.
Interestingly though, around 6% of those in the CCT arm still required traction to deliver the placenta. Furthermore, a breach in trial protocol in one of the countries where they used Syntometrine rather than oxytocin for prophylaxis found that the use it Syntometrine without CCT lead to a large increase in retained placenta rates. This association was not seen in sites using oxytocin alone. This adds to earlier suspicions that the use of ergometrine for prophylaxis is not only a cause of significant side-effects to the woman such as high blood pressure and vomiting, but also increases the rate of retained placenta.
Carbetocin, a rather expensive synthetic long-acting version of oxytocin, had been hoped to provide the extended action of ergometrine without the side effects thus making it the ideal oxytocin for prophylaxis. To the disappointment of many however, the recent CHAMPION study has shown that there is absolutely no difference in efficacy between carbetocin and oxytocin (Widmer 2018).
The one potential benefit is that this new version is heat-stable, although it still needs to be given intramuscularly. Thus, there may be a few places where it is possible to give injections but where there is an unstable cold chain - and in these areas it might be cost-effective to use intramuscular carbetocin rather than oxytocin. This will depend however on the manufacturers who are still finalising their price of carbetocin for low resource settings.
Attention has now turned to the ideal way to administer oxytocin. With concerns about the use of ergometrine, and the finding that misoprostol was not as effective as oxytocin, the standard advice had been to use oxytocin 10 international units intramuscularly as first-line prophylaxis. This seemed to be a solution that was both effective and relatively free from side-effects, a factor that is critical when giving prophylaxis to healthy, normal women (the majority of whom will not develop postpartum haemorrhage).
It has always been thought that it did not matter whether oxytocin was given intramuscularly or intravenously. Indeed, one large randomised trial conducted by the WHO in 2003 comparing oxytocin and misoprostol for the prevention of PPH did not even collect data on which was used (Gulmezoglu 2001). To resolve this, a cluster randomised trial was conducted in Turkey. Although it remains unpublished as yet, the presented results suggest that using intravenous oxytocin might be far more effective than the intramuscular equivalent.
The publication of the LabOR trial in the BMJ now confirms that finding (Adnan 2018). Over 1000 women were randomised to receive 10 units of oxytocin either intramuscularly or as a slow intravenous injection, and the findings were clear. The rate of postpartum haemorrhage (as judged by blood loss of 1000 mls) was reduced in the intravenous arm, as was the need for blood transfusion.
There was no difference in side-effects between the two groups. A rapid injection of oxytocin intravenously causes a rapid, transient drop in blood pressure of around 20mmHg and has been implicated in maternal deaths - so it was very reassuring that they saw no such effects in this study.
Subgroup analysis found that the benefits of intravenous oxytocin over intramuscular oxytocin were largely restricted to nulliparous women and those who were induced, groups which also had higher rates of PPH.
So where does this leave us with the AMTSL protocol? It is beyond debate now that the cord clamping should be delayed, whilst CCT is only necessary in the event of a prolonged third stage. It is clear that it is the oxytocic that has the main role in reducing PPH rates. Oxytocin 10iu given slowly intravenously over 1 min seems the best option in those at high risk.
As the LabOR study showed the benefits to be mainly in nulliparous and induced women, a pragmatic arrangement would be to give the intravenous oxytocin to those with a cannula already in situ: those who have been induced or augmented, those at risk because of intrapartum bleeding or multiple pregnancy, and those with epidurals already in situ. Alternatives for those in low resource settings include misoprostol 600 µg (where there is no skilled provider to give an injection), or carbetocin when the cold chain is uneffectual.
An attractive option which is being explored is the use of secondary prevention (where the oxytocic is only given to those whom start to bleed), reducing the number given medication from 100% to about 20-50%. This targeted approach might be good both for the mother and the health systems due to the reduced cost. Further studies are awaited to see whether this delay in prophylaxis has any detrimental effects.
Physiological management remains an option for those at low risk. For whilst oxytocin reduces third stage blood loss, a delay in administration (i.e. giving it as a treatment rather than as prophylaxis) seems to have little effect on the major morbidity or mortality.
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 BMJ 2018; 362 :k3546.
Duley L, Dorling J, Pushpa-Rajah A, Oddie SJ, Yoxall CW, Schoonakker B, et al. Randomised trial of cord clamping and initial stabilisation at very preterm birth. Arch Dis Child Fetal Neonatal Ed. 2018 Jan;103(1):F6-F14.
Gülmezoglu AM, Villar J, Ngoc NT, Piaggio G, Carroli G, Adetoro L, et al. WHO multicentre randomised trial of misoprostol in the management of the third stage of labour. Lancet. 2001 Sep 1;358(9283):689-95.
Gülmezoglu AM, Lumbiganon P, Landoulsi S, Widmer M, Abdel-Aleem H, Festin M, et al. Active management of the third stage of labour with and without controlled cord traction: a randomised, controlled, non-inferiority trial. Lancet. 2012 May 5;379(9827):1721-7.
Tarnow-Mordi W, Morris J, Kirby A, Robledo K, Askie L, Brown R, et al. Delayed versus Immediate Cord Clamping in Preterm Infants. N Engl J Med. 2017 Dec 21;377(25):2445-2455.
Widmer M, Piaggio G, Nguyen TMH, Osoti A, Owa OO, Misra S, et al. Heat-Stable Carbetocin versus Oxytocin to Prevent Hemorrhage after Vaginal Birth. N Engl J Med. 2018 Aug 23;379(8):743-752.