Place of carbetocin in HK’s evolving postpartum haemorrhage landscape

PPH incidence on the rise
In Hong Kong, the incidence of pri­mary PPH (≥500 mL within 24 hours af­ter delivery) is reported to have increased from 5–10 percent in the last decade to >10 percent in the 2020s, and is further increasing. [Hospital Authority Clinical Data Analysis and Reporting System (CDARS)]

“Several factors are at play,” explained Leung. “Computerization of medical re­cords and improved coding allow for more reliable reporting of PPH. In addition, in re­cent years, awareness of PPH has been growing and the culture within the health­care system is gradually shifting towards greater openness, acceptance and learn­ing. Finally, maternal risk factors, such as age, in particular, and increasing rates of Caesarean-section [C-section] deliveries contribute to rising PPH incidence.” [Hong Kong Medical Diary 2019;24:2-3; J Matern Fetal Neonatal Med 2014;27:243-246]

Current PPH management landscape
Uterine atony is the most common cause of PPH. [WHO recommendations for the prevention and treatment of postpar­tum haemorrhage, 2012] Routine prophy­lactic use of uterotonic drugs can reduce the risk of PPH by 50 percent in the overall obstetric population. [Cochrane Database Syst Rev 2013;doi:10.1002/14651858. CD001808.pub2]

“Universal prophylaxis minimizes PPH risk and, as a result, may help to promote a positive experience of childbirth. This is particularly relevant in Hong Kong, as local birth rate is low and has been in decline for several years,” remarked Leung. [Hong Kong Monthly Digest of Statistics, 2023: Fertility Trend in Hong Kong, 1991–2021]

Four uterotonics are currently licensed for PPH prophylaxis or treatment in Hong Kong: synthetic oxytocin (SO), fixed-dose combination (FDC) of SO with ergometrine, carboprost, and carbetocin.

SO structurally resembles natural oxytocin and is the most widely used oxytocic. It has an immediate onset of action. Due to its short biological half-life, SO needs to be adminis­tered as a continuous intravenous (IV) infusion for sustained effect. Compared with placebo, SO provides >40 percent reductions in risk of PPH >500 mL (risk ratio [RR], 0.53; 95 per­cent confidence interval [CI], 0.38–0.74) and the need for therapeutic uterotonics (RR, 0.56; 95 percent CI, 0.36–0.87). [Cochrane Database Syst Rev 2013;doi:10.1002/14651858. CD001808.pub2]

As a synthetic version of a natural hormone, SO carries minimal contraindi­cations. It is associated with a <3 percent risk of tachycardia and hypotension, but caution should be exercised in cases of massive PPH as the patient may already be in a state of hypovolaemia. [Hong Kong Medical Diary 2019;24:4-5]

The SO/ergometrine FDC is easily administered via intramuscular (IM) injection. Its uterotonic effect sets in 3 minutes and lasts 3 hours. The FDC is associated with a significantly lower rate of PPH of ≥500 mL but also a greater incidence of side effects vs SO alone. [Cochrane Database Syst Rev 2018;doi:10.1002/14651858.CD005456. pub3] The FDC's PPH risk reduction does not appear to translate to blood loss of >1,000 mL, where no significant differ­ence was seen vs SO. [Br Paramed J 2019;3:15-22] Due to the ergometrine component, this FDC may increase blood pressure and precipitate headache and vomiting. [Cochrane Database Syst Rev 2018;doi:10.1002/14651858.CD011689. pub3] It is contraindicated in patients with valvular heart disease and severe hyperten­sion, which are not uncommon in the mod­ern obstetric population. [Anesthesiol Clin 2017;35:207-219]

Carboprost is a synthetic prostaglandin analogue of PGF2α, which can be admin­istered as an IM or intramyometrial injection for treatment of PPH refractory to conven­tional oxytocics and/or ergometrine. It is not intended for prophylactic use and is con­traindicated in patients with active cardiac, pulmonary (including significant history of asthma), renal or hepatic disease.

Carbetocin: Advantages, role in HK’s public hospitals
Carbetocin is a synthetic analogue of oxytocin, with enhanced half-life, duration of action and heat stability. [Eur J Obstet Gynecol Reprod Biol 2009;147:15-20] Its side-effect profile is similar to that of SO and more favourable than that of SO plus ergometrine. Carbetocin is contraindicated in mothers with serious cardiovascular dis­orders, epilepsy, and hepatic and renal im­pairment.

Carbetocin is administered as a slow IV injection over 1 minute or as an IM in­jection. The onset of uterine contractions is rapid (within 2 minutes) and sustained (several hours). [Hong Kong Medical Diary 2019;24:4-5] “Sustained contractility is car­betocin’s main advantage over oxytocin,” noted Leung.

Carbetocin is effective in prevention of PPH of ≥1,000 mL and was found to be more effective than oxytocin at preventing PPH of ≥500 mL in a meta-analysis of 140 random­ized trials involving 88,947 women, which compared multiple uterotonics. [Cochrane Database Syst Rev 2018;doi:10.1002/14651858.CD011689.pub3]

“Carbetocin was included in Hospital Au­thority's [HA] Drug Formulary in 2017 and was initially used for prevention of PPH in women undergoing C-section with risk factors, such as twin pregnancy, large fibroids, polyhydramnios, and prolonged induction of labour. Such cases account for approximately 10 percent of all de­liveries,” said Leung.

“Subsequently, HA hospitals extended carbetocin eligibility to vaginal deliveries with risk factors, including multiparity and history of PPH,” he continued. “As research evidence for carbetocin continued to mount, its use became even more widespread. A reasonable next step would be to give carbetocin as PPH prophylax­is for all C-sections and vaginal deliveries with risk factors, which constitute approximately 40 percent of all cases.”

Although carbetocin’s cost per course of PPH prevention is 12–25 times higher than oxytocin's, a study by the Chinese University of Hong Kong (CUHK), which used local data, found carbetocin to be the preferred cost-effective option for PPH pre­vention from a public healthcare perspec­tive. Compared with oxytocin, PPH-related cost with carbetocin was reduced by USD 29 per birth, while incidence of PPH with ≥500 mL and ≥1,500 mL blood loss was reduced by 13.7 cases and 1.9 cases per 1,000 births, respectively. [PLoS One 2022;doi:10.1371/journal.pone.0279130] “Treatment of PPH is more costly than its prevention, requires more manpower, and may entail a stay at an intensive care or high dependency unit,” remarked Leung. “CUHK’s cost-effectiveness study has the potential to serve as a triggering factor for further escalating carbetocin’s use in the public sector.”

Ultimate goal
“While there has been a positive dy­namic in terms of carbetocin’s increasing uptake in the HA since its introduction in 2017, we are yet to achieve the ultimate goal of carbetocin being used as a univer­sal PPH prophylactic in the public sector, irrespective of any risk factors or mode of delivery,” said Leung. “Universal and uniform PPH prophylaxis with carbetocin is desirable, because approximately half of all PPH cases have no discernible risk factors, and some of the less obvious risk factors are easy to miss at a busy public maternity ward.”

“As local data continue to accumulate and as the proportion of deliveries using carbetocin is increasing, we should be able to implement an audit cycle, where improvement in outcomes would lead to universal use of carbetocin, while stagna­tion or reports of negative outcomes would inform reversion to an earlier step of using carbetocin in select cases,” concluded Leung. (Figure)