Oxytocin Not Best for Postpartum Hemorrhage Prevention, Study Finds

Postpartum hemorrhage (PPH), defined as maternal blood loss of 500 mL or more within 24 hours after delivery, is the leading cause of maternal mortality worldwide. The World Health Organization (WHO) currently recommends treatment with oxytocin to reduce the risk for excessive postpartum bleeding, but a new meta-analysis suggests that other drug regimens may be more effective.



The meta-analysis included data on more than 88,000 women. Ergometrine plus oxytocin, carbetocin monotherapy, or misoprostol plus oxytocin were all associated with a reduced risk for PPH compared with oxytocin alone, Ioannis D. Gallos, MD, from Tommy's National Center for Miscarriage Research, Institute of Metabolism and Systems Research, University of Birmingham, UK, and colleagues report. Their findings were published online April 25 in the Cochrane Database of Systemic Reviews.

However, the analysis does not include results from two key studies that were ongoing at the time these findings were published, the authors add. "Both trials are expected to report in 2018 and these results will be incorporated when this review is updated."

Also, most of the evidence ranged from moderate to very low quality, with only one group of studies associated with high-quality evidence. In addition, the authors warn that more information is needed on practical issues identified as priorities for women and their families.


Avoidable Drain on Resources

PPH accounted for up to one third of the 303,000 postpartum maternal deaths that occurred in 2015, mostly in low- and middle-income countries, Gallos and colleagues write. Even when death is avoided, these patients often require hysterectomy, blood transfusions, and additional care that can tax limited resources in these nations.

Seventy-five percent of PPH cases result from uterine atony, or failure of the uterus to contract following childbirth. To prevent this and lower the risk for PPH, uterotonic agents are recommended as part of the active management of the third stage of labor to promote uterine contraction.

Currently, oxytocin is the most widely used of several uterotonic agents and is the one recommended by WHO, but "it is still debatable which drug is best," the authors explain. Their aim in this review "was to find out which drug is most effective in preventing excessive blood loss at childbirth and has the least side effects. We collected and analyzed all the relevant studies to answer this question."

Questions About Data Quality

The network meta-analysis included 140 randomized controlled comparisons or cluster trials of effectiveness or side effects of uterotonic agents. Altogether, there were data on 88,947 women.

Most of the trials were conducted in hospital settings on women undergoing vaginal delivery at more than 37 weeks of gestation. The authors caution that the risk of bias was uncertain as a result of poor study design, particularly in the carbetocin trials.

Gallos and colleagues found that about 10.5% of women treated with oxytocin alone experienced PPH associated with blood loss of 500 mL or more, compared with 7.2%, 7.6%, and 7.7% of women treated with ergometrine plus oxytocin, carbetocin alone, or misoprostol plus oxytocin, respectively.

Compared with oxytocin, the risk ratio (RR) for blood loss of 500 mL or more associated with ergometrine plus oxytocin was 0.69 (95% confidence interval [CI], 0.57 - 0.83). Carbetocin had an RR of 0.72 (95% CI, 0.52 - 1.00), and misoprostol plus oxytocin, of 0.73 (95% CI, 0.60 - 0.90). The evidence underpinning these studies ranged from moderate to very low quality.

In a similar analysis of treatment preventing PPH of 1000 mL or more, ergometrine plus oxytocin was associated with an RR of 0.77 (95% CI, 0.61 - 0.95); carbetocin, of 0.70 (95% CI, 0.38 - 1.28); and misoprostol plus oxytocin, of 0.90 (95% CI, 0.72 - 1.14), compared with oxytocin alone. The evidence for ergometrine plus oxytocin was high quality; for the other studies, it ranged from moderate to low quality.

However, the ergometrine-oxytocin combination also was associated with a higher risk for vomiting compared with oxytocin (RR, 3.10; 95% CI, 2.11 - 4.56; high-quality evidence) and hypertension (RR, 1.77; 95% CI, 0.55 - 5.66; low-quality evidence), and misoprostol-oxytocin carried a higher risk for fever (RR, 3.18; 95% CI, 2.22 - 4.55; moderate-quality evidence). "Carbetocin had similar risk for side effects compared with oxytocin although the quality evidence was very low for vomiting and for fever, and was low for hypertension," the authors report.

Of the two studies slated for publication in 2018, one is a multicenter study comparing the effectiveness of oxytocin to a new carbetocin preparation in women undergoing vaginal delivery. The trial is being conducted in 10 countries, includes approximately 30,000 women, and is being led by WHO.

The second UK-based trial has enrolled more than 6000 women and consists of a three-group comparison among carbetocin, oxytocin, and the ergometrine-oxytocin combination.


More Attention to Patient Concerns Needed

On the basis of the current analysis, "ergometrine plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination were more effective for preventing PPH ≥ 500 mL than the current standard oxytocin," the authors conclude. "Ergometrine plus oxytocin combination was more effective for preventing PPH ≥ 1000 mL than oxytocin."

However, they caution that the evidence for misoprostol plus oxytocin was less consistent, perhaps as a result of variations in doses and administration routes used in the various studies.

Carbetocin was associated with the most benign side-effect profile, although most of the relevant trials "were small and at high risk of bias."

Future studies should address issues that are of concern to patients and their families but rarely covered in current research, such as questions about specific drugs, clinical signs of PPH, any impact on ability to breastfeed, and risk for admission to the neonatal unit, the authors add. "Consumers also considered the side effects of uterotonic drugs to be important and these were often not reported."

In addition to information on the findings of the two large trials now underway, future updates of this review will include a set of standardized PPH outcomes that are currently being developed. "We would hope that future trials would also consider adopting those outcomes," the authors write.

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