Uterotonic agents for first-line treatment of postpartum haemorrhage: a network meta-analysis

William R Parry Smith, Argyro Papadopoulou, Eleanor Thomas, Aurelio Tobias, Malcolm J Price, Shireen Meher, Zarko Alfirevic, Andrew D Weeks, G Justus Hofmeyr, Ahmet Metin Gülmezoglu, Mariana Widmer, Olufemi T Oladapo, Joshua P Vogel, Fernando Althabe, Arri Coomarasamy, Ioannis D Gallos, William R Parry Smith, Argyro Papadopoulou, Eleanor Thomas, Aurelio Tobias, Malcolm J Price, Shireen Meher, Zarko Alfirevic, Andrew D Weeks, G Justus Hofmeyr, Ahmet Metin Gülmezoglu, Mariana Widmer, Olufemi T Oladapo, Joshua P Vogel, Fernando Althabe, Arri Coomarasamy, Ioannis D Gallos

Abstract

Background: Postpartum haemorrhage (PPH), defined as a blood loss of 500 mL or more after birth, is the leading cause of maternal death worldwide. The World Health Organization (WHO) recommends that all women giving birth should receive a prophylactic uterotonic agent. Despite the routine administration of a uterotonic agent for prevention, PPH remains a common complication causing one-quarter of all maternal deaths globally. When prevention fails and PPH occurs, further administration of uterotonic agents as 'first-line' treatment is recommended. However, there is uncertainty about which uterotonic agent is best for the 'first-line' treatment of PPH.

Objectives: To identify the most effective uterotonic agent(s) with the least side-effects for PPH treatment, and generate a meaningful ranking among all available agents according to their relative effectiveness and side-effect profile.

Search methods: We searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (5 May 2020), and the reference lists of all retrieved studies.

Selection criteria: All randomised controlled trials or cluster-randomised trials comparing the effectiveness and safety of uterotonic agents with other uterotonic agents for the treatment of PPH were eligible for inclusion.

Data collection and analysis: Two review authors independently assessed all trials for inclusion, extracted data and assessed each trial for risk of bias. Our primary outcomes were additional blood loss of 500 mL or more after recruitment to the trial until cessation of active bleeding and the composite outcome of maternal death or severe morbidity. Secondary outcomes included blood loss-related outcomes, morbidity outcomes, and patient-reported outcomes. We performed pairwise meta-analyses and indirect comparisons, where possible, but due to the limited number of included studies, we were unable to conduct the planned network meta-analysis. We used the GRADE approach to assess the certainty of evidence.

Main results: Seven trials, involving 3738 women in 10 countries, were included in this review. All trials were conducted in hospital settings. Randomised women gave birth vaginally, except in one small trial, where women gave birth either vaginally or by caesarean section. Across the seven trials (14 trial arms) the following agents were used: six trial arms used oxytocin alone; four trial arms used misoprostol plus oxytocin; three trial arms used misoprostol; one trial arm used Syntometrine® (oxytocin and ergometrine fixed-dose combination) plus oxytocin infusion. Pairwise meta-analysis of two trials (1787 participants), suggests that misoprostol, as first-line treatment uterotonic agent, probably increases the risk of blood transfusion (risk ratio (RR) 1.47, 95% confidence interval (CI) 1.02 to 2.14, moderate-certainty) compared with oxytocin. Low-certainty evidence suggests that misoprostol administration may increase the incidence of additional blood loss of 1000 mL or more (RR 2.57, 95% CI 1.00 to 6.64). The data comparing misoprostol with oxytocin is imprecise, with a wide range of treatment effects for the additional blood loss of 500 mL or more (RR 1.66, 95% CI 0.69 to 4.02, low-certainty), maternal death or severe morbidity (RR 1.98, 95% CI 0.36 to 10.72, low-certainty, based on one study n = 809 participants, as the second study had zero events), and the use of additional uterotonics (RR 1.30, 95% CI 0.57 to 2.94, low-certainty). The risk of side-effects may be increased with the use of misoprostol compared with oxytocin: vomiting (2 trials, 1787 participants, RR 2.47, 95% CI 1.37 to 4.47, high-certainty) and fever (2 trials, 1787 participants, RR 3.43, 95% CI 0.65 to 18.18, low-certainty). According to pairwise meta-analysis of four trials (1881 participants) generating high-certainty evidence, misoprostol plus oxytocin makes little or no difference to the use of additional uterotonics (RR 0.99, 95% CI 0.94 to 1.05) and to blood transfusion (RR 0.95, 95% CI 0.77 to 1.17) compared with oxytocin. We cannot rule out an important benefit of using the misoprostol plus oxytocin combination over oxytocin alone, for additional blood loss of 500 mL or more (RR 0.84, 95% CI 0.66 to 1.06, moderate-certainty). We also cannot rule out important benefits or harms for additional blood loss of 1000 mL or more (RR 0.76, 95% CI 0.43 to 1.34, moderate-certainty, 3 trials, 1814 participants, one study reported zero events), and maternal mortality or severe morbidity (RR 1.09, 95% CI 0.35 to 3.39, moderate-certainty). Misoprostol plus oxytocin increases the incidence of fever (4 trials, 1866 participants, RR 3.07, 95% CI 2.62 to 3.61, high-certainty), and vomiting (2 trials, 1482 participants, RR 1.85, 95% CI 1.16 to 2.95, high-certainty) compared with oxytocin alone. For all outcomes of interest, the available evidence on the misoprostol versus Syntometrine® plus oxytocin combination was of very low-certainty and these effects remain unclear. Although network meta-analysis was not performed, we were able to compare the misoprostol plus oxytocin combination with misoprostol alone through the common comparator of oxytocin. This indirect comparison suggests that the misoprostol plus oxytocin combination probably reduces the risk of blood transfusion (RR 0.65, 95% CI 0.42 to 0.99, moderate-certainty) and may reduce the risk of additional blood loss of 1000 mL or more (RR 0.30, 95% CI 0.10 to 0.89, low-certainty) compared with misoprostol alone. The combination makes little or no difference to vomiting (RR 0.75, 95% CI 0.35 to 1.59, high-certainty) compared with misoprostol alone. Misoprostol plus oxytocin compared to misoprostol alone are compatible with a wide range of treatment effects for additional blood loss of 500 mL or more (RR 0.51, 95% CI 0.20 to 1.26, low-certainty), maternal mortality or severe morbidity (RR 0.55, 95% CI 0.07 to 4.24, low-certainty), use of additional uterotonics (RR 0.76, 95% CI 0.33 to 1.73, low-certainty), and fever (RR 0.90, 95% CI 0.17 to 4.77, low-certainty).

Authors' conclusions: The available evidence suggests that oxytocin used as first-line treatment of PPH probably is more effective than misoprostol with less side-effects. Adding misoprostol to the conventional treatment of oxytocin probably makes little or no difference to effectiveness outcomes, and is also associated with more side-effects. The evidence for most uterotonic agents used as first-line treatment of PPH is limited, with no evidence found for commonly used agents, such as injectable prostaglandins, ergometrine, and Syntometrine®.

Trial registration: ClinicalTrials.gov NCT00116350 NCT00116480 NCT01462422 NCT02304055 NCT01116050 NCT01485562 NCT01508429 NCT01600612 NCT01619072 NCT02306733 NCT02410759 NCT03584854 NCT03870503.

Conflict of interest statement

William R Parry‐Smith (WRPS) is an Executive Board member of AmmaLife (UK registered charity 1120236), and a member of The UK Membership Board of The Royal College of Obstetricians and Gynaecologists (UK registered charity 213280). He was also a Trustee of Baby Lifeline (UK registered charity 1006457) until April 2019. He does not receive payment for these roles but has received payment from these organisations for travel for activities not related to this review. He has also received payment from the Liverpool School of Tropical Medicine for an invited lecture on cervical cancer and women's health. AmmaLife contributed to this review by funding literature/library costs.

Argyro Papadopoulou (AP): none known.

Eleanor Thomas (ET): none known.

Aurelio Tobias (AT): none known.

Malcolm J Price (MJP): none known.

Shireen Meher (SM): none known.

Zarko Alfirevic (ZA): none known.

Andrew Weeks (AW): voluntarily runs the not‐for‐profit misoprostol.org website that provides information about the optimal doses of misoprostol, including for the treatment of PPH. He also has two large clinical trial grants (from NIHR) on PPH treatment. These studies could potentially be eligible for inclusion in subsequent updates of this review, but he will not participate in decisions regarding these trials. He is also a consultant to Gynuity Health projects (unpaid) and to Azanta A/S and Monash University (both pay consultancy fees to his institution (University of Liverpool). He is also the inventor of the PPH Butterfly device and one of the inventors of the LifeStart neonatal resuscitation trolley. He may in future receive personal payments in connection to the PPH Butterfly for which the University of Liverpool holds the patent.

G Justus Hofmeyr (GJH): is an author of trials included in the review. GJH did not participate in decisions regarding these trials.

A Metin Gülmezoglu (AMG): none known.

Mariana Widmer (MW): is an author of trials included in the review. MW did not participate in decisions regarding these trials.

Olufemi T Oladapo (OTO): none known.

Joshua Vogel (JV): none known.

Fernando Althabe (FA): none known.

Arri Coomarasamy (AC): is the founder of Ammalife (UK registered charity 1120236), and remains an active member of the Executive Board of this organisation. He does not receive any payment for this relationship.

Ioannis D Gallos (IDG): none known.