Uterotonics for management of retained placenta.
Retained placenta is a significant cause of maternal death from postpartum haemorrhage. Traditionally, it is managed by manual removal under anaesthesia, which carries risks of haemorrhage, infection, and uterine perforation. Uterotonics may offer an alternative for delivering the retained placenta since they induce uterine contractions. However, evidence regarding uterotonic agents for retained placenta is still limited.
To assess the benefits and harms of uterotonics for women with retained placenta after vaginal delivery for preventing postpartum haemorrhage.
We searched CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, and WHO ICTRP; and checked references of included studies and pertinent systematic reviews to identify additional studies. The latest search date was 25 April 2024.
We included randomised controlled trials (RCTs) and non-randomised studies of interventions in women who underwent vaginal delivery with retained placenta comparing one uterotonic with another uterotonic, placebo, or no treatment. We excluded studies that compared different uterotonics administered by umbilical vein injection.
Our main outcomes were manual removal of the placenta; postpartum haemorrhage of 1000 mL or more; adverse effects, such as shivering; blood transfusion; maternal death; severe morbidity (admission to the intensive care unit); and blood loss in millilitres. The primary time point of interest for all outcomes was the end of the study period.
We used the Cochrane RoB 2 tool to assess bias in RCTs and the ROBINS-I tool to assess bias in non-randomised studies of interventions.
We synthesised results for each outcome using a random-effects meta-analysis, where possible, employing Mantel-Haenszel with risk ratio (RR) or inverse variance with mean difference (MD), as appropriate. Where this was not possible due to the nature of the data, we synthesised results using narrative synthesis methods. We used GRADE to assess the certainty of evidence for each outcome.
We included five studies with 560 women, comprising four RCTs and one non-randomised study. The studies were conducted in the Netherlands, Tanzania, and Egypt. Three RCTs compared uterotonics (sulprostone or misoprostol) with placebo or no treatment. One RCT compared oxytocin, intravenous carbetocin, and sublingual misoprostol. One non-randomised study compared intraumbilical oxytocin to oxytocin infusion.
Systemic uterotonic agents versus placebo or no treatment Sulprostone or misoprostol may result in little to no difference in the rate of manual removal of the placenta (RR 0.82, 95% confidence interval (CI) 0.54 to 1.27; 3 RCTs, 244 women; low-certainty evidence), and probably results in little to no difference in postpartum haemorrhage (RR 0.80, 95% CI 0.55 to 1.15; 2 RCTs, 194 women; moderate-certainty evidence), and blood transfusion (RR 0.72, 95% CI 0.43 to 1.22; 3 RCTs, 244 women; moderate-certainty evidence) compared to placebo or no treatment. We are very uncertain about the effect of misoprostol on shivering (RR 10.00, 95% CI 1.40 to 71.49; 1 RCT, 70 women; very low-certainty evidence) and the effects of uterotonic agents on mean blood loss (MD -205.26 mL, 95% CI -536.31 to 125.79; 3 RCTs, 244 women; very low-certainty evidence). No study assessed maternal death or severe morbidity. Intravenous carbetocin versus sublingual misoprostol Intravenous carbetocin probably does not reduce the need for manual removal of the placenta (RR 0.79, 95% CI 0.52 to 1.20; 1 RCT, 185 women; moderate-certainty evidence), and may not reduce blood transfusion (RR 0.48, 95% CI 0.09 to 2.58; 1 RCT, 185 women; low-certainty evidence) compared to sublingual misoprostol. The study did not assess postpartum haemorrhage of 1000 mL or more, adverse effects (shivering), maternal death, severe morbidity, and blood loss. Sublingual misoprostol versus oxytocin intraumbilical venous injection Sublingual misoprostol probably results in little to no difference in the rate of manual removal of the placenta (RR 1.09, 95% CI 0.73 to 1.61; 1 RCT, 187 women; moderate-certainty evidence) and may not reduce the need for blood transfusion (RR 1.05, 95% CI 0.27 to 4.09; 1 RCT, 187 women; low-certainty evidence) compared to oxytocin intraumbilical venous injection. The study did not assess postpartum haemorrhage of 1000 mL or more, adverse effects (shivering), maternal death, severe morbidity, and blood loss. Intravenous carbetocin versus oxytocin intraumbilical venous injection Intravenous carbetocin probably does not reduce the rate of manual removal of the placenta (RR 0.86, 95% CI 0.56 to 1.32; 1 RCT, 190 women; moderate-certainty evidence), and may result in little to no difference in reducing blood transfusions (RR 0.51, 95% CI 0.10 to 2.72; 1 RCT, 190 women; low-certainty evidence) compared to intraumbilical venous injection. The study did not assess postpartum haemorrhage of 1000 mL or more, adverse effects (shivering), maternal death, severe morbidity, and blood loss. Oxytocin infusion versus oxytocin intraumbilical venous injection The evidence from one non-randomised study is very uncertain about the effect of oxytocin infusion on manual removal of the placenta compared to oxytocin intraumbilical venous injection (RR 0.90, 95% CI 0.71 to 1.13; 1 study, 35 women; very low-certainty evidence). The study did not assess our other outcomes of interest.
Current evidence suggests that uterotonic agents (such as misoprostol and sulprostone) may result in little to no difference in the rates of manual removal of the placenta, and probably result in little to no difference in postpartum haemorrhage and the need for blood transfusions, compared to placebo or no treatment in the management of retained placenta. The evidence is very uncertain about their effects on blood loss and the effect of misoprostol on shivering. There is probably little to no difference in effects and there may be no difference in safety between one uterotonic agent over another. We found no useable data for maternal death and admission to the intensive care unit. Further large-scale studies are necessary to evaluate uterotonics versus placebo, compare different uterotonic agents, or assess combined uterotonic regimens. Additional research should focus on identifying specific adverse effects, maternal satisfaction and well-being, breastfeeding rates at discharge, and postpartum anaemia.
This Cochrane review was funded by UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP).
Registration (13 July 2024): Prospero, CRD42024564386.
Sothornwit J
，Ngamjarus C
，Pattanittum P
，Waidee T
，Jampathong N
，Jongjakapun A
，Kongwattanakul K
，Lumbiganon P
... -
《Cochrane Database of Systematic Reviews》
Tranexamic acid for preventing postpartum haemorrhage after caesarean section.
Postpartum haemorrhage (PPH) is common and potentially life-threatening. The antifibrinolytic drug tranexamic acid (TXA) is recommended for treating PPH; it reduces the risk of death from haemorrhage by one-third when given soon after bleeding onset, but not overall risk of death. Interest in whether TXA may be effective in preventing PPH is growing. Evidence indicates that TXA given more than three hours after injury to bleeding trauma patients increases mortality. Potential harm becomes critical in prophylactic use of TXA. Reliable evidence of the effect and safety profile of TXA is required before widespread prophylactic use can be considered.
To assess the effects of TXA for preventing PPH compared to placebo or no treatment (with or without uterotonic co-treatment) in women during caesarean birth.
We searched CENTRAL, MEDLINE, Embase, and WHO ICTRP to 20 February 2024 and searched reference lists of retrieved studies.
We included randomised controlled trials (RCTs) evaluating the use of TXA alone or plus uterotonics during caesarean birth for preventing PPH. Trials needed to be prospectively registered (i.e. before starting recruitment). We applied a trustworthiness checklist.
The critical outcome was blood loss ≥ 1000 mL, measured using estimated or calculated methods. Important outcomes included maternal death, severe morbidity, blood transfusion, the use of additional surgical interventions to control PPH, thromboembolic events, use of additional uterotonics, hysterectomy, maternal satisfaction, and breastfeeding at discharge.
We assessed risk of bias in the included studies using Cochrane's RoB 1 tool.
Two review authors independently selected trials, extracted data, and assessed risk of bias and trial trustworthiness. We pooled data using random-effects meta-analysis. We assessed the certainty of the evidence using GRADE.
We included six RCTs with 15,981 participants. All 12 trials in the previous version of this review were not included after review of trial registrations and trustworthiness checklists. Most included studies involved women at low risk of PPH and were conducted in high-resource settings.
Prophylactic TXA in addition to standard care compared to placebo in addition to standard care or standard care alone TXA results in little to no difference in estimated blood loss ≥ 1000 mL (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.79 to 1.11; 4 RCTs; n = 13,042; high certainty evidence), resulting in 8 fewer per 1000 women having estimated blood loss ≥ 1000 mL (from 30 fewer to 16 more). TXA likely results in a slight reduction in calculated blood loss ≥ 1000 mL (RR 0.83, 95% CI 0.76 to 0.92; 2 RCTs; n = 4327; moderate certainty evidence), resulting in 53 fewer per 1000 having calculated blood loss ≥ 1000 mL (from 75 fewer to 25 fewer). The evidence is very uncertain about the effect of TXA on maternal death (one event in placebo group, none in TXA group). No trials measured severe morbidity. TXA likely results in little to no difference in blood transfusion (RR 0.88, 95% CI 0.72 to 1.08; 5 RCTs; n = 15,740; moderate certainty evidence), resulting in 4 fewer per 1000 women requiring a blood transfusion (from 10 fewer to 3 more). TXA results in little to no difference in additional surgical interventions to control PPH (RR 1.02, 95% CI 0.86 to 1.22; 4 RCTs; n = 15,631; high certainty evidence), resulting in 1 more per 1000 women requiring additional surgical intervention (from 4 fewer to 7 more). The evidence is very uncertain about the effect of TXA on thromboembolic events (RR 1.40, 95% CI 0.22 to 8.90; 4 RCTs; n = 14,480; very low certainty evidence), resulting in 1 more per 1000 women having a thromboembolic event (from 2 fewer to 17 more). TXA results in little to no difference in the need for additional uterotonics (RR 0.88, 95% CI 0.78 to 1.00; 4 RCTs; n = 15,728; high certainty evidence), resulting in 15 fewer per 1000 women requiring additional uterotonics (from 27 fewer to 0 fewer). The evidence is very uncertain about the effect of TXA on hysterectomy (RR 0.80, 95% CI 0.20 to 3.29; 2 RCTs; n = 4546; very low certainty evidence), resulting in 3 fewer per 10,000 women requiring a hysterectomy (from 11 fewer to 31 more). One trial measuring maternal satisfaction reported no difference between groups at day two postpartum. No data were available on breastfeeding. Overall, studies had low risk of bias. We downgraded the certainty of evidence mainly for imprecision.
Prophylactic TXA in addition to standard care during caesarean birth results in little to no difference in estimated blood loss ≥ 1000 mL and likely results in a slight reduction in calculated blood loss ≥ 1000 mL compared to placebo. There were no data for severe morbidity due to PPH. Event rates for further interventions to control PPH were low and similar across groups. Prophylactic TXA thus results in little to no difference between groups for additional surgical interventions (32 versus 31 per 1000), and likely results in little to no difference between groups for blood transfusions (31 versus 36 per 1000) and use of additional uterotonics (107 versus 121 per 1000). There were very few events for the outcomes maternal death (1 in placebo group), thromboembolic events (2 versus 3 per 1000), and hysterectomy (1 per 1000 in each group). Evidence for these serious adverse events is therefore very uncertain. Decisions about implementing routine prophylactic TXA during caesarean birth should not only consider outcomes related to blood loss, but also the relatively low rates of PPH morbidity and uncertainty of serious adverse events. Most studies included women at low risk of PPH, thereby precluding any conclusions about women at high risk of PPH. Cost associated with routine use of an additional drug for all caesarean births needs to be considered.
This Cochrane review was funded in part by the World Health Organization.
The published protocol and updates to the review can be accessed: Protocol (2009) DOI: 10.1002/14651858.CD007872 Original Review (2010) DOI: 10.1002/14651858.CD007872.pub2 Review Update (2015) DOI: 10.1002/14651858.CD007872.pub3.
Rohwer C
，Rohwer A
，Cluver C
，Ker K
，Hofmeyr GJ
... -
《Cochrane Database of Systematic Reviews》
ResearchGate
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