Journal Club Papers
Randomized Trial of Early Detection and Treatment of Postpartum Hemorrhage. Devall et al. NEJM. 9 May 2023. DOI: 10.1056/NEJMoa2303966
Progress in reducing PPH related morbidity and mortality has stalled. This has been attributed to delayed or missed diagnoses; delayed and inconsistent use of interventions; and poor uptake of World Health Organisation (WHO) recommendations. To address this, the E-MOTIVE trial was launched across 80 hospitals in Kenya, Nigeria, South Africa, and Tanzania.
- 210,132 women undergoing vaginal delivery were included in this multinational, parallel, cluster-randomised trial.
- Before randomisation, all 80 hospitals completed a 7-month baseline period and were then randomised to standard care or the E-MOTIVE intervention for a further 7 months (meaning whole hospitals were randomised).
- Standard care consisted of visual estimation of blood loss and use of interventions in line with local or national guidelines.
- The E-MOTIVE intervention consisted of:
- A calibrated drape for early detection of PPH; and
- The WHO first-response treatment bundle, which was triggered at 300mL blood loss and additional abnormalities in vital signs or clinical observations. This included: uterine massage; oxytocic drugs, tranexamic acid, intravenous fluids, and a process for examination (empty bladder, evacuate clots, check for tears with external examination, and check placenta for completeness) and escalation if bleeding does not stop after first response, or if clinician is unable to identify or manage the cause of bleeding.
- The primary outcome was a composite of: PPH ≥1000mL (measured objectively using a blood collection drape); postpartum laparotomy for bleeding; or maternal death from bleeding.
The E-MOTIVE intervention reduced the risk of the primary composite outcome by 60% and almost doubled the detection of PPH.
- The composite primary outcome occurred among 1.6% (794/48,678) of women in the intervention group and 4.3% (2139/50,044) in the standard care group (RR 0.60 [95% CI 0.32-0.50], p<0.001). The components of the composite consisted of:
- PPH ≥1000mL: 786 (1.6%) vs 2,129 (4.3%) (RR 0.39 [95% CI 0.31-0.49]).
- Laparotomy for bleeding: 12 (<0.1%) vs 7 (<0.1%) (risk ratio 1.72 [95% CI 0.57-5.16]).
- Maternal death from bleeding: 17 (<0.1%) vs 28 (<0.1%) (risk ratio 0.75 [95% CI 0.40-1.31]).
- The rate of PPH detection was significantly increased in the intervention (calibrated drape) arm at 93.1% vs 51.1% in the standard care (visual estimation of blood loss) arm (rate ratio 1.58 [95% CI 1.41-1.76]).
- Adherence to the treatment bundle was 91.2% in the intervention group and 19.4% in the standard care group (rate ratio 4.94 [95% CI 3.88-6.28).
- The intervention was also associated with a reduced risk of PPH ≥ 500mL, blood transfusion for bleeding, and lower mean blood loss.
These findings demonstrate the utility of an objective measure of blood loss (calibrated drape triggered at ≥300mL blood loss) for improving the detection of PPH, and, in turn, timely and appropriate intervention to improve PPH related maternal morbidity. While the applicability of these findings in a high resource setting is unclear, it would be plausible to suspect this intervention would also work in such settings to reduce the incidence of PPH.
Tranexamic Acid to Prevent Obstetrical Hemorrhage after Cesarean Delivery. Pacheco et al. NJEM. 13 April 2023 DOI: 10.1056/NEJMoa2207419
Tranexamic acid (TXA) is an antifibrinolytic agent that is effective at controlling bleeding and often used to stem obstetric haemorrhage. However, it is unclear whether TXA may have benefit as a prophylactic agent at all caesarean section births. To address this, Pacheco et al. undertook a multicentre, double blinded, placebo-controlled trial, recruiting women undergoing a caesarean section birth across 31 hospitals in the US.
- 10,995 women having a planned or unplanned caesarean section were recruited. Importantly, the trial allowed only 50% of to be planned caesarean sections due to the lower risk of bleeding in this group.
- Women were randomised to either tranexamic acid (1g) (n=5529) or placebo (n=5471) immediately after cord clamping for 10 minutes.
- The primary outcome was a composite of maternal death or blood transfusion before discharge or 7 days postpartum, whichever occurred first.
- Secondary outcomes included intraoperative blood loss > 1000mL, a composite of treatments and interventions in response to bleeding and related complications within 7 days, infections within 6 weeks postpartum, the change in the preoperative haemoglobin, and maternal thromboembolic events.
There was no difference in the primary outcome between women in the tranexamic acid group vs placebo.
- The primary outcome of maternal death or blood transfusion occurred in 3.6% (201/5525) of women in the TXA group and 4.3% (223/5470) in the placebo group (RR 0.89; 95% CI 0.79-1.07, p=0.19)
- Intraoperative blood loss >1000ml was also not significantly different between groups (7.3% vs 8.0%; RR 0.91 [95% CI 0.79, 1.05])
- The composite of treatments and interventions in response to bleeding occurred in 16.1% in the TXA group and 18.0% in the placebo group (RR 0.90; 95% CI, 0.82 to 0.97). However, this difference was driven by lower use of uterotonic agents in the tranexamic acid group than in the placebo group.
- Safety outcomes: no significant difference in thromboembolic events (0.2% vs 0.3 %; RR 0.91 [95% CI 0.42, 1.99]) or seizures (<0.1% vs 0%).
This is the largest trial to assess tranexamic acid for postpartum haemorrhage after caesarean section. These findings demonstrate that prophylactic tranexamic acid after caesarean section does not reduce rates of maternal death or postpartum blood transfusion and thus, does not support routine administration of tranexamic acid at caesarean section births.
However, it dose provides reassurance from a large cohort that TXA does not increase thrombotic events. Also, given there was a trend towards benefit it remains possible TXA could still be useful in the setting of emergency caesarean sections where blood loss is higher.
Azithromycin to Prevent Sepsis or Death in Women Planning a Vaginal Birth. Tita et al. NEJM. 30 March 2023. DOI: 10.1056/NEJMoa2212111
In Australia and the US, antibiotic prophylaxis is recommended to be administered during caesarean birth to reduce maternal and neonatal sepsis. Following the Anode trial (Knight et al, Lancet 2019;393(10189):2395-2403) routine amoxicillin/clavulanic acid is now given after instrumental births. However, there are no recommendations for prophylactic antibiotic use for women planning vaginal delivery. To address this, Tita et al., undertook the Azithromycin Prevention in Labor Use Study (A-PLUS), a randomised controlled trial conducted across 7 low- and middle-income countries (Democratic Republic of Congo, Zambia, Guatemala, Bangladesh, India, Pakistan, and Kenya).
- Women planning vaginal delivery were enrolled and randomised to a single 2g oral dose of azithromycin (n=14,590), or placebo (n=14,637).
- The primary maternal outcome was a composite of maternal sepsis or death within six weeks of delivery. The primary neonatal outcome was a composite of neonatal sepsis, stillbirth, or neonatal death within four weeks of birth.
Azithromycin reduced the risk of maternal sepsis by 35% (RR 0.65 [95% CI 0.55, 0.77]). There was no significant effect on the risk of maternal death, or on the composite primary neonatal outcome.
- The composite primary maternal outcome occurred in 1.6% (227/14,590) of women in the azithromycin group and 2.4% (334/14637) in the placebo group (RR 0.67 [95% CI 0.56, 0.79]). This effect was largely driven by the reduced rate of sepsis (1.5% vs. 2.5%), as maternal death only occurred in 0.1% of both groups.
- The composite primary neonatal outcome occurred in 1540 infants (10.5%) in the azithromycin group vs 1526 infants (10.3%) in the placebo group (RR 1.02 [95% CI 0.95, 1.09]). Sepsis was the most common outcome (9.8% vs 9.6%, RR 1.03 [95% CI 0.96, 1.10]).
- Azithromycin also reduced the risk of the pre-specified secondary outcomes: endometritis (1.3% vs 2.0%), maternal wound infections (1.6% vs 2.2%), other maternal infections (1.0% vs 1.5%), maternal pyelonephritis (0.1% vs 0.3%), maternal readmission ≤42 days post-delivery (0.9% vs 1.3%), and maternal unscheduled healthcare visits (9.6% vs 12.2%).
- Adverse maternal events were similar between the azithromycin and placebo groups (7.6% vs 7.1%). However, there was a trend towards an increased incidence of neonatal pyloric stenosis in the azithromycin group (8 infants diagnosed) compared with the placebo group (3 infants diagnosed).
This study demonstrates a protective effect of azithromycin prophylaxis among women planning vaginal birth in low- and middle-income countries (but not for the neonate). The number needed to treat in this population was 125.
As the study was only conducted in low- and middle-income countries, its applicability to high resource settings is unclear because rates of sepsis and associated perinatal mortality are potentially lower. The authors note that it will be important to consider the potential adverse effects of azithromycin prophylaxis, such as antimicrobial resistance, potential side effects, and associated costs. These considerations will be particularly important in regions with low rates of maternal and neonatal infection.