Journal Club Papers
Evaluating Progestogens for Preventing Preterm Birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials. The EPPPIC group. The Lancet. March 2021
Progesterone has long been thought as an effective strategy for preventing preterm birth. A 2013 meta-analysis reported progesterone prolonged pregnancy and was associated with a significant reduction in perinatal morbidity and mortality, and preterm birth <37 weeks and <34 weeks. However, more recent trials (OPPTIMUM and PROLONG) have sparked debate around which progesterone should be used and questioned the overall benefit of progesterone for preventing preterm birth.
To address this, the EPPPIC study group undertook an individual participant data (IPD) meta-analysis, including individual level data rather than aggregate data, and assessed whether giving progesterone to asymptomatic women at high risk of preterm birth (short cervix or previous spontaneous preterm birth) reduces the risk of preterm birth.
- Individual level data was obtained from 31 trials including 11,644 women and 16,185 offspring.
- Vaginal progesterone vs control among singleton pregnancies (9 trials, n=3,769):
- Vaginal progesterone reduced the risk of preterm birth <34 weeks by 22% (relative risk 0.78 [95% CI 0.68, 0.90]). There were also trends in reducing preterm birth <37 weeks (RR 0.92 [95% CI 0.84, 1.00]) and <28 weeks (0.81 [95% CI 0.62, 1.06]).
- Non-significant trends towards reduced perinatal death (RR 0.74 [95% CI 0.52, 1.07]) and serious neonatal complications (RR 0.82 [95% CI 0.65, 1.04]) were seen among the vaginal progesterone group. A trend towards increased maternal complications (RR 1.14 [95% CI 0.93, 1.40]) was found, which was largely due to gestational hypertension and infection.
- Among additional neonatal outcomes, vaginal progesterone was associated with a reduced risk of low birthweight <2500g (RR 0.82 [95% CI 0.74, 0.91]), <1500g (RR 0.70 [95% CI 0.49, 0.99]), NICU admission (RR 0.78 [95% CI 0.68, 0.90]), respiratory distress syndrome (RR 0.73 [95% CI 0.58, 0.93]), respiratory support (RR 0.77 [95% CI 0.61, 0.99]); and a non-significant trend towards a lower chance of death after livebirth (RR 0.63 [95% CI 0.39, 1.02]).
- Oral progesterone vs controls among singleton pregnancies (2 trials, n=183)
- Compared with controls, oral progesterone reduced the risk of preterm birth <34 weeks (RR 0.60 [95% CI 0.40, 0.90])
- Among the two trials comparing vaginal progesterone and 17-OHCP there was no clear difference in effect between either treatment.
- Investigating multifetal pregnancies, neither vaginal progesterone (RR 1.01 [95% CI 0.84, 1.20], 8 trials, n=2406) nor 17-OHPC (RR 1.04 [0.92, 1.18], 8 trials, n=2253) reduced the risk of early preterm birth or other maternal or neonatal outcomes.
- Investigating efficacy by cervical length: 1) Women with a short cervix had similar results with overall effects, 2) Women with a cervix >25mm and no previous preterm birth had less benefit and 3) women with a cervix >30mm had no benefit from either vaginal progesterone or 17-OHCP.
This is the largest individual participant data meta-analysis to assess progesterone for preventing preterm birth. It provides reassuring data suggesting progesterone indeed reduces the risk of preterm birth <34 weeks, although its effectiveness (around 20%) is perhaps a little more modest than some of us had thought. Importantly however, it provides encouraging data suggesting progesterone reduces neonatal morbidity and mortality.
The findings also highlight the importance of appropriate patient selection. The most benefit arises from prescribing progesterone to those with a short cervix (which is what many of us currently do). There seems to be no benefit among multiple pregnancies, a reduced benefit among those with a cervix >25mm; and no benefit for those with a history of preterm birth or women with a cervix >30mm.
Hot off the press!
- This study was conducted during 2018-2020 as a multi-centre, double-blind RCT across France
- 4,551 women undergoing caesarean section at ³34 weeks gestation (elective or emergency) received a prophylactic IV uterotonic (within 3 minutes of birth), and then:
- 1g tranexamic acid or placebo
- The primary outcome was PPH, defined as an estimated blood loss >1000ml or red cell infusion given within 2 days of delivery
- Secondary outcomes included PPH based on laboratory measurement (Hb assessment) or care provider assessment of clinically significant PPH, use of additional uterotonics and need for postpartum blood transfusion
- The study was conducted as a modified intention to treat analysis whereby those that were randomised but had a vaginal delivery were excluded from analysis
- Women who received tranexamic acid were less likely to experience the primary outcome (PPH) (26.7% vs 31.6%) with an adjusted risk ratio of 0.84 (95%CI 0.74-0.95) – this was not altered by timing of administration of tranexamic acid or presence of known risk factors for PPH
- There was no significant difference between the groups with regards to the secondary outcomes
- Nausea and vomiting was significantly more likely in the tranexamic acid group
- Safety-related outcomes were also assessed and women who received tranexamic acid were more likely to experience a thromboembolic (DVT/PE) event (0.4% vs 0.1%) within 3 months of delivery than those who received the placebo (aRR 4.01, 95%CI 0.85-18.92 p=0.08) – underpowered to detect a significant difference.
The authors conclude that tranexamic acid administration reduced the incidence of the primary outcome (PPH) but not other blood loss-related secondary outcomes. Very good news.
Sadly, the findings suggested a trend towards a higher risk of thromboembolic events in the tranexamic acid group. It is unclear whether this is a true observation but certainly warrants further investigation. And it likely to stoke controversy. Our thoughts at this early stage:
- The association with clots is not significant, and it is a secondary outcome. Hence, the link has not been proven and may be a chance finding. Of note, no increase in thromboembolic events were observed in the WOMAN trial (tranexamic acid given to around 20,000 women with a postpartum haemorrhage: Lancet 2017).
- However, the possibility that the link is real merits further reflection as it is biologically plausible. And clots are a serious outcome.
- We suggest at present, tranexamic acid is certainly merited for those with a postpartum haemorrhage and perhaps for those known to be at increased risk. Whether tranexamic acid should be given at all caesars will depend on further expert analysis (aka furious debate) of the results arising from this report. In either case, it would be prudent for meticulous attention to be given to thromboprophylaxis among those who receive tranexamic acid.
The original 2018 RCT.
- In 2018, the same research group conducted a multi-centre, double-blind RCT in France to investigate whether prophylactic tranexamic acid, in addition to routine prophylactic oxytocin, would reduce the incidence of PPH (>500ml) following vaginal birth
- 4079 women in labour >35 weeks planning a vaginal delivery were recruited
- While there was a trend, tranexamic acid was not shown to significantly lower the incidence of PPH ((RR 0.83, 95%CI 0.68-1.01, p=0.07)
- The incidence of thromboembolic events up to 3 months post-partum did not differ between the groups (0.1% vs 0.2%, RR 0.25, 95%CI 0.03-2.24)
- This study was an international (Denmark and Netherlands), multi-centre, double-blind RCT.
- The aim was to determine whether discontinuing oxytocin stimulation in the active phase of labour was associated with lower caesarean section rates
- Population: 1200 women with a live, singleton, cephalic baby at term received stimulation with IV oxytocin (10IU/1000ml saline) during the latent phase of labour (up to 6cm dilation)
- Intervention: women were randomly assigned to have their oxytocin either ceased or continued during the active phase of labour (≥6cm dilatation)
- Primary outcome: delivery by caesarean section
- The intention-to-treat results showed a slightly increased but non-significant risk of caesarean in the discontinued group (16.6% vs 14/2%, RR 1.17, 95%CI 0.09-1.53)
- Amongst a small sub-group analysis of 94 parous women with no previous caesarean, the risk of caesarean was higher amongst the discontinued group (7.5 vs 0.6%, RR 11.6, 95%CI 1.15-88.7)
- The difference in risk was non-significant amongst sub-group analyses for nulliparous women, induced labours and women with PROM
- Discontinuation of oxytocin was associated with longer duration of labour (282 vs 201 min, p<0.001) but significantly reduced risk of uterine hyperstimulation (3.7% vs 12.9%, p<0.001) and fetal heart rate abnormalities (27.9% vs 40.8%, p<0.001)
- When results were analysed by actual treatment received, those that continued oxytocin had very low caesarean section rates (5.8% vs 23.5%, p<0.001)
- The authors conclude that in settings where fetal condition and uterine activity can be reliably monitored, discontinuation of oxytocin in the active phase of labour may lead to a small increase in caesarean section BUT a significantly lower rate of fetal heart rate abnormalities and hyperstimulation which may be important in settings where monitoring is not possible or reliable.
Thus, in parts of the world where there is good quality fetal monitoring, there may be no benefit in switching off the oxytocin once women arrive at active labour and 6 cm dilatation.