Evidence review

The EXPEDITE study ( Wing D et al. 2013 )

  • Design: phase III, double-blind, randomised multicentre (35 centres in the USA) study.

  • Population: the study included 1358 women (41% white) aged at least 18 years (median age 25 years; range 18 to 46 years), of parity 3 or less with singleton pregnancies (66% nulliparous), and of at least 36 weeks' gestation (mean 39.5 weeks). Women were included if they had an unfavourable cervix (baseline modified Bishop score of 4 or less; median 2) and a body mass index of 50 kg/m2 or less (mean 34 kg/m2). Exclusion criteria included active labour, uterine or cervical scarring or other uterine abnormality, fetal malpresentation and evidence of fetal compromise at baseline.

  • Intervention and comparison: women were randomised to receive either a 200 microgram misoprostol controlled-release vaginal insert or a 10 mg dinoprostone controlled-release vaginal insert (Propess) that were identical in appearance. Allocation was concealed. Demographic and baseline characteristics were not significantly different between the groups.

  • Follow-up: women remained in bed for at least 30 minutes after insertion of the drug. They were continuously monitored for uterine and fetal heart rate activity. Vaginal examinations were performed at 6, 12, 18 and 24 hours if delivery had not occurred, even if the insert had been removed, the woman was in active labour or a caesarean delivery was planned. The vaginal insert was removed at the onset of active labour; at the completion of the 24-hour dosing period; at the occurrence of any intrapartum adverse event; or at the woman's request. Oxytocin administration was permitted 30 minutes after removal of the insert if the woman was not in active labour and her fetus's status was reassuring. Women and neonates were observed for adverse events until hospital discharge; information was also collected on neonatal admissions and emergency room visits within 1 month of birth.

  • Outcomes: the primary efficacy measure was the time from study drug administration to vaginal delivery of the neonate. The primary safety measure was the rate of caesarean delivery. Key secondary efficacy end points were time to any delivery (vaginal or caesarean), time to onset of active labour, and the proportion of women requiring pre-delivery oxytocin. The proportion of women with vaginal delivery and any delivery within 12–24 hours was also assessed but is not discussed in this evidence summary. In addition to the rate of caesarean delivery, safety was assessed by comparing the incidences of intrapartum, maternal postpartum and neonatal adverse events. Efficacy analyses were performed using the intention-to-treat population, which included all randomised women who received the study drug. The safety population includes all women who received the study drug and their neonates.

Table 1 Summary of EXPEDITE ( Wing D et al. 2013 )

Misoprostol 200 micrograms

Dinoprostone 10 mg

Analysis

Randomised

n=678

n=680

Efficacy a

n=678

n=680

Primary efficacy outcome: median time to vaginal delivery (hours)

21.5 (95% CI 20.0 to 23.4)

32.8 (95% CI 30.2 to 34.9)

Difference −11.3 hours

p<0.001

Selected secondary outcomes:

Median time to vaginal or caesarean delivery (hours)

18.3 (95% CI 17.2 to 19.5)

27.3 (95% CI 26.2 to 28.9)

Difference −9.0 hours

p<0.001

Median time to active labour (hours)

12.1 (95% CI 12.0 to 12.9)

18.6 (95% CI 18.1 to 22.5)

Difference −6.5 hours

p<0.001

Women requiring pre-delivery oxytocinb

48.1% (324/674)

74.1% (497/671)

Difference −26%

p<0.001

Safety c

n=678

n=680

Primary safety outcome: rate of caesarean delivery

26.0% (176/678)

27.1% (184/680)

Difference −1.10% (−5.79% to 3.59%)

p=0.65d

Adverse events that resulted in a caesarean delivery

25.1% (170/678)

24.7% (168/680)

p value not reported

Adverse events in the intrapartum periode

55.5%

54.6%

p=0.74

Adverse events in the postpartum periode

21.4%

21.2%

p=0.95

Adverse events in the neonatal periode

53.4%

58.1%

p=0.09

Uterine tachysystole with category II or III fetal heart rate changes or tachysystole requiring interventionf

13.3% (90/678)

4.0% (27/680)

RR 3.34 (95% CI 2.20 to 5.07)

p<0.001

Tocolysis useg

12.2% (83/678)

4.1% (28/680)

RR 2.97 (95% CI 1.96 to 4.50)

p<0.05

Meconium in amniotic fluidh

17.7% (120/678)

13.5% (92/680)

RR 1.31 (95% CI 1.02 to 1.68)

p<0.05

Arrested labour (dilation or descent)

14.2% (96/678)

18.8% (128/680)

RR 0.75 (95% CI 0.59 to 0.96)

p<0.05

Chorioamnionitisi

5.6% (38/678)

8.7% (59/680)

RR 0.65 (95% CI 0.44 to 0.96)

p<0.05

Intrapartum IV or IM antibiotic use

5.6% (38/678)

8.7% (59/680)

RR 0.65 (95% CI 0.44 to 0.96)

p<0.05

Postpartum IV or IM antibiotic use

4.6% (31/678)

8.4% (57/680)

RR 0.55 (95% CI 0.36 to 0.83)

p<0.05

Abbreviations: CI, confidence interval; IM, intramuscular; IV, intravenous; p, p value; RR, relative risk.

a Efficacy analyses were performed using the intention-to-treat population, which included all randomised women who received the study drug.

b 14 women did not deliver after their first induction attempt.

c The safety population includes all women who received the study drug and their neonates.

d Non-inferiority of misoprostol could not be concluded for this co-primary end point based on the pre-specified non-inferiority margin.

e Numbers of events not reported.

f Tachysystole (uterine hyperstimulation) was defined as 5 or more contractions in 10 minutes over 3 consecutive 10-minute periods.

g Tocolysis may be used to suppress contractions if uterine hyperstimulation occurs during induction of labour.

h Meconium in the amniotic fluid can indicate fetal distress, and can cause problems to the neonate if it is inhaled during labour.

i Chorioamnionitis is inflammation of the fetal membranes caused by bacterial infection. It may also affect the placenta.

Clinical effectiveness

In EXPEDITE, the median time from study drug administration to vaginal delivery (the primary efficacy outcome) was statistically significantly reduced by 11.3 hours in women undergoing induction of labour who received a 200 microgram misoprostol controlled-release vaginal insert (n=678) compared with a 10 mg dinoprostone controlled-release vaginal insert (n=680). The median time from study drug administration to vaginal delivery for women of any parity was 21.5 hours (95% confidence interval [CI] 20.0 to 23.4 hours) for the misoprostol vaginal insert and 32.8 hours (95% CI 30.2 to 34.9 hours) for the dinoprostone vaginal insert (p<0.001).

The median time to vaginal delivery was also statistically significantly shorter in women receiving the misoprostol vaginal insert compared with the dinoprostone vaginal insert in both the nulliparous (n=892; 29.2 hours compared with 43.1 hours; difference 13.9 hours, p<0.001) and parous (n=466; 13.4 hours compared with 20.1 hours; difference 6.7 hours, p<0.001) subgroups.

Statistically significant improvements were also seen in the 3 key secondary efficacy end points. The median time to any delivery (vaginal or caesarean) was reduced by 9.0 hours (p<0.001); the median time to active labour was reduced by 6.5 hours (p<0.001); and in those women who delivered after the first induction attempt the proportion requiring pre-delivery oxytocin was reduced by 26% (p<0.001) with the misoprostol vaginal insert compared with the dinoprostone vaginal insert. See table 1 for more information.

A Cochrane systematic review found that vaginal misoprostol in dosages ranging from 25 micrograms 2 to 3 hourly, to 50 micrograms 4 hourly (most studies), to 100 micrograms 6 to 12 hourly, appeared to be more effective than oxytocin or dinoprostone for induction of labour. Lower dosage regimens of misoprostol were not less effective than higher doses in terms of failure to achieve vaginal birth within 24 hours.

This review was assessed as being up to date in May 2009. An updated search was performed in February 2012 and a large number of studies have been added to the awaiting classification section of the review. These may alter the conclusions of the review once assessed.

Safety

In EXPEDITE, the rate of caesarean delivery (the primary safety end point) was similar in the misoprostol and dinoprostone groups (26.0% compared with 27.1%; difference −1.10%, 95% CI −5.79% to 3.59%); p=0.65). However, non-inferiority of the misoprostol vaginal insert to the dinoprostone vaginal insert could not be concluded because the upper limit of the 95% CI (3.59%) exceeded the pre-specified non-inferiority margin (2.71%).

Adverse events were the most common reason for caesarean delivery in women treated with misoprostol and dinoprostone vaginal inserts (25.1% compared with 24.7% respectively; p value not reported). Other reasons were elective caesarean (0.1% compared with 0.9% respectively) and lack of efficacy (0.7% compared with 1.5% respectively).

Although the majority of adverse events leading to caesarean delivery were reported at similar rates in both groups and considered unrelated to the study drug, there were some differences between the groups. In the misoprostol group, category II fetal heart rate patterns (indeterminate, requiring evaluation and surveillance; 9.1% compared with 6.2% in the dinoprostone group) and uterine tachysystole with late decelerations, bradycardia or prolonged decelerations (1.9% compared with 0% in the dinoprostone group) were more common. Arrest of dilation or failure to dilate was more common in the dinoprostone group (12.5% compared with 8.6% in the misoprostol group). The statistical significance of these differences was not reported.

No fetal, maternal or neonatal deaths were reported and there were no significant differences between misoprostol and dinoprostone in the proportions of women or neonates who experienced any adverse events (not just those requiring caesarean delivery; see table 1 for more details). Rates of admission to neonatal intensive care, and the proportions of neonates with a low Apgar score at 1 minute or 5 minutes were similar between the groups.

Uterine tachysystole with category II or III fetal heart rate changes or tachysystole requiring intervention (uterine hyperstimulation) occurred in statistically significantly more women receiving misoprostol compared with dinoprostone (13.3% compared with 4.0%; relative risk 3.34, 95% CI 2.20 to 5.07; p<0.001). However, overall rates of fetal heart rate category II and category III (abnormal and requiring prompt evaluation) adverse events were not statistically significantly different between the misoprostol and dinoprostone vaginal inserts.

Tocolysis use and meconium in the amniotic fluid were seen statistically significantly more often in the misoprostol group (both p<0.05). Arrested labour, chorioamnionitis, and intrapartum and postpartum intravenous or intramuscular antibiotic use were more common in the dinoprostone group (all p<0.05). More information is available in table 1.

The Cochrane systematic review found that vaginal misoprostol in dosages ranging from 25 micrograms 2 to 3 hourly, to 50 micrograms 4 hourly (most studies), to 100 micrograms 6 to 12 hourly, statistically increased rates of uterine hyperstimulation. The trials included in the systematic review were not sufficiently large to assess the likelihood of uncommon, serious adverse perinatal and maternal complications. Adverse events were reduced with lower dosage regimens of misoprostol, with lower rates of uterine hyperstimulation and a trend to fewer admissions to neonatal intensive care. Concern was raised over several reports of uterine rupture after misoprostol use in women with and without previous caesarean section, and the increase in meconium in the amniotic fluid. Note that the unblinded nature of the studies included in the Cochrane review raises the likelihood of bias.

The summary of product characteristics for Mysodelle states that, according to 5 clinical studies (n=874), the most common adverse events, with an incidence of between 1 in 10 and 1 in 100, are abnormal uterine contractions, fetal heart rate disorder, abnormal labour affecting the fetus and meconium in the amniotic fluid.

Evidence strengths and limitations

The EXPEDITE study was well designed and well reported. It was a relatively large randomised, blinded, controlled study, allocation was concealed and analyses were by intention-to-treat. However, Ferring Pharmaceuticals provided funding for the study and all but 1 of the 6 authors were either employees of the company or had received research support.

The inclusion and exclusion criteria may limit the generalisability of the results of the study; for example, the requirement for women to have an unfavourable cervix (modified Bishop score 4 or less; median 2) and the exclusion of any fetus–woman pair with evidence of fetal compromise at baseline. The summary of product characteristics for Mysodelle points out that the safety and efficacy of the misoprostol vaginal insert has not been established in pregnant women aged under 18 years. Similarly, it has not been studied in women whose membranes have been ruptured for more than 48 hours before insertion, in multiple pregnancies, in women with more than 3 previous vaginal deliveries after 24 weeks' gestation, or in fetal malpresentation.

The study was too small to assess the likelihood of rare, serious adverse perinatal and maternal complications. Randomised trials large enough to assess rare events such as uterine rupture are not feasible. Post-marketing surveillance will be very important to detect potential adverse effects.