Overview for healthcare professionals

Induction of labour (NICE clinical guideline 70) recommends that, if a woman who has had an intrauterine fetal death (IUFD) chooses to proceed with induction of labour, oral mifepristone should be used, followed by vaginal prostaglandin E2 or vaginal misoprostol (prostaglandin E1, off-label). This evidence summary describes the risks and benefits of vaginal misoprostol, when used after oral mifepristone according to NICE guidance.

The Royal College of Obstetricians and Gynaecologists' (RCOG) guideline on the management of late IUFD (after 24 completed weeks of pregnancy) and stillbirth advises that the dose of misoprostol should be adjusted according to gestational age (100 micrograms 6-hourly before 26 weeks; 25 to 50 micrograms 4-hourly at 27 weeks or more). An update to the RCOG guideline in July 2011 noted that some hospitals in the UK were using larger doses of misoprostol than recommended in the 2010 guideline, potentially leading to an increased risk of adverse events. This evidence summary focusses particularly on the dose of misoprostol.

Regulatory status of misoprostol

Misoprostol is not currently licensed in the UK for the induction of labour in women with late IUFD.

Misoprostol 200 microgram oral tablets (Cytotec, Pharmacia Limited) are licensed in the UK for treating duodenal and gastric ulcers and preventing non-steroidal anti-inflammatory drug-induced ulcers in adults.

Medabon (Sun Pharmaceutical Industries Europe) is a combination pack containing 1 oral mifepristone 200 mg tablet and 4 vaginal misoprostol 200 microgram tablets. It received UK marketing authorisation in May 2012 for the termination of intrauterine pregnancy of up to 63 days of amenorrhoea.

MisoOne (Exelgyn) contains 400 micrograms of misoprostol for oral administration. In January 2013 it was licensed in the UK for the termination of intrauterine pregnancy, in sequential use with mifepristone, up to 49 days of amenorrhea.

The use of any of these products for the induction of labour in late IUFD is off-label. In line with the guidance from the General Medical Council (GMC), it is the responsibility of the prescriber to determine the clinical need of the patient and the suitability of using misoprostol outside its authorised indications.

Evidence statements

No randomised controlled trials were identified that compared the risks and benefits of vaginal misoprostol, when used after oral mifepristone according to NICE guidance on the induction of labour in late IUFD. This evidence summary includes 2 case series that compared a low-dose misoprostol treatment regimen with a higher dose regimen for induction of labour after late IUFD, using a historical control group.

  • The results of the first case series (Fairley et al. 2005, n=47) suggest that oral mifepristone followed by low doses of vaginal misoprostol (mean total dose 167 micrograms) is similarly effective to oral mifepristone followed by a combination of vaginal and oral misoprostol (mean total dose 828 micrograms). However, the statistical significance of any differences between the groups was not reported.

  • The results of the second case series (Vayrynen et al. 2007, n=130) suggest that oral mifepristone followed by a low dose of vaginal misoprostol (median total dose 100 micrograms) is similarly effective to a higher dose of vaginal misoprostol used on its own without mifepristone (median total dose 200 micrograms).

  • In both case series, the analysis of serious adverse effects is limited by the small numbers in the studies.

  • A Cochrane review on induction of labour in the second and third trimester for fetal anomaly or after IUFD states that vaginal misoprostol is as effective as other agents with a lower incidence of common gastrointestinal adverse effects, but there are insufficient data to assess the occurrence of rare but potentially life-threatening complications for the woman, including uterine rupture.

  • Although the summary of product characteristics for the licensed misoprostol preparation does not apply to this indication or route of administration, prescribers should take the listed adverse effects into account when considering safety for the induction of labour in women after late IUFD.

Summary of the evidence

This section gives a brief summary of the main evidence. A more thorough analysis is given in the Evidence review section.

This evidence summary includes 2 case series in which the groups of women being examined were studied over different time periods after a change in practice in the study hospitals. The aim of both case series was to compare the effects of 2 different regimens of misoprostol treatment for induction of labour after late IUFD.

Efficacy

Mifepristone plus vaginal and oral misoprostol compared with mifepristone plus vaginal misoprostol

The UK case series by Fairley et al. (2005) compared low-dose vaginal misoprostol (50 micrograms 3-hourly) with a higher dose administered both vaginally and orally (400 micrograms 4-hourly) in 47 women with late IUFD (24 weeks gestation or later). All women took mifepristone 200 mg orally before misoprostol was administered. The group that used the vaginal and oral misoprostol combination (n=29) was treated between February 1998 and December 2001, whereas the group that used vaginal misoprostol alone (n=18) was treated between March 2002 and May 2003. Information was gathered prospectively. Outcomes included the time from administration of the first dose of misoprostol (induction) to fetal delivery, analgesic requirements and adverse events. See table 1 for more details.

Women in the combined vaginal and oral administration group received a higher mean total dose of misoprostol (828 micrograms) compared with the vaginal administration only group (167 micrograms). The median induction to fetal delivery interval was 7 hours (range 1.5 to 29.5) in the combined vaginal and oral administration group and 10.2 hours (range 1.5 to 20.0) in the vaginal administration only group. The statistical significance of the difference in induction to delivery time was not reported.

Although women who received a higher dose of misoprostol delivered 3 hours faster on average, this study suggests that low-dose misoprostol (mean 167 micrograms) administered vaginally is effective for the induction of labour after IUFD at 24 weeks gestation or later.

Misoprostol alone compared with mifepristone plus misoprostol

The Finnish case series by Vayrynen et al. (2007) compared the use of vaginal misoprostol alone (between 1997 and 2001) with oral mifepristone 200 mg followed by vaginal misoprostol (between 2001 and 2005) in 130 women with IUFD (22 weeks gestation or later). Single 4-hourly doses of 25 to 400 micrograms (median 100 micrograms) were used in the vaginal misoprostol alone group (n=82) compared with 25 micrograms in the combination treatment group (n=48). Study outcomes included induction to delivery time, need for oxytocin or analgesia, and adverse events. See table 2 for more details.

The median total dose of misoprostol was significantly lower in the combination mifepristone and misoprostol treatment group compared with the misoprostol only group (100 micrograms compared with 200 micrograms, p=0.0028). However, the median number of doses needed was higher in the combination treatment group compared with the misoprostol only group (3 compared with 2, p=0.0019).

The study found no significant difference between the groups in the induction to delivery interval. The median induction to fetal delivery interval was 12.8 hours (range 3.2 to 12.9) in the combined mifepristone and misoprostol group and 13.3 hours (range 2.1 to 97.3) in the vaginal misoprostol only group.

The results of this study suggest that, when used after mifepristone according to NICE guidance, low-dose misoprostol (median 100 micrograms) is effective for the induction of labour after IUFD at 22 weeks gestation or later.

Table 1 Summary of Fairley et al. (2005)

Dosage and route of administration

Combined vaginal and oral

200 mg mifepristone + 400 micrograms vaginal misoprostol + up to 4 doses of 400 micrograms oral misoprostol 4-hourly

Vaginal only

200 mg mifepristone + 50 micrograms vaginal misoprostol + up to 4 doses of 50 micrograms vaginal misoprostol 3-hourly

Comment and analysis

Group allocation

n=29

n=18

Mean age in years (SD)

31 (5.4)

31 (4.8)

Median gestation: weeks (range)

28 (24 to 40)

31 (24 to 41)

Previous C-section (%)

3 (10%)

1 (6%)

Mean total dose of misoprostol: micrograms (range)

828 (400 to 1000)

167 (50 to 250)

Difference in mean dose: 661 micrograms

Statistical significance not reported

Efficacy

Median time from first dose of misoprostol to delivery: hours (range)

7 (1.5 to 29.5)

10.2 (1.5 to 20.0)

Difference in median times: 3.2 hours

Statistical significance not reported

Analgesia requirements

Parenteral opiates (controlled morphine infusion; intramuscular diamorphine)

69% (20 women)

Morphine: 14% (4 women)

Diamorphine: 55% (16 women)

78% (14 women)

Morphine: 0 (0 women)

Diamorphine: 78% (14 women)

Statistical significance not reported

Requested epidural analgesia

14% (4 women)

6% (1 woman)

Statistical significance not reported

Oral analgesia

Not reported

17% (3 women)

5 women (17%) from the combined vaginal and oral group were reported as receiving oral or no analgesia; numbers receiving oral analgesia not reported

Safety

Maternal death

None reported

None reported

Gastrointestinal adverse events

48%

35%

Numbers of women not reported.

Statistical significance not reported

Postpartum haemorrhage >1000 ml needing blood transfusion

10% (3 women)

11% (2 women)

In the combined vaginal and oral group there was an additional case of postpartum haemorrhage >1000 ml that did not need blood transfusion

Statistical significance not reported

Manual removal of placenta

14% (4 women)

6% (1 woman)

Statistical significance not reported

Abbreviations: C-section, caesarean section; SD, standard deviation.

Table 2 Summary of Vayrynen et al. (2007)

Misoprostol only

25 to 400 micrograms vaginal misoprostol 4-hourly

Mifepristone plus misoprostol

200 mg mifepristone + 25 micrograms vaginal misoprostol 4-hourly

Comment and analysis

Group allocation

n=82

n=48

Labour was initiated in 2 women in the mifepristone plus misoprostol group by mifepristone only

Mean age in years (range)

30 (17 to 44)

32 (21 to 42)

p=0.088

Median gestation: weeks + days (range)

30+4 (21+5 to 40+3)

32+2 (22+1 to 41+0)

Not significant, p value not reported

Previous C- section (%)

12 (14.6%)

4 (8.3%)

Not significant, p value not reported

Median total dose of misoprostol: micrograms

200 micrograms

100 micrograms

p=0.0028

Median misoprostol doses

2

3

p=0.0019

Efficacy

Median induction (with misoprostol) to delivery (all gestational ages): hours (range)

13.3 (2.1 to 97.3)

12.8 (3.3 to 126.9)

Not significant, p value not reported

Median induction (with misoprostol) to delivery for 21 to 25 weeks gestation: hours (range)

17.9 (6.4 to 90.6)

11.2 (3.7 to 126.9)

p=0.04

Median induction (with misoprostol) to delivery for 26 to 30 weeks gestation: hours (range)

17.6 (2.7 to 97.3)

(n=23)

15.7 (3.2 to 35.4)

(n=9)

Not significant, p value not reported

Median induction (with misoprostol) to delivery for 31 to 35 weeks gestation: hours (range)

15.7 (6.3 to 84.3)

(n=16)

23.1 (6.1 to 59.2)

(n=12)

Not significant, p value not reported

Median induction (with misoprostol) to delivery for 36 to 41 weeks gestation: hours (range)

9.5 (2.1 to 35.9)

12.6 (5.8 to 31.4)

Not significant, p value not reported

Delivery by 48 hours after the start of misoprostol

92.7%

93.5%

Not significant, p value not reported

% needing oxytocin administration (median dose)

46% (0.56 IU)

58% (0.65 IU)

Not significant, p value not reported

When analysed at 5-week intervals, use and dose of oxytocin was reported to be similar; figures not reported

Analgesia requirements

Nitrous oxide

38% (31 of 82)

52% (25 of 48)

Not significant, p value not reported

Epidural anaesthesia

66% (54 of 82)

63% (30 of 48)

Not significant, p value not reported

Opioid analgesia

88% (72 of 82)

88% (42 of 48)

Not significant, p value not reported

Safety

Maternal death

None reported

None reported

Need for transfusion

2 (2.4%)

4 (8.3%)

Not significant, p value not reported

There were 4 cases in total of excessive haemorrhage (1000 ml) in the misoprostol group and 4 cases in the mifepristone plus misoprostol group

Fever

2 (2.4%)

5 (10.4%)

p=0.052

Antibiotic use

6 (7.3%)

10 (20.8%)

p=0.024

Surgical evacuation of the uterus

6 (7.3%)

3 (6.3%)

Not significant, p value not reported

Abbreviations: C-section, caesarean section; IU, international units.

Note: except where stated, the results include all cases of intrauterine fetal death (IUFD), including cases between 21 and 24 weeks gestation.

Safety

Mifepristone plus vaginal and oral misoprostol compared with mifepristone plus vaginal misoprostol

The UK case series by Fairley et al. (2005) found that gastrointestinal adverse events were reported in 48% of the combined vaginal and oral misoprostol group and 35% of the vaginal misoprostol only group. The statistical significance of the difference was not reported.

The number of cases of postpartum haemorrhage and manual removal of the placenta was small. No cases of excessive uterine contraction frequency, uterine rupture, dehiscence, maternal coagulopathy or maternal death were reported.

Misoprostol alone compared with mifepristone plus misoprostol

The case series by Vayrynen et al. (2007) reported that women in the mifepristone and misoprostol group were statistically significantly more likely to need antibiotics (p=0.024) than women in the misoprostol alone group. However, the researchers reported that the rate of infections relating to delivery was no different between the groups. More women in the mifepristone and misoprostol group had fever but this was not significant (p=0.052).

The rates of other complications of delivery, including excessive haemorrhage, need for blood transfusion and surgical evacuation of the uterus, were small and similar between the groups. One case of coagulopathy was reported in the combination treatment group. Gastrointestinal adverse events were not reported.

Summary of product characteristics

The summary of product characteristics for the licensed oral misoprostol preparation states that diarrhoea and rash are very common adverse events (1 or more in every 10 people) associated with misoprostol use when used for the preventing and treating duodenal and gastric ulcers. Common adverse events (between 1 in 100 and 1 in 10) include dizziness, headache, abdominal pain, constipation, dyspepsia, flatulence, nausea and vomiting. The doses of misoprostol used for the licensed indications are higher than when misoprostol is used off-label for late IUFD.

The summary of product characteristics for oral misoprostol also notes that the risk of uterine rupture increases with advancing gestational age and with prior uterine surgery, including caesarean delivery.

Cost effectiveness and cost

No cost-effectiveness studies were identified that assessed the use of misoprostol for induction of labour for late IUFD compared with other treatments or placebo. No estimate of the current use of misoprostol for this indication in UK clinical practice was identified.

A pack of 60 misoprostol 200 microgram tablets (Cytotec) costs £10.03 (Drug Tariff, February 2013). At the time of publication, costs are not available for Medabon or MisoOne.