Misoprostol after mifepristone for inducing medical abortion between 10+1 and 24+0 weeks’ gestation

National Guideline Alliance (UK)

Misoprostol after mifepristone for inducing medical abortion between 10+1 and 24+0 weeks’ gestation

Abortion care

Evidence review J

NICE Guideline, No. 140

Authors

National Guideline Alliance (UK).

London: National Institute for Health and Care Excellence (NICE); 2019 Sep.

ISBN-13: 978-1-4731-3539-0

Misoprostol after mifepristone for inducing medical abortion between 10⁺¹ and 24⁺⁰ weeks’ gestation

Review question

What is the optimal regimen and route of administration of misoprostol after mifepristone, for inducing medical abortion from 10⁺¹ to 24⁺⁰ weeks?

Introduction

The aim of this review is to determine the optimal regimen and route of administration for misoprostol (after mifepristone) between 10⁺¹ and 24⁺⁰ weeks’ gestation for medical abortion.

At the time of development, the title of this guideline was ‘Termination of pregnancy’ and this term was used throughout the guideline. In response to comments from stakeholders, the title was changed to ‘Abortion care’ and abortion has been used throughout. Therefore, both terms appear in this evidence report.

PICO table

See Table 1 for a summary of the population, intervention, comparison and outcome (PICO) characteristics of this review.

Table 1

Summary of the protocol (PICO table).

Clinical evidence

Included studies

Only studies conducted from 1985 onwards were considered for this review question, as mifepristone was made available in the UK in 1991 and evidence to support the use of mifepristone in practice was unlikely to be more than 5 years before its licensing in 1991.

Eleven randomised controlled trials (RCTs; number of participants, n=1,951) were included in the review (Abbas 2016; Brouns 2010; Chai 2009; Dickinson 2014; El-Refaey 1995; Hamoda 2005; Ho 1997; Hou 2010; Mentula 2011; Ngai 2000; Tang 2005).

Four RCTs (Abbas 2016; Chai 2009; Hou 2010; Mentula 2011) compared mifepristone-misoprostol dosing intervals (simultaneous versus 24 hours, simultaneous versus 36 to 38 hours, 24 hours versus 48 hours); 6 RCTs (Dickinson 2014; El-Rafaey 1995; Hamoda 2005; Ho 1997; Ngai 2000; Tang 2005) compared 2 or more different misoprostol routes of administration (oral versus vaginal, sublingual versus vaginal, oral versus sublingual versus vaginal) and 1 RCT (Brouns 2010) compared 2 different doses of misoprostol (400 micrograms versus 200 micrograms).

There was no subgroup data available based on medical conditions, gestational age, parity and history of previous caesarean section.

The included studies are summarised in Table 2.

Table 2

Summary of included studies.

See the literature search strategy in appendix B and study selection flow chart in appendix C.

Excluded studies

Studies not included in this review with reasons for their exclusions are provided in appendix K.

Summary of clinical studies included in the evidence review

A summary of the studies that were included in this review are presented in Table 2.

See the full evidence tables in appendix D and the forest plots in appendix E.

Quality assessment of clinical studies included in the evidence review

See the clinical evidence profiles in appendix F.

Economic evidence

Included studies

A systematic review of the economic literature was conducted but no economic studies were identified which were applicable to this review question.

A single economic search was undertaken for all topics included in the scope of this guideline. See supplementary material 2 for details.

Excluded studies

No full-text copies of articles were requested for this review and so there is no excluded studies list.

Economic model

No economic modelling was undertaken for this review because the committee agreed that other topics were higher priorities for economic evaluation.

Evidence statements

Comparison 1. 200 mcg versus 400 mcg vaginal misoprostol (at 4 hour intervals) 36 to 48 hours after oral mifepristone 200 mg

Critical outcomes

Time to expulsion

RCT evidence showed that the time to expulsion was statistically^a significantly longer in the 200 mcg vaginal misoprostol group (median [range]=9.2 [7.1 to 11.3] hours) compared with the 400 mcg vaginal misoprostol group (median [range]=8.0 [7.1 to 8.9] hours; 1 RCT, n=176; low quality)

Complete abortion without the need for surgical intervention

RCT evidence did not detect a clinically important difference in complete abortion rate without the need for surgical intervention (at 48 hours) between the 200 mcg vaginal misoprostol group and the 400 mcg vaginal misoprostol group (1 RCT, n=176; RR=0.9 [95% CI 0.74, 1.10]; low quality); however, there was uncertainty around the estimate.

Incomplete abortion with the need for surgical intervention

RCT evidence did not detect a clinically important difference in the incomplete abortion rate with the need for surgical intervention between the 200 mcg vaginal misoprostol group and the 400 mcg vaginal misoprostol group (1 RCT, n=176; RR=1.26 [95% CI 0.80, 1.99]; low quality); however, there was uncertainty around the estimate.

Important outcomes

Haemorrhage requiring transfusion or >500 ml of blood loss

RCT evidence did not detect a clinically important difference in the rate of haemorrhage requiring transfusion or >500 ml of blood loss between the 200 mcg vaginal misoprostol group and the given 400 mcg vaginal misoprostol group (1 RCT, n=176; RR=1.4 [95% CI 0.32, 6.05]; low quality); however, there was uncertainty around the estimate.

Vomiting

RCT evidence did not detect a clinically important difference in the rate of vomiting between the 200 mcg vaginal misoprostol group and the 400 mcg vaginal misoprostol group (1 RCT, n=176; RR=0.76 [95% CI 0.51, 1.14]; moderate quality); however, there was uncertainty around the estimate.

Patient satisfaction

No evidence was identified to inform this outcome.

Diarrhoea

RCT evidence did not detect a clinically important difference in the rate of diarrhoea between the 200 mcg vaginal misoprostol group and the 400 mcg vaginal misoprostol group (1 RCT, n=176; RR=0.52 [95% CI 0.19, 1.47]; low quality); however, there was uncertainty around the estimate.

Comparison 2. Vaginal versus oral misoprostol (400 mcg, at 3 hour intervals up to 4 doses following a loading dose of vaginal misoprostol 600 mcg) 36 to 48 hours after oral mifepristone 600 mg

Critical outcomes

Time to expulsion

RCT evidence showed there was no clinically important difference in the time to expulsion between the 400 mcg vaginal misoprostol group and the 400 mcg oral misoprostol group (1 RCT, n=69; MD= −0.7 [95% CI −2.03, 0.63]; high quality)

Complete abortion without the need for surgical intervention

RCT evidence did not a detect a clinically important difference in the complete abortion rate without the need for surgical intervention (at 48 hours) between the 400 mcg vaginal misoprostol group and the 400 mcg oral misoprostol group (1 RCT, n=69; RR=1.0 [95% CI 0.92, 1.09]; low quality); however, there was uncertainty around the estimate.

Incomplete abortion with the need for surgical intervention

RCT evidence did not detect a clinically important difference in the incomplete abortion rate with the need for surgical intervention between the 400 mcg vaginal misoprostol group and the 400 mcg oral misoprostol group (1 RCT, n=69; RR=3.09 [95% CI 0.13, 73.21]; low quality); however, there was uncertainty around the estimate.

Important outcomes

Haemorrhage requiring transfusion or >500ml of blood loss

RCT evidence reported no events of haemorrhage requiring transfusion or >500 ml of blood loss in either the 400 mcg vaginal misoprostol group or the 400 mcg oral misoprostol group; therefore differences between groups could not be estimated (1 RCT, n=69;low quality).

Vomiting

RCT evidence did not detect a clinically important difference in the rate of vomiting between the 400 mcg vaginal misoprostol group and the 400 mcg oral misoprostol group (1 RCT, n=69; RR=0.93 [95% CI 0.63, 1.37]; low quality); however, there was uncertainty around the estimate.

Patient satisfaction

No evidence was identified to inform this outcome.

Diarrhoea

RCT evidence did not detect a clinically important difference in the rate of diarrhoea between the 400 mcg vaginal misoprostol group and the 400 mcg oral misoprostol group (1 RCT, n=69; RR=0.81 [95% CI 0.40, 1.62]; low quality); however, there was uncertainty around the estimate.

Comparison 3. Vaginal versus oral misoprostol (400 mcg; at 4 hour intervals for vaginal misoprostol and 3 hour intervals for oral misoprostol, up to 5 doses following a loading dose of vaginal misoprostol 800 mcg) 24 to 48 hours after oral mifepristone 200 mg

Critical outcomes

Time to expulsion

RCT evidence showed that the time to expulsion was statistically^b significantly shorter in the 400 mcg vaginal misoprostol group (median [range]=7.4 [6.5 to 8.2] hours) compared with the 400 mcg oral misoprostol group (median [range]=9.5 (8.5 to 11.4) hours; 1 RCT, n=200; moderate quality).

Complete abortion without the need for surgical intervention

No evidence was identified to inform this outcome.

Incomplete abortion with the need for surgical intervention

No evidence was identified to inform this outcome.

Important outcomes

Haemorrhage requiring transfusion or >500ml of blood loss

RCT evidence did not detect a clinically important difference in the rate of haemorrhage requiring transfusion or >500 ml of blood loss between the 400 mcg vaginal misoprostol group and the 400 mcg oral misoprostol group (1 RCT, n=200; RR=0.50 [95% CI 0.05, 5.43]; low quality); however, there was uncertainty around the estimate.

Vomiting

No evidence was identified to inform this outcome.

Patient satisfaction (opinion of procedure score)

RCT evidence did not detect a clinically important difference in the opinion of procedure (with lower scores indicating “better than expected” and higher scores indicating “worse than expected”) patient satisfaction score between the 400 mcg vaginal misoprostol group (median [range]=50 [26 to 50]) and the 400 mcg oral misoprostol group (median [range]=50 [20 to 50]; 1 RCT, n=200; low quality); however, there was uncertainty around the estimate.

Diarrhoea

No evidence was identified to inform this outcome.

Comparison 4. Vaginal versus oral misoprostol (200 mcg; at 3 hour intervals, up to 5 doses) ± placebo 36 to 48 hours after 200 mg oral mifepristone

Critical outcomes

Time to expulsion

RCT evidence showed a shorter clinically important difference in the time to expulsion in the 200 mcg vaginal misoprostol group compared with the 200 mcg oral misoprostol group (1 RCT, n=98; MD=-13 [95% CI −23.23, −2.77]; low quality).

Complete abortion without the need for surgical intervention

RCT evidence did not detect a clinically important difference in the complete abortion rate without the need for surgical intervention (at 48 hours) between the 200 mcg vaginal misoprostol group and the 200 mcg oral misoprostol group (1 RCT, n=98; RR=1.24 [95% CI 0.93, 1.65]; low quality); however, there was uncertainty around the estimate.

Incomplete abortion with the need for surgical intervention

No evidence was identified to inform this outcome.

Important outcomes

Haemorrhage requiring transfusion or >500ml of blood loss

No evidence was identified to inform this outcome.

Vomiting

RCT evidence did not detect a clinically important difference in the rate of vomiting between the 200 mcg vaginal misoprostol group and the 200 mcg oral misoprostol group (1 RCT, n=98; RR=1.40 [95% CI 0.69, 2.84]; low quality); however, there was uncertainty around the estimate.

Patient satisfaction

No evidence was identified to inform this outcome.

Diarrhoea

RCT evidence did not detect a clinically important difference in the rate of diarrhoea between the 200 mcg vaginal misoprostol group and the 200 mcg oral misoprostol group (1 RCT, n=98; RR=0.56 [95% CI 0.28, 1.15]; moderate quality); however, there was uncertainty around the estimate.

Comparison 5. Oral versus vaginal misoprostol (400 mcg at 3 hour intervals, up to 5 doses) ± placebo 36 to 48 hours after oral mifepristone 200 mg

Critical outcomes

Time to expulsion

RCT evidence showed there was no clinically important difference in the time to expulsion between the 400 mcg oral misoprostol group and the 400 mcg vaginal misoprostol group (1 RCT, n=139; MD=-1.3 [95% CI −8.7, 11.33]; moderate quality).

Complete abortion without the need for surgical intervention

RCT evidence did not detect a clinically important difference in the complete abortion rate without the need for surgical intervention (at 48 hours) between the 400 mcg oral misoprostol group and the 400 mcg vaginal misoprostol group (1 RCT, n=139; RR=0.97 [95% CI 0.83, 1.13]; very low quality); however, there was uncertainty around the estimate.

Incomplete abortion with the need for surgical intervention

RCT evidence reported no events of incomplete abortion with the need for surgical intervention in either the 400 mcg oral misoprostol group or the 400 mcg vaginal misoprostol group; therefore differences between groups could not be estimated (1 RCT, n=139; very low quality).

Important outcomes

Haemorrhage requiring transfusion or >500ml of blood loss

No evidence was identified to inform this outcome.

Vomiting

RCT evidence did not detect a clinically important difference in the rate of vomiting between the 400 mcg oral misoprostol group and the 400 mcg vaginal misoprostol group (1 RCT, n=139; RR=1.05 [95% CI 0.72, 1.54]; very low quality); however, there was uncertainty around the estimate.

Patient satisfaction

No evidence was identified to inform this outcome.

Diarrhoea

RCT evidence showed a higher clinically important difference in the rate of diarrhoea in the 400 mcg oral misoprostol group compared to the 400 mcg vaginal misoprostol group (1 RCT, n=139; RR=1.73 [95% CI 1.03, 2.89]; low quality).

Comparison 6. Sublingual versus oral misoprostol (400 mcg; at 3 hour intervals, up to 5 doses following a loading dose of vaginal misoprostol 800 mcg) 24 to 48 hours after oral mifepristone 200 mg

Critical outcomes

Time to expulsion

RCT evidence showed that the time to expulsion was statistically^c significantly shorter in the 400 mcg sublingual misoprostol group (median [range]=7.8 [7.0 to 9.2] hours) compared with the 400 mcg oral misoprostol group (median [range]=9.5 [8.5 to 11.4] hours; 1 RCT, n=202; moderate quality).

Complete abortion without the need for surgical intervention

No evidence was identified to inform this outcome.

Incomplete abortion with the need for surgical intervention

No evidence was identified to inform this outcome.

Important outcomes

Haemorrhage requiring transfusion or >500ml of blood loss

RCT evidence did not detect a clinically important difference in the rate of haemorrhage requiring transfusion or >500 ml of blood loss between the 400 mcg sublingual misoprostol group and the 400 mcg oral misoprostol group (1 RCT, n=202; RR=0.98 [95% CI 0.14, 6.83]; low quality); however, there was uncertainty around the estimate.

Vomiting

No evidence was identified to inform this outcome.

Patient satisfaction (opinion of procedure score)

RCT evidence did not detect a clinically important difference in the opinion of procedure (with lower scores indicating “better than expected” and higher scores indicating “worse than expected”) patient satisfaction score between the 400 mcg sublingual misoprostol group (median [range]=50 [19 to 50]) and the 400 mcg oral misoprostol group (median [range]=50 [20 to 50]; 1 RCT, n=202; low quality); however, there was uncertainty around the estimate.

Diarrhoea

No evidence was identified to inform this outcome.

Comparison 7. Sublingual versus oral misoprostol (400 mcg, at 3 hour intervals up to 5 doses) 36 to 48 hours after oral mifepristone 200 mg

Critical outcomes

Time to expulsion

RCT evidence showed that the time to expulsion was statistically^d significantly shorter in the 400 mcg sublingual misoprostol group (median [range]=5.5 [1.4 to 43.2] hours) compared with the 400 mcg oral misoprostol group (median [range]=7.5 [2.4 to 38.8] hours; 1 RCT, n=118; low quality).

Complete abortion without the need for surgical intervention

RCT evidence did not detect a clinically important difference in the complete abortion rate without the need for surgical intervention (at 48 hours) between the 400 mcg sublingual misoprostol group and the 400 mcg oral misoprostol group (1 RCT, n=118; RR=1.07 [95% CI 0.99-1.17]; moderate quality); however, there was uncertainty around the estimate.

Incomplete abortion with the need for surgical intervention

RCT evidence showed did not detect a clinically important difference in the incomplete abortion rate with the need for surgical intervention between the 400 mcg sublingual misoprostol group and the 400 mcg oral misoprostol group (1 RCT, n=118; RR=1.48 [95% CI 0.60, 3.62]; low quality); however, there was uncertainty around the estimate.

Important outcomes

Haemorrhage requiring transfusion or >500ml of blood loss

No evidence was identified to inform this outcome.

Vomiting

No evidence was identified to inform this outcome.

Patient satisfaction

No evidence was identified to inform this outcome.

Diarrhoea

RCT evidence showed did not detect a clinically important difference in the rate of diarrhoea between the 400 mcg sublingual misoprostol group and the 400 mcg oral misoprostol group (1 RCT, n=118; RR=0.64 [95% CI 0.29, 1.42]; low quality); however, there was uncertainty around the estimate.

Comparison 8. Sublingual (600 mcg; followed by 400 mcg at 3 hour intervals up to 5 doses) versus vaginal (800 mcg; followed by 400 mcg at 3 hour intervals up to 5 doses) misoprostol, 36 to 48 hours after oral mifepristone 200 mg

Critical outcomes

Time to expulsion

RCT evidence did not detect a clinically important difference in the time to expulsion between the 600 mcg sublingual misoprostol group (median [range]=5.27 [0.55 to 29.35] hours) and the 800 mcg vaginal misoprostol group (median [range]=5.40 [2.10 to 13.00] hours; 1 RCT, n=76; low quality); however, there was uncertainty around the estimate.

Complete abortion without the need for surgical intervention

No evidence was identified to inform this outcome.

Incomplete abortion with the need for surgical intervention

RCT evidence did not detect a clinically important difference in the rate of incomplete abortion with the need for surgical intervention between the 600 mcg sublingual misoprostol group and the 800 mcg vaginal misoprostol group (1 RCT, n=76; RR=3.33 [95% CI 0.36, 30.63]; low quality); however, there was uncertainty around the estimate.

Important outcomes

Haemorrhage requiring transfusion or >500ml of blood loss

No evidence was identified to inform this outcome.

Vomiting

RCT evidence did not detect a clinically important difference in the rate of vomiting between the 600 mcg sublingual misoprostol group and the 800 mcg vaginal misoprostol group (1 RCT, n=76; RR=1.11 [95% CI 0.80, 1.54]; low quality); however, there was uncertainty around the estimate.

Patient satisfaction (satisfied with the route of administration)

RCT evidence did not detect a clinically important difference in the rate of women who were “satisfied” with the route of administration of misoprostol between the 600 mcg sublingual misoprostol group and the 800 mcg vaginal misoprostol group (1 RCT, n=76; RR=1.07 [95% CI 0.76, 1.49]; very low quality); however, there was uncertainty around the estimate.

Diarrhoea

RCT evidence did not detect a clinically important difference in the rate of diarrhoea between the 600 mcg sublingual misoprostol group and the 800 mcg vaginal misoprostol group (1 RCT, n=76; RR=1.01 [95% CI 0.66, 1.54]; low quality); however, there was uncertainty around the estimate.

Comparison 9. Oral misoprostol (400 mcg; every 6 hours, up to 2 doses) 1 versus 2 days after oral mifepristone 200 mg + 600 mcg vaginal misoprostol

Critical outcomes

Time to expulsion

RCT evidence showed there was no clinically important difference in the time to expulsion between the oral misoprostol 1 day after oral mifepristone group and the oral misoprostol 2 days after oral mifepristone group (1 RCT, n=100; MD=0.20 [95% CI −1.25,1.65]; low quality).

Complete abortion without the need for surgical intervention

RCT evidence showed a lower clinically important difference in the rate of complete abortion without the need for surgical intervention (at 24 hours) in the oral misoprostol 1 day after oral mifepristone group compared with the oral misoprostol 2 days after oral mifepristone group (1 RCT, n=100; RR=0.68 [95% CI 0.47, 0.97]; low quality).

Incomplete abortion with the need for surgical intervention

RCT evidence did not detect a clinically important difference in the rate of incomplete abortion with the need for surgical intervention between the oral misoprostol 1 day after oral mifepristone group and the oral misoprostol 2 days after oral mifepristone group (1 RCT, n=100; RR=3 [95% CI 0.13, 71.92]; very low quality); however, there was uncertainty around the estimate..

Important outcomes

Haemorrhage requiring transfusion or >500ml of blood loss

No evidence was identified to inform this outcome.

Vomiting

RCT evidence showed no clinically important difference in the rate of vomiting between the oral misoprostol 1 day after oral mifepristone group and the oral misoprostol 2 days after oral mifepristone group (1 RCT, n=100; RR=0.93 [95% CI 0.51, 1.72]; very low quality).

Patient satisfaction

No evidence was identified to inform this outcome.

Diarrhoea

RCT evidence showed no clinically important difference in the rate of diarrhoea between the oral misoprostol 1 day after oral mifepristone group and the oral misoprostol 2 days after oral mifepristone group (1 RCT, n=100; RR=2.25 [95% CI 0.74, 6.83]; very low quality).

Comparison 10. Vaginal misoprostol (400 mcg; at 3 hour intervals, up to 5 doses per 24 hours) 1 versus 2 days after oral mifepristone 200 mg

Critical outcomes

Time to expulsion

RCT evidence showed that the time to expulsion was statistically^e significantly longer in the 400 mcg vaginal misoprostol 1 day after oral mifepristone group (median [range]=8.5 [6.3 to 12.3)] hours) compared with the 400 mcg vaginal misoprostol 2 days after oral mifepristone group (median [range]=7.2 [5.8 to 9.2] hours; 1 RCT, n=227; moderate quality).

Complete abortion without the need for surgical intervention

No evidence was identified to inform this outcome.

Incomplete abortion with the need for surgical intervention

RCT evidence did not detect a clinically important difference in the rate of incomplete abortion with the need for surgical intervention between the 400 mcg vaginal misoprostol 1 day after oral mifepristone group and the 400 mcg vaginal misoprostol 2 days after oral mifepristone group (1 RCT, n=227; RR=0.69 [95% CI 0.46, 1.03]; moderate quality); however, there was uncertainty around the estimate.

Important outcomes

Haemorrhage requiring transfusion or >500ml of blood loss

RCT evidence did not detect a clinically important difference in the rate of haemorrhage requiring transfusion or >500 ml blood loss between the 400 mcg vaginal misoprostol 1 day after oral mifepristone group and the 400 mcg vaginal misoprostol 2 days after oral mifepristone group (1 RCT, n=227; RR=1.11 [95% CI 0.42, 2.97]; low quality); however, there was uncertainty around the estimate.

Vomiting

RCT evidence did not detect a clinically important difference in the rate of vomiting (need for anti-emetic drugs) between the 400 mcg vaginal misoprostol 1 day after oral mifepristone group and the 400 mcg vaginal misoprostol 2 days after oral mifepristone group (1 RCT, n=227; RR=1.22 [95% CI 0.76, 1.95]; very low quality); however, there was uncertainty around the estimate.

Patient satisfaction

No evidence was identified to inform this outcome.

Diarrhoea

No evidence was identified to inform this outcome.

Comparison 11. Vaginal misoprostol (600 mcg; followed by 400 mcg at 3 hour intervals, up to 4 doses) simultaneous with mifepristone 200 mg versus 36 to 38 hours after 200 mg oral mifepristone

Critical outcomes

Time to expulsion

RCT evidence showed that the time to expulsion was statistically^f significantly longer in the 600 mcg vaginal misoprostol simultaneously with oral mifepristone group (median [range]=10.0 [3.5 to 126] hours) compared with the 600 mcg vaginal misoprostol 36 to 38 hours after oral mifepristone group (median [range]=4.9 [1.8 to 13.8] hours; 1 RCT, n=141; low quality).

Complete abortion without the need for surgical intervention

RCT evidence did not detect a clinically important difference in the rate of complete abortion without the need for surgical intervention between the 600 mcg vaginal misoprostol simultaneously with oral mifepristone group and the 600 mcg vaginal misoprostol 36 to 38 hours after oral mifepristone group (1 RCT, n=141; RR=0.99 [95% CI 0.95, 1.03]; low quality); however, there was uncertainty around the estimate.

Incomplete abortion with the need for surgical intervention

RCT evidence did not detect a clinically important difference in the rate of incomplete abortion with the need for surgical intervention between the 600 mcg vaginal misoprostol simultaneously with oral mifepristone group and the 600 mcg vaginal misoprostol 36 to 38 hours after oral mifepristone group (1 RCT, n=141; RR=4.93 [95% CI 0.59, 41.13]; low quality); however, there was uncertainty around the estimate.

Important outcomes

Haemorrhage requiring transfusion or >500ml of blood loss

RCT evidence reported no events of haemorrhage requiring transfusion or >500ml of blood loss in either the 600 mcg vaginal misoprostol simultaneously with oral mifepristone group or the 600 mcg vaginal misoprostol 36 to 38 hours after oral mifepristone group; therefore differences between groups could not be estimated (1 RCT, n=141;; low quality).

Vomiting

No evidence was identified to inform this outcome.

Patient satisfaction

No evidence was identified to inform this outcome.

Diarrhoea

RCT evidence did not detect a clinically important difference in the rate of diarrhoea (> 3 episodes) between the 600 mcg vaginal misoprostol simultaneously with oral mifepristone group and the 600 mcg vaginal misoprostol 36 to 38 hours after oral mifepristone group (1 RCT, n=141; RR=1.77 [95% CI 0.88, 3.57]; moderate quality); however, there was uncertainty around the estimate..

Comparison 12. Buccal misoprostol 400 mcg (at 3 hour intervals) ± placebo simultaneous with mifepristone 200 mg versus 1 day following oral mifepristone 200 mg

Critical outcomes

Time to expulsion

RCT evidence showed that the time to expulsion was statistically^g significantly longer in the buccal misoprostol simultaneously with oral mifepristone group (median [range]=13.0 [4.9 to 47.8] hours) compared with the 400 mcg buccal misoprostol 1 day after oral mifepristone group (median [range]=7.7 [2.1 to 40.3] hours; 1 RCT, n=505; moderate quality).

Complete abortion without the need for surgical intervention

RCT evidence did not detect a clinically important difference in the rate of complete abortion without the need for surgical intervention at 48 hours between the 400 mcg buccal misoprostol simultaneously with oral mifepristone group and the 400 mcg buccal misoprostol 1 day after oral mifepristone group (1 RCT, n=505; RR=0.99 [95% CI 0.95, 1.02]; low quality); however, there was uncertainty around the estimate.

Incomplete abortion with the need for surgical intervention

RCT evidence did not detect a clinically important difference in the rate of incomplete abortion with the need for surgical intervention between the 400 mcg buccal misoprostol simultaneously with oral mifepristone group and the 400 mcg buccal misoprostol 1 day after oral mifepristone group (1 RCT, n=505; RR=1.98 [95% CI 0.18, 21.66]; very low quality); however, there was uncertainty around the estimate.

Important outcomes

Haemorrhage requiring transfusion or >500ml of blood loss

RCT evidence did not detect a clinically important difference in the rate of haemorrhage requiring transfusion or >500ml of blood loss between the 400 mcg buccal misoprostol simultaneously with oral mifepristone group and the 400 mcg buccal misoprostol 1 day after oral mifepristone group (1 RCT, n=505; RR=2.96 [95% CI 0.12, 72.43]; very low quality); however, there was uncertainty around the estimate.

Vomiting

RCT evidence did not detect a clinically important difference in the rate of vomiting between the 400 mcg buccal misoprostol simultaneously with oral mifepristone group and the 400 mcg buccal misoprostol 1 day after oral mifepristone group (1 RCT, n=505; RR=1.09 [95% CI 0.8, 1.49]; very low quality); however, there was uncertainty around the estimate.

Patient satisfaction (satisfied or very satisfied)

RCT evidence showed there was no clinically important difference in the rate of patient satisfaction (satisfied or very satisfied) between the 400 mcg buccal misoprostol simultaneously with oral mifepristone group and the 400 mcg buccal misoprostol 1 day after oral mifepristone group (1 RCT, n=505; RR=1 [95% CI 0.98, 1.02]; moderate quality).

Diarrhoea

RCT evidence showed there was a higher clinically important difference in the rate of diarrhoea in the 400 mcg buccal misoprostol simultaneously with oral mifepristone group compared to the 400 mcg buccal misoprostol 1 day after oral mifepristone group (1 RCT, n=505; RR=1.63 [95% CI 1.32, 2.01]; moderate quality).

The committee’s discussion of the evidence

Interpreting the evidence

The outcomes that matter most

The main aim of this review was to determine the optimal dose regimen and route of administration of misoprostol, following mifepristone for the medical abortion of pregnancy between 10⁺¹ and 24⁺⁰ weeks. The committee agreed that, the time to expulsion should be prioritised as a critical outcome as it varies with the dose regimen, the route of administration and the dosing interval of misoprostol and was critical for decision making given its implications for the woman and the health care resources. Complete abortion without the need for surgical intervention and incomplete abortion with the need for surgical intervention were selected as critical outcomes as they may have implications for the woman in terms of having to undergo surgical intervention and also impact resources. Haemorrhage requiring transfusion of greater than 500 ml of blood loss was considered an important outcome for decision making, because of the seriousness of the outcome. Patient satisfaction was considered as an important outcome as abortion is an area where women are known to have strong preferences. Vomiting and diarrhoea were included as important outcomes to allow for a balance of the benefits and harms as the likelihood of these occurring differs with the dose regimens, routes of administration and dosing intervals of misoprostol and they are likely to impact patient satisfaction.

The quality of the evidence

The evidence in the pairwise comparisons was assessed using the GRADE methodology. Evidence for time to expulsion ranged from low to high quality; the main reason evidence was downgraded was for imprecision caused by few events of interest but there was also risk of bias due to unclear randomization and unclear allocation concealment methods. Evidence for complete abortion without the need for surgical intervention ranged from very low to moderate quality; the main reason evidence was downgraded was due to imprecision caused by 95% confidence intervals crossing minimally important difference (MID) values and risk of bias caused by inadequate information regarding randomization and allocation concealment for studies comparing misoprostol regimens. The evidence for rate of incomplete abortion with the need for surgical intervention was very low to moderate quality. As with complete abortion rate, the reasons to downgrade the evidence was imprecision and risk of bias in studies reporting this outcome. The evidence for the outcome, haemorrhage requiring transfusion or >500 ml of blood loss was very low to low quality. The reasons for downgrading of evidence were imprecision caused by a small number or no events of interest and risk of bias in the included studies due to unclear randomization methods. Evidence for vomiting and diarrhoea ranged from very low to moderate quality; the most common reasons for downgrading evidence was imprecision due to wide confidence intervals and risk of bias due to attrition and insufficient information about randomization and allocation concealment methods. Evidence for patient satisfaction was of very low to moderate quality, mainly due to risk of bias because of lack of blinding and imprecision due to small number of events of interest.

Benefits and harms

There was evidence from 11 randomised controlled trials regarding the comparison of dose regimens for the medical abortion between 10⁺¹ and 24⁺⁰ weeks of gestation. The randomised trials compared dose regimens with different misoprostol doses, misoprostol routes and mifepristone-misoprostol intervals. Despite the fact that there were more than 1 study reporting the comparison between 2 routes of administration or mifepristone-misoprostol intervals, pooling of results of the trials was not possible due to the difference in drug regimens, including the loading dose and intervals between two doses. Hence, pairwise comparison was conducted for all comparisons. The committee discussed that most studies included a loading dose of vaginal misoprostol in their regimen. The committee noted the biological plausibility of administering a loading dose in this gestation age group to harness the prostaglandin sensitivity. There was some evidence regarding the administration of misoprostol by oral, sublingual and vaginal routes following a loading dose of 800 mcg vaginal misoprostol. There was also evidence from dose regimens using buccal route of administration. The committee noted that presently, a loading dose of 800 mcg vaginal misoprostol is administered for abortion before 10 weeks, and discussed that using the same loading dose after 10 weeks would keep the loading dose regimen standardised and it would be operationally easier for the staff to follow the same regimen up to 24 weeks. Hence, the committee made the recommendation regarding the misoprostol loading dose regimen of 800 mcg vaginal misoprostol followed by 400 mcg doses of misoprostol every 3 hours until expulsion (vaginal, sublingual or buccal route). The committee recognised that, for some women vaginal route may not be the preferred route of administration. There was some evidence that there was no difference in time to expulsion, the rate of complete abortion and gastrointestinal side effects between sublingual and vaginal routes of misoprostol administration. Hence, the committee discussed that if vaginal route was not preferred by the woman, then a loading dose of misoprostol could be administered sublingually. The sublingual loading dose was taken from this study comparing regimens with loading dose of 800 mcg vaginal misoprostol and 600 mcg sublingual misoprostol.

Although only 1 trial directly compared the follow up dose of 400 mcg of misoprostol administered through oral, sublingual and vaginal routes but the vast majority of included studies used 400 mcg doses of misoprostol. Considering the weight of the evidence and the evidence from 1 trial showing that a direct comparison of 200 mcg with 400 mcg showed a longer time to expulsion with 200 mcg, the committee agreed that following the loading dose, 400 mcg of misoprostol should be offered every 3 hours until expulsion.

There was evidence that the time to expulsion was statistically significantly longer with the simultaneous administration of misoprostol with mifepristone or a shorter mifepristone-misoprostol interval. It was unclear whether there was a clinically important difference in the outcome between the treatment groups because the way it was reported in 3 studies (as medians) precluded the possibility of calculation of minimally important differences. The committee discussed that a shorter time to expulsion following larger interval between mifepristone and misoprostol administration was biologically plausible between 10⁺¹ and 24⁺⁰ weeks’ gestation, as a larger fetus may benefit from a greater cervical dilation effect of mifepristone and sensitisation of the uterus. Time to expulsion was 1 of the critical outcomes for this review and hence, the committee agreed that misoprostol should be administered 36 to 48 hours after the administration of mifepristone for abortion between 10⁺¹ and 24⁺⁰ weeks’ gestation. The interval of 36 to 48 hours was chosen as there was evidence of effectiveness for dose regimens with this interval for vaginal and sublingual misoprostol with the same loading and follow-up doses, as included in the recommendation. It was also the most commonly used dosing interval in the included trials, reported in 4 out of 11 included trials.

The committee recognised that, sometimes it may not be possible to have the dosing interval of 36 to 48 hours between mifepristone and misoprostol as the women may not prefer a long interval between the 2 drugs, either due to service provision or other factors making it less convenient for her. The committee agreed that convenience of women should be an important consideration, and hence, the committee agreed that, in such situations, a shorter mifepristone-misoprostol interval should be considered. However, the committee noted that, in such circumstances, the woman should be informed regarding the longer time to induction associated with a shorter duration between mifepristone and misoprostol administration.

As there was sufficient evidence to inform the recommendations, the committee decided to prioritise other areas addressed by the guideline for future research and therefore made no research recommendations regarding the optimal regimen and route of administration of misoprostol after mifepristone for inducing medical abortion between 10⁺¹ and 24⁺⁰ weeks.

Cost effectiveness and resource use

A systematic review of the economic literature was conducted but no relevant studies were identified which were applicable to this review question.

The committee considered that there was unlikely to be a significant resource impact from the recommendations made. The use of oral misoprostol, which has a longer time to expulsion and higher number of adverse effects than vaginal or sublingual route, is likely to reduce with the recommendations. Any net effect of this change is likely to be cost saving with reduction in the hospitalisation time.

Other consideration

There was some evidence that vaginal and sublingual routes of administration were associated with a shorter time to expulsion and vaginal route was associated with fewer gastrointestinal side effects, when compared to oral route of administration of misoprostol. Hence, the committee did not make a recommendation about administering misoprostol by oral route. However, the committee discussed that practitioners could consider administering misoprostol orally for repeat doses if other routes of administration are not acceptable to the woman or not appropriate. The committee also noted that, when doing so, it is important that women are advised that oral administration of misoprostol is associated with a longer induction to expulsion interval than administration by other routes.

The committee were aware of guidelines from the Royal College of Obstetricians and Gynaecologists that recommend feticide is used for abortion after 21⁺⁶ weeks’ gestation (RCOG 2011).

The evidence considered for this review question covered the gestational age range between 10⁺¹ and 24⁺⁰ weeks’ gestation. However, recommendations were made for women between 10⁺¹ and 23⁺⁶ weeks’ gestation to be consistent with the requirements of the 1967 Abortion Act.

References

Abbas 2016
Abbas, D. F., Blum, J., Ngoc, N. T. N., Nga, N. T. B., Chi, H. T. K., Martin, R., Winikoff, B.(2016). Simultaneous Administration Compared with a 24-Hour Mifepristone-Misoprostol Interval in Second-Trimester Abortion, Obstetrics and Gynecology, 128, 1077–1083. [PubMed: 27741182]
Brouns 2010
Brouns, J. F. G. M., Van Wely, M., Burger, M. P. M., Van Wijngaarden, W. J. (2010). Comparison of two dose regimens of misoprostol for second-trimester pregnancy termination, Contraception, 82, 266–275. [PubMed: 20705156]
Chai 2009
Chai, J., Tang, O. S., Hong, Q. Q., Chen, Q. F., Cheng, L. N., Ng, E., Ho, P. C..(2009). A randomized trial to compare two dosing intervals of misoprostol following mifepristone administration in second trimester medical abortion, Human Reproduction, 24, 320–324. [PubMed: 19049993]
Dickinson 2014
Dickinson, J. E., Jennings, B. G., Doherty, D. A. (2014). Mifepristone and oral, vaginal, or sublingual misoprostol for second-trimester abortion: a randomized controlled trial, Obstetrics & GynecologyObstet Gynecol, 123, 1162–8. [PubMed: 24807339]
El-Refaey 1995
El-Refaey, H., Templeton, A. (1995). Induction of abortion in the second trimester by a combination of misoprostol and mifepristone: A randomized comparison between two misoprostol regimens, 10, 475–478. [PubMed: 7769082]
Hamoda 2005
Hamoda, H., Ashok, P. W., Flett, G. M. M., Templeton, A. (2005). A randomized trial of mifepristone in combination with misoprostol administered sublingually or vaginally for medical abortion at 13-20 weeks’ gestation, Human Reproduction, 20, 2348–2354. [PubMed: 15878927]
Ho 1997
Ho, P. C., Ngai, S. W., Liu, K. L., Wong, G. C. Y., Lee, S. W. H. (1997).Vaginal misoprostol compared with oral misoprostol in termination of second-trimester pregnancy, 90, 735–738. [PubMed: 9351755]
Hou 2010
Hou,S., Zhang,L., Chen,Q., Fang,A., Cheng,L.(2010). One- and two-day mifepristone-misoprostol intervals for second trimester termination of pregnancy between 13 and 16 weeks of gestation, International Journal of Gynaecology and Obstetrics, 111, 126–130. [PubMed: 20705290]
Mentula 2011
Mentula, M, Suhonen, S, Heikinheimo, O. (2011). One- and two-day dosing intervals between mifepristone and misoprostol in second trimester medical termination of pregnancy--a randomized trial, Human reproduction (Oxford, England), 26, 2690–2697. [PubMed: 21798991]
Ngai 2000
Ngai, S. W., Tang, O. S., Ho, P. C. (2000). Randomized comparison of vaginal (200 mug every 3 h) and oral (400 mug every 3 h) misoprostol when combined with mifepristone in termination of second trimester pregnancy, Human Reproduction, 15, 2205–2208. [PubMed: 11006200]
RCOG 2011
Royal College of Obstetricians and Gynaecologists (2011). The care of women requesting induced abortion: Evidence-based clinical guideline number 7. London: RCOG Press.
Tang 2005
Tang, O. S., Chan, C. C. W., Kan, A. S. Y., Ho, P. C. (2005). A prospective randomized comparison of sublingual and oral misoprostol when combined with mifepristone for medical abortion at 12-20 weeks’ gestation, Human Reproduction, 20, 3062–3066. [PubMed: 16037110]

Appendices

Appendix A. Review protocols

Review protocol for review question: What is the optimal regimen and route of administration of misoprostol after mifepristone, for inducing medical abortion from 10⁺¹ to 24⁺⁰ weeks?

Table

Women who are having a medical termination of pregnancy between 10+1 and 24+0 weeks’ gestation Exclusions: -Any studies with an indirect population

Appendix B. Literature search strategies

Literature search strategy for review question: What is the optimal regimen and route of administration of misoprostol after mifepristone, for inducing medical abortion from 10⁺¹ to 24⁺⁰ weeks?

The search for this topic was last run on 14^th June 2018. It was decided not to undertake a re-run for this topic in November 2018 as this is not a fast moving evidence base and there were unlikely to be any new studies published which would affect the recommendations.

Database: Medline & Embase (Multifile)

Last searched on Embase Classic+Embase 1947 to 2018 June 13, Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present

Date of last search: 14^th June 2018

Database: Cochrane Library via Wiley Online

Date of last search: 14^th June 2018

Appendix C. Clinical evidence study selection

Clinical evidence study selection for review question: What is the optimal regimen and route of administration of misoprostol after mifepristone, for inducing medical abortion from 10⁺¹ to 24⁺⁰ weeks?

Figure 1. Study selection flow chart

Appendix D. Clinical evidence tables

Clinical evidence tables for review question: What is the optimal regimen and route of administration of misoprostol after mifepristone, for inducing medical abortion from 10⁺¹ to 24⁺⁰ weeks?

Download PDF (512K)

Appendix E. Forest plots

Forest plots for review question: What is the optimal regimen and route of administration of misoprostol after mifepristone, for inducing medical abortion from 10⁺¹ to 24⁺⁰ weeks?

No meta-analysis was undertaken for this review.

Appendix F. GRADE tables

GRADE tables for review question: What is the optimal regimen and route of administration of misoprostol after mifepristone, for inducing medical abortion from 10⁺¹ to 24⁺⁰ weeks?

Table 3. Clinical evidence profile: Comparison 1. 200 mcg versus 400 mcg vaginal misoprostol (at 4 hour intervals) 36 to 48 hours after oral mifepristone 200 mg

Table 4. Clinical evidence profile: Comparison 2. Vaginal versus oral misoprostol (400 mcg, at 3 hour intervals up to 4 doses following a loading dose of vaginal misoprostol 600 mcg) 36 to 48 hours after oral mifepristone 600 mg

Table 5. Clinical evidence profile: Comparison 3. Vaginal versus oral misoprostol (400 mcg; at 4 hour intervals for vaginal misoprostol and 3 hour intervals for oral misoprostol, up to 5 doses following a loading dose of vaginal misoprostol 800 mcg) 24 to 48 hours after oral mifepristone 200 mg

Table 6. Clinical evidence profile: Comparison 4. Vaginal versus oral misoprostol (200 mcg; at 3 hour intervals, up to 5 doses) ± placebo 36 to 48 hours after 200 mg oral mifepristone

Table 7. Clinical evidence profile: Comparison 5. Oral versus vaginal misoprostol (400 mcg at 3 hour intervals, up to 5 doses) ± placebo 36 to 48 hours after oral mifepristone 200 mg

Table 8. Clinical evidence profile: Comparison 6. Sublingual versus oral misoprostol (400 mcg; at 3 hour intervals, up to 5 doses following a loading dose of vaginal misoprostol 800 mcg) 24 to 48 hours after oral mifepristone 200 mg

Table 9. Clinical evidence profile: Comparison 7. Sublingual versus oral misoprostol (400 mcg, at 3 hour intervals up to 5 doses) 36 to 48 hours after oral mifepristone 200 mg

Table 10. Clinical evidence profile: Comparison 8. Sublingual (600 mcg; followed by 400 mcg at 3 hour intervals up to 5 doses) versus vaginal (800 mcg; followed by 400 mcg at 3 hour intervals up to 5 doses) misoprostol, 36 to 48 hours after oral mifepristone 200 mg

Table 11. Clinical evidence profile: Comparison 9. Oral misoprostol (400 mcg; every 6 hours, up to 2 doses) 1 versus 2 days after oral mifepristone 200 mg + 600 mcg vaginal misoprostol

Table 12. Clinical evidence profile: Comparison 10. Vaginal misoprostol (400 mcg; at 3 hour intervals, up to 5 doses per 24 hours) 1 versus 2 days after oral mifepristone 200 mg

Table 13. Clinical evidence profile: Comparison 11. Vaginal misoprostol (600 mcg; followed by 400 mcg at 3 hour intervals, up to 4 doses) simultaneous with mifepristone 200 mg versus 36 to 38 hours after 200 mg oral mifepristone

Table 14. Clinical evidence profile: Comparison 12. Buccal misoprostol 400 mcg (at 3 hour intervals) ± placebo simultaneous with mifepristone 200 mg versus 1 day following oral mifepristone 200 mg

Appendix G. Economic evidence study selection

Economic evidence for review question: What is the optimal regimen and route of administration of misoprostol after mifepristone, for inducing medical abortion from 10⁺¹ to 24⁺⁰ weeks?

No economic evidence was identified which was applicable to this review question.

Appendix H. Economic evidence tables

Economic evidence tables for review question: What is the optimal regimen and route of administration of misoprostol after mifepristone, for inducing medical abortion from 10⁺¹ to 24⁺⁰ weeks?

No economic evidence was identified which was applicable to this review question.

Appendix I. Economic evidence profiles

Economic evidence profiles for review question: What is the optimal regimen and route of administration of misoprostol after mifepristone, for inducing medical abortion from 10⁺¹ to 24⁺⁰ weeks?

No economic evidence was identified which was applicable to this review question.

Appendix J. Economic analysis

Economic analysis for review question: What is the optimal regimen and route of administration of misoprostol after mifepristone, for inducing medical abortion from 10⁺¹ to 24⁺⁰ weeks?

No economic analysis was conducted for this review question.

Appendix K. Excluded studies

Excluded studies for review question: What is the optimal regimen and route of administration of misoprostol after mifepristone, for inducing medical abortion from 10⁺¹ to 24⁺⁰ weeks?

Clinical studies

Table

Economic studies

No economic evidence was identified for this review. See supplementary material 2 for further information.

Appendix L. Research recommendations

No research recommendations were made for this review.

Footnotes

a: Due to the use of medians for which there are no established or default GRADE MIDs it is unclear whether these differences are clinically important.

b: Due to the use of medians for which there are no established or default GRADE MIDs it is unclear whether these differences are clinically important.

c: Due to the use of medians for which there are no established or default GRADE MIDs it is unclear whether these differences are clinically important.

d: Due to the use of medians for which there are no established or default GRADE MIDs it is unclear whether these differences are clinically important.

e: Due to the use of medians for which there are no established or default GRADE MIDs it is unclear whether these differences are clinically important.

f: Due to the use of medians for which there are no established or default GRADE MIDs it is unclear whether these differences are clinically important.

g: Due to the use of medians for which there are no established or default GRADE MIDs it is unclear whether these differences are clinically important.

Final

Evidence reviews

These evidence reviews were developed by the National Guideline Alliance hosted by the Royal College of Obstetricians and Gynaecologists

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK561115PMID: 32813465

Table 1Summary of the protocol (PICO table)

Population	Women who are having a medical termination of pregnancy between 10⁺⁰ and 24⁺⁰ weeks’ gestation
Intervention	Route of misoprostol administration: Vaginal Oral Sublingual Buccal Dose of misoprostol: 200 micrograms (mcg) 400 mcg 600 mcg 800 mcg Dose interval
Comparison	All combinations of the routes of administration, doses, number of doses, and dosing intervals listed above will be compared.
Outcome	Critical outcomes: Time to expulsion Complete abortion without the need for surgical intervention Incomplete abortion with the need for surgical intervention Important outcomes: Haemorrhage requiring transfusion or >500 ml of blood loss Vomiting Patient satisfaction Diarrhoea

: mcg: micrograms

Table 2Summary of included studies

Study and setting

Population

Intervention/ comparison

Outcomes

Abbas 2016

RCT

Vietnam

n=505

Women with a live foetus eligible for medical abortion, with closed cervical os, no vaginal bleeding and no contraindications to study drugs 13 to 22 weeks’ gestation

Simultaneous administration of mifepristone and misoprostol:

Placebo followed 24 hours later by 200 mg mifepristone and 400 mcg buccal misoprostol followed by 400 mcg buccal misoprostol every 3 hours until expulsion of foetus or 48 hours

24 hour interval between mifepristone and misoprostol:

200 mg mifepristone followed 24 hours later by 200 mg placebo and 400 mcg buccal misoprostol followed by 400 mcg buccal misoprostol every 3 hours until expulsion of foetus or 48 hours

Time to expulsion
Complete abortion without the need for surgical intervention
Incomplete abortion with the need for surgical intervention
Haemorrhage requiring transfusion or >500 ml of blood loss
Vomiting
Patient satisfaction
Diarrhoea

Brouns 2010

RCT

The Netherlands

n =176

Women requesting abortion

14 to 24 weeks’ gestation

200 mcg vaginal misoprostol: 200 mcg vaginal misoprostol at 4 hour intervals, 36 to 48 hours following oral mifepristone 200 mg

400 mcg vaginal misoprostol: 400 mcg vaginal misoprostol at 4 hour intervals, 36 to 48 hours following oral mifepristone 200 mg

Time to expulsion
Complete abortion without the need for surgical intervention
Incomplete abortion with the need for surgical intervention
Haemorrhage requiring transfusion or >500 ml of blood loss
Vomiting
Diarrhoea

Chai 2009

RCT

China

n=141

Healthy women, more than 18 years old, requesting abortion and willing to comply with follow to up

12 to 20 weeks’ gestation

Simultaneous administration of mifepristone and misoprostol:

200 mg mifepristone orally followed by 600 mcg vaginal misoprostol immediately, which was then followed by 400 mcg vaginal misoprostol every 3 hours up to 4 doses

36 to 38 hour interval between mifepristone and misoprostol:

200 mg mifepristone orally followed by 600 mcg vaginal misoprostol 36 to 38 hours later followed by 400 mcg vaginal misoprostol every 3 hours up to 4 doses

Time to expulsion
Complete abortion without the need for surgical intervention
Incomplete abortion with the need for surgical intervention
Haemorrhage requiring transfusion or >500 ml of blood loss
Diarrhoea

Dickinson 2014

RCT

Australia

n=302

Women requesting a second trimester medical abortion for foetal abnormality or maternal medical complication

14 to 24 weeks’ gestation

Oral misoprostol: mifepristone 200 mg followed 24 to 48 hours later by 800 mcg vaginal misoprostol followed by 400 mcg oral misoprostol every 3 hours up to 5 doses

Vaginal misoprostol: mifepristone 200 mg followed 24 to 48 hours later by 800 mcg vaginal misoprostol followed by 400 mcg vaginal misoprostol every 4 hours up to 5 doses

Sublingual misoprostol: mifepristone 200 mg followed 24 to 48 hours later by 800 mcg vaginal misoprostol followed by 400 mcg sublingual misoprostol every 3 hours up to 5 doses

Time to expulsion
Complete abortion without the need for surgical intervention
Haemorrhage requiring transfusion or >500 ml of blood loss
Patient satisfaction

El-Refaey 1995

RCT

United Kingdom

n=69

Women requesting abortion for socioeconomic reasons

13 to 20 weeks’ gestation

Vaginal misoprostol: 600 mg mifepristone orally followed by 600 mcg vaginal misoprostol 36 to 48 hours later and then misoprostol 400 mcg vaginal every 3 hours up to 4 doses.

Oral misoprostol: 600 mg mifepristone orally followed by 600 mcg vaginal misoprostol 36 to 48 hours later and then 400 mcg oral misoprostol every 3 hours up to 4 doses.

Time to expulsion
Complete abortion without the need for surgical intervention
Haemorrhage requiring transfusion or >500 ml of blood loss
Vomiting
Diarrhoea

Hamoda 2005

RCT

United Kingdom

n=76

Women with viable singleton pregnancies requesting medical abortion

13 to 20 weeks’ gestation

Sublingual misoprostol: 200 mg mifepristone followed 36 to 48 hours later by 600 mcg sublingual misoprostol. Further 3 hourly doses of 400 mcg sublingual misoprostol up to 5 doses

Vaginal misoprostol: 200 mg mifepristone followed 36 to 48 hours later by vaginal misoprostol 800 mcg. Further 3 hourly doses of 400 mcg vaginal misoprostol up to 5 doses

Time to expulsion
Incomplete abortion with the need for surgical intervention
Vomiting
Patient satisfaction
Diarrhoea

Ho 1997

RCT

China

n=98

Healthy women aged 16 to 35 years with singleton pregnancies

14 to 20 weeks’ gestation

Oral misoprostol: 200 mg mifepristone followed 36 to 48 hours later by 200 mcg oral misoprostol and vaginal placebo every 3 hours up to 5 doses

Vaginal misoprostol: 200 mg mifepristone followed 36 to 48 hours later by 200 mcg misoprostol vaginally and a placebo orally every 3 hours up to 5 doses

Time to expulsion
Complete abortion without the need for surgical intervention
Incomplete abortion with the need for surgical intervention
Vomiting
Diarrhoea

Hou 2010

RCT

China

n=100

Healthy women aged 18 to 45 years requesting abortion and willing to comply with follow-up visits

13 to 16 weeks’ gestation

1 day interval: 200 mg oral mifepristone followed 1 day later by 600 mcg vaginal misoprostol and 400 mcg oral misoprostol every 6 hours up to 2 doses

2 day interval: 200 mg oral mifepristone followed 2 days later by 600 mcg vaginal misoprostol and 400 mcg oral misoprostol every 6 hours up to 2 doses

Time to expulsion
Complete abortion without the need for surgical intervention
Incomplete abortion with the need for surgical intervention
Vomiting
Diarrhoea

Mentula 2011

RCT

Finland

n=227

Women more than 18 years age, with a viable singleton pregnancy and a legal indication for abortion

1 day interval: 200 mg mifepristone oral followed by 400 mcg vaginal misoprostol 20 to 28 hours later and then every 3 hours, for up to 5 doses per 24 hours

2 day interval: 200 mg mifepristone orally followed by 400 mcg vaginal misoprostol 2 days (40 to 48 hours) later and every 3 hours with up to 5 doses per 24 hours

Time to expulsion
Incomplete abortion with the need for surgical intervention
Haemorrhage requiring transfusion or >500 ml of blood loss
Vomiting

Ngai 2000

RCT

China

n=139

Healthy women aged 16 to 35 years requesting legal abortion

14 to 20 weeks’ gestation

Oral misoprostol 400 mcg: 200 mg mifepristone oral followed 36 to 48 hours later by 400 mcg oral misoprostol every 3 hours up to 5 doses + vaginal vitamin B6 placebo

Vaginal misoprostol 200 mcg: 200 mg mifepristone oral followed 36 to 48 hours later by 200 mcg vaginal misoprostol every 3 hours up to 5 doses + oral vitamin B6 placebo

Time to expulsion
Complete abortion without the need for surgical intervention
Incomplete abortion with the need for surgical intervention
Vomiting
Diarrhoea

Tang 2005

RCT

China

n=118

Women more than 18 years old, requesting a legal abortion

12 to 20 weeks’ gestation

Sublingual misoprostol: 200 mg mifepristone oral followed 36 to 48 hours later by sublingual misoprostol 400 mcg every 3 hours up to 5 doses

Oral misoprostol: 200 mg oral mifepristone followed 36 to 48 hours later by oral misoprostol 400 mcg every 3 hours up to 5 doses

Time to expulsion
Complete abortion without the need for surgical intervention
Incomplete abortion with the need for surgical intervention
Diarrhoea

: mcg: micrograms; RCT: randomised controlled trial

Field (based on PRISMA-P	Content
Review question in SCOPE	What is the optimal dose and route of administration of misoprostol after mifepristone, for inducing medical termination in the second trimester?
Review question in guideline	What is the optimal regimen and route of administration of misoprostol after mifepristone, for inducing medical termination from 10+1 to 24+0 weeks
Type of review question	Intervention
Objective of the review	To determine the optimal regimen and route of administration for misoprostol (after mifepristone) between 10+1 and 24+0 weeks’ gestation
Eligibility criteria – population	Women who are having a medical termination of pregnancy between 10+1 and 24+0 weeks’ gestation Exclusions: - Any studies with an indirect population
Eligibility criteria – intervention(s)	Route of misoprostol administration: Vaginal Oral Sublingual Buccal Dose of misoprostol: 200 mcg 400 mcg 600 mcg 800 mcg Dose interval
Eligibility criteria – comparator(s)/control	All combinations of the routes of administration, doses, number of doses, and dosing intervals listed above will be compared.
Outcomes and prioritisation	Critical outcomes: Time to expulsion Complete abortion without the need for surgical intervention Incomplete abortion with the need for surgical intervention Important outcomes: Haemorrhage requiring transfusion or > 500 ml of blood loss Vomiting Patient satisfaction Diarrhoea
Eligibility criteria – study design	- Systematic reviews of RCTs - RCTs
Other inclusion exclusion criteria	Inclusion: - English-language
Proposed sensitivity/sub-group analysis, or meta-regression	Stratified analyses based on the following sub-groups of women, where possible: Medical conditions: - Complex pre-existing medical conditions - No complex pre-existing medical conditions Gestational age: - 10+1 weeks to 13+6 weeks - 14+0 weeks to 24+0 weeks Caesarean section: - Previous caesarean section - No previous caesarean section Parity: - Nulliparous - Parous
Selection process – duplicate screening/selection/analysis	Dual weeding will not be performed for this question Sifting, data extraction, appraisal of methodological quality and GRADE assessment will be performed by the systematic reviewer. Quality control will be performed by the senior systematic reviewer. Dual data extraction will not be performed for this question.
Data management (software)	Pairwise meta-analyses will be performed using Cochrane Review Manager (RevMan5). ‘GRADEpro’ will be used to assess the quality of evidence for each outcome. NGA STAR software will be used for study sifting, data extraction, recording quality assessment using checklists and generating bibliographies/citations,
Information sources – databases and dates	Sources to be searched: Medline, Medline In-Process, CCTR, CDSR, DARE, HTA, Embase Limits (e.g. date, study design): Apply standard animal/non-English language exclusion Limit to RCTs and systematic reviews Dates: from 1985 Only studies conducted from 1985 onwards will be considered for this review question, as mifepristone was made available in the UK in 1991 and evidence to support the use of mifepristone in practice is unlikely to be more than 5 years before its licensing in 1991.
Identify if an update	Not an update
Author contacts	For details please see the guideline in development web site.
Highlight if amendment to previous protocol	For details please see Section 4.5 of Developing NICE guidelines: the manual
Search strategy – for one database	For details please see appendix B
Data collection process – forms/duplicate	A standardised evidence table format will be used, and published as appendix D (clinical evidence tables) or appendix H (economic evidence tables).
Data items – define all variables to be collected	For details please see evidence tables in appendix D (clinical evidence tables) or appendix H (economic evidence tables).
Methods for assessing bias at outcome/study level	Standard study checklists will be used to critically appraise individual studies. For details please see section 6.2 of Developing NICE guidelines: the manual Appraisal of methodological quality: The methodological quality of each study will be assessed using an appropriate checklist: RoBIS for systematic reviews Cochrane risk of bias tool for RCTs The risk of bias across all available evidence will be evaluated for each outcome using an adaptation of the ‘Grading of Recommendations Assessment, Development and Evaluation (GRADE) toolbox’ developed by the international GRADE working group http://www.gradeworkinggroup.org/
Criteria for quantitative synthesis (where suitable)	For details please see Section 6.4 of Developing NICE guidelines: the manual
Methods for analysis – combining studies and exploring (in)consistency	Synthesis of data: Pairwise meta-analysis will be conducted where appropriate for all other outcomes. When meta-analysing continuous data, change scores will be pooled in preference to final scores. For details regarding inconsistency, please see the methods chapter Minimally important differences: ‘Haemorrhage requiring transfusion or >500 loss’: Statistical significance ‘Complete abortion without the need for surgical intervention’: 3% (with the upper limit of the 95% CI ≤ 5%) All other outcomes default values will be used of: 0.8 and 1.25 for dichotomous outcomes (relative risks); 0.5 times SD (of the control group) for continuous outcomes
Meta-bias assessment – publication bias, selective reporting bias	For details please see Section 6.2 of Developing NICE guidelines: the manual. If sufficient relevant RCT evidence is available, publication bias will be explored using RevMan software to examine funnel plots.
Assessment of confidence in cumulative evidence	For details please see Sections 6.4 and 9.1 of Developing NICE guidelines: the manual
Rationale/context – Current management	For details please see the introduction to the evidence review.
Describe contributions of authors and guarantor	A multidisciplinary committee developed the guideline. The committee was convened by The National Guideline Alliance and chaired by Profession Iain Cameron in line with section 3 of Developing NICE guidelines: the manual. Staff from The National Guideline Alliance will undertake systematic literature searches, appraise the evidence, conduct meta-analysis and cost-effectiveness analysis where appropriate, and draft the guideline in collaboration with the committee. For details please see the methods chapter.
Sources of funding/support	The National Guideline Alliance is funded by NICE and hosted by the Royal College of Obstetricians and Gynaecologists
Name of sponsor	The National Guideline Alliance is funded by NICE and hosted by the Royal College of Obstetricians and Gynaecologists
Roles of sponsor	NICE funds The National Guideline Alliance to develop guidelines for those working in the NHS, public health, and social care in England
PROSPERO registration number	Not registered

: CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation; mcg: micrograms; NHS: National Health Service; NICE: National Institute for Health and Care Excellence; NGA: National Guideline Alliance; RCT: randomised controlled trial; RoBIS: risk of bias in systematic reviews; SD: standard deviation

Date of last search: 14^th June 2018

#	Searches
1	exp abortion/ use emczd
2	exp pregnancy termination/ use emczd
3	exp Abortion, Induced/ use ppez
4	Abortion Applicants/ use ppez
5	exp Abortion, Spontaneous/ use ppez
6	exp Abortion, Criminal/ use ppez
7	Aborted fetus/ use ppez
8	fetus death/ use emczd
9	abortion.mp.
10	(abort$ or postabort$ or preabort$).mp.
11	((f?etal$ or f?etus$ or gestat$ or midtrimester$ or pregnan$ or prenatal$ or pre natal$ or trimester$) and terminat$).mp.
12	((f?etal$ or f?etus$) adj loss$).mp.
13	((gestat$ or midtrimester$ or pregnan$ or prenatal$ or pre natal$ or trimester$) adj3 loss$).mp.
14	(((elective$ or threaten$ or voluntar$) adj3 interrupt$) and pregnan$).mp.
15	1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14
16	Misoprostol/ use ppez
17	misoprostol/ use emczd
18	(misoprostol$ or cytotec$ or arthrotec$ or oxaprost$ or cyprostol$ or mibetec$ or prostokos$ or misotrol$).mp.
19	16 or 17 or 18
20	(controlled clinical trial or pragmatic clinical trial or randomized controlled trial).pt. or drug therapy.fs. or (groups or placebo or randomi#ed or randomly or trial).ab.
21	crossover procedure/ or double blind procedure/ or randomized controlled trial/ or single blind procedure/ or (assign* or allocat* or crossover* or cross over* or ((doubl* or singl) adj blind) or factorial* or placebo* or random* or volunteer*).ti,ab.
22	meta-analysis/
23	meta-analysis as topic/
24	systematic review/
25	meta-analysis/
26	(meta analy* or metanaly* or metaanaly*).ti,ab.
27	((systematic or evidence) adj2 (review* or overview*)).ti,ab.
28	((systematic* or evidence) adj2 (review or overview*)).ti,ab.
29	(reference list* or bibliograph* or hand search* or manual search* or relevant journals).ab.
30	(search strategy or search criteria or systematic search or study selection or data extraction).ab.
31	(search* adj4 literature).ab.
32	(medline or pubmed or cochrane or embase or psychlit or psyclit or psychinfo or psycinfo or cinahl or science citation index or bids or cancerlit).ab.
33	cochrane.jw.
34	((pool* or combined) adj2 (data or trials or studies or results)).ab.
35	letter/
36	editorial/
37	news/
38	exp historical article/
39	Anecdotes as Topic/
40	comment/
41	case report/
42	(letter or comment*).ti.
43	35 or 36 or 37 or 38 or 39 or 40 or 41 or 42
44	randomized controlled trial/ or random*.ti,ab.
45	43 not 44
46	animals/ not humans/
47	exp Animals, Laboratory/
48	exp Animal Experimentation/
49	exp Models, Animal/
50	exp Rodentia/
51	(rat or rats or mouse or mice).ti.
52	45 or 46 or 47 or 48 or 49 or 50 or 51
53	letter.pt. or letter/
54	note.pt.
55	editorial.pt.
56	case report/ or case study/
57	(letter or comment*).ti.
58	53 or 54 or 55 or 56 or 57
59	randomized controlled trial/ or random*.ti,ab.
60	58 not 59
61	animal/ not human/
62	nonhuman/
63	exp Animal Experiment/
64	exp Experimental Animal/
65	animal model/
66	exp Rodent/
67	(rat or rats or mouse or mice).ti.
68	60 or 61 or 62 or 63 or 64 or 65 or 66 or 67
69	52 use ppez
70	68 use emczd
71	69 or 70
72	20 use ppez
73	21 use emczd
74	72 or 73
75	(or/22-23,26,28-33) use ppez
76	(or/24-27,29-34) use emczd
77	75 or 76
78	15 and 19
79	71 and 78
80	78 not 79
81	74 or 77
82	80 and 81
83	remove duplicates from 82
84	limit 83 to english language
85	limit 84 to yr="1985 -Current”

Date of last search: 14^th June 2018

#	Searches
#1	MeSH descriptor: [Abortion, Induced] explode all trees
#2	MeSH descriptor: [Abortion Applicants] explode all trees
#3	MeSH descriptor: [Abortion, Spontaneous] explode all trees
#4	MeSH descriptor: [Abortion, Criminal] explode all trees
#5	MeSH descriptor: [Aborted Fetus] explode all trees
#6	“abortion":ti,ab,kw (Word variations have been searched)
#7	(abort* or postabort* or preabort*):ti,ab,kw (Word variations have been searched)
#8	((fetal* or fetus* or foetal* or foetus* or gestat* or midtrimester* or pregnan* or prenatal* or pre natal* or trimester) and terminat):ti,ab,kw (Word variations have been searched)
#9	((fetal* or fetus* or foetal* or foetus) next loss):ti,ab,kw (Word variations have been searched)
#10	((gestat* or midtrimester* or pregnan* or prenatal* or pre natal* or trimester) near/3 loss):ti,ab,kw (Word variations have been searched)
#11	(((elective* or threaten* or voluntar) near/3 interrupt) and pregnan*):ti,ab,kw (Word variations have been searched)
#12	#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11
#13	MeSH descriptor: [Misoprostol] this term only
#14	(misoprostol* or cytotec* or arthrotec* or oxaprost* or cyprostol* or mibetec* or prostokos* or misotrol*):ti,ab,kw (Word variations have been searched)
#15	#13 or #14
#16	#12 and #15

Figure 1Study selection flow chart

Table 3Clinical evidence profile: Comparison 1. 200 mcg versus 400 mcg vaginal misoprostol (at 4 hour intervals) 36 to 48 hours after oral mifepristone 200 mg

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	200 mcg vaginal misoprostol	400 mcg vaginal misoprostol	Relative (95% CI)	Absolute	Quality	Importance
Time to expulsion (Better indicated by lower values)
1 (Brouns 2010)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious¹	None	Median (range) 9.2 (7.1 to 11.3; n=86)	Median (range) 8.0 (7.1 to 8.9; n=90)	Not estimable²	Not estimable²	LOW	CRITICAL
Complete abortion without the need for surgical intervention (follow-up mean 48 hours)
1 (Brouns 2010)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious³	None	57/86 (66.3%)	66/90 (73.3%)	RR 0.9 (0.74 to 1.1)	73 fewer per 1000 (from 191 fewer to 73 more)	LOW	CRITICAL
Incomplete abortion with the need for surgical intervention
1 (Brouns 2010)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious⁴	None	29/86 (33.7%)	24/90 (26.7%)	RR 1.26 (0.8 to 1.99)	69 more per 1000 (from 53 fewer to 264 more)	LOW	CRITICAL
Haemorrhage requiring transfusion or >500 ml of blood loss
1 (Brouns 2010)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious⁵	None	4/86 (4.7%)	3/90 (3.3%)	RR 1.4 (0.32 to 6.05)	13 more per 1000 (from 23 fewer to 168 more)	LOW	IMPORTANT
Vomiting
1 (Brouns 2010)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Serious⁵	None	27/86 (31.4%)	37/90 (41.1%)	RR 0.76 (0.51 to 1.14)	99 fewer per 1000 (from 201 fewer to 58 more)	MODERATE	IMPORTANT
Diarrhoea
1 (Brouns 2010)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious⁴	None	5/86 (5.8%)	10/90 (11.1%)	RR 0.52 (0.19 to 1.47)	53 fewer per 1000 (from 90 fewer to 52 more)	LOW	IMPORTANT

: CI: confidence interval; MID: minimally important difference; RR: risk ratio

1: As this outcome is only reported as medians and ranges for which there are no established or default GRADE MIDs, the imprecision ratings were undertaken by using the optimum information size so that if the total n≥400, then the quality was not downgraded, if n=200-399, then the quality was downgraded by 1 level and if the total n<200, then the quality was downgraded by 2 levels

2: Cannot be rated/calculated as the study only reports medians and ranges (hours), not means and standard deviations, which were: 200 mcg: Median (range) 9.2 (7.1 to 11.3; n=86); 400 mcg: Median (range) 8.0 (7.1 to 8.9; n=90); p < 0.05 (log rank test)

3: The MID for this outcome is 3%, and the imprecision ratings were undertaken on that basis by using the absolute effect estimates so that if the CI crosses 30 fewer (3% of 1000) or 30 more, then the quality was downgraded by 1 level. If the CI crosses both, then the quality was downgraded by 2 levels

4: The quality of evidence was downgraded by 2 levels as the 95% confidence interval crosses 2 MIDs

5: The MID for this outcome is statistical significance, and the imprecision ratings were undertaken on that basis by using the optimum information size so that if the total event rate ≥300, then the quality was not downgraded, if the event rate = 150-299, then the quality was downgraded by 1 level and if the event rate <150, then the quality was downgraded by 2 levels

6: The quality of evidence was downgraded by 1 level as the 95% confidence interval crosses 1 MID

Table 4Clinical evidence profile: Comparison 2. Vaginal versus oral misoprostol (400 mcg, at 3 hour intervals up to 4 doses following a loading dose of vaginal misoprostol 600 mcg) 36 to 48 hours after oral mifepristone 600 mg

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Vaginal misoprostol	Oral misoprostol	Relative (95% CI)	Absolute	Quality	Importance
Time to expulsion (Better indicated by lower values)
1 (El Rafaey 1995)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Noserious imprecision	None	35	34	-	MD 0.7 lower (2.03 lower to 0.63 higher)	HIGH	CRITICAL
Complete abortion without the need for surgical intervention (follow-up mean 48 hours)
1 (El Rafaey 1995)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious²	None	34/35 (97.1%)	33/34 (97.1%)	RR 1 (0.92 to 1.09)	0 fewer per 1000 (from 78 fewer to 87 more)	LOW	CRITICAL
Incomplete abortion with the need for surgical intervention
1 (El Rafaey 1995)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious³	None	1/34 (2.9%)	0/35 (0%)	RR 3.09 (0.13 to 73.21)	Not estimable	LOW	CRITICAL
Haemorrhage requiring transfusion or >500 ml of blood loss
1 (El Rafaey 1995)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious⁴	None	0/35 (0%)	0/34 (0%)	Not estimable	Not estimable	LOW	IMPORTANT
Vomiting
1 (El Rafaey 1995)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious³	None	20/35 (57.1%)	21/34 (61.8%)	RR 0.93 (0.63 to 1.37)	43 fewer per 1000 (from 229 fewer to 229 more)	LOW	IMPORTANT
Diarrhoea
1 (El Rafaey 1995)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious³	None	10/35 (28.6%)	12/34 (35.3%)	RR 0.81 (0.4 to 1.62)	67 fewer per 1000 (from 212 fewer to 219 more)	LOW	IMPORTANT

: CI: confidence interval; MD: mean difference; MID: minimally important difference; RR: risk ratio

1: MID boundaries −2.18, 0.78 (−0.7 +/− 2.95 * 0.5); clinically important effect = 2.95*0.5 = 1.48 higher or lower)

2: The MID for this outcome is 3%, and the imprecision ratings were undertaken on that basis by using the absolute effect estimates so that if the CI crosses 30 fewer (3% of 1000) or 30 more, then the quality was downgraded by 1 level. If the CI crosses both, then the quality was downgraded by 2 levels

3: The quality of evidence was downgraded by 2 levels as the 95% confidence interval crosses 2 MIDs.

4: The MID for this outcome is statistical significance, and the imprecision ratings were undertaken on that basis by using the optimum information size so that if the total event rate ≥300, then the quality was not downgraded, if the event rate = 150-299, then the quality was downgraded by 1 level and if the event rate <150, then the quality was downgraded by 2 levels

Table 5Clinical evidence profile: Comparison 3. Vaginal versus oral misoprostol (400 mcg; at 4 hour intervals for vaginal misoprostol and 3 hour intervals for oral misoprostol, up to 5 doses following a loading dose of vaginal misoprostol 800 mcg) 24 to 48 hours after oral mifepristone 200 mg

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Vaginal misoprostol 400 mcg	Oral misoprostol 400 mcg	Relative (95% CI)	Absolute	Quality	Importance
Time to expulsion (Better indicated by lower values)
1 (Dickinson 2014)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Serious¹	None	Median (range) 7.4 (6.5 to 8.2; n=100)	Median (range) 9.5 (8.5 to 11.4; n=100)	Not estimable²	Not estimable²	MODERAT	CRITICAL
Haemorrhage requiring transfusion or >500 ml of blood loss
1 (Dickinson 2014)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious³	None	1/100 (1%)	2/100 (2%)	RR 0.5 (0.05 to 5.43)	10 fewer per 1000 (from 19 fewer to 89 more)	LOW	IMPORTANT
Patient satisfaction (opinion of procedure score; Better indicated by lower values)
1 (Dickinson 2014)	Randomised trials	Serious⁴	No serious inconsistency	No serious indirectness	Serious¹	None	Median (range) 50 (26 to 50; n=100)	Median (range) 50 (20 to 50; n=100)	Not estimable⁵	Not estimable⁵	LOW	IMPORTANT

: CI: confidence interval; MID: minimally important difference; RR: risk ratio

1: As this outcome is only reported as medians and ranges for which there are no established or default GRADE MIDs, the imprecision ratings were undertaken by using the optimum information size so that if the total n≥400, then the quality was not downgraded, if n=200-399, then the quality was downgraded by 1 level and if the total n<200, then the quality was downgraded by 2 levels

2: Cannot be rated/calculated as the study only reports medians and ranges (hours), not means and standard deviations, which were: Vaginal misoprostol: Median (range) 7.4 (6.5 to 8.2; n=100); Oral misoprostol: Median (range) 9.5 (8.5 to 11.4; n=100); p < 0.05 (log rank test)

3: The MID for this outcome is statistical significance, and the imprecision ratings were undertaken on that basis by using the optimum information size so that if the total event rate ≥300, then the quality was not downgraded, if the event rate = 150-299, then the quality was downgraded by 1 level and if the event rate <150, then the quality was downgraded by 2 levels

4: The quality of evidence was downgraded by 1 level due to serious risk of bias because of lack of blinding for this subjective outcome

5: Cannot be rated/calculated as the study only reports medians and ranges (opinion of procedure score), not means and standard deviations, which were: Vaginal misoprostol: Median (range) 50 (26 to 50; n=100); Oral misoprostol: Median (range) 50 (20 to 50; n=100); not significant

Table 6Clinical evidence profile: Comparison 4. Vaginal versus oral misoprostol (200 mcg; at 3 hour intervals, up to 5 doses) ± placebo 36 to 48 hours after 200 mg oral mifepristone

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Vaginal misoprostol	Oral misoprostol	Relative (95% CI)	Absolute	Quality	Importance
Time to expulsion (Better indicated by lower values)
1 (Ho 1997)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious¹	None	49	49	-	MD 13 lower (23.23 to 2.77 lower)	LOW	CRITICAL
Complete abortion without the need for surgical intervention (follow-up mean 48 hours)
1 (Ho 1997)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious²	None	36/49 (73.5%)	29/49 (59.2%)	RR 1.24 (0.93 to 1.65)	142 more per 1000 (from 41 fewer to 385 more)	LOW	CRITICAL
Vomiting
1 (Ho 1997)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious³	None	14/49 (28.6%)	10/49 (20.4%)	RR 1.4 (0.69 to 2.84)	82 more per 1000 (from 63 fewer to 376 more)	LOW	IMPORTANT
Diarrhoea
1 (Ho 1997)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Serious⁴	None	9/49 (18.4%)	16/49 (32.7%)	RR 0.56 (0.28 to 1.15)	144 fewer per 1000 (from 235 fewer to 49 more)	MODERATE	IMPORTANT

: CI: confidence interval; MD: mean difference; MID: minimally important difference; RR: risk ratio; SD: standard deviation

1: The quality of evidence was downgraded by 2 levels as the 95% confidence interval crosses 2 MID (MID boundaries −22.1,−3.9(−13 +/− 18.2 * 0.5); clinically important effect = 18.2*0.5 = 9.1 higher or lower)

2: The MID for this outcome is 3%, and the imprecision ratings were undertaken on that basis by using the absolute effect estimates so that if the CI crosses 30 fewer (3% of 1000) or 30 more, then the quality was downgraded by 1 level. If the CI crosses both, then the quality was downgraded by 2 levels

3: The quality of evidence was downgraded by 2 levels as the 95% confidence interval crosses 2 MIDs

4: The quality of evidence was downgraded by 1 level as the 95% confidence interval crosses 1 MID

Table 7Clinical evidence profile: Comparison 5. Oral versus vaginal misoprostol (400 mcg at 3 hour intervals, up to 5 doses) ± placebo 36 to 48 hours after oral mifepristone 200 mg

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Oral misoprostol	Vaginal misoprostol	Relative (95% CI)	Absolute	Quality	Importance
Time to expulsion (Better indicated by lower values)
1 (Ngai 2000)	Randomised trials	Serious¹	No serious inconsistency	No serious indirectness	No serious imprecision²	None	70	69	-	MD 1.3 lower (8.7 lower to 11.33 higher)	MODERATE	CRITICAL
Complete abortion without the need for surgical intervention (follow-up mean 48 hours)
1 (Ngai 2000)	Randomised trials	Serious¹	No serious inconsistency	No serious indirectness	Very serious³	None	57/70 (81.4%)	58/69 (84.1%)	RR 0.97 (0.83 to 1.13)	25 fewer per 1000 (from 143 fewer to 109 more)	VERY LOW	CRITICAL
Incomplete abortion with the need for surgical intervention
1 (Ngai 2000)	Randomised trials	Serious¹	No serious inconsistency	No serious indirectness	Very serious⁴	None	0/70 (0%)	0/69 (0%)	Not estimable	Not estimable	VERY LOW	CRITICAL
Vomiting
1 (Ngai 2000)	Randomised trials	Serious¹	No serious inconsistency	No serious indirectness	Very serious⁵	None	31/70 (44.3%)	29/69 (42%)	RR 1.05 (0.72 to 1.54)	21 more per 1000 (from 118 fewer to 227 more)	VERY LOW	IMPORTANT
Diarrhoea
1 (Ngai 2000)	Randomised trials	Serious¹	No serious inconsistency	No serious indirectness	Serious⁶	None	28/70 (40%)	16/69 (23.2%)	RR 1.73 (1.03 to 2.89)	169 more per 1000 (from 7 more to 438 more)	LOW	IMPORTANT

: CI: confidence interval; MD: mean difference; MID: minimally important difference; RR: risk ratio

1: The quality of evidence was downgraded by 1 level due to serious risk of bias arising from unclear method of randomization

2: MID boundaries (−18.45, 15.85(−1.3 +/− 34.3 * 0.5); clinically important effect = 34.3*0.5 = 17.15 higher or lower)

3: The MID for this outcome is 3%, and the imprecision ratings were undertaken on that basis by using the absolute effect estimates so that if the CI crosses 30 fewer (3% of 1000) or 30 more, then the quality was downgraded by 1 level. If the CI crosses both, then the quality was downgraded by 2 levels

4: The quality of evidence was downgraded by 2 levels due to very serious imprecision because of small number of events

5: The quality of evidence was downgraded by 2 levels as the 95% confidence interval crosses 2 MIDs

6: The quality of evidence was downgraded by 1 level as the 95% confidence interval crosses 1 MID

Table 8Clinical evidence profile: Comparison 6. Sublingual versus oral misoprostol (400 mcg; at 3 hour intervals, up to 5 doses following a loading dose of vaginal misoprostol 800 mcg) 24 to 48 hours after oral mifepristone 200 mg

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Sublingual misoprostol	Oral misoprostol	Relative (95% CI)	Absolute	Quality	Importance
Time to expulsion (Better indicated by lower values)
1 (Dickinson 2014)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Serious¹	None	Median (range) 7.8 (7 to 9.2 n=102)	Median (range) 9.5 (8.5 to 11.4; n=100)	Not estimable²	Not estimable²	MODERATE	CRITICAL
Haemorrhage requiring transfusion or >500 ml of blood loss
1 (Dickinson 2014)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious³	None	2/102 (2%)	2/100 (2%)	RR 0.98 (0.14 to 6.83)	0 fewer per 1000 (from 17 fewer to 117 more)	LOW	IMPORTANT
Patient satisfaction (opinion of procedure score; Better indicated by lower values)
1 (Dickinson 2014)	Randomised trials	Serious⁴	No serious inconsistency	No serious indirectness	Serious¹	None	Median (range) 50 (19-50; n=102)	Median (range) 50 (20-50; n=100)	Not estimable⁵	Not estimable⁵	LOW	IMPORTANT

: CI: confidence interval; MID: minimally important difference; RR: risk ratio

1: As this outcome is only reported as medians and ranges for which there are no established or default GRADE MIDs, the imprecision ratings were undertaken by using the optimum information size so that if the total n≥400, then the quality was not downgraded, if n=200-399, then the quality was downgraded by 1 level and if the total n<200, then the quality was downgraded by 2 levels

2: Cannot be rated/calculated as the study only reports medians and ranges (hours), not means and standard deviations, which were: Sublingual misoprostol: Median (range) 7.8 (7 to 9.2; n=102); Oral misoprostol: Median (range) 9.5 (8.5 to 11.4; n=100); p < 0.05 (log rank test)

3: The MID for this outcome is statistical significance, and the imprecision ratings were undertaken on that basis by using the optimum information size so that if the total event rate ≥300, then the quality was not downgraded, if the event rate = 150-299, then the quality was downgraded by 1 level and if the event rate <150, then the quality was downgraded by 2 levels

4: The quality of evidence was downgraded by 1 level due to serious risk of bias because of lack of blinding for this subjective outcome

5: Cannot be rated/calculated as the study only reports medians and ranges (opinion of procedure scores), not means and standard deviations, which were: Sublingual misoprostol: Median (range) 50 (19 to 50; n=102); Oral misoprostol: Median (range) 50 (20 to 50; n=100); not significant

Table 9Clinical evidence profile: Comparison 7. Sublingual versus oral misoprostol (400 mcg, at 3 hour intervals up to 5 doses) 36 to 48 hours after oral mifepristone 200 mg

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Sublingual misoprostol	Oral misoprostol	Relative (95% CI)	Absolute	Quality	Importance
Time to expulsion (Better indicated by lower values)
1 (Tang 2005)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious¹	None	Median (range) 5.5 (1.4 to 43.2; n=58)	Median (range) 7.5 (2.4 to 38.8; n=60)	Not estimable²	Not estimable²	LOW	CRITICAL
Complete abortion without the need for surgical intervention (follow-up mean 48 hours)
1 (Tang 2005)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Serious³	None	57/58 (98.3%)	55/60 (91.7%)	RR 1.07 (0.99 to 1.17)	64 more per 1000 (from 9 fewer to 156 more)	MODERATE	CRITICAL
Incomplete abortion with the need for surgical intervention
1 (Tang 2005)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious⁴	None	10/58 (17.2%)	7/60 (11.7%)	RR 1.48 (0.6 to 3.62)	56 more per 1000 (from 47 fewer to 306 more)	LOW	CRITICAL
Diarrhoea
1 (Tang 2005)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious⁴	None	8/58 (13.8%)	13/60 (21.7%)	RR 0.64 (0.29 to 1.42)	78 fewer per 1000 (from 154 fewer to 91 more)	LOW	IMPORTANT

: CI: confidence interval; MID: minimally important difference; RR: risk ratio

1: As this outcome is only reported as medians and ranges for which there are no established or default GRADE MIDs, the imprecision ratings were undertaken by using the optimum information size so that if the total n≥400, then the quality was not downgraded, if n=200-399, then the quality was downgraded by 1 level and if the total n<200, then the quality was downgraded by 2 levels

2: Cannot be rated/calculated as the study only reports medians and ranges (hours), not means and standard deviations, which were: Sublingual misoprostol: Median (range) 5.5(1.4 to 43.2; n=58); Oral misoprostol: Median (range) 7.5 (2.4 to 38.8; n=100); p < 0.05 (Mann-Whitney U-Test)

3: The MID for this outcome is 3%, and the imprecision ratings were undertaken on that basis by using the absolute effect estimates so that if the CI crosses 30 fewer (3% of 1000) or 30 more, then the quality was downgraded by 1 level. If the CI crosses both, then the quality was downgraded by 2 levels

4: The quality of evidence was downgraded by 2 levels as the 95% confidence interval crosses 2 MIDs

Table 10Clinical evidence profile: Comparison 8. Sublingual (600 mcg; followed by 400 mcg at 3 hour intervals up to 5 doses) versus vaginal (800 mcg; followed by 400 mcg at 3 hour intervals up to 5 doses) misoprostol, 36 to 48 hours after oral mifepristone 200 mg

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Sublingual misoprostol	Vaginal misoprostol	Relative (95% CI)	Absolute	Quality	Importance
Time to expulsion (Better indicated by lower values)
1 (Hamoda 2005)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious¹	None	Median (range) 5.27 (0.55 to 29.35; n=36)	Median (range) 5.40 (2.10 to 13.00; n=40)	Not estimable²	Not estimable²	LOW	CRITICAL
Incomplete abortion with the need for surgical intervention
1 (Hamoda 2005)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious³	None	3/36 (8.3%)	1/40 (2.5%)	RR 3.33 (0.36 to 30.63)	58 more per 1000 (from 16 fewer to 741 more)	LOW	CRITICAL
Vomiting
1 (Hamoda 2005)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious³	None	25/36 (69.4%)	25/40 (62.5%)	RR 1.11 (0.80 to 1.54)	69 more per 1000 (from 125 fewer to 337 more)	LOW	IMPORTANT
Satisfaction (satisfied with the route of administration of misoprostol)
1 (Hamoda 2005)	Randomised trials	Serious⁴	No serious inconsistency	No serious indirectness	Very serious³	None	24/36 (66.7%)	25/40 (62.5%)	RR 1.07 (0.76 to 1.49)	44 more per 1000 (from 150 fewer to 306 more)	VERY LOW	IMPORTANT
Diarrhoea
1 (Hamoda 2005)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious³	None	19/36 (52.8%)	21/40 (52.5%)	RR 1.01 (0.66 to 1.54)	5 more per 1000 (from 178 fewer to 283 more)	LOW	IMPORTANT

: CI: confidence interval; MID: minimally important difference; RR: risk ratio

1: As this outcome is only reported as medians and ranges for which there are no established or default GRADE MIDs, the imprecision ratings were undertaken by using the optimum information size so that if the total n≥400, then the quality was not downgraded, if n=200-399, then the quality was downgraded by 1 level and if the total n<200, then the quality was downgraded by 2 levels

2: Cannot be rated/calculated as the study only reports medians and ranges (hours), not means and standard deviations, which were: Sublingual misoprostol: Median (range) 5.27(0.55 to 29.35; n=36); Vaginal misoprostol: Median (range) 5.40 (2.10 to 13.00; n=40); not significant (Mann-Whitney U-Test)

3: The quality of evidence was downgraded by 2 levels as the 95% confidence interval crosses 2 MIDs

4: The quality of evidence was downgraded by 1 level due to serious risk of bias because of lack of blinding for this subjective outcome

Table 11Clinical evidence profile: Comparison 9. Oral misoprostol (400 mcg; every 6 hours, up to 2 doses) 1 versus 2 days after oral mifepristone 200 mg + 600 mcg vaginal misoprostol

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	1 day interval	2 day interval	Relative (95% CI)	Absolute	Quality	Importance
Time to expulsion (Better indicated by lower values)
1 (Hou 2010)	Randomised trials	Serious¹	No serious inconsistency	No serious indirectness	No serious imprecision²	None	50	50	-	MD 0.20 (1.25 lower to 1.65 higher)	MODERATE	CRITICAL
Complete abortion without the need for surgical intervention (follow-up mean 24 hours)
1 (Hou 2010)	Randomised trials	Serious¹	No serious inconsistency	No serious indirectness	Serious³	None	23/50 (46%)	34/50 (68%)	RR 0.68 (0.47 to 0.97)	18 fewer per 1000 (from 20 fewer to 360 fewer)	LOW	CRITICAL
Incomplete abortion with the need for surgical intervention
1 (Hou 2010)	Randomised trials	Serious¹	No serious inconsistency	No serious indirectness	Very serious⁴	None	1/50 (2%)	0/50 (0%) 0%	RR 3.00 (0.13 to 71.92)	Not estimable	VERY LOW	CRITICAL
Vomiting (Nausea/Vomiting)
1 (Hou 2010)	Randomised trials	Very serious⁵	No serious inconsistency	Serious⁶	Very serious⁴	None	14/50 (28%)	15/50 (30%)	RR 0.93 (0.51 to 1.72)	21 fewer per 1000 (from 147 fewer to 216 more)	VERY LOW	IMPORTANT
Diarrhoea
1 (Hou 2010)	Randomised trials	Very serious⁵	No serious inconsistency	No serious indirectness	Very serious⁴	None	9/50 (18%)	4/50 (8%)	RR 2.25 (0.74 to 6.83)	100 more per 1000 (from 21 fewer to 466 more)	VERY LOW	IMPORTANT

: CI: confidence interval; MD: mean difference; MID: minimally important difference; RR: risk ratio

1: The quality of evidence was downgraded by 1 level due to serious risk of bias arising from unclear allocation concealment method

2: MID boundaries (−1.3, 1.7(0.2 +/− 3 * 0.5); clinically important effect = 3*0.5 = 1.5 higher or lower))

3: The MID for this outcome is 3%, and the imprecision ratings were undertaken on that basis by using the absolute effect estimates so that if the CI crosses 30 fewer (3% of 1000) or 30 more, then the quality was downgraded by 1 level. If the CI crosses both, then the quality was downgraded by 2 levels

4: The quality of evidence was downgraded by 2 levels as the 95% confidence interval crosses 2 MIDs

5: The quality of evidence was downgraded by 2 levels due to very serious risk of bias from unclear allocation concealment method and attrition bias

6: The quality of evidence was downgraded by 1 level due to indirectness of outcome reported as all cases of nausea and vomiting, instead of vomiting alone

Table 12Clinical evidence profile: Comparison 10. Vaginal misoprostol (400 mcg; at 3 hour intervals, up to 5 doses per 24 hours) 1 versus 2 days after oral mifepristone 200 mg

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	1 day interval	2 day interval	Relative (95% CI)	Absolute	Quality	Importance
Time to expulsion (Better indicated by lower values)
1 (Mentula 2011)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Serious¹	None	Median (range) 8.5 (6.3 to 12.3; n=115)	Median (range) 7.2 (5.8 to 9.2; n=112)	Not estimable²	Not estimable²	MODERATE	CRITICAL
Incomplete abortion with the need for surgical intervention
1 (Mentula 2011)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Serious³	None	29/115 (25.2%)	41/112 (36.6%)	RR 0.69 (0.46 to 1.03)	113 fewer per 1000 (from 198 fewer to 11 more)	MODERATE	CRITICAL
Haemorrhage requiring transfusion or >500 ml of blood loss
1 (Mentula 2011)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious⁴	None	8/115 (7%)	7/112 (6.3%)	RR 1.11 (0.42 to 2.97)	7 more per 1000 (from 36 fewer to 123 more)	LOW	IMPORTANT
Vomiting (The need for anti-emetic drugs)
1 (Mentula 2011)	Randomised trials	No serious risk of bias	No serious inconsistency	Serious⁵	Very serious⁶	None	30/115 (26.1%)	24/112 (21.4%)	RR 1.22 (0.76 to 1.95)	47 more per 1000 (from 51 fewer to 204 more)	VERY LOW	IMPORTANT

: CI: confidence interval; MID: minimally important difference; RR: risk ratio

1: As this outcome is only reported as medians and ranges for which there are no established or default GRADE MIDs, the imprecision ratings were undertaken by using the optimum information size so that if the total n≥400, then the quality was not downgraded, if n=200-399, then the quality was downgraded by 1 level and if the total n<200, then the quality was downgraded by 2 levels

2: Cannot be rated/calculated as the study only reports medians and ranges (hours), not means and standard deviations, which were: 1 day interval: Median (range) 8.5 (6.3 to 12.3; n=115); 2 day interval: Median (range)= 7.2 (5.8 to 9.2; n=112); p<0.05 (Mann-Whitney U-Test)

3: The quality of evidence was downgraded by 1 level as the 95% confidence interval crosses 1 MID

4: The MID for this outcome is statistical significance, and the imprecision ratings were undertaken on that basis by using the optimum information size so that if the total event rate ≥300, then the quality was not downgraded, if the event rate = 150-299, then the quality was downgraded by 1 level and if the event rate <150, then the quality was downgraded by 2 levels

5: The quality of evidence was downgraded by 1 level due to indirectness of outcome reported as women needing anti-emetic drugs instead of those experiencing vomiting

6: The quality of evidence was downgraded by 2 levels as the 95% confidence interval crosses 2 MIDs

Table 13Clinical evidence profile: Comparison 11. Vaginal misoprostol (600 mcg; followed by 400 mcg at 3 hour intervals, up to 4 doses) simultaneous with mifepristone 200 mg versus 36 to 38 hours after 200 mg oral mifepristone

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Simultaneous administration	36 to 38 hours interval	Relative (95% CI)	Absolute	Quality	Importance
Time to expulsion (Better indicated by lower values)
1 (Chai 2009)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious¹	None	Median (range) 10.0 (3.5 to 126; n=71)	Median (range) 4.9 (1.8 to 13.8; n=70)	Not estimable²	Not estimable²	LOW	CRITICAL
Complete abortion without the need for surgical intervention (follow-up mean 48 hours)
1 (Chai 2009)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious³	None	70/71 (98.6%)	70/70 (100%)	RR 0.99 (0.95 to 1.03)	10 fewer per 1000 (from 50 fewer to 30 more)	LOW	CRITICAL
Incomplete abortion with the need for surgical intervention
1 (Chai 2009)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious⁴	None	5/71 (7%)	1/70 (1.4%)	RR 4.93 (0.59 to 41.13)	56 more per 1000 (from 6 fewer to 573 more)	LOW	CRITICAL
Haemorrhage requiring transfusion or >500 ml of blood loss
1 (Chai 2009)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious⁵	None	0/71 (0%)	0/70 (0%)	Not estimable	Not estimable	LOW	IMPORTANT
Diarrhoea (>3 episodes)
1 (Chai 2009)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Serious⁶	None	18/71 (25.4%)	10/70 (14.3%)	RR 1.77 (0.88 to 3.57)	110 more per 1000 (from 17 fewer to 367 more)	MODERATE	IMPORTANT

: CI: confidence interval; MID: minimally important difference; RR: risk ratio

1: As this outcome is only reported as medians and ranges for which there are no established or default GRADE MIDs, the imprecision ratings were undertaken by using the optimum information size so that if the total n≥400, then the quality was not downgraded, if n=200-399, then the quality was downgraded by 1 level and if the total n<200, then the quality was downgraded by 2 levels

2: Cannot be rated/calculated as the study only reports medians and ranges (hours), not means and standard deviations, which were: Simultaneous administration: Median (range) 10.0 (3.5 to 126; n=71); 36 to 38 hours interval: Median (range) 4.9 (1.8 to 13.8; n=70); p<0.0001 (Mann-Whitney U-Test)

3: The MID for this outcome is 3%, and the imprecision ratings were undertaken on that basis by using the absolute effect estimates so that if the CI crosses 30 fewer (3% of 1000) or 30 more, then the quality was downgraded by 1 level. If the CI crosses both, then the quality was downgraded by 2 levels

4: The quality of evidence was downgraded by 2 levels as the 95% confidence interval crosses 2 MIDs

5: The MID for this outcome is statistical significance, and the imprecision ratings were undertaken on that basis by using the optimum information size so that if the total event rate ≥300, then the quality was not downgraded, if the event rate = 150-299, then the quality was downgraded by 1 level and if the event rate <150, then the quality was downgraded by 2 levels

6: The quality of evidence was downgraded by 1 level as the 95% confidence interval crosses 1 MID

Table 14Clinical evidence profile: Comparison 12. Buccal misoprostol 400 mcg (at 3 hour intervals) ± placebo simultaneous with mifepristone 200 mg versus 1 day following oral mifepristone 200 mg

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Simultaneous administration	1 day interval	Relative (95% CI)	Absolute	Quality	Importance
Time to expulsion (Better indicated by lower values)
1 (Abbas 2016)	Randomised trials	Serious¹	No serious inconsistency	No serious indirectness	No serious imprecision²	None	Median (range) 13.0 (4.9 to 47.8; n=254)	Median (range) 7.7 (2.1 to 40.3; n=251)	Not estimable³	Not estimable³	MODERATE	CRITICAL
Complete abortion without the need for surgical intervention(at 48 hours)
1 (Abbas 2016)	Randomised trials	Serious¹	No serious inconsistency	No serious indirectness	Serious⁴	None	243/254 (95.7%)	243/251 (96.8%)	RR 0.99 (0.95 to 1.02)	10 fewer per 1000 (from 48 fewer to 19 more)	LOW	CRITICAL
Incomplete abortion with the need for surgical intervention
1 (Abbas 2016)	Randomised trials	Serious¹	No serious inconsistency	No serious indirectness	Very serious⁵	None	2/254 (0.79%)	1/251 (0.4%)	RR 1.98 (0.18 to 21.66)	4 more per 1000 (from 3 fewer to 82 more)	VERY LOW	CRITICAL
Haemorrhage requiring transfusion or >500 ml of blood loss
1 (Abbas 2016)	Randomised trials	Serious¹	No serious inconsistency	No serious indirectness	Very serious⁶	None	1/254 (0.39%)	0/251 (0%)	RR 2.96 (0.12 to 72.43)	Not estimable	VERY LOW	IMPORTANT
Vomiting
1 (Abbas 2016)	Randomised trials	Serious¹	No serious inconsistency	No serious indirectness	Very serious⁵	None	63/254 (24.8%)	57/251 (22.7%)	RR 1.09 (0.8 to 1.49)	20 more per 1000 (from 45 fewer to 111 more)	VERY LOW	IMPORTANT
Patient satisfaction (satisfied or very satisfied)
1 (Abbas 2016)	Randomised trials	Serious¹	No serious inconsistency	No serious indirectness	No serious imprecision	None	252/254 (99.2%)	249/251 (99.2%)	RR 1 (0.98 to 1.02)	0 fewer per 1000 (from 20 fewer to 20 more)	MODERATE	IMPORTANT
Diarrhoea
1 (Abbas 2016)	Randomised trials	Serious¹	No serious inconsistency	No serious indirectness	No serious imprecision	None	137/254 (53.9%)	83/251 (33.1%)	RR 1.63 (1.32 to 2.01)	208 more per 1000 (from 106 more to 334 more)	MODERATE	IMPORTANT

: CI: confidence interval; MID: minimally important difference; RR: risk ratio

1: The quality of evidence was downgraded by 2 levels due to serious risk of bias arising from unclear randomization methods

2: As this outcome is only reported as medians and ranges for which there are no established or default GRADE MIDs, the imprecision ratings were undertaken by using the optimum information size so that if the total n≥400, then the quality was not downgraded, if n=200-399, then the quality was downgraded by 1 level and if the total n<200, then the quality was downgraded by 2 levels

3: Cannot be rated/calculated as the study only reports medians and ranges (hours), not means and standard deviations, which were: Simultaneous administration: Median (range) 13.0 (4.9 to 47.8; n=254); 1 day interval: Median (range) 7.7 (2.1 to 40.3); n=251); p<0.001 (Mann-Whitney U-test)

4: The MID for this outcome is 3%, and the imprecision ratings were undertaken on that basis by using the absolute effect estimates so that if the CI crosses 30 fewer (3% of 1000) or 30 more, then the quality was downgraded by 1 level. If the CI crosses both, then the quality was downgraded by 2 levels

5: The quality of evidence was downgraded by 2 levels as the 95% confidence interval crosses 2 MIDs

6: The MID for this outcome is statistical significance, and the imprecision ratings were undertaken on that basis by using the optimum information size so that if the total event rate ≥300, then the quality was not downgraded, if the event rate = 150-299, then the quality was downgraded by 1 level and if the event rate <150, then the quality was downgraded by 2 levels

Study	Reason for Exclusion
Agrawal, S., Misoprostol for second trimester medical abortion - a comparison of three routes of administration, International journal of gynaecology and obstetrics, 107, 2009	Mifepristone is not included in this regimen
Al, R. A., Yapca, O. E., Vaginal misoprostol compared with buccal misoprostol for termination of second-trimester pregnancy, Obstetrics and gynecology, 126, 593-598, 2015	Mifepristone is not included in this regimen
Azra, B, Shakeel, S, Nilofer, M, A comparison of two protocols of intra vaginal misoprostol for second trimester medical termination of pregnancy, Pakistan armed forces medical journal, 57, 61-65, 2007	Mifepristone is not included in this regimen
Bebbington,M.W., Kent,N., Lim,K., Gagnon,A., Delisle,M.F., Tessier,F., Wilson,R.D., A randomized controlled trial comparing two protocols for the use of misoprostol in midtrimester pregnancy termination, American Journal of Obstetrics and Gynecology, 187, 853-857, 2002	Mifepristone not included in this regimen
Behrashi, M., Mahdian, M., Vaginal versus oral misoprostol for second-trimester pregnancy termination: A randomized trial, Pakistan Journal of Biological Sciences, 11, 2505-2508, 2008	Mifepristone is not included in this regimen
Bhattacharjee, N., Saha, S. P., Ganguly, R. P., Patra, K. K., Jha, T., Barui, G., Saha, M., A randomized comparative study on vaginal administration of acetic acid-moistened versus dry misoprostol for mid-trimester pregnancy termination, Archives of gynecology and obstetrics, 285, 311-316, 2012	Mifepristone is not included in this regimen
Bhattacharjee, N., Saha, S. P., Ghoshroy, S. C., Bhowmik, S., Barui, G., A randomised comparative study on sublingual versus vaginal administration of misoprostol for termination of pregnancy between 13 to 20 weeks, Australian and New Zealand Journal of Obstetrics and Gynaecology, 48, 165-171, 2008	Mifepristone is not included in this regimen
Bhattacharyya, S. K., Mukherji, J., Kamilya, G. S., Ray, S., Hazra, A., Two regimens of vaginal misoprostol in second trimester termination of pregnancy: a prospective randomised trial, Acta obstetricia ET gynecologica scandinavica, 85, 1458-62, 2006	Mifepristone is not included in this regimen
Cabrera, Y., FernUndez-Guisasola, J., Lobo, P., G. Umir S, Ulvarez, J., Comparison of sublingual versus vaginal misoprostol for second-trimester pregnancy termination: A meta-analysis, Australian and New Zealand Journal of Obstetrics and Gynaecology, 51, 158-165, 2011	Mifepristone is not included in the regimen of studies included in this meta-analysis
Caliskan, E., Dilbaz, S., Doger, E., Ozeren, S., Dilbaz, B., Erratum: Randomized comparison of 3 misoprostol protocols for abortion induction at 13-20 weeks of gestation (Journal of Reproductive Medicine (2005) 50 (173-180)), Journal of reproductive medicine for the obstetrician and gynecologist, 50, 732, 2005	This article is an erratum for another excluded study (Caliskan 2005)
Caliskan, E., Dilbaz, S., Doger, E., Ozeren, S., Dilbaz, B., Randomized comparison of 3 misoprostol protocols for abortion induction at 13-20 weeks of gestation, Journal of reproductive medicine for the obstetrician and gynecologist, 50, 173-180, 2005	Mifepristone is not included in this regimen
Caliskan, E., Doger, E., Cakiroglu, Y., Corakci, A., Yucesoy, I., Sublingual misoprostol 100 microgram versus 200 microgram for second trimester abortion: a randomised trial, European Journal of Contraception and Reproductive Health Care, 14, 55-60, 2009	Mifepristone is not included in this regimen
Carbonell, J. L., Torres, M. A., Reyes, R., Ortega, L., Garcia-Gallego, F., Sanchez, C., Second-trimester pregnancy termination with 600-mug vs. 400-mug vaginal misoprostol and systematic curettage postexpulsion: a randomized trial, Contraception, 77, 50-55, 2008	Mifepristone is not included in this regimen
Cetin, C., Buyukkurt, S., Seydaoglu, G., Kahveci, B., Soysal, C., Ozgunen, F. T., Comparison of two misoprostol regimens for mid-trimester pregnancy terminations after FIGO’s misoprostol dosage recommendation in 2012, Journal of Maternal-Fetal & Neonatal MedicineJ Matern Fetal Neonatal Med, 29, 1314-7, 2016	Not a randomised controlled trial
Chaudhuri, S., Banerjee, P. K., Mundle, M., Mitra, S. N., A comparison of two regimens of misoprostol for second trimester medical termination of pregnancy: A randomized trial, Tropical doctor, 40, 144-148, 2010	Mifepristone is not included in this regimen
Chen,Q.J., Zhang,J., Huang,Z.R., Fan,X.F., Wang,H.Y., Zhu,H., Hou,S.P., Liu,Y.H., Qiao,Q.Q., Zhang,P., Liu,Y., Qian,C.M., Tan,Y.D., Li,A.H., Meads,C., Zhang,W.H., Cheng,L.N., Mifepristone in combination with misoprostol for the termination of pregnancy at 8-16 weeks’ gestational age: A multicentre randomized controlled trial, Journal of Reproduction and Contraception, 24, 101-113, 2013	Mixed population of first and second trimester (period of gestation 8 to16 weeks), with a total of n=1112 of whom n=669 were the target population. Results for this subgroup could not be extracted.
Chen,Q.J., Hou,S.P., Meads,C., Huang,Y.M., Hong,Q.Q., Zhu,H.P., Cheng,L.N., Mifepristone in combination with prostaglandins for termination of 10-16 weeks gestation: A systematic review, European Journal of Obstetrics Gynecology and Reproductive Biology, 159, 247-254, 2011	Systematic review with English and Chinese studies including comparison of different regimens of mifepristone with prostaglandins for abortion. Relevant studies are included individually in the current review.
Cheng, L, Termination of 10-16 weeks’ gestation with mifepristone plus misoprostol: a multicentre randomized clinical trial, Zhonghua fu chan ke za zhi, 34, 268-271, 1999	Full text not written in English
Crane, J. M., Young, D., Butt, K., Delaney, M., Hutchens, D., Carlan, S. J., Safety and efficacy of misoprostol orally and vaginally: A randomized trial [3], Obstetrics and gynecology, 98, 875-876, 2001	Letter to Editor
Dalenda,C., Ines,N., Fathia,B., Malika,A., Bechir,Z., Ezzeddine,S., Hela,C., Badis,C.M., Two medical abortion regimens for late first-trimester termination of pregnancy: a prospective randomized trial, Contraception, 81, 323-327, 2010	First trimester abortion
Dickinson, J. E., Evans, S. F., A comparison of oral misoprostol with vaginal misoprostol administration in second-trimester pregnancy termination for fetal abnormality, Obstetrics and gynecology, 101, 1294-1299, 2003	Mifepristone is not included in this regimen
Dickinson, J. E., Evans, S. F., The optimization of intravaginal misoprostol dosing schedules in second-trimester pregnancy termination, American journal of obstetrics and gynecology, 186, 470-474, 2002	Mifepristone is not included in this regimen
Ellis, S. C., Kapp, N., Vragpvoc, O., Borgata, L., Randomized trial of buccal versus vaginal misoprostol for induction of second trimester abortion, Contraception, 81, 441-445, 2010	Mifepristone is not included in this regimen
Eslamian, L, Gosili, R, Jamal, A, Alyassin, A, A prospective randomized controlled trial of two regimens of vaginal misoprostol in second trimester termination of pregnancy, Acta medica iranica, 45, 497-500, 2007	Mifepristone is not included in this regimen
Feldman, D. M., Borgida, A. F., Rodis, J. F., Leo, M. V., Campbell, W. A., A randomized comparison of two regimens of misoprostol for second-trimester pregnancy termination, American journal of obstetrics and gynecology, 189, 710-713, 2003	Mifepristone is not included in this regimen
Gilbert, A., Reid, R., A randomised trial of oral versus vaginal administration of misoprostol for the purpose of mid-trimester termination of pregnancy, Australian and New Zealand Journal of Obstetrics and Gynaecology, 41, 407-410, 2001	Mifepristone is not included in this regimen
Gomez Ponce de Leon, R., Wing, D. A., Misoprostol for termination of pregnancy with intrauterine fetal demise in the second and third trimester of pregnancy - a systematic review, Contraception, 79, 259-71, 2009	Systematic review including second and third trimester abortion and regimen does not include mifepristone
Guix, C, Palacio, M, Figueras, F, Bennasar, M, Zamora, L, Coll, O, Efficacy of two regimens of misoprostol for early second-trimester pregnancy termination, Fetal diagnosis and therapy, 20, 544-548, 2005	Mifepristone is not included in this regimen
Guo, Q., Qian, Z., Huang, L., Two cervical preparation regimens prior to surgical abortion at 10-14 weeks of gestation: A randomized clinical trial, Journal of Maternal-Fetal and Neonatal Medicine, 30, 2686-2689, 2017	Mifepristone is not included in this regimen
Heikinheimo, O., Suhonen, S., Haukkamaa, M., One- and 2-day mifepristone-misoprostol intervals are both effective in medical termination of second-trimester pregnancy, Reproductive BioMedicine Online, 8, 236-9, 2004	Not a randomised controlled trial
Herabutya,Y., Chanarachakul,B., Punyavachira,P., Induction of labor with vaginal misoprostol for second trimester termination of pregnancy in the scarred uterus, International Journal of Gynaecology and Obstetrics, 83, 293-297, 2003	Mifepristone is not included in this regimen
Jain, J. K., Kuo, J., Mishell, D. R., Jr., A comparison of two dosing regimens of intravaginal misoprostol for second-trimester pregnancy termination, Obstetrics and Gynecology, 93, 571-575, 1999	Mifepristone is not included in this regimen
Jyothi, S, Pallavi, Mnv, Medical abortion by mifepristone with oral versus vaginal misoprostol, 56, 529-531, 2006	Includes only first trimester pregnancies
Kapp,N., Borgatta,L., Stubblefield,P., Vragovic,O., Moreno,N., Mifepristone in second-trimester medical abortion: a randomized controlled trial, Obstetrics and Gynecology, 110, 1304-1310, 2007	Comparison of mifepristone versus digoxin
Karsidag,A.Y.K., Buyukbayrak,E.E., Kars,B., Dansuk,R., Unal,O., Turan,M.C., Vaginal versus sublingual misoprostol for second-trimester pregnancy termination and effect on Doppler measurements, International Journal of Gynecology and Obstetrics, 106, 250-253, 2009	Mifepristone is not included in this regimen
Khazardoost, S., Hantoushzadeh, S., Madani, M. M., A randomised trial of two regimens of vaginal misoprostol to manage termination of pregnancy of up to 16 weeks, Australian and New Zealand Journal of Obstetrics and Gynaecology, 47, 226-229, 2007	Mifepristone is not included in this regimen
Kurshid, R., Ahmed, A., Mir, S., Ul Shamas, I., To assess the efficacy of two regimens of misoprostol for second trimester pregnancy termination-a randomized comparison, Internet journal of gynecology and obstetrics, 14, 2010	Mifepristone is not included in this regimen
Mahjabeen,, Khawaja, N. P., Rehman, R., Comparison of oral versus vaginal misoprostol for mid-trimester pregnancy termination, Jcpsp, Journal of the College of Physicians & Surgeons - Pakistan, 19, 359-62, 2009	Mifepristone is not included in this regimen
Milani, F., Sharami, S. H., Arjmandi, S., Comparison of sublingual and vaginal misoprostol for second-trimester pregnancy terminations, Journal of family and reproductive health, 8, 41-44, 2014	Mifepristone is not included in this regimen
Nct,, A Comparison of Sublingual and Buccal Misoprostol Regimens After Mifepristone for Mid-trimester Abortion, Https://clinicaltrials.gov/show/nct02708446, 2016	This is a clinical trial record, without details of the study
Nct,, Comparison of Two Regimens of Misoprostol for Second Trimester Medical Termination of Pregnancy, Https://clinicaltrials.gov/show/nct00401440, 2006	This is a clinical trial record, without details of the study
Nct,, Misoprostol for Second Trimester Termination of Pregnancy, Https://clinicaltrials.gov/show/nct00945997, 2009	This is a clinical trial record, without details of the study
Nigam, A., Singh, V. K., Prakash, A., Vaginal vs. oral misoprostol for mid-trimester abortion, International Journal of Gynecology and Obstetrics, 92, 270-271, 2006	Mifepristone is not included in this regimen
Ozerkan, K., Ocakoglu, G., Rehimli, S., Uncu, G., Develioglu, O., A comparison of low-dose and high-dose protocols of vaginal misoprostol for second trimester termination of pregnancy, Clinical and Experimental Obstetrics and Gynecology, 36, 245-247, 2009	Mifepristone is not included in this regimen
Rahimi-Sharbaf, F., Adabi, K., Valadan, M., Shirazi, M., Nekuie, S., Ghaffari, P., Khansari, N., The combination route versus sublingual and vaginal misoprostol for the termination of 13 to 24 week pregnancies: A randomized clinical trial, Taiwanese Journal of Obstetrics and Gynecology, 54, 660-665, 2015	Mifepristone is not included in this regimen
Roy, G, Ferreira, E, Hudon, L, Marquette, G, The efficacy of oral versus vaginal misoprostol for second-trimester termination of pregnancy: a double-blind, randomized, placebo controlled trial, American journal of obstetrics and gynecology, 189, S70, 2003	Mifepristone is not included in this regimen
Saha,S., Bal,R., Ghosh,S., Krishnamurthy,P., Medical abortion in late second trimester - A comparative study with misoprostol through vaginal versus oral followed by vaginal route, Journal of the Indian Medical Association, 104, 81-84, 2006	Mifepristone is not included in this regimen
Shaheen, S., Khattak, N. N., Parveen, T., The use of vaginal misoprostol to terminate the pregnancy in second trimester, Medical Forum Monthly, 25, 20-2, 2014	Mifepristone is not included in this regimen
Shaw, K. A., Topp, N. J., Shaw, J. G., Blumenthal, P. D., Mifepristone-misoprostol dosing interval and effect on induction abortion times: a systematic review, Obstetrics & GynecologyObstet Gynecol, 121, 1335-47, 2013	Systematic review including comparison of different regimens of mifepristone and misoprostol dosing interval. Relevant studies are included individually in the current review.
Tang, O. S., Lau, W. N., Chan, C. C., Ho, P. C., A prospective randomised comparison of sublingual and vaginal misoprostol in second trimester termination of pregnancy, 111, 1001-5, 2004	Mifepristone is not included in this regimen
Tang, O. S., Lee, S. W. H., Ho, P. C., A prospective randomized study on the measured blood loss in medical termination of early pregnancy by three different misoprostol regimens after pretreatment with mifepristone, Human Reproduction, 17, 2865-2868, 2002	Includes pregnancies in first trimester only
Tanha, F. D., Golgachi, T., Niroomand, N., Ghajarzadeh, M., Nasr, R., Sublingual versus vaginal misoprostol for second trimester termination: A randomized clinical trial, Archives of Gynecology and Obstetrics, 287, 65-69, 2013	Mifepristone is not included in this regimen
Von Hertzen, H., Piaggio, G., Wojdyla, D., Huong, N. T. M., Marions, L., Okoev, G., Khomassuridze, A., Kereszturi, A., Mittal, S., Nair, R., Daver, R., Pretnar-Darovec, A., Dickson, K., Hinh, N. D., Bao, N. H., Tuyet, H. T. D., Peregoudov, A., Comparison of vaginal and sublingual misoprostol for second trimester abortion: Randomized controlled equivalence trial, Human Reproduction, 24, 106-112, 2009	Mifepristone is not included in this regimen
Wang, Z, Zheng, Jq, Lin, Xh, Comparison of 3 methods of induction delivery for terminating midtrimester pregnancy of ulterus with scar, 17, 189-190, 2008	Full text not written in English
Webster, D., Penney, G. C., Templeton, A., A comparison of 600 and 200 mg mifepristone prior to second trimester abortion with the prostaglandin misoprostol, British Journal of Obstetrics and Gynaecology, 103, 706-709, 1996	Includes comparison of mifepristone doses, with similar misoprostol regimen for both groups.
Wong, K. S., Ngai, C. S. W., Yeo, E. L. K., Tang, L. C. H., Ho, P. C., A comparison of two regimens of intravaginal misoprostol for termination of second trimester pregnancy: A randomized comparative trial, Human Reproduction, 15, 709-712, 2000	Mifepristone is not included in this regimen
Yazdani, S. H., Zeinalzadeh, M., Bouzari, Z., Golsorkhtabar-Amiri, M., Effects of vaginal versus oral misoprostol to terminate second-trimester pregnancy, Clinical and Experimental Obstetrics and Gynecology, 39, 529-531, 2012	Mifepristone is not included in this regimen