Medicaltreatmentforearlyfetaldeath(lessthan24weeks) (Review)

Cochrane Database of Systematic Reviews

Medical treatment for early fetal death (less than 24 weeks)

(Review)

Lemmers M Verschoor MAC Kim BV Hickey M Vazquez JC Mol BWJ Neilson JP

Lemmers M Verschoor MAC Kim BV Hickey M Vazquez JC Mol BWJ Neilson JP


Cochrane Database of Systematic Reviews 2019 Issue 6 Art No CD002253

DOI 10100214651858CD002253pub4

wwwcochranelibrarycom

Medical treatment for early fetal death (less than 24weeks) (Review)

Copyright copy 2019 The Cochrane Collaboration Published by John Wiley amp Sons Ltd

T A B L E O F C O N T E N T S

1HEADER 1ABSTRACT 2PLAIN LANGUAGE SUMMARY 4SUMMARY OF FINDINGS FOR THE MAIN COMPARISON 6BACKGROUND 7OBJECTIVES 7METHODS

11RESULTS Figure 1 12Figure 2 14Figure 3 15

24ADDITIONAL SUMMARY OF FINDINGS 27DISCUSSION 29AUTHORSrsquo CONCLUSIONS 29ACKNOWLEDGEMENTS 30REFERENCES 43CHARACTERISTICS OF STUDIES

116DATA AND ANALYSES Analysis 11 Comparison 1 Vaginal misoprostol versus placebo Outcome 1 Complete miscarriage 125Analysis 12 Comparison 1 Vaginal misoprostol versus placebo Outcome 2 Death or serious complications uterine

perforation 126Analysis 13 Comparison 1 Vaginal misoprostol versus placebo Outcome 3 Blood transfusion 126Analysis 14 Comparison 1 Vaginal misoprostol versus placebo Outcome 4 Blood loss haemoglobin difference gt 10

gL 127Analysis 15 Comparison 1 Vaginal misoprostol versus placebo Outcome 5 Days of bleeding vaginal bleeding 2 weeks

after treatment 127Analysis 16 Comparison 1 Vaginal misoprostol versus placebo Outcome 6 Nausea 128Analysis 17 Comparison 1 Vaginal misoprostol versus placebo Outcome 7 Diarrhoea 128Analysis 18 Comparison 1 Vaginal misoprostol versus placebo Outcome 8 Pain (opiate use) 129Analysis 19 Comparison 1 Vaginal misoprostol versus placebo Outcome 9 Womanrsquos satisfaction with treatment 129Analysis 21 Comparison 2 Vaginal misoprostol versus expectant management Outcome 1 Complete miscarriage 130Analysis 22 Comparison 2 Vaginal misoprostol versus expectant management Outcome 2 Pelvic infection 130Analysis 31 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 1 Complete miscarriage 131Analysis 32 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 2 Uterine perforation 132Analysis 33 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 3 Blood loss post-treatment

haematocrit () 132Analysis 34 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 4 Pain relief 133Analysis 35 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 5 Pelvic infection 133Analysis 36 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 6 Nausea 134Analysis 37 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 7 Diarrhoea 134Analysis 38 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 8 Womanrsquos satisfaction 135Analysis 41 Comparison 4 Vaginal misoprostol versus vaginal dinoprostone Outcome 1 Complete miscarriage 135Analysis 42 Comparison 4 Vaginal misoprostol versus vaginal dinoprostone Outcome 2 Blood transfusion 136Analysis 43 Comparison 4 Vaginal misoprostol versus vaginal dinoprostone Outcome 3 Nausea 136Analysis 44 Comparison 4 Vaginal misoprostol versus vaginal dinoprostone Outcome 4 Duration of hospital stay

(days) 137Analysis 51 Comparison 5 Vaginal misoprostol lower versus higher-dose regimens Outcome 1 Complete miscarriage lt 13

weeks 137Analysis 52 Comparison 5 Vaginal misoprostol lower versus higher-dose regimens Outcome 2 Complete miscarriage 13-

23 weeks 138Analysis 53 Comparison 5 Vaginal misoprostol lower versus higher-dose regimens Outcome 3 Nausea 139

iMedical treatment for early fetal death (less than 24 weeks) (Review)


Analysis 54 Comparison 5 Vaginal misoprostol lower versus higher-dose regimens Outcome 4 Diarrhoea 139Analysis 61 Comparison 6 Vaginal misoprostol wet versus dry vaginal preparations Outcome 1 Complete miscarriage 140Analysis 62 Comparison 6 Vaginal misoprostol wet versus dry vaginal preparations Outcome 2 Diarrhoea 141Analysis 63 Comparison 6 Vaginal misoprostol wet versus dry vaginal preparations Outcome 3 Vomiting 141Analysis 64 Comparison 6 Vaginal misoprostol wet versus dry vaginal preparations Outcome 4 Acceptability of method

would wishprobably wish same treatment in future nonviable pregnancy 142Analysis 71 Comparison 7 Vaginal misoprostol + methotrexate versus vaginal misoprostol alone Outcome 1 Complete

miscarriage 142Analysis 72 Comparison 7 Vaginal misoprostol + methotrexate versus vaginal misoprostol alone Outcome 2

Haemorrhage 143Analysis 73 Comparison 7 Vaginal misoprostol + methotrexate versus vaginal misoprostol alone Outcome 3 Pain relief 143Analysis 81 Comparison 8 Vaginal misoprostol plus laminaria tents versus vaginal misoprostol alone Outcome 1 Complete

miscarriage 144Analysis 91 Comparison 9 Vaginal misoprostol versus sublingual misoprostol Outcome 1 Complete miscarriage lt 13

weeks 145Analysis 92 Comparison 9 Vaginal misoprostol versus sublingual misoprostol Outcome 2 Complete miscarriage 13-23

weeks 146Analysis 93 Comparison 9 Vaginal misoprostol versus sublingual misoprostol Outcome 3 Blood loss excessive (gt

menstruation) 146Analysis 94 Comparison 9 Vaginal misoprostol versus sublingual misoprostol Outcome 4 Pain 147Analysis 95 Comparison 9 Vaginal misoprostol versus sublingual misoprostol Outcome 5 Nausea 148Analysis 96 Comparison 9 Vaginal misoprostol versus sublingual misoprostol Outcome 6 Vomiting 149Analysis 97 Comparison 9 Vaginal misoprostol versus sublingual misoprostol Outcome 7 Diarrhoea 149Analysis 101 Comparison 10 Vaginal misoprostol versus intravenous oxytocin Outcome 1 Complete miscarriage 13-23

weeks 150Analysis 102 Comparison 10 Vaginal misoprostol versus intravenous oxytocin Outcome 2 Blood loss excessive 151Analysis 111 Comparison 11 Vaginal misoprostol versus vaginal gemeprost Outcome 1 Complete miscarriage 13-23

weeks 151Analysis 112 Comparison 11 Vaginal misoprostol versus vaginal gemeprost Outcome 2 Opiates for pain relief 152Analysis 113 Comparison 11 Vaginal misoprostol versus vaginal gemeprost Outcome 3 Vomiting 152Analysis 114 Comparison 11 Vaginal misoprostol versus vaginal gemeprost Outcome 4 Diarrhoea 153Analysis 121 Comparison 12 Sublingual misoprostol versus oral misoprostol Outcome 1 Complete miscarriage 153Analysis 122 Comparison 12 Sublingual misoprostol versus oral misoprostol Outcome 2 Pain 154Analysis 123 Comparison 12 Sublingual misoprostol versus oral misoprostol Outcome 3 Nausea andor vomiting 155Analysis 124 Comparison 12 Sublingual misoprostol versus oral misoprostol Outcome 4 Diarrhoea 156Analysis 125 Comparison 12 Sublingual misoprostol versus oral misoprostol Outcome 5 Womanrsquos satisfaction with

treatment 157Analysis 131 Comparison 13 Sublingual powdery versus sublingual compact misoprostol Outcome 1 Complete

miscarriage 157Analysis 132 Comparison 13 Sublingual powdery versus sublingual compact misoprostol Outcome 2 Nauseavomiting 158Analysis 133 Comparison 13 Sublingual powdery versus sublingual compact misoprostol Outcome 3 Diarrhoea 158Analysis 141 Comparison 14 Sublingual misoprostol with versus without extended course Outcome 1 Complete

miscarriage 159Analysis 142 Comparison 14 Sublingual misoprostol with versus without extended course Outcome 2 Nausea 160Analysis 143 Comparison 14 Sublingual misoprostol with versus without extended course Outcome 3 Pain 160Analysis 144 Comparison 14 Sublingual misoprostol with versus without extended course Outcome 4 Vomiting 161Analysis 145 Comparison 14 Sublingual misoprostol with versus without extended course Outcome 5 Diarrhoea 161Analysis 151 Comparison 15 Sublingual + vaginal misoprostol versus only vaginal misoprostol Outcome 1 Complete

miscarriage 162Analysis 152 Comparison 15 Sublingual + vaginal misoprostol versus only vaginal misoprostol Outcome 2 Blood loss

haemoglobin level 162Analysis 153 Comparison 15 Sublingual + vaginal misoprostol versus only vaginal misoprostol Outcome 3 Nausea 163Analysis 154 Comparison 15 Sublingual + vaginal misoprostol versus only vaginal misoprostol Outcome 4 Vomiting 163

iiMedical treatment for early fetal death (less than 24 weeks) (Review)


Analysis 155 Comparison 15 Sublingual + vaginal misoprostol versus only vaginal misoprostol Outcome 5 Diarrhoea 164Analysis 156 Comparison 15 Sublingual + vaginal misoprostol versus only vaginal misoprostol Outcome 6 Pain 164Analysis 157 Comparison 15 Sublingual + vaginal misoprostol versus only vaginal misoprostol Outcome 7 Womanrsquos

satisfaction with treatment 165Analysis 161 Comparison 16 Oral misoprostol versus vaginal misoprostol Outcome 1 Complete miscarriage lt 13

weeks 165Analysis 162 Comparison 16 Oral misoprostol versus vaginal misoprostol Outcome 2 Complete miscarriage gt 13-23

weeks 166Analysis 163 Comparison 16 Oral misoprostol versus vaginal misoprostol Outcome 3 Blood loss excessive 167Analysis 164 Comparison 16 Oral misoprostol versus vaginal misoprostol Outcome 4 Pain (visual analogue scale) 167Analysis 165 Comparison 16 Oral misoprostol versus vaginal misoprostol Outcome 5 Pain 168Analysis 166 Comparison 16 Oral misoprostol versus vaginal misoprostol Outcome 6 Vomiting 168Analysis 167 Comparison 16 Oral misoprostol versus vaginal misoprostol Outcome 7 Nausea 169Analysis 168 Comparison 16 Oral misoprostol versus vaginal misoprostol Outcome 8 Diarrhoea 170Analysis 169 Comparison 16 Oral misoprostol versus vaginal misoprostol Outcome 9 Womanrsquos satisfaction with

treatment 170Analysis 171 Comparison 17 Oral misoprostol + mifepristone versus expectant management Outcome 1 Complete

miscarriage 171Analysis 172 Comparison 17 Oral misoprostol + mifepristone versus expectant management Outcome 2 Blood loss

(severe) 172Analysis 173 Comparison 17 Oral misoprostol + mifepristone versus expectant management Outcome 3 Days of

bleeding 172Analysis 174 Comparison 17 Oral misoprostol + mifepristone versus expectant management Outcome 4 Pain 173Analysis 175 Comparison 17 Oral misoprostol + mifepristone versus expectant management Outcome 5 Pelvic

infection 173Analysis 176 Comparison 17 Oral misoprostol + mifepristone versus expectant management Outcome 6 Womanrsquos

satisfaction with treatment (visual analogue scale day 14) 174Analysis 181 Comparison 18 Buccal misoprostol lower versus higher-dose regimen Outcome 1 Complete miscarriage 13-

23 weeks 175Analysis 182 Comparison 18 Buccal misoprostol lower versus higher-dose regimen Outcome 2 Nausea 176Analysis 183 Comparison 18 Buccal misoprostol lower versus higher-dose regimen Outcome 3 Vomiting 176Analysis 184 Comparison 18 Buccal misoprostol lower versus higher-dose regimen Outcome 4 Diarrhoea 177Analysis 185 Comparison 18 Buccal misoprostol lower versus higher-dose regimen Outcome 5 Pain 178Analysis 186 Comparison 18 Buccal misoprostol lower versus higher-dose regimen Outcome 6 Womanrsquos satisfaction with

treatment (satisfied or very satisfied) 178Analysis 191 Comparison 19 Mifepristone versus placebo Outcome 1 Complete miscarriage 179Analysis 192 Comparison 19 Mifepristone versus placebo Outcome 2 Days of bleeding 180Analysis 193 Comparison 19 Mifepristone versus placebo Outcome 3 Pain 180Analysis 201 Comparison 20 Mifepristone + vaginal misoprostol versus vaginal misoprostol alone Outcome 1 Complete

miscarriage 181Analysis 202 Comparison 20 Mifepristone + vaginal misoprostol versus vaginal misoprostol alone Outcome 2 Blood

transfusion 182Analysis 203 Comparison 20 Mifepristone + vaginal misoprostol versus vaginal misoprostol alone Outcome 3 Pelvic

infection 182Analysis 204 Comparison 20 Mifepristone + vaginal misoprostol versus vaginal misoprostol alone Outcome 4 nausea 183Analysis 205 Comparison 20 Mifepristone + vaginal misoprostol versus vaginal misoprostol alone Outcome 5

Diarrhoea 183Analysis 206 Comparison 20 Mifepristone + vaginal misoprostol versus vaginal misoprostol alone Outcome 6 Womanrsquos

satisfaction 184Analysis 211 Comparison 21 Vaginal gemeprost versus surgical evacuation of uterus Outcome 1 Complete miscarriage 184Analysis 212 Comparison 21 Vaginal gemeprost versus surgical evacuation of uterus Outcome 2 Death or serious

complications (uterine perforation) 185Analysis 213 Comparison 21 Vaginal gemeprost versus surgical evacuation of uterus Outcome 3 Nausea 186

iiiMedical treatment for early fetal death (less than 24 weeks) (Review)


Analysis 221 Comparison 22 Misoprostol intravaginal extraamniotic versus vaginal misoprostol Outcome 1 Completemiscarriage 186

Analysis 222 Comparison 22 Misoprostol intravaginal extraamniotic versus vaginal misoprostol Outcome 2 Nausea 187Analysis 223 Comparison 22 Misoprostol intravaginal extraamniotic versus vaginal misoprostol Outcome 3 Vomiting 187Analysis 224 Comparison 22 Misoprostol intravaginal extraamniotic versus vaginal misoprostol Outcome 4 Diarrhoea 188Analysis 225 Comparison 22 Misoprostol intravaginal extraamniotic versus vaginal misoprostol Outcome 5 Pain (use of

analgesics) 188Analysis 226 Comparison 22 Misoprostol intravaginal extraamniotic versus vaginal misoprostol Outcome 6 Time to

expulsion 189Analysis 231 Comparison 23 Vaginal misoprostol with versus without extended course Outcome 1 Complete

miscarriage 189Analysis 232 Comparison 23 Vaginal misoprostol with versus without extended course Outcome 2 Nausea 190Analysis 233 Comparison 23 Vaginal misoprostol with versus without extended course Outcome 3 Vomiting 190Analysis 234 Comparison 23 Vaginal misoprostol with versus without extended course Outcome 4 Diarrhoea 191Analysis 235 Comparison 23 Vaginal misoprostol with versus without extended course Outcome 5 Pain (use of

analgesics) 192Analysis 236 Comparison 23 Vaginal misoprostol with versus without extended course Outcome 6 Womanrsquos satisfaction

with treatment 192192APPENDICES 193WHATrsquoS NEW 193HISTORY 193CONTRIBUTIONS OF AUTHORS 194DECLARATIONS OF INTEREST 194SOURCES OF SUPPORT 195DIFFERENCES BETWEEN PROTOCOL AND REVIEW 196INDEX TERMS

ivMedical treatment for early fetal death (less than 24 weeks) (Review)


[Intervention Review]


Marike Lemmers1 Marianne AC Verschoor1 Bobae Veronica Kim2 Martha Hickey3 Juan C Vazquez4 Ben Willem J Mol5 James PNeilson6

1Department of Obstetrics and Gynaecology Academic Medical Center Amsterdam Netherlands 2Robinson Research InstituteSchool of Medicine The University of Adelaide Adelaide Australia 3The University of Melbourne The Royal Womenrsquos Hospital Mel-bourne Australia 4Departamento de Salud Reproductiva Instituto Nacional de Endocrinologia (INEN) Habana Cuba 5Departmentof Obstetrics and Gynaecology Monash University Clayton Australia 6The University of Liverpool Liverpool UK

Contact address James P Neilson The University of Liverpool Liverpool UK jneilsonliverpoolacuk

Editorial group Cochrane Pregnancy and Childbirth GroupPublication status and date New search for studies and content updated (no change to conclusions) published in Issue 6 2019

Citation Lemmers M Verschoor MAC Kim BV Hickey M Vazquez JC Mol BWJ Neilson JP Medical treatment forearly fetal death (less than 24 weeks) Cochrane Database of Systematic Reviews 2019 Issue 6 Art No CD002253 DOI10100214651858CD002253pub4


A B S T R A C T

Background

In most pregnancies that miscarry arrest of embryonic or fetal development occurs some time (often weeks) before the miscarriage occursUltrasound examination can reveal abnormal findings during this phase by demonstrating anembryonic pregnancies or embryonic orfetal death Treatment has traditionally been surgical but medical treatments may be effective safe and acceptable as may be waitingfor spontaneous miscarriage This is an update of a review first published in 2006

Objectives

To assess from clinical trials the effectiveness and safety of different medical treatments for the termination of non-viable pregnancies

Search methods

For this update we searched Cochrane Pregnancy and Childbirthrsquos Trials Register ClinicalTrialsgov the WHO International ClinicalTrials Registry Platform (ICTRP) (24 October 2018) and reference lists of retrieved studies

Selection criteria

Randomised trials comparing medical treatment with another treatment (eg surgical evacuation) or placebo or no treatment forearly pregnancy failure Quasi-randomised studies were excluded Cluster-randomised trials were eligible for inclusion as were studiesreported in abstract form if sufficient information was available to assess eligibility

Data collection and analysis

Two review authors independently assessed trials for inclusion and risk of bias extracted data and checked them for accuracy Weassessed the quality of the evidence using the GRADE approach

Main results

Forty-three studies (4966 women) were included The main interventions examined were vaginal sublingual oral and buccal miso-prostol mifepristone and vaginal gemeprost These were compared with surgical management expectant management placebo ordifferent types of medical interventions were compared with each other The review includes a wide variety of different interventionswhich have been analysed across 23 different comparisons Many of the comparisons consist of single studies We limited the grading of

1Medical treatment for early fetal death (less than 24 weeks) (Review)


the quality of evidence to two main comparisons vaginal misoprostol versus placebo and vaginal misoprostol versus surgical evacuationof the uterus Risk of bias varied widely among the included trials The quality of the evidence varied between the different comparisonsbut was mainly found to be very-low or low quality

Vaginal misoprostol versus placebo

Vaginal misoprostol may hasten miscarriage when compared with placebo eg complete miscarriage (5 trials 305 women risk ratio(RR) 423 95 confidence interval (CI) 301 to 594 low-quality evidence) No trial reported on pelvic infection rate for thiscomparison Vaginal misoprostol made little difference to rates of nausea (2 trials 88 women RR 138 95 CI 043 to 440 low-quality evidence) diarrhoea (2 trials 88 women RR 221 95 CI 035 to 1406 low-quality evidence) or to whether women weresatisfied with the acceptability of the method (1 trial 32 women RR 117 95 CI 083 to 164 low-quality evidence) It is uncertainwhether vaginal misoprostol reduces blood loss (haemoglobin difference gt 10 gL) (1 trial 50 women RR 125 95 CI 038 to 412very-low quality) or pain (opiate use) (1 trial 84 women RR 500 95 CI 025 to 10111 very-low quality) because the quality ofthe evidence for these outcomes was found to be very low

Vaginal misoprostol versus surgical evacuation

Vaginal misoprostol may be less effective in accomplishing a complete miscarriage compared to surgical management (6 trials 943women average RR 040 95 CI 032 to 050 Heterogeneity Tausup2 = 003 Isup2 = 46 low-quality evidence) and may be associatedwith more nausea (1 trial 154 women RR 2185 95 CI 131 to 36437 low-quality evidence) and diarrhoea (1 trial 154 womenRR 4085 95 CI 252 to 66257 low-quality evidence) There may be little or no difference between vaginal misoprostol and surgicalevacuation for pelvic infection (1 trial 618 women RR 073 95 CI 039 to 137 low-quality evidence) blood loss (post-treatmenthaematocrit () (1 trial 50 women mean difference (MD) 140 95 CI -351 to 071 low-quality evidence) pain relief (1 trial154 women RR 142 95 CI 082 to 246 low-quality evidence) or womenrsquos satisfactionacceptability of method (1 trial 45 womenRR 067 95 CI 040 to 111 low-quality evidence)

Other comparisons

Based on findings from a single trial vaginal misoprostol was more effective at accomplishing complete miscarriage than expectantmanagement (614 women RR 125 95 CI 109 to 145) There was little difference between vaginal misoprostol and sublingualmisoprostol (5 trials 513 women average RR 084 95 CI 061 to 116 Heterogeneity Tausup2 = 010 Isup2 = 871 or between oraland vaginal misoprostol in terms of complete miscarriage at less than 13 weeks (4 trials 418 women) average RR 068 95 CI 045to 103 Heterogeneity Tausup2 = 013 Isup2 = 90) However there was less abdominal pain with vaginal misoprostol in comparison tosublingual (3 trials 392 women RR 058 95 CI 046 to 074) A single study (46 women) found mifepristone to be more effectivethan placebo miscarriage complete by day five after treatment (46 women RR 950 95 CI 249 to 3619) However the quality ofthis evidence is very low there is a very serious risk of bias with signs of incomplete data and no proper intention-to-treat analysis inthe included study and serious imprecision with wide confidence intervals Mifepristone did not appear to further hasten miscarriagewhen added to a misoprostol regimen (3 trials 447 women RR 118 95 CI 095 to 147)

Authorsrsquo conclusions

Available evidence from randomised trials suggests that medical treatment with vaginal misoprostol may be an acceptable alternativeto surgical evacuation or expectant management In general side effects of medical treatment were minor consisting mainly of nauseaand diarrhoea There were no major differences in effectiveness between different routes of administration Treatment satisfaction wasaddressed in only a few studies in which the majority of women were satisfied with the received intervention Since the quality ofevidence is low or very low for several comparisons mainly because they included only one or two (small) trials further research isnecessary to assess the effectiveness safety and side effects optimal route of administration and dose of different medical treatmentsfor early fetal death

P L A I N L A N G U A G E S U M M A R Y


What is the issue

A miscarriage is the spontaneous death andor expulsion of an embryo or fetus from the uterus before it is able to survive on its ownThis natural death of an embryo or fetus (rsquonon-viable pregnancyrsquo or rsquointrauterine fetal deathrsquo depending on the duration of pregnancy)



can be identified by ultrasound before symptoms like blood loss and abdominal pain occur Sometimes an embryo may not have evendeveloped (rsquoempty sacrsquo) In the past treatment for a deceived embryofetus has usually been by dilatation and curettage (DampC) surgerybut drugs have now been developed to replace the need for surgery which may be helpful for the expulsion to happen Misoprostoland gemeprost are synthetic prostaglandin E analogues that can stimulate expulsion of the embryofetus from the uterus Mifepristoneblocks the activity of progesterone a hormone that supports pregnancy These and similar drugs may be useful in bringing on expulsionin women with a non-viable pregnancy and can be used before 24 weeksrsquo gestation

Waiting for spontaneous expulsion is also possible Women who retain the dead embryofetus can experience severe blood loss ordevelop an infection of the womb These are rare complications Gastro-intestinal side effects such as nausea and diarrhoea crampingor abdominal pain and fever have been reported with misoprostol

Why is this important

Surgical treatment has the disadvantage of requiring anaesthesia It carries risks of damage to the uterus or cervix and possible developmentof fibrous tissue in the inner lining of the uterus These can be avoided if the non-viable pregnancy is treated with medication or if thewoman is able to wait for a spontaneous expulsion

We set out to determine if medical treatment is as good as or better than surgical treatment or expectant management (waiting forthe expulsion to happen) Furthermore we compared different doses and administration routes in order to detect which regimen mostoften induces a complete miscarriage with the fewest side effects

What evidence did we find

For this updated review 43 randomised clinical trials involving 4966 women with non-viable pregnancies at less than 24 weeksrsquogestation were included The main interventions examined were vaginal sublingual oral and buccal misoprostol mifepristone andvaginal gemeprost These were compared with surgical management expectant management placebo or different types of medicalinterventions were compared with each other Fourteen comparisons had only one trial The studies varied in risk of bias The qualityof the evidence ranged from very low or low for most comparisons

Vaginal misoprostol may hasten miscarriage when compared with placebo but made little difference to rates of nausea diarrhoea orto whether women were satisfied with the acceptability of the method It is uncertain whether vaginal misoprostol when compared toplacebo reduces blood loss or pain because the quality of the evidence for these outcomes was found to be very low

Vaginal misoprostol was less effective in accomplishing a complete miscarriage compared to surgical management and may be associatedwith more nausea and diarrhoea Vaginal misoprostol made little difference to pelvic infection blood loss pain or womenrsquos satisfactionacceptability of method when compared to surgical management

There was little difference between different routes of giving misoprostol when trials compared the vaginal route with placing it underthe tongue or between oral and vaginal misoprostol Single studies found mifepristone to be more effective than placebo and vaginalmisoprostol to be more effective than expectant management However the quality of this evidence was found to be very low and sowe are not convinced of these findings Mifepristone did not appear to provide any additional benefit when added to misoprostol

What does this mean

Using misoprostol as an alternative to surgical treatment may decrease the need for surgery for women with an early fetal death The useof misoprostol can have some side effects such as nausea and diarrhoea but risks of severe blood loss or pelvic infection were not highercompared to surgical treatment or expectant management Further research is needed on drug doses routes of administration andpotential adverse effects including future fertility and also on womenrsquos views of drug treatment surgery and waiting for spontaneousmiscarriage



S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Vaginal misoprostol compared to placebo for early fetal death (less than 24 weeks)

Patient or population early fetal death (less than 24 weeks)

Setting worldwide

Intervention vaginal m isoprostol

Comparison placebo

Outcomes Anticipated absolute effectslowast (95 CI) Relative effect

(95 CI)

of participants

(studies)

Certainty of the evi-

dence

(GRADE)

Comments

Risk with placebo Risk with vaginal miso-

prostol

Complete miscarriage Study populat ion RR 423

(301 to 594)

305 women

(5 RCTs)

oplusopluscopycopy

LOW 12

There were dif ferences

in t im ing of outcome

measurement af ter 24

hours (2 studies) af ter

48 hours (2 studies) or

af ter 7 days (1 study)

189 per 1000 800 per 1000

(569 to 1000)

Pelvic infect ion Study populat ion not est imable (studies) -

0 per 1000 0 per 1000

(0 to 0)

Nausea Study populat ion RR 138

(043 to 440)

88 women

(2 RCTs)

oplusopluscopycopy

LOW 34

93 per 1000 128 per 1000

(40 to 409)

Diarrhoea Study populat ion RR 221

(035 to 1406)

88 women

(2 RCTs)

oplusopluscopycopy

LOW 34

23 per 1000 51 per 1000

(8 to 327)

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tfo

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feta

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eath

(less

than

24

weeks)

(Revie

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Blood loss haemoglo-

bin dif f erence gt 10 g L

Study populat ion RR 125

(038 to 412)

50 women

(1 RCT)

opluscopycopycopy

VERY LOW 56

160 per 1000 200 per 1000

(61 to 659)

Pain (opiate use) Study populat ion RR 500

(025 to 10111)

84 women

(1 RCT)

opluscopycopycopy46

VERY LOW

0 per 1000 0 per 1000

(0 to 0)

Womanrsquos sat isfact ion

acceptability of method


(083 to 164)

32 women

(1 RCT)

oplusopluscopycopy

LOW 6

750 per 1000 878 per 1000

(622 to 1000)

The risk in the intervention group (and its 95 conf idence interval) is based on the assumed risk in the comparison group and the relative effect of the intervent ion (and its

95CI)

CI Conf idence interval RR Risk rat io

GRADE Working Group grades of evidence

High certainty We are very conf ident that the true ef fect lies close to that of the est imate of the ef fect

Moderate certainty We are moderately conf ident in the ef fect est imate The true ef fect is likely to be close to the est imate of the ef fect but there is a possibility that it is

substant ially dif f erent

Low certainty Our conf idence in the ef fect est imate is lim ited The true ef fect may be substant ially dif f erent f rom the est imate of the ef fect

Very low certainty We have very lit t le conf idence in the ef fect est imate The true ef fect is likely to be substant ially dif f erent f rom the est imate of ef fect

1 Serious indirectness dif f erences in medicat ion regimens used between the included studies However very strong

associat ion dose-response relat ion (-1)2 Serious risk of bias problems with blinding in various studies downgraded because of lim itat ion in study design (-1)3 Serious imprecision only two studies with relat ively few patients (-1)4 Serious risk of bias unclear allocat ion concealment (-1)5 Serious risk of indirect evidence haematocrit dif f erence was used to est imate the amount of blood loss (-1)6 Serious imprecision only one study included wide conf idence interval (-2)

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B A C K G R O U N D

Miscarriage is the most frequent pregnancy complication with anincidence of at least 10 to 15 of all pregnancies (Grudzinskas1995 Howie 1995 Simpson 1991) Traditionally early non-vi-able pregnancies (less than 14 weeks) have been terminated by sur-gical evacuation However the use of medical treatment for earlynon-viable pregnancies is increasing Later pregnancies (14 to 24weeks) have been ended by medical induction of miscarriage (Say2002)

Description of the condition

A miscarriage is defined as an intrauterine pregnancy demise con-firmed by ultrasound or histology up to 13 weeks of gestationThere are different forms of non-viable pregnancies such as rsquoanem-bryonic pregnanciesrsquo (formerly called rsquoblighted ovarsquo) if no embryohas developed within the gestational sac or rsquomissed abortionsrsquo ifan embryo or fetus is present but is dead When fetal death oc-curs in later pregnancy (14 to 24 weeks of gestation) it is calledintrauterine fetal demiseThe widespread use of ultrasound in early pregnancy for eitherspecific reasons (for example vaginal bleeding) or as a routineexamination (Whitworth 2015) reveals rsquonon-viable pregnanciesrsquodestined inevitably to miscarry in due course

Description of the intervention

Traditionally early non-viable pregnancies (less than 14 weeks)have been terminated by surgical evacuation Later pregnancies(14 to 24 weeks) have been ended by medical induction of mis-carriage (Say 2002) Although clotting problems occasionally oc-cur in women with prolonged retention of a dead fetus this israre and does not usually happen within the first month after fetaldeath There are therefore not pressing medical reasons to termi-nate non-viable pregnancies Although anecdotally many womenfavour early termination so-called rsquoexpectant managementrsquo (thatis awaiting spontaneous miscarriage) is a legitimate alternativeand this policy should be considered in clinical care and in plan-ning trials (Nanda 2012 Wieringa 2002) More recently medicaltreatment is used as an alternative to surgical termination of non-viable pregnancies There are various types of medical treatmentthat could be used as alternatives to surgical treatment misopros-tol mifepristone gemeprost methotrexate or oxytocin The drugmost frequently investigated and now used is misoprostol Thisdrug can be administered via several different routes oral sublin-gual vaginal and extra amniotic and as a single drug therapy orcombined with other types of medication such as mifepristonemethotrexate or oxytocin Furthermore the optimal dose of miso-prostol is not known and therefore different doses are used rang-ing from 100 mg up to 800 mg per dose

How the intervention might work

Misoprostol is a synthetic prostaglandin E1 analogue It is a typeof medication that was first registered as treatment for peptic ul-cers It is also used as medical treatment for terminating an un-wanted or non-viable pregnancy Misoprostol ripens the cervixand causes uterine contractions Furthermore it is cost-effective(Costa 1993 Graziosi 2005 Norman 1991) Misoprostol couldbe especially useful in low-income countries where transport andstorage facilities are inadequate and the availability of uterotonicagents and blood is limited Its use in obstetrics and gynaecologyhas been explored especially to induce first and second trimesterabortion (Ashok 1998 Bugalho 1996) for the induction of labour(Alfirevic 2014 Hofmeyr 2010) and for the prevention of post-partum haemorrhage (Tunccedilalp 2012) despite the fact that it hasnot been registered for such use The sensitivity of the uterus formisoprostol increases with the duration of pregnancy Though theoptimal dose for the induction of first or second trimester mis-carriage is not known and remains a subject of interest in theincluded studiesDinoproston is a natural prostaglandin E2 It advances uterinecontraction and also ripens the cervix though its exact mecha-nism is not known Other uterotonic drugs include ergometrine(while it acts at alpha-adrenergic dopaminergic and serotonin re-ceptors it exerts on the uterus a stimulant effect) and oxytocin(a synthetic nano peptide identical to oxytocin produced by thepituitary gland causing rhythmic contractions of the uterus)Other uterotonic drugs that could have a role in the induction ofmiscarriage include ergometrine oxytocinThe progesterone antagonist mifepristone is of value in terminat-ing early unwanted pregnancies and may be useful in non-viablepregnancies and spontaneous miscarriage (Baulieu 1986 Kovacs1984) alone or in combination with prostaglandin (Cameron1986) Methotrexate has been researched for medical treatmentof ectopic pregnancy and might have a place in the treatment ofintrauterine non-viable pregnancies as well

Why it is important to do this review

The use of medical treatment in termination of non-viable preg-nancies is increasing Since miscarriage is the most frequent com-plication of pregnancy it is important to have knowledge aboutthe different types of medical treatment their (cost) effectivenessand their side effectsThe initial protocol for this review aimed to combine trials ofmedical treatments for both non-viable pregnancies and for in-complete miscarriage but on further reflection this was illogicalNon-viable pregnancies contain viable trophoblast (placental) tis-sue which produces hormones which may in theory make thesepregnancies more susceptible to anti-hormone therapy and moreresistant to uterotonic (stimulating uterine contractions) therapythan pregnancies in which (incomplete) miscarriage has already



taken place This review will therefore focus exclusively on non-vi-able pregnancies before miscarriage Another review assesses trialsof medical treatments after miscarriage has occurred (Kim 2017)A further review compares expectant management with surgicaltreatment for miscarriage (Nanda 2012)Our review was first published in 2006 It was last edited andpublished online on January 21 2009 Since the publication ofthe review in 2006 multiple new clinical trials concerning medicaltreatment of early fetal death have been conducted and resultspublished The review therefore needed to be updated

O B J E C T I V E S

To assess from clinical trials the effectiveness and safety of dif-ferent medical treatments for the termination of non-viable preg-nancies

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomised clinical trials comparing a medical treatment withanother treatment (for example surgical evacuation) or placeboor no treatment to terminate non-viable pregnancies Quasi-ran-domised studies were excluded Cluster-randomised trials were el-igible for inclusion as were studies reported in abstract form ifsufficient information was available to assess eligibility

Types of participants

Women with non-viable pregnancies (ie where the embryo orfetus had died in utero and in whom miscarriage would havehappened inevitably in due course) if less than 24 weeks estimatedgestational age If applicable subgroup analyses were performedfor women in first and women in the second trimester (up to24 weeks of gestational age) of pregnancy Since different studiesmight use different cut-off values to consider a pregnancy in itssecond trimester (varying between 12 and 15 weeks of gestationalage) in the subgroup analysis the exact gestational age that wasused in the included studies is mentioned

Types of interventions

Trials were considered if they compared medical treatment withother methods (for example expectant management placebo or

any other intervention including surgical evacuation) Compar-isons between different routes of administration of medical treat-ment (for example oral versus vaginal) or between different drugsor doses of drug or duration or timing of treatment were alsoincluded if data existed

Types of outcome measures

Trials were considered if any of the following outcomes were mea-sured

Primary outcomes

1 Complete miscarriage (ie no pregnancy tissues remainingin uterus - based on clinical findings at surgery or ultrasoundexamination or both after a specific period or an uncomplicatedfollow-up period or both without the need for additionalsurgical intervention)

2 Death or serious complications (eg uterine ruptureuterine perforation hysterectomy organ failure intensive careunit admission)

Secondary outcomes

1 Blood transfusion2 Haemorrhage3 Blood loss (measured amount of blood post-treatment

haemoglobin or post-treatment haematocrit or both)4 Days of bleeding5 Pain (relief ) (defined as 1 differences in pain scores

between the different treatment methods andor 2 the increaseor decrease in pain score after a certain treatment) andor 3incidence of pain as a complaint andor 4 the use of painmedication after a certain treatment)

6 Pelvic infection (defined by the authors as fever most likelycaused by pelvic infection or documented pelvic infection orboth)

7 Cervical damage8 Digestive disorders (nausea or vomiting or diarrhoea)9 Hypertensive disorders

10 Time to expulsion11 Duration of stay in hospital12 Psychological effects13 Subsequent fertility14 Womanrsquos satisfactionacceptability of method15 Costs

Search methods for identification of studies

The following methods section of this review is based on a standardtemplate used by Cochrane Pregnancy and Childbirth



Electronic searches

We searched Cochrane Pregnancy and Childbirthrsquos Trials Registerby contacting their Information Specialist (24 October 2018)The Register is a database containing over 24000 reports of con-trolled trials in the field of pregnancy and childbirth It representsover 30 years of searching For full current search methods usedto populate Pregnancy and Childbirthrsquos Trials Register includingthe detailed search strategies for CENTRAL MEDLINE Em-base and CINAHL the list of handsearched journals and confer-ence proceedings and the list of journals reviewed via the currentawareness service please follow this linkBriefly Cochrane Pregnancy and Childbirthrsquos Trials Register ismaintained by their Information Specialist and contains trialsidentified from

1 monthly searches of the Cochrane Central Register ofControlled Trials (CENTRAL)

2 weekly searches of MEDLINE (Ovid)3 weekly searches of Embase (Ovid)4 monthly searches of CINAHL (EBSCO)5 handsearches of 30 journals and the proceedings of major

conferences6 weekly current awareness alerts for a further 44 journals

plus monthly BioMed Central email alertsSearch results are screened by two people and the full text of allrelevant trial reports identified through the searching activities de-scribed above is reviewed Based on the intervention describedeach trial report is assigned a number that corresponds to a spe-cific Pregnancy and Childbirth review topic (or topics) and isthen added to the Register The Information Specialist searches theRegister for each review using this topic number rather than key-words This results in a more specific search set that has been fullyaccounted for in the relevant review sections (Included studiesExcluded studies Ongoing studies)In addition we searched ClinicalTrialsgov and the WHO Inter-national Clinical Trials Registry Platform ( ICTRP) (24 October2018) for unpublished planned and ongoing trial reports usingthe search terms given in Appendix 1

Searching other resources

We searched the reference lists of retrieved studiesWe did not apply any language or date restrictions


For methods used in the previous version of this review see Neilson2006For this update the following methods were used for assessing thereports that were identified as a result of the updated search

Selection of studies

Two review authors independently assessed for inclusion all thepotential studies we identified as a result of the search strategyPotential trials were assessed for eligibility according to the criteriadescribed in the lsquoEligibility criteriarsquo section above If study eligi-bility needed to be further clarified we contacted the investigatorsto request further information Studies published in abstracts onlywere assessed in the same way as full-text papers If there was suffi-cient information presented in the abstract to demonstrate that itmet the eligibility criteria it was included in analyses Otherwise itwas excluded with reasons noted in the Characteristics of excludedstudies tableWe resolved any disagreement through discussion or if requiredwe consulted a third review author

Data extraction and management

Data were extracted from each relevant publication using a datacollection formIn addition to the main outcome measures listed above infor-mation on the setting of the study (country type of populationsocioeconomic status) the method of randomisation a detaileddescription of the regimen used (drug(s) route dose frequency)definitions of the outcomes (if provided) and whether or not clin-icians and participants were rsquoblindrsquo to treatment allocated werecollected Furthermore any information on completeness of fol-low-up was collected as well Also we collected the key conclu-sions of the included studies as reported by their authorsFor eligible studies two review authors extracted the data usingthe agreed form We resolved discrepancies through discussion orif required we consulted a third review authorData were imported in Review Manager software (RevMan 2014)and checked for accuracyWhen information regarding any of the above was unclear weattempted to contact authors of the original reports to providefurther details

Assessment of risk of bias in included studies

Two review authors independently assessed risk of bias for eachstudy using the criteria outlined in the Cochrane Handbook for Sys-tematic Reviews of Interventions (Higgins 2011) Any disagreementwas resolved by discussion or by involving a third assessor

(1) Random sequence generation (checking for possible

selection bias)

We described for each included study the method used to generatethe allocation sequence in sufficient detail to allow an assessmentof whether it should produce comparable groupsWe assessed the method as

bull low risk of bias (any truly random process eg randomnumber table computer random number generator)



bull high risk of bias (any non-random process eg odd or evendate of birth hospital or clinic record number) if during dataextraction we found that the trial was quasi-randomised weexcluded it from further analysis

bull unclear risk of bias

(2) Allocation concealment (checking for possible selection

bias)

We described for each included study the method used to con-ceal allocation to interventions prior to assignment and assessedwhether intervention allocation could have been foreseen in ad-vance of or during recruitment or changed after assignmentWe assessed the methods as

bull low risk of bias (eg telephone or central randomisationconsecutively numbered sealed opaque envelopes)

bull high risk of bias (open random allocation unsealed or non-opaque envelopes)


(31) Blinding of participants and personnel (checking for

possible performance bias)

We described for each included study the methods used if any toblind study participants and personnel from knowledge of whichintervention a participant received We considered that studieswere at low risk of bias if they were blinded or if we judged that thelack of blinding was unlikely to affect results We assessed blindingseparately for different outcomes or classes of outcomesWe assessed the methods as

bull low high or unclear risk of bias for participantsbull low high or unclear risk of bias for personnel

(32) Blinding of outcome assessment (checking for possible

detection bias)

We described for each included study the methods used if any toblind outcome assessors from knowledge of which intervention aparticipant received We assessed blinding separately for differentoutcomes or classes of outcomesWe assessed methods used to blind outcome assessment as

bull low high or unclear risk of bias

(4) Incomplete outcome data (checking for possible attrition

bias due to the amount nature and handling of incomplete

outcome data)

We described for each included study and for each outcome orclass of outcomes the completeness of data including attrition andexclusions from the analysis We stated whether attrition and ex-clusions were reported and the numbers included in the analysis ateach stage (compared with the total randomised participants) rea-sons for attrition or exclusion where reported and whether miss-ing data were balanced across groups or were related to outcomes

Where sufficient information was reported or could be suppliedby the trial authors we planned to re-include missing data in theanalyses which we undertookWe assessed methods as

bull low risk of bias (eg no missing outcome data missingoutcome data balanced across groups)

bull high risk of bias (eg numbers or reasons for missing dataimbalanced across groups lsquoas treatedrsquo analysis done withsubstantial departure of intervention received from that assignedat randomisation)


(5) Selective reporting (checking for reporting bias)

We described for each included study how we investigated thepossibility of selective outcome reporting bias and what we foundWe assessed the methods as

bull low risk of bias (where it is clear that all of the studyrsquos pre-specified outcomes and all expected outcomes of interest to thereview have been reported)

bull high risk of bias (where not all the studyrsquos pre-specifiedoutcomes have been reported one or more reported primaryoutcomes were not pre-specified outcomes of interest arereported incompletely and so cannot be used study fails toinclude results of a key outcome that would have been expectedto have been reported)


(6) Other bias (checking for bias due to problems not

covered by (1) to (5) above)

We described for each included study any important concerns wehad about other possible sources of bias

(7) Overall risk of bias

We made explicit judgements about whether studies were at highrisk of bias according to the criteria given in the Handbook (Higgins 2011) With reference to (1) to (6) above we planned toassess the likely magnitude and direction of the bias and whetherwe considered it is likely to impact on the findings In futureupdates we will explore the impact of the level of bias throughundertaking sensitivity analyses - see Sensitivity analysis

Assessment of the quality of the evidence using the

GRADE approach

For this update the quality of the evidence was assessed using theGRADE approach as outlined in the GRADE handbook in orderto assess the quality of the body of evidence relating to the primaryand if applicable secondary outcomes for the main comparisons(with a maximum of seven outcomes) The following outcomeswere assessed

1 Complete miscarriage



2 Pelvic infection3 Nausea4 Diarrhoea5 Blood loss6 Pain (relief )7 Womanrsquos satisfactionacceptability of method

These outcomes were assessed (if applicable) for all 23 compar-isons The most clinically meaningful comparisons are presentedin (Summary of findings for the main comparison Summary offindings 2) these were

1 vaginal misoprostol versus placebo2 vaginal misoprostol versus surgical evacuation

We used the GRADEpro Guideline Development Tool to importdata from Review Manager 53 (RevMan 2014) in order to createthe rsquoSummary of findingsrsquo tables A summary of the interventioneffect and a measure of quality for each of the above outcomes wasproduced using the GRADE approach The GRADE approachuses five considerations (study limitations consistency of effectimprecision indirectness and publication bias) to assess the qualityof the body of evidence for each outcome The evidence can bedowngraded from rsquohigh qualityrsquo by one level for serious (or bytwo levels for very serious) limitations depending on assessmentsfor risk of bias indirectness of evidence serious inconsistencyimprecision of effect estimates or potential publication bias

Measures of treatment effect

Dichotomous data

For dichotomous data we presented results as summary risk ratiowith 95 confidence intervals

Continuous data

For continuous data we use the mean difference if outcomes aremeasured in the same way between trials In future updates if ap-plicable we will use the standardised mean difference to combinetrials that measure the same outcome but use different methods

Unit of analysis issues

Cluster-randomised trials

Our protocol stated that we would include cluster-randomisedtrials in the analyses along with individually-randomised trialsWe planned to adjust their standard errors using the methods de-scribed in the Handbook (Section 1636) using an estimate of theintracluster correlation co-efficient (ICC) derived from the trial(if possible) from a similar trial or from a study of a similar popu-lation If we used ICCs from other sources we planned to reportthis and to conduct sensitivity analyses to investigate the effect ofvariation in the ICC If we had identified both cluster-randomised

trials and individually-randomised trials we planned to synthe-sise the relevant information We would consider it reasonable tocombine the results from both if there is little heterogeneity be-tween the study designs and the interaction between the effect ofintervention and the choice of randomisation unit is consideredto be unlikely No cluster-randomised trials were included in thisupdate

Cross-over trials

It is unlikely that cross-over designs would be a valid study designfor this particular review and so were expected to be excluded Inthe unlikely event that cross-over trials would have a valid designand were eligible for inclusion in the review we would use specificmethods for rsquoRisk of biasrsquo assessment and analysis as described inthe Handbook (Section 164)

Other unit of analysis

It was likely that we would identify trials with more than twotreatment groups for example trials comparing surgical medicaland expectant management of non-viable pregnancies If so wefirst determined which intervention groups addressed the reviewobjective If applicable pair-wise comparisons of interventionswere included in the appropriate analysis

Dealing with missing data

For included studies we noted levels of attrition In future updatesif more eligible studies are included we will explore the impactof including studies with high levels of missing data in the overallassessment of treatment effect by using sensitivity analysisFor all outcomes analyses were carried out as far as possible onan intention-to-treat basis ie we attempted to include all partici-pants randomised to each group in the analyses The denominatorfor each outcome in each trial was the number randomised minusany participants whose outcomes were known to be missing

Assessment of heterogeneity

We assessed statistical heterogeneity in each meta-analysis usingthe Tausup2 Isup2 and Chisup2 statistics We regarded heterogeneity as sub-stantial if an Isup2 was greater than 30 and either the Tausup2 wasgreater than zero or there was a low P value (less than 010) inthe Chisup2 test for heterogeneity If we identified substantial hetero-geneity (above 30) we tried to explore it by subgroup analysis

Assessment of reporting biases

We planned to investigate reporting biases (such as publicationbias) using funnel plots We would have assessed funnel plot asym-metry visually If asymmetry was suggested by a visual assessmentwe planned to perform exploratory analyses to investigate it



Data synthesis

We carried out statistical analysis using the Review Manager soft-ware (RevMan 2014) We used fixed-effect meta-analysis for com-bining data where it was reasonable to assume that studies wereestimating the same underlying treatment effect ie where trialswere examining the same intervention and the trialsrsquo populationsand methods were judged sufficiently similarIf there was clinical heterogeneity sufficient to expect that the un-derlying treatment effects differed between trials or if substan-tial statistical heterogeneity was detected we used random-effectsmeta-analysis to produce an overall summary if an average treat-ment effect across trials was considered clinically meaningful Therandom-effects summary was treated as the average of the rangeof possible treatment effects and we discussed the clinical impli-cations of treatment effects differing between trials If the averagetreatment effect was not clinically meaningful we did not combinetrials Where we used random-effects analyses the results werepresented as the average treatment effect with 95 confidence in-tervals and the estimates of Tausup2 and Isup2

Subgroup analysis and investigation of heterogeneity

If heterogeneity was identified we checked if there were clinicalsubgroups of interest and if there were that would be the mainreason to perform subgroup analysis We considered whether anoverall summary was meaningful and if it was used random-effects analysis to produce itSeparate comparisons were made of different drug regimensgrouped where appropriate by number of doses given and the routeof administration Furthermore subgroup analyses were madefor comparisons that included studies with variation in dosagesof medication time in between different administrations andortime until follow-up examination and subgroup analyses of firstversus second trimester pregnancies were performed All of thesementioned differences might influence the chance of successfuloutcome For example in later gestational age (second trimesterpregnancies) the prostaglandin receptors are more developed and

therefore the outcomes of interventions with a same dosage ofmisoprostol could differ between first and second trimester An-other example when different routes of administration are as-sessed the dosage and whether repeat dosages are applied mightinfluence the outcome which means these should be consideredas different subgroups of interestThe primary and secondary outcomes used in subgroup analysiswere the same as the outcomes used in the overall analysis

Sensitivity analysis

We planned to carry out sensitivity analyses to explore the effect oftrial quality assessed by concealment of allocation high attritionrates or both with poor quality studies being excluded from theanalyses in order to assess whether this made any difference to theoverall result

R E S U L T S

Description of studies

Results of the search

See Figure 1 We retrieved 162 trial reports to assess from thedatabase searching (52 new reports plus 108 that were alreadyawaiting further classification and two that were ongoing in theprevious version of the review (Neilson 2006) In addition wefound three more published reports from following up clinicaltrial registry records (we subsequently excluded these trials as itwas clear from the full report that they were not eligible) Of the165 reports we assessed we included 21 new trials (27 reports)excluded 112 (124 reports) and six are ongoing trials We alsoadded one new trial report to a previously included study andseven new reports to previously excluded studies



Figure 1 Study flow diagram



The original review included 24 studies One of these studies waspublished as an abstract (Heard 2002) Since there were seriousconcerns about the methodology and no full-text article was pub-lished this study was excluded from the updated review We alsoreassessed and excluded another previously included study (Fadalla2004)The review now has 43 included studies

Included studies

This review has included 43 studies comparing vaginal miso-prostol versus expectant management (Trinder 2006) placebo(Bagratee 2004 Herabutya 1997 Kovavisarach 2002 Lister 2005Wood 2002) surgical evacuation (Demetroulis 2001 Fang 2009Ganguly 2010 Graziosi 2004 Muffley 2002 Trinder 2006) oralor sublingual misoprostol (Chittacharoen 2003 Creinin 1997Dehbashi 2016 Marwah 2016 Ngoc 2004 Rita 2006 Shah2010 Sonsanoh 2014 Tang 2003 Tanha 2010a) other types ofvaginal or intracervical prostaglandin preparation (Al Inizi 2003Eng 1997 Kara 1999) oxytocin (Abediasl 2016) extra-amni-otic preparations (Mitwaly 2016) different doses (Kovavisarach2005 Mizrachi 2017 Niromanesh 2005 Petersen 2013) andpreparations (Gilles 2004) of vaginal misoprostol the addition tovaginal misoprostol of methotrexate (Autry 1999) or laminariatents (Jain 1996) Furthermore there were studies comparingsublingual misoprostol versus oral misoprostol (Ayudhaya 2006Kushwah 2009) different doses (Tang 2006) and preparations(Saichua 2009) of sublingual misoprostol and one study on buc-cal misoprostol in different doses (Bracken 2014) Studies usingother types of medication other than (only) misoprostol involvedmifepristone versus placebo (Lelaidier 1993) mifepristone plusoral misoprostol versus expectant management (Nielsen 1999)mifepristone plus oral misoprostol versus misoprostol alone (Fang2009 Schreiber 2018 Sinha 2018) and vaginal gemeprost versussurgical evacuation (Egarter 1995)The Bagratee 2004 trial used a comparison of vaginal misopros-tol versus placebo to explore comparisons with expectant manage-ment (up to seven days) and therefore differed in concept fromthe Herabutya 1997 and Wood 2002 studies in which early sur-gical intervention occurred after respectively 24 and 48 hoursEight of the 43 included studies addressed medical treatmentof non-viable pregnancies in the second trimester The defini-tion of second trimester however varied from gestational age(GA) gt 12 weeks to GA gt 15 weeks (Abediasl 2016 Bracken2014 Chittacharoen 2003 Eng 1997 Jain 1996 Kara 1999Mitwaly 2016 Niromanesh 2005) One study (Shah 2010)included women with non-viable pregnancies up to a GA of 20weeks but made subgroup analyses for first and second trimesterpregnancies These studies are labelled with an asterisk for ease ofinterpretation

There are additional trials that included data on women with bothnon-viable pregnancies and incomplete miscarriages or that in-cluded women with a GA of more than 24 weeks We contactedseveral authors to ask for separated data Four authors respondedbut were not able to send us the separated data (Brouns 2010Eslamian 2007 Hidar 2005 Petrou 2006 (additional report toTrinder 2006) Promwangkwa 2017) One author responded andsent separated data (Bracken 2014) this study was included inthe review The authors that did not respond are listed under rsquoEx-cluded studiesrsquo

Dates of study

Included studies date from 1993 until 2018

Funding

Among the included studies no information on funding was avail-able in 29 trials In 12 trials the funding was independent andmainly provided by the university hospital One trial mentionednot to have received funding at all and one trial mentioned tohaving received a donation from a pharmaceutical company forthe execution of the trial

Declaration of interest

Declaration of interest was not mentioned in 28 trials One trialof which the authors received a donation from a pharmaceuticalcompany reported this donation in their declaration of interestThe remaining 14 trials reported not to have any interests to de-clare

Excluded studies

The trials that were excluded in the initial review were checkedto ensure that no trial has been excluded for non-reporting ofoutcomes and that reasons are still valid according to currentCochrane standards There are 162 excluded studies and theseare listed in the reference section under Excluded studies The ta-ble Characteristics of excluded studies states the reasons for ex-clusion from this review These reasons mainly include studynot randomised study including women with ongoing or in-complete miscarriage only studies assessing medical treatmentfor fetal demise gt 24 weeks of gestational age (GA) and stud-ies including women having termination of pregnancy We havealso excluded studies where we tried to contact the authors fordata that separates treatment of non-viable pregnancies with othertypes of patients (with either incomplete miscarriage gt 24 weeksor planned termination of pregnancy) however either the au-thors did not respond or they were not able to provide suitable



data (Behrashi 2008 Biswas 2007 Brouns 2010 Caliskan 2005Dickinson 1998 Dickinson 2002 Elhassan 2008 El Sokkary2016 Eppel 2005 Eslamian 2007 Fadalla 2004 Feldman 2003Ghorab 1998 Gonzalez 2001 Grimes 2004 Herabutya 1997aHidar 2001 Hidar 2005 Hogg 2000 Hughes 1996 Imran 2010Jain 1994 Jain 1999 Kurshid 2010 Kyaw 2015 Makhlouf 2003Mostafa-Gharebaghi 2010 Nakintu 2001 Ngai 2001 Niinimaki2006 Nuutila 1997 Owen 1999 Promwangkwa 2017 Ramsey2004 Tanha 2013 Thavarasah 1986 Thida 2015 Toptas 2011Torre 2012 Van Mensel 2009 Zhang 2000 Zhang 2005) Eightreferences turned out to be trial protocols or conference abstractsregarding studies that were also retrieved in our search and wereadded as additional reports to the reference of the published studyresults (Bracken 2014 Lughmani 2008 Mitwaly 2016 Nassar2006 Nuthalapaty 2005 Stockheim 2006 Tanha 2013 Torre2012) Sixteen studies were excluded because only a conferenceabstract was available and full data publication could not be re-trieved (Abdel Fattah 1997 Anderman 2000 Anderson 2009 Ara

2009 Aye 2017 Chowdhury 2012 Heard 2002 Hombalegowda2015 Linn 2015 Machtinger 2004 Nasreen 2009 Roy 2003Shaikh 2008 Shobeira 2007 Suchonwanit 1999 Surita 1997)One study was published twice (Kushwah 2009) these two refer-ences were grouped together as one studySeveral studies turned out to be secondary analyses (cost-anal-yses follow-up on fertility outcome of subsequent pregnanciesetcetera) of previous randomised controlled trials and were addedas additional reports to the main references (five additional reportsto Zhang 2005 two to Trinder 2006 two to Bracken 2014 andone extra reference to respectively Elami-Suzin 2013 Niinimaki2006 and Kovavisarach 2002) These reports however did not pro-vide suitable additional data for meta-analysis

Risk of bias in included studies

Please see Figure 2 Figure 3 for a summary of rsquoRisk of biasrsquo assess-ments

Figure 2 rsquoRisk of biasrsquo graph review authorsrsquo judgements about each risk of bias item presented as

percentages across all included studies



Figure 3 rsquoRisk of biasrsquo summary review authorsrsquo judgements about each risk of bias item for each included

study



Allocation

In 30 studies the risk of bias concerning random sequence gen-eration was assessed as being at low risk of bias (Abediasl 2016Autry 1999 Ayudhaya 2006 Bagratee 2004 Bracken 2014Chittacharoen 2003 Creinin 1997 Demetroulis 2001 Fang2009 Ganguly 2010 Gilles 2004 Graziosi 2004 Jain 1996Kovavisarach 2005 Kushwah 2009 Lelaidier 1993 Lister 2005Marwah 2016 Mitwaly 2016 Mizrachi 2017 Muffley 2002Ngoc 2004 Petersen 2013 Saichua 2009 Schreiber 2018 Sinha2018 Tang 2003 Tang 2006 Tanha 2010a Wood 2002) Thesestudies mainly used (computer-generated) random number ta-bles In one study (Eng 1997) randomisation was carried out byldquoblindly picking a sealed number from a box and then odd num-bers were assigned to group A (misoprostol) and even numbers togroup B (gemeprost)rdquo and so although the picking of the num-ber from a box describes a random component to the methodof sequence generation we are unclear about the use of an oddand even number to assign thereafter We therefore consideredthis as potentially high risk of bias In the remaining 12 studiesrandom sequence generation was not (adequately) described (AlInizi 2003 Dehbashi 2016 Egarter 1995 Herabutya 1997 Kara1999 Kovavisarach 2002 Nielsen 1999 Niromanesh 2005Rita 2006 Shah 2010 Sonsanoh 2014 Trinder 2006) Threestudies mentioned the use of block randomisation without furtherdescription The risk of bias was for random sequence generationwas therefore considered unclearTwenty-five studies used robust methods of allocation conceal-ment Most studies used sequentially numbered sealed opaque en-velopes or numbered and sealed packets containing study med-ication Furthermore randomisation using a computer programto guarantee allocation concealment was used (Abediasl 2016Autry 1999 Bagratee 2004 Bracken 2014 Chittacharoen 2003Creinin 1997 Demetroulis 2001 Ganguly 2010 Gilles 2004Graziosi 2004 Kovavisarach 2005 Lelaidier 1993 Lister 2005Marwah 2016 Mitwaly 2016 Mizrachi 2017 Muffley 2002Ngoc 2004 Petersen 2013 Saichua 2009 Schreiber 2018 Sinha2018 Sonsanoh 2014 Trinder 2006 Wood 2002) For these stud-ies the risk of bias was considered low risk for allocation con-cealment Sixteen reports failed to describe the process of allo-cation concealment (Al Inizi 2003 Ayudhaya 2006 Dehbashi2016 Egarter 1995 Fang 2009 Herabutya 1997 Jain 1996Kara 1999 Kovavisarach 2002 Kushwah 2009 Nielsen 1999Niromanesh 2005 Rita 2006 Tang 2003 Tang 2006 Tanha2010a) In these studies risk of bias for allocation concealment wasunclear This was also the case for two more studies (Eng 1997Shah 2010) In these studies numbers were picked from a boxand depending on the randomness of the sequence blinding ofallocation cannot be guaranteed

Blinding

Seven studies describe both doctors and women were blinded forthe treatment allocation and used matching placebo medication toestablish this (Bagratee 2004 Bracken 2014 Kovavisarach 2005Lelaidier 1993 Lister 2005 Sinha 2018 Wood 2002) The risk ofbias was therefore considered low Two other studies mention theuse of placebo medication (Herabutya 1997 Kovavisarach 2002)It is therefore likely that women were blinded for the interventionHowever the authors fail to describe if placebo tablets look similarto medication and therefore it is unsure whether doctors werealso blinded for the intervention Performance bias was unclearfor these two studies In the remaining 33 studies blinding waseither not possible (due to the nature of the intervention) or notperformed In these studies performance bias was assessed highFor the six double-blind placebo-controlled trials (Bagratee 2004Bracken 2014 Kovavisarach 2005 Lelaidier 1993 Lister 2005Wood 2002) it was very likely that outcome assessors were blindedfor the intervention and detection bias was therefore consideredlow This was also the case for two more studies (Ganguly 2010and Sinha 2018) which described outcome assessors were blindedfor the intervention Two more studies used placebo medication(Herabutya 1997 Kovavisarach 2002) and it is therefore likelierthat outcome assessors were blinded for the intervention This ishowever not clearly described Risk of bias was assessed as unclearfor these two studies One study describes nurses being in charge ofthe administration of medication (sublingual or oral misoprostol)(Ayudhaya 2006) and since doctors were the outcome assessors itcould have been that they were blinded for the intervention This ishowever not described Risk of detection bias was assessed unclearin this case In the remaining 32 studies blinding of the outcomewas either not possible (due to the nature of the intervention) ornot described We considered it to be very unlikely that in thesecases outcome assessors were blinded for the intervention In theseremaining 32 studies risk of detection bias was considered high

Incomplete outcome data

Data were incomplete in at least three studies (Dehbashi 2016Fang 2009 Lelaidier 1993) In these studies women were allo-cated to a specific treatment and then wrongfully excluded fromanalysis Risk of bias was considered high for these studies In fourmore studies risk of attrition bias was unclear (Ayudhaya 2006Ngoc 2004 Niromanesh 2005 Rita 2006) For these studies lostto follow up was lt 10 secondary outcomes were not availablefor all included women or failed to report on loss to follow-up Inthe remaining 36 studies risk of attrition bias was considered lowbecause primary outcomes were available for nearly all includedwomen



Selective reporting

Five studies (Ayudhaya 2006 Herabutya 1997 Ngoc 2004Saichua 2009 Schreiber 2018) had inconsistencies in outcomereporting and showed evidence of omission of outcomes in re-sults Furthermore there was one study mentioning that severalsecondary outcomes were not reported in this paper It was unclearwhether these outcomes were reported elsewhere These studieswere considered to have a high risk on reporting bias For 18 stud-ies (Bracken 2014 Creinin 1997 Dehbashi 2016 Egarter 1995Ganguly 2010 Gilles 2004 Graziosi 2004 Kovavisarach 2002Lister 2005 Muffley 2002 Niromanesh 2005 Petersen 2013Rita 2006 Shah 2010 Tang 2003 Tang 2006 Tanha 2010a)reporting bias was unclear due to the problem that all studies re-ported on outcomes that were not prespecified in the method sec-tion It was therefore impossible to assess whether all outcomeswere reported upon One study (Egarter 1995) failed to present aclear description of primary and secondary outcomes in the meth-ods section which makes it difficult to give a judgment on selectivereporting and the risk was therefore also labelled as unclear Riskof reporting bias was considered low in 19 studies that reportedon all outcomes that were mentioned in their method section

Other potential sources of bias

For none of the included studies other potential sources of biaswere detected

Effects of interventions

See Summary of findings for the main comparison Vaginalmisoprostol compared to placebo for early fetal death (less than 24weeks) Summary of findings 2 Vaginal misoprostol comparedto surgical evacuation of uterus for early fetal death (less than 24weeks)Forty-three studies with a total of 4966 women were includedTwenty-two of the studies addressed termination of non-viablepregnancies before 14 weeks There were few reports of seriousadverse effects in the reported trials but one woman required abowel resection after uterine perforation at evacuation of the uterus(Egarter 1995)

Subgroup analyses

For a number of comparisons with subgroups of clinical interestextra subgroup analyses were carried out These included the fol-lowingFor comparison 1 vaginal misoprostol versus placebo primaryoutcome complete miscarriage

1 complete miscarriage less than one day2 complete miscarriage less than two days3 complete miscarriage less than seven days

For comparison 6 vaginal misoprostol wet versus dry preparationsprimary outcome complete miscarriage

1 complete miscarriage less than three days2 complete miscarriage less than eight days3 complete miscarriage less than 15 days4 complete miscarriage less than 30 days

For comparison 8 vaginal misoprostol plus laminaria tents versusvaginal misoprostol alone primary outcome complete miscarriage

1 complete miscarriage less than one day2 complete miscarriage less than two days

For comparison 18 buccal misoprostol lower versus higher regi-men primary outcome complete miscarriage 13 to 23 weeks


For comparison 19 mifepristone versus placebo primary outcomecomplete miscarriage

1 complete miscarriage less than two days2 complete miscarriage less than three days3 complete miscarriage less than four days4 complete miscarriage less than five days

All results per comparison are mentioned in the following para-graphs

1 Vaginal misoprostol versus placebo

Primary outcomes

Treatment with vaginal misoprostol hastens miscarriage (passageof products of conception whether complete or incomplete) whencompared with placebo miscarriage less than 24 hours (2 trials138 women risk ratio (RR) 473 95 confidence interval (CI)270 to 828) miscarriage less than 48 hours (2 (other) trials 84women RR 574 95 CI 270 to 1219) complete miscarriagewithout need for surgical intervention at seven days (1 trial 83women RR 299 95 CI 180 to 499) For these five studiescombined (total of 305 women) RR of successful evacuation withmisoprostol compared to placebo was 423 95 CI 301 to 594low-quality evidence Analysis 11 In the GRADE assessment therisk of bias was considered as serious because several studies lacked(information) on blinding Furthermore there was serious indi-rectness since there were differences in timing of outcome mea-surement after 24 hours (two studies) after 48 hours (two studies)or after seven days (one study) which might have influenced theincidence of successful outcome though effect of the outcome wasconsidered large The quality of evidence was therefore assessedas low (Summary of findings for the main comparison) In onestudy one women in the placebo group had a uterine perforationafter surgical evacuation was performed (1 trial 84 women RR033 95 CI 001 to 796) (Herabutya 1997) (Analysis 12)

Secondary outcomes



There was no difference in the need for blood transfusion (1 study84 women RR 020 95 CI 001 to 404) no difference in hae-moglobin level after treatment (1 study 50 women RR 125 95CI 038 to 412 very-low quality evidence) or duration of bleed-ing (in days) (1 study 32 women RR 100 95 CI 041 to 245Analysis 13 Analysis 14 Analysis 15) There was no increase inadverse effects nausea (2 trials 88 women RR 138 95 CI 043to 440 low-quality evidence) diarrhoea (2 trials 88 women RR221 95 CI 035 to 1406 low-quality evidence Analysis 16Analysis 17) In one small study (Herabutya 1997) two out of 42women used opiates for pain relief when treated with misoprostolcompared to 0 out of 42 women in the placebo group (1 trial84 women RR 500 95 CI 025 to 10111 very-low qualityevidence Analysis 18) According to one study a similar numberof women (58) who would choose the same treatment strategyin the future (Graziosi 2004) although more women who hadcomplete miscarriage after misoprostol (76) would choose thistreatment than those who required subsequent curettage (38) (1trial 32 women RR 117 95 CI 083 to 164 low-quality evi-dence Analysis 19) For all these secondary outcomes there weresome limitations in study design with unclear allocation conceal-ment for some studies there was evidence of rsquoimprecisionrsquo withsmall numbers of studies and wide CIs contributing to effect es-timates and also some evidence of indirectness for one study (seeSummary of findings for the main comparison)The following secondary outcomes were not reported in the trialsfor this comparison haemorrhage pelvic infection cervical dam-age hypertensive disorders time to expulsion duration of stay inhospital psychological effects subsequent fertility and costs

2 Vaginal misoprostol versus expectant management

Primary outcomes

One study was included (614 women) in which a complete mis-carriage (described as no need for additional intervention) oc-curred more often after misoprostol treatment compared to expec-tant management (RR 125 95 CI 109 to 145 Analysis 21)The quality of this evidence in GRADE assessment was down-graded because of serious risk of bias (only one study included noblinding performed) and serious imprecision and was thereforeassessed as lowDeath or serious complications were not reported in the trial

Secondary outcomes

Although the total number of events was low in the misoprostolgroup more infections occurred within eight weeks after study en-try compared to the expectant management group (1 study 618women RR 805 95 CI 187 to 3472 Analysis 22) in theincluded trial (Trinder 2006) infections were defined as two ormore of purulent vaginal discharges pyrexia more than 380degC

tenderness over the uterus on abdominal examination and a whitecell count above 15x10ˆ9L Risk of bias was considered serioussince no blinding was performed and there was serious impreci-sion with very wide CIs because of few events in the treatmentarms The GRADE certainty of evidence is therefore consideredlowThe following secondary outcomes were not reported in the trialsfor this comparison blood transfusion haemorrhage blood lossdays of bleeding pain (relief ) cervical damage digestive disorders(nausea or vomiting or diarrhoea) hypertensive disorders timeto expulsion duration of stay in hospital psychological effectssubsequent fertility womanrsquos satisfactionacceptability of methodand costs

3 Vaginal misoprostol versus surgical evacuation of

uterus

Primary outcomes

Complete miscarriage was lower after initial misoprostol treatmentcompared to primary surgical treatment (6 studies 943 womenaverage RR 040 95 CI 032 to 050 low-quality evidenceHeterogeneity Tau2003 I2 = 46 Analysis 31) The GRADEcertainty of evidence was assessed as low there was a serious riskof bias with no blinding performed in all studies but one andconcerns due to inconsistency but the effect was large and therewere no other serious risks (Summary of findings 2) Though in thewomen who were treated successfully with misoprostol surgerycould be avoided One study reported on uterine perforation (Graziosi 2004) and occurred in one woman (1 trial 154 womenRR 032 95 CI 001 to 765 Analysis 32)

Secondary outcomes

One study (Muffley 2002) assessed blood loss in women treatedwith vaginal misoprostol compared to surgical evacuation andshowed no difference in haematocrit level post treatment (1study 50 women mean difference (MD) -140 95 CI -351 to071 low-quality evidence Analysis 33) The use of pain relief wassimilar among women treated with vaginal misoprostol and sur-gical evacuation (1 study 154 women RR 142 95 CI 082 to446 low-quality evidence Analysis 34) The rate of infections lessthan eight weeks after study entry was similar (1 trial 618 womenRR 073 95 CI 039 to 137 low-quality evidence Analysis35) Misoprostol treatment was associated with more nausea (1trial 154 women RR 2185 95 CI 131 to 36437 low-qualityevidence) and diarrhoea (1 trial 154 women RR 4085 95 CI252 to 66257 low-quality evidence Analysis 36 Analysis 37)Womanrsquos satisfaction was not better when treated with curettagecompared to misoprostol (1 study 45 women RR 067 95 CI040 to 111 low-quality evidence Analysis 38) The quality ofevidence was low because of serious risk of bias concerns some



inconsistency with varied sampling and different medication regi-mens and much of the data for outcomes were from single studieswith wide CIs (see Summary of findings 2) In one trial (Graziosi2004) one women in the surgical evacuation group developedAsherman syndromeThe following secondary outcomes were not reported in the tri-als for this comparison blood transfusion haemorrhage cervi-cal damage hypertensive disorders time to expulsion durationof stay in hospital psychological effects subsequent fertility andcosts

4 Vaginal misoprostol versus vaginal dinoprostone

Primary outcomes

Vaginal misoprostol is more effective to achieve a complete mis-carriage than vaginal dinoprostone for pregnancies lt 14 weeks aswell as gt 14 weeks (2 trials 125 women RR 183 95 CI 137 to246 Analysis 41) However there was a very serious risk of biaswith no information on randomisation method in the includedstudies no information on allocation concealment and no blind-ing The quality of the evidence was therefore considered very lowDeath or serious complications were not reported in the trial

Secondary outcomes

In the misoprostol group two women needed blood transfusion(1 trial 60 women RR 607 95 CI 030 to 12133 Analysis42) The incidence of nausea was similar in the one small trialthat was included in this comparison (65 women RR 103 95CI 028 to 378 Analysis 43) The mean duration of hospital stayin days was lower in the misoprostol group (1 trial 60 womenMD -238 95 CI -336 to -140 Analysis 44) The GRADEquality of evidence for these outcomes was very low because of veryserious risk of bias (no clear randomisation method no blinding)and serious imprecision (study not powered for this outcome wideCI)The following secondary outcomes were not reported in the trialsfor this comparison haemorrhage blood loss days of bleedingpain (relief ) pelvic infection cervical damage digestive disorders(vomiting or diarrhoea) hypertensive disorders time to expulsionpsychological effects subsequent fertility womanrsquos satisfactionacceptability of method and costs

5 Vaginal misoprostol lower versus higher-dose

regimens

Primary outcomes

Vaginal misoprostol has been administered in doses of 400 mcg600 mcg and 800 mcg in trials higher-dose regimens were no

more effective in producing miscarriage lt 13 weeks (2 studies397 women average RR 082 95 CI 058 to 114 Heterogene-ity Tau2 = 005 I2 = 73) or 13 to 23 weeks (1 study 100 womenRR 105 95 CI 087 to 126 Analysis 51 Analysis 52) Therewas risk of bias because lack of proper blinding in two of the in-cluded studies (Niromanesh 2005 Petersen 2013) and there wasserious inconsistency between the studies with differences in thegestational age (GA) of included patients (lt or gt 14 weeks) differ-ences in misoprostol regimen and differences in time to outcomemeasurements (24 hours 48 hours or seven days) There seemedto be a dose-response gradient the quality of the evidence wasassessed as moderateDeath or serious complications were not reported in the trial

Secondary outcomes

There were no differences in nausea (2 trials 214 women RR067 95 CI 031 to 141) and diarrhoea (2 trials 214 womenRR 054 95 CI 1015 to 191) between higher- or lower-doseregimens (Analysis 53 Analysis 54) However because the riskof bias and the inconsistencies described above at the primaryoutcomes the quality of the evidence were assessed as lowThe following secondary outcomes were not reported in the trialsfor this comparison blood transfusion haemorrhage blood lossdays of bleeding pain (relief ) pelvic infection cervical damagedigestive disorders (nausea or vomiting or diarrhoea) hypertensivedisorders time to expulsion duration of stay in hospital psycho-logical effects subsequent fertility and costs

6 Vaginal misoprostol wet versus dry vaginal

preparations

Primary outcomes

Based on one trial there seems no clear advantage to administeringa rsquowetrsquo preparation of vaginal misoprostol compared to a rsquodryrsquopreparation miscarriage less than three days (1 trial 80 womenRR 114 95 CI 085 to 154 Analysis 61) When the outcomecomplete miscarriage was assessed on day eight 15 or 30 therewas still no clear advantage of a rsquowetrsquo preparation compared to arsquodryrsquo preparation Since there was serious risk of bias with only onestudy included no blinding performed and a small sample sizethe quality was assessed as being low-qualityDeath or serious complications were not reported in the trial

Secondary outcomes

There were no differences in diarrhoea (1 trial 77 women RR175 95 CI 089 to 342) and vomiting (1 trial 77 women RR093 95 CI 033 to 262) (Analysis 62 Analysis 63) Womanrsquossatisfaction as measured by whether they would wishprobablywish same treatment in the future suggests no difference between



wet and dry vaginal preparations (1 trial 73 women RR 11895 CI 093 to 149 Analysis 64) Again the quality of theevidence was considered very lowThe following secondary outcomes were not reported in the trialsfor this comparison blood transfusion haemorrhage blood lossdays of bleeding pain (relief ) pelvic infection cervical damagehypertensive disorders time to expulsion duration of stay in hos-pital psychological effects subsequent fertility and costs

7 Vaginal misoprostol + methotrexate versus vaginal

misoprostol

Primary outcomes

Adding methotrexate treatment to vaginal misoprostol has notbeen demonstrated to be advantageous in the single small trialto address this complete miscarriage after treatment (21 womenRR 113 95 CI 085 to 150 Analysis 71) The quality of thisevidence is very low because of very serious risk of bias (only onesmall study included no blinding)Death or serious complications were not reported in the trial

Secondary outcomes

In the small trial with 21 women that was included in this compar-ison there were no differences in incidence of haemorrhage (RR231 95 CI 010 to 5085 Analysis 72) and in pain relief (RR075 95 CI 025 to 222 Analysis 73) but due to the smallnumber of participants and a serious risk of bias (no blinding) thequality of this evidence is very lowThe following secondary outcomes were not reported in the trialsfor this comparison blood transfusion blood loss days of bleed-ing pelvic infection cervical damage hypertensive disorders timeto expulsion duration of stay in hospital psychological effectssubsequent fertility womanrsquos satisfactionacceptability of methodand costs

8 Vaginal misoprostol plus laminaria tents versus

vaginal misoprostol alone

Laminaria tents were not proven useful adjuncts to vaginal miso-prostol during the second trimester complete miscarriage less than24 hours (1 trial 38 women RR 090 95 CI 065 to 125) or48 hours (Analysis 81) GRADE score on quality of the evidencewas downgraded two levels because of serious risk of bias (onlyone small study included no blinding) and imprecision and wasconsidered very lowDeath or serious complications were not reported in the trial Nosecondary outcomes were reported

9 Vaginal misoprostol versus sublingual misoprostol

Primary outcome

No differences in effects were established when comparing vaginalversus sublingual preparations of misoprostol in inducing com-plete miscarriage lt 13 weeks although the evidence was limited bysmall sample sizes and heterogeneity of the included trials (five tri-als 513 women random-effects model average RR 084 95 CI061 to 116 heterogeneity Tausup2 = 010 Isup2 = 82 Analysis 91)One trial comparing vaginal misoprostol and sublingual misopros-tol for miscarriage 13 to 23 weeks also showed no difference andalso included very limited numbers (9 women RR 050 95 CI013 to 200) The quality of evidence was downgraded becauseof serious risk of bias (no blinding performed in the includingstudies) and therefore assessed as lowDeath or serious complications were not reported in the trial

Secondary outcomes

Although there seemed to be no differences between vaginal andsublingual misoprostol regarding nausea (4 trials 302 womenRR 042 95 CI 012 to 144 Analysis 95) vomiting (2 trials300 women RR 076 95 CI 046 to 126 Analysis 96) andexcessive blood loss (2 trials 340 women RR 054 95 CI 015to 189 Analysis 93) these results are based on relatively smalltrials with large heterogeneity Vaginal misoprostol caused less painthan sublingual misoprostol (3 trials 392 women RR 058 95CI 046 to 074 Analysis 94) and less diarrhoea (4 trials 472women RR 071 95 CI 054 to 092 Analysis 97) becauseof serious risk of bias described in the primary outcome abovethe GRADE assessment showed a very low quality of evidenceQuality of evidence was very low because of serious risk of biasserious imprecision and serious inconsistency with differences inGA and misoprostol regimen of the included studies)The following secondary outcomes were not reported in the tri-als for this comparison blood transfusion haemorrhage days ofbleeding pelvic infection cervical damage hypertensive disor-ders time to expulsion duration of stay in hospital psychologicaleffects subsequent fertility womanrsquos satisfactionacceptability ofmethod and costs

10 Vaginal misoprostol versus intravenous oxytocin

Primary outcomes

Misoprostol and oxytocin had similar efficacy in inducing com-plete evacuation of the uterus in second trimester fetal death (1trial 85 women RR 110 95 CI 096 to 125 Analysis 101)The quality of evidence was assessed as low because of very seriousrisk of bias (only one small study included no blinding)



Death or serious complications were not reported in the trial

Secondary outcomes

The incidence of excessive blood loss was not different betweenthe groups however the total number of events was very low (1trial 85 women RR 056 95 CI 005 to 597) the quality ofevidence is low because of the same reasons as described in theprimary outcome) (Analysis 102)No other secondary outcomes were reported

11 Vaginal misoprostol versus vaginal gemeprost

Primary outcomes

There was no difference between vaginal misoprostol and geme-prost in the induction of miscarriage less than 24 hours for fetaldeath after 13 weeks (1 trial 50 women RR 124 95 CI 090to 170 Analysis 111) GRADE assessment produced a low qual-ity of evidence because of a very serious risk of bias (no blindingdoubtful randomisation report and some signs of selective report-ing)Death or serious complications were not reported in the trial

Secondary outcomes

One study reported on the use of opiates for pain relief (Eng1997) In this study none of the women either treated with miso-prostol or gemeprost used opiates for pain relief The incidencesof vomiting and diarrhoea did not differ between the misopros-tol and the gemeprost group (1 trial 50 patients respectively RR300 95 CI 013 to 7030 RR 014 95 CI 001 to 263)however the studies were relatively small (Analysis 113 Analysis114) The quality of evidence for the outcomes which were as-sessed were low because of the very serious risk of bias as describedpreviouslyNo other secondary outcomes were reported

12 Sublingual + vaginal misoprostol versus only

vaginal misoprostol

Primary outcomes

Sublingual and oral misoprostol did not differ in inducing a com-plete miscarriage (2 studies 238 women RR 107 95 CI 088to 130 Analysis 121) There was a serious risk of bias in the twoincluded studies (no blinding no clear allocation concealment)and there were serious inconsistencies (differences between the in-cluded studies regarding misoprostol regimen) which was partlycompensated by a dose-response gradient The GRADE qualityof evidence was therefore assessed as moderate


Secondary outcomes

There were no differences in abdominal pain diarrhoea and pa-tients satisfaction (Analysis 122 Analysis 124 Analysis 125)Gastro-intestinal side effects (nausea vomiting) occurred less inthe sublingual misoprostol group (2 studies 238 women RR 05995 CI 041 to 085 Analysis 123) For fever nausea diarrhoeaand abdominal pain the quality of evidence is low because of se-rious risk of bias and serious inconsistencies For patients satis-faction with treatment the quality was downgraded to very lowbecause only one small study was included at high risk of bias forblindingNo other secondary outcomes were reported

13 Sublingual powdery versus sublingual compact

misoprostol

Primary outcomes

According to the small trial included in this comparison there isno clear advantage of administering a powdery preparation of sub-lingual misoprostol compared to a compact preparation completemiscarriage (1 trial 54 women RR 096 95 CI 066 to 141Analysis 131) Since there is only one study included in which noblinding was performed and that showed signs of selective report-ing there was a very serious risk of bias and the quality of evidenceis very lowDeath or serious complications were not reported in the trial

Secondary outcomes

The incidence of nauseavomiting and diarrhoea was similar be-tween the groups (Analysis 132 Analysis 133) Again the qualityof evidence is very low because of the very serious risk of bias asdescribed in the primary outcomeNo other secondary outcomes were reported

14 Sublingual misoprostol with versus without

extended course

Primary outcomes

An extended course of daily 400 mcg misoprostol for a week afterinitial misoprostol treatment does not lead to more cases withcomplete miscarriage (1 trial 180 women RR 101 95 CI 093to 110 Analysis 141) The quality of evidence was downgradedbecause of a very serious risk of bias (only one small study includedno blinding performed signs of selective reporting) which was



partly compensated by a dose-response gradient and was assessedas lowDeath or serious complications were not reported in the trial

Secondary outcomes

The extended course of misoprostol produces more diarrhoea (1trial 180 women RR 200 95 CI 125 to 319 Analysis 145)The incidence of other side effects like nausea vomiting and painwas not different (Analysis 142 Analysis 143 Analysis 144again quality of evidence was assessed as low since these compar-isons included the same trial as was described in the primary out-come)No other secondary outcomes were reported

15 Sublingual misoprostol versus oral misoprostol

Primary outcomes

Adding sublingual misoprostol to vaginal misoprostol does notlead to more complete miscarriages (1 trial 80 women RR 10095 CI 085 to 118 Analysis 151) In this comparison onlyone study was included (Tang 2003) with a small number ofparticipants no blinding and no allocation concealment whichmeans a very serious risk of bias The GRADE quality of evidencetherefore is very lowDeath or serious complications were not reported in the trial

Secondary outcomes

While efficacy seemed not to differ adding sublingual misopros-tol to a vaginal misoprostol treatment produces more diarrhoea(1 trial 80 women RR 255 95 CI 148 to 438 quality ofevidence very low because of the reasons described above) The in-cidence of other side effects like nausea vomiting and pain was nodifferent between the groups (respectively RR 120 95 CI 080to 179 RR 078 95 CI 032 to 188 RR 075 95 CI 029to 197 Analysis 153 Analysis 154 Analysis 156) A large pro-portion of women was satisfied with either sublingual and vaginalmisoprostol or vaginal misoprostol alone There was no differencein womenrsquos satisfaction (1 study 77 women RR 099 95 CI079 to 125 Analysis 157) Again the quality of evidence forthese outcomes is very lowNo other secondary outcomes were reported

16 Oral misoprostol versus vaginal misoprostol

Primary outcomes

Overall oral misoprostol seemed to be less effective than vaginalmisoprostol in producing complete miscarriage lt 13 weeks but

this was not clearly shown in the effect estimates (4 studies 418women average RR 068 95 CI 045 to 103 HeterogeneityTau2 = 013 I2 = 90) A difference was seen only with the 400mcg oral versus 800 mcg vaginal dose in first trimester miscarriages(1 trial 20 women RR 029 95 CI 010 to 079) and withthe 400 mcg oral versus 600 mcg vaginal dose in first trimestermiscarriage (1 trial 100 women RR 045 95 CI 030 to 067Analysis 161) In one trial (Chittacharoen 2003) all participat-ing women using oral and vaginal misoprostol had a completemiscarriage thus both regimens were equally effective GRADEassessment showed serious risk of bias and serious inconsistenciesbecause of differences between the studies regarding GA miso-prostol regimen and timing of outcome measurement and blind-ing was performed in non of the included studies Since a dose-response gradient could be suspected the quality of evidence wasassessed as moderateDeath or serious complications were not reported in the trial

Secondary outcomes

There seemed to be no differences in the incidence of vomiting (2trials 290 women random-effects model average RR 073 95CI 011 to 489 Heterogeneity Tausup2 = 152 Isup2 = 80) nausea (3trials 220 women RR 118 95 CI 093 to 148) and diarrhoea(4 trials 410 women RR 106 95 CI 072 to 158 Analysis166 Analysis 167 Analysis 168) However oral misoprostolseemed to cause slightly more often pain than vaginal misoprostol(2 trials 200 women RR 160 95 CI 101 to 255 Analysis165) There were high (and similar) levels of satisfaction withtreatment (1 trial 198 women RR 096 95 CI 086 to 106but the quality of evidence for this outcome is very low since onlyone trial was included)No other secondary outcomes were reported

17 Oral misoprostol + mifepristone versus expectant

management

Primary outcomes

In the single study included in this comparison there was no dif-ference in medical treatment compared to expectant managementfor complete miscarriage after five days (1 study 122 women RR108 95 CI 090 to 130 Analysis 171) The quality of evi-dence is low because of very serious risk of bias (only one studyincluded no blinding performed)Death or serious complications were not reported in the trial

Secondary outcomes

A difference in severe blood loss could not be established betweenthe groups (1 study 122 women RR 034 95 CI 001 to 829)but this was based on one study with large CIs (Analysis 172)



Furthermore the incidence of pelvic inflammatory disease (RR052 95 CI 005 to 555 Analysis 175) did not differ butthe total number of events for this outcome was low Womanrsquossatisfaction was not different for both treatment modalities (1study 122 women MD 340 95 CI -554 to 1234 Analysis176) The quality of evidence was calculated as very low in theGRADE assessment because of a very serious risk of bias andserious imprecision (only one study included wide CIs)No other secondary outcomes were reported

18 Buccal misoprostol lower versus higher-dose

regimen

Primary outcomes

The efficacy of a higher-dose regimen of buccal misoprostol isbetter than a lower dose complete miscarriage within two days(1 study 135 women RR 076 95 CI 060 to 096) completeevacuation less than one day (1 study 135 women RR 064 95CI 046 to 089 Analysis 181) The quality of evidence was cal-culated as low in the GRADE assessment because of a very seri-ous risk of bias (only one small study included signs of selectivereporting)Death or serious complications were not reported in the trial

Secondary outcomes

A higher-dose regimen caused more vomiting (1 study 135women RR 030 95 CI 012 to 076) and diarrhoea (RR 04095 CI 019 to 082 Analysis 183 Analysis 184) The incidenceof nausea was similar between the groups (RR 061 95 CI 028to 134) as well as the incidence of pain (RR 096 95 CI 087to 106 Analysis 182 Analysis 185) The quality of evidence forthe secondary outcomes was low because of the reasons describedaboveNo other secondary outcomes were reported

19 Mifepristone versus placebo

Primary outcomes

The single study included in this comparison found mifepristoneto be more effective than placebo miscarriage complete by dayfive after treatment (46 women RR 950 95 CI 249 to 3619Analysis 191) However the quality of this evidence is very lowthere is a very serious risk of bias with signs of incomplete dataand no proper intention-to-treat analysis in the included studyand serious imprecision with wide confidence intervalsDeath or serious complications were not reported in the trial

Secondary outcomes

The incidence of vaginal bleeding before day five was higher inthe misoprostol group (1 trial 44 women RR 392 95 CI 189to 810 Analysis 192) There were no major differences in theincidence of pain (1 trial 44 women RR 219 95 CI 093to 517 Analysis 193) but again the quality of evidence is verylow according to the GRADE assessment for the same reasons asdescribed in the primary outcomeNo other secondary outcomes were reported

20 Mifepristone + misoprostol versus misoprostol

alone

Primary outcomes

Three studies were included in this comparison and showed no ad-ditional value of mifepristone for the complete miscarriage rate (3studies 447 participants RR 118 95 CI 095 to 147 Analysis201) This quality of these studies was assessed moderate twostudies were not blinded though in one of these the outcome as-sessor was blinded for the intervention

Secondary outcomes

One trial reported on the need for blood transfusion pelvic infec-tion nausea and diarrhoea Incidence of transfusion was low wassimilar in both groups (300 women RR 304 95 CI 032 to2890 Analysis 202) Similarly incidence of pelvic infection waslow and equal in both groups (300 women RR 101 95 CI 014to 710 Analysis 203) Nausea and diarrhoea were more com-mon side effects but incidence did not differ between both groups(nausea 300 women RR 101 95 CI 076 to 136 Analysis204 and diarrhoea 300 women RR 094 95 CI 066 to 135)Two trials reported on womanrsquos satisfaction Women were moresatisfied when treated with mifepristone + misoprostol comparedto misoprostol alone (two trials 135 women RR 136 95 CI106 to 175 Analysis 206)

21 Vaginal gemeprost versus surgical evacuation of

uterus

Primary outcomes

In the one study included in this comparison (Egarter 1995) sur-gical evacuation was more effective than gemeprost treatment (87women RR 080 95 CI 067 to 096 Analysis 211) In thesurgical group two of 44 women underwent additional treatmentone because of persistent vaginal bleeding and one because of am-biguous histology results based on what later turned out to be atubal pregnancy Two patients in the surgical evacuation group



had a perforation of the uterus (RR (Non-event) 105 95 CI097 to 113) (45 Analysis 212) In the GRADE assessmentthe score was downgraded because of a very serious risk of bias noclear description of primary and secondary outcomes in the meth-ods of the included study There is also serious imprecision onlyone small study included especially for the secondary outcomesthere are wide CI The quality of evidence is therefore calculatedas very low

Secondary outcomes

The incidence of nausea was similar in both groups (RR 17995 CI 056 to 568 Analysis 213) with very low quality ofevidence because of the reasons described aboveNo other secondary outcomes were reported

22 Intravaginal extraamniotic misoprostol versus

vaginal misoprostol

Primary outcomes

In the one study included in this comparison (Mitwaly 2016)women receive either misoprostol dissolved in saline through aFoley catheter (extraamniotic route) or vaginal misoprostol Thereseemed to be no differences in inducing complete miscarriage (180women RR 110 95 CI 100 to 122 Analysis 221) The qual-ity of evidence was low because of a very serious risk of bias withonly one study included there was no blinding performed andthere was very serious imprecision since the study was not poweredfor the secondary outcomesDeath or serious complications were not reported in the trial

Secondary outcomes

The time to expulsion (in hours) was shorter for the extra-am-niotic preparation (MD -481 95 CI -566 to -396 Analysis226) Although incidences of diarrhoea and vomiting were sim-ilar (Analysis 223 Analysis 224) there were more complaintsof nausea in the group receiving vaginal misoprostol (1 trial 180

women RR 157 95 CI 133 to 185 Analysis 222) The qual-ity of evidence for the secondary outcomes is assessed as very lowbecause of the very serious risk of bias described in the primaryoutcome and imprecision with wide CIs especially for diarrhoeaNo other secondary outcomes were reported

23 Vaginal misoprostol with or without extended

course

Primary outcomes

In one study included in this comparison (Mizrachi 2017) womenwere treated with 800 mcg of vaginal misoprostol either once ortwice with an interval of four days In the other study included(Tang 2006) women were treated with 600mcg of sublingualmisoprostol every three hours on the first day Half of the womenwere treated with an extended course of misoprostol 400mcg ofsublingual misoprostol from day two until day eight There wereno differences in inducing complete miscarriage (351 women RR100 95 CI 092 to 109 Analysis 231) The quality of evidenceis low because of a very serious risk of bias (two studies includedno blinding of outcome assessors performed)Death or serious complications were not reported in the trial

Secondary outcomes

There were no differences found in the incidence of nausea vom-iting and diarrhoea (Analysis 232 Analysis 233 Analysis 234)Fewer women required analgesia for pain in the single dose group(171 women RR 084 95 CI 071 to 100 Analysis 235) Pa-tients satisfaction was similar for both treatment arms the major-ity of women would probably choose this treatment again (171women RR 101 95 CI 084 to 122 Analysis 236)No other secondary outcomes were reported

Sensitivity analyses

We had planned to perform sensitivity analyses but since toofew studies were included in any analysis to carry out meaningfulsensitivity analysis this was not performed



A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]

Vaginal misoprostol compared to surgical evacuation of uterus for early fetal death (less than 24 weeks)


Setting worldwide


Comparison surgical evacuat ion of uterus


(95 CI)

of participants

(studies)


dence

(GRADE)

Comments

Risk with surgical

evacuation of uterus

Risk with vaginal miso-

prostol


(032 to 050)

943 women

(6 RCTs)

oplusopluscopycopy

LOW 12

Blinding of pat ients and

treat ing personnel was

impossible due to the

nature of the interven-

t ions All studies used

the same dosage of

misoprostol (800 mcg)

921 per 1000 368 per 1000

(295 to 460)

Pelvic infect ion Study populat ion RR 073

(039 to 137)

618 women

(1 RCT)

oplusopluscopycopy

LOW 34

Only 1 study included

but with relat ively large

pat ient numbers71 per 1000 52 per 1000

(28 to 97)


(131 to 36437)

154 women

(1 RCT)

oplusopluscopycopy

LOW 34

0 per 1000 22 per 1000

(1 to 364)


(252 to 66257)

154 women

(1 RCT)

oplusopluscopycopy

LOW 34

0 per 1000 41 per 1000

(3 to 663)

25

Med

icaltre

atm

en

tfo

rearly

feta

ld

eath

(less

than

24

weeks)

(Revie

w)

Co

pyrig

ht

copy2019

Th

eC

och

ran

eC

olla

bo

ratio

nP

ub

lished

by

Joh

nW

iley

ampS

on

sL

td

Blood loss post-treat-

ment haematocrit ()

The mean blood loss

post-treatment haema-

tocrit () was 355

mean 140 lower

(351 lower to 071

higher)

- 50 women

(1 RCT)

oplusopluscopycopy

LOW 34

Pain relief Study populat ion RR 142 (082 t0 246) 154 women

(1 RCT)

oplusopluscopycopy

LOW 45

213 per 1000 303 per 1000

(175 to 525)



Study populat ion RR 067 (040 to 111) 45 women

(1 RCT)

oplusopluscopycopy

LOW 67

800 per 1000 536 per 1000

(320 to 888)


95CI)








1 Serious risk of bias only one study blinded the outcome assessors All other studies were not blinded (-1)2 Serious inconsistency varied sampling dif f erent medicat ion regimes I2 = 46 (-1)3 Serious risk of bias no blinding of outcome assessors (-1)4 Serious imprecision only one study with relat ively few patients small number of events and wide conf idence intervals (-1)5 Serious risk of bias high risk of select ive report ing and unclear allocat ion concealment (-1)6 Serious risk of bias high risk of bias for blinding and attrit ion (-1)7 Serious imprecision only one study with relat ively few patients (-1)

26

Med

icaltre

atm

en

tfo

rearly

feta

ld

eath

(less

than

24

weeks)

(Revie

w)

Co

pyrig

ht

copy2019

Th

eC

och

ran

eC

olla

bo

ratio

nP

ub

lished

by

Joh

nW

iley

ampS

on

sL

td

D I S C U S S I O N

Summary of main results

The majority of included trials (4143) assessed the use of miso-prostol (mainly by vaginal administration) Vaginal misoprostolis an effective treatment option for early fetal death compared toexpectant management or placebo in effecting a complete mis-carriage Compared to surgical evacuation there are more gastro-intestinal side effects such as nausea and diarrhoea However sur-gical evacuation may have particular risks that can be avoided byprimary medical treatment (for example perforation of the uteruslesions of the cervix) Higher-dose regimens of vaginal misoprostolseemed not to be more effective than lower-dose regimens witha similar incidence of adverse effects Furthermore a repeat doseof vaginal misoprostol after a certain time period seems not tofurther increase the number of complete miscarriages For vaginalmisoprostol treatment adding methotrexate or laminaria tents hasno advantage Based on one trial a wet preparation does not seemto be more effective than dry preparations of misoprostolMisoprostol can be administered through different routes Thevaginal route is well studied Other routes that were assessed intrials were sublingual oral or buccal administrations None of theother administration routes were superior to vaginal misoprostolThe efficacy of vaginally or sublingually administered misopros-tol is similar but sublingual administration seems to cause morepain Adding sublingual misoprostol to a vaginal course does notimprove outcomes while it may have more side effects especiallydiarrhoea Using a powdery sublingual preparation has no advan-tage compared to compact tablets Sublingual misoprostol is aseffective as oral misoprostol but gives less gastro-intestinal side ef-fectsOral misoprostol seems to be less effective than vaginal misopros-tol For buccal administrations a higher dose improves completemiscarriage but may lead to more side effectsVaginal misoprostol has equivalent efficacy compared toprostaglandin analogues (dinoprostone gemeprost) and (in sec-ond trimester fetal death) to intravenous oxytocinOther medications that were assessed in this review were mifepris-tone (versus placebo) and vaginal gemeprost (versus surgical evac-uation) Mifepristone was more effective than placebo in inducingcomplete miscarriage Treatment with vaginal gemeprost was lesseffective than curettage for complete miscarriage with a similarincidence of side effects (nausea)

Overall completeness and applicability ofevidence

This review comprises 23 comparisons of medication (comparedto other medication or to other types of treatment) that can be

used for treatment of early fetal death Several types of prepara-tions routes of administration and dosages were assessed espe-cially for misoprostol treatment This large heterogeneity in med-ication regimens makes it difficult to present robust statements onthe efficacy of misoprostol in general especially since for severalcomparisons the level of evidence was low or even very low Formisoprostol treatment alone 30 different regimens were used inthe included trials Most investigated were 800 mcg of misopros-tol vaginally in one dosage (eight trials) 800 mcg of vaginal miso-prostol repeated once after 24 hours (six trials) or four days (onetrial) and 600 mcg of oral or sublingual misoprostol repeated everythree hours with a maximum of four dosages (four trials) Espe-cially for the higher dose of vaginal misoprostol (800 mcg) andthe higher dose of sublingual misoprostol (600 mcg) it is safe tosay that these are effective treatment options for early fetal deathThe other routes of administration and dosages require more in-vestigation to compose more robust results

Quality of the evidence

There were large differences in quality of evidence among the dif-ferent comparisons In 16 comparisons only one trial was includedwhich meant a downgrade of at least one level in the GRADEassessment for certainty of evidence In general the quality of ev-idence for comparisons that included more trials was higher thancomparisons in which only one trial was includedrsquoSummary of findingsrsquo tables are presented for the two comparisonsthat we considered clinically most meaningful vaginal misoprostolversus placebo (Summary of findings for the main comparison)and vaginal misoprostol versus surgical evacuation (Summary offindings 2) The first of these comparisons presents the resultsof (vaginal) medical treatment itself while the latter presents theresults for medical treatment compared to the most applied othertreatment option surgical evacuation of the uterus Since we foundno major differences in effectiveness between different routes ofadministration these findings might be generalised to other routesof administration as wellThe GRADE score for vaginal misoprostol compared to placebowas assessed as low quality for complete miscarriage nausea anddiarrhoea and for treatment satisfaction For treatment blood lossand pain the quality of the evidence was assessed as very low Sinceno included studies for this comparison reported on pelvic infec-tion GRADE scores could not be established for this outcomeThe main reasons for downgrading the quality of evidence weredue to risk of bias concerns with unclear allocation concealmentand blinding and also due to concerns regarding imprecision andindirectness of the evidenceThe quality of the evidence for the comparison vaginal misoprostolversus curettage was assessed as low quality for all outcomes com-plete miscarriage pelvic infection nausea diarrhoea blood losspain and womanrsquos satisfaction Quality of evidence was down-graded because for these outcomes due to imprecision with only



one trial providing data for these outcomes Furthermore blind-ing was not possible due to the nature of the intervention andreports were inconsistentThe risk of bias varied among the included trials (Figure 2) For12 trials randomisation procedure had an unclear risk of bias dueto inadequate description of the random sequence allocation andin 16 trials allocation concealment was unclear Improper alloca-tion concealment might have influenced the results in these trialsespecially in trials where patients and personnel were not blindedfor the type of intervention One trial (Eng 1997) was consideredto have a high risk of bias In this trial even and odd numberswere used for sequence allocation and this is of course not ran-dom (Figure 3) In several trials blinding would have been verydifficult or even impossible due to the nature of the interventionsfor example in trials that compared medical treatment to sur-gical evacuation For trials that compared vaginal versus sublin-gual or oral medication one could argue that the use of placebowould have been possible one group should receive vaginal med-ication and oral or sublingual placebo the other group oralsub-lingual medication and vaginal placebo This is laborious and insome cases more inconvenient for the patients but it would havebeen a manner to guarantee proper blinding Furthermore evenif blinding of patients was impossible still the outcome assessorcould have been blinded In only eight of the 43 trials blindingof patients personnel andor outcome assessors was mentioned(Bagratee 2004 Bracken 2014 Ganguly 2010 Kovavisarach2005 Lelaidier 1993 Lister 2005 Sinha 2018 Wood 2002) Inmost trials outcome was assessed by performing (transvaginal) ul-trasound However ultrasound after miscarriage might have inter-and even intra-observer variability without blinding of the out-come assessor this imposes a risk of bias Other concerns in riskof bias were the reporting of incomplete outcome data in threetrials (Dehbashi 2016 Fang 2009 Lelaidier 1993) and signs ofselective reporting in five trials (Ayudhaya 2006 Herabutya 1997Ngoc 2004 Saichua 2009 Schreiber 2018) In 18 other trials itwas unclear whether there was selective reporting in most of thesetrials the methods section stated that rsquoadverse effectsrsquo or rsquoside ef-fectsrsquo were measured without further specification while the re-sults section showed detailed outcomes on specific side effects butit was unclear if that were all the effects that were measuredSince the quality of evidence is low or very low for several compar-isons mainly because they included only one or two (small) trialsfurther research is necessary to assess the effectiveness safety andside effects of medical treatment in different medication regimes

Potential biases in the review process

We have conducted a thorough investigation but still there couldbe biases in the review processScreening for eligible articles from the updated search and dataextraction was performed by at least two review authors using theprespecified set of inclusion and exclusion criteria There were

some discrepancies but we resolved these through mutual discus-sion The inclusion or exclusion of conference abstracts was dis-cussed in detail We decided to exclude conference abstracts thatwere not clearly randomised trials or did not present applicableresults Furthermore we searched for full-text articles that mighthave been published on these trials and in some cases we contactedthe authors to ask for full results of their studies Unfortunatelynone of them replied thus in the end we excluded all conferenceabstractsThere were several trials that could have been useful for the re-view but that included patients with a gestational age more than24 weeks as well or patients with induced abortionterminationof pregnancy (for example because of congenital malformations)We contacted the authors of these trials to ask for subgroup anal-yses or individual data If the authors did not respond immedi-ately we sent them a reminder If still they did not respond weexcluded their trial Some articles did not provide contact detailsfor the authors in which case we searched for other articles fromthese authors to find contact details or we tried to find them onsocial media (Research Gate) For most of these authors we foundcontact details but none of them responded to our questions Webelieve that this approach was the best in order to obtain as muchinformation as possible however it did not provide us with extradata except for one trial (Bracken 2014) Not having includedresults from these trials (especially in comparisons where currentlyonly one trial is included) could have biased our results in two dif-ferent ways either over- or underestimating the potential effectsAssessment of the level of evidence was also performed by twoauthors any discrepancies were resolved through discussion Wethink our assessment was as thorough and complete as possible

Agreements and disagreements with otherstudies or reviews

The reproductive use of misoprostol is considered in otherCochrane Reviews for indications that include treatment of in-complete miscarriage (Kim 2017) termination of unwanted preg-nancies (Kulier 2011 Say 2002) induction of labour (Alfirevic2014 Hofmeyr 2010 Muzonzini 2004) and prevention and treat-ment of postpartum haemorrhage (Mousa 2014 Tunccedilalp 2012)For treatment of incomplete miscarriage (Kim 2017) there ap-peared to be a slightly lower incidence of complete miscarriage withmisoprostol in comparison to surgical evacuation (average risk ra-tio (RR) 096 95 confidence interval (CI) 094 to 098 15 stud-ies 3862 women random-effects very low-quality evidence) butwith success rate high for both methods Overall there were fewersurgical evacuations with misoprostol (average RR 005 95 CI002 to 011 13 studies 3070 women random-effects very low-quality evidence) but more unplanned procedures (average RR503 95 CI 271 to 935 11 studies 2690 women random-effects low-quality evidence)



In termination of unwanted pregnancies the rate of abortionsnot completed with the intended method was higher in theprostaglandin group (RR 27 95 CI 11 to 68) compared tosurgery (Say 2002) This is in line with our finding that miso-prostol is less effective than surgery In incomplete miscarriage thecervical ostium is already open therefore misoprostol for incom-plete miscarriage might be more effective than misoprostol for fe-tal death Nonetheless for all indications misoprostol still reducesthe overall number of patients that receive surgical evacuationSince surgical evacuation has some specific risks (in our review forexample there were patients with uterus perforation or Ashermansyndrome) misoprostol would be a good alternative as primarytreatmentThe incidence of pelvic infection in our review was comparable totreatment of incomplete miscarriage and termination of unwantedpregnancy Duration of bleeding was longer for medical treatmentcompared to surgery in termination of pregnancy (Say 2002) Inour review duration of bleeding for this comparison was not as-sessed but post treatment haematocrit was comparable betweenthe groups (Analysis 33)Compared to expectant management in incomplete miscarriagethere was no difference identified in the need for surgical evacu-ation if patients were treated with misoprostol compared to ex-pectant management (average RR 062 95 CI 017 to 226 2studies 308 women random-effects low-quality evidence) Fur-thermore there was no difference in complete miscarriage (averageRR 123 95 CI 072 to 210 2 studies 150 women random-effects very low-quality evidence) (Kim 2017) On the contraryin our review misoprostol decreases the need for surgical evacua-tion in patients with early fetal death In incomplete miscarriagethe mechanism of miscarriage is already in motion for examplethe cervical ostium is dilated and there might be contractions ofthe uterus Therefore expectant management in incomplete mis-carriage might be more effective than expectant management inearly fetal death when the ostium is closed and there are no con-tractions There was no difference identified in pelvic infectionbetween misoprostol and expectant management in incompletemiscarriage (average RR 242 95 CI 059 to 998 3 studies333 women Kim 2017) while in our review incidence of pelvicinfection was higher in the misoprostol groupFor termination of unwanted pregnancy misoprostol adminis-tered orally is less effective (more failures) than the vaginal route(RR 300 95 CI 144 to 624 Kulier 2011) and may be associ-ated with more frequent side effects such as nausea and diarrhoeaThis is in line with our findings Sublingual routes in inducedabortion were similarly effective compared to the vaginal route(Kulier 2011) but had higher rates of side effects while in ourreview side effects were similar apart from abdominal pain Bothin our review as in the review by Kulier and colleagues there waslarge variety in medication regimens this might have influencedthe incidence of side effects higher dosages that are repeated more

often might lead to a higher incidence and more severe side effects

A U T H O R S rsquo C O N C L U S I O N S

Implications for practice

Available evidence from randomised trials supports the use ofmisoprostol as one possible option for the treatment of non-viablepregnancies before 24 weeks In general side effects of medicaltreatment were minor There were no major differences in effec-tiveness between different routes of administration Treatment sat-isfaction was addressed in only a few studies in which the majorityof women were satisfied with the received intervention

There is intense interest in the reproductive uses of misoprostolbecause it appears a potent method for pregnancy interruption aswell as being cheap and stable at room temperature Using miso-prostol as an alternative to surgical treatment for early fetal deathcould decrease the number of curettages thus preventing womenfrom the specific risks that are related to surgical intervention

Implications for research

Ultrasound demonstration of early pregnancy failure before 14weeks is a common problem that merits greater research effort thanhas occurred to date Further research to assess the effectivenesssafety and side effects of misoprostol including optimal route ofadministration and dose should focus on the dose regimens thattend to be most effective according to our review results vagi-nal or sublingual misoprostol in higher dosages Womenrsquos viewsabout the acceptability of medical treatment surgical treatmentand expectant management could be integral to future researchprotocols as could economic assessments Long-term outcomesnotably subsequent fertility deserves further study in appropri-ately powered randomised controlled studies

A C K N O W L E D G E M E N T S

As part of the pre-publication editorial process this review has beencommented on by two peers (an editor and referee who are externalto the editorial team) one or more members of the Pregnancyand Childbirth Grouprsquos international panel of consumers and theGrouprsquos Statistical Adviser

This project was supported by the National Institute for HealthResearch via Cochrane Infrastructure funding to Cochrane Preg-nancy and Childbirth The views and opinions expressed thereinare those of the authors and do not necessarily reflect those of theSystematic Reviews Programme NIHR NHS or the Departmentof Health



R E F E R E N C E S

References to studies included in this review

Abediasl 2016 published data only

Abediasl Z Sheikh M Pooransari P Farahani Z KalaniF Vaginal misoprostol versus intravenous oxytocin forthe management of second-trimester pregnancies withintrauterine fetal death a randomized clinical trial Journalof Obstetrics and Gynaecology Research 201642(3)246ndash51

Al Inizi 2003 published data only

Al Inizi SA Ezimokhai M Vaginal misoprostol versusdinoprostone for the management of missed abortionInternational Journal of Gynecology amp Obstetrics 20038373ndash4

Autry 1999 published data only

Autry A Jacobson G Sandhu R Isbill K Medicalmanagement of non-viable early first trimester pregnancyInternational Journal of Gynecology amp Obstetrics 199967(1)9ndash13

Ayudhaya 2006 published data only

Ayudhaya OP Herabutya Y Chanrachakul B Ayuthaya NIO-Prasertsawat P A comparison of the efficacy of sublingualand oral misoprostol 400 microgram in the managementof early pregnancy failure a randomized controlled trialJournal of the Medical Association of Thailand 200689

(Suppl 4)S5ndashS10

Bagratee 2004 published data only

Bagratee JS Khullar V Regan L Moodley J Kagoro HA randomized controlled trial comparing medical andexpectant management of first trimester miscarriageHuman Reproduction 200419266ndash71

Bracken 2014 published data only

Bracken H Ngoc NT Banks E Blumenthal P Derman RPatel A et al Misoprostol for treatment of intrauterine fetaldeath at 14-28 weeks of pregnancy American Journal ofObstetrics and Gynecology 2013208 (1Suppl)S62ndash3 DOI101016jcontraception201311014 CRSREF 3292934lowast Bracken H Ngoc NT Banks E Blumenthal PD DermanRJ Patel A et al Buccal misoprostol for treatment offetal death at 14-28 weeks of pregnancy a double-blindrandomized controlled trial Contraception 201489(3)187ndash92Winikoff B Misoprostol for treatment of fetal death at14-28 weeks of pregnancy inclusive not accompaniedby complete expulsion of the contents of the uterusclinicaltrialsgovct2showrecordNCT00671060 (firstreceived 29 April 2008)

Chittacharoen 2003 published data only

Chittacharoen A Herabutya Y Punyavachira P Arandomized trial of oral and vaginal misoprostol to managedelivery in cases of fetal death Obstetrics amp Gynecology

200310170ndash3

Creinin 1997 published data only

Creinin MD Moyer R Guido R Misoprostol for medicalevacuation of early pregnancy failure Obstetrics ampGynecology 199789768ndash72

Dehbashi 2016 published data only

Dehbashi Z Moosazadeh M Afshari M Comparisonbetween sublingual and vaginal route of misoprostol inmanagement of first trimester miscarriage missing MateriaSocio-Medica 201628(4)271ndash3

Demetroulis 2001 published data onlylowast Demetroulis C Saridogan E Kunde D Naftalin AA Aprospective randomized control trial comparing medicaland surgical treatment for early pregnancy failure Human

Reproduction 200116365ndash9Demetroulis C Saridogan E Kunde D Naftalin AA Aprospective randomized control trial comparing medicaland surgical treatment for early pregnancy failure XVIFIGO World Congress of Obstetrics and Gynecology 2000Sept 3-8 Washington DC USA 2000

Egarter 1995 published data only

Egarter C Lederhilger J Kurz C Karas H Reisenberger KGemeprost for first trimester missed abortion Archives ofGynecology and Obstetrics 199525629ndash32

Eng 1997 published data only

Eng NS Guan AC Comparative study of intravaginalmisoprostol with gemeprost as an abortifacient in secondtrimester missed abortion Australian and New Zealand

Journal of Obstetrics and Gynaecology 199737331ndash4

Fang 2009 published data only

Fang AH Chen QF Zheng W Li YH Chen RYTermination of missed abortion in a combined procedurea randomized controlled trial Journal of Reproduction andContraception 200920(1)45ndash9

Ganguly 2010 published data only

Ganguly RP Mukhopadhyay S Burman SK Patra KK JhaT Mukherji J A randomized trial of misoprostol comparedwith manual vacuum aspiration for early pregnancy failureNepal Journal of Obstetrics and Gynaecology 20105(2)8ndash13

Gilles 2004 published data only

Barnhart KT Bader T Huang X Frederick MM TimbersKA Zhang JJ Hormone pattern after misoprostoladministration for a nonviable first-trimester gestationFertility and Sterility 2004811099ndash105Creinin MD Harwood B Guido RS Fox MC ZhangJ NICHD Early Pregnancy Failure Trial Endometrialthickness after misoprostol use for early pregnancy failureInternational Journal of Gynecology amp Obstetrics 20048622ndash6Davis AR Robilotto CM Westhoff CL Forman S ZhangJ NICHD Management of Early Pregnancy Failure TrialBleeding patterns after vaginal misoprostol for treatment



of early pregnancy failure Human Reproduction 2004191655ndash8Gilles J Creinin MM Barnhart KT Westhoff C FrederickMM Zang J et al Wet versus dry misoprostol applicationfor treatment of early pregnancy failure Fertility and

Sterility 200278S64ndashS65lowast Gilles JM Creinin MD Barnhart K Westhoff CFrederick MM Zhang J A randomized trial of salinesolution-moistened misoprostol versus dry misoprostol forthe first-trimester pregnancy failure American Journal ofObstetrics and Gynecology 2004190389ndash94

Graziosi 2004 published data only

Graziosi GC Bruinse HW Reuwer PJ Teteringen O MolBW Fertility outcome after a randomized trial comparingcurettage with misoprostol for treatment of early pregnancyfailure Human Reproduction 2005201749ndash50Graziosi GC Bruinse HW Reuwer PJ van Kessel PHWesterweel PE Mol BW Misoprostol versus curettage inwomen with early pregnancy failure impact on womenrsquoshealth-related quality of life A randomized controlled trialHuman Reproduction 2005202340ndash7lowast Graziosi GC Mol BW Reuwer PJ Drogtrop A BruinseHW Misoprostol versus curettage in women with earlypregnancy failure after initial expectant management arandomized trial Human Reproduction 2004191894ndash9Graziosi GC van der Steeg JW Reuwer PH Drogtrop APBruinse HW Mol BW Economic evaluation of misoprostolin the treatment of early pregnancy failure comparedto curettage after an expectant management Human

Reproduction 2005201067ndash71

Herabutya 1997 published data only

Herabutya Y O-Prasertsawat P Misoprostol in themanagement of missed abortion International Journal of

Gynecology amp Obstetrics 199756263ndash6

Jain 1996 published data only

Jain JK Mishell DR A comparison of misoprostol with andwithout laminaria tents for induction of second-trimesterabortion American Journal of Obstetrics and Gynecology1996175173ndash7

Kara 1999 published data only

Kara M Ozden S Eroglu M Cetin A Arioglu PComparison of misoprostol and dinoproston administrationfor the induction of labour in second trimester pregnanciesin cases of intrauterine fetal loss Italian Journal ofGynecology and Obstetrics 1999113ndash6

Kovavisarach 2002 published data onlylowast Kovavisarach E Sathapanachai U Intravaginal 400micrograms misoprostol for pregnancy termination in casesof blighted ovum a randomised controlled trial Australian

and New Zealand Journal of Obstetrics and Gynaecology200242161ndash3Sathapanachai U Intravaginal 400 micrograms misoprostolfor pregnancy termination in cases of blighted ovum Thai

Journal of Obstetrics and Gynaecology 200012(4)363

Kovavisarach 2005 published data only

Kovavisarach E Jamnansiri C Intravaginal misoprostol600mcg and 800mcg for the treatment of early pregnancyfailure International Journal of Gynecology amp Obstetrics200590208ndash12

Kushwah 2009 published data onlylowast Kushwah B Singh A Sublingual versus oral misoprostolfor uterine evacuation following early pregnancy failureInternational Journal of Gynecology amp Obstetrics 2009106

(1)43ndash5Kushwah DS Kushwah B Salman MT Verma VKAcceptability and safety profile of oral and sublingualmisoprostol for uterine evacuation following early fetaldemise Indian Journal of Pharmacology 201143(3)306ndash10 DOI 1041030253-761381513 CRSREF3293000

Lelaidier 1993 published data only

Lelaidier C Baton-Saint-Mleux C Fernandez H BourgetP Frydman R Mifepristone (RU 486) induces embryoexpulsion in first trimester non-developing pregnancies aprospective randomized trial Human Reproduction 19938492ndash5

Lister 2005 published data only

Lister MS Shaffer LE Bell JG Lutter KQ Moorma KHRandomized double-blind placebo-controlled trial ofvaginal misoprostol for management of early pregnancyfailures American Journal of Obstetrics and Gynecology 20051931338ndash43

Marwah 2016 published data only

Marwah S Gupta S Batra NP Bhasin V Sarna V Kaur N Acomparative study to evaluate the efficacy of vaginal vs oralprostaglandin E1 analogue (misoprostol) in managementof first trimester missed abortion Journal of Clinical and

Diagnostic Research 201610(5)QC14ndash8

Mitwaly 2016 published data only

Mitwally AB Intra uterine extra amniotic (200 microg) versusvaginal (200 microg) misoprostol for second trimester pregnancytermination randomized controlled trial clinicaltrialsgovct2showNCT02669420 (first received 1 February 2016)lowast Mitwaly AB Abbas AM Abdellah MS Intra uterineextra-amniotic versus vaginal misoprostol for termination ofsecond trimester miscarriage a randomized controlled trialInternational Journal of Reproductive Biomedicine 201614

(10)643ndash8

Mizrachi 2017 published data only

Mizrachi Y Dekalo A Gluck O Miremberg H Dafna LFeldstein O et al Single versus repeat doses of misoprostolfor treatment of early pregnancy loss-a randomized clinicaltrial Human Reproduction 201732(6)1202ndash7

Muffley 2002 published data only

Muffley PE Stitely ML Gherman RB Early intrauterinepregnancy failure a randomized trial of medical versussurgical treatment American Journal of Obstetrics and

Gynecology 2002187321ndash6



Ngoc 2004 published data only

Ngoc NT Blum J Westheimer E Quan TTV Winikoff BMedical treatment of missed abortion using misoprostolInternational Journal of Gynecology amp Obstetrics 200487138ndash42

Nielsen 1999 published data only

Nielsen S Hahlin M Platz-Christensen J Expectantmanagement or pharmacological treatment for firsttrimester spontaneous abortion a randomised trial ActaObstetricia et Gynecologica Scandinavica 199776(1672)77lowast Nielsen S Hahlin M Platz-Christensen J Randomisedtrial comparing expectant with medical management forfirst trimester miscarriages British Journal of Obstetrics andGynaecology 1999106804ndash7

Niromanesh 2005 published data only

Niromanesh S Hashemi-Feasharaki M Mosavi-Jarrahi ASecond trimester abortion using intravaginal misoprostolInternational Journal of Gynecology amp Obstetrics 200589276ndash7

Petersen 2013 published data only

Petersen SG Perkins A Gibbons K Bertolone J Devenish-Meares P Cave D et al Can we use a lower intravaginal doseof misoprostol in the medical management of miscarriageA randomised controlled study Australian amp New Zealand

Journal of Obstetrics amp Gynaecology 201353(1)64ndash73

Rita 2006 published data only

Rita Gupta S Kumar S A randomised comparison of oraland vaginal misoprostol for medical management of firsttrimester missed abortion JK Science 20068(1)35ndash8

Saichua 2009 published data only

Saichua C Phupong V A randomized controlled trialcomparing powdery sublingual misoprostol and sublingualmisoprostol tablet for management of embryonic deathor anembryonic pregnancy Archives of Gynecology and

Obstetrics 2009280(3)431ndash5

Schreiber 2018 published data only

Schreiber CA Sonalkar S Barnhart KT Ratcliffe SJCreinin MD Atrio J Mifepristone pretreatment for themedical management of early pregnancy loss New England

Journal of Medicine 2018378(23)2161ndash70

Shah 2010 published data only

Shah N Azam SI Khan NH Sublingual versus vaginalmisoprostol in the management of missed miscarriageJPMA - Journal of the Pakistan Medical Association 201060

(2)113ndash6

Sinha 2018 published data only

Sinha P Suneja A Guleria K Aggarwal R Vaid NBComparison of mifepristone followed by misoprostol withmisoprostol alone for treatment of early pregnancy failure arandomized double-blind placebo-controlled trial Journalof Obstetrics and Gynecology of India 201868(1)39ndash44

Sonsanoh 2014 published data only

Sonsanoh A Chullapram T Comparison of sublingualand vaginal misoprostol for termination of early pregnancyfailure a randomized controlled trial Thai Journal of

Obstetrics and Gynaecology 201422(3)128ndash36

Tang 2003 published data only

Tang OS Lau WN Ng EHY Lee SW Ho PC A prospectiverandomized study to compare the use of repeated doses ofvaginal with sublingual misoprostol in the management offirst trimester silent miscarriage Human Reproduction 200318176ndash81


Tang OS Ong CY Tse KY Ng EH Lee SW Ho PCA randomized trial to compare the use of sublingualmisoprostol with or without an additional 1 week coursefor the management of first trimester silent miscarriageHuman Reproduction 200621(1)189ndash92

Tanha 2010a published data only

Tanha FD Feizi M Shariat M Sublingual versus vaginalmisoprostol for the management of missed abortionJournal of Obstetrics and Gynaecology Research 201036(3)525ndash32

Trinder 2006 published data only

Petrou S Trinder J Brocklehurst P Smith L Economicevaluation of alternative management methods of first-trimester miscarriage based on results from the MISTtrial BJOG An International Journal of Obstetrics ampGynaecology 2006113(8)879ndash89 DOI 101111j1471-0528200600998x CRSREF 3293040Smith L Extension to randomised controlled trial ofexpectant medical and surgical management of earlymiscarriage Research Findings Register (wwwrefernhsuk)(accessed 7 March 2006) 2006lowast Trinder J Brocklehurst P Porter R Read M Vyas S SmithL Management of miscarriage expectant medical orsurgical Results of randomised controlled trial (miscarriagetreatment (MIST) trial) BMJ 2006332(7552)1235ndash40

Wood 2002 published data only

Wood SL Brain PH Medical management of missedabortion a randomized clinical trial Obstetrics amp


References to studies excluded from this review

Abbas 2018 published data only

Abbas AM NCT03584698 The effect of adding vaginalevening primrose oil to misoprostol during inductionof second-trimester missed miscarriage a randomizedcontrolled trial httpsclinicaltrialsgovct2showNCT03584698 (12 July 2018)

Abdel Fattah 1997 published data only

Abdel Fattah IH PGE1 analogue for the induction ofmidtrimester abortion in cases of intrauterine fetal deathActa Obstetricia et Gynecologica Scandinavica Supplement

199776(1672)26

Abd-El-Maeboud 2012 published data only

Abd-El-Maeboud KH Ghazy A Ibrahim A Hassan N El-Bohoty A Gamal-El-Din I Vaginal acidity enhancementwith a 3 acetic acid gel prior to misoprostol treatment forpregnancy termination in the midtrimester International

Journal of Gynecology and Obstetrics 2012119(3)248ndash52



Al-Bdour 2007 published data only

Al-Bdour AN Akasheh H Al-Jayousi T Missed abortiontermination using single-dose versus two doses of vaginalmisoprostol tablets Pakistan Journal of Medical Sciences200723(6)920ndash3

Ali 2018 published data only

Ali MK Botros HA Mostafa SA Foleyrsquos catheter balloonfor induction of mid-trimester missed abortion with orwithout traction applied a randomized controlled trialJournal of Maternal-Fetal amp Neonatal Medicine 2018[Epub ahead of print]

Almog 2005 published data only

Almog B Levin I Winkler N Fainaru O Pauzner DLessing JB et al The contribution of laminaria placementfor cervical ripening in second trimester terminationof pregnancy induced by intra-amniotic injection ofprostaglandin F2alpha followed by concentrated oxytocininfusion European Journal of Obstetrics amp Gynecology and

Reproductive Biology 200511832ndash5

Altaf 2006 published data only

Altaf F Sultana N Iqbal N Therapeutic abortionsefficacy of intra-vaginal misoprostol in comparison to extraamniotically administered prostaglandin f2a ProfessionalMedical Journal 200613(3)417ndash22

Amjad 1999 published data only

Amjad T Akhtar S Termination of pregnancy with foetaldeath in second trimester Foleyrsquos catheter versus extraamniotic prostaglandins Journal of College of Physicians ampSurgeons Pakistan 19999(9)403ndash5

Anderman 2000 published data only

Anderman S Jaschevatzky OE Ballas S Comparisonbetween a double balloon device and the foley catheter inextraamniotic prostaglandin F2a infusion for termination ofmidtrimester missed abortion XVI FIGO World Congressof Obstetrics amp Gynecology 2000 Sept 3-8 WashingtonDC USA 2000162

Anderson 2009 published data only

Anderson J Gouk E Young L Turnbull L Sayeed GElattar A et al A randomised controlled trial of oral versusvaginal misoprostol for medical management of early fetaldemise International Journal of Gynecology amp Obstetrics

2009107(Suppl 2)S533

Ara 2009 published data only

Ara G Nargis S Khatun R Saha A Vaginal misoprostol as amedical management in early pregnancy loss InternationalJournal of Gynecology amp Obstetrics 2009107(Suppl 2)S533ndashS534

Arellano 2009 published data only

Arellano M Durocher J Leon W Montesinos R Pena MWinikoff B Introduction of misoprostol for incompleteabortion care in Latin America evidence from EcuadorInternational Journal of Gynecology amp Obstetrics 2009107

(Suppl 2)S49

Avila-Vergara 1997 published data only

Avila-Vergara MA Morgan-Ortiz F Fragoza-Sosa O Haro-Garcia L Cervical labor induction with prostaglandin

E2 in patients with fetal death [Maduracion cervicalcon prostaglandina E2 en pacientes con feto muerto]Ginecologia y Obstetricia de Mexico 199765155ndash8

Aye 2017 published data only

Aye TT Aung KL Myint SS A comparative study on effectof sublingual versus vaginal misoprostol in management offirst trimester miscarriage in Magway Teaching HospitalJournal of Obstetrics and Gynaecology Research 201743185-6 Abstract no 9020

Azra 2007 published data only

Azra B Shakeel S Nilofer M A comparison of twoprotocols of intra vaginal misoprostol for second trimestermedical termination of pregnancy Pakistan Armed Forces

Medical Journal 200757(1)61ndash5


Bagratee J Regan L Khullar V Moodley J Connolly CDoes the volume of retained products of conception andhormonal parameters influence the success of conservativemethods of management of first trimester miscarriageInternational Journal of Gynecology amp Obstetrics 2009107

(Suppl 2)S116

Bani-Irshaid 2006 published data only

Bani-Irshaid I Athamneh TZ Bani-Khaled D Al-MomaniM Dahamsheh H Termination of second and early thirdtrimester pregnancy comparison of 3 methods EasternMediterranean Health Journal 200612(5)605ndash9

Bartz 2013 published data only

Bartz D Maurer R Allen RH Fortin J Kuang B GoldbergAB Buccal misoprostol compared with synthetic osmoticcervical dilator before surgical abortion a randomizedcontrolled trial Obstetrics and Gynecology 2013122(1)57ndash63

Bebbington 2002 published data only

Bebbington MW Kent N Lim K Gagnon A Delisle MFTessier F et al A randomized controlled trial comparingtwo protocols for the use of misoprostol in midtrimesterpregnancy termination American Journal of Obstetrics and


Behrashi 2008 published data only

Behrashi M Mahdian M Vaginal versus oral misoprostolfor second-trimester pregnancy termination a randomizedtrial Pakistan Journal of Biological Sciences 200811(21)2505ndash8


Behrashi M Comparison between the oral and vaginalmisoprostol effects on pregnancy termination in secondtrimester irctirtrial129 (first received 29 August 2008)

Ben-Meir 2009 published data only

Ben-Meir A Erez Y Feigenberg T Hamani Y LauferN Rojansky N Mifepristone followed by high-doseoxytocin drip for second-trimester abortion a randomizeddouble-blind placebo-controlled pilot study Journal of

Reproductive Medicine 200954(8)511ndash6

Betstadt 2007 published data only

Betstadt SJ MiMi a randomized trial of mifepristoneand misoprostol for treatment of early pregnancy failure



clinicaltrialsgovct2showNCT00468299 (first received 1May 2007)

Bique 2007 published data only

Bique C Usta M Debora B Chong E Westheimer EWinikoff B Comparison of misoprostol and manualvacuum aspiration for the treatment of incomplete abortionInternational Journal of Gynecology amp Obstetrics 200798(3)222ndash6

Biswas 2007 published data only

Biswas SC Dey R Jana R Chattopadhyay N Comparativestudy of intravaginal misoprostol and extra amnioticethacridine lactate instillation for mid trimester pregnancytermination Journal of Obstetrics and Gynaecology of India

200757(3)211ndash3

Blohm 2005 published data only

Blohm F Friden BE Milsom I Platz-Christensen JJ NielsenS A randomised double blind trial comparing misoprostolor placebo in the management of early miscarriage BJOG

an international journal of obstetrics and gynaecology 2005112(8)1090ndash5

Brouns 2010 published data only

Brouns JF van Wely M Burger MP van WijngaardenWJ Comparison of two dose regimens of misoprostol forsecond-trimester pregnancy termination Contraception

201082(3)266ndash75

Cabrol 1990 published data only

Cabrol D Dubois C Cronje H Gonnet JM Guillot MMaria B et al Induction of labour with mifepristone(RU 486) in intrauterine fetal death American Journal ofObstetrics and Gynecology 1990163540ndash2

Caliskan 2005 published data only

Caliskan E Dilbaz S Doger E Ozeren S Dilbaz BRandomized comparison of 3 misoprostol protocols forabortion induction at 13-20 weeks of gestation Journal of



Caliskan E Doger E Cakiroglu Y Corakci A YucesoyI Sublingual misoprostol 100 microgram versus 200microgram for second trimester abortion a randomisedtrial European Journal of Contraception amp Reproductive

Health Care 200914(1)55ndash60

Chaudhuri 2015 published data onlylowast Chaudhuri P Datta S Mifepristone and misoprostolcompared with misoprostol alone for induction of laborin intrauterine fetal death a randomized trial JournalObstetrics and Gynaecology Research 201541(12)1884ndash90Datta S A randomized double-blind study to compareefficacy of mifepristone and misoprostol versus misoprostolalone for induction of labour in intrauterine foetal deathctrinicinClinicaltrialspmaindet2phptrialid=7823 (firstreceived 21 March 2014)

Chowdhury 2012 published data only

Chowdhury S Uddin AW Misoprostol in the managementof second trimester missed abortion a randomizedcontrolled trial International Journal of Gynaecology and

Obstetrics 2012119(Suppl 3)S310

Clevin 2001 published data only

Clevin L Munk T Hansen TR Spontaneous abortionDrug treatment versus surgery [Spontan abort Medicinskversus kirurgisk behandling] Ugeskrift for Laeger 2001163

(15)2136ndash9

Dabash 2009 published data only

Dabash R Cherine M Darwish E Blum J Hassanein NAbdel Daiem T et al Bleeding following surgical (MVA)and medical (400 ug sublingual misoprostol) treatment ofincomplete abortion International Journal of Gynecology amp

Obstetrics 2009107(Suppl 2)S150ndashS151

Dao 2007 published data only

Dao B Blum J Thieba B Raghavan S Ouedraego MLankoande J et al Is misoprostol a safe effective andacceptable alternative to manual vacuum aspiration forpostabortion care Results from a randomised trial inBurkina Faso West Africa BJOG an international journal

of obstetrics and gynaecology 2007114(11)1368ndash75

Das 2014 published data only

Das CM Sharma M Pardeep K Khurshid F To comparethe safety and efficacy of manual vacuum aspiration withmisoprostol (st mom) 600mg in incomplete miscarriageJournal of the Liaquat University of Medical and HealthSciences 2014 Vol 13 issue 393ndash6

David 2003 published data only

David M Chen FC Lichtenegger W NO-donornitroglycerin versus the prostaglandin gemeprost for cervicalripening in first trimester missed abortion InternationalJournal of Gynecology amp Obstetrics 20038371ndash2


David M Chen FC Comparison of isosorbide mononitrate(Mono Mack) and misoprostol (Cytotec) for cervicalripening in the first trimester missed abortion Archives of

Gynecology and Obstetrics 2005273(3)144ndash5

Demirezen 2018 published data only

Demirezen G Aslan Cetin B Aydogan Mathyk B KorogluN Yildirim G Efficiency of the Foley catheter versus thedouble balloon catheter during the induction of secondtrimester pregnancy terminations a randomized controlledtrial Archives of Gynecology and Obstetrics 2018298(5)881-7

Dickinson 1998 published data only

Dickinson JE Godfrey M Evans SF Efficacy of intravaginalmisoprostol in second-trimester pregnancy terminationa randomized controlled trial Journal of Maternal-FetalMedicine 19987115ndash9


Dickinson JE Evans SF The optimization of intravaginalmisoprostol dosing schedules in second-trimester pregnancytermination American Journal of Obstetrics and Gynecology2002186470ndash4


Dickinson JE Evans SF A comparison of oral misoprostolwith vaginal misoprostol administration in second-trimesterpregnancy termination for fetal abnormality Obstetrics amp




Diop 2009 published data only

Diop A Raghavan S Rakotovao JP Comendant RBlumenthal PD Winikoff B Two routes of administrationfor misoprostol in the treatment of incomplete abortiona randomized clinical trial Contraception 200979(6)456ndash62

Elami-Suzin 2013 published data onlylowast Elami-Suzin M Freeman MD Porat N RojanskyN Laufer N Ben-Meir A Mifepristone followed bymisoprostol or oxytocin for second-trimester abortion arandomized controlled trial Obstetrics and Gynecology

2013122(4)815ndash20Freeman MD Porat N Rojansky N Elami-SuzinM Winograd O Ben-Meir A Physical symptomsand emotional responses among women undergoinginduced abortion protocols during the second trimesterInternational Journal of Gynaecology and Obstetrics 2016135

(2)154ndash7 DOI 101016jijgo201605008

Elhassan 2008 published data only

Elhassan EM Abubaker MS Adam I Sublingual comparedwith oral and vaginal misoprostol for termination ofpregnancy with second-trimester fetal demise InternationalJournal of Gynecology amp Obstetrics 2008100(1)82ndash3

El Sokkary 2016 published data only

El Sokkary HH Comparison between sublingual andvaginal administration of misoprostol in management ofmissed abortion Journal of Obstetrics and Gynaecology of

India 201666(S1)S24ndashS29

Eppel 2005 published data only

Eppel W Facchinetti F Schleussner E Piccinini F PizziC Gruber DM et al Second trimester abortion usingisosorbide mononitrate in addition to gemeprost comparedwith gemeprost alone a double blind randomized placebo-controlled multicenter trial American Journal of Obstetrics

and Gynecology 2005192856ndash61

Eslamian 2007 published data only

Eslamian L Gosili R Jamal A Alyassin A A prospectiverandomized controlled trial of two regimens of vaginalmisoprostol in second trimester termination of pregnancyActa Medica Iranica 200745(6)497ndash500

Fadalla 2004 published data only

Fadalla FA Mirghani OA Adam I Oral misoprostolvs vaginal misoprostol for termination of pregnancywith intrauterine fetal demise in the second-trimesterInternational Journal of Gynecology amp Obstetrics 20048652ndash3

Feldman 2003 published data only

Feldman DM Borgida AF Rodis JF Leo MV CampbellWA A randomized comparison of two regimens ofmisoprostol for second-trimester pregnancy terminationAmerican Journal of Obstetrics and Gynecology 2003189710ndash3

Fernlund 2018 published data only

Fernlund A Jokubkiene L Sladkevicius P Valentin L Arandomised controlled trial comparing misoprostol toexpectant care in early pregnancy failure Ultrasound in

Obstetrics amp Gynecology 201750(Suppl 1)15 Abstract noOC0803lowast Fernlund A Jokubkiene L Sladkevicius P Valentin LMisoprostol treatment vs expectant management in womenwith early non-viable pregnancy and vaginal bleedinga pragmatic randomized controlled trial Ultrasound inObstetrics amp Gynecology 201851(1)24ndash32

Fiala 2005 published data only

Fiala C Swahn ML Stephansson O Gemzell-DanielssonK The effect of non-steroidal anti-inflammatory drugs onmedical abortion with mifepristone and misoprostol at 13-22 weeks gestation Human Reproduction 200520(11)3072ndash7

Ghorab 1998 published data only

Ghorab MN El Helw BA Second-trimester terminationof pregnancy by extra-amniotic prostaglandin F2alpha orendocervical misoprostol Acta Obstetricia et GynecologicaScandinavica 199877429ndash32

Gonzalez 2001 published data only

Gonzalez JA Carlan SJ Alverson MW Outpatient secondtrimester pregnancy termination Contraception 20016389ndash93

Grimes 2004 published data only

Grimes DA Smith MS Witham AD Mifepristoneand misoprostol versus dilatation and evacuation formidtrimester abortion a pilot randomised controlled trialBJOG an international journal of obstetrics and gynaecology2004111148ndash53

Gronland 2002 published data only

Gronland A Gronland L Clevin L Andersen B PalmegrenN Lidegaard O Management of missed abortioncomparison of medical treatment with either mifepristone +misoprostol or misoprostol alone with surgical evacuationA multi-center trial in Copenhagen county Denmark ActaObstetricia et Gynecologica Scandinavica 2002811060ndash5

Guix 2005 published data only

Guix C Palacio M Figueras F Bennasar M Zamora L CollO et al Efficacy of two regimens of misoprostol for earlysecond-trimester pregnancy termination Fetal Diagnosis

and Therapy 200520(6)544ndash8

Halimi 2004 published data only

Halimi M Therapeutic termination of second trimesterpregnancy a comparison of extra-amniotic foleylsquos catheterballoon alone with the combined use of foleylsquos catheterballoon and extra-amniotic instillation of prostaglandin f2-alpha Journal of Postgraduate Medical Institute 200418(3)408ndash18

Hassan 2007 published data only

Hassan FI Mostapha MK Sattar MA Marouf E AzimSA Oral versus rectal route of misoprostol administrationa randomized controlled trial Middle East Fertility Society

Journal 200712(1)53ndash6

Hausler 1997 published data only

Haumlusler MC Koroschetz F Tamussino K Walcher W Isa curettage after spontaneous abortion still relevant Aprospective randomised study [Ist eine Curettage nach



Abortus completus noch zeitgemaumlb Eine prospektivrandomisierte Studie] Geburtshilfe und Frauenheilkunde199757396ndash9

Heard 2002 published data only

Heard MJ Stewart GM Buster JE Carson SA Miller HJOutpatient management of missed abortion with vaginalmisoprostol [abstract] Obstetrics amp Gynecology 200299(4Suppl)20S

Herabutya 1997a published data only

Herabutya Y O-Prasertsawat P A comparison of intravaginalmisoprostol with intracervical prostaglandin E2 gel forthe management of dead fetus in utero Thai Journal of



Herabutya Y Chanrachakul B Punyavachira P Arandomised controlled trial of 6 and 12 hourlyadministration of vaginal misoprostol for second trimesterpregnancy termination BJOG an international journal of

obstetrics and gynaecology 20051121297ndash301

Hidar 2001 published data only

Hidar S Fekih M Chaieb A Bibi M Mellouli R Khairi HOxytocin and misoprostol administered intravaginally fortermination of pregnancy at 13-29 weeks of amenorrheaA prospective randomized trial [Apport de lrsquoassociationdrsquoocytocine au misoprostol administre en intravaginal aucours des interruptions de grossesses entre 13 et 29 semainesdrsquoamenorrhee Essai clinique prospectif randomise] Journal

de Gynecologie Obstetrique et Biologie de la Reproduction200130439ndash43


Hidar S Bouddebous M Chaieb A Jerbi M Bibi M KhairiH Randomized controlled trial of vaginal misoprostolversus vaginal misoprostol and isosorbide dinitrate fortermination of pregnancy at 13-29 weeks Archives ofGynecology and Obstetrics 2005273(3)157ndash60

Hill 1991 published data only

Hill NC Selinger M Ferguson J MacKenzie IZManagement of intra-uterine fetal death with vaginaladministration of gemeprost or prostaglandin E2 arandom allocation controlled trial Journal of Obstetrics andGynaecology 199111422ndash6

Hinshaw 1993 published data only

Henshaw RC Hinshaw K Smith NC Templeton AA Themedical management of miscarriage Fertility Society ofAustralia Australian Gynaecological Endoscopy Society1995 November 19-25 Melbourne Australia 1995FSA75lowast Hinshaw K Rispin N Smith N Templeton A Medicalversus surgical management in first trimester miscarriage aprospective pragmatic random allocation trial Journal ofObstetrics and Gynaecology 199313404ndash5Hinshaw K Rispin R Henshaw R Smith N Templeton AMedical versus surgical uterine evacuation in first trimestermiscarriage a prospective pragmatic randomised trial

27th British Congress of Obstetrics and Gynaecology 1995July 4-7 Dublin 19954Rispin R Hinshaw K Henshaw R Smith N TempletonA New aspects of care in the management of miscarriageProceedings of Research in Midwifery Conference 1993September 14 Birmingham UK 1993

Hogg 2000 published data only

Hogg B Owen J Laminaria versus extraamniotic salineinfusion (EASI) for cervical ripening and mid-trimesterlabor induction American Journal of Obstetrics and

Gynecology 2000182(1 Pt 2)S135

Hombalegowda 2015 published data only

Hombalegowda RB Samapthkumar S Vana H Jogi PRamaiah R A randomized controlled trial comparingdifferent doses of intravaginal misoprostol for earlypregnancy failure Contraception 201592(4)364ndash5

Hughes 1996 published data only

Hughes J Ryan M Hinshaw K Henshaw R RispinR Templeton A The costs of treating miscarriage acomparison of medical and surgical management British

Journal of Obstetrics and Gynaecology 1996103(12)1217ndash21

Imran 2010 published data only

Imran F Anser A Danish N Fatima N Misoprostol forthe purpose of mid-trimester termination of pregnancy acomparative study with prostaglandin F2 alpha Journal

of Ayub Medical College Abbottabad JAMC 201022(4)87ndash91

Islam 2006 published data only

Islam A Abbasi AN Sarwar I Use of Foleyrsquos catheter andprostaglandin F-2 alpha in second trimester terminationof pregnancy Journal of Ayub Medical College Abbottabad

200618(3)35ndash9

Jabir 2009a published data only

Jabir M Smeet RI Comparison of oral and vaginalmisoprostol for cervical ripening before evacuation of firsttrimester missed miscarriage Saudi Medical Journal 200930(1)82ndash7

Jabir 2009b published data only

Jabir M Smeet R Comparison of oral and vaginalmisoprostol for cervical ripening before evacuation offirst trimester missed miscarriage International Journal of

Gynecology amp Obstetrics 2009107(Suppl 2)S209


Jain JK Mishell DR A comparison of intravaginalmisoprostol with prostaglandin E2 for termination ofsecond-trimester pregnancy New England Journal of

Medicine 1994331290ndash3


Jain JK Kuo J Mishell DR A comparison of two dosingregimens of intravaginal misoprostol for second-trimesterpregnancy termination Obstetrics amp Gynecology 199993571ndash5

Johnson 1997 published data only

Johnson N Priestnall M Marsay T Ballard P Watters JA randomised trial evaluating pain and bleeding after a



first trimester miscarriage treated surgically or medicallyEuropean Journal of Obstetrics amp Gynecology and ReproductiveBiology 199772(2)213ndash5

Kamal 2005 published data only

Kamal R Parveeen F Mazhar SB Role of misoprostol invaginal versus double oro-vaginal route for termination ofpregnancy in mid trimester pregnancy Annals of Pakistan

Institute of Medical Sciences 20051(4)196ndash200

Kanhai 1989 published data onlylowast Kanhai HH Keirse MJ Induction of labour after fetaldeath a randomized controlled trial of two prostaglandinregimens British Journal of Obstetrics and Gynaecology 1989961400ndash4Kanhai HH Keirse MJ Intravenous administration ofsulfprostone for the induction of labour after fetal deatha randomised comparison of two dose schedules WorldCongress of Gynecology and Obstetrics 1988 October 23-28 Brazil 1988201ndash2Kanhai HH Keirse MJC Intravenous administrationof sulfprostone for the induction of labour after fetaldeath a randomised comparison of two dose schedulesProceedings of 1st European Congress on Prostaglandins inReproduction 1988 July 6-9 Vienna Austria 198845

Kapp 2007 published data only

Kapp N Todd CS Yadgarova KT Alibayeva G NazarovaD Loza O et al A randomized comparison of misoprostolto intrauterine instillation of hypertonic saline plus aprostaglandin F2alpha analogue for second-trimesterinduction termination in Uzbekistan Contraception 200776(6)461ndash6

Khosravi 2017 published data only

Khosravi D IRCT2017040633255N1 Comparison of theeffect between two dose (800 microgday amp 400 microg6) of vaginalmisoprostol in the termination of first-trimester pregnancya double-blinded randomized trial httpsenirctirtrial25706 (25 June 2017)

Kong 2013 published data only

Kong GW Lok IH Yiu AK Hui AS Lai BP Chung TKClinical and psychological impact after surgical medicalor expectant management of first-trimester miscarriage -a randomised controlled trial Australian amp New ZealandJournal of Obstetrics amp Gynaecology 201353(2)170ndash7

Kurshid 2010 published data only

Kurshid R Ahmed A Mir S Ul Shamas I To assess theefficacy of two regimens of misoprostol for second trimesterpregnancy termination-a randomized comparison InternetJournal of Gynecology and Obstetrics 2010 Vol 14 issue1

Kyaw 2015 published data only

Kyaw O Yi KH Thida M A comparison of medicalevacuation using single dose vaginal misoprostol (800mug)versus surgical evacuation in management of early pregnancyloss in North Okkalapa General and Teaching HospitalYangon Journal of Obstetrics and Gynaecology Research

2015413 Abstract no YGA O 06

Linn 2015 published data only

Linn TW Nyunt KK Ku SK Effectiveness of low dosesvaginal misoprostol in intrauterine fetal death Journal of

Obstetrics and Gynaecology Research 201541(Suppl S1)60Abstract no FC 1012

Lippert 1978 published data only

Lippert TH Luthi A Induction of labour withprostaglandin E2 gel in cases of intrauterine fetal deathProstaglandins 197815533ndash42

Lu 2014 published data only

Lu PH Lu J Zou S Comparisons of the effects ofmisoprostol by two different application on the treatmentof missed abortion Chinese Journal of Pharmaceutical

Biotechnology 201421(2)159ndash61

Lughmani 2008 published data onlylowast Lughmani ST A comparison of intravaginal misoprostolwith prostaglandin E2 for termination of 1st trimesterpregnancy BJOG an international journal of obstetrics and

gynaecology 2008115(s1)179Lughmani ST A comparison of intravaginal misoprostolwith prostaglandin E2 for termination of 1st trimesterpregnancy Double blind randomized trial [abstract]31st British International Congress of Obstetrics andGynaecology London UK 2007 July 4ndash6 Vol 209CRSREF 3293006]

Machtinger 2004 published data only

Machtinger R Stockheim D Shulman A Dulitzki MSchiff E Seidman DS A randomized prospective studycomparing the effectiveness of four protocols for treatmentof first trimester spontaneous abortion Fertility and Sterility200482 Suppl 2S80

Mahjabeen 2009 published data only

Mahjabeen Khawaja NP Rehman R Comparison of oralversus vaginal misoprostol for mid-trimester pregnancytermination Journal of the College of Physicians amp Surgeons

Pakistan 200919(6)359ndash62

Makenzius 2017 published data only

Makenzius M Oguttu MA Odera T Klingberg-AllvinM Gemzell-Danielsson K Faxelid E Post-abortion care(PAC) and contraceptive counselling by midwives orphysicians A facility based study in Kisumu WesternKenya 31st International Confederation of MidwivesTriennial Congress Midwives - Making a Difference in theWorld 2017 June 18-22 Toronto Canada 2017Abstractno F1401

Makhlouf 2003 published data only

Makhlouf AM Al-Hussaini TK Habib DM MakaremMH Second-trimester pregnancy termination comparisonof three different methods Journal of Obstetrics andGynaecology 200323407ndash11

Martin 1965 published data only

Martin RH Menzies DN Oestrogen therapy in missedabortion and labour Journal of Obstetrics and Gynaecology of

the British Commonwealth 196562256ndash8



Montesinos 2011 published data only

Montesinos R Durocher J Leon W Arellano M Pena MPinto E et al Oral misoprostol for the management ofincomplete abortion in Ecuador International Journal ofGynecology amp Obstetrics 2011115(2)135ndash9

Moran 2005 published data only

Moran T Deutsch R Methotrexatemisoprostol vs amore standard approach for termination of pregnancies ofundetermined location a randomized controlled trialJournal of Reproductive Medicine 200550(10)784ndash92

Mostafa-Gharebaghi 2010 published data only

Mostafa-Gharebaghi P Mansourfar M Sadeghi-BazarganiH Low dose vaginal misoprostol versus prostaglandin E2suppository for early uterine evacuation a randomizedclinical trial Pakistan Journal of Biological Sciences 201013

(19)946ndash50

Mulayim 2009 published data only

Mulayim B Celik NY Onalan G Zeyneloglu HB KuscuE Sublingual misoprostol after surgical management ofearly termination of pregnancy Fertility amp Sterility 200992

(2)678ndash81

Naghshineh 2015 published data onlylowast Naghshineh E Allame Z Farhat F The effectiveness ofusing misoprostol with and without letrozole for successfulmedical abortion A randomized placebo-controlled clinicaltrial Journal of Research in Medical Sciences 201520(6)585ndash9 PUBMED 26600834]Shabestari PS Comparison the effect of letrozole plusmisoprostol and misoprostol alone in termination ofnonviable first trimester pregnancies a single blindedrandomized trial ensearchirctirtrial13912 (first received14 March 2014)

Nakintu 2001 published data only

Nakintu N A comparative study of vaginal misoprostol andintravenous oxytocin for induction of labour in womenwith intrauterine fetal death in Mulago Hospital UgandaAfrican Health Sciences 2001155ndash9

Nasreen 2009 published data only

Nasreen Z What for early pregnancy failure manualvacuum aspiration (MVA) with small dose misoprostol ormisoprostol alone International Journal of Gynecology amp


Nassar 2006 published data only

Nassar AH A randomized trial of two regimens ofmisoprostol for second trimester intrauterine fetal deathclinicaltrialsgovct2showNCT00141895 2006

NCT02141555 published data only

NCT02141555 Mody S Comparing buccal and vaginalmisoprostol in management of early pregnancy loss a pilotrandomized controlled trial clinicaltrialsgovct2showrecordNCT02141555 (first received 19 May 2014)


NCT02573051 Misoprostol plus isosorbide mononitrateversus misoprostol for termination of anembryonic

pregnancy clinicaltrialsgovct2showrecordNCT02573051 (first received 9 October 2015)

Ng 2015 published data only

Ng BK Annamalai R Lim PS Aqmar Suraya S NurAzurah AG Muhammad Abdul Jamil MY Outpatientversus inpatient intravaginal misoprostol for the treatmentof first trimester incomplete miscarriage a randomisedcontrolled trial Archives of Gynecology and Obstetrics 2015291(1)105ndash13

Ngai 2001 published data only

Ngai SW Chan YM Tang OS Ho PC Vaginal misoprostolas medical treatment for first trimester spontaneousmiscarriage Human Reproduction 200116(7)1493ndash6

Nguyen 2005 published data only

Nguyen TN Blum J Durocher J Quan TT Winikoff B Arandomized controlled study comparing 600 versus 1200micrograms oral misoprostol for medical management ofincomplete abortion Contraception 200572(6)438ndash42

Niinimaki 2006 published data onlylowast Niinimaki M Jouppila P Martikainen H Talvensaari-Mattila A A randomized study comparing efficacy andpatient satisfaction in medical or surgical treatment ofmiscarriage Fertility and Sterility 200686(2)367ndash72Niinimaki M Karinen P Hartikainen AL Pouta A Treatingmiscarriages a randomised study of cost-effectiveness inmedical or surgical choice BJOG an international journalof obstetrics and gynaecology 2009116(7)984ndash90 DOI101111j1471-0528200902161x

Nor 2006 published data only

Nor Azlin MI Abdullah HS Zainul Rashid MR Jamil MAMisoprostol (alone) in second trimester terminations ofpregnancy as effective as Gemeprost Journal of Obstetricsand Gynaecology 200626(6)546ndash9

Nuthalapaty 2005 published data only

Nuthalapaty F Ramsey P Biggio J Owen J Comparativeefficacy of high dose vaginal misoprostol versus concentratedoxytocin + low dose vaginal misoprostol for mid-trimesterlabor induction American Journal of Obstetrics andGynecology 2004191(6 Suppl 1)S73lowast Nuthalapaty FS Ramsey PS Biggio JR Owen J High-dose vaginal misoprostol versus concentrated oxytocinplus low-dose vaginal misoprostol for midtrimester laborinduction a randomized trial American Journal of Obstetrics

and Gynecology 2005193(3 Pt 2)1065ndash70

Nuutila 1997 published data only

Nuutila M Toivonen J Ylikorkala O Halmesmaki E Acomparison between two doses of intravaginal misoprostoland gemeprost for induction of second-trimester abortionObstetrics amp Gynecology 199790896ndash900

Owen 1999 published data only

Owen J Hauth JC Vaginal misoprostol vs concentratedoxytocin plus low-dose prostaglandin E2 for secondtrimester pregnancy termination Journal of Maternal-Fetal




Paraskevaides 1992 published data only

Paraskevaides E Prendiville W Stuart B Scanaill SNWalsh D McGuinness N et al Medical evacuation of firsttrimester (twelve weeks gestation) incomplete abortion andmissed abortion Journal of Gynecologic Surgery 19928159ndash63

Paritakul 2010 published data only

Paritakul P Phupong V Comparative study between oraland sublingual 600 microg misoprostol for the treatment ofincomplete abortion Journal of Obstetrics and Gynaecology

Research 201036(5)978ndash83

Patua 2013 published data only

Patua B Dasgupta M Bhattacharyya SK Bhattacharya SHasan SH Saha S An approach to evaluate the efficacy ofvaginal misoprostol administered for a rapid managementof first trimester spontaneous onset incomplete abortion incomparison to surgical curettage Archives of Gynecology andObstetrics 2013288(6)1243ndash8

Perry 1999 published data only

Perry KG Rinehart BK Terrone DA Martin RW MayWL Roberts WE Second-trimester uterine evacuationa comparison of intra-amniotic (15S)-15-methyl-prostaglandin F2alpha and intravaginal misoprostolAmerican Journal of Obstetrics and Gynecology 19991811057ndash61

Piotrowski 1979 published data only

Piotrowski J Basta A Klimczyk K Malolepazy ADluzniewska M Splawinski JA Indomethacin increasesabortifacient effect of PGE2 in man Prostaglandins 197917451ndash9

Pongsatha 2004 published data only

Pongsatha S Tongsong T Intravaginal misoprostol forpregnancy termination International Journal of Gynecology

amp Obstetrics 200487176ndash7

Prasartsakulchai 2004 published data only

Prasartsakulchai C Tannirandorn Y A comparison ofvaginal misoprostol 800 microg versus 400 microg in earlypregnancy failure a randomized controlled trial Journalof the Medical Association of Thailand 200487 Suppl 3S18ndash23

Promwangkwa 2017 published data only

Promwangkwa K Puntitpong B Chirdchim WSananpanichkul P Efficacy of sublingual misoprostol withor without loading vaginal misoprostol in second trimestertermination of pregnancy a randomized controlled trialJournal of the Medical Association of Thailand 2017100(10)1050ndash5

Rahimi-Sharbaf 2015 published data only

Rahimi-Sharbaf F Adabi K Valadan M Shirazi M NekuieS Ghaffari P et al The combination route versus sublingualand vaginal misoprostol for the termination of 13 to 24week pregnancies a randomized clinical trial TaiwaneseJournal of Obstetrics amp Gynecology 201554(6)660ndash5

Ramadan 2009 published data only

Ramadan MC Misoprostol versus MVA for incompleteabortion results from a randomized controlled trial in

Egypt International Journal of Gynecology amp Obstetrics

2009107(Suppl 2)S68ndash9

Ramsey 2004 published data only

Ramsey PS Savage K Lincoln T Owen J Vaginalmisoprostol versus concentrated oxytocin and vaginalPGE2 for second-trimester labor induction Obstetrics amp


Reeves 2006 published data only

Reeves MF Lohr PA Harwood B Creinin MDSonographic findings after misoprostol or vacuum aspirationfor early pregnancy failure Contraception 200674(2)182


Reeves MF Lohr PA Harwood BJ Creinin MDUltrasonographic endometrial thickness after medical andsurgical management of early pregnancy failure Obstetrics

amp Gynecology 2008111(1)106ndash12

Rivero-Lopez 1998 published data only

Rivero-Lopez E Marquez-Maraver F Duenas-Diez JLCabezas-Sanchez B Deferred miscarriage effectiveness ofintravaginal misoprostol versus laminaria alone [Abortodiferido eficacia del misoprostol intravaginal versus laaplicacion de tallos de laminaria] Progresos de Obstetricia y

Ginecologia 199841579ndash81

Robledo 2007 published data only

Robledo C Zhang J Troendle J Barnhart K CreininMD Westhoff C et al Clinical indicators for successof misoprostol treatment after early pregnancy failureInternational Journal of Gynecology amp Obstetrics 200799(1)46ndash51

Roy 2003 published data only

Roy G Ferreira E Hudon L Marquette G The efficacyof oral versus vaginal misoprostol for second-trimestertermination of pregnancy a double blind randomizedplacebo-controlled trial American Journal of Obstetrics and

Gynecology 2003189(6)S70

Ruangchainikhom 2006 published data only

Ruangchainikhom W Phongphissanou E Bhekasuta JSarapak S Effectiveness of 400 or 600 micrograms ofvaginal misoprostol for terminations of early pregnanciesJournal of the Medical Association of Thailand 200689(7)928ndash33

Saeed 2018 published data only

Saeed S Manzoor R Tazion S Butt F Badar N Misoprostolfor 1st trimester miscarriage efficacy of vaginal versus oralmisoprostol Pakistan Journal of Medical and Health Sciences201812(2)849ndash52

Salamalekis 1990 published data only

Salamalekis E Loghis C Kassanos D Traka A Zourlas PAComparison of extra-amniotic prostaglandin F2alpha anddinoprostone use for labor induction after second trimesterintrauterine fetal death Proceedings of 12th EuropeanCongress of Perinatal Medicine 1990 Lyon France 1990228

Salari 2012 published data only

Salari Z Comparison of the efficacy of vaginal misoprostolwith and without laminaria in second trimester induction



abortion in patients referring to afzalipour hospital in 2008-2009 International Journal of Gynecology and Obstetrics2012119(Suppl 3)S582

Shaheen 2017 published data only

Shaheen H Khosa MS Hanif H Comparison of efficacy ofmanual vacuum aspiration (MVA) and medical treatmentin the management of first trimester missed miscarriagePakistan Journal of Medical and Health Sciences 201711(1)270ndash3

Shaikh 2008 published data only

Shaikh ZA Comparison between misoprostol aloneand misoprostol with manual vacuum aspiration for thetreatment of missed and incomplete miscarriage BJOG an

international journal of obstetrics and gynaecology 2008115

(s1)83

Shelley 2005 published data only

Shelley JM Healy D Grover S A randomised trial ofsurgical medical and expectant management of firsttrimester spontaneous miscarriage Australian and NewZealand Journal of Obstetrics and Gynaecology 200545122ndash7

Shobeira 2007 published data only

Shobeira JM Atashkhoii S Second trimester pregnancytermination by intravaginal and parenteral form ofprostaglandin E2 [abstract] 31st British InternationalCongress of Obstetrics and Gynaecology 2007 July 4-6London UK 2007210

Shochet 2012 published data only

Shochet T Diop A Gaye A Nayama M Sall AB Bukola Fet al Sublingual misoprostol versus standard surgical carefor treatment of incomplete abortion in five sub-SaharanAfrican countries BMC Pregnancy and Childbirth 201212127

Shokry 2009 published data only

Shokry M Shahin AY Fathalla MM Shaaban OM Oralmisoprostol reduces vaginal bleeding following surgicalevacuation for first trimester spontaneous abortionInternational Journal of Gynecology amp Obstetrics 2009107

(2)117ndash20

Shuaib 2013 published data only

Shuaib AA Alharazi AH Medical versus surgicaltermination of the first trimester missed miscarriageAlexandria Journal of Medicine 20134913ndash6

Shwekerela 2007 published data only

Shwekerela B Kalumuna R Kipingili R Mashaka NWestheimer E Clark W et al Misoprostol for treatment ofincomplete abortion at the regional hospital level resultsfrom Tanzania BJOG an international journal of obstetrics

and gynaecology 2007114(11)1363ndash7

Smith 2006a published data only

Smith LF Frost J Levitas R Bradley H Garcia J Womenrsquosexperiences of three early miscarriage management optionsa qualitative study British Journal of General Practice 200656(524)198ndash205

Smith 2009 published data only

Smith LF Ewings PD Quinlan C Incidence of pregnancyafter expectant medical or surgical management ofspontaneous first trimester miscarriage long term follow-up of miscarriage treatment (MIST) randomised controlledtrial BMJ 2009339b3827

Srikhao 2005 published data only

Srikhao N Tannirandorn Y A comparison of vaginalmisoprostol 800 microg versus 400 microg for anembryonicpregnancy a randomized comparative trial Journal of theMedical Association of Thailand 200588(Suppl 2)S41ndash7

Sripramote 2000 published data only

Sripramote M Chatsuphang W A randomized comparisonof oral and vaginal misoprostol for cervical priming beforeuterine curettage in the first trimester of pregnancy VajiraMedical Journal 200044(3)207ndash15

Stockheim 2006 published data only

Machtinger R Stockheim D Goldenberg M Soriano DAtlas M Seidman DS A randomized prospective studyof misoprostol alone or combined with mifepristone fortreatment of first trimester spontaneous abortion Fertilityand Sterility 200278(3 Suppl 1)S64lowast Stockheim D Machtinger R Wiser A DulitzkyM Soriano D Goldenberg M et al A randomizedprospective study of misoprostol or mifepristone followedby misoprostol when needed for the treatment of womenwith early pregnancy failure Fertility and Sterility 200686

(4)956ndash60

Su 2005 published data only

Su LL Biswas A Choolani M Kalaichelvan V Singh K Aprospective randomized comparison of vaginal misoprostolversus intra-amniotic prostaglandins for midtrimestertermination of pregnancy American Journal of Obstetricsand Gynecology 20051931410ndash4

Suchonwanit 1999 published data only

Suchonwanit P Comparative study between vaginalmisoprostol 200 mg and 400 mg in first trimesterintrauterine fetal death and anembryonic gestation Thai


Surita 1997 published data only

Surita FG Cecatti JG Pinto e Silva JL Misoprostol versuslaminaria for cervical ripening in intrauterine fetal deathActa Obstetricia et Gynecologica Scandinavica Supplement

199776(1672)32

Tam 2005 published data only

Tam WH Tsui MH Lok IH Yip SK Yuen PM ChungTK Long-term reproductive outcome subsequent tomedical versus surgical treatment for miscarriage HumanReproduction 200520(12)3355ndash9

Tanha 2013 published data only

Tanha FD Comparison of the efficacy of two routes ofmisoprostol administration (sublingual and vaginal) fortermination of second trimester pregnancy enirctirtrial2327 2010 CRSREF 3293102]lowast Tanha FD Golgachi T Niroomand N Ghajarzadeh MNasr R Sublingual versus vaginal misoprostol for second



trimester termination a randomized clinical trial Archives

of Gynecology and Obstetrics 2013287(1)65ndash9

Taylor 2011 published data only

Taylor J Diop A Blum J Dolo O Winikoff B Oralmisoprostol as an alternative to surgical management forincomplete abortion in Ghana International Journal of

Gynecology amp Obstetrics 2011112(1)40ndash4

Thavarasah 1986 published data only

Thavarasah AS Almohdzar SA Prostaglandin (F2alpha)in missed abortion Intravenous extra-amniotic andintramuscular administration - a randomized studyBiological Research in Pregnancy 19867106ndash10

Thida 2015 published data only

Thida M Shwe MM Htun KT Maung NM Khine EPWin KS et al A randomised clinical trial comparingdifferent routes of administration of repeated doses of400ug misoprostol for management of missed miscarriagesand anembryonic gestations in North Okkalapa GeneralHospital Yangon Myanmar BJOG an internationaljournal of obstetrics and gynaecology 2015122(Suppl S1)26ndash7

Toppozada 1994 published data only

Toppozada MK Shaala SA Anwar MY Haiba NAAbdrabbo S El-Absy HM Termination of pregnancy withfetal death in the second and third trimesters - the doubleballoon versus extra-amniotic prostaglandin InternationalJournal of Gynecology amp Obstetrics 199445269ndash73

Toptas 2011 published data only

Toptas T Mendilcioglu I Simsek M Taskin O Comparisonof intravaginal misoprostol alone to combination ofintravaginal misoprostol and extraamniotic Foley catheterfor the second trimester of pregnancies American Journal of

Obstetrics and Gynecology 2011204(1 Suppl)S126

Torre 2012 published data only

Rosenberg P Expectant versus immediate medicalmanagement for the evacuation of the non evolutivepregnancies before 13 GW clinicaltrialsgovct2showNCT00190294 (first received 19 September 2005)lowast Torre A Huchon C Bussieres L Machevin E Camus EFauconnier A Immediate versus delayed medical treatmentfor first-trimester miscarriage a randomized trial American

Journal of Obstetrics amp Gynecology 2012206(3)215e1ndash6

Van Mensel 2009 published data only

Van Mensel K Claerhout F Debois P Keirse MJ HanssensM A randomized controlled trial of misoprostol andsulprostone to end pregnancy after fetal death [Article ID496320] Obstetrics and Gynecology International 2009

Yapar 1996 published data only

Yapar EG Senoz S Urkutur M Batioglu S Gokmen OSecond trimester pregnancy termination including fetaldeath comparison of five different methods European

Journal of Obstetrics amp Gynecology and Reproductive Biology19966997ndash102

Yilmaz 2005 published data only

Yilmaz B Kelekci S Ertas IE Kahyaoglu S Ozel M SutN et al Misoprostol moistened with acetic acid or saline

for second trimester pregnancy termination a randomizedprospective double-blind trial Human Reproduction 200520(11)3067ndash71


Yilmaz B Kelekci S Ertas IE Ozel M Sut NMollamahmutoglu L et al Randomized comparison ofsecond trimester pregnancy termination utilizing salinemoistened or dry misoprostol Archives of Gynecology andObstetrics 2007276(5)511ndash6

Zanganeh 2012 published data only

Zanganeh M Comparing the effects of multiple doses ofmisoprostol with single dose of misoprostol plus oxitocin ininduction of second trimester abortion enirctirtrial3910(first received 12 June 2010)lowast Zangeneh M Malek-Khosravi S Veisi F Rezavand NRezaee M Rajatee M Multiple-dose vaginal misoprostoland single-dose misoprostol plus oxytocin for terminationof second-trimester pregnancy International Journal of

Gynaecology and Obstetrics 2012117(1)78ndash80 PUBMED22261129]

Zhang 2000 published data only

Zhang C Cheng W A contrastive analysis of the efficacyof misoprostol and li fan nuo in intermediate term ofpregnancy Journal of Wuhan University of Science and

Technology (Natural Science Edition) 200023(4)409ndash11


Chen BA Reeves MF Creinin MD Gilles JM BarnhartK Westhoff C et al Misoprostol for treatment of earlypregnancy failure in women with previous uterine surgeryAmerican Journal of Obstetrics amp Gynecology 2008198(6)626e1ndash626e5 DOI doiorg101016jajog200711045Creinin MD Huang X Westhoff C Barnhart K Gilles JMZhang J et al Factors related to successful misoprostoltreatment for early pregnancy failure Obstetrics amp

Gynecology 2006107(4)901ndash7Davis AR Hendlish SK Westhoff C Frederick MM ZhangJ Gilles JM et al Bleeding patterns after misoprostol vssurgical treatment of early pregnancy failure results froma randomized trial American Journal of Obstetrics andGynecology 2007196(1)31 101016jajog200607053]Harwood B Nansel T National Institute of ChildHealth and Human Development Management of EarlyPregnancy Failure Trial Quality of life and acceptabilityof medical versus surgical management of early pregnancyfailure BJOG an international journal of obstetricsand gynaecology 2008115(4)501ndash8 DOI 101111j1471-0528200701632xRausch M Lorch S Chung K Frederick M Zhang JBarnhart K A cost-effectiveness analysis of surgical versusmedical management of early pregnancy loss Fertility

and Sterility 201297(2)355ndash60e1 DOI 101016jfertnstert201111044lowast Zhang J Gilles JM Barnhart K Creinin MD Westhoff CFrederick MM et al A comparison of medical managementwith misoprostol and surgical management for early



pregnancy failure New England Journal of Medicine 2005353761ndash9Zhang J Gilles K Barnhart K Creinin M Westhoff CFrederick M Medical management with misoprostolfor early pregnancy failure a multicenter randomizedequivalence trial Fertility and Sterility 200482 Suppl 2S53ndashS54

References to ongoing studies

ACTRN12615000483550 published data only

Abdellah AS Clinical randomized trial to compareefficacy and safety of vaginal and buccal misoprostol insecond trimester abortion due to intrauterine fetal deathanzctrorgauTrialRegistrationTrialReviewaspxid=367522 (first received 15 May 2015)


Ali MK NCT03148314 Home-based extended low dosebuccal misoprostol versus hospital-based standard vaginaldose in management of first trimester missed abortionhttpsclinicaltrialsgovct2showNCT03148314 (firstreceived 11 May 2017)

El Shahawy 2016 published data only

El Shahawy A NCT02686840 Sublingual versus vaginalmisoprostol in medical treatment of first trimestric missedmiscarriage a randomized controlled trial httpsclinicaltrialsgovct2showNCT02686840 (first received22 February 2016)


Atrio J Mifepristone induction for fetal demise arandomized control trial clinicaltrialsgovct2showNCT02620904 (first received 1 December 2015)


Bracken H Mifepristone and misoprostol versus misoprostolalone for treatment of fetal death at 14-28 weeks ofpregnancy a randomized placebo-controlled double-blinded trial clinicaltrialsgovct2showNCT02633761(first received 17 December 2015)

NCT03212352 2017 published data only

NCT03212352 Comparing two medical treatments forearly pregnancy failure httpsclinicaltrialsgovshownct03212352 (first received 11 July 2017)

Additional references

Alfirevic 2014

Alfirevic Z Aflaifel N Weeks A Oral misoprostol forinduction of labour Cochrane Database of Systematic Reviews

2014 Issue 6 DOI 10100214651858CD001338pub3

Ashok 1998

Ashok PW Penney GC Flett GM Templeton A Aneffective regimen for early medical abortion a report of2000 consecutive cases Human Reproduction 1998132962ndash5

Baulieu 1986

Baulieu E Ulmann A Antiprogesterone activity of RU-486 and its contragestive and other applications Human

Reproduction 19861107ndash10 [PUBMED 3031127]

Bugalho 1996

Bugalho A Faundes A Jamisse L Usfa M Maria E BiqueC Evaluation of the effectiveness of vaginal misoprostolto induce first trimester abortion Contraception 199653244ndash6

Cameron 1986

Cameron IT Michie AF Baird DT Therapeutic abortionin early pregnancy with antiprogestogen RU486 alone orin combination with prostaglandin analogue (gemeprost)Contraception 198634(5)459ndash68 [PUBMED 3816230]

Costa 1993

Costa SH Vessey MP Misoprostol and illegal abortionin Rio de Janeiro Brazil Lancet 19933411258ndash61[PUBMED 8098402]

Graziosi 2005

Graziosi GC van der Steeg JW Reuwer PJ Drogtrop ABruinse HW Mol BW Economic evaluation of misoprostolin the treatment of early pregnancy failure comparedto curettage after an expectant management Human


Grudzinskas 1995

Grudzinskas JG Endocrinological and metabolicalassessment of early pregnancy In Chamberlain G editor(s) Turnbullrsquos Obstetrics London Pearson Professional Ltd1995185ndash93

Higgins 2011

Higgins JP Green S editors Cochrane Handbook forSystematic Reviews of Interventions Version 510 [updatedMarch 2011] The Cochrane Collaboration 2011Available from wwwcochrane-handbookorg

Hofmeyr 2010

Hofmeyr GJ Guumllmezoglu AM Pileggi C Vaginalmisoprostol for cervical ripening and induction of labourCochrane Database of Systematic Reviews 2010 Issue 10DOI 10100214651858CD000941pub2

Howie 1995

Howie PG Abortion and ectopic pregnancy In WhitfieldCR editor(s) Dewhurstrsquos Textbook of Obstetrics andGynecology for Postgraduates Oxford Blackwell ScienceLtd 1995140ndash63

Kim 2017

Kim C Barnard S Neilson JP Hickey M Vazquez JCDou L Medical treatments for incomplete miscarriageCochrane Database of Systematic Reviews 2017 Issue 1DOI 10100214651858CD007223pub4

Kovacs 1984

Kovacs L Sas M Resch BA Ugocsai G Swahn MLBygdeman et al Termination of very early pregnancy byRU 486--an antiprogestational compound Contraception198429(5)399ndash410



Kulier 2011

Kulier R Kapp N Gulmezoglu AM Hofmeyr GJ ChengLN Campana A Medical methods for first trimesterabortion Cochrane Database of Systematic Reviews 2011Issue 11 DOI 10100214651858CD002855pub4

Mousa 2014

Mousa HA Blum J Abou El Senoun G Shakur H AlfirevicZ Treatment for primary postpartum haemorrhageCochrane Database of Systematic Reviews 2014 Issue 2DOI 10100214651858CD003249pub3

Muzonzini 2004

Muzonzini G Hofmeyr GJ Buccal or sublingualmisoprostol for cervical ripening and induction of labourCochrane Database of Systematic Reviews 2004 Issue 4DOI 10100214651858CD004221pub2

Nanda 2012

Nanda K Lopez LM Grimes DA Peloggia A Nanda GExpectant care versus surgical treatment for miscarriageCochrane Database of Systematic Reviews 2012 Issue 3DOI 10100214651858CD003518pub3

Petrou 2006

Petrou S Trinder J Brocklehurst P Smith L Economicevaluation of alternative management methods of first-trimester miscarriage based on results from the MISTtrial BJOG an international journal of obstetrics ampgynaecology 2006113(8)879ndash89 DOI 101111j1471-0528200600998x CRSREF 3293040

RevMan 2014 [Computer program]

The Nordic Cochrane Centre The Cochrane CollaborationReview Manager (RevMan) Version 53 CopenhagenThe Nordic Cochrane Centre The Cochrane Collaboration2014

Say 2002

Say L Kulier R Gulmezoglu AM Campana A Medicalversus surgical methods for first trimester termination of

pregnancy Cochrane Database of Systematic Reviews 2002Issue 4 DOI 10100214651858CD003037pub2

Tunccedilalp 2012

Tunccedilalp Ouml Hofmeyr GJ Guumllmezoglu AM Prostaglandinsfor preventing postpartum haemorrhage Cochrane Database

of Systematic Reviews 2012 Issue 8 DOI 10100214651858CD000494pub4

Whitworth 2015

Whitworth M Bricker L Mullan C Ultrasound forfetal assessment in early pregnancy Cochrane Databaseof Systematic Reviews 2015 Issue 7 DOI 10100214651858CD007058pub3

Wieringa 2002

Wieringa-de Waard M Vos J Bonsel GJ Bindels PJAnkum WM Management of miscarriage a randomizedcontrolled trial of expectant management versus surgicalevacuation Human Reproduction 200217(9)2445ndash50

References to other published versions of this review

Neilson 2006

Neilson JP Hickey M Vazquez JC Medical treatment forearly fetal death (less than 24 weeks) Cochrane Databaseof Systematic Reviews 2006 Issue 3 DOI 10100214651858CD002253pub3

Vazquez 2000

Vazquez JC Hickey M Neilson JP Medical managementfor miscarriage Cochrane Database of Systematic Reviews2000 Issue 3 DOI 10100214651858CD002253

Vazquez 2006

Vazquez JC Hickey M Neilson JP Medical managementfor miscarriage Cochrane Database of Systematic Reviews

2006 Issue 2 DOI 10100214651858CD002253pub2lowast Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Abediasl 2016

Methods RCT Computerised random-number generator was used for sequence generation Par-ticipants 85 pregnant women with confirmed IUFD who were admitted for labour in-duction at Shariati Hospital Bandar Abbas Iran from January 2013 through January2014

Participants The inclusion criteria were pregnant women with documented IUFD a gestational ageof 15-24 weeks and a Bishop score lt 4

Interventions Intervention the starting dose was 200 mcg misoprostol vaginal tablets The tablet waswet with a drop of water for injection and inserted into the posterior fornix of the vaginausing a speculum and a spatula After 12 hours if the conception products were notexpelled and the effective uterine contractions (gt 3 contractions10 minutes) were notestablished another dose of 200 mcg misoprostol vaginal tablets was inserted reachinga maximal total dose of 400 mcg (n = 40)Control oxytocin infusion was given in 500 cm3 of 5 dextrose with the startingoxytocin dose of 6 mUminute If no effective uterine contractions were noted the dosewas increased at a rate of 6 mUminute at 45-minute intervals to reach a maximal doseof 40 mUminute (n = 45)

Outcomes The primary outcome of the study was the time of induction-to-delivery interval Sec-ondary outcomes were the success rate (evacuation lt 24 hours) duration of admissionpostpartum haemorrhage and complications of labour induction

Funding This research was funded by the Maternal Fetal and Neonatal Research Center TehranUniversity of Medical Sciences and Hormozgan University of Medical Sciences

Declarations of interest The authors declare that they have no conflicts of interest

Notes

Risk of bias

Bias Authorsrsquo judgement Support for judgement

Random sequence generation (selectionbias)

Low risk Quote ldquoA computerized random-numbergenerator was used for sequence genera-tion which was carried out by MS Simplerandomization was used in this studyrdquo

Allocation concealment (selection bias) Low risk Quote ldquoWe used consecutive opaque en-velopes for the concealment of allocationwhich was performed by FK The en-velopes were opaque when held to the lightand opened sequentially and only after the



Abediasl 2016 (Continued)

participantrsquos name and other detailsrdquo

Incomplete outcome data (attrition bias)All outcomes

Low risk Comment 8 women with induction failurewere analysed according an intention-to-treat principle There was no informationon lost to follow-up

Selective reporting (reporting bias) Low risk Comment all outcomes mentioned in themethods section are presented in the resultsection

Other bias Low risk No other source of bias could be detected

Blinding of participants and personnel(performance bias)All outcomes

High risk Quote ldquoThe implementation of assign-ments was carried out by ZA which isanother person then the persons who per-formed the randomizationrdquoComment the article does not furtherstate whether patients and personnel wereblinded however due to the nature of theinterventions blinding would be practi-cally impossible Not blinding of person-nel might have had an impact on outcomeassessment (see detection bias)

Blinding of outcome assessment (detectionbias)All outcomes

High risk Comment the article does not statewhether there was blinding of outcome as-sessment If there was no blinding thismight have had an impact on judgment ofsuccessful outcome (empty uterus)

Al Inizi 2003

Methods rsquoRandom allocationrsquo Details unknownStudy conducted at Tawam Hospital- a teaching hospital tertiary care unit in the UnitedArab Emirates Duration of study not mentioned

Participants 60 women with early non-viable pregnancies diagnosed by ultrasound

Interventions Vaginal misoprostol 400 mcg repeated twice a day to maximum of 1600 mcg (n = 27)vs dinoprostone (PGE2) vaginal tablets repeated at 6-hourly intervals to maximum of36 mg (n = 33)

Outcomes Complete miscarriageneed for surgical evacuation

Funding No information on funding

Declarations of interest No information on conflicts of interest



Al Inizi 2003 (Continued)

Notes Authors contacted

Risk of bias



Unclear risk Quote ldquo60 women with a diagnosis ofmissed abortion were randomly allocatedrdquoComment no further information on ran-dom sequence generation

Allocation concealment (selection bias) Unclear risk Comment no information on allocationconcealment


Low risk Comment 60 women were randomisedand for all 60 women outcomes were re-ported (table 1)

Selective reporting (reporting bias) Low risk Comment there is no information on howmany eligible women were counselled butrefused participation Apart from that thereare no signs of selective reporting all out-come measures mentioned in the methodssection were presented in the results section



High risk Comment there is no information onblinding of participants and personnel


High risk Comment there is no information onblinding of outcome assessment

Autry 1999

Methods Randomisation using a random number tables Allocation concealment was accom-plished in sequentially numbered opaque sealed envelopes made available at the time ofenrolment in the study Intention-to-treat analysisSinai Samaritan Medical Center and the Medical College of Wisconsin no informationon study duration

Participants 21 women diagnosed with a non-viable first trimester intrauterine pregnancy up to49 days gestation Evidence of non-viability included 1 of the following findings onTVS 1) mean gestational sac diameter greater than 18 mm and no embryonic pole 2)embryonic pole 5 mm to 10 mm without cardiac activity 3) intrauterine gestational sacwith abnormal hCG titres Others entry criteria 1) 18 years of age or greater 2) closed



Autry 1999 (Continued)

cervix on digital exam 3) no known intolerance or allergy to misoprostol or MTX 4)haemoglobin of 9 gdL or greater 5) platelet count of 100000microL or greater 6) nohistory of blood clotting disorders 7) no active liver or renal disease 8) ability andwillingness to comply with visit schedule 9) hCG less than 40000 IUL and 10) easyaccess to a telephone and transportation

Interventions Combined group (n = 12) IM MTX 50 mgm2 body surface area (day 1) followed2 days later (day 3) by vaginal misoprostol 800 mcg (by vaginal placement of 4 200mcg tablets of misoprostol) If the gestational sac was present vaginal misoprostol wasrepeated Misoprostol only group (n = 9) 4 200 mcg tablets placed in the vagina on day1 The remainder of the follow-up was similar to that for combined group

Outcomes Successful complete abortion MTX plus misoprostol 1212 vs misoprostol only 89No blood transfusion or antibiotics Positive urine pregnancy test at the initial follow-up appointment 29 vs 77 Pain relief 412 vs 49



Notes Wisconsin Milwaukee USA All women received 1) prescription for 10 tablets ac-etaminophen with codeine (300 mg30 mg) and 8 tablets of ibuprofen (600 mg) 2) in-struction sheet including phone number to contact physician 24 hoursday and a diarysheet to record symptoms side effects and pain medication use Data about side effects(headache nausea and emesis) and womenrsquos satisfaction reported as no separate dataAuthors conclude that both treatments are effective regimens for the complete evacua-tion of non-viable early first trimester pregnancy and represent a reasonable alternativefor women wishing to avoid surgery

Risk of bias



Low risk Quote ldquoRandomization was performed us-ing a random number table for each centrerdquo

Allocation concealment (selection bias) Low risk Quote ldquoAllocation concealment was ac-complished in sequentially numberedopaque sealed envelopes made available atthe time of enrolment in the studyrdquoComment adequate type of allocation con-cealment


Low risk Comment according to the results sec-tion outcomes were measured for all 21 in-cluded patients no signs of loss to follow-up or incomplete data




Selective reporting (reporting bias) Low risk Comment no signs of selective reportingall outcomes mentioned in the methodssection were presented in the results section



High risk Comment no information on blinding ofparticipants and personnel probably notdone


High risk Comment no information on blinding ofoutcome assessor probably not done

Ayudhaya 2006

Methods Parallel randomised controlled trial Randomisation according to computer-generatednumbers Performed in antenatal care clinic of department of Obstetrics and Gynaecol-ogy at Ramathibodi Hospital in Bangkok Thailand 138 women with diagnosis of earlypregnancy failure were included between November 2004-December 2005

Participants Pregnant women with gestational age 7-12 weeks and on ultrasound1 intrauterine fetal sac gt 2 cm without fetal pole or2 presence of fetal pole without cardiac activity orgestational sac lt 2 cm with no interval growth or persistent absence of fetal cardiacpulsation on rescanning after 7-10 days

Interventions 400 mcg misoprostol sublingually every 4 hours up to 6 doses (n = 70) vs 400 mcgmisoprostol orally every 4 hours up to 6 doses (n = 68)

Outcomes Outcomes1 Complete abortion defined as cervical os closed no bleeding and endometrial thick-ness lt 1 cm mean induction to abortion interval2 Secondary outcome adverse effects (abdominal pain diarrhoea nauseavomitingfever chills)



Notes

Risk of bias



Low risk Comment women were randomised ac-cording to computer-generated numbers



Ayudhaya 2006 (Continued)



Unclear risk Comment outcome group oral misopros-tol 68 women were randomised after which2 women were excluded due to incompletehospital records However table 2 reportsof 68 women and not of 66 women

Selective reporting (reporting bias) High risk Comment the methods section states thatprimary outcome is induction-to-deliveryinterval however in the results section alsodichotomous success rates are mentioned(complete or incomplete abortion) Therewere 68 patients in the intervention groupbut for only 66 patients outcome is de-scribed Furthermore the methods sectionmentions lsquoadverse effectsrsquo as secondary out-come without further specification There-fore is it unclear whether the adverse ef-fects mentioned in the results section arethe only ones that were measured



High risk Comment due to the nature of the in-tervention blinding would be difficult theonly way for blinding both participantsand personnel would be to give group Aoral misoprostol and sublingual placeboand group B oral placebo and sublingualmisoprostol The article does not state thatplacebos were used


Unclear risk Comment medication was administeredby nurses outcome assessment was per-formed by doctors according to the arti-cle The article does not state whether thesedoctors were blinded for type of interven-tion



Bagratee 2004

Methods Computer-generated random allocation of study number Numbered envelopes contain-ing misoprostol or placeboAll women presenting to the Early Pregnancy Assessment Unit (EPAU) at St MaryrsquosHospital London UK from August 2001 to March 2002

Participants 104 women who attended Early Pregnancy Unit St Maryrsquos Hospital with incompletemiscarriage or early pregnancy failure lt 13 weeks

Interventions 600 mcg misoprostol (n = 52) or placebo [expectant management] (n = 52) Seconddose next day unless complete miscarriage had occurred in meantime Review day 7 andsurgical evacuation if miscarriage not complete Further review at day 14

Outcomes Primary complete miscarriage without need for ERPC by day 7 Secondary outcomesclinical side effects satisfaction and future choices



Notes Primary outcome reported for both non-viable pregnancies and incomplete miscarriagesbut not for secondary outcomes These will be added if authors can provide data separatelyfor non-viable pregnancies and incomplete miscarriages

Risk of bias



Low risk Quote ldquoComputer-based allocationrdquo allo-cation ldquoaccording to the random schedulerdquo

Allocation concealment (selection bias) Low risk Quote ldquoThree misoprostol or placebotablets were placed in each of two small en-velopes and sealed These small envelopeswere then placed in consecutively num-bered larger envelopes according to the ran-dom schedule and sealed by staff not in-volved in the studyrdquoComment adequate allocation conceal-ment


Low risk Quote ldquoThe 104 women randomized tothe trial attended the scheduled visits as perprotocol and completed the trialrdquoComment no signs of missing data

Selective reporting (reporting bias) Low risk Comment all outcomes mentioned in themethods section were presented in the re-sults section no signs of selective reporting



Bagratee 2004 (Continued)



Low risk Quote ldquoThree misoprostol or placebotablets were placed in each of two small en-velopes and sealed These small envelopeswere then placed in consecutively num-bered larger envelopes according to the ran-dom schedule and sealed by staff not in-volved in the studyrdquoComment this means both patients as wellas the doctor randomising the patients wereunaware of the type of treatment


Low risk Comment patients and doctors randomis-ing the patients were blinded for treatmentallocation (see blinding of participants andpersonnel above) assuming the doctor as-sessing the outcome was the same as the 1randomising the patients there was suffi-cient blinding of outcome assessment

Bracken 2014

Methods Double-blind randomised trial Randomised using a simple randomisation sequencegenerated by computer with blocks of 10 Randomisation was stratified by study siteMontefiore Medical Center Stanford University Stroger Hospital Christiana HealthSystem the Huong Vuong Hospital in Ho Chi Minh City Viet Nam from December2008 to December 2011

Participants Women who sought medical care for possible fetal demise in pregnancies of between 14and 28 weeks from December 2008 to December 2011 Confirmation of fetal demiseand final gestational age were determined by ultrasound

Interventions Intervention 100 mcg buccal misoprostol (n = 63)Study drug was administered at 6-hourly intervals for a maximum of 8 dosesControl 200 mcg buccal misoprostol (n = 72)Study drug was administered at 6-hourly intervals for a maximum of 8 doses

Outcomes The primary outcome was the fetal-placental delivery rate within 48 hours of misoprostolcommencement without any additional intervention Rates of success were comparedacross study arms

Funding This study was funded by a grant from the Office of Orphan Products Development ofthe United States Food and Drug Administration

Declarations of interest The authors declare no conflicts of interest



Bracken 2014 (Continued)

Notes This study included patients with gestational age gt 24 weeks We contacted the authorwho could provided us with subgroup analysis for patients with gestational age lt 24weeks therefore we were able to include this study in the review

Risk of bias



Low risk Quote ldquoThe groups were created by Gy-nuity Health Projects using a simple ran-domization sequence generated by com-puter with blocks of 10 Randomizationwas stratified by study siterdquoComment this is an adequate type of ran-dom sequence generation

Allocation concealment (selection bias) Low risk Comment the article states that researchassistants created packages of medicationbut randomisation seems to be done bydoctors there probably was allocation con-cealment for the doctor randomising thepatient


Low risk Comment the flowchart shows that dis-continuation was lt 5 All patients thatwere initially randomised were included inthe analysis Since there was no loss to fol-low-up and discontinuation was very lowit is likely data outcome data were complete

Selective reporting (reporting bias) Unclear risk Comment the results section presents sec-ondary outcome measures that were notmentioned in the methods section Unclearwhether these were all the outcomes mea-sured or if other variables were measuredbut not presented



Low risk Quote ldquoA research assistant prepared num-bered and sealed randomization packetsbefore beginning enrolment Each packetcontained eight individually labelled doseenvelopes Each woman was administereda randomization envelope containing twotabletsrsquo (100 mcg misoprostol tablet +placebo resembling this tablet or 2 tabletsof 100 mcg misoprostol)rdquo




Comment probably the packets werehanded out to the patients by other per-sonnel than the research assistant prepar-ing them so there was probably blindingof both patients and personnel


Low risk Comment the care taking physician wasblinded for the intervention and thereforealso blinded during assessment of the out-come

Chittacharoen 2003

Methods Parallel randomised controlled trial computer-generated random numbers in sealedopaque envelopesDepartment of Obstetrics and Gynaecology Ramathibodi Hospital Bangkok Thailandbetween July 1999 and June 2001

Participants Women at 16-41 weeksrsquo gestation with intrauterine fetal death subgroup analysis ongestational age 16-22 weeks available

Interventions Group A (n = 40) 2 tablets of 200 mcg of misoprostol orally The progression of labourwas evaluated by cervical examination before subsequent dosage at 4-hour intervals untildelivery group B (n = 40) 1 tablet of 200 mcg of misoprostol inserted high in theposterior fornix and a subsequent dose of 200 mcg at 12-hour intervals until delivery

Outcomes Success (complete abortion) within 48 hours



Notes

Risk of bias



Low risk Comment computer-generated randomnumbers in sealed opaque envelopes

Allocation concealment (selection bias) Low risk Comment sealed opaque envelopes


Low risk Comment outcomes were presented for all80 patients



Chittacharoen 2003 (Continued)

Selective reporting (reporting bias) Low risk Comment no signs of selective reportingal outcomes mentioned in the methods sec-tion were presented in the results section



High risk Comment due to the nature of thetreatment (medication orally vs vaginally)blinding is difficult probably not done


High risk Comment no description of blinding onoutcome no statement that the doctorassessing the outcome was another per-son than the one randomising the patientProbably not done

Creinin 1997

Methods Sealed numbered sequential envelopes containing instructions based on computer-gen-erated random number table Department of Obstetrics Gynecology and ReproductiveSciences University of Pittsburgh School of Medicine Magee-Womens Hospital Pitts-burgh Pennsylvania no information on study duration

Participants 20 women with non-viable pregnancies diagnosed by transvaginal ultrasound lt 9 weeksclosed cervix no contra-indication to misoprostol no heavy bleeding

Interventions 400 mcg misoprostol orally repeated after 24 hours if the pregnancy had not beenexpelled (n = 12) vaginal misoprostol 800 mcg - repeated after 24 hours if necessary (asabove) (n = 8) Surgical evacuation offered to women in both groups after 48 hours iftreatment unsuccessful

Outcomes Miscarriage pain (visual analogue scale) side effects

Funding Supported by a grant from the Magee Womenrsquos Health Foundation


Notes Pilot study

Risk of bias



Low risk Quote ldquoRandomization was performed us-ing a computer-generated random numbertable to account for 25 patientsrdquoComment adequate type of random se-



Creinin 1997 (Continued)

quence generation

Allocation concealment (selection bias) Low risk Quote ldquoThe group was assigned by open-ing the next sequentially numbered sealedopaque envelope Randomization and en-velope preparation were performed by aperson not directly associated with thestudyrdquoComment adequate type of allocation con-cealment


Low risk Comment there is no description of miss-ing data other than for 2 patients bHCGlevel was missing (which was not the pri-mary outcome)

Selective reporting (reporting bias) Unclear risk Quote rsquoTwo subjects in group 1 upon re-view did not appropriately meet the ultra-sound criteria for early pregnancy failurersquoComment apart from these 2 excluded pa-tients there might have been selective re-porting in the methods section is statedthat side effects were measured but nofurther specification In the results sectionnausea vomiting and diarrhoea were pre-sented unclear whether these were all out-comes that were measured



High risk Quote ldquoNeither the clinician nor the pa-tient was blinded to the treatment grouprdquoComment due to the nature of the inter-ventions blinding was practically impossi-ble but not blinding might have influencedoutcome


High risk Comment no information on blinding ofoutcome assessment probably not done

Dehbashi 2016

Methods Randomised clinical trial April 2014-Nov 2014 in Amiralmomenin hospital in Zabolcity (Iran)

Participants Women in first trimester admitted for pregnancy termination because of fetal IUFD ormissed abortion



Dehbashi 2016 (Continued)

Interventions Sublingual misoprostol 400 mcg repeated every 4 hours max 5 times (n = 25) vaginalmisoprostol 400 mcg repeated every 4 hours max 5 times (n = 27)

Outcomes Complete miscarriage lt 24 hours secondary outcomes side effects like nausea diarrhoea


Declarations of interest The authors report no conflict of interest related to this paper

Notes

Risk of bias



Unclear risk Quote rdquorandomly assigned because ofsmall sample size block randomization wasperformed according to the time of admis-sionldquo

Allocation concealment (selection bias) Unclear risk Quote rdquoSingle blind allocation and inter-vention were conducted by a nurserdquo


High risk Comment in sublingual group 1 of thepatients did not respond to medical abor-tion that underwent curettage surgery andwas thus excluded Another one had severeabdominal pain that was also excluded be-cause on intolerability

Selective reporting (reporting bias) Unclear risk Quote ldquoIn sublingual group one of thesubjects did not respond to medical abor-tion that underwent curettage surgery andwas thus excluded Another one had severeabdominal pain that was also excluded be-cause on intolerabilityrdquo



High risk Comment blinding was not performedDue to the nature of the intervention blind-ing was difficult the only way to achievethis would have been to give the rsquosublin-gual misoprostol grouprsquo vaginal placebosand vice versa

Blinding of outcome assessment (detectionbias)

High risk Comment blinding of outcome assess-ment is not described




All outcomes

Demetroulis 2001

Methods Randomisation by opening sealed opaque envelope containing computer-generated al-location code number No attempt at masking given the manifest differences betweenmedical and surgical interventionsNewham General Hospital no information on study duration

Participants 80 women with incomplete miscarriage or anembryonic pregnancy or missed miscarriagelt 13 weeks diagnosed by ultrasound The data in this review are derived only fromthe subgroup with non-viable pregnancies (n = 50) and not those with incompletemiscarriages Women were reviewed 8-10 hours after medical treatment if they hadempty uteruses on ultrasound examination they were discharged home if not surgicalevacuation was arranged

Interventions Vaginal misoprostol 800 mcg once only (n = 26) vs surgical evacuation of the uterus (n= 24)

Outcomes Need for surgical evacuation symptoms including pain and bleeding rsquosatisfactionrsquo



Notes Authors contacted for information on outcomes according to indication for treatmentOnly usable data currently available are on incidence of surgical evacuation

Risk of bias



Low risk Comment computer-generated numbers

Allocation concealment (selection bias) Low risk Comment use of sealed opaque envelopes


Low risk Comment no missing data it seems thatall patients completed the study

Selective reporting (reporting bias) Low risk Comment no signs of selective reporting94 patients were counselled 14 declinedstudy participation and chose surgical evac-uation All outcome measures mentionedin the methods section were reported in theresults section




Demetroulis 2001 (Continued)


High risk Quote ldquoNo attempt was made to concealthe intervention assignment schedule fromthe patients or clinicians as the treatmentmethods for the study and control were ob-viously different () No attempt was madeto mask the intervention as the study com-pared a medical treatment with a surgicalprocedurerdquoComment this might have influenced(perception of ) outcome


High risk Comment not performedQuote ldquoNo attempt was made to mask theintervention as the study compared a med-ical treatment with a surgical procedurerdquo

Egarter 1995

Methods Women quote ldquorandomly assignedrdquo no detailsDepartment of Gynecology and Obstetrics University of Vienna no information onstudy duration

Participants 87 women in Austria with non-viable pregnancies between 8 and 12 weeks diagnosedby ultrasound

Interventions Vaginal gemeprost 1 mg every 3 hours up to maximum of 3 mg daily for 2 days (n = 43)vs uterine curettage (n = 44)

Outcomes Need for surgical curettage Adverse effects



Notes

Risk of bias



Unclear risk Comment no information on randomsequence generation other than rsquopatientswere randomly assignedrsquo




Egarter 1995 (Continued)


Low risk Comment all patients that were ran-domised completed the study for all ran-domised patients outcome was presented

Selective reporting (reporting bias) Unclear risk Comment no clear description of primaryand secondary outcomes in methods sec-tion unclear what precise outcome mea-sure was Several outcomes were presentedin the results section unclear if this was allthat was measured Furthermore it is un-clear how it was measured



High risk Comment not mentioned probably notdone



Eng 1997

Methods Randomised by quote ldquoblindly picking a sealed number from a boxrdquo Treatment alloca-tion was then based on whether the number was odd or evenHospital Kuala Lumpur Malaysia June 1995 to January 1996

Participants 50 women with IUFD at 13-26 weeks of pregnancy

Interventions Vaginal misoprostol 200 mcg 3-hourly up to a maximum dose of 1200 mcg (n = 25) vsvaginal gemeprost 1 mg 3-hourly up to a maximum dose of 5 mg (n = 25)

Outcomes Main outcome quote ldquotreatment failurerdquo defined as failure to miscarry within 24 hoursor side effects severe enough to preclude use of additional dose of drug



Notes

Risk of bias




Eng 1997 (Continued)


High risk Quote ldquoRandomization was carried out byblindly picking a sealed number from a boxOdd numbers were assigned to group A(misoprostol) and even numbers to groupB (gemeprost)rdquoComment no information on who put thenumbers in the box

Allocation concealment (selection bias) Unclear risk Comment inadequate allocation conceal-ment a sealed number was picked froma box not clear if the investigators usedopaque envelopes not clear who put thenumbers in the box


Low risk Comment it seems that all 50 patientscompleted the study

Selective reporting (reporting bias) Unclear risk Comment the methods section states thatrsquoside effectsrsquo were measured without fur-ther specification It is unclear whether theside effects that are mentioned in the resultssection were all that were measured



High risk Comment no information on blindingparticipants and personnel probably notdone



Fang 2009

Methods Women with IUFD were randomised into 3 groups Group A (n = 30) vaginal miso-prostol (MP) 04 mg 3 hours before vacuum aspiration group B (n = 30) vaginal MP04 mg every 3 hours up to 5 doses group C (n = 30) oral mifepristone (MF) 200 mg36 to 48 hours before vaginal MP 04 mg MP was given every 3 hours up to 5 dosesThis trial covered women hospitalised for treatment on missed abortion from 20050901 to 20070228

Participants Patients of missed abortion identified via ultrasound a) irregular intrauterine gestationsac in a max diameter gt 20 mm no embryo observed b) impaired intrauterine gestationalsac development gt 1 week c) intrauterine gestational sac gt 6 mm in max diameterembryo visualised without cardiac canal beating 4) Impaired intrauterine gestational sacdevelopment gestational age lt 84 days (12 weeks)



Fang 2009 (Continued)

Interventions Vaginal misoprostol 400 mcg every 3 hours up to 5 doses vs oral mifepristone 200 mg36 to 48 hours before vaginal misoprostol 400 mcg every 3 hours up to 5 doses

Outcomes Complete miscarriage womenrsquos satisfaction



Notes Outcome was only reported for 15 of 30 women receiving vaginal misoprostol treatmentThe other 15 women were excluded from the analysis because emergency curettage wasperformed due to blood loss

Risk of bias



Low risk Quote ldquoWomen enrolled were randomized(computer-generated random numbers)rdquo

Allocation concealment (selection bias) Unclear risk Allocation concealment was not described


High risk Outcome was only reported for 15 of 30women receiving vaginal misoprostol treat-ment The other 15 women were excludedfrom the analysis because emergency curet-tage was performed due to blood loss

Selective reporting (reporting bias) Low risk All outcomes pre specified were reported






Ganguly 2010

Methods Parallel randomised controlled trial Computer-generated random number list Thestudy was conducted at RG Car Medical College and Hospital Kolkata India between1st May 2007 and 30th April 2008



Ganguly 2010 (Continued)

Participants Anembryonic gestation or embryonic or fetal death with CRL 5 mm to 40 mm withoutcardiac activity inevitable miscarriage with gestational sac lt 45 mm or embryonic polelt 40 mm open cervical os and vaginal bleeding

Interventions Intervention 800 mcg misoprostol vaginally (n = 120)Control manual vacuum aspiration under iv sedation (n = 60)

Outcomes Success rate (complete evacuation at day 8) secondary outcomes adverse events (haem-orrhage cervical tearperforation fever nausea diarrhoea abdominal pain satisfaction(would use this treatment again)



Notes Subgroup analyses on fetal death and anembryonic gestation available therefore thestudy was included

Risk of bias



Low risk Comment computer-generated randomnumber list

Allocation concealment (selection bias) Low risk Comment opaque sealed envelope


Low risk Comment for all 180 patients outcomewas presented

Selective reporting (reporting bias) Unclear risk Comment in the results section severaloutcome measures are presented that werenot mentioned in the methods section un-clear whether there were more outcomemeasures



High risk Comment there is no information onblinding of participants and personnelDue to the nature of the intervention blind-ing would have practically be impossi-ble However especially the secondary out-comes (experience of pain and satisfactionamong the non-blinded patients) mighthave been influenced by type of interven-tion





Low risk Quote ldquoOutcome assessors of the studywere blindedrdquo

Gilles 2004

Methods Random allocation by computer-automated telephone response system Stratification bypregnancy type Random permuted blocks of size 4 or 8Participants were recruited from 4 clinical centres between September 2001 and February2002

Participants 80 women with anembryonic pregnancy lt 46 mm sac diameter or embryonicfetal deathwith crown-rump length lt 41 mm 4 centres

Interventions Quote ldquoWet misoprostolrdquo 800 mcg + 2 mL saline vaginally (n = 41) vs ldquodry misoprostolrdquo(as above without saline) (n = 39) Second dose given day 3 if no miscarriage

Outcomes Primary outcome miscarriage without need for curettage before 30 days Secondaryoutcomes miscarriage lt 3 lt 8 and lt 15 days side effects womenrsquos views

Funding Supported by National Institute of Child Health and Human Development NationalInstitutes of Health Department of Health and Human Services under contracts NoN01-HD-1-3321 through 3325

Declarations of interest The following persons and institutions participated in the National Institute for ChildHealth and Human Development Management of Early Pregnancy Failure Trial (princi-pal investigators are indicated by asterisks) J Zhang and T Nansel (National Instituteof Child Health and Human Development) C Westhoff A Davis and C Robilotto(Columbia University) J Gilles J Kang F Doyle and N Vazquez (University of Mi-ami) K Barnhart T Bader and K Timbers(University of Pennsylvania) M Creinin B Harwood R Guido M Fox L Reid(University of Pittsburgh) and M Frederick S Forman and X K Huang (ClinicalTrials and Surveys Corporation)No further information on conflicts of interest

Notes

Risk of bias



Low risk Quote ldquoRandomization was performedwith a computer automated telephone re-sponse system The subjects were stratifiedby pregnancy type with the use of randompermuted blocks of size 4 or 8 The DataCoordinating Center developed the processfor randomizationrdquo



Gilles 2004 (Continued)

Allocation concealment (selection bias) Low risk Quote ldquoThe enrolment sequence was con-cealed from investigatorsrdquoComment adequate allocation conceal-ment


Low risk Comment 2 patients were lost to follow-up (both in group I) from day 15 (accord-ing to table 1) primary outcome was stillmeasured for them before so for primaryoutcome there were no incomplete data

Selective reporting (reporting bias) Unclear risk Comment some outcomes in the resultssection (for example abdominal pain) werenot mentioned in the methods section Un-clear how many secondary outcomes weremeasured



High risk Quote ldquoNeither the investigators nor thesubjects were masked because the additionof saline solution made the interventionsvisibly differentrdquoComment this might have influenced the(perception of ) outcome


High risk Comment no information on blinding ofoutcome assessment considering that in-vestigators and subjects were not maskedfor the intervention this was probably notdone

Graziosi 2004

Methods Consent for study obtained at time of diagnosis of early pregnancy failure Randomisedafter at least 1 week of expectant management Computer programme with block ran-domisation sequence Stratification by previous vaginal birth gestational age lt or gt 10weeks centreThe study was performed in 3 teaching hospitals in the Netherlands (St Antonius Hos-pital Nieuwegein St Elisabeth Hospital Tilburg and Tweesteden Hospital Tilburg) be-tween November2001 and June 2003

Participants 154 women with ultrasound-diagnosed early pregnancy failure - either anembryonicpregnancy or fetal death at 6-14 weeks 6-centre study in the Netherlands

Interventions Vaginal misoprostol 800 mcg repeated after 24 hours if ultrasound indicated remainingtissue in the uterus Curettage after 3 days if miscarriage hadnrsquot occurred or was incom-



Graziosi 2004 (Continued)

plete (n = 79) or suction curettage within a week of randomisation (n = 75)

Outcomes Primary complete evacuation Secondary side effects pain and need for analgesia in-tensityduration of bleeding



Notes Of 241 eligible women 87 (36) declined to participate and chose curettage

Risk of bias



Low risk Comment computer program with a blockrandomisation sequence

Allocation concealment (selection bias) Low risk Quote ldquoRandomization was performed bytheir treating gynaecologist using a com-puter program with a block randomizationsequence thus guaranteeing the conceal-ment of allocationrdquoComment adequate type of allocation con-cealment


Low risk Comment flowchart (fig 1) shows detailedinformation on follow-up of patients Nosigns of incomplete data

Selective reporting (reporting bias) Unclear risk Comment methods section states thatside effects were measured without furtherspecification Unclear whether the side ef-fects that are presented in the results are allthat were measured



High risk Comment no information on blinding ofparticipants and personnel probably notdone considering the type of intervention(medication vs surgical evacuation)


High risk Comment no information on blinding ofoutcome assessment probably not doneconsidering the type of intervention (med-ication vs surgical evacuation)



Herabutya 1997

Methods Quote ldquoRandom allocationrdquo but method not discussed in paperRamathibodi Hospital between March 1995 and April 1996 Bangkok Thailand

Participants 84 women with ultrasound confirmation of fetal death with uterine size lt 14 weeks nobleeding and cervix closed

Interventions Misoprostol (200 mcg vaginally) (n = 42) or vaginal placebo (n = 42) on admission tohospital

Outcomes Primary outcome was miscarriage within 24 hours of treatment Some informationavailable on complications



Notes Much of the outcome data reported describes only the subgroups who did miscarrybefore surgical evacuation

Risk of bias



Unclear risk Comment no information on random se-quence generation



Low risk Comment for all 84 randomised patientsoutcome was presented

Selective reporting (reporting bias) High risk Comment The methods section states thatside effects were registered but they werenot reported in the results Much of theoutcome data reported describes only thesubgroups who did miscarry before surgicalevacuation



Unclear risk Comment no information on blinding ofpatients and personnel Sinces patients re-ceived either misoprostol or placebo it islikely that they were blinded but this is notdescribed



Herabutya 1997 (Continued)


Unclear risk Comment there is no information onblinding of outcome assessment Consid-ering that placebo was used as comparisonthere might have been blinding of the out-come assessor assuming this was not theperson providing the medication (and thuscapable of recognising a placebo if it hadanother shape than the misoprostol)

Jain 1996

Methods ldquoRandom number tablerdquoFrom the Department of Obstetrics and Gynecology University of SouthernCalifornia School of Medicine no information on study duration

Participants 70 women in Los Angeles USA with either fetal death (n = 40) or medical or geneticindications for termination of pregnancy (n = 30) at 12-22 weeks Only data frompregnancies complicated by fetal death included here

Interventions Vaginal misoprostol 200 mcg 12-hourly plus laminaria tents (n = 20) vs vaginal miso-prostol 200 mcg 12-hourly alone (n = 18)

Outcomes Miscarriage



Notes Adverse effects are described for the groups as wholes so are not included here 2 womenexcluded from analyses - 1 protocol violation 1 was found to have interstitial ectopicpregnancy

Risk of bias



Low risk Comment use of a random number table



Low risk Comment outcome was described for all38 patients 2 patients were excluded beforeanalyses (1 protocol violation and 1 foundto have interstitial ectopic pregnancy)



Jain 1996 (Continued)

Selective reporting (reporting bias) Low risk Comment no signs of selective reporting



High risk Comment no information on blinding ofpatients and personnel Due to the natureof the intervention (misoprostol with orwithout laminaria tents) it is unlikely thatthere was blinding


High risk Comment there is no information onblinding of outcome assessment Consid-ering the type of treatment (laminaria tentsor not) it is unlikely that there was blinding

Kara 1999

Methods Quote ldquoRandom allocationrdquo No detailsZeynep Kamil Women and Childrens Hospital Istanbul Turkey No information onstudy duration

Participants 65 women in Istanbul Turkey with ultrasound-diagnosed fetal death in second trimester

Interventions Vaginal misoprostol 200 mcg (n = 32) vs intracervical dinoprostone 05 mg (n = 33)Intravenous oxytocin started after 6 hours if no rsquoeffective contractionsrsquo

Outcomes Complete miscarriage Adverse effects



Notes Misoprostol dose reported as 200 mg Assumed to be 200 mcg Time to miscarriage notincluded as standard deviations seem incorrect

Risk of bias



Unclear risk Comment quote ldquoRandom allocationrdquoNo details



Low risk Comment 65 patients were randomisedfor all of them outcomes were presentedthere seems to be no missing data



Kara 1999 (Continued)

Selective reporting (reporting bias) Low risk Comment misoprostol dose reported as200 mg Assumed to be 200 mcg Otherthan these findings no signs of selective orunclear reporting



High risk Comment no information on blinding ofparticipants and personnel considering thetype of intervention (different number andshape of tablets used) probably not done



Kovavisarach 2002

Methods Quote ldquoRandom allocationrdquo Method not discussedBetween 1 July 1998 and 31 January 1999 at the gynaecologic clinic at Rajavithi HospitalBangkok Thailand

Participants 54 women with anembryonic pregnancies lt 12 weeks diagnosed by TVS Single centrestudy in Bangkok Thailand

Interventions Vaginal misoprostol 400 mcg (n = 27) or placebo (n = 27) Reviewed after 24 hours andcurettage offered if no or incomplete miscarriage Further review after 1 week

Outcomes Primary complete miscarriage within 24 hours of treatment



Notes

Risk of bias



Unclear risk Quote ldquoPatients were randomly allocatedrdquoComment method not discussed




Kovavisarach 2002 (Continued)


Low risk Comment 54 women were recruited in thestudy for all of them outcomes were re-ported

Selective reporting (reporting bias) Unclear risk Comment in the results section several sideeffects (nausea pain) are reported that werenot mentioned in the methods section un-clear if these were the only side effects thatwere measured



Unclear risk Comment no information on blinding ofpatients and personnel Sinces patients re-ceived either misoprostol or placebo it islikely that they were blinded Blinding ofpersonnel that might recognise misopros-tol if the placebo tablets had another shaperemains unclear



Kovavisarach 2005

Methods Random allocation using sealed sequentially numbered envelopes prepared using pub-lished table of random numbersBetween 25 November 2002 and 31 July 2003 Rajavithi Hospital Bangkok Thailand

Participants 114 women in Bangkok Thailand with non-viable pregnancies (anembryonic or fetaldeaths) at lt 12 weeks diagnosed by TVS Women with open cervices were not eligiblefor recruitment

Interventions Vaginal misoprostol 600 mcg (n = 57) or 800 mcg (n = 57) If complete miscarriage noteffected within 24 hours or if clinical circumstances dictated (pain bleeding) uterinecurettage was performed

Outcomes Primary complete miscarriage without need for uterine curettage within 24 hours Sec-ondary adverse effects






Notes

Risk of bias



Low risk Quote ldquoWomen were randomly assignedto either dose of misoprostol using sealedsequentially numbered envelopes that hadbeen prepared using a published table ofrandom numbersrdquo

Allocation concealment (selection bias) Low risk Quote ldquoThe drugs had been placed in theopaque envelopes by a nurse who was notinvolved in any of the other study pro-cessesrdquo Comment adequate type of alloca-tion concealment


Low risk Quote ldquoNo women withdrew from thetrialrdquoComment no signs of incomplete outcomedata

Selective reporting (reporting bias) Low risk Comment no signs of selective reportingvariables that were measured according tothe methods section were presented in theresults section



Low risk Quote ldquoThe drugs had been placed in theopaque envelopes by a nurse who was notinvolved in any of the other study processesAll other staff and patients were blindedto regimen allocationrdquo Group A received 3tablets of misoprostol and 1 placebo groupB received 4 tablets of misoprostol


Low risk Comment staff was blinded to regimen al-location



Kushwah 2009

Methods Parallel group randomised controlled trial Patients were randomly assigned to 1 of 2groups by computer-generated numbers The study was conducted from April 2003to March 2004 with 100 women attending the prenatal clinic of the Department ofObstetrics and Gynecology of Sucheta Kriplani Hospital Delhi India All had earlypregnancy failure confirmed by ultrasound between the 7th and 14th week

Participants The inclusion criteria were (1) a gestational sac of 25 mm in mean diameter or largerwith no embryo present (an anembryonic pregnancy) or (2) the presence of a fetal polewithout cardiacpulsations (a missed abortion)

Interventions Group 1 200 mg mifepristone + 600 mcg misoprostol sublingually with up to 3 sup-plemental doses of 400 mcg after 12 15 and 18 hours (if 4 hours after last dose still noexpulsion surgical evacuation) (n = 50)Group 2 200 mg mifepristone + 600 mcg misoprostol orally with up to 3 supplementaldoses of 400 mcg after 12 15 and 18 hours (if 4 hours after last dose still no expulsionsurgical evacuation) (n = 50)

Outcomes The primary outcome was the mean induction-to-evacuation interval defined as thetime between when the first dose of misoprostol was taken and the time when the POCwere expelled The secondary outcome was the incidence of the 5 following adverseeffects blood loss abdominal pain nausea vomiting diarrhoea and fever Regimenacceptability was defined as whether it would be accepted again if needed



Notes

Risk of bias



Low risk Quote ldquoPatients were then randomly as-signed to one of 2 groups by computer gen-erated numbersrdquo

Allocation concealment (selection bias) Unclear risk Comment no adequate description of theconcealment process


Low risk Comment for all 100 patients outcomeswere presented

Selective reporting (reporting bias) Low risk Comment outcome measures that werementioned in the methods section werepresented in the results section




Kushwah 2009 (Continued)


High risk Comment due to the nature of the in-tervention blinding would be difficult theonly way for blinding both participantsand personnel would be to give group Aoral misoprostol and sublingual placeboand group B oral placebo and sublingualmisoprostol The article does not state thatplacebos were used This might particularlyhave influenced patients experiences thatwere assessed as secondary outcomes



Lelaidier 1993

Methods Drug or identical placebo supplied by pharmacy using randomisation list using permu-tation blocks of 4Department of Obstetrics and Gynaecology Hopital ABeclere Clamart France Studyduration 6 months no further information

Participants 46 women with non-viable pregnancies diagnosed by ultrasound on 2 examinationsseparated by 1 week lt 14 weeks No bleeding or pain

Interventions Mifepristone 600 mg orally (n = 23) or placebo (n = 23) All women were reviewed after5 days and if miscarriage had not occurred surgical evacuation was performed that day

Outcomes Primary outcome was expulsion of the pregnancy Symptoms also recorded



Notes 2 women in the placebo group underwent surgical evacuation by private practitionersbefore 5th day review Both were in the process of miscarriage and were classed asexpulsion positive no information available on symptoms

Risk of bias



Low risk Comment drug or identical placebo sup-plied by pharmacy using randomisation listusing permutation blocks of 4



Lelaidier 1993 (Continued)

Allocation concealment (selection bias) Low risk Comment identical placebo were usedsupplied by pharmacy


High risk Quote rdquoOf the 46 patients included inthis trial two were not included in the re-sults since contradictory advice from pri-vate clinicians ended in regular dilatationand aspiration They both came from theplacebo group and were excluded from thedenominator when calculating percentagesof spontaneous abortionldquoComment this is not an adequate inten-tion-to-treat analysis

Selective reporting (reporting bias) Low risk Comment no signs of selective reportingoutcome measures mentioned in the resultssection were presented in the results section



Low risk Quote rdquoThis study was prospective ran-domized and double-blindrdquoComment adequate blinding by use ofidentical placebo in control group


Low risk Comment no specific information onblinding of outcome assessment Consider-ing that blinding of patients and personnelwas adequate this was probably also done

Lister 2005

Methods Random allocation - blocked and stratified by physician office and by day of recruitment- day of diagnosis or after day of diagnosisPatients were enrolled between February 152002 and March 19 2003 at RiversideMethodist Hospitals Columbus USA

Participants 34 women in Columbus Ohio USA with early pregnancy failure (anembryonic preg-nancies or early fetal deaths) diagnosed by TVS

Interventions Vaginal misoprostol 800 mcg repeated after 24 hours if sac still present on TVS (n =18) or placebo (n = 16)

Outcomes Primary miscarriage complete at 48 hours

Funding Supported by Riverside Methodist Hospital Medical Research Foundation



Lister 2005 (Continued)


Notes Planned sample size 84 but trial stopped after interim analysis of first 36 women 2women excluded from analysis - 1 protocol violation 1 did not meet entry criteria 2women did not come for assessment 2 weeks after initial treatment

Risk of bias



Low risk Quote ldquoThe study epidemiologist gener-ated the allocation sequence Randomiza-tion to misoprostol or placebo was blockedand stratified by physician office and tim-ing of treatment in relation to diagnosis (onthe day of diagnosis or 1-14 days after di-agnosis)rdquo

Allocation concealment (selection bias) Low risk Comment opaque randomisation packetswith instruction sheets and either miso-prostol or matching placebo


Low risk Comment 2 patients withdrew consent be-fore treatment These were not includedin the analyses All other 34 patients wereanalysed

Selective reporting (reporting bias) Unclear risk Comment table 3 shows side effects thesewere not mentioned in the methods sec-tion Unclear whether these were all the sideaffects that were measured



Low risk Comment physicians randomising andtreating the patients received opaque ran-domisation packets containing misoprostolor matching placebo


Low risk Comment not described but consideringthe treating physician was blinded for inter-vention blinding of outcome assessmentwas probably also done



Marwah 2016

Methods Governmental multi-speciality hospital Chandigarh India from June 2013-June 2014

Participants Women aged 18-45 gestational age lt 12 weeks diagnosis of missed abortion on ultra-sound minor vaginal blood loss but cervical os closed Haemoglobin level gt= 9 mgdLaxillary temperature lt 375 degree C no history of inflammatory bowel disease asthmaliver disease or contraindication to use of misoprostol place of residence within 100 kmfrom of the hospital willingness and ability to give informed consent willingness toabstain from intercourse for first 14 days of study

Interventions 400 mcg vaginal misoprostol (wet preparation) every 6 hours max 3 doses (n = 50) 400mcg oral misoprostol every 6 hours max 3 doses (n = 50)

Outcomes No need for surgical evacuation (AP diameter lt 15 mm) lt 12 hours after last dose ofmisoprostol

Funding Financial interests none

Declarations of interest Other competing interests none

Notes

Risk of bias



Low risk Quote ldquorandomly assigned to one of thetwo regimens using computer generatedsequentially numbered envelopesrdquo

Allocation concealment (selection bias) Low risk Quote ldquosequentially numbered envelopesrdquo


Low risk Comment data of all included womenwere presented

Selective reporting (reporting bias) Low risk Comment no signs of selective reportingdata of all included women were presented



High risk Comment due to the nature of the inter-vention blinding would have been very dif-ficult and would only be achieve by usingoral placebos for the rsquovaginal grouprsquo andvice versa


High risk Comment blinding of outcome assessorwas not described



Mitwaly 2016

Methods Randomised controlled trial Assiut womenrsquos health hospital Egypt 1 Feb 2015-1 Dec2015

Participants Women 13-24 weeks of gestation with IUFD confirmed by ultrasound

Interventions Intrauterine extra-amniotic misoprostol 200 mcg in saline dissolute solution adminis-tered through Foley catheter per 4 hours (n = 90) vaginal misoprostol 200 mcg (wetpreparation) every 4 hours (n = 90)

Outcomes Induction to (fetal) expulsion intervalSecondary dose of misoprostol used need for analgesics and need for surgical evacuationin cases of retained placenta and occurrence of side effects


Declarations of interest The authors declare that they have no conflict of interest

Notes

Risk of bias



Low risk Quote ldquoA statistician prepared a computergenerated random tablerdquo

Allocation concealment (selection bias) Low risk Quote ldquoplaced the allocation data inserially numbered sealed envelopes Theenvelopes opened only by the clinicianaccording to the order of attendance ofwomen Allocation unchanged after open-ing the closed envelopesrdquo


Low risk Comment all data on randomised womenwere available

Selective reporting (reporting bias) Low risk Comment there are no signs of selectivereporting all pre described outcomes werepresented in results



High risk Comment due to the nature of the inter-vention blinding of personnel nor partici-pants was possible





Mizrachi 2017

Methods Randomised controlled trial single university affiliated tertiary medical centre betweenAugust 2015 and June 2016

Participants Women diagnosed with early pregnancy loss in the gynaecologic emergency room eitheranembryonic gestation or embryonic death were eligible for inclusion if pregnancy sizeby TVS was up to 12 weeksrsquo gestation

Interventions 800 mcg vaginal misoprostol + 800 mcg vaginal misoprostol on day 4 (n = 84) 800 mcgvaginal misoprostol (n = 87)

Outcomes The primary outcome was treatment success defined as no need for surgical interventionup to Day 8 This included emergent and elective surgical interventions Secondaryoutcomes were adverse effects pain level OTC analgesics use treatment acceptabilityand the need for late intervention as reported by the participants by telephone on day45

Funding The authors did not receive funding for this study

Declarations of interest The authors declare no conflict of interest

Notes

Risk of bias



Low risk Quote ldquosubjects were randomly assignedto either a single-dose protocol or a re-peat-dose protocol in a 11 ratio A blockedrandomization scheme was created using acomputer generated list of random num-bers Each block consisted of 30 partici-pantsrdquo

Allocation concealment (selection bias) Low risk Quote ldquoTreatment allocation was con-cealed by placing assignments in sequen-tially numbered opaque envelopesrdquo


Low risk Comment flow chart displays all outcomedata available Missing data are explained

Selective reporting (reporting bias) Low risk Comment no signs of selective reportingall outcomes described are presented in re-sults




Mizrachi 2017 (Continued)


High risk Comment due to the nature of the inter-vention blinding would be difficult


High risk Comment blinding of outcome assessor isnot described

Muffley 2002

Methods Computer-generated random number table with blocked permutations - group assign-ments recorded in sealed opaque numbered envelopesThis clinical study was conducted between June 1999 and March 2000 at Naval MedicalCenter Portsmouth

Participants 50 women with non-viable pregnancies diagnosed by ultrasound (anembryonic or em-bryonicfetal deaths) lt 12 weeks Exclusions excessive bleeding anaemia unstable vitalsigns coagulopathy asthma or other contra-indication to prostaglandin treatment in-fection open cervix

Interventions 800 mcg misoprostol vaginally repeated after 24 hours if ultrasound showed tissue stillpresent in uterus final review after further 24 hours - if tissue still present surgicalevacuation performed (n = 25) Suction curettage (n = 25)

Outcomes Primary outcome miscarriage

Funding Supported by the Chief Navy Bureau of Medicine and Surgery Washington DC ClinicalInvestigation Program (CIP No 99-037)

Declarations of interest The views expressed in this article are those of the authors and do not reflect the officialposition of the Department of Defense the Department of the Navy or the UnitedStates Government

Notes Analysis by intention-to-treat Details about nausea vomiting diarrhoea reported onlyfor misoprostol group

Risk of bias



Low risk Comment use of computer-generated ran-dom number table with blocked permuta-tions

Allocation concealment (selection bias) Low risk Commentgroup assignments were recorded in sealedopaque numbered envelopes



Muffley 2002 (Continued)


Low risk Quote rsquoldquoTwenty-five women were placedrandomly in the medical arm of the studyand 25 women were placed randomly inthe surgical arm 2 patients in the surgicalarm had spontaneous pregnancy loss be-fore their scheduled procedures All but 2of the subjects had a complete post proce-dure evaluationrdquoComment this means a loss to follow upof lt 10

Selective reporting (reporting bias) Unclear risk Comment in the results section there arereports about nausea vomiting and haem-orrhage These side effects were not men-tioned in the methods section Unclearwhether these were all the side effects thatwere measured



High risk Comment randomisation and envelopepreparation was performed by a personnot directly associated with the studyHow-ever due to the nature of the interventions(medication vs surgical evacuation) blind-ing would be practically impossible and wasprobably not done


High risk Comment there is no information onblinding of outcome assessment Probablynot done

Ngoc 2004

Methods Randomised by opening sequentially numbered envelope - prepared by computer-gen-erated code in blocks of 10Recruitment took place at Hung Vuong Hospital in Ho Chi Minh City Vietnam fromJanuary through August 2003

Participants 200 women in Ho Chi Minh City Vietnam with non-viable first trimester pregnancies(anembryonic or early fetal death) diagnosed by ultrasound cervix closed

Interventions Oral misoprostol 800 mcg (n = 100) vs vaginal misoprostol 800 mcg (n = 98) Womenreviewed after 48 hours if retained products present they were given option of surgicalevacuation or further review after another 5 days (when evacuation was performed ifthere were still products present)



Ngoc 2004 (Continued)

Outcomes Primary complete miscarriage without need for surgical evacuation Secondary adverseeffects

Funding Funding by David and Lucile Packard Foundation


Notes 2 women lost to follow-up

Risk of bias



Low risk Comment the randomisation scheme wascreated by Population Council staff usinga computer-generated code in blocks of 10

Allocation concealment (selection bias) Low risk Quote ldquoThe study investigator opened thenext sequentially numbered randomizedenvelope to determine the treatment armrdquo


Unclear risk Quote ldquoTwo women in the vaginal groupand one in the oral group were lost to fol-low-up One woman in the vaginal groupwas later reached by telephonerdquoComment table 2 shows side effects for190 patients (not 200 patients) so there aresome missing data This was lt 10 of totalstudy population

Selective reporting (reporting bias) High risk Comment in table 2 side effects were pre-sented for 95 patients per treatment armwhich is a sign of missing data Analysesfor these side effects were measured as anpercentage of 95 women instead of 100women This influences the outcomes



High risk Quote ldquoNeither the investigator nor thewoman was blinded to the treatment as-signmentrdquoComment due to the nature of the inter-ventions (oral vs vaginal medication) blind-ing would have been difficult Nonethelessthis might have influenced (perception of )outcome





High risk Comment no blinding of outcome assess-ment

Nielsen 1999

Methods Randomisation method not discussed in paperSahlgrenska University Hospital Sweden No information on study duration

Participants 122 women lt 13 weeks with symptoms of threatened miscarriage (bleeding +- pain) aclosed cervix and ultrasound demonstration of pregnancy non-viability (anembryonicpregnancy n = 44 embryonicfetal death n = 46 rsquocomplex mass with deformed gestationalsacrsquo n = 32) Surgical evacuation at day 5 if transvaginal ultrasound showed retainedproducts gt 15 mm diameter

Interventions Mifepristone (400 mg orally) followed by oral misoprostol (400 mcg) 48 hours later (n= 60) vs expectant management (n = 62)

Outcomes Clinical events routine transvaginal ultrasound at 5 days to identify retained productsvisual analogue scale to assess pain at day 5 visual analogue scale to assess satisfaction atday 14



Notes Seeking clarification from authors if ldquocomplex mass with deformed gestational sacrdquorepresents missed or incomplete miscarriage Data included in meantime

Risk of bias



Unclear risk Comment randomisation method not dis-cussed in paper



Low risk Comment no loss to follow-up no signsof missing data





Nielsen 1999 (Continued)


High risk Comment article does not state that inthe expectant management group placebowere used Therefore there probably was noblinding of participants and personnel



Niromanesh 2005

Methods Randomisation method not discussed in paperMirza Khochak khan Hospital Tehran Iran No information on study duration

Participants 100 women in Tehran Iran with fetal deaths between 14 and 25 weeks

Interventions Vaginal misoprostol 400 mcg (n = 50) vs 600 mcg (n = 50) - both 12-hourly for 48hours

Outcomes Miscarriage surgical evacuation adverse effects



Notes

Risk of bias






Unclear risk Comment no information on loss to fol-low up number of eligible patients etcetera

Selective reporting (reporting bias) Unclear risk Comment side effects mentioned in theresults (table 2) were not mentioned in themethods section unclear if these were alloutcomes that were measured




Niromanesh 2005 (Continued)


High risk Comment no information on blindingalso no statements on use of placebo Prob-aby no blinding (since the difference be-tween 2 or 3 tablets would be clear for bothpatients as well as personnel



Petersen 2013

Methods This was a parallel group randomised controlled study performed between September2005 and July 2010 at 2 hospitals in Australia Randomisation was performed using acomputer-generated model with a block size of 6 stratified for study site

Participants Inclusion criteriaClinically confirmed early pregnancy loss 6 + 0 and 12 + 6 weeksrsquo gestationHaemodynamically stable and not requiring emergency treatmentWillingness and consenting to undergo medical managementReady access to emergency medical care (lives within 30 minutes of hospital)Immediate availability of another responsible adult with a driverrsquos licenseAbility to understand spoken English instructions without the need of a translator

Interventions Intervention 400 mcg (n = 158) vaginal misoprostol if needed repeated the next day vs800 mcg (n = 152) vaginal misoprostol if needed repeated the next day

Outcomes Outcomes the primary outcome was the effectiveness to induce complete miscarriageevaluated using 2 different methods1 Ultrasound criteria complete = no gestational sac + an endometrial thickness lt 30 mmon day 7 scan incomplete = gestational sac or endometrial thickness gt 30 mm32 Clinical criteria resolution of bleeding and pain and return to a normal menstrualcycle without the need for DampC at the completion of follow-upSecondary outcomes included patient satisfaction and clinical outcomes - need for seconddose patient-reported side effects recorded in Study Questionnaire 1 adverse eventsunplanned visits to a doctor or hospital Emergency Department fall in haemoglobinfrom baseline

Funding Completion of this study was supported in part by a grant from the Toowoomba HospitalFoundation

Declarations of interest The authors have nothing to declare

Notes

Risk of bias




Petersen 2013 (Continued)


Low risk Comment randomisation was performedusing a computer-generated model with ablock size of 6 stratified for study site

Allocation concealment (selection bias) Low risk Comment allocation to the study groupswas made by opening the next consecu-tively numbered sealed


Low risk Comment data on incomplete follow-upare provided in figure 2 (participation flowchart)

Selective reporting (reporting bias) Unclear risk Comment methods section states that ad-verse events were measured without furtherspecification It is unclear if the outcomesmentioned in table 3 were all that weremeasured



High risk Comment the allocated dose was recordedin the medication chart and administeredby the non blinded attending staff The al-located dose was not revealed to the studypopulation (although they would probablynotice the difference between 2 or 4 tablets)


High risk Comment the allocated dose was recordedin the medication chart and administeredby the non-blinded attending staff This at-tending staff seems to also have performedthe ultrasounds after treatment

Rita 2006

Methods Parallel randomised controlled trial permuted block method randomisation This studywas carried out in the department of obstetrics and gynaecology SMGS Hospital Gov-ernment Medical College Jammu JampK in the year 2002-2003

Participants A total of 100 women consented to participate in the study The specified inclusioncriteria were a period of gestation less than 13 weeks haemodynamically stable womenwith haemoglobin more than 10gm closed cervical os axillary temperature of less than3750 C no previous history of inflammatory bowel disease or allergy to misoprostol

Interventions Intervention 400 mcg of misoprostol was given orally and repeated every 4 hours for amaximum of 3 doses if required (n = 50)Control 600 mcg of misoprostol was inserted in posterior vaginal fornix and the seconddose was repeated after 4 hours (n = 50)



Rita 2006 (Continued)

Outcomes The primary outcome evaluated was drug-induced complete expulsion of the conceptus(within 10-12 hours)Secondary outcome evaluated were side effects induction expulsion interval number ofdoses required and permeability of cervical canal in those women who required surgicalevacuation



Notes

Risk of bias



Unclear risk Comment method of randomisation otherthan permuted block method not men-tioned

Allocation concealment (selection bias) Unclear risk Comment allocation concealment is notdescribed


Unclear risk Comment no mentioning of missing data

Selective reporting (reporting bias) Unclear risk Comment methods section states thatside effects were measured without furtherspecification It is unclear if the outcomesmentioned in the results section were all theoutcomes that were measured



High risk Comment due to the nature of the inter-vention (oral vs vaginal medication) blind-ing of participants and personnel would bevery difficult


High risk Comment there is no description of an in-dependent doctor assessing the outcome



Saichua 2009

Methods Parallel randomised controlled trial Randomisation scheme was generated using a ran-dom number table This RCT was performed at Department of Obstetrics and Gyne-cology Faculty of Medicine Chulalongkorn University Bangkok Thailand from June2007 to May 2008

Participants Pregnant women withmiddot13 weeks of gestation who came to antenatal care clinic or gy-naecologic outpatient department diagnosed with embryonic death or anembryonicpregnancy by transvaginal ultrasound were recruited into the study Embryonic deathwas defined as an intrauterine pregnancy with a fetal pole longer than 6 mm withoutcardiac activity Anembryonic pregnancy was defined as an intrauterine gestational sacof diameter more than 20 mm without embryonic pole or yolk sac

Interventions Intervention 600 mcg powdery sublingual misoprostol (n = 26)Control 600 mcg sublingual misoprostol (n = 28)

Outcomes The primary outcome measure was complete abortionThe secondary outcome measure was the duration of complete abortion and side effects


Declarations of interest rsquoConflicts of interest statement nonersquo

Notes

Risk of bias



Low risk Quote ldquoRandomization scheme was gen-erated using a random number table Theco investigator generated the allocation se-quence and study staff enrolled partici-pants and assigned participants to theirgroups When a woman met the studyinclusion criteria the study staff pickeda sequentially numbered opaque envelopewhich contained a ticket indicating treat-ment grouprdquo

Allocation concealment (selection bias) Low risk Quote ldquoThe co investigator generated theallocation sequence and study staff en-rolled participants and assigned partici-pants to their groupsrdquoComment study staff assigned patients to agroup by picking a sequentially numberedopaque envelope Adequate type of alloca-tion concealment



Saichua 2009 (Continued)


Low risk Comment according to the flowchart therewere no patients lost to follow up further-more there were no patients who discon-tinued the intervention

Selective reporting (reporting bias) High risk Comment the methods section states thata specific outcome (headache) was mea-sured however this was not reported in theresults section



High risk Quote ldquoNeither the provider nor thewoman was blinded to the treatment regi-mensrdquo


High risk Comment no information on blindingof outcome assessment considering theprovider was not blinded also outcome as-sessment was probably not blinded

Schreiber 2018

Methods Parallel multi-centre randomised controlled trial

Participants Women with an anembryonic pregnancy embryonic or fetal death with a gestationalage between five and 12 weeks

Interventions 200 mg of mifepristone administered orally followed by 800 mcg of misoprostol ad-ministered vaginally (mifepristone-pretreatment group) or 800 mcg of misoprostol aloneadministered vaginally (misoprostol-alone group)

Outcomes Treatment success (defined as complete expulsion without the need of additional vacuumaspiration within 30 days after treatment)Secondary outcomes reported were rate of vacuum aspiration blood transfusion pelvicinfection side effects of medication such as nausea diarrhoea headache and fever

Funding Supported by the National Institute of Child Health and Human Development of theNational Institutes of Health (Eunice Kennedy Shriver award number R01-HD0719-20 [to Dr Schreiber] and Womenrsquos Reproductive Health Research award number K12-HD001265-18 [to Dr Sonalkar])

Declarations of interest Dr Creinin reports receiving consulting fees from Danco Laboratories No other poten-tial conflict of interest relevant to this article was reported

Notes

Risk of bias



Schreiber 2018 (Continued)



Low risk Quote ldquoParticipants were randomly as-signed in permuted blocks of two to eightstratified according to trial site with the useof Research Electronic Data Capture soft-warerdquo

Allocation concealment (selection bias) Low risk Quote ldquoParticipants were randomly as-signed in permuted blocks of two to eightstratified according to trial site with the useof Research Electronic Data Capture soft-warerdquo


Low risk Comment 2 women lost to follow-up inintervention arm 1 in the control arm For2 women reasons for lost to follow-up werenot mentioned In 1 women there was a sus-picion of caesarean section scar pregnancy

Selective reporting (reporting bias) High risk Quote ldquoassessments of quality of life costsand biomarkers that predict complete ges-tational sac expulsion were performed butthe data are not presented hererdquoIt is not mentioned if these outcomes areor will be presented elsewhere

Other bias Low risk No other bias could be detected


High risk Comment no placebo was used thereforeblinding was not possible for both person-nel and participants


Low risk At the initial follow-up visit an investigatorwho was unaware of the treatment-groupassignments assessed the outcome by meansof endovaginal ultrasonography

Shah 2010

Methods This was a prospective randomised open-labelled trial conducted in the Departmentof Obstetrics and Gynaecology Unit-III at Civil Hospital Karachi No information onstudy duration

Participants The inclusion criteria was an ultrasound diagnosis of missed miscarriage lt 20 weeksrsquogestation



Shah 2010 (Continued)

Interventions Intervention (n = 25) 400 mcg of misoprostol sublingually every 3 hours for a maximumof 5 doses Patients having a gestational age of more than 12 weeks whose uterine sizewas also more than 12 weeks were given 200 mcg of misoprostol instead of 400 mcg inboth sublingual and vaginal groupsControl (n = 25) 400 mcg of misoprostol vaginally every 3 hours for a maximum of 5doses Patients having a gestational age of more than 12 weeks whose uterine size wasalso more than 12 weeks were given 200 mcg of misoprostol instead of 400 mcg in bothsublingual and vaginal groups

Outcomes The primary outcome measures were complete evacuation of POC mean induction todelivery time and the occurrence of side effects



Notes

Risk of bias



Unclear risk Comment article states the study was arandomised controlled trial however thereis no information on type of random se-quence generation

Allocation concealment (selection bias) Unclear risk Comment allocation was concealed usingsealed envelopes though depending on therandomness allocation might have beenpredictable


Low risk Comment outcomes are presented for all50 patients

Selective reporting (reporting bias) Unclear risk Comment there seems to be no loss to fol-low-up or incomplete data outcomes werereported for all 50 patients Table 3 showsrsquoside effectsrsquo without further specificationunclear which side effects were measured



High risk Comment there is no information onblinding in the article Due to the natureof the interventions (sublingual vs vaginalmedication) blinding would be difficult





High risk Comment outcome seems not to be as-sessed by an independent doctor

Sinha 2018

Methods This study was a parallel double-blind RCT conducted at University College of MedicalSciences and Guru Teg Bahadur Hospital Delhi from October 2011 to April 2013

Participants Women with early pregnancy failure lt 12 weeks of gestation

Interventions women were randomised to 200mg of oral mifepristone or placebo 48 Hours later800mcg of vaginal misoprostol and if necessary 400 mcg misoprostol were given orallyat 3-hourly interval to a maximum of 2 doses in women lt 9 weeks by scan and 4 dosesin women gt 9 weeks by scan similarly in both groups

Outcomes Primary outcome was complete expulsion within 14 days after start treatment Treatmentsuccess was defined as not needing any surgical interventionSecondary outcomes were the need for surgical intervention due to heavy bleeding orincomplete expulsion by day 14 Other secondary outcomes were nauseavomitingbleeding and treatment acceptability

Funding no funding was mentioned

Declarations of interest It was stated there were no conflicts of interest

Notes

Risk of bias



Low risk Quote ldquosealed packets were numberedfrom 1 to 92 by simple randomization us-ing computer generated random tablesrdquo

Allocation concealment (selection bias) Low risk Quote ldquoThe third party used to dispensethe coded sealed packet to the treating ob-stetricianrdquo


Low risk Comment there was one participant lostto follow-up in both groups

Selective reporting (reporting bias) Low risk Comment all pre-defined outcome mea-sures were reported in the results section




Sinha 2018 (Continued)


Low risk Comment this was a placebo-controlleddouble-blind trial The placebo consistedof tablets of 500 mg calcium who weresimilarly looking to the tablets of 200 mgmifepristone Blinding seems adequate


Low risk Comment the outcome was assessedblinded since both caregiver and partici-pant were blinded for the intervention

Sonsanoh 2014

Methods A prospective randomised trial was done to 120 healthy pregnant women with earlypregnancy failure from August 2012 to August 2013 at the Department of Obstetricsand Gynecology Chonburi Hospital Thailand

Participants Women with early pregnancy failure defined as 1) an intrauterine gestational sac witha mean diameter of 25 mm or greater and no visible embryonic pole 2) an embryonicpole of 5 mm to14 mm with no cardiac activity and 3) abnormal growth or persistentabsence of fetal cardiac activity on a second scan 7-10 days later(16) In addition allparticipants should be over 18 years old

Interventions In Group 1 (n = 60) they were given 4 tablets of 200 mcg misoprostol with 2-3 dropsof normal saline placed in the posterior vaginal fornix by digital insertionIn Group 2 (n = 60) 4 tablets of 200 mcg misoprostol were sublingually given

Outcomes Complete abortion defined as the termination of pregnancy with the complete expulsionof conceptus without the need for surgical intervention or additional misoprostol doseIf the complete abortion did not occur the repeated induction in the same route wouldbe done every 6 hours for maximum of 3 doses The treatment was considered a failureif the pregnancy was still continuing after 48 hours from the third dose of misoprostolFurthermore adverse effects were measured


Declarations of interest The authors do not have any conflict of interest

Notes

Risk of bias



Unclear risk Quote ldquoWe used and assigned blocks offour randomizations to two groups of par-ticipantsrdquoComment This does not state how the ran-domisation list was created



Sonsanoh 2014 (Continued)

Allocation concealment (selection bias) Low risk QuoteldquolsquoCards labelled with the assignedroute were placed in sealed opaque en-velopes which were filled and labelled inaccordance with the list of randomizationsThe allocation was concealed by the use ofsealed number of treatmentsrdquo


Low risk Comment according to table 2 all 120 pa-tients randomised completed the study 19patients did not have complete abortiontherefore in table 3 (time-to-delivery inter-val) only 50 and 51 patients in each groupare described This does make sense

Selective reporting (reporting bias) Low risk Comment there are no signs of selec-tive outcome reporting All outcomes men-tioned in the methods section were pre-sented in the results section



High risk Comment blinding is not described Dueto the nature of the intervention (vaginal vssublingual medication) blinding would bedifficult nonetheless this might have influ-enced (perception of ) outcome


High risk Comment the article does not state thatoutcome assessors were blinded

Tang 2003

Methods Randomisation by quote ldquocomputer-generated random numbersrdquoQueen Mary Hospital Hong Kong SAR China No information on study duration

Participants 80 women with non-viable pregnancies diagnosed by ultrasound lt 13 weeks

Interventions Group 1 600 mcg misoprostol sublingually every 3 hours for maximum of 3 doses (n= 40) group 2 600 mcg misoprostol vaginally every 3 hours for maximum of 3 doses(n = 40) Women discharged home after completion of treatment and reassessed day 7 -when surgical evacuation performed if gestation sac still present or retained POC plusheavy bleeding

Outcomes Primary outcome complete miscarriage (defined as no need for surgical evacuation upuntil return of menstruation)




Tang 2003 (Continued)


Notes

Risk of bias



Low risk Comment computer-generated randomnumbers



Low risk Comment outcomes were presented for all80 patients that were initially randomised

Selective reporting (reporting bias) Unclear risk Comment table 3 shows several side ef-fects The methods section states only thatrsquoside effectsrsquo were measured without furtherspecification It is unclear if other side ef-fects than the ones presented in table 3 werealso measured



High risk Comment no blinding of participantsand personnel Sublingual misoprostol wastaken by the patient itself while vaginalmisoprostol was administered by a researchnurse


High risk Comment no information on blinding ofoutcome assessment Probably not done

Tang 2006

Methods Open parallel RCT Eligible women were randomised according to computer-generatedrandom numbers into 2 groups The study was carried out from July 2002 to January2004 Queen Mary Hospital Hong Kong SAR China

Participants Women with (i) intrauterine gestational sac with a mean sac diameter of ge 2 cm withouta fetal pole (ii) presence of a fetal pole with no cardiac pulsation (iii) the gestational sacwas lt 2 cm with no interval growth or persistent absence of fetal cardiac pulsation onrescanning 7-10 days later




Interventions Women in both groups (total n = 180) received 600 mcg misoprostol sublingually every3 hours for a maximum of 3 doses (day 1) Additionally women in group 2 (n = 90) alsoreceived 400 mcg misoprostol sublingually daily for a further week (day 2-8)

Outcomes The outcome of the study was assessed on day 9 A transvaginal ultrasound examinationof the pelvis was performed The primary outcome measure was the complete miscar-riage rate The incidence of side effects duration of vaginal bleeding and the change inhaemoglobin level were also studied

Funding The work described in this paper was supported by a grant from the Committee onResearch and Conference Grants of The University of Hong Kong of the Hong KongSpecial Administrative Region China


Notes

Risk of bias



Low risk Quote ldquoEligible women were randomizedaccording to computer-generated randomnumbers into two groupsrdquo



Low risk Comment according to the flowchartthere was no loss to follow up and no miss-ing data

Selective reporting (reporting bias) Unclear risk Comment table 3 shows several side ef-fects The methods section only states thatrsquoside effectsrsquo were measured without furtherspecification It is unclear if the effects men-tioned in table 3 were the only side effectsthat were measured



High risk Quote ldquoThis was an open randomizedstudy and both the subjects and the investi-gators knew the treatment that the womenhad receivedrdquoComment due to the nature of the inter-ventions blinding was practically impossi-ble





High risk Comment there is no information onblinding of outcome assessment availableit seems that outcome was not assessed byan independent doctor

Tanha 2010a

Methods Parallel randomised controlled trial Randomisation using a computer-generated codeRecruitment took place at Mirza Kochak Khan Hospital a premier research and referralfacility in Tehran Iran from January 2005 through to February 2007

Participants (i) intrauterine gestational sac with a mean sac diameter of lt 2 cm without a fetal pole(ii) presence of a fetal pole with no cardiac activity and (iii) gestational sac lt 2 cm withno interval growth or persistent absence of fetal cardiac pulsation on rescanning 7-10days later Additional eligibility criteria included having no known contraindications tomisoprostol general good health and no vaginal bleeding

Interventions Intervention 400 mcg tablets every 6 hours sublingually (n = 110)Control 400 mcg tablets every 6 hours vaginally (n = 110)

Outcomes The primary outcome measure was efficacy of the treatment in inducing complete abor-tion which was defined as passing of the POC without needing vacuum aspiration ordilatation or curettage incomplete abortion as expulsion of the fetus but some POCremaining in the uterus needing evacuation and missed abortion as a gestational sacin the uterus without cardiac activity on ultrasound examination needing emptying ofthe uterus Success rate was defined as no need for surgical intervention If a womanfrom either group did not bleed within 48 hours after completing the protocol shewas requested for a TVS scan If a gestational sac was still found on TVS examinationsurgical evacuation was performedOther outcome measures were side effects recorded 1 hour up to 24 hours after everyadministration of misoprostol at the hospital by women after the treatment until thefirst follow-up visit Side effects were classified as pregnancy-related treatment-relatedand those related to the abortion process itself


Declarations of interest This study is Dr Mohadeseh Feizirsquos postgraduate thesis

Notes

Risk of bias



Low risk Comment using a computer-generatedcode



Tanha 2010a (Continued)

Allocation concealment (selection bias) Unclear risk Quote ldquoThe study investigator opened thenext sequentially numbered randomizedenvelope to determine the treatment armThis randomization scheme was createdby Population Council staff using a com-puter-generated coderdquoComment it is still unclear who put therandomisation scheme in the envelopes andif the envelopes were opaque


Low risk Comment all 220 patients were analysed

Selective reporting (reporting bias) Unclear risk Comment the methods section states thatrsquoside effectsrsquo were measured without furtherspecification it is unclear if the side effectspresented in the results are the only onesmeasured



High risk Quote ldquoNeither the investigator nor thewoman was blinded to the treatment as-signmentrdquoComment due to the nature of interven-tion blinding would be practically impos-sible


High risk Comment outcome was not assessed by in-dependent doctors

Trinder 2006

Methods Randomised controlled trial comparing medical and expectant management with sur-gical management of first trimester miscarriage This was a multi-centre trial with 7participating hospitals each of which had an early pregnancy clinic Recruitment startedin May 1997 and finished in December 2001

Participants Women with a pregnancy of less than 13 weeksrsquo gestation who had been diagnosed ashaving either an incomplete miscarriage or early fetalembryonic demise were eligible

Interventions Intervention in the medical management arm women with an incomplete miscarriagewere admitted to hospital and given a single vaginal dose of 800 mcg misoprostol1200women with early fetal or embryonic demise were pre-treated with a single oral dose of200 mg mifepristone21 then admitted to hospital 24-48 hours later for a single vaginaldose of 800 mcg misoprostol (n = 398)Control women in the expectant management arm were allowed home with no inter-



Trinder 2006 (Continued)

vention (n = 399)Control women in the surgical management arm were admitted for surgical suctioncurettage under general anaesthesia (n = 403)

Outcomes Confirmed gynaecological infection at 14 days and 8 weeks need for unplanned admis-sion or surgical intervention

Funding The MIST study was funded by a South and West NHS Executive research and devel-opment grant A donation of pound20 000 was accepted from Exelgyn Neither the NHSExecutive nor Exelgyn had any role in the study design collection analysis or interpre-tation of data writing of the report or the decision to submit the paper for publication

Declarations of interest The study group accepted a donation of pound20 000 from Exelgyn the manufacturers ofmifepristone The authors have no other competing interests

Notes

Risk of bias



Unclear risk Quote ldquoRandomisation was by a centraltelephone system at the Clinical Trials Ser-vices Unit Oxford We used minimisationto ensure comparability between womenwith respect to participating centre paritytype of miscarriage and gestationrdquoComment this still does not state how therandomisation scheme was generated

Allocation concealment (selection bias) Low risk Comment use of a central telephone sys-tem for randomisation operated by otherpersons than the doctors randomising thepatients


Low risk Comment according to the flowchart lossto follow-up was lt 10

Selective reporting (reporting bias) Low risk Comment flow chart displays all eligibleand recruited women No signs of selectivereporting all outcomes mentioned in themethods section were presented in the re-sults section



High risk Comment there is no information onblinding of patients and personnel How-ever due to the nature of the interventions




blinding would be practically impossible



Wood 2002

Methods Computer-generated random number list in blocks Pharmacy prepared numbered en-velopes Tablets not identical so placed by nurse in opaque vaginal introducer for physi-cian to insert - to maintain allocation concealmentDepartment of Obstetrics and Gynecology University of Calgary Calgary AlbertaCanada between February 1999 and April 2000

Participants 50 women with ultrasound diagnosed non-viable pregnancies Gestational age 7-17weeks but women not included if fetal size by ultrasound gt 12 weeks equivalent Alsoexcluded from recruitment if experiencing uterine cramping or bleeding

Interventions Misoprostol (800 mcg vaginally) (n = 25) or vaginal placebo (n = 25) If completemiscarriage not suspected after 24 hours treatment was repeated At 48 hours if nomiscarriage or miscarriage thought to be incomplete uterine curettage was offered

Outcomes Sample size based on reduction of uterine curettage from 50 to 10 Womenrsquos satis-faction also assessed but are not included in analyses as data not reported from controlgroup

Funding This work was supported by a grant from the Office of the Associate Dean of ResearchFaculty of Medicine University of Calgary


Notes Analysis by intention-to-treat

Risk of bias



Low risk Comment computer-generated randomnumber list in blocks

Allocation concealment (selection bias) Low risk Comment pharmacy prepared numberedenvelopes Tablets not identical so placedby nurse in opaque vaginal introducer forphysician to insert - to maintain allocationconcealment



Wood 2002 (Continued)


Low risk Comment it seems that all patients com-pleted the study Outcomes were presentedfor all patients

Selective reporting (reporting bias) Low risk Comment no signs of selective report-ing Outcome measures mentioned in themethods section were presented in the re-sults section



Low risk Comment tablets not identical so placedby nurse in opaque vaginal introducer forphysician to insert - to maintain allocationconcealment This assures blinding of pa-tients and personnel


Low risk Comment no information on blindingof outcome assessment Considering thatthere was blinding of the physician treatingthe patient (by the use of a opaque vagi-nal introducer with either misoprostol orplacebo) probably the physician was alsoblinded for outcome assessment

AP diameter anterior-posterior diameterbHCG beta human chorionic gonadotrophinCRL crown-rump lengthERPC evacuation of retained products of conceptionhCG human chorionic gonadotropinIM intramuscularIU international unitsIUFD intrauterine fetal deathmcg microgrammm millimetreMTX methotrexatePOC products of conceptionRCT randomised controlled trialTVS transvaginal sonographyvs versusmicroL microlitre



Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Abbas 2018 Participants do not meet inclusion criteria (includes women undergoing termination of pregnancy forother reasons than non vital pregnancies and up to a GA of 27 weeks)

Abd-El-Maeboud 2012 Termination of rsquoviablersquo pregnancies the intervention is priming before medical treatment and not thetreatment itself

Abdel Fattah 1997 Conference abstract No information about GA but given title probably includes pregnancies gt 24weeks as well as lt 24 weeks

Al-Bdour 2007 Quasi-randomised trial patients assigned to treatment according to military ID number

Ali 2018 Different topic study includes women induced with balloon catheters and not with medication

Almog 2005 Termination of rsquoviablersquo pregnancies - mainly with fetal anomalies

Altaf 2006 Not a randomised study No subgroup analysis with only patients with missed abortion and GA lt 24weeks

Amjad 1999 Other subject lsquoprimingrsquo of cervix while Foley catheter in situ

Anderman 2000 Conference abstract Includes pregnancies gt 24 weeks as well as lt 24 weeks

Anderson 2009 Conference abstract Duration of pregnancy unclear

Ara 2009 Conference abstract

Arellano 2009 Conference abstract on other subject Treatment of incomplete abortion

Avila-Vergara 1997 Intrauterine deaths mainly third trimester

Aye 2017 Conference abstract further results not published It is not clear if also women with incomplete mis-carriage were included in this study

Azra 2007 Termination of pregnancies for congenital malformations as well as non-viable pregnancies No subgroupanalyses

Bagratee 2009 Conference abstract on other subject Predictiveetiologic study size of RPOC as predictor of successfultreatment

Bani-Irshaid 2006 Other subject (TOP) no subgroup analysis of women with GA lt 24 weeks

Bartz 2013 Other subject randomised trial of 2 methods for dilatation of the cervix before surgical evacuation

Bebbington 2002 Termination of viable pregnancies



(Continued)

Behrashi 2008 Includes patients with GA lt 24 weeks and gt 24 weeks and patients with rsquoviablersquo pregnancies Nosubgroup analyses performed We tried to contact the authors by e-mail but they could not be reached

Behrashi 2010 Not a publication of study results but a registration of a RCT in Iranian Trial Register

Ben-Meir 2009 RCT comparing priming with misoprostol vs placebo before oxytocin induction Patients with GA gt24 weeks included

Betstadt 2007 Registration of trial protocol no results published Author was contacted stated that the trial wasstopped prematurely because of a lack of participants

Bique 2007 Trial concerning treatment of incomplete abortion

Biswas 2007 Termination of pregnancy because of various reasons no subgroup analyses on patients with missedmiscarriage or early fetal death We tried to contact the authors but could not reach them

Blohm 2005 Includes patients with incomplete (ongoing) miscarriage (with gestational residue between 15 mm to50 mm)

Brouns 2010 Trial also includes patients with legal termination of viable pregnancies We contacted the authors toask for subgroup analyses of only patients with non-viable pregnancies but the original data were notaccessible to them anymore

Cabrol 1990 Trial of mifepristone for induction of labour after intrauterine death - but mainly late second and thirdtrimester pregnancies

Caliskan 2005 Includes all patients with indication for termination of pregnancy but does not state which indicationsare meant We tried to contact the authors but could not reach them

Caliskan 2009 Other subject (termination of pregnancy)

Chaudhuri 2015 Reference of trial registration Results were published in 2015 Study participants included women withsecond and third trimester intrauterine fetal death No subgroup analyses for GA lt 24 weeks

Chowdhury 2012 Conference abstract No information on GA

Clevin 2001 Abstract in Danish A prospective randomised study carried out to clarify the effect of vaginal ad-ministration of a prostaglandin E1 analogue (gemeprost) versus surgical management (curettage) onmiscarriages at up to 12 weeks of gestation 3 groups 1 (n = 27) 2A (n = 17) and 2B (n = 17) allocatedaccording the endometrial thickness The measured outcomes were reduction of endometrial thicknessduration of vaginal bleeding and pain reported in a non-suitable format for analysis

Dabash 2009 Conference abstract other subject (treatment of incomplete abortion)

Dao 2007 Other subject (treatment of incomplete abortion)

Das 2014 Other subject treatment of incomplete miscarriage



(Continued)

David 2003 Randomised trial (details of randomisation unclear) of 2 methods to soften the cervix before surgicalevacuation for early non-viable pregnancies No usable clinical data given short timescale betweentreatment and surgery

David 2005 Other subject (cervical priming before surgical evacuation)

Demirezen 2018 The participants in this study do not meet the inclusion criteria for this review (gestational age up to 28weeks and termination of both vital and non vital pregnancies) The intervention studied (inductionwith different type of balloon catheter) does not meet the inclusion criteria for this review

Dickinson 1998 Trial included women with fetal malformations and maternal indications for pregnancy terminationbetween 14 and 28 weeks as well as pregnancies with fetal death We tried to contact the authors butcould not reach them


Dickinson 2003 Randomised trial comparing oral with vaginal administration of misoprostol to terminate pregnancieswith fetal malformations - not non-viable pregnancies

Diop 2009 Other subject treatment of incomplete abortion

El Sokkary 2016 Unclear up to which GA patients were included and if there were subgroup analyses made for patientswith GA eligible for this review Furthermore unclear what type of randomisation was used and thereforeif this truly was a randomised controlled trial We tried to contact the author but there was no response

Elami-Suzin 2013 Trial included also patients with therapeutic abortion no subgroup analysis on only missed miscarriageother than 1 remark in text (time until expulsion shorter than therapeutic abortionrsquo but that is not anoutcome in our review) Furthermore all women underwent curettage after medication so it would beimpossible to draw conclusions about the primary outcome in the review (complete evacuation) becauseit would be unclear whether the uterus was empty because of the medication or because of the curettage

Elhassan 2008 Includes patients with GA up to 28 weeks We e-mailed the authors to ask for a subgroup analysis ofpatients with GA lt 24 weeks but they did not respond

Eppel 2005 Trial included women with fetal malformations and maternal indications for pregnancy terminationbetween 14 and 23 weeks as well as pregnancies with fetal death We tried to contact the authors butcould not reach them

Eslamian 2007 Study group also includes patients with maternal medical disorders TOP because of congenital mal-formations and PPROM We contacted the authors there were no subgroup analyses of only patientswith fetal demise

Fadalla 2004 Women included in this trial had a GA 13-28 weeks no subgroup analysis for GA lt 24 weeks wasavailable



(Continued)

Feldman 2003 Trial included women with fetal malformations and maternal indications for pregnancy terminationbetween 14 and 23 weeks as well as pregnancies with fetal death We tried to contact the authors butcould not reach them

Fernlund 2018 Includes women with ongoing miscarriage (vaginal blood loss in combination with a sonographicallydiagnosed non vital first trimester pregnancy)

Fiala 2005 Other subject (pain medication in requested abortion for socio-economic reasons)

Ghorab 1998 Trial included women with fetal malformations for pregnancy termination as well as pregnancies withfetal death We tried to contact the authors but could not reach them

Gonzalez 2001 Trial included women with fetal malformations and maternal indications for pregnancy terminationbetween 14 and 23 weeks as well as pregnancies with fetal death We tried to contact the authors butcould not reach them

Grimes 2004 Trial included women with other reasons for pregnancy termination as well as pregnancies with fetaldeath We tried to contact the authors but could not reach them

Gronland 2002 Not a randomised trial 3-centre study of women with non-viable pregnancies comparing 3 treatmentregimens misoprostol mifepristone + misoprostol surgical evacuation - with treatment regimen chang-ing at each hospital every 4 months

Guix 2005 Trial includes patients seeking termination of pregnancy because of congenital malformations

Halimi 2004 Trial includes patients with termination of pregnancy because of fetal demise or congenital malforma-tions up to GA of 28 weeks No subgroup analyses available

Hassan 2007 Quasi-randomised trial other subject (treatment of incomplete abortion)

Hausler 1997 Prospective RCT evaluating 3 interventions for complete spontaneous abortion Diagnosis was basedon positive pregnant test vaginal bleeding andor evacuation of tissue from the vagina a closed uterineorifice with only slight bleeding on admission and a possible clear sonographic pregnancy diagnosis inthe history Interventions A) n = 15 curettage B) n = 20 only controlled and C) n = 15 additionallytreated for 10 days with an oral hormone intake of 2 mg norethisterone acetate and 001 mg ethinyloestradiol 3 x day Randomisation by sealed unmarked envelopes 63 patients were included in thestudy and allocated randomly to each group 13 women (206) were excluded from the study afterrandomisation 10 did not report for the planned follow-up control 1 did not report for curettage in1 the height of the endometrium was gt 8 mm and in 1 an ectopic pregnancy was diagnosed 6 daysafter the randomisation The study only presents outcomes in a non-suitable format regarding hCGclearing time and duration of the secondary haemorrhage from the day of randomisation

Heard 2002 Conference abstract Unclear what type of randomisation 12 patients were assigned to group A and21 to group B which seems odd in cases of 11 and even in case of 12 randomisation no furtherinformation on methodology No full article for this trial found

Herabutya 1997a Includes patients with all GA no subgroup analyses of only patients with GA lt 24 weeks authors couldnot be reached for further clarification



(Continued)

Herabutya 2005 RCT of misoprostol for terminating viable pregnancies

Hidar 2001 Trial included women with fetal malformations and maternal indications for pregnancy terminationbetween 13 and 29 weeks as well as pregnancies with fetal death We tried to contact the authors butcould not reach them

Hidar 2005 Trial includes patients with GA gt 29 weeks and patients with TOP because of congenital anomaliesor PPROM We contacted the authors there were no subgroup analysis available of only patients withintrauterine fetal death

Hill 1991 Trial includes fetal deaths in both second and third trimesters

Hinshaw 1993 Henshaw 1995 conference abstract No subgroup analysis of randomised proportion (trial was partlyrandomised and partly treatment according to patients preference)Hinshaw 1993 interim results of partially randomised trial no subgroup analysis on randomised pa-tients full results in other articleHinshaw 1995 interim results of partially randomised trial no subgroup analysis on randomised pa-tients full results in other articleRispin 1993 conference abstract concerning study protocol of ongoing study no results presented

Hogg 2000 Abstract Trial included women with other reasons for pregnancy termination as well as pregnancieswith fetal death We tried to contact the authors but could not reach them

Hombalegowda 2015 Conference abstract No article with full results found We tried to contact the authors to ask for suchan article but could not reach them

Hughes 1996 Cost-effectiveness analysis of previous study that included patients with incomplete miscarriage (nosubgroup analysis on patients with fetal demise) partly randomised trial We contacted authors forsubgroup analysis on RCT patients with fetal demise however they did not respond

Imran 2010 Includes patients with GA gt 24 weeks and TOP because of congenital malformations We tried tocontact the authors to ask for subgroup analyses but they did not respond

Islam 2006 Not randomised patients were divided in 2 equal groups Trial included patients seeking TOP becauseof congenital malformations no subgroup analysis on patients with fetal demise

Jabir 2009a Conference abstract Other subject (cervical dilation before surgical evacuation)

Jabir 2009b Conference abstract Other subject (cervical preparation 3 hours before surgical evacuation)

Jain 1994 Trial included women with fetal malformations and maternal indications for pregnancy terminationbetween 12 and 22 weeks as well as pregnancies with fetal death We tried to contact the authors butcould not reach them




(Continued)

Johnson 1997 RCT evaluating pain and bleeding and comparing surgical to medical treatment Surgical arm (n =12) uterine curettage under general anaesthesia Medical arm (n = 17) include 3 different participantconditions and treatments a) no treatment if women had a complete abortion and uterine cavity echo(myometrium) less than 15 mm b) women with incomplete abortion 1 mg pessary of gemeprost(Cervagem May and Baker) and remained in hospital for 4 hours or until they had passed POC andc) women with intact gestational sac (but non-viable fetus) 200 mg RU 486 (mifepristone) and thenallowed home readmitted 36-48 hours later for 1 mg of vaginal Cervagem Data from each subgroupin the medical arm are not separated The sample size is too small to detect any difference among suchnumber of groups

Kamal 2005 Quasi-experimental study no RCT Includes patients with GA gt 24 weeks and with TOP because ofmaternal or fetal reasons

Kanhai 1989 Includes both second and third trimester fetal deaths

Kapp 2007 Quasi-randomised trial trial includes patients seeking termination of pregnancy indication for termi-nation unclear

Khosravi 2017 Trial registration includes women with termination of first trimester pregnancies for early fetal demiseas well as termination on maternal indication

Kong 2013 Trial includes also patients with incomplete miscarriage There is 1 sentence in results section thatprovides success rates for only patients with silent miscarriage (ldquoFocussing on women who were diagnosedto have silent miscarriage at recruitment complete miscarriage rate after surgical treatment medicalevacuation and expectant management was 977 63 and 625 respectivelyrdquo) but when thesepercentages are used to calculate the number of patients with successful treatment using the numberof study participants in each group (49 surgical 46 medical and 25 expectant management see table1) the outcomes are impossible So it looks like either the percentages are not right or not all patientswith missed miscarriage were analyses Unfortunately for this group there was no specific informationon missing data

Kurshid 2010 Trial includes patients wit indication for TOP because of IUFD congential malformations PPROMWe tried to contact the authors for subgroup analyses on only patients with IUFD but could not reachthem

Kyaw 2015 Conference abstract No information on method of randomisation Authors could not be reached forfurther clarification

Linn 2015 Conference abstract Trial includes patients with GA gt 24 weeks no subgroup analysis of only patientswith GA lt 24 weeks available

Lippert 1978 Second and third trimester fetal deaths Not obviously randomised

Lu 2014 Article in Chinese after translation signs of weak methodology no exact description of dosages ofmedication Furthermore no information on type of randomisation

Lughmani 2008 Conference abstract Unclear if time span between treatment is too short (looks like surgical evacuationis performed within 12 hours after misoprostol treatment) Authors could not be reached for furtherclarification



(Continued)

Machtinger 2004 Abstract Appears to include both non-viable pregnancies and miscarriages

Mahjabeen 2009 Quasi-randomised trial Includes patients with therapeutic TOP unclear what indication for this TOPwas

Makenzius 2017 Trial that compares miscarriage care by midwife to care by physician other topic

Makhlouf 2003 Not clear from paper if all pregnancies complicated by fetal death Seeking clarification from authors

Martin 1965 Allocation based on alternation not randomisation Alternation violated

Montesinos 2011 Wrong patient population lsquoincomplete abortionrsquo

Moran 2005 Other topic (treatment of pregnancy of unknown location)

Mostafa-Gharebaghi 2010 Trial includes patients with termination of pregnancy because of fetal death congenital malformationsPPROM and rsquoother causesrsquo We tried to contact the authors for subgroup analyses on only patients withfetal death but could not reach them

Mulayim 2009 Other subject (misoprostol after surgical treatment for miscarriage)

Naghshineh 2015 Trial included women with spontaneous miscarriage (non-viable pregnancy) lt 17 weeks as well asinduced abortion No subgroup analyses for spontaneous miscarriage only

Nakintu 2001 Both second and third trimester fetal deaths Seeking separate data from author

Nasreen 2009 Conference abstract Trial includes patients with incomplete miscarriage

Nassar 2006 Reference is trial registration Trial was ended prematurely because of difficulties in recruitment ofpatients

NCT02141555 Reference of trial registration According to the trial register the current recruitment status is unknownlast updated in 2014 We did not find any published results

NCT02573051 Reference of trial registration According to the trial register the current recruitment status is unknownlast update in October 2015 We could not find any published results

Ng 2015 Wrong patient population-lsquoincomplete abortionrsquo

Ngai 2001 Includes data on women with both non-viable pregnancies and incomplete miscarriages If these datacan be separated by the researchers these data may be included in the future

Nguyen 2005 Other subject treatment of incomplete abortion

Niinimaki 2006 Trial also includes patients with incomplete miscarriage We contacted the authors to ask for subgroupanalyses on only patients with missed miscarriage and anembryonic gestation however they did notrespond



(Continued)

Nor 2006 Other subject (termination of pregnancy indication unclear) trial includes patients up to GA of 26weeks no subgroup analysis on patients with GA lt 24 weeks

Nuthalapaty 2005 Includes patients with induction because of congential malformations or maternal indications 1 of theoutcome measures was live birth rate () We tried to contact the authors for further clarification butcould not reach them

Nuutila 1997 Trial included women with fetal malformations and maternal indications for pregnancy terminationbetween 12 and 24 weeks as well as pregnancies with fetal death We tried to contact the authors butcould not reach them

Owen 1999 Trial included women with fetal malformations and maternal indications for pregnancy terminationbetween 16 and 24 weeks as well as pregnancies with fetal death We tried to contact the authors butcould not reach them

Paraskevaides 1992 Small study of 16 women ldquorandomisedrdquo to surgical evacuation or prostaglandin F2alpha or Trilostanetreatment No details about clinical presentation or ultrasound and clinical findings but from abstractincludes both women with non-viable pregnancies and incomplete miscarriage

Paritakul 2010 Wrong patient population-lsquoincomplete abortionrsquo

Patua 2013 Other subject treatment of incomplete miscarriage

Perry 1999 Excluded women with fetal deaths

Piotrowski 1979 Not clear that this was a randomised trial

Pongsatha 2004 Trial excluded women with fetal deaths

Prasartsakulchai 2004 Quasi-randomised patients could choose for medical surgical or expectant management Only patientswho chose medical management were further randomised However patients did not meet inclusioncriteria for the review as they already experienced abdominal pain and vaginal bleeding eg ongoingmiscarriage which is beyond the scope of this review

Promwangkwa 2017 Participants in this study had a gestational age 14-24 weeks Indications for termination of pregnancyincluded intra uterine fetal demise but also termination of pregnancy of live fetus for other fetal andmaternal indications No subgroup analyses were made for IUFD up to 20 weeks of gestation

Rahimi-Sharbaf 2015 Trial studies women with termination of pregnancy with GA 13-24 weeks because of congenital ofmaternal indications No subgroup analyses were performed for only women with IUFD

Ramadan 2009 Conference abstract Other subject incomplete abortion

Ramsey 2004 Trial included women with other reasons for pregnancy termination as well as pregnancies with fetaldeath We tried to contact the authors but could not reach them

Reeves 2006 Other subject (endometrial thickness as predictor for further intervention) no subgroup analyses ononly patients with missed abortion



(Continued)


Rivero-Lopez 1998 Other subject cervical priming before intervention

Robledo 2007 Other subject predictive study (to identify indicators for success of misoprostol treatment)

Roy 2003 Abstract Not clear if fetal death included as indication for termination

Ruangchainikhom 2006 Other subject (termination of pregnancy because of obstetric reasons) Full data unavailable

Saeed 2018 This trial meets all inclusion criteria However data extraction was not possible The table presentingthe main results contained numbers of unknown origin It was unclear whether percentages or numberof participants were displayed The numbers in this table did also not correspond with the main textattributing to further doubt as to what the numbers in the table represent

Salamalekis 1990 Abstract only Treatment allocation by alternation not by randomisation

Salari 2012 Conference abstract Other subject (other patient population) therapeutic abortion

Shaheen 2017 In this trial women were not adequately randomised The paper describes a quasi randomised trial withwomen being ldquodivided into two groupsrdquo

Shaikh 2008 Conference abstract No subgroup analysis on missed miscarriage

Shelley 2005 Other subject treatment of incomplete or ongoing miscarriage

Shobeira 2007 Conference abstract No article with full study results found Authors could not be reached to ask forsuch an article

Shochet 2012 Other subject (incomplete abortion)

Shokry 2009 Other subject other intervention (reduction of bleeding after surgical evacuation)

Shuaib 2013 The type of randomisation is unclear It seems that both groups had different types of follow up especiallyfor the surgically treated group it is unclear if they really all had successful outcome (for example noinformation on ultrasound follow-up) Weak methodology high risk of bias on all fronts

Shwekerela 2007 Other subject (reduction of bleeding after surgical evacuation)

Smith 2006a This was a qualitative study No numeric comparison between the groups Furthermore study groupincludes women with an incomplete miscarriage no subgroup analyses were performed for only patientswith missed miscarriage

Smith 2009 Study includes also patients with incomplete miscarriage There was no subgroup analysis available foronly patients with a non-viable pregnancy



(Continued)

Srikhao 2005 Since patients participating in this study already experienced vaginal blood loss and abdominal pain thisis considered ongoing or incomplete miscarriage therefore this study is not eligible for the review

Sripramote 2000 Other subject cervical priming before surgical evacuation

Stockheim 2006 The data presented in this trial were reciprocal It is not valid to present reciprocal data for outcomesfrom trials because they are not reported in the way we have specified the review This study was thereforenot included in this review

Su 2005 Termination of pregnancy for fetal anomalies social reasons or maternal disease not for non-viablepregnancies

Suchonwanit 1999 Abstract of residents research paper No article with full study results found author could not be reachedto ask for such an article

Surita 1997 Abstract only May include third trimester fetal deaths

Tam 2005 Study investigating reproductive outcome after miscarriage treatment patients were included in a previ-ous trial This previous trial was not retrieved from the search but was identified screening the referencelist of an excluded study this trial also included patients with incomplete miscarriage There were nosubgroup analyses available for only patients with a non-viable pregnancy

Tanha 2013 Unclear whether all patients meet inclusion criteria for review it seems like also patients with legalabortion or TOP because of congenital malformations were included We tried to contact the authorsfor further clarification but could not reach them

Taylor 2011 Other subject treatment of incomplete abortion

Thavarasah 1986 Unclear from paper but allocation may have been by alternation We tried to contact the authors butcould not reach them

Thida 2015 Conference abstract We searched for full study results but could not find them We tried to contact theauthors to ask if there is an article with study results published but could not reach them

Toppozada 1994 Includes third trimester fetal deaths

Toptas 2011 Conference abstract No subgroup analysis of only patients with termination because of IUFD Authorscould no be reached for further clarification

Torre 2012 Trial also includes patients with incomplete miscarriage We tried to contact the authors for subgroupanalysis on patients with missed miscarriage but they did not respond

Van Mensel 2009 Trial includes patients with GA gt 24 weeks We tried to contact the authors to ask for subgroup analyseson patients with GA lt 24 weeks but they did not respond

Yapar 1996 Includes indications for termination other than fetal death High degree of protocol violation (60400) Results not presented as intention-to-treat



(Continued)

Yilmaz 2005 Other subject termination of pregnancy because of congenital or chromosomal abnormalities

Yilmaz 2007 Other subject termination of pregnancy because of congenitalchromosomal abnormalities

Zanganeh 2012 Other subject termination of pregnancy because of fetal or maternal problems

Zhang 2000 Seems to be a trial about cervical priming before delivery Outcome measures irrelevant for this review

Zhang 2005 Includes both non-viable pregnancies and miscarriages We tried to contact the authors to retrieve dataon non-viable pregnancies only but we could not reach them

GA gestational agehCG human chorionic gonadotropinIUFD intrauterine fetal deathmg milligrammm millimetrePOC products of conceptionPPROM preterm premature rupture of membranesRCT randomised controlled trialRPOC retained products of conceptionTOP termination of pregnancy

Characteristics of ongoing studies [ordered by study ID]

ACTRN12615000483550

Trial name or title Buccal versus vaginal (200 microgram) misoprostol for second trimester abortion termination

Methods Clinical randomised trial to compare efficacy and safety of vaginal and buccal misoprostol in second trimesterabortion due to intrauterine fetal death

Participants 1 Women who are pregnant between 13 and 27 weeks2 Termination of pregnancy is indicated due to intrauterine fetal death

Interventions The study had 2 treatment groups group I received a dose of misoprostol (200 microg) (1 tablet of Misotac 200microg Sigma co Cairo Egypt) every 4 hours buccally (and the patient was instructed not to swallow it for 1hour) till expulsion of the fetus for maximum 24 hoursGroup II received a dose of moistened misoprostol (200 microg) (1 tablet of Misotac 200 ug Sigma co CairoEgypt) every 4 hours vaginally (tablet was put into the posterior fornix) till expulsion of the fetus for maximum24 hours

Outcomes The primary outcome measure is the induction interval the time from the initial misoprostol dose untilcomplete fetal expulsionIncidence of side effects of misoprostol (such as nausea vomiting fever chills diarrhoea tachycardia andheadache)



ACTRN12615000483550 (Continued)

Number of misoprostol doses

Starting date 17072012

Contact information Dr Mohammad Sayed Abdellah msayed21yahoocom

Notes Last patient should have been included in 2013 It seems that the results have not been published (yet)no publications by the mentioned authors regarding this randomised controlled trial were retrieved in ourextensive search

Ali 2017

Trial name or title Vaginal misoprostol in management of first trimester missed abortion

Methods Randomised parallel assignment open-label trial

Participants Inclusion criteria1 Single dead fetus up-to 12 weeks2 No low lying placenta3 No scarred uterus4 No or mild bleeding5 No evidence of infection6 Accepting to participate in the study

Interventions Vaginal misoprostol (800 microg x 2 doses 3 hours) versus buccalsublingual misoprostol (200 microg x 6 doses 4hours)

Outcomes Not specified

Starting date Not yet recruiting

Contact information Dr Mohammed Khairy Ali Assiut University

Notes

El Shahawy 2016

Trial name or title Sublingual versus vaginal misoprostol in medical treatment of first trimestric missed miscarriage

Methods Single-blind randomised parallel-assignment trial

Participants Inclusion criteria1 All women above 18 years of age2 Less than 12 weeks of gestation3 Pregnancy is confirmed by pregnancy test or ultrasound scan4 Missed abortion5 Normal general and gynaecological examination



El Shahawy 2016 (Continued)

6 The size of the uterus on pelvic examination was compatible with the estimated duration of pregnancy

Interventions Sublingual misoprostol versus vaginal misoprostol

Outcomes Primary outcome completeness of abortion (expulsion of products of conception by visual inspection

Starting date January 2016

Contact information Ahmed Abdel Shafy El Shahawy Ains Sham University

Notes

NCT02620904

Trial name or title Mifepristone induction for fetal demise a randomised control trial

Methods Double-blinded randomised controlled trial with 11 allocation of mifepristone or placebo at initiation ofinduction of labour for fetal demise 20 weeks estimated gestational age or greater

Participants Inclusion criteria1 Intrauterine fetal death as confirmed by absence of cardiac motion on ultrasound by attending

physician at the time of admission to the hospital2 Estimated gestational age greater than 20 weeks3 Haemodynamically stable and appropriate for induction of labour as per primary clinical health team

in house4 Women with 1 prior low transverse caesarean delivery

Interventions Interventional arm ingest 200 mg tablet of mifepristone orally Control arm ingest a placebo tablet orallywith similar physical properties

Outcomes Time to delivery of fetus [time frame from the initiation of medical therapy for induction to delivery of fetus]

Starting date February 2016

Contact information Montefiore medical centre principal investigator Jessica Atrio MD jatriomontefioreorg

Notes

NCT02633761

Trial name or title Mifepristone and misoprostol versus misoprostol alone for treatment of fetal death at 14-28 weeks of preg-nancy a randomised placebo-controlled double-blinded trial

Methods Allocation randomisedIntervention model parallel assignmentMasking quadruple (participant care provider investigator outcomes assessor)Primary purpose treatment



NCT02633761 (Continued)

Participants Inclusion criteria1 Demised fetus of between 14 to 28 weeks duration confirmed by ultrasound2 Have no contraindications to study procedure according to provider3 Be able to consent to procedure either by reading consent document or by having consent document

read to her4 Be willing to follow study procedures

Interventions Active comparator group 1 200 mg mifepristone followed in 24 hours by repeated doses of 200 microg buccalmisoprostol given every 3 hoursPlacebo comparator group 2 placebo followed in 24 hours by 200 microg buccal misoprostol given every 3 hours

Outcomes Complete uterine evacuation of the fetus and placenta without surgical intervention [time frame 48 hours]Complete uterine evacuation of fetus and placenta using study drug alone without recourse to any additionalsurgical intervention

Starting date April 2015

Contact information Hillary Bracken PhD hbrackengynuityorg

Notes

NCT03212352 2017

Trial name or title Comparing two medical treatments for early pregnancy failure

Methods Double-blind placebo-controlled randomised trial - parallel group assignment

Participants Women with ultrasonographically confirmed early pregnancy failure (6-14 weeks postmenstrual) managedexpectantly for at least 1 week

Interventions Oral mifepristone (600 mg) or oral placebo

Outcomes Primary outcome complete evacuation 6 weeks after initial treatment (whether or not complete evacuation(total endometrial thickness lt 15 mm) will be assessed through ultrasonography

Starting date June 27 2018 estimated primary completion date = January 1 2020

Contact information Charlotte C Hamel lhamelcwznl 0031243658750Marcus P Snijders msnijderscwznl 0031243658750Radboud University The NetherlandsCollaborators Innovatiefonds Zorgverzekeraars Canisius-Wilhelmina Hospital

Notes

mg milligrammm millimetre



microg microgram



D A T A A N D A N A L Y S E S

Comparison 1 Vaginal misoprostol versus placebo

Outcome or subgroup titleNo of

studies

No of

participants Statistical method Effect size

1 Complete miscarriage 5 305 Risk Ratio (M-H Fixed 95 CI) 423 [301 594]

11 Complete miscarriage lt 1day

2 138 Risk Ratio (M-H Fixed 95 CI) 473 [270 828]

12 Complete miscarriage lt 2days




2 Death or serious complicationsuterine perforation


3 Blood transfusion 1 84 Risk Ratio (M-H Fixed 95 CI) 02 [001 404]

4 Blood loss haemoglobindifference gt 10 gL


5 Days of bleeding vaginalbleeding 2 weeks aftertreatment


6 Nausea 2 88 Risk Ratio (M-H Fixed 95 CI) 138 [043 440]7 Diarrhoea 2 88 Risk Ratio (M-H Fixed 95 CI) 221 [035 1406]8 Pain (opiate use) 1 84 Risk Ratio (M-H Fixed 95 CI) 50 [025 10111]

9 Womanrsquos satisfaction withtreatment


Comparison 2 Vaginal misoprostol versus expectant management


studies

No of


1 Complete miscarriage 1 614 Risk Ratio (M-H Fixed 95 CI) 125 [109 145]2 Pelvic infection 1 618 Risk Ratio (M-H Fixed 95 CI) 805 [187 3472]



Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus


studies

No of


1 Complete miscarriage 6 943 Risk Ratio (M-H Random 95 CI) 040 [032 050]2 Uterine perforation 1 154 Risk Ratio (M-H Fixed 95 CI) 032 [001 765]

3 Blood loss post-treatmenthaematocrit ()

1 50 Mean Difference (IV Fixed 95 CI) -140 [-351 071]

4 Pain relief 1 154 Risk Ratio (M-H Fixed 95 CI) 142 [082 246]5 Pelvic infection 1 618 Risk Ratio (M-H Fixed 95 CI) 073 [039 137]6 Nausea 1 154 Risk Ratio (M-H Fixed 95 CI) 2185 [131 36437]7 Diarrhoea 1 154 Risk Ratio (M-H Fixed 95 CI) 4085 [252 66257]8 Womanrsquos satisfaction 1 45 Risk Ratio (M-H Fixed 95 CI) 067 [040 111]

Comparison 4 Vaginal misoprostol versus vaginal dinoprostone


studies

No of


1 Complete miscarriage 2 125 Risk Ratio (M-H Fixed 95 CI) 183 [137 246]2 Blood transfusion 1 60 Risk Ratio (M-H Fixed 95 CI) 607 [030 12133]3 Nausea 1 65 Risk Ratio (M-H Fixed 95 CI) 103 [028 378]4 Duration of hospital stay (days) 1 60 Mean Difference (IV Fixed 95 CI) -238 [-336 -140]

Comparison 5 Vaginal misoprostol lower versus higher-dose regimens


studies

No of


1 Complete miscarriage lt 13weeks

2 397 Risk Ratio (M-H Random 95 CI) 082 [058 114]

2 Complete miscarriage 13-23weeks


3 Nausea 2 214 Risk Ratio (M-H Fixed 95 CI) 067 [031 141]4 Diarrhoea 2 214 Risk Ratio (M-H Fixed 95 CI) 054 [015 191]



Comparison 6 Vaginal misoprostol wet versus dry vaginal preparations


studies

No of







13 Complete miscarriage lt15 days




2 Diarrhoea 1 77 Risk Ratio (M-H Fixed 95 CI) 175 [089 342]3 Vomiting 1 77 Risk Ratio (M-H Fixed 95 CI) 093 [033 262]

4 Acceptability of method wouldwishprobably wish sametreatment in future nonviablepregnancy


Comparison 7 Vaginal misoprostol + methotrexate versus vaginal misoprostol alone


studies

No of


1 Complete miscarriage 1 21 Risk Ratio (M-H Fixed 95 CI) 113 [085 150]2 Haemorrhage 1 21 Risk Ratio (M-H Fixed 95 CI) 231 [010 5085]3 Pain relief 1 21 Risk Ratio (M-H Fixed 95 CI) 075 [025 222]

Comparison 8 Vaginal misoprostol plus laminaria tents versus vaginal misoprostol alone


studies

No of









Comparison 9 Vaginal misoprostol versus sublingual misoprostol


studies

No of






3 Blood loss excessive (gtmenstruation)


4 Pain 3 392 Risk Ratio (M-H Fixed 95 CI) 058 [046 074]5 Nausea 4 302 Risk Ratio (M-H Random 95 CI) 042 [012 144]6 Vomiting 2 300 Risk Ratio (M-H Fixed 95 CI) 076 [046 126]7 Diarrhoea 4 472 Risk Ratio (M-H Fixed 95 CI) 071 [054 092]

Comparison 10 Vaginal misoprostol versus intravenous oxytocin


studies

No of




2 Blood loss excessive 1 85 Risk Ratio (M-H Fixed 95 CI) 056 [005 597]21 Gestation 15-24 weeks 1 85 Risk Ratio (M-H Fixed 95 CI) 056 [005 597]

Comparison 11 Vaginal misoprostol versus vaginal gemeprost


studies

No of




2 Opiates for pain relief 1 50 Risk Ratio (M-H Fixed 95 CI) 00 [00 00]3 Vomiting 1 50 Risk Ratio (M-H Fixed 95 CI) 30 [013 7030]4 Diarrhoea 1 50 Risk Ratio (M-H Fixed 95 CI) 014 [001 263]



Comparison 12 Sublingual misoprostol versus oral misoprostol


studies

No of


1 Complete miscarriage 2 238 Risk Ratio (M-H Random 95 CI) 107 [088 130]2 Pain 2 238 Risk Ratio (M-H Random 95 CI) 078 [036 167]

21 400 mcg sublingualmisoprostol 4hourly versus 400mcg oral misoprostol 4hourly


22 200 mg mifepristone+ 600 mcg sublingualmisoprostol versus 200 mgmifepristone + 600 mcg oralmisoprostol


3 Nausea andor vomiting 2 338 Risk Ratio (M-H Random 95 CI) 059 [041 085]31 Nausea andor vomiting 1 138 Risk Ratio (M-H Random 95 CI) 065 [011 376]32 Nausea 1 100 Risk Ratio (M-H Random 95 CI) 065 [041 105]33 Vomiting 1 100 Risk Ratio (M-H Random 95 CI) 05 [027 092]

4 Diarrhoea 2 238 Risk Ratio (M-H Random 95 CI) 085 [060 122]

41 400 mcg sublingualmisoprostol 4 hourly versus400 mcg oral misoprostol 4hourly






Comparison 13 Sublingual powdery versus sublingual compact misoprostol


studies

No of


1 Complete miscarriage 1 54 Risk Ratio (M-H Fixed 95 CI) 096 [066 141]2 Nauseavomiting 1 54 Risk Ratio (M-H Fixed 95 CI) 108 [016 710]3 Diarrhoea 1 54 Risk Ratio (M-H Fixed 95 CI) 108 [044 265]



Comparison 14 Sublingual misoprostol with versus without extended course


studies

No of


1 Complete miscarriage 1 180 Risk Ratio (M-H Fixed 95 CI) 101 [093 110]2 Nausea 1 180 Risk Ratio (M-H Fixed 95 CI) 138 [072 265]3 Pain 1 180 Risk Ratio (M-H Fixed 95 CI) 112 [096 131]4 Vomiting 1 180 Risk Ratio (M-H Fixed 95 CI) 50 [060 4195]5 Diarrhoea 1 180 Risk Ratio (M-H Fixed 95 CI) 20 [125 319]

Comparison 15 Sublingual + vaginal misoprostol versus only vaginal misoprostol


studies

No of


1 Complete miscarriage 1 80 Risk Ratio (M-H Fixed 95 CI) 10 [085 118]2 Blood loss haemoglobin level 1 80 Mean Difference (IV Fixed 95 CI) 010 [-038 058]3 Nausea 1 80 Risk Ratio (M-H Fixed 95 CI) 12 [080 179]4 Vomiting 1 80 Risk Ratio (M-H Fixed 95 CI) 078 [032 188]5 Diarrhoea 1 80 Risk Ratio (M-H Fixed 95 CI) 255 [148 438]6 Pain 1 80 Risk Ratio (M-H Fixed 95 CI) 075 [029 197]



Comparison 16 Oral misoprostol versus vaginal misoprostol


studies

No of




2 Complete miscarriage gt 13-23weeks


3 Blood loss excessive 1 100 Risk Ratio (M-H Fixed 95 CI) 30 [032 2787]4 Pain (visual analogue scale) 1 18 Mean Difference (IV Fixed 95 CI) -190 [-482 102]5 Pain 2 200 Risk Ratio (M-H Fixed 95 CI) 16 [101 255]6 Vomiting 2 290 Risk Ratio (M-H Random 95 CI) 073 [011 489]7 Nausea 3 220 Risk Ratio (M-H Fixed 95 CI) 118 [093 148]8 Diarrhoea 4 410 Risk Ratio (M-H Fixed 95 CI) 106 [072 158]





Comparison 17 Oral misoprostol + mifepristone versus expectant management


studies

No of


1 Complete miscarriage 1 122 Risk Ratio (M-H Fixed 95 CI) 108 [090 130]2 Blood loss (severe) 1 122 Risk Ratio (M-H Fixed 95 CI) 034 [001 829]3 Days of bleeding 1 122 Mean Difference (IV Fixed 95 CI) 070 [-043 183]4 Pain 1 122 Mean Difference (IV Fixed 95 CI) 410 [-592 1412]5 Pelvic infection 1 122 Risk Ratio (M-H Fixed 95 CI) 052 [005 555]

6 Womanrsquos satisfaction withtreatment (visual analogue scaleday 14)

1 122 Mean Difference (IV Fixed 95 CI) 340 [-554 1234]

Comparison 18 Buccal misoprostol lower versus higher-dose regimen


studies

No of








2 Nausea 1 135 Risk Ratio (M-H Fixed 95 CI) 061 [028 134]21 Gestation 14-24 weeks 1 135 Risk Ratio (M-H Fixed 95 CI) 061 [028 134]

3 Vomiting 1 135 Risk Ratio (M-H Fixed 95 CI) 030 [012 076]31 Gestation 14-24 weeks 1 135 Risk Ratio (M-H Fixed 95 CI) 030 [012 076]

4 Diarrhoea 1 135 Risk Ratio (M-H Fixed 95 CI) 040 [019 082]41 Gestation 14-24 weeks 1 135 Risk Ratio (M-H Fixed 95 CI) 040 [019 082]

5 Pain 1 135 Risk Ratio (M-H Fixed 95 CI) 096 [087 106]51 Gestation 14-24 weeks 1 135 Risk Ratio (M-H Fixed 95 CI) 096 [087 106]

6 Womanrsquos satisfaction withtreatment (satisfied or verysatisfied)


61 Gestation 14-24 weeks 1 135 Risk Ratio (M-H Fixed 95 CI) 095 [078 117]



Comparison 19 Mifepristone versus placebo


studies

No of


1 Complete miscarriage 1 Risk Ratio (M-H Fixed 95 CI) Subtotals only









2 Days of bleeding 1 44 Risk Ratio (M-H Fixed 95 CI) 392 [189 810]3 Pain 1 44 Risk Ratio (M-H Fixed 95 CI) 219 [093 517]

Comparison 20 Mifepristone + vaginal misoprostol versus vaginal misoprostol alone


studies

No of


1 Complete miscarriage 3 447 Risk Ratio (M-H Random 95 CI) 118 [095 147]2 Blood transfusion 1 300 Risk Ratio (M-H Fixed 95 CI) 304 [032 2890]3 Pelvic infection 1 300 Risk Ratio (M-H Fixed 95 CI) 101 [014 710]4 nausea 1 300 Risk Ratio (M-H Fixed 95 CI) 101 [076 136]5 Diarrhoea 1 300 Risk Ratio (M-H Fixed 95 CI) 094 [066 135]6 Womanrsquos satisfaction 2 135 Risk Ratio (M-H Random 95 CI) 136 [106 175]

Comparison 21 Vaginal gemeprost versus surgical evacuation of uterus


studies

No of



2 Death or serious complications(uterine perforation)


3 Nausea 1 87 Risk Ratio (M-H Fixed 95 CI) 179 [056 568]



Comparison 22 Misoprostol intravaginal extraamniotic versus vaginal misoprostol


studies

No of


1 Complete miscarriage 1 180 Risk Ratio (M-H Fixed 95 CI) 110 [100 122]2 Nausea 1 180 Risk Ratio (M-H Fixed 95 CI) 157 [133 185]3 Vomiting 1 180 Risk Ratio (M-H Fixed 95 CI) 025 [005 114]4 Diarrhoea 1 180 Risk Ratio (M-H Fixed 95 CI) 02 [001 411]5 Pain (use of analgesics) 1 180 Risk Ratio (M-H Fixed 95 CI) 030 [016 058]6 Time to expulsion 1 180 Mean Difference (IV Fixed 95 CI) -481 [-566 -396]

Comparison 23 Vaginal misoprostol with versus without extended course


studies

No of


1 Complete miscarriage 2 351 Risk Ratio (M-H Fixed 95 CI) 100 [092 109]2 Nausea 2 351 Risk Ratio (M-H Fixed 95 CI) 081 [063 104]3 Vomiting 2 351 Risk Ratio (M-H Fixed 95 CI) 118 [068 206]4 Diarrhoea 2 351 Risk Ratio (M-H Fixed 95 CI) 100 [082 122]5 Pain (use of analgesics) 1 171 Risk Ratio (M-H Fixed 95 CI) 084 [071 100]





Analysis 11 Comparison 1 Vaginal misoprostol versus placebo Outcome 1 Complete miscarriage

Review Medical treatment for early fetal death (less than 24 weeks)


Outcome 1 Complete miscarriage

Study or subgroup Misoprostol Placebo Risk Ratio Weight Risk Ratio

nN nN M-HFixed95 CI M-HFixed95 CI

1 Complete miscarriage lt 1 day

Herabutya 1997 3542 642 207 583 [ 275 1239 ]

Kovavisarach 2002 1727 527 172 340 [ 146 789 ]

Subtotal (95 CI) 69 69 379 473 [ 270 828 ]

Total events 52 (Misoprostol) 11 (Placebo)

Heterogeneity Chi2 = 089 df = 1 (P = 035) I2 =00

Test for overall effect Z = 544 (P lt 000001)

2 Complete miscarriage lt 2 days

Lister 2005 1518 216 73 667 [ 179 2478 ]

Wood 2002 2125 425 138 525 [ 210 1310 ]

Subtotal (95 CI) 43 41 211 574 [ 270 1219 ]





Bagratee 2004 3945 1138 411 299 [ 180 499 ]

Subtotal (95 CI) 45 38 411 299 [ 180 499 ]


Heterogeneity not applicable

Test for overall effect Z = 420 (P = 0000026)

Total (95 CI) 157 148 1000 423 [ 301 594 ]




Test for subgroup differences Chi2 = 246 df = 2 (P = 029) I2 =19

001 01 1 10 100

Favours placebo Favours misoprostol



Analysis 12 Comparison 1 Vaginal misoprostol versus placebo Outcome 2 Death or serious

complications uterine perforation



Outcome 2 Death or serious complications uterine perforation



Herabutya 1997 042 142 1000 033 [ 001 796 ]

Total (95 CI) 42 42 1000 033 [ 001 796 ]




Test for subgroup differences Not applicable

001 01 1 10 100

Favours misoprostol Favours placebo

Analysis 13 Comparison 1 Vaginal misoprostol versus placebo Outcome 3 Blood transfusion



Outcome 3 Blood transfusion



Herabutya 1997 042 242 1000 020 [ 001 404 ]

Total (95 CI) 42 42 1000 020 [ 001 404 ]





0001 001 01 1 10 100 1000




Analysis 14 Comparison 1 Vaginal misoprostol versus placebo Outcome 4 Blood loss haemoglobin

difference gt 10 gL



Outcome 4 Blood loss haemoglobin difference gt 10 gL



Wood 2002 525 425 1000 125 [ 038 412 ]

Total (95 CI) 25 25 1000 125 [ 038 412 ]





01 02 05 1 2 5 10


Analysis 15 Comparison 1 Vaginal misoprostol versus placebo Outcome 5 Days of bleeding vaginal

bleeding 2 weeks after treatment



Outcome 5 Days of bleeding vaginal bleeding 2 weeks after treatment



Lister 2005 616 616 1000 100 [ 041 245 ]

Total (95 CI) 16 16 1000 100 [ 041 245 ]





01 02 05 1 2 5 10




Analysis 16 Comparison 1 Vaginal misoprostol versus placebo Outcome 6 Nausea



Outcome 6 Nausea



Kovavisarach 2002 227 127 239 200 [ 019 2077 ]

Lister 2005 418 316 761 119 [ 031 451 ]

Total (95 CI) 45 43 1000 138 [ 043 440 ]





001 01 1 10 100


Analysis 17 Comparison 1 Vaginal misoprostol versus placebo Outcome 7 Diarrhoea



Outcome 7 Diarrhoea



Kovavisarach 2002 227 027 321 500 [ 025 9951 ]

Lister 2005 118 116 679 089 [ 006 1308 ]

Total (95 CI) 45 43 1000 221 [ 035 1406 ]





001 01 1 10 100




Analysis 18 Comparison 1 Vaginal misoprostol versus placebo Outcome 8 Pain (opiate use)



Outcome 8 Pain (opiate use)



Herabutya 1997 242 042 1000 500 [ 025 10111 ]

Total (95 CI) 42 42 1000 500 [ 025 10111 ]





0001 001 01 1 10 100 1000


Analysis 19 Comparison 1 Vaginal misoprostol versus placebo Outcome 9 Womanrsquos satisfaction with

treatment



Outcome 9 Womanrsquos satisfaction with treatment



Lister 2005 1416 1216 1000 117 [ 083 164 ]

Total (95 CI) 16 16 1000 117 [ 083 164 ]





01 02 05 1 2 5 10




Analysis 21 Comparison 2 Vaginal misoprostol versus expectant management Outcome 1 Complete

miscarriage




Study or subgroup Misoprostol

Expectantmanage-

ment Risk Ratio Weight Risk Ratio


Trinder 2006 192308 152306 1000 125 [ 109 145 ]

Total (95 CI) 308 306 1000 125 [ 109 145 ]

Total events 192 (Misoprostol) 152 (Expectant management)




02 05 1 2 5

Favours expectant Favours misoprostol

Analysis 22 Comparison 2 Vaginal misoprostol versus expectant management Outcome 2 Pelvic infection



Outcome 2 Pelvic infection


Expectantmanage-



Trinder 2006 16308 2310 1000 805 [ 187 3472 ]

Total (95 CI) 308 310 1000 805 [ 187 3472 ]





001 01 1 10 100

Favours misoprostol Favours expectant



Analysis 31 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 1 Complete

miscarriage




Study or subgroup Misoprostol Surgical evacuation Risk Ratio Weight Risk Ratio

nN nN

M-HRandom95

CI

M-HRandom95

CI

Demetroulis 2001 626 2424 86 025 [ 013 048 ]

Fang 2009 530 3030 71 018 [ 008 039 ]

Ganguly 2010 37 34 42 057 [ 020 159 ]

Graziosi 2004 3779 7375 293 048 [ 038 061 ]

Muffley 2002 1025 2325 137 043 [ 027 071 ]

Trinder 2006 116308 278310 371 042 [ 036 049 ]

Total (95 CI) 475 468 1000 040 [ 032 050 ]

Total events 177 (Misoprostol) 431 (Surgical evacuation)

Heterogeneity Tau2 = 003 Chi2 = 921 df = 5 (P = 010) I2 =46



01 02 05 1 2 5 10

Favours surgical Favours misoprostol



Analysis 32 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 2 Uterine

perforation



Outcome 2 Uterine perforation

Study or subgroup Misoprostol Evacuation Risk Ratio Weight Risk Ratio


Graziosi 2004 079 175 1000 032 [ 001 765 ]

Total (95 CI) 79 75 1000 032 [ 001 765 ]

Total events 0 (Misoprostol) 1 (Evacuation)




001 01 1 10 100

Favours misoprostol Favours evacuation

Analysis 33 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 3 Blood loss

post-treatment haematocrit ()



Outcome 3 Blood loss post-treatment haematocrit ()

Study or subgroup Misoprostol Surgical evacuationMean

Difference WeightMean

Difference

N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI

Muffley 2002 25 341 (5) 25 355 (2) 1000 -140 [ -351 071 ]

Total (95 CI) 25 25 1000 -140 [ -351 071 ]




-10 -5 0 5 10

Favours evacuation Favours misoprostol



Analysis 34 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 4 Pain relief



Outcome 4 Pain relief



Graziosi 2004 2479 1675 1000 142 [ 082 246 ]

Total (95 CI) 79 75 1000 142 [ 082 246 ]





01 02 05 1 2 5 10


Analysis 35 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 5 Pelvic

infection




Study or subgroup Vaginal misoprostol Surgical evacuation Risk Ratio Weight Risk Ratio


Trinder 2006 16308 22310 1000 073 [ 039 137 ]

Total (95 CI) 308 310 1000 073 [ 039 137 ]

Total events 16 (Vaginal misoprostol) 22 (Surgical evacuation)




001 01 1 10 100

Favours misoprostol Favours surgical



Analysis 36 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 6 Nausea



Outcome 6 Nausea



Graziosi 2004 1179 075 1000 2185 [ 131 36437 ]

Total (95 CI) 79 75 1000 2185 [ 131 36437 ]





0001 001 01 1 10 100 1000


Analysis 37 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 7 Diarrhoea



Outcome 7 Diarrhoea



Graziosi 2004 2179 075 1000 4085 [ 252 66257 ]

Total (95 CI) 79 75 1000 4085 [ 252 66257 ]





0001 001 01 1 10 100 1000




Analysis 38 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 8 Womanrsquos

satisfaction



Outcome 8 Womanrsquos satisfaction

Study or subgroup misoprostol curettage Risk Ratio Weight Risk Ratio


Fang 2009 815 2430 1000 067 [ 040 111 ]

Total (95 CI) 15 30 1000 067 [ 040 111 ]

Total events 8 (misoprostol) 24 (curettage)




001 01 1 10 100

curettage misoprostol

Analysis 41 Comparison 4 Vaginal misoprostol versus vaginal dinoprostone Outcome 1 Complete

miscarriage




Study or subgroup Misoprostol PGE2 Risk Ratio Weight Risk Ratio


Al Inizi 2003 1927 833 268 290 [ 151 557 ]

Kara 1999 2832 2033 732 144 [ 106 196 ]

Total (95 CI) 59 66 1000 183 [ 137 246 ]

Total events 47 (Misoprostol) 28 (PGE2)




01 02 05 1 2 5 10

Favours PGE2 Favours misoprostol



Analysis 42 Comparison 4 Vaginal misoprostol versus vaginal dinoprostone Outcome 2 Blood transfusion






Al Inizi 2003 227 033 1000 607 [ 030 12133 ]

Total (95 CI) 27 33 1000 607 [ 030 12133 ]





0001 001 01 1 10 100 1000

Favours misoprostol Favours PGE2

Analysis 43 Comparison 4 Vaginal misoprostol versus vaginal dinoprostone Outcome 3 Nausea



Outcome 3 Nausea



Kara 1999 432 433 1000 103 [ 028 378 ]

Total (95 CI) 32 33 1000 103 [ 028 378 ]





01 02 05 1 2 5 10




Analysis 44 Comparison 4 Vaginal misoprostol versus vaginal dinoprostone Outcome 4 Duration of

hospital stay (days)



Outcome 4 Duration of hospital stay (days)

Study or subgroup Misoprostol PGE2Mean


Difference


Al Inizi 2003 27 162 (056) 33 4 (28) 1000 -238 [ -336 -140 ]

Total (95 CI) 27 33 1000 -238 [ -336 -140 ]




-10 -5 0 5 10


Analysis 51 Comparison 5 Vaginal misoprostol lower versus higher-dose regimens Outcome 1 Complete

miscarriage lt 13 weeks



Outcome 1 Complete miscarriage lt 13 weeks

Study or subgroup Lower Higher Risk Ratio Weight Risk Ratio

nN nN

M-HRandom95

CI

M-HRandom95

CI

Kovavisarach 2005 2657 3957 399 067 [ 048 093 ]

Petersen 2013 111149 107134 601 093 [ 082 106 ]

Total (95 CI) 206 191 1000 082 [ 058 114 ]

Total events 137 (Lower) 146 (Higher)




01 02 05 1 2 5 10

Favours higher dose Favours lower dose




miscarriage 13-23 weeks



Outcome 2 Complete miscarriage 13-23 weeks



Niromanesh 2005 4250 4050 1000 105 [ 087 126 ]

Total (95 CI) 50 50 1000 105 [ 087 126 ]





001 01 1 10 100

Favours higher Favours lower



Analysis 53 Comparison 5 Vaginal misoprostol lower versus higher-dose regimens Outcome 3 Nausea



Outcome 3 Nausea



Kovavisarach 2005 257 757 467 029 [ 006 132 ]

Niromanesh 2005 850 850 533 100 [ 041 246 ]

Total (95 CI) 107 107 1000 067 [ 031 141 ]





001 01 1 10 100

Favours lower dose Favours higher dose

Analysis 54 Comparison 5 Vaginal misoprostol lower versus higher-dose regimens Outcome 4 Diarrhoea



Outcome 4 Diarrhoea



Kovavisarach 2005 057 257 385 020 [ 001 408 ]

Niromanesh 2005 350 450 615 075 [ 018 318 ]

Total (95 CI) 107 107 1000 054 [ 015 191 ]





0001 001 01 1 10 100 1000




Analysis 61 Comparison 6 Vaginal misoprostol wet versus dry vaginal preparations Outcome 1 Complete

miscarriage




Study or subgroup Wet Dry Risk Ratio Weight Risk Ratio



Gilles 2004 3041 2539 200 114 [ 085 154 ]

Subtotal (95 CI) 41 39 200 114 [ 085 154 ]

Total events 30 (Wet) 25 (Dry)




Gilles 2004 3441 3139 248 104 [ 084 129 ]

Subtotal (95 CI) 41 39 248 104 [ 084 129 ]





Gilles 2004 3441 3539 280 092 [ 078 110 ]

Subtotal (95 CI) 41 39 280 092 [ 078 110 ]





Gilles 2004 3441 3439 272 095 [ 079 114 ]

Subtotal (95 CI) 41 39 272 095 [ 079 114 ]




Total (95 CI) 164 156 1000 100 [ 090 112 ]





01 02 05 1 2 5 10

Favours dry Favours wet



Analysis 62 Comparison 6 Vaginal misoprostol wet versus dry vaginal preparations Outcome 2 Diarrhoea



Outcome 2 Diarrhoea



Gilles 2004 1740 937 1000 175 [ 089 342 ]

Total (95 CI) 40 37 1000 175 [ 089 342 ]





01 02 05 1 2 5 10

Favours wet Favours dry

Analysis 63 Comparison 6 Vaginal misoprostol wet versus dry vaginal preparations Outcome 3 Vomiting



Outcome 3 Vomiting



Gilles 2004 640 637 1000 093 [ 033 262 ]

Total (95 CI) 40 37 1000 093 [ 033 262 ]





01 02 05 1 2 5 10




Analysis 64 Comparison 6 Vaginal misoprostol wet versus dry vaginal preparations Outcome 4

Acceptability of method would wishprobably wish same treatment in future nonviable pregnancy



Outcome 4 Acceptability of method would wishprobably wish same treatment in future nonviable pregnancy



Gilles 2004 3136 2737 1000 118 [ 093 149 ]

Total (95 CI) 36 37 1000 118 [ 093 149 ]





01 02 05 1 2 5 10


Analysis 71 Comparison 7 Vaginal misoprostol + methotrexate versus vaginal misoprostol alone





Study or subgroup MTX + Misoprostol Misoprostol Risk Ratio Weight Risk Ratio


Autry 1999 1212 89 1000 113 [ 085 150 ]

Total (95 CI) 12 9 1000 113 [ 085 150 ]

Total events 12 (MTX + Misoprostol) 8 (Misoprostol)




001 01 1 10 100

Favours MTX + miso Favours misoprostol




Outcome 2 Haemorrhage






Autry 1999 112 09 1000 231 [ 010 5085 ]

Total (95 CI) 12 9 1000 231 [ 010 5085 ]





001 01 1 10 100

Favours MTX + misoprostol Favours misoprostol








Autry 1999 412 49 1000 075 [ 025 222 ]

Total (95 CI) 12 9 1000 075 [ 025 222 ]





001 01 1 10 100




Analysis 81 Comparison 8 Vaginal misoprostol plus laminaria tents versus vaginal misoprostol alone





Study or subgroup Tents Misoprostol Risk Ratio Weight Risk Ratio



Jain 1996 1520 1518 484 090 [ 065 125 ]

Subtotal (95 CI) 20 18 484 090 [ 065 125 ]

Total events 15 (Tents) 15 (Misoprostol)




Jain 1996 1920 1618 516 107 [ 088 129 ]

Subtotal (95 CI) 20 18 516 107 [ 088 129 ]




Total (95 CI) 40 36 1000 099 [ 082 118 ]





01 02 05 1 2 5 10

Favours misoprostol Favours miso + tents



Analysis 91 Comparison 9 Vaginal misoprostol versus sublingual misoprostol Outcome 1 Complete





Study or subgroup Vaginal

Sublingualevery 3

hours Risk Ratio Weight Risk Ratio

nN nN

M-HRandom95

CI

M-HRandom95

CI

Dehbashi 2016 925 1027 116 097 [ 047 199 ]

Shah 2010 1019 1122 142 105 [ 058 191 ]

Sonsanoh 2014 3660 4160 234 088 [ 067 115 ]

Tang 2003 3540 3540 260 100 [ 085 118 ]

Tanha 2010a 51110 93110 248 055 [ 044 068 ]

Total (95 CI) 254 259 1000 084 [ 061 116 ]

Total events 141 (Vaginal) 190 (Sublingual every 3 hours)




001 01 1 10 100

Favours sublingual Favours vaginal








Study or subgroup vaginal sublingual Risk Ratio Weight Risk Ratio


Shah 2010 26 23 1000 050 [ 013 200 ]

Total (95 CI) 6 3 1000 050 [ 013 200 ]

Total events 2 (vaginal) 2 (sublingual)




001 01 1 10 100

sublingual vaginal

Analysis 93 Comparison 9 Vaginal misoprostol versus sublingual misoprostol Outcome 3 Blood loss

excessive (gt menstruation)



Outcome 3 Blood loss excessive (gt menstruation)

Study or subgroup Vaginal Sublingual Risk Ratio Weight Risk Ratio

nN nN

M-HRandom95

CI

M-HRandom95

CI

Sonsanoh 2014 360 1260 395 025 [ 007 084 ]

Tanha 2010a 48110 54110 605 089 [ 067 118 ]

Total (95 CI) 170 170 1000 054 [ 015 189 ]

Total events 51 (Vaginal) 66 (Sublingual)




001 01 1 10 100

Favours vaginal Favours sublingual



Analysis 94 Comparison 9 Vaginal misoprostol versus sublingual misoprostol Outcome 4 Pain



Outcome 4 Pain



Dehbashi 2016 025 127 14 036 [ 002 843 ]

Sonsanoh 2014 1960 2760 256 070 [ 044 112 ]

Tanha 2010a 42110 77110 730 055 [ 042 071 ]

Total (95 CI) 195 197 1000 058 [ 046 074 ]





001 01 1 10 100




Analysis 95 Comparison 9 Vaginal misoprostol versus sublingual misoprostol Outcome 5 Nausea



Outcome 5 Nausea

Study or subgroup Vaginal misoprostol

Sublingualmisopros-

tol Risk Ratio Weight Risk Ratio

nN nN

M-HRandom95

CI

M-HRandom95

CI

Dehbashi 2016 025 627 128 008 [ 000 140 ]

Shah 2010 125 1525 198 007 [ 001 047 ]

Sonsanoh 2014 760 660 304 117 [ 042 327 ]

Tang 2003 2040 2440 370 083 [ 056 124 ]

Total (95 CI) 150 152 1000 042 [ 012 144 ]

Total events 28 (Vaginal misoprostol) 51 (Sublingual misoprostol)




001 01 1 10 100




Analysis 96 Comparison 9 Vaginal misoprostol versus sublingual misoprostol Outcome 6 Vomiting



Outcome 6 Vomiting



Tang 2003 940 740 241 129 [ 053 312 ]

Tanha 2010a 13110 22110 759 059 [ 031 111 ]

Total (95 CI) 150 150 1000 076 [ 046 126 ]





001 01 1 10 100


Analysis 97 Comparison 9 Vaginal misoprostol versus sublingual misoprostol Outcome 7 Diarrhoea



Outcome 7 Diarrhoea



Dehbashi 2016 525 627 69 090 [ 031 258 ]

Sonsanoh 2014 360 460 48 075 [ 018 321 ]

Tang 2003 1140 2840 334 039 [ 023 068 ]

Tanha 2010a 40110 46110 549 087 [ 062 121 ]

Total (95 CI) 235 237 1000 071 [ 054 092 ]





001 01 1 10 100




Analysis 101 Comparison 10 Vaginal misoprostol versus intravenous oxytocin Outcome 1 Complete





Study or subgroup Vaginal misoprostol Oxytocin Risk Ratio Weight Risk Ratio


Abediasl 2016 3840 3945 1000 110 [ 096 125 ]

Total (95 CI) 40 45 1000 110 [ 096 125 ]

Total events 38 (Vaginal misoprostol) 39 (Oxytocin)




001 01 1 10 100

Favours misoprostol Favours oxytocin



Analysis 102 Comparison 10 Vaginal misoprostol versus intravenous oxytocin Outcome 2 Blood loss

excessive



Outcome 2 Blood loss excessive



1 Gestation 15-24 weeks

Abediasl 2016 140 245 1000 056 [ 005 597 ]

Total (95 CI) 40 45 1000 056 [ 005 597 ]





001 01 1 10 100


Analysis 111 Comparison 11 Vaginal misoprostol versus vaginal gemeprost Outcome 1 Complete





Study or subgroup Misoprostol Gemeprost Risk Ratio Weight Risk Ratio


Eng 1997 2125 1725 1000 124 [ 090 170 ]

Total (95 CI) 25 25 1000 124 [ 090 170 ]

Total events 21 (Misoprostol) 17 (Gemeprost)




01 02 05 1 2 5 10

Favours gemeprost Favours misoprostol



Analysis 112 Comparison 11 Vaginal misoprostol versus vaginal gemeprost Outcome 2 Opiates for pain

relief



Outcome 2 Opiates for pain relief



Eng 1997 025 025 Not estimable

Total (95 CI) 25 25 Not estimable



Test for overall effect not applicable


01 02 05 1 2 5 10

Favours misoprostol Favours gemeprost

Analysis 113 Comparison 11 Vaginal misoprostol versus vaginal gemeprost Outcome 3 Vomiting



Outcome 3 Vomiting



Eng 1997 125 025 1000 300 [ 013 7030 ]

Total (95 CI) 25 25 1000 300 [ 013 7030 ]





001 01 1 10 100




Analysis 114 Comparison 11 Vaginal misoprostol versus vaginal gemeprost Outcome 4 Diarrhoea



Outcome 4 Diarrhoea



Eng 1997 025 325 1000 014 [ 001 263 ]

Total (95 CI) 25 25 1000 014 [ 001 263 ]





0001 001 01 1 10 100 1000


Analysis 121 Comparison 12 Sublingual misoprostol versus oral misoprostol Outcome 1 Complete

miscarriage




Study or subgroup Sublingual Oral Risk Ratio Weight Risk Ratio

nN nN

M-HRandom95

CI

M-HRandom95

CI

Ayudhaya 2006 1570 1768 97 086 [ 047 158 ]

Kushwah 2009 4650 4250 903 110 [ 095 127 ]

Total (95 CI) 120 118 1000 107 [ 088 130 ]

Total events 61 (Sublingual) 59 (Oral)




001 01 1 10 100

Favours sublingual Favours oral



Analysis 122 Comparison 12 Sublingual misoprostol versus oral misoprostol Outcome 2 Pain



Outcome 2 Pain


nN nN

M-HRandom95

CI

M-HRandom95

CI

1 400 mcg sublingual misoprostol 4hourly versus 400 mcg oral misoprostol 4hourly

Ayudhaya 2006 4770 4068 507 114 [ 088 148 ]

Subtotal (95 CI) 70 68 507 114 [ 088 148 ]




2 200 mg mifepristone + 600 mcg sublingual misoprostol versus 200 mg mifepristone + 600 mcg oral misoprostol

Kushwah 2009 2350 4450 493 052 [ 038 072 ]

Subtotal (95 CI) 50 50 493 052 [ 038 072 ]




Total (95 CI) 120 118 1000 078 [ 036 167 ]





001 01 1 10 100




Analysis 123 Comparison 12 Sublingual misoprostol versus oral misoprostol Outcome 3 Nausea andor

vomiting



Outcome 3 Nausea andor vomiting


nN nN

M-HRandom95

CI

M-HRandom95

CI

1 Nausea andor vomiting

Ayudhaya 2006 270 368 43 065 [ 011 376 ]

Subtotal (95 CI) 70 68 43 065 [ 011 376 ]




2 Nausea

Kushwah 2009 1750 2650 600 065 [ 041 105 ]

Subtotal (95 CI) 50 50 600 065 [ 041 105 ]




3 Vomiting

Kushwah 2009 1150 2250 357 050 [ 027 092 ]

Subtotal (95 CI) 50 50 357 050 [ 027 092 ]




Total (95 CI) 170 168 1000 059 [ 041 085 ]





001 01 1 10 100




Analysis 124 Comparison 12 Sublingual misoprostol versus oral misoprostol Outcome 4 Diarrhoea



Outcome 4 Diarrhoea


nN nN

M-HRandom95

CI

M-HRandom95

CI

1 400 mcg sublingual misoprostol 4 hourly versus 400 mcg oral misoprostol 4 hourly

Ayudhaya 2006 670 768 118 083 [ 029 235 ]

Subtotal (95 CI) 70 68 118 083 [ 029 235 ]





Kushwah 2009 2450 2850 882 086 [ 059 125 ]

Subtotal (95 CI) 50 50 882 086 [ 059 125 ]




Total (95 CI) 120 118 1000 085 [ 060 122 ]





001 01 1 10 100




Analysis 125 Comparison 12 Sublingual misoprostol versus oral misoprostol Outcome 5 Womanrsquos

satisfaction with treatment






Kushwah 2009 4650 3650 1000 128 [ 106 155 ]

Total (95 CI) 50 50 1000 128 [ 106 155 ]





001 01 1 10 100

Favours oral Favours sublingual

Analysis 131 Comparison 13 Sublingual powdery versus sublingual compact misoprostol Outcome 1

Complete miscarriage




Study or subgroup

600mcgpowdery

misoprosto

600mcgcompact

misoprosto

RiskRatio(Non-

event) Weight

RiskRatio(Non-

event)


Saichua 2009 926 928 1000 096 [ 066 141 ]

Total (95 CI) 26 28 1000 096 [ 066 141 ]

Total events 9 (600mcg powdery misoprosto) 9 (600mcg compact misoprosto)




001 01 1 10 100

Favours compact Favours powdery




Nauseavomiting



Outcome 2 Nauseavomiting

Study or subgroup

600mcgpowdery

misoprosto

600mcgcompact

misoprosto Risk Ratio Weight Risk Ratio


Saichua 2009 226 228 1000 108 [ 016 710 ]

Total (95 CI) 26 28 1000 108 [ 016 710 ]





001 01 1 10 100

Favours powdery Favours compact


Diarrhoea



Outcome 3 Diarrhoea

Study or subgroup

600mcgpowdery

misoprosto

600mcgcompact



Saichua 2009 726 728 1000 108 [ 044 265 ]

Total (95 CI) 26 28 1000 108 [ 044 265 ]





001 01 1 10 100




Analysis 141 Comparison 14 Sublingual misoprostol with versus without extended course Outcome 1





Study or subgroup Extended course Normal course Risk Ratio Weight Risk Ratio


Tang 2006 8490 8390 1000 101 [ 093 110 ]

Total (95 CI) 90 90 1000 101 [ 093 110 ]

Total events 84 (Extended course) 83 (Normal course)




01 02 05 1 2 5 10

Favours normal Favours extended




Nausea



Outcome 2 Nausea



Tang 2006 1890 1390 1000 138 [ 072 265 ]

Total (95 CI) 90 90 1000 138 [ 072 265 ]





001 01 1 10 100

Favours extended Favours normal


Pain



Outcome 3 Pain



Tang 2006 7490 6690 1000 112 [ 096 131 ]

Total (95 CI) 90 90 1000 112 [ 096 131 ]





001 01 1 10 100





Vomiting



Outcome 4 Vomiting



Tang 2006 590 190 1000 500 [ 060 4195 ]

Total (95 CI) 90 90 1000 500 [ 060 4195 ]





001 01 1 10 100



Diarrhoea



Outcome 5 Diarrhoea



Tang 2006 3890 1990 1000 200 [ 125 319 ]

Total (95 CI) 90 90 1000 200 [ 125 319 ]





001 01 1 10 100




Analysis 151 Comparison 15 Sublingual + vaginal misoprostol versus only vaginal misoprostol Outcome 1





Study or subgroup Sublingual Vaginal Risk Ratio Weight Risk Ratio


Tang 2003 3540 3540 1000 100 [ 085 118 ]

Total (95 CI) 40 40 1000 100 [ 085 118 ]

Total events 35 (Sublingual) 35 (Vaginal)




01 02 05 1 2 5 10



Blood loss haemoglobin level



Outcome 2 Blood loss haemoglobin level

Study or subgroup Sublingual VaginalMean


Difference


Tang 2003 40 126 (11) 40 125 (11) 1000 010 [ -038 058 ]

Total (95 CI) 40 40 1000 010 [ -038 058 ]




-10 -5 0 5 10





Nausea



Outcome 3 Nausea



Tang 2003 2440 2040 1000 120 [ 080 179 ]

Total (95 CI) 40 40 1000 120 [ 080 179 ]





01 02 05 1 2 5 10



Vomiting



Outcome 4 Vomiting



Tang 2003 740 940 1000 078 [ 032 188 ]

Total (95 CI) 40 40 1000 078 [ 032 188 ]





01 02 05 1 2 5 10





Diarrhoea



Outcome 5 Diarrhoea



Tang 2003 2840 1140 1000 255 [ 148 438 ]

Total (95 CI) 40 40 1000 255 [ 148 438 ]





01 02 05 1 2 5 10



Pain



Outcome 6 Pain



Tang 2003 640 840 1000 075 [ 029 197 ]

Total (95 CI) 40 40 1000 075 [ 029 197 ]





01 02 05 1 2 5 10





Womanrsquos satisfaction with treatment






Tang 2003 3038 3139 1000 099 [ 079 125 ]

Total (95 CI) 38 39 1000 099 [ 079 125 ]





01 02 05 1 2 5 10


Analysis 161 Comparison 16 Oral misoprostol versus vaginal misoprostol Outcome 1 Complete





Study or subgroup Oral misoprostol Vaginal misoprostol Risk Ratio Weight Risk Ratio

nN nN

M-HRandom95

CI

M-HRandom95

CI

Creinin 1997 312 78 111 029 [ 010 079 ]

Marwah 2016 3750 4050 305 093 [ 075 115 ]

Ngoc 2004 89100 9198 328 096 [ 088 105 ]

Rita 2006 1850 4050 256 045 [ 030 067 ]

Total (95 CI) 212 206 1000 068 [ 045 103 ]

Total events 147 (Oral misoprostol) 178 (Vaginal misoprostol)

Heterogeneity Tau2 = 013 Chi2 = 2864 df = 3 (Plt000001) I2 =90



05 07 1 15 2

Favours vaginal Favours oral




miscarriage gt 13-23 weeks



Outcome 2 Complete miscarriage gt 13-23 weeks



Chittacharoen 2003 2020 2424 1000 100 [ 092 109 ]

Total (95 CI) 20 24 1000 100 [ 092 109 ]





02 05 1 2 5

favours vaginal favours oral



Analysis 163 Comparison 16 Oral misoprostol versus vaginal misoprostol Outcome 3 Blood loss

excessive






Marwah 2016 350 150 1000 300 [ 032 2787 ]

Total (95 CI) 50 50 1000 300 [ 032 2787 ]





001 01 1 10 100

Favours oral Favours vaginal

Analysis 164 Comparison 16 Oral misoprostol versus vaginal misoprostol Outcome 4 Pain (visual

analogue scale)



Outcome 4 Pain (visual analogue scale)

Study or subgroup Oral misoprostol Vaginal misoprostolMean


Difference


Creinin 1997 11 4 (36) 7 59 (27) 1000 -190 [ -482 102 ]

Total (95 CI) 11 7 1000 -190 [ -482 102 ]




-10 -5 0 5 10




Analysis 165 Comparison 16 Oral misoprostol versus vaginal misoprostol Outcome 5 Pain



Outcome 5 Pain



Marwah 2016 2450 1550 750 160 [ 096 267 ]

Rita 2006 850 550 250 160 [ 056 456 ]

Total (95 CI) 100 100 1000 160 [ 101 255 ]





001 01 1 10 100


Analysis 166 Comparison 16 Oral misoprostol versus vaginal misoprostol Outcome 6 Vomiting



Outcome 6 Vomiting


nN nN

M-HRandom95

CI

M-HRandom95

CI

Ngoc 2004 495 1495 521 029 [ 010 084 ]

Rita 2006 650 350 479 200 [ 053 756 ]

Total (95 CI) 145 145 1000 073 [ 011 489 ]





001 01 1 10 100




Analysis 167 Comparison 16 Oral misoprostol versus vaginal misoprostol Outcome 7 Nausea



Outcome 7 Nausea



Creinin 1997 612 58 107 080 [ 037 174 ]

Marwah 2016 3650 3050 536 120 [ 090 160 ]

Rita 2006 2550 2050 357 125 [ 081 194 ]

Total (95 CI) 112 108 1000 118 [ 093 148 ]





01 02 05 1 2 5 10




Analysis 168 Comparison 16 Oral misoprostol versus vaginal misoprostol Outcome 8 Diarrhoea



Outcome 8 Diarrhoea



Creinin 1997 512 38 96 111 [ 036 340 ]

Marwah 2016 750 650 160 117 [ 042 323 ]

Ngoc 2004 2495 2395 612 104 [ 064 171 ]

Rita 2006 550 550 133 100 [ 031 324 ]

Total (95 CI) 207 203 1000 106 [ 072 158 ]





01 02 05 1 2 5 10


Analysis 169 Comparison 16 Oral misoprostol versus vaginal misoprostol Outcome 9 Womanrsquos







Ngoc 2004 86100 8898 1000 096 [ 086 106 ]

Total (95 CI) 100 98 1000 096 [ 086 106 ]





01 02 05 1 2 5 10




Analysis 171 Comparison 17 Oral misoprostol + mifepristone versus expectant management Outcome 1





Study or subgroup Medical Expectant Risk Ratio Weight Risk Ratio


Nielsen 1999 4960 4762 1000 108 [ 090 130 ]

Total (95 CI) 60 62 1000 108 [ 090 130 ]

Total events 49 (Medical) 47 (Expectant)




01 02 05 1 2 5 10

Favours expectant Favours medical




Blood loss (severe)



Outcome 2 Blood loss (severe)



Nielsen 1999 060 162 1000 034 [ 001 829 ]

Total (95 CI) 60 62 1000 034 [ 001 829 ]





001 01 1 10 100

Favours medical Favours expectant


Days of bleeding



Outcome 3 Days of bleeding

Study or subgroup Medical ExpectantMean


Difference


Nielsen 1999 60 11 (326) 62 103 (311) 1000 070 [ -043 183 ]

Total (95 CI) 60 62 1000 070 [ -043 183 ]




-10 -5 0 5 10





Pain



Outcome 4 Pain



Difference


Nielsen 1999 60 661 (263) 62 62 (301) 1000 410 [ -592 1412 ]

Total (95 CI) 60 62 1000 410 [ -592 1412 ]




-100 -50 0 50 100



Pelvic infection






Nielsen 1999 160 262 1000 052 [ 005 555 ]

Total (95 CI) 60 62 1000 052 [ 005 555 ]





001 01 1 10 100





Womanrsquos satisfaction with treatment (visual analogue scale day 14)



Outcome 6 Womanrsquos satisfaction with treatment (visual analogue scale day 14)



Difference


Nielsen 1999 60 286 (248) 62 252 (256) 1000 340 [ -554 1234 ]

Total (95 CI) 60 62 1000 340 [ -554 1234 ]




-100 -50 0 50 100




Analysis 181 Comparison 18 Buccal misoprostol lower versus higher-dose regimen Outcome 1 Complete





Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal

misoprostol Risk Ratio Weight Risk Ratio



Bracken 2014 2763 4872 457 064 [ 046 089 ]

Subtotal (95 CI) 63 72 457 064 [ 046 089 ]

Total events 27 (100mcg buccal misoprostol) 48 (200mcg buccal misoprostol)




Bracken 2014 3863 5772 543 076 [ 060 096 ]

Subtotal (95 CI) 63 72 543 076 [ 060 096 ]




Total (95 CI) 126 144 1000 071 [ 058 086 ]





001 01 1 10 100

Favours 200mcg Favours 100mcg



Analysis 182 Comparison 18 Buccal misoprostol lower versus higher-dose regimen Outcome 2 Nausea



Outcome 2 Nausea

Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 863 1572 1000 061 [ 028 134 ]

Total (95 CI) 63 72 1000 061 [ 028 134 ]





001 01 1 10 100


Analysis 183 Comparison 18 Buccal misoprostol lower versus higher-dose regimen Outcome 3 Vomiting



Outcome 3 Vomiting

Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 563 1972 1000 030 [ 012 076 ]

Total (95 CI) 63 72 1000 030 [ 012 076 ]





001 01 1 10 100




Analysis 184 Comparison 18 Buccal misoprostol lower versus higher-dose regimen Outcome 4 Diarrhoea



Outcome 4 Diarrhoea

Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 863 2372 1000 040 [ 019 082 ]

Total (95 CI) 63 72 1000 040 [ 019 082 ]





001 01 1 10 100




Analysis 185 Comparison 18 Buccal misoprostol lower versus higher-dose regimen Outcome 5 Pain



Outcome 5 Pain

Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 5763 6872 1000 096 [ 087 106 ]

Total (95 CI) 63 72 1000 096 [ 087 106 ]





001 01 1 10 100


Analysis 186 Comparison 18 Buccal misoprostol lower versus higher-dose regimen Outcome 6 Womanrsquos

satisfaction with treatment (satisfied or very satisfied)



Outcome 6 Womanrsquos satisfaction with treatment (satisfied or very satisfied)

Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 4563 5472 1000 095 [ 078 117 ]

Total (95 CI) 63 72 1000 095 [ 078 117 ]





001 01 1 10 100




Analysis 191 Comparison 19 Mifepristone versus placebo Outcome 1 Complete miscarriage




Study or subgroup Mifepristone Placebo Risk Ratio Weight Risk Ratio



Lelaidier 1993 223 023 1000 500 [ 025 9875 ]

Subtotal (95 CI) 23 23 1000 500 [ 025 9875 ]

Total events 2 (Mifepristone) 0 (Placebo)




Lelaidier 1993 923 023 1000 1900 [ 117 30840 ]

Subtotal (95 CI) 23 23 1000 1900 [ 117 30840 ]





Lelaidier 1993 1423 123 1000 1400 [ 200 9788 ]

Subtotal (95 CI) 23 23 1000 1400 [ 200 9788 ]





Lelaidier 1993 1923 223 1000 950 [ 249 3619 ]

Subtotal (95 CI) 23 23 1000 950 [ 249 3619 ]





001 01 1 10 100

Favours placebo Favours mifepristone



Analysis 192 Comparison 19 Mifepristone versus placebo Outcome 2 Days of bleeding






Lelaidier 1993 2323 521 1000 392 [ 189 810 ]

Total (95 CI) 23 21 1000 392 [ 189 810 ]





01 02 05 1 2 5 10

Favours mifepristone Favours placebo

Analysis 193 Comparison 19 Mifepristone versus placebo Outcome 3 Pain



Outcome 3 Pain



Lelaidier 1993 1223 521 1000 219 [ 093 517 ]

Total (95 CI) 23 21 1000 219 [ 093 517 ]





01 02 05 1 2 5 10




Analysis 201 Comparison 20 Mifepristone + vaginal misoprostol versus vaginal misoprostol alone





Study or subgroupmifepriston+misoprostol misoprostol Risk Ratio Weight Risk Ratio

nN nN

M-HRandom95

CI

M-HRandom95

CI

Fang 2009 2330 2530 292 092 [ 071 119 ]

Schreiber 2018 135148 113149 433 120 [ 108 133 ]

Sinha 2018 3945 2645 274 150 [ 114 197 ]

Total (95 CI) 223 224 1000 118 [ 095 147 ]

Total events 197 (mifepriston+ misoprostol) 164 (misoprostol)




02 05 1 2 5

misoprostol mifepriston + misoprostol










Schreiber 2018 3149 1151 1000 304 [ 032 2890 ]

Total (95 CI) 149 151 1000 304 [ 032 2890 ]





001 01 1 10 100

mifepriston+ misoprostol misoprostol








Schreiber 2018 2149 2151 1000 101 [ 014 710 ]

Total (95 CI) 149 151 1000 101 [ 014 710 ]





001 01 1 10 100





Outcome 4 nausea



Outcome 4 nausea



Schreiber 2018 56149 56151 1000 101 [ 076 136 ]

Total (95 CI) 149 151 1000 101 [ 076 136 ]





001 01 1 10 100



Outcome 5 Diarrhoea



Outcome 5 Diarrhoea



Schreiber 2018 41149 44151 1000 094 [ 066 135 ]

Total (95 CI) 149 151 1000 094 [ 066 135 ]





001 01 1 10 100

misoprostol mifepriston+ misoprostol









nN nN

M-HRandom95

CI

M-HRandom95

CI

Fang 2009 1630 715 152 114 [ 060 216 ]

Sinha 2018 3845 2745 848 141 [ 107 184 ]

Total (95 CI) 75 60 1000 136 [ 106 175 ]





001 01 1 10 100


Analysis 211 Comparison 21 Vaginal gemeprost versus surgical evacuation of uterus Outcome 1





Study or subgroup Gemeprost Evacuation Risk Ratio Weight Risk Ratio


Egarter 1995 3343 4244 1000 080 [ 067 096 ]

Total (95 CI) 43 44 1000 080 [ 067 096 ]

Total events 33 (Gemeprost) 42 (Evacuation)




01 02 05 1 2 5 10

Favours evacuation Favours gemeprost



Analysis 212 Comparison 21 Vaginal gemeprost versus surgical evacuation of uterus Outcome 2 Death or

serious complications (uterine perforation)



Outcome 2 Death or serious complications (uterine perforation)

Study or subgroup Gemeprost Evacuation

RiskRatio(Non-

event) Weight

RiskRatio(Non-

event)


Egarter 1995 043 244 1000 105 [ 097 113 ]

Total (95 CI) 43 44 1000 105 [ 097 113 ]





01 02 05 1 2 5 10




Analysis 213 Comparison 21 Vaginal gemeprost versus surgical evacuation of uterus Outcome 3 Nausea



Outcome 3 Nausea



Egarter 1995 743 444 1000 179 [ 056 568 ]

Total (95 CI) 43 44 1000 179 [ 056 568 ]





01 02 05 1 2 5 10

Favours gemeprost Favours evacuation

Analysis 221 Comparison 22 Misoprostol intravaginal extraamniotic versus vaginal misoprostol Outcome





Study or subgroup Extraamniotic Vaginal Risk Ratio Weight Risk Ratio


Mitwaly 2016 8590 7790 1000 110 [ 100 122 ]

Total (95 CI) 90 90 1000 110 [ 100 122 ]

Total events 85 (Extraamniotic) 77 (Vaginal)




001 01 1 10 100

Favours vaginal Favours extraamniotic




2 Nausea



Outcome 2 Nausea

Study or subgroup Extraamniotic Vaginal

RiskRatio(Non-

event) Weight

RiskRatio(Non-

event)


Mitwaly 2016 290 3490 1000 157 [ 133 185 ]

Total (95 CI) 90 90 1000 157 [ 133 185 ]





001 01 1 10 100



3 Vomiting



Outcome 3 Vomiting



Mitwaly 2016 290 890 1000 025 [ 005 114 ]

Total (95 CI) 90 90 1000 025 [ 005 114 ]





001 01 1 10 100

Favours extraamniotic Favours vaginal




4 Diarrhoea



Outcome 4 Diarrhoea



Mitwaly 2016 090 290 1000 020 [ 001 411 ]

Total (95 CI) 90 90 1000 020 [ 001 411 ]





001 01 1 10 100



5 Pain (use of analgesics)



Outcome 5 Pain (use of analgesics)



Mitwaly 2016 1090 3390 1000 030 [ 016 058 ]

Total (95 CI) 90 90 1000 030 [ 016 058 ]





001 01 1 10 100





6 Time to expulsion



Outcome 6 Time to expulsion

Study or subgroup Extraamniotic VaginalMean


Difference


Mitwaly 2016 90 511 (266) 90 992 (312) 1000 -481 [ -566 -396 ]

Total (95 CI) 90 90 1000 -481 [ -566 -396 ]




-100 -50 0 50 100


Analysis 231 Comparison 23 Vaginal misoprostol with versus without extended course Outcome 1





Study or subgroup Single dose Multiple doses Risk Ratio Weight Risk Ratio


Mizrachi 2017 6787 6484 437 101 [ 086 119 ]

Tang 2006 8390 8490 563 099 [ 091 107 ]

Total (95 CI) 177 174 1000 100 [ 092 109 ]

Total events 150 (Single dose) 148 (Multiple doses)




001 01 1 10 100

Favours single dose Favours multiple doses




Nausea



Outcome 2 Nausea



Mizrachi 2017 2887 3584 442 077 [ 052 115 ]

Tang 2006 3890 4590 558 084 [ 061 116 ]

Total (95 CI) 177 174 1000 081 [ 063 104 ]





001 01 1 10 100



Vomiting



Outcome 3 Vomiting



Mizrachi 2017 1187 684 304 177 [ 069 457 ]

Tang 2006 1390 1490 696 093 [ 046 186 ]

Total (95 CI) 177 174 1000 118 [ 068 206 ]





001 01 1 10 100





Diarrhoea



Outcome 4 Diarrhoea



Mizrachi 2017 2587 2284 262 110 [ 067 179 ]

Tang 2006 6190 6390 738 097 [ 080 118 ]

Total (95 CI) 177 174 1000 100 [ 082 122 ]





001 01 1 10 100




Analysis 235 Comparison 23 Vaginal misoprostol with versus without extended course Outcome 5 Pain

(use of analgesics)






Mizrachi 2017 6087 6984 1000 084 [ 071 100 ]

Total (95 CI) 87 84 1000 084 [ 071 100 ]





001 01 1 10 100

Favours single dose Favoursmultiple doses








Mizrachi 2017 6487 6184 1000 101 [ 084 122 ]

Total (95 CI) 87 84 1000 101 [ 084 122 ]





001 01 1 10 100




A P P E N D I C E S

Appendix 1 Search terms for ClinicalTrialsgov and ICTRP

Each line was run separatelyfetal deathanembryonic pregnancyfetal demisepregnancy lossnon viable pregnancy

W H A T rsquo S N E W

Date Event Description

24 October 2018 New citation required but conclusions have notchanged

This update has added 21 new studies Two studiespreviously included have now been excluded (Fadalla2004 Heard 2002)Ten new comparisons have been added The review nowincludes a total of 23 comparisons including a widevariety of different interventions mainly consisting ofsingle studiesThe available evidence from randomised control trialsstill supports the use of vaginal misoprostol

24 October 2018 New search has been performed Search updated rsquoSummary of findingsrsquo tables incorpo-rated

H I S T O R Y

Protocol first published Issue 3 2000

Review first published Issue 3 2006


8 August 2012 Amended Search updated One hundred reports added to Studies awaiting classification

18 September 2008 Amended Converted to new review format



C O N T R I B U T I O N S O F A U T H O R S

Marike Lemmers screening for inexclusion data extraction data analyses quality of evidence assessment completing first draft andfurther revisions of the updated review

Marianne Verschoor review update protocol development screening for inexclusion data extraction data entry analyses quality ofevidence assessment assisting first draft of the updated review

Bobae Kim data extraction data entry quality of evidence assessment revisions to first draft of the updated review

Martha Hickey original protocol development and revisions to the first draft of the original review

Juan Vazquez original protocol development and revisions to first draft of the original review

Ben Willem Mol supervision of review update protocol development supervision of data extractions data entry and analyses revisionsto first draft of the updated review

Jim Neilson supervision of original protocol development completion of first draft of original review Supervision of total process ofpreparing the updated review

D E C L A R A T I O N S O F I N T E R E S T

Marike Lemmers for previous work (the MisoREST trial) which focuses on miscarriage treatment my institution (AMC) received aZonMW grant ZonMW is a Dutch governmental organization for Health Research and Development

Marianne AC Verschoor my institution linked received a ZonMW grant for the MisoREST study

Bobae Veronica Kim none known

Martha Hickey none known

Juan C Vazquez none known

Ben Willem J Mol my institution and I have received payment for consultancy from ObsEva Geneva I have received payment forreview preparation from Eur J Obste Gynaecol and I have received travelaccommodationmeeting expenses for various non-commercialscientific meetings

James P Neilson none known

S O U R C E S O F S U P P O R T

Internal sources

bull America Arias Hospital Havana Cubabull The University of Liverpool UKbull Academic Medical Centre Amsterdam Netherlands



External sources

bull HRPWHO Geneva Switzerland

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

The protocol for this review aimed to include both trials for treatment of both ultrasound-diagnosed non-viable pregnancies andincomplete miscarriage For the reasons described in the review two separate reviews now address these topics - thus the change intitle from rsquoMedical management for miscarriagersquo to lsquoMedical treatment for early fetal death (less than 24 weeks)rsquo

In this update the evidence has been assessed for quality using the GRADE approach and rsquoSummary of findingsrsquo tables have beenincorporated

Several subgroup analyses that were not prespecified have been performed because there were subgroups of clinical interest Theseincluded the following

For comparison 1 vaginal misoprostol versus placebo primary outcome complete miscarriage

1 complete miscarriage less than one day

2 complete miscarriage less than two days

3 complete miscarriage less than seven days

For comparison 6 vaginal misoprostol wet versus dry preparations primary outcome complete miscarriage

1 complete miscarriage less than three days

2 complete miscarriage less than eight days

3 complete miscarriage less than 15 days


For comparison 8 vaginal misoprostol plus laminaria tents versus vaginal misoprostol alone primary outcome complete miscarriage



For comparison 18 buccal misoprostol lower versus higher regimen primary outcome complete miscarriage 13 to 23 weeks



For comparison 19 mifepristone versus placebo primary outcome complete miscarriage



3 complete miscarriage less than four days

4 complete miscarriage less than five days

In the protocol ldquopain relief rdquo was determined as outcome However various articles had different ways to assess pain relief or pain Wetherefore added an extra definition to this outcome to further specify

in the 2018 update we added in an additional search of ClinicalTrialsgov and the WHO International Clinical Trials Registry Platform( ICTRP) for unpublished planned and ongoing trial reports



I N D E X T E R M S

Medical Subject Headings (MeSH)

lowastFetal Death [diagnostic imaging] Abortifacient Agents [lowasttherapeutic use] Abortion Induced [lowastmethods] Administration Intravagi-nal Administration Oral Mifepristone [lowasttherapeutic use] Misoprostol [lowasttherapeutic use] Randomized Controlled Trials as TopicUltrasonography Prenatal

MeSH check words

Female Humans Pregnancy



T A B L E O F C O N T E N T S

1HEADER 1ABSTRACT 2PLAIN LANGUAGE SUMMARY 4SUMMARY OF FINDINGS FOR THE MAIN COMPARISON 6BACKGROUND 7OBJECTIVES 7METHODS

11RESULTS Figure 1 12Figure 2 14Figure 3 15

24ADDITIONAL SUMMARY OF FINDINGS 27DISCUSSION 29AUTHORSrsquo CONCLUSIONS 29ACKNOWLEDGEMENTS 30REFERENCES 43CHARACTERISTICS OF STUDIES

116DATA AND ANALYSES Analysis 11 Comparison 1 Vaginal misoprostol versus placebo Outcome 1 Complete miscarriage 125Analysis 12 Comparison 1 Vaginal misoprostol versus placebo Outcome 2 Death or serious complications uterine

perforation 126Analysis 13 Comparison 1 Vaginal misoprostol versus placebo Outcome 3 Blood transfusion 126Analysis 14 Comparison 1 Vaginal misoprostol versus placebo Outcome 4 Blood loss haemoglobin difference gt 10

gL 127Analysis 15 Comparison 1 Vaginal misoprostol versus placebo Outcome 5 Days of bleeding vaginal bleeding 2 weeks

after treatment 127Analysis 16 Comparison 1 Vaginal misoprostol versus placebo Outcome 6 Nausea 128Analysis 17 Comparison 1 Vaginal misoprostol versus placebo Outcome 7 Diarrhoea 128Analysis 18 Comparison 1 Vaginal misoprostol versus placebo Outcome 8 Pain (opiate use) 129Analysis 19 Comparison 1 Vaginal misoprostol versus placebo Outcome 9 Womanrsquos satisfaction with treatment 129Analysis 21 Comparison 2 Vaginal misoprostol versus expectant management Outcome 1 Complete miscarriage 130Analysis 22 Comparison 2 Vaginal misoprostol versus expectant management Outcome 2 Pelvic infection 130Analysis 31 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 1 Complete miscarriage 131Analysis 32 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 2 Uterine perforation 132Analysis 33 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 3 Blood loss post-treatment

haematocrit () 132Analysis 34 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 4 Pain relief 133Analysis 35 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 5 Pelvic infection 133Analysis 36 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 6 Nausea 134Analysis 37 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 7 Diarrhoea 134Analysis 38 Comparison 3 Vaginal misoprostol versus surgical evacuation of uterus Outcome 8 Womanrsquos satisfaction 135Analysis 41 Comparison 4 Vaginal misoprostol versus vaginal dinoprostone Outcome 1 Complete miscarriage 135Analysis 42 Comparison 4 Vaginal misoprostol versus vaginal dinoprostone Outcome 2 Blood transfusion 136Analysis 43 Comparison 4 Vaginal misoprostol versus vaginal dinoprostone Outcome 3 Nausea 136Analysis 44 Comparison 4 Vaginal misoprostol versus vaginal dinoprostone Outcome 4 Duration of hospital stay

(days) 137Analysis 51 Comparison 5 Vaginal misoprostol lower versus higher-dose regimens Outcome 1 Complete miscarriage lt 13

weeks 137Analysis 52 Comparison 5 Vaginal misoprostol lower versus higher-dose regimens Outcome 2 Complete miscarriage 13-

23 weeks 138Analysis 53 Comparison 5 Vaginal misoprostol lower versus higher-dose regimens Outcome 3 Nausea 139

iMedical treatment for early fetal death (less than 24 weeks) (Review)
























































A B S T R A C T

Background


Objectives


Search methods


Selection criteria




Main results









Other comparisons






What is the issue














What does this mean







Setting worldwide


Comparison placebo


(95 CI)

of participants

(studies)


dence

(GRADE)

Comments


prostol


(301 to 594)

305 women

(5 RCTs)

oplusopluscopycopy

LOW 12







189 per 1000 800 per 1000

(569 to 1000)


0 per 1000 0 per 1000

(0 to 0)


(043 to 440)

88 women

(2 RCTs)

oplusopluscopycopy

LOW 34

93 per 1000 128 per 1000

(40 to 409)


(035 to 1406)

88 women

(2 RCTs)

oplusopluscopycopy

LOW 34

23 per 1000 51 per 1000

(8 to 327)

4M

ed

icaltre

atm

en

tfo

rearly

feta

ld

eath

(less

than

24

weeks)

(Revie

w)

Co

pyrig

ht

copy2019

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ratio

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by

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td




(038 to 412)

50 women

(1 RCT)

opluscopycopycopy

VERY LOW 56

160 per 1000 200 per 1000

(61 to 659)


(025 to 10111)

84 women

(1 RCT)

opluscopycopycopy46

VERY LOW

0 per 1000 0 per 1000

(0 to 0)




(083 to 164)

32 women

(1 RCT)

oplusopluscopycopy

LOW 6

750 per 1000 878 per 1000

(622 to 1000)


95CI)










5M

ed

icaltre

atm

en

tfo

rearly

feta

ld

eath

(less

than

24

weeks)

(Revie

w)

Co

pyrig

ht

copy2019

Th

eC

och

ran

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olla

bo

ratio

nP

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by

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on

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td

B A C K G R O U N D













O B J E C T I V E S


M E T H O D S


Types of studies









Primary outcomes



Secondary outcomes











Electronic searches

















selection bias)








bias)










detection bias)





outcome data)

















GRADE approach










Dichotomous data


Continuous data






Cross-over trials












Data synthesis







R E S U L T S










Included studies



Dates of study


Funding




Excluded studies













study



Allocation


Blinding






Selective reporting






Subgroup analyses













Primary outcomes


Secondary outcomes





Primary outcomes


Secondary outcomes




uterus

Primary outcomes


Secondary outcomes






Primary outcomes


Secondary outcomes



regimens

Primary outcomes



Secondary outcomes



preparations

Primary outcomes


Secondary outcomes






misoprostol

Primary outcomes


Secondary outcomes






Primary outcome


Secondary outcomes



Primary outcomes





Secondary outcomes



Primary outcomes


Secondary outcomes



vaginal misoprostol

Primary outcomes



Secondary outcomes



misoprostol

Primary outcomes


Secondary outcomes



extended course

Primary outcomes





Secondary outcomes



Primary outcomes


Secondary outcomes



Primary outcomes



Secondary outcomes



management

Primary outcomes


Secondary outcomes






regimen

Primary outcomes


Secondary outcomes



Primary outcomes


Secondary outcomes



alone

Primary outcomes


Secondary outcomes



uterus

Primary outcomes





Secondary outcomes



vaginal misoprostol

Primary outcomes


Secondary outcomes




course

Primary outcomes


Secondary outcomes









Setting worldwide




(95 CI)

of participants

(studies)


dence

(GRADE)

Comments

Risk with surgical



prostol


(032 to 050)

943 women

(6 RCTs)

oplusopluscopycopy

LOW 12






the same dosage of


921 per 1000 368 per 1000

(295 to 460)


(039 to 137)

618 women

(1 RCT)

oplusopluscopycopy

LOW 34




(28 to 97)


(131 to 36437)

154 women

(1 RCT)

oplusopluscopycopy

LOW 34

0 per 1000 22 per 1000

(1 to 364)


(252 to 66257)

154 women

(1 RCT)

oplusopluscopycopy

LOW 34

0 per 1000 41 per 1000

(3 to 663)

25

Med

icaltre

atm

en

tfo

rearly

feta

ld

eath

(less

than

24

weeks)

(Revie

w)

Co

pyrig

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Th

eC

och

ran

eC

olla

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ratio

nP

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lished

by

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ment haematocrit ()

The mean blood loss


tocrit () was 355

mean 140 lower

(351 lower to 071

higher)

- 50 women

(1 RCT)

oplusopluscopycopy

LOW 34


(1 RCT)

oplusopluscopycopy

LOW 45

213 per 1000 303 per 1000

(175 to 525)




(1 RCT)

oplusopluscopycopy

LOW 67

800 per 1000 536 per 1000

(320 to 888)


95CI)









26

Med

icaltre

atm

en

tfo

rearly

feta

ld

eath

(less

than

24

weeks)

(Revie

w)

Co

pyrig

ht

copy2019

Th

eC

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ratio

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lished

by

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D I S C U S S I O N































R E F E R E N C E S










(Suppl 4)S5ndashS10







200310170ndash3
















































(10)643ndash8



























(2)113ndash6






















199776(1672)26





















2009107(Suppl 2)S533





(Suppl 2)S49











(Suppl 2)S116
























200757(3)211ndash3






201082(3)266ndash75















(15)2136ndash9





























(2)154ndash7 DOI 101016jijgo201605008








































































200618(3)35ndash9





























































(19)946ndash50



(2)678ndash81

























































































(s1)83









(2)117ndash20
















(4)956ndash60








199776(1672)32





























































Alfirevic 2014


2014 Issue 6 DOI 10100214651858CD001338pub3

Ashok 1998


Baulieu 1986



Bugalho 1996


Cameron 1986


Costa 1993


Graziosi 2005



Grudzinskas 1995


Higgins 2011


Hofmeyr 2010


Howie 1995


Kim 2017


Kovacs 1984




Kulier 2011


Mousa 2014


Muzonzini 2004


Nanda 2012


Petrou 2006




Say 2002



Tunccedilalp 2012



Whitworth 2015


Wieringa 2002



Neilson 2006


Vazquez 2000


Vazquez 2006







Abediasl 2016







Notes

Risk of bias

















Al Inizi 2003











Risk of bias













Autry 1999












Risk of bias
















Ayudhaya 2006







Notes

Risk of bias


















Bagratee 2004








Risk of bias
















Bracken 2014











Risk of bias

















Chittacharoen 2003







Notes

Risk of bias
















Creinin 1997







Notes Pilot study

Risk of bias







quence generation










Dehbashi 2016










Notes

Risk of bias
















All outcomes

Demetroulis 2001








Risk of bias
















Egarter 1995







Notes

Risk of bias
















Eng 1997







Notes

Risk of bias
















Fang 2009











Risk of bias













Ganguly 2010











Risk of bias
















Gilles 2004







Notes

Risk of bias
















Graziosi 2004












Risk of bias















Herabutya 1997








Risk of bias
















Jain 1996








Risk of bias
















Kara 1999








Risk of bias
















Kovavisarach 2002







Notes

Risk of bias
















Kovavisarach 2005










Notes

Risk of bias















Kushwah 2009







Notes

Risk of bias
















Lelaidier 1993








Risk of bias
















Lister 2005











Risk of bias















Marwah 2016







Notes

Risk of bias















Mitwaly 2016







Notes

Risk of bias















Mizrachi 2017







Notes

Risk of bias
















Muffley 2002








Risk of bias
















Ngoc 2004











Risk of bias
















Nielsen 1999








Risk of bias
















Niromanesh 2005







Notes

Risk of bias
















Petersen 2013







Notes

Risk of bias
















Rita 2006










Notes

Risk of bias















Saichua 2009







Notes

Risk of bias
















Schreiber 2018







Notes

Risk of bias
















Shah 2010










Notes

Risk of bias
















Sinha 2018







Notes

Risk of bias
















Sonsanoh 2014







Notes

Risk of bias
















Tang 2003










Notes

Risk of bias













Tang 2006










Notes

Risk of bias
















Tanha 2010a







Notes

Risk of bias
















Trinder 2006











Notes

Risk of bias

















Wood 2002








Risk of bias










































(Continued)




















(Continued)
















(Continued)
















(Continued)

















(Continued)















(Continued)






















(Continued)



















(Continued)





















(Continued)



















(Continued)








ACTRN12615000483550













Ali 2017








Notes

El Shahawy 2016












Notes

NCT02620904










Notes

NCT02633761












Notes

NCT03212352 2017








Notes




microg microgram






studies

No of





















studies

No of







studies

No of








studies

No of





studies

No of











studies

No of
















studies

No of





studies

No of











studies

No of











studies

No of







studies

No of









studies

No of

















studies

No of







studies

No of





studies

No of







studies

No of













studies

No of







studies

No of



















studies

No of














studies

No of





studies

No of










studies

No of





studies

No of














Herabutya 1997 3542 642 207 583 [ 275 1239 ]

Kovavisarach 2002 1727 527 172 340 [ 146 789 ]

Subtotal (95 CI) 69 69 379 473 [ 270 828 ]





Lister 2005 1518 216 73 667 [ 179 2478 ]

Wood 2002 2125 425 138 525 [ 210 1310 ]

Subtotal (95 CI) 43 41 211 574 [ 270 1219 ]





Bagratee 2004 3945 1138 411 299 [ 180 499 ]

Subtotal (95 CI) 45 38 411 299 [ 180 499 ]




Total (95 CI) 157 148 1000 423 [ 301 594 ]





001 01 1 10 100











Herabutya 1997 042 142 1000 033 [ 001 796 ]

Total (95 CI) 42 42 1000 033 [ 001 796 ]





001 01 1 10 100








Herabutya 1997 042 242 1000 020 [ 001 404 ]

Total (95 CI) 42 42 1000 020 [ 001 404 ]





0001 001 01 1 10 100 1000





difference gt 10 gL






Wood 2002 525 425 1000 125 [ 038 412 ]

Total (95 CI) 25 25 1000 125 [ 038 412 ]





01 02 05 1 2 5 10









Lister 2005 616 616 1000 100 [ 041 245 ]

Total (95 CI) 16 16 1000 100 [ 041 245 ]





01 02 05 1 2 5 10







Outcome 6 Nausea



Kovavisarach 2002 227 127 239 200 [ 019 2077 ]

Lister 2005 418 316 761 119 [ 031 451 ]

Total (95 CI) 45 43 1000 138 [ 043 440 ]





001 01 1 10 100





Outcome 7 Diarrhoea



Kovavisarach 2002 227 027 321 500 [ 025 9951 ]

Lister 2005 118 116 679 089 [ 006 1308 ]

Total (95 CI) 45 43 1000 221 [ 035 1406 ]





001 01 1 10 100










Herabutya 1997 242 042 1000 500 [ 025 10111 ]

Total (95 CI) 42 42 1000 500 [ 025 10111 ]





0001 001 01 1 10 100 1000



treatment






Lister 2005 1416 1216 1000 117 [ 083 164 ]

Total (95 CI) 16 16 1000 117 [ 083 164 ]





01 02 05 1 2 5 10





miscarriage





Expectantmanage-



Trinder 2006 192308 152306 1000 125 [ 109 145 ]

Total (95 CI) 308 306 1000 125 [ 109 145 ]





02 05 1 2 5







Expectantmanage-



Trinder 2006 16308 2310 1000 805 [ 187 3472 ]

Total (95 CI) 308 310 1000 805 [ 187 3472 ]





001 01 1 10 100





miscarriage





nN nN

M-HRandom95

CI

M-HRandom95

CI

Demetroulis 2001 626 2424 86 025 [ 013 048 ]

Fang 2009 530 3030 71 018 [ 008 039 ]

Ganguly 2010 37 34 42 057 [ 020 159 ]

Graziosi 2004 3779 7375 293 048 [ 038 061 ]

Muffley 2002 1025 2325 137 043 [ 027 071 ]

Trinder 2006 116308 278310 371 042 [ 036 049 ]

Total (95 CI) 475 468 1000 040 [ 032 050 ]





01 02 05 1 2 5 10





perforation






Graziosi 2004 079 175 1000 032 [ 001 765 ]

Total (95 CI) 79 75 1000 032 [ 001 765 ]





001 01 1 10 100









Difference


Muffley 2002 25 341 (5) 25 355 (2) 1000 -140 [ -351 071 ]

Total (95 CI) 25 25 1000 -140 [ -351 071 ]




-10 -5 0 5 10










Graziosi 2004 2479 1675 1000 142 [ 082 246 ]

Total (95 CI) 79 75 1000 142 [ 082 246 ]





01 02 05 1 2 5 10



infection






Trinder 2006 16308 22310 1000 073 [ 039 137 ]

Total (95 CI) 308 310 1000 073 [ 039 137 ]





001 01 1 10 100







Outcome 6 Nausea



Graziosi 2004 1179 075 1000 2185 [ 131 36437 ]

Total (95 CI) 79 75 1000 2185 [ 131 36437 ]





0001 001 01 1 10 100 1000





Outcome 7 Diarrhoea



Graziosi 2004 2179 075 1000 4085 [ 252 66257 ]

Total (95 CI) 79 75 1000 4085 [ 252 66257 ]





0001 001 01 1 10 100 1000





satisfaction






Fang 2009 815 2430 1000 067 [ 040 111 ]

Total (95 CI) 15 30 1000 067 [ 040 111 ]





001 01 1 10 100



miscarriage






Al Inizi 2003 1927 833 268 290 [ 151 557 ]

Kara 1999 2832 2033 732 144 [ 106 196 ]

Total (95 CI) 59 66 1000 183 [ 137 246 ]





01 02 05 1 2 5 10










Al Inizi 2003 227 033 1000 607 [ 030 12133 ]

Total (95 CI) 27 33 1000 607 [ 030 12133 ]





0001 001 01 1 10 100 1000





Outcome 3 Nausea



Kara 1999 432 433 1000 103 [ 028 378 ]

Total (95 CI) 32 33 1000 103 [ 028 378 ]





01 02 05 1 2 5 10











Difference


Al Inizi 2003 27 162 (056) 33 4 (28) 1000 -238 [ -336 -140 ]

Total (95 CI) 27 33 1000 -238 [ -336 -140 ]




-10 -5 0 5 10








nN nN

M-HRandom95

CI

M-HRandom95

CI

Kovavisarach 2005 2657 3957 399 067 [ 048 093 ]

Petersen 2013 111149 107134 601 093 [ 082 106 ]

Total (95 CI) 206 191 1000 082 [ 058 114 ]





01 02 05 1 2 5 10











Niromanesh 2005 4250 4050 1000 105 [ 087 126 ]

Total (95 CI) 50 50 1000 105 [ 087 126 ]





001 01 1 10 100







Outcome 3 Nausea



Kovavisarach 2005 257 757 467 029 [ 006 132 ]

Niromanesh 2005 850 850 533 100 [ 041 246 ]

Total (95 CI) 107 107 1000 067 [ 031 141 ]





001 01 1 10 100





Outcome 4 Diarrhoea



Kovavisarach 2005 057 257 385 020 [ 001 408 ]

Niromanesh 2005 350 450 615 075 [ 018 318 ]

Total (95 CI) 107 107 1000 054 [ 015 191 ]





0001 001 01 1 10 100 1000





miscarriage







Gilles 2004 3041 2539 200 114 [ 085 154 ]

Subtotal (95 CI) 41 39 200 114 [ 085 154 ]





Gilles 2004 3441 3139 248 104 [ 084 129 ]

Subtotal (95 CI) 41 39 248 104 [ 084 129 ]





Gilles 2004 3441 3539 280 092 [ 078 110 ]

Subtotal (95 CI) 41 39 280 092 [ 078 110 ]





Gilles 2004 3441 3439 272 095 [ 079 114 ]

Subtotal (95 CI) 41 39 272 095 [ 079 114 ]




Total (95 CI) 164 156 1000 100 [ 090 112 ]





01 02 05 1 2 5 10







Outcome 2 Diarrhoea



Gilles 2004 1740 937 1000 175 [ 089 342 ]

Total (95 CI) 40 37 1000 175 [ 089 342 ]





01 02 05 1 2 5 10





Outcome 3 Vomiting



Gilles 2004 640 637 1000 093 [ 033 262 ]

Total (95 CI) 40 37 1000 093 [ 033 262 ]





01 02 05 1 2 5 10











Gilles 2004 3136 2737 1000 118 [ 093 149 ]

Total (95 CI) 36 37 1000 118 [ 093 149 ]





01 02 05 1 2 5 10









Autry 1999 1212 89 1000 113 [ 085 150 ]

Total (95 CI) 12 9 1000 113 [ 085 150 ]





001 01 1 10 100











Autry 1999 112 09 1000 231 [ 010 5085 ]

Total (95 CI) 12 9 1000 231 [ 010 5085 ]





001 01 1 10 100









Autry 1999 412 49 1000 075 [ 025 222 ]

Total (95 CI) 12 9 1000 075 [ 025 222 ]





001 01 1 10 100












Jain 1996 1520 1518 484 090 [ 065 125 ]

Subtotal (95 CI) 20 18 484 090 [ 065 125 ]





Jain 1996 1920 1618 516 107 [ 088 129 ]

Subtotal (95 CI) 20 18 516 107 [ 088 129 ]




Total (95 CI) 40 36 1000 099 [ 082 118 ]





01 02 05 1 2 5 10










Sublingualevery 3


nN nN

M-HRandom95

CI

M-HRandom95

CI

Dehbashi 2016 925 1027 116 097 [ 047 199 ]

Shah 2010 1019 1122 142 105 [ 058 191 ]

Sonsanoh 2014 3660 4160 234 088 [ 067 115 ]

Tang 2003 3540 3540 260 100 [ 085 118 ]

Tanha 2010a 51110 93110 248 055 [ 044 068 ]

Total (95 CI) 254 259 1000 084 [ 061 116 ]





001 01 1 10 100











Shah 2010 26 23 1000 050 [ 013 200 ]

Total (95 CI) 6 3 1000 050 [ 013 200 ]





001 01 1 10 100

sublingual vaginal







nN nN

M-HRandom95

CI

M-HRandom95

CI

Sonsanoh 2014 360 1260 395 025 [ 007 084 ]

Tanha 2010a 48110 54110 605 089 [ 067 118 ]

Total (95 CI) 170 170 1000 054 [ 015 189 ]





001 01 1 10 100







Outcome 4 Pain



Dehbashi 2016 025 127 14 036 [ 002 843 ]

Sonsanoh 2014 1960 2760 256 070 [ 044 112 ]

Tanha 2010a 42110 77110 730 055 [ 042 071 ]

Total (95 CI) 195 197 1000 058 [ 046 074 ]





001 01 1 10 100







Outcome 5 Nausea


Sublingualmisopros-


nN nN

M-HRandom95

CI

M-HRandom95

CI

Dehbashi 2016 025 627 128 008 [ 000 140 ]

Shah 2010 125 1525 198 007 [ 001 047 ]

Sonsanoh 2014 760 660 304 117 [ 042 327 ]

Tang 2003 2040 2440 370 083 [ 056 124 ]

Total (95 CI) 150 152 1000 042 [ 012 144 ]





001 01 1 10 100







Outcome 6 Vomiting



Tang 2003 940 740 241 129 [ 053 312 ]

Tanha 2010a 13110 22110 759 059 [ 031 111 ]

Total (95 CI) 150 150 1000 076 [ 046 126 ]





001 01 1 10 100





Outcome 7 Diarrhoea



Dehbashi 2016 525 627 69 090 [ 031 258 ]

Sonsanoh 2014 360 460 48 075 [ 018 321 ]

Tang 2003 1140 2840 334 039 [ 023 068 ]

Tanha 2010a 40110 46110 549 087 [ 062 121 ]

Total (95 CI) 235 237 1000 071 [ 054 092 ]





001 01 1 10 100











Abediasl 2016 3840 3945 1000 110 [ 096 125 ]

Total (95 CI) 40 45 1000 110 [ 096 125 ]





001 01 1 10 100





excessive







Abediasl 2016 140 245 1000 056 [ 005 597 ]

Total (95 CI) 40 45 1000 056 [ 005 597 ]





001 01 1 10 100









Eng 1997 2125 1725 1000 124 [ 090 170 ]

Total (95 CI) 25 25 1000 124 [ 090 170 ]





01 02 05 1 2 5 10





relief












01 02 05 1 2 5 10





Outcome 3 Vomiting



Eng 1997 125 025 1000 300 [ 013 7030 ]

Total (95 CI) 25 25 1000 300 [ 013 7030 ]





001 01 1 10 100







Outcome 4 Diarrhoea



Eng 1997 025 325 1000 014 [ 001 263 ]

Total (95 CI) 25 25 1000 014 [ 001 263 ]





0001 001 01 1 10 100 1000



miscarriage





nN nN

M-HRandom95

CI

M-HRandom95

CI

Ayudhaya 2006 1570 1768 97 086 [ 047 158 ]

Kushwah 2009 4650 4250 903 110 [ 095 127 ]

Total (95 CI) 120 118 1000 107 [ 088 130 ]





001 01 1 10 100







Outcome 2 Pain


nN nN

M-HRandom95

CI

M-HRandom95

CI


Ayudhaya 2006 4770 4068 507 114 [ 088 148 ]

Subtotal (95 CI) 70 68 507 114 [ 088 148 ]





Kushwah 2009 2350 4450 493 052 [ 038 072 ]

Subtotal (95 CI) 50 50 493 052 [ 038 072 ]




Total (95 CI) 120 118 1000 078 [ 036 167 ]





001 01 1 10 100





vomiting





nN nN

M-HRandom95

CI

M-HRandom95

CI


Ayudhaya 2006 270 368 43 065 [ 011 376 ]

Subtotal (95 CI) 70 68 43 065 [ 011 376 ]




2 Nausea

Kushwah 2009 1750 2650 600 065 [ 041 105 ]

Subtotal (95 CI) 50 50 600 065 [ 041 105 ]




3 Vomiting

Kushwah 2009 1150 2250 357 050 [ 027 092 ]

Subtotal (95 CI) 50 50 357 050 [ 027 092 ]




Total (95 CI) 170 168 1000 059 [ 041 085 ]





001 01 1 10 100







Outcome 4 Diarrhoea


nN nN

M-HRandom95

CI

M-HRandom95

CI


Ayudhaya 2006 670 768 118 083 [ 029 235 ]

Subtotal (95 CI) 70 68 118 083 [ 029 235 ]





Kushwah 2009 2450 2850 882 086 [ 059 125 ]

Subtotal (95 CI) 50 50 882 086 [ 059 125 ]




Total (95 CI) 120 118 1000 085 [ 060 122 ]





001 01 1 10 100











Kushwah 2009 4650 3650 1000 128 [ 106 155 ]

Total (95 CI) 50 50 1000 128 [ 106 155 ]





001 01 1 10 100







Study or subgroup

600mcgpowdery

misoprosto

600mcgcompact

misoprosto

RiskRatio(Non-

event) Weight

RiskRatio(Non-

event)


Saichua 2009 926 928 1000 096 [ 066 141 ]

Total (95 CI) 26 28 1000 096 [ 066 141 ]





001 01 1 10 100





Nauseavomiting




Study or subgroup

600mcgpowdery

misoprosto

600mcgcompact



Saichua 2009 226 228 1000 108 [ 016 710 ]

Total (95 CI) 26 28 1000 108 [ 016 710 ]





001 01 1 10 100



Diarrhoea



Outcome 3 Diarrhoea

Study or subgroup

600mcgpowdery

misoprosto

600mcgcompact



Saichua 2009 726 728 1000 108 [ 044 265 ]

Total (95 CI) 26 28 1000 108 [ 044 265 ]





001 01 1 10 100











Tang 2006 8490 8390 1000 101 [ 093 110 ]

Total (95 CI) 90 90 1000 101 [ 093 110 ]





01 02 05 1 2 5 10





Nausea



Outcome 2 Nausea



Tang 2006 1890 1390 1000 138 [ 072 265 ]

Total (95 CI) 90 90 1000 138 [ 072 265 ]





001 01 1 10 100



Pain



Outcome 3 Pain



Tang 2006 7490 6690 1000 112 [ 096 131 ]

Total (95 CI) 90 90 1000 112 [ 096 131 ]





001 01 1 10 100





Vomiting



Outcome 4 Vomiting



Tang 2006 590 190 1000 500 [ 060 4195 ]

Total (95 CI) 90 90 1000 500 [ 060 4195 ]





001 01 1 10 100



Diarrhoea



Outcome 5 Diarrhoea



Tang 2006 3890 1990 1000 200 [ 125 319 ]

Total (95 CI) 90 90 1000 200 [ 125 319 ]





001 01 1 10 100











Tang 2003 3540 3540 1000 100 [ 085 118 ]

Total (95 CI) 40 40 1000 100 [ 085 118 ]





01 02 05 1 2 5 10









Difference


Tang 2003 40 126 (11) 40 125 (11) 1000 010 [ -038 058 ]

Total (95 CI) 40 40 1000 010 [ -038 058 ]




-10 -5 0 5 10





Nausea



Outcome 3 Nausea



Tang 2003 2440 2040 1000 120 [ 080 179 ]

Total (95 CI) 40 40 1000 120 [ 080 179 ]





01 02 05 1 2 5 10



Vomiting



Outcome 4 Vomiting



Tang 2003 740 940 1000 078 [ 032 188 ]

Total (95 CI) 40 40 1000 078 [ 032 188 ]





01 02 05 1 2 5 10





Diarrhoea



Outcome 5 Diarrhoea



Tang 2003 2840 1140 1000 255 [ 148 438 ]

Total (95 CI) 40 40 1000 255 [ 148 438 ]





01 02 05 1 2 5 10



Pain



Outcome 6 Pain



Tang 2003 640 840 1000 075 [ 029 197 ]

Total (95 CI) 40 40 1000 075 [ 029 197 ]





01 02 05 1 2 5 10











Tang 2003 3038 3139 1000 099 [ 079 125 ]

Total (95 CI) 38 39 1000 099 [ 079 125 ]





01 02 05 1 2 5 10








nN nN

M-HRandom95

CI

M-HRandom95

CI

Creinin 1997 312 78 111 029 [ 010 079 ]

Marwah 2016 3750 4050 305 093 [ 075 115 ]

Ngoc 2004 89100 9198 328 096 [ 088 105 ]

Rita 2006 1850 4050 256 045 [ 030 067 ]

Total (95 CI) 212 206 1000 068 [ 045 103 ]





05 07 1 15 2











Chittacharoen 2003 2020 2424 1000 100 [ 092 109 ]

Total (95 CI) 20 24 1000 100 [ 092 109 ]





02 05 1 2 5





excessive






Marwah 2016 350 150 1000 300 [ 032 2787 ]

Total (95 CI) 50 50 1000 300 [ 032 2787 ]





001 01 1 10 100



analogue scale)






Difference


Creinin 1997 11 4 (36) 7 59 (27) 1000 -190 [ -482 102 ]

Total (95 CI) 11 7 1000 -190 [ -482 102 ]




-10 -5 0 5 10







Outcome 5 Pain



Marwah 2016 2450 1550 750 160 [ 096 267 ]

Rita 2006 850 550 250 160 [ 056 456 ]

Total (95 CI) 100 100 1000 160 [ 101 255 ]





001 01 1 10 100





Outcome 6 Vomiting


nN nN

M-HRandom95

CI

M-HRandom95

CI

Ngoc 2004 495 1495 521 029 [ 010 084 ]

Rita 2006 650 350 479 200 [ 053 756 ]

Total (95 CI) 145 145 1000 073 [ 011 489 ]





001 01 1 10 100







Outcome 7 Nausea



Creinin 1997 612 58 107 080 [ 037 174 ]

Marwah 2016 3650 3050 536 120 [ 090 160 ]

Rita 2006 2550 2050 357 125 [ 081 194 ]

Total (95 CI) 112 108 1000 118 [ 093 148 ]





01 02 05 1 2 5 10







Outcome 8 Diarrhoea



Creinin 1997 512 38 96 111 [ 036 340 ]

Marwah 2016 750 650 160 117 [ 042 323 ]

Ngoc 2004 2495 2395 612 104 [ 064 171 ]

Rita 2006 550 550 133 100 [ 031 324 ]

Total (95 CI) 207 203 1000 106 [ 072 158 ]





01 02 05 1 2 5 10









Ngoc 2004 86100 8898 1000 096 [ 086 106 ]

Total (95 CI) 100 98 1000 096 [ 086 106 ]





01 02 05 1 2 5 10











Nielsen 1999 4960 4762 1000 108 [ 090 130 ]

Total (95 CI) 60 62 1000 108 [ 090 130 ]





01 02 05 1 2 5 10





Blood loss (severe)






Nielsen 1999 060 162 1000 034 [ 001 829 ]

Total (95 CI) 60 62 1000 034 [ 001 829 ]





001 01 1 10 100



Days of bleeding






Difference


Nielsen 1999 60 11 (326) 62 103 (311) 1000 070 [ -043 183 ]

Total (95 CI) 60 62 1000 070 [ -043 183 ]




-10 -5 0 5 10





Pain



Outcome 4 Pain



Difference


Nielsen 1999 60 661 (263) 62 62 (301) 1000 410 [ -592 1412 ]

Total (95 CI) 60 62 1000 410 [ -592 1412 ]




-100 -50 0 50 100



Pelvic infection






Nielsen 1999 160 262 1000 052 [ 005 555 ]

Total (95 CI) 60 62 1000 052 [ 005 555 ]





001 01 1 10 100











Difference


Nielsen 1999 60 286 (248) 62 252 (256) 1000 340 [ -554 1234 ]

Total (95 CI) 60 62 1000 340 [ -554 1234 ]




-100 -50 0 50 100









Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 2763 4872 457 064 [ 046 089 ]

Subtotal (95 CI) 63 72 457 064 [ 046 089 ]





Bracken 2014 3863 5772 543 076 [ 060 096 ]

Subtotal (95 CI) 63 72 543 076 [ 060 096 ]




Total (95 CI) 126 144 1000 071 [ 058 086 ]





001 01 1 10 100







Outcome 2 Nausea

Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 863 1572 1000 061 [ 028 134 ]

Total (95 CI) 63 72 1000 061 [ 028 134 ]





001 01 1 10 100





Outcome 3 Vomiting

Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 563 1972 1000 030 [ 012 076 ]

Total (95 CI) 63 72 1000 030 [ 012 076 ]





001 01 1 10 100







Outcome 4 Diarrhoea

Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 863 2372 1000 040 [ 019 082 ]

Total (95 CI) 63 72 1000 040 [ 019 082 ]





001 01 1 10 100







Outcome 5 Pain

Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 5763 6872 1000 096 [ 087 106 ]

Total (95 CI) 63 72 1000 096 [ 087 106 ]





001 01 1 10 100







Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 4563 5472 1000 095 [ 078 117 ]

Total (95 CI) 63 72 1000 095 [ 078 117 ]





001 01 1 10 100











Lelaidier 1993 223 023 1000 500 [ 025 9875 ]

Subtotal (95 CI) 23 23 1000 500 [ 025 9875 ]





Lelaidier 1993 923 023 1000 1900 [ 117 30840 ]

Subtotal (95 CI) 23 23 1000 1900 [ 117 30840 ]





Lelaidier 1993 1423 123 1000 1400 [ 200 9788 ]

Subtotal (95 CI) 23 23 1000 1400 [ 200 9788 ]





Lelaidier 1993 1923 223 1000 950 [ 249 3619 ]

Subtotal (95 CI) 23 23 1000 950 [ 249 3619 ]





001 01 1 10 100










Lelaidier 1993 2323 521 1000 392 [ 189 810 ]

Total (95 CI) 23 21 1000 392 [ 189 810 ]





01 02 05 1 2 5 10





Outcome 3 Pain



Lelaidier 1993 1223 521 1000 219 [ 093 517 ]

Total (95 CI) 23 21 1000 219 [ 093 517 ]





01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI

Fang 2009 2330 2530 292 092 [ 071 119 ]

Schreiber 2018 135148 113149 433 120 [ 108 133 ]

Sinha 2018 3945 2645 274 150 [ 114 197 ]

Total (95 CI) 223 224 1000 118 [ 095 147 ]





02 05 1 2 5











Schreiber 2018 3149 1151 1000 304 [ 032 2890 ]

Total (95 CI) 149 151 1000 304 [ 032 2890 ]





001 01 1 10 100









Schreiber 2018 2149 2151 1000 101 [ 014 710 ]

Total (95 CI) 149 151 1000 101 [ 014 710 ]





001 01 1 10 100





Outcome 4 nausea



Outcome 4 nausea



Schreiber 2018 56149 56151 1000 101 [ 076 136 ]

Total (95 CI) 149 151 1000 101 [ 076 136 ]





001 01 1 10 100



Outcome 5 Diarrhoea



Outcome 5 Diarrhoea



Schreiber 2018 41149 44151 1000 094 [ 066 135 ]

Total (95 CI) 149 151 1000 094 [ 066 135 ]





001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Fang 2009 1630 715 152 114 [ 060 216 ]

Sinha 2018 3845 2745 848 141 [ 107 184 ]

Total (95 CI) 75 60 1000 136 [ 106 175 ]





001 01 1 10 100









Egarter 1995 3343 4244 1000 080 [ 067 096 ]

Total (95 CI) 43 44 1000 080 [ 067 096 ]





01 02 05 1 2 5 10










RiskRatio(Non-

event) Weight

RiskRatio(Non-

event)


Egarter 1995 043 244 1000 105 [ 097 113 ]

Total (95 CI) 43 44 1000 105 [ 097 113 ]





01 02 05 1 2 5 10







Outcome 3 Nausea



Egarter 1995 743 444 1000 179 [ 056 568 ]

Total (95 CI) 43 44 1000 179 [ 056 568 ]





01 02 05 1 2 5 10









Mitwaly 2016 8590 7790 1000 110 [ 100 122 ]

Total (95 CI) 90 90 1000 110 [ 100 122 ]





001 01 1 10 100





2 Nausea



Outcome 2 Nausea


RiskRatio(Non-

event) Weight

RiskRatio(Non-

event)


Mitwaly 2016 290 3490 1000 157 [ 133 185 ]

Total (95 CI) 90 90 1000 157 [ 133 185 ]





001 01 1 10 100



3 Vomiting



Outcome 3 Vomiting



Mitwaly 2016 290 890 1000 025 [ 005 114 ]

Total (95 CI) 90 90 1000 025 [ 005 114 ]





001 01 1 10 100





4 Diarrhoea



Outcome 4 Diarrhoea



Mitwaly 2016 090 290 1000 020 [ 001 411 ]

Total (95 CI) 90 90 1000 020 [ 001 411 ]





001 01 1 10 100









Mitwaly 2016 1090 3390 1000 030 [ 016 058 ]

Total (95 CI) 90 90 1000 030 [ 016 058 ]





001 01 1 10 100





6 Time to expulsion






Difference


Mitwaly 2016 90 511 (266) 90 992 (312) 1000 -481 [ -566 -396 ]

Total (95 CI) 90 90 1000 -481 [ -566 -396 ]




-100 -50 0 50 100









Mizrachi 2017 6787 6484 437 101 [ 086 119 ]

Tang 2006 8390 8490 563 099 [ 091 107 ]

Total (95 CI) 177 174 1000 100 [ 092 109 ]





001 01 1 10 100





Nausea



Outcome 2 Nausea



Mizrachi 2017 2887 3584 442 077 [ 052 115 ]

Tang 2006 3890 4590 558 084 [ 061 116 ]

Total (95 CI) 177 174 1000 081 [ 063 104 ]





001 01 1 10 100



Vomiting



Outcome 3 Vomiting



Mizrachi 2017 1187 684 304 177 [ 069 457 ]

Tang 2006 1390 1490 696 093 [ 046 186 ]

Total (95 CI) 177 174 1000 118 [ 068 206 ]





001 01 1 10 100





Diarrhoea



Outcome 4 Diarrhoea



Mizrachi 2017 2587 2284 262 110 [ 067 179 ]

Tang 2006 6190 6390 738 097 [ 080 118 ]

Total (95 CI) 177 174 1000 100 [ 082 122 ]





001 01 1 10 100





(use of analgesics)






Mizrachi 2017 6087 6984 1000 084 [ 071 100 ]

Total (95 CI) 87 84 1000 084 [ 071 100 ]





001 01 1 10 100









Mizrachi 2017 6487 6184 1000 101 [ 084 122 ]

Total (95 CI) 87 84 1000 101 [ 084 122 ]





001 01 1 10 100




A P P E N D I C E S








H I S T O R Y

























Internal sources




External sources






























I N D E X T E R M S



MeSH check words


























































A B S T R A C T

Background


Objectives


Search methods


Selection criteria




Main results









Other comparisons






What is the issue














What does this mean







Setting worldwide


Comparison placebo


(95 CI)

of participants

(studies)


dence

(GRADE)

Comments


prostol


(301 to 594)

305 women

(5 RCTs)

oplusopluscopycopy

LOW 12







189 per 1000 800 per 1000

(569 to 1000)


0 per 1000 0 per 1000

(0 to 0)


(043 to 440)

88 women

(2 RCTs)

oplusopluscopycopy

LOW 34

93 per 1000 128 per 1000

(40 to 409)


(035 to 1406)

88 women

(2 RCTs)

oplusopluscopycopy

LOW 34

23 per 1000 51 per 1000

(8 to 327)

4M

ed

icaltre

atm

en

tfo

rearly

feta

ld

eath

(less

than

24

weeks)

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(038 to 412)

50 women

(1 RCT)

opluscopycopycopy

VERY LOW 56

160 per 1000 200 per 1000

(61 to 659)


(025 to 10111)

84 women

(1 RCT)

opluscopycopycopy46

VERY LOW

0 per 1000 0 per 1000

(0 to 0)




(083 to 164)

32 women

(1 RCT)

oplusopluscopycopy

LOW 6

750 per 1000 878 per 1000

(622 to 1000)


95CI)










5M

ed

icaltre

atm

en

tfo

rearly

feta

ld

eath

(less

than

24

weeks)

(Revie

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B A C K G R O U N D













O B J E C T I V E S


M E T H O D S


Types of studies









Primary outcomes



Secondary outcomes











Electronic searches

















selection bias)








bias)










detection bias)





outcome data)

















GRADE approach










Dichotomous data


Continuous data






Cross-over trials












Data synthesis







R E S U L T S










Included studies



Dates of study


Funding




Excluded studies













study



Allocation


Blinding






Selective reporting






Subgroup analyses













Primary outcomes


Secondary outcomes





Primary outcomes


Secondary outcomes




uterus

Primary outcomes


Secondary outcomes






Primary outcomes


Secondary outcomes



regimens

Primary outcomes



Secondary outcomes



preparations

Primary outcomes


Secondary outcomes






misoprostol

Primary outcomes


Secondary outcomes






Primary outcome


Secondary outcomes



Primary outcomes





Secondary outcomes



Primary outcomes


Secondary outcomes



vaginal misoprostol

Primary outcomes



Secondary outcomes



misoprostol

Primary outcomes


Secondary outcomes



extended course

Primary outcomes





Secondary outcomes



Primary outcomes


Secondary outcomes



Primary outcomes



Secondary outcomes



management

Primary outcomes


Secondary outcomes






regimen

Primary outcomes


Secondary outcomes



Primary outcomes


Secondary outcomes



alone

Primary outcomes


Secondary outcomes



uterus

Primary outcomes





Secondary outcomes



vaginal misoprostol

Primary outcomes


Secondary outcomes




course

Primary outcomes


Secondary outcomes









Setting worldwide




(95 CI)

of participants

(studies)


dence

(GRADE)

Comments

Risk with surgical



prostol


(032 to 050)

943 women

(6 RCTs)

oplusopluscopycopy

LOW 12






the same dosage of


921 per 1000 368 per 1000

(295 to 460)


(039 to 137)

618 women

(1 RCT)

oplusopluscopycopy

LOW 34




(28 to 97)


(131 to 36437)

154 women

(1 RCT)

oplusopluscopycopy

LOW 34

0 per 1000 22 per 1000

(1 to 364)


(252 to 66257)

154 women

(1 RCT)

oplusopluscopycopy

LOW 34

0 per 1000 41 per 1000

(3 to 663)

25

Med

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than

24

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ment haematocrit ()

The mean blood loss


tocrit () was 355

mean 140 lower

(351 lower to 071

higher)

- 50 women

(1 RCT)

oplusopluscopycopy

LOW 34


(1 RCT)

oplusopluscopycopy

LOW 45

213 per 1000 303 per 1000

(175 to 525)




(1 RCT)

oplusopluscopycopy

LOW 67

800 per 1000 536 per 1000

(320 to 888)


95CI)









26

Med

icaltre

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(less

than

24

weeks)

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D I S C U S S I O N































R E F E R E N C E S










(Suppl 4)S5ndashS10







200310170ndash3
















































(10)643ndash8



























(2)113ndash6






















199776(1672)26





















2009107(Suppl 2)S533





(Suppl 2)S49











(Suppl 2)S116
























200757(3)211ndash3






201082(3)266ndash75















(15)2136ndash9





























(2)154ndash7 DOI 101016jijgo201605008








































































200618(3)35ndash9





























































(19)946ndash50



(2)678ndash81

























































































(s1)83









(2)117ndash20
















(4)956ndash60








199776(1672)32





























































Alfirevic 2014


2014 Issue 6 DOI 10100214651858CD001338pub3

Ashok 1998


Baulieu 1986



Bugalho 1996


Cameron 1986


Costa 1993


Graziosi 2005



Grudzinskas 1995


Higgins 2011


Hofmeyr 2010


Howie 1995


Kim 2017


Kovacs 1984




Kulier 2011


Mousa 2014


Muzonzini 2004


Nanda 2012


Petrou 2006




Say 2002



Tunccedilalp 2012



Whitworth 2015


Wieringa 2002



Neilson 2006


Vazquez 2000


Vazquez 2006







Abediasl 2016







Notes

Risk of bias

















Al Inizi 2003











Risk of bias













Autry 1999












Risk of bias
















Ayudhaya 2006







Notes

Risk of bias


















Bagratee 2004








Risk of bias
















Bracken 2014











Risk of bias

















Chittacharoen 2003







Notes

Risk of bias
















Creinin 1997







Notes Pilot study

Risk of bias







quence generation










Dehbashi 2016










Notes

Risk of bias
















All outcomes

Demetroulis 2001








Risk of bias
















Egarter 1995







Notes

Risk of bias
















Eng 1997







Notes

Risk of bias
















Fang 2009











Risk of bias













Ganguly 2010











Risk of bias
















Gilles 2004







Notes

Risk of bias
















Graziosi 2004












Risk of bias















Herabutya 1997








Risk of bias
















Jain 1996








Risk of bias
















Kara 1999








Risk of bias
















Kovavisarach 2002







Notes

Risk of bias
















Kovavisarach 2005










Notes

Risk of bias















Kushwah 2009







Notes

Risk of bias
















Lelaidier 1993








Risk of bias
















Lister 2005











Risk of bias















Marwah 2016







Notes

Risk of bias















Mitwaly 2016







Notes

Risk of bias















Mizrachi 2017







Notes

Risk of bias
















Muffley 2002








Risk of bias
















Ngoc 2004











Risk of bias
















Nielsen 1999








Risk of bias
















Niromanesh 2005







Notes

Risk of bias
















Petersen 2013







Notes

Risk of bias
















Rita 2006










Notes

Risk of bias















Saichua 2009







Notes

Risk of bias
















Schreiber 2018







Notes

Risk of bias
















Shah 2010










Notes

Risk of bias
















Sinha 2018







Notes

Risk of bias
















Sonsanoh 2014







Notes

Risk of bias
















Tang 2003










Notes

Risk of bias













Tang 2006










Notes

Risk of bias
















Tanha 2010a







Notes

Risk of bias
















Trinder 2006











Notes

Risk of bias

















Wood 2002








Risk of bias










































(Continued)




















(Continued)
















(Continued)
















(Continued)

















(Continued)















(Continued)






















(Continued)



















(Continued)





















(Continued)



















(Continued)








ACTRN12615000483550













Ali 2017








Notes

El Shahawy 2016












Notes

NCT02620904










Notes

NCT02633761












Notes

NCT03212352 2017








Notes




microg microgram






studies

No of





















studies

No of







studies

No of








studies

No of





studies

No of











studies

No of
















studies

No of





studies

No of











studies

No of











studies

No of







studies

No of









studies

No of

















studies

No of







studies

No of





studies

No of







studies

No of













studies

No of







studies

No of



















studies

No of














studies

No of





studies

No of










studies

No of





studies

No of














Herabutya 1997 3542 642 207 583 [ 275 1239 ]

Kovavisarach 2002 1727 527 172 340 [ 146 789 ]

Subtotal (95 CI) 69 69 379 473 [ 270 828 ]





Lister 2005 1518 216 73 667 [ 179 2478 ]

Wood 2002 2125 425 138 525 [ 210 1310 ]

Subtotal (95 CI) 43 41 211 574 [ 270 1219 ]





Bagratee 2004 3945 1138 411 299 [ 180 499 ]

Subtotal (95 CI) 45 38 411 299 [ 180 499 ]




Total (95 CI) 157 148 1000 423 [ 301 594 ]





001 01 1 10 100











Herabutya 1997 042 142 1000 033 [ 001 796 ]

Total (95 CI) 42 42 1000 033 [ 001 796 ]





001 01 1 10 100








Herabutya 1997 042 242 1000 020 [ 001 404 ]

Total (95 CI) 42 42 1000 020 [ 001 404 ]





0001 001 01 1 10 100 1000





difference gt 10 gL






Wood 2002 525 425 1000 125 [ 038 412 ]

Total (95 CI) 25 25 1000 125 [ 038 412 ]





01 02 05 1 2 5 10









Lister 2005 616 616 1000 100 [ 041 245 ]

Total (95 CI) 16 16 1000 100 [ 041 245 ]





01 02 05 1 2 5 10







Outcome 6 Nausea



Kovavisarach 2002 227 127 239 200 [ 019 2077 ]

Lister 2005 418 316 761 119 [ 031 451 ]

Total (95 CI) 45 43 1000 138 [ 043 440 ]





001 01 1 10 100





Outcome 7 Diarrhoea



Kovavisarach 2002 227 027 321 500 [ 025 9951 ]

Lister 2005 118 116 679 089 [ 006 1308 ]

Total (95 CI) 45 43 1000 221 [ 035 1406 ]





001 01 1 10 100










Herabutya 1997 242 042 1000 500 [ 025 10111 ]

Total (95 CI) 42 42 1000 500 [ 025 10111 ]





0001 001 01 1 10 100 1000



treatment






Lister 2005 1416 1216 1000 117 [ 083 164 ]

Total (95 CI) 16 16 1000 117 [ 083 164 ]





01 02 05 1 2 5 10





miscarriage





Expectantmanage-



Trinder 2006 192308 152306 1000 125 [ 109 145 ]

Total (95 CI) 308 306 1000 125 [ 109 145 ]





02 05 1 2 5







Expectantmanage-



Trinder 2006 16308 2310 1000 805 [ 187 3472 ]

Total (95 CI) 308 310 1000 805 [ 187 3472 ]





001 01 1 10 100





miscarriage





nN nN

M-HRandom95

CI

M-HRandom95

CI

Demetroulis 2001 626 2424 86 025 [ 013 048 ]

Fang 2009 530 3030 71 018 [ 008 039 ]

Ganguly 2010 37 34 42 057 [ 020 159 ]

Graziosi 2004 3779 7375 293 048 [ 038 061 ]

Muffley 2002 1025 2325 137 043 [ 027 071 ]

Trinder 2006 116308 278310 371 042 [ 036 049 ]

Total (95 CI) 475 468 1000 040 [ 032 050 ]





01 02 05 1 2 5 10





perforation






Graziosi 2004 079 175 1000 032 [ 001 765 ]

Total (95 CI) 79 75 1000 032 [ 001 765 ]





001 01 1 10 100









Difference


Muffley 2002 25 341 (5) 25 355 (2) 1000 -140 [ -351 071 ]

Total (95 CI) 25 25 1000 -140 [ -351 071 ]




-10 -5 0 5 10










Graziosi 2004 2479 1675 1000 142 [ 082 246 ]

Total (95 CI) 79 75 1000 142 [ 082 246 ]





01 02 05 1 2 5 10



infection






Trinder 2006 16308 22310 1000 073 [ 039 137 ]

Total (95 CI) 308 310 1000 073 [ 039 137 ]





001 01 1 10 100







Outcome 6 Nausea



Graziosi 2004 1179 075 1000 2185 [ 131 36437 ]

Total (95 CI) 79 75 1000 2185 [ 131 36437 ]





0001 001 01 1 10 100 1000





Outcome 7 Diarrhoea



Graziosi 2004 2179 075 1000 4085 [ 252 66257 ]

Total (95 CI) 79 75 1000 4085 [ 252 66257 ]





0001 001 01 1 10 100 1000





satisfaction






Fang 2009 815 2430 1000 067 [ 040 111 ]

Total (95 CI) 15 30 1000 067 [ 040 111 ]





001 01 1 10 100



miscarriage






Al Inizi 2003 1927 833 268 290 [ 151 557 ]

Kara 1999 2832 2033 732 144 [ 106 196 ]

Total (95 CI) 59 66 1000 183 [ 137 246 ]





01 02 05 1 2 5 10










Al Inizi 2003 227 033 1000 607 [ 030 12133 ]

Total (95 CI) 27 33 1000 607 [ 030 12133 ]





0001 001 01 1 10 100 1000





Outcome 3 Nausea



Kara 1999 432 433 1000 103 [ 028 378 ]

Total (95 CI) 32 33 1000 103 [ 028 378 ]





01 02 05 1 2 5 10











Difference


Al Inizi 2003 27 162 (056) 33 4 (28) 1000 -238 [ -336 -140 ]

Total (95 CI) 27 33 1000 -238 [ -336 -140 ]




-10 -5 0 5 10








nN nN

M-HRandom95

CI

M-HRandom95

CI

Kovavisarach 2005 2657 3957 399 067 [ 048 093 ]

Petersen 2013 111149 107134 601 093 [ 082 106 ]

Total (95 CI) 206 191 1000 082 [ 058 114 ]





01 02 05 1 2 5 10











Niromanesh 2005 4250 4050 1000 105 [ 087 126 ]

Total (95 CI) 50 50 1000 105 [ 087 126 ]





001 01 1 10 100







Outcome 3 Nausea



Kovavisarach 2005 257 757 467 029 [ 006 132 ]

Niromanesh 2005 850 850 533 100 [ 041 246 ]

Total (95 CI) 107 107 1000 067 [ 031 141 ]





001 01 1 10 100





Outcome 4 Diarrhoea



Kovavisarach 2005 057 257 385 020 [ 001 408 ]

Niromanesh 2005 350 450 615 075 [ 018 318 ]

Total (95 CI) 107 107 1000 054 [ 015 191 ]





0001 001 01 1 10 100 1000





miscarriage







Gilles 2004 3041 2539 200 114 [ 085 154 ]

Subtotal (95 CI) 41 39 200 114 [ 085 154 ]





Gilles 2004 3441 3139 248 104 [ 084 129 ]

Subtotal (95 CI) 41 39 248 104 [ 084 129 ]





Gilles 2004 3441 3539 280 092 [ 078 110 ]

Subtotal (95 CI) 41 39 280 092 [ 078 110 ]





Gilles 2004 3441 3439 272 095 [ 079 114 ]

Subtotal (95 CI) 41 39 272 095 [ 079 114 ]




Total (95 CI) 164 156 1000 100 [ 090 112 ]





01 02 05 1 2 5 10







Outcome 2 Diarrhoea



Gilles 2004 1740 937 1000 175 [ 089 342 ]

Total (95 CI) 40 37 1000 175 [ 089 342 ]





01 02 05 1 2 5 10





Outcome 3 Vomiting



Gilles 2004 640 637 1000 093 [ 033 262 ]

Total (95 CI) 40 37 1000 093 [ 033 262 ]





01 02 05 1 2 5 10











Gilles 2004 3136 2737 1000 118 [ 093 149 ]

Total (95 CI) 36 37 1000 118 [ 093 149 ]





01 02 05 1 2 5 10









Autry 1999 1212 89 1000 113 [ 085 150 ]

Total (95 CI) 12 9 1000 113 [ 085 150 ]





001 01 1 10 100











Autry 1999 112 09 1000 231 [ 010 5085 ]

Total (95 CI) 12 9 1000 231 [ 010 5085 ]





001 01 1 10 100









Autry 1999 412 49 1000 075 [ 025 222 ]

Total (95 CI) 12 9 1000 075 [ 025 222 ]





001 01 1 10 100












Jain 1996 1520 1518 484 090 [ 065 125 ]

Subtotal (95 CI) 20 18 484 090 [ 065 125 ]





Jain 1996 1920 1618 516 107 [ 088 129 ]

Subtotal (95 CI) 20 18 516 107 [ 088 129 ]




Total (95 CI) 40 36 1000 099 [ 082 118 ]





01 02 05 1 2 5 10










Sublingualevery 3


nN nN

M-HRandom95

CI

M-HRandom95

CI

Dehbashi 2016 925 1027 116 097 [ 047 199 ]

Shah 2010 1019 1122 142 105 [ 058 191 ]

Sonsanoh 2014 3660 4160 234 088 [ 067 115 ]

Tang 2003 3540 3540 260 100 [ 085 118 ]

Tanha 2010a 51110 93110 248 055 [ 044 068 ]

Total (95 CI) 254 259 1000 084 [ 061 116 ]





001 01 1 10 100











Shah 2010 26 23 1000 050 [ 013 200 ]

Total (95 CI) 6 3 1000 050 [ 013 200 ]





001 01 1 10 100

sublingual vaginal







nN nN

M-HRandom95

CI

M-HRandom95

CI

Sonsanoh 2014 360 1260 395 025 [ 007 084 ]

Tanha 2010a 48110 54110 605 089 [ 067 118 ]

Total (95 CI) 170 170 1000 054 [ 015 189 ]





001 01 1 10 100







Outcome 4 Pain



Dehbashi 2016 025 127 14 036 [ 002 843 ]

Sonsanoh 2014 1960 2760 256 070 [ 044 112 ]

Tanha 2010a 42110 77110 730 055 [ 042 071 ]

Total (95 CI) 195 197 1000 058 [ 046 074 ]





001 01 1 10 100







Outcome 5 Nausea


Sublingualmisopros-


nN nN

M-HRandom95

CI

M-HRandom95

CI

Dehbashi 2016 025 627 128 008 [ 000 140 ]

Shah 2010 125 1525 198 007 [ 001 047 ]

Sonsanoh 2014 760 660 304 117 [ 042 327 ]

Tang 2003 2040 2440 370 083 [ 056 124 ]

Total (95 CI) 150 152 1000 042 [ 012 144 ]





001 01 1 10 100







Outcome 6 Vomiting



Tang 2003 940 740 241 129 [ 053 312 ]

Tanha 2010a 13110 22110 759 059 [ 031 111 ]

Total (95 CI) 150 150 1000 076 [ 046 126 ]





001 01 1 10 100





Outcome 7 Diarrhoea



Dehbashi 2016 525 627 69 090 [ 031 258 ]

Sonsanoh 2014 360 460 48 075 [ 018 321 ]

Tang 2003 1140 2840 334 039 [ 023 068 ]

Tanha 2010a 40110 46110 549 087 [ 062 121 ]

Total (95 CI) 235 237 1000 071 [ 054 092 ]





001 01 1 10 100











Abediasl 2016 3840 3945 1000 110 [ 096 125 ]

Total (95 CI) 40 45 1000 110 [ 096 125 ]





001 01 1 10 100





excessive







Abediasl 2016 140 245 1000 056 [ 005 597 ]

Total (95 CI) 40 45 1000 056 [ 005 597 ]





001 01 1 10 100









Eng 1997 2125 1725 1000 124 [ 090 170 ]

Total (95 CI) 25 25 1000 124 [ 090 170 ]





01 02 05 1 2 5 10





relief












01 02 05 1 2 5 10





Outcome 3 Vomiting



Eng 1997 125 025 1000 300 [ 013 7030 ]

Total (95 CI) 25 25 1000 300 [ 013 7030 ]





001 01 1 10 100







Outcome 4 Diarrhoea



Eng 1997 025 325 1000 014 [ 001 263 ]

Total (95 CI) 25 25 1000 014 [ 001 263 ]





0001 001 01 1 10 100 1000



miscarriage





nN nN

M-HRandom95

CI

M-HRandom95

CI

Ayudhaya 2006 1570 1768 97 086 [ 047 158 ]

Kushwah 2009 4650 4250 903 110 [ 095 127 ]

Total (95 CI) 120 118 1000 107 [ 088 130 ]





001 01 1 10 100







Outcome 2 Pain


nN nN

M-HRandom95

CI

M-HRandom95

CI


Ayudhaya 2006 4770 4068 507 114 [ 088 148 ]

Subtotal (95 CI) 70 68 507 114 [ 088 148 ]





Kushwah 2009 2350 4450 493 052 [ 038 072 ]

Subtotal (95 CI) 50 50 493 052 [ 038 072 ]




Total (95 CI) 120 118 1000 078 [ 036 167 ]





001 01 1 10 100





vomiting





nN nN

M-HRandom95

CI

M-HRandom95

CI


Ayudhaya 2006 270 368 43 065 [ 011 376 ]

Subtotal (95 CI) 70 68 43 065 [ 011 376 ]




2 Nausea

Kushwah 2009 1750 2650 600 065 [ 041 105 ]

Subtotal (95 CI) 50 50 600 065 [ 041 105 ]




3 Vomiting

Kushwah 2009 1150 2250 357 050 [ 027 092 ]

Subtotal (95 CI) 50 50 357 050 [ 027 092 ]




Total (95 CI) 170 168 1000 059 [ 041 085 ]





001 01 1 10 100







Outcome 4 Diarrhoea


nN nN

M-HRandom95

CI

M-HRandom95

CI


Ayudhaya 2006 670 768 118 083 [ 029 235 ]

Subtotal (95 CI) 70 68 118 083 [ 029 235 ]





Kushwah 2009 2450 2850 882 086 [ 059 125 ]

Subtotal (95 CI) 50 50 882 086 [ 059 125 ]




Total (95 CI) 120 118 1000 085 [ 060 122 ]





001 01 1 10 100











Kushwah 2009 4650 3650 1000 128 [ 106 155 ]

Total (95 CI) 50 50 1000 128 [ 106 155 ]





001 01 1 10 100







Study or subgroup

600mcgpowdery

misoprosto

600mcgcompact

misoprosto

RiskRatio(Non-

event) Weight

RiskRatio(Non-

event)


Saichua 2009 926 928 1000 096 [ 066 141 ]

Total (95 CI) 26 28 1000 096 [ 066 141 ]





001 01 1 10 100





Nauseavomiting




Study or subgroup

600mcgpowdery

misoprosto

600mcgcompact



Saichua 2009 226 228 1000 108 [ 016 710 ]

Total (95 CI) 26 28 1000 108 [ 016 710 ]





001 01 1 10 100



Diarrhoea



Outcome 3 Diarrhoea

Study or subgroup

600mcgpowdery

misoprosto

600mcgcompact



Saichua 2009 726 728 1000 108 [ 044 265 ]

Total (95 CI) 26 28 1000 108 [ 044 265 ]





001 01 1 10 100











Tang 2006 8490 8390 1000 101 [ 093 110 ]

Total (95 CI) 90 90 1000 101 [ 093 110 ]





01 02 05 1 2 5 10





Nausea



Outcome 2 Nausea



Tang 2006 1890 1390 1000 138 [ 072 265 ]

Total (95 CI) 90 90 1000 138 [ 072 265 ]





001 01 1 10 100



Pain



Outcome 3 Pain



Tang 2006 7490 6690 1000 112 [ 096 131 ]

Total (95 CI) 90 90 1000 112 [ 096 131 ]





001 01 1 10 100





Vomiting



Outcome 4 Vomiting



Tang 2006 590 190 1000 500 [ 060 4195 ]

Total (95 CI) 90 90 1000 500 [ 060 4195 ]





001 01 1 10 100



Diarrhoea



Outcome 5 Diarrhoea



Tang 2006 3890 1990 1000 200 [ 125 319 ]

Total (95 CI) 90 90 1000 200 [ 125 319 ]





001 01 1 10 100











Tang 2003 3540 3540 1000 100 [ 085 118 ]

Total (95 CI) 40 40 1000 100 [ 085 118 ]





01 02 05 1 2 5 10









Difference


Tang 2003 40 126 (11) 40 125 (11) 1000 010 [ -038 058 ]

Total (95 CI) 40 40 1000 010 [ -038 058 ]




-10 -5 0 5 10





Nausea



Outcome 3 Nausea



Tang 2003 2440 2040 1000 120 [ 080 179 ]

Total (95 CI) 40 40 1000 120 [ 080 179 ]





01 02 05 1 2 5 10



Vomiting



Outcome 4 Vomiting



Tang 2003 740 940 1000 078 [ 032 188 ]

Total (95 CI) 40 40 1000 078 [ 032 188 ]





01 02 05 1 2 5 10





Diarrhoea



Outcome 5 Diarrhoea



Tang 2003 2840 1140 1000 255 [ 148 438 ]

Total (95 CI) 40 40 1000 255 [ 148 438 ]





01 02 05 1 2 5 10



Pain



Outcome 6 Pain



Tang 2003 640 840 1000 075 [ 029 197 ]

Total (95 CI) 40 40 1000 075 [ 029 197 ]





01 02 05 1 2 5 10











Tang 2003 3038 3139 1000 099 [ 079 125 ]

Total (95 CI) 38 39 1000 099 [ 079 125 ]





01 02 05 1 2 5 10








nN nN

M-HRandom95

CI

M-HRandom95

CI

Creinin 1997 312 78 111 029 [ 010 079 ]

Marwah 2016 3750 4050 305 093 [ 075 115 ]

Ngoc 2004 89100 9198 328 096 [ 088 105 ]

Rita 2006 1850 4050 256 045 [ 030 067 ]

Total (95 CI) 212 206 1000 068 [ 045 103 ]





05 07 1 15 2











Chittacharoen 2003 2020 2424 1000 100 [ 092 109 ]

Total (95 CI) 20 24 1000 100 [ 092 109 ]





02 05 1 2 5





excessive






Marwah 2016 350 150 1000 300 [ 032 2787 ]

Total (95 CI) 50 50 1000 300 [ 032 2787 ]





001 01 1 10 100



analogue scale)






Difference


Creinin 1997 11 4 (36) 7 59 (27) 1000 -190 [ -482 102 ]

Total (95 CI) 11 7 1000 -190 [ -482 102 ]




-10 -5 0 5 10







Outcome 5 Pain



Marwah 2016 2450 1550 750 160 [ 096 267 ]

Rita 2006 850 550 250 160 [ 056 456 ]

Total (95 CI) 100 100 1000 160 [ 101 255 ]





001 01 1 10 100





Outcome 6 Vomiting


nN nN

M-HRandom95

CI

M-HRandom95

CI

Ngoc 2004 495 1495 521 029 [ 010 084 ]

Rita 2006 650 350 479 200 [ 053 756 ]

Total (95 CI) 145 145 1000 073 [ 011 489 ]





001 01 1 10 100







Outcome 7 Nausea



Creinin 1997 612 58 107 080 [ 037 174 ]

Marwah 2016 3650 3050 536 120 [ 090 160 ]

Rita 2006 2550 2050 357 125 [ 081 194 ]

Total (95 CI) 112 108 1000 118 [ 093 148 ]





01 02 05 1 2 5 10







Outcome 8 Diarrhoea



Creinin 1997 512 38 96 111 [ 036 340 ]

Marwah 2016 750 650 160 117 [ 042 323 ]

Ngoc 2004 2495 2395 612 104 [ 064 171 ]

Rita 2006 550 550 133 100 [ 031 324 ]

Total (95 CI) 207 203 1000 106 [ 072 158 ]





01 02 05 1 2 5 10









Ngoc 2004 86100 8898 1000 096 [ 086 106 ]

Total (95 CI) 100 98 1000 096 [ 086 106 ]





01 02 05 1 2 5 10











Nielsen 1999 4960 4762 1000 108 [ 090 130 ]

Total (95 CI) 60 62 1000 108 [ 090 130 ]





01 02 05 1 2 5 10





Blood loss (severe)






Nielsen 1999 060 162 1000 034 [ 001 829 ]

Total (95 CI) 60 62 1000 034 [ 001 829 ]





001 01 1 10 100



Days of bleeding






Difference


Nielsen 1999 60 11 (326) 62 103 (311) 1000 070 [ -043 183 ]

Total (95 CI) 60 62 1000 070 [ -043 183 ]




-10 -5 0 5 10





Pain



Outcome 4 Pain



Difference


Nielsen 1999 60 661 (263) 62 62 (301) 1000 410 [ -592 1412 ]

Total (95 CI) 60 62 1000 410 [ -592 1412 ]




-100 -50 0 50 100



Pelvic infection






Nielsen 1999 160 262 1000 052 [ 005 555 ]

Total (95 CI) 60 62 1000 052 [ 005 555 ]





001 01 1 10 100











Difference


Nielsen 1999 60 286 (248) 62 252 (256) 1000 340 [ -554 1234 ]

Total (95 CI) 60 62 1000 340 [ -554 1234 ]




-100 -50 0 50 100









Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 2763 4872 457 064 [ 046 089 ]

Subtotal (95 CI) 63 72 457 064 [ 046 089 ]





Bracken 2014 3863 5772 543 076 [ 060 096 ]

Subtotal (95 CI) 63 72 543 076 [ 060 096 ]




Total (95 CI) 126 144 1000 071 [ 058 086 ]





001 01 1 10 100







Outcome 2 Nausea

Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 863 1572 1000 061 [ 028 134 ]

Total (95 CI) 63 72 1000 061 [ 028 134 ]





001 01 1 10 100





Outcome 3 Vomiting

Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 563 1972 1000 030 [ 012 076 ]

Total (95 CI) 63 72 1000 030 [ 012 076 ]





001 01 1 10 100







Outcome 4 Diarrhoea

Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 863 2372 1000 040 [ 019 082 ]

Total (95 CI) 63 72 1000 040 [ 019 082 ]





001 01 1 10 100







Outcome 5 Pain

Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 5763 6872 1000 096 [ 087 106 ]

Total (95 CI) 63 72 1000 096 [ 087 106 ]





001 01 1 10 100







Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 4563 5472 1000 095 [ 078 117 ]

Total (95 CI) 63 72 1000 095 [ 078 117 ]





001 01 1 10 100











Lelaidier 1993 223 023 1000 500 [ 025 9875 ]

Subtotal (95 CI) 23 23 1000 500 [ 025 9875 ]





Lelaidier 1993 923 023 1000 1900 [ 117 30840 ]

Subtotal (95 CI) 23 23 1000 1900 [ 117 30840 ]





Lelaidier 1993 1423 123 1000 1400 [ 200 9788 ]

Subtotal (95 CI) 23 23 1000 1400 [ 200 9788 ]





Lelaidier 1993 1923 223 1000 950 [ 249 3619 ]

Subtotal (95 CI) 23 23 1000 950 [ 249 3619 ]





001 01 1 10 100










Lelaidier 1993 2323 521 1000 392 [ 189 810 ]

Total (95 CI) 23 21 1000 392 [ 189 810 ]





01 02 05 1 2 5 10





Outcome 3 Pain



Lelaidier 1993 1223 521 1000 219 [ 093 517 ]

Total (95 CI) 23 21 1000 219 [ 093 517 ]





01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI

Fang 2009 2330 2530 292 092 [ 071 119 ]

Schreiber 2018 135148 113149 433 120 [ 108 133 ]

Sinha 2018 3945 2645 274 150 [ 114 197 ]

Total (95 CI) 223 224 1000 118 [ 095 147 ]





02 05 1 2 5











Schreiber 2018 3149 1151 1000 304 [ 032 2890 ]

Total (95 CI) 149 151 1000 304 [ 032 2890 ]





001 01 1 10 100









Schreiber 2018 2149 2151 1000 101 [ 014 710 ]

Total (95 CI) 149 151 1000 101 [ 014 710 ]





001 01 1 10 100





Outcome 4 nausea



Outcome 4 nausea



Schreiber 2018 56149 56151 1000 101 [ 076 136 ]

Total (95 CI) 149 151 1000 101 [ 076 136 ]





001 01 1 10 100



Outcome 5 Diarrhoea



Outcome 5 Diarrhoea



Schreiber 2018 41149 44151 1000 094 [ 066 135 ]

Total (95 CI) 149 151 1000 094 [ 066 135 ]





001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Fang 2009 1630 715 152 114 [ 060 216 ]

Sinha 2018 3845 2745 848 141 [ 107 184 ]

Total (95 CI) 75 60 1000 136 [ 106 175 ]





001 01 1 10 100









Egarter 1995 3343 4244 1000 080 [ 067 096 ]

Total (95 CI) 43 44 1000 080 [ 067 096 ]





01 02 05 1 2 5 10










RiskRatio(Non-

event) Weight

RiskRatio(Non-

event)


Egarter 1995 043 244 1000 105 [ 097 113 ]

Total (95 CI) 43 44 1000 105 [ 097 113 ]





01 02 05 1 2 5 10







Outcome 3 Nausea



Egarter 1995 743 444 1000 179 [ 056 568 ]

Total (95 CI) 43 44 1000 179 [ 056 568 ]





01 02 05 1 2 5 10









Mitwaly 2016 8590 7790 1000 110 [ 100 122 ]

Total (95 CI) 90 90 1000 110 [ 100 122 ]





001 01 1 10 100





2 Nausea



Outcome 2 Nausea


RiskRatio(Non-

event) Weight

RiskRatio(Non-

event)


Mitwaly 2016 290 3490 1000 157 [ 133 185 ]

Total (95 CI) 90 90 1000 157 [ 133 185 ]





001 01 1 10 100



3 Vomiting



Outcome 3 Vomiting



Mitwaly 2016 290 890 1000 025 [ 005 114 ]

Total (95 CI) 90 90 1000 025 [ 005 114 ]





001 01 1 10 100





4 Diarrhoea



Outcome 4 Diarrhoea



Mitwaly 2016 090 290 1000 020 [ 001 411 ]

Total (95 CI) 90 90 1000 020 [ 001 411 ]





001 01 1 10 100









Mitwaly 2016 1090 3390 1000 030 [ 016 058 ]

Total (95 CI) 90 90 1000 030 [ 016 058 ]





001 01 1 10 100





6 Time to expulsion






Difference


Mitwaly 2016 90 511 (266) 90 992 (312) 1000 -481 [ -566 -396 ]

Total (95 CI) 90 90 1000 -481 [ -566 -396 ]




-100 -50 0 50 100









Mizrachi 2017 6787 6484 437 101 [ 086 119 ]

Tang 2006 8390 8490 563 099 [ 091 107 ]

Total (95 CI) 177 174 1000 100 [ 092 109 ]





001 01 1 10 100





Nausea



Outcome 2 Nausea



Mizrachi 2017 2887 3584 442 077 [ 052 115 ]

Tang 2006 3890 4590 558 084 [ 061 116 ]

Total (95 CI) 177 174 1000 081 [ 063 104 ]





001 01 1 10 100



Vomiting



Outcome 3 Vomiting



Mizrachi 2017 1187 684 304 177 [ 069 457 ]

Tang 2006 1390 1490 696 093 [ 046 186 ]

Total (95 CI) 177 174 1000 118 [ 068 206 ]





001 01 1 10 100





Diarrhoea



Outcome 4 Diarrhoea



Mizrachi 2017 2587 2284 262 110 [ 067 179 ]

Tang 2006 6190 6390 738 097 [ 080 118 ]

Total (95 CI) 177 174 1000 100 [ 082 122 ]





001 01 1 10 100





(use of analgesics)






Mizrachi 2017 6087 6984 1000 084 [ 071 100 ]

Total (95 CI) 87 84 1000 084 [ 071 100 ]





001 01 1 10 100









Mizrachi 2017 6487 6184 1000 101 [ 084 122 ]

Total (95 CI) 87 84 1000 101 [ 084 122 ]





001 01 1 10 100




A P P E N D I C E S








H I S T O R Y

























Internal sources




External sources






























I N D E X T E R M S



MeSH check words









































A B S T R A C T

Background


Objectives


Search methods


Selection criteria




Main results









Other comparisons






What is the issue














What does this mean







Setting worldwide


Comparison placebo


(95 CI)

of participants

(studies)


dence

(GRADE)

Comments


prostol


(301 to 594)

305 women

(5 RCTs)

oplusopluscopycopy

LOW 12







189 per 1000 800 per 1000

(569 to 1000)


0 per 1000 0 per 1000

(0 to 0)


(043 to 440)

88 women

(2 RCTs)

oplusopluscopycopy

LOW 34

93 per 1000 128 per 1000

(40 to 409)


(035 to 1406)

88 women

(2 RCTs)

oplusopluscopycopy

LOW 34

23 per 1000 51 per 1000

(8 to 327)

4M

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24

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(038 to 412)

50 women

(1 RCT)

opluscopycopycopy

VERY LOW 56

160 per 1000 200 per 1000

(61 to 659)


(025 to 10111)

84 women

(1 RCT)

opluscopycopycopy46

VERY LOW

0 per 1000 0 per 1000

(0 to 0)




(083 to 164)

32 women

(1 RCT)

oplusopluscopycopy

LOW 6

750 per 1000 878 per 1000

(622 to 1000)


95CI)










5M

ed

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tfo

rearly

feta

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(less

than

24

weeks)

(Revie

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B A C K G R O U N D













O B J E C T I V E S


M E T H O D S


Types of studies









Primary outcomes



Secondary outcomes











Electronic searches

















selection bias)








bias)










detection bias)





outcome data)

















GRADE approach










Dichotomous data


Continuous data






Cross-over trials












Data synthesis







R E S U L T S










Included studies



Dates of study


Funding




Excluded studies













study



Allocation


Blinding






Selective reporting






Subgroup analyses













Primary outcomes


Secondary outcomes





Primary outcomes


Secondary outcomes




uterus

Primary outcomes


Secondary outcomes






Primary outcomes


Secondary outcomes



regimens

Primary outcomes



Secondary outcomes



preparations

Primary outcomes


Secondary outcomes






misoprostol

Primary outcomes


Secondary outcomes






Primary outcome


Secondary outcomes



Primary outcomes





Secondary outcomes



Primary outcomes


Secondary outcomes



vaginal misoprostol

Primary outcomes



Secondary outcomes



misoprostol

Primary outcomes


Secondary outcomes



extended course

Primary outcomes





Secondary outcomes



Primary outcomes


Secondary outcomes



Primary outcomes



Secondary outcomes



management

Primary outcomes


Secondary outcomes






regimen

Primary outcomes


Secondary outcomes



Primary outcomes


Secondary outcomes



alone

Primary outcomes


Secondary outcomes



uterus

Primary outcomes





Secondary outcomes



vaginal misoprostol

Primary outcomes


Secondary outcomes




course

Primary outcomes


Secondary outcomes









Setting worldwide




(95 CI)

of participants

(studies)


dence

(GRADE)

Comments

Risk with surgical



prostol


(032 to 050)

943 women

(6 RCTs)

oplusopluscopycopy

LOW 12






the same dosage of


921 per 1000 368 per 1000

(295 to 460)


(039 to 137)

618 women

(1 RCT)

oplusopluscopycopy

LOW 34




(28 to 97)


(131 to 36437)

154 women

(1 RCT)

oplusopluscopycopy

LOW 34

0 per 1000 22 per 1000

(1 to 364)


(252 to 66257)

154 women

(1 RCT)

oplusopluscopycopy

LOW 34

0 per 1000 41 per 1000

(3 to 663)

25

Med

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ment haematocrit ()

The mean blood loss


tocrit () was 355

mean 140 lower

(351 lower to 071

higher)

- 50 women

(1 RCT)

oplusopluscopycopy

LOW 34


(1 RCT)

oplusopluscopycopy

LOW 45

213 per 1000 303 per 1000

(175 to 525)




(1 RCT)

oplusopluscopycopy

LOW 67

800 per 1000 536 per 1000

(320 to 888)


95CI)









26

Med

icaltre

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than

24

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D I S C U S S I O N































R E F E R E N C E S










(Suppl 4)S5ndashS10







200310170ndash3
















































(10)643ndash8



























(2)113ndash6






















199776(1672)26





















2009107(Suppl 2)S533





(Suppl 2)S49











(Suppl 2)S116
























200757(3)211ndash3






201082(3)266ndash75















(15)2136ndash9





























(2)154ndash7 DOI 101016jijgo201605008








































































200618(3)35ndash9





























































(19)946ndash50



(2)678ndash81

























































































(s1)83









(2)117ndash20
















(4)956ndash60








199776(1672)32





























































Alfirevic 2014


2014 Issue 6 DOI 10100214651858CD001338pub3

Ashok 1998


Baulieu 1986



Bugalho 1996


Cameron 1986


Costa 1993


Graziosi 2005



Grudzinskas 1995


Higgins 2011


Hofmeyr 2010


Howie 1995


Kim 2017


Kovacs 1984




Kulier 2011


Mousa 2014


Muzonzini 2004


Nanda 2012


Petrou 2006




Say 2002



Tunccedilalp 2012



Whitworth 2015


Wieringa 2002



Neilson 2006


Vazquez 2000


Vazquez 2006







Abediasl 2016







Notes

Risk of bias

















Al Inizi 2003











Risk of bias













Autry 1999












Risk of bias
















Ayudhaya 2006







Notes

Risk of bias


















Bagratee 2004








Risk of bias
















Bracken 2014











Risk of bias

















Chittacharoen 2003







Notes

Risk of bias
















Creinin 1997







Notes Pilot study

Risk of bias







quence generation










Dehbashi 2016










Notes

Risk of bias
















All outcomes

Demetroulis 2001








Risk of bias
















Egarter 1995







Notes

Risk of bias
















Eng 1997







Notes

Risk of bias
















Fang 2009











Risk of bias













Ganguly 2010











Risk of bias
















Gilles 2004







Notes

Risk of bias
















Graziosi 2004












Risk of bias















Herabutya 1997








Risk of bias
















Jain 1996








Risk of bias
















Kara 1999








Risk of bias
















Kovavisarach 2002







Notes

Risk of bias
















Kovavisarach 2005










Notes

Risk of bias















Kushwah 2009







Notes

Risk of bias
















Lelaidier 1993








Risk of bias
















Lister 2005











Risk of bias















Marwah 2016







Notes

Risk of bias















Mitwaly 2016







Notes

Risk of bias















Mizrachi 2017







Notes

Risk of bias
















Muffley 2002








Risk of bias
















Ngoc 2004











Risk of bias
















Nielsen 1999








Risk of bias
















Niromanesh 2005







Notes

Risk of bias
















Petersen 2013







Notes

Risk of bias
















Rita 2006










Notes

Risk of bias















Saichua 2009







Notes

Risk of bias
















Schreiber 2018







Notes

Risk of bias
















Shah 2010










Notes

Risk of bias
















Sinha 2018







Notes

Risk of bias
















Sonsanoh 2014







Notes

Risk of bias
















Tang 2003










Notes

Risk of bias













Tang 2006










Notes

Risk of bias
















Tanha 2010a







Notes

Risk of bias
















Trinder 2006











Notes

Risk of bias

















Wood 2002








Risk of bias










































(Continued)




















(Continued)
















(Continued)
















(Continued)

















(Continued)















(Continued)






















(Continued)



















(Continued)





















(Continued)



















(Continued)








ACTRN12615000483550













Ali 2017








Notes

El Shahawy 2016












Notes

NCT02620904










Notes

NCT02633761












Notes

NCT03212352 2017








Notes




microg microgram






studies

No of





















studies

No of







studies

No of








studies

No of





studies

No of











studies

No of
















studies

No of





studies

No of











studies

No of











studies

No of







studies

No of









studies

No of

















studies

No of







studies

No of





studies

No of







studies

No of













studies

No of







studies

No of



















studies

No of














studies

No of





studies

No of










studies

No of





studies

No of














Herabutya 1997 3542 642 207 583 [ 275 1239 ]

Kovavisarach 2002 1727 527 172 340 [ 146 789 ]

Subtotal (95 CI) 69 69 379 473 [ 270 828 ]





Lister 2005 1518 216 73 667 [ 179 2478 ]

Wood 2002 2125 425 138 525 [ 210 1310 ]

Subtotal (95 CI) 43 41 211 574 [ 270 1219 ]





Bagratee 2004 3945 1138 411 299 [ 180 499 ]

Subtotal (95 CI) 45 38 411 299 [ 180 499 ]




Total (95 CI) 157 148 1000 423 [ 301 594 ]





001 01 1 10 100











Herabutya 1997 042 142 1000 033 [ 001 796 ]

Total (95 CI) 42 42 1000 033 [ 001 796 ]





001 01 1 10 100








Herabutya 1997 042 242 1000 020 [ 001 404 ]

Total (95 CI) 42 42 1000 020 [ 001 404 ]





0001 001 01 1 10 100 1000





difference gt 10 gL






Wood 2002 525 425 1000 125 [ 038 412 ]

Total (95 CI) 25 25 1000 125 [ 038 412 ]





01 02 05 1 2 5 10









Lister 2005 616 616 1000 100 [ 041 245 ]

Total (95 CI) 16 16 1000 100 [ 041 245 ]





01 02 05 1 2 5 10







Outcome 6 Nausea



Kovavisarach 2002 227 127 239 200 [ 019 2077 ]

Lister 2005 418 316 761 119 [ 031 451 ]

Total (95 CI) 45 43 1000 138 [ 043 440 ]





001 01 1 10 100





Outcome 7 Diarrhoea



Kovavisarach 2002 227 027 321 500 [ 025 9951 ]

Lister 2005 118 116 679 089 [ 006 1308 ]

Total (95 CI) 45 43 1000 221 [ 035 1406 ]





001 01 1 10 100










Herabutya 1997 242 042 1000 500 [ 025 10111 ]

Total (95 CI) 42 42 1000 500 [ 025 10111 ]





0001 001 01 1 10 100 1000



treatment






Lister 2005 1416 1216 1000 117 [ 083 164 ]

Total (95 CI) 16 16 1000 117 [ 083 164 ]





01 02 05 1 2 5 10





miscarriage





Expectantmanage-



Trinder 2006 192308 152306 1000 125 [ 109 145 ]

Total (95 CI) 308 306 1000 125 [ 109 145 ]





02 05 1 2 5







Expectantmanage-



Trinder 2006 16308 2310 1000 805 [ 187 3472 ]

Total (95 CI) 308 310 1000 805 [ 187 3472 ]





001 01 1 10 100





miscarriage





nN nN

M-HRandom95

CI

M-HRandom95

CI

Demetroulis 2001 626 2424 86 025 [ 013 048 ]

Fang 2009 530 3030 71 018 [ 008 039 ]

Ganguly 2010 37 34 42 057 [ 020 159 ]

Graziosi 2004 3779 7375 293 048 [ 038 061 ]

Muffley 2002 1025 2325 137 043 [ 027 071 ]

Trinder 2006 116308 278310 371 042 [ 036 049 ]

Total (95 CI) 475 468 1000 040 [ 032 050 ]





01 02 05 1 2 5 10





perforation






Graziosi 2004 079 175 1000 032 [ 001 765 ]

Total (95 CI) 79 75 1000 032 [ 001 765 ]





001 01 1 10 100









Difference


Muffley 2002 25 341 (5) 25 355 (2) 1000 -140 [ -351 071 ]

Total (95 CI) 25 25 1000 -140 [ -351 071 ]




-10 -5 0 5 10










Graziosi 2004 2479 1675 1000 142 [ 082 246 ]

Total (95 CI) 79 75 1000 142 [ 082 246 ]





01 02 05 1 2 5 10



infection






Trinder 2006 16308 22310 1000 073 [ 039 137 ]

Total (95 CI) 308 310 1000 073 [ 039 137 ]





001 01 1 10 100







Outcome 6 Nausea



Graziosi 2004 1179 075 1000 2185 [ 131 36437 ]

Total (95 CI) 79 75 1000 2185 [ 131 36437 ]





0001 001 01 1 10 100 1000





Outcome 7 Diarrhoea



Graziosi 2004 2179 075 1000 4085 [ 252 66257 ]

Total (95 CI) 79 75 1000 4085 [ 252 66257 ]





0001 001 01 1 10 100 1000





satisfaction






Fang 2009 815 2430 1000 067 [ 040 111 ]

Total (95 CI) 15 30 1000 067 [ 040 111 ]





001 01 1 10 100



miscarriage






Al Inizi 2003 1927 833 268 290 [ 151 557 ]

Kara 1999 2832 2033 732 144 [ 106 196 ]

Total (95 CI) 59 66 1000 183 [ 137 246 ]





01 02 05 1 2 5 10










Al Inizi 2003 227 033 1000 607 [ 030 12133 ]

Total (95 CI) 27 33 1000 607 [ 030 12133 ]





0001 001 01 1 10 100 1000





Outcome 3 Nausea



Kara 1999 432 433 1000 103 [ 028 378 ]

Total (95 CI) 32 33 1000 103 [ 028 378 ]





01 02 05 1 2 5 10











Difference


Al Inizi 2003 27 162 (056) 33 4 (28) 1000 -238 [ -336 -140 ]

Total (95 CI) 27 33 1000 -238 [ -336 -140 ]




-10 -5 0 5 10








nN nN

M-HRandom95

CI

M-HRandom95

CI

Kovavisarach 2005 2657 3957 399 067 [ 048 093 ]

Petersen 2013 111149 107134 601 093 [ 082 106 ]

Total (95 CI) 206 191 1000 082 [ 058 114 ]





01 02 05 1 2 5 10











Niromanesh 2005 4250 4050 1000 105 [ 087 126 ]

Total (95 CI) 50 50 1000 105 [ 087 126 ]





001 01 1 10 100







Outcome 3 Nausea



Kovavisarach 2005 257 757 467 029 [ 006 132 ]

Niromanesh 2005 850 850 533 100 [ 041 246 ]

Total (95 CI) 107 107 1000 067 [ 031 141 ]





001 01 1 10 100





Outcome 4 Diarrhoea



Kovavisarach 2005 057 257 385 020 [ 001 408 ]

Niromanesh 2005 350 450 615 075 [ 018 318 ]

Total (95 CI) 107 107 1000 054 [ 015 191 ]





0001 001 01 1 10 100 1000





miscarriage







Gilles 2004 3041 2539 200 114 [ 085 154 ]

Subtotal (95 CI) 41 39 200 114 [ 085 154 ]





Gilles 2004 3441 3139 248 104 [ 084 129 ]

Subtotal (95 CI) 41 39 248 104 [ 084 129 ]





Gilles 2004 3441 3539 280 092 [ 078 110 ]

Subtotal (95 CI) 41 39 280 092 [ 078 110 ]





Gilles 2004 3441 3439 272 095 [ 079 114 ]

Subtotal (95 CI) 41 39 272 095 [ 079 114 ]




Total (95 CI) 164 156 1000 100 [ 090 112 ]





01 02 05 1 2 5 10







Outcome 2 Diarrhoea



Gilles 2004 1740 937 1000 175 [ 089 342 ]

Total (95 CI) 40 37 1000 175 [ 089 342 ]





01 02 05 1 2 5 10





Outcome 3 Vomiting



Gilles 2004 640 637 1000 093 [ 033 262 ]

Total (95 CI) 40 37 1000 093 [ 033 262 ]





01 02 05 1 2 5 10











Gilles 2004 3136 2737 1000 118 [ 093 149 ]

Total (95 CI) 36 37 1000 118 [ 093 149 ]





01 02 05 1 2 5 10









Autry 1999 1212 89 1000 113 [ 085 150 ]

Total (95 CI) 12 9 1000 113 [ 085 150 ]





001 01 1 10 100











Autry 1999 112 09 1000 231 [ 010 5085 ]

Total (95 CI) 12 9 1000 231 [ 010 5085 ]





001 01 1 10 100









Autry 1999 412 49 1000 075 [ 025 222 ]

Total (95 CI) 12 9 1000 075 [ 025 222 ]





001 01 1 10 100












Jain 1996 1520 1518 484 090 [ 065 125 ]

Subtotal (95 CI) 20 18 484 090 [ 065 125 ]





Jain 1996 1920 1618 516 107 [ 088 129 ]

Subtotal (95 CI) 20 18 516 107 [ 088 129 ]




Total (95 CI) 40 36 1000 099 [ 082 118 ]





01 02 05 1 2 5 10










Sublingualevery 3


nN nN

M-HRandom95

CI

M-HRandom95

CI

Dehbashi 2016 925 1027 116 097 [ 047 199 ]

Shah 2010 1019 1122 142 105 [ 058 191 ]

Sonsanoh 2014 3660 4160 234 088 [ 067 115 ]

Tang 2003 3540 3540 260 100 [ 085 118 ]

Tanha 2010a 51110 93110 248 055 [ 044 068 ]

Total (95 CI) 254 259 1000 084 [ 061 116 ]





001 01 1 10 100











Shah 2010 26 23 1000 050 [ 013 200 ]

Total (95 CI) 6 3 1000 050 [ 013 200 ]





001 01 1 10 100

sublingual vaginal







nN nN

M-HRandom95

CI

M-HRandom95

CI

Sonsanoh 2014 360 1260 395 025 [ 007 084 ]

Tanha 2010a 48110 54110 605 089 [ 067 118 ]

Total (95 CI) 170 170 1000 054 [ 015 189 ]





001 01 1 10 100







Outcome 4 Pain



Dehbashi 2016 025 127 14 036 [ 002 843 ]

Sonsanoh 2014 1960 2760 256 070 [ 044 112 ]

Tanha 2010a 42110 77110 730 055 [ 042 071 ]

Total (95 CI) 195 197 1000 058 [ 046 074 ]





001 01 1 10 100







Outcome 5 Nausea


Sublingualmisopros-


nN nN

M-HRandom95

CI

M-HRandom95

CI

Dehbashi 2016 025 627 128 008 [ 000 140 ]

Shah 2010 125 1525 198 007 [ 001 047 ]

Sonsanoh 2014 760 660 304 117 [ 042 327 ]

Tang 2003 2040 2440 370 083 [ 056 124 ]

Total (95 CI) 150 152 1000 042 [ 012 144 ]





001 01 1 10 100







Outcome 6 Vomiting



Tang 2003 940 740 241 129 [ 053 312 ]

Tanha 2010a 13110 22110 759 059 [ 031 111 ]

Total (95 CI) 150 150 1000 076 [ 046 126 ]





001 01 1 10 100





Outcome 7 Diarrhoea



Dehbashi 2016 525 627 69 090 [ 031 258 ]

Sonsanoh 2014 360 460 48 075 [ 018 321 ]

Tang 2003 1140 2840 334 039 [ 023 068 ]

Tanha 2010a 40110 46110 549 087 [ 062 121 ]

Total (95 CI) 235 237 1000 071 [ 054 092 ]





001 01 1 10 100











Abediasl 2016 3840 3945 1000 110 [ 096 125 ]

Total (95 CI) 40 45 1000 110 [ 096 125 ]





001 01 1 10 100





excessive







Abediasl 2016 140 245 1000 056 [ 005 597 ]

Total (95 CI) 40 45 1000 056 [ 005 597 ]





001 01 1 10 100









Eng 1997 2125 1725 1000 124 [ 090 170 ]

Total (95 CI) 25 25 1000 124 [ 090 170 ]





01 02 05 1 2 5 10





relief












01 02 05 1 2 5 10





Outcome 3 Vomiting



Eng 1997 125 025 1000 300 [ 013 7030 ]

Total (95 CI) 25 25 1000 300 [ 013 7030 ]





001 01 1 10 100







Outcome 4 Diarrhoea



Eng 1997 025 325 1000 014 [ 001 263 ]

Total (95 CI) 25 25 1000 014 [ 001 263 ]





0001 001 01 1 10 100 1000



miscarriage





nN nN

M-HRandom95

CI

M-HRandom95

CI

Ayudhaya 2006 1570 1768 97 086 [ 047 158 ]

Kushwah 2009 4650 4250 903 110 [ 095 127 ]

Total (95 CI) 120 118 1000 107 [ 088 130 ]





001 01 1 10 100







Outcome 2 Pain


nN nN

M-HRandom95

CI

M-HRandom95

CI


Ayudhaya 2006 4770 4068 507 114 [ 088 148 ]

Subtotal (95 CI) 70 68 507 114 [ 088 148 ]





Kushwah 2009 2350 4450 493 052 [ 038 072 ]

Subtotal (95 CI) 50 50 493 052 [ 038 072 ]




Total (95 CI) 120 118 1000 078 [ 036 167 ]





001 01 1 10 100





vomiting





nN nN

M-HRandom95

CI

M-HRandom95

CI


Ayudhaya 2006 270 368 43 065 [ 011 376 ]

Subtotal (95 CI) 70 68 43 065 [ 011 376 ]




2 Nausea

Kushwah 2009 1750 2650 600 065 [ 041 105 ]

Subtotal (95 CI) 50 50 600 065 [ 041 105 ]




3 Vomiting

Kushwah 2009 1150 2250 357 050 [ 027 092 ]

Subtotal (95 CI) 50 50 357 050 [ 027 092 ]




Total (95 CI) 170 168 1000 059 [ 041 085 ]





001 01 1 10 100







Outcome 4 Diarrhoea


nN nN

M-HRandom95

CI

M-HRandom95

CI


Ayudhaya 2006 670 768 118 083 [ 029 235 ]

Subtotal (95 CI) 70 68 118 083 [ 029 235 ]





Kushwah 2009 2450 2850 882 086 [ 059 125 ]

Subtotal (95 CI) 50 50 882 086 [ 059 125 ]




Total (95 CI) 120 118 1000 085 [ 060 122 ]





001 01 1 10 100











Kushwah 2009 4650 3650 1000 128 [ 106 155 ]

Total (95 CI) 50 50 1000 128 [ 106 155 ]





001 01 1 10 100







Study or subgroup

600mcgpowdery

misoprosto

600mcgcompact

misoprosto

RiskRatio(Non-

event) Weight

RiskRatio(Non-

event)


Saichua 2009 926 928 1000 096 [ 066 141 ]

Total (95 CI) 26 28 1000 096 [ 066 141 ]





001 01 1 10 100





Nauseavomiting




Study or subgroup

600mcgpowdery

misoprosto

600mcgcompact



Saichua 2009 226 228 1000 108 [ 016 710 ]

Total (95 CI) 26 28 1000 108 [ 016 710 ]





001 01 1 10 100



Diarrhoea



Outcome 3 Diarrhoea

Study or subgroup

600mcgpowdery

misoprosto

600mcgcompact



Saichua 2009 726 728 1000 108 [ 044 265 ]

Total (95 CI) 26 28 1000 108 [ 044 265 ]





001 01 1 10 100











Tang 2006 8490 8390 1000 101 [ 093 110 ]

Total (95 CI) 90 90 1000 101 [ 093 110 ]





01 02 05 1 2 5 10





Nausea



Outcome 2 Nausea



Tang 2006 1890 1390 1000 138 [ 072 265 ]

Total (95 CI) 90 90 1000 138 [ 072 265 ]





001 01 1 10 100



Pain



Outcome 3 Pain



Tang 2006 7490 6690 1000 112 [ 096 131 ]

Total (95 CI) 90 90 1000 112 [ 096 131 ]





001 01 1 10 100





Vomiting



Outcome 4 Vomiting



Tang 2006 590 190 1000 500 [ 060 4195 ]

Total (95 CI) 90 90 1000 500 [ 060 4195 ]





001 01 1 10 100



Diarrhoea



Outcome 5 Diarrhoea



Tang 2006 3890 1990 1000 200 [ 125 319 ]

Total (95 CI) 90 90 1000 200 [ 125 319 ]





001 01 1 10 100











Tang 2003 3540 3540 1000 100 [ 085 118 ]

Total (95 CI) 40 40 1000 100 [ 085 118 ]





01 02 05 1 2 5 10









Difference


Tang 2003 40 126 (11) 40 125 (11) 1000 010 [ -038 058 ]

Total (95 CI) 40 40 1000 010 [ -038 058 ]




-10 -5 0 5 10





Nausea



Outcome 3 Nausea



Tang 2003 2440 2040 1000 120 [ 080 179 ]

Total (95 CI) 40 40 1000 120 [ 080 179 ]





01 02 05 1 2 5 10



Vomiting



Outcome 4 Vomiting



Tang 2003 740 940 1000 078 [ 032 188 ]

Total (95 CI) 40 40 1000 078 [ 032 188 ]





01 02 05 1 2 5 10





Diarrhoea



Outcome 5 Diarrhoea



Tang 2003 2840 1140 1000 255 [ 148 438 ]

Total (95 CI) 40 40 1000 255 [ 148 438 ]





01 02 05 1 2 5 10



Pain



Outcome 6 Pain



Tang 2003 640 840 1000 075 [ 029 197 ]

Total (95 CI) 40 40 1000 075 [ 029 197 ]





01 02 05 1 2 5 10











Tang 2003 3038 3139 1000 099 [ 079 125 ]

Total (95 CI) 38 39 1000 099 [ 079 125 ]





01 02 05 1 2 5 10








nN nN

M-HRandom95

CI

M-HRandom95

CI

Creinin 1997 312 78 111 029 [ 010 079 ]

Marwah 2016 3750 4050 305 093 [ 075 115 ]

Ngoc 2004 89100 9198 328 096 [ 088 105 ]

Rita 2006 1850 4050 256 045 [ 030 067 ]

Total (95 CI) 212 206 1000 068 [ 045 103 ]





05 07 1 15 2











Chittacharoen 2003 2020 2424 1000 100 [ 092 109 ]

Total (95 CI) 20 24 1000 100 [ 092 109 ]





02 05 1 2 5





excessive






Marwah 2016 350 150 1000 300 [ 032 2787 ]

Total (95 CI) 50 50 1000 300 [ 032 2787 ]





001 01 1 10 100



analogue scale)






Difference


Creinin 1997 11 4 (36) 7 59 (27) 1000 -190 [ -482 102 ]

Total (95 CI) 11 7 1000 -190 [ -482 102 ]




-10 -5 0 5 10







Outcome 5 Pain



Marwah 2016 2450 1550 750 160 [ 096 267 ]

Rita 2006 850 550 250 160 [ 056 456 ]

Total (95 CI) 100 100 1000 160 [ 101 255 ]





001 01 1 10 100





Outcome 6 Vomiting


nN nN

M-HRandom95

CI

M-HRandom95

CI

Ngoc 2004 495 1495 521 029 [ 010 084 ]

Rita 2006 650 350 479 200 [ 053 756 ]

Total (95 CI) 145 145 1000 073 [ 011 489 ]





001 01 1 10 100







Outcome 7 Nausea



Creinin 1997 612 58 107 080 [ 037 174 ]

Marwah 2016 3650 3050 536 120 [ 090 160 ]

Rita 2006 2550 2050 357 125 [ 081 194 ]

Total (95 CI) 112 108 1000 118 [ 093 148 ]





01 02 05 1 2 5 10







Outcome 8 Diarrhoea



Creinin 1997 512 38 96 111 [ 036 340 ]

Marwah 2016 750 650 160 117 [ 042 323 ]

Ngoc 2004 2495 2395 612 104 [ 064 171 ]

Rita 2006 550 550 133 100 [ 031 324 ]

Total (95 CI) 207 203 1000 106 [ 072 158 ]





01 02 05 1 2 5 10









Ngoc 2004 86100 8898 1000 096 [ 086 106 ]

Total (95 CI) 100 98 1000 096 [ 086 106 ]





01 02 05 1 2 5 10











Nielsen 1999 4960 4762 1000 108 [ 090 130 ]

Total (95 CI) 60 62 1000 108 [ 090 130 ]





01 02 05 1 2 5 10





Blood loss (severe)






Nielsen 1999 060 162 1000 034 [ 001 829 ]

Total (95 CI) 60 62 1000 034 [ 001 829 ]





001 01 1 10 100



Days of bleeding






Difference


Nielsen 1999 60 11 (326) 62 103 (311) 1000 070 [ -043 183 ]

Total (95 CI) 60 62 1000 070 [ -043 183 ]




-10 -5 0 5 10





Pain



Outcome 4 Pain



Difference


Nielsen 1999 60 661 (263) 62 62 (301) 1000 410 [ -592 1412 ]

Total (95 CI) 60 62 1000 410 [ -592 1412 ]




-100 -50 0 50 100



Pelvic infection






Nielsen 1999 160 262 1000 052 [ 005 555 ]

Total (95 CI) 60 62 1000 052 [ 005 555 ]





001 01 1 10 100











Difference


Nielsen 1999 60 286 (248) 62 252 (256) 1000 340 [ -554 1234 ]

Total (95 CI) 60 62 1000 340 [ -554 1234 ]




-100 -50 0 50 100









Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 2763 4872 457 064 [ 046 089 ]

Subtotal (95 CI) 63 72 457 064 [ 046 089 ]





Bracken 2014 3863 5772 543 076 [ 060 096 ]

Subtotal (95 CI) 63 72 543 076 [ 060 096 ]




Total (95 CI) 126 144 1000 071 [ 058 086 ]





001 01 1 10 100







Outcome 2 Nausea

Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 863 1572 1000 061 [ 028 134 ]

Total (95 CI) 63 72 1000 061 [ 028 134 ]





001 01 1 10 100





Outcome 3 Vomiting

Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 563 1972 1000 030 [ 012 076 ]

Total (95 CI) 63 72 1000 030 [ 012 076 ]





001 01 1 10 100







Outcome 4 Diarrhoea

Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 863 2372 1000 040 [ 019 082 ]

Total (95 CI) 63 72 1000 040 [ 019 082 ]





001 01 1 10 100







Outcome 5 Pain

Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 5763 6872 1000 096 [ 087 106 ]

Total (95 CI) 63 72 1000 096 [ 087 106 ]





001 01 1 10 100







Study or subgroup

100mcgbuccal

misoprostol

200mcgbuccal




Bracken 2014 4563 5472 1000 095 [ 078 117 ]

Total (95 CI) 63 72 1000 095 [ 078 117 ]





001 01 1 10 100











Lelaidier 1993 223 023 1000 500 [ 025 9875 ]

Subtotal (95 CI) 23 23 1000 500 [ 025 9875 ]





Lelaidier 1993 923 023 1000 1900 [ 117 30840 ]

Subtotal (95 CI) 23 23 1000 1900 [ 117 30840 ]





Lelaidier 1993 1423 123 1000 1400 [ 200 9788 ]

Subtotal (95 CI) 23 23 1000 1400 [ 200 9788 ]





Lelaidier 1993 1923 223 1000 950 [ 249 3619 ]

Subtotal (95 CI) 23 23 1000 950 [ 249 3619 ]





001 01 1 10 100










Lelaidier 1993 2323 521 1000 392 [ 189 810 ]

Total (95 CI) 23 21 1000 392 [ 189 810 ]





01 02 05 1 2 5 10





Outcome 3 Pain



Lelaidier 1993 1223 521 1000 219 [ 093 517 ]

Total (95 CI) 23 21 1000 219 [ 093 517 ]





01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI

Fang 2009 2330 2530 292 092 [ 071 119 ]

Schreiber 2018 135148 113149 433 120 [ 108 133 ]

Sinha 2018 3945 2645 274 150 [ 114 197 ]

Total (95 CI) 223 224 1000 118 [ 095 147 ]





02 05 1 2 5











Schreiber 2018 3149 1151 1000 304 [ 032 2890 ]

Total (95 CI) 149 151 1000 304 [ 032 2890 ]





001 01 1 10 100









Schreiber 2018 2149 2151 1000 101 [ 014 710 ]

Total (95 CI) 149 151 1000 101 [ 014 710 ]





001 01 1 10 100





Outcome 4 nausea



Outcome 4 nausea



Schreiber 2018 56149 56151 1000 101 [ 076 136 ]

Total (95 CI) 149 151 1000 101 [ 076 136 ]





001 01 1 10 100



Outcome 5 Diarrhoea



Outcome 5 Diarrhoea



Schreiber 2018 41149 44151 1000 094 [ 066 135 ]

Total (95 CI) 149 151 1000 094 [ 066 135 ]





001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Fang 2009 1630 715 152 114 [ 060 216 ]

Sinha 2018 3845 2745 848 141 [ 107 184 ]

Total (95 CI) 75 60 1000 136 [ 106 175 ]





001 01 1 10 100









Egarter 1995 3343 4244 1000 080 [ 067 096 ]

Total (95 CI) 43 44 1000 080 [ 067 096 ]





01 02 05 1 2 5 10










RiskRatio(Non-

event) Weight

RiskRatio(Non-

event)


Egarter 1995 043 244 1000 105 [ 097 113 ]

Total (95 CI) 43 44 1000 105 [ 097 113 ]





01 02 05 1 2 5 10







Outcome 3 Nausea



Egarter 1995 743 444 1000 179 [ 056 568 ]

Total (95 CI) 43 44 1000 179 [ 056 568 ]





01 02 05 1 2 5 10









Mitwaly 2016 8590 7790 1000 110 [ 100 122 ]

Total (95 CI) 90 90 1000 110 [ 100 122 ]





001 01 1 10 100





2 Nausea



Outcome 2 Nausea


RiskRatio(Non-

event) Weight

RiskRatio(Non-

event)


Mitwaly 2016 290 3490 1000 157 [ 133 185 ]

Total (95 CI) 90 90 1000 157 [ 133 185 ]





001 01 1 10 100



3 Vomiting



Outcome 3 Vomiting



Mitwaly 2016 290 890 1000 025 [ 005 114 ]

Total (95 CI) 90 90 1000 025 [ 005 114 ]





001 01 1 10 100





4 Diarrhoea



Outcome 4 Diarrhoea



Mitwaly 2016 090 290 1000 020 [ 001 411 ]

Total (95 CI) 90 90 1000 020 [ 001 411 ]





001 01 1 10 100









Mitwaly 2016 1090 3390 1000 030 [ 016 058 ]

Total (95 CI) 90 90 1000 030 [ 016 058 ]





001 01 1 10 100





6 Time to expulsion






Difference


Mitwaly 2016 90 511 (266) 90 992 (312) 1000 -481 [ -566 -396 ]

Total (95 CI) 90 90 1000 -481 [ -566 -396 ]




-100 -50 0 50 100









Mizrachi 2017 6787 6484 437 101 [ 086 119 ]

Tang 2006 8390 8490 563 099 [ 091 107 ]

Total (95 CI) 177 174 1000 100 [ 092 109 ]





001 01 1 10 100





Nausea



Outcome 2 Nausea



Mizrachi 2017 2887 3584 442 077 [ 052 115 ]

Tang 2006 3890 4590 558 084 [ 061 116 ]

Total (95 CI) 177 174 1000 081 [ 063 104 ]





001 01 1 10 100



Vomiting



Outcome 3 Vomiting



Mizrachi 2017 1187 684 304 177 [ 069 457 ]

Tang 2006 1390 1490 696 093 [ 046 186 ]

Total (95 CI) 177 174 1000 118 [ 068 206 ]





001 01 1 10 100





Diarrhoea



Outcome 4 Diarrhoea



Mizrachi 2017 2587 2284 262 110 [ 067 179 ]

Tang 2006 6190 6390 738 097 [ 080 118 ]

Total (95 CI) 177 174 1000 100 [ 082 122 ]





001 01 1 10 100





(use of analgesics)






Mizrachi 2017 6087 6984 1000 084 [ 071 100 ]

Total (95 CI) 87 84 1000 084 [ 071 100 ]





001 01 1 10 100









Mizrachi 2017 6487 6184 1000 101 [ 084 122 ]

Total (95 CI) 87 84 1000 101 [ 084 122 ]





001 01 1 10 100




A P P E N D I C E S








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Documents

Medicaltreatmentforearlyfetaldeath(lessthan24weeks) (Review)