Medical methods for first trimester abortion

Jing Zhang; Kunyan Zhou; Dan Shan; Xiaoyan Luo

doi:10.1002/14651858.CD002855.pub5

. 2022 May 24;2022(5):CD002855. doi: 10.1002/14651858.CD002855.pub5

Medical methods for first trimester abortion

Jing Zhang ^1,^2,³, Kunyan Zhou ^1,^2,^3,^✉, Dan Shan ^1,^2,³, Xiaoyan Luo ^1,^2,³

Editor: Cochrane Fertility Regulation Group

PMCID: PMC9128719 PMID: 35608608

Abstract

Background

Medical abortion became an alternative method of pregnancy termination following the development of prostaglandins and antiprogesterone in the 1970s and 1980s. Recently, synthesis inhibitors of oestrogen (such as letrozole) have also been used to enhance efficacy. The most widely researched drugs are prostaglandins (such as misoprostol, which has a strong uterotonic effect), mifepristone, mifepristone with prostaglandins, and letrozole with prostaglandins. More evidence is needed to identify the best dosage, regimen, and route of administration to optimise patient outcomes. This is an update of a review last published in 2011.

Objectives

To compare the effectiveness and side effects of different medical methods for first trimester abortion.

Search methods

We searched CENTRAL, MEDLINE, Embase, Global Health, and LILACs on 28 February 2021. We also searched Clinicaltrials.gov and the World Health Organization's (WHO) International Clinical Trials Registry Platform, and reference lists of retrieved papers.

Selection criteria

We considered randomised controlled trials (RCTs) that compared different medical methods for abortion before the 12th week of gestation. The primary outcome is failure to achieve complete abortion. Secondary outcomes are mortality, surgical evacuation, ongoing pregnancy at follow‐up, time until passing of conceptus, blood transfusion, side effects and women's dissatisfaction with the method.

Data collection and analysis

Two review authors independently selected and evaluated studies for inclusion, and assessed the risk of bias. We processed data using Review Manager 5 software. We assessed the certainty of the evidence using the GRADE approach.

Main results

We included 99 studies in the review (58 from the original review and 41 new studies).

1. Combined regimen mifepristone/prostaglandin

Mifepristone dose: high‐dose (600 mg) compared to low‐dose (200 mg) mifepristone probably has similar effectiveness in achieving complete abortion (RR 1.07, 95% CI 0.87 to 1.33; I² = 0%; 4 RCTs, 3494 women; moderate‐certainty evidence).

Prostaglandin dose: 800 µg misoprostol probably reduces abortion failure compared to 400 µg (RR 0.63, 95% CI 0.51 to 0.78; I²= 0%; 3 RCTs, 4424 women; moderate‐certainty evidence).

Prostaglandin timing: misoprostol administered on day one probably achieves more success on complete abortion than on day three (RR 1.94, 95% CI 1.05 to 3.58; 1489 women; 1 RCT; moderate‐certainty evidence).

Administration strategy: there may be no difference in failure of complete abortion with self‐administration at home compared with hospital administration (RR 1.63, 95% CI 0.68 to 3.94; I² = 84%; 2263 women; 4 RCTs; low‐certainty evidence), but failure may be higher when administered by nurses in hospital compared to by doctors in hospital (RR 2.69, 95% CI 1.39 to 5.22; I² = 66%; 3 RCTs, 3056 women; low‐certainty evidence).

Administration route: oral misoprostol probably leads to more failures than the vaginal route (RR 2.38, 95% CI 1.46 to 3.87; I² = 39%; 3 RCTs, 1704 women; moderate‐certainty evidence) and may be associated with more frequent side effects such as nausea (RR 1.14, 95% CI 1.03 to 1.26; I² = 0%; 2 RCTs, 1380 women; low‐certainty evidence) and diarrhoea (RR 1.80 95% CI 1.49 to 2.17; I² = 0%; 2 RCTs, 1379 women). Compared with the vaginal route, complete abortion failure is probably lower with sublingual (RR 0.68, 95% CI 0.22 to 2.11; I² = 59%; 2 RCTs, 3229 women; moderate‐certainty evidence) and may be lower with buccal administration (RR 0.71, 95% CI 0.34 to 1.46; I² = 0%; 2 RCTs, 479 women; low‐certainty evidence), but sublingual or buccal routes may lead to more side effects. Women may experience more vomiting with sublingual compared to buccal administration (RR 1.33, 95% CI 1.01 to 1.77; low‐certainty evidence).

2. Mifepristone alone versus combined regimen

The efficacy of mifepristone alone in achieving complete abortion compared to combined mifepristone/prostaglandin up to 12 weeks is unclear (RR of failure 3.25, 95% CI 0.81 to 13.09; I² = 83%; 3 RCTs, 273 women; very low‐certainty evidence).

3. Prostaglandin alone versus combined regimen

Nineteen studies compared prostaglandin alone to a combined regimen (prostaglandin combined with mifepristone, letrozole, estradiol valerate, tamoxifen, or methotrexate). Compared to any of the combination regimens, misoprostol alone may increase the risk for failure to achieve complete abortion (RR of failure 2.39, 95% CI 1.89 to 3.02; I² = 64%; 18 RCTs, 3471 women; low‐certainty evidence), and with more diarrhoea.

4. Prostaglandin alone (route of administration)

Oral misoprostol alone may lead to more failures in complete abortion than the vaginal route (RR 3.68, 95% CI 1.56 to 8.71, 2 RCTs, 216 women; low‐certainty evidence). Failure to achieve complete abortion may be slightly reduced with sublingual compared with vaginal (RR 0.69, 95% CI 0.37 to 1.28; I² = 87%; 5 RCTs, 2705 women; low‐certainty evidence) and oral administration (RR 0.58, 95% CI 0.11 to 2.99; I² = 66%; 2 RCTs, 173 women). Failure to achieve complete abortion may be similar or slightly higher with sublingual administration compared to buccal administration (RR 1.11, 95% CI 0.71 to 1.74; 1 study, 401 women).

Authors' conclusions

Safe and effective medical abortion methods are available. Combined regimens (prostaglandin combined with mifepristone, letrozole, estradiol valerate, tamoxifen, or methotrexate) may be more effective than single agents (prostaglandin alone or mifepristone alone). In the combined regimen, the dose of mifepristone can probably be lowered to 200 mg without significantly decreasing effectiveness. Vaginal misoprostol is probably more effective than oral administration, and may have fewer side effects than sublingual or buccal. Some results are limited by the small numbers of participants on which they are based. Almost all studies were conducted in settings with good access to emergency services, which may limit the generalisability of these results.

Plain language summary

Are medical methods for early termination of pregnancy effective and do they cause unwanted effects?

Key messages ‐ Medical abortion is a safe and effective way to terminate pregnancy in the first three months.

‐ Mifepristone combined with misoprostol is more effective than using these medications on their own.

‐ Misoprostol is more effective when placed in the vagina than when swallowed, and is less uncomfortable than placing it under the tongue or in the cheek.

What is medical abortion?

Medical abortion uses one or more medicines alone or in combination to end a pregnancy. The most common medicines are the hormones prostaglandin and mifepristone. Other medicines include methotrexate (a kind of chemotherapy), and letrozole, which slows the production of the hormone oestrogen. These medicines work by softening the cervix (neck of the womb) and causing the uterus (womb) to contract. They may be swallowed (taken orally), put under the tongue or in the cheek, or put in the vagina. They can be given by a nurse or a doctor in hospital, or taken by women at home.

Medical abortion methods may cause unwanted effects such as heavy bleeding, pain, nausea, vomiting and diarrhoea, Failed abortion is an infrequent but important complication of medical abortion. Medical methods for early abortion are already widely available in some countries, and new medicines are being developed.

What did we want to find out?

We wanted to find out which medicines were most successful in achieving complete abortion in the first three months of pregnancy, and if the dose or way they were given made a difference. We also wanted to know if there were any unwanted effects

What did we do?

We searched for studies that investigated different medicines, doses and ways of giving the medicines to women having medical abortion in the first three months of pregnancy.  Study characteristics

We included 99 studies that investigated 24 different medicine combinations, doses, and ways of giving the medicine.

Main results

Misoprostol put into the vagina is probably more effective to achieve abortion than taken orally, and may be associated with less stomach discomfort than if put under the tongue or between the tongue and cheek. Misoprostol alone and mifepristone alone may result in more failed abortions than misoprostol and mifepristone taken together. There may be little or no difference in the success rate of abortions based on whether the medicines are given at home or in hospital, the dosage of mifepristone, or single versus repeated doses of prostaglandin. However, abortions may be more successful if the medicines are given by a doctor in hospital rather than a nurse in hospital.

What are the limitations of the evidence?

Overall, our confidence in the evidence is limited or very limited for several reasons. Most studies included enough participants and used adequate methods to select them and allocate them to a particular treatment. However, it was difficult to ensure that they and the doctors treating them didn't know what treatment they had received. Several studies did not publish their aims before they started, so it is hard to evaluate whether they measured and reported all their points of interest. Almost all the studies took place in high‐income countries, where women can return for a check‐up. We don't know if results would have been different in low‐income countries.

How up to date is the evidence? This is a update of a review last published in 2011. The evidence is up to date to February 2021.

Summary of findings

Background

Description of the condition

It is estimated that around 40 million abortions occur every year, either legal or illegal, resulting in an abortion rate of 35 per 1000 women (Sedgh 2016). Medical abortion has the potential to expand abortion services, where surgical services are limited, and to expand women's choice of abortion method and experience.

Description of the intervention

Medical abortion became an alternative method of pregnancy termination with the availability of prostaglandins in the early 1970s followed by the development of an antiprogesterone in the 1980s. Large, uncontrolled studies suggested that early medical abortion with mifepristone and a prostaglandin would be an effective method for pregnancy termination (Urquhart 1997).

Various drugs have been used for first trimester medical abortion. The most widely researched are prostaglandins alone, mifepristone alone, methotrexate alone, mifepristone with prostaglandins and methotrexate with prostaglandins. Prostaglandins soften the cervix, cause uterine contractions and are used orally (swallowed; put on sublingual mucosa or buccal mucosa) or vaginally (put on vaginal mucosa) for ripening the cervix before surgical or medical abortion. The most commonly used prostaglandins are misoprostol administered either orally or vaginally.

How the intervention might work

Misoprostol is a prostaglandin analogue registered for use in nonsteroidal anti‐inflammatory drug (NSAID)‐induced gastric ulcer prevention and treatment. It has a strong uterotonic effect and is used alone to induce pregnancy terminations, illegally in some parts of the world (Blanchard 1999; Costa 1998), as well as legally, in areas where mifepristone is not available. The reported complete abortion rate for misoprostol alone varies between 61% for single use and 93% for repeat doses (Bugalho 1996; Carbonell 1997a). Gemeprost used alone appears to be less effective in inducing complete abortion than when used in combination with mifepristone (Norman 1992).

Mifepristone, an antiprogestogen, blocks the receptors for progesterone and glucocorticosteroid and increases the sensitivity of the uterus to prostaglandins (Bygdeman 1985). This blockage results in the breakdown of maternal capillaries in the decidua, the synthesis of prostaglandins by the epithelium of decidual glands and inhibition of prostaglandin dehydrogenase (WHO 1997).

Mifepristone has been licensed in France and China since 1988, in the UK since 1991 and, in the USA and India since 2000 and 2002, respectively. Mifepristone given alone has been shown to result in abortion only in 60% to 80% of cases, depending on the gestational age and the dose given (WHO 1997). However, in combination with a prostaglandin at up to 63 days of amenorrhoea, it leads to complete abortion in about 95% of pregnancies or more. The effect of mifepristone develops over a time period of 24 to 48 hours; therefore, prostaglandins have usually been administered after 36 to 48 hours. Currently, different regimens are in use. The recommended regimen by the manufacturer is mifepristone 600 mg followed by misoprostol (between 400 µg to 800 µg) or gemeprost (0.5 mg to 1 mg vaginally) and is registered for abortion in pregnancies up to 49 days in France and up to 63 days of amenorrhoea in the UK. However, a reduced dose of mifepristone combined with a prostaglandin has similar effectiveness and has the advantage of being much less expensive (WHO 1997).

Methotrexate has been used successfully for the treatment of unruptured tubal pregnancy. It is a folic acid antagonist that inhibits purine and pyrimidine synthesis and is cytotoxic to the trophoblast. The use of methotrexate with misoprostol for first trimester abortion was first introduced in 1993 (Creinin 1993; Grimes 1997). This combination was more effective when misoprostol was administered seven days after methotrexate compared to three days, leading to a complete abortion rate of 98% (Creinin 1995).

Letrozole is one of the aromatase inhibitors, which is used to block the synthesis of oestrogen, and stimulate ovulation. It is suggested that prescription of aromatase inhibitors prior to misoprostol or mifepristone for inducing medical abortion, might increase efficiency of the treatment regimen and decrease the need for surgical interventions (Yeung 2012).

Why it is important to do this review

Side‐effects of medical methods are heavy bleeding, pain, nausea, vomiting and diarrhoea, varying in severity according to the protocols and gestational age (Baiju 2019). In two studies included in the Cochrane Review of the topic, compared to surgical procedures, medical methods are associated with a longer duration of bleeding (Say 2010).

Failed abortion is an infrequent but important complication of medical abortion. Both methotrexate and misoprostol may lead to fetal anomalies if the pregnancy persists (Grimes 1997). However, other reports state that none of the malformations reported could be conclusively related to medications used for medical abortion (Wiebe 2006).

Some women prefer medical to surgical abortion. Reasons some women opted for a medical abortion included 'more natural', 'being easier', 'more private', and 'can be done earlier in pregnancy' (Creinin 1996). Characteristics such as the method being newer, less invasive and the possibility of verifying the expulsion were reported by others (Bachelot 1992).

Medical methods for first trimester abortion are already widely available in some countries and increasingly available throughout the world. New medication has been identified for use in medical abortion, it is therefore important to identify the best available agents and regimen for use. This review is an update of a previous review, which was first published in 2004, and updated twice, in 2004 and 2011. Comparison of medical methods with surgical evacuation in the first trimester is the subject of another Cochrane Review, Say 2010.

Objectives

To compare the effectiveness and side effects of different medical methods for first trimester abortion.

Methods

Criteria for considering studies for this review

Types of studies

We considered randomised controlled trials (RCTs) that compared different medical methods (e.g. single drug or combined, ways of application, or different dose regimens for medical abortion.

Types of participants

Women, pregnant in the first trimester, undergoing medical abortion.

Types of interventions

Different medical methods used for first trimester abortion, compared with each other.

Types of outcome measures

Primary outcomes

The main outcome measure was failure to achieve complete abortion two weeks after medical abortion.

Sonography was performed to verify abortion completion. If the sonographer reported that the uterus was empty, with no products of conception identified, complete success and efficacy of the drug were recorded.

Secondary outcomes

We also assessed other unwanted outcomes, such as side effects:

surgical evacuation (as emergency procedure, non‐emergency procedure, or undefined);
ongoing pregnancy at follow‐up, time until passing of conceptus (greater than three to six hours);
blood transfusion;
blood loss (measured or clinically relevant drop in haemoglobin);
days of bleeding;
pain resulting from the procedure (reported by the women or measured by use of analgesics, especially for abdominal pain);
additional uterotonics used (reported as repeated medical abortion in some studies);
women's dissatisfaction with the procedure;
Nausea;
Vomiting;
Diarrhoea.

Although mortality is considered an important outcome, we did not anticipate analysing abortion‐related mortality within the context of these studies. To date, no studies have reported mortality.

Search methods for identification of studies

The Cochrane Fertility Regulation Information Specialist conducted a search for all published, unpublished, and ongoing studies, without restrictions on language or publication status. The search strategies for each database were modelled on the updated search strategy designed for MEDLINE ALL (all update search strategies are available in Appendix 1, previous search strategies are available in Appendix 2). We contacted authors of included studies for data clarification and further information. We considered adverse effects described in included studies only. Searches were date limited from 2010 to February 2021 to extend from and include literature published since the last review. POPLINE database ceased publication in the interim and thus was not searched for this update. Searches were conducted in 2003 and 2011 for the original reviews, with update searches in February 2021.

Electronic searches

We searched the following databases:

Cochrane Central Register of Controlled Trials (CENTRAL) via EBM Reviews (Ovid, January 2010 to February 2021);
MEDLINE ALL (Ovid) (January 2010 to February 2021);
Embase.com (January 2010 to February 2021);
Global Health (Ovid) (January 2010 to February 2021);
LILACs lilacs.bvsalud.org/en/ (January 2010 to February 2021).

We searched the following trials registries:

ClinicalTrials.gov www.clinicaltrials.gov (January 2010 to February 2021);
World Health Organization International Clinical Trials Registry Platform www.who.int/trialsearch (January 2010 to February 2021).

Searching other resources

We handsearched reference lists from articles identified by the search, as well as key review articles, to identify additional articles.

Data collection and analysis

See: Characteristics of included studies; Characteristics of excluded studies; Additional tables

Selection of studies

Two review authors (ZJ, ZK) independently selected studies for inclusion in the review using Covidence, after employing the search strategy described previously. The review authors evaluated studies under consideration for appropriateness for inclusion and methodological quality without consideration of their results. We included only RCTs.

After the initial screen of titles and abstracts retrieved by the search conducted by ZJ and ZK, we retrieved the full texts of the potentially eligible studies for further classification. Two review authors (ZJ, ZK) independently examined the full text of the studies claimed to be randomised. Only the studies with random allocation were included in this updated review. We resolved disagreements by discussion or by consultation with a third review author (SD). We documented the selection process with a PRISMA flow chart (Page 2021; Figure 1).

Data extraction and management

Two review authors (ZJ, ZK), independently extracted data using Covidence. If there were any discrepancies between review authors in either the inclusion or exclusion of studies, or in data extraction, we resolved them by consensus. We attempted to obtain additional information from study authors if required (ZJ, LX). We examined whether the primary study carried out an intention‐to‐treat analysis.

Two review authors (ZJ, ZK) independently extracted the study characteristics and outcome data of the included studies using a data extraction form designed according to Cochrane guidelines (Li 2021; Characteristics of included studies). Discrepancies were described and resolved by discussion (ZJ, ZK, SD).

Failure to achieve complete abortion is defined as an abortion that is not completed by the described intended method within two weeks. Other outcomes are failure of expulsion after four to six hours, expulsion time, side effects (nausea, vomiting, diarrhoea, abdominal pain), and mean duration of days of bleeding, bleeding volume, and blood transfusion (see Types of outcome measures). We further divided studies into early (49 days or fewer of amenorrhoea) and late (more than 49 days) gestational age at the time of abortion for subgroup analysis. Complications are defined as any serious complication described by the study authors and that was not a failure or side effect.

Assessment of risk of bias in included studies

Two review authors (ZJ, ZK) independently assessed the risk of bias for the update included studies using Cochrane tools and criteria (Higgins 2017). These were the six domains of: selection (random sequence generation and allocation concealment); performance (blinding of participants and personnel); detection (blinding of outcome assessors); attrition (incomplete outcome data); reporting (selective reporting); and other bias (such as funding). We assigned each study a judgement of low risk of bias, high risk of bias, or unclear risk of bias. We stated and resolved disagreements by consensus (ZJ, ZK, SD). We described all judgements fully and presented our conclusions in the risk of bias table (Characteristics of included studies). We described the risk of bias data in detail in the Results and facilitated the interpretation of the reliability of the results by quoting the original text or listing the reasons for judgements in the risk of bias table (see: Risk of bias in included studies and Characteristics of included studies). We took care to search for within‐study selective reporting, which is studies failing to report obvious outcomes or reporting them in insufficient detail. We searched for published protocols of studies online and compared the outcomes specified in the protocol versus those reported in the final published study (LX).

Measures of treatment effect

For dichotomous data, we used the numbers of events in the control and experimental groups of each study to calculate Mantel‐Haenszel risk ratios (RRs). For continuous data, if all studies reported exactly the same outcomes, we planned to calculate mean difference (MD) between treatment groups. If they reported similar outcomes on different scales, we planned to calculate the standardised mean difference (SMD). We reported confidence intervals (95% CI) for all outcomes. We conducted intention‐to‐treat (ITT) analysis to measure the treatment effect. We converted continuous data reported as medians and quartiles in studies to means and standard deviations (SD).

Unit of analysis issues

The unit of analysis was each woman randomised. Three update studies had multiple treatment groups; we included only one study with four arms in the meta‐analysis (von Hertzen 2010). We synthesised the four arms into two arms based on the identical application route or dosage of misoprostol. We could not pool the other two studies, but have narratively synthesised them (Chen 2015a; Li 2015).

Dealing with missing data

We described for each included study, and for each outcome, the completeness of data including attrition and exclusions from the analysis. We stated whether studies reported attrition and exclusions and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where studies reported, or study authors could supply sufficient information, we planned to re‐include missing data in the analyses that we undertook. We analysed the data on an ITT basis for the studies with participant depletion. We imputed individual values for attrition of dichotomous data, assuming events existing in the control group, but absent in the experimental group, such as the outcome of failure to achieve complete abortion.

Assessment of heterogeneity

We evaluated clinical heterogeneity by looking at the variability in participant factors (such as baseline characteristics and diagnostic criteria), interventions (such as therapeutic strategies, co‐intervention, and time of treatment), and the outcomes studied (such as definition, format and time points of measurement). We assessed methodological heterogeneity from differences in the design factors of studies (such as randomisation methods).

The clinical heterogeneity documented in Characteristics of included studies was high among these studies, especially for the different interventions, gestational week and follow‐up duration. We performed subgroup analysis based on different gestational week for resolving clinical heterogeneity.

Clinical and methodological diversity can contribute to statistical heterogeneity. We used two methods to evaluate statistical heterogeneity: the Chi² test (P value) and I² statistic (Higgins 2003). A low P value (< 0.10) qualitatively indicated heterogeneity of intervention effects. The I² statistic quantitatively estimated the heterogeneity across studies: an I² statistic greater than 50% was taken to indicate substantial heterogeneity (Deeks 2021).

Assessment of reporting biases

In view of the difficulty of detecting and correcting for publication bias and other reporting biases, review authors aimed to minimise their potential impact by ensuring a comprehensive search for eligible studies and by staying alert for duplication of data. We evaluated selective reporting by comparing the protocols of RCTs with the published full‐texts if the protocols were available.

We assessed potential publication bias using a funnel plot for the outcome of failure to achieve complete abortion, if there were 10 or more included studies (Analysis 15.1). Possible sources of asymmetry of funnel plots include publication bias and other biases, so the visual inspection of the funnel plot may be misleading, and we will not place excessive emphasis on it.

15.1 — Comparison 15: Prostaglandin alone vs combined regimen (all), Outcome 1: Failure to achieve complete abortion

Data synthesis

We processed data using Review Manager 5 software (Review Manager 2020). The studies in this field use various combinations of agents, doses, intervals between the antiprogesterone and prostaglandin, and route of administration for prostaglandin. Since all of these variables may affect the outcomes, we did not consider it appropriate to combine similar studies into meta‐analysis in many cases. However, it was possible to identify an experimental intervention and a constant (fixed) intervention, which enabled us to group the studies as follows, then use the random‐effects model for significant clinical heterogeneity.

Combined regimen mifepristone/prostaglandin

Comparison 1: different doses of mifepristone
Comparison 2: different doses of prostaglandin
Comparison 3: type of prostaglandin (gemeprost versus misoprostol; PGF2alpha versus misoprostol)
Comparison 4: timing of prostaglandin
Comparison 5: administration strategy of prostaglandin
Comparison 6: route of administration of misoprostol ‐ oral versus vaginal
Comparison 7: route of administration of misoprostol ‐ buccal versus vaginal
Comparison 8: route of administration of misoprostol ‐ buccal versus oral
Comparison 9: route of administration of misoprostol ‐ sublingual versus vaginal
Comparison 10: route of administration of misoprostol ‐ sublingual versus oral
Comparison 11: route of administration of misoprostol ‐ sublingual versus buccal
Comparison 12: single versus split dose of prostaglandin
Comparison 13: single versus continuous misoprostol
Comparison 14: mifepristone alone versus combined regimen mifepristone/prostaglandin
Comparison 15: prostaglandin alone versus a combined regimen (all)

Single regimen

Comparison 16: prostaglandin alone ‐ route of administration
Comparison 17: mifepristone alone ‐ high versus low dose

Combined regimen methotrexate/prostaglandin

Comparison 18: timing of prostaglandin
Comparison 19: route of methotrexate ‐ intramuscular versus oral
Comparison 20: dose of methotrexate
Comparison 21: route of prostaglandin

Tamoxifen versus methotrexate (combined with prostaglandin)

Comparison 22: low‐dose tamoxifen (40 mg)
Comparison 23: high‐dose tamoxifen (160 mg)

Combined regimen mifepristone/prostaglandin versus mifepristone/prostaglandin plus tamoxifen

Comparison 24: combined mifepristone/prostaglandin versus mifepristone/prostaglandin plus tamoxifen

Subgroup analysis and investigation of heterogeneity

Where possible we performed subgroup analyses for early and late first trimester abortions as the performance of some methods may differ with gestational age.

Abortion up to 49 days
Abortion over 49 days of amenorrhoea, such as in the comparison group of 1, 2, 4, 8, 10, 11, 13, 15 and 16

Sensitivity analysis

We conducted sensitivity analyses (if we identified at least three studies) for the outcome of failure to achieve complete abortion to determine whether conclusions were robust to different decisions made regarding eligibility and analysis (Analysis 15.1). These analyses included consideration of whether review conclusions would have differed if we had restricted eligibility to studies at low risk of bias (studies with low risk of bias in the domains of random sequence generation and allocation concealment) or if we had restricted analyses to studies without imputed data.

Summary of findings and assessment of the certainty of the evidence

We used the GRADE approach to assess the certainty of the evidence relating to the main outcomes (failure to achieve complete abortion, nausea, women's dissatisfaction and blood transfusion) for 10 comparisons relating to administration dose, strategy, route and regimen as below.

Mifepristone (600 mg) combined with prostaglandin versus mifepristone (200 mg) combined with prostaglandin
Misoprostol 800 µg combined with mifepristone 200 mg versus misoprostol 400 µg combined with mifepristone 200 mg
Medical abortion self‐administered at home versus hospital‐administered
Medical abortion administered by nurses versus administered by doctors
Mifepristone/prostaglandin: misoprostol oral versus vaginal
Mifepristone/prostaglandin: misoprostol sublingual versus vaginal
Mifepristone alone versus mifepristone/prostaglandin
Prostaglandin alone versus combined regimen
Prostaglandin alone: misoprostol oral versus vaginal
Prostaglandin alone: misoprostol sublingual versus vaginal

We used GRADEpro GDT to import data from Review Manager 5 (Review Manager 2020), in order to create summary of findings tables. We produced a summary of the intervention effect and a measure of certainty for the main outcomes using the GRADE approach. The GRADE approach uses five considerations (risk of bias, inconsistency, imprecision, indirectness and publication bias) to assess the certainty of the body of evidence for the outcomes. The evidence can be downgraded from 'high certainty' by one level for serious (or by two levels for very serious) limitations, depending on assessments for risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates or potential publication bias. Two review authors (ZJ, SD), working independently, made judgements about evidence certainty (high, moderate, low or very low), with disagreements resolved by discussion (ZJ, ZK, SD). We justified and documented our judgements, and incorporated them into reporting of results for the outcomes.

Results

Description of studies

The search for the previous latest version of the review was conducted in 2011 and there were 58 included studies. The updated search, conducted in February 2021, identified 1870 records.

Results of the search

During this updated search, we screened 1473 records after excluding 397 duplicates. Of these 1473 records, we excluded 1327 records for the following reasons: non‐RCT, surgical abortion, second trimester abortion or duplications after screening abstracts. We tried to retrieve 136 full texts for further evaluation; we excluded 79 for different reasons (Characteristics of excluded studies). We could not assess the full texts for 10 records; we contacted study authors for more information (Characteristics of studies awaiting classification). Eleven ongoing studies are waiting for completion and publication (Characteristics of ongoing studies). We added and updated 41 new studies (including 46 articles), and included 99 studies in total in this updated review (Characteristics of included studies). Of the 41 included studies, five studies presented data in two different publications respectively, including 10 published articles (Klingberg Allvin 2015; Iyengar 2015; Kopp Kallner 2015; Warriner 2011; von Hertzen 2003). The PRISMA study flow of the updated review was illustrated in Figure 1 (Page 2021).

Included studies

See Characteristics of included studies.

Of the 41 newly added studies, four were multiple‐arm RCTs (Chen 2015a; Li 2015; Souizi 2020; von Hertzen 2010); the others were two‐arm RCTs. The participants include women with missed abortion (an abortion in which the fetus dies but is retained within the uterus, without bleeding or abdominal pain), incomplete abortion (a miscarriage in which some fetal or placental tissue remains in the uterus, with bleeding or abdominal pain) and normal first trimester pregnancy. The follow‐up duration of the included studies ranged from one day to 30 days. We added different strategies of administering medical abortions in this updated review, with seven included studies (Analysis 15.1). Administration was by a nurse or a doctor, at home or in hospital. Several studies divided women by gestational age at the time of abortion into subgroups: early (49 days or fewer of amenorrhoea) and late (more than 49 days of amenorrhoea) (Blum 2012; Chai 2013; Chong 2012; Lee 2011; Ngoc 2011; Raghavan 2010; Sheldon 2019; Song 2018). One study explored the efficacy of traditional Chinese medicine combined with mifepristone and misoprostol (Chen 2015a). Letrozole has recently been used to treat missed abortion, so we added studies that compared misoprostol and misoprostol combined with letrozole to the present review. However, tamoxifen and methotrexate have been used less frequently in recent years, so few studies referred to these abortion methods.

Our main outcome was failure to achieve complete abortion with the method intended. Three studies reported time until passing of conceptus as mean and SD (Javadi 2015; Sinha 2018; Torky 2018). Few studies reported blood loss measured in haemoglobin (Abdelshafy 2019; Chai 2013; Ng 2015; Qian 2015), and blood transfusion. Some studies chose the outcome bleeding more than expected (Iyengar 2015; Klingberg Allvin 2015; Kopp Kallner 2015; Ngoc 2011; Raghavan 2010; Schreiber 2018; Sonsanoh 2014; Tanha 2010; Torky 2018; Warriner 2011). Hospitalisation and unscheduled visits were the primary outcomes in studies performing medical abortion at home (Iyengar 2015; Li 2017; Song 2018; Shrestha 2014). Acceptability and completion were further reported in studies administrating medical abortion by nurse (Kopp Kallner 2015). Time spent in hospital, cost, and menstruation were evaluated (Li 2017; Kopp Kallner 2015). Pelvic infection was reported by only one study (Schreiber 2018). Five studies defined additional uterotonics used as repeated medical abortion (Iyengar 2015; Ngoc 2011; Sheldon 2019; Sinha 2018; Teimoori 2019). As well as nausea, vomiting, diarrhoea and abdominal pain, several studies also reported other side effects, such as fever, chills, dizziness and headache (Iyengar 2015; Klingberg Allvin 2015; Kopp Kallner 2015; Ngoc 2011; Raghavan 2010; Sheldon 2019; Shrestha 2014; Song 2018; Sonsanoh 2014; Souizi 2020; Tanha 2010; Torky 2018; Verma 2017; von Hertzen 2010).

Of the 58 previously included studies, one study presented data in two different publications (von Hertzen 2003). One study used two different comparisons (Wiebe 1999a, Wiebe 1999b). Five studies used different regimens, doses or timing of the medicines that could not be combined with any of the other regimens in the comparisons and were therefore listed separately in Table 11 (Liao 2004; Wang 2000; WHO 1989; WHO 1991; Wiebe 2006). Instead of failure to achieve complete abortion, 14 studies used either other definitions (i.e. surgical intervention) or administered additional prostaglandins (Carbonell 1997b; Creinin 1994; Creinin 1995; Creinin 1996a; Creinin 1997; Creinin 2001a; Creinin 2001b; Hamoda 2005; Jain 1999; Koopersmith 1996; Ozeren 1999; Schaff 2000; Wiebe 1999a; Wiebe 1999b).

1. Other studies included in the review.

Study	Intervention	Outcomes
Chen 2015a	Day 1‐3: antibiotic and oestrogen. After gestational sac passed out: oxytocin, 20 U, IM Day 3: mifepristone 150 mg, oral Day 4: misoprostol 600 µg, vaginal Group 1: Shenghua decoction from day 1 to 2 weeks after gestational sac passed out Group 2: Shenghua decoction from day 4 to 2 weeks after gestational sac passed out Group 3: without Shenghua decoction	Bleeding duration Time until passing of conceptus
Li 2015	Day 1: oral mifepristone from 150‐50 mg Day 2: 200 µg of oral misoprostol Group 1: 6 pills of mifepristone (150 mg) Group 2: 5 pills of mifepristone plus 1 pill of placebo (125 mg) Group 3: 4 pills of mifepristone plus 2 pills of placebo (100 mg) Group 4: 3 pills of mifepristone plus 3 pills of placebo (75 mg) Group 5: 2 pills of mifepristone plus 4 pills of placebo (50 mg)	Failure to achieve complete abortion Group 1: 24/500 Group 2: 27/500 Group 3: 25/500 Group 4: 22/500 Group 5: 28/500 Ongoing pregnancy Group 1: 18/500 Group 2: 20/500 Group 3: 18/500 Group 4: 19/500 Group 5: 25/500 Nausea Group 1: 211/500 Group 2: 203/500 Group 3: 197/500 Group 4: 109/500 Group 5: 84/500 Vomiting Group 1: 64/500 Group 2: 62/500 Group 3: 55/500 Group 4: 43/500 Group 5: 32/500 Diarrhoea Group 1: 50/500 Group 2: 50/500 Group 3: 37/500 Group 4: 29/500 Group 5: 24/500 Abdominal pain Group 1: 394/500 Group 2: 380/500 Group 3: 354/500 Group 4: 299/500 Group 5: 119/500
Liao 2004	Group 1: mifepristone given: 50 mg, then 12 h later 25 mg, then 12 h later 50 mg, and finally, 12 h later, 25 mg mifepristone. 24 h after, 600 µg misoprostol oral (total: 150 mg) Group 2: mifepristone given 30 mg, then 15 mg every 12 h for 3 doses. 24 h after last dose, 600 µg misoprostol given oral (total: 75 mg)	Failure to achieve complete abortion Group 1: 11/240 Group 2: 9/240 Ongoing pregnancy Group 1: 2/240 Group 2: 1/240
Wang 2000	Group 1: Day 1: mifepristone 50 mg/oral/12‐hourly, 2 doses, day 2‐7: mifepristone 25 mg oral/day Day 3: misoprostol 600 µg/oral, day 4‐6: misoprostol 200 µg/day Group 2: Day 1: mifepristone 50 mg, followed by 25 mg/12‐hourly/4 times Day 3: misoprostol 600 µg, oral	Failure to achieve complete abortion Group 1: 18/1118 Group 2: 59/494 Ongoing pregnancy Group 1: 2/1118 Group 2: 6/494
WHO 1989	Group 1: mifepristone 25 mg/twice daily for 3 days (total 150 mg) and sulprostone 0.25 mg IM on morning of 3rd day Group 2: mifepristone 25 mg /twice daily for 4 days (total 200 mg) and sulprostone 0.25 mg IM on morning of fourth day	Failure to achieve complete abortion Group 1: 15/125 Group 2: 13/126 Ongoing pregnancy Group 1: 3/125 Group 2: 3/126
WHO 1991	Group 1: mifepristone 25 mg/12‐hourly, 5 doses (total 125 mg) and gemeprost 1 mg vaginally 60 h after the start of the treatment Group 2: mifepristone 600 mg single dose and gemeprost 1 mg vaginally 60 h after the start of the treatment	Failure to achieve complete abortion Group 1: 12/181 Group 2: 15/187
Wiebe 2006	Group 1: methotrexate 50 mg/m² followed by >/72 h by 400 µg misoprostol vaginal Group 2: misoprostol 400 µg sublingual and 400 µg misoprostol vaginal	Failure to achieve complete abortion Group 1: 62/149 Group 2: 57/149 Nausea Group 1: 53/49 Group 2: 54/149 Vomiting Group 1: 17/149 Group 2: 21/149 Diarrhoea Group 1: 16/149 Group 2: 41/149 Surgical abortion Group 1: 9/149 Group 2: 18/149
IM: intramuscular

Mifepristone (600 mg) combined with prostaglandin compared to mifepristone (200 mg) combined with prostaglandin for first trimester abortion
Patient or population: women undergoing first trimester abortion Setting: hospital outpatient Intervention: mifepristone (600 mg) combined with prostaglandin Comparison: mifepristone (200 mg) combined with prostaglandin
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
	Risk with mifepristone (200 mg) combined with prostaglandin	Risk with mifepristone (600 mg) combined with prostaglandin
Failure to achieve complete abortion	Study population		RR 1.07 (0.87 to 1.33)	3494 (4 RCTs)	⊕⊕⊕⊝ Moderate^a
	86 per 1000	92 per 1000 (75 to 114)
Nausea	Study population		RR 1.02 (0.95 to 1.09)	2432 (2 RCTs)	⊕⊕⊕⊝ Moderate^a
	450 per 1000	459 per 1000 (428 to 491)
Women's dissatisfaction with the procedure	Not reported
Blood transfusion	Not reported
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Misoprostol (800 µg) compared to misoprostol (400 µg) for first trimester abortion as combined with mifepristone
Patient or population: women undergoing first trimester abortion Setting: hospital outpatient Intervention: misoprostol 800 µg combined with mifepristone 200 mg Comparison: misoprostol 400 µg combined with mifepristone 200 mg
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
	Risk with misoprostol 400 µg combined with mifepristone 200 mg	Risk with misoprostol 800 µg combined with mifepristone 200 mg
Failure to achieve complete abortion	Study population		RR 0.63 (0.51 to 0.78)	4424 (3 RCTs)	⊕⊕⊕⊝ Moderate^a
	94 per 1000	59 per 1000 (48 to 73)
Nausea	Study population		RR 0.99 (0.94 to 1.05)	4424 (3 RCTs)	⊕⊕⊕⊝ Moderate^a
	479 per 1000	474 per 1000 (450 to 503)
Women's dissatisfaction with the procedure	Study population		RR 0.75 (0.60 to 0.93)	4420 (3 RCTs)	⊕⊕⊕⊝ Moderate^a
	82 per 1000	61 per 1000 (49 to 76)
Blood transfusion	Not reported
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Medical abortion self‐administered at home compared to administered in hospital for first trimester abortion
Patient or population: women undergoing first trimester abortion Setting: at home or hospital outpatient Intervention: self‐administered at home Comparison: administered in hospital
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
	Risk with hospital‐administered	Risk with self‐administered at home
Failure to achieve complete abortion	Study population		RR 1.63 (0.68 to 3.94)	2263 (4 RCTs)	⊕⊕⊝⊝ Low^a,b
	50 per 1000	82 per 1000 (34 to 199)
Nausea	Study population		RR 1.09 (0.74 to 1.61)	1532 (3 RCTs)	⊕⊕⊝⊝ Low^a,b
	236 per 1000	258 per 1000 (175 to 380)
Women's dissatisfaction with the procedure	Study population		RR 1.63 (0.95 to 2.80)	2155 (4 RCTs)	⊕⊕⊝⊝ Low^a,b
	50 per 1000	82 per 1000 (48 to 140)
Blood transfusion	Study population		RR 0.33 (0.01 to 8.18)	731 (1 RCT)	⊕⊝⊝⊝ Very low^c,d
	3 per 1000	1 per 1000 (0 to 22)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Medical abortion administrated by nurses compared to by doctors for first trimester abortion
Patient or population: women undergoing first trimester abortion Setting: hospital outpatient Intervention: administrated by nurses Comparison: administrated by doctors
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
	Risk with administrated by doctors	Risk with administrated by nurses
Failure to achieve complete abortion	Study population		RR 2.69 (1.39 to 5.22)	3056 (3 RCTs)	⊕⊕⊝⊝ Low^a,b
	25 per 1000	68 per 1000 (35 to 133)
Nausea	Not reported
Women's dissatisfaction with the procedure	Study population		RR 2.70 (0.16 to 44.49)	1988 (2 RCTs)	⊕⊝⊝⊝ Very low^a,b,c
	6 per 1000	16 per 1000 (1 to 266)
Blood transfusion	Study population		not estimable	1068 (1 RCT)	⊕⊕⊝⊝ Low^d
	0 per 1000	0 per 1000 (0 to 0)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Oral misoprostol compared to vaginal misoprostol for first trimester abortion in combined regimen mifepristone/prostaglandin
Patient or population: women undergoing first trimester abortion Setting: hospital outpatient Intervention: oral mifepristone and oral misoprostol Comparison: oral mifepristone and vaginal misoprostol
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
	Risk with vaginal misoprostol	Risk with oral misoprostol
Failure to achieve complete abortion	Study population		RR 2.38 (1.46 to 3.87)	1704 (3 RCTs)	⊕⊕⊕⊝ Moderate^a,b
	43 per 1000	103 per 1000 (63 to 168)
Nausea	Study population		RR 1.14 (1.03 to 1.26)	1380 (2 RCTs)	⊕⊕⊝⊝ Low^a,b
	482 per 1000	549 per 1000 (496 to 607)
Women's dissatisfaction with the procedure	Not reported
Blood transfusion	Not reported
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Sublingual misoprostol compared to vaginal misoprostol for first trimester abortion in combined regimen mifepristone/prostaglandin
Patient or population: women undergoing first trimester abortion Setting: hospital outpatient Intervention: oral mifepristone and sublingual misoprostol Comparison: oral mifepristone and vaginal misoprostol
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
	Risk with vaginal misoprostol	Risk with sublingual misoprostol
Failure to achieve complete abortion	Study population		RR 0.68 (0.22 to 2.11)	3229 (2 RCTs)	⊕⊕⊕⊝ Moderate^a
	86 per 1000	58 per 1000 (19 to 180)
Nausea	Study population		RR 1.11 (0.93 to 1.33)	3543 (3 RCTs)	⊕⊕⊕⊝ Moderate^a
	536 per 1000	595 per 1000 (499 to 713)
Women's dissatisfaction with the procedure	Study population		RR 1.67 (0.80 to 3.50)	3303 (2 RCTs)	⊕⊕⊕⊝ Moderate^a
	66 per 1000	110 per 1000 (52 to 230)
Blood transfusion	Not reported
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Mifepristone alone compared to mifepristone/prostaglandin for first trimester abortion
Patient or population: women undergoing first trimester abortion Setting: hospital outpatient Intervention: mifepristone alone Comparison: mifepristone/prostaglandin
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
	Risk with mifepristone/prostaglandin	Risk with mifepristone alone
Failure to achieve complete abortion	Study population		RR 3.25 (0.81 to 13.09)	273 (3 RCTs)	⊕⊝⊝⊝ Very low^a,b,c
	139 per 1000	451 per 1000 (113 to 1000)
Nausea	Not reported
Women's dissatisfaction with the procedure	Not reported
Blood transfusion	Not reported
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Prostaglandin alone compared to combined regimen for first trimester abortion
Patient or population: women undergoing first trimester abortion Setting: hospital outpatient Intervention: prostaglandin alone Comparison: combined regimen
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
	Risk with combined regimen	Risk with prostaglandin alone
Failure to achieve complete abortion	Study population		RR 2.39 (1.89 to 3.02)	3471 (18 RCTs)	⊕⊕⊝⊝ Low^a,b
	135 per 1000	323 per 1000 (255 to 408)
Nausea	Study population		RR 0.90 (0.74 to 1.10)	2722 (12 RCTs)	⊕⊕⊝⊝ Low^a,b
	412 per 1000	371 per 1000 (305 to 453)
Women's dissatisfaction with the procedure	Study population		RR 1.65 (0.75 to 3.64)	1485 (5 RCTs)	⊕⊕⊝⊝ Low^a,b
	127 per 1000	209 per 1000 (95 to 461)
Blood transfusion	Study population		RR 0.33 (0.03 to 3.13)	300 (1 RCT)	⊕⊕⊝⊝ Low^a,c
	20 per 1000	7 per 1000 (1 to 63)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Oral misoprostol alone compared to vaginal misoprostol alone for first trimester abortion
Patient or population: women undergoing first trimester abortion Setting: hospital outpatient Intervention: oral misoprostol alone Comparison: vaginal misoprostol alone
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
	Risk with vaginal misoprostol alone	Risk with oral misoprostol alone
Failure to achieve complete abortion	Study population		RR 3.68 (1.56 to 8.71)	216 (2 RCTs)	⊕⊕⊝⊝ Low^a,b
	53 per 1000	195 per 1000 (83 to 462)
Nausea	Study population		RR 1.21 (0.92 to 1.61)	216 (2 RCTs)	⊕⊕⊝⊝ Low^a,b
	283 per 1000	343 per 1000 (261 to 456)
Women's dissatisfaction with the procedure	Study population		RR 1.25 (0.65 to 2.39)	100 (1 RCT)	⊕⊕⊝⊝ Low^a,b
	240 per 1000	300 per 1000 (156 to 574)
Blood transfusion	Not reported
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Sublingual misoprostol alone compared to vaginal misoprostol alone for first trimester abortion
Patient or population: first trimester abortion Setting: hospital outpatient Intervention: sublingual misoprostol alone Comparison: vaginal misoprostol alone
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
	Risk with vaginal misoprostol alone	Risk with sublingual misoprostol alone
Failure to achieve complete abortion	Study population		RR 0.69 (0.37 to 1.28)	2705 (5 RCTs)	⊕⊕⊝⊝ Low^a,b
	199 per 1000	137 per 1000 (74 to 254)
Nausea	Study population		RR 1.61 (0.78 to 3.33)	2505 (4 RCTs)	⊕⊕⊝⊝ Low^a,b
	226 per 1000	364 per 1000 (176 to 753)
Women's dissatisfaction with the procedure	Study population		RR 0.14 (0.07 to 0.29)	220 (1 RCT)	⊕⊕⊝⊝ Low^{a, c}
	464 per 1000	65 per 1000 (32 to 134)
Blood transfusion	Study population		RR 5.00  (0.24 to 102.96)	220  (1 RCT)	⊕⊝⊝⊝  Very low ^{a, d}
	0 per 1000	0 per 1000  (0 to 0)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Failure to achieve complete abortion	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.1.1 600 mg vs 200 mg	4	3494	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.87, 1.33]
1.1.2 200 mg vs 100 mg (> 49 days)	1	1182	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.61, 1.29]
1.1.3 600 mg vs 200 mg with gemeprost 1 mg vaginal	2	1685	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.72, 1.45]
1.1.4 200 mg vs 100 mg (≤ 49 days)	1	941	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.47, 1.33]
1.2 Side effects	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.2.1 Nausea	2	2432	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.95, 1.09]
1.2.2 Vomiting	1	1584	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.87, 1.19]
1.2.3 Diarrhoea	1	1584	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.58, 1.09]
1.3 Time until passing of conceptus > 3 to 6 hours	2	1116	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.69, 1.10]
1.4 Ongoing pregnancy	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Failure to achieve complete abortion	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
3.1.1 Gemeprost vs misoprostol	2	1687	Risk Ratio (M‐H, Random, 95% CI)	1.28 [0.28, 5.81]
3.1.2 PGF2α vs misoprostol	2	17974	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.44, 1.58]
3.2 Side effects	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.2.1 Vomiting	1	910	Risk Ratio (M‐H, Fixed, 95% CI)	1.49 [1.06, 2.10]
3.2.2 Diarrhoea	1	910	Risk Ratio (M‐H, Fixed, 95% CI)	2.66 [1.35, 5.26]
3.3 Ongoing pregnancy	2	1687	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.28, 1.48]
3.4 Time until passing of conceptus > 3 to 6 hours	1	910	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.77, 1.23]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Failure to achieve complete abortion	10		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
4.1.1 Day 3 vs day 1	1	1489	Risk Ratio (M‐H, Random, 95% CI)	1.94 [1.05, 3.58]
4.1.2 Day 3 vs day 2	1	1521	Risk Ratio (M‐H, Random, 95% CI)	1.69 [0.95, 3.01]
4.1.3 Day 2 vs day 1 (all)	4	3887	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.61, 1.61]
4.1.4 Day 2 vs day 1 (≤ 49 days)	2	1116	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.58, 1.38]
4.1.5 Day 2 vs day 1 (> 49 days)	2	1207	Risk Ratio (M‐H, Random, 95% CI)	1.57 [1.09, 2.27]
4.1.6 Day 2 vs day 0	3	711	Risk Ratio (M‐H, Random, 95% CI)	0.53 [0.25, 1.09]
4.1.7 Day 1 vs day 0 (all)	3	2236	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.46, 0.91]
4.1.8 Day 1 vs day 0 (≤ 49 days)	3	1078	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.38, 1.11]
4.1.9 Day 1 vs day 0 (> 49 days)	2	1158	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.42, 1.06]
4.2 Side effects	8		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
4.2.1 Nausea day 3 vs day 1	1	1358	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.96, 1.14]
4.2.2 Nausea day 3 vs day 2	1	1384	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.91, 1.06]
4.2.3 Nausea day 2 vs day 1	1	1434	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.98, 1.16]
4.2.4 Nausea day 2 vs day 0	3	644	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.58, 0.98]
4.2.5 Vomiting day 3 vs day 1	1	1358	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.86, 1.19]
4.2.6 Vomiting day 3 vs day 2	1	1384	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.83, 1.13]
4.2.7 Vomiting day 2 vs day 1	2	1634	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.91, 1.22]
4.2.8 Vomiting day 2 vs day 0	3	644	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.66, 1.38]
4.2.9 Diarrhoea day 3 vs day 1	1	1358	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.99, 1.48]
4.2.10 Diarrhoea day 3 vs day 2	1	1384	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.95, 1.42]
4.2.11 Diarrhoea day 2 vs day 1	2	1634	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.09, 2.77]
4.2.12 Diarrhoea day 2 vs day 0	3	644	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.42, 1.02]
4.2.13 Nausea day 1 vs day 0	3	2217	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.81, 1.32]
4.2.14 Vomiting day 1 vs day 0	3	2217	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.82, 1.63]
4.2.15 Diarrhoea day 1 vs day 0	3	2217	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.60, 1.21]
4.2.16 Abdominal pain day 1 vs day 0	1	80	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.12, 3.78]
4.3 Surgical evacuation	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
4.3.1 Day 3 vs day 1	1	1489	Risk Ratio (M‐H, Random, 95% CI)	1.49 [0.78, 2.83]
4.3.2 Day 3 vs day 2	1	1521	Risk Ratio (M‐H, Random, 95% CI)	1.80 [0.92, 3.52]
4.3.3 Day 2 vs day 1	2	3681	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.68, 1.67]
4.3.4 Day 2 vs day 0	2	511	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.19, 0.86]
4.3.5 Day 1 vs day 0	2	1208	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.36, 1.16]
4.4 Ongoing pregnancy	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
4.4.1 Day 3 vs day 1	1	1489	Risk Ratio (M‐H, Fixed, 95% CI)	1.56 [0.51, 4.73]
4.4.2 Day 3 vs day 2	1	1521	Risk Ratio (M‐H, Fixed, 95% CI)	2.71 [0.72, 10.16]
4.4.3 Day 2 vs day 1 (all)	2	3681	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.45, 1.90]
4.4.4 Day 1 vs day 0	3	2288	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.07, 1.66]
4.5 Women's dissatisfaction with the procedure	2	1429	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.80, 1.23]
4.6 Time until passing of conceptus	1	80	Mean Difference (IV, Fixed, 95% CI)	‐0.55 [‐1.27, 0.17]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Failure to achieve complete abortion	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
5.1.1 Home vs hospital	4	2263	Risk Ratio (M‐H, Random, 95% CI)	1.63 [0.68, 3.94]
5.1.2 Nurse vs doctor	3	3056	Risk Ratio (M‐H, Random, 95% CI)	2.69 [1.39, 5.22]
5.2 Surgical evacuation	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
5.2.1 Home vs hospital	2	1331	Risk Ratio (M‐H, Random, 95% CI)	1.71 [0.37, 7.87]
5.2.2 Nurse vs doctor	2	2172	Risk Ratio (M‐H, Random, 95% CI)	3.36 [1.67, 6.78]
5.3 Ongoing pregnancy	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
5.4 Side effects	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
5.4.1 Nausea	3	1532	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.74, 1.61]
5.4.2 Vomiting	3	1532	Risk Ratio (M‐H, Random, 95% CI)	1.78 [0.97, 3.26]
5.4.3 Diarrhoea	2	932	Risk Ratio (M‐H, Random, 95% CI)	1.40 [0.80, 2.45]
5.4.4 Abdominal pain	4	3071	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.95, 1.32]
5.5 Women's dissatisfaction with the procedure	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
5.5.1 Home vs hospital	4	2155	Risk Ratio (M‐H, Random, 95% CI)	1.63 [0.95, 2.80]
5.5.2 Nurse vs doctor	2	1988	Risk Ratio (M‐H, Random, 95% CI)	2.70 [0.16, 44.49]
5.6 Additional uterotonics used	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.7 Days of bleeding	3	1532	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.25, 0.22]
5.8 Blood transfusion	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
5.8.1 Home vs hospital	1	731	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 8.18]
5.8.2 Nurse vs doctor	1	1068	Risk Ratio (M‐H, Random, 95% CI)	Not estimable

Date	Event	Description
3 October 2011	New citation required but conclusions have not changed	New author Nathalie Kapp helped updating this review and 19 new studies were added
15 April 2008	Amended	Converted to new review format.
17 October 2003	New citation required and conclusions have changed	Substantive amendment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Failure to achieve complete abortion	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.1.1 Combined dosage comparison: gemeprost 1 mg versus 0.5 mg with different dosage of mifepristone	2	1034	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.31, 0.60]
2.1.2 Misoprostol 800 µg vs 400 µg all	3	4424	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.51, 0.78]
2.1.3 Misoprostol 800 µg vs 400 µg ≤ 49 days	1	545	Risk Ratio (M‐H, Random, 95% CI)	2.24 [0.79, 6.36]
2.1.4 Misoprostol 800 µg vs 400 µg > 49 days	1	570	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.26, 1.30]
2.1.5 Misoprostol vaginal 800 µg vs oral 400 µg	1	637	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.59, 2.12]
2.2 Surgical evacuation	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.2.1 Misoprostol 800 µg vs 400 µg	2	934	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.44, 1.55]
2.3 Ongoing pregnancy	4	5060	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.26, 0.65]
2.3.1 Misoprostol 800 µg vs 400 µg	3	4424	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.26, 0.65]
2.3.2 Misoprostol vaginal 800 µg vs oral 400 µg	1	636	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
2.4 Nausea	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.4.1 Misoprostol 800 µg vs 400 µg	3	4424	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.94, 1.05]
2.4.2 Misoprostol vaginal 800 µg vs oral 400 µg	2	734	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.67, 1.28]
2.5 Vomiting	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.5.1 Misoprostol 800 µg vs 400 µg	3	4424	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.77, 1.57]
2.5.2 Misoprostol vaginal 800 µg vs oral 400 µg	2	734	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.32, 2.15]
2.6 Diarrhoea	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.6.1 Misoprostol 800 µg vs 400 µg	2	3302	Risk Ratio (M‐H, Random, 95% CI)	1.70 [1.43, 2.03]
2.6.2 Misoprostol vaginal 800 µg vs oral 400 µg	2	734	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.59, 1.73]
2.7 Abdominal pain	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.7.1 Misoprostol 800 µg vs 400 µg	2	4127	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.89, 1.15]
2.8 Women's dissatisfaction with the procedure	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.8.1 Misoprostol 800 µg vs 400 µg	3	4420	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.60, 0.93]
2.8.2 Misoprostol vaginal 800 µg vs oral 400 µg	2	735	Risk Ratio (M‐H, Random, 95% CI)	1.31 [0.89, 1.92]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Failure to achieve complete abortion	3	1704	Risk Ratio (M‐H, Random, 95% CI)	2.38 [1.46, 3.87]
6.2 Side effects	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
6.2.1 Nausea	2	1380	Risk Ratio (M‐H, Random, 95% CI)	1.14 [1.03, 1.26]
6.2.2 Vomiting	2	1219	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.51, 1.90]
6.2.3 Diarrhoea	2	1379	Risk Ratio (M‐H, Random, 95% CI)	1.80 [1.49, 2.17]
6.3 Bleeding volume	1	297	Mean Difference (IV, Random, 95% CI)	8.00 [‐2.94, 18.94]
6.4 Time until passing of conceptus	1	297	Mean Difference (IV, Fixed, 95% CI)	0.50 [‐0.71, 1.71]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Failure to achieve complete abortion	2	479	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.34, 1.46]
7.2 Side effects	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
7.2.1 Nausea	2	479	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.97, 1.27]
7.2.2 Vomiting	2	479	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.89, 1.51]
7.2.3 Diarrhoea	2	479	Risk Ratio (M‐H, Random, 95% CI)	1.51 [1.12, 2.03]
7.3 Surgical evacuation	1	50	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.81]
7.4 Women's dissatisfaction with the procedure	1	50	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.01, 3.97]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Failure to achieve complete abortion	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
8.1.1 Failure to achieve complete abortion (all)	1	847	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.40, 0.96]
8.1.2 Failure to achieve complete abortion ≤ 49 days	1	418	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.25, 2.04]
8.1.3 Failure to achieve complete abortion > 49 days	1	429	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.18, 0.73]
8.2 Ongoing pregnancy	1	847	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.09, 1.08]
8.2.1 Ongoing pregnancy ≤ 49 days	1	418	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.11, 3.80]
8.2.2 Ongoing pregnancy > 49 days	1	429	Risk Ratio (M‐H, Random, 95% CI)	0.18 [0.04, 0.78]
8.3 Side effects	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
8.3.1 Nausea	1	830	Risk Ratio (M‐H, Random, 95% CI)	1.10 [1.01, 1.19]
8.3.2 Vomiting	1	830	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.94, 1.27]
8.3.3 Diarrhoea	1	830	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.94, 1.31]
8.4 Women's dissatisfaction with the procedure	1	835	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.76, 1.91]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Failure to achieve complete abortion	2	3229	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.22, 2.11]
9.2 Surgical evacuation	1	327	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.18, 3.53]
9.3 Ongoing pregnancy	2	3229	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.13, 3.47]
9.4 Women's dissatisfaction with the procedure	2	3303	Risk Ratio (M‐H, Random, 95% CI)	1.67 [0.80, 3.50]
9.5 Side effects	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
9.5.1 Diarrhoea	3	3543	Risk Ratio (M‐H, Random, 95% CI)	1.83 [1.33, 2.50]
9.5.2 Nausea	3	3543	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.93, 1.33]
9.5.3 Vomiting	3	3543	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.88, 1.66]
9.5.4 Abdominal pain	1	3005	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.87, 1.12]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Failure to achieve complete abortion	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
10.1.1 All	2	564	Risk Ratio (M‐H, Random, 95% CI)	0.26 [0.10, 0.68]
10.1.2 ≤ 49 days	1	422	Risk Ratio (M‐H, Random, 95% CI)	0.28 [0.08, 0.99]
10.1.3 > 49 days	1	48	Risk Ratio (M‐H, Random, 95% CI)	0.09 [0.00, 1.60]
10.2 Ongoing pregnancy	1	93	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.01, 8.50]
10.3 Surgical evacuation	1	93	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.08, 1.67]
10.4 Women's dissatisfaction with the procedure	1	471	Risk Ratio (M‐H, Random, 95% CI)	1.96 [0.94, 4.09]
10.5 Side effects	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
10.5.1 Nausea	2	564	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.27, 1.41]
10.5.2 Vomiting	2	564	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.25, 1.62]
10.5.3 Diarrhea	1	93	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.09, 1.09]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
11.1 Failure to achieve complete abortion	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
11.1.1 All	2	640	Risk Ratio (M‐H, Random, 95% CI)	1.43 [0.64, 3.23]
11.1.2 ≤ 49 days	2	512	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.30, 2.53]
11.1.3 > 49 days	2	117	Risk Ratio (M‐H, Random, 95% CI)	1.42 [0.18, 11.31]
11.2 Surgical evacuation	2	640	Risk Ratio (M‐H, Random, 95% CI)	1.72 [0.75, 3.96]
11.3 Ongoing pregnancy	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
11.3.1 All	2	640	Risk Ratio (M‐H, Random, 95% CI)	2.59 [0.88, 7.61]
11.3.2 ≤ 49 days	1	48	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
11.3.3 > 49 days	1	42	Risk Ratio (M‐H, Random, 95% CI)	3.60 [0.16, 83.60]
11.4 Side effects	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
11.4.1 Vomiting	2	640	Risk Ratio (M‐H, Random, 95% CI)	1.33 [1.01, 1.77]
11.4.2 Nausea	2	640	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.88, 1.27]
11.4.3 Diarrhoea	2	640	Risk Ratio (M‐H, Random, 95% CI)	2.19 [0.56, 8.51]
11.4.4 Abdominal pain	2	640	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.79, 1.52]
11.5 Women's dissatisfaction with the procedure	1	550	Risk Ratio (M‐H, Random, 95% CI)	2.54 [1.14, 5.66]
11.6 Haemoglobin level	1	90	Mean Difference (IV, Random, 95% CI)	0.00 [‐0.40, 0.40]
11.7 Time until passing of conceptus	1	90	Mean Difference (IV, Random, 95% CI)	‐0.88 [‐2.44, 0.68]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
12.1 Failure to achieve complete abortion	1	154	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.21, 2.39]
12.2 Side effects	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
12.2.1 Nausea	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
12.2.2 Vomiting	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
12.2.3 Diarrhoea	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
13.1 Failure to achieve complete abortion	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
13.1.1 All oral vs vaginal and continuous oral	2	1581	Risk Ratio (M‐H, Random, 95% CI)	1.48 [1.01, 2.16]
13.1.2 All oral vs single vaginal	2	1578	Risk Ratio (M‐H, Random, 95% CI)	1.19 [0.83, 1.70]
13.1.3 Vaginal and continuous oral vs single vaginal	2	1579	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.54, 1.19]
13.1.4 All oral vs vaginal & continuous oral ≤ 49 days	1	476	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.57, 2.41]
13.1.5 All oral vs vaginal and continuous oral > 49 days	1	1004	Risk Ratio (M‐H, Random, 95% CI)	1.60 [1.00, 2.57]
13.1.6 All oral vs single vaginal ≤ 49 days	1	459	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.60, 2.74]
13.1.7 All oral vs single vaginal > 49 days	1	1014	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.73, 1.70]
13.1.8 Vaginal and continuous oral vs single vaginal ≤ 49days	1	463	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.50, 2.40]
13.1.9 Vaginal and continuous oral vs single vaginal > 49 days	1	1010	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.43, 1.13]
13.2 Diarrhoea	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
13.2.1 All oral vs vaginal and continuous oral	1	1481	Risk Ratio (M‐H, Random, 95% CI)	1.83 [1.11, 3.01]
13.2.2 All oral vs single vaginal	1	1478	Risk Ratio (M‐H, Random, 95% CI)	2.09 [1.24, 3.53]
13.2.3 Vaginal and continuous oral vs single vaginal	1	1479	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.63, 2.07]
13.3 Nausea	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
13.3.1 All oral vs vaginal and continuous oral	1	1481	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.65, 1.09]
13.3.2 All oral vs single vaginal	1	1478	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.72, 1.24]
13.3.3 Vaginal and continuous oral vs single vaginal	1	1479	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.87, 1.45]
13.4 Vomiting	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
13.4.1 All oral vs vaginal and continuous oral	1	1481	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.49, 1.30]
13.4.2 All oral vs single vaginal	1	1478	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.53, 1.43]
13.4.3 Vaginal and continuous oral vs single vaginal	1	1479	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.68, 1.74]
13.5 Ongoing pregnancy at follow‐up	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
13.5.1 All oral vs vaginal and continuous oral	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
13.5.2 All oral vs single vaginal	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
13.5.3 Vaginal and continuous oral vs single vaginal	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

PERMALINK

Medical methods for first trimester abortion

Jing Zhang

Kunyan Zhou

Dan Shan

Xiaoyan Luo

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

1.

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

15.1. Analysis.

Data synthesis

Combined regimen mifepristone/prostaglandin

Single regimen

Combined regimen methotrexate/prostaglandin

Tamoxifen versus methotrexate (combined with prostaglandin)

Combined regimen mifepristone/prostaglandin versus mifepristone/prostaglandin plus tamoxifen

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

Included studies

1. Other studies included in the review.

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings 1. Mifepristone (600 mg) plus prostaglandin versus mifepristone (200 mg) plus prostaglandin for first trimester abortion.

Summary of findings 2. Misoprostol 800 µg plus mifepristone 200 mg versus misoprostol 400 µg plus mifepristone 200 mg for first trimester abortion.

Summary of findings 3. Medical abortion self‐administered at home compared to administered in hospital for first trimester abortion.

Summary of findings 4. Medical abortion administered by nurses compared to by doctors for first trimester abortion.

Summary of findings 5. Oral misoprostol compared to vaginal misoprostol for first trimester abortion in combined regimen mifepristone/prostaglandin.

Summary of findings 6. Sublingual misoprostol compared to vaginal misoprostol for first trimester abortion in combined regimen mifepristone/prostaglandin.

Summary of findings 7. Mifepristone alone compared to mifepristone/prostaglandin for first trimester abortion.

Summary of findings 8. Prostaglandin alone compared to combined regimen for first trimester abortion.

Summary of findings 9. Oral misoprostol alone compared to vaginal misoprostol alone for first trimester abortion.

Summary of findings 10. Sublingual misoprostol alone compared to vaginal misoprostol alone for first trimester abortion.

1. Combined regimen mifepristone/prostaglandin

Comparison 1: different doses of mifepristone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
15.1 Failure to achieve complete abortion	18		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
15.1.1 All	18	3471	Risk Ratio (M‐H, Random, 95% CI)	2.39 [1.89, 3.02]
15.1.2 All without Jain 1999	17	3321	Risk Ratio (M‐H, Random, 95% CI)	2.45 [1.92, 3.14]
15.1.3 With letrozole combined	6	1008	Risk Ratio (M‐H, Random, 95% CI)	2.29 [1.62, 3.24]
15.1.4 ≤ 49 days	4	785	Risk Ratio (M‐H, Random, 95% CI)	4.65 [2.65, 8.16]
15.1.5 > 49 days	4	447	Risk Ratio (M‐H, Random, 95% CI)	2.33 [1.48, 3.65]
15.1.6 With methotrexate combined regimen	3	333	Risk Ratio (M‐H, Random, 95% CI)	1.97 [0.74, 5.26]
15.1.7 With estradiol valerate	1	100	Risk Ratio (M‐H, Random, 95% CI)	4.25 [2.19, 8.25]
15.2 Time until passing of conceptus	6	988	Std. Mean Difference (IV, Random, 95% CI)	0.43 [0.05, 0.80]
15.3 Surgical evacuation	7	1307	Risk Ratio (M‐H, Random, 95% CI)	2.90 [2.26, 3.73]
15.4 Additional uterotonics used	3	592	Risk Ratio (M‐H, Random, 95% CI)	2.05 [1.26, 3.34]
15.5 Ongoing pregnancy	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
15.5.1 All	5	1353	Risk Ratio (M‐H, Random, 95% CI)	3.63 [1.18, 11.16]
15.5.2 ≤ 49 days	3	632	Risk Ratio (M‐H, Random, 95% CI)	10.12 [3.07, 33.44]
15.5.3 > 49 days	3	358	Risk Ratio (M‐H, Random, 95% CI)	3.33 [0.86, 12.89]
15.6 Side effects	13		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
15.6.1 Diarrhoea	11	2342	Risk Ratio (M‐H, Random, 95% CI)	1.26 [1.11, 1.43]
15.6.2 Nausea	12	2722	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.74, 1.10]
15.6.3 Vomiting	9	2029	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.66, 1.15]
15.6.4 Pelvic infection	1	300	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.14, 6.91]
15.6.5 Abdominal pain	6	1827	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.90, 1.37]
15.7 Women's dissatisfaction with the procedure	5	1485	Risk Ratio (M‐H, Random, 95% CI)	1.65 [0.75, 3.64]
15.8 Blood transfusion	1	300	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.03, 3.13]
15.9 Days of bleeding	2	420	Mean Difference (IV, Random, 95% CI)	‐1.13 [‐1.69, ‐0.57]
15.10 Haemoglobin level	1	128	Mean Difference (IV, Random, 95% CI)	‐0.41 [‐0.75, ‐0.07]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
16.1 Failure to achieve complete abortion	10		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
16.1.1 Misoprostol oral vs vaginal	2	216	Risk Ratio (M‐H, Random, 95% CI)	3.68 [1.56, 8.71]
16.1.2 Misoprostol sublingual vs vaginal	5	2705	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.37, 1.28]
16.1.3 Misoprostol sublingual vs oral	1	109	Risk Ratio (M‐H, Random, 95% CI)	0.24 [0.05, 1.06]
16.1.4 Misoprostol sublingual vs buccal	1	401	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.71, 1.74]
16.1.5 Misoprostol repeat vs single	1	180	Risk Ratio (M‐H, Random, 95% CI)	1.30 [0.78, 2.15]
16.1.6 Administration model of misoprostol	2	1164	Risk Ratio (M‐H, Random, 95% CI)	2.09 [0.56, 7.81]
16.1.7 ≤ 49 days	1	248	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.56, 1.76]
16.1.8 > 49 days	1	141	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.18, 1.41]
16.2 Blood transfusion	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
16.2.1 Misoprostol sublingual vs vaginal	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
16.3 Ongoing pregnancy	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
16.3.1 Misoprostol sublingual vs buccal	1	401	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.50, 2.45]
16.3.2 Misoprostol sublingual vs vaginal	2	340	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.21, 1.51]
16.3.3 > 49 days	1	141	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.03, 2.21]
16.3.4 ≤ 49 days	1	248	Risk Ratio (M‐H, Random, 95% CI)	0.16 [0.02, 1.26]
16.4 Additional uterotonics used	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
16.4.1 Misoprostol sublingual vs buccal	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
16.5 Surgical evacuation	8		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
16.5.1 Misoprostol sublingual vs buccal	1	401	Risk Ratio (M‐H, Random, 95% CI)	1.49 [0.80, 2.79]
16.5.2 Misoprostol sublingual vs vaginal	3	540	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.26, 0.85]
16.5.3 Misoprostol sublingual vs oral	2	173	Risk Ratio (M‐H, Random, 95% CI)	2.21 [0.60, 8.10]
16.5.4 Misoprostol repeat vs single	1	180	Risk Ratio (M‐H, Random, 95% CI)	1.30 [0.78, 2.15]
16.5.5 Misoprostol nurse vs doctor	1	1010	Risk Ratio (M‐H, Random, 95% CI)	3.84 [2.16, 6.83]
16.6 Nausea	9		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
16.6.1 Misoprostol sublingual vs vaginal	4	2505	Risk Ratio (M‐H, Random, 95% CI)	1.61 [0.78, 3.33]
16.6.2 Misoprostol sublingual vs buccal	1	401	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.92, 1.44]
16.6.3 Misoprostol sublingual vs oral	1	109	Risk Ratio (M‐H, Random, 95% CI)	1.89 [0.50, 7.19]
16.6.4 Misoprostol oral vs vaginal	2	216	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.92, 1.61]
16.6.5 Misoprostol repeat vs single	1	180	Risk Ratio (M‐H, Random, 95% CI)	1.46 [1.00, 2.14]
16.6.6 Administration model of misoprostol	2	1164	Risk Ratio (M‐H, Random, 95% CI)	1.16 [1.02, 1.32]
16.7 Vomiting	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
16.7.1 Misoprostol sublingual vs vaginal	4	2605	Risk Ratio (M‐H, Random, 95% CI)	1.83 [1.22, 2.73]
16.7.2 Misoprostol sublingual vs buccal	1	401	Risk Ratio (M‐H, Random, 95% CI)	1.45 [1.00, 2.11]
16.7.3 Misoprostol sublingual vs oral	1	109	Risk Ratio (M‐H, Random, 95% CI)	2.21 [0.60, 8.10]
16.7.4 Misoprostol repeat vs single	2	296	Risk Ratio (M‐H, Random, 95% CI)	1.83 [0.31, 10.82]
16.7.5 Misoprostol nurse vs doctor	1	1010	Risk Ratio (M‐H, Random, 95% CI)	1.35 [1.08, 1.68]
16.8 Diarrhoea	10		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
16.8.1 Misoprostol sublingual vs vaginal	5	2725	Risk Ratio (M‐H, Random, 95% CI)	1.73 [1.41, 2.12]
16.8.2 Misoprostol sublingual vs buccal	1	401	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.99, 1.29]
16.8.3 Misoprostol sublingual vs oral	1	109	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.17, 3.02]
16.8.4 Misoprostol oral vs vaginal	2	216	Risk Ratio (M‐H, Random, 95% CI)	1.42 [0.60, 3.37]
16.8.5 Misoprostol repeat vs single	1	180	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.71, 1.76]
16.8.6 Administration model of misoprostol	2	1164	Risk Ratio (M‐H, Random, 95% CI)	1.22 [1.00, 1.49]
16.9 Abdominal pain	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
16.9.1 Misoprostol sublingual vs vaginal	3	459	Risk Ratio (M‐H, Random, 95% CI)	1.38 [0.49, 3.86]
16.9.2 Misoprostol sublingual vs oral	1	109	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.96, 1.09]
16.9.3 Misoprostol oral vs vaginal	2	216	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.48, 3.21]
16.9.4 Administration model of misoprostol	2	1164	Risk Ratio (M‐H, Random, 95% CI)	1.28 [0.55, 2.97]
16.10 Women's dissatisfaction with the procedure	5		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
16.10.1 Misoprostol sublingual vs buccal	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
16.10.2 Misoprostol sublingual vs vaginal	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
16.10.3 Misoprostol sublingual vs oral	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
16.10.4 Misoprostol oral vs vaginal	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
16.10.5 Misoprostol nurse vs doctor	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
16.11 Days of bleeding	3		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
16.11.1 Misoprostol sublingual vs vaginal	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
16.11.2 Administration model of misoprostol	2		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
16.12 Time until passing of conceptus	4		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only
16.12.1 Misoprostol sublingual vs vaginal	2	320	Std. Mean Difference (IV, Random, 95% CI)	‐1.10 [‐1.34, ‐0.87]
16.12.2 Misoprostol sublingual vs oral	1	64	Std. Mean Difference (IV, Random, 95% CI)	0.15 [‐0.34, 0.64]
16.12.3 Misoprostol oral vs vaginal	1	100	Std. Mean Difference (IV, Random, 95% CI)	0.71 [0.31, 1.12]
16.13 Haemoglobin level	2		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
17.1 Failure to achieve complete abortion	1	101	Risk Ratio (M‐H, Random, 95% CI)	1.32 [0.74, 2.38]
17.2 Side effects	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
17.2.1 Nausea	1	101	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.19, 0.84]
17.2.2 Vomiting	1	101	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.07, 1.78]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
18.1 Failure to achieve complete abortion	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
18.1.1 Misoprostol day 7 vs day 3	1	86	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.02, 1.10]
18.1.2 Misoprostol day 5 vs day 3	2	387	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.36, 1.45]
18.1.3 Misoprostol day 5 vs day 4	2	394	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.38, 1.49]
18.1.4 Misoprostol day 4 vs day 3	2	393	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.52, 1.80]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
19.1 Failure to achieve complete abortion	1	100	Risk Ratio (M‐H, Random, 95% CI)	2.04 [0.51, 8.07]
19.2 Side effects	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
19.2.1 Nausea	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.22, 1.25]
19.2.2 Vomiting	1	100	Risk Ratio (M‐H, Random, 95% CI)	4.89 [0.57, 42.21]
19.2.3 Diarrhoea	1	100	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.18, 8.34]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
20.1 Failure to achieve complete abortion	2	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
20.1.1 methotrexate 60 mg vs 50 mg	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
20.1.2 methotrexate 50 mg vs 25 mg	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
21.1 Failure to achieve complete abortion	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
21.2 Side effects	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
21.2.1 Nausea	1	309	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.84, 1.42]
21.2.2 Vomiting	1	309	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.67, 1.56]
21.2.3 Diarrhoea	1	309	Risk Ratio (M‐H, Random, 95% CI)	1.40 [0.94, 2.07]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
22.1 Failure to achieve complete abortion	1	198	Risk Ratio (M‐H, Random, 95% CI)	2.04 [0.86, 4.84]
22.2 Side effects	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
22.2.1 Nausea	1	198	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.33, 0.97]
22.2.2 Vomiting	1	198	Risk Ratio (M‐H, Random, 95% CI)	1.70 [0.42, 6.92]
22.2.3 Diarrhoea	1	198	Risk Ratio (M‐H, Random, 95% CI)	1.53 [0.26, 8.96]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
23.1 Failure to achieve complete abortion	1	200	Risk Ratio (M‐H, Random, 95% CI)	1.96 [0.93, 4.15]
23.2 Side effects	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
23.2.1 Nausea	1	200	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.54, 1.10]
23.2.2 Vomiting	1	200	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.28, 1.53]
23.2.3 Diarrhoea	1	200	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.34, 4.43]

*Study characteristics*
Methods	Study design: RCT Study grouping: parallel‐group
Participants	Baseline characteristics LET+ MS Mean age (years): 29.21 ± 4.08 Mean pregnancy age based on LMP (weeks): 7.74 ± 0.95 Mean pregnancy age based on ultrasound (weeks): 8.09 ± 0.90 Missed abortion (%): 17.2% MS Mean age (years): 28.53 ± 5.24 Mean pregnancy age based on LMP (weeks): 8.52 ± 1.29 Mean pregnancy age based on ultrasound (weeks): 8.80 ± 1.17 Missed abortion (%): 14.1% Overall Mean age (years): unreported Mean pregnancy age based on LMP (weeks): unreported Mean pregnancy age based on ultrasound (weeks): unreported Missed abortion (%): unreported Inclusion criteria: minimum age of 18 years for mother, first trimester of pregnancy (< 12 weeks based on LMP), non‐viable fetus (missed abortion or blighted ovum), lack of any maternal diseases such as: heart disease, asthma, history of thromboembolism, cancer, renal failure, and liver diseases, and consent of women and her spouse to participate in the study Exclusion criteria: medical problem in women which would interfere and emergency treatment, history of allergy to misoprostol or LET drugs, women who had spontaneous abortion before taking misoprostol Pretreatment: no Study duration: June 2013 to April 2015
Interventions	Intervention characteristics LET + MS vs MS LET + MS: 10 mg oral LET for 3 days, 600 µg single dose oral MS MS: placebo of LET like intervention group and 600 µg single dose oral MS
Outcomes	Failure to achieve complete abortion Outcome type: dichotomous outcome Reporting: fully reported Direction: lower is better Data value: change from baseline Surgical evacuation Outcome type: dichotomous outcome Reporting: fully reported Direction: lower is better Data value: endpoint Nausea Outcome type: adverse event Reporting: fully reported Direction: lower is better Data value: endpoint Vomiting Outcome type: adverse event Reporting: fully reported Direction: lower is better Data value: endpoint Diarrhoea Outcome type: adverse event Reporting: fully reported Direction: lower is better Data value: endpoint Dizziness Outcome type: adverse event Reporting: fully reported Direction: lower is better Data value: endpoint Headache Outcome type: adverse event Reporting: fully reported Direction: lower is better Data value: endpoint Abdominal pain Outcome type: adverse event Reporting: fully reported Direction: lower is better Data value: endpoint Fever Outcome type: adverse event Reporting: fully reported Direction: lower is better Data value: endpoint Chills Outcome type: adverse event Reporting: fully reported Direction: lower is better Data value: endpoint Haemoglobin level Outcome type: continuous outcome Reporting: fully reported Unit of measure: mg/dL Direction: Higher is better Data value: endpoint Bleeding duration Outcome type: adverse event Reporting: fully reported Direction: lower is better Data value: endpoint
Identification	Sponsorship source: Women's Reproductive Health Research Center; pharmaceutical companies (Iran Hormone and Samisaz) Country: Iran Setting: Department of Gynecology and Obstetrics, Women’s Reproductive Health Research Center, Tabriz University of Medical Science Author(s): Fatemeh Abbasalizadeh, M.D. 1; Farnaz Sahhaf, M.D. 1; Paria Sadeghi‐Shabestari, M.D. 1; Mohammad Mirza‐Aghazadeh‐Attari, M.D. 2; Mohammad Naghavi‐Behzad, M.D. Institution: 1 Department of Gynecology and Obstetrics, Women’s Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; 2 Medical Philosophy and History Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Email: dr.naghavii@gmail.com Address: Daneshgah Street, Tabriz, Eastern Azerbaijan, Iran
Notes	Follow up duration: 14 days
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomly selected in two intervention and control groups using Rand list (version 1.2) software." Judgement comment: computer randomisation adequate
Allocation concealment (selection bias)	High risk	Judgement comment: unreported by authors
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Through the study single blinding was applied and patients were not aware of studied groups" Judgement comment: single (participants), placebo of LET
Blinding of outcome assessment (detection bias) All outcomes	High risk	Judgement comment: single blinding (participants)
Incomplete outcome data (attrition bias) All outcomes	Low risk	Judgement comment: none lost to follow‐up
Selective reporting (reporting bias)	Low risk	Quote: "IRCT2014030114293N1" Judgement comment: both efficacy and side effects were reported.
Other bias	Unclear risk	Quote: "Acknowledgements: Present study was conducted in cooperation with two pharmaceutical companies (Iran Hormone and Samisaz), and we sincerely appreciate the..." Judgement comment: pharmaceutical company support