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The objective was to describe the efficacy of medical abortion using mifepristone and misoprostol for gestations less than 6 weeks.
Study design
We searched PubMed and Cochrane databases for articles in any language that examined the success of mifepristone and misoprostol abortion at gestational ages <42 days. Data were independently abstracted by two authors and graded for evidence quality. A pooled analysis of efficacy and a summary odds ratio of abortion failure of <42 days’ gestation compared with gestational week 42–49 days were performed for randomized trials as well as for prospective studies.
Results
Six randomized controlled trials and nine prospective observational studies met inclusion criteria. Included studies varied greatly in regimens of mifepristone and misoprostol used, and assessment of and timing of outcome of abortion. A pooled proportion of the randomized trials estimated a proportion of unsuccessful abortion of 0.02 (95% confidence interval 0.01–0.03). In the prospective studies, the proportions ranged between 0.02 and 0.17, with considerable heterogeneity in the pooled estimate. However, the two largest observational studies reflected the estimates of the randomized trials (range 0.02–0.03). The summary odds ratios indicated that the odds of unsuccessful abortion were not significantly different between gestational age groups (<42 days versus >42–49 days).
Discussion
These analyses support the use of medical abortion at gestational ages <42 days. Efficacy rates are high overall and appear to reflect those observed during the seventh week of pregnancy. Women who prefer to initiate treatment as soon as early pregnancy is diagnosed may do so without delay.
Implications
Women can expect success using medical abortion regimens as soon as pregnancy is diagnosed; further research of abortion outcomes disaggregated by gestational age and visualization of the gestational sac is warranted.
Safety, efficacy, and acceptability of medical abortion in China, Cuba, and India: a comparative trial of mifepristone-misoprostol versus surgical abortion.
]. Medical abortion at less than 9 weeks of gestation accounted for 31% of all clinic-based abortions in 2014 in the US, as compared with 24% in 2011 [
]. Given the few medical requirements for safe provision of medical abortion drugs and that the abortion process is generally managed at a woman's home on her own, medical abortion has expanded women's access to induced abortion globally. Improved access to medical abortion is a strategy to reduce recourse to unsafe abortion, which remains a significant threat to the lives and well-being of women across the world [
Global, regional, and national levels and trends in maternal mortality between 1990 and 2015, with scenario-based projections to 2030: a systematic analysis by the UN maternal mortality estimation inter-agency group.
]. Identifying effective strategies to further expand access to medical abortion may ensure safe abortion care where trained providers are limited. Simplifying the process of obtaining a medical abortion by expanding the earlier gestational ages at which it can safely be used has the potential to improve access.
Multiple medical abortion regimens exist for use in the first weeks of pregnancy [
]. The most effective combine mifepristone with misoprostol; however, there is variation in both the doses of medicine used, and the timing and route of administration of the two drugs [
]. A large body of evidence and global practice supports the efficacy of a dose of mifepristone 200 mg followed by misoprostol 800 mcg in pregnancies up to 63 days’ gestational age [
Less is known regarding the efficacy of medical abortion in very early pregnancies (<42 days’ gestational age), and case–control study evidence has indicated the possibility of a higher failure rate in gestations of less than 7 weeks [
]. Even less efficacy data have been available for pregnancies in which it is too early to visualize a gestational sac on ultrasound. As most women seeking abortion care are at gestations of 6 or more weeks, data are limited in the lower age range from any single clinical trial. There are many reasons why a woman may prefer to terminate a pregnancy as early as the diagnosis of pregnancy is made or even as early as when she misses her menses. The objective of this review is to synthesize the evidence on the efficacy of medical abortion using mifepristone with misoprostol in pregnancies less than 42 days’ gestation.
2. Materials and methods
We searched Pubmed and Cochrane databases for peer-reviewed articles which reported the efficacy of medical abortion among women with a pregnancy of less than 42 days’ gestation. We searched from database inception through January 2017. A combination of medical subject headings, MeSH, keywords and text words were used. Search terms included induced abortion, first trimester, misoprostol and mifepristone.
Our criteria for inclusion included studies which collected data prospectively of any design and in any language that reported on efficacy outcomes of medical abortion with mifepristone and misoprostol. Included studies reported outcomes for participants with gestational ages less than 42 days. Our primary outcome of interest was successful abortion, defined as no surgical intervention needed to achieve complete expulsion of the pregnancy.
Two authors participated in summarizing and systematically assessing the evidence in the included studies using standard data abstraction forms (M.K.B. and N.K.). The quality of each individual piece of evidence was assessed independently using the United States Preventive Services Task Force grading system (https://www.uspreventiveservicestaskforce.org/Page/Name/grade-definitions). In case of any disagreement, the assessment of the third author was sought (M.I.R.).
We planned a pooled estimate of the proportion of the success of the abortion in the randomized trials and prospective studies identified. Where data were available by gestational age week, we planned a summary odds ratio (OR) comparing odds of unsuccessful medical abortion at <42 days with abortion between 43 and 49 days. Analyses were conducted using Stata version 12 (Statacorp, College Station, TX, USA) and RevMan version 5.3 (Copenhagen, Denmark: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014).
3. Results
The search strategy identified 174 articles, of which 15 met our inclusion criteria (Table 1, Table 2) [
Safety, efficacy, and acceptability of medical abortion in China, Cuba, and India: a comparative trial of mifepristone-misoprostol versus surgical abortion.
A multicentre randomized comparative clinical trial of 200 mg RU486 (mifepristone) single dose followed by either 5 mg 9-methylene PGE(2) gel (meteneprost) or 600 microg oral PGE(1) (misoprostol) for termination of early pregnancy within 28 days of missed menstrual period.
Mifepristone plus vaginal misoprostol vs vaginal misoprostol alone for medical abortion in gestation 63 days or less in Nepalese women: a quasi-randomized controlled trial.
Effectiveness and safety of lower doses of mifepristone combined with misoprostol for the termination of ultra-early pregnancy: a dose-ranging randomized controlled trial.
Efficacy, safety, and acceptability of low-dose mifepristone and self-administered misoprostol for ultra-early medical abortion: a randomized controlled trial.
]. Seven articles met criteria but did not report data disaggregated by gestational age less than 42 days; corresponding authors were contacted to ask for these data [
A prospective randomized, double-blinded, placebo-controlled trial comparing mifepristone and vaginal misoprostol to vaginal misoprostol alone for elective termination of early pregnancy.
A prospective, randomized, placebo-controlled trial on the use of mifepristone with sublingual or vaginal misoprostol for medical abortions of less than 9 weeks gestation.
A multicentre randomized comparative clinical trial of 200 mg RU486 (mifepristone) single dose followed by either 5 mg 9-methylene PGE(2) gel (meteneprost) or 600 microg oral PGE(1) (misoprostol) for termination of early pregnancy within 28 days of missed menstrual period.
Mifepristone plus vaginal misoprostol vs vaginal misoprostol alone for medical abortion in gestation 63 days or less in Nepalese women: a quasi-randomized controlled trial.
Effectiveness and safety of lower doses of mifepristone combined with misoprostol for the termination of ultra-early pregnancy: a dose-ranging randomized controlled trial.
Efficacy, safety, and acceptability of low-dose mifepristone and self-administered misoprostol for ultra-early medical abortion: a randomized controlled trial.
No surgical intervention Hospital administration: observed expulsion by 6 h or >50% hCG decline, weekly hCG and ultrasound Self-administration: pregnancy test and phone follow-up Timing: by next menses
Outcomes assessed differently by group, 7 subjects in self-administration lost to follow-up and not analyzed
Safety, efficacy, and acceptability of medical abortion in China, Cuba, and India: a comparative trial of mifepristone-misoprostol versus surgical abortion.
Included studies ranged in quality from poor to good. Studies ranged in both doses and routes of mifepristone and misoprostol used, as well as differed in inclusion criteria such as how pregnancy was diagnosed and outcome assessment and timing.
3.1 Randomized trials
Six randomized controlled trials reporting on successful medical abortion at less than 42 days’ gestation were identified (Table 1) [
A multicentre randomized comparative clinical trial of 200 mg RU486 (mifepristone) single dose followed by either 5 mg 9-methylene PGE(2) gel (meteneprost) or 600 microg oral PGE(1) (misoprostol) for termination of early pregnancy within 28 days of missed menstrual period.
Mifepristone plus vaginal misoprostol vs vaginal misoprostol alone for medical abortion in gestation 63 days or less in Nepalese women: a quasi-randomized controlled trial.
Effectiveness and safety of lower doses of mifepristone combined with misoprostol for the termination of ultra-early pregnancy: a dose-ranging randomized controlled trial.
Efficacy, safety, and acceptability of low-dose mifepristone and self-administered misoprostol for ultra-early medical abortion: a randomized controlled trial.
]. The quality of the studies ranged from fair to good. No studies were randomized evaluating abortion success based on gestational age (<42 days versus >42 days). Mifepristone doses ranged from 50 to 200 mg, administered 24–48 h prior to misoprostol. Misoprostol dosing was more varied between studies: 200–800 mcg, administered by oral, buccal or vaginal routes.
Method used to assess gestational age and location varied among studies, with a combination of history, clinical exam, hCG testing and use of ultrasonography. Of the six identified trials, four used ultrasound routinely to document pregnancy on study enrollment [
Mifepristone plus vaginal misoprostol vs vaginal misoprostol alone for medical abortion in gestation 63 days or less in Nepalese women: a quasi-randomized controlled trial.
Effectiveness and safety of lower doses of mifepristone combined with misoprostol for the termination of ultra-early pregnancy: a dose-ranging randomized controlled trial.
Efficacy, safety, and acceptability of low-dose mifepristone and self-administered misoprostol for ultra-early medical abortion: a randomized controlled trial.
A multicentre randomized comparative clinical trial of 200 mg RU486 (mifepristone) single dose followed by either 5 mg 9-methylene PGE(2) gel (meteneprost) or 600 microg oral PGE(1) (misoprostol) for termination of early pregnancy within 28 days of missed menstrual period.
All studies assessed abortion completion; however, differing time points and methods for assessing completion were used. Evaluation of abortion completion occurred between 10 and 36 days following misoprostol administration. A combination of history, observation of expelled products, serial hCG tests and ultrasound examination was used to confirm complete abortion. The majority utilized ultrasound to document a successful abortion [
Mifepristone plus vaginal misoprostol vs vaginal misoprostol alone for medical abortion in gestation 63 days or less in Nepalese women: a quasi-randomized controlled trial.
Effectiveness and safety of lower doses of mifepristone combined with misoprostol for the termination of ultra-early pregnancy: a dose-ranging randomized controlled trial.
Efficacy, safety, and acceptability of low-dose mifepristone and self-administered misoprostol for ultra-early medical abortion: a randomized controlled trial.
]. One trial predominantly used ultrasound, except for one site where physical examination and history were the first approach, with ultrasound where needed [
]. Only one study evaluated completion of abortion without ultrasound routinely: a negative urine pregnancy test and pelvic exam at day 22 were used to document completion [
A multicentre randomized comparative clinical trial of 200 mg RU486 (mifepristone) single dose followed by either 5 mg 9-methylene PGE(2) gel (meteneprost) or 600 microg oral PGE(1) (misoprostol) for termination of early pregnancy within 28 days of missed menstrual period.
We calculated a pooled proportion of the randomized trials to estimate proportion of unsuccessful abortions. This resulted in an estimate for unsuccessful abortion of 0.02 (95% CI 0.01–0.03) (Fig. 1). This estimate excludes the Chawdhary et al. study, which could not be included in the calculation given that it reported no unsuccessful abortions [
Mifepristone plus vaginal misoprostol vs vaginal misoprostol alone for medical abortion in gestation 63 days or less in Nepalese women: a quasi-randomized controlled trial.
A multicentre randomized comparative clinical trial of 200 mg RU486 (mifepristone) single dose followed by either 5 mg 9-methylene PGE(2) gel (meteneprost) or 600 microg oral PGE(1) (misoprostol) for termination of early pregnancy within 28 days of missed menstrual period.
]. This fair-quality study utilized a different method of outcome assessment than the other studies: successful abortion was defined by both a negative pregnancy test and pelvic exam confirming the uterus had returned to nonpregnant size on exam by day 22. As the remaining included trials had estimates with a narrow confidence interval (CI) ranging from 0.01 to 0.02, the outcome assessment criteria used are a possible explanation for this outlier in the efficacy outcome.
Fig. 1Meta-analysis of proportions of unsuccessful medical abortions in randomized controlled trials including gestational ages <42 days.
Safety, efficacy, and acceptability of medical abortion in China, Cuba, and India: a comparative trial of mifepristone-misoprostol versus surgical abortion.
]. Quality of the identified studies ranged from poor to good. Mifepristone doses ranged from 50 to 600 mg with the majority of studies using a 200-mg dose. Misoprostol dosing ranged from 400 to 800 mcg, and the oral, vaginal and buccal routes were all included. As noted with the randomized trials, differences existed in how studies determined pregnancy on study enrollment. The majority relied on transvaginal ultrasonography to document pregnancy location and gestational age. Three studies indicated that while transvaginal ultrasound was routinely performed, it was not mandatory for inclusion [
Safety, efficacy, and acceptability of medical abortion in China, Cuba, and India: a comparative trial of mifepristone-misoprostol versus surgical abortion.
Ultrasonography was the most common technique used for confirming complete abortion. The largest study directly observed passage of products of conception, as women remained in-clinic following misoprostol [
]. Range of days to assess outcome was 1 week to 36 days or next menses.
The proportion of unsuccessful abortion in the prospective studies ranged between 0.02 and 0.17. A pooled proportion of these data result in an estimate of 0.04 (95% CI 0.03–0.06) with considerable heterogeneity (Fig. 2). The two largest studies, each with more than 500 women, reported estimates similar to that of the randomized controlled trials in the range of 0.02–0.03 [
The heterogeneity of the prospective observational data, due at least in part to the differing study designs with variable measures of outcome assessment, reasons for surgical intervention and length of follow-up, threatens the validity of the pooled proportion estimate. For insight into whether a different analysis of pooled data might be more informative and increase validity, we conducted a summary OR for the primary outcome compared with the gestational age week of 43–49 days to mitigate some heterogeneity between studies by providing a comparison of outcome estimates within each study (Fig. 3). These data include four of the randomized controlled trials, which provided data by the two gestational age ranges [
A multicentre randomized comparative clinical trial of 200 mg RU486 (mifepristone) single dose followed by either 5 mg 9-methylene PGE(2) gel (meteneprost) or 600 microg oral PGE(1) (misoprostol) for termination of early pregnancy within 28 days of missed menstrual period.
Mifepristone plus vaginal misoprostol vs vaginal misoprostol alone for medical abortion in gestation 63 days or less in Nepalese women: a quasi-randomized controlled trial.
]. The summary OR for the randomized controlled trials was 0.51 (0.21–1.27), and that for the prospective observational studies was 0.90 (0.60–1.33), although substantial heterogeneity remained. This analysis indicates that the odds of unsuccessful abortion were not significantly different between gestational age groups (<42 days versus >42–49 days) and, if anything, were somewhat less likely among pregnancies <42 days.
Fig. 3Summary odds ratio of unsuccessful medical abortion <42 days’ gestation versus 43–49 days’ gestation.
Our results demonstrate that mifepristone and misoprostol are effective for early medical abortion (<42 days’ gestation), and support the practice of advising women that use of medical abortion at the time of the diagnosis of unwanted pregnancy is safe and effective. When medical abortion is desired, requiring women to wait to reach a specific gestational age, development stage or until a gestational sac is visualized on ultrasound introduces an unnecessary barrier to abortion. The data in this report refute previous findings that suggest an increase in failure rates before 7 weeks’ gestation, possibly due to progesterone levels being too low for a maximal response to mifepristone [
Although the randomized controlled trials were not randomized based on gestational age, they were generally of good quality — indicating rigorous conduct — and demonstrated consistent results. Findings from observational studies of good quality, including those reviewed by the FDA for the regulatory approval of mifepristone, reported abortion success concordant with the results in the randomized trials. Substantial variation was noted in smaller observational studies that were generally of fair to poor quality.
Data reported here reflect those of studies where recruited women were confirmed to be pregnant. The possibility of administering mifepristone and misoprostol proactively, meaning before menses is missed, was recently explored in a study from China [
Effectiveness and safety of lower doses of mifepristone combined with misoprostol for the termination of ultra-early pregnancy: a dose-ranging randomized controlled trial.
]. The Chinese investigators administered mifepristone (50-mg dose) and misoprostol the day prior to expected menses for women not on contraception and not desiring pregnancy. Of 678 women who followed the regimen, 158 were found to be pregnant by hCG which was analyzed retrospectively. Success was high among those found to be pregnant, with only 2 (1.5%) having ongoing pregnancies.
Interpretation of the findings in this review should recognize the limitations of the data presented. Studies varied in many design elements, particularly in assessment and timing of the outcome of abortion, which makes comparing outcomes challenging. Inclusion criteria ranged across the studies from history of amenorrhea to transvaginal ultrasound. A wide range of doses and routes of misoprostol was also used, which may affect observed abortion success. Although a dose of mifepristone 200 mg was most commonly used among included studies, early ones used the original 600-mg dose and two Chinese studies used doses lower than 200 mg, which may also affect medical abortion success. Our main outcome, efficacy, as measured by complete abortion, was evaluated differently across studies. While most studies relied upon diagnostic ultrasound, completion was assessed at a wide range of time points. No single study was either randomized or powered to assess differences in complete abortion rates between pregnancies <42 days with other gestational ages. A comparison including pregnancies <35 days would be more informative of successful use at the time of missed menses; however, too few data exist to make a meaningful comparison, and even fewer exist for further parsing by gestational week.
The distinction between the comparison groups may be advantageous to the interpretation of these data. Some studies included pregnancies of 42 days’ gestation in a ≤42-day group, and others included them in a 42–49-day group. This may have resulted in some misclassification bias at 42 days’ gestation; however, the majority of subjects (82%) in the lower gestational age group were ≤35 days. Therefore, it is unlikely that subjects very close to the gestational age cutoff significantly influenced the outcome for either category.
Awaiting for visualization of a gestational sac on ultrasound before administration of early medical abortion has been a standard in many settings due to the concern for undiagnosed ectopic pregnancy, although WHO guidelines have not necessitated it [
]. As most studies in this review utilized transvaginal ultrasound for inclusion and excluded those with ectopic pregnancy, we were unable to assess ectopic rates in this analysis. However, the three studies that enrolled subjects without a visualized gestational sac reported few ectopic pregnancies [
Effectiveness and safety of lower doses of mifepristone combined with misoprostol for the termination of ultra-early pregnancy: a dose-ranging randomized controlled trial.
Efficacy, safety, and acceptability of low-dose mifepristone and self-administered misoprostol for ultra-early medical abortion: a randomized controlled trial.
]. When no gestational sac was present, the protocol for all three studies was to collect serial, serum hCG levels to confirm abortion completion. Initial serum hCG levels above the discriminatory zone or failure to decline precipitously was an indication to proceed with evaluation for ectopic pregnancy. No studies reported the relative success of medical abortion between those without a visualized gestational sac and those with a visualized sac <42 days’ gestation.
Li et al. reported no ectopic pregnancies in a cohort of 2500 asymptomatic women enrolled with estimated gestational age of ≤35 days in one study [
Effectiveness and safety of lower doses of mifepristone combined with misoprostol for the termination of ultra-early pregnancy: a dose-ranging randomized controlled trial.
Efficacy, safety, and acceptability of low-dose mifepristone and self-administered misoprostol for ultra-early medical abortion: a randomized controlled trial.
]. When the two Li et al. studies are considered together, an estimated 1021 subjects underwent medical abortion with no visible gestational sac on transvaginal ultrasonography in a cohort with 98% follow-up. Schaff et al. reported confirmed ectopic pregnancy in 2 of 30 subjects and ongoing pregnancy of unknown location in a third, who underwent management with methotrexate [
]. This study enrolled subjects without an upper limit of estimated gestational age, but mean age was 40±9 days. One ectopic pregnancy was identified with initial hCG above the discriminatory zone (16,922 at 39 days amenorrhea) and the other with significant hCG rise following the abortion. The low proportion of ectopic pregnancy in the included studies is likely due to the criteria used for enrollment, including asymptomatic exam, and the low overall prevalence in the population of women seeking early abortion.
Despite variations between design and reporting in the included studies, this analysis supports the use of medical abortion at gestational ages <42 days. Efficacy rates are high overall and appear to reflect those observed during the seventh week of pregnancy. For women preferring to initiate treatment as soon as the diagnosis of early pregnancy is made, delaying care is not indicated. Further research is needed to substantiate that this regimen would be as effective if used at the time of missed menses and to determine the appropriate clinical protocol for this scenario.
References
Rodriguez M.I.
Seuc A.
Kapp N.
von Hertzen H.
Huong N.T.
Wojdyla D.
et al.
Acceptability of misoprostol-only medical termination of pregnancy compared with vacuum aspiration: an international, multicentre trial.
Safety, efficacy, and acceptability of medical abortion in China, Cuba, and India: a comparative trial of mifepristone-misoprostol versus surgical abortion.
Global, regional, and national levels and trends in maternal mortality between 1990 and 2015, with scenario-based projections to 2030: a systematic analysis by the UN maternal mortality estimation inter-agency group.
A multicentre randomized comparative clinical trial of 200 mg RU486 (mifepristone) single dose followed by either 5 mg 9-methylene PGE(2) gel (meteneprost) or 600 microg oral PGE(1) (misoprostol) for termination of early pregnancy within 28 days of missed menstrual period.
Mifepristone plus vaginal misoprostol vs vaginal misoprostol alone for medical abortion in gestation 63 days or less in Nepalese women: a quasi-randomized controlled trial.
Effectiveness and safety of lower doses of mifepristone combined with misoprostol for the termination of ultra-early pregnancy: a dose-ranging randomized controlled trial.
Efficacy, safety, and acceptability of low-dose mifepristone and self-administered misoprostol for ultra-early medical abortion: a randomized controlled trial.
A prospective randomized, double-blinded, placebo-controlled trial comparing mifepristone and vaginal misoprostol to vaginal misoprostol alone for elective termination of early pregnancy.
A prospective, randomized, placebo-controlled trial on the use of mifepristone with sublingual or vaginal misoprostol for medical abortions of less than 9 weeks gestation.
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