Medical termination for pregnancy in early first trimester (≤ 63 days): a systematic review

Background A wide range of drugs have been studied for first trimester medical abortion. Studies evaluating different regimens, including combination mifepristone and misoprostol and misoprostol alone regimens, show varying results related to safety, efficacy and other outcomes. Objectives To compare the safety, effectiveness and acceptability of medical abortion and to compare medical methods with surgical methods of abortion ≤ 63 days of gestation. Methods Pubmed and EMBASE were systematically searched from inception through January 2019 using a combination of MeSH, keywords and text words. Randomized controlled trials on induced abortion at ≤ 63 days that compared different regimens of medical abortion using mifepristone and/or misoprostol and trials that compared medical with surgical methods of abortion were included. We extracted data into a pre‐designed form, calculated effect estimates, and performed meta‐analyses where possible. The primary outcomes were ongoing pregnancy and successful abortion. Results Combined regimens using mifepristone and misoprostol had lower rates of ongoing pregnancy and higher rates of successful abortion compared to misoprostol only regimen. Conclusion In this systematic review, we establish medical methods of abortion utilizing combination mifepristone/misoprostol or misoprostol alone are effective, safe and acceptable. In combined regimen, misoprostol 800 μg given vaginally or sublingually had lower rates of ongoing pregnancy and higher rates of successful abortion with moderate certainty of evidence.


Abstract
Background A wide range of drugs have been studied for first trimester medical abortion.
Studies evaluating different regimens, including combination mifepristone and misoprostol and misoprostol alone regimens, show varying results related to safety, efficacy and other outcomes. Objectives To compare the safety, effectiveness and acceptability of medical abortion and to compare medical methods with surgical methods of abortion ≤ 63 days of gestation.
Methods Pubmed and EMBASE were systematically searched from inception through January 2019 using a combination of MeSH, keywords and text words. Randomized controlled trials on induced abortion at ≤ 63 days that compared different regimens of medical abortion using mifepristone and/or misoprostol and trials that compared medical with surgical methods of abortion were included. We extracted data into a pre-designed form, calculated effect estimates, and performed meta-analyses where possible. The primary outcomes were ongoing pregnancy and successful abortion.
Results Combined regimens using mifepristone and misoprostol had lower rates of ongoing pregnancy and higher rates of successful abortion compared to misoprostol only regimen.
Conclusion In this systematic review, we establish medical methods of abortion utilizing combination mifepristone/misoprostol or misoprostol alone are effective, safe and acceptable. In combined regimen, misoprostol 800 μg given vaginally or sublingually had lower rates of ongoing pregnancy and higher rates of successful abortion with moderate certainty of evidence.

Background
Medical methods emerged as an alternative to surgical abortion with the discovery of prostaglandins in the early 1970s [1,2,3]. Their use has evolved in the last two decades and various drugs have been used for first trimester medical abortion. Several studies have explored utilization of mifepristone, methotrexate and various prostaglandins with different doses, routes and intervals of administration [4]. A Cochrane review compared the different medical methods for first trimester abortion in 2011 and since that time, there has been growing evidence assessing effectiveness and safety of the medical methods, in particular with the combination regimen (mifepristone and misoprostol) and misoprostol alone [5].
However, individual studies evaluating medical management of abortion at ≤63 days have not demonstrated superiority of one regimen. Specifically, studies have looked at different routes and doses of misoprostol in combined regimens [6,7], as well comparing different intervals between mifepristone and misoprostol [8][9][10].
The 2012 World Health Organization (WHO) safe abortion guideline had varying regimens for induced abortion at < 12 weeks. With the emergence of new evidence, this systematic review was done as part of the evidence synthesis for the WHO guidance on medical abortion. Thus, the objectives of this review were to compare the effectiveness, safety and acceptability of different regimens of medical abortion containing mifepristone and misoprostol and to compare medical with surgical methods of abortion at ≤63 days of gestational age.

Search strategy
We searched Pubmed and EMBASE for randomized controlled trials on induced abortion at ≤ 63 days. Our search was from inception through January 2019 using a combination of MeSH, keywords and text words. (Additional file 1) Selection criteria Inclusion criteria included randomized controlled trials (RCTs) that compared different medication regimens for induced abortion at ≤ 63 days using mifepristone and/or misoprostol; different frequencies of administration of misoprostol in combination regimens; different doses and dosing intervals of misoprostol in combination regimens; different routes of misoprostol in combination regimens; and different dosing regimens and routes in misoprostol only regimens. We also included trials that compared surgical abortion with medical abortion using combination or misoprostol alone regimens. We excluded studies that included induced abortion > 63 days, missed abortion, miscarriage, fetal demise and those that did not report on the primary outcomes. We also excluded studies comparing medical regimens beyond mifepristone and/or misoprostol, such as those using methotrexate, gemeprost, as well as studies that compared various mifepristone dosages beyond the WHO recommended 200mg dose.
All search results (titles, abstracts and when necessary, full articles) were screened independently by two authors (FAA and CK) using the Covidence tool [11]. Any discrepancies between the reviewers were reviewed by a third author (MIR) and resolved by consensus.

Data collection and Analysis
Data extraction was performed using a standardized data-abstraction form. Two authors (FAA and CK) independently performed the data extraction and assessed risk of bias.
Disagreements were resolved by discussion with the third author (MIR).
The primary outcomes were ongoing pregnancy and successful abortion (defined as uterine evacuation without need for surgical intervention). Secondary outcomes were: safety (defined as serious adverse events and complications; such as hospitalization; blood transfusion; need for further surgery beyond interventions to complete removal of products; or death), expulsion time from initiation of treatment, side effects (including bleeding; pain; and vomiting) and satisfaction.
For dichotomous data (e.g., complete abortion rate), we used the number of events in the control and intervention groups of each study to calculate Risk Ratios (RRs) with 95% confidence intervals for our primary outcome, and secondary outcomes as available.
We used GRADEpro software and Cochrane methods to evaluate the overall quality of the body of evidence for the main review outcomes. We relied on GRADE criteria (e.g., risk of bias, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of the evidence. The Cochrane Risk of Bias Assessment tool was used to assess risk of bias across studies [12]. We specifically assessed: 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 biases. Studies were ranked as low risk, high risk, or unclear risk using the criteria outlined by the Cochrane Handbook for Systematic Review of Intervention [9]. Two review authors (FAA and CK) worked independently to judge the evidence quality (e.g., high, moderate, low, or very low) and risk of bias. Any disagreements were arbitrated by a third author (MIR) and resolved by discussion.

Results
The initial search yielded 1,506 articles of which 33 articles fit our inclusion criteria.
Studies included for this review were conducted across 19 countries. Using the World Bank's 2018 classification of economies, the articles represent data from six high income economies, six upper-middle income economies, six lower-middle income economies and one low income economy [13]. The year of publication ranged from 1994 to 2017. The characteristics of the included studies are shown in Table 1.
Approximately 85% of the included studies had a low risk of selection bias based on random sequence generation and 78% had a high risk of performance bias (Additional file 2).

Medical regimens
Different regimens of medical abortion management containing combination mifepristone/misoprostol, or misoprostol alone were reviewed. Six studies compared combined mifepristone/misoprostol vs. misoprostol alone, 6 studies compared different doses of misoprostol in combined regimens, 8 studies compared the timing interval between mifepristone and misoprostol in combined regimens, 13 compared routes of misoprostol in combined regimens, 2 compared various misoprostol alone regimens and 1 study compared medical with suction evacuation.

1.
Combination mifepristone/misoprostol compared with misoprostol alone [14,15,16] Women treated with a combined regimen had lower rates of ongoing pregnancy (RR 0.16 CI 95% 0.08-0.31, low certainty of evidence) and higher rates of successful abortion (RR Women treated with 400 μg oral misoprostol had lower rates of ongoing pregnancy (RR 0.33 CI 95% 0.01-8.10) and higher rates of successful abortion (RR 1.01 CI 95% 0.91-1.13). More women treated with 400 μg oral misoprostol were satisfied with their regimen.
The certainty of evidence is low for the reported outcomes. (Table S2F, Additional file 3).

Comparison of dosing intervals between mifepristone and misoprostol in combined regimen
Eight studies assessed different time intervals between mifepristone and misoprostol dosing in the combined regimen. These include comparisons between < 8 hours vs. > 24 hours [8,9] [8,9] Women who took misoprostol < 8hours after mifepristone had higher rates of ongoing pregnancy (RR 2.23 CI 95% 0.69-7.2) and lower rates of successful abortion (RR 0.98 CI 95% 0.91-1.06). The certainty of evidence is moderate for both outcomes. (Table S3A) Women treated with misoprostol < 8 hours after mifepristone had lower rates of successful abortion (RR 0.91 CI 95% 0.66-1.25). There was no difference in the rate of ongoing pregnancy between the two groups. The certainty of evidence is very low for the reported outcomes. (Table S3D, Additional file 3).

Comparisons of misoprostol routes in combined mifepristone-misoprostol regimen
Thirteen studies assessed different routes of misoprostol in combined regimen (Table S6) The same study also compared oral misoprostol 400 μg every 3 hours for 4 doses to oral misoprostol 800 μg every 6 hours twice. Women treated with oral misoprostol 400 μg had higher rates of ongoing pregnancy (RR 1.75 CI 95% 0.62-4.90) and lower rates of successful abortion (RR 0.84 CI 95% 0.44-1.59). In addition, more women using 800 μg found the regimen acceptable compared to women treated with oral misoprostol 400 μg.
The certainty of evidence is very low for the reported outcomes (Table S5C, Additional file 3).

Comparisons of medical versus surgical management [38]
One study compared surgical management with medical management using a single dose of 800 μg vaginal misoprostol. There was no difference in the rates of ongoing pregnancy.
More women who were managed with misoprostol had successful abortion compared to women who were managed with the surgical method (RR

Discussion
In this review we identified 33 trials conducted across different settings with a total of 22,275 participants. The results indicate that medical methods are effective, safe and acceptable for termination of pregnancy for ≤63 days of gestation. We used satisfaction, which was reported in 25 of the included studies, as a proxy indicator of acceptability.
A combined regimen of mifepristone and misoprostol was found to be more effective in terms of lower rates of ongoing pregnancy and higher rates of successful abortion compared to the misoprostol alone regimen.
There have been multiple studies that focus on the combination regimen, comparing various misoprostol doses and routes and the interval between mifepristone and misoprostol. From the studies that compared different doses of misoprostol in combined mifepristone/misoprostol regimen, the use of 800 μg of misoprostol in the combined regimen had lower rates of ongoing pregnancy and higher rates of successful abortion based on moderate certainty of evidence. Regimens including 800 μg were also associated with higher satisfaction rates. In one study that compared 400 μg versus 800 μg buccal misoprostol [6], treatment with 400 μg misoprostol showed lower rates of ongoing pregnancy and higher rates of successful abortion. However, a higher satisfaction rate was noted in the 800 μg arm. In addition, women treated with single dose 800 μg misoprostol group had lower rates of bleeding and pain compared to those treated with 400 μg administered twice 2 hours apart [18,19].
Of the studies that compared the interval timing between mifepristone and misoprostol, a Thus, further study is needed to assess the impact of dosing interval on this outcome and how it relates to the acceptability of the procedure to women.
Though vaginal and sublingual routes of misoprostol in combined regimen were more effective in terms of ongoing pregnancy and success, oral administration was found to have lower rates of serious adverse events and higher satisfaction compared to vaginal route. Thus, woman should be given the full range options factoring in their satisfaction towards a particular treatment regimen.

Strengths and limitations
This review has several strengths. We used a comprehensive and replicable search strategy to identify relevant articles. In addition, the included studies were conducted across different settings. We employed the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) system that can assist health care providers, program managers and policy makers to design and implement best practice recommendation and guidelines.
Limitations of this review include the inclusion of only RCTs and using satisfaction as a proxy for acceptability. Specifically, inclusion of observational studies could be more informative about client satisfaction and acceptability of treatment regimens.
Furthermore, for some of the comparisons arms (medical vs. surgical, misoprostol only regimens), there are a limited number of studies. Furthermore, some of the included studies have a high risk of performance bias and detection bias. Thus, we recommend future researches to consider blinding of outcome assessor as it is feasible to blind the individual who is assessing the success of the abortion (whether by history, physical exam or ultrasound) and this in turn can improve the quality of data.

Conclusion
In this systematic review, we establish that medical methods of abortion are effective, safe and acceptable. Specifically, a combined regimen of mifepristone and misoprostol containing 800 μg of misoprostol given 24 hours after mifepristone either vaginally or sublingually was found to be an effective, safe and acceptable method for termination of Availability of data and materials The datasets supporting the conclusions of this article are included within the article and its additional files.

Competing interests
The authors declare that they have no competing interests.