Misoprostol At 1 Weeks Pregnancy

In this systematic review, we find that medical methods of abortion utilizing combination mifepristone and misoprostol or misoprostol alone are both safe and effective for early pregnancy termination. Misoprostol can be administered at home by women themselves, which may have a beneficial effect on reducing the cost, pain and anxiety associated with surgical abortion procedures.

In this review, we find that medical methods of abortion utilizing combination mifepristone and misoprostol or misoprostol alone are more effective than placebo regarding termination of pregnancy. However, they have side effects such as nausea and vomiting. We recommend that clinicians recommend oral analgesic treatment during and after the process of the abortion when patients exhibit such symptoms.

In the study, the authors found that medical methods of abortion utilizing combination mifepristone and misoprostol or misoprostol alone are equally effective at ending pregnancy. They also note that surgical procedures such as dilation and curettage (D&C) have higher levels of side effects.

This study reviews the evidence on medical methods of abortion utilizing combination mifepristone and misoprostol or misoprostol alone, including how they should be used and how effective they are in comparison with surgical abortion.

Our objective was to examine the efficacy, effectiveness, and safety of medical methods of abortion utilizing combination mifepristone and misoprostol (MM) or misoprostol alone as compared with surgical abortion in a clinical setting.

Can Misoprostol Be Used Alone Without Mifepristone

To summarize available data on the effectiveness and safety of single-agent misoprostol for medical abortion in the first trimester.

Data Sources:

We searched Medline, CABI, Cochrane, EMBASE, LILACS, and the Web of Science, and ClinicalTrials.gov for English language studies that evaluated misoprostol alone for abortion of viable pregnancy in the first trimester.

Methods of Study Selection:

Our search yielded 1562 citations, of which 38 included data from 53 trial groups that met our inclusion and exclusion criteria.

Tabulation, Integration, and Results:

We abstracted data about each trial group, including study characteristics, treatment regimen, clinical protocol, number of women treated and followed, and numbers with outcomes of interest. We used meta-analytic methods and logistic regression to examine factors associated with surgical intervention after treatment. Among all 12,829 evaluable women, 2536 (meta-analytic estimate 22.0%, 95% CI 18.8%, 25.5%) had surgical uterine evacuation. Multiple factors were significantly associated with this proportion, including misoprostol amount per dose and route of administration, loss to follow-up rate, publication date, geographic region, number of misoprostol doses, duration of dosing, and time between dosing and evaluation. Of 6359 evaluable women, 384 (meta-analytic estimate 6.8%, 95% CI 5.3%, 8.5%) had ongoing pregnancy. At most 26 of 12,184 evaluable women (meta-analytic estimate 0.7%, 95% CI 0.4%, 1.0%)were transfused or hospitalized for abortion-related reasons. In trials that provided satisfaction data, most of women were satisfied or very satisfied with the treatment (meta-analytic estimate 78%, 95% CI 71%, 85%).

Conclusions:

Misoprostol alone is effective and safe and is a reasonable option for women seeking abortion in the first trimester. Research is indicated to further refine the regimen and to establish efficacy in the late first trimester.

Systematic Review Registration:

PRECIS

Treatment regimens that contain only misoprostol can be effective and safe for first-trimester medical abortion.

INTRODUCTION

For early medical abortion, the primary regimens recommended by current clinical guidelines include two drugs: mifepristone and misoprostol. Because mifepristone potentiates the abortifacient action of misoprostol, the combination is highly effective, resulting in complete abortion in more than 95% of women through 63 days of gestation1,2 and 93% between 64 and 70 days.2,3 However, mifepristone is costly and is unavailable in many settings. In the United States, although the drug is approved for marketing, the Food and Drug Administration has imposed restrictions on its distribution that substantially limit both patients’ and providers’ access to it.4 For women who cannot obtain mifepristone, use of misoprostol alone, which is inexpensive and is widely used for various obstetric and gastrointestinal indications, can serve as an important alternative option. A systematic review published in 2007 found that the efficacy of misoprostol single-agent regimens at gestational ages ≤63 days ranged from 84% to 96%,5 but since then, additional studies have been published. We performed this systematic review to summarize available data on the effectiveness and safety of medical abortion with misoprostol alone in the first trimester of pregnancy. The primary outcome of our analysis was surgical evacuation of the uterus to complete the abortion; secondary outcomes were viable ongoing pregnancy after taking the prescribed misoprostol regimen, transfusions and hospitalizations.

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SOURCES

We registered our systematic review protocol on PROSPERO (CRD42018083589) before beginning data collection and followed MOOSE guidelines6 in reporting the results. With the assistance of a librarian, we searched six databases (Medline, CABI, Cochrane, EMBASE, LILACS, and the Web of Science,) on November 17, 2017, and ClinicalTrials.gov on June 20 2018, for English language studies that evaluated misoprostol alone for medical abortion of a known or presumed viable pregnancy in the first trimester. We did not exclude studies based on study design, date, or any other criteria. Our search strategy for Medline is indicated in Box 1.

Box 1. Search strategy for Medline

(Early trimester OR less than ten weeks OR early pregnancy OR first trimester OR less than thirteen weeks) AND (Medical abortion OR medical termination OR oral medication abortion OR oral medication termination OR non-surgical abortion OR non-surgical termination OR elective abortion OR termination of pregnancy OR induced abortion OR induced termination of pregnancy) AND (misoprostol OR cytotec) AND (single agent OR single-agent OR alone OR only).

Search strategies for other databases were substantively similar. In addition, we reviewed the reference lists of relevant articles, and we contacted experts in the field for information about any published or unpublished trials not discovered in our search.

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STUDY SELECTION

Two authors (MH and EGR) separately reviewed the title, abstract, and full text if necessary of each paper identified by the search to select all language reports of studies that included women with viable pregnancies who were treated in the first trimester (91 days or less) with misoprostol alone to cause abortion. The same two authors then reviewed each selected study together and systematically abstracted relevant data about these women into a custom database. We excluded women who received abortifacient drugs other than misoprostol, women who were treated in the second trimester, women who had missed abortions or non-viable pregnancies before treatment, and women who did not take any misoprostol after study enrollment. Some studies evaluated more than one misoprostol regimen; in our abstraction process, we recorded data about women who received each regimen in each study as a separate trial group.

The primary data abstracted included the number of women treated with the misoprostol regimen in each group, details of the misoprostol regimen (specifically, the number of misoprostol doses provided, the amount of misoprostol in each dose and route of administration, and the intervals between doses), abortion outcomes (specifically, whether surgical evacuation of the uterus was performed and whether the patient had a viable ongoing pregnancy at the time of surgery), the numbers of reported hospitalizations and transfusions, and information about patient satisfaction. We also recorded data about specified factors that we postulated could cause heterogeneity or bias in assessment of efficacy and safety, including information about the trial design, conduct, and publication, the maximum gestational age and other inclusion criteria, location of misoprostol administration (facility or home), follow-up rates, and timing and method of outcome assessment. We contacted some authors to obtain additional data or to clarify details about the studies. We used our judgment to interpret certain details in some reports and to correct apparent errors and inconsistencies.

We combined data across groups to estimate the proportion of patients who had surgical evacuation of the uterus to complete the abortion and viable ongoing pregnancy using meta-analytic methods, conducted in R, version 3.5.0, with the “metafor” package, version 2.0.7,8 We applied the Freeman-Tukey double arcsine transformation, and we report p-values from the chi-square test of heterogeneity and associated I2 statistic. We calculated estimates and 95% confidence intervals using the DerSimonian-Laird random-effects model.

To explore possible explanations for heterogeneity among trial groups in the proportions who had surgery, we examined associations between this outcome and selected characteristics of the trial groups. Many of these characteristics were highly correlated across trial groups, with numerous zero cells in cross-classifications. Therefore, we opted to present only unadjusted results. We used generalized estimating equations with a logistic link and an independence working correlation matrix to control for nesting of trial groups within paper. The response for the models was the ratio of the number of surgeries to the number of evaluable patients for each trial group (conducted in SAS, version 9.4, SAS Institute, Cary, NC, USA); thus model results were weighted by trial group sample size. We included all trial groups in our examination of misoprostol amount per dose and route of administration. We restricted our examination of other factors to groups treated with an initial dose of 800 mcg misoprostol administered vaginally, the most common combination, because most characteristics did not vary across groups treated with other dose-route combinations. We categorized each characteristic considering both clinical interest and the distribution of the data, and we estimated odds ratios and 95% confidence intervals. We tested for linear trends using linear contrasts of model parameters. We made no adjustment for multiple comparisons. In reviewing the results, we focused on associations that were both substantial (odds ratio>1.5 or <0.67) and significant (p<0.05).

To further evaluate the association between number of misoprostol doses and efficacy, we estimated the proportion of women reported to have had complete abortion after taking only the doses required for all women in that trial group before any doses that were contingent on abortion status. This analysis included only those trial groups that reported these data. We estimated unadjusted odds ratios with confidence intervals and tested for linear trend as described above for amount of misoprostol in the initial dose.

We assessed safety by computing the proportion of women across all trial groups who were reported to have been hospitalized or receive transfusions after treatment. We did not abstract data on non-serious side effects because ascertainment and reporting was not standardized across studies.

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RESULTS

Our search yielded 1562 unique citations, of which 37 reported at least one group of women who were treated with misoprostol alone for abortion of viable pregnancy at ≤91 days of gestation945 and one additional group in which the maximum gestational age was 98 days46 (Figure 1). We included the last of these because most of the women in the study were ≤91 days; the mean gestational age was 64 days. We also identified one additional study (ClinicalTrials.gov Identifier: NCT02299401) that has to date been published only as an abstract, but the authors declined to provide final data for this review because of concern about jeopardizing the planned primary publication.

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Figure 1.

Study selection flow diagram.

The 38 papers included 42 studies conducted in at least 16 countries over at least the past 24 years (Appendix 1, available online at http://links.lww.com/xxx). Of these studies, 21 were non-comparative case series studies, 7 were randomized trials or cohort studies comparing different misoprostol-only regimens, and 14 were randomized trials or cohort studies comparing misoprostol-only regimens to other abortion treatments (aspiration, methotrexate, or misoprostol combined with mifepristone, methotrexate, tamoxifen, letrozole, or laminaria).

The 42 studies included 53 trial groups of women treated with misoprostol alone (Table 1). The total number of treated subjects in all groups combined was 13,573. The two largest groups, both retrospective case series in anonymous Latin American countries where abortion was legally restricted, constituted 44% of this total.9,10 Over all groups, 744 women (5%) were lost before abortion outcome was ascertained. The proportion lost was 0–7% in 51 groups; the proportions in the other two groups, which were the two largest, were 10% and 13%. Our analysis included 12,829 evaluable women across all trial groups.

Table 1.

Characteristics of studies

Trial groups
N=53
Evaluable women
N=12829
n%n%
Number of treated women per group
 3–1002751%124710%
 101–5001936%347227%
 501–72059%276622%
 2805–322524%534442%
Lost to follow-up
 None3974%448435%
 ≤10%1223%300123%
 >10%24%534442%
Publication date
 1994–19991426%160913%
 2000–20041426%509340%
 2005–20091834%523741%
 2010-present713%8907%
Study design
 randomized trial2343%331526%
 non-randomized prospective2445%352727%
 non-randomized retrospective611%598747%
Region
 Latin or South America1121%766460%
 North America1121%10238%
 Asia1732%9808%
 other or multiple1426%316225%
Planned maximum gestational age
 42–56 days1936%417333%
 57–63 days1732%456336%
 64–70 days713%324725%
 ≥71 days1019%8467%
First misoprostol dose and route
 200 mcg vaginal24%1111%
 400 mcg vaginal48%1601%
 600 mcg vaginal12%891%
 800 mcg vaginal3158%1001078%
 800 mcg buccal36%5845%
 800 mcg sublingual24%10218%
 800 mcg oral48%1191%
 1000 mcg vaginal12%3002%
 400 mcg vaginal + 400 mcg sublingual12%1491%
 400 mcg vaginal + 400 mcg oral12%50%
 800 mcg vaginal + 400 mcg buccal12%981%
 800 mcg vaginal + 400 mcg sublingual12%761%
 800 mcg oral + 400 mcg sublingual12%1071%
Misoprostol moistened before vaginal administration*
 no or not stated2047%654359%
 Yes2353%445541%
Number of required doses
 13464%359828%
 2713%337426%
 3917%565144%
 424%1861%
 512%200%
Duration of required dosing
 0 (only 1 required dose)3464%359828%
 1–24h1630%625149%
 25–48h12%290023%
 73h-7d24%801%
Total number of allowed doses
 159%3303%
 21121%306924%
 32547%805963%
 459%4584%
 512%200%
 6611%8937%
Maximum duration of dosing if all allowed contingent doses were taken
 0 (only 1 dose allowed)59%3303%
 1–24h1936%499539%
 25–48h1325%568244%
 49–72h48%2692%
 73h-7d917%11559%
 >7d36%3983%
Protocol permitted patient to take misoprostol at home
 all917%518840%
 some1528%548343%
 none2955%215817%
Evaluated by ultrasound prior to decision to perform surgery
 all patients4687%1019979%
 some or no patients713%263021%
Earliest timing of decision re. surgery
 ≤24h24%1281%
 25–48h713%4383%
 49–72h1223%468537%
 73h-7d1630%186415%
 >7d1630%571445%

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aDenominator for percents include only trial groups and evaluable women who took the first dose by the vaginal route.

The admission criteria for all studies were broad: in general, any woman requesting medical abortion who had no medical contraindication to the abortifacient drug treatment and whose gestational age was less than a specified maximum (42–98 days) was eligible. In 48 groups, which included 95% of evaluable women, gestational age was routinely determined by ultrasound. One study included only women aged ≤17 years,43 one included only women with ≥2 prior cesarean deliveries,26 and one included only women with gestational ages of 64–84 days.18

The 53 groups used a multitude of misoprostol regimens. In all groups, women were required to take a specified minimum number (1 to 5) of doses of misoprostol vaginally, buccally, orally, sublingually, or by a combination of routes (Table 1). In all but 4 groups,13,14,21 the initial dose was 800 mcg or was administered vaginally; the combination 800 mcg vaginally was used in 31 groups that collectively included 10,010 (78%) of the evaluable women. Misoprostol was moistened before vaginal insertion in 41% of evaluable women who took the drug by that route. In 39 of the 48 groups in which more than one dose was allowed, subsequent doses used the same amount per dose and route of misoprostol as the first dose. Multiple doses were administered 3–48 hours apart, such that the longest duration of the required treatment was 96 hours. In 35 groups (38% of evaluable women), if complete abortion had not occurred after the required doses, women were instructed to take additional contingent doses up to a specified maximum, after which a decision regarding surgical intervention was made. The maximum total number of allowed doses (required + contingent) in any group was 6, and the maximum duration of dosing if all allowed doses were taken was 14 days. Across all groups, most women were instructed to take no more than 3 doses within a maximum of 48 hours. Nine studies,1824,43,45 7 of which were conducted by the same group of investigators, provided extra misoprostol to some or all women who were determined not to need surgery in order to evacuate “remains” from the uterus or for an unspecified reason, and one study provided a dose of misoprostol to all women who were scheduled for surgery.30 We did not count those extra doses in this analysis because they were given after the outcome had been determined and thus did not contribute to the outcome. In at least 24 groups (83% of evaluable women), women were allowed to take some or all of the misoprostol doses at home.

In 46 groups (79% of evaluable women), all women were assessed with ultrasound before the decision of whether to perform surgery, whereas in 6 groups, ultrasound was used only if clinically indicated, and in one group, abortions were provided by community health workers who apparently rarely used ultrasound.42 The earliest point at which surgical intervention was considered varied from 24 hours to 14 days after the first misoprostol dose. No paper provided explicit criteria for the decision to resort to surgical uterine evacuation, hospitalization or transfusion.

Among all 12,829 evaluable subjects (Table 1), 2,536 (20%) underwent surgical uterine evacuation (meta-analytic estimate 22.0%, 95% CI 18.8%, 25.5%). Across trial groups, the proportion with this outcome ranged from 0 to 77% (Figure 2, Panel A). More than 90% of the evaluable subjects were in trial groups in which the failure proportion was 24% or less.

Misoprostol Side Effects in Future Pregnancy

Pharmacists can play an important role in counseling women who experience early pregnancy loss. It is important for patients to know that routine activities, such as exercise, sexual intercourse, and working, do not cause early pregnancy loss. About 50% of all cases of early pregnancy loss are attributable to fetal chromosomal abnormalities.1

The American College of Obstetricians and Gynecologists (ACOG) defines early pregnancy loss as a nonviable, intrauterine pregnancy with either an empty gestational sac or a gestational sac containing an embryo or fetus without a heartbeat within the first 12 weeks of gestation.1 During the first trimester, the terms “early pregnancy loss,” “miscarriage,” and “spontaneous abortion” are used interchangeably.1 Options for early pregnancy loss include allowing the miscarriage to progress naturally (expectant management), medical treatment, and surgical evacuation.2

Here are 5 things pharmacists should know about misoprostol for early pregnancy loss management:

1. Misoprostol has been studied for early pregnancy loss. Misoprostol, a prostaglandin E1 analogue, reduces the need of suction dilation and curettage (D&C) by up to 60% and shortens the time to completion compared with placebo.1 The addition of mifepristone (progesterone receptor antagonist) to misoprostol has been studied as a treatment for early pregnancy loss. However, there is insufficient evidence to demonstrate that this regimen is superior to misoprostol alone. The ACOG does not recommend the routine use of mifepristone for the treatment of early pregnancy loss.1

2. Vaginal administration of misoprostol is recommended for increased efficacy. The recommended dose of misoprostol is 800 mcgs (4 200-mcg tablets) inserted vaginally.Study results have demonstrated that vaginal administration is more effective than oral use of misoprostol. One dose is about 70% effective, and 2 is about 84% effective.1

3. Patient counseling is important for appropriate administration. Pharmacists should educate patients about the proper administration of the tablets. Administration should take place in the morning or early afternoon. Patients should wash their hands with soap and water and place each tablet one at a time into the vagina as high as possible. Instruct patients to rest for about 30 minutes after inserting the medication.

4. Tell patients that heavy bleeding may occur. Bleeding usually occurs within 4 to 48 hours after misoprostol administration. If bleeding does not occur within 48 hours, then a repeat misoprostol dose should be administered.1 Counsel patients that bleeding is usually heavier than menses and is generally accompanied by severe cramping. It is normal to see the passage of blood clots and tissue. Heavy bleeding and cramping usually last for about 4 hours. Patients should be relaxing during this time and not engaging in strenuous activity. Educate patients about the importance of having a family member or friend stay with them for support. Recommend that patients contact their obstetrician-gynecologist (OB-GYN) if they are soaking 2 maxi pads per hour for 2 consecutive hours.1 Misoprostol adverse effects may include diarrhea and dizziness. Light bleeding may last for about 2 weeks.

Patients may take OTC acetaminophen to help manage the pain or prescription pain medication (eg, acetaminophen with codeine), along with the misoprostol may be used. It is important for patients not to take both OTC and prescription pain medication to avoid exceeding the daily recommended dose of acetaminophen.

Women who are Rh(D) negative should receive Rh(D)-immune globulin within 72 hours of the first misoprostol administration.1

5. Follow-up is important after misoprostol administration. Advise patients to follow up with their OB-GYN within 7 to 14 days for an ultrasound to ensure the complete passage of tissue.If tissue remains, then patients can repeat the misoprostol dose or have a D&C.1

Pharmacists can provide education and support for patients experiencing early pregnancy loss.

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