INTRODUCTION — Medical methods for pregnancy termination are safe, effective, and feasible alternatives to surgical methods (ie, uterine aspiration, dilation and evacuation [D&E]) and expand a patient's treatment options [1].
For patients undergoing medication abortion, combined treatment with mifepristone followed by misoprostol is more effective than treatment with misoprostol alone, and thus is considered the gold standard for medication abortion [2,3]. However, misoprostol-alone regimens may be the treatment of choice in settings in which mifepristone is not available or is too costly. In particular, misoprostol is commonly used as a single agent for second-trimester induced abortion in the United States and many other parts of the world [4,5].
This topic review will discuss use of misoprostol as a single agent for medical termination of pregnancy. Use of mifepristone plus misoprostol, in addition to other medical and surgical approaches to pregnancy termination, and use of misoprostol for pregnancy loss or labor induction are reviewed separately:
●(See "First-trimester pregnancy termination: Medication abortion".)
●(See "Second-trimester pregnancy termination: Induction (medication) termination".)
●(See "Pregnancy loss (miscarriage): Clinical presentations, diagnosis, and initial evaluation".)
●(See "Induction of labor: Techniques for preinduction cervical ripening".)
PREPROCEDURE CONSIDERATIONS
Contraindications — Contraindications to medication abortion with misoprostol alone are similar to those for medication abortion with misoprostol plus mifepristone and are discussed in detail separately. (See "First-trimester pregnancy termination: Medication abortion", section on 'Contraindications' and "Overview of second-trimester pregnancy termination", section on 'Indications and contraindications'.)
Patients with a uterine scar — Presence of a uterine scar is not a contraindication for misoprostol. However, as pregnancy advances, regimens with lower cumulative misoprostol doses (ie, lowest dose, longest dosing interval, lowest number or total doses) [6,7], or a surgical procedure (ie, uterine aspiration, dilation and evacuation [D&E]) may be preferred, especially for patients with a history of multiple cesarean births or other extensive uterine surgery (eg, multiple myomectomies). (See "Overview of pregnancy termination", section on 'How to choose' and "Overview of second-trimester pregnancy termination", section on 'Choosing dilation and evacuation versus induction termination'.)
Although rare, case reports have described uterine rupture during first- and second-trimester pregnancy termination with misoprostol [8-19]. The risk of rupture may increase with increasing gestational age, particularly in the late second trimester [13], and may be higher in patients with classical, T-shaped, or transfundal uterine incisions. However, uterine rupture can also occur in patients without a uterine scar. Other factors associated with uterine rupture include advanced gestational age, high gravidity (≥3 pregnancies) [14,15], uterine anomalies, and use of oxytocin in addition to misoprostol [14,15].
There are no high-quality data regarding the risk of uterine rupture with use of misoprostol for first- or second-trimester pregnancy termination. In a systematic review including 15 studies and 512 pregnant patients receiving misoprostol for induction in the second trimester, the risk of uterine rupture was higher among those with two or more compared with no previous cesarean births (2.5 versus 0.08 percent, relative risk 17.6, 95% CI 3-102.8) [20]. However, data are limited, and risk of rupture remains unquantified because studies often exclude patients with scarred uteri or have low numbers of patients with different types of uterine scars.
Clinical manifestations of uterine rupture following medical termination of pregnancy are variable and include severe and persistent abdominal pain, hypotension (ranging from subtle to severe [hypovolemic shock]), cessation of uterine contractions, uterine tenderness, or loss of fetal station on digital examination in the second trimester. Hematuria may occur if the rupture extends to the bladder. Vaginal bleeding is not a cardinal symptom, as it may be modest, despite major intraabdominal hemorrhage. Ultrasound examination may confirm the diagnosis [11,21]. Rupture or dehiscence is managed with exploratory laparotomy, with either uterine repair (and removal of the pregnancy tissue) or hysterectomy. This is discussed in detail separately. (See "Uterine rupture: After previous cesarean birth" and "Uterine rupture: Unscarred uterus".)
Planning and preparation — General procedure planning, as well as preparation prior to misoprostol-only medication abortion, includes:
●A nondirective discussion of alternatives (abortion or continuing pregnancy with parenting or adoption). (See "Counseling in abortion care".)
●Counseling regarding procedure type (medication or surgical) and the risks and benefits of each. (See "Overview of pregnancy termination", section on 'Choice of procedure' and "Overview of second-trimester pregnancy termination", section on 'Choosing dilation and evacuation versus induction termination'.)
●Assessment of gestational age. (See "Overview of pregnancy termination", section on 'Determining gestational age'.)
●The role of laboratory testing for hemoglobin or hematocrit, RhD typing (and administration of anti-D immune globulin to D-negative individuals) (table 1), and chlamydia and/or gonorrhea. (See "Overview of pregnancy termination", section on 'Laboratory testing' and "Overview of pregnancy termination", section on 'Alloimmunization prevention'.)
●Plan for contraception. (See "Overview of pregnancy termination", section on 'Plan for contraception'.)
●Counseling regarding warning signs and when to call their provider (table 2).
Prophylactic antibiotics and cervical dilators are typically not used for medication (ie, misoprostol with or without mifepristone) abortion. (See "Overview of pregnancy termination", section on 'Cervical dilation and preparation' and "Second-trimester pregnancy termination: Induction (medication) termination", section on 'Cervical dilation'.)
A discussion about indications for induced fetal demise is also provided separately. (See "Induced fetal demise".)
PROTOCOL — The US Food and Drug Administration (FDA) approved mifepristone, in a regimen with misoprostol, for early abortion [22]. However, the off-label use of misoprostol as a single agent for medical termination of pregnancy is endorsed by the World Health Organization (WHO) and professional medical associations including the American College of Obstetricians and Gynecologists (ACOG) and the Society for Family Planning (SFP) and is widely used for this purpose in the United States and globally [23-25].
Accepted regimens — Accepted regimens for medication abortion with misoprostol alone, as recommended by the WHO and the International Federation of Gynecology and Obstetrics (FIGO), are listed in the table (table 3).
The WHO guidelines do not specify a dosing interval for pregnancies <12 weeks but note that repeat doses of misoprostol can be considered to achieve a success with the abortion process [26]. The FIGO recommendations offer additional insight into clinical regimens across a wider array of gestational age thresholds [27]. All gestational ages refer to weeks of amenorrhea. Other professional medical associations, including the ACOG and the National abortion federation (NAF), have guidelines that are consistent with these regimens [24,28,29].
If fetal and placental expulsion has not occurred at 24 to 40 hours, the protocol may be repeated, or a uterine evacuation procedure may be performed [30-32]. There are insufficient data on the safety and effectiveness of using alternative uterotonics (eg, other prostaglandins, oxytocin) [33], and precautions should be taken to avoid uterine hyperstimulation. (See 'Patients with a uterine scar' above.)
Management of placenta — For patients beyond 12 weeks of gestation, expulsion of the placenta usually occurs shortly after the fetus is delivered but may take as long as 30 minutes to four hours after delivery of the fetus [34]. If two or more hours have passed and the placenta has not delivered, an infusion of oxytocin 10 units in 500 mL of normal saline administered intravenously at a rate of 20 to 30 drops per minute may be given. Repeat doses of misoprostol can be continued where oxytocin is not available [33]. Manual or surgical removal of the placenta may be required in selected cases (eg, placenta does not deliver after medical management, excessive bleeding, signs of intrauterine infection). (See "Second-trimester pregnancy termination: Induction (medication) termination", section on 'Retained placenta'.)
After expulsion, the placenta is examined to ensure the entire placenta has been expelled.
DRUG ADMINISTRATION — Misoprostol administration in pregnancy induces cervical softening and dilation and uterine contractions at all gestational ages, thereby facilitating uterine evacuation [35]. The potency of misoprostol's effect on uterine contractions, however, varies with gestational age, as well as route of administration, dose, dosing interval, and cumulative dose.
Setting — Early in pregnancy (≤11 weeks of gestation), misoprostol is typically self-administered by the patient at home [36]. Patients are counseled about expected symptoms (eg, vaginal bleeding, abdominal pain, nausea, vomiting, fevers) and given a telephone number to call with questions, in case of an emergency (eg, bleeding that does not decrease after pregnancy tissue is passed, soaking two maxi pads per hour for two consecutive hours), or if they do not think they passed the pregnancy. (See "First-trimester pregnancy termination: Medication abortion", section on 'Counseling and informed consent' and "First-trimester pregnancy termination: Medication abortion", section on 'Expected symptoms'.)
In the United States, for patients with pregnancies beyond 12 weeks, treatment is usually administered in a clinic or hospital setting. While complete expulsion is probable at such gestations, products of conception are examined to determine whether the abortion is complete. During treatment with misoprostol, the frequency and strength of uterine contractions are monitored. Practice varies, and monitoring may be with patient report, external palpation, or external tocodynamometry. Additional doses of misoprostol may be deferred if uterine contractions are strong and/or too frequent (>3 contractions/10 min) [33]. (See "Overview of second-trimester pregnancy termination", section on 'Procedure setting'.)
Route — While misoprostol can be administered by buccal, sublingual, vaginal, oral, or rectal routes [37-42], buccal, sublingual, and vaginal routes of administration are preferred for most patients undergoing first- and second-trimester termination. Oral administration is no longer recommended as a primary route for medication abortion, except in very early pregnancy, as its effectiveness decreases with increasing gestational age [43-45]. In a meta-analysis of two randomized trials including 216 patients undergoing first-trimester medication abortion, those receiving oral compared with vaginal misoprostol had more incomplete abortions (19.5 versus 5.3 percent, relative risk 3.68, 95% CI 1.56-8.71), however, the certainty of this evidence was low [46]. Oral dosing was also associated with more frequent side effects (eg, nausea, diarrhea, fevers).
Pharmacokinetic profiles vary by route [37,38,41,42]. For example, sublingual administration creates high peaks in serum levels, sometimes causing very painful contractions and more frequent other side effects. However, all three of the most commonly used routes (ie, buccal, sublingual, vaginal) are effective [43-63], and provide regular and sustained uterine activity [42]. Practice varies, and the choice among these preferred routes depends on patient, provider, and institutional preference, and local abortion regulations. In settings where abortion is criminalized, vaginal misoprostol may be avoided as fragments of the pill can be present hours after placement and may be found during pelvic examinations.
Regimens that combine routes of administration (such as an initial vaginal dose of misoprostol followed by oral or buccal routes) were previously used for some terminations after 12 weeks but are no longer recommended [47]. These mixed route protocols can be confusing and cumbersome to implement, and single-route regimens perform equally well [64-68].
Additional evidence of route of misoprostol administration is presented separately. (See "First-trimester pregnancy termination: Medication abortion", section on 'Misoprostol'.)
Dose and dosing interval — Examples of misoprostol dose and dosing intervals are listed in the table (table 3). The sensitivity of the uterus to prostaglandins increases with gestational age [35]. For this reason, providers generally use decreasing amounts of misoprostol with increasing gestational age.
The optimal dose and dosing interval generates sufficient and sustained uterine activity while minimizing adverse effects [36]. Longer dosing intervals have the benefit of exposing a patient to a decreased risk of side effects. Conversely, shorter dosing intervals (closer to three hours) may be necessary to generate sufficient uterine activity, in particular if misoprostol is given via a route with a rapid rise and fall in serum levels (ie, oral and sublingual) [38]. Uterine hyperstimulation is rare, especially in the first trimester; however, the risk may increase with shorter dosing intervals.
In pregnancies at ≤12 weeks of gestation, one to three doses of misoprostol are typically sufficient for pregnancy expulsion. Early in pregnancy, there is little increase in effectiveness after the second dose of misoprostol [69,70], although most studies have evaluated regimens of three to five doses [36]. As an example, in one randomized trial including 125 patients undergoing first-trimester pregnancy termination with misoprostol alone, effectiveness after a second or third dose was similar (86 and 88 percent, respectively) [70].
Data on second-trimester medical terminations with misoprostol show that multiple compared with single doses are highly effective [25,55,56]. As noted above, recommended doses are lower than doses used earlier in pregnancy since the uterus is more sensitive to misoprostol and the risk of rupture appears greater. The need for repeat doses is based on lack of relevant clinical signs of progression (eg, insufficient uterine activity or cervical dilation).
Side effects — Misoprostol is a safe and well-tolerated medication [71]. When side effects do occur, they are generally transient and self limiting; such side effects may include:
●Gastrointestinal symptoms – Gastrointestinal symptoms (nausea, vomiting, diarrhea) are the most common adverse effects of misoprostol [71]. The majority of cases can be managed expectantly or with antiemetic or antidiarrheal medication. Such symptoms have been observed with all four routes of administration; severity may be dose and interval dependent (ie, higher doses and shorter dosing intervals may lead to increased symptoms) [36,49,72].
Pretreatment with analgesics and antidiarrheal medications may slightly reduce the severity of gastrointestinal adverse effects. In a non-concurrent cohort study including 200 patients undergoing pregnancy termination at ≤56 days with vaginal administered misoprostol (800 mcg), pretreatment with loperamide 4 mg and acetaminophen 500 mg compared with no pretreatment led to a reduction in incidence of diarrhea (23 versus 44 percent, odds ratio [OR] 0.38, 95% CI 0.2–0.7) but similar incidence of vomiting [73].
●Fever – Fever, in the absence of infection, is a common effect of misoprostol in patients undergoing first-trimester abortion [35,36,74]. It is more common with sublingual or oral administration and is dependent on dose and frequency of administration. At least one case of severe hyperthermia (41.9°C/107.4°F) in a patient who received misoprostol for postpartum hemorrhage prophylaxis has been reported [75]. Fever associated with misoprostol should subside within several hours, and antipyretics and cold compresses may be used as needed. If fever persists beyond 24 hours, the patient should be evaluated for infection (eg, infected retained products of conception).
In addition, patients who administer misoprostol alone compared with combined therapy may experience more fever, chills, and pain, likely because of the need for higher and repeated doses [76].
Teratogenicity — The teratogenic risk of misoprostol appears to be low and generally limited to early first-trimester exposure [77,78]. Despite the low risk, patients who do not abort after induction with misoprostol in the first half of the first trimester should be counseled about the risk of fetal malformation (eg, Moebius syndrome, limb deformities) with an ongoing pregnancy. (See "First-trimester pregnancy termination: Medication abortion", section on 'Teratogenicity'.)
No harmful effects have been noted among infants exposed to misoprostol in breast milk. While misoprostol is excreted transiently and at low levels in human breast milk [79], and levels appear to rise and decline within three to five hours of administration [35,79], patients should be informed that breastfeeding can continue without interruption [80].
EFFICACY — A combined regimen of mifepristone and misoprostol is more effective than misoprostol alone [70,81], but the misoprostol-only regimen is a reasonable option in settings where mifepristone is not available.
Rates of successful medical abortion with single-agent misoprostol vary depending on the dose and timing of administration. In a meta-analysis of 42 studies (27 observational studies and 15 randomized trials) including over 12,800 patients with gestations up to 13 weeks (mean 9 weeks) gestation undergoing medication abortion with single-agent misoprostol (typically 800 mcg vaginally), the pooled success rate (defined as not requiring surgical uterine evacuation) was 78 percent (95% CI 74-81 percent) [82]. Studies using protocols that allowed for ≥3 doses (maximum six doses) reported higher success rates. Beyond 13 weeks, reported success rates with repeat doses of misoprostol range from 80 to 90 percent [33].
Other regimens (eg, methotrexate plus misoprostol, other prostaglandins [dinoprostone, carboprost]) are less effective than misoprostol-only and misoprostol plus mifepristone regimens and are discussed in detail separately. (See "First-trimester pregnancy termination: Medication abortion", section on 'Methotrexate-based regimens' and "Second-trimester pregnancy termination: Induction (medication) termination", section on 'Type of prostaglandin'.)
FOLLOW-UP — In many instances, no follow-up is needed for patients who experience complete expulsion of the pregnancy. A follow-up visit may be helpful for patients who experience prolonged heavy bleeding, pain, fever or, conversely, no bleeding at all. As routine follow-up visits are not mandatory, patients should be counseled prior to the procedure regarding warning signs and when to call their provider. (See 'Planning and preparation' above.)
Specific follow-up details, as they relate to trimester, are discussed separately. (See "First-trimester pregnancy termination: Medication abortion", section on 'Follow-up' and "Overview of second-trimester pregnancy termination", section on 'Postprocedure considerations'.)
COMPLICATIONS — Medical termination of pregnancy with misoprostol alone is a safe procedure and the risk of a major complication is low.
In the systematic review including over 12,800 patients treated with single agent misoprostol discussed above (see 'Efficacy' above), transfusion or hospitalization for abortion-related complications was uncommon (0.7 percent) [82]. No deaths or ectopic pregnancies were reported. While serious infection and deaths have been reported (eg, Clostridia-associated fatal toxic shock syndrome), such cases are rare and occurred mostly in the early 2000s [83-90]. (See "Toxic shock syndrome due to Paeniclostridium sordellii", section on 'Abortion'.)
Complications of medication abortion with misoprostol alone are similar to those of medication abortion with misoprostol plus mifepristone and are described in detail separately. (See "Overview of pregnancy termination", section on 'Complications'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pregnancy termination".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Abortion (pregnancy termination) (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Clinical application – A combined regimen of misoprostol and mifepristone is generally considered the gold standard for medication abortion since it is more effective than single-agent regimens. This is discussed in detail separately. (See 'Introduction' above and "First-trimester pregnancy termination: Medication abortion", section on 'Efficacy'.).
However, misoprostol-alone regimens may be the treatment of choice in settings where mifepristone is not available or is too costly. Misoprostol is commonly used for second-trimester pregnancy termination in the United States and many other parts of the world. (See 'Introduction' above and "Second-trimester pregnancy termination: Induction (medication) termination", section on 'Protocol'.)
●Patients with a uterine scar – Presence of a uterine scar is not a contraindication for misoprostol. While case reports have described uterine rupture during first- and second-trimester pregnancy termination with misoprostol, uterine rupture can also occur in patients without a uterine scar. As pregnancy advances, regimens with lower cumulative misoprostol doses (ie, lowest dose, longest dosing interval, lowest number or total doses) or a surgical procedure (ie, uterine aspiration, D&E) may be preferred, especially for patients with a history of multiple cesarean births or with certain types of uterine incisions (eg, classical, T-shaped, transfundal). (See 'Patients with a uterine scar' above.)
●Protocol
•Accepted regimens for misoprostol-only medication abortion are listed in the table (table 3). (See 'Accepted regimens' above.)
•If fetal and placental expulsion has not occurred after 24 to 40 hours of the first dose of misoprostol, we suggest either repeating the protocol or performing a uterine evacuation procedure rather than using alternative uterotonics (eg, other prostaglandins, oxytocin) (Grade 2C). (See 'Accepted regimens' above.)
•For patients beyond 12 weeks of gestation, expulsion of the placenta usually occurs shortly after the fetus is delivered but may take as long as 30 minutes to four hours from delivery of the fetus. If the placenta still does not deliver or the patient starts bleeding excessively, manual or surgical removal of the placenta may be required. (See 'Management of placenta' above.)
●Side effects – Gastrointestinal symptoms (nausea, vomiting, diarrhea) and fever are the most common side effects of misoprostol. These are generally transient and self-limiting. Pretreatment with analgesics, antipyretics, and/or antidiarrheal medications may be used as needed. (See 'Side effects' above.)
●Complications – Medical termination of pregnancy with misoprostol alone is a safe procedure and the risk of a major complication is low. Such complications are similar to those undergoing medication abortion with misoprostol plus mifepristone and are described in detail separately. (See 'Complications' above and "Overview of pregnancy termination", section on 'Complications'.)
●Efficacy – Rates of successful medication abortion with single-agent misoprostol vary depending on the dose and timing of administration. When given at up to 13 weeks of gestation, the success rate is 78 percent (ie, 22 percent of treated patients require surgical uterine evacuation). Reported success rates with repeat doses of misoprostol given beyond 13 weeks range from 80 to 90 percent. These estimates are considerably lower than with a combined regimen of mifepristone and misoprostol. (See 'Efficacy' above.)
●Counseling and follow-up – Patients should be counseled prior to the procedure regarding warning signs and when to call their provider (table 2). (See 'Planning and preparation' above.)
Routine follow-up is usually not necessary for patients who experience complete expulsion of the pregnancy. Specific follow-up details, as they relate to trimester, are discussed separately. (See 'Follow-up' above and "First-trimester pregnancy termination: Medication abortion", section on 'Follow-up' and "Overview of second-trimester pregnancy termination", section on 'Postprocedure considerations'.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Wesley Clark, MD, MPH, who contributed to an earlier version of this topic review.
10 : Misoprostol for second-trimester pregnancy termination in women with a prior cesarean delivery.
41 : Comparison of misoprostol plasma concentrations following buccal and sublingual administration.
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