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خرید پکیج
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Misoprostol as a single agent for medical termination of pregnancy

Misoprostol as a single agent for medical termination of pregnancy
Authors:
Monica Dragoman, MD, MPH
Caitlin Shannon, MPH
Beverly Winikoff, MD, MPH
Section Editor:
Jody Steinauer, MD, MAS
Deputy Editor:
Alana Chakrabarti, MD
Literature review current through: Aug 2021. | This topic last updated: Apr 08, 2021.

INTRODUCTION — Medical methods for induced abortion have emerged over the past three decades as safe, effective, and feasible alternatives to surgery. Nonsurgical alternatives expand a patient's treatment options and, in turn, the quality of care [1]. Moreover, in some settings, surgical options are not available or are not medically feasible.

In first- and second-trimester abortion, combined treatment with misoprostol and mifepristone is more effective than treatment with misoprostol alone, and thus are 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 in pregnancy termination. Use of mifepristone and other medical and surgical approaches to pregnancy termination and use of misoprostol for fetal demise or labor induction are reviewed separately. (See "First-trimester pregnancy termination: Medication abortion" and "Overview of pregnancy termination" and "Pregnancy loss (miscarriage): Clinical presentations, diagnosis, and initial evaluation" and "Stillbirth: Incidence, risk factors, etiology, and prevention" and "Induction of labor: Techniques for preinduction cervical ripening".)

PHARMACOKINETICS — While the US Food and Drug Administration (FDA) has approved misoprostol for medication abortion, they require it be used in conjunction with mifepristone (a progesterone receptor antagonist). However, its off-label use as a single agent for medical termination of pregnancy is endorsed by the World Health Organization and professional medical associations including the American College of Obstetricians and Gynecologists and the Society for Family Planning [6-8].

Misoprostol administration in pregnancy induces cervical softening and dilation and uterine contractions at all gestational ages, thereby facilitating uterine evacuation [9]. The potency of misoprostol's effect, however, varies with gestational age, as well as with route of administration, dose, dosing interval, and cumulative dose.

Gestational age – The sensitivity of the uterus to prostaglandins increases with gestational age [9]. For this reason, providers generally use decreasing amounts of misoprostol with increasing gestational age.

Route of administration – Misoprostol can be administered by the following routes: vaginal, sublingual, buccal, oral or rectal [10-15]. Sublingual, buccal, and vaginal routes of administration are preferred; oral administration is no longer recommended as a primary route for misoprostol administration for medication abortion. This is discussed in more detail below. (See 'Preferred routes of administration' below.)

The pharmacokinetic profile varies by route [10,11,14,15]. Sublingual administration leads to a rapid peak in serum level, which appears to decrease in one to three hours. Conversely, with vaginal or buccal dosing, serum levels peak later and remain elevated longer [14,15]. In a crossover study comparing the pharmacokinetic parameters of 800 micrograms oral, sublingual, and buccal misoprostol in healthy nonpregnant patients, sublingual misoprostol achieved the highest bioavailability and buccal misoprostol produced the lowest peak concentration; half-lives were similar between the three groups [16].

Uterine activity – Regular and sustained uterine activity is more likely following vaginal, sublingual, or buccal compared with oral administration [15].

Moist versus dry tablets – While moistening misoprostol tablets with normal saline or acetic acid prior to vaginal administration may result in increased absorption, there does not appear to be an increase in clinical effectiveness [17-21].

CONTRAINDICATIONS

Absolute contraindications

Suspected or confirmed ectopic pregnancy

Gestational trophoblastic disease

High risk of uterine rupture (ie, second- or third-trimester inductions in patients with more than one prior hysterotomy, a prior classical or T-shaped uterine incision, or extensive transfundal uterine surgery)

Intrauterine device (IUD, must be removed before misoprostol is administered)

Allergy to prostaglandins

Contraindications to medical or surgical uterine evacuations (eg, hemodynamically unstable, coagulopathy) (see "Overview of pregnancy termination")

Relative contraindications — Misoprostol-alone regimens should be used with caution in patients who are at risk for complications of pregnancy termination (eg, coagulopathy). Precautions specific to misoprostol are considered here. A full discussion of abortion complications is presented separately. (See "Overview of pregnancy termination", section on 'Complications'.)

Risk factors for uterine rupture — Although rare, case reports have described misoprostol-associated uterine rupture during first- and second-trimester pregnancy termination, including a pregnancy at 8 weeks of gestation, as shown in the table (table 1) [22-33]. A uterine scar appears to be the most common risk factor, but advanced gestational age, high gravidity (≥3 pregnancies), and uterine anomalies also appear to play a role.

Scarred uterus – We counsel patients that a uterine scar is not a contraindication for misoprostol induction, but that the risk of rupture may increase with increasing gestational age, particularly in the late second trimester. Thus, patients with a scarred uterus should be monitored for signs of rupture.

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 deliveries (2.5 versus 0.08 percent, relative risk 17.6, 95% CI 3.0-102.8) [34].

According to observational data regarding obstetric labor induction in the third trimester, misoprostol induction is contraindicated in patients with more than one hysterotomy, a prior classical or T-shaped uterine incision, or extensive transfundal uterine surgery. It has not been established whether these risks apply equally to patients undergoing first- or second-trimester induction. (See "Choosing the route of delivery after cesarean birth", section on 'Inappropriate candidates' and "Cervical ripening and induction of labor in women with a prior cesarean birth", section on 'Use of prostaglandins'.)

Unscarred uterus – In reports of uterine rupture in patients without previous uterine surgery, risk factors included grand multiparity [28,29], gestational age greater than 23 weeks [27], and use of oxytocin in addition to misoprostol [28]. However, oxytocin can generally be used safely in combination with misoprostol [29]. For pregnancies at 23 or more weeks, it is controversial whether it is necessary to decrease the misoprostol dose or increase the dosing interval, though it may be prudent to do so [35,36].

Breastfeeding — 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 [37], and levels appear to rise and decline within three to five hours of administration [9,37], patients should be informed that breastfeeding can continue without interruption [38].

PRETREATMENT EVALUATION AND PREPARATION — All patients should undergo an initial evaluation, including a medical history and a physical examination confirming gestational age. Ultrasound is necessary only if there is uncertainty about gestational age, pregnancy location or the presence of gestational trophoblastic disease. If an ultrasound is not performed, the pregnancy should be confirmed with a urine or serum human chorionic gonadotropin (hCG). Blood type and antibody status are checked and Rh immune globulin given if indicated. If a patient has an intrauterine device (IUD), it must be removed.

One of the advantages of misoprostol induction is that it can be performed safely and effectively without mechanical dilation (eg, rigid or osmotic dilators). Further, there is no evidence that pretreatment with osmotic dilators for medication abortion offers any clinical benefit in the second trimester. Two randomized trials in patients undergoing second-trimester termination reported that use of laminaria compared with no mechanical dilation did not reduce (16 and 17 hours) [39] and may actually prolong (14 versus 11 hours) [40] induction time; one trial found an increase in the use of morphine in patients treated with laminaria [40]. A full discussion of cervical preparation for pregnancy termination can be found separately. (See "Pregnancy termination: Cervical preparation for surgical procedures".)

Expert groups recommend against the use of prophylactic antibiotics for medication abortion; uterine infection is uncommon following medication abortion, and there is no high-quality evidence to support routine antibiotic prophylaxis. This is discussed in more detail elsewhere. (See "First-trimester pregnancy termination: Medication abortion", section on 'Prophylactic antibiotics' and "Second-trimester pregnancy termination: Induction (medication) termination", section on 'Prophylactic antibiotics' and 'Fever' below.)

Pretreatment evaluation for pregnancy termination is discussed in detail separately. (See "Overview of pregnancy termination", section on 'Preprocedure evaluation' and "RhD alloimmunization: Prevention in pregnant and postpartum patients".)

DATA ON DRUG ADMINISTRATION — The optimal misoprostol regimen at any gestational age is determined by achieving a balance among effectiveness, adverse effects, and acceptability to patients. As an example, higher doses and shorter dosing intervals increase effectiveness but also may result in higher rates of adverse effects and complications [9].

Preferred routes of administration — Because oral administration is less effective, sublingual, buccal, and vaginal routes of administration are preferred for both first- and second-trimester terminations [41].  

Sublingual versus vaginal dosing – In pregnancies at 12 weeks of gestation or less, data suggest that the sublingual route may be as effective as the vaginal route when dosed appropriately [42-44]. In a randomized trial that compared two vaginal and two sublingual regimens in 2000 participants, vaginal misoprostol administered every 3 or 12 hours and sublingual misoprostol every three hours were similarly effective (83 to 85 percent), but sublingual misoprostol every 12 hours was less effective (78 percent) [44]. Patients preferred sublingual to vaginal administration. Side effects tended to be more common among those taking misoprostol at 3-hour compared with 12-hour intervals, vaginal or sublingual; and this finding was significant for incidence of fever. Diarrhea and chills were slightly more common in those taking misoprostol sublingually compared with vaginally, but this difference was not statistically significant and, regardless, may not be clinically relevant.

Similarly, the sublingual route may be as effective as the vaginal route for termination after 12 weeks [45-51]. One meta-analysis demonstrated that efficacy at 24 hours was similar (pooled relative risk [RR] 1.04, 95% CI 0.93-1.7), but that vaginal misoprostol may be more successful at 48 hours (pooled RR 0.96, 95% CI 0.93-0.99) and may shorten the induction-to-abortion interval (weighted mean difference [WMD] -4.54, 95% CI -8.03 to -1.05) [50]. A second meta-analysis of 40 randomized trials examining medical methods of uterine evacuation for patients 12 to 28 weeks pregnant found that while misoprostol was more frequently vaginally administered, sublingual administration was equally effective [51]. Rates of adverse effects are similar between the two types of dosing; however, patients prefer the sublingual route [45,47,48].

Buccal versus vaginal dosing – Buccal administration of misoprostol as a single agent for medical termination of pregnancy in the first trimester appears to be as effective as vaginal dosing. Randomized trial data for administration of misoprostol in combination with mifepristone for pregnancy up to eight to nine weeks of gestation have found that the efficacy of buccal dosing is similar to vaginal and better than oral dosing [52-54]. Buccal administration was associated with a slight increase in nausea over vaginal dosing. Patient satisfaction was high across all routes. Used as a single agent, buccal misoprostol was found to have an efficacy of 76 percent among patients less than 9 weeks pregnant (n = 147) [55].

Studies of buccal dosing in the second trimester have also yielded favorable results, but there are no studies regarding use of buccal misoprostol as a single agent for second-trimester pregnancy termination [56,57]. In one randomized trial, the initial misoprostol dose was administered vaginally, and subsequent doses were given either buccally or vaginally [58]. The median time to abortion in the buccal group did not differ significantly compared with vaginal dosing groups (15 versus 12 hours); no difference was found in patient preference for route of administration.

Buccal versus sublingual dosing – Sublingual administration of misoprostol may be superior to buccal administration; sublingual administration may have a faster onset of action, higher peak plasma concentration, and greater bioavailability compared with buccal administration [14,59]. In one randomized trial including over 400 patients receiving three doses of 800 mcg misoprostol for pregnancy termination at ≤10 weeks gestation, at the first follow-up visit, sublingual compared with buccal dosing resulted in lower rates of ongoing pregnancy (1.1 versus 5.5 percent) and complete abortion in 87 and 85 percent of patients, respectively [60].

Less preferred regimens

Oral dosing – Oral administration is no longer recommended as a primary route for medication abortion. While oral dosing can be effective very early in pregnancy, its effectiveness decreases with increasing gestational age [42,52,53].

Combined-route regimens for second-trimester terminations – Regimens that combine an initial vaginal misoprostol dose followed by other routes (eg, oral, buccal) are no longer recommended [41]. Combined regimens were previously used for terminations after 12 weeks; however, given they appear to be as effective as vaginal-only regimens [40,61-64], and can be confusing and cumbersome to implement, we no longer use mixed regimens in our practice.

Dose and dosing interval — The optimal regimen is a dose and dosing interval balance which generates sufficient and sustained uterine activity while minimizing adverse effects [65]. Longer dosing intervals have the benefit of exposing a patient to a decreased risk of adverse 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) [11]. Uterine hyperstimulation is rare, especially in the first trimester; however, the risk may increase with shorter dosing intervals.

In pregnancies at ≤12 weeks 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 [66,67], although most studies have evaluated regimens of three to five doses [65]. As an example, in one study, effectiveness after a second or third dose was similar (86 and 88 percent) [67].

Data on second-trimester medical terminations with misoprostol show that multiple doses are highly effective compared with single doses. 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 [6,50,51]. The need for repeat doses should be evaluated prior to administration and based on lack of relevant clinical signs of progression (eg, insufficient uterine activity or cervical dilation).

CLINICAL REGIMEN — The regimens listed in the table (table 2) are evidence-based regimens for medication abortion with misoprostol alone as recommended by the World Health Organization (WHO) and the International Federation of Gynecology and Obstetrics (FIGO). 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 [68]. The FIGO recommendations offer additional insight into clinical regimens across a wider array of gestational age thresholds [69]. All gestational ages refer to weeks of amenorrhea.

Early in pregnancy (≤11 weeks gestation), misoprostol is usually administered at home [65]. Beyond 12 weeks, treatment is usually administered in a clinic setting. Between 12 and 23 weeks, if fetal and placental expulsion has not occurred at 24 hours, the protocol may be repeated [70,71].

MONITORING DURING TREATMENT — Patients are monitored during treatment whether it occurs at home or in a clinic setting. The goals of monitoring are to assess abortion success and complications.

At-home treatment — A patient undergoing medical termination at home should have easy access to a clinician who can answer questions and manage complications medically or surgically. Patient education should include a description of what the patient is most likely to experience, how to recognize potential complications (eg, fever, abdominal pain, or prolonged or excessive bleeding), and how and where to seek help, if needed (table 3).

Importantly, a patient should also know to call the provider if it does not seem that the treatment has been effective. Typically, if 48 hours have passed since completion of treatment and a patient has not had bleeding greater than a menstrual period, it is likely that the patient may have an incomplete abortion or continuing pregnancy [72].

Facility-based treatment — Examination of presumed products of conception or pelvic examination are performed before each additional misoprostol dose is administered in order to determine whether the abortion is complete. The frequency and strength of uterine contractions are also monitored, and additional doses should be deferred if uterine contractions are strong (strong to palpation or by patient report) and/or too frequent (>3 contractions/10 min) [73].

If a patient does not abort after 24 hours, repeat doses of misoprostol can be given, or uterine evacuation can be offered [70,74]. There are insufficient data on the safety and effectiveness of augmentation with other uterotonics (eg, prostaglandins or oxytocin) [73]. As with misoprostol, if additional uterotonics are used, precautions should be taken to avoid uterine hyperstimulation, as it may lead to rupture.

Expulsion of the placenta should be confirmed. Expulsion usually occurs shortly after the fetus is delivered. After expulsion, the placenta should be examined to see whether it is complete.

Advice regarding time interval to wait for placental expulsion following fetal expulsion varies from 30 minutes to 4 hours; in a retrospective study, there was no morbidity associated with a waiting period of four hours [75]. 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 [73]. If the placenta still does not deliver or the patient starts bleeding excessively, manual or surgical removal of the placenta may be required.

Before a patient is discharged from the clinic, clinicians should monitor vital signs and for any sign of complications, including severe abdominal pain or excessive vaginal bleeding. Patients can be discharged when they are feeling well and are ready to leave and when their vital signs are stable.

If 48 hours have passed and abortion is not complete, uterine evacuation is typically performed [73].

FOLLOW-UP — After treatment, patients should be educated about how to recognize complications (eg, fever, abdominal pain, or prolonged or excessive bleeding) (table 3). Routine follow-up visits are not mandatory but can be conducted at one to two weeks posttreatment for patients who undergo at-home treatment.

The most important questions to ask at the follow-up visit are:

Do you feel pregnant?

Did you see the expulsion of the products of conception?

How much bleeding did you have?

Are you still bleeding?

If there is any concern that the patient did not completely expel the pregnancy, a pelvic examination (to evaluate uterine size [uterine involution versus no or continued growth], bleeding, and infection), ultrasound examination (to assess for retained products of conception and fetal cardiac activity), and/or pregnancy test can be performed. This is discussed in detail separately. (See "First-trimester pregnancy termination: Medication abortion", section on 'Ultrasound or hCG'.)

There is no consensus regarding the upper limit of endometrial thickness associated with a successful medication abortion; therefore, it is not a good diagnostic tool for determining whether future intervention may be required [76-80].

Contraceptive methods can be started as soon as possible.

OUTCOME — The efficacy (defined as complete abortion) of single agent misoprostol is variable. In a systematic review including 42 studies and over 12,000 patients receiving single agent misoprostol for medication abortion up to 13 weeks gestation, approximately 22 percent (95% CI 19-25.5 percent) required procedural intervention and 6.8 percent experienced ongoing pregnancy; transfusion or hospitalization for abortion-related complications was uncommon (0.7 percent) [81].

Beyond 13 weeks, effectiveness approaches 80 to 90 percent with repeat doses of misoprostol [73].

ADVERSE EFFECTS — Misoprostol is a safe and well-tolerated medication [82]. Gastrointestinal symptoms (nausea, diarrhea) and fever are the most common adverse effects of misoprostol. These are generally transient and self-limiting.

Gastrointestinal symptoms — Diarrhea is the major adverse reaction that has been reported consistently, but it is usually mild and self-limiting. Nausea and vomiting may also occur [82]. The majority of cases can be managed expectantly or with antiemetic or antidiarrheal medication.

These 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) [44,65,83].

Fever — Fever, even in the absence of infection, is a common effect of misoprostol, reported in 5 to 88 percent of patients undergoing first-trimester abortion [9,65,84]. There is one case report of severe hyperthermia (41.9°C/107.4°F) in a patient who received misoprostol for postpartum hemorrhage prophylaxis [85]. Fever associated with misoprostol should subside within 24 hours, and antipyretics may be given as needed. If fever persists beyond 24 hours, the patient should be evaluated for infection.

Serious infection is very uncommon. Though deaths have been reported from Clostridia-associated fatal toxic shock syndrome following use of mifepristone and misoprostol for early pregnancy termination [86-89], such cases are rare [90-93]. (See "Toxic shock syndrome due to Clostridium sordellii", section on 'Abortion'.)

Prevention of adverse effects — Pretreatment with analgesics and antidiarrheal medications may slightly reduce the severity of gastrointestinal adverse effects [94]. In a randomized trial of participants undergoing pregnancy termination at ≤7 weeks with vaginal administration misoprostol 800 mcg, pretreatment with loperamide 4 mg and acetaminophen 500 mg compared with no pretreatment led to a significant reduction in incidence of diarrhea (23 versus 44 percent) but no difference in vomiting or fever/chills.

COMPLICATIONS — Complications specific to misoprostol-only pregnancy termination are discussed below. As with any uterine evacuation procedure, bleeding or infection may occur. (See "Overview of pregnancy termination", section on 'Complications'.)

Incomplete abortion

First trimester — Clinically stable patients found to have an ongoing pregnancy at follow-up may choose expectant management, medical management, or vacuum aspiration for treatment. Anyone opting for expectant or additional medical management requires further follow-up to confirm successful treatment.

Second trimester — For patients in the second trimester, management of retained products of conception (POCs) depends on the point in the process at which they are suspected or diagnosed.

After fetal expulsion and before discharge from the hospital or clinic, clinicians should confirm that the fetus and placenta have been completely expelled.

Many clinicians manage incomplete abortion in the second trimester with uterine evacuation. Clinicians can choose either electric or manual vacuum aspiration with appropriately sized cannula (up to 16 mm), depending on the clinical situation, to evacuate retained tissue; sharp curettage is rarely indicated. (See "First-trimester pregnancy termination: Uterine aspiration" and "Overview of second-trimester pregnancy termination".)

However, some clinicians treat incomplete abortion following a second-trimester induction with an additional dose or two of misoprostol. The efficacy of this practice has not been established in the literature, but avoiding surgical intervention may be preferable to some patients, and there are no known dangers of giving additional misoprostol doses after fetal expulsion.

It is rare for retained POCs to be detected only after discharge from the clinic, and there is no standard approach. Management (expectant management, additional misoprostol, or surgery) should be tailored to the patient's preferences and the clinical situation.

Uterine rupture — Misoprostol, and other agents which stimulate uterine contractions (eg, oxytocin, other prostaglandins), may increase risk of dehiscence of a prior uterine scar or uterine rupture. (See 'Risk factors for uterine rupture' above.)

Preprocedure screening of patients for risk factors and close observation during treatment are crucial to prevent or detect early signs of uterine rupture. In addition, the minimum cumulative misoprostol dose should be used (ie, lowest dose, longest dosing interval, lowest number or total doses).

Clinical manifestations of uterine rupture following medical termination of pregnancy are variable. In patients with known uterine scarring, uterine rupture should always be strongly considered if severe and persistent abdominal pain and/or signs of intraabdominal hemorrhage are present. Vaginal bleeding is not a cardinal symptom, as it may be modest, despite major intraabdominal hemorrhage. Other clinical manifestations include hypotension ranging from subtle to severe (hypovolemic shock), cessation of uterine contractions, and uterine tenderness. Hematuria may occur if the rupture extends to the bladder. In a stable patient, ultrasound examination may confirm the diagnosis [25,95]. (See "Choosing the route of delivery after cesarean birth", section on 'Inappropriate candidates'.)

Rupture or dehiscence is managed with exploratory laparotomy, with either uterine repair or hysterectomy. Conservative surgery also requires completion of the pregnancy termination.

Teratogenicity — Questions regarding the teratogenicity of misoprostol may arise in cases where complete abortion is not achieved after one or more doses and a patient does not follow up or chooses to continue a pregnancy. The teratogenic risk of misoprostol appears to be low and generally limited to first-trimester exposure, according to a review of case reports [96]. Despite the low risk, patients who do not abort after induction with misoprostol should be counseled about the risk of fetal malformation with an ongoing pregnancy.

The mechanism for misoprostol-associated fetal malformations appears to be vascular disruption, possibly due to alteration of fetal blood flow due to uterine contractions [73,96-99].

MISOPROSTOL-ALONE COMPARED WITH OTHER REGIMENS

Misoprostol versus other prostaglandins — Compared with other prostaglandins, misoprostol has less adverse effects, is orally active, temperature stable, less expensive, and widely available, including: PGE2 (dinoprostone) and PGF2alpha (carboprost) [100].

In a systematic review of randomized trials in patients undergoing pregnancy termination in the second or third trimester, vaginal misoprostol compared with gemeprost (another PGE1) was associated with reduced narcotic analgesia (RR 0.64, 95% CI 0.49-0.84) and reduced surgical evacuation of the uterus (RR 0.71, 95% CI 0.53-0.95) [101].

Misoprostol versus mifepristone/misoprostol — A combined regimen of mifepristone and misoprostol is more effective than misoprostol alone [67,102], but the misoprostol-only regimen would be of use in those settings where mifepristone is not available.

In addition, compared with combined therapy, patients who administer misoprostol alone may experience more fever and chills (probably due to higher and repeated doses), whereas patients administered the combined therapy may experience more nausea and vomiting [103]. Pretreatment with mifepristone may also reduce the pain associated with the procedure.

Misoprostol versus methotrexate/misoprostol — Choice of misoprostol-alone and combined methotrexate/misoprostol is controversial [3]. Data from randomized trials regarding the comparative efficacy of the two regimens are variable. Data from a large retrospective series reported that use of methotrexate with misoprostol was more effective than misoprostol alone [2]. However, methotrexate is more cumbersome to use than mifepristone and misoprostol and misoprostol alone. Also, it is only well-documented through seven weeks of gestation.

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

Pretreatment considerations

For patients seeking pregnancy termination, we recommend mifepristone with misoprostol versus misoprostol alone (Grade 1A). However, in settings where mifepristone is not available, use of misoprostol alone for early pregnancy termination is an appropriate and effective choice. (See 'Misoprostol-alone compared with other regimens' above.)

Misoprostol is commonly used as a single agent for second-trimester induced abortion in the United States and many other parts of the world. (See 'Introduction' above.)

In patients undergoing pregnancy termination at 14 or more weeks, we recommend misoprostol over gemeprost (Grade 1A). (See 'Misoprostol versus other prostaglandins' above.)

For patients undergoing second-trimester pregnancy termination who are at high risk of uterine rupture (more than one hysterotomy, a prior classical or T-shaped uterine incision, or extensive transfundal uterine surgery [eg, myomectomy]), we suggest against using misoprostol (Grade 2B). Misoprostol induction for pregnancy termination appears to be safe in patients with one prior low transverse hysterotomy. Rupture is rarely associated with misoprostol use in the first trimester. (See 'Risk factors for uterine rupture' above and "Choosing the route of delivery after cesarean birth", section on 'Inappropriate candidates'.)

Clinical protocol

In patients undergoing pregnancy termination with misoprostol alone, we suggest sublingual, rather than vaginal or oral, misoprostol dosing (Grade 2B). Buccal dosing may be a reasonable alternative to sublingual. Sublingual and vaginal administration appear to be comparable in effectiveness and safety in randomized trials. (See 'Preferred routes of administration' above.)

For patients at ≤11 weeks gestation, misoprostol is often administered at home. At >12 weeks gestation, misoprostol is often administered in a clinic setting. (See 'Clinical regimen' above.)

The potency of the effect of misoprostol varies with gestational age, as well as with route of administration, dose, dosing interval, and cumulative dose. Clinical protocols vary by gestational age (table 3). (See 'Data on drug administration' above and 'Clinical regimen' above.)

Gastrointestinal symptoms (nausea, vomiting, diarrhea) and fever are the most common adverse effects of misoprostol. These are generally transient and self-limiting. It is reasonable to give prophylactic antidiarrheal medication to decrease the incidence of diarrhea; pretreatment does not appear to decrease other side effects. (See 'Adverse effects' above.)

Posttreatment issues

Patients should be educated about what is normal to expect following a medication abortion as well as how to recognize complications (eg, fever, abdominal pain, or prolonged or excessive bleeding) and how and when to seek help, if needed. (See 'Follow-up' above.)

Incomplete abortion or continuing pregnancy are the most common complications of medication abortion. This can be managed expectantly, medically, or surgically. (See 'Complications' above.)

Uterine rupture is a rare complication but should be suspected in a patient with severe or persistent abdominal pain and signs of intraabdominal bleeding. Prompt laparotomy is indicated in patients with a presumptive diagnosis of uterine rupture. (See 'Complications' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Wesley Clark, MD, MPH, who contributed to an earlier version of this topic review.

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  22. Kim JO, Han JY, Choi JS, et al. Oral misoprostol and uterine rupture in the first trimester of pregnancy: a case report. Reprod Toxicol 2005; 20:575.
  23. Daskalakis GJ, Mesogitis SA, Papantoniou NE, et al. Misoprostol for second trimester pregnancy termination in women with prior caesarean section. BJOG 2005; 112:97.
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  29. Al-Hussaini TK. Uterine rupture in second trimester abortion in a grand multiparous woman. A complication of misoprostol and oxytocin. Eur J Obstet Gynecol Reprod Biol 2001; 96:218.
  30. Syed S, Noreen H, Kahloon LE, Chaudhri R. Uterine rupture associated with the use of intra-vaginal misoprostol during second-trimester pregnancy termination. J Pak Med Assoc 2011; 61:399.
  31. Cuellar Torriente M. Silent uterine rupture with the use of misoprostol for second trimester termination of pregnancy : a case report. Obstet Gynecol Int 2011; 2011:584652.
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  34. Andrikopoulou M, Lavery JA, Ananth CV, Vintzileos AM. Cervical ripening agents in the second trimester of pregnancy in women with a scarred uterus: a systematic review and metaanalysis of observational studies. Am J Obstet Gynecol 2016; 215:177.
  35. Lalitkumar S, Bygdeman M, Gemzell-Danielsson K. Mid-trimester induced abortion: a review. Hum Reprod Update 2007; 13:37.
  36. Ngai SW, Tang OS, Ho PC. Prostaglandins for induction of second-trimester termination and intrauterine death. Best Pract Res Clin Obstet Gynaecol 2003; 17:765.
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  42. Blanchard K, Shochet T, Coyaji K, et al. Misoprostol alone for early abortion: an evaluation of seven potential regimens. Contraception 2005; 72:91.
  43. Tang OS, Miao BY, Lee SW, Ho PC. Pilot study on the use of repeated doses of sublingual misoprostol in termination of pregnancy up to 12 weeks gestation: efficacy and acceptability. Hum Reprod 2002; 17:654.
  44. von Hertzen H, Piaggio G, Huong NT, et al. Efficacy of two intervals and two routes of administration of misoprostol for termination of early pregnancy: a randomised controlled equivalence trial. Lancet 2007; 369:1938.
  45. Bhattacharjee N, Saha SP, Ghoshroy SC, et al. A randomised comparative study on sublingual versus vaginal administration of misoprostol for termination of pregnancy between 13 to 20 weeks. Aust N Z J Obstet Gynaecol 2008; 48:165.
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  47. Tang OS, Lau WN, Chan CC, Ho PC. A prospective randomised comparison of sublingual and vaginal misoprostol in second trimester termination of pregnancy. BJOG 2004; 111:1001.
  48. von Hertzen H, Piaggio G, Wojdyla D, et al. Comparison of vaginal and sublingual misoprostol for second trimester abortion: randomized controlled equivalence trial. Hum Reprod 2009; 24:106.
  49. Ganguly RP, Saha SP, Mukhopadhyay S, et al. A comparative study on sublingual versus oral and vaginal administration of misoprostol for late first and early second trimester abortion. J Indian Med Assoc 2010; 108:283.
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  53. Middleton T, Schaff E, Fielding SL, et al. Randomized trial of mifepristone and buccal or vaginal misoprostol for abortion through 56 days of last menstrual period. Contraception 2005; 72:328.
  54. Blum J, Raghavan S, Dabash R, et al. Comparison of misoprostol-only and combined mifepristone-misoprostol regimens for home-based early medical abortion in Tunisia and Vietnam. Int J Gynaecol Obstet 2012; 118:166.
  55. Ngoc NT, Blum J, Raghavan S, et al. Comparing two early medical abortion regimens: mifepristone+misoprostol vs. misoprostol alone. Contraception 2011; 83:410.
  56. Kapp N, Borgatta L, Stubblefield P, et al. Mifepristone in second-trimester medical abortion: a randomized controlled trial. Obstet Gynecol 2007; 110:1304.
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  63. Makhlouf AM, Al-Hussaini TK, Habib DM, Makarem MH. Second-trimester pregnancy termination: comparison of three different methods. J Obstet Gynaecol 2003; 23:407.
  64. Feldman DM, Borgida AF, Rodis JF, et al. A randomized comparison of two regimens of misoprostol for second-trimester pregnancy termination. Am J Obstet Gynecol 2003; 189:710.
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  66. Carbonell JL, Varela L, Velazco A, Fernández C. The use of misoprostol for termination of early pregnancy. Contraception 1997; 55:165.
  67. Jain JK, Dutton C, Harwood B, et al. A prospective randomized, double-blinded, placebo-controlled trial comparing mifepristone and vaginal misoprostol to vaginal misoprostol alone for elective termination of early pregnancy. Hum Reprod 2002; 17:1477.
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  73. Ho PC, Blumenthal PD, Gemzell-Danielsson K, et al. Misoprostol for the termination of pregnancy with a live fetus at 13 to 26 weeks. Int J Gynaecol Obstet 2007; 99 Suppl 2:S178.
  74. Dickinson JE, Evans SF. The optimization of intravaginal misoprostol dosing schedules in second-trimester pregnancy termination. Am J Obstet Gynecol 2002; 186:470.
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  76. Harwood B, Meckstroth KR, Mishell DR, Jain JK. Serum beta-human chorionic gonadotropin levels and endometrial thickness after medical abortion. Contraception 2001; 63:255.
  77. Luise C, Jermy K, Collons WP, Bourne TH. Expectant management of incomplete, spontaneous first-trimester miscarriage: outcome according to initial ultrasound criteria and value of follow-up visits. Ultrasound Obstet Gynecol 2002; 19:580.
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  83. Honkanen H, Piaggio G, Hertzen H, et al. WHO multinational study of three misoprostol regimens after mifepristone for early medical abortion. BJOG 2004; 111:715.
  84. Carbonell JL, Velazco A, Varela L, et al. Misoprostol for abortion at 9-12 weeks' gestation in adolescents. Eur J Contracept Reprod Health Care 2001; 6:39.
  85. Durocher J, Bynum J, León W, et al. High fever following postpartum administration of sublingual misoprostol. BJOG 2010; 117:845.
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  94. Jain JK, Harwood B, Meckstroth KR, Mishell DR. Early pregnancy termination with vaginal misoprostol combined with loperamide and acetaminophen prophylaxis. Contraception 2001; 63:217.
  95. Daskalakis G, Papantoniou N, Mesogitis S, et al. Sonographic findings and surgical management of a uterine rupture associated with the use of misoprostol during second-trimester abortion. J Ultrasound Med 2005; 24:1565.
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  100. Csapo AI. The prospects of PGs in postconceptional therapy. Prostaglandins 1973; 3:245.
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  102. Allanson ER, Copson S, Spilsbury K, et al. Pretreatment With Mifepristone Compared With Misoprostol Alone for Delivery After Fetal Death Between 14 and 28 Weeks of Gestation: A Randomized Controlled Trial. Obstet Gynecol 2021; 137:801.
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Topic 5434 Version 20.0

References

1 : Misoprostol as the primary agent for medical abortion in a low-income urban setting.

2 : Does methotrexate confer a significant advantage over misoprostol alone for early medical abortion? A retrospective analysis of 8678 abortions.

3 : Misoprostol alone vs. methotrexate followed by misoprostol for early abortion.

4 : Misoprostol alone vs. methotrexate followed by misoprostol for early abortion.

5 : Medical abortion in late second trimester--a comparative study with misoprostol through vaginal versus oral followed by vaginal route.

6 : Clinical guidelines. Labor induction abortion in the second trimester.

7 : WHO recommendations for misoprostol use for obstetric and gynecologic indications.

8 : Practice bulletin no. 143: medical management of first-trimester abortion.

9 : Misoprostol: pharmacokinetic profiles, effects on the uterus and side-effects.

10 : Absorption kinetics of misoprostol with oral or vaginal administration.

11 : Pharmacokinetics of different routes of administration of misoprostol.

12 : Comparison between oral and vaginal administration of misoprostol on uterine contractility.

13 : Preference and acceptability of oral versus vaginal administration of misoprostol in medical abortion with mifepristone.

14 : Comparison of misoprostol plasma concentrations following buccal and sublingual administration.

15 : Misoprostol administered by epithelial routes: Drug absorption and uterine response.

16 : A crossover pharmacokinetic study of misoprostol by the oral, sublingual and buccal routes.

17 : A randomized trial of the effect of moistening misoprostol before vaginal administration when used with methotrexate for abortion.

18 : The effect of tablet moistening on labor induction with intravaginal misoprostol: a randomized trial.

19 : A randomized comparative study on vaginal administration of acetic acid-moistened versus dry misoprostol for mid-trimester pregnancy termination.

20 : Randomized controlled study comparing misoprostol moistened with normal saline and with acetic acid for second-trimester pregnancy termination. Is it different?

21 : A randomized comparison of pharmacokinetics of a single vaginal dose of dry misoprostol or misoprostol moistened with normal saline or with acetic acid.

22 : Oral misoprostol and uterine rupture in the first trimester of pregnancy: a case report.

23 : Misoprostol for second trimester pregnancy termination in women with prior caesarean section.

24 : Misoprostol for second-trimester pregnancy termination in women with a prior cesarean delivery.

25 : Ultrasound diagnosis of uterine dehiscence following mifepristone/misoprostol regime in early second trimester termination.

26 : Termination of pregnancy in patients with previous cesarean section.

27 : Uterine rupture during second trimester abortion with misoprostol.

28 : Uterine rupture in a patient with an unscarred uterus: a case study.

29 : Uterine rupture in second trimester abortion in a grand multiparous woman. A complication of misoprostol and oxytocin.

30 : Uterine rupture associated with the use of intra-vaginal misoprostol during second-trimester pregnancy termination.

31 : Silent uterine rupture with the use of misoprostol for second trimester termination of pregnancy : a case report.

32 : What is your diagnosis?

33 : Misoprostol and pregnancy.

34 : Cervical ripening agents in the second trimester of pregnancy in women with a scarred uterus: a systematic review and metaanalysis of observational studies.

35 : Mid-trimester induced abortion: a review.

36 : Prostaglandins for induction of second-trimester termination and intrauterine death.

37 : Misoprostol versus methylergometrine: pharmacokinetics in human milk.

38 : Misoprostol versus methylergometrine: pharmacokinetics in human milk.

39 : A comparison of misoprostol with and without laminaria tents for induction of second-trimester abortion.

40 : A randomized clinical trial of the addition of laminaria to misoprostol and hypertonic saline for second-trimester induction abortion.

41 : A randomized clinical trial of the addition of laminaria to misoprostol and hypertonic saline for second-trimester induction abortion.

42 : Misoprostol alone for early abortion: an evaluation of seven potential regimens.

43 : Pilot study on the use of repeated doses of sublingual misoprostol in termination of pregnancy up to 12 weeks gestation: efficacy and acceptability.

44 : Efficacy of two intervals and two routes of administration of misoprostol for termination of early pregnancy: a randomised controlled equivalence trial.

45 : A randomised comparative study on sublingual versus vaginal administration of misoprostol for termination of pregnancy between 13 to 20 weeks.

46 : Randomized comparison of 3 misoprostol protocols for abortion induction at 13-20 weeks of gestation.

47 : A prospective randomised comparison of sublingual and vaginal misoprostol in second trimester termination of pregnancy.

48 : Comparison of vaginal and sublingual misoprostol for second trimester abortion: randomized controlled equivalence trial.

49 : A comparative study on sublingual versus oral and vaginal administration of misoprostol for late first and early second trimester abortion.

50 : Comparison of sublingual versus vaginal misoprostol for second-trimester pregnancy termination: a meta-analysis.

51 : Medical methods for mid-trimester termination of pregnancy.

52 : Two distinct oral routes of misoprostol in mifepristone medical abortion: a randomized controlled trial.

53 : Randomized trial of mifepristone and buccal or vaginal misoprostol for abortion through 56 days of last menstrual period.

54 : Comparison of misoprostol-only and combined mifepristone-misoprostol regimens for home-based early medical abortion in Tunisia and Vietnam.

55 : Comparing two early medical abortion regimens: mifepristone+misoprostol vs. misoprostol alone.

56 : Mifepristone in second-trimester medical abortion: a randomized controlled trial.

57 : Adequacy and safety of buccal misoprostol for cervical preparation prior to termination of second-trimester pregnancy.

58 : Randomized trial of buccal versus vaginal misoprostol for induction of second trimester abortion.

59 : The pharmacokinetics and different regimens of misoprostol in early first-trimester medical abortion.

60 : Early abortion with buccal versus sublingual misoprostol alone: a multicenter, randomized trial.

61 : A comparison of oral misoprostol with vaginal misoprostol administration in second-trimester pregnancy termination for fetal abnormality.

62 : Therapeutic termination of second trimester pregnancies with low dose misoprostol.

63 : Second-trimester pregnancy termination: comparison of three different methods.

64 : A randomized comparison of two regimens of misoprostol for second-trimester pregnancy termination.

65 : Misoprostol for the termination of pregnancy up to 12 completed weeks of pregnancy.

66 : The use of misoprostol for termination of early pregnancy.

67 : A prospective randomized, double-blinded, placebo-controlled trial comparing mifepristone and vaginal misoprostol to vaginal misoprostol alone for elective termination of early pregnancy.

68 : A prospective randomized, double-blinded, placebo-controlled trial comparing mifepristone and vaginal misoprostol to vaginal misoprostol alone for elective termination of early pregnancy.

69 : FIGO's updated recommendations for misoprostol used alone in gynecology and obstetrics.

70 : A comparison of two regimens of intravaginal misoprostol for termination of second trimester pregnancy: a randomized comparative trial.

71 : A randomised controlled trial of 6 and 12 hourly administration of vaginal misoprostol for second trimester pregnancy termination.

72 : A randomised controlled trial of 6 and 12 hourly administration of vaginal misoprostol for second trimester pregnancy termination.

73 : Misoprostol for the termination of pregnancy with a live fetus at 13 to 26 weeks.

74 : The optimization of intravaginal misoprostol dosing schedules in second-trimester pregnancy termination.

75 : Intervention rates for placental removal following induction abortion with misoprostol.

76 : Serum beta-human chorionic gonadotropin levels and endometrial thickness after medical abortion.

77 : Expectant management of incomplete, spontaneous first-trimester miscarriage: outcome according to initial ultrasound criteria and value of follow-up visits.

78 : Endometrial thickness after misoprostol use for early pregnancy failure.

79 : How should success be defined when attempting medical resolution of first-trimester missed abortion?

80 : Endometrial thickness following medical abortion is not predictive of subsequent surgical intervention.

81 : Efficacy of Misoprostol Alone for First-Trimester Medical Abortion: A Systematic Review.

82 : Medical abortion in the first trimester.

83 : WHO multinational study of three misoprostol regimens after mifepristone for early medical abortion.

84 : Misoprostol for abortion at 9-12 weeks' gestation in adolescents.

85 : High fever following postpartum administration of sublingual misoprostol.

86 : A consensus regimen for early abortion with misoprostol.

87 : Infection after medical abortion: a review of the literature.

88 : Fatal toxic shock syndrome associated with Clostridium sordellii after medical abortion.

89 : Toxic shock syndrome due to Clostridium sordellii: a dramatic postpartum and postabortion disease.

90 : Fatal Clostridium sordellii infections after medical abortions.

91 : infectious disease. RU-486-linked deaths open debate about risky bacteria.

92 : Clostridium sordellii infection in medical abortion.

93 : Misoprostol impairs female reproductive tract innate immunity against Clostridium sordellii.

94 : Early pregnancy termination with vaginal misoprostol combined with loperamide and acetaminophen prophylaxis.

95 : Sonographic findings and surgical management of a uterine rupture associated with the use of misoprostol during second-trimester abortion.

96 : Sonographic findings and surgical management of a uterine rupture associated with the use of misoprostol during second-trimester abortion.

97 : Epidemiological assessment of misoprostol teratogenicity.

98 : Teratogenicity of misoprostol: data from the Latin-American Collaborative Study of Congenital Malformations (ECLAMC)

99 : Methotrexate embryopathy in a surviving intrauterine fetus after presumed diagnosis of ectopic pregnancy: case report.

100 : The prospects of PGs in postconceptional therapy.

101 : Misoprostol versus cervagem for the induction of labour to terminate pregnancy in the second and third trimester: a systematic review.

102 : Pretreatment With Mifepristone Compared With Misoprostol Alone for Delivery After Fetal Death Between 14 and 28 Weeks of Gestation: A Randomized Controlled Trial.

103 : Randomized comparison of vaginal (200 microg every 3 h) and oral (400 microg every 3 h) misoprostol when combined with mifepristone in termination of second trimester pregnancy.