Misoprostol as a Single Agent for Medical Termination of Pregnancy

Misoprostol as a single agent for medical termination of pregnancy

Authors

Wesley Clark, MD, MPH

Caitlin Shannon, MPH

Beverly Winikoff, MD, MPH Section Editor

Mimi Zieman, MD Deputy Editor

Sandy J Falk, MD

Last literature review version 19.1: January 2011 | This topic last updated: September 22, 2010 (More)

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

In first trimester abortion, combined therapies of misoprostol with mifepristone [2] or methotrexate appear to be more effective than misoprostol-alone regimens [2-4], and thus, are considered the gold standard for medical induction. However, misoprostol-alone regimens may be the treatment of choice in settings in which mifepristone or methotrexate are not available or are too costly.

Misoprostol is commonly used as a single agent for second trimester induced abortion in the United States and many other parts of the world [5,6].

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 "Mifepristone for the medical termination of pregnancy" and "Overview of pregnancy termination" and "Spontaneous abortion: Management" and "Incidence, etiology, and prevention of fetal demise" and "Techniques for cervical ripening prior to labor induction".)

PHARMACOKINETICS — Misoprostol is a synthetic E1 prostaglandin (PGE1) developed and approved originally for the prevention of gastric ulcers. Misoprostol is not approved by the United States Food and Drug Administration for uterine evacuation in pregnant women.

Misoprostol administration in pregnancy induces cervical effacement and uterine contractions at all gestational ages, thereby facilitating uterine evacuation [7]. 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 [7]. 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, oral, sublingual, buccal, or rectal [8-13].Serum level — The pharmacokinetic profile varies by route [8,9,12,13]. Oral or 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 [12,13].Uterine activity — Regular and sustained uterine activity is more likely following vaginal, sublingual, or buccal compared with oral administration [13].Moist versus dry tablets — Moistening of misoprostol tablets does not appear to increase clinical effectiveness [14,15]. A randomized trial evaluated first trimester abortion using methotrexate followed by wet versus dry misoprostol; no difference was found between the two groups [14].

CONTRAINDICATIONS

Absolute contraindications:

• Suspected or confirmed ectopic pregnancy • Gestational trophoblastic disease • High risk of uterine rupture (ie, second or third trimester inductions in women 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 women 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 — Uterine rupture is a risk of misoprostol use at any time during pregnancy. While the risk is likely higher is women with a uterine scar, there are few reports of this complication (table 1) [16]. In a systematic review of available studies, the risk of rupture was 0.3 percent among women with a prior cesarean delivery who were undergoing second trimester misoprostol-induced abortion [17]. Advanced gestational age, high gravidity (≥3 pregnancies) or uterine anomalies may also increase risk of rupture.

Uterine rupture has only been reported once in women undergoing first trimester ruptures [18].

In the second trimester, uterine rupture is rare, but has been reported more frequently than in the first trimester [19-25]. Case reports of uterine rupture in women undergoing second trimester abortion with misoprostol include women with scarred [19-24] and unscarred uteri [24,25].

• Scarred uterus — There are no high quality data regarding the risk of uterine rupture with use of misoprostol for first or second trimester pregnancy termination. The two largest case series of women with a prior cesarean section who were undergoing second trimester misoprostol abortion (n =101 and 108) reported no cases of uterine rupture [19,20]; however, they were underpowered to detect this rare complication. According to observational data regarding obstetric labor induction, misoprostol induction is contraindicated in women 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'.) We counsel women that a uterine scar is not a contraindication for first trimester misoprostol induction, but that the risk may increase with increasing gestational age, particularly in the late second trimester. We counsel women about risk and monitor them for signs of rupture.

• Unscarred uterus — In reports of uterine rupture in women without previous uterine surgery, risk factors included grand multiparity [24,25], gestational age greater than 23 weeks [23], and use of oxytocin in addition to misoprostol [24]. However, oxytocin can generally be used safely in combination with misoprostol [25]. For pregnancies at 23 or more weeks, it is controversial whether it is necessary to decrease the misoprostol dose or increase dosing interval, though it may be prudent to do so [26,27].

Breastfeeding — Misoprostol is excreted transiently and at low levels in human breast milk [28]. It appears that the levels rise and decline within three to five hours of administration [7,28]. It is reasonable to counsel women who receive misoprostol while breastfeeding to pump and discard all milk produced within five hours after each dose.

PRETREATMENT EVALUATION AND PREPARATION — All women 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 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). Some providers augment the procedure with pretreatment laminaria for inductions after 15 weeks. However, two randomized trials in women undergoing second trimester termination reported that use of laminaria compared with no mechanical dilation did not reduce (16 and 17 hours) [29] and may prolong (11 versus 14 hours) [30] induction time; one trial found an increase in the use of morphine in patients treated with laminaria [30]. A full discussion of cervical preparation for pregnancy termination can be found separately. (See "Overview of pregnancy termination", section on 'Cervical preparation'.)

There is no high quality evidence regarding the use of antibiotic prophylaxis for medical abortion (ie, no invasive methods for cervical preparation or uterine evacuation). However, due to several deaths due to clostridial sepsis in the United States in patients who received vaginal misoprostol in combination with mifepristone, some organizations, such as Planned Parenthood (the largest abortion provider in the United States), are now using either oral or buccal misoprostol and have introduced the use of prophylactic antibiotics. (See "Mifepristone for the medical termination of pregnancy", section on 'Prophylactic antibiotics'.)

Pretreatment evaluation for pregnancy termination is discussed in detail separately. (See "Overview of pregnancy termination", section on 'Preoperative considerations' and "Prevention of Rh(D) alloimmunization".)

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 [7].

Route of administration — Effectiveness (defined as complete abortion without surgical intervention) is higher with vaginal compared with oral administration in both first and second trimesters [31-34]. However, in a randomized trial, women prefer oral rather than vaginal dosing [11]. Accumulating evidence regarding sublingual administration appears promising regarding effectiveness and patient acceptability [35-37]. Buccal misoprostol is also used frequently in combination with mifepristone, but has not been evaluated for use a single agent.

There have been cases of fatal sepsis in women who underwent first trimester abortion using mifepristone in combination with vaginal administration of misoprostol. It is uncertain whether use of the vaginal route increases the risk of such infections. (See "Mifepristone for the medical termination of pregnancy", section on 'Infection'.)

• Oral versus vaginal dosing — At 8 or less weeks of gestation, a comparative study evaluated three oral and four vaginal regimens in 260 women showed that the rate of complete abortion is higher with vaginal compared with oral administration (43 to 80 versus 39 to 50 percent) [31]. For pregnancies between 9 and 12 weeks, there are no high quality data comparing

vaginal with oral administration. However, observational studies of vaginal misoprostol use have reported consistently high rates of complete abortion (85 to 90 percent) [38-48]. At 13 or more weeks, randomized trials comparing vaginal with oral dosing found that the vaginal route was more effective (86 to 100 versus 45 to 89 percent) and had a shorter induction-to-delivery interval (10 to 15 hours versus 12 to 35 hours) [6,33,34,49]. Adverse effects were similar between the two routes, with the possible exception of a higher incidence of fever with vaginal dosing [33], and of nausea and diarrhea with oral dosing [49]. Findings on adverse effects are not consistent and thus do not provide high quality evidence for guiding route of administration.

• 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 [31,35,50]. In a randomized trial that compared two vaginal and two sublingual regimens in 2000 women, 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) [50]. Women preferred sublingual to vaginal administration. Side effects tended to be more common among women taking misoprostol at 3-hour compared to 12-hour intervals, vaginal or sublingual; and this finding was significant for incidence of fever. Diarrhea and chills were slightly more common in women taking misoprostol sublingually compared to vaginally, but this difference was not statistically significant and, regardless, may not be clinically relevant. The superiority of vaginal or sublingual misoprostol administration for termination after 12 weeks has not been established [37,49,51,52]. Randomized trial data vary regarding whether the rate of fetal expulsion at 24 hours is equivocal. One trial demonstrated equivalence [37], one favored vaginal [51] and a third favored sublingual [49] administration. Parity determined the most effective route in one large randomized trial (n = 681), in which nulliparous women had a significantly higher abortion rate (complete or incomplete) with vaginal versus sublingual dosing (87 versus 69 percent); no difference was seen in abortion rates between administration routes in parous women (85 and 89 percent) [52]. Rates of adverse effects are similar between the two types of dosing; however, patients prefer the sublingual route [37,51,52]Buccal versus oral or vaginal dosing —

• Buccal administration of misoprostol as a single agent for medical termination of pregnancy in the first trimester appears promising since 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 [53,54]. Buccal administration was associated with a

slight increase in nausea over either oral or vaginal dosing. Patient satisfaction was high across all routes. Studies regarding 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 [55,56]. In one randomized trial, the initial misoprostol dose was administered vaginally, and subsequent doses were given either buccally or vaginally [57]. The median time to abortion in the buccal group did not differ significantly in the buccal compared with vaginal dosing groups (15 versus 12 hours); no difference was found in patient preference for route of administration.

• Combined-route regimens for second trimester terminations — Regimens that combine an initial vaginal misoprostol dose followed by oral doses have been commonly used for terminations after 12 weeks and appear to be as effective as vaginal-only regimens [30,34,58-60]. The rationale is to maximize effectiveness and acceptability, while minimizing induction-to-delivery interval, adverse effects and complications. In a randomized trial of 43 women at 13 to 23 weeks of gestation, an initial 800 mcg vaginal misoprostol dose was followed every eight hours by 400 mcg given either orally or vaginally; effectiveness (82 and 87 percent) and induction-to-delivery interval (16 and 21 hours) were similar between the oral and vaginal groups [60].

Dose and dosing interval — The optimal regimen is a dose and dosing interval balance which generate sufficient and sustained uterine activity while minimizing adverse effects [61]. Longer dosing intervals have the benefit of exposing a woman 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) [9]. Uterine hyperstimulation is rare, however, the risk may increase with shorter dosing intervals.

• 9 or less weeks — Vaginal administration of misoprostol appears to be more effective at 800 mcg (generally 80 to 90 percent) than 200 or 400 mcg (23 to 46 percent), according to observational data [40]. This dosing is higher than for gastrointestinal indications, and thus, this off-label use may need to be clarified with the pharmacist. A vaginal dosing interval of 3 to 24 hours (800 mcg PV; total of three to five doses) is typically used to terminate pregnancies up to nine weeks, with reported success rates of 85 to 93 percent in non-comparative studies [61]. There are no high quality data comparing different doses of sublingual misoprostol for terminations at ≤12 weeks. In studies of sublingual-dosing alone and comparative trials with vaginal dosing, 400 to 800 mcg SL is typically used [31,35,50]. As noted above, 3- rather than 12-hour dosing interval was found to be significantly more effective in a

randomized trial (84 versus 78 percent) [50].

• 10 to 12 weeks — Lower success rates for misoprostol-alone have been reported for pregnancies at 10 to 12 weeks of gestation (84 to 87 percent) in a few descriptive studies [40,46,47,62,63]. The most effective regimen appears to be 800 mcg PV every 12 to 24 hours for a maximum of three doses [46,47]. Data from a case series of 50 women suggest that sublingual administration is also effective; the regimen used was 600 mcg SL every three hours up to five doses [35].

• 13 to 22 weeks — Two misoprostol regimens, 400 mcg PV every three hours OR 600 PV mcg every 12 hours were safe, effective, and resulted in low induction-to-delivery interval in randomized trials [64-66]. However, these two regimens have not been compared to each other. As noted above, it is unclear whether sublingual administration is more or less effective than vaginal in this gestational age range. More study is needed to determine whether sublingual administration should be used in these women, and the appropriate regimen (see 'Route of administration' above).

• 23 to 26 weeks — Many studies have examined the use of misoprostol-alone regimens beyond 23 weeks of gestation, and data show that the method, employing a variety of regimens, can be safely and effectively used in women with advanced gestations [34,58,65-70]. In general, however, termination after 23 weeks is not common in the United States, and an optimal regimen has not been established. As noted above, uterine sensitivity to prostaglandins and risk of uterine rupture increase with gestational age. Therefore, it may be prudent to use a decreased dose or increased dosing interval in this gestational age range [71] (see 'Pharmacokinetics' above).

Number of doses — In pregnancies at 12 or less weeks, it appears that there is little increase in effectiveness after the second dose of misoprostol [48,72], although most studies have evaluated regimens of three to five doses [61]. As an example, in one study, effectiveness after a second or third dose were similar (86 and 88 percent) [72].

Repeated doses of misoprostol are necessary to success in second trimester medical termination. As noted above, lower doses are always used, in comparison to regimens followed for first trimester procedures. As risk of uterine rupture increases with increasing gestational age, lower doses have been suggested for late second trimester and third trimester procedures. As an example, 25 to 50 mcg doses are generally used for labor induction in the third trimester. 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 below are consistent with the regimens proposed by a meeting convened by the World Health Organization (WHO) as a prelude to WHO guidelines (table 2) [61,71,73]. All gestational ages refer to weeks of amenorrhea.

9 or less weeks — Misoprostol may be administered either in a clinic or at home.

• 800 mcg SL every three hours for up to three doses [50] OR800 mcg PV every 3 to 12 hours for up to three doses [31,50].

10 to 12 weeks — We suggest administration in a clinic only due to increased risk of excessive bleeding and possibly of uterine rupture [61].

• 800 mcg PV every 3 to 12 hours for up to three doses [46,47]

13 to 22 weeks — Treatment should be administered only in a clinic setting with immediate access to emergency surgery and blood transfusion. If delivery has not occurred at 24 hours, the protocol may be repeated [64,65].

• 400 mcg PV every three to four hours (max five doses) [64] OR • 600 mcg PV every 12 hours [65]

23 or more weeks — Treatment should be administered only in a clinic setting with immediate access to emergency surgery and blood transfusion. As noted above, there is no established regimen for this gestational age range, however, it may be prudent to use a decreased dose (200 to 400 mcg) or increased dosing interval (six hours). One option is to give 400 mcg PV every six hours [19,20] (see 'Dose and dosing interval' above).

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

At-home treatment — A woman 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 how to recognize complications (eg, fever, abdominal pain, or prolonged or excessive bleeding) (table 2).

In addition, a woman should also call her provider if it does not seem that the treatment has been effective. Typically, if 48 hours have passed since completion of treatment and a woman has not had bleeding greater than a menstrual period, it is likely that she may have an incomplete abortion or continuing pregnancy [74].

In-clinic 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 fetus has been expelled. 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 too frequent (>3 contractions/10 min) [71].

In pregnancies at 13 weeks or greater, if a woman does not abort after 24 hours, a second course of misoprostol treatment surgical evacuation can be offered [64,66]. There are insufficient data on the safety and effectiveness of adding other prostaglandins or oxytocin [71].

If 48 hours have passed and abortion is not complete, surgical evacuation is typically performed [71]. As with misoprostol, if additional uterotonics are used (eg, oxytocin or other prostaglandins), precautions should be taken to avoid uterine hyperstimulation, as it may lead to rupture.

Management of the placenta — The placenta is usually expelled shortly after the fetus. If two 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 [71]. If the placenta is not delivered after infusion of oxytocin or the woman starts bleeding excessively, manual or surgical removal of the placenta may be required.

After expulsion, the placenta should be examined to see whether it is complete. If all or part of the placenta is retained, surgical evacuation is indicated. Advice regarding time interval to wait for placental expulsion varies from 30 minutes to four hours; in a retrospective study, there was no morbidity associated with a waiting period of four hours [75].

Before discharge from the clinic, clinicians should observe women for at least four hours to monitor vital signs and observe for severe abdominal pain or excessive vaginal bleeding.

FOLLOW-UP — After treatment, women should be educated about how to recognize complications (eg, fever, abdominal pain, or prolonged or excessive bleeding) (table 2). A follow-up visit is conducted at one to two weeks post-treatment. A thorough clinical history and bimanual pelvic examination is performed to evaluate uterine size, bleeding, and assess for infection.

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

• Do you feel pregnant? • Did you see the expulsion of the gestational sac or fetus? • How much bleeding did you have? • Are you still bleeding?

These questions and a pelvic examination to determine uterine size are sufficient to detect most women in need of further treatment for incomplete abortion (retained products of conception, no or inconsistent uterine growth, and lack of cardiac activity on ultrasound) or ongoing pregnancy (uterine growth consistent with the time elapsed between the first and follow-up visits and cardiac activity on vaginal ultrasound).

If there is uncertainty about whether there is an incomplete abortion (retained products of conception, no or inconsistent uterine growth, and lack of cardiac activity on ultrasound) or ongoing pregnancy (uterine growth consistent with the time elapsed between the first and follow-up visits and cardiac activity on vaginal ultrasound), a vaginal ultrasound examination may be necessary. Generally speaking, a serum hCG is only used when there is concern about non-uterine pregnancy and/or when ultrasound is not available.

While hCG concentration may remain elevated for weeks after complete abortion, a measurement that falls to less than 20 percent of its pre-procedure value generally indicates successful pregnancy termination. Also, there is no consensus regarding the upper limit of endometrial thickness associated with a successful medical abortion; therefore, it is not a good diagnostic tool for determining whether further intervention may be required. (See "Mifepristone for the medical termination of pregnancy", section on 'Third clinic visit'.)

Contraceptive method can be started as soon as possible. (See "Overview of pregnancy termination", section on 'Contraception'.)

OUTCOME — In early pregnancy, some studies suggest that pregnancy termination efficacy may be higher among women at six weeks and less [76,77] compared with those at six to eight weeks [76,77]. This trend toward higher effectiveness with decreasing gestational age is similar to the results seen in large trials of combined mifepristone-misoprostol [44].

Effectiveness (defined as complete abortion) of misoprostol alone for pregnancy termination is as follows.

• ≤9 weeks (weeks of amenorrhea): 75 to 85 percent [50,61] • 10 to 12 weeks: 80 to 85 percent [61] • ≥13 weeks: 80 to 90 percent [71]

ADVERSE EFFECTS — Misoprostol is a safe and well-tolerated medication [78]. 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 [78]. The majority of cases can be managed expectantly or with anti-emetic or anti-/diarrheal 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) [50,61,76,79].

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 [7,40,61]. There is one case report of severe hyperthermia (41.9 C/107.4 F) in a woman who received misoprostol for postpartum hemorrhage prophylaxis [80]. Fever associated with misoprostol should subside within 24 hours,

and antipyretics may be given as needed. If fever persists beyond 24 hours, a women should be evaluated for infection.

Concern has emerged in North America following the reports of six cases of Clostridia-associated fatal toxic shock syndrome following use of mifepristone and misoprostol for early pregnancy termination (five cases associated with sordellii and one with perfringens) [81-84]. An additional case (of perfringens) was recently reported in a woman who used laminaria and misoprostol for second trimester termination. Although several hypotheses on the mechanism of infection have been put forth, no consensus has been reached [85-87] (see "Mifepristone for the medical termination of pregnancy", section on 'Infection').

Prevention of adverse effects — Pretreatment with antipyretic and antidiarrheal medications may slightly reduce the severity of gastrointestinal adverse effects [88]. In a randomized trial of women undergoing pregnancy termination at ≤7 weeks, pretreatment with loperamide 4 mg of loperamide and acetaminophen 500 mg prior to misoprostol 800 mcg pv compared to 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 — For women undergoing first trimester inductions, management of ongoing pregnancy (cardiac activity on ultrasound) or incomplete abortion (sac or other evidence of products of conception, but no gestational growth and no cardiac activity on ultrasound) are generally different. We assess women at the follow-up visit (one to two weeks) and advise surgery for all ongoing pregnancies. For incomplete abortion, we advise expectant management or a second dose of misoprostol. For women who receive a second dose, we schedule a second follow-up assessment at one to two weeks.

We generally don't give more than one additional dose. This is because the cumulative benefit of additional doses is not established and requiring multiple follow-up visits increases the chance of loss-to-follow-up.

Second trimester — For women in 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 retained products of conception (POCs) with surgical evacuation. Clinicians can choose either dilatation and curettage or manual vacuum aspiration, depending on

the clinical situation. (See "Surgical termination of pregnancy: First trimester" and "Termination of pregnancy: Second trimester".)

However, some clinicians treat retained POCs after 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 is always recommended, 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 or 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 women 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 [21,89]. (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 woman 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 [90]. Despite the low risk, women who do not abort after induction with misoprostol should be counseled about the risk of fetal malformation.

The mechanism for misoprostol-associated fetal malformations appears to be vascular disruption, possibly due to alteration of fetal blood flow due to uterine contractions [71,90-93].

MISOPROSTOL-ALONE COMPARED TO 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) [94].

In a systematic review of randomized trials in women 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 surgical evacuation of the uterus (RR 0.71, 95% CI 0.53–0.95) [95].

Misoprostol versus mifepristone/misoprostol — A combined regimen of mifepristone and misoprostol is more effective than misoprostol-alone in a randomized trial [72]; the misoprostol-only regimen would be of use in those settings where mifepristone is not available.

In addition, compared with combined therapy, women who administer misoprostol-alone may experience more fever and chills (probably due to higher and repeated doses), whereas women administered the combined therapy may experience more nausea and vomiting [77]. 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 [3,4]. Data from randomized trials regarding the comparative efficacy of the two regimens are variable. However, data from a large retrospective series reported that use of methotrexate with misoprostol was more effective than misoprostol-alone [2].

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Abortion (pregnancy termination)".) We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

SUMMARY AND RECOMMENDATIONS

Pretreatment considerations

• In women seeking pregnancy termination at nine or less weeks of gestation, we recommend mifepristone with misoprostol versus misoprostol alone (Grade 1A). Alternatively, we suggest methotrexate with misoprostol versus misoprostol alone (Grade 2B). However, in settings where other medications are not accessible, use of misoprostol-alone for early pregnancy termination is an appropriate and effective choice. (See 'Misoprostol-alone compared to 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 women undergoing pregnancy termination at 14 or more weeks, we recommend misoprostol over gemeprost (Grade 1A). (See 'Misoprostol versus other prostaglandins' above.)

• In women 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 women with one prior low transverse hysterotomy. Rupture is rarely associated with misoprostol use in 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 women 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. Vaginal administration is more effective than oral, however, equivalent safety has not been confirmed. (See 'Route of administration' above.)

• For women at nine or less weeks, misoprostol can be administered at home or in a clinic setting. At 10 or more weeks, we conduct misoprostol treatment and monitoring in a clinic. (See 'Clinical regimen' above.)

• The potency of misoprostol's effect varies with gestational age, as well as with route of administration, dose, dosing interval, and cumulative dose. Clinical protocols vary by gestational age. (See 'Data on drug administration' above and 'Clinical regimen' above.) (table 2).

• 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 anti-diarrheal medication to decrease the incidence of diarrhea; pretreatment does not appear to decrease other side effects. (See 'Adverse effects' above.)

Posttreatment issues

Women should be educated about how to recognize complications (eg, fever, abdominal pain, or prolonged or excessive bleeding). (See 'Follow-up' above.)Incomplete abortion or continuing pregnancy are the most common complications of medical abortion. This can be managed expectantly, medically, or surgically. (See 'Complications' above.)Uterine rupture should be suspected in a woman 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.)

REFERENCES

1. Borgatta L, Mullally B, Vragovic O, et al. Misoprostol as the primary agent for medical abortion in a low-income urban setting. Contraception 2004; 70:121.

2. Aldrich T, Winikoff B. Does methotrexate confer a significant advantage over misoprostol alone for early medical abortion? A retrospective analysis of 8678 abortions. BJOG 2007; 114:555.

3. Wiebe ER, Trouton KJ, Lima R. Misoprostol alone vs. methotrexate followed by misoprostol for early abortion. Int J Gynaecol Obstet 2006; 95:286.

4. Ozeren M, Bilekli C, Aydemir V, Bozkaya H. Methotrexate and misoprostol used alone or in combination for early abortion. Contraception 1999; 59:389.

5. United Nations Development Program/United Nations Fund for Population Activities/World Health Organization/World Bank Special Program of Research Development and Research Training in Human Reprod. Annual Technical Report, 1997. World Health Organization, Geneva, Switzerland 1998.

6. Saha S, Bal R, Ghosh S, Krishnamurthy P. Medical abortion in late second trimester--a comparative study with misoprostol through vaginal versus oral followed by vaginal route. J Indian Med Assoc 2006; 104:81.

7. Tang OS, Gemzell-Danielsson K, Ho PC. Misoprostol: pharmacokinetic profiles, effects on the uterus and side-effects. Int J Gynaecol Obstet 2007; 99 Suppl 2:S160.

8. Zieman M, Fong SK, Benowitz NL, et al. Absorption kinetics of misoprostol with oral or vaginal administration. Obstet Gynecol 1997; 90:88.

9. Tang OS, Schweer H, Seyberth HW, et al. Pharmacokinetics of different routes of administration of misoprostol. Hum Reprod 2002; 17:332.

10. Danielsson KG, Marions L, Rodriguez A, et al. Comparison between oral and vaginal administration of misoprostol on uterine contractility. Obstet Gynecol 1999; 93:275.

11. Arvidsson C, Hellborg M, Gemzell-Danielsson K. Preference and acceptability of oral versus vaginal administration of misoprostol in medical abortion with mifepristone. Eur J Obstet Gynecol Reprod Biol 2005; 123:87.

12. Schaff EA, DiCenzo R, Fielding SL. Comparison of misoprostol plasma concentrations following buccal and sublingual administration. Contraception 2005; 71:22.

13. Meckstroth KR, Whitaker AK, Bertisch S, et al. Misoprostol administered by epithelial routes: Drug absorption and uterine response. Obstet Gynecol 2006; 108:582.

14. Creinin MD, Carbonell JL, Schwartz JL, et al. A randomized trial of the effect of moistening misoprostol before vaginal administration when used with methotrexate for abortion. Contraception 1999; 59:11.

15. Sanchez-Ramos L, Danner CJ, Delke I, Kaunitz AM. The effect of tablet moistening on labor induction with intravaginal misoprostol: a randomized trial. Obstet Gynecol 2002; 99:1080.

16. Goldberg AB, Greenberg MB, Darney PD. Misoprostol and pregnancy. N Engl J Med 2001; 344:38.

17. Goyal V. Uterine rupture in second-trimester misoprostol-induced abortion after cesarean delivery: a systematic review. Obstet Gynecol 2009; 113:1117.

18. 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.

19. Daskalakis GJ, Mesogitis SA, Papantoniou NE, et al. Misoprostol for second trimester pregnancy termination in women with prior caesarean section. BJOG 2005; 112:97.

20. Dickinson JE. Misoprostol for second-trimester pregnancy termination in women with a prior cesarean delivery. Obstet Gynecol 2005; 105:352.

21. El-Matary A, Navaratnarajah R, Economides DL. Ultrasound diagnosis of uterine dehiscence following mifepristone/misoprostol regime in early second trimester termination. J Obstet Gynaecol 2006; 26:578.

22. Mazouni C, Provensal M, Porcu G, et al. Termination of pregnancy in patients with previous cesarean section. Contraception 2006; 73:244.

23. Nayki U, Taner CE, Mizrak T, et al. Uterine rupture during second trimester abortion with misoprostol. Fetal Diagn Ther 2005; 20:469.

24. Mazzone ME, Woolever J. Uterine rupture in a patient with an unscarred uterus: a case study. WMJ 2006; 105:64.

25. 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.

26. Lalitkumar S, Bygdeman M, Gemzell-Danielsson K. Mid-trimester induced abortion: a review. Hum Reprod Update 2007; 13:37.

27. 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.

28. Vogel D, Burkhardt T, Rentsch K, et al. Misoprostol versus methylergometrine: pharmacokinetics in human milk. Am J Obstet Gynecol 2004; 191:2168.

29. Jain JK, Mishell DR Jr. A comparison of misoprostol with and without laminaria tents for induction of second-trimester abortion. Am J Obstet Gynecol 1996; 175:173.

30. Borgatta L, Chen AY, Vragovic O, et al. A randomized clinical trial of the addition of laminaria to misoprostol and hypertonic saline for second-trimester induction abortion. Contraception 2005; 72:358.

31. Blanchard K, Shochet T, Coyaji K, et al. Misoprostol alone for early abortion: an evaluation of seven potential regimens. Contraception 2005; 72:91.

32. Gilbert A, Reid R. A randomised trial of oral versus vaginal administration of misoprostol for the purpose of mid-trimester termination of pregnancy. Aust N Z J Obstet Gynaecol 2001; 41:407.

33. Bebbington MW, Kent N, Lim K, et al. A randomized controlled trial comparing two protocols for the use of misoprostol in midtrimester pregnancy termination. Am J Obstet Gynecol 2002; 187:853.

34. Dickinson JE, Evans SF. A comparison of oral misoprostol with vaginal misoprostol administration in second-trimester pregnancy termination for fetal abnormality. Obstet Gynecol 2003; 101:1294.

35. 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.

36. Cheung W, Tang OS, Lee SW, Ho PC. Pilot study on the use of sublingual misoprostol in termination of pregnancy up to 7 weeks gestation. Contraception 2003; 68:97.

37. 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.

38. Salakos N, Kountouris A, Botsis D, et al. First-trimester pregnancy termination with 800 microg of vaginal misoprostol every 12 h. Eur J Contracept Reprod Health Care 2005; 10:249.

39. Carbonell JL, Rodríguez J, Velazco A, et al. Oral and vaginal misoprostol 800 microg every 8 h for early abortion. Contraception 2003; 67:457.

40. 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.

41. Carbonell JL, Rodriguez J, Aragón S, et al. Vaginal misoprostol 1000 microg for early abortion. Contraception 2001; 63:131.

42. Velazco A, Varela L, Tanda R, et al. Misoprostol for abortion up to 9 weeks' gestation in adolescents. Eur J Contracept Reprod Health Care 2000; 5:227.

43. Ngai SW, Tang OS, Chan YM, Ho PC. Vaginal misoprostol alone for medical abortion up to 9 weeks of gestation: efficacy and acceptability. Hum Reprod 2000; 15:1159.

44. Tang OS, Wong KS, Tang LC, Ho PC. Pilot study on the use of repeated doses of misoprostol in termination of pregnancy at less than 9 weeks of gestation. Adv Contracept 1999; 15:211.

45. Esteve JL, Varela L, Velazco A, et al. Early abortion with 800 micrograms of misoprostol by the vaginal route. Contraception 1999; 59:219.

46. Carbonell Esteve JL, Varela L, Velazco A, et al. Vaginal misoprostol for late first trimester abortion. Contraception 1998; 57:329.

47. Carbonell JL, Varela L, Velazco A, et al. Vaginal misoprostol for abortion at 10-13 weeks' gestation. Eur J Contracept Reprod Health Care 1999; 4:35.

48. Carbonell JL, Varela L, Velazco A, Fernández C. The use of misoprostol for termination of early pregnancy. Contraception 1997; 55:165.

49. Caliskan E, Dilbaz S, Doger E, et al. Randomized comparison of 3 misoprostol protocols for abortion induction at 13-20 weeks of gestation. J Reprod Med 2005; 50:173.

50. 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.

51. 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.

52. 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.

53. Winikoff B, Dzuba IG, Creinin MD, et al. Two distinct oral routes of misoprostol in mifepristone medical abortion: a randomized controlled trial. Obstet Gynecol 2008; 112:1303.

54. 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.

55. Kapp N, Borgatta L, Stubblefield P, et al. Mifepristone in second-trimester medical abortion: a randomized controlled trial. Obstet Gynecol 2007; 110:1304.

56. Patel A, Talmont E, Morfesis J, et al. Adequacy and safety of buccal misoprostol for cervical preparation prior to termination of second-trimester pregnancy. Contraception 2006; 73:420.

57. Ellis SC, Kapp N, Vragpvoc O, Borgata L. Randomized trial of buccal versus vaginal misoprostol for induction of second trimester abortion. Contraception 2010; 81:441.

58. Liaquat NF, Javed I, Shuja S, et al. Therapeutic termination of second trimester pregnancies with low dose misoprostol. J Coll Physicians Surg Pak 2006; 16:464.

59. Makhlouf AM, Al-Hussaini TK, Habib DM, Makarem MH. Second-trimester pregnancy termination: comparison of three different methods. J Obstet Gynaecol 2003; 23:407.

60. 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.

61. Faúndes A, Fiala C, Tang OS, Velasco A. Misoprostol for the termination of pregnancy up to 12 completed weeks of pregnancy. Int J Gynaecol Obstet 2007; 99 Suppl 2:S172.

62. Guix C, Palacio M, Figueras F, et al. Efficacy of two regimens of misoprostol for early second-trimester pregnancy termination. Fetal Diagn Ther 2005; 20:544.

63. Bugalho A, Faúndes A, Jamisse L, et al. Evaluation of the effectiveness of vaginal misoprostol to induce first trimester abortion. Contraception 1996; 53:244.

64. Wong KS, Ngai CS, Yeo EL, et al. A comparison of two regimens of intravaginal misoprostol for termination of second trimester pregnancy: a randomized comparative trial. Hum Reprod 2000; 15:709.

65. Herabutya Y, Chanrachakul B, Punyavachira P. A randomised controlled trial of 6 and 12 hourly administration of vaginal misoprostol for second trimester pregnancy termination. BJOG 2005; 112:1297.

66. Dickinson JE, Evans SF. The optimization of intravaginal misoprostol dosing schedules in second-trimester pregnancy termination. Am J Obstet Gynecol 2002; 186:470.

67. Edwards RK, Sims SM. Outcomes of second-trimester pregnancy terminations with misoprostol: comparing 2 regimens. Am J Obstet Gynecol 2005; 193:544.

68. Dodd J, O'Brien L, Coffey J. Misoprostol for second and third trimester termination of pregnancy: a review of practice at the Women's and Children's Hospital, Adelaide, Australia. Aust N Z J Obstet Gynaecol 2005; 45:25.

69. Langer BR, Peter C, Firtion C, et al. Second and third medical termination of pregnancy with misoprostol without mifepristone. Fetal Diagn Ther 2004; 19:266.

70. Prachasilpchai N, Russameecharoen K, Borriboonhirunsarn D. Success rate of second-trimester termination of pregnancy using misoprostol. J Med Assoc Thai 2006; 89:1115.

71. 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.

72. 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.

73. Shaw D. Misoprostol for reproductive health: Dosage recommendations. Int J Gynaecol Obstet 2007; 99 Suppl 2:S155.

74. Safe abortion: Technical and policy guidelines for health systems. World Health Organization, Geneva, 2003.

75. Green J, Borgatta L, Sia M, et al. Intervention rates for placental removal following induction abortion with misoprostol. Contraception 2007; 76:310.

76. 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.

77. Ngai SW, Tang OS, Ho PC. 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. Hum Reprod 2000; 15:2205.

78. Baird DT. Medical abortion in the first trimester. Best Pract Res Clin Obstet Gynaecol 2002; 16:221.

79. Jain JK, Meckstroth KR, Park M, Mishell DR Jr. A comparison of tamoxifen and misoprostol to misoprostol alone for early pregnancy termination. Contraception 1999; 60:353.

80. Chong YS, Chua S, Arulkumaran S. Severe hyperthermia following oral misoprostol in the immediate postpartum period. Obstet Gynecol 1997; 90:703.

81. Philip NM, Winikoff B, Moore K, Blumenthal P. A consensus regimen for early abortion with misoprostol. Int J Gynaecol Obstet 2004; 87:281.

82. Shannon C, Brothers LP, Philip NM, Winikoff B. Infection after medical abortion: a review of the literature. Contraception 2004; 70:183.

83. Fischer M, Bhatnagar J, Guarner J, et al. Fatal toxic shock syndrome associated with Clostridium sordellii after medical abortion. N Engl J Med 2005; 353:2352.

84. Sinave C, Le Templier G, Blouin D, et al. Toxic shock syndrome due to Clostridium sordellii: a dramatic postpartum and postabortion disease. Clin Infect Dis 2002; 35:1441.

85. Couzin J. infectious disease. RU-486-linked deaths open debate about risky bacteria. Science 2006; 312:986.

86. Winikoff B. Clostridium sordellii infection in medical abortion. Clin Infect Dis 2006; 43:1447.

87. Aronoff DM, Hao Y, Chung J, et al. Misoprostol impairs female reproductive tract innate immunity against Clostridium sordellii. J Immunol 2008; 180:8222.

88. Jain JK, Harwood B, Meckstroth KR, Mishell DR. Early pregnancy termination with vaginal misoprostol combined with loperamide and acetaminophen prophylaxis. Contraception 2001; 63:217.

89. 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.

90. Misoprostol and teratology: Reviewing the evidence, Philip, N, Shannon, C, Winikoff, B (Eds), Population Council, New York 2002.

91. Orioli IM, Castilla EE. Epidemiological assessment of misoprostol teratogenicity. BJOG 2000; 107:519.

92. Castilla EE, Orioli IM. Teratogenicity of misoprostol: data from the Latin-American Collaborative Study of Congenital Malformations (ECLAMC). Am J Med Genet 1994; 51:161.

93. Addar MH. Methotrexate embryopathy in a surviving intrauterine fetus after presumed diagnosis of ectopic pregnancy: case report. J Obstet Gynaecol Can 2004; 26:1001.

94. Csapo AI. The prospects of PGs in postconceptional therapy. Prostaglandins 1973; 3:245.

95. Dodd JM, Crowther CA. Misoprostol versus cervagem for the induction of labour to terminate pregnancy in the second and third trimester: a systematic review. Eur J Obstet Gynecol Reprod Biol 2006; 125:3.