10/27/2017 Second-trimester pregnancy termination: Induction (medication) termination - UpToDate

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Second-trimester pregnancy termination: Induction (medication) termination

Author: Cassing Hammond, MD

Section Editor: Jody Steinauer, MD, MAS
Deputy Editor: Sandy J Falk, MD, FACOG

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2017. | This topic last updated: May 24, 2017.

INTRODUCTION — Second-trimester (14 to <28 weeks of gestation) pregnancy terminations comprise 10 to 15

percent of the approximately 42 million abortions performed annually worldwide [1]. The United States Centers
for Disease Control and Prevention (CDC) reported that 7.1 percent of abortions were performed between 14 to
20 weeks and 1.3 percent at or after 21 weeks [2].

Induction abortion (also referred to as medication or medical abortion) is performed by inducing labor with
medications. Women have historically relied upon a variety of herbal and other substances to stimulate labor to
abort an undesired pregnancy. Women may choose medication abortion if they prefer more awareness of the
termination process, if they prefer an intact fetus, or they want to avoid surgery. An intact fetus may be desirable
if the patient desires to hold the fetus or, in cases of fetal anomalies, if an intact fetus is beneficial for a
morphologic evaluation. In some healthcare settings, there is more access to second-trimester induction abortion
than surgical abortion.

Second-trimester induction termination is reviewed here. An overview of second-trimester pregnancy termination

and the technique for surgical abortion are discussed separately. First trimester medication abortion is also
discussed separately. (See "Overview of second-trimester pregnancy termination" and "First-trimester medication
abortion (termination of pregnancy)".)

PREPROCEDURE PREPARATION — Women desiring second-trimester induction termination require

preoperative evaluation to establish gestational age, assess general medical status, and identify any medical
factors that may impact the choice of induction versus surgical termination. Many of the medical factors favoring
medical abortion are "provider-dependent" in that they derive from a specific provider’s skill in a particular
situation.

Choice of procedure is discussed in detail separately. (See "Overview of second-trimester pregnancy

termination", section on 'Choosing dilation and evacuation versus induction termination'.)

Laws regarding abortion vary by country and by state in the United States. Most states restrict abortion after
viability, although the definition of viability varies by state and maternal-fetal exemptions that countermand the
viability statute vary by state. Physicians offering abortion must be familiar with restrictions in their own locality.

Prophylactic antibiotics — Prophylactic antibiotics are not typically advised for second-trimester medication
abortion. The Society of Family Planning (SFP) advises that prophylactic antibiotics may lower the risk of serious
infection, but advises against universal use [3]. (See 'Infection' below.)

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The issue of antibiotic prophylaxis is similar for first trimester medication abortion, which is discussed in detail
separately. (See "First-trimester medication abortion (termination of pregnancy)", section on 'Prophylactic
antibiotics'.)

Cervical preparation — Traditionally, many clinicians began induction termination by placing osmotic dilators in
the cervix in an effort to facilitate induction through concomitant cervical ripening. There is no evidence that
osmotic cervical dilation facilitates induction using prostaglandin analogues [4,5].

Induced fetal demise — Clinicians induce demise prior to abortion either to facilitate the abortion procedure or
to prevent live birth. SFP 2010 guidelines found that induction of fetal demise prior to medical abortion might
shorten induction to abortion interval, particularly if potassium chloride is utilized [6].

Induced fetal demise is discussed in detail separately. (See "Induced fetal demise".)

Anesthesia — Women undergoing medical induction can receive analgesia or anesthesia similar to that used for
obstetric labor induction. Intermittent narcotic administration suffices for some patients, while others desire
epidural anesthesia since this completely eliminates pain during more prolonged inductions. (See
"Pharmacologic management of pain during labor and delivery".)

PROTOCOL — Current protocols for second-trimester induction abortion typically include a prostaglandin (PG),
usually misoprostol, and may utilize mifepristone or oxytocin.

Type of prostaglandin — A variety of chemical agents have been used to induce abortion throughout history,
many of them self-administered. Modern medication abortion began in the 1940s with the instillation of
hypertonic saline or hyperosmolar urea into the amnionic sac to "salt out" the fetus. Use of hyperosmolar
instillation was often followed by uterotonic medications to induce contractions. Induction abortion with these
agents has now been largely abandoned due to risks such as hypernatremia, coagulopathy, and hemorrhage
[7,8]. In comparison with current methods of labor induction abortion (typically with misoprostol), randomized trial
data show that instillation abortion results in longer induction times and higher rates of both blood transfusion
and retained placenta [8].

Oxytocin, the most commonly used induction agent at later gestational ages, fails to induce labor as effectively
as other single agent therapy at midtrimester because the uterus has relatively fewer oxytocin receptors at less
than 20 weeks of gestation. Oxytocin is associated with longer induction abortion intervals than newer methods,
as well as higher risks of side effects such as postpartum hemorrhage and even water intoxication [9,10].
Patients desiring medical abortion in the second trimester now have safer, more effective options, utilizing PG
agents either alone or in combination with progesterone antagonists.

Several PG agents have been used to induce abortion:

● Misoprostol and gemeprost, both PG E1 analogues, are the most common medications used for induction
abortion.

Comparative studies have found that both misoprostol and gemeprost induce labor more effectively and with
fewer side effects than other prostaglandins (eg, carboprost, sulprostone) and single agent oxytocin or
oxytocin in combination with other types of prostaglandins [11-15]. Both misoprostol and gemeprost induce
labor at a variety of gestational ages [16]. The dose decreases as pregnancy advances because the uterus
becomes more sensitive to PG with decreasing dose requirements as pregnancy advances.

Misoprostol is typically the preferred agent due to lower rates of certain adverse effects and complications
and based on practical considerations. Gemeprost and misoprostol have been found to have similar efficacy
in randomized trials [17-21]. As an example, in one trial of 81 women between 12 to 25 weeks of gestation,

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pregnancy termination with misoprostol (200 mcg every 12 hours) compared with gemeprost (1 mg every 3
hours) resulted in a significantly higher rate of complete abortion (61 versus 32 percent), but a longer
induction-to-abortion interval (27.8 versus 14.5 hours). The mean blood loss was significantly lower in the
misoprostol group. Women treated with misoprostol had fewer adverse effects (eg, nausea, vomiting).

The advantages of misoprostol in comparison with gemeprost are: reduced need for narcotic analgesia, less
frequent need for surgical evacuation of the uterus, has more routes of administration, is less expensive,
and does not require refrigeration [16].

● Carboprost, a PG F2alpha analogue, results in more systemic side effects than PG E analogues [22].

● Sulprostone, a PG E2 analogue, has fallen out of favor because it has been associated with myocardial
infarction [11].

Route and regimen — The route of administration, dose, and dosing interval of misoprostol vary across
protocols. There are limited high quality data to establish the optimal protocol. In general, misoprostol
administered by the buccal route has been found to have higher bioavailability than oral, and with fewer adverse
effects. Sublingual administration has similar efficacy to vaginal dosing. However, for first trimester medication
abortion, many experts advise avoiding vaginal administration due to concerns regarding infection. A systematic
review of randomized trials found that the vaginal route was preferable although, among multiparous women,
sublingual administration appeared equally effective [21]. A subsequent randomized trial found that vaginal or
sublingual dosing were associated with a shorter time to pregnancy completion than oral dosing [23].

General principles of the dose, route of administration, and timing of misoprostol are discussed in detail
separately. (See "First-trimester medication abortion (termination of pregnancy)", section on 'Misoprostol' and
"Misoprostol as a single agent for medical termination of pregnancy", section on 'Data on drug administration'.)

For the second trimester, the dose of misoprostol ranges from 200 to 800 mcg. In regimens using misoprostol or
gemeprost alone, median induction-to-abortion intervals are approximately 12 to 16 hours [24]. The abortion time
interval is decreased with more frequent dosing. Two randomized trials demonstrated a significantly shorter
induction time with vaginal administration of misoprostol 400 mcg every three hours compared with every six
hours, without a significant increase in side effects [25,26].

Use of mifepristone — Mifepristone may be used in combination with misoprostol to decrease the induction-
to-abortion interval and minimize pain. Mifepristone is an antiprogestin that competitively blocks both
progesterone and glucocorticoid receptors. By opposing the activity of progesterone, mifepristone elicits a variety
of effects that make the uterus more susceptible to abortion. These effects include cervical dilation, decidual
necrosis, increased endogenous prostaglandin production, and increasing uterine sensitivity to exogenously
administered prostaglandin. Mifepristone administration gradually elicits a five-fold increase in sensitivity to
prostaglandin 24 to 48 hours after its administration [27]. The synergy between mifepristone and prostaglandin
permits greater efficacy of prostaglandin at lower doses, potentially minimizing side effects [28].

The improved efficacy with mifepristone was best illustrated in a randomized trial that compared second-
trimester abortion with intraamniotic digoxin and misoprostol (buccal 400 mcg, then 200 mcg every six hours)
preceded by either mifepristone (oral 200 mg) or placebo (oral vitamin C) [29]. Women in the mifepristone group
had a significantly shorter median procedure time (10 versus 18 hours). In addition, the mifepristone group had a
nonsignificant association with lower rates of retained placenta (3.1 versus 6.3 percent) and analgesic
requirements (27.2 versus 39.3 mg morphine). Side effects were similar between groups.

Regimens utilizing mifepristone and misoprostol, alone or in combination, result in fetal expulsion within 24 hours
during more than 90 percent of inductions [30,31]. Women failing to deliver the fetus after five doses of
misoprostol, if otherwise clinically stable, may stop the abortion process for 12 to 24 hours before resuming the
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induction cycle. Patients who do not wish to do so, or who are clinically unstable, may convert to a surgical
abortion if cervical dilation is adequate and a skilled provider is available.

The World Health Organization (WHO), American College of Obstetricians and Gynecologists (ACOG), Society
of Family Planning, and the United Kingdom Royal College of Obstetricians and Gynaecologists (RCOG)
recommend regimens in which mifepristone precedes use of either misoprostol or gemeprost [30,32-34].

Mifepristone and misoprostol use in the second trimester has been consistently found to be safe and effective
[12,24,35]. Use of mifepristone and misoprostol in the first trimester has been associated with a small number of
cases of maternal deaths associated with clostridial sepsis. This has been reported in only one case in the
second trimester [36]. Use of mifepristone in the first trimester is discussed in detail separately. (See "First-
trimester medication abortion (termination of pregnancy)", section on 'Clostridial sepsis'.)

Use of mifepristone followed by oxytocin compared with mifepristone followed by misoprostol was compared in
one randomized trial that found no significant difference in success rate (100 versus 96 percent). Time to fetal
expulsion was longer in the oxytocin group (11.3 versus 7.0 hours), but the rate of fever and shivers was lower
[9].

A systematic review analyzed results from 20 randomized trials and 9 observational studies [37]. Pooled data
demonstrated that administration of misoprostol 12 to 24 hours after mifepristone modestly increased induction
abortion intervals by one to two hours. The overall abortion times, the time from administration of mifepristone to
delivery, were substantially lower, though primarily because practitioners started inductions earlier. In our
practice, we begin inductions 36 hours after mifepristone administration, but we advise practitioners that
beginning inductions as soon as 12 to 24 hours is safe and effective. Certainly, providers have considerable
latitude to accommodate patients’ personal needs and the availability of induction services without fear of
compromising safety.

Medical society protocols — ACOG recommends the following protocols for second-trimester induction
abortion [32]:

● Mifepristone, 200 mg, administered orally followed by

• Misoprostol, 800 mcg, administered vaginally, followed by 400 mcg administered vaginally or
sublingually every three hours for up to a maximum of five doses.

OR

• Misoprostol, 400 mcg, administered buccally every three hours for up to a maximum of five doses also
may be used.

● If mifepristone is not available

• Misoprostol, 400 mcg, administered vaginally or sublingually every three hours for up to five doses.
Vaginal dosage is superior to sublingual dosage for nulliparous women.

OR

• A vaginal loading dose of 600 to 800 mcg of misoprostol followed by 400 mcg administered vaginally or
sublingually every three hours may be more effective.

● If misoprostol is not available

• Oxytocin, 20 to 100 units, infused intravenously over three hours, followed by one hour without oxytocin
to allow diuresis. Oxytocin dosage may be slowly increased to a maximum of 300 units over three
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hours.

The evidence-based regimen of the RCOG is 400 mcg of vaginal misoprostol every three hours, up to five doses,
in pregnancies between 13 to 22 weeks [22].

In our practice, we prefer to administer mifepristone before induction with misoprostol or other agents. We
administer mifepristone at least 24 hours prior to induction.

Termination after 23 weeks is not common in the United States, and an optimal regimen has not been
established. When pregnancy termination is performed at ≥24 weeks, the indication is generally a fetal anomaly.
For gestational ages 24 to 28 weeks, the Society of Family Planning (SFP) has published a systematic review
and guidelines for pregnancy termination from 24 to 28 weeks; these include data and recommendations for
pregnancy termination and labor induction for fetal demise [38]. For mifepristone-misoprostol regimens, seven
observational studies were included, and showed that a dosing regimen of misoprostol 200 mcg or 400 mcg
every four hours is associated with 24-hour expulsion rates of 80 to 97 percent, with mean expulsion times
ranging from 8.5 to 13.6 hours. The SFP advised that mifepristone 200 mg or 600 mg be followed by misoprostol
36 to 48 hours later. Misoprostol-only regimens for this gestational age range are discussed separately. (See
"Misoprostol as a single agent for medical termination of pregnancy", section on '23 or more weeks'.)

Use of other medications — There is variation in the approach to second-trimester abortion across medical
settings. In China, approximately 7.63 million abortions were performed in 2007 [39]. The most common method
of second-trimester abortion in China has been intra-amniotic injection of ethacridine lactate, a dye with
antiseptic properties. A systematic review of 15 randomized trials conducted in China evaluated mifepristone
combined with the misoprostol versus intra-amniotic injection of ethacridine lactate and found that
mifepristone/misoprostol has lower failures rates (2 to 6 percent versus 7 to 21 percent; risk ratio 0.37, 95% CI
0.17-0.80) and shorter time of labor (an average of 1.9 hours shorter). More gastrointestinal side effects occurred
in the mifepristone/misoprostol group, but cervical injury was more frequent in the ethacridine lactate group.

OUTCOME AND COMPLICATIONS — Second-trimester surgical abortion is a safe and effective procedure.
Most terminations are completed as inductions, but some women require a surgical procedure for a retained
placenta. In addition to retained products of conception, potential complications include uterine rupture, cervical
laceration, hemorrhage, and infection.

Incomplete abortion — Incomplete abortion is more common in second-trimester induction abortion than in
surgical abortion (1 to 7 versus 0 percent) [32,40,41].

Retained placenta — In induction procedures with mifepristone and misoprostol, 2 to 10 percent of women have
a retained placenta [24,42,43]. Induction protocols that include misoprostol inductions less commonly require
surgical intervention for delivery of the placenta than induction with other agents, though rates of retained
placenta are higher for all medical methods compared with dilation and evacuation (D&E) [40,41,44].

Traditionally, in an induction abortion, clinicians have performed curettage if the placenta remained undelivered
30 to 120 minutes following delivery of the fetus. This is based upon reports regarding a technique that is now
used infrequently, hyperosmolar saline and prostaglandin E2, which was associated with higher rates of
complications with an increasing interval from the delivery of the fetus to the placenta [45,46]. With misoprostol
inductions, some data suggest that waiting for up to four hours is acceptable. As an example, in one
retrospective study of 233 women who underwent second-trimester induction with misoprostol, 59 percent of
placentas delivered within one hour of fetal expulsion. The overall rate of surgical intervention for retained
placenta was 6 percent and 11 of 14 surgical procedures were performed to expedite hospital discharge [47]. An
interval of four or more hours for the delivery of the placenta was not associated with increased morbidity.

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In our practice, for hemodynamically stable patients, we manage delivery of the placenta expectantly for four
hours after delivery of the fetus before intervening to remove the placenta.

Uterine rupture — Uterine rupture can occur in women with a scarred or unscarred uterus [48]. In a systematic
review of second-trimester abortion with misoprostol, the risk of uterine rupture among women with prior
cesarean delivery was 0.28 percent, whereas the risk in women without prior cesarean was 0.04 percent [49].
The Society for Family Planning (SFP) in the United States supports second-trimester induction abortion in
women with prior cesarean delivery [30]. No studies have evaluated the safety of medical abortion among
women with uterine scarring secondary to prior myomectomy or surgery for correction of Müllerian uterine
anomalies.

Cervical laceration — Cervical laceration may occur in either induction or surgical abortion. (See "Second-
trimester pregnancy termination: Dilation and evacuation", section on 'Cervical laceration'.)

Infection — The medications used for induction abortion, particularly misoprostol, often result in pyrexia, which
makes it difficult to evaluate the rate of infection. A literature review by the SFP reported a 1 to 3 percent
incidence of infection, not solely pyrexia, following second-trimester medication abortion [3].

Hemorrhage — Hemorrhage resulting in transfusion complicates less than 1 percent of induction terminations.
The risk of hemorrhage increases with gestational age and duration of induction. Common causes include
retained products of conception, uterine atony and trauma to the lower genital tract [50]. Although clinicians often
treat postabortal atony similar to postpartum atony, the second-trimester uterus has fewer oxytocin receptors,
limiting response to high-dose oxytocin. Carboprost 250 mcg intramuscularly every 15 minutes up to eight doses
and low-dose cervical vasopressin have both been described in the setting of postabortal hemorrhage [51].
Balloon tamponade with intrauterine balloon catheters, uterine compression sutures, and angiographic
embolization might become necessary in more severe cases of hemorrhage [52-54]. Intractable hemorrhage
refractory to other therapy can require hysterectomy.

Other complications — Meaningful mortality data, stratified according to induction regimen used, are
unavailable. Given a very low number of deaths reported annually for all second-trimester abortions, it is unlikely
that any commonly used medical regimen confers a significant risk of maternal death.

FOLLOW-UP — Follow-up for second-trimester induction abortion is the same as for surgical abortion. This is
discussed in detail separately. (See "Overview of second-trimester pregnancy termination", section on 'Follow-
up'.)

SPECIAL CIRCUMSTANCES — Management of patients with special issues of concern (eg, uterine anomalies,
low lying placenta, multiple gestation) is discussed separately. (See "Overview of second-trimester pregnancy
termination", section on 'Special circumstances'.)

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".)

SUMMARY AND RECOMMENDATIONS

● Second-trimester induction abortion (also referred to as medication or medical abortion) is performed using
solely medications. One advantage of this approach compared with surgical abortion is that it results in an
intact fetus, which may be preferable for a patient in certain circumstances. (See 'Introduction' above.)

● Prophylactic antibiotics are not typically advised for second-trimester medication abortion. (See 'Prophylactic
antibiotics' above.)

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● Osmotic dilators do not facilitate second-trimester medical abortion. Some clinicians use osmotic dilators if
there is a high likelihood of conversion of the procedure to a surgical uterine evacuation. (See 'Cervical
preparation' above.)

● Feticidal injections are often given to prevent live birth. Another potential goal of induced fetal demise is to
facilitate labor induction. (See 'Induced fetal demise' above.)

● Women undergoing induction termination can receive analgesia or anesthesia similar to that used for
obstetric labor induction. Intermittent narcotic administration suffices for some patients, while others desire
epidural anesthesia. (See 'Anesthesia' above.)

● Current protocols for second-trimester induction abortion typically include a prostaglandin, usually
misoprostol, and may utilize mifepristone or oxytocin. Prior protocols that used hypertonic saline have been
largely abandoned due to risks such as hypernatremia, coagulopathy, and hemorrhage. (See 'Protocol'
above.)

● For women undergoing second-trimester induction abortion, we suggest use of misoprostol combined with
mifepristone rather than misoprostol alone (Grade 2B). (See 'Protocol' above.)

● Protocols for induction abortion vary. (See 'Protocol' above.)

An example of a protocol is mifepristone, 200 mg, administered orally followed by either:

• Misoprostol, 800 mcg, administered vaginally, followed by 400 mcg administered vaginally or
sublingually every three hours for up to a maximum of five doses.

OR

• Misoprostol, 400 mcg, administered buccally every three hours for up to a maximum of five doses also
may be used.

● Potential complications of induction abortion include: retained placenta, uterine rupture, cervical laceration,
infection, or hemorrhage. (See 'Outcome and complications' above.)

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Topic 90163 Version 9.0

Contributor Disclosures
Cassing Hammond, MD Nothing to disclose Jody Steinauer, MD, MAS Nothing to disclose Sandy J Falk,
MD, FACOG Nothing to disclose

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