Labor induction abortion, although not superior to surgical abortion in the second trimester, does provide access to abortion services when there are no providers trained in second trimester surgical abortion techniques. Studies conducted in the late 1970s and early 1980s that compared morbidity and mortality from second trimester dilation and evacuation (D&E) procedures and instillation induction of labor procedures found lower overall complication rates with D&E.^1,2 However, these comparisons evaluated procedures that are largely outdated. The D&E techniques studied rarely used osmotic dilators for cervical preparation before the procedure and the instillation methods studied are uncommonly used in clinical practice today. Recently, one study compared second trimester D&E to induction of labor as it is practiced today. This dual cohort analysis similarly found that D&E was associated with fewer complications than induction of labor and that newer labor induction techniques using misoprostol were associated with fewer complications than older instillation methods.³

Although 96% of second trimester abortions performed in the United States are performed surgically,⁴ second trimester induction of labor may expand access to abortion services where D&E is not available. Induction of labor is also indicated in some cases of pregnancy termination for fetal abnormalities, such as when an intact fetus is important for diagnosis or for the patient's grieving process. However, an intact fetus is not necessary solely to confirm prenatal diagnosis of a genetic abnormality; accurate chromosomal analysis can be performed in almost every case after a D&E procedure.⁵

In the late second trimester and third trimester, labor induction is the primary method of elective termination in cases of lethal abnormalities. The minimal availability of intact dilation and extraction (D&X) contributes to this method being the primary option. When termination of a desired pregnancy is necessary for maternal indications, gestational age and the likelihood of fetal survival are key factors in the choice of a treatment regimen.

In the United States in 1999, approximately 75,000 second trimester abortion procedures were reported to the Centers for Disease Control (CDC). This number is an underestimate of the total number of second trimester abortions performed in the United States, because it comes from only 41 states, New York City, and the District of Columbia. Of the procedures with gestational age and type of procedure reported, 96% were performed surgically, 1.3% used intrauterine instillation techniques, .7% were performed medically (primarily using intravaginal prostaglandins), and 1.8% used other techniques (including hysterotomy and hysterectomy).⁴

Intra-Amniotic Instillation

Instillation methods are not frequently used at present, largely because alternative methods, including surgical options, have fewer side effects, lower risk of complications, and more rapid completion times. These invasive procedures require special skills to minimize risks such as a bloody tap and maternal intravascular injection, introduction of infection, and rupture of membranes. Table 1 presents an overview of efficacy and side effects of second trimester induction abortion methods.

Table 1. Overview of Outcomes of Labor Induction Abortion Methods

Click Here to View Table.

Hypertonic Saline

One of the first described instillation methods was hypertonic saline. Early use resulted in maternal death that was attributable to poor technique, a free-flow system (rather than a drip infusion), and use of concentrations exceeding 20%.⁶ Major complications included maternal hypernatremia and coagulopathy, which was clinically evident in 3 of 1000 cases.⁷

When used alone, intra-amniotic hypertonic saline has a long latent period until the onset of contractions. Only 20% of women will abort within the first 24 hours and 81% will abort by 48 hours, with a mean time to abortion of 30 hours.⁸ Addition of oxytocin to this regimen improves the efficacy and expulsion time. In a series of 5000 saline inductions at 14 to 24 weeks' gestation⁷ using a drip intra-amniotic infusion of 20% saline and intravenous oxytocin at less than 50 mU per minute, average time to abortion ranged from 22.5 to 25 hours; 99.6% of patients were successfully induced and retained placenta occurred in 13% of cases. Significant complications included hemorrhage in 2.3%, transfusion in .5%, clinical coagulopathy in .3%, and cervical laceration in .3%. Two patients who received high doses of oxytocin (more than 150 milliunits per minute) had uterine rupture, one of which required hysterectomy.

A similar series from the Joint Program for the Study of Abortion (JPSA), a multicenter prospective observational study conducted by the United States CDC,⁹ found that among 4778 patients from 13 to 24 weeks' gestation treated with intra-amniotic hypertonic saline and intravenous oxytocin, mean induction interval was 25.6 hours, the rate of retained placenta was 14.8%, and the rate of transfusion was 1.7%.

Urea

Urea initially appeared to be a potentially safer agent than hypertonic saline for intra-amniotic instillation. Unlike hypertonic saline, urea is relatively safe when an inadvertent intravascular injection occurs, because urea rapidly traverses cell membranes and is an osmotic diuretic. When used alone, urea has a long instillation to abortion interval. As such, various additional agents have been evaluated and used in combination with urea to provide a clinically acceptable method of second trimester abortion.

Initial experience most commonly combined intra-amniotic urea, 80 to 90 g, with intravenous oxytocin.^10,11,12 Early studies found varying success rates of 85% to 97% within 48 hours and an average time to expulsion of 19 to 29 hours, with the differences most likely caused by differences in the gestational ages of the treated population and variable amounts of oxytocin.^10,11 Higher success rates were reported with high-dose oxytocin (332 mU per minute);¹⁰ however, these rapid oxytocin infusions were associated with oliguria caused by the antidiuretic effect of high-dose oxytocin. The oxytocin-induced oliguria was reversible several hours after discontinuing the oxytocin.¹¹

A nonrandomized study suggested more rapid expulsion with the use of laminaria before the instillation of urea.¹² Among 75 patients from 16 to 20 weeks' gestation who received 80 g of intra-amniotic urea followed by intravenous oxytocin at 200 mU per minute, the average time to abortion was 21.3 hours among women pretreated with laminaria and 29.4 hours for the group without laminaria. The rates of infection (2% to 3%) and retained placenta (18% to 19%) were not different.

Intra-Amniotic Prostaglandins

Instillation of prostaglandin made sense as a medical method of labor induction abortion because the amniotic fluid would act as a reservoir, slowly allowing the prostaglandin to cross the sac to stimulate the myometrium. Natural prostaglandins such as PGE₂ and PGF_2α were investigated in large multicenter and multinational studies in the 1970s.

In one study of 700 women at 12 to 22 weeks' gestation (mean: 17.1 weeks), 5 mg of intra-amniotic PGE₂ were instilled in 500 patients, and 10 mg were instilled in 200 patients; intravenous oxytocin at 100 mU per minute was begun 6 hours later.¹³ If no delivery had occurred within 18 to 24 hours, the PGE₂ instillation was repeated or the oxytocin infusion was increased. The abortion rates at 24 hours were 90% for those who received 5-mg instillations and 88% for 10-mg instillations, and mean times to abortion were 15.5 and 14.5 hours, respectively. Vomiting was reported in 39%, diarrhea in 5%, hemorrhage in 1.5%, transfusion in .7%, genital trauma in .3%, and infection in .4%.

The World Health Organization⁸ reported a comparative analysis of 1503 women who had abortions at 13 to 22 weeks' gestation with either intra-amniotic PGF_2α or hypertonic saline. The regimens consisted of 25 mg of intra-amniotic PGF_2α with a repeat dose 6 hours later or hypertonic saline (20% NaCl) 200 mL as a single instillation. The abortion rates at 24 hours were 61% and 20% and at 48 hours were 86% and 80%, respectively. The mean times to abortion were 19.7 hours for PGF_2α and 30.0 hours for saline. Approximately 33% of patients in both groups required curettage for retained placenta or incomplete abortion. Although side effects like diarrhea (15% versus 1.3%) and vomiting (54% versus 19%) were more common after instillation of PGF_2α, there were no statistically significant differences in serious complications such as hemorrhage (4.5% PGF_2α group versus 1.5% saline group) or transfusion (3.1% and .8%, respectively).

Grimes and associates¹⁴ reported data from the JPSA comparing side effects and complications between 1241 PGF_2α instillation abortions and 10,013 using hypertonic saline. In this series, the dose of PGF_2α included 25 mg (23%), 40 mg (44%), and 50 mg (7%) as single-dose instillations. Intravenous oxytocin was added in 61% of women receiving PGF_2α and 90% of those with saline. Most subjects did not receive laminaria. The major complication rate was 2.9% for the PGF_2α abortions and 1.8% for saline. The uncorrected and corrected relative risk of a serious complication was 1.6. Specifically, the risks of hemorrhage, retained placenta, infection, convulsions, and re-admission were increased with PGF_2α abortions. There were no statistical differences in the rate of cervical injuries. The risk of a serious complication did not vary by dose of PGF_2α. Thus, although PGF_2α appears more effective than hypertonic saline at successfully terminating pregnancy, it is also associated with more side effects and complications.

Prostaglandin analogues, specifically 15-methyl PGF_2α, have a prolonged duration of action because they are not inactivated by the 15-dehydrogenase enzyme. Subsequently, their development led to investigations of whether they would be as effective for labor induction abortion. The World Health Organization¹⁵ performed three studies, including two randomized trials, comparing a single instillation of 2.5 mg of 15-methyl PGF_2α to 40 mg and 50 mg of PGF_2α. The abortion rates for the women receiving15-methyl PGF_2α was similar in all three studies: 72% to 76% at 24 hours and 93% to 96% at 48 hours. These rates were significantly better than the rates of either 40-mg PGF_2α (54% at 24 hours and 82% at 48 hours) or 50-mg PGF_2α (68% at 24 hours and 87% at 48 hours). The mean time to abortion was 18 to 20 hours for all of the treatment groups. Use of 15-methyl PGF_2α resulted in significantly lower rates of hemorrhage (1% to 2% versus 3% to 4%), vomiting (1.3% to 1.5% versus 1.7% to 2.1%), and diarrhea (.4% to .5% versus 1.2% to 1.3%). Cervical injury occurred equally in both groups (2.9%); the only serious complication in the entire study was an extension of one of these lacerations into the lower uterine segment. Thus, 15-methyl PGF_2α seems to be a better agent than the natural PGF_2α at effecting labor induction abortion in the doses tested.

Intra-Amniotic Medication Combinations

In efforts to further improve efficacy of second trimester inductions and to decrease the induction to abortion interval, combinations of intrauterine agents have been investigated.

HYPERTONIC SALINE PLUS PROSTAGLANDIN F_2α

In a study of 508 women from 14 to 24 weeks' gestation (mean: 19.9 weeks), 20 mg of PGF_2α was added to an instillation of hypertonic saline. Ninety-six percent of women delivered by 24 hours, the mean instillation to abortion time was 16.1 hours, and 24% of the patients required curettage for retained placenta.¹⁶ Such high success and rapid delivery did result in undesirable side effects. Nausea, vomiting, diarrhea, and fever occurred in 48%, 33%, 1%, and 3%, respectively. Serious side effects included coagulopathy in 1%, hemorrhage in 2%, and transfusion in 2%. One case of uterine rupture and one case of sepsis also occurred.

UREA PLUS PROSTAGLANDIN F_2α

The use of urea combined only with intravenous oxytocin, as described previously, was abandoned because regimens that also included the instillation of prostaglandins were found to be more effective.¹⁰ When these data were expanded to investigate the effects of varying doses of PGF_2α, use of laminaria, and history of previous cesarean section, varying degrees of success were noted.¹⁷ Specifically, successful induction rates were approximately 90% for women with no previous cesarean and 60% for women with a previous cesarean section.¹⁷ Laminaria appeared to be of benefit in those women who were nulliparous or who had a previous cesarean section. Additionally, a dose of 5 mg of PGF_2α appeared to work as well as a dose of 10 mg; however, the number of patients who received each type of treatment was so small that definitive conclusions could not be made. Uterine rupture was reported in 1 of the 76 (1.3%) patients who had a previous cesarean section as compared with 5 of the 1580 (0.3%) who did not have a previous cesarean section. The risk of uterine rupture appeared to be related to an induction of longer than 24 hours, possibly caused by increasing amounts of oxytocin infusion.

The addition of intra-amniotic PGF_2α to intra-amniotic urea and intravenous oxytocin does result in more complete and rapid expulsion; however, the trade-off is a higher rate of side effects and complications.¹⁰ Nausea and vomiting occur in approximately 73% of patients treated with intra-amniotic urea and PGF_2α and intravenous oxytocin as compared to 53% of those who receive just the intra-amniotic urea and intravenous oxytocin. Similarly, diarrhea occurs in 5% and 1%, respectively. The hemorrhage (9% to 10% and 5%, respectively) and cervical laceration (3% and 1%, respectively) rates are also greater. Coagulopathy (.08% and .15%) and infection (9% to 10%) rates were similar between the groups.

The outcomes and complications associated with urea–prostaglandin (PGF_2α) and hypertonic saline instillation abortions were compared using data from the JPSA.⁹ Between 1975 and 1978, data on 4778 saline and 2805 urea–PGF_2α abortions was collected. The PGF_2α dose varied from 5 to 10 mg. Intravenous oxytocin was used in 99% of the saline procedures and 80% of the urea–PGF_2α abortions. The time to abortion was more rapid with the urea–PGF_2α instillations, averaging 16.1 hours when laminaria were not used and 11.6 hours with laminaria. The interval to abortion with saline and oxytocin was 20.6 hours and the addition of laminaria did not improve this. The overall rate of serious complications was lower with urea–PGF_2α abortions (1% versus 2%) with an adjusted relative risk for a serious complication of 2.1 for the use of hypertonic saline as compared with hyperosmolar urea–PGF_2α. The rates of hemorrhage requiring transfusion (1.7% and .3%) and retained placenta (14.8% and 10.3%) were significantly higher for saline abortions; however, some minor complications such as hemorrhage not requiring transfusion (2.2% versus 6.2%), infection (5.0% versus 6.3%), and cervical injury (.4% versus 1.3%) were higher for urea–PGF_2α instillations. Thus, it appeared that urea–PGF2a for second trimester instillation abortion was faster and safer than hypertonic saline but was still not ideal as rates of nonserious complications were still relatively high.

The combination of urea with 15-methyl PGF_2α, has also been evaluated.¹⁸ In a small series (n = 62) of women at 16 to 27 weeks' gestation (mean: 21.0 weeks), laminaria were inserted immediately before instillation of urea 80 g and 2 mg of 15-methyl PGF_2α. The success rate at 24 hours was 97% with a mean time to abortion of 13.2 hours. Curettage was necessary for incomplete abortion or retained placenta in 61% of cases. Vomiting occurred in 34%, diarrhea in 13%, hemorrhage in 2%, and infection in 2%. This series suggests that use of 15-methyl PGF_2α, combined with intra-amniotic urea and intracervical laminaria, has similar overall efficacy and speed as a similar regimen using PGF_2α¹⁷ but 15-methyl PGF_2α is associated with fewer side effects and does not require intravenous high-dose oxytocin to obtain this outcome.

Thus, the addition of intra-amniotic prostaglandins to other instillation agents like hypertonic saline and urea results in more rapid abortion, but more side effects.

Extra-Amniotic Instillation

PROSTAGLANDINS

Extra-amniotic PGE₂ instillation through the cervical os was first described in the early 1970s. The preparation of PGE₂ in a cellulose gel allowed administration without constant infusion. In a series of 1608 patients treated with 1.5 mg or 2.5 mg of PGE₂ gel injected via a catheter through the internal os into the extra-amniotic space plus intravenous oxytocin beginning 6 hours after gel administration, abortion occurred within 24 hours in approximately 78% of those women who received 1.5 mg and 90% who received 2.5 mg.¹³ The mean time to abortion was also significantly different, 15.7 hours versus 14.0 hours, respectively. Vomiting was reported in 45%, diarrhea in 17%, transfusion in .5%, infection in .2%, and a cervical laceration in .06%. Only 35% had a complete abortion and did not require surgical evacuation for retained placenta. A small study¹⁹ used a lower concentration of PGE₂ gel (.75 mg) with reapplication in 5 hours followed by intravenous oxytocin administration. Success rates were 80% at 24 hours and the mean time to abortion was 17.6 hours. Vomiting was reported in 30% and diarrhea in 5%. Retained placenta occurred in 20% of patients. This suggests that a lower dose of PGE₂ gel may be used with similar efficacy to a 2.5-mg dose, although the time to delivery is slightly longer in exchange for fewer side effects. Further treatment of an additional 41 women by the same investigators found similar results but higher rates of diarrhea (11%), retained placenta (39%), and hemorrhage requiring transfusion (8%).²⁰ Even lower doses have been tested but have unacceptable success rates and longer times for delivery.²⁰

ETHACRIDINE LACTATE

This method is scarcely described in the English literature; historically, it has been described more commonly in German and Japanese reports. The most common place in which this method is still used on occasion is some Eastern European and Asian countries. Ethacridine lactate is a yellow dye with antiseptic properties that was reported, in unsubstantiated work in the early part of this century, to have some uterine contractile effects in experimental animals. Scattered reports have turned up in the English literature over the past three decades, suggesting that there is some action of this agent to effect abortion, but not as quickly or effectively as other commonly used agents.

Ingemanson²¹ instilled a .1%-solution of ethacridine lactate into the extra-amniotic space through a sterile catheter at a dose of 10 mL per gestational week to a maximum of 150 mL. No oxytocin was administered. In 29 women at 13 to 16 weeks' gestation, the abortion rate was 45% at 24 hours, 72% at 48 hours, and 93% at 72 hours. In 24 women at 17 to 20 weeks' gestation, the abortion rate was 29% at 24 hours and 96% at 48 hours. In both groups, the rate was significantly greater than that for a comparison group of women who received extra-amniotic hypertonic saline (20% NaCl). Additionally, no gastrointestinal side effects were noted. Ten percent of the ethacridine lactate patients had significant temperature elevation and 1% had infection.

Two separate reports from Ankara, Turkey have also described limited experience with this method compared with other induction techniques. Inan and colleagues²² used the same dosing method for ethacridine lactate as described, except the maximum dose was 200 mL. The authors found an abortion rate of approximately 80% at 24 hours in groups of 48 and 49 women, respectively, who received the ethacridine lactate alone or in combination with intravenous oxytocin. Yapar and associates²³ used even more .1% ethacridine lactate (250 to 300 mL) combined with intravenous oxytocin if needed (only used in 50%) in 82 patients from 14 to 28 (mean: 19.4) weeks; gestation. The abortion rate was 69% at 24 hours and 99% at 48 hours with a mean time to delivery of 16 hours. Notable side effects were coagulopathy in 2% and hemorrhage secondary to uterine atony in 2%.

Ethacridine lactate appears to be an interesting agent for labor induction abortion in the second trimester but the clinical applicability in facilities with other resources appears limited by the relatively long period of time for delivery to occur.

A concentrated high-dose oxytocin regimen was first described by Winkler and associates²⁴ in a retrospective evaluation of 22 subjects. Beginning with a dose of 100 units per 500 mL of D5NS, the 500 mL is infused over 3 hours, and then 1 hour is allowed for diuresis to preclude water intoxication. The dose of oxytocin is increased 50 units per 500 mL of D5NS until delivery is achieved, to a maximum of 300 units. This method was compared with a cohort of 59 women receiving vaginal PGE₂ (20 mg every 4 hours for 24 hours). Both groups included women at 17 to 24 weeks' gestation, with a mean of 21.3 weeks for the oxytocin group and 19.3 weeks for the PGE₂ group. This method effected delivery in 91% of women receiving the oxytocin regimen, with a mean time to delivery of 8.2 hours. The PGE₂ group had a similar rate of efficacy (93%) but had a significantly longer mean time to delivery (13.1 hours). As compared with the PGE₂ group, those receiving the oxytocin infusion had less nausea (46% versus 9%), vomiting (37% versus 9%), fever (64% versus 0), diarrhea (20% versus 0), and live births (8.5% versus 0). These side effects occurred despite premedication of women in the prostaglandin group with antipyretic, antiemetic, and antidiarrheal agents.

This evaluation was followed by the same group with a prospective randomized trial using the same regimens in a similar population.²⁵ In this trial, all women with intact membranes and a closed cervix had hygroscopic dilator (Dilapan) placement 4 hours before initiation of treatment. Approximately 20% of the subjects in both groups had a fetal demise. The abortion rates by 24 hours were similar, 86% and 80% for the PGE₂ and oxytocin groups, as were the mean times to delivery, 13.2 and 12.6 hours, respectively. As with the preliminary study, women who received prostaglandin had more nausea (62% versus 33%), vomiting (54% versus 18%), fever (21% versus 0), diarrhea (24% versus 0), and live births (18% versus 3%). One subject in the oxytocin group had a uterine rupture and required hysterectomy. Thus, use of this high-dose oxytocin regimen appears, in small randomized studies, to be equivalent to intravaginal prostaglandin with fewer side effects.

Yapar and colleagues²³ reported their experience in Turkey with a less concentrated regimen of oxytocin in 36 women at 14 to 28 weeks' gestation (mean: 20.2 weeks). This regimen started with 5 units per 500 mL of D5NS infused over 3 hours, followed by 1 hour of D5NS. This 4-hour cycle is repeated, increasing the oxytocin concentration by 5 units each time to a maximum of 30 units. The abortion rates were 92% at 24 hours and 97% at 48 hours. Two patients were reported to have significant fever, two had coagulopathy, one had hemorrhage without requiring transfusion, and one patient had uterine rupture and maternal death (a patient at 24 weeks' gestation with an intrauterine fetal demise).

Prostaglandin E₂

In 1978, vaginally administered PGE₂ became available for abortion in the second trimester. These suppositories are not stable at room temperature and require refrigeration. Typical doses are a single suppository (20 mg) every 3 or 4 hours. Abortion rates are approximately 50% at 12 hours^26,27 after initial administration and 81% to 96% at 24 hours.^{24,25,26,27,28,29} In nonrandomized studies, addition of oxytocin and pretreatment with laminaria do not appear to shorten the time to delivery.^24,26 The average interval to delivery is approximately 12 to 14 hours,^{24,25,26,27,28,29,30} but earlier gestations respond more slowly than those of 16 weeks or more.^26,27

Vaginally administered PGE₂ was a potentially attractive alternative to both intra-amniotic instillations and extra-amniotic administration of prostaglandins, because of the relatively rapid time to delivery and ease of administration. Unfortunately, side effects occur at a very undesirable rate despite pretreatment with antipyretic, antiemetic, and antidiarrheal agents. Vomiting is reported in approximately 30% to 80% of women, diarrhea in 15% to 39%, and pyrexia (temperature exceeding 38(C) in 21% to 64%.^{24,25,26,27,29,30} Between 42% and 50% of women will need a curettage for retained placenta or incomplete abortion.^24,30 These side effects rates appear similar to those with extra-amniotic PGE₂ gel administration. Live birth has been reported to occur in 1% to 21% of vaginal PGE₂ inductions.^{24,25,26,27,28} Rare side effects such as severe hypotension^25,30 and hypertension^24,30 have also been reported with the use of PGE₂ suppositories, but not at a rate greater than with intra-amniotic PGF_2α.³⁰

One more recent randomized trial compared intramuscular (IM) 15-methyl PGF_2α (.25 mg every 3 hours) to intravaginal PGE₂ suppositories (20 mg every 3 hours).²⁸ Of the 26 women at 14 to 24 weeks' gestation who received the IM regimen, only 69% were delivered at 24 hours compared with 96% for the PGE₂ group. The mean times to abortion were 21.2 and 12.2 hours, respectively. This intramuscular regimen does not provide a clinically acceptable rate of abortion given other options available to clinicians.

Prostaglandin E₁ Analogue: Gemeprost

Gemeprost, a PGE₁ analogue, is a vaginally administered prostaglandin analogue more commonly used in Europe. Like PGE₂, these suppositories are not stable at room temperature and require refrigeration. Typical doses were initially a single suppository (1 mg) every 3 hours with abortion rates of approximately 80% at 24 hours after initial administration and 95% at 48 hours.^31,32 In the past decade, some investigators have questioned whether a regimen with less frequent administration would provide equal efficacy with fewer side effects. Two prospective randomized studies performed in the United Kingdom compared vaginal gemeprost 1 mg every 3 hours for a maximum of 5 doses in 24 hours to 1 mg every 6 hours for 4 doses in 24 hours.^33,34 The regimens were repeated 24 hours after the initial treatment and intravenous oxytocin was started if the abortion had not occurred within 36 to 48 hours. These two studies found that although more frequent dosing was associated with a somewhat more rapid abortion interval, the cumulative abortion rates within 24 hours, the overall rate of side effects and the rate of surgical intervention for incomplete abortion was the same in both groups.^33,34 These data suggest that a 6-hour interval between dosing for gemeprost is statistically identical to the 3-hour regimen in terms of overall efficacy, time to abortion, side effects, and pain medication requirements, thereby allowing fewer dosings and lower costs.

Prostaglandin E1 Analogue: Misoprostol

Vaginal misoprostol, another PGE₁ analogue, has more recently been evaluated in second trimester abortion. This preparation has the advantage of being stable at room temperature and inexpensive. In an initial study of primarily early second trimester patients administered an 800-microgram dose followed by 400 micrograms at 18 and 24 hours if needed, 102 of 128 (80%) aborted within the first 18 hours, with a mean interval to abortion of 11.8 hours.³⁵ No severe side effects were reported and pain was minimal, with only 20% of patients requiring paracetamol. All patients had curettage after expulsion of the fetus, so the rate of retained placenta was unable to be evaluated.

Since that report, several randomized controlled trials have investigated the use of misoprostol for second trimester induction of labor. Comparing or combining data from these studies is difficult for several reasons. First, different studies use different definitions of successful induction. Some studies define success as complete abortion, such that no curettage is required. This definition is similar to the definition used for successful medical abortion in the first trimester.³⁶ Other studies define success as delivery of the fetus within a prespecified time frame, usually 24 or 48 hours. Also, different studies managed patients with prolonged inductions (undelivered at 24 or 48 hours) differently. In some studies, all patients undelivered at 24 or 48 hours underwent D&E, and in other studies they were managed with alternative medications. Combining these reports is further complicated by differences in the mean gestational age of patients enrolled, by the use of additional interventions (such as fetal injections with intracardiac KCl and intracervical laminaria) and by the inclusion of patients with spontaneous fetal demise. All of these factors may have significant impact on outcomes. Because nearly all studies present data on successful delivery of the fetus at 48 hours and mean or median time to delivery of the fetus, Table 2 provides these main outcomes for randomized controlled trials of misoprostol for second trimester induction of labor.

Table 2. Randomized Controlled Trials of Misoprostol for Second Trimester Induction of Labor

Summarizing these data, randomized trials have been conducted comparing misoprostol with PGE₂ suppositories alone,²⁹ high-dose oxytocin combined with PGE₂ suppositories,³⁷ gemeprost,^38,39,40 intra-amniotic PGF_2α,⁴¹ and intra-amniotic 15-methyl PGF_2α.⁴² In these comparisons, misoprostol was as effective as vaginal PGE₂ alone,²⁹ intra-amniotic PGF_2α,⁴¹ and equal to or more effective than gemeprost.^38,39,40 In contrast, misoprostol was less effective than intra-amniotic 15-methyl PGF_2α or high-dose oxytocin combined with vaginal PGE₂.^37,42 However, these findings may be strongly influenced by the dose of misoprostol studied. Generally, higher doses and more frequent dosing of misoprostol have been associated with greater success rates and a decreased induction to abortion interval.

Although several randomized controlled trials have investigated different dosing regimens for misoprostol,^{39,43,44,45,46,47} the ideal dosing for second trimester induction of labor remains unclear. These studies suggest that the ideal dose of vaginal misoprostol for second trimester induction is between 200 and 600 micrograms and the ideal dosing interval is between 3 and 12 hours. One study comparing 400 micrograms of misoprostol administered vaginally every 3 hours versus every 6 hours found greater success rates (91% versus 76%) and more rapid time to delivery (15 versus 19 hours) with more frequent dosing.⁴⁴ Two subsequent studies evaluating misoprostol 400 micrograms vaginally every 4 to 6 hours found that 76% to 85% of women delivered within 24 hours,^46,47 and the time to delivery was 19.6 hours (mean)⁴⁷ and 15.1 hours (median).⁴⁶ Compared with a 600-microgram dose, the 400-microgram dose was associated with less vomiting (28% versus 37%), diarrhea (2% versus 10%) and fever.⁴⁶ However, the incidence of fever using the 400-microgram dose every 4 hours was still high (25%).⁴⁷ Despite the presence of fever, none of the patients had an infection diagnosed, and all fevers resolved after delivery. Consistently, all studies that have included patients with spontaneous fetal demise have demonstrated more rapid time to delivery in these patients compared with patients beginning induction with a nondemised fetus.^29,43,46,48

It is unclear if pretreatment with laminaria decreases the induction interval. One randomized study found no decrease in time to abortion when laminaria were placed at the time of initiating misoprostol.⁴⁸ In contrast, studies of older induction methods found a marked decrease in abortion interval when laminaria were placed approximately 18 hours before treatment with prostaglandins.⁴⁹ Similarly, it is unclear if feticide before second trimester induction of labor decreases the induction to abortion interval. Most studies that include women with fetuses close to the limits of viability use feticide to prevent live births, and studies of misoprostol inductions when feticide is not used do not report on the frequency of live births.

Uterine rupture has been reported in five women undergoing second trimester abortion with misoprostol.^{50,51,52,53,54} Three of these five women had a previous uterine scar and all were between 18 and 25 weeks' gestation. Two women had received a single 200-microgram dose of misoprostol and the other three women had received multiple doses. The absolute risk of uterine rupture with misoprostol induction of labor in the second trimester is unknown, but is likely fairly low. Although misoprostol is contraindicated for induction of labor in the third trimester with a viable fetus, there is insufficient evidence to contraindicate its use for women with a uterine scar undergoing second trimester induction abortion. It is also unclear if using other agents for second trimester induction of labor in women with a uterine scar confers any lower risk.

Mifepristone and Prostaglandin Analogues

The most dramatic improvement in second trimester induction abortion technology has come with the introduction of mifepristone. The induction to abortion interval has been dramatically reduced when mifepristone is used before prostaglandin analogues.⁵⁵

The classic dose of mifepristone is 600 mg administered orally, followed 36 to 48 hours later by hospital admission for administration of prostaglandin. Initially, the prostaglandin used was gemeprost, 1 mg every 3 hours for a maximum of 5 doses in 24 hours. The largest experience published with this regimen is a multicenter trial of 267 gestations between 12 and 24 weeks (mean: 16.6 weeks) from 20 centers.⁵⁶ Two percent of women aborted just from the mifepristone, 100% aborted within 75 hours of beginning treatment, and the mean induction to abortion time was 7 hours after gemeprost administration. Vomiting occurred in 6% and diarrhea in 1% of women; these rates are much lower than those seen with other methods. Surgical evacuation for retained placenta or incomplete abortion was performed in 53% of patients. Two patients (.7%) required a blood transfusion and one patient with a previous cesarean section had a rupture of her uterus 51 hours after initiation of gemeprost (she had received two full courses of gemeprost and then an extra-amniotic PGE₂ infusion).

In a cohort of 100 women at 12 to 21 weeks' gestation (mean: 15 weeks), Thong and Baird demonstrated that 200 mg of mifepristone could be used as successfully as 600 mg.⁵⁷ At 36 to 48 hours after mifepristone administration, subjects received gemeprost 1 mg every 6 hours for the first 24 hours, and then every 3 hours for the next 12 hours followed by intravenous oxytocin. Two subjects also received an initial dose of intra-amniotic urea. By 8 hours, 57% of women had aborted, and 96% and 99% aborted within 24 and 48 hours, respectively. The average time to delivery was 7.5 hours after gemeprost administration, and a total of 33% required some surgical intervention. No blood transfusions were necessary and one patient had a cervical laceration that required repair. Vomiting occurred in 31% and diarrhea in 5% of subjects.

As with early first trimester abortions, misoprostol has also been evaluated in combination with mifepristone. The advantages of misoprostol over gemeprost are lower cost and no need for refrigeration of the medication. Initially, two randomized controlled trials compared misoprostol with gemeprost when used after mifepristone for second trimester induction of labor.^58,59 These studies both demonstrated that, when administered 36 to 48 hours after mifepristone, misoprostol and gemeprost are equally effective, with similar induction to abortion intervals and side effect rates (Table 3).

Table 3. Randomized Controlled Trials of Mifepristone and Misoprostol for Second Trimester Induction of Labor

Similar to other mifepristone dosing studies, a randomized trial demonstrated equal efficacy and similar rates of side effects and complications with 200-mg and 600-mg doses of mifepristone used 36 to 48 hours before misoprostol⁶⁰ (see Table 3). In this study, 11% of women had a retained placenta and one woman in each group required a transfusion.⁶⁰ Because mifepristone is an expensive drug, these data suggest that a decreased dose of mifepristone can be used with equal efficacy and much reduced cost.

Three randomized controlled trials then compared a variety of misoprostol dosing regimens. In each study, misoprostol was initiated 36 to 48 hours after mifepristone (see Table 3). El-Rafaey and colleagues⁶¹ used a single loading dose of 600 micrograms of vaginal misoprostol in all women and then compared repeat misoprostol doses of 400 micrograms every 3 hours, administered either orally or vaginally (to a maximum of 5 doses). No significant differences were found in success rates, time to abortion, side effects, and complications. Ho⁶² compared 200 micrograms of misoprostol dosed every 3 hours, administered either orally or vaginally. He found a higher success rate and more rapid time to abortion using the vaginal route of administration. Ngai⁶³ compared 200 micrograms of misoprostol administered vaginally to 400 micrograms administered orally, given at the same interval, and found these doses to be equivalent (see Table 3).

In a large case series of 500 women at 13 to 21 weeks' gestation who received 200 mg of mifepristone followed 36 to 48 hours later by an 800-microgram loading dose of vaginal misoprostol, and then repeat oral misoprostol doses of 400 micrograms every 3 hours, 97% of women aborted within 15 hours of their first misoprostol dose. In this study the median induction to abortion interval was 6.5 hours and 9.4% of women required surgical evacuation.⁶⁴

These trials suggest that 200 mg of mifepristone followed 36 to 48 hours later by misoprostol is very effective at inducing abortion within 24 hours after the first misoprostol dose. Higher doses of misoprostol have been associated with greater efficacy and shorter induction to abortion intervals. Data primarily from the United Kingdom have shown the highest complete abortion rates, using a vaginal loading dose of 600 to 800 micrograms of misoprostol followed by 400 micrograms orally every 3 hours. The efficacy of this regimen, and rates of transient fetal survival, for women late in the second trimester is unknown, because most of these trials only included women at 20 weeks' gestation or less.

Comparison of labor induction methods and D&E is difficult because the medical literature comparing modern methods of both techniques is sparse. Generally, physicians within a community tend to perform either one type of procedure or the other, making comparisons difficult.

One of the first reports to compare labor induction to D&E was published in 1984 by Kafrissen and associates¹ from the United States CDC. In this study, 2805 patients at 13 to 24 weeks' gestation (95% between 17 and 24 weeks) were treated with intra-amniotic urea combined with PGF2_α. Eighty percent of women also received intravenous oxytocin and 41% received intracervical laminaria. The comparative group of D&E included 9572 patients, of which 91% were between 13 and 16 weeks' gestation and 9% between 17 and 24 weeks. Laminaria were used for cervical dilation in only 23% of the D&E procedures. The techniques studied and the distributions of the patients by gestational age were reflective of practice patterns in the 1970s.

Overall, the serious complication rate was 1.03% for the instillation abortion and .49% for D&E, with a relative risk of 2.1. When the risk was adjusted for age, race, parity, medical conditions, and follow-up, the relative risk remained significantly elevated (1.9; 95% confidence intervals [CI]: 1.2, 3.1). Instillation abortion patients were more likely to have fever, retained products, endometritis, and cervical injury requiring repair. However, women having D&E were more likely to have a perforation (.2% versus 0%). The incidences of coagulopathy and death were rare for both procedures (1 to 2 per 10,000) and not significantly different. Finally, those patients who had urea-PGF_2α instillation were 12-times more likely to require another technique to complete the abortion compared with D&E (1.7% versus 0.15%, respectively). The authors separately evaluated abortions performed at 17 to 20 weeks' gestation and found no differences in complications rates between techniques.

Recent studies of modern second trimester D&E techniques have shown the procedure as currently practiced to be extremely safe. One case series of 171 patients undergoing D&E at 18 to 22 weeks' gestation reported an overall complication rate of 1.2%.⁶⁵ Another study comparing suction curettage at less than 15 weeks' gestation to D&E at 15 to 20 weeks' gestation (N = 3355) found an overall complication rate of 5.1% for suction curettage and 2.9% for D&E (p = .056).⁶⁶ In this large comparative study, the complications with D&E included infection in 2% (hospitalization in .4%), incomplete abortion in .4%, perforation in one patient (.2%), transfusion in one patient (.2%) and disseminated intravascular coagulation in one patient (.2%). According to CDC-defined criteria,² the overall serious complication rate was .2%.

More recently, Autry and associates³ compared complication rates among 158 women undergoing second trimester induction abortion and 139 undergoing D&E. The patients ranged from 14 to 24 weeks' gestation and had a mean gestational age of 20.3 weeks in the induction group and 18.4 in the D&E group (p < .001). Of the induction group, 125 women were treated with misoprostol and the remaining women were managed with other techniques. Complications included failed medical abortion (requiring dilation and curettage), hemorrhage requiring transfusion, infection requiring intravenous antibiotics, retained products of conception requiring evacuation, organ damage that required additional surgery (including uterine perforation), cervical laceration that required repair, and readmission to the hospital. Using this definition, 29% (45/158) of women in the induction group had at least one complication compared with 4% (5/139) in the D&E group (p < .001). Of the 52 complications in the induction group (several women had more than one complication), 33 were retained products requiring evacuation and 11 were failed initial method. One woman in each group had hemorrhage requiring transfusion, two women in the induction group and none in the D&E group had organ damage requiring surgery (including uterine rupture or perforation), and two women in the induction group versus three in the D&E group had a cervical laceration requiring repair. Women who underwent induction of labor with misoprostol had fewer complications than women who were induced using other methods (22% versus 55%; p < .001); however, misoprostol induction patients still had more complications than D&E patients (22% versus 4%; p < .001). After controlling for gestational age and other potential confounding variables in a logistic regression analysis, these associations remained statistically significant (D&E group, odds ratio [OR] for all complications = .1; 95% CI: .0 to .3). Although this study suggests that modern techniques of D&E are associated with lower complication rates than modern techniques of induction of labor, the data comparing these two procedures as currently practiced are extremely limited. Further work will be necessary to compare modern methods of labor induction and D&E, including overall risk and cost.

Labor induction abortion provides a relatively safe method of terminating pregnancies in the second trimester. With the introduction of new prostaglandin analogues and mifepristone, there have been major changes in efficacy, side effect profiles, and clinical practice. Mifepristone followed 36 to 48 hours later by a vaginal prostaglandin analogue (primarily misoprostol) appears to be the most effective and efficient method of labor induction (see Table 1). With this regimen, all medications are administered either orally or vaginally, and generally no invasive techniques are required. Using this combination of medications the overall success rate and speed of the abortion is unsurpassed. However, the published experience with mifepristone and misoprostol for second trimester induction abortion is still relatively small compared with the thousands of women reported in the medical literature who have had abortions with instillation techniques. To date, most of the clinical trials of mifepristone for second trimester induction abortion have been conducted in the United Kingdom or Asia, and most include women at a mean gestational age of 15 to 17 weeks. Since 1999, mifepristone has become available in many more countries; however, it is expensive and access remains limited in many places. Access to mifepristone and D&E training must continue to expand and further studies must be performed to better understand the relative differences in second trimester pregnancy termination techniques, taking into account gestational age and comparing efficacy, efficiency, complications, side effects, and patient preferences.

Whether a second trimester abortion is performed medically by labor induction or surgically by D&E, appropriate training and clinical skill is paramount to maximizing safety and efficacy and minimizing side effects and complications.

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