Advertisement

Labor induction abortion in the second trimester

      Abstract

      Labor induction abortion is effective throughout the second trimester. Patterns of use and gestational age limits vary by locality. Earlier gestations (typically 12 to 20 weeks) have shorter abortion times than later gestational ages, but differences in complication rates within the second trimester according to gestational age have not been demonstrated. The combination of mifepristone and misoprostol is the most effective and fastest regimen. Typically, mifepristone 200 mg is followed by use of misoprostol 24–48 h later. Ninety-five percent of abortions are complete within 24 h of misoprostol administration. Compared with misoprostol alone, the combined regimen results in a clinically significant reduction of 40% to 50% in time to abortion and can be used at all gestational ages. However, mifepristone is not widely available. Accordingly, prostaglandin analogues without mifepristone (most commonly misoprostol or gemeprost) or high-dose oxytocin are used. Misoprostol is more widely used because it is inexpensive and stable at room temperature. Misoprostol alone is best used vaginally or sublingually, and doses of 400 mcg are generally superior to 200 mcg or less. Dosing every 3 h is superior to less frequent dosing, although intervals of up to 12 h are effective when using higher doses (600 or 800 mcg) of misoprostol. Abortion rates at 24 h are approximately 80%–85%. Although gemeprost has similar outcomes as compared to misoprostol, it has higher cost, requires refrigeration, and can only be used vaginally. High-dose oxytocin can be used in circumstances when prostaglandins are not available or are contraindicated. Osmotic dilators do not shorten induction times when inserted at the same time as misoprostol; however, their use prior to induction using misoprostol has not been studied. Preprocedure-induced fetal demise has not been studied systematically for possible effects on time to abortion. While isolated case reports and retrospective reviews document uterine rupture during second-trimester induction with misoprostol, the magnitude of the risk is not known. The relationship of individual uterotonic agents to uterine rupture is not clear. Based on existing evidence, the Society of Family Planning recommends that, when labor induction abortion is performed in the second trimester, combined use of mifepristone and misoprostol is the ideal regimen to effect abortion quickly and completely. The Society of Family Planning further recommends that alternative regimens, primarily misoprostol alone, should only be used when mifepristone is not available.

      Keywords

      Background

      These guidelines focus on the technique of labor induction abortion from 13 to 24 weeks of pregnancy. Labor induction abortion affects expulsion of the fetus from the uterus without instrumentation. A failed labor induction abortion occurs when the fetus is not expelled within a specific timeframe, and an additional procedure is necessary. This terminology is not to be confused with medical (or medication) abortion, which involves the use of medications to cause abortion in the first trimester, commonly as an outpatient. Similar techniques may be used for labor induction abortion from the late first trimester into the early third trimester. Uterine instrumentation may be necessary either for removal of the fetus or retained placenta.
      These guidelines consider abortion of a living fetus during the second trimester of pregnancy and do not consider labor induction abortion for a pregnancy complicated by fetal demise. Pregnancies with fetal demise may be treated similarly in most cases; however, the dosage necessary to cause fetal expulsion is lower, and the induction process is typically shorter [
      • Jain J.K.
      • Mishell D.R.
      Comparison of intravaginal misoprostol with prostaglandin-E(2) for termination of 2nd-trimester pregnancy.
      ,
      • Jain J.K.
      • Mishell D.R.
      A comparison of misoprostol with and without laminaria tents for induction of second-trimester abortion.
      ,
      • Jain J.K.
      • Kuo J.
      • Mishell Jr, D.R.
      A comparison of two dosing regimens of intravaginal misoprostol for second-trimester pregnancy termination.
      ,
      • Dickinson J.E.
      • Evans S.F.
      The optimization of intravaginal misoprostol dosing schedules in second-trimester pregnancy termination.
      ].
      The majority of second-trimester abortions performed in the United States are performed surgically by dilation and evacuation (D&E) [
      • Strauss L.T.
      • Gamble S.B.
      • Parker W.Y.
      • Cook D.A.
      • Zane S.B.
      • Hamdan S.
      Abortion surveillance — United States, 2004.
      ]. The frequency of labor induction abortion increases as gestational age advances. In the late second trimester and early third trimester, labor induction is the primary method of termination in cases of fetal abnormalities. In many other countries, however, induction is the primary method of abortion throughout the second trimester. Whereas labor induction abortion represents approximately 2% of second-trimester abortions in the United States, [
      • Gamble S.B.
      • Strauss L.T.
      • Parker W.Y.
      • Cook D.A.
      • Zane S.B.
      • Hamdan S.
      Abortion surveillance — United States, 2005.
      ] more than 80% of abortions throughout the second trimester in Sweden and other Nordic countries are inductions [

      Socialstyrelsen. Aborter 2005. Stockholm, Sweden; 2006. Report No.: Report: 2006-42-2 (Evidence Grade: III).

      ].
      Comparing or combining data from studies investigating labor induction abortion is problematic because biologic differences, such as parity or fetal anomaly or demise, may influence outcomes. Additional problems include the following:
      • Gestational age: reports may include various gestational age ranges, such as 12–16, 12–20, 12–23 weeks, or be restricted to the latter part of the second trimester, for example, 18–23 weeks.
      • Additional interventions: use of additional interventions, such as oxytocin, or induced fetal demise complicates interpretation of the data. Some studies include women both with and without spontaneous fetal demise. All of these factors may impact outcome measures of success.
      • Procedure length: comparisons of labor induction abortion methods usually include an assessment of the length of the procedure, for which there is no universally accepted definition. Abortion time, induction time, and time to abortion are used synonymously. These guidelines consider abortion time or induction time as the interval from the start of uterotonic medication to fetal expulsion. Some reports consider the abortion time to be the interval from the start of medication to placental delivery. Since the interval from fetal expulsion to placental delivery is highly dependent on practice patterns regarding management of the placenta, these guidelines consider the interval from fetal expulsion to placental delivery separately from the abortion time. Since these assessments are “time-to-event” measurement, nonparametric techniques are appropriate, and times should be reported as the median value. However, in many studies, the mean time to abortion is reported, which limits the ability to interpret the data.
      • Definitions of successful abortion: 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. Some studies define success as delivery of the fetus within a prespecified time frame, usually 24 or 48 h. The most common definition of success, and the one that is used in these guidelines, is that the fetus is expelled by the medical method intended. We considered instrumental procedures to include any procedure where an instrument was passed into the uterine cavity. Procedures for fetal removal, which are uncommon, are distinguished from procedures for placental removal, which are much more common. Treatment of failure may be surgical or pharmacologic.

      Agents used for labor induction abortion

      Induction procedures, by definition, are dependent on uterine contractions sufficient to expel the fetus and placenta. The prostaglandin E1 (PGE1) analogues misoprostol and gemeprost, either alone or in combination with other agents, have supplanted most other methods because of high efficacy and the relative ease of use.
      Mifepristone is an antiprogestin that can be used 24–48 h before prostaglandin analogue administration.
      Misoprostol is a PGE1 analogue available in a tablet form that is stable at room temperature and inexpensive. It is formulated for oral use but is effective by vaginal, buccal, or sublingual administration for the purposes of abortion [
      • Ho P.C.
      • Blumenthal P.D.
      • Gemzell-Danielsson K.
      • Gomez Ponce de L.R.
      • Mittal S.
      • Tang O.S.
      Misoprostol for the termination of pregnancy with a live fetus at 13 to 26 weeks.
      ]. Both the route of administration and the dose influence the frequency of side effects, which are mostly gastrointestinal and include nausea, vomiting, intestinal cramping, and diarrhea. Transient pyrexia is also seen in 5%–10% of women. Fever may be confused with infection but resolves within several hours of stopping misoprostol. Side effects increase with both increasing higher doses and the cumulative dose of misoprostol [
      • Dodd C.M.
      • Crowther C.A.
      Misoprostol versus cervagem for the induction of labour to terminate pregnancy in the second and third trimester: a systematic review.
      ].
      Gemeprost is a PGE1 analogue that is chemically similar to misoprostol. It is formulated as a vaginal suppository that requires refrigeration and is not as widely available as misoprostol. Gemeprost is not available in the United States.
      Oxytocin can be used in doses that are much higher than those used for term induction. Higher doses are needed because of the relative paucity of oxytocin receptors early in gestation. Oxytocin alters the characteristics of uterine contractions by increasing contraction frequency, baseline tone (transiently) and contraction amplitude (strength) [
      • Shmygol A.
      • Gullam J.
      • Blanks A.
      • Thornton S.
      Multiple Mechanisms involved in oxytocin-induced modulation of myometrial conrtactility.
      ].
      Ethacridine lactate, a nonprostaglandin, is infused slowly into the extra-amniotic space appears to be a very safe agent to use [
      • Boza A.V.
      • de Leon R.G.
      • Castillo L.S.
      • Marino D.R.
      • Mitchell E.M.
      Misoprostol preferable to ethacridine lactate for abortions at 13–20 weeks of pregnancy: Cuban experience.
      ,
      • Kelekci S.
      • Erdemoglu E.
      • Inan I.
      Randomized study on the effect of adding oxytocin to ethacridine lactate or misoprostol for second-trimester termination of pregnancy.
      ].

      Clinical questions and recommendations

      At what gestational ages can labor induction abortion techniques be used?

      Gestational age parameters for induction abortion services are generally based on facility practices, patient and provider preference, applicable laws, and public policy. The minimum gestational age in individual reports varies from 12 to 18 weeks. The upper gestational age limit is frequently 20 or 22 weeks, but some reports include gestational ages to 24 or 26 weeks, and a few have limits up to 29 weeks.
      Su et al. [
      • Su L.L.
      • Biswas A.
      • Choolani M.
      • Kalaichelvan V.
      • Singh K.
      A prospective, randomized comparison of vaginal misoprostol versus intra-amniotic prostaglandins for midtrimester termination of pregnancy.
      ], in a series of women receiving misoprostol alone, noted shortened time to abortion in women with gestations up to 19 weeks compared to women with pregnancies over 19 weeks. Increasing gestational age is also correlated with increased induction time when using mifepristone and misoprostol from 12 to 20 weeks [
      • Ashok P.W.
      • Templeton A.
      • Wagaarachchi P.T.
      • Flett G.M.M.
      Midtrimester medical termination of pregnancy: a review of 1002 consecutive cases.
      ]. This relationship of gestational age to abortion time may be less evident as gestational age advances. In two smaller series of women with misoprostol induction at gestational ages 18–23 weeks' gestation, induction time was not related to gestational age [
      • Borgatta L.
      • Chen A.Y.
      • Vragovic O.
      • Stubblefield P.G.
      • Magloire C.A.
      A randomized clinical trial of the addition of laminaria to misoprostol and hypertonic saline for second-trimester induction abortion.
      ,
      • Kapp N.
      • Borgatta L.
      • Stubblefield P.G.
      • Vragovic O.
      • Moreno N.
      Mifepristone in midtrimester medical abortion: a randomized controlled trial.
      ]. In contrast to surgical abortion, complication rates do not appear to increase with advancing gestational age. In a retrospective study of terminations for fetal anomalies using vaginal misoprostol, Lo et al. [
      • Lo T.K.
      • Lau W.L.
      • Lai F.K.
      • et al.
      The effect of gestational age on the outcome of second-trimester termination of pregnancies for foetal abnormalities.
      ] noted that pregnancies less than 17 weeks had a higher rate of incomplete abortion and operative procedures as compared to pregnancies greater than 20 weeks. Unlike most other studies, these authors had follow-up data through 6 weeks postinduction.

      How does labor induction abortion compare to surgical abortion?

      Where both methods are available, the choice between induction and D&E may be made for either personal or medical reasons. In some instances, the woman may wish to see or hold her fetus. Examination of an intact fetus may improve the chances for accurate diagnosis of anatomic abnormalities. When an intact fetus is necessary for these reasons or others, use of induction techniques is required. However, chromosomal analysis can be performed with specimens obtained by D&E [
      • Shulman L.P.
      • Ling F.W.
      • Meyers C.M.
      • Shanklin D.R.
      • Simpson J.L.
      • Elias S.
      Dilation and evacuation for second-trimester genetic pregnancy termination.
      ]. These procedures do not have an effect on bereavement; women who self-select their technique have similar measures of grief resolution [
      • Burgoine G.A.
      • Van Kirk S.D.
      • Romm J.
      • Edelman A.B.
      • Jacobson S.L.
      • Jensen J.T.
      Comparison of perinatal grief after dilation and evacuation or labor induction in second trimester terminations for fetal anomalies.
      ].
      The choice of labor induction abortion over surgical abortion may be affected by the presence of infection or anemia. Acute cervical infection or pelvic infection is a relative contraindication to performing surgical abortion until antibiotic treatment has been started, whereas labor induction techniques can be started immediately. However, a serious pelvic infection may be associated with impaired uterine contractility, which can limit the effectiveness of induction methods. In the case of severe anemia, or if there is significant vaginal bleeding from placental abruption, a D&E procedure will generally stop bleeding promptly, unless there is an intraoperative injury or placental implantation abnormality. However, the delay to completing a D&E, if pretreatment with osmotic dilators is necessary, may also be a consideration. An induction method may be preferable if the woman has a relative contraindication to anesthesia. If she does need an operative procedure, it is most likely to be a placental removal, which can often be managed under local anesthesia with or without mild to moderate intravenous conscious sedation.
      Very few studies compare labor induction and D&E abortion, with only two randomized trials. One older study compared women predominantly at 13–16 weeks' gestation undergoing D&E to women at 17–24 weeks' gestation undergoing labor induction abortion with prostaglandin F2 (PGF2) or urea [
      • Kafrissen M.E.
      • Schulz K.F.
      • Grimes D.A.
      • Cates Jr., W.
      Midtrimester abortion. Intra-amniotic instillation of hyperosmolar urea and prostaglandin F2 alpha v dilatation and evacuation.
      ]. Major complications were more common in the induction group than in the D&E group (1.03 vs. 0.49 per 100 abortions). The incidences of coagulopathy or cardiac arrest were rare for D&E (1 to 2 per 10,000) and not reported with labor induction, although the numbers were too small to be significantly different. Overall, an additional technique was necessary to complete the procedure more frequently with labor induction than D&E (1.7% vs. 0.15%, respectively; RR 11.7 [95% confidence interval (CI), 7.3–18.7]).
      A second study comparing D&E with mifepristone and misoprostol induction was terminated early secondary to inadequate enrollment [
      • Grimes D.A.
      • Smith M.S.
      • Witham A.D.
      Mifepristone and misoprostol versus dilation and evacuation for midtrimester abortion: a pilot randomised controlled trial.
      ]. The number of women experiencing adverse events was lower among those who received D&E than with mifepristone and misoprostol (odds ratio, 0.06; 95% CI, 0.01–0.76). Women receiving mifepristone and misoprostol reported significantly more pain than those who underwent D&E; analgesia for labor induction was continuous morphine intravenous infusion with a patient-controlled system, while women having a D&E received light general anesthesia without intubation for D&E procedures. Efficacy and acceptability were similar between the two groups.
      Autry and associates [
      • Autry A.M.
      • Hayes E.C.
      • Jacobson G.F.
      • Kirby R.S.
      A comparison of medical induction and dilation and evacuation for second-trimester abortion.
      ] retrospectively compared complication rates of the two methods of abortion. Complications were defined as failed induction, transfusion, infection, retained products of conception, organ damage (including uterine perforation) requiring additional surgery, cervical laceration requiring repair, and hospital readmission. Complication rates were 29% for induction versus 4% for D&E (p<.001). The severity of the complications is important to understand as their implications are different. When labor induction abortions were limited to those just using misoprostol, the complication rates were still lower with D&E (22% vs. 4%, respectively; p<.001).
      A comparison of D&E and induction mortality rates from 1972 to 1987 showed that D&E had lower death rates under 20 weeks of gestation, while induction had lower rates after 20 weeks [
      • Lawson H.W.
      • Frye A.
      • Atrash H.K.
      • Smith J.C.
      • Shulman H.B.
      • Ramick M.
      Abortion mortality, United States, 1972 through 1987.
      ]. Cowett et al. [
      • Cowett A.A.
      • Golub R.M.
      • Grobman W.A.
      Cost-effectiveness of dilation and evacuation versus the induction of labor for second-trimester pregnancy termination.
      ], using decision analysis, reported that D&E is more cost effective than labor induction abortion using misoprostol alone.
      Although induction abortion and surgical abortion are dissimilar, intermediate or hybrid procedures have been described. Hern [
      • Hern W.M.
      Laminaria, induced fetal demise and misoprostol in late abortion.
      ] used preprocedure feticide and serial osmotic dilators prior to induction methods. On the day of abortion, he removed the dilators, performed an amniotomy, and administered intravaginal misoprostol. In some women, fetal expulsion was completed medically, while others had surgical completion. Multiple other techniques in use lack any evidence regarding efficacy or safety; examples include starting induction in the morning and completing the abortion by D&E for those women undelivered by late afternoon [

      National Abortion Federation Annual Clinical Meeting, Portland, Oregon, April 25, 2009.

      ]. This regimen allowed virtually all women to go home without an inpatient admission.
      Realistically, comparison of labor induction abortion methods to D&E is difficult because physicians generally perform one or the other. In many institutions, a choice between surgical and medical methods does not exist; only one method of abortion is available to women for reasons of either technical capability or of facility availability. If well-trained D&E providers are not available, induction is the safer method. Hospital services are usually necessary (or available for backup) for induction procedures. Local or state health policy or statutory restrictions may dictate one procedure or the other. Using the same published safety data, countries have developed policies and practices that are almost opposite from each other, as demonstrated by the predominance of surgical methods in the United States and the predominance of labor induction abortion in many other countries.

      What is the role for mifepristone prior to labor induction abortion?

      Using mifepristone prior to administering a prostaglandin analogue markedly reduced induction times compared to simply using the prostaglandin analogue alone for labor induction abortion. Mifepristone followed 36–48 h later by misoprostol or gemeprost consistently demonstrates mean induction times following prostaglandin administration of 6–8 h [
      • Royal College of Obstetricians and Gynaecologists
      The care of women requesting induced abortion.
      ].
      As in first trimester abortion, 200 mg of mifepristone is as effective as 600 mg when used from 13 to 20 weeks [
      • Webster D.
      • Penney G.C.
      • Templeton A.
      A comparison of 600 and 200 mg mifepristone prior to second trimester abortion with the prostaglandin misoprostol.
      ]. In a randomized controlled trial of 600 mg compared with 200 mg of mifepristone, each followed 36–48 h later by vaginal misoprostol, the two regimens had the same mean induction times, 6.9 h. Similar findings were obtained using gemeprost, with an average time to fetal expulsion of 7.5 h [
      • Thong K.J.
      • Baird D.T.
      Induction of 2nd trimester abortion with mifepristone and gemeprost.
      ]. Addition of mifepristone appears to lower nausea and vomiting rates as compared to prostaglandin alone, possibly because the induction is shorter and fewer doses of prostaglandin are needed [
      • Urquhart D.R.
      • Templeton A.A.
      The use of mifepristone prior to prostaglandin-induced midtrimester-abortion.
      ].
      Early studies used 600 mg of mifepristone 36–48 h before misoprostol, similar to initial first trimester abortion studies. The largest published study of this dosage used mifepristone 600 mg followed by gemeprost 1 mg every 3 h. This multicenter trial of 267 women from 12 to 24 weeks of pregnancy reported that the mean induction time was 7 h [
      UK Multicenter Study Group
      Oral mifepristone 600 mg and vaginal gemeprost for mid-trimester induction of abortion. An open multicenter study.
      ].
      Misoprostol regimens vary considerably among all studies using 200 mg of mifepristone. One of the most commonly used regimens is mifepristone 200 mg followed 36–48 h by misoprostol 800 mcg vaginally, then an additional 400 mcg vaginally every 3 h, to a maximum of 5 doses in 12 h. If abortion is not complete at that time, the woman has a 12-h rest before starting the cycle again [
      • Ashok P.W.
      • Templeton A.
      • Wagaarachchi P.T.
      • Flett G.M.M.
      Midtrimester medical termination of pregnancy: a review of 1002 consecutive cases.
      ,
      • Nigam A.
      • Singh V.K.
      • Prakash A.
      Vaginal vs. oral misoprostol for mid-trimester abortion.
      ,
      • Goh S.E.
      • Thong K.J.
      Induction of second trimester abortion (12–20 weeks) with mifepristone and misoprostol: a review of 386 consecutive cases.
      ,
      • Rose S.B.
      • Shand C.
      • Simmons A.
      Mifepristone- and misoprostol-induced mid-trimester termination of pregnancy: a review of 272 cases.
      ]. In the largest published series (n =1002, gestational ages 13–21 weeks), 97% of women aborted within 24 h, with mean induction times of 5.9 h for multiparous women and 6.6 h for nulliparous women [
      • Ashok P.W.
      • Templeton A.
      • Wagaarachchi P.T.
      • Flett G.M.M.
      Midtrimester medical termination of pregnancy: a review of 1002 consecutive cases.
      ]. This regimen is the basis of recommendations by World Health Organization and Royal College of Obstetricians and Gynaecologists, based on trials that included women predominantly at 20 weeks' gestation or less.
      Similar results are found with mifepristone followed by gemeprost [
      • Tang O.S.
      • Thong K.J.
      • Baird D.T.
      Second trimester medical abortion with mifepristone and gemeprost: a review of 956 cases.
      ]. The largest series (n=956, gestational ages 12–24 weeks) used 1 mg gemeprost suppositories every 6 h for 4 doses. If abortion was not complete at 24 h, the dosing frequency was increased to every 3 h. The median induction time was 7.8 h.
      A more complex regimen of mifepristone followed 36–48 h later by misoprostol and Dilapan™ osmotic dilators did not result in outcomes different than that reported with the use of misoprostol alone [
      • Esteve J.L.
      • Gallego F.G.
      • Llorente M.P.
      • Bermúdez S.B.
      • Sala E.S.
      • González L.V.
      • et al.
      Late second-trimester abortions induced with mifepristone, misoprostol and oxytocin: a report of 428 consecutive cases.
      ]. Investigators administered misoprostol 800 mcg vaginally and place two dilators. Four hours later, the dilators were removed, and a second dose of misoprostol 600 mcg was placed unless amniotomy could be performed. After amniotomy, intravenous oxytocin was initiated, and misoprostol was discontinued. The mean induction time was 6.9 h for both regimens.
      Tang et al. [
      • Tang O.S.
      • Chan C.C.W.
      • Kan A.S.Y.
      • Ho P.C.
      A prospective randomized comparison of sublingual and oral misoprostol when combined with mifepristone for medical abortion at 12–20 weeks gestation.
      ,
      • Tang O.S.
      • Lau W.N.
      • Chan C.C.
      • Ho P.C.
      A prospective randomised comparison of sublingual and vaginal misoprostol in second trimester termination of pregnancy.
      ] showed shorter median abortion times — 5.5 h versus 7.5 h — when mifepristone was followed 3 h later by sublingual misoprostol as compared to oral administration at 12–20 weeks. Side effects were similar between groups, except for transient fever that was more likely in the sublingual group. Hamoda et al. [
      • Hamoda H.
      • Ashok P.W.
      • Flett G.M.M.
      • Templeton A.
      A randomized trial of mifepristone in combination with misoprostol administered sublingually or vaginally for medical abortion at 13–20 weeks gestation.
      ] compared mifepristone followed 36–48 h later by vaginal misoprostol 800 mcg or sublingual misoprostol 600 mcg, as initial doses, followed by 400 mcg given by the same route every 3 h. Rates of complete abortion, side effects and patient satisfaction were similar between groups.
      Recent studies have investigated shorter intervals between the mifepristone and prostaglandin analogue. Kapp et al. [
      • Kapp N.
      • Borgatta L.
      • Stubblefield P.G.
      • Vragovic O.
      • Moreno N.
      Mifepristone in midtrimester medical abortion: a randomized controlled trial.
      ] randomized women at 18 to 23 weeks gestation to mifepristone 24 h before buccal misoprostol or misoprostol alone. The median abortion time with mifepristone was 10 h, a 45% reduction in time compared to the group without mifepristone. Nilas et al. [
      • Nilas L.
      • Glavind-Kristensen M.
      • Vejborg T.
      • Knudsen U.B.
      One or two day mifepristone-misoprostol interval for second trimester abortion.
      ] compared cohorts of women using a 1- or 2-day interval between mifepristone and vaginal misoprostol at 17–22 weeks. The women in the 1-day group had longer induction times, 9.8 versus 7.5 h (p<.01); 98% of the women in each group delivered within 24 h of receiving misoprostol. Heikinheimo et al. [
      • Heikinheimo O.
      • Suhonen S.
      • Haukkamaa M.
      One- and two-day mifepristone-misoprostol intervals are both effective in medical termination of second- trimester pregnancy.
      ] reported two cohorts of women with a mean gestational age of 16 weeks who had either 1- or 2-day intervals between mifepristone and vaginal misoprostol. The 1-day group had a higher proportion of multiparous and older women as well as a longer time to delivery, 7.25 h versus 6.2 h. The difference was more marked in multiparous women and at higher gestational ages. In contrast, Urquhart and Templeton [
      • Urquhart D.R.
      • Templeton A.A.
      The use of mifepristone prior to prostaglandin-induced midtrimester-abortion.
      ], using mifepristone and extra-amniotic PGE2, found that induction times did not differ whether given 24, 36, or 48 h apart, despite an increase in measured uterine contractility at 36 and 48 h.
      Overall, induction times are markedly reduced by the addition of mifepristone pretreatment prior to misoprostol or gemeprost administration. Misoprostol is effective with vaginal, buccal, or sublingual routes when used in combination with mifepristone. Although regimens commonly use a 36- to 48-h interval between the mifepristone and initiation of the prostaglandin analogue, the interval can be decreased substantially to 24 h while maintaining acceptable abortion times. Although a shorter interval may increase the time to delivery slightly, the overall abortion time for the woman is significantly reduced as compared to a prostaglandin analogue alone.

      How does misoprostol compare to other agents for induction abortion?

      Labor induction abortion with the PGE1 analogue misoprostol either alone or in combination with other agents has supplanted most other methods because of high efficacy, low cost, and relative ease of use. Misoprostol has been compared directly to multiple agents, as summarized in Table 1 [
      • Autry A.M.
      • Hayes E.C.
      • Jacobson G.F.
      • Kirby R.S.
      A comparison of medical induction and dilation and evacuation for second-trimester abortion.
      ]. It has not been compared directly to some older agents like urea, which had been replaced with other agents by the time misoprostol became available.
      Table 1Complication rates among labor induction abortions and D&E (mean± SD)
      Labor induction (n=158)D&E (n=139)p
      Any complication45±28.55±3.6<.001
      Failed initial method11±7.00±0<.01
      Hemorrhage with transfusion1±0.61±0.7NS
      Infection with intravenous antibiotics2±1.30±0NS
      Retained products of conception
      Requiring dilation and curettage for labor induction abortions or reoperation for surgical abortions.
      33±20.91±0.7<.001
      Cervical laceration with repair2±1.33±2.2NS
      Organ damage (including perforation)2±1.30±0NS
      Hospital readmission1±0.61±0.7NS
      NS, not significant. Adapted from Autry et al.
      • Autry A.M.
      • Hayes E.C.
      • Jacobson G.F.
      • Kirby R.S.
      A comparison of medical induction and dilation and evacuation for second-trimester abortion.
      .
      a Requiring dilation and curettage for labor induction abortions or reoperation for surgical abortions.
      In the available studies comparing misoprostol to either intra- or extra-amniotic PGF2α, vaginal PGE2 (dinoprostone), or intravenous oxytocin, studies that use an adequate dose of misoprostol demonstrate a shorter or equal induction time (Table 2). Ethacridine lactate, a nonprostaglandin compound that is infused slowly into the extra-amniotic space, appears to be a very safe agent to use but, however, has a longer abortion time than misoprostol [
      • Boza A.V.
      • de Leon R.G.
      • Castillo L.S.
      • Marino D.R.
      • Mitchell E.M.
      Misoprostol preferable to ethacridine lactate for abortions at 13–20 weeks of pregnancy: Cuban experience.
      ,
      • Kelekci S.
      • Erdemoglu E.
      • Inan I.
      Randomized study on the effect of adding oxytocin to ethacridine lactate or misoprostol for second-trimester termination of pregnancy.
      ].
      Table 2Selected comparisons of vaginal misoprostol to other agents
      AgentSample sizeGestational ages (weeks)Agent abortion time (median or mean) (h)Rate (%) of nausea and vomiting
      Nausea/vomiting.
      Misoprostol comparator dose (vaginal)Misoprostol abortion time (h)Rates (%) of nausea and vomitingCommentsReferences
      Ethacridine lactate extra-amniotic38813–2029
      – indicates not stated.
      400 mcg every 8 h, 800 mcg every 8 h after 24 h2029/20Retrospective cohort, ethacridine lactate group had higher gestational ages
      • Ho P.C.
      • Blumenthal P.D.
      • Gemzell-Danielsson K.
      • Gomez Ponce de L.R.
      • Mittal S.
      • Tang O.S.
      Misoprostol for the termination of pregnancy with a live fetus at 13 to 26 weeks.
      93% of misoprostol group vs. 76% of ethacridine group delivered within 24 h
      38813–2014.2400 mcg every 6–12 for gestational ages <16 weeks10.8Side effects “similar in all of the groups”; 10% had vomiting overall
      • Dodd C.M.
      • Crowther C.A.
      Misoprostol versus cervagem for the induction of labour to terminate pregnancy in the second and third trimester: a systematic review.
      13.2
      Treated with oxytocin in addition.
      200 mcg every 6–12 for 16–20 weeks; doses doubles after 24 h9.9
      Treated with oxytocin in addition.
      PGF2α intra-amniotic10016–2210.7200 mcg every 6 × 4 doses13.6Used laminaria 18 h before induction
      • Paz B.
      • Ohel G.
      • Tal T.
      • Degani S.
      • Sabo E.
      • Levitan Z.
      Second trimester abortion by laminaria followed by vaginal misoprostol or intrauterine prostaglandin F2alpha: a randomized trial.
      Misoprostol group was more likely to complete abortion within 24 h (88% vs. 72%)
      Misoprostol group used less analgesia
      21715–2421.1
      Nausea and vomiting were expressed as number of episodes.
      400 mcg every 4 h18.3Vaginal misoprostol had fewer side effects and was more acceptable
      • Akoury H.A.
      • Hannah M.E.
      • Chitayat D.
      • Thomas M.
      • Winsor E.
      • Ferris L.E.
      • et al.
      Randomized controlled trial of misoprostol for second-trimester pregnancy termination associated with fetal malformation.
      Misoprostol had fewer episodes of nausea and vomiting
      11716–2221400 mcg oral misoprostol 4 hSimilar rates of abortion at 24 h. PGF group more likely to have retained placenta
      • Marquette G.P.
      • Skoll M.A.
      • Dontigny L.
      A randomized trial comparing oral misoprostol with intra-amniotic prostaglandin F2alpha for second trimester terminations.
      13212–2420.828/23400 mcg every 3 h16.216/16Difference more marked for multiparous women
      • Su L.L.
      • Biswas A.
      • Choolani M.
      • Kalaichelvan V.
      • Singh K.
      A prospective, randomized comparison of vaginal misoprostol versus intra-amniotic prostaglandins for midtrimester termination of pregnancy.
      Shivering and fever more common among misoprostol users
      PGF2α extra-amniotic5117–2417.535/8200 mcg every 12 h2232/12Side effects similar
      • Perry Jr., K.G.
      • Rinehart B.K.
      • Terrone D.A.
      • Martin R.W.
      • May W.L.
      • Roberts W.E.
      Second-trimester uterine evacuation: a comparison of intra-amniotic (15S)-15-methyl-prostaglandin F2alpha and intravaginal misoprostol.
      4016–2416–/45200 mcg every 8 h10.3–/5PGF2α group had more vomiting, diarrhea and pyrexia
      • Ghorab M.N.
      • El Helw B.A.
      Second-trimester termination of pregnancy by extra-amniotic prostaglandin F2alpha or endocervical misoprostol. A comparative study.
      Intravenous d-cloprostenol (PGF analogue 2.5 mg) with intra-amniotic hypertonic saline23314–2329–/8400 mcg every 3 h13.1–/5Retained placenta and hemorrhage less common in misoprostol group
      • Dickinson J.E.
      • Evans S.F.
      A comparison of oral misoprostol with vaginal misoprostol administration in second-trimester pregnancy termination for fetal abnormality.
      Misoprostol more acceptable to patients and staff
      PGE2 vaginally8013–2825–/27100 mcg every 4 h10.6–/34Included some women with fetal demise
      • Makhlouf A.
      • Al-Hussaini T.
      • Habib D.
      • Makarem M.
      Second-trimester pregnancy termination: comparison of three different methods.
      5512–2210.6–/33200 mcg every 12 h12.0–/4PGE2 more likely to result in pyrexia, nausea, vomiting or diarrhea
      • Jain J.K.
      • Mishell D.R.
      Comparison of intravaginal misoprostol with prostaglandin-E(2) for termination of 2nd-trimester pregnancy.
      PGE2 vaginally combined with high-dose intravenous oxytocin3016–241847/–100 mcg every 12 h2247/–Vomiting more common in misoprostol group
      • Owen J.
      • Hauth J.C.
      Vaginal misoprostol vs. concentrated oxytocin plus low-dose prostaglandin E2 for second trimester pregnancy termination.
      12616–241742
      Nausea and/or vomiting.
      600 mcg and 400 mcg every 4 h1225dThe misoprostol group had fewer gastrointestinal side effects
      • Goyal V.
      Uterine rupture in second-trimester misoprostol-induced abortion after cesarean delivery: a systematic review.
      High-dose intravenous oxytocin4713–3221.7–/0400 mcg every 4 h15.2–/17Cohort study. Some women had fetal demise. Side effects not significantly different; small size of study
      • Ramin K.D.
      • Ogburn P.L.
      • Danilenko D.R.
      • Ramsey P.S.
      High-dose oral misoprostol for mid-trimester pregnancy interruption.
      High-dose intravenous oxytocin plus low-dose misoprostol3814–241825/15400 mcg every 4 h1256/11Study stopped early as misoprostol was more effective. Side effects were similar
      • Nuthalapaty F.S.
      • Ramsey P.S.
      • Biggio J.R.
      • Owen J.
      High-dose vaginal misoprostol versus concentrated oxytocin plus low-dose vaginal misoprostol for midtrimester labor induction: a randomized trial.
      Studies reported are randomized trials unless otherwise indicated. Misoprostol was used vaginally unless otherwise indicated.
      a Nausea/vomiting.
      b – indicates not stated.
      c Nausea and vomiting were expressed as number of episodes.
      d Nausea and/or vomiting.
      low asterisk Treated with oxytocin in addition.
      Early studies evaluated gemeprost as a single suppository (1 mg) every 3 h with abortion rates of approximately 80% at 24 h after initial administration and 95% at 48 h [
      • Cameron I.T.
      • Michie A.F.
      • Baird D.T.
      Prostaglandin-induced pregnancy termination: further studies using gemeprost (16,16 dimethyl-trans-delta 2-PGE1 methyl ester) vaginal pessaries in the early second trimester.
      ,
      • Thong K.J.
      • Baird D.T.A.
      Study of gemeprost alone, dilapan or mifepristone in combination with gemeprost for the termination of 2nd trimester pregnancy.
      ,
      • Thong K.J.
      • Baird D.T.
      Uterine rupture in midtrimester abortion. A complication of gemeprost vaginal pessaries and oxytocin. Case report.
      ]. Two prospective randomized studies performed in the UK compared vaginal gemeprost 1 mg every 3 h for a maximum of 5 doses in 24 h to 1 mg every 6 h for a maximum of 4 doses in 24 h [
      • Thong K.J.
      • Baird D.T.A.
      Study of gemeprost alone, dilapan or mifepristone in combination with gemeprost for the termination of 2nd trimester pregnancy.
      ,
      • Armatage R.J.
      • Luckas M.J.
      A randomized trial of 2 regimens for the administration of vaginal prostaglandins (gemeprost) for the induction of midtrimester abortion.
      ]. The regimens were repeated 24 h after the initial treatment, and intravenous oxytocin was initiated if the abortion had not occurred within 36–48 h. These two studies found that although more frequent dosing was associated with a somewhat shorter abortion time, the cumulative abortion rates within 24 h, the overall rate of side effects, and the rate of surgical intervention for incomplete abortion were the same in both groups [
      • Thong K.J.
      • Baird D.T.A.
      Study of gemeprost alone, dilapan or mifepristone in combination with gemeprost for the termination of 2nd trimester pregnancy.
      ,
      • Armatage R.J.
      • Luckas M.J.
      A randomized trial of 2 regimens for the administration of vaginal prostaglandins (gemeprost) for the induction of midtrimester abortion.
      ].
      The rates of nausea in these studies, where stated, ranged from 16% to 56%, and the rates of vomiting ranged from 4% to 20%. There is no clear pattern of either superiority or inferiority, in terms of side effects, when misoprostol is compared to the other agents.
      When the PGE1 analogues used alone are compared directly, outcomes are related to the misoprostol dose [
      • Nuutila M.
      • Toivonen J.
      • Ylikorkala O.
      • Halmesmaki A.E.
      A comparison between two doses of intravaginal misoprostol and gemeprost for induction of second-trimester abortion.
      ]. In one study, gemeprost was superior to 100 mcg of misoprostol used every 6 h, but comparable to 200 mcg of misoprostol every 12 h [
      • Nuutila M.
      • Toivonen J.
      • Ylikorkala O.
      • Halmesmaki A.E.
      A comparison between two doses of intravaginal misoprostol and gemeprost for induction of second-trimester abortion.
      ]. In other studies, misoprostol was equivalent to or more efficacious than gemeprost [
      • Nuutila M.
      • Toivonen J.
      • Ylikorkala O.
      • Halmesmaki A.E.
      A comparison between two doses of intravaginal misoprostol and gemeprost for induction of second-trimester abortion.
      ,
      • Caliskan E.
      • et al.
      Sublingual misoprostol 100 microgram versus 200 microgram for second trimester abortion: a randomized trial.
      ,
      • Wong K.S.
      • Ngai C.S.W.
      • Wong A.Y.K.
      • Tang L.C.H.
      • Ho P.C.
      Vaginal misoprostol compared with vaginal gemeprost in termination of second trimester pregnancy — a randomized trial.
      ,
      • Nor Azlin M.
      • Abdullah H.
      • Zainul Rashid M.
      • Jamil M.
      Misoprostol (alone) in second trimester terminations of pregnancy: as effective as Gemeprost?.
      ]. Two randomized controlled trials compared misoprostol with gemeprost after pretreatment with 600 mg mifepristone [
      • el-Rafaey H.
      • Hinshaw K.
      • Templeton A.
      The abortifacient effect of misoprostol in the second trimester. A randomized comparison with gemeprost in patients pre-treated with mifepristone (RU486).
      ,
      • el-Refaey H.
      • Templeton A.
      Induction of abortion in the second trimester by a combination of misoprostol and mifepristone: a randomized comparison between two misoprostol regimens.
      ]. Neither showed a faster induction time. Similarly, neither Nuutila et al. [
      • Nuutila M.
      • Toivonen J.
      • Ylikorkala O.
      • Halmesmaki A.E.
      A comparison between two doses of intravaginal misoprostol and gemeprost for induction of second-trimester abortion.
      ] nor Ho et al. [
      • Ho P.C.
      • Chan Y.F.
      • Lau W.
      Misoprostol is as effective as gemeprost in termination of second trimester pregnancy when combined with mifepristone: a randomised comparative trial.
      ] showed a difference in induction time when 200 mg of mifepristone was used. Bartley and Baird [
      • Bartley J.
      • Baird D.T.
      A randomised study of misoprostol and gemeprost in combination with mifepristone for induction of abortion in the second trimester of pregnancy.
      ] had similar results, with median induction times of 6.0 and 6.1 h for gemeprost and misoprostol, respectively, when pretreatment with mifepristone was included.
      A meta-analysis of randomized trials comparing various regimens of misoprostol to gemeprost in midtrimester abortion demonstrated that vaginal misoprostol compared with gemeprost vaginal suppositories was associated with a reduced need for narcotic analgesia and surgical evacuation of the uterus [
      • Dodd C.M.
      • Crowther C.A.
      Misoprostol versus cervagem for the induction of labour to terminate pregnancy in the second and third trimester: a systematic review.
      ]. No other statistically significant differences were observed.
      High-dose oxytocin is an option when misoprostol is not available or when there is a desire to avoid prostaglandin use and side effects. However, it requires intravenous access and a relatively complicated regimen to avoid serious complications, and induction times are likely to be prolonged. Several regimens using only oxytocin for induction have been described. Winkler and associates [
      • Winkler C.L.
      • Gray S.E.
      • Hauth J.C.
      • Owen J.
      • Tucker J.M.
      Mid-second-trimester labor induction: concentrated oxytocin compared with prostaglandin E2 vaginal suppositories.
      ], in a small retrospective evaluation of 22 subjects, used a regimen that began with 100 units of oxytocin infused over 3 h followed by 1 h without oxytocin to allow diuresis for prevention of water intoxication. The dose of oxytocin was increased 50 units per 3 h until fetal expulsion was achieved, to a maximum of 300 units over 3 h. Women in the oxytocin group had a gestational range of 17–24 weeks' (mean of 21.3 weeks). The mean induction time was 8.2 h, which was shorter than the induction time compared with PGE2 group. Owen et al. [
      • Owen J.
      • Hauth J.C.
      • Winkler C.L.
      • Gray S.E.
      Midtrimester pregnancy termination: a randomized trial of prostaglandin E2 versus concentrated oxytocin.
      ] found similar outcomes for PGE2 and concentrated oxytocin inductions. Using a regimen of less concentrated oxytocin; 20 units over 3 h, Yapar reported a 24-h cumulative abortion rate of 90% [
      • Yapar E.G.
      • Senoz S.
      • Urkutur M.
      • Batioglu S.
      • Gokmen O.
      Second trimester pregnancy termination including fetal death: comparison of five different methods.
      ] in women with a mean gestational age of 20 weeks.
      Owen et al. [
      • Owen J.
      • Hauth J.C.
      Vaginal misoprostol vs. concentrated oxytocin plus low-dose prostaglandin E2 for second trimester pregnancy termination.
      ] compared vaginal misoprostol to a combination of intravenous oxytocin and low-dose PGE2 and concluded that misoprostol was inferior; however, an inadequate misoprostol dose of 100 mcg every 12 h was used. When compared to oral misoprostol 400 mcg every 4 h, high-dose oxytocin use is associated with longer induction times [
      • Ramin K.D.
      • Ogburn P.L.
      • Danilenko D.R.
      • Ramsey P.S.
      High-dose oral misoprostol for mid-trimester pregnancy interruption.
      ]. Nuthalapaty et al. [
      • Nuthalapaty F.S.
      • Ramsey P.S.
      • Biggio J.R.
      • Owen J.
      High-dose vaginal misoprostol versus concentrated oxytocin plus low-dose vaginal misoprostol for midtrimester labor induction: a randomized trial.
      ] compared women at 14–24 weeks undergoing induction, using either escalating high-dose oxytocin combined with low-dose misoprostol (starting at 400 mcg vaginally and decreasing to 100 mcg for repeat doses), or misoprostol alone (600 mcg of misoprostol initially followed by 400 mcg every 4 h). The median induction times were 18 and 12 h, respectively (p<.01). The success rate for misoprostol compared with oxytocin at 12 h, 60% versus 12%, was also strikingly different.
      Overall, misoprostol appears to be more effective than PGF , PGE2, high-dose oxytocin, and ethacridine lactate when adequate doses are used. Both PGE2 and PGF analogues are expensive and require refrigeration, in contrast to misoprostol, which is inexpensive and stable at room temperature. Compared to the agents presented in this section, misoprostol is the preferred agent. There is no overwhelming argument for use of either misoprostol or gemeprost based on clinical outcome. However, the restriction of gemeprost to vaginal use, and storage and availability issues, make it less attractive than misoprostol.

      What is the optimal dose and dosing schedule for misoprostol?

      There is a large range of effective misoprostol dosing, ranging from 100 to 800 mcg for an individual dose and using various schedules, including regimens with loading doses.
      Most early studies used low doses of misoprostol, such as 200 mcg vaginally every 6–12 h [
      • Jain J.K.
      • Mishell D.R.
      A comparison of misoprostol with and without laminaria tents for induction of second-trimester abortion.
      ,
      • Jain J.K.
      • Kuo J.
      • Mishell Jr, D.R.
      A comparison of two dosing regimens of intravaginal misoprostol for second-trimester pregnancy termination.
      ,
      • Perry Jr., K.G.
      • Rinehart B.K.
      • Terrone D.A.
      • Martin R.W.
      • May W.L.
      • Roberts W.E.
      Second-trimester uterine evacuation: a comparison of intra-amniotic (15S)-15-methyl-prostaglandin F2alpha and intravaginal misoprostol.
      ,
      • Owen J.
      • Hauth J.C.
      Vaginal misoprostol vs. concentrated oxytocin plus low-dose prostaglandin E2 for second trimester pregnancy termination.
      ,
      • Nuutila M.
      • Toivonen J.
      • Ylikorkala O.
      • Halmesmaki A.E.
      A comparison between two doses of intravaginal misoprostol and gemeprost for induction of second-trimester abortion.
      ]. Induction times varied from 14 to 22 h. Although a regimen using 100 mcg vaginally was less effective than the one using 200 mg [
      • Nuutila M.
      • Toivonen J.
      • Ylikorkala O.
      • Halmesmaki A.E.
      A comparison between two doses of intravaginal misoprostol and gemeprost for induction of second-trimester abortion.
      ], a more recent randomized trial comparing 100 and 200 mcg of misoprostol sublingually every 2 h showed similar efficacy, with mean abortion times of 14.75 and 15.2 h, respectively, [
      • Caliskan E.
      • et al.
      Sublingual misoprostol 100 microgram versus 200 microgram for second trimester abortion: a randomized trial.
      ].
      However, higher doses are generally more effective when misoprostol is used alone. Accordingly, lower doses should be abandoned. A prospective randomized, double-blinded controlled trial found that misoprostol 400 mcg every 6 h was more effective than 200 mcg used every 6 h [
      • Dickinson J.E.
      • Evans S.F.
      The optimization of intravaginal misoprostol dosing schedules in second-trimester pregnancy termination.
      ]. Misoprostol doses of 400 and 600 mcg appear to have similar efficacy regardless of a 4- or 6-h dosing interval time (time to abortion, 11–12 h) [
      • Carbonell J.L.
      • Torres M.A.
      • Reyes R.
      • Ortega L.
      • Garcia-Gallego F.
      • Sanchez C.
      Second-trimester pregnancy termination with 600-microg vs. 400-microg vaginal misoprostol and systematic curettage postexpulsion: a randomized trial.
      ]. With a dosing interval of 12 h, 600- and 800-mcg doses also showed similar abortion times (15.2 h) [
      • Herabutya Y.
      • Chanrachakul B.
      • Punyavachira P.
      Second trimester pregnancy termination: a comparison of 600 and 800 micrograms of intravaginal misoprostol.
      ], although a noncomparative cohort study in women receiving 800 mcg every 12 h found a slightly shorter average time of 12 h [
      • Carbonell J.L.
      • Rodriguez J.
      • Delgado E.
      • Sanchez C.
      • Vargas F.
      • Valera L.
      • et al.
      Vaginal misoprostol 800 microg every 12 h for second-trimester abortion.
      ].
      Multiple dosing frequency regimens have been studied. Although initial studies considered dosing intervals of 6 to 12 h with vaginal misoprostol, randomized trials have demonstrated shorter abortion times with vaginal administration every 3 h [
      • Wong K.S.
      • Ngai C.S.W.
      • Yeo E.L.K.
      • Tang L.C.H.
      • Ho P.C.
      A comparison of two regimens of intravaginal misoprostol for termination of second trimester pregnancy: a randomized comparative trial.
      ,
      • Guix C.
      • Palacio M.
      • Figueras F.
      • Bennasar M.
      • Zamora L.
      • Coll O.
      • et al.
      Efficacy of two regimens of misoprostol for early second-trimester pregnancy termination.
      ]. In general, it appears that increased time to abortion is related more to the dosing interval than the dose itself.
      Lower doses of misoprostol are effective, however, when they are preceded by a “loading dose” (a higher initial dose) or mifepristone. One of the earliest larger studies (n=128) in the early second trimester used 800 mcg misoprostol vaginally, followed by 400 mcg at 18 and 24 h, if needed [
      • Bugalho A.
      • Bique C.
      • Almeida L.
      • Bergstrom S.
      Pregnancy interruption by vaginal misoprostol.
      ]. Abortion occurred at a mean of 11.8 h, with 102 women (80%) aborting within the first 18 h. All patients had routine curettage after expulsion of the fetus, so the rate of retained placenta was not evaluated.
      A misoprostol-only regimen using a loading dose of 600 mcg vaginally followed by 200 mcg vaginally every 3 h resulted in similar mean abortion times and success rates at 24 and 48 h as compared to a regimen of 400 mcg of misoprostol vaginally every 3 h [
      • Dickinson J.E.
      • Evans S.F.
      The optimization of intravaginal misoprostol dosing schedules in second-trimester pregnancy termination.
      ]. Ngai et al. [
      • Ngai S.W.
      • Tang O.S.
      • Ho P.C.
      Randomized comparison of vaginal (200 mu g every 3 h) and oral (400 mu g every 3 h) misoprostol when combined with mifepristone in termination of second trimester pregnancy.
      ] showed similar outcomes using mifepristone 200 mg followed 36–48 h later by misoprostol 200 mcg vaginally or 400 mcg orally every 3 h.
      Overall, when misoprostol is used alone, 400 mcg appears to be the minimum effective dose. Although many regimens in the past used longer dosing intervals, repeating the dose approximately every 3 h has the same efficacy but will shorten the abortion time. Most ideally, a loading dose of 600 to 800 mcg should be administered, which will allow for lower dose of misoprostol to be used (200 mcg vaginally) every 3 h.

      What is the optimal route of administration of misoprostol?

      Although misoprostol is labeled for oral ingestion, it is also effective for induced abortion when administered by vaginal, sublingual, and buccal routes. Vaginal administration is associated with shorter induction times compared to oral administration [
      • Nigam A.
      • Singh V.K.
      • Prakash A.
      Vaginal vs. oral misoprostol for mid-trimester abortion.
      ,
      • Dickinson J.E.
      • Evans S.F.
      A comparison of oral misoprostol with vaginal misoprostol administration in second-trimester pregnancy termination for fetal abnormality.
      ,
      • Ho P.C.
      • Ngai S.W.
      • Liu K.L.
      • Wong G.C.Y.
      • Lee S.W.H.
      Vaginal misoprostol compared with oral misoprostol in termination of second-trimester pregnancy.
      ,
      • Gilbert A.
      • Reid R.
      A randomised trial of oral versus vaginal administration of misoprostol for the purpose of mid-trimester termination of pregnancy.
      ,
      • Bebbington M.W.
      • Kent N.
      • Lim K.
      • Gagnon A.
      • Delisle M.F.
      • Tessier F.
      • et al.
      A randomized controlled trial comparing two protocols for the use of misoprostol in midtrimester pregnancy termination.
      ]. The incidence of side effects is also lower for vaginal use except for transient fever [
      • Bebbington M.W.
      • Kent N.
      • Lim K.
      • Gagnon A.
      • Delisle M.F.
      • Tessier F.
      • et al.
      A randomized controlled trial comparing two protocols for the use of misoprostol in midtrimester pregnancy termination.
      ]. The abortion rate is not improved by moistening the misoprostol tablets [
      • Tang O.S.
      • Schweer H.
      • Seyberth H.W.
      • Lee S.W.
      • Ho P.C.
      Pharmacokinetics of different routes of administration of misoprostol.
      ,
      • Yilmaz B.
      • Kelekci S.
      • Ertas I.E.
      • Ozel M.
      • Sut N.
      • Mollamahmutoglu L.
      • et al.
      Randomized comparison of second trimester pregnancy termination utilizing saline moistened or dry misoprostol.
      ]. Sublingual administration appears to be similar to vaginal and also is superior to oral. von Hertzen et al. [

      von Hertzen H, Piaagio G, Wojdyla D, et al. Comparison of vaginal and sublingual misoprostol for second trimester abortion: randomized controlled equivalence trial. Hum Reprod 24:106–12 (Evidence Grade: I).

      ] found that vaginal administration of 400 mcg every 3 h was associated with higher rates of abortion by 24 h (86% vs. 80%) than using the same schedule with sublingual administration. Outcomes were very similar for multiparous women, but significantly different for nulliparous women. In this study, side effects were similar in the two groups, but 72% of women preferred the sublingual route. A single recent study is the only published report of buccal misoprostol alone for labor induction abortion at 18–22 weeks. Ellis et al. [
      • Ellis S.C.
      • Kapp N.
      • Vragpvoc O.
      • Borgata L.
      Randomized trial of buccal versus vaginal misoprostol for induction of second trimester abortion.
      ] administered misoprostol 400 mcg vaginally to 64 women then randomized the women to receive subsequent doses of 200 mcg misoprostol every 6 h either buccally or vaginally. The median abortion times in the buccal and vaginal groups were 15 and 12 h, respectively (p=.44).
      Ho et al. [
      • Ho P.C.
      • Ngai S.W.
      • Liu K.L.
      • Wong G.C.Y.
      • Lee S.W.H.
      Vaginal misoprostol compared with oral misoprostol in termination of second-trimester pregnancy.
      ] found oral administration to be more acceptable to women than vaginal administration for labor induction abortion. The most common reasons cited for not liking vaginal administration were pain and inconvenience with insertion. The authors, however, did not describe how the tablets were administered vaginally. Ellis et al. [
      • Ellis S.C.
      • Kapp N.
      • Vragpvoc O.
      • Borgata L.
      Randomized trial of buccal versus vaginal misoprostol for induction of second trimester abortion.
      ] found no difference in acceptability in a group of women randomized to buccal or vaginal misoprostol.
      Combined oral and vaginal regimens may be as effective as vaginal alone regimens. el-Rafaey et al. [
      • el-Rafaey H.
      • Hinshaw K.
      • Templeton A.
      The abortifacient effect of misoprostol in the second trimester. A randomized comparison with gemeprost in patients pre-treated with mifepristone (RU486).
      ] randomized women to receive an initial dose of vaginal misoprostol with repeat doses by oral or vaginal routes. Abortion times and side effects were the same for both groups. Feldman et al. [
      • Feldman D.M.
      • Borgida A.F.
      • Rodis J.F.
      • Leo M.V.
      • Campbell W.A.
      A randomized comparison of two regimens of misoprostol for second-trimester pregnancy termination.
      ] compared women who received 400 mcg of misoprostol every 8 h, either orally or vaginally, after a loading dose of 800 mcg vaginally. No significant differences either in abortion time or in side effects were found. Similar results are found when mifepristone is used before misoprostol.
      Overall, misoprostol, when used alone for labor induction abortion, should be administered vaginally or sublingually. However, when a vaginal loading dose is administered, outcomes following subsequent oral and vaginal administration are similar. Only a single small study has evaluated buccal misoprostol; more research would be needed before recommending this route when using misoprostol alone.

      Does the use of osmotic dilators affect the abortion time?

      Labor induction abortion studies using natural prostaglandins found that placing osmotic dilators 4–24 h before induction decreased abortion time [
      • Urquhart D.R.
      • Templeton A.A.
      The use of mifepristone prior to prostaglandin-induced midtrimester-abortion.
      ,
      • Blumenthal P.D.
      Prospective comparison of dilapan and laminaria for pretreatment of the cervix in 2nd-trimester induction abortion.
      ,
      • Strauss J.H.
      • Wilson M.
      • Caldwell D.
      • Otterson W.
      • Martin A.O.
      Laminaria use in midtrimester abortions induced by intra-amniotic prostaglandin-f2-alpha with urea and intravenous oxytocin.
      ,
      • Atlas R.O.
      • Lemus J.
      • Reed J.
      • Atkins D.
      • Alger L.S.
      Second trimester abortion using prostaglandin E-2 suppositories with or without intracervical Laminaria japonica: a randomized study.
      ,
      • Stubblefield P.G.
      • Naftolin F.
      • Frigoletto F.
      • Ryan K.J.
      Laminaria augmentation of intra-amniotic Pgf2Alpha for midtrimester pregnancy termination.
      ,
      • Karim S.M.M.
      • Ratnam S.S.
      • Lim A.L.
      • Yeo K.C.
      • Choo H.T.
      Termination of 2nd trimester pregnancy with laminaria and intramuscular 16-phenoxy-omega-17,18,19,20 tetranor Pge2 methylsulfonylamide (Sulprostone) — a randomized study.
      ,
      • Papageorgiou I.
      • Minaretzis D.
      • Tsionou C.
      • Michalas S.
      Late midtrimester medical pregnancy terminations — 3 different procedures with prostaglandin-F2-alpha and laminaria tents.
      ]. However, this adjunctive benefit does not occur when modern prostaglandin analogues are used.
      Two randomized studies examined the use of cervical preparation with laminaria at the time of misoprostol induction [
      • Jain J.K.
      • Mishell D.R.
      A comparison of misoprostol with and without laminaria tents for induction of second-trimester abortion.
      ,
      • Borgatta L.
      • Chen A.Y.
      • Vragovic O.
      • Stubblefield P.G.
      • Magloire C.A.
      A randomized clinical trial of the addition of laminaria to misoprostol and hypertonic saline for second-trimester induction abortion.
      ]. One study used feticide with hypertonic saline prior to misoprostol administration [
      • Borgatta L.
      • Chen A.Y.
      • Vragovic O.
      • Stubblefield P.G.
      • Magloire C.A.
      A randomized clinical trial of the addition of laminaria to misoprostol and hypertonic saline for second-trimester induction abortion.
      ]. Both studies demonstrated that laminaria placement actually increased the abortion interval, and this difference was statistically different in one of the trials [
      • Jain J.K.
      • Mishell D.R.
      A comparison of misoprostol with and without laminaria tents for induction of second-trimester abortion.
      ,
      • Borgatta L.
      • Chen A.Y.
      • Vragovic O.
      • Stubblefield P.G.
      • Magloire C.A.
      A randomized clinical trial of the addition of laminaria to misoprostol and hypertonic saline for second-trimester induction abortion.
      ]. Additionally, women who received laminaria had increased analgesic needs during the induction procedure [
      • Borgatta L.
      • Chen A.Y.
      • Vragovic O.
      • Stubblefield P.G.
      • Magloire C.A.
      A randomized clinical trial of the addition of laminaria to misoprostol and hypertonic saline for second-trimester induction abortion.
      ].
      Laminaria use has also been compared to mifepristone, which has cervical ripening properties [
      • Stubblefield P.G.
      • Naftolin F.
      • Frigoletto F.
      • Ryan K.J.
      Laminaria augmentation of intra-amniotic Pgf2Alpha for midtrimester pregnancy termination.
      ]. Ho et al. [
      • Ho P.C.
      • Tsang S.S.K.
      • Ma H.K.
      Reducing the induction to abortion interval in termination of 2nd trimester pregnancies — a comparison of mifepristone with laminaria tent.
      ] compared mifepristone given 36 h and laminaria placed 12 h prior to gemeprost induction. Mifepristone was more effective than laminaria at shortening the induction interval. Prairie et al. [
      • Prairie B.
      • Lauria M.
      • Kapp N.
      • MacKenzie T.
      • Baker E.
      • George K.
      Mifepristone versus laminaria: a randomized controlled trial of cervical ripening in midtrimester termination.
      ] compared mifepristone to laminaria 24 h prior to misoprostol induction, also finding that mifepristone resulted in significantly shorter induction intervals. Dilapan has also proven to be of no benefit in regimens with gemeprost [
      • Thong K.J.
      • Baird D.T.
      A study of gemeprost alone, dilapan or mifepristone in combination with gemeprost for the termination of 2nd trimester pregnancy.
      ].
      There are few studies on the use of osmotic dilators in advance of starting induction with misoprostol alone. Hern [
      • Hern W.M.
      Laminaria, induced fetal demise and misoprostol in late abortion.
      ], using a combination of medical techniques and assisted delivery or D&E, reported no failed procedures and rare complications in a large observational series. A series of women treated with mifepristone 48 h prior to misoprostol, combined with laminaria 12 h before misoprostol, had a mean abortion time of 4 h [
      • Hoffer M.C.
      • Charlier C.
      • Giacalone P.L.
      • Zimbris L.
      • Astruc M.
      • Boulot P.
      Evaluation of combination RU 486-laminaria tents-misoprostol-peridural anesthesia in second and third trimester induced abortions.
      ].
      Overall, there appears to be no benefit to inserting osmotic dilators at the same time as misoprostol or gemeprost, as induction times may be prolonged and side effects may be increased. Whether prior insertion of dilators is of benefit for labor induction abortion is not clear.

      How should expulsion of the placenta be managed with labor induction abortion?

      There have been a variety of approaches to management of the placenta with labor induction abortion. Some practitioners perform curettage routinely after delivery of the placenta, whether the placenta is delivered spontaneously or not. Recommendations for active placental removal (manually or with curettage) are often based on policy rather than medical necessity. Historically, placental extraction rates vary from 15% to 50% with various agents [
      • el-Refaey H.
      • Templeton A.
      Induction of abortion in the second trimester by a combination of misoprostol and mifepristone: a randomized comparison between two misoprostol regimens.
      ,
      • Surrago E.J.
      • Robins J.
      Mid-trimester pregnancy termination by intra-vaginal administration of prostaglandin-E2.
      ,
      Prostaglandins and abortion. III. Comparison of single intra-amniotic injections of 15-methyl prostaglandin F2alpha and prostaglandin F2alpha for termination of second-trimester pregnancy: an international multicenter study. World Health Organization Task Force on the Use of Prostaglandins forthe Regulation of Fertility.
      ,
      • Kerenyi T.D.
      • Mandelman N.
      • Sherman D.H.
      Five thousand consecutive saline inductions.
      ,
      • Anonymous
      Comparison of intra-amniotic prostaglandin F2 alpha and hypertonic saline for induction of second-trimester abortion.
      ]. These rates do not seem to vary with agents used today including gemeprost [
      • Thong K.J.
      • Baird D.T.A.
      Study of gemeprost alone, dilapan or mifepristone in combination with gemeprost for the termination of 2nd trimester pregnancy.
      ] and misoprostol [
      • Leader J.
      • Bujnovsky M.
      • Carlan S.J.
      • Triana T.
      • Richichi K.
      Effect of oral misoprostol after second-trimester delivery: a randomized, blinded study.
      ,
      • Green J.
      • Borgatta L.
      • Sia M.
      • Kapp N.
      • Saia K.
      • Carr-Ellis S.
      • et al.
      Intervention rates for placental removal following induction abortion with misoprostol.
      ].
      Some investigators recommend placental removal 30 min after fetal expulsion when prostaglandin E2 is used [
      • Kirz D.S.
      • Haag M.K.
      Management of the 3rd stage of labor in pregnancies terminated by prostaglandin-E2.
      ] or after 2 h when saline infusion is used [
      • Kafrissen M.E.
      • Schulz K.F.
      • Grimes D.A.
      • Cates Jr., W.
      Midtrimester abortion. Intra-amniotic instillation of hyperosmolar urea and prostaglandin F2 alpha v dilatation and evacuation.
      ], based on an increase in bleeding after the recommended time period. Such recommendations may not be applicable for agents more commonly used today.
      Few studies follow the natural time course of placental expulsion without intervention for placental delivery. In women receiving misoprostol alone for labor induction abortion, Leader et al. [
      • Leader J.
      • Bujnovsky M.
      • Carlan S.J.
      • Triana T.
      • Richichi K.
      Effect of oral misoprostol after second-trimester delivery: a randomized, blinded study.
      ] found that about half of women deliver the placenta within an hour, and there was no increase in bleeding when women were observed past 2 h. This study also showed that routine misoprostol administration after fetal expulsion did not decrease the time to placental delivery. Green et al. [
      • Green J.
      • Borgatta L.
      • Sia M.
      • Kapp N.
      • Saia K.
      • Carr-Ellis S.
      • et al.
      Intervention rates for placental removal following induction abortion with misoprostol.
      ] in a retrospective series of 233 women using misoprostol alone concluded that there was no increase in bleeding for at least 4 h; 59% of women delivered the placenta within an hour, and the rate of operative removal was 6%. Dickinson and Evans [
      • Dickinson J.E.
      • Evans S.F.
      A comparison of oral misoprostol with vaginal misoprostol administration in second-trimester pregnancy termination for fetal abnormality.
      ] randomized women to receive intramuscular oxytocin, oral misoprostol, or no medication after fetal delivery. After oxytocin, 90% of women expelled the placenta within an hour, compared to 71% and 69% after misoprostol or no medication.
      Low rates of intervention for placental delivery are also reported for regimens using mifepristone and misoprostol [
      • Hamoda H.
      • Ashok P.W.
      • Flett G.M.M.
      • Templeton A.
      A randomized trial of mifepristone in combination with misoprostol administered sublingually or vaginally for medical abortion at 13–20 weeks gestation.
      ,
      • Ngai S.W.
      • Tang O.S.
      • Ho P.C.
      Randomized comparison of vaginal (200 mu g every 3 h) and oral (400 mu g every 3 h) misoprostol when combined with mifepristone in termination of second trimester pregnancy.
      ,
      • Phillips K.
      • Berry C.
      • Mathers A.M.
      Uterine rupture during second trimester termination of pregnancy using mifepristone and a prostaglandin.
      ]. It is not clear whether these low rates reflect a pharmacologic effect or practice patterns. In a small study that noted the time to placental delivery after mifepristone abortion and buccal misoprostol, only 1 (3%) of 32 women required placental removal [
      • Kapp N.
      • Borgatta L.
      • Stubblefield P.G.
      • Vragovic O.
      • Moreno N.
      Mifepristone in midtrimester medical abortion: a randomized controlled trial.
      ].
      Overall, routine surgical intervention for removal of the placenta after an arbitrary time period is not required following labor induction abortion using prostaglandin analogues alone or in combination with mifepristone.

      What is the relationship of prior cesarean delivery to outcome of induction abortion?

      Although prior hysterotomy is suspected to be a risk factor for uterine rupture during labor induction abortion, most published literature consists of case reports or small series and include rupture in both scarred and unscarred uteri. Uterine rupture is a catastrophic complication that often results in hysterectomy and can occur in a scarred or an unscarred uterus during induction. Uterine rupture during labor induction abortion has been reported with almost all agents including high-dose oxytocin [
      • Yapar E.G.
      • Senoz S.
      • Urkutur M.
      • Batioglu S.
      • Gokmen O.
      Second trimester pregnancy termination including fetal death: comparison of five different methods.
      ,
      • Edwards R.K.
      • Sims S.M.
      Outcomes of second-trimester pregnancy terminations with misoprostol: comparing 2 regimens.
      ], ethacridine lactate [
      • Malhotra N.
      • Chanana C.
      Silent rupture of unscarred uterus: an unusual presentation at second trimester abortion.
      ], urea/PGF [
      • Isada N.B.
      • Pryde P.G.
      • Johnson M.P.
      • Hallak M.
      • Blessed W.B.
      • Evans M.I.
      Fetal intracardiac potassium-chloride injection to avoid the hopeless resuscitation of an abnormal abortus. 1. Clinical issues.
      ], saline/PGF [
      • Dickinson J.E.
      • Evans S.F.
      A comparison of oral misoprostol with vaginal misoprostol administration in second-trimester pregnancy termination for fetal abnormality.
      ] and misoprostol [
      • Edwards R.K.
      • Sims S.M.
      Outcomes of second-trimester pregnancy terminations with misoprostol: comparing 2 regimens.
      ,
      • Al-Hussaini T.K.
      Uterine rupture in second trimester abortion in a grand multiparous woman. A complication of misoprostol and oxytocin.
      ,
      • Berghahn L.
      • Christensen D.
      • Droste S.
      Uterine rupture during second-trimester abortion associated with misoprostol.
      ,
      • Chen M.
      • Shih J.C.
      • Chiu W.T.
      • Hsieh F.J.
      Separation of cesarean scar during second-trimester intravaginal misoprostol abortion.
      ,
      • Letourneur B.
      • Parant O.
      • Tofani V.
      • Berrebi A.
      Uterine rupture on unscarred uterus following labor induction for 2nd trimester termination of pregnancy with oral misoprostol: conservative management.
      ,
      • Nayki U.
      • Taner C.E.
      • Mizrak T.
      • Nayki C.
      • Derin G.
      Uterine rupture during second trimester abortion with misoprostol.
      ]. Approximately half have been in unscarred uteri, and most have occurred in women with pregnancies of 18–25 weeks gestational age. The lowest total misoprostol dose administered prior to uterine rupture was a single dose of 200 mcg [
      • Nayki U.
      • Taner C.E.
      • Mizrak T.
      • Nayki C.
      • Derin G.
      Uterine rupture during second trimester abortion with misoprostol.
      ], but several women received multiple doses prior to uterine rupture. Rupture has been reported when mifepristone was used in combination with misoprostol [
      • Phillips K.
      • Berry C.
      • Mathers A.M.
      Uterine rupture during second trimester termination of pregnancy using mifepristone and a prostaglandin.
      ,
      • Bagga R.
      • Chaudhary N.
      • Kalra J.
      Rupture in an unscarred uterus during second trimester pregnancy termination with mifepristone and misoprostol.
      ] and gemeprost [
      UK Multicenter Study Group
      Oral mifepristone 600 mg and vaginal gemeprost for mid-trimester induction of abortion. An open multicenter study.
      ,
      • Thong K.J.
      • Baird D.T.
      Uterine rupture in midtrimester abortion. A complication of gemeprost vaginal pessaries and oxytocin. Case report.
      ].
      In addition to case reports and series, retrospective cohort studies have contrasted uterine rupture rates in women with scarred and unscarred uteri. Goyal [
      • Goyal V.
      Uterine rupture in second-trimester misoprostol-induced abortion after cesarean delivery: a systematic review.
      ] reviewed multiple labor induction publications in which misoprostol was used alone or with other agents, such as oxytocin. The risk of uterine rupture for women with a prior cesarean delivery was 0.28% (95% CI, 0.08–1.0) compared with the rate for unscarred uteri, 0.04% (95% CI, 0.02–0.20).
      Labor induction abortion outcomes, including abortion time, do not differ between women with and without a prior cesarean delivery [
      • Bhattacharjee N.
      • Ganguly R.P.
      • Saha S.P.
      Misoprostol for termination of mid-trimester post-caesarean pregnancy.
      ]. Mazouni et al. [
      • Mazouni C.
      • Provensal M.
      • Porcu G.
      • Guidicelli B.
      • Heckenroth H.
      • Gamerre M.
      • et al.
      Termination of pregnancy in patients with previous cesarean section.
      ] and Herabutya et al. [
      • Herabutya Y.
      • Chanarachakul B.
      • Punyavachira P.
      Induction of labor with vaginal misoprostol for second trimester termination of pregnancy in the scarred uterus.
      ] also found similar outcomes but did report slightly higher rates of retained placenta for women with prior cesarean delivery.
      Overall, there is no clear evidence of an increased risk of uterine rupture with labor induction abortion in women with one prior cesarean delivery. Retained placenta may be slightly higher with labor induction abortion in women with a prior cesarean delivery as compared to women without such a history. There is insufficient information to make evidence-based recommendations for women who have had multiple cesarean deliveries.

      10 What is the effect of feticide on labor induction abortion outcome?

      Deliberately causing demise of the fetus before labor induction abortion is performed primarily to avoid transient fetal survival after expulsion; this approach may be for the comfort of both the woman and the staff, to avoid futile resuscitation efforts. Some providers allege that feticide also facilitates delivery, although little data support this claim.
      Transient fetal survival is very unlikely after intra-amniotic installation of saline or urea, which are directly feticidal. Transient survival with misoprostol for labor induction abortion at greater than 18 weeks ranges from 0% to 50% [
      • Ramin K.D.
      • Ogburn P.L.
      • Danilenko D.R.
      • Ramsey P.S.
      High-dose oral misoprostol for mid-trimester pregnancy interruption.
      ] and has been observed in up to 13% of abortions performed with high-dose oxytocin [
      • Nuthalapaty F.S.
      • Ramsey P.S.
      • Biggio J.R.
      • Owen J.
      High-dose vaginal misoprostol versus concentrated oxytocin plus low-dose vaginal misoprostol for midtrimester labor induction: a randomized trial.
      ]. Factors associated with a higher likelihood of transient fetal survival with labor induction abortion include increasing gestational age, decreasing abortion interval and the use of nonfeticidal inductive agents such as the PGE1 analogues [
      • Ramsey P.S.
      • Savage K.
      • Lincoln T.
      • Owen J.
      Vaginal misoprostol versus concentrated oxytocin and vaginal PGE2 for second-trimester labor induction.
      ].
      Fetal demise may be induced using a variety of medications. Fetal intracardiac potassium chloride (KCl) injection is highly effective but requires expertise and time for observation after injection to ensure cardiac cessation [
      • Isada N.B.
      • Pryde P.G.
      • Johnson M.P.
      • Hallak M.
      • Blessed W.B.
      • Evans M.I.
      Fetal intracardiac potassium-chloride injection to avoid the hopeless resuscitation of an abnormal abortus. 1. Clinical issues.
      ,
      • Pasquini L.
      • Pontello V.
      • Kumar S.
      Intracardiac injection of potassium chloride as method for feticide: experience from a single UK tertiary centre.
      ]. Very rare serious complications, including maternal cardiac arrest, have occurred from injection into the maternal circulation [
      • Coke G.A.
      • Baschat A.A.
      • Mighty H.E.
      • Malinow A.M.
      Maternal cardiac arrest associated with attempted fetal injection of potassium chloride.
      ]. Fetal intracardiac injection of lidocaine, with similar technical considerations as KCl, has also been used, although the risk to the woman may be less [
      • Senat M.V.
      • Fischer C.
      • Bernard J.P.
      • Ville Y.
      The use of lidocaine for fetocide in late termination of pregnancy.
      ].
      Digoxin has been administered by intra-amniotic, intrafetal and intracardiac routes. Currently, there is limited documentation about its effectiveness. In one report, intra-amniotic injection had a failure rate (cardiac activity on ultrasound 24 h after injection) of 5 (8%) of 62 [
      • Jackson R.A.
      • Teplin V.L.
      • Drey E.A.
      • Thomas L.J.
      • Darney P.D.
      Digoxin to facilitate late second-trimester abortion: a randomized, masked, placebo-controlled trial.
      ]. In a retrospective study, intra-amniotic injection of 0.5 mg had a failure rate of 3 (8%) of 36, while intrafetal injection had a failure rate of 36 (4%) of 993 [
      • Molaei M.
      • Jones H.E.
      • Weiselberg T.
      • McManama M.
      • Bassell J.
      • Westhoff C.L.
      Effectiveness and safety of digoxin to induce fetal demise prior to second-trimester abortion.
      ]. In the same series, intrafetal injection of 1 mg had a failure rate of 0 (0%) of 107; intra-amniotic injection of 1 mg was not assessed. Feticidal digoxin doses of 1 mg produce maternal serum levels at or below one therapeutic level; higher doses have not been evaluated systematically [
      • Drey E.A.
      • Thomas L.J.
      • Benowitz N.L.
      • Goldschlager N.
      • Darney P.D.
      Safety of intra-amniotic digoxin administration before late second-trimester abortion by dilation and evacuation.
      ], and toxicity has not been reported.
      There is limited documentation of the effect of feticide on abortion outcome. Elimian et al. [
      • Elimian A.
      • Verma U.
      • Tejani N.
      Effect of causing fetal cardiac asystole on second-trimester abortion.
      ], in a retrospective study of women having PGE2 abortion, reported shorter abortion times in women who had undergone feticide by intracardiac KCl injection. An intriguing small retrospective study of 15 women with placenta previa undergoing induction noted a significant decrease in blood loss and need for transfusion in the nine women in whom feticide had been performed [
      • Ruano R.
      • Dumez Y.
      • Cabrol D.
      • Dommergues M.
      Second- and third-trimester therapeutic terminations of pregnancy in cases with complete placenta previa — does feticide decrease postdelivery maternal hemorrhage?.
      ].
      Overall, multiple agents are effective for feticide. Fetal intracardiac KCl is technically more difficult to perform but provides verification of demise. More information about the effectiveness of various doses and routes of digoxin is needed. Although many practitioners have historically felt that labor induction abortion is aided by feticide, there is limited medical literature to support this claim.

      Conclusions and recommendations

      The following recommendations are based on good and consistent scientific evidence (Grade A):
      • Mifepristone followed in 24–48 h by initiation of repeated doses of misoprostol or gemeprost is the most effective regimen available for labor induction abortion.
      • Misoprostol as a single agent is effective for labor induction abortion when administered vaginally or sublingually. Gemeprost has similar efficacy to misoprostol; however, it does not demonstrate superiority and has other drawbacks related to cost, route of administration and storage.
      • When misoprostol treatment is used alone, the optimal dosing is 400 mcg vaginally or sublingually every 3 h. A vaginal “loading” dose of 600–800 mcg of misoprostol followed by 400 mcg vaginally or sublingually every 3 h may be more effective.
      The following recommendations are based on limited or inconsistent scientific information (Evidence Grade B):
      • After mifepristone, repeat doses of misoprostol dose may be decreased to 200 mcg.
      • Misoprostol may be used by buccal administration.
      • Repeat doses of misoprostol may be given by vaginal, sublingual, buccal or oral routes.
      • When misoprostol treatment is being used alone, vaginal dosing is superior to sublingual dosing for nulliparous women.
      • High-dose oxytocin is an alternative to misoprostol for labor induction abortion.
      • Routine placental removal is not warranted.
      The following recommendations are based primarily on consensus or expert opinion (Grade C).
      • Women with one prior cesarean delivery may be at increased risk of uterine rupture during labor induction abortion; however, the magnitude of the risk, if any, is small.
      • Preprocedure feticide may facilitate the time to expulsion with labor induction abortion.
      In addition, SFP recognized that other organization have guidelines or recommendation for labor induction abortion, including the World Health Organization, the Royal College of Obstetricians and Gynaecologists, and the Federación Latino American de Sociedades de Obstetrica y Ginecología.

      Important questions to be answered

      There are multiple effective labor induction abortion regimens, including using a higher dose of misoprostol at 12-h intervals. Few direct comparisons have been performed. Sublingual and vaginal routes of administration have similar outcomes in most circumstances; however, oral administration is convenient and preferable to some women. Oral ingestion may be equally effective to other routes when used for repeat doses or as the primary route after mifepristone pretreatment. Relative effectiveness and acceptability of all routes of administration, including buccal, need to be better evaluated.
      The management of women who fail to abort in 24 h has not been studied systematically. More data are needed to inform whether such women would benefit from a period of rest, a change in dose or schedule, or another agent and when D&E should be considered.
      Mechanical preparation prior to induction may decrease abortion time. Although simultaneous laminaria use is not helpful with PGE1 analogue regimens, use of osmotic dilators the day prior to induction with misoprostol has not been systematically studied.
      Preprocedure feticide prior to labor induction abortion may be widely practiced, but there is little literature to support its use. Demonstration of the effect of feticide on labor induction abortion outcome, as distinct from avoiding transient fetal survival or legal restrictions, would be useful.
      There are several important questions regarding the safety of induction techniques compared to D&E. Randomized trials comparing induction abortion with D&E are unlikely to be done: blinding is impossible, and it may be difficult to find facilities and providers willing to participate. A well-designed ongoing system of monitoring outcomes of both D&E and induction abortion might yield useful comparative information.

      References

        • Jain J.K.
        • Mishell D.R.
        Comparison of intravaginal misoprostol with prostaglandin-E(2) for termination of 2nd-trimester pregnancy.
        N Engl J Med. 1994; 331 (Evidence Grade: I): 290-293
        • Jain J.K.
        • Mishell D.R.
        A comparison of misoprostol with and without laminaria tents for induction of second-trimester abortion.
        Am J Obstet Gynecol. 1996; 175 (Evidence Grade: I): 173-177
        • Jain J.K.
        • Kuo J.
        • Mishell Jr, D.R.
        A comparison of two dosing regimens of intravaginal misoprostol for second-trimester pregnancy termination.
        Obstet Gynecol. 1999; 93 (Evidence Grade: I): 571-575
        • Dickinson J.E.
        • Evans S.F.
        The optimization of intravaginal misoprostol dosing schedules in second-trimester pregnancy termination.
        Am J Obstet Gynecol. 2002; 186 (Evidence Grade: I): 470-474
        • Strauss L.T.
        • Gamble S.B.
        • Parker W.Y.
        • Cook D.A.
        • Zane S.B.
        • Hamdan S.
        Abortion surveillance — United States, 2004.
        MMWR Surveill Summ. 2007; 56 (Evidence Grade: III): 1-33
        • Gamble S.B.
        • Strauss L.T.
        • Parker W.Y.
        • Cook D.A.
        • Zane S.B.
        • Hamdan S.
        Abortion surveillance — United States, 2005.
        MMWR Surveill Summ. 2008; 57 (Evidence Grade: III): 1-32
      1. Socialstyrelsen. Aborter 2005. Stockholm, Sweden; 2006. Report No.: Report: 2006-42-2 (Evidence Grade: III).

        • Ho P.C.
        • Blumenthal P.D.
        • Gemzell-Danielsson K.
        • Gomez Ponce de L.R.
        • Mittal S.
        • Tang O.S.
        Misoprostol for the termination of pregnancy with a live fetus at 13 to 26 weeks.
        Int J Gynaecol Obstet. 2007; 99 (Evidence Grade: III): S178-S181
        • Dodd C.M.
        • Crowther C.A.
        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 (Evidence Grade: III): 3-8
        • Shmygol A.
        • Gullam J.
        • Blanks A.
        • Thornton S.
        Multiple Mechanisms involved in oxytocin-induced modulation of myometrial conrtactility.
        Acta Pharmacol Sin. 2006; 27: 827-832
        • Boza A.V.
        • de Leon R.G.
        • Castillo L.S.
        • Marino D.R.
        • Mitchell E.M.
        Misoprostol preferable to ethacridine lactate for abortions at 13–20 weeks of pregnancy: Cuban experience.
        Reprod Health Matters. 2008; 16 (Evidence Grade: II-2): 189-195
        • Kelekci S.
        • Erdemoglu E.
        • Inan I.
        Randomized study on the effect of adding oxytocin to ethacridine lactate or misoprostol for second-trimester termination of pregnancy.
        Acta Obstet Gynecol Scand. 2006; 85 (Evidence Grade: I): 825-829
        • Su L.L.
        • Biswas A.
        • Choolani M.
        • Kalaichelvan V.
        • Singh K.
        A prospective, randomized comparison of vaginal misoprostol versus intra-amniotic prostaglandins for midtrimester termination of pregnancy.
        Am J Obstet Gynecol. 2005; 193 (Evidence Grade: III): 1410-1414
        • Ashok P.W.
        • Templeton A.
        • Wagaarachchi P.T.
        • Flett G.M.M.
        Midtrimester medical termination of pregnancy: a review of 1002 consecutive cases.
        Contraception. 2004; 69 (Evidence Grade: III): 51-58
        • Borgatta L.
        • Chen A.Y.
        • Vragovic O.
        • Stubblefield P.G.
        • Magloire C.A.
        A randomized clinical trial of the addition of laminaria to misoprostol and hypertonic saline for second-trimester induction abortion.
        Contraception. 2005; 72 (Evidence Grade: I): 358-361
        • Kapp N.
        • Borgatta L.
        • Stubblefield P.G.
        • Vragovic O.
        • Moreno N.
        Mifepristone in midtrimester medical abortion: a randomized controlled trial.
        Obstet Gynecol. 2007; 110 (Evidence Grade: I): 1304-1310
        • Lo T.K.
        • Lau W.L.
        • Lai F.K.
        • et al.
        The effect of gestational age on the outcome of second-trimester termination of pregnancies for foetal abnormalities.
        Prenat Diagn. 2008; 28 (Evidence Grade: II-2): 508-511
        • Shulman L.P.
        • Ling F.W.
        • Meyers C.M.
        • Shanklin D.R.
        • Simpson J.L.
        • Elias S.
        Dilation and evacuation for second-trimester genetic pregnancy termination.
        Obstet Gynecol. 1990; 75 (Evidence Grade: II-2): 1037-1040
        • Burgoine G.A.
        • Van Kirk S.D.
        • Romm J.
        • Edelman A.B.
        • Jacobson S.L.
        • Jensen J.T.
        Comparison of perinatal grief after dilation and evacuation or labor induction in second trimester terminations for fetal anomalies.
        Am J Obstet Gynecol. 2005; 192 (Evidence Grade: II-2): 1928-1932
        • Kafrissen M.E.
        • Schulz K.F.
        • Grimes D.A.
        • Cates Jr., W.
        Midtrimester abortion. Intra-amniotic instillation of hyperosmolar urea and prostaglandin F2 alpha v dilatation and evacuation.
        JAMA. 1984; 251 (Evidence Grade II-2): 916-919
        • Grimes D.A.
        • Smith M.S.
        • Witham A.D.
        Mifepristone and misoprostol versus dilation and evacuation for midtrimester abortion: a pilot randomised controlled trial.
        BJOG. 2004; 111 (Evidence Grade: II-2): 148-153
        • Autry A.M.
        • Hayes E.C.
        • Jacobson G.F.
        • Kirby R.S.
        A comparison of medical induction and dilation and evacuation for second-trimester abortion.
        Am J Obstet Gynecol. 2002; 187 (Evidence Grade: III): 393-397
        • Lawson H.W.
        • Frye A.
        • Atrash H.K.
        • Smith J.C.
        • Shulman H.B.
        • Ramick M.
        Abortion mortality, United States, 1972 through 1987.
        Am J Obstet Gynecol. 1994; 171 (Evidence Grade: III): 1365-1372
        • Cowett A.A.
        • Golub R.M.
        • Grobman W.A.
        Cost-effectiveness of dilation and evacuation versus the induction of labor for second-trimester pregnancy termination.
        Am J Obstet Gynecol. 2006; 194 (Evidence Grade: II-2): 768-773
        • Hern W.M.
        Laminaria, induced fetal demise and misoprostol in late abortion.
        Int J Gynaecol Obstet. 2001; 75 (Evidence Grade: III): 279-286
      2. National Abortion Federation Annual Clinical Meeting, Portland, Oregon, April 25, 2009.

        • Royal College of Obstetricians and Gynaecologists
        The care of women requesting induced abortion.
        Royal College of Obstetricians and Gynaecologists, London2004 (Evidence Grade: III)
        • Webster D.
        • Penney G.C.
        • Templeton A.
        A comparison of 600 and 200 mg mifepristone prior to second trimester abortion with the prostaglandin misoprostol.
        Br J Obstet Gynaecol. 1996; 103 (Evidence Grade: I): 706-709
        • Thong K.J.
        • Baird D.T.
        Induction of 2nd trimester abortion with mifepristone and gemeprost.
        Br J Obstet Gynaecol. 1993; 100 (Evidence Grade: III): 758-761
        • Urquhart D.R.
        • Templeton A.A.
        The use of mifepristone prior to prostaglandin-induced midtrimester-abortion.
        Hum Reprod. 1990; 5 (Evidence Grade: I): 883-886
        • UK Multicenter Study Group
        Oral mifepristone 600 mg and vaginal gemeprost for mid-trimester induction of abortion. An open multicenter study.
        Contraception. 1997; 56 (Evidence Grade II): 361-366
        • Nigam A.
        • Singh V.K.
        • Prakash A.
        Vaginal vs. oral misoprostol for mid-trimester abortion.
        Int J Gynaecol Obstet. 2006; 92 (Evidence Grade: I): 270-271
        • Goh S.E.
        • Thong K.J.
        Induction of second trimester abortion (12–20 weeks) with mifepristone and misoprostol: a review of 386 consecutive cases.
        Contraception. 2006; 73 (Evidence Grade: III): 516-519
        • Rose S.B.
        • Shand C.
        • Simmons A.
        Mifepristone- and misoprostol-induced mid-trimester termination of pregnancy: a review of 272 cases.
        Aust N Z J Obstet Gynaecol. 2006; 46 (Evidence Grade: III): 479-485
        • Tang O.S.
        • Thong K.J.
        • Baird D.T.
        Second trimester medical abortion with mifepristone and gemeprost: a review of 956 cases.
        Contraception. 2001; 64 (Evidence Grade: III): 29-32
        • Esteve J.L.
        • Gallego F.G.
        • Llorente M.P.
        • Bermúdez S.B.
        • Sala E.S.
        • González L.V.
        • et al.
        Late second-trimester abortions induced with mifepristone, misoprostol and oxytocin: a report of 428 consecutive cases.
        Contraception. 2008; 78 (Evidence Grade:): 52-60
        • Tang O.S.
        • Chan C.C.W.
        • Kan A.S.Y.
        • Ho P.C.
        A prospective randomized comparison of sublingual and oral misoprostol when combined with mifepristone for medical abortion at 12–20 weeks gestation.
        Hum Reprod. 2005; 20 (Evidence Grade: I): 3062-3066
        • Tang O.S.
        • Lau W.N.
        • Chan C.C.
        • Ho P.C.
        A prospective randomised comparison of sublingual and vaginal misoprostol in second trimester termination of pregnancy.
        BJOG. 2004; 111 (Evidence Grade: I): 1001-1005
        • Hamoda H.
        • Ashok P.W.
        • Flett G.M.M.
        • Templeton A.
        A randomized trial of mifepristone in combination with misoprostol administered sublingually or vaginally for medical abortion at 13–20 weeks gestation.
        Hum Reprod. 2005; 20 (Evidence Grade: I): 2348-2354
        • Nilas L.
        • Glavind-Kristensen M.
        • Vejborg T.
        • Knudsen U.B.
        One or two day mifepristone-misoprostol interval for second trimester abortion.
        Acta Obstet Gynecol Scand. 2007; 86 (Evidence Grade: I): 1117-1121
        • Heikinheimo O.
        • Suhonen S.
        • Haukkamaa M.
        One- and two-day mifepristone-misoprostol intervals are both effective in medical termination of second- trimester pregnancy.
        Reprod Biomed Online. 2004; 8 (Evidence Grade: I): 236-239
        • Paz B.
        • Ohel G.
        • Tal T.
        • Degani S.
        • Sabo E.
        • Levitan Z.
        Second trimester abortion by laminaria followed by vaginal misoprostol or intrauterine prostaglandin F2alpha: a randomized trial.
        Contraception. 2002; 65 (Evidence Grade III): 411-413
        • Akoury H.A.
        • Hannah M.E.
        • Chitayat D.
        • Thomas M.
        • Winsor E.
        • Ferris L.E.
        • et al.
        Randomized controlled trial of misoprostol for second-trimester pregnancy termination associated with fetal malformation.
        Am J Obstet Gynecol. 2004; 190 (Evidence Grade I): 755-762
        • Marquette G.P.
        • Skoll M.A.
        • Dontigny L.
        A randomized trial comparing oral misoprostol with intra-amniotic prostaglandin F2alpha for second trimester terminations.
        J Obstet Gynaecol Can. 2005 Nov; 27 (Evidence Grade I): 1013-1018
        • Perry Jr., K.G.
        • Rinehart B.K.
        • Terrone D.A.
        • Martin R.W.
        • May W.L.
        • Roberts W.E.
        Second-trimester uterine evacuation: a comparison of intra-amniotic (15S)-15-methyl-prostaglandin F2alpha and intravaginal misoprostol.
        Am J Obstet Gynecol. 1999; 181 (Evidence Grade: I): 1057-1061
        • Ghorab M.N.
        • El Helw B.A.
        Second-trimester termination of pregnancy by extra-amniotic prostaglandin F2alpha or endocervical misoprostol. A comparative study.
        Acta Obstet Gynecol Scand. 1998; 77 (Evidence Grade I): 429-432
        • Dickinson J.E.
        • Evans S.F.
        A comparison of oral misoprostol with vaginal misoprostol administration in second-trimester pregnancy termination for fetal abnormality.
        Obstet Gynecol. 2003; 101 (Evidence Grade: I): 1294-1299
        • Makhlouf A.
        • Al-Hussaini T.
        • Habib D.
        • Makarem M.
        Second-trimester pregnancy termination: comparison of three different methods.
        J Obstet Gynaecol. 2003; 23 (Evidence Grade I): 407-411
        • Owen J.
        • Hauth J.C.
        Vaginal misoprostol vs. concentrated oxytocin plus low-dose prostaglandin E2 for second trimester pregnancy termination.
        J Matern Fetal Med. 1999; 8 (Evidence Grade: I): 48-50
        • Goyal V.
        Uterine rupture in second-trimester misoprostol-induced abortion after cesarean delivery: a systematic review.
        Obstet Gynecol. 2009; 113: 1117-1123
        • Ramin K.D.
        • Ogburn P.L.
        • Danilenko D.R.
        • Ramsey P.S.
        High-dose oral misoprostol for mid-trimester pregnancy interruption.
        Gynecol Obstet Invest. 2002; 54 (Evidence Grade: II-2): 176-179
        • Nuthalapaty F.S.
        • Ramsey P.S.
        • Biggio J.R.
        • Owen J.
        High-dose vaginal misoprostol versus concentrated oxytocin plus low-dose vaginal misoprostol for midtrimester labor induction: a randomized trial.
        Am J Obstet Gynecol. 2005; 193 (Evidence Grade: I): 1065-1070
        • Cameron I.T.
        • Michie A.F.
        • Baird D.T.
        Prostaglandin-induced pregnancy termination: further studies using gemeprost (16,16 dimethyl-trans-delta 2-PGE1 methyl ester) vaginal pessaries in the early second trimester.
        Prostaglandins. 1987; 34 (Evidence Grade: III): 111-117
        • Thong K.J.
        • Baird D.T.A.
        Study of gemeprost alone, dilapan or mifepristone in combination with gemeprost for the termination of 2nd trimester pregnancy.
        Contraception. 1992; 46 (Evidence Grade: I): 11-17
        • Thong K.J.
        • Baird D.T.
        Uterine rupture in midtrimester abortion. A complication of gemeprost vaginal pessaries and oxytocin. Case report.
        Br J Obstet Gynaecol. 1991; 98 (Evidence Grade: III): 416
        • Armatage R.J.
        • Luckas M.J.
        A randomized trial of 2 regimens for the administration of vaginal prostaglandins (gemeprost) for the induction of midtrimester abortion.
        Aust N Z J Obstet Gynaecol. 1996; 36 (Evidence Grade: I): 296-299
        • Nuutila M.
        • Toivonen J.
        • Ylikorkala O.
        • Halmesmaki A.E.
        A comparison between two doses of intravaginal misoprostol and gemeprost for induction of second-trimester abortion.
        Obstetrics and Gynecology. 1997; 90 (Evidence Grade: I): 896-900
        • Caliskan E.
        • et al.
        Sublingual misoprostol 100 microgram versus 200 microgram for second trimester abortion: a randomized trial.
        Eur J Contracept Repro Health Care. 2009; 24 (Evidence Grade: 1): 55-60
        • Wong K.S.
        • Ngai C.S.W.
        • Wong A.Y.K.
        • Tang L.C.H.
        • Ho P.C.
        Vaginal misoprostol compared with vaginal gemeprost in termination of second trimester pregnancy — a randomized trial.
        Contraception. 1998; 58 (Evidence Grade: I): 207-210
        • Nor Azlin M.
        • Abdullah H.
        • Zainul Rashid M.
        • Jamil M.
        Misoprostol (alone) in second trimester terminations of pregnancy: as effective as Gemeprost?.
        J Obstet Gynaecol. 2006; 26 (Evidence Grade: I): 546-549
        • el-Rafaey H.
        • Hinshaw K.
        • Templeton A.
        The abortifacient effect of misoprostol in the second trimester. A randomized comparison with gemeprost in patients pre-treated with mifepristone (RU486).
        Hum Reprod. 1993; 8 (Evidence Grade: I): 1744-1746
        • el-Refaey H.
        • Templeton A.
        Induction of abortion in the second trimester by a combination of misoprostol and mifepristone: a randomized comparison between two misoprostol regimens.
        Hum Reprod. 1995; 10 (Evidence Grade: I): 475-478
        • Ho P.C.
        • Chan Y.F.
        • Lau W.
        Misoprostol is as effective as gemeprost in termination of second trimester pregnancy when combined with mifepristone: a randomised comparative trial.
        Contraception. 1996; 53 (Evidence Grade: I): 281-283
        • Bartley J.
        • Baird D.T.
        A randomised study of misoprostol and gemeprost in combination with mifepristone for induction of abortion in the second trimester of pregnancy.
        Bjog-An International Journal of Obstetrics and Gynaecology. 2002; 109 (Evidence Grade: I): 1290-1294
        • Winkler C.L.
        • Gray S.E.
        • Hauth J.C.
        • Owen J.
        • Tucker J.M.
        Mid-second-trimester labor induction: concentrated oxytocin compared with prostaglandin E2 vaginal suppositories.
        Obstet Gynecol. 1991; 77 (Evidence Grade: I): 297-300
        • Owen J.
        • Hauth J.C.
        • Winkler C.L.
        • Gray S.E.
        Midtrimester pregnancy termination: a randomized trial of prostaglandin E2 versus concentrated oxytocin.
        Am J Obstet Gynecol. 1992; 167 (Evidence Grade: l): 1112-1116
        • Yapar E.G.
        • Senoz S.
        • Urkutur M.
        • Batioglu S.
        • Gokmen O.
        Second trimester pregnancy termination including fetal death: comparison of five different methods.
        Eur J Obstet Gynecol Reprod Biol. 1996; 69 (Evidence Grade: II-3): 97-102
        • Carbonell J.L.
        • Torres M.A.
        • Reyes R.
        • Ortega L.
        • Garcia-Gallego F.
        • Sanchez C.
        Second-trimester pregnancy termination with 600-microg vs. 400-microg vaginal misoprostol and systematic curettage postexpulsion: a randomized trial.
        Contraception. 2008; 77 (Evidence Grade: III): 50-55
        • Herabutya Y.
        • Chanrachakul B.
        • Punyavachira P.
        Second trimester pregnancy termination: a comparison of 600 and 800 micrograms of intravaginal misoprostol.
        J Obstet Gynaecol Res. 2001; 27 (Evidence Grade: I): 125-128
        • Carbonell J.L.
        • Rodriguez J.
        • Delgado E.
        • Sanchez C.
        • Vargas F.
        • Valera L.
        • et al.
        Vaginal misoprostol 800 microg every 12 h for second-trimester abortion.
        Contraception. 2004; 70 (Evidence Grade: I): 55-60
        • Wong K.S.
        • Ngai C.S.W.
        • Yeo E.L.K.
        • Tang L.C.H.
        • Ho P.C.
        A comparison of two regimens of intravaginal misoprostol for termination of second trimester pregnancy: a randomized comparative trial.
        Hum Reprod. 2000; 15 (Evidence Grade: I): 709-712
        • Guix C.
        • Palacio M.
        • Figueras F.
        • Bennasar M.
        • Zamora L.
        • Coll O.
        • et al.
        Efficacy of two regimens of misoprostol for early second-trimester pregnancy termination.
        Fetal Diagn Ther. 2005; 20 (Evidence Grade: II-1): 544-548
        • Bugalho A.
        • Bique C.
        • Almeida L.
        • Bergstrom S.
        Pregnancy interruption by vaginal misoprostol.
        Gynecol Obstet Invest. 1993; 36 (Evidence Grade: III): 226-229
        • Ngai S.W.
        • Tang O.S.
        • Ho P.C.
        Randomized comparison of vaginal (200 mu g every 3 h) and oral (400 mu g every 3 h) misoprostol when combined with mifepristone in termination of second trimester pregnancy.
        Hum Reprod. 2000; 15 (Evidence Grade: I): 2205-2208
        • Ho P.C.
        • Ngai S.W.
        • Liu K.L.
        • Wong G.C.Y.
        • Lee S.W.H.
        Vaginal misoprostol compared with oral misoprostol in termination of second-trimester pregnancy.
        Obstet Gynecol. 1997; 90 (Evidence Grade I): 735-738
        • 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 (Evidence Grade: I): 407-410
        • Bebbington M.W.
        • Kent N.
        • Lim K.
        • Gagnon A.
        • Delisle M.F.
        • Tessier F.
        • et al.
        A randomized controlled trial comparing two protocols for the use of misoprostol in midtrimester pregnancy termination.
        Am J Obstet Gynecol. 2002; 187 (Evidence Grade: I): 853-857
        • Tang O.S.
        • Schweer H.
        • Seyberth H.W.
        • Lee S.W.
        • Ho P.C.
        Pharmacokinetics of different routes of administration of misoprostol.
        Hum Reprod. 2002; 17 (Evidence Grade: I): 332-336
        • Yilmaz B.
        • Kelekci S.
        • Ertas I.E.
        • Ozel M.
        • Sut N.
        • Mollamahmutoglu L.
        • et al.
        Randomized comparison of second trimester pregnancy termination utilizing saline moistened or dry misoprostol.
        Arch Gynecol Obstet. 2007; 276 (Evidence Grade: I): 511-516
      3. von Hertzen H, Piaagio G, Wojdyla D, et al. Comparison of vaginal and sublingual misoprostol for second trimester abortion: randomized controlled equivalence trial. Hum Reprod 24:106–12 (Evidence Grade: I).

        • Ellis S.C.
        • Kapp N.
        • Vragpvoc O.
        • Borgata L.
        Randomized trial of buccal versus vaginal misoprostol for induction of second trimester abortion.
        Contraception. 2010; 81 (Evidence Grade: I): 441-445
        • Feldman D.M.
        • Borgida A.F.
        • Rodis J.F.
        • Leo M.V.
        • Campbell W.A.
        A randomized comparison of two regimens of misoprostol for second-trimester pregnancy termination.
        Am J Obstet Gynecol. 2003; 189 (Evidence Grade: I): 710-713
        • Blumenthal P.D.
        Prospective comparison of dilapan and laminaria for pretreatment of the cervix in 2nd-trimester induction abortion.
        Obstet Gynecol. 1988; 72 (Evidence Grade: I): 243-246
        • Strauss J.H.
        • Wilson M.
        • Caldwell D.
        • Otterson W.
        • Martin A.O.
        Laminaria use in midtrimester abortions induced by intra-amniotic prostaglandin-f2-alpha with urea and intravenous oxytocin.
        Am J Obstet Gynecol. 1979; 134 (Evidence Grade: I): 260-264
        • Atlas R.O.
        • Lemus J.
        • Reed J.
        • Atkins D.
        • Alger L.S.
        Second trimester abortion using prostaglandin E-2 suppositories with or without intracervical Laminaria japonica: a randomized study.
        Obstet Gynecol. 1998; 92 (Evidence Grade: I): 398-402
        • Stubblefield P.G.
        • Naftolin F.
        • Frigoletto F.
        • Ryan K.J.
        Laminaria augmentation of intra-amniotic Pgf2Alpha for midtrimester pregnancy termination.
        Prostaglandins. 1975; 10 (Evidence Grade III): 413-422
        • Karim S.M.M.
        • Ratnam S.S.
        • Lim A.L.
        • Yeo K.C.
        • Choo H.T.
        Termination of 2nd trimester pregnancy with laminaria and intramuscular 16-phenoxy-omega-17,18,19,20 tetranor Pge2 methylsulfonylamide (Sulprostone) — a randomized study.
        Prostaglandins. 1982; 23 (Evidence Grade: I): 257-263
        • Papageorgiou I.
        • Minaretzis D.
        • Tsionou C.
        • Michalas S.
        Late midtrimester medical pregnancy terminations — 3 different procedures with prostaglandin-F2-alpha and laminaria tents.
        Prostaglandins. 1991; 41 (Evidence Grade: II-3): 487-493
        • Ho P.C.
        • Tsang S.S.K.
        • Ma H.K.
        Reducing the induction to abortion interval in termination of 2nd trimester pregnancies — a comparison of mifepristone with laminaria tent.
        Br J Obstet Gynaecol. 1995; 102 (Evidence Grade: I): 648-651
        • Prairie B.
        • Lauria M.
        • Kapp N.
        • MacKenzie T.
        • Baker E.
        • George K.
        Mifepristone versus laminaria: a randomized controlled trial of cervical ripening in midtrimester termination.
        Contraception. 2007; 76 (Evidence Grade: I): 383-388
        • Thong K.J.
        • Baird D.T.
        A study of gemeprost alone, dilapan or mifepristone in combination with gemeprost for the termination of 2nd trimester pregnancy.
        Contraception. 1992; 46 (Evidence Grade: I): 11-17
        • Hoffer M.C.
        • Charlier C.
        • Giacalone P.L.
        • Zimbris L.
        • Astruc M.
        • Boulot P.
        Evaluation of combination RU 486-laminaria tents-misoprostol-peridural anesthesia in second and third trimester induced abortions.
        J Gynecol Obstet Biol Reprod (Paris). 1998; 27 (Evidence Grade: II-3): 83-86
        • Surrago E.J.
        • Robins J.
        Mid-trimester pregnancy termination by intra-vaginal administration of prostaglandin-E2.
        Contraception. 1982; 26 (Evidence Grade: II-1): 285-294
      4. Prostaglandins and abortion. III. Comparison of single intra-amniotic injections of 15-methyl prostaglandin F2alpha and prostaglandin F2alpha for termination of second-trimester pregnancy: an international multicenter study. World Health Organization Task Force on the Use of Prostaglandins forthe Regulation of Fertility.
        Am J Obstet Gynecol. 1977; 129 (Evidence Grade: II-2): 601-606
        • Kerenyi T.D.
        • Mandelman N.
        • Sherman D.H.
        Five thousand consecutive saline inductions.
        Am J Obstet Gynecol. 1973; 116 (Evidence Grade III): 593-600
        • Anonymous
        Comparison of intra-amniotic prostaglandin F2 alpha and hypertonic saline for induction of second-trimester abortion.
        Br Med J. 1976; 1 (Evidence Grade II-2): 1373-1376
        • Leader J.
        • Bujnovsky M.
        • Carlan S.J.
        • Triana T.
        • Richichi K.
        Effect of oral misoprostol after second-trimester delivery: a randomized, blinded study.
        Obstet Gynecol. 2002; 100 (Evidence Grade I): 689-694
        • Green J.
        • Borgatta L.
        • Sia M.
        • Kapp N.
        • Saia K.
        • Carr-Ellis S.
        • et al.
        Intervention rates for placental removal following induction abortion with misoprostol.
        Contraception. 2007; 76 (Evidence Grade III): 310-313
        • Kirz D.S.
        • Haag M.K.
        Management of the 3rd stage of labor in pregnancies terminated by prostaglandin-E2.
        Am J Obstet Gynecol. 1989; 160 (Evidence Grade III): 412-414
        • Phillips K.
        • Berry C.
        • Mathers A.M.
        Uterine rupture during second trimester termination of pregnancy using mifepristone and a prostaglandin.
        Eur J Obstet Gynecol Reprod Biol. 1996; 65 (Evidence Grade III): 175-176
        • Edwards R.K.
        • Sims S.M.
        Outcomes of second-trimester pregnancy terminations with misoprostol: comparing 2 regimens.
        Am J Obstet Gynecol. 2005; 193 (Evidence Grade III): 544-548
        • Malhotra N.
        • Chanana C.
        Silent rupture of unscarred uterus: an unusual presentation at second trimester abortion.
        Arch Gynecol Obstet. 2007; 275 (Evidence Grade III): 283-284
        • Isada N.B.
        • Pryde P.G.
        • Johnson M.P.
        • Hallak M.
        • Blessed W.B.
        • Evans M.I.
        Fetal intracardiac potassium-chloride injection to avoid the hopeless resuscitation of an abnormal abortus. 1. Clinical issues.
        Obstet Gynecol. 1992; 80 (Evidence Grade III): 296-299
        • Al-Hussaini T.K.
        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 (Evidence Grade III): 218-219
        • Berghahn L.
        • Christensen D.
        • Droste S.
        Uterine rupture during second-trimester abortion associated with misoprostol.
        Obstet Gynecol. 2001; 98 (Evidence Grade III): 976-977
        • Chen M.
        • Shih J.C.
        • Chiu W.T.
        • Hsieh F.J.
        Separation of cesarean scar during second-trimester intravaginal misoprostol abortion.
        Obstet Gynecol. 1999; 94 (Evidence Grade III): 840
        • Letourneur B.
        • Parant O.
        • Tofani V.
        • Berrebi A.
        Uterine rupture on unscarred uterus following labor induction for 2nd trimester termination of pregnancy with oral misoprostol: conservative management.
        J Gynecol Obstet Biol Reprod (Paris). 2002; 31 (Evidence Grade III): 371-373
        • Nayki U.
        • Taner C.E.
        • Mizrak T.
        • Nayki C.
        • Derin G.
        Uterine rupture during second trimester abortion with misoprostol.
        Fetal Diagn Ther. 2005; 20 (Evidence Grade III): 469-471
        • Bagga R.
        • Chaudhary N.
        • Kalra J.
        Rupture in an unscarred uterus during second trimester pregnancy termination with mifepristone and misoprostol.
        Int J Gynaecol Obstet. 2004; 87 (Evidence Grade III): 42-43
        • Bhattacharjee N.
        • Ganguly R.P.
        • Saha S.P.
        Misoprostol for termination of mid-trimester post-caesarean pregnancy.
        ANZ J Obstet Gynaecol. 2007; 47 (Evidence Grade III): 23-25
        • Mazouni C.
        • Provensal M.
        • Porcu G.
        • Guidicelli B.
        • Heckenroth H.
        • Gamerre M.
        • et al.
        Termination of pregnancy in patients with previous cesarean section.
        Contraception. 2006; 73 (Evidence Grade III): 244-248
        • Herabutya Y.
        • Chanarachakul B.
        • Punyavachira P.
        Induction of labor with vaginal misoprostol for second trimester termination of pregnancy in the scarred uterus.
        Int J Gynaecol Obstet. 2003; 83 (Evidence Grade III): 293-297
        • Ramsey P.S.
        • Savage K.
        • Lincoln T.
        • Owen J.
        Vaginal misoprostol versus concentrated oxytocin and vaginal PGE2 for second-trimester labor induction.
        Obstet Gynecol. 2004; 104 (Evidence Grade 1): 138-145
        • Pasquini L.
        • Pontello V.
        • Kumar S.
        Intracardiac injection of potassium chloride as method for feticide: experience from a single UK tertiary centre.
        BJOG. 2008; 115 (Evidence Grade III): 528-531
        • Coke G.A.
        • Baschat A.A.
        • Mighty H.E.
        • Malinow A.M.
        Maternal cardiac arrest associated with attempted fetal injection of potassium chloride.
        Int J Obstet Anesth. 2004; 13 (Evidence Grade III): 287-290
        • Senat M.V.
        • Fischer C.
        • Bernard J.P.
        • Ville Y.
        The use of lidocaine for fetocide in late termination of pregnancy.
        BJOG. 2003; 110 (Evidence Grade III): 296-300
        • Jackson R.A.
        • Teplin V.L.
        • Drey E.A.
        • Thomas L.J.
        • Darney P.D.
        Digoxin to facilitate late second-trimester abortion: a randomized, masked, placebo-controlled trial.
        Obstet Gynecol. 2001; 97 (Evidence Grade I): 471-476
        • Molaei M.
        • Jones H.E.
        • Weiselberg T.
        • McManama M.
        • Bassell J.
        • Westhoff C.L.
        Effectiveness and safety of digoxin to induce fetal demise prior to second-trimester abortion.
        Contraception. 2008; 77 (Evidence Grade II-3): 223-225
        • Drey E.A.
        • Thomas L.J.
        • Benowitz N.L.
        • Goldschlager N.
        • Darney P.D.
        Safety of intra-amniotic digoxin administration before late second-trimester abortion by dilation and evacuation.
        Am J Obstet Gynecol. 2000; 182 (Evidence Grade III): 1063-1066
        • Elimian A.
        • Verma U.
        • Tejani N.
        Effect of causing fetal cardiac asystole on second-trimester abortion.
        Obstet Gynecol. 1999; 94 (Evidence Grade III): 139-141
        • Ruano R.
        • Dumez Y.
        • Cabrol D.
        • Dommergues M.
        Second- and third-trimester therapeutic terminations of pregnancy in cases with complete placenta previa — does feticide decrease postdelivery maternal hemorrhage?.
        Fetal Diagn Ther. 2004; 19 (Evidence Grade III): 475-478