Misoprostol for women’s health: a review 1

REVIEW

Misoprostol for Women’s Health: A Review Kelly Blanchard, MSc, Shelley Clark, PhD, Beverly Winikoff, MD, MPH, Gayle Gaines, MD, Ghazala Kabani, MHS, and Caitlin Shannon, MPH OBJECTIVE: To review published literature on misoprostol for women’s health indications to provide a synthesis of available information and highlight areas in need of additional research. DATA SOURCES: Studies were identified through searches of medical literature databases including MEDLINE, Cochrane Database, and Popline, in addition to a review of references from identified articles. STUDY SELECTION: We included all studies reported in English and published before March 31, 2001, which evaluated the efficacy of misoprostol alone for labor and delivery, evacuation of the uterus after pregnancy failure and induced abortion. Studies were not excluded based on quality or sample size. TABULATION, INTEGRATION, AND RESULTS: Misoprostol shows promise for all of the women’s health indications addressed. Currently available data, though, are often hard to interpret because of variations in regimen, dose, and outcome measures. The low cost, ease of administration and storage, and widespread availability of misoprostol make it particularly appealing for developing countries. Because many of the women’s health problems for which misoprostol could be prescribed currently cause significant mortality and morbidity, increased access to and information on use of misoprostol could help improve women’s health especially where these problems are most severe. CONCLUSION: Further research is needed to identify optimal regimens for misoprostol for obstetric and gynecologic health indications. Registering misoprostol with national drug regulatory authorities for any of several women’s health indications could help increase access to and safe use of this drug. Provider training would be a logical subsequent step. (Obstet Gynecol 2002;99:316 –32. © 2002 by the American College of Obstetricians and Gynecologists.)

From the Population Council, Johannesburg, South Africa, and New York, New York. We would like to thank the Hewlett Foundation for their support of work on misoprostol for reproductive health indications.

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Misoprostol is a prostaglandin E1 analogue marketed for prevention and treatment of gastric ulcers secondary to chronic treatment with nonsteroidal anti-inflammatory drugs. It also has potential use for a wide range of obstetric and gynecologic indications, which fall into three broad categories: labor and delivery, evacuation of the uterus after pregnancy failure, and induced abortion. Misoprostol has a number of advantages for clinical obstetric and gynecologic use. It costs approximately 100 times less than other prostaglandins,1 has a long shelf life, is easy to administer, and does not require refrigeration. Furthermore, it is registered in more than 80 countries and is therefore widely available. Despite these advantages and a large and growing body of literature on various indications, misoprostol has yet to be registered for its women’s health applications. We have attempted to synthesize the published research on misoprostol used alone for obstetric and gynecologic indications. We summarize findings for uses where a significant body of literature exists (labor induction, second-trimester abortion) and examine individual research studies in more depth for indications that are less well documented. We do not cover literature on misoprostol used alone for early abortion, as a comprehensive literature review on this topic was recently published.2

DATA SOURCES We selected studies using MEDLINE, searching for the term misoprostol, misoprostol in combination with each of the indications described (labor induction/cervical ripening; postpartum hemorrhage; spontaneous, incomplete, and missed abortion; intrauterine fetal death; second-trimester abortion) and other terms commonly used to refer to these indications (including mid-trimester abortion, third stage of labor, miscarriage, delivery, and pregnancy loss). In addition, we searched Popline and the Cochrane database, and consulted with experts in the field to identify relevant studies and authors. We also reviewed reference lists of pivotal studies and reviews.

VOL. 99, NO. 2, FEBRUARY 2002 © 2002 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.

0029-7844/02/$22.00 PII S0029-7844(01)01701-X

STUDY SELECTION We included all studies published in English through March 31, 2001. We did not exclude studies based on study design, sample size, or other measures of data quality, but rather aimed to present a complete picture of research conducted to date on misoprostol for women’s health indications.

TABULATION, INTEGRATION, AND RESULTS Labor and Delivery Labor induction is a relatively common obstetric procedure, occurring in more than 15% of deliveries.3 Misoprostol has been shown to be an effective labor induction agent, and there is extensive literature on this indication,1,4 – 61 as well as several recent excellent reviews.62– 66 We will highlight the main themes of this literature. Two recent systematic reviews63,64 and a meta-analysis of trials of misoprostol for induction of labor62 have shown misoprostol to be more effective than placebo or other prostaglandins. Misoprostol had a higher rate of vaginal delivery within 24 hours (70.3% compared with 50.9%), shorter mean interval from start of induction to delivery, and a significantly lower overall cesarean delivery rate (15.6% compared with 21.5%) than pooled figures for the control groups.62 Misoprostol was also more likely to result in a successful induction (relative risk of failure to achieve vaginal delivery in 24 hours 0.48, 95% confidence interval 0.35, 0.66).64 SanchezRamos et al found rates of fetal tachysystole were higher with misoprostol, but rates of maternal uterine hyperstimulation, 5-minute Apgar scores less than 7, and admissions to the neonatal intensive care unit were similar in the misoprostol and control groups.62 In a later review, Hofmeyr et al found misoprostol-treated women had increased rates of uterine hyperstimulation with and without fetal heart rate abnormalities (relative risk 2.54, 95% confidence interval 1.12, 5.77).64 The significance of increased fetal tachysystole or uterine hyperstimulation is not known. Researchers continue to try to establish the ideal misoprostol dose and regimen for labor induction. Both oral and vaginal misoprostol are effective, and there is no consensus in the literature on which is preferable. A vaginal dose of 25 ␮g is often recommended as the most prudent choice for labor induction because it is associated with a lower incidence of uterine hyperstimulation. It is comparable to a 50-␮g dose in achieving delivery within 24 hours.23,45,59,63 The dose of misoprostol in oral regimens is generally higher, with similar rates of suc-

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cess. The ideal interval between repeated doses has yet to be identified for either vaginal or oral regimens. Many authors recommend that misoprostol, like other prostaglandins, be avoided for women with prior cesarean deliveries. This recommendation is largely based on case reports of disruption of uterine scars associated with its use for induction of labor. In their meta-analysis, Plaut et al reported a 5.6% rate of uterine rupture associated with the use of misoprostol compared with 0.2% in patients attempting vaginal birth after cesarean delivery with no stimulation (P ⬍ .001).66 Misoprostol also holds considerable promise in treating and preventing postpartum hemorrhage. It is well suited to developing country settings where access to drugs for these purposes may be limited. Twenty-eight percent of maternal deaths are attributed to postpartum hemorrhage,67 and a disproportionate number of these deaths occur in resource-poor countries. Measuring the efficacy of misoprostol for reducing postpartum hemorrhage presents many methodologic challenges. Blood loss is typically measured by visual estimation, which is clearly imprecise. There is also no consensus on the level of blood loss associated with negative maternal outcomes and therefore clinically significant, although 500 mL and 1000 mL have typically been used as endpoints. Similarly, there is no one proxy outcome that has been shown to predict a reduction in postpartum hemorrhage. Researchers have typically used mean change in hemoglobin, mean blood loss, and need for additional oxytocics. Finally, available studies have not evaluated directly comparable regimens or protocols. These factors make it difficult to interpret the meaning of existing data (Table 1).68 –78 To date, there have been two prospective trials68 (El-Refaey H, O’Brien P, Morafa W, Walder J, Rodeck C. Misoprostol for third stage of labour [letter]. Lancet 1996;347:1257) and ten randomized controlled trials comparing misoprostol with placebo69 –71 or standard therapies (oxytocin and methylergometrine, alone or in combination)72–78 for prevention of postpartum hemorrhage, including a total of 5682 women. Two of these trials evaluated oral misoprostol doses, ranging from 400 – 600 ␮g; one trial evaluated rectal misoprostol.69,72 In the three placebo controlled trials, more women in the control group required additional oxytocic therapy. The incidence of blood loss greater than 500 mL or 1000 mL was also higher among controls, although this difference was not statistically significant.69 –71 In all three trials, women who began to bleed heavily were given conventional oxytocics, which might have limited the total amount of bleeding experi-

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Table 1. Misoprostol for Prevention of Postpartum Hemorrhage Sample sizes

Blood loss ⬎500 mL % (n)

Misoprostol 600 ␮g, oral Misoprostol 600 ␮g, oral

100 237

6 (6) 6 (13)

Misoprostol 400 ␮g, rectal Placebo, rectal Misoprostol 400 ␮g, oral Placebo, oral Misoprostol 600 ␮g, oral Placebo, oral

271 275 250 250 31 34

7 (2) 15 (4)

Misoprostol 400 ␮g, rectal Syntometrine,† IM Misoprostol 600 ␮g, oral Methylergometrine, oral Misoprostol 400 ␮g, oral Oxytocin 10 IU or syntometrine† (both IM) Misoprostol 600 ␮g, oral Misoprostol 400 ␮g, oral Oxytocin 10 IU, IM Misoprostol 500 ␮g, oral Standard treatments‡ Misoprostol 400 ␮g, oral Oxytocin 10 IU, IM Misoprostol 600 ␮g, oral Syntometrine† 1 mL, IM

241 250 100 100 424 439

0.9 (2) 0.4 (1) 7.3 (7) 4.3 (4) 15 (63) 6 (24)

199 198 200 501 499 203 198 1026 1032

12 (62) 11 (56) 0 (0) 1.0 (2) 5.8 (60) 4.3 (44)

Study Prospective noncomparative trials El-Refaey et al, Lancet 1996;347:1257 El-Refaey et al, 199768 Randomized placebo-controlled trials Bamigboye et al, 199869 Hofmeyr et al, 199870 Surbek et al, 199971 Randomized controlled trials with standard oxytocics Bamigboye et al, 199872 Amant et al, 199973 Cook et al, 199974 Lumbinganon et al, 199975 El-Refaey et al, 200076 Walley et al, 200077 Ng et al, 200078

Regimen used

Blood loss ⬎1000 mL % (n)

0 (0) 4.8 (13) 7 (19) 6 (15) 9.2 (23)

1 (1) 0 (0) 3 (13) 2 (7)

2 (9) 2 (10) 0.5 (5) 0.4 (4)

Hb ⫽ hemoglobin; IM ⫽ intramuscular. * Difference statistically significant (P ⱕ .05). † 5 IU of oxytocin and 0.5 mg of ergometrine. ‡ Postpartum hemorrhage defined as estimated blood loss ⬎500 mL.

enced in the placebo arm. In the seven randomized controlled trials comparing misoprostol with standard oxytocic therapies, the only significant difference was a greater need for additional oxytocics in the misoprostol groups.72–78 However, several of these trials were not masked and therefore subject to bias.74,76,78 One study examined the efficacy of misoprostol in treatment of severe postpartum hemorrhage.79 Fourteen women with continued uncontrolled blood loss unresponsive to standard oxytocic treatments were given 1000 ␮g of misoprostol rectally. In each case, bleeding was controlled within 3 minutes. However, this trial was small and noncomparative, and provides only preliminary evidence for the efficacy of misoprostol for treatment of postpartum hemorrhage. Two prospective studies, which used a dose of 600 ␮g of oral misoprostol, reported a high incidence of shivering (over 60% of women)68 (El-Refaey H et al. Lancet 1996;347:1257). In a trial that used a lower dose of oral misoprostol (400 ␮g), only 19% of women reported

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shivering, significantly higher than in the control arm.70 In contrast, a randomized placebo-controlled study using rectal administration of misoprostol showed no increase in the incidence of shivering.69 In all of these studies, other side effects such as vomiting, nausea, and diarrhea were rare. Although two studies have shown a reduced incidence of side effects, particularly shivering, using misoprostol rectally (Ramsey PS. Rectal misoprostol in the prevention of postpartum hemorrhage [letter]. Am J Obstet Gynecol 1999;180:1601–2. Ramsey P. Rectally administered misoprostol for the treatment of postpartum hemorrhage unresponsive to oxytocin and ergometrine: A descriptive study [letter]. Obstet Gynecol 1999;93:157– 8), the pharmacokinetic properties of rectal administration have not yet been studied, and the rate of absorption and bioavailability of the drug are unknown. Nonetheless, these studies provide prima facie evidence of rectal absorption, bioavailability, and clinically significant physiologic effects.

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Mean blood loss (mL) 200

345 ⫾ 19.5 417 ⫾ 25.9 187 ⫾ 92 183 ⫾ 68

Additional oxytocic therapy % (n)

⌬ Hb

6 (6) 5 (12) 5.2 (14) 9.1 (25) 8.4 (21) 13 (33) 16 (5) 38 (13)*

279 ⫾ 14.6 209 ⫾ 9.0

12.8 (12) 4.4 (4) 22 (95) 8 (34)*

341 ⫾ 295 371 ⫾ 327 353 ⫾ 310 256 ⫾ 12 251 ⫾ 12 190 ⫾ 78 187 ⫾ 91 296 ⫾ 160 254 ⫾ 157

14 (68) 10 (50) 3.6 (6) 4.6 (8) 22.6 (232) 14.0 (144)*

⫺1.6 ⫾ 0.3 ⫺2.6 ⫾ 0.3 ⫺0.23 ⫾ 1.6 ⫺0.28 ⫾ 1.9 ⫺6.9 ⫾ 17.5 ⫺4.0 ⫾ 16.7

⫺0.60 ⫾ 0.93 ⫺0.55 ⫾ 0.73 1.34 ⫾ 1.27 1.34 ⫾ 1.27

Evacuation of the Uterus After Pregnancy Failure For nearly 70 years, the universal standard of care for women who present with missed or incomplete abortions during the first trimester has been curettage of the uterus. There is growing interest in treating incomplete and missed abortions with either expectant management or medical methods of uterine evacuation. Avoiding surgical procedures could potentially reduce the workload in gynecologic services and also possibly decrease the rates of complications such as infection, cervical tears, and uterine perforation. We reviewed 12 studies that investigated the use of misoprostol for treatment of incomplete or missed abortion (Table 2).80 –91 Five studies have examined oral use of misoprostol to treat incomplete abortions.80 – 84 Two of these studies evaluated administration of a single 400-␮g dose.80,82 One reported a success rate of 95% (the group also included an unknown number of women who received a 0.5-mg dose of sulprostone).80 The success rate was 13% in the other.82 The difference in efficacy may be attributed to differences in the definition of success (defined as a reduction in pain, bleeding, or

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uterine size in one80 and reduction of bleeding in the other82) or in the clinical evaluation of patients. Chung et al studied three different regimens for managing incomplete abortion. In two studies, they evaluated a regimen of 400 ␮g of oral misoprostol every 4 hours (to a maximum dose of 1200 ␮g); outcome was determined 24 hours after the initial dose.81,84 The third study tested a similar regimen (400 ␮g of oral misoprostol up to three times per day), but outcome was determined at 48 hours.83 In all three studies, over 50% of women did not require surgical intervention. Demetroulis et al evaluated a higher dose (800 ␮g) of vaginal misoprostol for women presenting with incomplete abortion, which resulted in 92.9% success 8 to 10 hours after misoprostol administration.91 Chung et al84 compared complication rates between groups of women randomized to receive either misoprostol or a surgical evacuation. The immediate, shortterm, and medium-term medical complications were significantly lower in the misoprostol group than in the surgical group. Six studies have examined the use of misoprostol alone to treat missed abortion during the first trimester.85–90 Missed abortion is distinguished from incomplete abortion by presentation with a closed cervical os and minimal, if any, spotting or bleeding. Diagnosis is usually made by ultrasound. Because bleeding is minimal in women presenting with missed abortion, vaginal misoprostol is often the preferred route of administration. A small randomized study comparing the efficacy of oral (400 ␮g) and vaginal (800 ␮g) misoprostol for missed abortion found vaginal administration to be more effective (88% and 25% for vaginal and oral, respectively).86 Another study compared the rates of complete evacuation among women with missed abortion given a lower dose of vaginal misoprostol (200 ␮g) or placebo. One day later, 83% of women in the misoprostol group, but only 17% in the placebo group, had had a complete expulsion.85 A third study repeated the 200-␮g vaginal dose every 4 hours (maximum dose 800 ␮g) until an expulsion occurred. Eighty-eight percent of women had an expulsion within 10 hours, usually after the second dose of misoprostol.88 Other researchers have looked at 800-␮g vaginal doses at various intervals and have reported rates of success from 71– 89%.87,89,91 Increasing the interval between doses appears to increase success rates. In comparison, an evaluation of a 600-␮g dose demonstrated a lower efficacy (56.8% complete at 12 hours).90 Together, these studies suggest that repeated doses of misoprostol given at longer time intervals (8 –12

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Table 2. Misoprostol for Treatment of Incomplete and Missed Abortion Sample sizes

Regimens used

1

2

Gestational age (wk)

Incomplete abortion Henshaw et al, 199380

24

20

ⱕ13

Oral misoprostol 400 ␮g

Chung et al, 199581

141

ⱕ18

de Jonge et al, 199582 Chung et al, 199783

23 225

27 137

ⱕ14 Not given

Chung et al, 199984

321

314

Not given

Oral misoprostol 400 ␮g q 4 h ⫻ three doses Oral misoprostol 400 ␮g Oral misoprostol 400 ␮g ⫻ three doses (for 48 h) Oral misoprostol 400 ␮g q4h

42

42

ⱕ14

Vaginal misoprostol 200 ␮g

Vaginal placebo

12

8

ⱕ8

Oral misoprostol 400 ␮g repeated 24 h later if gestational sac present Vaginal misoprostol 800 ␮g q 12 h ⫻ two doses Vaginal misoprostol 200 ␮g soaked in saline q 4 h ⫻ four doses Vaginal misoprostol 800 ␮g, repeated 10–14 days as needed

Vaginal misoprostol 800 ␮g repeated 24 h later if gestational sac present

Study

Missed abortion Herabutya and O-Prasertsawat 199785 Creinin et al, 199786 Wakabayashi et al, 199887 Zalanyi, 199888 Autry et al, 199989

7

ⱕ13

25

ⱕ13

9

Ayres-de-Campos et al, 200090 Both incomplete and missed abortion Demetroulis et al, 200191

12

74

40

40

ⱕ7

1

ⱕ13

Vaginal misoprostol 600 ␮g q 4 h ⫻ two doses

ⱕ13

Vaginal misoprostol 800 ␮g, surgical evacuation 8–10 h later if unsuccessful

2 IM sulprostone 0.5 mg

Surgical curettage Surgical evacuation Surgical evacuation

Methotrexate 50 mg/m2 (day 1), vaginal misoprostol 800 ␮g (day 3), repeated misoprostol (days 10–14) as needed

Surgical evacuation

IM ⫽ intramuscular; q ⫽ every; CI ⫽ confidence interval; NA ⫽ not applicable. Success rate defined as complete evacuation of retained products of conception without surgical intervention. * This study combined results for the cases (misoprostol) and the controls (sulprostone 0.5 mg IM).

hours) and evaluation after 24 hours can result in high rates of complete expulsions with minimal side effects and complications. Intrauterine fetal death in the second and third trimester may also require uterine evacuation. We found four studies that used misoprostol for treatment of late intrauterine fetal death (Table 3).92–95 Two studies conducted by Bugalho et al92,93 in Mozambique evaluated two different regimens of vaginal misoprostol: a regimen of 100 ␮g and a regimen combining both 50-␮g and 200-␮g doses. In the first study, 100% of women had aborted by 48 hours and 92% in less than 24 hours.92 The average induction to delivery interval was 12.6 hours. In the second study, all women in the misoprostol group were successfully induced, and 81% of women began the abortion after receiving less than 100 ␮g of

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misoprostol.93 The induction to delivery interval was shorter for women receiving misoprostol than for women receiving oxytocin. The authors reported no maternal side effects in either experimental group, although in the second study, 4% of women in the misoprostol group and 6% in the oxytocin group received blood transfusions.93 Merrell and Koch examined the efficacy of 100 ␮g of vaginal misoprostol in women with second-trimester and third-trimester intrauterine fetal death.94 Seventy-eight percent of women with second-trimester and 90% of women with third-trimester intrauterine fetal death had a successful induction of labor. The induction to abortion intervals were 13.2 and 13.4 hours, respectively. All women classified as successes aborted with two doses of misoprostol.94

OBSTETRICS & GYNECOLOGY

Success rate 1 ⬃95% 12–18 h after treatment* 62% by following morning

2 ⬃95% 12–18 h after treatment

13% 12 h after treatment 69.6% after 48 h

97% 97%

50.5% by next day

NA

83.3% by next day

17.1%

25% (CI 1–50%) by 24 h after second dose

88% (CI 65–100%) by 24 h after second dose

71.4% 88% after 10 h 89%

100%

56.8% after 12 h

Overall: 82.5% Incomplete: 92.9% Missed: 76.9%

100%

Eng and Guan completed a randomized controlled trial comparing misoprostol (200 ␮g vaginally every 3 hours) with gemeprost (1 mg vaginally every 3 hours) among 50 women with intrauterine fetal death at 13–26 weeks.95 Success rates within 24 hours were 84% and 68% in the misoprostol and gemeprost groups, respectively; side effects were rare and similar in the two groups. Additional data on treatment of second-trimester intrauterine fetal death are included in the section below on second-trimester abortion. Induced Abortion Dilatation of the cervix before a surgical abortion can be the most difficult and painful aspect of an abortion procedure, particularly for nulliparous women. Current pharmacologic approaches to cervical dilatation, including mifepristone, gemeprost, and dinoprostone, all have considerable drawbacks such as limited access, high cost, or need for refrigeration.

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Nineteen randomized controlled trials have evaluated the efficacy, safety, and acceptability for cervical dilatation (Table 4).96 –113 In five trials, misoprostol was compared with a placebo,96,98,102,105,113 whereas in eight trials (one of which also had a placebo group105), misoprostol was compared with other mechanical and medical methods of cervical dilatation and softening.97,99,100,103,105,106,108,112 In most of these studies, three main outcome variables were assessed: quantified cervical dilatation immediately before surgery, ease of dilatation (as determined by the provider), and blood loss (either before or during the procedure). The five placebo-controlled studies found that either oral or vaginal administration of misoprostol significantly eased the dilatation of the cervix when compared with a placebo.96,98,102,105,113 Furthermore, when compared with other methods, misoprostol proved at least equally effective.97,99,100,103,105,106,108,112 Eight studies specifically examined the timing, dose, and route of administration of misoprostol for cervical dilatation before surgical abortion.100,101,104,107–111 Higher doses of misoprostol are associated with increased cervical dilatation, greater ease of dilatation, and a higher percentage of adequate dilatation.104,107,109,110 Moreover, there is growing consensus in the literature as to the best vaginal regimen for misoprostol. Several studies that tested various doses and timing intervals concluded that administering 400 ␮g vaginally 3– 4 hours before surgery provides optimal dilatation with minimal side effects (including pain) and acceptable vaginal bleeding.104,107–110 This regimen was recommended in a recent review article.114 Different doses of vaginal misoprostol are more effective than placebo 96 but less effective (200-␮g dose)104 or less well tolerated (600- or 800-␮g dose)107,110 than the 400-␮g vaginal regimen. One small study of a 400-␮g dose given either orally or vaginally found increased cervical dilatation and decreased need for additional dilatation with the vaginal route.108 Some evidence seems to indicate that oral administration may achieve similar results when given earlier (ie, more than 8 hours before surgery),101 but pretreating even earlier (17–19 hours before surgery) shows no further benefit.100 We reviewed 15 studies on the use of misoprostol alone for induction of abortion in the second trimester (Table 5).115–129 We did not include studies where misoprostol was used in combination with other therapies. We reviewed studies addressing second-trimester abortion with live or both live and dead fetuses. Although there is no consensus on the best misoprostol regimen for second-trimester abortion, according to the World Health Organization, misoprostol is already the standard of care in some places.130

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Table 3. Misoprostol for Treatment of Intrauterine Fetal Death in the Second or Third Trimester Sample size Study

1 92

72

Bugalho et al, 199593

120

Bugalho et al, 1994

Merrell and Koch, 199594 Eng and Guan, 199795

2

18–40 wk 36

A1* 27 A2† 21 25

Duration of pregnancy

Second or third trimester

Second or third trimester 25

13–26 wk

Regimen 1 100 ␮g vaginal misoprostol q 12 h up to 48 h 50 ␮g vaginal misoprostol q 18 h ⫻ two doses, if no abortion 6 h post last dose, 200 ␮g q 6 h ⫻ four doses 100 ␮g vaginal misoprostol q 4 h ⫻ four doses 200 ␮g vaginal misoprostol q 3 h (max 1200 ␮g)

2

15 IU IV oxytocin per minute, doubling q 30 min

1 mg vaginal gemeprost q 3 h (max 5 mg)

q ⫽ every; IV ⫽ intravenous. * A1 ⫽ second-trimester fetal death. † A2 ⫽ third-trimester fetal death.

Outcome measures commonly used in the study of agents for second-trimester abortion induction are the abortion rate (also referred to as the success rate, tallying the percent of women who begin the abortion process with a certain time period), the induction to abortion interval (the mean time from application of the first dose of misoprostol or other agent until the abortion begins), and the percent of patients with complete abortion. Results from randomized trials indicate that a regimen of 200 ␮g of misoprostol given vaginally every 12 hours up to 48 hours shows good success116 –118,128,129 and has been recommended in a recent review.114 However, Bugalho et al115 and Herabutya and O-Prasertsawat126 tested a range of doses (200, 400, 600, and 800 ␮g, and 200, 400, and 600 ␮g), and both teams found an increase in success rate with increased dose. Success rates were greater than 80% in all but one study group.126 Herabutya and O-Prasertsawat noted that the success rate reported depends on the time at which the outcome is determined, ie, the longer the waiting period, the higher the reported success rate.126 One additional study of vaginal misoprostol for second-trimester abortion looked at an 800-␮g dose repeated up to 3 times at 24-hour intervals.123 The authors reported 80% of 151 women had successful outcomes (defined as having a complete abortion without recourse to surgical intervention). Oral misoprostol and misoprostol gel (one 200-␮g tablet crushed and mixed with K-Y Jelly (Johnson &

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Johnson, New Brunswick, NJ) have also been evaluated.119,121,122 More than 90% of women began their abortion within 48 hours in all three studies. Studies of the misoprostol gel also showed that women with dead fetuses aborted at a faster rate and required less analgesia.122 Three randomized controlled trials compared vaginal misoprostol with gemeprost for second-trimester abortion among women with live and dead fetuses.120,124,127 In all of these studies, misoprostol was found to be equally as effective as, or more effective than, gemeprost. In one study, the induction to abortion interval was significantly shorter for gemeprost,120 and in another study, it was significantly shorter for misoprostol.127 Moreover, misoprostol caused fewer side effects, such as vomiting, diarrhea, and nausea. However, in one study, fever was reported more frequently in the misoprostol group.127 Misoprostol has also been compared with other prostaglandins.116,118,125 Misoprostol was equally as effective as prostaglandin E2 gel (in 24 hours, 89% compared with 81%)116 and more effective than prostaglandin F2␣ (in 24 hours, 100% compared with 80%).125 In both reports, misoprostol was also associated with fewer side effects. DISCUSSION The volume and variety of studies on misoprostol for women’s health indications show the interest in this drug, and point to the potential impact of greater avail-

OBSTETRICS & GYNECOLOGY

Induction to abortion interval

Success 1

2

92% at 24 h 100% at 48 h 100%

12 h from last dose: A1 78% A2 90% 84%

1

2

12.6 h 100%

Bishop ⬍6 14.8 h Bishop ⬎6 6.6 h

Bishop ⬍6 31.0 h Bishop ⬎6 8.7 h

A1 13.2 h A2 13.4 h 68%

ability for these purposes. For many of these indications, alternatives to misoprostol are not available or not accessible. For instance, oxytocic drugs, the standard of care for prevention and treatment of postpartum hemorrhage, are often not available in developing countries because of their cost and delivery requirements. Alternative prostaglandins, often used for labor induction or second-trimester abortion, are generally much more expensive than misoprostol and require refrigeration. Misoprostol could therefore prove particularly useful in developing country settings where alternative therapies are not available. Even in less resource-constrained settings, misoprostol could prove to be the drug of choice for some of these indications. In many cases, misoprostol causes fewer side effects than the standard alternatives, and its simpler delivery and lower cost could save health care resources. Accumulated evidence of the efficacy of misoprostol for indications such as labor induction or second-trimester abortion supports clinical use of the drug. A recent excellent review provides a summary of regimens that can be recommended for clinical use.114 For all of the indications we reviewed, even those where less information is available, there are sufficient data to support continued research. Optimal regimens have yet to be identified for any of the indications. In all cases, large, rigorous, convincing studies are needed to support more widespread use of the drug, and to promote access to misoprostol where it could have the greatest benefit. A synthesis of the data, including firm conclusions about ideal regimens for each of the indications, is hampered by differences in the doses and timing of misoprostol, routes of administration, and eligibility criteria in the

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different studies. This is likely because of the ad hoc nature of research on misoprostol for women’s health, and the fact that individual researchers, rather than a large pharmaceutical company, have taken up the task of exploring its potential for new indications. A number of specific research questions emerge from this review. Research to date indicates that misoprostol is more effective than other labor induction/cervical ripening agents and costs considerably less. It is not clear, though, whether the increased rates of fetal tachysystole or maternal hyperstimulation associated with misoprostol use are associated with negative maternal or fetal outcomes. Larger studies of the most promising regimens could better address this issue and could provide firm evidence for more widespread use of misoprostol as a labor induction agent. The evidence also strongly supports the conclusion that misoprostol is effective for induction of secondtrimester abortion. Larger studies, though, are needed to clarify whether different regimens should be used for women with live versus dead fetuses. In addition, some of the data indicate that vaginal misoprostol might be more effective than oral misoprostol, but a study of oral versus vaginal misoprostol used in conjunction with mifepristone for second-trimester abortion showed vaginal misoprostol to be less acceptable.131 Improved regimens using oral administration may therefore be needed. Because of the impact of postpartum hemorrhage on maternal mortality in developing countries, this may be one of the most important indications in which to invest research resources. In addition, unlike standard therapies, misoprostol is not contraindicated in women with hypertension, and could prove an important option for women with preeclampsia. Given the small sample sizes of studies to date and the relatively low incidence of severe postpartum hemorrhage, evidence on the benefit of this drug over alternative treatments is still inconclusive. To fill this void, the World Health Organization has completed a study of 20,000 women in nine countries to test whether orally administered misoprostol is as effective as the currently used oxytocic agents in preventing severe postpartum hemorrhage and reducing the need for additional uterotonic agents.132 Unfortunately, this study does not tell us whether misoprostol is better than no treatment where alternatives are not available. Further research is also needed on whether misoprostol is effective for treatment of postpartum hemorrhage. The value of misoprostol for treatment of incomplete or missed abortion is also not clearly quantified, but the potential for avoiding surgical procedures (and thus attendant morbidity and cost) means that a successful regimen for these indications could also be important. It

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323

Table 4. Randomized Controlled Trials of Misoprostol for Cervical Ripening Before Surgical Abortion Sample size 1

2

Bugalho et al, 199496

Study

50

50

El-Refaey et al, 199497

30

30

Ngai et al, 1995 nulliparas

21

22

multiparas

15

17

32

Platz-Christensen et al, 1995100 100

3

Regimens used 1 Vaginal misoprostol 200 ␮g 6 h before surgery

30

98

Vaginal misoprostol 600 ␮g 2–4 h before surgery

2 Vaginal placebo (not specified), 6 h before surgery No treatment

Oral misoprostol 400 ␮g 12 h before surgery taken at home

Oral placebo (Vitamin B6 50 mg), 12 h before surgery taken at home

32

Oral misoprostol 400 ␮g 12 h before surgery taken at home

44

44

Platz-Christensen et al, 1995

66

73

Oral misoprostol 600 ␮g 17–19 h before surgery Oral misoprostol 600 ␮g 8–10 h before surgery

Oral placebo 12 h before surgery taken at home and vaginal gemeprost 1 mg 3 h before surgery Vaginal gemeprost 1 mg 3–5 h before surgery Oral misoprostol 600 ␮g 17–19 h before surgery

Lawrie et al, 1996101

30

30

Oral misoprostol 400 ␮g 12 h before surgery

Ficicioglu et al, 1996102

40

20

Ngai et al, 1996103

45

48

Fong et al, 1998104

30

30

Vaginal misoprostol 200 ␮g with Gyno-Flor, 5 h before surgery Oral placebo 36 h and oral misoprostol 400 ␮g 12 h before surgery Vaginal misoprostol 400 ␮g 3–4 h before surgery

Bokstrom et al, 1998105

15

15

Sparrow et al, 1998106

160

153

Singh et al, 1998107

30

30

MacIsaac et al, 1999108

99

Ngai et al, 1995

47

45

109

Singh et al, 1999

30

30

Singh et al, 1999110

60

60

Singh et al, 1999111

60

60

Ashok et al, 2000112

30

30

139

139

de Jonge et al, 2000113

15

30

Oral misoprostol 600 ␮g 16–20 h before surgery Oral misoprostol 400 ␮g 1 h before surgery, if no effect in 30 min repeat dose of 200 ␮g orally Vaginal misoprostol 400 ␮g 3–4 h before surgery Vaginal misoprostol 400 ␮g 4 h before surgery Vaginal misoprostol 400 ␮g 3 h before surgery

60

Vaginal misoprostol 400 ␮g 3 h before surgery Vaginal misoprostol 200 ␮g dissolved in acetic acid 3–4 h before surgery

30

Vaginal misoprostol 800 ␮g 2–4 h before surgery Vaginal misoprostol 600 ␮g 2–4 h before surgery

Vaginal misoprostol 800 ␮g 2–4 h before surgery Vaginal placebo (not specified) with GynoFlor 5 h before surgery Oral mifepristone 200 mg 36 h and oral placebo 12 h before surgery Vaginal misoprostol 200 ␮g 3–4 h before surgery Oral placebo (not specified) Vaginal dinoprostone 3 mg 12 h or 18–24 h before surgery Vaginal misoprostol 600 ␮g 3–4 h before surgery Oral misoprostol 400 ␮g 4 h before surgery Vaginal misoprostol 600 ␮g 2 h before surgery Vaginal misoprostol 600 ␮g 2 h before surgery Vaginal misoprostol 200 ␮g dissolved in water 3–4 h before surgery 200 mg mifepristone 24 h before surgery Vaginal placebo (not specified) 2–4 h before surgery

3

Vaginal gemeprost 1 mg 2–4 h before surgery

Mifepristone 200 mg 24 h and 48 h before surgery

Vaginal misoprostol 800 ␮g 3–4 h before surgery Laminaria

Vaginal misoprostol 800 ␮g 2 h before surgery

200 mg mifepristone 48 h before surgery

* Mean ⫾ standard deviations or median (range) and % for proportions of women achieving a cervical dilatation of ⱖ8 mm. † Indicates a statistically significant difference (P ⱕ .05) between groups in cervical dilatation. ‡ Mean dilatation was significantly greater in groups 1 and 3 compared with group 2. § Dilatation measured using average circumference from Pratt dilator. 㛳 Mean dilatation was significantly greater in group 1 than group 2.

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OBSTETRICS & GYNECOLOGY

Cervical dilatation* 1 74% ⱖ 8 mm ‡

2

3 †

10% ⱖ 8 mm

8 (6–9)

7 (3–9)

7.4 ⫾ 2 9.2 ⫾ 1.7

4.1 ⫾ 1.4† 6.5 ⫾ 1.5†

8.1 ⫾ 1.7

7 ⫾ 1.7†

7.5 (5–10)

6.6 (3–11)

6.9 (0–11)

6.9 (2–11)

6.91 (4–9)

6.99 (4–9)

72.5% ⱖ 8 mm

10.0% ⱖ 8 mm†

8.0 ⫾ 1.6

7.7 ⫾ 1.2

8.2 ⫾ 0.8

6.4 ⫾ 1.3†

5.9 ⫾ 1.5‡

4.5 ⫾ 0.9

8 (4–9)‡

6.9 ⫾ 0.9‡

83.8% easy to dilate 81.0% easy to dilate†

8.2 ⫾ 0.8

8.5 ⫾ 0.7

9.9 ⫾ 0.8†

28.0 ⫾ 7.3§

24.2 ⫾ 4.8§㛳

25.9 ⫾ 5.8§

93.3% ⱖ 8 mm

16.7% ⱖ 8 mm†

91.7% ⱖ 8 mm

18.3% ⱖ 8 mm

23% ⱖ 8 mm

20% ⱖ 8 mm

7.6 ⫾ 1.4

7.5 ⫾ 1.2

67.3% ⱖ 7 mm

30.9% ⱖ 7 mm†

VOL. 99, NO. 2, FEBRUARY 2002

25.0% ⱖ 8 mm

8.3 ⫾ 0.9†

is also possible that women will find a medical intervention more acceptable than the standard surgical treatment. Initially, smaller-scale studies evaluating two or more regimens are needed to provide preliminary data on efficacy and acceptability and inform the design of larger trials. A similar approach could help to clarify an optimal regimen of misoprostol for treatment of intrauterine fetal death. The evidence reviewed indicates that pretreatment with misoprostol makes surgical abortion easier to perform. Further research is needed to clarify an optimal regimen and timing and should also clarify the impact of misoprostol on pain from the surgical procedure. Pretreatment potentially could decrease pain, particularly where analgesia is not routinely used or available. Misoprostol use could prove more acceptable to women than, for example, a cervical block. It may also be a useful alternative to systemic analgesics that often have unpleasant side effects and may be expensive. Manual vacuum aspiration preceded by misoprostol should be evaluated further to establish whether the procedure is easier to do, less painful, or more acceptable to women. Route of administration is a potential acceptability issue that cuts across most indications. For many indications, vaginal administration has received the bulk of attention. Oral administration should not be overlooked, however, because in many cases it may be feasible and more acceptable to women. Indeed, because the current regulatory information on misoprostol is for the oral route, registration of an oral regimen for a reproductive health indication may be simpler. The buccal route has not been widely studied but may also prove acceptable to women, and anecdotal information suggests that it may prove effective, although there is no published research currently available on this indication (Population Council Meeting, Misoprostol in Clinical Research and Practice: Past, Present and Future, May 7– 8, 2001). Typically, the burden of developing and marketing the safest and most effective regimens for promising new indications rests with the pharmaceutical industry. Yet, the drug company that produces misoprostol has refused to take on this responsibility with respect to women’s health indications for misoprostol. Nonetheless, inspired by misoprostol’s clear potential for obstetric and gynecologic health, providers and researchers have taken the initiative to fill this void. Although several additional, and potentially large, studies are still needed for some of the indications, it is rare to have a technology already at hand which could, with a relatively small amount of investment, reap such a large return for women’s health around the globe.

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Misoprostol for Women’s Health

325

Table 5. Misoprostol for Second-Trimester Abortion Sample size Study

1 115

2

169

Bugalho et al, 1993

No

Jain and Mishell 1994116

28

27

Yes

Jain and Mishell 1996117

33

35

Yes

Yapar et al, 1996118

Regimen

Included fetal deaths?

1. 82 4. 49 2. 100 5. 73 3. 36

Yes

Batioglu et al, 1997119

42

Nuutila et al, 1997120

53

Srisomboon et al, 1997121

50

No

Srisomboon et al, 1998122

89

Yes

Carbonell et al, 1998123

151

No

Dickinson et al, 1998124

53

47

Yes

Ghorab and El Helw, 1998125

20

20

Yes

No

28

Yes

1 800, 600, 400, or 200 ␮g vaginal misoprostol repeated at 24 h 200 ␮g vaginal misoprostol q 12 h 200 ␮g vaginal misoprostol q 12 h (up to 48 h) without laminaria 1. Extra-amniotic ethacridine lactate 2. Intracervical PGE2 gel 3. IV oxytocin 200 ␮g oral misoprostol q 1 h (max six doses, repeated on day 2 if no abortion) 100 ␮g vaginal misoprostol q 6 h up to 36 h, 200 ␮g vaginal misoprostol q 12 h up to 36 h 200 ␮g cervicovaginal misoprostol gel q 12 h 200 ␮g cervicovaginal misoprostol gel q 12 h

Herabutya and O-Prasertsawat, 1998126 Wong et al, 1998127

151 35

35

No

Owen and Hauth 1999128

15

15

Yes

800 ␮g vaginal misoprostol q 24 h for three doses 200 ␮g vaginal misoprostol q 6 h (max four doses) 200 ␮g intracervical misoprostol q 8 h (max four doses) 200, 400, or 600 ␮g vaginal misoprostol q 12–48 h 400 ␮g vaginal misoprostol q 3 h (max five doses in 24 h) 200 ␮g vaginal misoprostol q 12 h

Jain et al, 1999129

47

37

Yes

200 ␮g vaginal misoprostol q 6 h

No

2

20 mg vaginal PGE2 q 3 h 200 ␮g vaginal misoprostol q 12 h (up to 48 h) with laminaria 4. Vaginal misoprostol 200 ␮g q 12 h (max three doses) 5. Balloon insertion

1 mg vaginal gemeprost q 3 h up to 36 h

1 mg vaginal gemeprost q 3 h (max five doses) IV syntocinon

1 mg vaginal gemeprost q 3 h (max five doses in 24 h) Oxytocin and PGE2 suppositories 10 mg q 6 h 200 ␮g vaginal misoprostol q 12 h

q ⫽ every; PG ⫽ prostaglandin; IV ⫽ intravenous. * Difference statistically significant (P ⱕ .05).

REFERENCES 1. Chuck FJ, Huffaker BJ. Labor induction with intravaginal misoprostol versus intracervical prostaglandin E2 gel (Prepidil gel): A randomized comparison. Am J Obstet Gynecol 1995;173:1137– 42. 2. Blanchard K, Winikoff B, Ellertson C. Misoprostol used alone for the termination of early pregnancy: A review of the evidence. Contraception 1999;59:209 –17. 3. American College of Obstetricians and Gynecologists

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Committee on Obstetrics. Induction of labor. ACOG technical bulletin no. 217. Washington, DC: American College of Obstetricians and Gynecologists, 1995. 4. Abramovici D, Goldwasser S, Mabie BC, Mercer BM, Goldwasser R, Sibai BM. A randomized comparison of oral misoprostol versus Foley catheter and oxytocin for induction of labor at term. Am J Obstet Gynecol 1999; 181:1108 –12. 5. Adair CD, Weeks JW, Barrilleaux S, Edwards M, Burli-

OBSTETRICS & GYNECOLOGY

Duration of pregnancy (wk)

Complete abortion

Success 1

2

1

Induction to abortion interval 2

1

2

12–23

91% within 48 h

12–22

89% within 24 h

81% within 24 h

43%

32%

12.0 h

10.6 h

12–22

84.8% within 48 h

91.4% within 48 h

39.3%

37.5% 15.7 h

17.4 h

14–28

In 48 h: 1. 98.8% 2. 90% 3. 97.3% In 48 h: 92.9%

In 48 h: 4. 77.5% 5. 97.2%

12–24

100 ␮g 74% 200 ␮g 92%

89%

14–27

In 24 h: 54% In 48 h: 92% In 12 h: 15% live, 50% dead* In 24 h: 55% live, 83% dead* In 48 h: 93% live, 97% dead

14–28

14–28

13–15

14.3 h

1. 15.7 h 2. 20 h 3. 12.2 h 59.6%

4. 24 h 5. 16 h

9h

100 ␮g 63% 200 ␮g 39%

68%

100 ␮g 23.1 h 200 ␮g 27.8 h

14.5 h

80%

27.5 h

Live 79% Dead 92%

Live 27 h Dead 15 h*

80%

9.1 h (in those who aborted after first dose) 16.9 h 13.7 h

14–28

In 24 h: 74.9%

16–24

14–20

100% within 20 h, 100% within 28 h, 10.3 h 90% within 13 h 80% within 24 h 200 ␮g 70.6%, 400 ␮g 200 ␮g 64.7%, 400 ␮g 200 ␮g 45 h, 400 ␮g 82%, 600 ␮g 96% 72%, 600 ␮g 78% 33.4 h, 600 ␮g 22.3 h In 24 h: 80% In 24 h: 58.6% 60% 58.6% 14.1 h

19.5 h

16–24

In 24 h: 67%

In 24 h: 87%

18 h

12–22

In 48 h: 87.2%

In 48 h: 89.2%

Mean ⫽ 19

In 24 h: 75.1%

son K, Lewis DF. Oral or vaginal misoprostol administration for induction of labor: A randomized, doubleblind trial. Obstet Gynecol 1998;92:810 –3. 6. Bartha JL, Comino-Delgado R, Garcia-Benasach F, Martinez-Del-Fresno P, Moreno-Corral LJ. Oral misoprostol and intracervical dinoprostone for cervical ripening and labor induction: A randomized comparison. Obstet Gynecol 2000;96:465–9. 7. Belfrage P, Smedvig E, Gjessing L, Eggebo TM, Okland I. A randomized prospective study of misoprostol and dinoprostone for induction of labor. Acta Obstet Gynecol Scand 2000;79:1065– 8.

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22 h 43.9%

33.3% 13.8 h

16 h

14.0 h

8. Bennett KA, Butt K, Crane JM, Hutchens D, Young DC. A masked randomized comparison of oral and vaginal administration of misoprostol for labor induction. Obstet Gynecol 1998;92:481– 6. 9. Bique C, Bugalho A, Bergstrom S. Labor induction by vaginal misoprostol in grand multiparous women. Acta Obstet Gynecol Scand 1999;78:198 –201. 10. Blanchette HA, Nayak S, Erasmus S. Comparison of the safety and efficacy of intravaginal misoprostol (prostaglandin E1) with those of dinoprostone (prostaglandin E2) for cervical ripening and induction of labor in a

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11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

328

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25. Fletcher HM, Mitchell S, Frederick J, Simeon D, Brown D. Intravaginal misoprostol versus dinoprostone as cervical ripening and labor-inducing agents. Obstet Gynecol 1994;83:244 –7. 26. Gottschall DS, Borgida AF, Mihalek JJ, Sauer F, Rodis JF. A randomized clinical trial comparing misoprostol with prostaglandin E2 gel for preinduction cervical ripening. Am J Obstet Gynecol 1997;177:1067–70. 27. Herabutya Y, O-Prasertsawat P, Pokpirom J. A comparison of intravaginal misoprostol and intracervical prostaglandin E2 gel for ripening of unfavorable cervix and labor induction. J Obstet Gynaecol Res 1997;23:369 –74. 28. Hoffmann RA, Anthony J, Fawcus S. Oral misoprostol vs. placebo in the management of prelabor rupture of membranes at term. Int J Gynaecol Obstet 2001;72: 215–21. 29. Kadanali S, Kucukozkan T, Zor N, Kumtepe Y. Comparison of labor induction with misoprostol vs. oxytocin/ prostaglandin E2 in term pregnancy. Int J Gynaecol Obstet 1996;55:99 –104. 30. Kolderup L, McClean L, Grullon K, Safford K, Kilpatrick SJ. Misoprostol is more efficacious for labor induction than prostaglandin E2, but is it associated with more risk? Am J Obstet Gynecol 1999;180:1543–50. 31. Kramer RL, Gilson GJ, Morrison DS, Martin D, Gonzales JL, Qualls CR. A randomized trial of misoprostol and oxytocin for induction of labor: Safety and efficacy. Obstet Gynecol 1997;89:387–91. 32. Lee HY. A randomised double-blind study of vaginal misoprostol vs dinoprostone for cervical ripening and labour induction in prolonged pregnancy. Singapore Med J 1997;38:292– 4. 33. Liu HS, Chu TY, Chang YK, Yu MH, Chen WH. Intracervical misoprostol as an effective method of labor induction at term. Int J Gynaecol Obstet 1999;64:49 –53. 34. Magitibay PM, Ramin KD, Harris DY, Ramsey PS, Ogburn PL. Misoprostol as a labor induction agent. J Matern Fetal Med 1998;17:15– 8. 35. Mundle WR, Young DC. Vaginal misoprostol for induction of labor: A randomized controlled trial. Obstet Gynecol 1996;88:521–5. 36. Neiger R, Greaves PC. Comparison between vaginal misoprostol and cervical dinoprostone for cervical ripening and labor induction. Tenn Med 2001;94:25–7. 37. Ngai SW, To WK, Lao T, Ho PC. Cervical priming with oral misoprostol in pre-labor rupture of membranes at term. Obstet Gynecol 1996;87:923– 6. 38. Ngai SW, Chan YM, Lam SW, Lao TT. Labour characteristics and uterine activity: Misoprostol compared with oxytocin in women at term with prelabour rupture of membranes. Br J Obstet Gynaecol 2000;107:222–7. 39. Nunes F, Rodrigues R, Meirinho M. Randomized comparison between intravaginal misoprostol and dinoprostone for cervical ripening and induction of labor. Am J Obstet Gynecol 1999;181:626 –9.

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