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Obstetrics & Gynecology 2004;104:138-145
© 2004 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Vaginal Misoprostol Versus Concentrated Oxytocin and Vaginal PGE2 for Second-Trimester Labor Induction

Patrick S. Ramsey, MD, Karen Savage, RN, Tina Lincoln, RN and John Owen, MD

From the Center for Research in Women's Health, Division of Maternal–Fetal Medicine, Department of Obstetrics/Gynecology, University of Alabama at Birmingham, Birmingham, Alabama.

Address reprint requests to: Patrick S. Ramsey, MD, Division of Maternal–Fetal Medicine, Department of Obstetrics/Gynecology, Center for Research in Women's Health, University of Alabama at Birmingham, 619 19th Street South – 458 Old Hillman Building, Birmingham, AL 35249–7333; e-mail: pramsey{at}uab.edu.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To compare the efficacy, side effects, and complications of high-dose vaginal misoprostol with concentrated intravenous oxytocin plus low-dose vaginal prostaglandin (PGE2) for second-trimester labor induction.

METHODS: One hundred twenty-six consenting women with maternal or fetal indications for pregnancy termination and no prior cesarean delivery were randomly assigned to receive either vaginal misoprostol 600 µg 1x, 400 µg every 4 hours 5x (misoprostol group, n = 60) or escalating-dose concentrated oxytocin infusions (277–1,667 mU/min) plus vaginal PGE2 10 mg every 6 hours 4x (oxytocin group, n = 66). Both groups received concurrent extra-amniotic saline infusion for cervical ripening. Women who failed their assigned regimen received 20 mg of PGE2 suppositories every 4 hours until delivery. Analysis was by intent to treat.

RESULTS: Demographic characteristics were similar between study groups. Median induction-to-delivery interval was significantly shorter in the misoprostol group (12 hours) than in the oxytocin group (17 hours; P < .001). There was a higher induction success rate at 24 hours in the misoprostol group (95%) than in the oxytocin group (85%; P = .06), although this difference did not reach statistical significance. The incidence of live birth (25% versus 17%), chorioamnionitis (5% versus 2%), and postpartum hemorrhage greater than 500 mL (3% versus 3%) were similar between the misoprostol and oxytocin groups, respectively. Diarrhea (2% versus 11%; P = .04), nausea/emesis (25% versus 42%; P = .04), and retained placenta requiring curettage (2% versus 15%; P = .008) were significantly less common in the misoprostol group when compared with the oxytocin group, respectively. Isolated intrapartum fever, however, was more frequent in the misoprostol group (67%) than in the oxytocin group (21%; P < .001).

CONCLUSION: Compared with concentrated oxytocin plus low-dose vaginal PGE2, high-dose vaginal misoprostol is associated with significantly shorter induction-to-delivery intervals, fewer side effects, a lower incidence of retained placenta, and comparable incidence of live birth.

LEVEL OF EVIDENCE: I

Various management strategies have been used for second-trimester pregnancy termination.1,2 These include dilation and evacuation, intra-amniotic prostaglandin F2{alpha} instillation, PGE2 vaginal suppositories, prostaglandin E1, and high-dose oxytocin.1,2 Although dilation and evacuation is an effective approach for second-trimester pregnancy termination, the availability of adequately trained individuals limits the use of this surgical method for the termination of pregnancy.1 Of the medical regimens used, PGE2 is among the most widely used agents for the termination of pregnancy in the second trimester.1 One significant limitation of the PGE2-based regimens is the high incidence of maternal side effects, including fever, nausea/emesis, and diarrhea, which necessitates pretreatment with antiemetic, antipyretic, and antidiarrhea medications.1,3 Prostaglandin-based regimens also can be associated with higher rates of live birth when compared with other agents used for second-trimester pregnancy termination.1 We have shown previously that the combined use of low-dose intravaginal PGE2 and an escalating-dose oxytocin regimen, concomitant with either laminaria or extra-amniotic saline infusion, is highly effective for second-trimester pregnancy termination and has a lower incidence of side effects and live birth than vaginal PGE2.1,3,4 Side effects still occur, however, and so prophylactic medications are still advised. Because the goal of a successful therapeutic strategy should be to combine efficacy, that is, shortened interval from induction to delivery, with reduced side-effect profile and low live-birth rate, further refinements of medical regimens for second-trimester labor induction are needed.

Misoprostol (Cytotec, PGE1; G. D. Searle and Co, Skokie, IL) is a potent uterotonic agent that has been shown to be highly effective for cervical ripening and labor induction.5–7 Misoprostol has also been evaluated in the setting of second-trimester pregnancy interruption.1,8–20 Various dosing strategies have evolved, including low-dose, high-dose, and combination therapy with mifepristone.1,8–20 The use of a low-dose misoprostol regimen (200 µg every 12 hours) has previously been shown to be inferior in efficacy to a combined low-dose intravaginal PGE2 with an escalating high-dose oxytocin regimen.12 Several recent investigations have suggested that higher doses of misoprostol may be more efficacious and have a more acceptable side-effect profile when compared with currently available PGE2-based regimens.8–11,13–20 Data from a recent retrospective study that evaluated the efficacy of high-dose misoprostol versus concentrated oxytocin regimen suggest that misoprostol may be superior to concentrated oxytocin for second-trimester pregnancy interruption.15 Although efficacious, a higher live-birth rate was noted among women treated with misoprostol.15 Based on the above literature, we performed a prospective, randomized clinical trial designed to compare the efficacy, side-effect profile, and complication rates of a high-dose intravaginal misoprostol regimen with a concentrated oxytocin plus low-dose PGE2 regimen for second-trimester pregnancy termination. We hypothesized that the high-dose intravaginal misoprostol regimen would be associated with a shorter induction-to-delivery interval, fewer side effects, and a comparable live-birth rate versus our current concentrated oxytocin plus low-dose PGE2 regimen for second-trimester pregnancy termination.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
This randomized clinical trial compared a high-dose vaginal misoprostol regimen with concentrated oxytocin plus low-dose vaginal PGE2 for second-trimester pregnancy termination. All women presenting to the University of Alabama at Birmingham University Hospital labor and delivery unit for an indicated labor induction with an unfavorable cervix (< 2-cm dilatation) between 16 and 24 weeks of gestation (according to the best obstetric dating criteria) were evaluated for participation. Women were excluded from participation if any of the following criteria were encountered: 1) clinical chorioamnionitis, 2) spontaneous labor (regular uterine contractions with cervical change), 3) contraindication to prostaglandin therapy (eg, unstable cardiopulmonary status, hypersensitivity to prostaglandins), 4) complete or partial placenta previa, or 5) previous cesarean delivery or other significant uterine surgery. Women who met the above requirements were invited to participate, and those who gave informed consent were enrolled. The investigation was approved by the Institutional Review Board at the University of Alabama at Birmingham

After obtaining informed consent, eligible women were randomly assigned to receive treatment with either high-dose vaginal misoprostol or concentrated oxytocin plus low-dose vaginal PGE2. Randomization was accomplished with sequentially numbered sealed, opaque envelopes to maintain concealed treatment allocation. A stratified block (block size = 6) randomization schedule was independently created by using a computer-generated random number table, with 4 main randomization strata based on induction indication: 1) fetal anomaly/aneuploidy, 2) fetal demise, and 3) preterm premature rupture of membranes, and 4) primary maternal indication (eg, severe preeclampsia). Women randomized to the high-dose vaginal misoprostol group received an initial 600-µg (three 200-µg tablets) dose of misoprostol (Cytotec, G.D. Searle and Co) placed intravaginally. Women could then receive an additional 400 µg (two 200-µg tablets) of misoprostol administered intravaginally every 4 hours (maximum of 5 applications of the 400-µg dose; total 2,600 µg). Women assigned to the concentrated oxytocin plus low-dose vaginal PGE2 group received escalating doses of concentrated oxytocin according to an established protocol3,4,12 (50 X units of oxytocin in a 500-mL bag of normal saline administered intravenously over 3 hours followed by a 1-hour washout before next dose increment, where X ranged progressively from 1 to a maximum of 6, plus 10 mg of vaginally administered PGE2; Prostin, Upjohn Pharmaceutical Co, Kalamazoo, MI) every 6 hours.3,4,12

All study participants were initially premedicated with acetaminophen 650 mg, promethazine 25 mg, and diphenoxylate hydrochloride plus atropine (2 tablets Lomotil; G.D. Searle and Co) as a prophylaxis against fever, nausea, and diarrhea, respectively. Subsequent dosing of these medications, however, was based on the occurrence of the above noted side effects. Pain was controlled with intravenously administered narcotics and/or epidural analgesia as indicated by patient preference. Side effects were recorded by the obstetric nurses and house staff in the medical record and were abstracted after delivery by trained study chart abstractors. All intrapartum and postpartum management was conducted by the labor and delivery house staff. Neither the patients nor the managing physicians were blinded to treatment allocation. In addition to the assigned treatment, all women enrolled in this investigation (except for those women with ruptured membranes) received concurrent extra-amniotic saline infusion through a transcervical Foley catheter to promote cervical ripening.4 Briefly, a 26-French (or smaller) Foley catheter (C.R. Bard Inc, Covington, GA) was placed by the managing physician under sterile conditions and direct visualization through the internal cervical os. The 30-mL Foley balloon was then inflated and room temperature normal saline was infused at 30 mL/h until the catheter was either spontaneously expelled or was removed. A subsequent cervical examination was performed 6 hours later, and if the catheter had been dislodged, the balloon was deflated and catheter removed. Otherwise, the catheter remained in place for an additional 6 hours and was removed after a total of 12 hours.

The primary study outcome for the investigation was the rate of live birth. Secondary outcomes assessed included induction success, induction-to-delivery interval, maternal side effects, medication use, and complications. Induction success was defined as an induction-to-delivery interval of 24 hours or less. Women in either group who were undelivered by 24 hours subsequently received 20-mg PGE2 vaginal suppositories (Prostin, Upjohn Pharmaceutical Co) every 4 hours until delivery. Management of women who remained undelivered after 48 hours was individualized. After delivery, all women received active management of the third stage of labor, which included up to 3 hours of a 50-unit concentrated oxytocin infusion to facilitate separation of the placenta. If the placenta remained undelivered after 3 hours, an attempt was made at manual extraction. If manual extraction failed or if significant vaginal bleeding was noted during the third stage, uterine curettage was performed. Retained placenta was defined as the need for uterine curettage for placental removal. Postpartum hemorrhage was defined as estimated blood loss greater than 500 mL. Live birth was defined by a 1-minute Apgar score of 1 or greater.

Planned sample size for this investigation was based a clinically significant difference in the live-birth rate. Using {alpha} = 0.05 and ß = 0.2, 1-sided, a sample size of 50 women per treatment group with a live fetus would be required to detect a 67% reduction in the live-birth rate between the treatment groups (as from 30% to 10%). Clinical estimates for live-birth rates with misoprostol and concentrated oxytocin and low-dose PGE2 were derived from the literature.1,3,4,11,13 We used a 1-sided test because of prior observations of higher live-birth rates among women receiving PGE1 (20–50%)11,13 compared with concentrated oxytocin-based regimens (3–15%).1,3,4 Analysis was by intent to treat. Statistical analyses were performed with the SAS software (SAS Institute Inc, Cary, NC). Proportional data were compared with the {chi}2 or the Fisher exact test, as determined by the expected cell size. Continuous data were compared with either the Student t test or the Wilcoxon rank-sum test, as determined by the Shapiro-Wilk statistic for test of normality.21 Statistical significance was defined as P ≤ .05.


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Between April 1999 and May 2002, a total of 161 women were screened for possible study participation (Fig. 1). Of these, a total of 126 women met eligibility criteria, consented to participate, and were randomized for participation in the study (Fig. 1). Two of the randomized women did not receive assigned treatment. These 2 women were randomized to receive misoprostol treatment but were subsequently found to have a history of a previous cesarean delivery. In both situations, the managing physicians elected to use our institution's standard induction regimen with concentrated oxytocin plus low-dose PGE2 as described above (Fig. 1). No other protocol violations were reported. All women who had treatment initiated were delivered during the index hospital admission. Outcome data were not collected on screened women who were ineligible or declined participation. The majority of these women were excluded from participation because of a history of uterine surgery.



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  		Fig. 1. Study outline/population flow. Numbers of women screened and randomized for the investigation are depicted in the figure. * Concentrated oxytocin. {dagger} Two women were treated with concentrated oxytocin plus PGE2.

Ramsey. Second-Trimester Labor Induction. Obstet Gynecol 2004.

 

No significant differences were noted between the study groups with respect to maternal age, gestational age at time of induction initiation, parity, and race (Table 1). Indication for induction was also similar between groups, with the dominant indication being the presence of a fetal anomaly or aneuploidy (Table 2). Median induction-to-delivery interval was significantly shorter (approximately 5 hours) in the misoprostol group when compared with the concentrated oxytocin and low-dose PGE2 group (Table 3). The rate of successful induction, defined as an induction-to-delivery interval of 24 hours or less, was higher among women receiving misoprostol; however, the noted difference did not reach statistical significance (P = .06; Table 3). Among the women undelivered at 24 hours, all of the women in the misoprostol group and 8 of the 10 women in the concentrated oxytocin group completed delivery by 48 hours. By 52 hours postinduction initiation, all women had attained successful vaginal delivery.


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  		Table 1. Patient Demographics

 

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  		Table 2. Indication for Induction

 

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  		Table 3. Labor Induction Results

 

Although the incidence of live birth was higher in women who received high-dose misoprostol, the difference did not reach statistical significance (P = .37). The incidence of other complications, including postpartum hemorrhage, symptomatic hypotension, and chorioamnionitis, were comparable between the high-dose misoprostol and concentrated oxytocin plus low-dose PGE2 groups (Table 4). The incidence of diarrhea, nausea/emesis, and retained placenta requiring curettage was significantly lower in the high-dose misoprostol group when compared with the concentrated oxytocin plus low-dose PGE2 group (Table 4). Change in hematocrit from pre- to postinduction (8–12 hours after delivery) also was significantly less in the women treated with misoprostol (Table 4). Isolated intrapartum fever, however, occurred more frequently in the high-dose misoprostol group than in the concentrated oxytocin group (Table 4).


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  		Table 4. Adverse Obstetric Outcomes

 

Although the use of epidural anesthesia for relief of labor pain was similar between the 2 study groups, the use of meperidine for adjuvant pain control was significantly greater in the women treated with concentrated oxytocin plus PGE2 than in the misoprostol group (Table 5). Use of acetaminophen (for fever) and promethazine (for nausea) was similar between the study groups (Table 5). However, the use of additional medications for nausea (metoclopramide) and diarrhea (Lomotil) was significantly greater among the women treated with concentrated oxytocin plus PGE2 than in the misoprostol group (Table 5).


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  		Table 5. Intrapartum Pharmacologic Therapy

 


   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Misoprostol is a potent uterotonic agent that is highly efficacious for labor induction.1,5–7 The use of a low-dose misoprostol regimen (200 µg vaginally every 12 hours) for second-trimester pregnancy interruption was initially described by Jain and Mishell in 1994.8 Although this regimen was shown to have comparable induction-to-delivery intervals and 24-hour success rates when compared to a U.S. Food and Drug Administration–approved PGE2 (Prostin, Upjohn Pharmaceutical Co) regimen, others have reported disparate results with this dosing regimen.10,12 Several recent investigations have suggested that higher-dose misoprostol regimens may be more efficacious.1,10,11,13–20 Dickinson and Evans11 conducted a prospective randomized clinical trial evaluating several dosing regimens of intravaginal misoprostol and demonstrated that the higher-dose regimen (400 µg every 6 hours) resulted in a significantly shorter median induction-to-delivery interval (15.1 hours) and a greater percentage of patients delivered within 24 hours (76%) compared with lower-dose (200 µg every 6 hours) regimens (18.2 hours and 59%, respectively). Herabutya and Prasertsawat10 reported similar findings in their study of 150 patients undergoing second-trimester pregnancy interruption, noting that a misoprostol regimen of 600 µg intravaginally every 12 hours was superior to lower-dose regimens (200 µg every 12 hours or 400 µg every 12 hours).

There are limited data available comparing the effectiveness of misoprostol versus that of oxytocin for second-trimester labor induction.1,12,15 Owen and Hauth12 compared low-dose vaginal misoprostol (200 µg every 12 hours) with concentrated oxytocin plus low-dose vaginal PGE2 for second-trimester labor induction, demonstrating that the low-dose misoprostol regimen was inferior with regard to 24-hour induction success, mean labor duration, incidence of retained placenta, and incidence of live birth. Ramin and colleagues,15 however, in a retrospective cohort study, suggested that a high-dose misoprostol regimen (400 µg orally every 4 hours) was superior in efficacy to concentrated oxytocin for second-trimester labor induction.

In the present study, we have confirmed that the use of high-dose vaginal misoprostol is highly efficacious as an agent for second-trimester labor induction. Although comparable rates of induction success were noted between the high-dose misoprostol regimen and the concentrated oxytocin plus PGE2 group, overall time to delivery was significantly shortened by the use of misoprostol. In addition, women treated with misoprostol experienced fewer side effects, required less medication for the treatment of side effects, and had a significantly lower incidence of retained placenta requiring dilation and curettage. Interestingly, women treated with misoprostol had a significantly higher incidence of unexplained isolated fever when compared with the concentrated oxytocin group. This finding is consistent with several recent studies, which have reported a dose-related incidence in isolated fever and shivering in women receiving misoprostol.11,19,20,22,23

The live-birth rate in our study was higher in the misoprostol group, but this difference was not significantly different from that observed in the concentrated oxytocin plus low-dose PGE2 group. Our sample had diminished power to detect differences in the live-birth rate, which were smaller than planned. We chose to design our study with live-birth rate as a primary outcome, given the previous observations that misoprostol and other prostaglandin analogues have been associated with a higher rate of live birth than concentrated oxytocin-based regimens.12,14,15 With our sample size, we had sufficient power to detect a 20% absolute difference in the live-birth rate. Based on the observed difference between the study groups in our trial, a post hoc sample size calculation revealed that a sample size of 542 per treatment group would be needed to detect a significant difference in the live-birth rate as small as from 25% to 17%. However, this might not be considered a clinically significant difference. As live birth is a potential complication of any second-trimester medical induction with a living fetus, a clear management plan for such an occurrence is essential.1 Use of misoprostol for second-trimester labor induction is advantageous because of the low cost and ease of use. Although previously contraindicated for use in pregnancy as a labor-induction agent, the U.S. Food and Drug Administration recently revised the labeling for misoprostol so that it is only contraindicated in pregnancy for the treatment/prevention of nonsteroidal anti-inflammatory drug-induced ulcers. Thus, the use of misoprostol in pregnancy for other indications is no longer contraindicated.24 Concerns remain regarding the potential for uterine rupture, especially when misoprostol is used in women with a previous cesarean delivery.25–28 Because of this issue, we elected to exclude women with a previous cesarean delivery from participation in our investigation as our investigation would have been substantially underpowered to address this uncommon outcome if women with a prior cesarean delivery had been included.

We have demonstrated that high-dose vaginal misoprostol is superior to concentrated oxytocin plus low-dose PGE2 for second-trimester labor induction, as noted by a significant shortening in the induction-to-delivery interval, reduction in side effects, and fewer cases of retained placenta requiring dilation and curettage. Based on the findings from this investigation, we have adopted the use of the high-dose vaginal misoprostol regimen as our institutional treatment of choice for second-trimester labor induction in women without prior uterine surgery. Further refinement of strategies to facilitate second-trimester labor induction, however, are needed to optimize induction success rates while minimizing side effects and live-birth rates associated with such inductions.


   Footnotes
 
Received January 12, 2004. Received in revised form February 29, 2004. Accepted April 1, 2004.

Supported by grants K12-HD01402 (to P.S.R.) and K24-HD43314-2 (to J.O.) from the National Institute of Child Health and Human Development.

Presented at the 51st Annual Clinical Meeting of the American College of Obstetrics and Gynecology, New Orleans, Louisiana, April 26–30, 2003.

10.1097/01.AOG.0000128947.31887.94


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Ramsey PS, Owen J. Midtrimester cervical ripening and labor induction [review]. Clin Obstet Gynecol 2000;43:495–512.[Medline]

2. Rosenfield A. The difficult issue of second-trimester abortion. N Engl J Med 1994;331:324–5.[Free Full Text]

3. Owen J, Hauth JC. Concentrated oxytocin plus low-dose prostaglandin E2 compared with prostaglandin E2 vaginal suppositories for second-trimester pregnancy termination. Obstet Gynecol 1996;88:110–3.[Abstract]

4. Hogg BB, Owen J. Laminaria versus extra-amniotic saline infusion for cervical ripening in second-trimester labor inductions. Am J Obstet Gynecol 2001;184:1145–8.[Medline]

5. Ramsey PS, Ramin KD. Misoprostol, a prostaglandin E1 analog, for prelabour ripening of the unfavorable uterine cervix. Fetal Matern Med Rev 1996;217–27.

6. Wing DA, Rahall A, Jones MM, Goodwin TM, Paul RH. Misoprostol: an effective agent for cervical ripening and labor induction. Am J Obstet Gynecol 1995;172:1811–6.[Medline]

7. Sanchez-Ramos L, Kaunitz AM, Wears RL, Delke I, Gaudier FL. Misoprostol for cervical ripening and labor induction: a meta-analysis. Obstet Gynecol 1997;89:633–42.[Abstract]

8. Jain JK, Mishell DR. A comparison of intravaginal misoprostol with prostaglandin E2 for termination of second-trimester pregnancy. N Engl J Med 1994;331:290–3.[Abstract/Free Full Text]

9. Jain JK, Mishell DR. A comparison of misoprostol with and without laminaria tents for induction of second-trimester abortion. Am J Obstet Gynecol 1996;175:173–7.[Medline]

10. Herabutya Y, O-Prasertsawat P. Second trimester abortion using intravaginal misoprostol. Int J Gynecol Obstet 1998;60:161–5.[Medline]

11. Dickinson JE, Evans SF. The optimization of intravaginal misoprostol dosing schedules in second-trimester pregnancy termination. Am J Obstet Gynecol 2002;186:470–4.[Medline]

12. Owen J, Hauth JC. Vaginal misoprostol vs. concentrated oxytocin plus low-dose prostaglandin E2 for second trimester pregnancy termination. J Matern Fetal Med 1999;8:48–50.[Medline]

13. Scheepers HC, van Erp EJ, van den Bergh AS. Use of misoprostol in first and second trimester abortion: a review. Obstet Gynecol Surv 1999;54:592–600.[Medline]

14. Yapar EG, Senoz S, Urkutur M, Batioglu S, Gokmen O. Second trimester pregnancy termination including fetal death: comparison of five different methods. Eur J Obstet Gynecol 1996;69:97–102.[Medline]

15. Ramin KD, Ogburn PL, Danilenko DR, Ramsey PS. High-dose oral misoprostol for mid-trimester pregnancy interruption. Gynecol Obstet Invest 2002;54:176–9.[Medline]

16. Nuutila M, Toivonen J, Ylikorkala O, Halmesmaki E. A comparison between two doses of intravaginal misoprostol and gemeprost for induction of second-trimester abortion. Obstet Gynecol 1997;90:896–900.[Abstract]

17. Ho PC, Chan YF, Lau W. Misoprostol is as effective as gemeprost in termination of second trimester pregnancy when combined with mifepristone: a randomized comparative trial. Contraception 1996;53:281–3.[Medline]

18. 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;10:475–8.[Abstract/Free Full Text]

19. Bebbington MW, Kent N, Lim K, Gagnon A, Delisle MF, 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;187:853–7.[Medline]

20. Wong KS, Ngai CS, Yeo EL, Tang LC, Ho PC. A comparison of two regimens of intravaginal misoprostol for termination of second trimester pregnancy: a randomized comparative trial. Hum Reprod 2000;15:709–12.[Abstract/Free Full Text]

21. Shapiro SS, Wilk MB. An analysis of variance test for normality (complete samples). Biometrika 1965;52:591–611.[Free Full Text]

22. Chong YS, Chua S, Arulkumaran S. Severe hyperthermia following oral misoprostol in the immediate postpartum period. Obstet Gynecol 1997;90:703–4.[Medline]

23. Hofmeyr GJ, Nikodem VC, de Jager M, Drakely A. Side-effects of oral misoprostol in the third stage of labour: a randomised placebo-controlled trial. S Afr Med J 2001;91:432–5.[Medline]

24. New U.S. Food and Drug Administration labeling on Cytotec (misoprostol) use in pregnancy. ACOG Committee Opinion No. 283. American College of Obstetricians and Gynecologists. Obstet Gynecol 2003;101:1049–50.[Medline]

25. American College of Obstetricians and Gynecologists. Induction of labor with misoprostol. ACOG Committee Opinion 228. Washington, DC: ACOG; 1999.

26. American College of Obstetricians and Gynecologists. Response to Searle's drug warning on misoprostol. Committee Opinion 248. Washington, DC: ACOG; 2000.

27. Hofmeyr GJ, Gulmezoglu AM, Alfirevic Z. Misoprostol for induction of labour: a systematic review [review]. Br J Obstet Gynaecol 1999;106:798–803.[Medline]

28. Goldberg AB, Greenberg MB, Darney PD. Drug therapy: misoprostol and pregnancy [review]. N Engl J Med 2001;344:38–47.[Free Full Text]




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