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doi:10.1111/jog.12333
J. Obstet. Gynaecol. Res. Vol. 40, No. 4: 897–906, April 2014
Efficacy and safety of intravaginal misoprostol versus intracervical dinoprostone for labor induction at term: A systematic review and meta-analysis Aihai Liu1, Jieqiang Lv1, Yue Hu1, Junzhe Lang2, Luhang Ma1 and Wenbing Chen1 1 Gynecology Department, The Second Affiliated Hospital of Wenzhou Medical University, and 2Orthopedics Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Abstract Aim: Recent studies suggest that misoprostol may be more effective than dinoprostone in pregnant women with unfavorable cervix. The objective here is to investigate and compare the efficacy and safety of intravaginal misoprostol and intracervical dinoprostone for labor induction, including incidence of cesarean section, vaginal delivery rate within 24 h, uterine hyperstimulation, tachysystole, oxytocin augmentation, neonatal intensive care unit (NICU) admissions, and Apgar score of less than 7 at 1 and 5 min. Methods: Databases searched were MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials, up to July 2013. Randomized controlled trials comparing intravaginal misoprostol with intracervical dinoprostone in women with singleton pregnancy, intact membranes and unfavorable cervix (Bishop’s 37 weeks); (ii) singleton pregnancy with cephalic presentation and no contraindication to vaginal delivery; (iii) unfavorable cervix (Bishop’s 50%) and χ2-test (P < 0.1), which estimated the appropriateness of pooling the individual study results.
Results The study selection process is detailed in Figure 1. A total of 1651 studies were retrieved in the initial electronic search. After removal of duplicates, 1290 records remained. After title and abstract screening, 1224
studies were excluded. The remaining 66 studies were considered adequate by one or both reviewers. During the second phase of the inclusion process, 56 were excluded for the following reasons: (i) 42 articles compared intravaginal/intracervical/oral/sublingual misoprostol with intravaginal dinoprostone; (ii) three articles included premature rupture of membranes; (iii) six articles included gestational age of less than 37 weeks or Bishop’s score of more than 6; and (iv) five articles were reviews.
Description of included studies Ten RCT8–17 evaluating intravaginal misoprostol versus intracervical dinoprostone for labor induction in pregnant women at term met the inclusion criteria. The sample size ranged 44–200 women with a total of 1061 women. Of these 10 trials, six articles administrated 50 mcg misoprostol intravaginally, while four studies administrated 25 mcg. Meanwhile, all included articles used 0.5 mg dinoprostone gel intracervically. Nine studies received oxytocin for augmentation when there were no changes in cervical dilatation for more than 2 h in the active phase of labor. Characteristics of the articles included in the meta-analysis are shown in Table 1. Risk of bias in included studies As summarized in Table 2, we assessed the risk of bias with the Cochrane Handbook for Systematic Reviews of Interventions. The number of criteria corresponding ranged from two to five of the eight criteria. Seven included studies described the method of random sequence generation.8–11,13,14,16 Five trials reported allocation concealment.8–11,13 No double-blinding was found in any of the 10 RCT, five studies reported the blinding of participants, one article described blinding of the investigator10 and one study described blinding of the assessor.13 One article8 reported withdrawal and intention-to-treat analyses, the remainder had no dropout. Non-selective reporting presented in three trials.8,10,13 Five studies had a certain degree of other potential threats to validity. Except for the clinical studies of Ramsey et al.10 and Nanda et al.,13 the risk of bias was high or medium for the majority of trials. Main outcomes Vaginal delivery at less than 24 h
Figure 1 Published work search and selection process.
Three studies14,16,17 with a total of 500 women reported data for the outcome of clinical pregnancy. Vaginal delivery at less than 24 h occurred in 153 of 235 (65.1%)
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
899
900 69
155 73 84 44
100
130 66
140
200
Varaklis, 199518
Buser, 199719
Ramsey, 200320
Urban, 200321
Sharma, 200522
Nanda, 200723
Denguezli, 200724
Shakya, 201025
Saxena, 201126
Chitrakar, 201227
M: 41.40 ± 1.05 D: 41.29 ± 1.14
M: 22.81 ± 2.95 D: 23.92 ± 3.41
M: 3.36 ± 1.13 D: 3.42 ± 1.12
M: 2.38 ± 1.4 D: 2.90 ± 1.25
M: 39.05 ± 2.5 D: 39.80 ± 1.2
Not mentioned
100
70
35
M: 3.00 ± 0.90 D: 3.35 ± 0.91
Not mentioned
More than 37 weeks
50
23
44
38
76
36
n
65
M: 279.6 ± 12.6 D: 279.0 ± 12.3 (days)
M: 27.2 ± 4.6 D: 29.9 ± 5.4
M: 2.74 ± 1.24 D: 2.66 ± 1.41
M: 3.2 ± 1.2 D: 3.4 ± 1.0
M: 3.0 ± 1.2 D: 3.0 ± 1.1 M: 4.0 ± 2.0 D: 3.2 ± 0.5
M: 2.66 ± 1.3 D: 2.64 ± 1.4
M: 3 (median) D: 3
Initial bishop score
M: 2.1 ± 1.20 D: 2.3 ± 1.29
M: 39.98 ± 1.34 D: 39.35 ± 1.47
M: 39.2 ± 1.3 D: 39.3 ± 1.6 After 41 weeks
M: 28.0 ± 4.4 D: 27.9 ± 4.6 M: 26.5 ± 0.82 D: 26.2 ± 0.82
M: 22.72 ± 2.55 D: 23.06 ± 3.11
M: 39.2 ± 1.9 D: 39.3 ± 1.8
M: 27.7 ± 5.6 D: 27.1 ± 5.8
At term
M: 39.52 ± 2.40 D: 38.96 ± 1.89
M: 26.75 ± 5.95 D: 28.00 ± 6.53
Not mentioned
Gestational age (weeks)
Mean age (year ± SD)
D, dinoprostone; M, misoprostol; SD, standard deviation.
Total patients
Study, year (reference)
Table 1 Characteristics of included studies
25 mcg intravaginal repeated every 2 h, maximum 150 mcg 50 mcg intravaginal repeated every 4 h, maximum 150 mcg 50 mcg intravaginal repeated every 6 h 50 mcg intravaginal repeated every 4 h, maximum 300 mcg 50 mcg intravaginal repeated every 6 h, maximum 100 mcg 25 mcg intravaginal repeated every 3 h, maximum 200 mcg 50 mcg intravaginal repeated every 6 h, maximum 200 mcg 50 mcg intravaginal repeated every 6 h, maximum 300 mcg 25 mcg intravaginal repeated every 6 h, maximum 75 mcg 25 mcg intravaginal repeated every 6 h, maximum 50 mcg
Misoprostol group treatment
100
70
31
65
50
21
40
35
79
33
n
0.5 mg intracervical repeated every 6 h, maximum 1.5 mg 0.5 mg intracervical repeated every 6 h, maximum 1.0 mg
0.5 mg intracervical repeated every 6 h, maximum 1.5 mg 0.5 mg intracervical repeated every 6 h 0.5 mg intracervical repeated every 6 h, maximum 1.0 mg 0.5 mg intracervical repeated every 6 h, maximum 1.0 mg 0.5 mg intracervical repeated every 6 h, maximum 1.5 mg 0.5 mg intracervical repeated every 6 h, maximum 2.0 mg 0.5 mg intracervical repeated every 6 h
0.5 mg intracervical repeated every 6 h
Dinoprostone group treatment
A. Liu et al.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Misoprostol or dinoprostone
Table 2 Risk of bias of included studies
Varaklis, 199518 Buser, 199719 Ramsey, 200320 Urban, 200321 Sharma, 200522 Nanda, 200723 Denguezli, 200724 Shakya, 201025 Saxena, 201126 Chitrakar, 201227
A
B
C
D
E
F
G
H
+ + + + ? + + ? + ?
+ + + + ? + ? ? ? ?
– ? + ? ? ? ? – ? –
– ? ? ? ? + ? – ? –
– ? ? ? ? ? ? – ? –
+ + + + + + + + + +
+ ? + ? ? + ? ? ? ?
– + ? – + ? + + + +
Studies fulfilling the criteria: A, adequate sequence generation; B, concealment of allocation; C, blinding (patient); D, blinding (investigator); E, blinding (assessor); F, incomplete outcome data addressed (ITT analysis); G, free of selective reporting; H, other potential thereat to validity. +, yes; –, no; ?, unclear.
for those treated with dinoprostone (9/391, 2.3%), in which the pooled analysis of eight trials was reported (RR = 3.15; 95% CI, 1.58–6.28; P = 0.001; Fig. 5). No significant heterogeneity existed in this comparison (P = 0.54, I2 = 0%). TS Pooled analysis of six studies that estimated the incidence of TS, in association with misoprostol and dinoprostone in each study group, showed that there was a significantly higher incidence of TS in misoprostol protocol, when compared with dinoprostone (RR = 2.02; 95% CI, 1.28–3.19; P = 0.003; Fig. 6), and there was no heterogeneity among studies (P = 0.11, I2 = 44%). NICU admission
women randomized to misoprostol and in 135 of 265 (50.9%) women randomized to dinoprostone. The use of misoprostol was significantly effective in increasing the rate of vaginal delivery at less than 24 h compared with dinoprostone (RR = 1.27; 95% CI, 1.10–1.48; P = 0.002; Fig. 2). No heterogeneity existed (P = 0.70, I2 = 0%).
Five studies provided data on the incidence of NICU admission. No significant differences between the misoprostol group and dinoprostone group were observed (RR = 0.95; 95% CI, 0.62–1.45; P = 0.80; Fig. 7). No heterogeneity emerged in this comparison (P = 0.59, I2 = 0%).
Cesarean delivery
Apgar score at 1 and 5 min
The effect of misoprostol and dinoprostone on cesarean delivery was evaluated in 10 studies for a total of 1061 patients. Cesarean delivery emerged in 132 of 537 (24.6%) women randomized to misoprostol and in 135 of 524 (25.8%) randomized to dinoprostone. The use of misoprostol did not result in a statistically significant higher rate of cesarean delivery as compared with dinoprostone (RR = 0.95; 95% CI, 0.78–1.17; P = 0.66; Fig. 3). No significant statistical heterogeneity was detected (P = 0.23, I2 = 23%).
The mean (±standard deviation [SD]) data of Apgar score at 1 and 5 min were both similar for pregnant women treated with misoprostol compared with those treated with dinoprostone, in which the pooled analysis of three trials was administered (1 min: MD, 0.03; 95% CI, −0.38 to 0.43; P = 0.90; 5 min: MD, 0.02; 95% CI, −0.33 to 0.38; P = 0.89; Fig. 8). Significant heterogeneity existed at 5 min, so the random-effects model was used (P = 0.13, I2 = 56%; Fig. 8), and no heterogeneity emerged at 1 min (P = 0.23, I2 = 31%; Fig. 8). Meanwhile, we also reported four studies on the rate of Apgar score of less than 7 at 1 min and 5 min, and no statistically significant difference occurred between the two groups (1 min: RR = 0.99; 95% CI, 0.61–1.60; P = 0.96; 5 min: RR = 0.58; 95% CI, 0.19–1.76; P = 0.34; Fig. 8). No heterogeneity was found (1 min: P = 0.37, I2 = 5%; 5 min: P = 0.56, I2 = 0%; Fig. 8).
Oxytocin augmentation Nine studies reported data on development of oxytocin augmentation. With a total of 988 patients, 172 out of 499 (34.5%) women randomized to misoprostol, and 270 out of 489 (55.2%) randomized to dinoprostone, needed oxytocin augmentation. This demonstrated that there was less statistical significance for administration of oxytocin for misoprostol compared with dinoprostone (RR = 0.62; 95% CI, 0.54–0.72; P < 0.00001; Fig. 4). No significant heterogeneity was suggested (P = 0.10, I2 = 40%). Uterine hyperstimulation The rate of uterine hyperstimulation was higher for women treated with misoprostol (31/401, 7.7%) than
Discussion This study is the first meta-analysis regarding the therapeutic effects of intravaginal misoprostol and intracervical dinoprostone in singleton pregnant women with unfavorable cervix at term. Intravaginal misoprostol has higher efficacy than intracervical
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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Figure 2 Vaginal delivery at less than 24 h for misoprostol versus dinoprostone in pregnant women with unfavorable cervix. CI, confidence interval; M-H, Mantel–Haenszel.
Figure 3 Cesarean delivery rate for misoprostol versus dinoprostone. CI, confidence interval; M-H, Mantel–Haenszel.
dinoprostone with regards to vaginal delivery at less than 24 h and oxytocin augmentation while the incidences of uterine hyperstimulation and TS were shown to be significantly higher in the misoprostol than dinoprostone groups. Furthermore, we found no differences in the rate of cesarean delivery, NICU admission, and Apgar score at 1 and 5 min among the study groups. This study had some limitations. The methodological quality of the included 10 RCT was generally weak, and only two studies10,13 presented a low risk of bias. Most included articles did not report whether or not allocation concealment was fully attained and blinding requirements were fully met. Hence, selective bias may have existed in the trials. Paucity of double blinding(s) is prone to potential bias due to physician and patient awareness of treatment allocation. Studies have shown that trials with inadequate allocation concealment over-
902
stated treatment efficacy by 30–40% compared with trials that had adequate allocation concealment.28 Nonselective reporting was found only in three trials,8,10,13 meanwhile, our inclusion criterion limited language to English, with studies that indicated a statistically significant effect of treatment being more likely to be published,18,29,30 published in English,31 cited by other authors32 and generate multiple publications33,34 than other studies. Such studies are also more likely to be brought into systematic reviews, which may therefore overestimate the beneficial effects of treatment,35 ultimately leading to language bias and publication bias. The following factors have strengthened this metaanalysis. Studies were included or excluded according to strict criteria. Women with ruptured membranes, previous cesarean delivery, favorable cervix and gestational age of less than 37 weeks were excluded without hesitation, and those who used intravaginal
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Misoprostol or dinoprostone
Figure 4 Oxytocin augmentation for misoprostol versus dinoprostone for pregnant women with unfavorable cervix. CI, confidence interval; M-H, Mantel–Haenszel.
Figure 5 Uterine hyperstimulation for misoprostol versus dinoprostone. CI, confidence interval; M-H, Mantel–Haenszel.
dinoprostone were also excluded. In addition, the heterogeneity of results used in the different studies makes the overall interpretation of data difficult. Fortunately, except for the mean (±SD) data of Apgar score at 5 min, which used the fixed-effects model, no heterogeneity existed in other outcomes. Misoprostol increased vaginal delivery within 24 h and reduced need for oxytocin augmentation when compared with dinoprostone; meanwhile, we found that misoprostol was similar to dinoprostone with respect to cesarean delivery, which are coincident with other systematic reviews comparing misoprostol with other prostaglandins for cervical ripening and labor induction. In most countries, doctors are prone to use
dinoprostone in the form of a vaginal insert for unprepared cervix. However, both vaginal insert and gel are recognized to be equally effective in overall time to mode of birth and neonatal outcome.36 Misoprostol has been used for induction of labor since the 1990s. The World Health Organization expert committee included 25 μg intravaginal misoprostol in the complementary list of the model list for the induction of labor at-term.19 The International Federation of Gynecology and Obstetrics also recently recommended intravaginal administration of 25 μg misoprostol every 4 h for a maximum of six doses for induction of labor at term.20 Hofmeyr et al.21 suggested that lower doses of misoprostol compared with higher doses did not
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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Figure 6 Comparison of tachysystole with misoprostol and dinoprostone for pregnant women with unfavorable cervix. CI, confidence interval; M-H, Mantel–Haenszel.
Figure 7 Neonatal intensive care unit admission between misoprostol and dinoprostone. CI, confidence interval; M-H, Mantel–Haenszel.
reveal significant differences except for more need for oxytocin augmentation. Others8,22,23 found that oxytocin augmentation was used more often in the 25-μg dose group than higher dose. Owing to various doses and various routes of misoprostol included in our review, subgroup analysis seemed to be unsuitable. A Cochrane review reported that a 25-mcg dose of misoprostol was associated with less uterine hyperstimulation when compared with a 50-mcg dose.7 American Congress of Obstetricians and Gynecologists warns that higher doses (50 mcg every 6 h) of misoprostol could result in more uterine hyperstimulation and FHR decelerations, and recommends a 25-mcg dose of misoprostol inserted into the posterior vaginal fornix, repeated every 3–6 h as needed.24 It seems that a 25-mcg dose of misoprostol may be the optimal treatment; more and larger studies comparing different doses are necessary to demonstrate this viewpoint.
904
The incidence of uterine hyperstimulation and TS were higher in the misoprostol protocol than dinoprostone protocol; however, similar efficacy happened in NICU admission and Apgar score at 1 and 5 min. The preferred term, ‘tachysystole’ (TS), is defined as more than five contractions in 10 min, averaged over a 30-min window. A very recent study which focused on TS during early labor of women who received misoprostol, found that TS was associated with decelerations, but not adverse infant outcomes.25 Heuser et al.26 indicated that TS events increased the rate of NICU admission and composite adverse neonatal outcome by approximately 30%. Uterine hyperstimulation has been associated with abnormal FHR patterns due to inadequate uterine relaxation time. Physiologically, the frequent compression of the uterine spiral arterioles without adequate relaxation time is thought to lead to diminished placental perfusion and destroyed delivery of oxygen to the fetus,
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Misoprostol or dinoprostone
Figure 8 Apgar score at 1 and 5 min between misoprostol and dinoprostone for pregnant women with unfavorable cervix (a: mean data of Apgar score at 1 min; b: mean data of Apgar score at 5 min; c: Apgar score less than 7 at 1 min; d: Apgar score less than 7 at 5 min). CI, confidence interval; M-H, Mantel–Haenszel; SD, standard deviation.
increasing the likelihood of fetal hypoxia and acidosis.27 In conclusion, intravaginal misoprostol appears to be more efficient for labor induction than intracervical
dinoprostone; however, dinoprostone seems to be more safe, due to the lower rate of uterine hyperstimulation and TS. In the future, larger and meticulously designed clinical trials will be indispensable for better definition.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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References 1. Laughon SK, Zhang J, Grewal J, Sundaram R, Beaver J, Reddy UM. Induction of labor in a contemporary obstetric cohort. Am J Obstet Gynecol 2012; 206: 486. e481–489. 2. Crane JM. Factors predicting labor induction success: A critical analysis. Clin Obstet Gynecol 2006; 49: 573–584. 3. Tang OS, Gemzell-Danielsson K, Ho PC. Misoprostol: Pharmacokinetic profiles, effects on the uterus and side-effects. Int J Gynaecol Obstet 2007; 99 (Suppl 2): S160–S167. 4. Shannon CS, Winikoff B. Misoprostol: An Emerging Technology for Women’s Health: Report of a Seminar. New York, NY: Population Council, 2004. 5. Hawkins JS, Wing DA. Current pharmacotherapy options for labor induction. Expert Opin Pharmacother 2012; 13: 2005– 2014. 6. Church S, Van Meter A, Whitfield R. Dinoprostone compared with misoprostol for cervical ripening for induction of labor at term. J Midwifery Womens Health 2009; 54: 405– 411. 7. Hofmeyr GJ, Gulmezoglu AM, Pileggi C. Vaginal misoprostol for cervical ripening and induction of labour. Cochrane Database Syst Rev 2010; (10): CD000941. 8. Varaklis K, Gumina R, Stubblefield PG. Randomized controlled trial of vaginal misoprostol and intracervical prostaglandin E2 gel for induction of labor at term. Obstet Gynecol 1995; 86: 541–544. 9. Buser D, Mora G, Arias F. A randomized comparison between misoprostol and dinoprostone for cervical ripening and labor induction in patients with unfavorable cervices. Obstet Gynecol 1997; 89: 581–585. 10. Ramsey PS, Harris DY, Ogburn PL, Jr, Heise RH, Magtibay PM, Ramin KD. Comparative efficacy and cost of the prostaglandin analogs dinoprostone and misoprostol as labor preinduction agents. Am J Obstet Gynecol 2003; 188: 560– 565. 11. Urban R, Lemancewicz A, Urban J, Skotnicki MZ, Kretowska M. Misoprostol and dinoprostone therapy for labor induction: A Doppler comparison of uterine and fetal hemodynamic effects. Eur J Obstet Gynecol Reprod Biol 2003; 106: 20–24. 12. Sharma Y, Kumar S, Mittal S, Misra R, Dadhwal V. Evaluation of glyceryl trinitrate, misoprostol, and prostaglandin E2 gel for preinduction cervical ripening in term pregnancy. J Obstet Gynaecol Res 2005; 31: 210–215. 13. Nanda S, Singhal SR, Papneja A. Induction of labour with intravaginal misoprostol and prostaglandin E2 gel: A comparative study. Trop Doct 2007; 37: 21–24. 14. Denguezli W, Trimech A, Haddad A et al. Efficacy and safety of six hourly vaginal misoprostol versus intracervical dinoprostone: A randomized controlled trial. Arch Gynecol Obstet 2007; 276: 119–124. 15. Shakya R, Shrestha J, Thapa P. Safety and efficacy of misoprostol and dinoprostone as cervical ripening agents. JNMA J Nepal Med Assoc 2010; 49: 33–37. 16. Saxena P, Puri M, Bajaj M, Mishra A, Trivedi SS. A randomized clinical trial to compare the efficacy of different doses of intravaginal misoprostol with intracervical dinoprostone for cervical ripening and labor induction. Eur Rev Med Pharmacol Sci 2011; 15: 759–763.
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17. Chitrakar NS. Comparison of Misoprostol versus Dinoprostone for pre-induction cervical ripening at-term. J Nepal Health Res Counc 2012; 10: 10–15. 18. Stern JM, Simes RJ. Publication bias: Evidence of delayed publication in a cohort study of clinical research projects. BMJ 1997; 315: 640–645. 19. The WHO Expert Committee on the selection and use of essential medicines met in Geneva from 7 to 11 March 2005. Expert Committee Report 2005; 44–45. 20. Weeks A, Faundes A. Misoprostol in obstetrics and gynecology. Int J Gynaecol Obstet 2007; 99 (Suppl 2): S156–S159. 21. Hofmeyr GJ, Gulmezoglu AM. Vaginal misoprostol for cervical ripening and induction of labour. Cochrane Database Syst Rev 2001; (10): CD000941. 22. 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– 1816. 23. Weaver SP, Cook J, Nashelsky J. Vaginal misoprostol for cervical ripening in term pregnancy. Am Fam Physician 2006; 73: 511–512. 24. Obstetrics ACoPB–. ACOG Practice Bulletin No. 107: Induction of labor. Obstet Gynecol 2009; 114: 386–397. 25. Stewart RD, Bleich AT, Lo JY, Alexander JM, McIntire DD, Leveno KJ. Defining uterine tachysystole: How much is too much? Am J Obstet Gynecol 2012; 207: 290 e291–296. 26. Heuser CC, Knight S, Esplin MS et al. Tachysystole in term labor: Incidence, risk factors, outcomes, and effect on fetal heart tracings. Am J Obstet Gynecol 2013; 209: 32 e291–296. 27. Parer JT, Nageotte MP. Intrapartum fetal surveillance. In: Creasy RK, Resnik R (eds). Maternal-Fetal Medicine. Philadelphia, PA: Elsevier, 2003; 412. 28. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995; 273: 408–412. 29. Easterbrook PJ, Berlin JA, Gopalan R, Matthews DR. Publication bias in clinical research. Lancet 1991; 337: 867–872. 30. Dickersin K, Min YI, Meinert CL. Factors influencing publication of research results. Follow-up of applications submitted to two institutional review boards. JAMA 1992; 267: 374–378. 31. Egger M, Zellweger-Zahner T, Schneider M, Junker C, Lengeler C, Antes G. Language bias in randomised controlled trials published in English and German. Lancet 1997; 350: 326–329. 32. Ravnskov U. Cholesterol lowering trials in coronary heart disease: Frequency of citation and outcome. BMJ 1992; 305: 15–19. 33. Tramer MR, Reynolds DJ, Moore RA, McQuay HJ. Impact of covert duplicate publication on meta-analysis: A case study. BMJ 1997; 315: 635–640. 34. Gotzsche PC. Multiple publication of reports of drug trials. Eur J Clin Pharmacol 1989; 36: 429–432. 35. Egger M, Dickersin K, Davey SG. Systematic Reviews in Health Care, Meta-Analysis in Context. Egger M, Davey Smith G, Altman DG (eds). London: BMJ Books, 2000. 36. Yount SM, Lassiter N. The pharmacology of prostaglandins for induction of labor. J Midwifery Womens Health 2013; 58: 133–144; quiz 238–139.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
doi:10.1111/jog.12333
J. Obstet. Gynaecol. Res. Vol. 40, No. 4: 897–906, April 2014
Efficacy and safety of intravaginal misoprostol versus intracervical dinoprostone for labor induction at term: A systematic review and meta-analysis Aihai Liu1, Jieqiang Lv1, Yue Hu1, Junzhe Lang2, Luhang Ma1 and Wenbing Chen1 1 Gynecology Department, The Second Affiliated Hospital of Wenzhou Medical University, and 2Orthopedics Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Abstract Aim: Recent studies suggest that misoprostol may be more effective than dinoprostone in pregnant women with unfavorable cervix. The objective here is to investigate and compare the efficacy and safety of intravaginal misoprostol and intracervical dinoprostone for labor induction, including incidence of cesarean section, vaginal delivery rate within 24 h, uterine hyperstimulation, tachysystole, oxytocin augmentation, neonatal intensive care unit (NICU) admissions, and Apgar score of less than 7 at 1 and 5 min. Methods: Databases searched were MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials, up to July 2013. Randomized controlled trials comparing intravaginal misoprostol with intracervical dinoprostone in women with singleton pregnancy, intact membranes and unfavorable cervix (Bishop’s 37 weeks); (ii) singleton pregnancy with cephalic presentation and no contraindication to vaginal delivery; (iii) unfavorable cervix (Bishop’s 50%) and χ2-test (P < 0.1), which estimated the appropriateness of pooling the individual study results.
Results The study selection process is detailed in Figure 1. A total of 1651 studies were retrieved in the initial electronic search. After removal of duplicates, 1290 records remained. After title and abstract screening, 1224
studies were excluded. The remaining 66 studies were considered adequate by one or both reviewers. During the second phase of the inclusion process, 56 were excluded for the following reasons: (i) 42 articles compared intravaginal/intracervical/oral/sublingual misoprostol with intravaginal dinoprostone; (ii) three articles included premature rupture of membranes; (iii) six articles included gestational age of less than 37 weeks or Bishop’s score of more than 6; and (iv) five articles were reviews.
Description of included studies Ten RCT8–17 evaluating intravaginal misoprostol versus intracervical dinoprostone for labor induction in pregnant women at term met the inclusion criteria. The sample size ranged 44–200 women with a total of 1061 women. Of these 10 trials, six articles administrated 50 mcg misoprostol intravaginally, while four studies administrated 25 mcg. Meanwhile, all included articles used 0.5 mg dinoprostone gel intracervically. Nine studies received oxytocin for augmentation when there were no changes in cervical dilatation for more than 2 h in the active phase of labor. Characteristics of the articles included in the meta-analysis are shown in Table 1. Risk of bias in included studies As summarized in Table 2, we assessed the risk of bias with the Cochrane Handbook for Systematic Reviews of Interventions. The number of criteria corresponding ranged from two to five of the eight criteria. Seven included studies described the method of random sequence generation.8–11,13,14,16 Five trials reported allocation concealment.8–11,13 No double-blinding was found in any of the 10 RCT, five studies reported the blinding of participants, one article described blinding of the investigator10 and one study described blinding of the assessor.13 One article8 reported withdrawal and intention-to-treat analyses, the remainder had no dropout. Non-selective reporting presented in three trials.8,10,13 Five studies had a certain degree of other potential threats to validity. Except for the clinical studies of Ramsey et al.10 and Nanda et al.,13 the risk of bias was high or medium for the majority of trials. Main outcomes Vaginal delivery at less than 24 h
Figure 1 Published work search and selection process.
Three studies14,16,17 with a total of 500 women reported data for the outcome of clinical pregnancy. Vaginal delivery at less than 24 h occurred in 153 of 235 (65.1%)
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
899
900 69
155 73 84 44
100
130 66
140
200
Varaklis, 199518
Buser, 199719
Ramsey, 200320
Urban, 200321
Sharma, 200522
Nanda, 200723
Denguezli, 200724
Shakya, 201025
Saxena, 201126
Chitrakar, 201227
M: 41.40 ± 1.05 D: 41.29 ± 1.14
M: 22.81 ± 2.95 D: 23.92 ± 3.41
M: 3.36 ± 1.13 D: 3.42 ± 1.12
M: 2.38 ± 1.4 D: 2.90 ± 1.25
M: 39.05 ± 2.5 D: 39.80 ± 1.2
Not mentioned
100
70
35
M: 3.00 ± 0.90 D: 3.35 ± 0.91
Not mentioned
More than 37 weeks
50
23
44
38
76
36
n
65
M: 279.6 ± 12.6 D: 279.0 ± 12.3 (days)
M: 27.2 ± 4.6 D: 29.9 ± 5.4
M: 2.74 ± 1.24 D: 2.66 ± 1.41
M: 3.2 ± 1.2 D: 3.4 ± 1.0
M: 3.0 ± 1.2 D: 3.0 ± 1.1 M: 4.0 ± 2.0 D: 3.2 ± 0.5
M: 2.66 ± 1.3 D: 2.64 ± 1.4
M: 3 (median) D: 3
Initial bishop score
M: 2.1 ± 1.20 D: 2.3 ± 1.29
M: 39.98 ± 1.34 D: 39.35 ± 1.47
M: 39.2 ± 1.3 D: 39.3 ± 1.6 After 41 weeks
M: 28.0 ± 4.4 D: 27.9 ± 4.6 M: 26.5 ± 0.82 D: 26.2 ± 0.82
M: 22.72 ± 2.55 D: 23.06 ± 3.11
M: 39.2 ± 1.9 D: 39.3 ± 1.8
M: 27.7 ± 5.6 D: 27.1 ± 5.8
At term
M: 39.52 ± 2.40 D: 38.96 ± 1.89
M: 26.75 ± 5.95 D: 28.00 ± 6.53
Not mentioned
Gestational age (weeks)
Mean age (year ± SD)
D, dinoprostone; M, misoprostol; SD, standard deviation.
Total patients
Study, year (reference)
Table 1 Characteristics of included studies
25 mcg intravaginal repeated every 2 h, maximum 150 mcg 50 mcg intravaginal repeated every 4 h, maximum 150 mcg 50 mcg intravaginal repeated every 6 h 50 mcg intravaginal repeated every 4 h, maximum 300 mcg 50 mcg intravaginal repeated every 6 h, maximum 100 mcg 25 mcg intravaginal repeated every 3 h, maximum 200 mcg 50 mcg intravaginal repeated every 6 h, maximum 200 mcg 50 mcg intravaginal repeated every 6 h, maximum 300 mcg 25 mcg intravaginal repeated every 6 h, maximum 75 mcg 25 mcg intravaginal repeated every 6 h, maximum 50 mcg
Misoprostol group treatment
100
70
31
65
50
21
40
35
79
33
n
0.5 mg intracervical repeated every 6 h, maximum 1.5 mg 0.5 mg intracervical repeated every 6 h, maximum 1.0 mg
0.5 mg intracervical repeated every 6 h, maximum 1.5 mg 0.5 mg intracervical repeated every 6 h 0.5 mg intracervical repeated every 6 h, maximum 1.0 mg 0.5 mg intracervical repeated every 6 h, maximum 1.0 mg 0.5 mg intracervical repeated every 6 h, maximum 1.5 mg 0.5 mg intracervical repeated every 6 h, maximum 2.0 mg 0.5 mg intracervical repeated every 6 h
0.5 mg intracervical repeated every 6 h
Dinoprostone group treatment
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© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Misoprostol or dinoprostone
Table 2 Risk of bias of included studies
Varaklis, 199518 Buser, 199719 Ramsey, 200320 Urban, 200321 Sharma, 200522 Nanda, 200723 Denguezli, 200724 Shakya, 201025 Saxena, 201126 Chitrakar, 201227
A
B
C
D
E
F
G
H
+ + + + ? + + ? + ?
+ + + + ? + ? ? ? ?
– ? + ? ? ? ? – ? –
– ? ? ? ? + ? – ? –
– ? ? ? ? ? ? – ? –
+ + + + + + + + + +
+ ? + ? ? + ? ? ? ?
– + ? – + ? + + + +
Studies fulfilling the criteria: A, adequate sequence generation; B, concealment of allocation; C, blinding (patient); D, blinding (investigator); E, blinding (assessor); F, incomplete outcome data addressed (ITT analysis); G, free of selective reporting; H, other potential thereat to validity. +, yes; –, no; ?, unclear.
for those treated with dinoprostone (9/391, 2.3%), in which the pooled analysis of eight trials was reported (RR = 3.15; 95% CI, 1.58–6.28; P = 0.001; Fig. 5). No significant heterogeneity existed in this comparison (P = 0.54, I2 = 0%). TS Pooled analysis of six studies that estimated the incidence of TS, in association with misoprostol and dinoprostone in each study group, showed that there was a significantly higher incidence of TS in misoprostol protocol, when compared with dinoprostone (RR = 2.02; 95% CI, 1.28–3.19; P = 0.003; Fig. 6), and there was no heterogeneity among studies (P = 0.11, I2 = 44%). NICU admission
women randomized to misoprostol and in 135 of 265 (50.9%) women randomized to dinoprostone. The use of misoprostol was significantly effective in increasing the rate of vaginal delivery at less than 24 h compared with dinoprostone (RR = 1.27; 95% CI, 1.10–1.48; P = 0.002; Fig. 2). No heterogeneity existed (P = 0.70, I2 = 0%).
Five studies provided data on the incidence of NICU admission. No significant differences between the misoprostol group and dinoprostone group were observed (RR = 0.95; 95% CI, 0.62–1.45; P = 0.80; Fig. 7). No heterogeneity emerged in this comparison (P = 0.59, I2 = 0%).
Cesarean delivery
Apgar score at 1 and 5 min
The effect of misoprostol and dinoprostone on cesarean delivery was evaluated in 10 studies for a total of 1061 patients. Cesarean delivery emerged in 132 of 537 (24.6%) women randomized to misoprostol and in 135 of 524 (25.8%) randomized to dinoprostone. The use of misoprostol did not result in a statistically significant higher rate of cesarean delivery as compared with dinoprostone (RR = 0.95; 95% CI, 0.78–1.17; P = 0.66; Fig. 3). No significant statistical heterogeneity was detected (P = 0.23, I2 = 23%).
The mean (±standard deviation [SD]) data of Apgar score at 1 and 5 min were both similar for pregnant women treated with misoprostol compared with those treated with dinoprostone, in which the pooled analysis of three trials was administered (1 min: MD, 0.03; 95% CI, −0.38 to 0.43; P = 0.90; 5 min: MD, 0.02; 95% CI, −0.33 to 0.38; P = 0.89; Fig. 8). Significant heterogeneity existed at 5 min, so the random-effects model was used (P = 0.13, I2 = 56%; Fig. 8), and no heterogeneity emerged at 1 min (P = 0.23, I2 = 31%; Fig. 8). Meanwhile, we also reported four studies on the rate of Apgar score of less than 7 at 1 min and 5 min, and no statistically significant difference occurred between the two groups (1 min: RR = 0.99; 95% CI, 0.61–1.60; P = 0.96; 5 min: RR = 0.58; 95% CI, 0.19–1.76; P = 0.34; Fig. 8). No heterogeneity was found (1 min: P = 0.37, I2 = 5%; 5 min: P = 0.56, I2 = 0%; Fig. 8).
Oxytocin augmentation Nine studies reported data on development of oxytocin augmentation. With a total of 988 patients, 172 out of 499 (34.5%) women randomized to misoprostol, and 270 out of 489 (55.2%) randomized to dinoprostone, needed oxytocin augmentation. This demonstrated that there was less statistical significance for administration of oxytocin for misoprostol compared with dinoprostone (RR = 0.62; 95% CI, 0.54–0.72; P < 0.00001; Fig. 4). No significant heterogeneity was suggested (P = 0.10, I2 = 40%). Uterine hyperstimulation The rate of uterine hyperstimulation was higher for women treated with misoprostol (31/401, 7.7%) than
Discussion This study is the first meta-analysis regarding the therapeutic effects of intravaginal misoprostol and intracervical dinoprostone in singleton pregnant women with unfavorable cervix at term. Intravaginal misoprostol has higher efficacy than intracervical
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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Figure 2 Vaginal delivery at less than 24 h for misoprostol versus dinoprostone in pregnant women with unfavorable cervix. CI, confidence interval; M-H, Mantel–Haenszel.
Figure 3 Cesarean delivery rate for misoprostol versus dinoprostone. CI, confidence interval; M-H, Mantel–Haenszel.
dinoprostone with regards to vaginal delivery at less than 24 h and oxytocin augmentation while the incidences of uterine hyperstimulation and TS were shown to be significantly higher in the misoprostol than dinoprostone groups. Furthermore, we found no differences in the rate of cesarean delivery, NICU admission, and Apgar score at 1 and 5 min among the study groups. This study had some limitations. The methodological quality of the included 10 RCT was generally weak, and only two studies10,13 presented a low risk of bias. Most included articles did not report whether or not allocation concealment was fully attained and blinding requirements were fully met. Hence, selective bias may have existed in the trials. Paucity of double blinding(s) is prone to potential bias due to physician and patient awareness of treatment allocation. Studies have shown that trials with inadequate allocation concealment over-
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stated treatment efficacy by 30–40% compared with trials that had adequate allocation concealment.28 Nonselective reporting was found only in three trials,8,10,13 meanwhile, our inclusion criterion limited language to English, with studies that indicated a statistically significant effect of treatment being more likely to be published,18,29,30 published in English,31 cited by other authors32 and generate multiple publications33,34 than other studies. Such studies are also more likely to be brought into systematic reviews, which may therefore overestimate the beneficial effects of treatment,35 ultimately leading to language bias and publication bias. The following factors have strengthened this metaanalysis. Studies were included or excluded according to strict criteria. Women with ruptured membranes, previous cesarean delivery, favorable cervix and gestational age of less than 37 weeks were excluded without hesitation, and those who used intravaginal
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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Figure 4 Oxytocin augmentation for misoprostol versus dinoprostone for pregnant women with unfavorable cervix. CI, confidence interval; M-H, Mantel–Haenszel.
Figure 5 Uterine hyperstimulation for misoprostol versus dinoprostone. CI, confidence interval; M-H, Mantel–Haenszel.
dinoprostone were also excluded. In addition, the heterogeneity of results used in the different studies makes the overall interpretation of data difficult. Fortunately, except for the mean (±SD) data of Apgar score at 5 min, which used the fixed-effects model, no heterogeneity existed in other outcomes. Misoprostol increased vaginal delivery within 24 h and reduced need for oxytocin augmentation when compared with dinoprostone; meanwhile, we found that misoprostol was similar to dinoprostone with respect to cesarean delivery, which are coincident with other systematic reviews comparing misoprostol with other prostaglandins for cervical ripening and labor induction. In most countries, doctors are prone to use
dinoprostone in the form of a vaginal insert for unprepared cervix. However, both vaginal insert and gel are recognized to be equally effective in overall time to mode of birth and neonatal outcome.36 Misoprostol has been used for induction of labor since the 1990s. The World Health Organization expert committee included 25 μg intravaginal misoprostol in the complementary list of the model list for the induction of labor at-term.19 The International Federation of Gynecology and Obstetrics also recently recommended intravaginal administration of 25 μg misoprostol every 4 h for a maximum of six doses for induction of labor at term.20 Hofmeyr et al.21 suggested that lower doses of misoprostol compared with higher doses did not
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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Figure 6 Comparison of tachysystole with misoprostol and dinoprostone for pregnant women with unfavorable cervix. CI, confidence interval; M-H, Mantel–Haenszel.
Figure 7 Neonatal intensive care unit admission between misoprostol and dinoprostone. CI, confidence interval; M-H, Mantel–Haenszel.
reveal significant differences except for more need for oxytocin augmentation. Others8,22,23 found that oxytocin augmentation was used more often in the 25-μg dose group than higher dose. Owing to various doses and various routes of misoprostol included in our review, subgroup analysis seemed to be unsuitable. A Cochrane review reported that a 25-mcg dose of misoprostol was associated with less uterine hyperstimulation when compared with a 50-mcg dose.7 American Congress of Obstetricians and Gynecologists warns that higher doses (50 mcg every 6 h) of misoprostol could result in more uterine hyperstimulation and FHR decelerations, and recommends a 25-mcg dose of misoprostol inserted into the posterior vaginal fornix, repeated every 3–6 h as needed.24 It seems that a 25-mcg dose of misoprostol may be the optimal treatment; more and larger studies comparing different doses are necessary to demonstrate this viewpoint.
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The incidence of uterine hyperstimulation and TS were higher in the misoprostol protocol than dinoprostone protocol; however, similar efficacy happened in NICU admission and Apgar score at 1 and 5 min. The preferred term, ‘tachysystole’ (TS), is defined as more than five contractions in 10 min, averaged over a 30-min window. A very recent study which focused on TS during early labor of women who received misoprostol, found that TS was associated with decelerations, but not adverse infant outcomes.25 Heuser et al.26 indicated that TS events increased the rate of NICU admission and composite adverse neonatal outcome by approximately 30%. Uterine hyperstimulation has been associated with abnormal FHR patterns due to inadequate uterine relaxation time. Physiologically, the frequent compression of the uterine spiral arterioles without adequate relaxation time is thought to lead to diminished placental perfusion and destroyed delivery of oxygen to the fetus,
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Misoprostol or dinoprostone
Figure 8 Apgar score at 1 and 5 min between misoprostol and dinoprostone for pregnant women with unfavorable cervix (a: mean data of Apgar score at 1 min; b: mean data of Apgar score at 5 min; c: Apgar score less than 7 at 1 min; d: Apgar score less than 7 at 5 min). CI, confidence interval; M-H, Mantel–Haenszel; SD, standard deviation.
increasing the likelihood of fetal hypoxia and acidosis.27 In conclusion, intravaginal misoprostol appears to be more efficient for labor induction than intracervical
dinoprostone; however, dinoprostone seems to be more safe, due to the lower rate of uterine hyperstimulation and TS. In the future, larger and meticulously designed clinical trials will be indispensable for better definition.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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