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Maternal and neonatal outcomes with mechanical cervical dilation plus misoprostol compared to misoprostol alone for cervical ripening; a systematic review of literature and metaanalysis
Systematic Review 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55
Maternal and neonatal outcomes with mechanical cervical dilation plus misoprostol compared to misoprostol alone for cervical ripening; a systematic review of literature and metaanalysis Q20 Q1
Dimitrios Nasioudis, MD; Sun Woo Kim, MD; Corina Schoen, MD; Lisa D. Levine, MD, MSCE
I
nduction of labor is the most common obstetric intervention, with approximately 932,000 women undergoing an induction annually in the United States.1 Patients who have an unfavorable cervix typically undergo cervical ripening with either prostaglandins or mechanical dilation before the administration of intravenous oxytocin.2 Misoprostol is a prostaglandin E1 analogue, which was used initially for the treatment of gastric ulcers, that can be administered orally or vaginally for cervical ripening.3 Given its low cost and stability at room temperature, its use worldwide is widespread.3 Additionally, mechanical dilation of the cervix can be achieved with the introduction of an intracervical balloon catheter, such as the single balloon Foley catheter, that simultaneously can dilate the cervix mechanically and stimulate the endogenous production of prostaglandins.4 Given the proposed mechanisms of action for both pharmacologic and meFrom the Maternal and Child Health Research Center, Department of Obstetrics & Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (Drs Nasioudis, Kim, and Levine); the Department of Obstetrics and Gynecology, University of Massachusetts Medical SchoolBaystate, Springfield, MA (Dr Schoen).
OBJECTIVE DATA: The aim of the present systematic review was to investigate the
efficacy and safety of cervical ripening for the combination of mechanical dilation and misoprostol administration compared with misoprostol alone by evaluating 2 primary outcomes: time to delivery and rate of cesarean delivery. STUDY: The Medline, EMBASE, and Web-of-Science electronic databases (from conception to end-of-search date December 31, 2018) were searched systematically. Randomized controlled trials that included patients with a singleton viable fetus who underwent induction of labor that required cervical ripening with an unfavorable cervix (Bishop 7) were eligible for inclusion. STUDY APPRAISAL AND SYNTHESIS METHODS: Data were pooled with the use of the random effects and fixed effects model after the assessment for the presence of heterogeneity. Risk of bias for each included study was assessed based on the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Eleven trials met the inclusion criteria and included a total of 922 and 947 subjects in the combination and misoprostol-only groups, respectively. There was no difference in the incidence of cesarean delivery between the 2 groups (relative risk, 0.95; 95% confidence interval, 0.80e1.13). The combination of mechanical dilation and misoprostol resulted in overall shorter time to delivery (mean difference, e3.65 hours; 95% confidence interval, 5.23 to e2.07), shorter time to vaginal delivery (mean difference, e4.53 hours; 95% confidence interval, e5.79 to e3.27), lower risk of neonatal intensive care unit admission (relative risk, 0.71; 95% confidence interval, 0.53e0.96), meconium-stained fluid (relative risk, 0.62; 95% confidence interval, 0.43e0.90), tachysystole with fetal heart trace changes (relative risk, 0.53; 95% confidence interval, 0.30e0.94), and terbutaline use (relative risk, 0.63; 95% confidence interval, 0.47e0.85) compared with the use of misoprostol alone. Risk of endometritis (relative risk, 1.07; 95% confidence interval, 0.43e2.61) and chorioamnionitis (relative risk, 1.58; 95% confidence interval, 0.88e2.84) was comparable between the 2 groups. CONCLUSION: The combination of mechanical cervical dilation with misoprostol for cervical ripening is associated with a shorter time to delivery, a similar rate of cesarean delivery, and a lower incidence of neonatal intensive care unit admission compared with the use of misoprostol alone. Key words: cervical ripening, combination methods, Foley catheter, intracervical catheter, mechanical dilation, misoprostol
Received March 31, 2019; revised June 3, 2019; accepted June 4, 2019. The authors report no conflict of interest. Corresponding author: Dimitrios Nasioudis, MD. [email protected] 2589-9333/$36.00 ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.ajogmf.2019.06.003
chanical cervical ripening, a synergistic or additive effect of these methods is plausible. Several randomized trials have investigated the combination of an intracervical catheter with misoprostol and demonstrated a trend towards a
faster time to delivery in the combination arm.5e15 However, there is skepticism regarding the safety of the combination methods because most randomized studies were not powered to detect rare outcomes, such as rate of MONTH 2019 AJOG MFM
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AJOG at a Glance Why was this study conducted? The purpose of this study was to investigate the efficacy and safety of cervical ripening for the combination of mechanical dilation and misoprostol administration compared with misoprostol alone. Key findings Women who had cervical ripening with combination methods delivered 3e4 hours faster, had a >50% lower risk of tachysystole with fetal heart rate changes, a 30% lower risk of neonatal intensive care unit admission, and a 40% lower risk of meconium with no difference in risk of cesarean delivery or chorioamnionitis. What does this add to what is known? The present study is the first to demonstrate superior neonatal outcomes for women who had cervical ripening with a combination of mechanical cervical dilation and misoprostol.
cesarean delivery, chorioamnionitis, and adverse neonatal outcomes.16 Therefore, the aim of the present systematic review and metaanalysis was to investigate the efficacy and safety of cervical ripening for the combination of mechanical dilation and misoprostol administration, compared with misoprostol alone, by evaluating 2 primary outcomes: time to delivery and rate of cesarean delivery.
Material and methods Search strategy This systematic review was conducted in accordance to the Preferred Reporting Items for Systematic Review and MetaAnalyses (PRISMA) guidelines17; a protocol was determined beforehand by the participating authors. The present study was registered at the PROSPERO database with the unique identifier (CRD42019122901). A comprehensive electronic search (from conception to end-of-search date December 31, 2018) of PubMed/Medline, EMBASE, and Web of Science databases was performed with the use of the following keywords: (“misoprostol” and [“foley” or “intracervical catheter”] and [“labor” or “labour”]). The reference list of all included articles were also hand searched to identify any potentially eligible studies. Eligibility of studies. Our investigation was limited to full articles that are available in the English language. Abstracts,
commentaries, reviews, short communications, and letters to the editor were excluded. Only prospective randomized trials were eligible for inclusion; quasirandomized trials were excluded. Eligible trials compared cervical ripening with concurrent mechanical cervical dilation with an intracervical single balloon Foley catheter and misoprostol (any dose or administration route) with misoprostol alone. The eligible population included patients with a viable singleton fetus and unfavorable cervix who underwent an induction of labor for any indication. An unfavorable cervix was defined differently in some studies, but all of them had a Bishop 7. Studies that included both preterm and term gestations were included in this review. Studies on second-trimester termination of pregnancy, those which included patients with a fetal death, or twins pregnancies were excluded. Data extraction. Two reviewers (D.N., S.W.K.) who worked independently extracted data from all eligible studies into custom-made data collection forms. Data were cross-checked, and any discrepancies were resolved with discussion. In the case of a disagreement a third reviewer (L.D.L.) was consulted. From each included study the following parameters were extracted when applicable: general study characteristics (author, country of origin, date of publication), cervical ripening protocol (dosing, frequency for misoprostol,
balloon inflation amount for intracervical catheter) in each study group, number of participants in each arm, percentage of nulliparous women, gestational age, and Bishop score on admission. Primary outcomes were cesarean delivery rate and time to delivery (defined as interval from the start of cervical ripening to delivery). Secondary outcomes included delivery within 24 hours, time to vaginal delivery (defined as time from start of cervical ripening to vaginal delivery), rate of oxytocin augmentation, indication for cesarean delivery, chorioamnionitis, endometritis, postpartum hemorrhage/ blood transfusion, meconium passage, uterine tachysystole with fetal heart rate changes, use of terbutaline for fetal distress mean cord pH, rate of neonatal intensive care unit (NICU) admission and 5-minute Apgar score of 7 in 5 minutes. Because 1 of the primary outcomes (cesarean delivery) was provided by all studies, no attempts were made to obtain additional data from the individual authors. Risk of bias of included studies. Risk of bias for each included study was assessed based on the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. Seven domains related to risk of bias were assessed, namely (1) random sequence generation, (2) allocation concealment, (3) blinding of participants and personnel, (4) blinding of outcome assessment, (5) incomplete outcome data, (6) selective reporting, and (7) other bias. Risk of bias was categorized as “low risk,” “high risk,” or “unclear risk.” Because blinding of participants and personnel was not feasible because of the nature of the intervention, all studies were considered to be low bias for that category. Synthesis of data. Level of statistical heterogeneity was evaluated with the Higgins I2 statistic. In the presence of heterogeneity (defined as I2 >20%) a randomeffect model (DerSimonian and Laird approach) was used to compare outcomes between the 2 groups; in the absence of heterogeneity, a fixed-effects model (Mantel-Haenszel approach) was selected. A summary relative risk (RR)
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223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 TABLE 1
Demographic and general characteristics of the included studies Bishop on score admission Foley and Misoprostol inclusion misoprostol only criteria
Bishop score on admission Nulliparous, n (%)
Gestational age, wk Foley and Mechanical misoprostol Foley and description, Misoprostol only misoprostol, Misoprostol dilation method only, n Country n mg description, mg
Author
Year Journal
Aduloju et al16
2016 Australian & New Nigeria Zealand Journal of Obstetrics & Gynaecology
Gestational age inclusion criteria, wk
Foley and Misoprostol Foley and Misoprostol misoprostol only misoprostol only
16F Foley, 30 mL
25 (vaginally 25 (vaginally every 37 every 6 hrs; 6 hrs; maximum, 4 maximum, 4 doses) doses)
40.031.56a 40.311.31a <6
2.71.08a
2.311.2a
100
Foley, 60 mL
25 (vaginally 25 (vaginally every 37 every 4 hrs; 4 hrs; maximum, 6 maximum, 6 doses) doses)
39.61.3a
<6
3.0 (2e4)b
2.0 (1.25e4)b 70 (70)
74 (74)
109
116
24F Foley, 50 mL
100 (oral every 4 100 (oral every 4 hrs; hrs; maximum, 4 maximum, 4 doses) doses)
38 37.9 <7 (35.7e40.2)b (36.1e40.6)b
3 (1e4)b
3 (2e4)b
72 (66.1)
60 (51.2)
United States
56
61
Foley, 60 mL 25 (vaginally 25 (vaginally every >24 every 4 hrs) 4 hrs)
39.51.4a
39.81.4a
<6
3 (0e6)b
3 (0e6)b
37 (67.3)
40 (65.6)
Chung et al9 2003 American Journal United of Obstetrics and States Gynecology
43
49
16F Foley, 30 mL
25 (vaginally 25 (vaginally every 28 every 3 hrs; 3 hrs; maximum, 6 maximum, 6 doses) doses)
39.92.5a
39.82.33a
6
N/A
N/A
31 (72.1)
33 (67.3)
106
126
24F Foley, 50 mL
100 (oral every 4e6 hrs; maximum, 4 doses)
N/A
N/A
4
3 (1e4)b
2 (0e3)b
64 (60)
80 (63)
Pakistan 161
157
16/18F Foley, 30 mL
50 (oral every 50 (oral every 4 37 hrs; maximum, 4 4 hrs; maximum, 4 doses) doses)
39 (37e41)b 39 (37e41)b 4
3 (0e3)b
3 (0e3)b
n/a
n/a
70
70
United States
100
Barrilleaux et al7
2002 American Journal United of Obstetrics and States Gynecology
Carbone et al8
2013 Obstetrics and Gynecology
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Al-Ibraheemi 2018 Obstetrics and et al6 Gynecology
Hill et al10
2009 American Journal United of Perinatology States
Husain et al11
2017 Journal of Obstetrics and Gynaecology Research
N/A
25 (vaginally >24 followed by 50 mg every 3e6 hrs; maximum, 8 doses)
39.41.4a
24 (34.3)
25 (35.7)
63
63
16F Foley, 30 mL
25 (vaginally 25 (vaginally every 28 every 4 hrs; 4 hrs; maximum, 8 maximum, 8 doses) doses)
39.131.48a 39.291.68a 4
1.841a
2.210.99a
50 (79.4)
49 (77.8)
United States
123
120
18F Foley, 60 mL
25 (vaginally 25 (vaginally every 37 every 3 hrs; 3 hrs; maximum, 6 maximum, 6 doses) doses)
39.6 39.1 6 (38.3e40.7)b (37.9e40.1)b
3 (2e4)b
3 (2e4)b
73 (59.4)
70 (58.3)
Rust et al14 2001 Journal of Reproductive Medicine
United States
41
40
25F Foley, 50 mL
25 (vaginally 25 (vaginally every N/A every 3 hrs; 3 hrs; maximum, 4 maximum, 4 doses) doses)
36.53.8a
373.8a
5
2 (0e5)b
2 (0e5)b
21 (51)
23 (57.5)
Ugwu et al15 2013 Journal of Obstetrics and Gynaecology
Nigeria
50
45
16F Foley, 30 mL
25 (vaginally 25 (vaginally every 37 every 4 hrs; 4 hrs; maximum, 6 maximum, 6 doses) doses)
40.71.5a
40.21.7a
5
3.81.5a
3.71.7a
22 (44)
19 (42)
Levine et al13
2016 Obstetrics and Gynecology
Q14
MONTH 2019 AJOG MFM
N/A, not available. a
Data are given as meanstandard deviation; b Data are given as median (interquartile range).
Q15
3
Nasioudis. Mechanical cervical dilation plus misoprostol compared to misoprostol alone for cervical ripening. AJOG MFM 2019.
Systematic Review
India
Lanka et al12 2014 Journal of Obstetrics and Gynaecology Research
Q13
279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334
Systematic Review 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390
with 95% confidence intervals (95% CI) was calculated for categoric variables; for a summary mean difference (95% CI) was calculated for continuous variables. If original data were presented as median (interquartile range or range), they were converted to mean and standard deviation with the use of previously validated mathematical formulas.18,19 A planned sensitivity analysis of primary outcomes that included only women who received misoprostol vaginally was performed. Graphic funnel plots were generated to determine the presence of publication bias by visual inspection. Probability values <.05 were considered statistically significant. Statistical analysis was performed with the Cochrane Review software (Review Manager version 5.3) by 1 of the reviewers (D.N.).20
Results Study selection and characteristics A total of 11 studies met the inclusion criteria and were included in the present metaanalysis. Supplemental Figure 1 shows the study selection flowchart. Most of the included studies (7 studies) originated from North America; 2 studies were from Asia, and 2 studies were from Africa. Supplemental Figure 2 summarizes the summary of risk of bias for each study. The majority of studies included patients with a Bishop score of 6, although starting cervical dilation was not reported consistently. Regarding inflation volume of the single balloon intracervical catheter, 45.5% of the studies (5/11) used a low volume (30 mL); 55.5% of the studies (6/11) used a high volume (50e60 mL). Regarding the route of administration for patients in the misoprostol-only arm, the majority of studies (81.8%; 9/11) used vaginally administered misoprostol (8 studies at a dose of 25 mg every 3e4 hours; in 1 study, 25 mg as a single dose was followed by 50 mg every 3e6 hours). Two studies used oral misoprostol at a dose of 50 mg every 4 hours and 100 mg every 4 hours, respectively. In the combination arm, the majority of studies (72.7%; 8/11) used vaginally
administered misoprostol (8 studies used 25 mg every 3e4 hours); 3 studies used oral misoprostol (2 studies at a dose of 100 mg every 3e6 hours, 1 of those studies at a dose of 50 mg every 4 hours). All but 1 study provided the number of nulliparous women in each arm. The percentage of nulliparous women in the combination and misoprostol-only group was 61% (464/ 761) and 59.9% (473/790), respectively. Ten studies excluded patients with ruptured membranes, although 1 study did not comment on the status of the membranes of the subjects included.14 Table 1 summarizes the general characteristics and cervical ripening protocols used in the included studies. Based on visual inspection of funnel plot, there was no publication bias detected. Synthesis of results For the 2 primary outcomes, all studies reported on cesarean delivery rates; 7 studies reported on time to delivery.6e8,11e14 There was no difference in the incidence of cesarean delivery between the combination and misoprostol-only groups (RR, 0.995; 95% CI, 0.80e1.13; I2, 19%; Figure 1). The combination of mechanical cervical dilation and misoprostol resulted in shorter time to delivery (primary outcome) compared with misoprostol use alone (mean difference, e3.65 hours; 95% CI, 5.23, e2.07; I2, 67%). Regarding secondary outcomes, the incidence of tachysystole with fetal heart rate changes was one-half as common with combination methods (5 studies: RR, 0.53; 95% CI, 0.30e0.94; I2, 60%5,7e9,12), and the use of terbutaline was 37% lower in the combination group (5 studies: RR, 0.63; 95% CI, 0.47e0.85; I2, 0%; Figure 2 7e10,13). The incidence of cesarean delivery for failed induction (RR, 0.75; 95% CI, 0.47e1.21; I2, 6%)5,6,11e13 and fetal distress/nonreassuring fetal heart tracing5e7,10e15 was comparable between the 2 groups (RR, 0.93; 95% CI, 0.76e1.13; I2, 0%). The combination of mechanical dilation and misoprostol resulted in shorter time
to vaginal delivery (mean difference, e4.53 hours; 95% CI, e5.79, e3.27; I2, 0%)6,9,10,12,13; the combination group had a 20% higher chance of delivery within 24 hours (RR, 1.22; 95% CI, 1.15e1.30; I2, 0%).7,8,10e13 The rate of oxytocin use (9 studies: RR, 0.99; 95% CI, 0.89e1.1; I2, 57%5,7e14), risk of assisted vaginal delivery (4 studies: RR, 0.97; 95% CI, 0.55e1.73; I2, 0% 6,9,12,15), chorioamnionitis (7 studies: RR, 1.58; 95% CI, 0.88e2.84; I2, 43%; Figure 3 6e10,12,13), endometritis (4 studies: RR, 0.94; 95% CI, 0.36e2.44; I2, 0% 8,9,11,13), and postpartum hemorrhage/blood transfusion (2 studies: RR, 0.45; 95% CI, 0.12e1.70; I2, 0%8,13) were comparable between the 2 groups. Regarding neonatal outcomes, based on 9 studies, the combination of cervical ripening with mechanical dilation and misoprostol had a 30% lower risk of NICU admission compared with misoprostol only (RR, 0.71; 95% CI, 0.53e0.96; I2, 0%; Figure 4).5,6,8e13,15 Results more strongly favored the combination methods when we excluded studies with preterm patients, which demonstrated a 40% reduction in NICU admission with combination methods compared with misoprostol alone (5 studies: RR, 0.61; 95% CI, 0.40e0.93; I2, 13%5,6,11,13,15). In addition, based on 8 studies, the incidence of meconium passage was almost 40% lower in the combination group (RR, 0.62; 95% CI, 0.43e0.90; I2, 0%).5e12 There was no difference in mean cord pH (4 studies: mean difference, 0; 95% CI, e0.01, 0.01; I2, 0%6,7,10,14), Apgar score 7 at 1 minute (3 studies: RR, 0.89; 95% CI, 0.54e1.46; I2, 0%5,9,15) and at 5 minutes between the 2 groups (4 studies: RR, 0.67; 95% CI, 0.36e1.25; I2, 15%5,9,11,15). Table 2 summarizes the results of the present metaanalysis. In a sensitivity analysis, we included studies that used only vaginally administered misoprostol in both arms. Based on data from 8 studies, the rate of cesarean delivery was comparable between the 2 groups (RR, 1.00; 95% CI, 0.83e1.20; I2, 0%)5,6,8,12e15; based on data from 5
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½F3
½T1
½F4
½F1
½T2 ½F2
391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446
Systematic Review FIGURE 1
Pooled incidence of cesarean delivery in the combination and misoprostol-only groups
web 4C=FPO
447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464Q7 465Q8 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500Q9 501Q10 502
. CI, confidence interval; M-H, Mantel-Haenszel. Nasioudis. Mechanical cervical dilation plus misoprostol compared to misoprostol alone for cervical ripening. AJOG MFM 2019.
studies, the time to delivery was shorter in the combination group (mean difference, e3.69 hours; 95% CI, e5.0, e2.38; I2, 16%)6,8,12e14
Comment Main findings In the present metaanalysis of 11 randomized trials, patients who underwent cervical ripening with mechanical dilation and misoprostol experienced a faster delivery and improved neonatal outcomes with no difference in risk of cesarean delivery when compared with misoprostol
alone. Specifically, we found that women who had combination methods delivered 3e4 hours faster and had >50% lower risk of tachysystole with fetal heart rate changes, 30% lower risk of NICU admission, and 40% lower risk of meconium, with no difference in risk of cesarean delivery. Strengths and limitations The main strength of the present study is the fact that we were able to pool data from 11 trials that included a total of 922 and 947 subjects in the
combination and misoprostol-only groups, respectively, that gave us the appropriate statistical power to investigate differences in rare outcomes, such as neonatal outcomes. However, certain limitations of the present study should be noted. First, the inclusion criteria in each randomized trial slightly varied, especially in terms of gestational age and Bishop score, although all of the studies did include patients with an unfavorable cervix. In addition, almost none of the studies reported data that were stratified by parity, which precluded us from performing a
FIGURE 2
web 4C=FPO
Pooled incidence of terbutaline use in the combination and misoprostol-only groups
. CI, confidence interval; M-H, Mantel-Haenszel. Nasioudis. Mechanical cervical dilation plus misoprostol compared to misoprostol alone for cervical ripening. AJOG MFM 2019.
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Systematic Review FIGURE 3
Pooled incidence of chorioamnionitis in the combination and misoprostol-only groups
web 4C=FPO
559 560 561Q11 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599Q12 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614
. Nasioudis. Mechanical cervical dilation plus misoprostol compared to misoprostol alone for cervical ripening. AJOG MFM 2019.
subanalysis by parity; 1 study did not provide the percentage of nulliparous women. Moreover, the size of the intracervical catheter, degree of inflation of the Foley balloon (30 vs 50e60 mL), and the regimen of misoprostol used (route and strength) were not the same in all trials. These confounders potentially could be controlled for in a future individual patient data metaanalysis. Although higher inflation volumes have been associated with a faster time to delivery,21 the inclusion of studies that used a lower inflation volume would only bias results towards the null. Differences in labor management in each institution (such as timing of amniotomy, duration, dosage of oxytocin, and number of cervical
examinations) may also contribute to observed differences. Last, very rare outcomes (such as maternal or fetal death and uterine rupture) were not reported by any study. Comparison with existing literature Data continue to support the fact that there is no superior cervical ripening method when it comes to lowering the risk of cesarean delivery.2 There are, however, other differences in outcomes among cervical ripening methods that are important to take into account, which include a shorter time to delivery and adverse maternal and neonatal outcomes. It is critically important that we are not compromising maternal or neonatal safety when trying to achieve a faster time
to delivery.16 The importance of assessment of neonatal risk when evaluating cervical ripening methods cannot be overstated. Before this metaanalysis, data on neonatal outcomes was mixed, mostly limited by the small sample sizes of the studies. In 6 of 9 of the studies that we included, there was a trend towards a lower NICU admission rate in the combination group that did not reach statistical significance, likely because of a lack of statistical power. Our results found a significantly lower risk of NICU admission, even when we excluded studies with preterm gestations. Only 2 studies that were included reported a trend towards a higher rate of NICU admission in the combination group, both of which originated from Africa.5,15
FIGURE 4
web 4C=FPO
Pooled rate of neonatal intensive care unit admission in the combination and misoprostol-only groups
. Nasioudis. Mechanical cervical dilation plus misoprostol compared to misoprostol alone for cervical ripening. AJOG MFM 2019.
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TABLE 2
Summary of maternal and neonatal outcomes in the combination and misoprostol-only groups Outcomes Cesarean delivery rate
Studies included, n
Patients, n
Cervical balloon and misoprostol, n
Misoprostol only, n
Relative riska or mean differenceb (95% confidence interval) a
Favors
I2, %
None
26
11
1869
922
947
0.95 (0.80e1.13)
Delivery within 24 hrs
6
1261
618
643
1.22 (1.15e1.30)a
Cervical balloon and misoprostol
0
Time to spontaneous vaginal delivery
5
597
292
305
e4.53 (e5.79, e3.27)b
Cervical balloon and misoprostol
0
Time to delivery
7
1310
653
657
e3.65 (e5.23, e2.07)b
Cervical balloon and misoprostol
67
Cesarean delivery for failed induction of labor
5
255
114
141
0.75 (0.47e1.21)a
None
6
Cesarean delivery for nonreassuring fetal heart tracing
9
447
210
237
0.93 (0.76e1.13)a
None
0
Assisted spontaneous vaginal delivery
4
350
176
174
0.97 (0.55e1.73)a
None
0
Terbutaline use
5
817
401
416
0.63 (0.47e0.85)a
Cervical balloon and misoprostol
0
Tachysystole with fetal heart tracing changes
5
700
341
359
0.53 (0.30e0.94)a
Cervical balloon and misoprostol
60
Oxytocin use
9
1574
772
802
0.99 (0.89e1.11)a
None
57
a
Chorioamnionitis
7
1235
600
635
1.58 (0.88e2.84)
None
43
Endometritis
4
770
383
387
0.94 (0.36e2.44)a
None
11
a
None
0
Postpartum hemorrhage or blood transfusion
2
360
179
181
0.45 (0.12e1.70)
Meconium
8
1450
708
742
0.62 (0.43e0.90)a
Cervical balloon and misoprostol
25
Neonatal intensive care unit admission
9
1563
772
791
0.71 (0.53e0.96)a
Cervical balloon and misoprostol
0
Apgar at 1 min (7)
3
327
163
164
0.89 (0.54e1.46)a
None
0
Apgar at 5 min (7)
4
645
324
321
0.67 (0.36e1.25)a
None
21
Umbilical cord pH
4
738
356
382
0.0 (e0.01, 0.01)b
None
0
Q16 Q17
Nasioudis. Mechanical cervical dilation plus misoprostol compared to misoprostol alone for cervical ripening. AJOG MFM 2019.
Although it may be counterintuitive initially, patients in the combination group had a lower incidence of uterine tachysystole with fetal heart tracing changes and requirement for terbutaline. This is hypothesized to be from the lower doses of misoprostol that are required when combination methods are used. Alternatively, it is possible that the mechanical dilation with the balloon catheter compresses cervical
capillaries and permits a more controlled absorption of misoprostol and exposure of the uterine muscle cells. Theoretically, the use of a cervical ripening catheter can result in an increased incidence of infectious morbidity, given the introduction of a foreign body to the uterus. However, a previous metaanalysis that included data from 26 randomized trials that
compared cervical ripening with a Foley catheter to prostaglandins alone concluded that the incidence of chorioamnionitis (RR, 0.96; 95% CI, 0.66e1.38), endometritis (RR, 1.03; 95% CI, 0.66e1.60), and neonatal infection (RR, 0.90; 95% CI, 0.58e1.39) were comparable between the 2 groups.22 Similarly, in the present study, we did not find an increased risk of chorioamnionitis or MONTH 2019 AJOG MFM
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Systematic Review 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822Q19 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838
endometritis in the mechanical cervical dilation group. It is plausible that a faster time to delivery may balance the theoretic risk of the inadvertent introduction of vaginal flora to the uterus by decreasing labor duration and number of cervical checks. Moreover, it should be mentioned that a cervical catheter typically is inserted when fetal membranes are still intact, which provides an adequate antimicrobial barrier. Recently another group published a similar systematic review and metaanalysis that was not registered previously at the PROSPERO registry.23 However, our study differs in several points. First, we discriminate between time to delivery and time to vaginal delivery. In addition, we excluded studies with patients who underwent induction of labor for fetal death24 and studies published as letters to the editor.25 Additionally, we reported on 9 additional important secondary outcomes (delivery within 24 hours, cesarean delivery for failed induction, cesarean delivery for nonreassuring heart tracing, assisted vaginal delivery, terbutaline use, oxytocin requirement, endometritis, postpartum hemorrhage, and meconium passage). Last, we performed a sensitivity analysis that excluded studies with preterm patients that confirmed the increased rate of NICU admission in the misoprostol-only group. Conclusions The combination of mechanical cervical dilation with misoprostol for cervical ripening is associated with a shorter time to delivery, a similar rate of cesarean delivery, and a lower incidence of NICU admission, compared with the use of misoprostol alone. The results of the present metaanalysis further support the safety and efficacy of cervical ripening with the combination of mechanical cervical dilation with misoprostol compared with misoprostol alone. Shortening the time to delivery is associated with decreased hospital costs and increased patient satisfaction; therefore, combination methods, given their safety
profile, should be considered when a faster delivery is of importance to the patient and providers.26
REFERENCES 1. Chauhan SP, Ananth CV. Induction of labor in the United States: a critical appraisal of appropriateness and reducibility. Semin Perinatol 2012;36:336–43. 2. Penfield CA, Wing DA. Labor induction techniques: which is the best? Obstet Gynecol Clin North Am 2017;44:567–82. 3. Stephenson ML, Wing DA. Misoprostol for induction of labor. Semin Perinatol 2015;39: 459–62. 4. Yang F, Huang S, Long Y, Huang L. Doubleballoon versus single-balloon catheter for cervical ripening and labor induction: a systematic review and meta-analysis. J Obstet Gynaecol Res 2018;44:27–34. 5. Aduloju OP, Akintayo AA, Adanikin AI, Ade-Ojo IP. Combined Foley’s catheter with vaginal misoprostol for pre-induction cervical ripening: a randomised controlled trial. Aust N Z J Obstet Gynaecol 2016;56: 578–84. 6. Al-Ibraheemi Z, Brustman L, Bimson BE, Porat N, Rosenn B. Misoprostol with Foley bulb compared with misoprostol alone for cervical ripening: a randomized controlled trial. Obstet Gynecol 2018;131:23–9. 7. Barrilleaux PS, Bofill JA, Terrone DA, Magann EF, May WL, Morrison JC. Cervical ripening and induction of labor with misoprostol, dinoprostone gel, and a Foley catheter: a randomized trial of 3 techniques. Am J Obstet Gynecol 2002;186:1124–9. 8. Carbone JF, Tuuli MG, Fogertey PJ, Roehl KA, Macones GA. Combination of Foley bulb and vaginal misoprostol compared with vaginal misoprostol alone for cervical ripening and labor induction: a randomized controlled trial. Obstet Gynecol 2013;121:247–52. 9. Chung JH, Huang WH, Rumney PJ, Garite TJ, Nageotte MP. A prospective randomized controlled trial that compared misoprostol, Foley catheter, and combination misoprostol-Foley catheter for labor induction. Am J Obstet Gynecol 2003;189: 1031–5. 10. Hill JB, Thigpen BD, Bofill JA, Magann E, Moore LE, Martin JN. A randomized clinical trial comparing vaginal misoprostol versus cervical foley plus oral misoprostol for cervical ripening and labor induction. Am J Perinatol 2009;26:33–8. 11. Husain S, Husain S, Izhar R. Oral misoprostol alone versus oral misoprostol and Foley’s catheter for induction of labor: a randomized controlled trial. J Obstet Gynaecol Res 2017;43:1270–7.
12. Lanka S, Surapaneni T, Nirmalan PK. Concurrent use of Foley catheter and misoprostol for induction of labor: a randomized clinical trial of efficacy and safety. J Obstet Gynaecol Res 2014;40:1527–33. 13. Levine LD, Downes KL, Elovitz MA, Parry S, Sammel MD, Srinivas SK. Mechanical and pharmacologic methods of labor induction: a randomized controlled trial. Obstet Gynecol 2016;128:1357–64. 14. Rust OA, Greybush M, Atlas RO, Jones KJ, Balducci J. Preinduction cervical ripening: a randomized trial of intravaginal misoprostol alone vs a combination of transcervical Foley balloon and intravaginal misoprostol. J Reprod Med [Internet] 2001 [cited 2019 Feb 7];46:899-904. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/11725734. Q2 Accessed . 15. Ugwu EO, Onah HE, Obi SN, et al. Effect of the Foley catheter and synchronous low dose misoprostol administration on cervical ripening: a randomised controlled trial. J Obstet Gynaecol 2013;33:572–7. 16. Visser L, de Graaf IM, Mol BW. Combination of foley bulb and vaginal misoprostol compared with vaginal misoprostol alone for cervical ripening and labor induction: a randomized controlled trial. Obstet Gynecol 2013;122:156. 17. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6: e1000097. 18. Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res 2018;27: 1785–805. 19. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 2014;14:135. 20. RevMan 5 j Cochrane Community [Internet]. [cited 2019 Feb 7]. Available at: https:// community.cochrane.org/help/tools-and-software/ Q3 revman-5. Accessed . 21. Schoen CN, Saccone G, Backley S, et al. Increased single-balloon Foley catheter volume for induction of labor and time to delivery: a systematic review and meta-analysis. Acta Obstet Gynecol Scand 2018;97:1051–60. 22. McMaster K, Sanchez-Ramos L, Kaunitz AM. Evaluation of a transcervical Foley catheter as a source of infection: a systematic review and meta-analysis. Obstet Gynecol 2015;126:539–51. 23. Ornat L, Alonso-Ventura V, BuenoNotivol J, Chedraui P, Pérez-López FR. Health Outcomes and Systematic Analyses (HOUSSAY) Research Group. Misoprostol combined with cervical single or double
8 AJOG MFM MONTH 2019 REV 5.6.0 DTD AJOGMF24_proof 25 June 2019 2:56 am ce
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Systematic Review 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950
balloon catheters versus misoprostol alone for labor induction of singleton pregnancies: a meta-analysis of randomized trials. J Matern Fetal Neonatal Med 2019:1–16. 24. Osoti A, Kibii DK, Tong TMK, Maranga I. Effect of extra-amniotic Foley’s catheter and vaginal misoprostol versus vaginal
misoprostol alone on cervical ripening and induction of labor in Kenya, a randomized controlled trial. BMC Pregnancy Childbirth 2018;18:300. 25. Kashanian M, Akbarian AR, Fekrat M. Cervical ripening and induction of labor with intravaginal misoprostol and Foley catheter
cervical traction. Int J Gynaecol Obstet 2006;92:79–80. 26. Shetty A, Burt R, Rice P, Templeton A. Women’s perceptions, expectations and satisfaction with induced labour: a questionnairebased study. Eur J Obstet Gynecol Reprod Biol 2005;123:56–61.
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951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006
Systematic Review Appendix Search strategy for articles Q4 (1) “misoprostol”: 22,662
(2) “foley or intracervical catheter”: 32,935 (3) “labor or labour”: 1,520,615
Combination of (1), (2) and (3): 490
SUPPLEMENTAL FIGURE 1
Study selection flowchart
web 4C=FPO
1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062
. Q5 IUFD, intrauterine fetal death. Nasioudis. Mechanical cervical dilation plus misoprostol compared to misoprostol alone for cervical ripening. AJOG MFM 2019.
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1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113 1114 1115 1116 1117 1118
Systematic Review 1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218 1219 1220 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230
SUPPLEMENTAL FIGURE 2
Summary of risk of bias for each study
web 4C=FPO
1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 Q6 1174
. Nasioudis. Mechanical cervical dilation plus misoprostol compared to misoprostol alone for cervical ripening. AJOG MFM 2019.
MONTH 2019 AJOG MFM REV 5.6.0 DTD AJOGMF24_proof 25 June 2019 2:56 am ce
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Maternal and neonatal outcomes with mechanical cervical dilation plus misoprostol compared to misoprostol alone for cervical ripening; a systematic review of literature and metaanalysis Q20 Q1
Dimitrios Nasioudis, MD; Sun Woo Kim, MD; Corina Schoen, MD; Lisa D. Levine, MD, MSCE
I
nduction of labor is the most common obstetric intervention, with approximately 932,000 women undergoing an induction annually in the United States.1 Patients who have an unfavorable cervix typically undergo cervical ripening with either prostaglandins or mechanical dilation before the administration of intravenous oxytocin.2 Misoprostol is a prostaglandin E1 analogue, which was used initially for the treatment of gastric ulcers, that can be administered orally or vaginally for cervical ripening.3 Given its low cost and stability at room temperature, its use worldwide is widespread.3 Additionally, mechanical dilation of the cervix can be achieved with the introduction of an intracervical balloon catheter, such as the single balloon Foley catheter, that simultaneously can dilate the cervix mechanically and stimulate the endogenous production of prostaglandins.4 Given the proposed mechanisms of action for both pharmacologic and meFrom the Maternal and Child Health Research Center, Department of Obstetrics & Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (Drs Nasioudis, Kim, and Levine); the Department of Obstetrics and Gynecology, University of Massachusetts Medical SchoolBaystate, Springfield, MA (Dr Schoen).
OBJECTIVE DATA: The aim of the present systematic review was to investigate the
efficacy and safety of cervical ripening for the combination of mechanical dilation and misoprostol administration compared with misoprostol alone by evaluating 2 primary outcomes: time to delivery and rate of cesarean delivery. STUDY: The Medline, EMBASE, and Web-of-Science electronic databases (from conception to end-of-search date December 31, 2018) were searched systematically. Randomized controlled trials that included patients with a singleton viable fetus who underwent induction of labor that required cervical ripening with an unfavorable cervix (Bishop 7) were eligible for inclusion. STUDY APPRAISAL AND SYNTHESIS METHODS: Data were pooled with the use of the random effects and fixed effects model after the assessment for the presence of heterogeneity. Risk of bias for each included study was assessed based on the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Eleven trials met the inclusion criteria and included a total of 922 and 947 subjects in the combination and misoprostol-only groups, respectively. There was no difference in the incidence of cesarean delivery between the 2 groups (relative risk, 0.95; 95% confidence interval, 0.80e1.13). The combination of mechanical dilation and misoprostol resulted in overall shorter time to delivery (mean difference, e3.65 hours; 95% confidence interval, 5.23 to e2.07), shorter time to vaginal delivery (mean difference, e4.53 hours; 95% confidence interval, e5.79 to e3.27), lower risk of neonatal intensive care unit admission (relative risk, 0.71; 95% confidence interval, 0.53e0.96), meconium-stained fluid (relative risk, 0.62; 95% confidence interval, 0.43e0.90), tachysystole with fetal heart trace changes (relative risk, 0.53; 95% confidence interval, 0.30e0.94), and terbutaline use (relative risk, 0.63; 95% confidence interval, 0.47e0.85) compared with the use of misoprostol alone. Risk of endometritis (relative risk, 1.07; 95% confidence interval, 0.43e2.61) and chorioamnionitis (relative risk, 1.58; 95% confidence interval, 0.88e2.84) was comparable between the 2 groups. CONCLUSION: The combination of mechanical cervical dilation with misoprostol for cervical ripening is associated with a shorter time to delivery, a similar rate of cesarean delivery, and a lower incidence of neonatal intensive care unit admission compared with the use of misoprostol alone. Key words: cervical ripening, combination methods, Foley catheter, intracervical catheter, mechanical dilation, misoprostol
Received March 31, 2019; revised June 3, 2019; accepted June 4, 2019. The authors report no conflict of interest. Corresponding author: Dimitrios Nasioudis, MD. [email protected] 2589-9333/$36.00 ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.ajogmf.2019.06.003
chanical cervical ripening, a synergistic or additive effect of these methods is plausible. Several randomized trials have investigated the combination of an intracervical catheter with misoprostol and demonstrated a trend towards a
faster time to delivery in the combination arm.5e15 However, there is skepticism regarding the safety of the combination methods because most randomized studies were not powered to detect rare outcomes, such as rate of MONTH 2019 AJOG MFM
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56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110
Systematic Review 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166
AJOG at a Glance Why was this study conducted? The purpose of this study was to investigate the efficacy and safety of cervical ripening for the combination of mechanical dilation and misoprostol administration compared with misoprostol alone. Key findings Women who had cervical ripening with combination methods delivered 3e4 hours faster, had a >50% lower risk of tachysystole with fetal heart rate changes, a 30% lower risk of neonatal intensive care unit admission, and a 40% lower risk of meconium with no difference in risk of cesarean delivery or chorioamnionitis. What does this add to what is known? The present study is the first to demonstrate superior neonatal outcomes for women who had cervical ripening with a combination of mechanical cervical dilation and misoprostol.
cesarean delivery, chorioamnionitis, and adverse neonatal outcomes.16 Therefore, the aim of the present systematic review and metaanalysis was to investigate the efficacy and safety of cervical ripening for the combination of mechanical dilation and misoprostol administration, compared with misoprostol alone, by evaluating 2 primary outcomes: time to delivery and rate of cesarean delivery.
Material and methods Search strategy This systematic review was conducted in accordance to the Preferred Reporting Items for Systematic Review and MetaAnalyses (PRISMA) guidelines17; a protocol was determined beforehand by the participating authors. The present study was registered at the PROSPERO database with the unique identifier (CRD42019122901). A comprehensive electronic search (from conception to end-of-search date December 31, 2018) of PubMed/Medline, EMBASE, and Web of Science databases was performed with the use of the following keywords: (“misoprostol” and [“foley” or “intracervical catheter”] and [“labor” or “labour”]). The reference list of all included articles were also hand searched to identify any potentially eligible studies. Eligibility of studies. Our investigation was limited to full articles that are available in the English language. Abstracts,
commentaries, reviews, short communications, and letters to the editor were excluded. Only prospective randomized trials were eligible for inclusion; quasirandomized trials were excluded. Eligible trials compared cervical ripening with concurrent mechanical cervical dilation with an intracervical single balloon Foley catheter and misoprostol (any dose or administration route) with misoprostol alone. The eligible population included patients with a viable singleton fetus and unfavorable cervix who underwent an induction of labor for any indication. An unfavorable cervix was defined differently in some studies, but all of them had a Bishop 7. Studies that included both preterm and term gestations were included in this review. Studies on second-trimester termination of pregnancy, those which included patients with a fetal death, or twins pregnancies were excluded. Data extraction. Two reviewers (D.N., S.W.K.) who worked independently extracted data from all eligible studies into custom-made data collection forms. Data were cross-checked, and any discrepancies were resolved with discussion. In the case of a disagreement a third reviewer (L.D.L.) was consulted. From each included study the following parameters were extracted when applicable: general study characteristics (author, country of origin, date of publication), cervical ripening protocol (dosing, frequency for misoprostol,
balloon inflation amount for intracervical catheter) in each study group, number of participants in each arm, percentage of nulliparous women, gestational age, and Bishop score on admission. Primary outcomes were cesarean delivery rate and time to delivery (defined as interval from the start of cervical ripening to delivery). Secondary outcomes included delivery within 24 hours, time to vaginal delivery (defined as time from start of cervical ripening to vaginal delivery), rate of oxytocin augmentation, indication for cesarean delivery, chorioamnionitis, endometritis, postpartum hemorrhage/ blood transfusion, meconium passage, uterine tachysystole with fetal heart rate changes, use of terbutaline for fetal distress mean cord pH, rate of neonatal intensive care unit (NICU) admission and 5-minute Apgar score of 7 in 5 minutes. Because 1 of the primary outcomes (cesarean delivery) was provided by all studies, no attempts were made to obtain additional data from the individual authors. Risk of bias of included studies. Risk of bias for each included study was assessed based on the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. Seven domains related to risk of bias were assessed, namely (1) random sequence generation, (2) allocation concealment, (3) blinding of participants and personnel, (4) blinding of outcome assessment, (5) incomplete outcome data, (6) selective reporting, and (7) other bias. Risk of bias was categorized as “low risk,” “high risk,” or “unclear risk.” Because blinding of participants and personnel was not feasible because of the nature of the intervention, all studies were considered to be low bias for that category. Synthesis of data. Level of statistical heterogeneity was evaluated with the Higgins I2 statistic. In the presence of heterogeneity (defined as I2 >20%) a randomeffect model (DerSimonian and Laird approach) was used to compare outcomes between the 2 groups; in the absence of heterogeneity, a fixed-effects model (Mantel-Haenszel approach) was selected. A summary relative risk (RR)
2 AJOG MFM MONTH 2019 REV 5.6.0 DTD AJOGMF24_proof 25 June 2019 2:56 am ce
167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222
223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 TABLE 1
Demographic and general characteristics of the included studies Bishop on score admission Foley and Misoprostol inclusion misoprostol only criteria
Bishop score on admission Nulliparous, n (%)
Gestational age, wk Foley and Mechanical misoprostol Foley and description, Misoprostol only misoprostol, Misoprostol dilation method only, n Country n mg description, mg
Author
Year Journal
Aduloju et al16
2016 Australian & New Nigeria Zealand Journal of Obstetrics & Gynaecology
Gestational age inclusion criteria, wk
Foley and Misoprostol Foley and Misoprostol misoprostol only misoprostol only
16F Foley, 30 mL
25 (vaginally 25 (vaginally every 37 every 6 hrs; 6 hrs; maximum, 4 maximum, 4 doses) doses)
40.031.56a 40.311.31a <6
2.71.08a
2.311.2a
100
Foley, 60 mL
25 (vaginally 25 (vaginally every 37 every 4 hrs; 4 hrs; maximum, 6 maximum, 6 doses) doses)
39.61.3a
<6
3.0 (2e4)b
2.0 (1.25e4)b 70 (70)
74 (74)
109
116
24F Foley, 50 mL
100 (oral every 4 100 (oral every 4 hrs; hrs; maximum, 4 maximum, 4 doses) doses)
38 37.9 <7 (35.7e40.2)b (36.1e40.6)b
3 (1e4)b
3 (2e4)b
72 (66.1)
60 (51.2)
United States
56
61
Foley, 60 mL 25 (vaginally 25 (vaginally every >24 every 4 hrs) 4 hrs)
39.51.4a
39.81.4a
<6
3 (0e6)b
3 (0e6)b
37 (67.3)
40 (65.6)
Chung et al9 2003 American Journal United of Obstetrics and States Gynecology
43
49
16F Foley, 30 mL
25 (vaginally 25 (vaginally every 28 every 3 hrs; 3 hrs; maximum, 6 maximum, 6 doses) doses)
39.92.5a
39.82.33a
6
N/A
N/A
31 (72.1)
33 (67.3)
106
126
24F Foley, 50 mL
100 (oral every 4e6 hrs; maximum, 4 doses)
N/A
N/A
4
3 (1e4)b
2 (0e3)b
64 (60)
80 (63)
Pakistan 161
157
16/18F Foley, 30 mL
50 (oral every 50 (oral every 4 37 hrs; maximum, 4 4 hrs; maximum, 4 doses) doses)
39 (37e41)b 39 (37e41)b 4
3 (0e3)b
3 (0e3)b
n/a
n/a
70
70
United States
100
Barrilleaux et al7
2002 American Journal United of Obstetrics and States Gynecology
Carbone et al8
2013 Obstetrics and Gynecology
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Al-Ibraheemi 2018 Obstetrics and et al6 Gynecology
Hill et al10
2009 American Journal United of Perinatology States
Husain et al11
2017 Journal of Obstetrics and Gynaecology Research
N/A
25 (vaginally >24 followed by 50 mg every 3e6 hrs; maximum, 8 doses)
39.41.4a
24 (34.3)
25 (35.7)
63
63
16F Foley, 30 mL
25 (vaginally 25 (vaginally every 28 every 4 hrs; 4 hrs; maximum, 8 maximum, 8 doses) doses)
39.131.48a 39.291.68a 4
1.841a
2.210.99a
50 (79.4)
49 (77.8)
United States
123
120
18F Foley, 60 mL
25 (vaginally 25 (vaginally every 37 every 3 hrs; 3 hrs; maximum, 6 maximum, 6 doses) doses)
39.6 39.1 6 (38.3e40.7)b (37.9e40.1)b
3 (2e4)b
3 (2e4)b
73 (59.4)
70 (58.3)
Rust et al14 2001 Journal of Reproductive Medicine
United States
41
40
25F Foley, 50 mL
25 (vaginally 25 (vaginally every N/A every 3 hrs; 3 hrs; maximum, 4 maximum, 4 doses) doses)
36.53.8a
373.8a
5
2 (0e5)b
2 (0e5)b
21 (51)
23 (57.5)
Ugwu et al15 2013 Journal of Obstetrics and Gynaecology
Nigeria
50
45
16F Foley, 30 mL
25 (vaginally 25 (vaginally every 37 every 4 hrs; 4 hrs; maximum, 6 maximum, 6 doses) doses)
40.71.5a
40.21.7a
5
3.81.5a
3.71.7a
22 (44)
19 (42)
Levine et al13
2016 Obstetrics and Gynecology
Q14
MONTH 2019 AJOG MFM
N/A, not available. a
Data are given as meanstandard deviation; b Data are given as median (interquartile range).
Q15
3
Nasioudis. Mechanical cervical dilation plus misoprostol compared to misoprostol alone for cervical ripening. AJOG MFM 2019.
Systematic Review
India
Lanka et al12 2014 Journal of Obstetrics and Gynaecology Research
Q13
279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334
Systematic Review 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390
with 95% confidence intervals (95% CI) was calculated for categoric variables; for a summary mean difference (95% CI) was calculated for continuous variables. If original data were presented as median (interquartile range or range), they were converted to mean and standard deviation with the use of previously validated mathematical formulas.18,19 A planned sensitivity analysis of primary outcomes that included only women who received misoprostol vaginally was performed. Graphic funnel plots were generated to determine the presence of publication bias by visual inspection. Probability values <.05 were considered statistically significant. Statistical analysis was performed with the Cochrane Review software (Review Manager version 5.3) by 1 of the reviewers (D.N.).20
Results Study selection and characteristics A total of 11 studies met the inclusion criteria and were included in the present metaanalysis. Supplemental Figure 1 shows the study selection flowchart. Most of the included studies (7 studies) originated from North America; 2 studies were from Asia, and 2 studies were from Africa. Supplemental Figure 2 summarizes the summary of risk of bias for each study. The majority of studies included patients with a Bishop score of 6, although starting cervical dilation was not reported consistently. Regarding inflation volume of the single balloon intracervical catheter, 45.5% of the studies (5/11) used a low volume (30 mL); 55.5% of the studies (6/11) used a high volume (50e60 mL). Regarding the route of administration for patients in the misoprostol-only arm, the majority of studies (81.8%; 9/11) used vaginally administered misoprostol (8 studies at a dose of 25 mg every 3e4 hours; in 1 study, 25 mg as a single dose was followed by 50 mg every 3e6 hours). Two studies used oral misoprostol at a dose of 50 mg every 4 hours and 100 mg every 4 hours, respectively. In the combination arm, the majority of studies (72.7%; 8/11) used vaginally
administered misoprostol (8 studies used 25 mg every 3e4 hours); 3 studies used oral misoprostol (2 studies at a dose of 100 mg every 3e6 hours, 1 of those studies at a dose of 50 mg every 4 hours). All but 1 study provided the number of nulliparous women in each arm. The percentage of nulliparous women in the combination and misoprostol-only group was 61% (464/ 761) and 59.9% (473/790), respectively. Ten studies excluded patients with ruptured membranes, although 1 study did not comment on the status of the membranes of the subjects included.14 Table 1 summarizes the general characteristics and cervical ripening protocols used in the included studies. Based on visual inspection of funnel plot, there was no publication bias detected. Synthesis of results For the 2 primary outcomes, all studies reported on cesarean delivery rates; 7 studies reported on time to delivery.6e8,11e14 There was no difference in the incidence of cesarean delivery between the combination and misoprostol-only groups (RR, 0.995; 95% CI, 0.80e1.13; I2, 19%; Figure 1). The combination of mechanical cervical dilation and misoprostol resulted in shorter time to delivery (primary outcome) compared with misoprostol use alone (mean difference, e3.65 hours; 95% CI, 5.23, e2.07; I2, 67%). Regarding secondary outcomes, the incidence of tachysystole with fetal heart rate changes was one-half as common with combination methods (5 studies: RR, 0.53; 95% CI, 0.30e0.94; I2, 60%5,7e9,12), and the use of terbutaline was 37% lower in the combination group (5 studies: RR, 0.63; 95% CI, 0.47e0.85; I2, 0%; Figure 2 7e10,13). The incidence of cesarean delivery for failed induction (RR, 0.75; 95% CI, 0.47e1.21; I2, 6%)5,6,11e13 and fetal distress/nonreassuring fetal heart tracing5e7,10e15 was comparable between the 2 groups (RR, 0.93; 95% CI, 0.76e1.13; I2, 0%). The combination of mechanical dilation and misoprostol resulted in shorter time
to vaginal delivery (mean difference, e4.53 hours; 95% CI, e5.79, e3.27; I2, 0%)6,9,10,12,13; the combination group had a 20% higher chance of delivery within 24 hours (RR, 1.22; 95% CI, 1.15e1.30; I2, 0%).7,8,10e13 The rate of oxytocin use (9 studies: RR, 0.99; 95% CI, 0.89e1.1; I2, 57%5,7e14), risk of assisted vaginal delivery (4 studies: RR, 0.97; 95% CI, 0.55e1.73; I2, 0% 6,9,12,15), chorioamnionitis (7 studies: RR, 1.58; 95% CI, 0.88e2.84; I2, 43%; Figure 3 6e10,12,13), endometritis (4 studies: RR, 0.94; 95% CI, 0.36e2.44; I2, 0% 8,9,11,13), and postpartum hemorrhage/blood transfusion (2 studies: RR, 0.45; 95% CI, 0.12e1.70; I2, 0%8,13) were comparable between the 2 groups. Regarding neonatal outcomes, based on 9 studies, the combination of cervical ripening with mechanical dilation and misoprostol had a 30% lower risk of NICU admission compared with misoprostol only (RR, 0.71; 95% CI, 0.53e0.96; I2, 0%; Figure 4).5,6,8e13,15 Results more strongly favored the combination methods when we excluded studies with preterm patients, which demonstrated a 40% reduction in NICU admission with combination methods compared with misoprostol alone (5 studies: RR, 0.61; 95% CI, 0.40e0.93; I2, 13%5,6,11,13,15). In addition, based on 8 studies, the incidence of meconium passage was almost 40% lower in the combination group (RR, 0.62; 95% CI, 0.43e0.90; I2, 0%).5e12 There was no difference in mean cord pH (4 studies: mean difference, 0; 95% CI, e0.01, 0.01; I2, 0%6,7,10,14), Apgar score 7 at 1 minute (3 studies: RR, 0.89; 95% CI, 0.54e1.46; I2, 0%5,9,15) and at 5 minutes between the 2 groups (4 studies: RR, 0.67; 95% CI, 0.36e1.25; I2, 15%5,9,11,15). Table 2 summarizes the results of the present metaanalysis. In a sensitivity analysis, we included studies that used only vaginally administered misoprostol in both arms. Based on data from 8 studies, the rate of cesarean delivery was comparable between the 2 groups (RR, 1.00; 95% CI, 0.83e1.20; I2, 0%)5,6,8,12e15; based on data from 5
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½T1
½F4
½F1
½T2 ½F2
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Systematic Review FIGURE 1
Pooled incidence of cesarean delivery in the combination and misoprostol-only groups
web 4C=FPO
447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464Q7 465Q8 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500Q9 501Q10 502
. CI, confidence interval; M-H, Mantel-Haenszel. Nasioudis. Mechanical cervical dilation plus misoprostol compared to misoprostol alone for cervical ripening. AJOG MFM 2019.
studies, the time to delivery was shorter in the combination group (mean difference, e3.69 hours; 95% CI, e5.0, e2.38; I2, 16%)6,8,12e14
Comment Main findings In the present metaanalysis of 11 randomized trials, patients who underwent cervical ripening with mechanical dilation and misoprostol experienced a faster delivery and improved neonatal outcomes with no difference in risk of cesarean delivery when compared with misoprostol
alone. Specifically, we found that women who had combination methods delivered 3e4 hours faster and had >50% lower risk of tachysystole with fetal heart rate changes, 30% lower risk of NICU admission, and 40% lower risk of meconium, with no difference in risk of cesarean delivery. Strengths and limitations The main strength of the present study is the fact that we were able to pool data from 11 trials that included a total of 922 and 947 subjects in the
combination and misoprostol-only groups, respectively, that gave us the appropriate statistical power to investigate differences in rare outcomes, such as neonatal outcomes. However, certain limitations of the present study should be noted. First, the inclusion criteria in each randomized trial slightly varied, especially in terms of gestational age and Bishop score, although all of the studies did include patients with an unfavorable cervix. In addition, almost none of the studies reported data that were stratified by parity, which precluded us from performing a
FIGURE 2
web 4C=FPO
Pooled incidence of terbutaline use in the combination and misoprostol-only groups
. CI, confidence interval; M-H, Mantel-Haenszel. Nasioudis. Mechanical cervical dilation plus misoprostol compared to misoprostol alone for cervical ripening. AJOG MFM 2019.
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Systematic Review FIGURE 3
Pooled incidence of chorioamnionitis in the combination and misoprostol-only groups
web 4C=FPO
559 560 561Q11 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599Q12 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614
. Nasioudis. Mechanical cervical dilation plus misoprostol compared to misoprostol alone for cervical ripening. AJOG MFM 2019.
subanalysis by parity; 1 study did not provide the percentage of nulliparous women. Moreover, the size of the intracervical catheter, degree of inflation of the Foley balloon (30 vs 50e60 mL), and the regimen of misoprostol used (route and strength) were not the same in all trials. These confounders potentially could be controlled for in a future individual patient data metaanalysis. Although higher inflation volumes have been associated with a faster time to delivery,21 the inclusion of studies that used a lower inflation volume would only bias results towards the null. Differences in labor management in each institution (such as timing of amniotomy, duration, dosage of oxytocin, and number of cervical
examinations) may also contribute to observed differences. Last, very rare outcomes (such as maternal or fetal death and uterine rupture) were not reported by any study. Comparison with existing literature Data continue to support the fact that there is no superior cervical ripening method when it comes to lowering the risk of cesarean delivery.2 There are, however, other differences in outcomes among cervical ripening methods that are important to take into account, which include a shorter time to delivery and adverse maternal and neonatal outcomes. It is critically important that we are not compromising maternal or neonatal safety when trying to achieve a faster time
to delivery.16 The importance of assessment of neonatal risk when evaluating cervical ripening methods cannot be overstated. Before this metaanalysis, data on neonatal outcomes was mixed, mostly limited by the small sample sizes of the studies. In 6 of 9 of the studies that we included, there was a trend towards a lower NICU admission rate in the combination group that did not reach statistical significance, likely because of a lack of statistical power. Our results found a significantly lower risk of NICU admission, even when we excluded studies with preterm gestations. Only 2 studies that were included reported a trend towards a higher rate of NICU admission in the combination group, both of which originated from Africa.5,15
FIGURE 4
web 4C=FPO
Pooled rate of neonatal intensive care unit admission in the combination and misoprostol-only groups
. Nasioudis. Mechanical cervical dilation plus misoprostol compared to misoprostol alone for cervical ripening. AJOG MFM 2019.
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Systematic Review 671 672 673Q18 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726
TABLE 2
Summary of maternal and neonatal outcomes in the combination and misoprostol-only groups Outcomes Cesarean delivery rate
Studies included, n
Patients, n
Cervical balloon and misoprostol, n
Misoprostol only, n
Relative riska or mean differenceb (95% confidence interval) a
Favors
I2, %
None
26
11
1869
922
947
0.95 (0.80e1.13)
Delivery within 24 hrs
6
1261
618
643
1.22 (1.15e1.30)a
Cervical balloon and misoprostol
0
Time to spontaneous vaginal delivery
5
597
292
305
e4.53 (e5.79, e3.27)b
Cervical balloon and misoprostol
0
Time to delivery
7
1310
653
657
e3.65 (e5.23, e2.07)b
Cervical balloon and misoprostol
67
Cesarean delivery for failed induction of labor
5
255
114
141
0.75 (0.47e1.21)a
None
6
Cesarean delivery for nonreassuring fetal heart tracing
9
447
210
237
0.93 (0.76e1.13)a
None
0
Assisted spontaneous vaginal delivery
4
350
176
174
0.97 (0.55e1.73)a
None
0
Terbutaline use
5
817
401
416
0.63 (0.47e0.85)a
Cervical balloon and misoprostol
0
Tachysystole with fetal heart tracing changes
5
700
341
359
0.53 (0.30e0.94)a
Cervical balloon and misoprostol
60
Oxytocin use
9
1574
772
802
0.99 (0.89e1.11)a
None
57
a
Chorioamnionitis
7
1235
600
635
1.58 (0.88e2.84)
None
43
Endometritis
4
770
383
387
0.94 (0.36e2.44)a
None
11
a
None
0
Postpartum hemorrhage or blood transfusion
2
360
179
181
0.45 (0.12e1.70)
Meconium
8
1450
708
742
0.62 (0.43e0.90)a
Cervical balloon and misoprostol
25
Neonatal intensive care unit admission
9
1563
772
791
0.71 (0.53e0.96)a
Cervical balloon and misoprostol
0
Apgar at 1 min (7)
3
327
163
164
0.89 (0.54e1.46)a
None
0
Apgar at 5 min (7)
4
645
324
321
0.67 (0.36e1.25)a
None
21
Umbilical cord pH
4
738
356
382
0.0 (e0.01, 0.01)b
None
0
Q16 Q17
Nasioudis. Mechanical cervical dilation plus misoprostol compared to misoprostol alone for cervical ripening. AJOG MFM 2019.
Although it may be counterintuitive initially, patients in the combination group had a lower incidence of uterine tachysystole with fetal heart tracing changes and requirement for terbutaline. This is hypothesized to be from the lower doses of misoprostol that are required when combination methods are used. Alternatively, it is possible that the mechanical dilation with the balloon catheter compresses cervical
capillaries and permits a more controlled absorption of misoprostol and exposure of the uterine muscle cells. Theoretically, the use of a cervical ripening catheter can result in an increased incidence of infectious morbidity, given the introduction of a foreign body to the uterus. However, a previous metaanalysis that included data from 26 randomized trials that
compared cervical ripening with a Foley catheter to prostaglandins alone concluded that the incidence of chorioamnionitis (RR, 0.96; 95% CI, 0.66e1.38), endometritis (RR, 1.03; 95% CI, 0.66e1.60), and neonatal infection (RR, 0.90; 95% CI, 0.58e1.39) were comparable between the 2 groups.22 Similarly, in the present study, we did not find an increased risk of chorioamnionitis or MONTH 2019 AJOG MFM
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Systematic Review 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822Q19 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838
endometritis in the mechanical cervical dilation group. It is plausible that a faster time to delivery may balance the theoretic risk of the inadvertent introduction of vaginal flora to the uterus by decreasing labor duration and number of cervical checks. Moreover, it should be mentioned that a cervical catheter typically is inserted when fetal membranes are still intact, which provides an adequate antimicrobial barrier. Recently another group published a similar systematic review and metaanalysis that was not registered previously at the PROSPERO registry.23 However, our study differs in several points. First, we discriminate between time to delivery and time to vaginal delivery. In addition, we excluded studies with patients who underwent induction of labor for fetal death24 and studies published as letters to the editor.25 Additionally, we reported on 9 additional important secondary outcomes (delivery within 24 hours, cesarean delivery for failed induction, cesarean delivery for nonreassuring heart tracing, assisted vaginal delivery, terbutaline use, oxytocin requirement, endometritis, postpartum hemorrhage, and meconium passage). Last, we performed a sensitivity analysis that excluded studies with preterm patients that confirmed the increased rate of NICU admission in the misoprostol-only group. Conclusions The combination of mechanical cervical dilation with misoprostol for cervical ripening is associated with a shorter time to delivery, a similar rate of cesarean delivery, and a lower incidence of NICU admission, compared with the use of misoprostol alone. The results of the present metaanalysis further support the safety and efficacy of cervical ripening with the combination of mechanical cervical dilation with misoprostol compared with misoprostol alone. Shortening the time to delivery is associated with decreased hospital costs and increased patient satisfaction; therefore, combination methods, given their safety
profile, should be considered when a faster delivery is of importance to the patient and providers.26
REFERENCES 1. Chauhan SP, Ananth CV. Induction of labor in the United States: a critical appraisal of appropriateness and reducibility. Semin Perinatol 2012;36:336–43. 2. Penfield CA, Wing DA. Labor induction techniques: which is the best? Obstet Gynecol Clin North Am 2017;44:567–82. 3. Stephenson ML, Wing DA. Misoprostol for induction of labor. Semin Perinatol 2015;39: 459–62. 4. Yang F, Huang S, Long Y, Huang L. Doubleballoon versus single-balloon catheter for cervical ripening and labor induction: a systematic review and meta-analysis. J Obstet Gynaecol Res 2018;44:27–34. 5. Aduloju OP, Akintayo AA, Adanikin AI, Ade-Ojo IP. Combined Foley’s catheter with vaginal misoprostol for pre-induction cervical ripening: a randomised controlled trial. Aust N Z J Obstet Gynaecol 2016;56: 578–84. 6. Al-Ibraheemi Z, Brustman L, Bimson BE, Porat N, Rosenn B. Misoprostol with Foley bulb compared with misoprostol alone for cervical ripening: a randomized controlled trial. Obstet Gynecol 2018;131:23–9. 7. Barrilleaux PS, Bofill JA, Terrone DA, Magann EF, May WL, Morrison JC. Cervical ripening and induction of labor with misoprostol, dinoprostone gel, and a Foley catheter: a randomized trial of 3 techniques. Am J Obstet Gynecol 2002;186:1124–9. 8. Carbone JF, Tuuli MG, Fogertey PJ, Roehl KA, Macones GA. Combination of Foley bulb and vaginal misoprostol compared with vaginal misoprostol alone for cervical ripening and labor induction: a randomized controlled trial. Obstet Gynecol 2013;121:247–52. 9. Chung JH, Huang WH, Rumney PJ, Garite TJ, Nageotte MP. A prospective randomized controlled trial that compared misoprostol, Foley catheter, and combination misoprostol-Foley catheter for labor induction. Am J Obstet Gynecol 2003;189: 1031–5. 10. Hill JB, Thigpen BD, Bofill JA, Magann E, Moore LE, Martin JN. A randomized clinical trial comparing vaginal misoprostol versus cervical foley plus oral misoprostol for cervical ripening and labor induction. Am J Perinatol 2009;26:33–8. 11. Husain S, Husain S, Izhar R. Oral misoprostol alone versus oral misoprostol and Foley’s catheter for induction of labor: a randomized controlled trial. J Obstet Gynaecol Res 2017;43:1270–7.
12. Lanka S, Surapaneni T, Nirmalan PK. Concurrent use of Foley catheter and misoprostol for induction of labor: a randomized clinical trial of efficacy and safety. J Obstet Gynaecol Res 2014;40:1527–33. 13. Levine LD, Downes KL, Elovitz MA, Parry S, Sammel MD, Srinivas SK. Mechanical and pharmacologic methods of labor induction: a randomized controlled trial. Obstet Gynecol 2016;128:1357–64. 14. Rust OA, Greybush M, Atlas RO, Jones KJ, Balducci J. Preinduction cervical ripening: a randomized trial of intravaginal misoprostol alone vs a combination of transcervical Foley balloon and intravaginal misoprostol. J Reprod Med [Internet] 2001 [cited 2019 Feb 7];46:899-904. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/11725734. Q2 Accessed . 15. Ugwu EO, Onah HE, Obi SN, et al. Effect of the Foley catheter and synchronous low dose misoprostol administration on cervical ripening: a randomised controlled trial. J Obstet Gynaecol 2013;33:572–7. 16. Visser L, de Graaf IM, Mol BW. Combination of foley bulb and vaginal misoprostol compared with vaginal misoprostol alone for cervical ripening and labor induction: a randomized controlled trial. Obstet Gynecol 2013;122:156. 17. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6: e1000097. 18. Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res 2018;27: 1785–805. 19. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 2014;14:135. 20. RevMan 5 j Cochrane Community [Internet]. [cited 2019 Feb 7]. Available at: https:// community.cochrane.org/help/tools-and-software/ Q3 revman-5. Accessed . 21. Schoen CN, Saccone G, Backley S, et al. Increased single-balloon Foley catheter volume for induction of labor and time to delivery: a systematic review and meta-analysis. Acta Obstet Gynecol Scand 2018;97:1051–60. 22. McMaster K, Sanchez-Ramos L, Kaunitz AM. Evaluation of a transcervical Foley catheter as a source of infection: a systematic review and meta-analysis. Obstet Gynecol 2015;126:539–51. 23. Ornat L, Alonso-Ventura V, BuenoNotivol J, Chedraui P, Pérez-López FR. Health Outcomes and Systematic Analyses (HOUSSAY) Research Group. Misoprostol combined with cervical single or double
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Systematic Review 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950
balloon catheters versus misoprostol alone for labor induction of singleton pregnancies: a meta-analysis of randomized trials. J Matern Fetal Neonatal Med 2019:1–16. 24. Osoti A, Kibii DK, Tong TMK, Maranga I. Effect of extra-amniotic Foley’s catheter and vaginal misoprostol versus vaginal
misoprostol alone on cervical ripening and induction of labor in Kenya, a randomized controlled trial. BMC Pregnancy Childbirth 2018;18:300. 25. Kashanian M, Akbarian AR, Fekrat M. Cervical ripening and induction of labor with intravaginal misoprostol and Foley catheter
cervical traction. Int J Gynaecol Obstet 2006;92:79–80. 26. Shetty A, Burt R, Rice P, Templeton A. Women’s perceptions, expectations and satisfaction with induced labour: a questionnairebased study. Eur J Obstet Gynecol Reprod Biol 2005;123:56–61.
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Systematic Review Appendix Search strategy for articles Q4 (1) “misoprostol”: 22,662
(2) “foley or intracervical catheter”: 32,935 (3) “labor or labour”: 1,520,615
Combination of (1), (2) and (3): 490
SUPPLEMENTAL FIGURE 1
Study selection flowchart
web 4C=FPO
1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062
. Q5 IUFD, intrauterine fetal death. Nasioudis. Mechanical cervical dilation plus misoprostol compared to misoprostol alone for cervical ripening. AJOG MFM 2019.
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Systematic Review 1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218 1219 1220 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230
SUPPLEMENTAL FIGURE 2
Summary of risk of bias for each study
web 4C=FPO
1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 Q6 1174
. Nasioudis. Mechanical cervical dilation plus misoprostol compared to misoprostol alone for cervical ripening. AJOG MFM 2019.
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