According to an American College of Obstetricians and Gynecologists (ACOG) practice bulletin, two prostaglandin E2 (PGE2) preparations are commercially available: a gel in a 2.5 mL syringe containing 0.5 mg of dinoprostone (Prepidil®) and a vaginal insert containing 10 mg of dinoprostone (Cervidil®), of which both are FDA approved for cervical ripening in women at or near term. Compared with placebo or oxytocin alone, vaginal prostaglandins used for cervical ripening have been observed to increase the likelihood of delivery within 24 hours, but with an increase of uterine tachysystole with associated fetal heart rate (FHR) changes and without a reduction in the rate of cesarean delivery. Misoprostol administered intravaginally has been reported to be either superior to or as efficacious as dinoprostone gel. Additionally, misoprostol has been found to cause less use of epidural analgesia, more vaginal deliveries within 24 hours, and more uterine tachysystole with or without FHR changes compared with dinoprostone and oxytocin. [1]
If there is inadequate cervical change with minimal uterine activity after one dose of intracervical dinoprostone, a second dose may be given 6 to 12 hours later. A cumulative dose of 1.5 mg of dinoprostone (three doses or 7.5 mL of gel) within a 24-hour period is recommended by the manufacturers. After use of 1.5 mg of dinoprostone in the cervix or 2.5 mg in the vagina, oxytocin induction should be delayed for 6 to 12 hours due to the heightened effect of prostaglandins with oxytocin. After use of dinoprostone in sustained-release form, delaying oxytocin induction for 30 to 60 minutes after removal is sufficient. Overall, ACOG suggests that intravaginal PGE2 for induction of labor in women with premature rupture of membranes appears to be safe and effective. [1]
The World Health Organization (WHO) recommends oral misoprostol (25 mcg every 2 hours) for labor induction, and this recommendation is classified as a “strong” recommendation, and the quality of evidence is stated to be moderate. It also provides a strong recommendation for low doses of vaginal prostaglandins for labor induction based on moderate-quality evidence. It is stated that low-dose vaginal misoprostol (25 mcg every 6 hours) is also a viable option; however, the strength of recommendation is weak. Of note, it recommends against using misoprostol in those with a history of cesarean section, and it is classified as a strong recommendation. Finally, it states intravenous oxytocin is recommended when prostaglandins are not available, and it recommends against amniotomy alone for labor induction. These are classified as weak recommendations based on moderate-quality evidence. [2]
In their summary of the evidence, it notes that vaginal misoprostol has demonstrated efficacy in achieving vaginal delivery, lower rates of cesarean section delivery, Apgar score being less than 7 at five minutes of life when compared to placebo, expectant management, oxytocin monotherapy, or other prostaglandins. However, it has been associated with a higher rate of uterine hyperstimulation with FHR changes when compared to other prostaglandins, although the risk appears to be lower with lower doses (25 mcg every 6 hours). Oral misoprostol also has demonstrated comparable or favorable outcomes compared to placebo, expected managements, oxytocin, or other prostaglandins in labor induction and relative outcomes. When the two formulations are compared, oral formulation has been associated with a lower risk of Apgar score being less than 7 at five minutes of life compared to vaginal formulations. It notes that misoprostol can also be administered buccally or sublingually; however, there is insufficient evidence to recommend these routes of administration. [2]
Other prostaglandins are stated to be safe and effective compared to placebo, regardless of regimens. When intracervical route is compared to intravaginal route, it states that results are generally favorable for the intravaginal route as a systematic review has suggested a higher risk of not achieving vaginal delivery at 24 hours with intracervical route (risk ratio [RR] 1.26; 95% confidence interval [CI] 1.12 to 1.4; N= 2,200 participants; N= 11 studies). Additionally, compared to oxytocin monotherapy, evidence shows vaginal prostaglandins results in favorable outcomes. When the gel formulation is compared to tablet or suppository formulations, all formulations result in similar outcomes; however, gel is associated with a lower risk of hyperstimulation compared to suppository. Regarding doses, when a low dose is compared to a higher dose, the lower dose is associated with favorable outcomes in uterine hyperstimulation with FHR changes, Apgar score being less than 7 at five minutes of life, and Cesarean section rates. It suggests the rate of neonatal intensive care unit (NICU) admission may also be lower with a lower dose of prostaglandins compared to a higher dose, although results from one study did not observe significant results (RR 0.51; 95% CI 0.24 to 1.09; N= 955 patients). Athough evidence shows favorable outcomes for oxytocin compared to placebo, oxytocin did not demonstrate superior efficacy compared to prostaglandins. [2]
A 2022 guideline from the World Health Organization on induction of labor at or beyond term only recommends induction when there are clear indications that continuing with a pregnancy poses a greater risk to the mother or baby than the risk of inducing labor. These are not significantly different than the 2011 guidelines on general labor induction. No specific medication is preferred, and women receiving oxytocin, misoprostol, or other prostaglandins should never be left unattended. [3]
The benefits of using oral misoprostol (Cytotec®) for labor induction are that it is low in cost, noninvasive, stable at room temperature, and is associated with lower cesarean rates than other induction methods. Additionally, it may lead to less uterine hyperstimulation with fetal heart rate (FHR) changes as compared to vaginal misoprostol. However, despite its’ benefits, it notes that the optimal dose for safety is yet to to be determined. Compared to the oral route, benefits of vaginal misoprostol (Cytotec®) are similar with additional benefit of achieving a higher plasma level. It also is stated to be more efficacious at cervical ripening and induction of labor compared to oxytocin and dinoprostone. However, it is noted that vaginal misoprostol is associated with more uterine hyperstimulation and meconium-stained fluid when compared to other vaginal induction methods. Furthermore, slow or erratic absorption can occur with vaginal misoprostol, which may result in inaccurate dosing. A stated advantage of using dinoprostone (Cervidil®) vaginal insert is that it is able to be removed quickly in the case of FHR changes, which may resolve within 15 minutes after removing the insert. It is noted, however, that vaginal dinoprostone is associated with a 5% chance of uterine hyperstimulation one hour after administration. [4]
Another review article suggests that when comparing intravaginal misoprostol to intracervical dinoprostone in women with an unfavorable cervix at term, misoprostol was more efficacious at resulting in delivery within 24 hours (RR 1.27; 95% CI 1.10 to 1.48; p= 0.002; I2= 0%;) and required less use of oxytocin as an augmentation strategy (RR 0.62; 95% CI 0.54 to 0.72; p<0.00001; I2= 40%). On the other hand, misoprostol use was associated with increased uterine hyperstimulation (RR 3.15; 95% CI,1.58 to 6.28; p= 0.001; I2= 0% ) and tachysystole (RR 2.02; 95% CI 1.28 to 3.19; p= 0.003; I2= 44%). There was no significant difference in the rate of cesarean delivery (p= 0.66), the incidence of neonatal intensive care unit (NICU) admission (p= 0.80), and Apgar scores at 1 and 5 minutes (1 min: p= 0.90; 5 min: p= 0.89). [5]
A Cochrane Review states oral misoprostol is an effective labor induction agent for vaginal birth. Compared to placebo, oral misoprostol 50 mcg is associated with a higher rate of vaginal birth within 24 hours (RR of not achieving vaginal birth 0.16; 95% CI 0.05 to 0.49, n= 1 study) and a lower rate of Cesarean sections (CS) (RR 0.72, 95% CI 0.54 to 0.95, I2= 0%). Compared to sublingual route (50 mcg), oral route (50 mcg) shows a higher rate of meconium-stained liquor (RR 10.50; 95% CI 4.07 to 27.09; n= 1 study); a lower rate of instrumental vaginal birth (RR 0.44; 95% CI 0.22 to 0.99; n= 1 study); and no difference in CS rate (RR 1.56; 95% CI 0.74 to 3.26; n= 1 study). Finally, compared to vaiginal route, there is no difference in vaginal delivery (RR of not achieving vaginal delivery 1.08, 95% CI 0.86-1.36, I2=84%), uterine hyperstimulation with fetal heart rate (FHR) changes (RR 0.71; 95% CI 0.47 to 1.19; I2= 53%), and CS rate (RR 0.93; 95% CI 0.81 to 1.07; I2= 44%). Moreover, no differences are seen in serious neonatal morbidity or perinatal death, serious maternal morbidity or death, serious maternal complications, uterine rupture, oxytocin augmentation, uterine hyperstimulation without FHR changes, need for epidural analgesia, instrumental vaginal delivery, neonatal intensive care unit admission rate, neonatal encephalopathy, perinatal death, overall maternal side effects, and patient satisfaction rates. [6]
However, oral route is associated with a lower rate of Apgar score less than seven at five minutes (RR 0.60; 95% CI 0.44 to 0.82; I2=0%). In subgroup analyses of doses, only 50 mcg shows a significant outcome in lower Apgar score. Data also show that oral route is associated with a lower rate of postpartum hemorrhage (RR 0.57; 95% CI 0.34 to 0.95; I2= 0%). However, oral route is associated with higher meconium-stained liquor (RR 1.22; 95% CI 1.03 to 1.44; I2= 17%). The authors further discuss that data show large heterogeneity, which limits the comparison between vaginal and oral route; however, given the improved outcomes seen with Apgar scores and postpartum hemorrhage as well as possibility of greater patient acceptance, the authors suggest oral route may be preferred over vaginal route. Regarding dosage, the review included various doses (25-200 mcg). It is suggested optimal dose of oral misoprostol is 20-25 mcg every two hours because lower doses are associated with lower rates of hyperstimulation, and this dose has shown lower rates of CS when compared to vaginal dinoprostone. [6]
A 2024 systematic review and meta-analysis examined the efficacy and safety of intravaginal misoprostol compared to dinoprostone for labor induction at term. This analysis involved eight randomized controlled trials (RCTs) with a total of 1,801 participants, including 937 women in the misoprostol group and 864 in the dinoprostone group. The study population consisted of singleton pregnant women with live intrauterine gestations and unfavorable cervices, ranging from 37 to 42 weeks of gestation. The primary objective was to analyze key maternal and neonatal outcomes, such as the rates of vaginal delivery within 24 hours, cesarean delivery, and the necessity for oxytocin augmentation. Misoprostol was associated with a significantly reduced need for oxytocin augmentation compared to dinoprostone (RR 0.83; 95% CI 0.71 to 0.97; p= 0.02). However, other outcomes, including cesarean delivery rates, uterine tachysystole, hyperstimulation, NICU admissions, and APGAR scores, showed no significant differences between the two groups, suggesting similar safety and efficacy profiles. Notably, the analysis revealed no significant heterogeneity among studies regarding vaginal delivery within 24 hours, cesarean delivery, and instrumental delivery. Despite varying dosages and administration regimens across trials, the authors suggest that intravaginal misoprostol is an effective and safe alternative to dinoprostone for labor induction in clinical settings, offering the advantage of requiring less oxytocin augmentation. [7]
Another 2024 systematic review and updated meta-analysis involving 53 RCTs (N= 10,455 patients) assessed the efficacy and safety of oral and vaginal misoprostol compared to dinoprostone for labor induction in women. Vaginal misoprostol showed a statistically significant higher success rate for labor induction compared to vaginal dinoprostone (RR 1.14; 95% CI 1.08 to 1.21; p<0.00001; I2= 69%), with less need for additional oxytocin (RR 0.67; 95% CI 0.59 to 0.76; p<0.00001; I2= 82%). However, vaginal misoprostol was associated with a higher incidence of uterine hyperstimulation, tachysystole, and abnormal cardiotocography compared to dinoprostone. There were no significant differences in cesarean section rates or neonatal intensive care unit admissions between the groups. Interestingly, oral misoprostol was found to have comparable safety profiles to vaginal dinoprostone, providing similar efficacy without increased risks of adverse outcomes, making it a potential alternative for labor induction. These findings suggest that while vaginal misoprostol is effective, its safety profile must be carefully considered, and oral misoprostol may offer a safer, equally effective option. [8]
A 2024 individual participant data meta-analysis of randomized trials examined the effectiveness and safety of induction of labor using low-dose vaginal misoprostol compared to vaginal dinoprostone. This analysis combined data from eight trials, encompassing 4,180 women (low-dose vaginal misoprostol, n= 2,077; vaginal dinoprostone, n= 2,103) to evaluate the primary outcomes, which included vaginal delivery rates, composite adverse perinatal outcomes, and composite adverse maternal outcomes. Low-dose vaginal misoprostol and vaginal dinoprostone were observed to have comparable rates of vaginal birth and similar perinatal safety profiles. Notably, use of low-dose vaginal misoprostol was associated with a significantly lower rate of composite adverse maternal outcomes compared to vaginal dinoprostone (adjusted odds ratio [OR] 0.80; 95% CI 0.65 to 0.98; p= 0.03; I2= 0%). Despite the comparable effectiveness in achieving vaginal delivery, the distinct advantage of low-dose vaginal misoprostol lies in its better maternal safety profile, characterized by a trend toward lower maternal infection rates and reduced intensive care unit admissions among participants. Overall, low-dose vaginal misoprostol may not only be a viable alternative to vaginal dinoprostone for cervical ripening and labor induction, but also offer benefits in terms of maternal safety, particularly in resource-limited settings where cost-effectiveness is crucial. [9]
A 2023 systematic review and meta-analysis synthesized data from 39 RCTs involving 15,993 participants to evaluate the safety profiles of misoprostol and dinoprostone for labor induction in women with singleton pregnancies beyond 36 weeks' gestation. Maternal outcomes analyzed included cesarean section rate, instrumental deliveries, tachysystole, uterine rupture, postpartum hemorrhage, and chorioamnionitis. Neonatal outcomes encompassed five-minute Apgar scores of less than 7, meconium-stained amniotic fluid, NICU admissions, and infant mortality. No statistically significant differences were identified between misoprostol and dinoprostone in the primary outcomes of cesarean delivery (OR 0.94; 95% CI 0.84 to 1.05) or instrumental delivery (OR 1.04; 95% CI 0.90 to 1.19). Rates of uterine tachysystole were comparable between groups overall (OR 1.21; 95% CI 0.91 to 1.60), though a subgroup analysis revealed heightened tachysystole with vaginal misoprostol compared to dinoprostone gel (OR 1.48; 95% CI 1.09 to 2.01). There was no significant difference in postpartum hemorrhage (OR 0.85; 95% CI 0.62 to 1.15), neonatal Apgar scores <7 (OR 0.83; 95% CI 0.61 to 1.12), or NICU admissions (OR 0.91; 95% CI 0.77 to 1.09). The findings suggest a comparable safety profile between the two agents, with no clear superiority for either in any maternal or neonatal outcomes. [10]
A 2015 meta-analysis compared the efficiency of dinoprostone insert with dinoprostone gel for cervical ripening and induction of labor in women at term. A total of 15 randomized trials involving 1,779 women of full-term pregnancy (not less than 37 weeks of gestation) with intact membrane and unfavorable cervix were included. Compared to dinoprostone gel, dinoprostone insert demonstrated a significantly higher chance of vaginal delivery (VD) within 24 h (OR 2.35; 95% CI 1.34 to 4.13; p= 0.003). However, the rates of VD, artificial assisted vaginal delivery, and cesarean section (CS) were not significantly different between the two formulations. Limited data also suggested advantages of dinoprostone insert posing a shorter hospital stay and less postpartum hemorrhage in contrast to gel, though researchers did not perform formal statistical analyses. Despite the lack of evaluations of certain maternal and fetal outcomes and low-to-medium quality of included studies, dinoprostone insert appeared to outperform dinoprostone gel in this setting. [11]
A 2016 meta-analysis compared the efficacy and safety of intravaginal misoprostol and the dinoprostone vaginal insert for labor induction at term. A total of 8 studies with 1,669 patients (misoprostol n= 903; dinoprostone n= 763) were eligible for inclusion. Dosing regimens varied across trials, with both dinoprostone gel and insert being used. Overall, the use of misoprostol showed less oxytocin augmentation when compared with dinoprostone (relative risk [RR] 0.78; 95% CI 0.67 to 0.90). Yet results for other outcomes, including the risk of tachysystole, uterine hyperstimulation, vaginal delivery within 24 h, cesarean delivery, Neonatal Intensive Care Unit admission, and Apgar scores 57 in 5 min revealed no significant differences between misoprostol and dinoprostone. Study findings may be limited to small-scale trials, which require further investigation. [12]
A 2010 meta-analysis compared intravaginal misoprostol with dinoprostone vaginal insert for cervical ripening and labor injection. From 11 included RCTs (N= 1,572), the pooled relative risk of vaginal delivery within 12 hours between dinoprostone and misoprostol was 0.65 (95% CI 0.44 to 0.96) and vaginal delivery within 24 hours was RR of 0.83 (0.74 to 0.94). Cesarean rates for induction reported a RR of 1.01 (95% CI 0.85 to 1.19). Uterine hyperstimulation and fetal tachysystole were similar but the dinoprostone group observed a significantly increased need for oxytocin augmentation (RR 1.45; 95% CI 1.20 to 1.74). No difference in fetal outcomes was observed. [13]
A 2012 meta-analysis assessing the efficacy and safety of dinoprostone vaginal insert compared to repeated prostaglandin administration in women at term included studies reporting data separately for nulliparous and/or multiparous women with unfavorable cervix and intact membranes (N= 7 RCTs; 911 patients). Dinoprostone vaginal insert was found to reduce the CS rate in nulliparous women by 24% compared to other ways of administration (RR 0.76; 95% CI 0.59 to 0.98) and in multiparous women by 23% (RR 0.77; 95% CI 0.60 to 0.99). However, dinoprostone vaginal insert significantly increased the risk of uterine hyperstimulation in nulliparous (RR 2.17; 95% CI 1.08 to 4.33) and multiparous women (RR 2.23; 95% CI 1.15 to 4.32) compared to other ways of administration. [14]
An extensive Cochrane review published in 2009 compared different PGE2 formulations. For the purpose of this summary, only comparisons between PGE2 gel and PGE2 suppository/pessary will be discussed as the only FDA-approved products are the dinoprostone gel and dinoprostone vaginal insert. PGE2 gel resulted in significantly less uterine hyperstimulation with FHR changes compared to PGE2 suppository/pessary (RR 0.16; 95% CI 0.03 to 0.87; p= 0.034). For all other outcomes, there was no difference between PGE2 gel and PGE2 suppository/pessary. [15]