Version May 2024
INTRODUCTION — When labor is induced, cervical status has an impact on the duration of induction and the likelihood of vaginal birth. If the cervical status is unfavorable, a ripening (also called priming) process is generally employed prior to induction to shorten the duration of oxytocin administration and maximize the possibility of vaginal birth.
The two major techniques for cervical ripening are (1) mechanical interventions, such as insertion of a balloon catheter or, less commonly, hygroscopic cervical dilators, and (2) application of pharmacologic agents, such as prostaglandins. These techniques will be reviewed in this topic. General issues regarding induction of labor and use of oxytocin are discussed separately (see "Induction of labor with oxytocin"). Cervical preparation before surgical pregnancy termination is also discussed separately. (See "Pregnancy termination: Cervical preparation for procedural abortion".)
GENERAL APPROACH
Candidates — Patients with unfavorable cervixes are candidates for cervical ripening. Compared with use of oxytocin alone, cervical ripening probably increases the chances of achieving vaginal birth within 24 hours and does not increase, and may decrease, the risk for cesarean birth.
There is no universally accepted definition of favorable or unfavorable cervix. Many clinicians consider a Bishop score <6 (table 1) indicative of an unfavorable cervix and the need for a ripening agent, while others use a lower threshold (eg, ≤3 or 4) [1].
If the cervix is assessed to be favorable, oxytocin typically is initiated for induction without use of a cervical ripening agent. (See "Induction of labor with oxytocin".)
Inpatient versus outpatient cervical ripening — Historically, most patients have undergone cervical ripening in the hospital. Outpatient approaches to cervical ripening (in circumstances when maternal and/or fetal monitoring are not otherwise necessary during the ripening phase) are feasible and could be useful for reducing the duration of hospitalization and costs of medical care [2-6]. Investigators have used mechanical methods or prostaglandins for outpatient ripening; in the United States, there has been a tendency to prefer mechanical methods (eg, intracervical balloon, hygroscopic dilators) because prostaglandins are associated with a greater chance of tachysystole and the related theoretic concern that they would not be as safe in the outpatient setting. Large trials with the power to detect differences in meaningful outcomes (either between inpatient versus outpatient ripening or between different outpatient ripening regimens) have not yet been performed, and as such, the available body of evidence does not support a recommendation for a specific approach [7]. Correspondingly, institutional approaches to outpatient cervical ripening vary widely.
A 2016 survey of United Kingdom obstetric providers indicated that more than 17 percent of units were currently or soon-to-be providing outpatient induction of labor [8]. The vast majority began the procedures in the hospital, used the time-released prostaglandin E2 (PGE2) insert, and monitored patients with cardiotocodynamometry after insertion.
Investigators in the United States have reported on their experience with outpatient preinduction cervical ripening using a balloon catheter in selected patients [9-12]. Synthetic hygroscopic cervical dilators (eg, Dilapan-S) have also been used and have the advantages of no protrusion from the introitus and no need to keep under tension, but can be more costly than balloon catheters. The procedure generally has been limited to low-risk individuals with a singleton, live, vertex fetus at ≥37 weeks of gestation; exclusion criteria have included previous cesarean birth, gestational hypertension or preeclampsia, fetal growth restriction, prelabor rupture of membranes, and factors that could preclude prompt return to the hospital in the event an urgent return is needed.
The cost-effectiveness of outpatient cervical ripening compared with an inpatient approach has not been established. In an Australian cost-effectiveness analysis run in parallel with a small randomized trial of inpatient prostaglandin gel administration versus outpatient catheter placement, the outpatient arm was not more cost-effective [13]. Although outpatient balloon catheter use resulted in fewer predelivery inpatient hours and costs, it did not reduce overall inpatient hours and failed to achieve comparable rates of vaginal birth within 12 hours of birthing unit admission. In a randomized trial in the United States comparing the inpatient versus outpatient setting in nulliparas who underwent cervical ripening with a balloon catheter, outcomes were similar, but the outpatient group had a shorter time (4.3 fewer hours) between hospital admission and birth [12].
Protocol — Institutions should create and follow a clear protocol that delineates not only general cervical ripening issues, but also distinguishes differences between inpatient and outpatient ripening (eg, eligibility criteria).
The protocol should:
●Describe preripening patient evaluation and criteria (eg, reactive nonstress test or biophysical profile score ≥8, confirmation of presentation, confirmation that the cervix is unfavorable).
●List contraindications for outpatient cervical ripening. There are no absolute medical contraindications to inpatient cervical ripening in patients who are candidates for labor and vaginal birth and have no sensitivities to the drug/device that will be used. Contraindications exist for outpatient cervical ripening since continuous maternal and fetal monitoring and prompt intervention are not possible. Some examples of contraindications to outpatient ripening that have been employed are as follows:
•Fetal conditions
-Fetal growth restriction
-Oligohydramnios or polyhydramnios
-Multiple gestation
-Major fetal anomalies
-Nonreassuring fetal assessment
•Maternal conditions
-Prior cesarean birth or uterine surgery involving removal of a full thickness of uterine tissue
-Clinically significant vaginal bleeding
-Hypertensive disorders of pregnancy
-A patient who is unable to return easily should symptoms arise
●Describe the fundamental steps of the procedure.
●Include a defined period of monitoring after initiation of ripening to assess for conditions (eg, nonreactive fetal heart rate [FHR], membrane rupture) that would preclude cessation of continuous monitoring if ripening is being performed as an inpatient procedure or preclude discharge of the patient to home if ripening is being performed with the expectation of outpatient use.
●Provide patient instructions for activity (eg, shower but no bathing), when to call the provider (eg, excessive bleeding, fever, labor, membrane rupture), and when to return to the hospital.
Choice of ripening agent for inpatient procedures — The following text and general principles apply to inpatient ripening. There is much less data derived from trials of outpatient cervical ripening.
●The choice of ripening agent should be based on provider and patient preference. There is no single, clear best practice with respect to the choice of agent used for cervical ripening: both mechanical and pharmacologic agents are acceptable options, unless the patient has a contraindication to use of a specific agent or technique. (See 'Contraindications' below and 'Contraindications' below.)
●A single method may be used (ie, either mechanical or pharmacologic), a mechanical method may be combined with a pharmacologic method (see 'Combination therapy (balloon catheter plus a prostaglandin or oxytocin)' below), or mechanical and pharmacologic methods may be used sequentially until cervical ripening is achieved.
●Balloon catheters have no or minimal side effects but necessitate a potentially uncomfortable vaginal procedure for catheter insertion. They have convenient storage requirements (eg, no refrigeration), which is an issue for some prostaglandin agents. (See 'Side effects' below.)
Prostaglandins reduce the need for additional use of oxytocin since prostaglandins promote myometrial contractility [14,15]. Disadvantages include the potential for excessive uterine activity leading to FHR abnormalities, and side effects (eg, diarrhea). However, in clinical trials, neither the advantages nor disadvantages resulted in differences in clinically important outcomes (eg, cesarean birth or neonatal morbidity rates). (See 'Side effects' below.)
Evidence — A 2016 network meta-analysis comparing the use of misoprostol (oral, vaginal), dinoprostone, and the balloon catheter for cervical ripening concluded that no method was clearly superior in terms of the rate of failure to achieve vaginal birth within 24 hours, tachysystole with adverse FHR changes, and cesarean birth [16]:
●Use of vaginal misoprostol or vaginal dinoprostone reduced the risk of failure to achieve vaginal birth within 24 hours compared with use of a balloon catheter, oral misoprostol, or intracervical dinoprostone, but increased the risk of uterine hyperstimulation with adverse FHR changes compared with other agents.
●Use of a balloon catheter for cervical ripening resulted in the lowest risk of uterine hyperstimulation with adverse FHR changes.
●Use of oral misoprostol resulted in the lowest risk of cesarean birth.
The analysis did not consider combined methods (balloon catheter and concurrent prostaglandin or oxytocin), which in some studies have shortened the time to vaginal birth and are becoming increasingly common.
Interpretation of data on cervical ripening is hindered by several factors, which make it difficult to identify the methods of cervical ripening and labor induction, either used alone or in combination, that are most effective and safe. These factors include:
●A basic lack of understanding of the physiologic events that initiate and sustain labor.
●Wide biologic variation in the progress of normal labor.
●Failure of studies to distinguish between cervical ripening and labor induction.
●Iatrogenic variation in indications for induction and management of induced labor.
●Variation in parity and gestational age at induction, as well as other demographic features that affect clinical results.
●Use of different clinical endpoints in research studies (eg, change in cervical status versus length of labor versus route of birth).
●Few trials comparing multiple methods.
●Inadequate data on patient-reported outcomes, such as satisfaction.
Initiation and discontinuation — Once a cervical ripening agent is initiated, the process is typically continued until the cervix is favorable (algorithm 1 and table 1). There is no evidence-based time cutoff that prohibits continued efforts at cervical ripening with the same or different methods when the cervix remains unfavorable. However, when using a balloon catheter, many clinicians will not continue efforts at cervical ripening if it falls out or if membranes spontaneously rupture.
MECHANICAL METHODS
Overview of use
Types — Insertion of a balloon catheter (eg, Foley bladder catheter) through the endocervical canal and into the extraamniotic space is the most common mechanical method currently in use. Placement of hygroscopic dilators into the endocervical canal and extending through the internal cervical os is an alternative mechanical method.
Mechanism of action — Mechanical methods of cervical ripening have been theorized to work both by direct physical pressure on the internal cervical os and by causing the release of prostaglandins from the decidua, adjacent membranes, and/or cervix [17]. These effects combine to promote a number of biochemical and biophysical changes that lead to cervical ripening and an increase in myometrial contractility.
Contraindications — For in-patient mechanical cervical ripening, there are few contraindications because the patient and fetus can be monitored frequently and rapid intervention for a warning sign is possible. For out-patient mechanical cervical ripening, there are additional contraindications to consider and practices vary among institutions. (See 'Protocol' above.)
Issues to consider:
●GBS – Group B Streptococcus (GBS) colonization is not a contraindication to use of mechanical methods of cervical ripening [18], but standard GBS antibiotic prophylaxis should be used when labor begins or at rupture of membranes, whichever occurs first. Antibiotic prophylaxis is reviewed separately. (See "Prevention of early-onset group B streptococcal disease in neonates", section on 'Patients undergoing obstetric procedures'.)
●Polyhydramnios – Polyhydramnios is not an absolute contraindication to use if induction is indicated, as long as there are no other contraindications to labor induction and vaginal birth (eg, malpresentation, which is more likely in the setting of polyhydramnios).
●Low-lying placenta – A low-lying placenta is a relative contraindication since the edge of the placenta may be disrupted by manipulation during placement of the device. Placement should be individualized, including based on the patient's history of vaginal bleeding and the actual proximity of the placenta to the internal os.
●Ruptured membranes – Most practitioners, including the author of this topic, never place a balloon catheter for cervical ripening in patients with ruptured membranes, given concerns about increasing the risk of clinical chorioamnionitis and lack of benefit in this setting. If membranes are intact when the device is placed but then rupture at any time after placement, a common practice is to remove the device, but some practitioners limit the duration of cervical ripening to 12 hours in such patients. The approach is the same regardless of fetal status (alive or dead). The same considerations apply to preinduction cervical ripening with hygroscopic dilators, which are less commonly used for this indication (although commonly used for cervical preparation prior to surgical procedures for pregnancy termination).
While there is not total consensus on optimal management in this setting, the package insert for the Cook Cervical Ripening Balloon lists ruptured membranes as a contraindication to placement and an indication for deflation and removal. The package insert for Dilapan-S lists clinically apparent genital tract infection as the only contraindication. Data on the safety and efficacy of balloon catheter use in patients with ruptured membranes are reviewed separately. (See "Prelabor rupture of membranes at term: Management", section on 'Active management'.)
●Intact membranes with intraamniotic infection – In patients with intact membranes who are undergoing cervical ripening for labor induction, the use of a balloon catheter is not absolutely contraindicated in the uncommon scenario of intraamniotic infection.
Side effects — Mechanical methods of cervical ripening do not cause systemic side effects and are associated with a lower rate of tachysystole with fetal heart rate changes than prostaglandins [19]. Meta-analyses of randomized trials have not found convincing evidence of an increased risk of infectious morbidity in mothers or neonates exposed to mechanical methods of cervical ripening compared with those exposed to prostaglandins [19,20].
Importantly, these trials typically have excluded patients with ruptured membranes. Very limited data in patients with ruptured membranes, most of whom were at term, are reviewed separately. (See "Prelabor rupture of membranes at term: Management", section on 'Balloon catheter'.)
Balloon catheter
Device selection — A double-balloon catheter specifically designed for cervical ripening is commercially available (figure 1); alternatively, a single-balloon catheter (eg, Foley bladder catheter) can be used. In meta-analysis of randomized trials, there were no clinically important differences in outcomes with use of a double- versus a single-balloon catheter [19]. However, the single-balloon catheter is less expensive and is usually more readily available.
Procedure — The balloon catheter is placed using aseptic technique. Although uterine activity and fetal heart rate (FHR) are often continuously monitored while it is in place, numerous investigators have demonstrated the safety of only transient monitoring (30 to 120 minutes) after placement [6,10,11].
After the balloon catheter is extruded or removed, oxytocin is begun and amniotomy is performed, if technically possible [21,22]. Alternatively, oxytocin can be initiated concurrently with the catheter in place. (See 'Combination therapy (balloon catheter plus a prostaglandin or oxytocin)' below.)
In a randomized trial, amniotomy within one hour of balloon catheter expulsion shortened the time to birth and increased the frequency of birth within 24 hours compared with expectant management in which the median time to amniotomy was 10 hours after balloon catheter expulsion [23].
Single-balloon catheter — A balloon portion of a single-balloon catheter is placed in the extraamniotic space.
●Insert the catheter – Ring forceps can be used to pass a deflated single-balloon catheter through the internal cervical os and into the extraamniotic space [24,25]. Alternatively, the catheter can be inserted manually, similar to an intrauterine pressure catheter. This is usually possible even if the cervix is not dilated since the pregnant cervix is soft and distensible and rarely tightly closed. If it is difficult to pass the catheter, a urologic sound or other rigid device can be inserted into the catheter to facilitate placement.
●Distend the balloon – The balloon is distended with 30 to 80 mL saline. If a sound or other rigid device was used, it is removed before or while beginning instillation of saline. The dilated balloon is then gently retracted so that it rests against the internal os without extending into the endocervical canal.
In a meta-analysis of randomized trials comparing use of larger (60 to 80 mL) versus smaller (30 mL) volumes during cervical ripening, larger balloon volumes resulted in a shorter time from induction to delivery (mean difference 1.97 hours, 95% CI -3.88 to -0.06) but had a similar cesarean birth rate, time to vaginal birth, time to catheter expulsion, and maternal and fetal complication rates [26]. These data suggest that either a large- or small-balloon volume is a reasonable choice.
●Maintain tension – Many clinicians tape the end of the catheter to the inner thigh, placing it on tension, with readjustment to maintain tension at occasional intervals. A randomized trial noted a decrease in time to balloon expulsion when traction was used but no effect on the time to birth [27].
Some clinicians attach a weight (eg, 1 L of fluid) to the end of the catheter and suspend it from the end of the bed. Weighted traction may shorten the time to spontaneous expulsion but did not shorten the time to birth in two randomized trials [27,28].
●Remove at 12 hours – The catheter is typically left in place until it is extruded; if not extruded, it is generally removed by 12 hours after insertion; however, there is no absolute contraindication to leaving the catheter in place for more than 12 hours.
The 12-hour duration of use is supported by a randomized trial that found removing nonextruded catheters after 12 hours and beginning oxytocin resulted in significantly more vaginal births within 24 hours than waiting 24 hours before removal and oxytocin induction (60 versus 21 percent), and did not lead to an increase in cesarean birth [29].
There is evidence that a time shorter than 12 hours is reasonable. Four trials have reported a shorter time from insertion to delivery with planned removal at 6 rather than 12 hours, without increasing the cesarean birth rate [30-33]. One of the trials used combination therapy of catheter insertion plus oxytocin administration [30].
Double-balloon catheter — The distal balloon of a double-balloon catheter is in the extraamniotic space adjacent to the internal os and the proximal balloon is in the vagina adjacent to the external os.
The procedure for inserting a double-balloon catheter is similar to that described above for the single-balloon catheter (see 'Single-balloon catheter' above), with the following modifications:
●Insertion – The catheter is inserted until the proximal balloon is in the cervical canal, at which point the distal balloon should be intrauterine and in the extraamniotic space.
●Distension
•The distal intrauterine balloon is inflated with 40 mL saline and gently retracted so that it rests against the internal os.
•The proximal balloon, which should now be in the vagina outside the external os, is inflated with 20 mL saline.
•If the balloons are correctly situated on either end of the cervix, they can now be inflated with up to 80 mL saline per balloon.
●Tension is not required
Efficacy — Use of balloon catheters has been associated with a 3.3 to 5.3 point mean change in Bishop score [34].
In meta-analyses of randomized trials:
●After balloon catheter placement, 94 percent of patients had a favorable cervix at 12 hours compared with 14 percent of those in the no treatment group (relative risk [RR] 0.07, 95% CI 0.03-0.19) [35].
●The balloon catheter and prostaglandin E2 (PGE2) were similarly effective for [19]:
•Vaginal birth not achieved in 24 hours (53.3 versus 52.8 percent; RR 1.01, 95% CI 0.82-1.26)
•Cesarean birth (23.8 percent in both groups; RR 1.00, 95% CI 0.92-1.09)
●The balloon catheter and low-dose vaginal misoprostol [19]:
•Were similarly effective for vaginal birth not achieved in 24 hours (4.5 versus 4.1 percent; RR 1.09, 95% CI 0.85-1.39)
•But the balloon catheter had a higher frequency of cesarean birth (31.1 versus 24.3 percent; RR 1.28, 95% CI 1.02-1.60)
●The balloon catheter was less effective than low-dose oral misoprostol for [19]:
•Vaginal birth not achieved in 24 hours (6.1 versus 4.8 percent; RR 1.28, 95% CI 1.13-1.46)
•Cesarean birth (25.9 versus 22.2 percent; RR 1.17, 95% CI 1.04-1.32)
●The balloon catheter resulted in lower risks of uterine tachysystole with FHR changes compared with prostaglandins (eg, 1.1 versus 3.1 percent with PGE2, RR 0.35, 95% CI 0.18-0.67; 1.3 versus 3.3 percent with vaginal misoprostol, RR 0.39, 95% CI 0.18-0.85 [19].
●The balloon catheter resulted in less serious neonatal morbidity or perinatal death compared with PGE2 (0.9 versus 2 percent; RR 0.48, 95% CI 0.25-0.93) [19].
●The effect of the balloon catheter versus prostaglandins on serious maternal morbidity or death was uncertain (1 versus 3 per 1000 for PGE2, RR 0.20, 95% CI 0.01-4.1; 1 versus 2 per 1000 for low dose oral misoprostol, RR 0.50, 95% CI 0.05-5.5) [19].
It should be noted, however, that much of the evidence in these meta-analyses was classified as low quality and when there was a statistical difference, the confidence intervals often approached unity.
Hygroscopic dilators — There are two types of hygroscopic dilators: One is made from natural seaweed (laminaria tents), and the other is a synthetic product (eg, Dilapan-S). Hygroscopic dilators are designed to absorb moisture and thus gradually expand within the cervical canal. In addition, disruption of the interface between the fetal membranes and decidua can lead to prostaglandin release, with consequent changes in cervical tissue beyond the passive mechanical stretching provided by the tent itself.
Hygroscopic dilators are as safe and effective as other cervical ripening agents [36,37], although they are more commonly used during pregnancy termination than for preinduction cervical ripening of term pregnancies. (See "Overview of pregnancy termination", section on 'Cervical dilation and preparation'.)
Although the balloon catheter has largely replaced use of hygroscopic dilators for induction of labor, some clinicians prefer to use hygroscopic dilators in patients with a prior cesarean birth. However, there is no strong evidence on which to base a recommendation favoring one approach over the other.
Procedure
●After prepping the cervix and vagina with an antiseptic, the cervix is held with a nontraumatic clamp, if necessary, and the maximum number of dilators that the endocervical canal can accommodate are inserted without using excessive force; some cramping is common.
●Dipping the laminaria in a sterile lubricant before insertion may facilitate placement.
●The dilators can be packed in place with two 4-by-4-inch gauze sponges tucked into the fornices; the number of dilators and gauze sponges that were inserted should be recorded in the patient's chart at insertion and at removal.
●Laminaria typically are removed 12 to 24 hours after placement, whereas synthetic dilators can be removed sooner, after 6 to 8 hours.
Efficacy — In a meta-analysis of randomized trials, the risk of tachysystole with adverse FHR changes was lower in the laminaria group compared with the any prostaglandin group (0 versus 5.9 percent; RR 0.13, 95% CI 0.04-0.48, five trials, 538 participants). The risk of cesarean birth was similar for the laminaria, any prostaglandin and balloon catheter groups. The addition of either prostaglandins or oxytocin to laminaria during cervical ripening did not clearly improve the chances of vaginal birth within 24 hours or reduce the chances of cesarean birth.
PROSTAGLANDINS
General principles
Mechanism of action — Prostaglandins promote several biochemical and biophysical changes that lead to cervical ripening and an increase in myometrial contractility. The mechanisms involved in prostaglandin-induced cervical ripening are beyond the scope of this topic but have been reviewed in detail elsewhere [38,39].
Contraindications
●Allergy to prostaglandins and contraindications to labor and vaginal birth are absolute contraindications to cervical ripening with prostaglandins.
●A prior cesarean birth or other prior major uterine surgery (eg, intramyometrial myomectomy that was likely to have significantly compromised the myometrium, repair of major congenital uterine anomalies) is a contraindication to use of misoprostol (prostaglandin E1) for cervical ripening because of the association with an increased risk for uterine rupture. However, in some countries use of prostaglandin E2 (PGE2) is acceptable in patients with prior uterine surgery who have no contraindication to a trial of labor. These data are reviewed separately. (See "Cervical ripening and induction of labor after a prior cesarean birth", section on 'Use of prostaglandins'.)
●Preexisting regular painful uterine activity is a relative contraindication to use of prostaglandins, given that the addition of an exogenous uterotonic agent could prompt excessive uterine activity. When administering prostaglandins for cervical ripening, clinicians should be mindful of baseline uterine activity and consider delaying or avoiding administration if the patient is having two to three or more painful contractions/10 minutes. This is most important in patients who have already received at least one dose of prostaglandin as there appears to be a cumulative uterotonic effect. However, good evidence as to the best threshold of uterine activity for avoiding prostaglandins is not available. Clinicians should use their clinical judgment in making this decision, taking into account patient-specific factors such as grand multiparity, fetal status, the degree of discomfort/pain that the patient has experienced with previous doses, and the total number of doses of prostaglandins administered.
Procedure
●Check uterine contraction frequency and intensity before administration. As discussed above, delaying or avoiding administration if the patient is having two to three or more painful contractions/10 minutes may reduce the risk of tachysystole. (See 'Contraindications' above.)
●Monitor uterine activity and fetal heart rate (FHR) continuously for at least 30 minutes after administration and maintain monitoring as long as regular uterine activity is present [1].
●If labor does not ensue and the cervix remains unfavorable, options include repeated dosing (timing depends on the specific agent), adding or switching to a mechanical method, or initiating oxytocin (timing depends on the specific agent). (See 'Use of specific agents' below and "Induction of labor with oxytocin", section on 'Oxytocin administration'.)
●Perform amniotomy when feasible and safe to shorten the time interval to birth [40,41].
Side effects — Side effects of prostaglandins include tachysystole, fever, chills, vomiting, and diarrhea. The frequency of these side effects depends upon the type of prostaglandin, dose, and route of administration. Uterine contractile abnormalities occur in up to 30 percent of patients, depending upon the vehicle and route of administration; other systemic effects occur in up to 5 percent of cases.
Management
●Fever, chills, vomiting – Treatment of maternal discomfort is supportive (eg, acetaminophen, warm blanket, antiemetic drugs).
●Tachysystole – If tachysystole with an abnormal FHR occurs after placement of a prostaglandin vaginal insert, removal of the insert usually reduces uterine contractility, normalizes the FHR, and does not appear to prolong the time to birth [42].
If a prostaglandin gel was applied, then removal of the remaining gel is not possible. A tocolytic drug (eg, terbutaline 250 mcg subcutaneously) can be administered if in utero resuscitation is indicated. Cervicovaginal lavage is not helpful for removing the drug or reversing adverse effects.
If a misoprostol tablet was inserted, theoretically any remnants can be removed from the vagina. A tocolytic drug (eg, terbutaline 250 mcg subcutaneously) can be administered if in utero resuscitation is indicated.
Efficacy — Multiple meta-analyses of randomized trials have established the efficacy of prostaglandins for cervical ripening (documented change in Bishop score) and improving the chances of vaginal birth within 12 or 24 hours, but a clear reduction in overall cesarean birth rates has not been demonstrated consistently [15,43-49].
Choice of prostaglandin — The optimal prostaglandin formulation, route of administration, dose, and frequency for cervical ripening has not been determined despite many studies. A network meta-analysis of 280 randomized trials reported the following relative findings, but reliable absolute rates of vaginal birth within 24 hours are difficult to cite because of variability in patients and procedures among the underlying trials [46]:
●Vaginal misoprostol tablet ≥50 mcg was the treatment with the highest probability of achieving a vaginal birth within 24 hours. The prostaglandins with poorest probability of achieving a vaginal birth within 24 hours were the vaginal PGE2 pessary (normal release), oral misoprostol <50 mcg, and intracervical PGE2.
●Vaginal misoprostol tablet ≥50 mcg was associated with a four-fold increase in the odds of uterine hyperstimulation compared with intracervical PGE2 (odds ratio [OR] 3.57, 95% CI 1.66-8.06). Vaginal misoprostol ≥50 mcg was also associated with a near three-fold increase in the odds of hyperstimulation compared with slow-release vaginal PGE2 (OR 2.73, 95% CI 1.08-7.40).
Most of the studies used four hourly and some opted for six hourly treatment regimens. Although 50 mcg misoprostol was more effective than 25 mcg for achieving birth within 24 hours, the 25 mcg dose is more commonly used because of its better safety profile.
Patient and provider preferences regarding factors such as convenience, side effects, and cost should also be considered.
Use of specific agents
Prostaglandin E1 (misoprostol) — Misoprostol (Cytotec) is a prostaglandin E1 analog available as 100 and 200 mcg tablets, which can be broken to provide 25 or 50 mcg doses. It is rapidly absorbed from both the oral and vaginal routes [50]. Either route is reasonable; one route of administration is not clearly better than another in terms of important health outcomes, although available data are difficult to interpret because of differences in dosing [46]. The 25 mcg dose is generally preferred because adverse effects are mostly seen at higher doses [1]. The existence of a toxic dose of misoprostol has not been determined and cumulative total daily doses of 1600 mcg have been tolerated, with only symptoms of gastrointestinal discomfort [51].
The approved indication for misoprostol is treatment and prevention of gastric ulcer disease related to chronic nonsteroidal anti-inflammatory drug use. Administration of this drug for cervical ripening and labor induction is considered an off-label use in the United States. However, there is good evidence that it is an effective alternative to PGE2 preparations for cervical ripening and labor induction [15,47-49,52]. The American College of Obstetricians and Gynecologists (ACOG) has stated that use of misoprostol appears as safe and efficacious as other prostaglandin agents when used as a cervical ripening and/or labor induction agent as described below [1].
Vaginal administration — The optimal dose and timing interval of intravaginally applied misoprostol have not been determined [47,53-56].
●Misoprostol 25 mcg vaginally, with redosing intervals of three to six hours is a common dose [1,47,57-61].
●Oxytocin may be initiated, if necessary, four hours after the final misoprostol dose.
●In some situations, such as inadequate uterine activity at lower doses, misoprostol 50 mcg vaginally at six-hour intervals may be appropriate; however, this dose has been associated with a higher risk of tachysystole [1].
●A misoprostol vaginal insert consisting of a controlled-release, retrievable polymer chip for gradual delivery of 200 mcg over 24 hours is available in some countries but not in the United States. In a large randomized trial comparing patients who received the misoprostol vaginal insert with those receiving a dinoprostone vaginal insert, use of the misoprostol vaginal insert resulted in a significantly shorter median time to vaginal birth (21.5 versus 32.8 hours) but also resulted in a higher chance of uterine tachysystole requiring intervention (13.3 versus 4 percent) and did not change the chance of cesarean birth [62].
A meta-analysis reported that the 50 mcg dose vaginally was more effective than the 25 mcg dose (eg, resulted in a higher chance of birth after a single dose and of delivery within 24 hours, and a lower chance of oxytocin use), but the 25 mcg dose resulted in lower rates of tachysystole, cesarean birth for nonreassuring FHR, neonatal intensive care units admission, and meconium passage [63].
Oral administration — When administered orally, the concentration peaks sooner and declines more rapidly than with vaginal administration (figure 2) [50]. The dose recommended by the World Health Organization is 25 mcg orally, with two-hour redosing intervals [60].
Oxytocin may be initiated, if necessary, four hours after the final misoprostol dose.
Randomized trials have used a wide variety of oral doses (20 to 200 mcg) and intervals of administration (1 to 6 hours) [64]. Despite many trials, there is no clear consensus as to the optimum oral dose or dosing interval, and whether the patient should swallow a tablet versus a titrated oral misoprostol solution.
A 2021 meta-analysis supported the use of low-dose oral misoprostol for induction of labor and suggested that a starting dose of 25 mcg may offer a good balance of efficacy and safety [49]. It should be noted, however, that the authors considered the recommendation to have only moderate-to-low certainty given imprecision, inconsistency, and study limitations. Included trials compared oral misoprostol protocols of one‐ to two‐hourly versus four‐ to six‐hourly dosing; doses of 20 to 25 mcg versus 50 mcg; and 20 mcg hourly titrated versus 25 mcg two‐hourly static.
A subsequent trial investigated a higher dose of oral misoprostol. This trial compared oral misoprostol 100 mcg every four hours for up to two doses with vaginal misoprostol 25 mcg every three hours for up to five doses, followed by a standardized oxytocin protocol, in 1322 patients at term [61]. Both groups had a similar rate of vaginal birth at first induction attempt (78 percent) and time to delivery (19.7 hours). The participants who were randomized to vaginal dosing had less tachysystole with fetal heart rate changes (3.5 versus 5.9 percent, RR 0.59, 95% CI 0.40-0.87). There were no statistically significant differences between groups in neonatal five-minute Apgar score, umbilical cord blood pH less than 7.0, or sepsis, but the participants who were randomized to vaginal dosing had a higher frequency of neonatal intensive care unit admission (2.0 versus 1.0 percent, adjusted RR 2.08, 95% CI 1.06-4.09), which was attributed to increased frequency of neonatal assisted ventilation or urgent pediatric surgical intervention. Some limitations of the trial are that maternal side effects (fever, nausea, vomiting, diarrhea) were not evaluated; it was underpowered to detect modest differences in neonatal outcomes; and potential lack of generalizability (mean age of participants: 26 to 27 years, nulliparas: approximately 50 percent, internal fetal monitoring: approximately 75 percent, white race: approximately 5 percent, oligohydramnios as indication for induction: 35 to 37 percent, mean body mass index [BMI] at first prenatal visit: approximately 30.7 kg/m2).
Buccal or sublingual administration — Other approaches to use of misoprostol, including buccal and sublingual administration, have been described, but are less well studied and should be considered investigational [65-68]. These routes of administration may avoid first-pass hepatic metabolism associated with oral ingestion and thus increase bioavailability similar to that achieved with vaginal administration. Pharmacokinetic data support the hypothesis that buccal and sublingual routes of administration are associated with more rapid onset of action and greater bioavailability than other routes [65]. Additionally, it is hypothesized that administration using these routes may reduce the risk of tachysystole by avoiding direct uterine effects.
However, a meta-analysis of five small trials (n = 740 patients) of sublingual versus vaginal administration found no statistically significant differences in rate of vaginal birth not achieved within 24 hours (OR 1.27, 95% CI 0.87-1.84), uterine hyperstimulation syndrome (OR 1.20, 95% CI 0.61-2.33), or cesarean birth (OR 1.33, 95% CI 0.96-1.85), but uterine tachysystole was increased in the sublingual misoprostol group (OR 1.70, 95% CI 1.02-2.83) [69]. A subsequent well-designed trial (IMPROVE) including 300 patients suggested vaginal misoprostol may be superior to the buccal route: time to vaginal birth was reduced by eight hours, and fewer emergency cesareans were performed for FHR abnormalities [70]. Regardless of route, the first dose was 25 mcg and subsequent doses, if needed, were 50 mcg at intervals no sooner than four hours after the previous dose.
Prostaglandin E2 — Prepidil and Cervidil are two PGE2 preparations commercially available for cervical ripening in the United States. Other formulations are available worldwide (eg, Prostin E2 gel containing 1 mg or 2 mg dinoprostone for vaginal insertion, Prostin E2 0.5 mg tablet for oral administration). These drugs are more costly than misoprostol.
Prepidil — Prepidil contains 0.5 mg of dinoprostone in 2.5 mL of gel for endocervical administration. The dose can be repeated in 6 to 12 hours if cervical change is inadequate and uterine activity is minimal following the first dose. The manufacturer recommends that the maximum cumulative dose of dinoprostone not exceed 1.5 mg (ie, three doses) within a 24-hour period.
The time interval between the final dose and initiation of oxytocin, if necessary, should be 6 to 12 hours because of the potential for uterine tachysystole with concurrent oxytocin and PGE2 prostaglandin administration. (See "Induction of labor with oxytocin", section on 'Complications of induction'.)
Cervidil — Cervidil is a vaginal insert containing 10 mg of dinoprostone in a timed-release formulation (the medication is released at 0.3 mg/hour). The insert is left in place until active labor begins or for 12 hours.
Oxytocin may be initiated, if necessary, anytime beyond 30 minutes after removal of the insert.
A theoretical advantage of the vaginal insert over the gel formulation is that the vaginal insert can be removed in cases of uterine tachysystole or abnormalities of the FHR tracing [71,72], although this possibility has not translated into better clinical outcomes than other ripening methods.
COMBINATION THERAPY (BALLOON CATHETER PLUS A PROSTAGLANDIN OR OXYTOCIN) — Some, but not all, trials have shown that the concurrent use of mechanical and pharmacologic ripening methods may have modest benefits over the use of a single method alone, without increasing the risk of adverse obstetric or perinatal outcomes. In a network meta-analysis (30 randomized trials, 6465 pregnancies), the combination of a balloon catheter plus a prostaglandin (cBC/P) or a balloon catheter plus oxytocin (cBC/O) compared with a balloon catheter alone [73]:
●Hastened the time to vaginal birth (cBC/P: -2.9 hours, 95% CI -5.7 to 0; cBC/O: -4.2 hours, 95% CI -6.5 to -1.9).
●Increased the chance of birth within 24 hours (cBC/P: odds ratio [OR] 1.80, 95% CI 1.02-3.20; cBC/O: OR 2.04, 95% CI 1.29-3.24).
●Did not significantly affect the risk for cesarean birth (cBC/P: OR 0.89, 95% CI 0.65-1.20; cBC/O: OR 0.99, 95% CI 0.74-1.33) or adverse events (chorioamnionitis, endometritis, tachysystole, meconium, neonatal intensive care unit admission, postpartum hemorrhage).
A meta-analysis that evaluated the efficacy of mechanical methods plus a prostaglandin or oxytocin versus medication alone found combined therapy had no clear benefit for achieving vaginal birth within 24 hours [19].
Data are insufficient to determine whether to routinely use combination therapy, which combination to use (cBC/P or cBC/O), and the optimum protocol.
OTHER APPROACHES
Other cervical ripening drugs and techniques — Relaxin [74-76], nitric oxide donors (eg, isosorbide mononitrate) [77,78], hyaluronidase [79], corticosteroids [80], castor oil [81], sexual intercourse [82,83], breast stimulation [84], and herbal preparations [85] have been used for cervical ripening, although we recommend not using these approaches because of limited data regarding safety and/or efficacy and the availability of proven alternatives.
Extraamniotic saline infusion is a procedure in which sterile saline is infused continuously via a balloon catheter placed in the extraamniotic space [86-89]. However, it does not have a clear advantage over other methods (balloon catheter alone, prostaglandins) [90-92].
SPECIAL POPULATIONS — Management of cervical ripening in the following two special populations is reviewed separately.
Fetal demise — (See "Stillbirth: Maternal care", section on 'Birth'.)
Previous cesarean birth — (See "Cervical ripening and induction of labor after a prior cesarean birth".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cervical ripening and labor induction".)
SUMMARY AND RECOMMENDATIONS
●Candidates – If the cervical status is unfavorable prior to induction, a ripening process is generally employed to shorten the duration of oxytocin administration and maximize the possibility of vaginal birth. If the cervix is favorable, oxytocin typically is initiated for induction without use of a cervical ripening agent. (See 'Candidates' above.)
•There is no universally accepted definition of favorable or unfavorable cervix. Many clinicians consider a Bishop score <6 (table 1) indicative of an unfavorable cervix and the need for a ripening agent, while others use a lower threshold (eg, ≤3 or 4). We recommend use of a cervical ripening agent for patients with a Bishop score ≤3 (Grade 1B). We consider both the Bishop score and noncervical factors when making this decision in patients with Bishop scores of 4, 5, or 6 and we feel cervical ripening is not required in patients with Bishop scores >6. (See 'Candidates' above and "Induction of labor with oxytocin", section on 'Assessing the chance of a successful induction'.)
●Protocol – Institutions should create and follow a clear protocol that delineates not only general cervical ripening issues, but also distinguishes differences between inpatient and outpatient ripening (eg, eligibility criteria). Once a cervical ripening agent is initiated, the process is typically continued until the cervix is favorable (algorithm 1 and table 1). (See 'Protocol' above and 'Inpatient versus outpatient cervical ripening' above and 'Initiation and discontinuation' above.)
●Choice of cervical ripening agent – For patients scheduled for labor induction with an unfavorable cervix, clinical outcomes are similar whether a balloon catheter or prostaglandins (E2 or E1) is used for cervical ripening. The choice of agent for a specific patient depends on multiple factors including institutional protocols, physician preferences, and patient preferences, which are influenced by convenience, cost, and side effects. (See 'Choice of ripening agent for inpatient procedures' above.)
●Balloon catheter
•Contraindications – A low-lying placenta is a relative contraindication since the edge of the placenta may be disrupted by manipulation during placement of the device. (See 'Contraindications' above.)
Ruptured membranes are often considered a contraindication, but practice patterns in this setting vary. (See 'Contraindications' above.)
•Administration – The catheter is placed using aseptic technique. Oxytocin can be started concurrently or after the catheter has been extruded or removed. (See 'Device selection' above and 'Procedure' above.)
•Side effects – There are no systemic side effects, and a lower rate of tachysystole than prostaglandins. (See 'Side effects' above.)
●Prostaglandins
•Contraindications – A prior cesarean birth or other prior major uterine surgery is a contraindication to use of misoprostol, with practice variation regarding use of PGE2 in this setting. Preexisting regular painful uterine activity is a relative contraindication. (See 'Contraindications' above.)
•Administration – The most common drugs and doses are:
-Misoprostol 25 mcg vaginally, with redosing intervals of three to six hours is a common dose. Oxytocin may be initiated, if necessary, four hours after the final misoprostol dose. (See 'Vaginal administration' above.)
-Misoprostol 25 mcg orally, with redosing at two-hour intervals. Oxytocin may be initiated, if necessary, four hours after the final misoprostol dose. (See 'Oral administration' above.)
-Prepidil gel (0.5 mg of dinoprostone in 2.5 mL of gel) for endocervical administration. The dose can be repeated in 6 to 12 hours for up to three doses in 24 hours if cervical change is inadequate and uterine activity is minimal following the first dose. Oxytocin may be initiated, if necessary, 6 to 12 hours after the final dose. (See 'Prepidil' above.)
-Cervidil vaginal insert (10 mg of dinoprostone in a timed-release formulation). The insert is left in place until active labor begins or for 12 hours. Oxytocin may be initiated, if necessary, 30 minutes after removal of the insert. (See 'Cervidil' above.)
•Side effects – Side effects of prostaglandins include tachysystole, fever, chills, vomiting, and diarrhea. The frequency of these side effects depends upon the type of prostaglandin, dose, and route of administration. Uterine contractile abnormalities occur in up to 30 percent of patients, depending upon the vehicle and route of administration; other systemic effects occur in up to 5 percent of cases. (See 'Side effects' above.)
-Treatment of maternal discomfort is supportive (eg, acetaminophen, blanket, antiemetic).
-If tachysystole with fetal heart rate (FHR) changes occurs after placement of a prostaglandin vaginal insert, removal of the insert usually reduces uterine contractility and normalizes FHR abnormalities. It may be possible to remove the remaining portion of a misoprostol pill, but prostaglandin gel cannot be removed. A tocolytic drug (eg, terbutaline 250 mcg subcutaneously) can be administered if in utero resuscitation is indicated.
●Combined use of a balloon catheter and a prostaglandin or oxytocin – The concurrent use of mechanical and pharmacologic ripening methods rather than a single method alone may have modest benefits (small reduction to time to vaginal birth, small increase in vaginal birth within 24 hours, but no change in cesarean rate), without increasing the risk of adverse obstetric or perinatal outcomes. If a provider chooses to give oxytocin concurrently, either a fixed low dose or standard incremental dose regimen is acceptable (table 2). (See 'Combination therapy (balloon catheter plus a prostaglandin or oxytocin)' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Deborah A Wing, MD, MBA, who contributed to an earlier version of this topic review.
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