In an ideal world, all pregnancies would go to term, and labor would begin spontaneously. In reality, it is often best to deliver the infant before the onset of natural labor. In making the decision for an early delivery, the physician relies on the clinical stability of the mother and fetus to decide between performing a cesarean section and inducing labor for a vaginal delivery.

Labor induction involves the stimulation of uterine contractions to produce delivery before the onset of spontaneous labor. This procedure has been commonly used since the synthesis of oxytocin (Pitocin) in the 1950s; labor is currently induced in about 13 percent of live births in the United States.¹ Most labor inductions are for postdate pregnancy (gestation of 42 weeks or more according to either early ultrasonography or two independent dating criteria), which occurs in about 10 percent of live births.^1,2

In the past decade, our knowledge of the mechanisms of labor has increased tremendously. In addition, the ability to detect and manage antepartum maternal and fetal complications has greatly improved. As a result, labor can be induced in an increasingly rational and successful manner. The most common indications for labor induction are noted in Table 1.^2–4 It is important that the pregnant patient be aware of the risks and benefits of labor induction and understand that the process may take several days. Anxiety and frustration may ensue if she expects delivery to occur at a particular time or day.

The contraindications to the induction of labor mirror those of spontaneous labor (Table 2).^2–4 Although not necessarily contraindications to induction, several obstetric conditions deserve special attention and may require consultation or assistance (Table 3). Several studies have shown that a history of one or more deliveries by low transverse cesarean section is not a contraindication to the induction of labor.^5,6 However, increased rates of cesarean section (31 percent versus 11 percent) and operative vaginal deliveries (31 percent versus 16 percent) have been reported in these patients compared with those without a prior cesarean section.⁶

In addition to the risks that normally occur with labor and delivery, inducing cervical ripening and labor adds the risks of uterine hyperstimulation, fetal distress and a greater likelihood of postpartum hemorrhage. Nursing staff who are properly trained in the use of uterine-stimulating agents should always monitor labor, with a physician or other health care professional nearby who is qualified to perform cervical assessments. Fetal heart rate (FHR) monitoring should be performed using a high-risk protocol, and a physician able to perform a cesarean section must be informed and available.

Physiology of Labor

The factors that initiate and promote labor are complex and not well understood. Oxytocin receptors in the uterus increase 100-fold by 32 weeks' gestation and 300-fold at parturition.⁷ Although important for the actual labor process, this increased sensitivity to oxytocin only minimally predicts the duration of labor, which is more affected by parity and cervical status at the onset of labor. A cervical scoring system, the Bishop system, has been developed for assessing multiparous women at the time of induction (Table 4).⁸ When the Bishop score exceeds 8, the likelihood of a successful vaginal delivery approaches that of spontaneous labor. The duration of pregnancy before spontaneous labor is inversely correlated with the score. Follow-up work has shown that a low Bishop score correlates with a prolonged labor or failed induction and the need for a cesarean delivery.³

Cervical ripening (the softening, effacement and dilation that occur before active labor) is mediated by multiple factors. Prostaglandin E₂ (PGE₂) and prostaglandin F_2α (PGF_2α) appear to be the final mediators in this process. Although the exact mechanism is unknown, exogenously applied prostaglandin agonists will induce cervical ripening.^9,10

Labor is generally defined as the progressive dilation of the uterine cervix in association with repetitive, strong uterine contractions. Endogenous or exogenous oxytocin is the main stimulator of uterine contractions. It also stimulates the production of PGE₂ and PGF_2α in vitro, and these may stimulate myometrial contractility.⁷

Methods of Cervical Ripening

Numerous methods have been used to promote cervical ripening, from the less orthodox—sexual intercourse, nipple stimulation, a variety of herbs and homeopathic solutions, castor oil, enemas and acupuncture—to more orthodox methods, such as stripping the membranes, mechanical dilation, amniotomy and pharmacologic preparations. A summary of the nonpharmacologic methods was recently published.⁹

OXYTOCIN

Some clinicians advocate administering a continuous infusion of oxytocin in a low dosage (no greater than 4 mU per minute). This method is effective for cervical ripening and has relatively few adverse effects.⁷ Patients will often progress to spontaneous labor in eight to 12 hours.

DINOPROSTONE: PGE2

PGE₂ (dinoprostone; Prepidil, Cervidil), administered intravaginally or intracervically, is the pharmacologic agent most widely used for ripening the cervix.^3,9,10 Prepidil gel containing 0.5 mg of dinoprostone has been labeled by the U.S. Food and Drug Administration for use in cervical ripening by intracervical administration.

Dinoprostone should be administered with the patient in or near a labor and delivery suite. The patient is expected to remain recumbent for the first 30 minutes and should be monitored for a further 30 to 120 minutes. When contractions occur, they usually appear within 60 minutes and peak within four hours.³ The optimal interval for administering another dose has not been determined, but six hours is commonly used. The gel should be kept refrigerated and brought to room temperature immediately before its use. The manufacturer recommends that no more than three doses be administered per 24 hours. End points for ripening include strong uterine contractions, a Bishop score of 8 or higher, or a change in the maternal or fetal status.

More recently, a PGE₂ vaginal insert has been developed for use in cervical ripening. Cervidil contains 10 mg of dinoprostone and provides a lower constant release of medication (0.3 mg per hour) than Prepidil does. Its efficacy is similar, and it is inserted and removed more easily if uterine hyperstimulation occurs. In addition, it does not require refrigeration. Extensive use of dinoprostone for cervical ripening has not revealed any serious adverse reactions.

Intravenous PGF_2α has been tried but offers no advantage over dinoprostone and has more side effects.¹¹

MISOPROSTOL: PGE1

Misoprostol (Cytotec) has been extensively investigated in the past few years for use in cervical ripening and labor induction. Marketed as a gastric cytoprotective agent, the drug is also an effective, safe and inexpensive agent for cervical ripening and labor induction, although it is not FDA-labeled for that purpose.^12–20

Misoprostol is a synthetic analog of PGE₁. When given orally, it is rapidly absorbed by the gastrointestinal tract and undergoes deesterification to its free acid, which is responsible for its clinical activity. The peak concentration and half-life of misoprostol acid, the active metabolite, are 12 and 21 minutes, respectively.²⁰ The total systemic bioavailability of vaginally administered misoprostol is three times greater than that of orally administered misoprostol.²¹

A meta-analysis¹² of eight randomized studies comprising 966 patients compared the use of intravaginal misoprostol for cervical ripening and labor induction with that of dinoprostone, oxytocin or placebo. Misoprostol was associated with a significantly lower overall rate of cesarean section, a higher incidence of vaginal delivery within 24 hours of application and a reduced need for oxytocin augmentation. Spontaneous labor occurred in nearly 85 percent of the women studied (Table 5).

The use of misoprostol has been associated with an increased incidence of tachysystole, defined as six or more uterine contractions in 10 minutes for two consecutive 10-minute periods.¹⁵ However, maternal outcomes, such as the need for cesarean delivery because of FHR abnormalities, the arrest of labor or the need for terbutaline (Bricanyl) administration, were not significantly different between the misoprostol group and the dinoprostone and oxytocin control groups.¹² Although the incidence of meconium staining was found in some studies to be higher with misoprostol, overall neonatal outcomes, including the frequency of meconium aspiration syndrome, the incidence of five-minute Apgar scores below 7 and the rate of neonatal resuscitation or admission to a neonatal intensive care unit, showed no significant differences between groups (Table 5).¹²

Other uterine contraction abnormalities occur with misoprostol, such as hypertonus and hyperstimulation syndrome (contractions lasting longer than 90 seconds or more than five contractions in 10 minutes). They can be managed by changing the maternal position and administering oxygen by face mask, terbutaline (0.25 mg) subcutaneously, or both. The incidence of hyperstimulation varies between 1 and 10 percent, depending on the dose of misoprostol and the frequency of administration.¹² Other uncommon complications resulting from misoprostol use include uterine rupture and fetal demise, but not at rates higher than in control subjects.²² Maternal effects such as nausea, vomiting or diarrhea are uncommon.^12,23,24

The primary advantages of misoprostol are cost and convenience. Prepidil and Cervidil cost $150 and $175 per insert, respectively, whereas a 100-μg Cytotec tablet costs $0.60.²⁵ Oxytocin costs only about $1.00 per 10-mU vial, but the expenses for the intravenous setup and monitoring must be included. The various methods for cervical ripening are compared in Table 6.

The optimal regimen for intravaginal misoprostol has not been firmly established. Most clinical trials used 25 to 100 μg prepared from oral tablets and inserted intravaginally. Misoprostol comes in 100- or 200-μg tablets, and the desired dose can be prepared in the pharmacy by dividing the tablet, which is then inserted into the posterior fornix. The most common dose is 50 μg, inserted either once or every four to six hours; however, inserting 25 μg every six hours is associated with the fewest side effects.^26,27 The maximum cumulative dosage of misoprostol has not been established, but a total dosage of up to 600 μg has been used safely in one clinical trial.¹² When oxytocin augmentation is necessary, a minimal interval of three hours is recommended after the last misoprostol dose.¹⁶ Continuous fetal monitoring is currently recommended for at least three hours after misoprostol application before the patient is allowed to ambulate.

Oral misoprostol is well tolerated for the management of upper gastrointestinal tract dysfunction. For this reason, oral administration of misoprostol for cervical ripening and labor induction has been tried. Investigators found that a single oral dose of 200 μg or a 50-μg dose given orally every four hours was effective, and adverse effects were no different from those in control subjects.^23,24 More studies are in progress to determine the optimal dosing regimen and to further define the safety and effectiveness of oral administration for induction of labor.

Informed consent should always be obtained from patients who are given misoprostol. No fetotoxic, teratogenic or carcinogenic effects have been observed in animal studies, and no untoward direct effects on neonates have been noted so far in any of the clinical trials.^{12–19,23,24,27}

Oxytocin Labor Induction

Once the cervix is ripe, oxytocin is still the favored pharmacologic agent for inducing labor. Typically, a patient with an unfavorable cervix is admitted to the hospital on the afternoon or evening before induction. Misoprostol, 25 to 50 μg, is administered intravaginally one to three times during the night. Oxytocin induction can proceed the next morning if the patient has not already gone into labor.

Oxytocin is prepared for use by placing 10 U in 1 L of isotonic intravenous solution to achieve a concentration of 10 mU per mL. Because severe hypotension can occur, especially with rapid intravenous administration, the drug is infused into the main intravenous line; a controlled infusion device must be used to determine its rate. It can be administered as a continuous infusion or in “pulsed” doses. Continuous infusions usually start with a dosage of 0.5 to 2.5 mU per minute, which is increased at the same increment every 15 to 60 minutes. The effect is noted within three to five minutes, and a steady state is achieved within 15 to 30 minutes. Studies show a wide range of effective dosages and change intervals, and no regimen has been shown to be clearly superior.^2,7,11

Oxytocin has many advantages: it is potent and easy to titrate, has a short half-life (one to five minutes) and is generally well tolerated. Dose-related adverse effects may occur, however. Because oxytocin is close to vasopressin in structure, it has an antidiuretic effect when given in high dosages (40 mU per minute); thus, water intoxication is a possibility in prolonged inductions.^2,3 Uterine hyperstimulation and uterine rupture can also occur. When the resting uterine tone remains above 20 mm Hg, uteroplacental insufficiency and fetal hypoxia can result. This outcome underscores the importance of continuous FHR monitoring.

If a worrisome FHR occurs during induction, the oxytocin dosage can usually be lowered rather than stopped completely. This allows the fetus to recover without unnecessarily slowing the entire labor. In emergency situations, the infusion can be stopped. Minor FHR abnormalities such as variable decelerations or lack of accelerations can be corrected by changing the mother's position, administering oxygen and increasing intravenous fluid administration. Induction using oxytocin has side effects, but because the drug does not cross the placental barrier, no direct fetal problems have been observed.