Induction of Labor

The history of labor induction dates back to Hippocrates' original descriptions of mammary stimulation and mechanical dilation of the cervical canal.¹ During the second century AD, Soranus practiced a combination of procedures to induce labor, including artificial rupture of the membranes. Other labor induction methods were introduced during this period; Moshion was the first to describe manual dilation of the cervix, and Casis invented several instruments capable of cervical dilation. Midway through the 16th century, Paré devised a technique that combined manual cervical dilation and internal podalic version in patients with uterine hemorrhage.² Bourgeois, a disciple of Paré, continued this practice and also induced and augmented labor with strong enemas and mixtures of several folk medicines.³

From the 2nd through the 17th centuries, mechanical methods to induce labor came into more common use. In 1756, at a meeting held in London, physicians discussed the efficacy and ethics of early delivery by rupturing the membranes to induce labor.⁴

In 1810, James was the first in the United States to utilize amniotomy to induce premature labor.⁵ Amniotomy and other mechanical methods remained the methods of labor induction most commonly employed until the 20th century.

In 1906, Dale observed that extracts from the infundibular lobe of the pituitary gland caused myometrial contractions.⁶ Three years later, Bell reported the first experience with use of a pituitary extract for labor induction.⁷ With the introduction of pituitary extract as a hormonal method of labor induction in 1913, the use of this method gained acceptance among obstetricians. However, due to the use of large doses and the impurity of the extract, numerous adverse effects were reported. Gradually, as the number of reported cases of uterine rupture increased, pituitary extract became discredited in many centers.

Initially, oxytocin (pituitary extract) was administered via intramuscular or subcutaneous routes. In 1943, Page suggested that the pituitary extract oxytocin be given in the form of an intravenous infusion,⁸ and in 1949, Theobald reported his initial results with this form of administration.⁹ Fourteen years later in 1953, the structural formula of oxytocin was discovered, and synthetic oxytocin has been in use since 1955.

In 1968, Karim and colleagues were the first to report the use of prostaglandins for labor induction.¹⁰ Since then, the use of prostaglandins, in different varieties and forms of administration, has become a common method of labor induction.¹¹ More recently, the synthetic prostaglandin analogue misoprostol has gained acceptance as an effective and safe method of labor induction.¹²

Although most patients experience spontaneous labor at term, induction of labor is sometimes indicated. Labor induction is a clinical intervention that has the potential to confer major benefits to the mother and newborn. Induction of labor is a common obstetric procedure. In 1993, approximately 640,000 births (16% of all live births) in the United States were a result of labor induction.¹³

Common indications for inducing labor include hypertensive disorders of pregnancy, postdatism, intraamniotic infection, suspected fetal jeopardy, and maternal medical problems including diabetes mellitus and chronic renal disease. However, labor induction is contraindicated when vaginal delivery would endanger the life of the mother or fetus. Common obstetrical complications that preclude labor induction include placenta previa, transverse fetal lie, prolapsed umbilical cord, and prior classical uterine incision.

The guiding principles for labor induction must be the obstetrician's judgment that the benefits to either the mother or the fetus outweigh those of continuing the pregnancy and that the induced labor must replicate spontaneous labor as closely as possible.

Successful labor induction is clearly related to the state of the cervix. Women with an unfavorable cervix, who have not experienced cervical ripening phase prior to labor, present the greatest challenge with regard to labor induction. In addition, the duration of labor induction is affected by parity and to a minor degree by baseline uterine activity and sensitivity to oxytocic drugs. Many investigators have identified the importance of assessing cervical status prior to induction of labor. Calkins and colleagues were the first to carry out systematic studies of the factors influencing the duration of the first stage of labor.¹⁴ They concluded that the length, thickness, and particularly the consistency of the cervix were important parameters. In 1955, Bishop devised a cervical scoring system for multiparous patients in which 0–3 points are given for each of five factors.^{15, 16} He determined that when the total score was at least 9, the likelihood of vaginal delivery following labor induction was similar to that observed in patients with spontaneous onset of labor. Although several modifications have been suggested, the Bishop score has become a classical parameter in obstetrics and has since been applied to nulliparous patients. In recent years, several studies have evaluated the possible role of transvaginal ultrasound examination of cervical length in the prediction of labor induction and outcome. A recently published systematic review with meta-analysis of 20 diagnostic studies concluded that sonographic cervical length was not an effective predictor of successful labor induction.¹⁷

Nonmedical methods

Numerous nonmedical methods for cervical ripening and labor induction have been employed (Table 1). Although popular with midwives, most are not routinely used by obstetricians, perhaps because they have not been subject to properly performed randomized trials.

Table 1. Nonmedical methods for cervical ripening and labor induction

  Sexual intercourse
  Breast stimulation
  Herbal preparations
  Homeopathic solutions
  Purgatives
  Enemas
  Acupuncture
  Stripping of the membranes

There is reasonable evidence to suggest that sexual intercourse and breast stimulation may be effective in ripening the cervix and inducing labor at term.^{18, 19} Due to the uncontrolled secretion of prostaglandins and/or oxytocin caused by these methods, it may be safer to limit these approaches to women at term with healthy, uncomplicated pregnancies.

The medical literature does not address the use of herbal preparations or homeopathic solutions. Purgatives such as castor oil and enemas were widely used in the past but have largely been abandoned as effective methods for labor induction. Acupuncture with either manual or electrical stimulation is an accepted method for labor induction in Asia and Europe; however, it is not widely employed in the United States.²⁰

Stripping of the membranes is perhaps the best studied nonmedical method for cervical ripening and labor induction. A number of randomized clinical trials have shown that membrane stripping successfully induces labor.^{21, 22} However, potential risks include infection, premature rupture of membranes, and bleeding from placental contact.

Mechanical methods

Mechanical methods, although mainly effective in causing cervical dilation, have been used for many years to induce labor.²³ The mechanical stimulation of the endocervical canal has been shown to trigger the release of prostaglandins. The more popular mechanical methods include amniotomy, balloon-tipped catheters, and natural and synthetic laminaria.

Amniotomy, or artificial rupture of the amniotic membranes, causes local synthesis and release of prostaglandins, leading to labor within 6 hours in nearly 90% of term patients. Turnbull and Anderson found that amniotomy without additional drug therapy successfully induced labor in approximately 75% of cases within 24 hours.²⁴

Mechanical dilation of the unripe cervix using balloon-tipped catheters has been employed for cervical ripening and labor induction for many years. Although various balloon catheters have been described, Foley catheters with 25–50-ml balloons are the most commonly used. Concomitant use of balloon-tipped catheters and pharmacologic agents has been effective in labor induction; however, the cost of combination therapy is markedly increased.²⁵

Natural and synthetic laminaria have been shown to be effective in cervical ripening, more so than labor induction. Although their safety and efficacy have been established in the second trimester, a high incidence of infection is associated with the use of laminaria during the third trimester of pregnancy.²⁶

Since mechanical agents represent foreign bodies placed into or through the cervix, many obstetricians feel that their use could increase infection risk. A recently published meta-analysis of 30 randomized trials comparing labor induction with mechanical methods with alternative pharmacologic agents or placebo demonstrated that maternal and neonatal infections were increased in women who underwent labor induction with mechanical methods.²⁷ This finding raises the question of whether prophylactic antibiotics are indicated in patients undergoing labor induction with mechanical methods.

Pharmacological methods

OXYTOCIN

Oxytocin, a neurohormone originating in the hypothalamus and secreted by the posterior lobe of the pituitary gland, represents the agent most frequently used for labor induction. A controlled intravenous infusion, with or without amniotomy, causes enough uterine activity to produce cervical dilation and effect delivery. Because oxytocin often does not promote cervical ripening, it is usually not effective in patients with unripe cervices. The incidence of failed inductions under these circumstances approaches 50% but can be markedly reduced with the use of pre-induction cervical ripening agents.²⁸

Due to the high activity of placental oxytocinase, the plasma half-life is short, and steady-state levels are achieved after 40 minutes of continuous intravenous infusion. Gestational age is a major factor affecting the dose response to oxytocin. Due to the appearance of oxytocin receptors in the myometrium, the uterus starts to respond to oxytocin at approximately 20 weeks' gestation. From 34 weeks' gestation until term, no change in sensitivity is noted. However, once spontaneous labor begins, uterine sensitivity increases rapidly.

The optimum initial oxytocin dose, interval and frequency of dosage increase, and methods of infusion are the subject of considerable debate. Several randomized trials have shown a wide range of dosages and frequencies to be successful.^{29, 30, 31} Dose increment schedules as short as 15 and 30 minutes have been compared using starting doses of 0.5–2.5 mU/minute with increases in the same amount; no significant difference was found between the two groups.

Most commonly, oxytocin is initiated at a dosage of 1 mU/minute, with increases of 1 or 2 mU/minute every 20–30 minutes until a maximum administration rate of 16–32 mU/minute is reached or adequate uterine activity is present. Other protocols for oxytocin infusion have been reported. A more conservative mode of infusion calls for a starting dose of 0.5 mU/minute with similar dose increases at intervals of 60 minutes. Both 20- and 40-minute dosage intervals have been shown to be safe and efficient when using oxytocin at starting doses of 6 mU/minute with equal increases.

The recognition that endogenous oxytocin is secreted in spurts during pregnancy and spontaneous labor has prompted exploration of a more physiologic manner of inducing labor with this agent. Cummiskey and Dawood³² performed a randomized trial to determine the safety and efficacy of pulsed administration of oxytocin in comparison with the traditional continuous infusion. The authors concluded that pulsed administration of oxytocin is as safe and effective as continuous infusion. One obvious advantage is the reduction of fluid volume required to administer the drug and the lower doses of oxytocin required.

Because the most common adverse effect of oxytocin infusion is fetal heart rate (FHR) deceleration associated with increased uterine activity, it is essential that FHR and uterine contractions be continuously monitored to observe any tachysystole or hyperstimulation requiring intervention. Water intoxication, a result of the antidiuretic effect of oxytocin, can occur when large volumes of electrolyte-free fluids are infused.

PROSTAGLANDINS

Induction of labor with prostaglandins (PGs) offers the advantage of promoting cervical ripening while stimulating myometrial contractility. The use of PGs as induction agents has been reported extensively in a variety of PG classes, doses, and routes of administration.^{33, 34, 35} The distinction between cervical ripening and labor induction is superfluous in patients receiving prostaglandins because many women will go into labor on receiving prostaglandins.

Dinoprostone (PGE₂) is the prostaglandin most commonly employed in obstetrics. This prostaglandin plays an important role in the cervical ripening process and in initiating and maintaining labor. The optimal route for administration of PGE₂ has not yet been determined. Generally, two routes of administration have been used: intravaginal and intracervical. The intracervical route has been used in approximately two thirds of reported clinical trials. Dinoprostone for intracervical application is approved for commercial use in the United States by the Food and Drug Administration (FDA) as Prepidil (dinoprostone; PGE₂). The commercial dinoprostone gel contains 0.5 mg of dinoprostone in 2.5 ml of triacetin and colloidal silicon dioxide gel in a prefilled applicator. Peak absorption of the drug occurs within 30–45 minutes of application. Repeat doses may be given at 6-hour intervals, with a maximum 24-hour dose of 1.5-mg dinoprostone. Placebo-controlled trials have shown that application of intracervical PGE₂ more often leads to successful cervical ripening and labor induction in patients with similar Bishop scores.^{36, 37}

A sustained-release 10-mg dinoprostone vaginal insert has also received FDA approval and is commercially available (Cervidil, Forest Laboratories, St Louis, MO). The vaginal insert consists of a thin, flat, polymeric hydrogel chip (29 × 9.5 × 0.8 mm) with rounded corners placed in a knitted polyester retrieval pouch. Each insert contains 10 mg of dinoprostone in a dried polymer matrix that releases dinoprostone at a controlled rate of 0.3 mg/hour for 12 hours when rehydrated on exposure to the vaginal mucosa. The insert has been shown to promote cervical ripening in pregnant women at or near term, producing a Bishop score of at least 3 by 12 hours. Active labor and vaginal delivery are more likely to occur within this 12-hour period, reducing the need for oxytocin infusion. Nearly three quarters of patients require only a single application.³⁸

Prior to FDA approval of the intracervical and vaginal insert dinoprostone preparations, hospital-prepared gel was frequently utilized. The majority of these preparations combined a dinoprostone suppository (Prostin E₂, Pharmacia & Upjohn, Kalamazoo, MI) with methylcellulose gel (K-Y Jelly) and were applied either vaginally (2.5–5 mg) or intracervically (0.5 mg). Comparative studies have not shown any benefit of the FDA-approved product over the hospital-prepared gels.^{39, 40}

The most common complications observed in patients treated with PGE₂ for cervical ripening and labor induction have been tachysystole and hyperstimulation of the uterus. These results appear to be dose related and are rarely seen in patients receiving small doses (0.5 mg). Other complications resulting from PGE₂ induction include uterine rupture, amniotic fluid embolism, and myocardial infarction. Fortunately, these serious complications are extremely rare.

Numerous reports, including a meta-analysis, have found that misoprostol, a synthetic PGE₁ analogue, safely and effectively ripens the cervix and induces labor in patients with unfavorable cervices.⁴¹ Intravaginal doses of 25–50 μg have been shown to shorten the interval from induction to vaginal delivery and to lower the cesarean delivery rate. Several studies have shown similar results with oral doses of 100 μg every 4 hours. Although tachysystole is frequently noted with repeated vaginal doses of 50 μg, the incidence of hyperstimulation syndrome (tachysystole associated with FHR abnormalities) is not increased. In addition to being a safe and effective method, it is very economical.

There are concerns that dividing the tablets may not provide accurate or consistent doses of misoprostol, and there is uncertainty about vaginal release characteristics from a tablet designed for oral use. Research is currently under way to assess the safety and efficacy of a misoprostol vaginal insert at doses of 50 and 100 μg. A recently published randomized controlled trial compared the misoprostol vaginal insert (50 and 100 μg) with the commercially available dinoprostone vaginal insert. The misoprostol vaginal insert with 100 μg and the dinoprostone insert had similar median time intervals to vaginal delivery. The 50 μg insert had significantly longer time to vaginal delivery.⁴²

Other pharmacologic methods

MIFEPRISTONE

The role of mifepristone (RU-486), a progesterone antagonist, in labor induction is not as well established as it is for therapeutic abortions. Mifepristone has been used with some success for the induction of labor in cases of intrauterine fetal demise of at least 16 weeks' gestation. A randomized double-blind trial employing 200 mg of mifepristone daily for 2 days resulted in a shorter interval to the onset of labor, and less oxytocin was required for those achieving vaginal delivery.⁴³ In the mifepristone group, 58% went into spontaneous labor, compared with 22.6% in the placebo group. The cesarean delivery rate did not differ between the two groups, and no side effects were encountered in the treatment group. More recently, Elliot and colleagues⁴⁴ compared the effects of 50 mg and 200 mg of oral mifepristone with placebo on cervical ripening and labor induction in primigravid women with unfavorable cervices at term. At a dose of 200 mg, mifepristone resulted in a favorable cervix or spontaneous labor more often than did placebo. Further studies are required to confirm the role of mifepristone as a labor-inducing agent.

RELAXIN

Relaxin is a polypeptide hormone, similar to insulin, produced by the ovaries, decidua, and chorion. Because it affects connective tissue remodeling, it has been studied as a cervical ripening agent. Several clinical trials using purified porcine relaxin, administered either vaginally or intracervically, demonstrated its effectiveness in cervical ripening. Recently, however, studies employing vaginal recombinant human relaxin (1–4 mg) have shown no significant benefit as a pre-induction cervical ripening agent.^{45, 46, 47}

CYTOKINES

The role of cytokines in cervical ripening is currently under investigation. These chemotactic agents promote the migration and activation of inflammatory cells, which in turn are a source of collagenase and other enzymes capable of digesting extracellular matrix proteins. Topical application of certain cytokines (interleukin-8 [IL-8] and IL-1β) have been shown to induce cervical ripening in pregnant guinea pigs without initiating frank uterine activity.⁴⁸

NITRIC OXIDE

Animal studies have shown that the free-radical gas nitric oxide is upregulated in the uterine cervix during labor and leads to cervical ripening.⁴⁹ Recent studies using nitric oxide donors (isosorbide monotitrate and glyceryl trinitrate) have shown enhancement of cervical ripening in patients undergoing first-trimester termination of pregnancy. The role of nitric oxide in cervical ripening and labor induction is still considered investigational.⁵⁰ Recent publications have assessed the efficacy and safety of vaginal nitric oxide (isosorbide mononitrate) for outpatient pre-induction cervical ripening. The results of these studies indicate that this agent show some promise as an effective cervical ripening agent.^{51, 52}

In general, clinicians favoring a trial of labor in a woman who has had a previous cesarean also consider labor induction an appropriate procedure when indicated. Likewise, some clinicians feel that if there is no contraindication to labor and delivery, there is no contraindication to cervical ripening, induced labor, or augmented labor for patients with a previous cesarean birth.

Most methods employed for cervical ripening and labor induction in patients with an unscarred uterus are also used in patients with previous cesarean delivery. Several trials have shown that cervical ripening and labor induction with oxytocin or PGE₂ is safe and effective in patients with previous cesarean.^{53, 54} Chez performed a literature review from 1981 to 1994 and found that the overall incidence of dehiscence (0.3%) and uterine rupture (0.5%) was similar in patients with previous cesarean undergoing labor induction compared with patients in spontaneous labor.⁵⁵ There are insufficient data with regard to the use of misoprostol for labor induction in patients with a previous cesarean. Because of three cases of uterine ruptures, two recent reports warned against the use of this drug in patients with scarred uteri.^{56, 57} However, these patients had unknown scars and received large amounts of oxytocin for augmentation.

In a recent systematic review, the rate of uterine rupture during labor induction in women with previous cesarean delivery ranged from 0.35%, in a propspective cohort study of oxytocin, to 4.35% in an observational study of amniotomy, oxytocin and dinoprostone. The results of this review indicated that there was no significant increase in uterine rupture rate among those induced compared with spontaneous labors. When compared with women in spontaneous labor, those who received oxytocin and dinoprostone had slightly increased cesarean delivery rates.⁵⁸

Labor induction performed when the cervix is unripe is associated with a higher incidence of prolonged labor, instrumental delivery, and cesarean birth. Bahn and associates⁵⁹ examined the effect of labor induction length on maternal and neonatal outcome. They concluded that prolonged induction is associated with a small increased risk of infectious morbidity, with an estimated 10% incidence noted after 40 hours in women who deliver vaginally.

Labor induction has been found to have variable effects on the cesarean delivery rate. Undoubtedly, labor induction in nulliparous women with an unfavorable cervix is associated with an increased cesarean delivery rate. A meta-analysis and extensive review of the literature did not demonstrate a significant reduction in cesarean delivery rates with the use of dinoprostone (PGE₂) preparations.¹¹ However, in a similar study, Sanchez-Ramos and colleagues concluded that labor induced using misoprostol was associated with a reduced incidence of cesarean deliveries.⁴¹

Neonatal outcomes following labor induction compare favorably with those achieved after spontaneous labor. The likelihood of abnormal Apgar scores, need for admission to the neonatal intensive care unit, or perinatal death is not significantly increased with labor induction. A higher incidence of neonatal hyperbilirubinemia has been reported with oxytocin-induced labors. More recently, a cohort study of 100 newborns whose mother had been induced with either oxytocin or misoprostol, concluded that neither agent appeared to have harmful effects on bilirubin levels in the neonate.⁶⁰

Labor induction appears to be a safe alternative to spontaneous labor. Regardless of the method employed, it is essential that the patient and her obstetrician understand the rationale for inducing labor, the risks of the method chosen, and the options that will be considered in case of failed induction. The goal of labor induction must always be to ensure the best possible outcome for mother and newborn.