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Chapter 71

Induction of Labor
Luis Sanchez-Ramos and Andrew M. Kaunitz
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Table Of Contents

Luis Sanchez-Ramos, MD
Professor, Division of Maternal-Fetal Medicine, University of Florida Health Science
Center, Jacksonville, Florida (Vol 2, Chap 71)
Andrew M. Kaunitz, MD
Professor and Assistant Chair, Department of Obstetrics and Gynecology, University of
Florida Health Science Center, Jacksonville, Florida (Vol 2, Chap 71; Vol 6, Chaps 15,
28)

HISTORY OF LABOR INDUCTION


INDICATIONS AND CONTRAINDICATIONS FOR LABOR INDUCTION
PRE-INDUCTION STATUS OF THE CERVIX
METHODS OF LABOR INDUCTION
LABOR INDUCTION IN WOMEN WITH PREVIOUS CESAREAN DELIVERY
EFFECT ON PREGNANCY OUTCOME
CONCLUSION
REFERENCES

HISTORY OF LABOR INDUCTION


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 A.D., 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, Par devised a technique
that combined manual cervical dilation and internal podalic version in
patients with uterine hemorrhage.2 Bourgeois, a disciple of Par,
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 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.7With 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

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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 ofoxytocin 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
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INDICATIONS AND CONTRAINDICATIONS FOR


LABOR INDUCTION
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.
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PRE-INDUCTION STATUS OF THE CERVIX


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 to 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.
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METHODS OF LABOR INDUCTION


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.17,18 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 ascastor 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.19
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.20,21 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. 22 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.23
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- to 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.24
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.25
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.26
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 tooxytocin. Due to the appearance
of oxytocin receptors in the myometrium, the uterus starts to respond
to oxytocinat 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.27,28,29 Dose increment
schedules as short as 15 and 30 minutes have been compared using
starting doses of 0.52.5 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 to 30 minutes until a
maximum administration rate of 16 to 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
Dawood30 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 ofoxytocin, 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.31,32,33 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 PGE2has 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 to 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.34,35
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 fourths of
patients require only a single application.36
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
to 5 mg) or intracervically (0.5 mg). Comparative studies have not
shown any benefit of the FDA-approved product over the hospitalprepared gels.37,38
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.39 Intravaginal doses of 25 to 50 g 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 g every 4 hours. Although tachysystole is
frequently noted with repeated vaginal doses of 50 g, 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.

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
ofmifepristone daily for 2 days resulted in a shorter interval to the
onset of labor, and less oxytocin was required for those achieving
vaginal delivery.40 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 colleagues41 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 (14 mg) have shown no significant benefit as a preinduction cervical ripening agent.42,43,44
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-1) have been shown to induce cervical ripening in
pregnant guinea pigs without initiating frank uterine activity.45
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.46 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 these agents in cervical ripening and labor
induction is presently investigational.47
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LABOR INDUCTION IN WOMEN WITH PREVIOUS


CESAREAN DELIVERY
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 withoxytocin or PGE2 is safe and effective
in patients with previous cesarean.48,49 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.50 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.51,52 However, these patients had unknown scars and received
large amounts of oxytocin for augmentation.
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EFFECT ON PREGNANCY OUTCOME


Labor induction performed when the cervix is unripe is associated with
a higher incidence of prolonged labor, instrumental delivery, and
cesarean birth. Bahn and associates53 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. 39
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
withoxytocin-induced labors.
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CONCLUSION
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.
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