induction of labor and pregnancy termination for termination
for fetal abnormality
induction of labor
definition
labor induction is
the stimulation of regular uterine contractions before the spontaneous onset of
labor, using mechanical or pharmacologic methods in order to generate
progressive cervical dilation and subsequent delivery. although the term
generally refers to patients who are at term, it is also employed for women who
are at least 20 weeks gestation. it is important to distinguish labor induction
from augmentation, which refers to stimulation of uterine contractions when
spontaneous contractions during labor have been considered inadequate.
introduction
induction of labor
is an important and common clinical procedure in obstetrics. the rate of labor
induction in the united states continues to rise significantly for all
gestational ages. preliminary data for the year 2002 from the national center
for health statistics indicate that the rate was 20.5% for the year 2001, more
than twice the 1989 level of 9%.[1]
the reason for this increase is unclear, although it may partly reflect a
growing use of labor induction for post-date pregnancies and an increasing
trend toward elective induction of labor for other indications (including
maternal request).
indications and contraindications
generally, labor
induction is indicated when the benefits of delivery to the mother or fetus
outweigh the potential risks of continuing the pregnancy. the most appropriate
timing for labor induction is the point at which the maternal or perinatal benefits
are greater if the pregnancy is interrupted than if the pregnancy is continued.
ideally, most pregnancies should be allowed to reach term, with the onset of
spontaneous labor being the sign of physiologic termination of pregnancy.
however, occasionally a woman is best delivered before the spontaneous onset of
labor. commonly accepted indications for labor induction are listed in table
68-1 . of the standard indications for labor induction, pregnancy-induced
hypertension and post-date pregnancies are among the most common, accounting
for more than 80% of reported inductions. given that there is an indication for
induction, the risks to mother and fetus must then be considered, to make sure
that the benefit outweighs these risks. the risks to the mother are mainly
related to an increased chance that she will need operative delivery, compared
with labor following the spontaneous onset of labor. the risks to the fetus are
those of prematurity. whenever there is evidence of fetal lung maturity, or the
pregnancy has reached at least 39 weeks (confirmed by an early ultrasound) the
decision to induce labor is not difficult. maternal consent to any increased
risk of operative delivery can be obtained, and the fetus is not likely to be
at risk for complications that cannot be dealt with in a modern neonatal unit.
however, the decision to induce labor prior to fetal maturity having been
achieved is far more difficult. in such cases, premature delivery should offer
the fetus clear benefits that outweigh the potential problems associated with
preterm birth. although elective induction of labor (without medical or
obstetric indications) is generally not recommended, logistic factors such as
distance from the hospital or a history of rapid labor and delivery may be
reasonable indications for elective induction. the issue of induction of labor
from 39 weeks at maternal request (usually due to intolerance of the
discomforts of pregnancy, but sometimes for social reasons, e.g., the limited
availability of the father to attend the birth) remains controversial.
requirements for labor induction
prior to inducing
labor, the obstetrician should carefully review the indication(s) for ending
the pregnancy and obtain informed consent. in addition, the mother and fetus
should be carefully examined and, if indicated, fetal pulmonary maturity should
be documented. in order to avoid iatrogenic prematurity, an amniocentesis to
assess fetal lung maturity may be required. table
68-3 lists criteria, which if met, allow fetal maturity to be assumed, so
that amniocentesis need not be performed.[2]
preinduction 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 a 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.[3]
the authors 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 with planned elective
induction of labor in which 0 to 3 points are given for each of five factors.[4]
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 a much wider group of patients. nulliparous women
with a bishop score no greater than 3 have a 23-fold increased risk of
induction failure and a two- to four-fold increased risk of cesarean delivery
compared with nulliparous women with a bishop score of at least 4.[5]
similarly, multiparous women with a bishop score of no greater than 3 have a
sixfold increased risk of failed induction and twofold increased risk of
cesarean birth compared with those women with higher bishop scores.[5][6]
the bishop score
has become the most commonly employed preinduction scoring system. several
recent studies have assessed the predictive accuracy of ultrasound for
successful labor induction.[7][8][9]
however, there is a lack of convincing evidence that this technique provides
significant additional information when compared to digital examination.
preinduction cervical ripening
cervical ripening
is the process that culminates in the softening and distensibility of the
cervix, thus facilitating labor and delivery. there is an inverse relationship
between the bishop score and the failure of labor induction, with low scores
being associated with a high rate of failed induction. moreover, not only is
inducing uterine contractions in the presence of an unripe cervix more likely
to lead to delivery by cesarean section, but even if vaginal delivery is
eventually achieved, the labor will often have been prolonged. this is a
particular problem if the
induction is for fetal indications, as then prolonged fetal monitoring is also
required. in addition, an extended exposure to uterine contractions and the
resulting reduction in intervillous blood flow can result in fetal hypoxia and
acidosis. thus, it is useful to employ cervical ripening agents to prepare the
unripe cervix for labor induction. ideally, a ripening agent would act upon the
cervix to make it more favorable without inducing uterine activity the length
of the active phase of labor would thereby be minimized, limiting the stress on
the fetus to the minimum. unfortunately, it has proved difficult to separate
methods of cervical ripening and labor induction. patients with an unripe
cervix may undergo cervical ripening without initiating labor contractions when
a pharmacologic agent such as dinoprostone (pge2) is employed, but sometimes
contractions ensue before the cervix has ripened. a considerable amount of
research has been directed toward various methods to prepare or ripen the
cervix prior to the induction of labor. although many of these methods also
initiate uterine activity, it should be appreciated that the principal role of
these agents is to soften the unripe cervix independently of uterine activity.
the various methods for cervical ripening can be divided into two categories ( table
68-4 ):
mechanical
pharmacologic
mechanical methods
foley catheter
mechanical
methods have been employed for many years to ripen the cervix prior to labor
induction.[10] barnes, in the mid-19th century, was one of the first to describe the
use of a balloon catheter to ripen the uterine cervix.[11] since that time several variations of this method have been
popularized. the balloon catheter currently most frequently used is a foley
catheter with a 25- to 50-ml balloon, which can be passed through an undilated
cervix before inflation of the balloon above the internal os. it is thought
that the mechanical separation of the fetal membranes from the cervix and lower
segment stimulates local cytokine and prostaglandin release, and these act upon
the ground substance of the cervix to break down the cross-links between the glycosaminoglycans.
more recently, extra-amniotic saline infusion has been a successful
modification to the use of balloon catheters for cervical ripening, presumably
by enhancing this effect.[12][13][14] a recent review of 13 trials in which balloon catheters were used for
cervical ripening concluded that with or without extra-amniotic saline infusion,
the method resulted in improved bishop scores and decreased
induction-to-delivery intervals.[15] simultaneous use of balloon-tipped catheters and pharmacologic agents
has been shown to be even more effective for cervical ripening than for labor
induction however, the cost of such combination therapy is substantial.
laminaria tents
laminaria tents,
natural and synthetic, have been used as a mechanical method for cervical
ripening for many years. although their safety and efficacy in the second
trimester have been established, use of laminaria during the third trimester of
pregnancy is associated with a high incidence of infection.[16] synthetic hygroscopic cervical dilators have also been used for many
years as agents to prepare the cervix for pregnancy termination. several
studies have shown that these osmotic dilators can also be successfully
employed for cervical ripening in viable pregnancies with an unripe cervix.[17][18][19] advantages to the use of osmotic dilators are their low cost and ease
of placement and removal.
membrane stripping
membrane
stripping (sometimes known as "membrane sweep") is a simple technique
not infrequently used to ripen the cervix, in which a finger is inserted
through the cervix and "swept" around the lower segment above the
internal os in a circular motion. as with the foley catheter, it appears to
work by release of prostaglandin (especially prostaglandin f2?) from the
decidua and the adjacent membranes. however, presumably because it is more
vigorous, it often stimulates uterine contractions as well as causing ripening.
a recent systematic review showed no evidence of an increase in the risk of
maternal or perinatal infection when "sweeping" is used.[20] however, there are adverse effects such as discomfort during the
necessarily vigorous vaginal examination and occasionally bleeding from the
cervix or placental margins if the placenta is low lying. moreover, if the
induction is for fetal compromise, the ensuing contractions mandate fetal
monitoring even if labor does not become established.
acupuncture
although much
more common in asia, acupuncture for cervical ripening and labor induction is
also becoming more available in the western world. a recent study concluded
that acupuncture at points li 4 (large intestine 4) and sp 6 (spleen 6) induces
cervical ripening at term, and in
postdated pregnancies it shortens the time interval between the estimated date
of confinement and the actual time of delivery.[21]
pharmacologic methods
prostaglandins
the use of
prostaglandins for cervical ripening has been reported extensively, involving a
variety of prostaglandin classes, doses, and routes of administration.[22][23][24] the distinction between cervical ripening and labor induction is
blurred in patients receiving prostaglandins because many women will go into
labor even when prostaglandins are being used primarily for ripening.
dinoprostone, or pge2, is the prostaglandin most commonly employed. the local
application of pge2 results in direct softening of the cervix by at least three
mechanisms: (1) it softens the cervix by altering the extracellular ground
substance of the cervix, (2) it increases the activity of the smooth muscle of
the cervix and uterus, and (3) it leads to gap junction formation that is
necessary for the coordinated uterine contractions of labor.[25][26]
meta-analyses
have shown that prostaglandins are superior to placebo and oxytocin alone in
ripening the cervix.[27][28] a systematic review including at least 5000 pregnancies from more
than 70 prospective trials suggests that pge2 is superior to placebo or no
therapy in enhancing cervical effacement and dilation.[27]
two forms of pge2
(dinoprostone) are available commercially in the united states, although even
more forms are available in other western countries. in randomized trials, the
two forms are similar in efficacy.[29][30][31] the first is formulated as a gel and is placed endocervically, but
not above the internal os. the application, 0.5 mg, can be repeated in 6 hours,
not to exceed three doses in 24 hours. the second form is a 10-mg vaginal
insert that is placed in the posterior fornix of the vagina. this formulation
allows for controlled release of dinoprostone over 12 hours, after which it is
removed.
misoprostol
(synthetic analogue of pge1) has been the subject of numerous recent articles
describing its use as a cervical ripening agent.[32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50] doses of 25 to 50 µg administered vaginally or orally have been shown
in several studies to be effective in inducing cervical ripening and labor.
however, because the majority of patients experience regular uterine
contractions soon after the initial dose, misoprostol should be considered
primarily a labor induction agent, which occasionally ripens the cervix without
uterine activity.
the role of
cytokines in cervical ripening has been the subject of several recent studies.[51] interleukin 8 (il-8) can lead to neutrophil chemotaxis, which is
associated with collagenase activity and cervical ripening.[52] these inflammatory agents may be particularly important as mediators
of cervical ripening associated with preterm labor. nitric oxide synthase (nos)
and nitric oxide (no) have been postulated to have a regulatory role in the
myometrium and cervix during pregnancy and parturition.[53][54][55] in the human cervix, ripening is associated with an increase in
inducible nos (inos) and neural nos expression in the cervix.
resident and
migrating inflammatory cells can cause an increase in inos activity. in the
primate, cervical ripening has many aspects of an inflammatory process: tissue
remodeling and breakage of chemical bridges between collagen fibers.
inflammatory agents such as il-1, tumor necrosis factor-alpha, and il-8 all
seem to be involved in cervical ripening.[56][57][58] currently, however, there is no commercial product available that
exploits these properties directly.
relaxin is a
polypeptide hormone, similar to insulin, produced by the ovaries, decidua, and
chorion. because of its effect on connective tissue remodeling, it has been
studied as a cervical ripening agent.[59][60] based on data from animal studies, relaxin was predicted to have a
cervical ripening effect in humans. the findings that porcine relaxin induces
cervical ripening in humans supported this prediction. however, because studies
showed that in fact administered human relaxin has no effect on the human
cervix, the usual role played by relaxin in human pregnancy and parturition is
unclear. at the present time, relaxin, either purified porcine or recombinant
human, is not produced commercially as a cervical ripening agent, and its
future potential in this context remains unclear.
pharmacologic methods for labor induction
oxytocin
oxytocin, a
neurohormone originating in the hypothalamus and secreted by the posterior lobe
of the pituitary gland, is the most commonly used drug for the purpose of labor
induction in viable pregnancies. this octapeptide is secreted in a pulsatile
manner, a fact that is reflected in the marked variability observed in minute-
to-minute measurements of maternal plasma oxytocin concentration.[61] the half-life of oxytocin is 10 to 12 minutes.[62] the metabolic clearance rate is similar for men, pregnant women, and
nonpregnant women: 20 to 27 ml/kg/minute.[63] the similarity of the metabolic clearance rate between men and
pregnant women is striking in view of the large increase that occurs during
pregnancy in the plasma concentration of leucineaminopeptidase, an enzyme
capable of hydrolyzing oxytocin. this suggests that factors other than this
enzyme are responsible for the degradation of oxytocin.
there is
considerable confusion regarding the pharmacokinetics of oxytocin much of the
original pharmacokinetic work was done prior to the availability of a reliable
radioimmunoassay for oxytocin.[64] indeed, the potency of oxytocin is still based on a bioassay of avian
vasopressive activity with 1 united states pharmacopeia (usp) unit being
equivalent to 2 µg of oxytocin. traditionally,
it has been held that oxytocin levels reached a steady-state level within 15 to
20 minutes of beginning an infusion or increasing the dosage. recent work using
a sensitive oxytocin radioimmunoassay has shown that approximately 40 minutes
are required for any particular dose of oxytocin to reach a steady-state plasma
concentration.[65]
it is well
established that there is a marked variability in the response of the uterus to
oxytocin, but in general, the sensitivity of the uterus to oxytocin increases
dramatically as pregnancy progresses.[66] this increase in responsiveness is likely due to the increasing
concentrations of oxytocin receptors in the myometrium and decidua with
increasing gestational age.[67] it appears that oxytocin has direct stimulatory effects on the
myometrium in addition to stimulating decidual prostaglandin production.[68] an increased level of prostaglandin f2? (pgf2?) metabolite was
demonstrated in women undergoing successful oxytocin induction of labor,
whereas this increase was not present in failed inductions.[69] the direct effect of oxytocin on the myometrium is believed to be
mediated by polyphosphoinositide hydrolysis with production of inositol
phosphates that act as a second messenger and lead to the mobilization of
intracellular calcium ion.[70]
other organs that
show a response to oxytocin include breast, vascular smooth muscle, and kidney.
oxytocin stimulates contraction of the myoepithelium surrounding the alveoli of
the mammary gland, leading to the milk ejection reflex. at dosages typically
used for the induction of labor, there is no demonstrable effect on vascular
smooth muscle tone. however, intravenous boluses of as little as 0.5 iu
transiently decrease peripheral vascular tone, leading to hypotension.[71] similarly, at low dosages, oxytocin exerts negligible effect on renal
function however, at high infusion rates, it exhibits a marked antidiuretic
effect (which is not surprising, given its similarity in structure to antidiuretic
hormone, also produced in the posterior pituitary). excessively high infusion
rates, coupled with infusion of crystalloid, have led to deaths from water
intoxication.
oxytocin can be
administered by any parenteral route. it is also absorbed by the buccal and
nasal mucosa. when administered orally and swallowed, oxytocin is rapidly
inactivated by trypsin. the intravenous route is now used almost exclusively to
stimulate the pregnant uterus because it allows precise measurement of the
amount of medication being administered and a relatively rapid discontinuation
of the effects of the drug when infusion is discontinued.
techniques for the administration of oxytocin
oxytocin is
administered as a dilute solution with the flow rate into the intravenous line
precisely regulated by an infusion pump. the health care professionals who
attend the patient during an induced labor must be familiar with the use and
potential complications of oxytocin. likewise, a qualified physician who is
able to manage any complications that may arise with the use of oxytocin should
be readily available. fetal monitoring is indicated prior to beginning the
infusion to assess the baseline level of uterine activity and fetal status, and
should then be continued during the infusion. either external or internal
monitoring is acceptable as long as uterine activity and fetal heart rate are
adequately documented. consideration should be given to the use of internal
monitoring when high doses of oxytocin are required or when satisfactory progress
in labor is not being made (see also chapter 69 on the augmentation of labor). the tracing should be inspected
frequently and carefully for any evidence of hyperstimulation as manifested by
increased baseline tonus, tachysystole, or the onset of late decelerations and
the infusion of oxytocin must be stopped immediately should they occur.
significant
difference of opinion exists regarding the initial dose of oxytocin and the
interval and frequency of dosage increase. a controlled intravenous oxytocin
infusion remains the preferred method of induction of labor. several trials
have compared various regimens of oxytocin dosage increase and time intervals
between dose increases.[72][73][74][75][76] starting doses have ranged from 0.5 to 2.0 mu/minute, with some as
high as 6 mu/minute. increments of dose increase have ranged from a low of 1 to
2 mu/minute up to 6 mu/minute, with adjustments for increased uterine activity.
time intervals between increases have ranged from 15 to 40 minutes. although
low-dose regimens (initial dose 0.5–2.0 mu/minute, with incremental increases
of 1–2 mu/minute every 15–40 minutes) are commonly utilized in the united
states, high-dose regimens (initial dose 6–8 mu/minute, with incremental
increases of 6 mu/minutes every 15–40 minutes) have been reported to be safe
and effective for labor induction in patients with viable pregnancies, provided
there was close fetal monitoring and early recourse to cesarean delivery in the
event of fetal distress.[77] a meta-analysis of 11 trials comparing low-dose with high-dose
oxytocin for labor induction found that larger dose increases and shorter
intervals between increases were associated with shorter labors and lower rates
of intraamniotic infections and cesarean delivery for dystocia, but more
hyperstimulation was noted.[78] based on recent pharmacokinetic data,[79][80] many obstetricians have moved to a regimen whereby the dose of
oxytocin is increased by 1 to 2 mu/minute every 40 minutes. advantages of this
regimen derive from not increasing the oxytocin dose before steady-state levels
of oxytocin have been reached. this leads to a lower total dosage of oxytocin
being used, in addition to a lower incidence of the hyperstimulation that can
result from increasing the oxytocin dose before a steady state is reached. a potential
disadvantage is that women who are relatively insensitive to oxytocin may have
a very prolonged course before adequate labor is established. nearly 90% of
patients will respond to 16 mu/minute or less, and it is most unusual for a
patient to require more than 20 to 40 mu/minute.[81]
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. in 1978, pavlou and associates were the first to describe a
protocol of pulsatile infusion.[82] more recently, several randomized trials have compared the safety and
efficacy of pulsatile oxytocin administration with continuous infusion.[83][84][85] most authors conclude that although there does not appear to be a
shortening of the induction-to-delivery interval, pulsatile administration of
oxytocin reduces the amount of oxytocin required for successful labor
induction.
side effects and complications of oxytocin infusion
although oxytocin
is a safe medication with appropriate administration and monitoring, there is
always the potential for adverse occurrences. the most common complication
related to oxytocin induction of labor is uterine hyperstimulation. uterine
hyperstimulation may present as tachysystole with more than five contractions
in 10 minutes, contractions of greater than 90 seconds duration, or an
increase in the baseline uterine tonus. the decreased intervillous blood flow
associated with hyperstimulation ultimately leads to decreased oxygen transfer
to the fetus, as indicated by the appearance of late decelerations. oxytocin
infusion should be discontinued immediately in the presence of
hyperstimulation. if there is evidence of fetal distress, standard intrauterine
resuscitation measures should be instituted, including oxygen administration
and positioning the patient in the left lateral decubitus position.
uterine rupture
is a very uncommon complication when oxytocin is used appropriately. there are
no prospective data in the literature describing the incidence of uterine
rupture in oxytocin-induced labor. retrospective series of uterine rupture have
implicated oxytocin in 4.3%[86] to 12.5%[87] of occurrences. factors that may reduce the risk of uterine rupture
include avoidance of oxytocin in the grand multipara, use of internal uterine
pressure monitoring for patients with previous cesarean delivery and when high
doses of oxytocin are required, and avoidance of oxytocin in obstructed labors.
water
intoxication, an infrequent complication of oxytocin administration, may be
avoided with appropriate management. the minimum effective dose of oxytocin
should be used to avoid the antidiuretic effects of high-dose oxytocin. the
risk of water intoxication increases in women who have received large volumes
of free water therefore, 5% dextrose solutions without electrolytes should
generally not be used during labor induction. symptoms occur as the plasma
sodium concentration falls below 120 to 125 meq/l and may include nausea and
vomiting, mental status changes, and ultimately seizures and coma. mild
instances of water intoxication can be treated by discontinuing the hypotonic
fluid and restricting fluid intake. with severe symptoms, correction of
hyponatremia by saline infusion may be necessary.
concern has been
raised regarding a possible association between oxytocin-induced labor and an
increased incidence of neonatal jaundice. many of the older studies claiming
that oxytocin leads to neonatal jaundice failed to control for confounding
variables such as gestational age and the infusion of large volumes of free
water. the more recent literature has not identified any correlation between
oxytocin induction and neonatal hyperbilirubinemia.[88][89]
prostaglandins
exogenous
prostaglandins, particularly dinoprostone (pge2), are frequently used as
cervical ripening agents.[90][91][92][93][94][95][96][97] because the prostaglandin-induced cervical ripening process often
includes initiation of labor, approximately half of treated women with
dinoprostone enter labor and deliver within 24 hours. prostaglandins have the
dual capability to ripen the cervix and initiate uterine contractility. as a
consequence, induced labor with prostaglandins appears to be similar to that of
spontaneous labor. the use of prostaglandins (pgs) as labor induction agents
has been reported extensively in a variety of pg classes, doses, and routes of
administration.[27] prior to 1992 most trials assessing the impact of prostaglandins as
cervical ripening and labor induction agents included various dosages of
intracervical (0.3–0.5 mg) or intravaginal (3–5 mg) dinoprostone (pge2). in
1992, the food and drug administration (fda) approved pge2 (0.5 mg
intracervically) for cervical ripening and labor induction. in 1995, a slow-release
10-mg dinoprostone vaginal insert also was approved for the same indications.
because most trials have compared these prostaglandin preparations with
placebo, the relative efficacy of these two prostaglandin preparations has been
difficult to assess. additionally, once cervical ripening was completed and
uterine activity initiated, most patients studied required further augmentation
with oxytocin.
the optimal route
for pge2 administration has not yet been determined. the intracervical route
has been used in the majority of trials, especially those comparing the
effectiveness of the fda-approved formulations (prepidil and cervidil).
although intracervical administration of gel is more difficult than
intravaginal administration, the former route appears to cause more significant
cervical ripening. the intracervical method also appears to be associated with
a lower risk of hyperstimulation. however, the easiest and most practical way
to apply pge2 in routine clinical practice is via the vaginal route. the most
commonly used doses are 3 to 5 mg. it has been suggested that the dose of pge2
should be varied according to the patient s cervical score, permitting a lower
dose of pge2 to be used in many cases. just as there is no consensus about the
optimal dose and route of administration of pge2, the optimal frequency of
administration is still a matter of debate. a commonly used approach to
cervical ripening and labor induction with pge2 is to administer
approximately 3 mg at 4- to 6-hour intervals for two doses, followed by
oxytocin induction or augmentation in 12 to 18 hours if necessary. irrespective
of the route and dose of pge2 employed, for the majority of patients,
dinoprostone preparations should be regarded mainly as cervical ripening
agents, and are not reliable as labor induction agents.
misoprostol for labor induction
misoprostol is a
synthetic prostaglandin e1 (pge1) analogue that has been marketed in the united
states since 1988 as a gastric protective agent for the prevention and
treatment of peptic ulcers. it was licensed in a tablet form designed for oral
absorption. early studies performed in the late 1980s and early 1990s
demonstrated that oral administration of misoprostol caused uterine
contractions in early pregnancy.[98][99][100] subsequent studies, performed abroad and in the united states, showed
that intravaginal administration of misoprostol tablets can terminate
first-trimester and second-trimester pregnancies.[101][102][103][104][105] a large number of published controlled trials have shown that
misoprostol, administered either vaginally or via the oral route, is an
effective agent for cervical ripening and labor induction in patients with
viable pregnancies.[32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][106][107][108][109][110][111][112][113][114] an initial meta-analysis suggested a significantly reduced cesarean
delivery rate for patients induced with misoprostol.[115] follow-up meta-analysis has shown that 84% of patients receiving
misoprostol go into active labor, with only 29.4% requiring oxytocin
augmentation. a significantly higher proportion of patients receiving
misoprostol achieved a vaginal delivery within 12 hours (37.6% versus 23.9%).
similarly, 68.1% of patients receiving misoprostol achieved a vaginal delivery
within 24 hours. use of misoprostol for cervical ripening and labor induction
is associated with an approximate 5-hour reduction of the interval from the
first dose to delivery when compared with dinoprostone. the reduced
induction-to-delivery interval seen with misoprostol compared with dinoprostone
implies that either it produces higher levels of uterine activity, or that it
is a more efficient cervical ripening agent. consistent with the former
hypothesis, compared with women receiving dinoprostone, foley catheter, or placebo,
women receiving misoprostol are twice as likely to experience tachysystole and
uterine hyperstimulation, with the incidence of these conditions closely
related to the dose of misoprostol administered.[115]
in relation to
cervical ripening, most of the individual studies in meta-analyses assessing
the efficacy and safety of misoprostol and dinoprostone have not shown a
significant reduction in the overall cesarean delivery rate. however, the lack
of a positive finding was probably because the sample sizes of the trials were small.
the 44 trials included in the recent meta-analysis[115] provide data for 5735 subjects participating in trials assessing the
impact of misoprostol treatment on the cesarean delivery rate. when all the
trials were pooled, subjects receiving misoprostol had a significantly lower cesarean
rate than subjects in the comparison groups (17.3% versus 22.9%). the most
common indications for cesarean delivery were arrest of dilation or descent,
failed induction, and abnormal fetal heart rate tracings. the rate of cesarean
deliveries performed because of fetal heart rate abnormalities was similar for
misoprostol-induced patients and those in the comparison group. similarly, no
difference was noted for the rate of cesarean deliveries because of dystocia.
patients receiving misoprostol had a significantly lower rate of cesarean
deliveries because of failed induction. this suggests that it may be better at
ripening the cervix than dinoprostone.
no evidence of
adverse perinatal or maternal effects has been noted.[116] the statistical power resulting from the aggregation of 44 studies
included in the metaanalysis increases confidence in our ability to assess
safety. the number of subjects studied affords a power of at least 90% to
detect a difference in neonatal intensive care unit admission rates of at least
4 percentage points (from 14% to 18%). sufficient power was also noted for the
detection of at least a doubling in the rate of abnormal 5-minute apgar scores
(from 1.4% to 2.8%).
accordingly,
these data provide strong support for the conclusion that misoprostol safely
decreases the cesarean delivery rate among women undergoing labor induction
compared with women receiving alternate inductionagents.
oral versus vaginal administration
initial
pharmacokinetic studies compared the pharmacokinetics of vaginal and oral
administration of misoprostol.[117][118][119][120] these studies showed that the peak plasma concentration of misoprostolic
acid was higher and achieved earlier after oral administration, but the
detectable plasma concentration lasted longer after vaginal administration.
systemic bioavailability of vaginally administered misoprostol was noted to be
three times higher than that of orally administered misoprostol.[117] in all patients studied, independent of the dose or route of
administration, the first effect of misoprostol treatment was an increase in
uterine tonus. after oral administration, the effect was more rapid and the
initial increase was more pronounced than after vaginal treatment. however,
after vaginal treatment, tonus remained at a higher level for a longer time.
a significant
proportion of the published randomized studies have evaluated the safety and
efficacy of vaginally administered misoprostol for cervical ripening and labor
induction. during the past few years, seven randomized trials have compared
oral versus vaginal administration of misoprostol for labor induction.[109][110][111][112][113][114][121] in aggregate, 1191 patients were randomized to receive misoprostol
orally (n = 602) or by the vaginal route (n = 589). the oral doses employed
ranged from 50 µg to 200 µg every 4 to 6 hours. vaginal misoprostol was
administered in doses ranging from 25 µg to 100 µg every 3 to 4 hours. no difference was noted in the
proportion of patients who delivered vaginally within 12 and 24 hours in each
group. similarly, the intervals from start of induction to vaginal delivery
were not different. the proportion of patients experiencing increased uterine
activity (tachysystole or hyperstimulation) was similar for both groups.
additionally, no difference was noted for the incidence of abnormal 5-minute
apgar scores and rates of nicu (neonatal intensive care unit) admissions.
interestingly, the rate of cesarean delivery was significantly lower among
those induced with oral misoprostol. although both routes of misoprostol
administration seem to be efficacious, the evidence documenting the safety of
vaginally administered misoprostol is much more extensive.
doses of misoprostol for labor induction
owing to the
small number of studies employing oral misoprostol, and the lack of uniformity
in dosage, the most appropriate dose of misoprostol for labor induction has not
been determined. at the present time, oral doses of 100 µg administered every 3
to 4 hours appear to be safe and effective. further studies are needed to
determine whether higher doses can improve efficacy without increasing the rate
of adverse maternal and perinatal outcomes.
since the
majority of studies have assessed the safety and efficacy of vaginal
administration, more data are available to determine the most appropriate dose.
although dosing regimens as high as 200 µg have been reported in the
literature, most authors have used vaginal misoprostol doses of 25 or 50 µg.
because of the increased incidence of uteronic effects, some authors have
advised against the use of doses greater than 25 µg. however, the data that
form the basis for this recommendation are limited. six randomized clinical
trials have been specifically designed to compare the safety and effectiveness
of 25 or 50 µg of misoprostol administered intravaginally.[122][123][124][125][126][127] these trials, although generally well designed, are hampered by small
sample size and thus prone to type ii errors. a systematic review with
meta-analysis of five randomized trials concluded that intravaginal misoprostol
at doses of 50 µg for cervical ripening and labor induction is more
efficacious, but it is unclear whether it is as safe as the 25-µg dose.[128]
in addition to
the six randomized trials and the systematic review, two separate studies have
compared the two doses (25 versus 50 µg). these two studies compared
intravaginal misoprostol with intracervical dinoprostone gel (prepidil).[37][38] the misoprostol dosage for the first study was 50 µg every 3 hours
for a maximum of six doses, whereas the second study used 25 µg every 3 hours
for a maximum of eight doses. taken together, these two studies indirectly
compared two doses of misoprostol: 25 µg and 50 µg. subjects allocated to
receive 50 µg experienced shorter intervals to vaginal delivery and no
differences in overall cesarean or operative delivery rates, cesarean deliveries
for fetal heart rate (fhr) abnormalities, or nicu admission rates. although
subjects receiving 50 µg of misoprostol experienced a greater incidence of
tachysystole, no significant increases in adverse maternal or perinatal
outcomes were noted. meconium-stained fluid was noted more frequently for those
receiving 50 µg of misoprostol. given the reassuring perinatal findings noted
previously, this latter finding, however, is of questionable importance.
because these two separate studies by wing and associates[37][38] indirectly compare two doses of misoprostol, 25 µg and 50 µg, they
were incorporated into the present analysis. altogether, 906 patients were
compared: 479 received doses of 25 µg and 427 received doses of 50 µg ( table 68-5 ). patients who received the 25-µg dose had a lower incidence of
tachysystole and hyperstimulation however, they also had a longer interval to
vaginal delivery, and a lower proportion of these patients delivered vaginally
within 12 and 24 hours. no differences were noted in the cesarean delivery
rate, cesareans performed for fhr abnormalities, operative delivery rates, or
nicu admissions.
a recent acog
(american college of obstetricians and gynecologists) committee opinion states
that if misoprostol is used for cervical ripening and labor induction, 25 µg
should be considered for the initial dose.[129] this opinion is based on the greater incidence of tachysystole noted
with larger doses of misoprostol. despite increased uterine activity with
greater doses, however, greater rates of adverse maternal or perinatal outcomes
have not been reported. although existing evidence suggests that both the 25-
and 50-µg doses of misoprostol are currently appropriate for intravaginal
administration, we agree that further large prospective trials are required to
define an optimal dosing regimen.
cervical ripening and labor induction in special circumstances
previous cesarean delivery
among patients
with a previous cesarean section, the incidence of uterine disruption is
greater with induced labor than with spontaneous labor (0.65% versus 0.40%).[130] patients in this group undergoing cervical ripening and labor
induction with pge2 (dinoprostone) experience a rupture rate of 0.9%.[131]
in women with
unscarred uteri, vaginal or oral administration of misoprostol has been found
safe and effective for patients with unfavorable cervices who require labor
induction. there are indirect data, however, from which to assess the risks and
benefits of using misoprostol to ripen the cervix and induce labor in women
with a previous lower uterine segment scar. recent publications have suggested
that the use of misoprostol in patients with previous cesarean delivery is
associated with a high frequency of uterine disruption (dehiscence or frank
rupture).[132][133][134][135][136][137][138] most of these publications consist of a few case reports or are based
on retrospective uncontrolled studies. a randomized trial designed to compare
the safety and efficacy of vaginally administered misoprostol in women with
previous cesarean deliveries was prematurely terminated.[133] at the time this study was halted, however, the study had not met
specific criteria for early termination.[139]
we used several
sources to identify all publications that have reported the use of misoprostol
for cervical ripening and labor induction in women with previous cesarean
delivery. eleven studies have been published indicating the use of misoprostol
for cervical ripening and labor induction in women with scarred uteri.[132][133][134][135][136][137][138][140][141][142][143] uterine disruptions, dehiscence, or rupture were reported in six of
the studies.[132][133][134][135][136][137] of 355 patients included in these 11 studies, 16 (4.5%) experienced
uterine disruption. because several confounding factors were present, however,
it is important to analyze these data in detail. data are available for 10 of
16 patients reported to have experienced uterine disruptions. the mean age of
the patients was 29.6 ± 4.7 years with a mean gestational age of 39.5 ± 2.1
weeks. three patients had two previous cesarean deliveries and, in two other
patients, the type of scar was unknown. although the information is not
precise, it appears that in at least in three cases, the patients had a
dehiscence of the previous incision. most patients were induced with single or
multiple vaginal doses of 25 µg of misoprostol. two patients received four
doses, and two others received at least three doses of misoprostol. the median
interval from the last dose of misoprostol until the diagnosis of uterine
disruption was 10 hours (interquartile range 8.5–17.2 hours). seven patients
received oxytocin infusion after misoprostol was administered and before the
diagnosis of uterine disruption. only two experienced tachysystole, and all
patients were delivered by cesarean. the mean birth weight was 3438 ± 572 g.
four cases of neonatal acidemia and one neonatal death were reported.
because of the
paucity of data, there is a lack of sufficient evidence from which to assess
the risks and benefits of using misoprostol or other prostaglandins to induce
labor in women with a scar from a previous lower segment cesarean delivery.
randomized controlled trials are needed to assess outcomes including vaginal
delivery rates, interval to delivery, and number of failed inductions. we are
currently completing a trial comparing intravaginal misoprostol with oxytocin
infusion in patients with previous cesarean delivery. because uterine
disruption is such an uncommon event, however, only a large multicenter
randomized controlled trial will yield adequate statistical power to assess
safety in this population of patients. to detect a difference in uterine
rupture from 1% to 3.7%, such a trial would have to include 565 patients in
each group (? = 0.05, ? = 0.80). until such a trial is performed, an
alternative approach would be to perform a case-control study. in the meantime,
the use of misoprostol for cervical ripening and labor induction in women with
a previously scarred uterus should occur only in the setting of a research
protocol.
twin pregnancies
twin pregnancies
frequently involve maternal and fetal complications, which require early
delivery. additionally, the optimal timing of birth for women with an otherwise
uncomplicated twin pregnancy at term is uncertain, with clinical support for
both elective delivery at 37 weeks as well as expectant management. elective
delivery at term may be performed via an elective cesarean or vaginally with
the use of mechanical or pharmacologic agents for cervical ripening and labor
induction. at present, there are insufficient data to support a practice of
elective cesarean delivery for women with an otherwise uncomplicated twin
pregnancy at term.
the safety and
efficacy of uterotonic agents, particularly oxytocin, for labor induction in
women with twins are not as clear as in those with singleton pregnancies. some
clinicians believe that the overdistended uterus encountered with twins is
resistant to oxytocin and may require high doses to obtain adequate uterine
contractions. additionally, some clinicians suspect that a gravida with twins
is prone to hyperstimulation or even uterine rupture with relatively low doses
of oxytocin. although there are no large randomized trials attesting to the
safety and efficacy of cervical ripening and labor induction in patients with
twin pregnancies, several retrospective studies have suggested that labor induction,
with a variety of induction agents, is acceptably safe. a recent case-matched
control study compared the safety and efficacy of labor induction with oxytocin
versus spontaneous labor in 62 women with twin pregnancies.[144] twin pregnancy had no adverse impact on the effectiveness or
efficiency of oxytocin labor stimulation indeed it appeared to be associated
with fewer side effects. additional case series of labor induction in twin
pregnancies have included the use of intrauterine balloon catheters,[145] oral dinoprostone or pge2,[146] and oxytocin.[147]
although
misoprostol has been shown to be a safe and effective agent for labor induction
in singleton pregnancies, there are no published studies in women with twin
pregnancies. if misoprostol is chosen for labor induction in twins, continuous
monitoring of the fetal heart rate and uterine contractions should be
performed. repeated doses should only be used if there is definitely no
evidence of regular uterine activity.
according to the
american college of obstetricians and gynecologists, twin pregnancies do not
necessarily constitute a contraindication to labor induction.[148] however, as with misoprostol, patients with twin pregnancies who
undergo labor induction with oxytocin, or with any other agent, need to be
monitored very closely.
fetal death
the ideal method
for termination of pregnancy in cases of intrauterine fetal demise should be
effective and safe and should have minimal side effects. in the past, oxytocin
infusion and pge2 vaginal suppositories (referred to as pessaries in the united
kingdom) were the most commonly used methods for labor induction in patients
with fetal death.
intravenous oxytocin
intravenous
oxytocin is a time-honored, effective, and safe method for inducing labor in
cases of intrauterine fetal demise. however, oxytocin infusion is less
effective when used in patients with a very unripe cervix and in those remote
from term. large doses and prolonged administration may be required,
circumstances that increase the risk of water intoxication and attendant
central nervous system complications. for patients who are remote from term,
some authors have reported the use of high-dose oxytocin.[149] one regimen describes the use of approximately 300 mu/minute (200
units of oxytocin in 500 ml of 5% dextrose lactated ringer solution or 5%
dextrose and half normal saline at 50 ml/hour). in this setting, 5% dextrose
and water has been associated with hyponatremia. electrolytes should be checked
before beginning oxytocin and should be repeated every 24 hours or if signs and
symptoms of water intoxication occur. attention should be paid to fluid intake
and urinary output. for patients at or near term, lower doses of oxytocin are
usually required. laminaria, or other mechanical means of cervical ripening,
may be beneficial before the use of oxytocin for induction.
prostaglandins
many cases of
fetal death can be managed simply and effective by pge2 vaginal suppositories.
the customary dose is one 20-mg suppository inserted vaginally every 4 hours
until contractions are sufficient to promote progressive cervical change.
generally, this dose is used only for patients who are at no more than 28
weeks gestation. however, some authors have reported safe use in the third
trimester.[150] reported side effects with higher doses (20 mg) of pge2 vaginal
suppositories include fever, nausea, vomiting, and diarrhea. these annoying
side effects may be ameliorated with appropriate and specific pretreatment
medications. although pge2 vaginal suppositories have been used safely in the
third trimester, the risk of uterine rupture is increased.
more recently,
misoprostol (synthetic analogue of pge1) has been used safely and effectively
for cervical ripening and labor induction in patients with fetal death.
mariani-neto and associates first reported the use of oral misoprostol (400 µg
every 4 hours) for induction of labor following fetal death.[151] the authors reported their experience with 20 patients with fetal
demise at 19 to 41 weeks gestation. all patients delivered successfully with a
mean interval to delivery of 552 minutes. the mean dose of misoprostol required
was 1000 µg (400 to 2800 µg). additional studies have assessed the safety and
efficacy of misoprostol in the management of fetal death.[152][153] the doses and routes of administration have varied significantly
among the studies. oral doses of 200 µg and vaginal doses ranging from 50 to
200 µg every 4 to 6 hours have been employed. some authors have combined
misoprostol with mifepristone patients receive a single dose of 200 mg
mifepristone orally, following which a 24- to 48-hour interval is recommended
prior to administering 100 to 200 µg of misoprostol in the vagina every 3
hours.[152][153]
wagaarachchi and
associates first reported a combination of vaginal and oral misoprostol after
priming with mifepristone.[154] women received a single dose of 200 mg mifepristone followed by a 24-
to 48-hour interval before administration of misoprostol. for gestations of 24
to 34 weeks, 200 µg of intravaginal misoprostol was administered, followed by
four oral doses of 200 µg at three 1-hour intervals. gestations over 34 weeks
were given a similar regimen but a reduced dose of 100 µg misoprostol. the
average induction-to-delivery interval was 8.5 hours, which was the shortest
among the previous regimens. improved patient acceptability and reduced risk of
introducing intrauterine infection are potential advantages of oral over
vaginal route.
high doses of
misoprostol (vaginal or oral administration) may be associated with fever,
chills, and diarrhea. pretreatment with antidiarrheal and antiemetic agents may
reduce adverse effects.
extra-amniotic
saline infusion
extra-amniotic
saline infusion has been shown to be successful in inducing labor in antepartum
deaths after 20 weeks gestation.[155 ] a size 18 foley catheter is inserted through the cervix under direct
vision. the balloon is inflated with 30 ml of sterile water, and the catheter
is usually strapped to the thigh under slight traction. normal saline (0.9%)
infusion is started to run at 30 dropingingingings per minute, and a maximum volume of 2 l
should be infused into the extra-amniotic space.