Expert Opinion on Drug Safety

ISSN: 1474-0338 (Print) 1744-764X (Online) Journal homepage: http://www.tandfonline.com/loi/ieds20

A safety review of medications used for labour

induction

Lili Sheibani & Deborah A. Wing

To cite this article: Lili Sheibani & Deborah A. Wing (2017): A safety review of medications used
for labour induction, Expert Opinion on Drug Safety, DOI: 10.1080/14740338.2018.1404573

To link to this article: http://dx.doi.org/10.1080/14740338.2018.1404573

Published online: 15 Nov 2017.

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 EXPERT OPINION ON DRUG SAFETY, 2018
https://doi.org/10.1080/14740338.2018.1404573

REVIEW

A safety review of medications used for labour induction

Lili Sheibania and Deborah A. Wingb
a
Obstetrics and Gynecology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA; bObstetrics & Gynecology,
University of California Irvine School of Medicine, Orange, CA, USA

ABSTRACT ARTICLE HISTORY

Introduction: Induction of labour is a commonly performed procedure around the world. There are Received 14 September 2017
various medications used for induction including those commonly used for cervical ripening (prosta- Accepted 8 November 2017
glandins) and oxytocin. The ideal agent is one that decreases the time to achieving delivery without KEYWORDS
compromising maternal or neonatal safety. The ‘optimal safe agent’ remains undetermined. Labour induction; cervical
Areas covered: This article reviews the safety of currently used induction agents. Prostaglandins and ripening; prostaglandins;
Downloaded by [Gothenburg University Library] at 17:10 17 November 2017

oxytocin have proven to be effective in labour induction, and their profiles will be reviewed in this misoprostol; dinoprostone;
article. We discuss the data that supports combining some of the agents. We also cover the safety of oxytocin; Foley balloon;
medications used for labour induction in setting of a scarred uterus. drug safety
Expert Opinion: There is continuous debate about the ideal induction agent: one that balances safety
with efficacy. We recommend the practice that there is not one perfect agent for all, and that the
clinical scenario and previous obstetric history should be considered before choosing an agent. In the
future, pharmacogenomics may show that genetics may affect the individual response and adverse
reactions to the various agents.

1. Introduction methods in comparison to vaginal prostaglandins such as vagi-

nal PGE2 and misoprostol [9] and found to have low incidence of
Labor induction is a commonly performed procedure in both the
associated neonatal and maternal morbidities. Previously it was
USA and around the world. In the USA, the rate of induction of
thought that there may be an increased risk of infection from use
labor rose to a high of 23.8% in 2015 [1,2]. The majority of
of a foreign body [10]; however, a more recent data meta-analy-
inductions require some form of cervical ripening, and medica-
sis data did not show an increased risk of infection [11]. One of
tions are one of the most commonly elected methods for this
the disadvantages of the Foley balloon can be maternal discom-
procedure. Cervical ripening physically softens the cervix, which
fort during placement.
leads to cervical effacement and dilatation [3–5]. The methodol-
ogy falls into two categories: mechanical, such as disruption of
the fetal membranes or insertion of dilators or a balloon catheter, 2.2. Prostaglandins
and application of cervical ripening agents, such as prostaglan-
A network meta-analysis comparing misoprostol (oral and
din compounds or oxytocin. This review will focus on the latter,
vaginal), dinoprostone, Foley balloon catheter for cervical
medications used for cervical ripening and induction of labor.
ripening, concluded that no method was clearly superior
with regard to the rates of failure to achieve vaginal delivery
2. Agents for cervical ripening/labor induction within 24 h, outcomes of tachysystole and cesarean delivery
[12]. In this review, while vaginal misoprostol followed by
In general, prostaglandins are the preferred agent in women
vaginal dinoprostone were the most effective methods for
with an unscarred uterus. This is because there is evidence to
achieving vaginal delivery within 24 h, these methods has
support their efficacy. They also have good safety profiles in
the highest rates of tachysystole. While the Foley catheter
this group of women and the rates of low Apgar score, meco-
was the least effective method for achieving vaginal delivery,
nium staining, neonatal intensive care unit admission, and
it had the lowest incidence of tachysystole. Finally, oral mis-
cesarean rates are equivalent to those rates from mechanical
oprostol was the best method for reducing the likelihood of
methods (Foley balloon) for ripening [6] [Table 1].
cesarean and caused less tachysystole than vaginal
misoprostol.
2.1. Foley balloon
2.2.1. Efficacy
Although the focus of this article is on medications used for
Randomized trials have established that prostaglandins (PG E1
induction, mechanical methods have been used for many years
and E2) are effective for both cervical ripening and labor
due to their low cost, convenience, and minimal side effects [9].
induction. A Cochrane review of more than 10,000 women
In some of the studies, tachysystole was lower with mechanical

CONTACT Deborah A. Wing dwing@uci.edu

© 2017 Informa UK Limited, trading as Taylor & Francis Group
 2 L. SHEIBANI AND D. A. WING

Hyponatremia due to antidiuretic affect. Symptoms usually do not appear until

Article highlights

● Prostaglandins are suggested for cervical ripening.

● Oxytocin should be used in setting of labour induction.
● Tachysystole and increase cesarean rates are the two primary safety
concerns with these agents, but there is sufficient data that when

plasma sodium <125 mEq/L. Hypotension if rapid infusion

used per established protocols, they are safe agents to use.
● In setting of TOLAC, oxytocin can be used with proper counseling,

Uterine tachysystole and fetal heart rate decelerations

Uterine tachysystole and fetal heart rate decelerations

Uterine tachysystole and fetal heart rate decelerations

but prostaglandins should be avoided.
● Consideration can be given to combination methods of Foley with
misoprostol or Foley with oxytocin with the caveat that these are not

Adverse effects
well studied methods in all populations
● A large randomized trial to properly compare these agents and assess
the efficacy, safety and patient satisfaction is needed

This box summarizes key points contained in the article.

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demonstrated the efficacy of locally applied vaginal or cervical

PGE1 as compared with oxytocin. There is continued debate
about the ideal dose, route, and frequency[13]. PGE2 (tablets,
gels, and pessaries) appear to be as effective as each other [14]
and have similar outcomes, with some small differences that
can be due to chance alone.

Contraindicated in women with history of prior

PGE1 used as an oral induction agent is as well effective at

abnormal fetal heart rate pattern is present

achieving vaginal birth. The authors of a Cochrane review

Any contraindication to induction of labor,

Any contraindication to induction of labor

Any contraindication to induction of labor

found that oral misoprostol is more effective than placebo
and as effective as vaginal misoprostol [15]. In this study,

cesarean birth or uterine surgery

Contraindication
they found fewer cesareans with this regimen than with vagi-
nal dinoprostone or oxytocin.
A misoprostol vaginal insert (MVI) consisting of a con-
trolled-release retrievable polymer delivering 200 mcg over
24 h is also available in some countries, but it is not in the
USA. In a large randomized trial, the use of this insert signifi-
cantly shortened median time to vaginal delivery (21.5 versus
32.8 h), time to onset of active labor (12.1 versus 18.6 h), and
requirement of pre-delivery oxytocin (48.1 versus 74.1%) [16]. Low dose: start at 0.5–2 mU/min (increase by 1–2 mU/min),

High dose: start at 6 mU/min (increase 3–6 mU/min) dosing

50 mcg orally may repeat every 4 h to maximum 6 doses
Cervical gel (Prepidil): 0.5 mg (in 2.5 mL syringe) inserted

25–50 mcg intravaginally. 100 mcg oral tablet is divided

Vaginal insert (Cervidil): 10-mg slow release at 0.3 mg/h

Misoprostol Vaginal Insert (MVI) delivers 200 mcg over

2.2.2. Dosing
into four 25- mcg pieces or two 50-mcg pieces

Misoprostol (Cytotec ) is a synthetic PGE1 analog and is US

®
Remains in place until active labor or for 12 h

FDA approved in its oral form for use as a gastric protectant in

patients. They have been used off-label as vaginally, orally,
into endocervix, may repeat 6–12 h
Maximum of 3 doses (1.5 mg) in 24 h
Dose and route

sublingually for over 20 years for cervical ripening and

24 h (not available in the USA)

induction.
It is available in 100 mcg or 200 mcg tablets, which can be
broken into 25 mcg or 50 mcg aliquots. It is rapidly absorbed
from both oral and vaginal routes [17]. Both routes are reason-
dosing 15–40 min

able and some believe that the oral route is more convenient
Cervidil Package Insert, Ferring, revised 02/2016.

to use. There is extensive evidence that it is an effective

15–40 min

alternative to PGE2 preparations for cervical ripening and

Table 1. Drugs for induction of labor.

labor induction [13,15,18–20]. Its use is still considered inves-

Prepidil Package Insert, Pfizer 2010.

tigational for cervical ripening in the USA, American College of

Obstetrics and Gynecologists (ACOG) states that it is a safe and
Misoprostol; prostaglandin

effective method for cervical ripening [7].

The optimal oral dosing for PGE1 is not yet established.
(Prepidil, Cervidil)
prostaglandin E2

Oxytocin (Pitocin)

One option is 50 mcg no more frequently than every 4 h. The

Generic (Brand)
Dinoprostone;

WHO suggests 25 mcg every 2 h [21]. Others have suggested

E1(Cytotec)

20–25 mcg at 2-h intervals [15]. Titrating the oral misoprostol

is another option to achieve similar labor outcomes (cesarean
[7,8].

rate, rate of vaginal delivery in 24 h, tachysystole) as vaginal


dinoprostone and avoids the tachysystole seen with tradi-
tional doses [22,23].
The optimal dose and timing of intravaginal misoprostol is
unknown [13,24,25]. A meta-analysis reported that 50 mcg
was more effective than 25 mcg, but that the 25-mcg dose
was safer (lower rates of tachysystole, cesarean, NICU admis-
sion, meconium passage) [26]. Therefore, lower rates should
be initially used with redosing as needed. The World Health
Organization (WHO) recommends 25 mcg every 6 h [21]. In
some cases, 50 mcg may be needed every 6 h (inadequate
uterine activity with lower dose), but there may an association
with tachysystole [7].
Finally, less well-studied approaches for misoprostol are
buccal and sublingual administration. In one randomized
study, 250 women received either misoprostol 50 mcg sublin-
gually or misoprostol 100 mcg orally every 4 h to a maximum
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of five doses [27]. Both routes had similar efficacy in achieving
vaginal delivery with 24 h and similar rates of tachysystole. In
another meta-analysis of five randomized trials comparing
sublingual misoprostol to vaginal misoprostol for induction,
there was no significant difference in rate of vaginal delivery in
24 h, tachysystole, or cesarean [28].
The optimal type, route, frequency, and dose of prostaglan-
dins for cervical ripening have not been established. Initially,
prostaglandins were given by intravenous or oral routes. Local
administration later became favorable to reduce the frequency
of side effects, while still maintain efficacy [29]. Intracervical
PGE2 is less effective than intravaginal PGE2 for achieving
vaginal delivery in 24 h (RR of not achieving vaginal delivery
1.26, 95% CI 1.12–1.41), they have similar cesarean and tachy-
systole rates [8]. A recent large meta-analysis again attempted
to assess the effectiveness of prostaglandins in setting of labor
induction [30]. In this study, they included 280 randomized
clinical trials, they found that low-dose (<50 µg) titrated oral
solution had the lowest probability of cesarean, whereas vagi-
nal misoprostol (≥50 µg) had the highest probability of achiev-
ing a vaginal delivery within 24 h[30]
2.2.3. Safety
The most important factor in assessment of any medication or
drug is its safety profile, both for maternal and neonatal safety
in obstetric medications. For the cervical ripening agents, the
increased rate of tachysystole is a concern. In most of the
studies, the presence of tachysystole did not increase the
cesarean rate or cause any differences in neonatal or maternal
outcomes, but the exact effect is unknown[31,32].
Some of the other side effects of prostaglandins in addition to
tachysystole include: fever, dose, type, and route of administra-
tion. One of the benefits of using an insert is that it can be
removed should tachysystole occur, as this will resolve the uter-
ine contractility, normalize fetal heart rate abnormalities and does
not prolong time to delivery [33]. However, if the formulation
used is a gel/tablet applied locally, the removal is not possible.
Regarding safety of MVI, in one study women who received
it had more tachysystole (13.3 versus 4.0) with a similar cesar-
ean rate [16]. In secondary analyses on the effect of MVI,
tachysystole was a safety concern, but the studies were not
powered for this outcome [31].
EXPERT OPINION ON DRUG SAFETY 3
In the most recent Cochrane Review, 70 randomized RCTs
were included (11,487 women), looking at both PGE2 for third
trimester cervical ripening. While they found that the risk of
tachysystole is increased, the cesarean rate is probably
reduced by about 10% [14]. After administration of prosta-
glandins, monitoring fetal heart rate and uterine activity
should be done for at least 30 min (to assess the maternal
and fetal response to the agent), Oxytocin can then be started
if necessary 4 h after the last misoprostol dose.
2.3. Oxytocin
2.3.1. Efficacy
In general, Oxytocin is less effective as a cervical ripening agent.
Many trials have compared oxytocin with prostaglandins and
other methods of cervical ripening [34]. In one study, they
compared the efficacy of labor induction with vaginal PGE2
with oxytocin in women with an unfavorable cervix. In this
study, PGE2 was more efficacious for labor induction, with
fewer women undelivered at 24 h. However, for inductions
that proceeded for 48 h, there was no difference in vaginal
delivery. In another study of women with an unfavorable cervix,
vaginally applied PGE2 was compared with oxytocin [35]. In this
study, there was a shorter time to active labor, fewer failed
inductions with PGE2 compared with oxytocin. There was no
difference in the rate of cesarean delivery. In a Cochrane review
of more than 11,000 women comparing oxytocin with vaginal
prostaglandins, oxytocin alone was associated with an increase
in unsuccessful vaginal delivery within 24 h but there was no
difference in the rate of cesarean delivery between the groups.
For intracervical prostaglandins compared with oxytocin, oxyto-
cin alone was associated with an increase in unsuccessful vagi-
nal delivery within 24 h and an increase in cesarean rate [14].
2.3.2. Safety
Oxytocin is similar to antidiuretic hormone and can cross react
with vasopressor receptor. With use of high doses, potentially
there can be excessive water retention and subsequent hypo-
natremia [36,37]. This would then manifest as headache, nau-
sea, vomiting, pain, and rarely neurologic injury. There are as
well epidemiological studies that have suggested an associa-
tion of oxytocin in labor with autism. These authors were
careful to point out limitations of this study and that it should
not change clinical practice [38]. Studies that test this associa-
tion are extremely limited, and this should not dictate deci-
sions regarding induction agents.
2.4. Combination methods
An active area of research is the combination of these indivi-
dually well-studied agents to see if together they would pro-
duce a synergistic effect over single-agent cervical ripening.
Most of these combination methods add Foley catheter to
either misoprostol or oxytocin. Initial studies did not find
that adding Foley catheter on top of misoprostol added any
benefit in comparison to misoprostol alone [39,40]. However,
some of the newer trials have had contradictory results. There
are several large randomized trials that found Foley balloon in
 4 L. SHEIBANI AND D. A. WING
combination with either oral or vaginal misoprostol reduced
the time to delivery and risk of cesarean than either method
alone [41–43]. Levine and colleagues found that after censor-
ing for cesarean delivery and adjusting for parity, misoprostol-
Foley resulted in twice the chance of delivery before any
single agent method [41]. Other studies found that combining
Foley catheter with prostaglandin leads to more rapid cervical
ripening and shortened time from induction to delivery [42].
A recent randomized controlled multicenter trial of women
undergoing induction showed that the combination of oxyto-
cin added to Foley increased the rate of delivery within 24 h in
all women compared with Foley followed by oxytocin [44].
Some of the safety outcomes evaluated included: tachysystole,
chorioamnionitis, meconium, and postpartum hemorrhage.
However, this study was not powered for safety in subgroups
such as preterm premature rupture of membranes (PPROM) or
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vaginal birth after cesarean. Additionally, some of the non-
significant secondary outcomes may be due to lack of statis-
tical power, therefore making this an ongoing area of research.
3. Induction agents in women with prior cesarean
delivery
In women with prior cesarean delivery, the risk of failed induc-
tion and uterine rupture is a major concern. The best agent for
induction in this population has not been well established
[45]. Most of the available studies in women with prior cesar-
ean delivery study an induction group compared to sponta-
neous labor. However, there is new information that those
with prior cesarean in spontaneous labor are not the most
appropriate control group. In a study of over 10,000 women
with singleton pregnancies ≥39 weeks and one previous low
transverse cesarean, those undergoing induction of labor at 39
0/7 to 39 3/7 weeks were more likely to delivery vaginally than
if expectantly managed [46]. Several studies have looked into
the question of induction in women attempting trial of labor
after previous cesarean (TOLAC). There are no randomized
trials, but there is a large prospective study that looked at
over 17,000 women undergoing TOLAC[47], and found the
incidence of uterine rupture at 0.4% for those who sponta-
neously labored, 0.9% with augmentation, and 1.0% for sub-
jects underwent induction. The highest risk for rupture was
with a combination of prostaglandins and oxytocin.
ACOG recommends oxytocin for induction and augmenta-
tion of women undergoing TOLAC and they encourage cau-
tion if the cervix is unfavorable [48]. However, with the recent
study showing that more women are likely to delivery vagin-
ally if induced than expectantly managed, it is likely that
results from many of the historical studies were impacted by
the use of a control group of spontaneous labor.
There are no large randomized trials and limited good-quality
studies on which to base a recommendation on use of prosta-
glandins alone or with other agents for cervical ripening or induc-
tion in TOLAC. Most data are from observational studies. The initial
concern arose after a population-based cohort study found the
rate of uterine rupture was significantly higher if labor was
induced with prostaglandins as opposed to elective repeat [49].
A systematic review of retrospectively collected data on
women with prior cesarean births did not find that the rate
of uterine scar disruption was significantly higher for women
who received oxytocin for induction of labor compared to
women who begin labor spontaneously (pooled OR 2.10,
95% CI 0.76–5.78)[50]. However, this should be interpreted
with caution as there is no data from large trials and there is
a lack of good quality controlled studies. Maximal oxytocin
infusion rates administered were rarely reported, thus a cut-off
above which the risk of uterine rupture is increased cannot be
determined from the existing data. This is important because a
dose–response relationship appears to exist between maxi-
mum oxytocin dose and uterine rupture [51,52].
At this time, however, there are no high-quality data for the
optimal maximum dose of oxytocin to be used during labor in
women with prior cesarean deliveries. Most use a careful
approach that adheres to the institution’s policy on use of
oxytocin. A low-dose infusion typically consists of an initial
dose between 0.5 and 2.0 mU/mL, with incremental increases
of 1–2 mU/mL at 15–40-min intervals [53].
The largest prospective study to evaluate the risk of rupture
by labor status in women with one or more cesarean deliveries
(n = 17,898 trials of labor and 15,801repeat cesarean deliv-
eries) was not included in the pooled analysis cited above[47].
In this series, women who underwent induction with oxytocin
alone had a significantly higher risk of uterine rupture than
those in spontaneous labor (OR 3.01, 95% CI 1.66–5.46).
Given the lack of definitive data showing a high risk of
rupture, oxytocin for induction of labor in TOLAC candidates
is an appropriate option when done so for standard obstetrical
indications. ACOG acknowledges that induction of labor may
be necessary for women with previous cesarean deliveries
[48]. They advise counseling patients on the risks and benefits
of oxytocin induction in women with prior cesarean and
selecting patients who are most likely to give birth vaginally.
As with oxytocin, there are no data from large randomized
trials and limited data from good-quality controlled studies to
base a recommendation on use of prostaglandins for induction
of labor in TOLAC. Most data on use of prostaglandins in women
with a prior cesarean delivery were derived from observational
studies in which misoprostol was used. Reports on use of other
prostaglandins are limited by their small size, the coadministra-
tion of oxytocin, and stratification by prior vaginal delivery.
A 2001 study raised concern over the use of prostaglandins
with data from approximately 20,000 primiparous women who
gave birth to live singleton infants subsequently delivered a
second singleton child [49]. The rate of uterine rupture was
highest in the prostaglandin group in comparison to the repeat
cesarean group RR 15.6 (95% CI 8.1–30.0). Unfortunately, this
study had several limitations, one being that it was performed
using hospital discharge coding and therefore likely contained
missing and inaccurate data regarding uterine ruptures or med-
ications utilized during the induction.
There are few studies that look at outcome for labors
induced by prostaglandins alone. In one study prostaglandins
alone were not associated with uterine rupture, but the sequen-
tial use of prostaglandin and oxytocin was associated with
uterine rupture (OR 3.07, 95% CI 0.98–9.88) [54]. A randomized
trial on use of misoprostol for cervical ripening or labor induc-
tion in women with previous cesarean births was stopped early
because of safety concerns [55]. Randomized controlled trials

on methods of induction of labor for women with a prior
cesarean are inadequate, and studies are underpowered for
clinically significant outcomes. Most importantly the infant out-
comes are limited in many of the studies. At this time observa-
tional studies, as described above are the best alternative [45].
ACOG advises against the use of misoprostol for cervical
ripening or labor induction in the third trimester in women
with prior uterine incision [48]. The society of Obstetricians
and Gynaecologists of Canada (SOGC) also similarly recom-
mends against prostaglandins in women with prior cesareans
but allows for prostaglandin E2 in very rare cases after appro-
priate counseling [56]. In contrast, The United Kingdom
National Institute for Clinical Excellence allows for cautious
use of vaginal prostaglandins in women with prior cesareans
based on both observational and extrapolated data [57]. For
women with unfavorable cervix who choose to be induced,
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risks and benefits of mechanical and pharmacologic options of
cervical ripening, as well as labor induction and augmentation
should be discussed. In general, prostaglandins are not recom-
mended in women with prior cesarean deliveries.
4. Conclusion
A large body of literature exists confirming the safety of
prostaglandins, with several published studies of the pharma-
cology and toxicology of these compounds. Misoprostol spe-
cifically has been used for over 25 years off label as a labor-
induction agent. The prostaglandins have been shown to be
efficacious and overall safe agents. There is a constant search
for ‘the best agent’ that not only maintains maternal/fetal
safety and is efficacious but also maintains patient satisfaction
with the induction process.
Either cervical ripening with prostaglandin E1 administered
vaginally or oral misoprostol is one option for induction of
labor. With safety as a concern, if there is a concern for ascend-
ing infection, oral regimen may be preferred over vaginal regi-
men [15]. Although this review does not focus on mechanical
agents, use of balloon catheters is a reasonable option for
induction agents. Randomized trials have found that they are
as effective as prostaglandins for cervical ripening, and result in
less tachysystole. However, misoprostol continues to remain
unlicensed for the induction of labor, therefore many may
prefer to use an approved product like PGE2.
Prostaglandins (PGE2) increase the chance of vaginal deliv-
ery in 24 h, while safety concern being increase in tachysystole.
Overall, there is no effect or may actually reduce cesarean rates.
They increase the likelihood of cervical change and do not
really increase operative delivery rates. The marginal differences
in the formulations (PGE2 tablets, gels, and pessaries) may be
important safety outcomes that are yet to be determined, but
in efficacy they appear to be as effective as each other.
In women with a low modified Bishop score, a cervical
ripening process is recommended. Regardless of which
method is employed, the patient should be thoroughly coun-
seled on the rationale for inducing labor, the risks of the
specific method elected, and the alternatives that are available
to the patient. Current practice is to limit elective induction to
at or above 39 weeks of gestation. When the cervix is
EXPERT OPINION ON DRUG SAFETY 5
unfavorable, prostaglandins can increase the probability of
successful labor induction, with dinoprostone and misoprostol
having similar safety profiles. Oxytocin, although it has an
excellent safety profile, is an agent for induction of labor as
opposed to cervical ripening.
Prostaglandins increase the rate of uterine rupture in
women with prior cesarean or uterine surgery and are not
recommended. After proper counseling, oxytocin for induction
of labor in TOLAC candidates is an appropriate option when
done so for standard obstetrical indications.
5. Expert opinion
In a large effort to decrease the primary cesarean rate, several of
the large organizations, such as The National Institute of Child
Health and Human Development (NICHD) and Society for
Maternal-Fetal Medicine (SMFM) have offered ways to promote
vaginal delivery and prevent primary cesarean delivery in the
large percentage of women who undergo induction of labor. For
this reason, there is continued interest in determining the ideal
agent that combines efficacy, safety, and patient satisfaction.
Despite years of research and well-conducted studies, the
ideal agent is yet to be identified. Additionally, the physiology
behind initiation and sustained labor needs to be understood
more clearly. There is wide variation among women in normal
labor and management of labor induction therefore studying
new agents is challenging. Although there are well-conducted
studies comparing directly approaches for cervical ripening, the
data regarding the actual methods that offer the most effec-
tive/safest profile is still lacking. These studies are certainly
difficult to conduct given the variation in indications used for
induction of labor, parity of women, initial Bishop score at
induction, along with the many other demographic factors
that can affect the results of these studies. A large randomized
trial to directly compare these agents in all aspects: efficacy,
safety, patient satisfaction, and cost are needed but the logistics
to conducting such a study make it nearly impossible.
Additionally, to fulfill hospital demand to keep patients mov-
ing, staff free, and cost/coverage challenges, there is a desire to
perform more outpatient approaches for initiating induction of
labor. However, to be clear, there is insufficient safety data to
suggest that these approaches should be utilized in circum-
stances outside of study protocols. The potential benefit to be
gained is that it would reduce duration of hospital stay, staff
needed, cost of labor and delivery and medical care. However,
large numbers are still needed to address safety concerns of
these outpatient approaches with either mechanical or medica-
tions for cervical ripening. There is also a need for comparative
research to establish the safety of outpatient induction. The
evidence to date suggests that it is a feasible option [58], but
again limited studies to support the procedure.
The rate of labor induction has significantly increased over
the previous decades and is not expected to decrease in the
near future. Therefore, innovative ways to induce labor are
almost required to meet the increased demand on all labor
and delivery units. Combination methods such as Foley with
misoprostol or Foley with oxytocin can be considered to
increase delivery rates within 24 h and decrease total time to
deliver. However, caution should be taken with regard to
 6 L. SHEIBANI AND D. A. WING
some of the safety outcomes. This is an ongoing area of
research and the subgroups such as PPROM or vaginal birth
after cesarean have not been powered for in these newer
studies. Additionally, the data are limited to support outpati-
ent cervical ripening.
Finally, a still emerging area of research in induction agents
involves a concept known as pharmacogenomics. It is the
study of genetic variations in drug response that are deter-
mined by specific genes. It is especially important with regards
to improving drug safety and decreasing the rate of drug
reactions [59–61]. Its use in obstetrics and gynecology holds
much promise, but there is a lack of evidence for routine use
in clinical practice. Some women are more susceptible to the
various approaches, formulations, mode of delivery, frequency
of drug administration. As an example, we have learned that
with oxytocin, there may be variations in the OXTR gene that
Downloaded by [Gothenburg University Library] at 17:10 17 November 2017
will make some women more susceptible to oxytocin. We
envision that in the years to come more will be understood
about why some women require two doses of an induction
agent while others respond to one. There may be inter-indivi-
dual differences that explain the various responses to these
induction agents. Still a new concept, but in the years to come
the cost of obtaining genetic information may decline, there-
fore making the application of pharmacogenomics more plau-
sible to choosing the safest agent for each patient. Prospective
clinical trials are needed to introduce pharmacogenomic test-
ing into clinical practice in ways that would improve health
outcomes. This would then lead to the use of the ideal drug:
one that best combines efficacy with safety.
Funding
This paper has not been funded.
Declaration of interest
DA Wing has been a consultant for Ferring Pharmaceuticals, Inc; prior to
that she received research support for the conduct of this trial. She has
attended an advisory board as a panel member, received support for
travel to a FDA meeting on behalf of the sponsor, to present research
findings at a major international scientific congress and to advise the
sponsor in a global obstetrics advisory council.
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