US Pharm. 2012;37(9):HS2-HS6.
Perhaps the greatest challenge facing health care
providers when administering pharmacologic agents during labor and
delivery is that most of the drugs are used off label.1
Furthermore, when selecting appropriate therapy, health care providers
need to consider the effect of the medication on both the mother and the
fetus. It is therefore imperative that providers be conversant with the
various options available and their associated restrictions. This
article discusses the medications that are commonly used during labor
and delivery, namely for cervical ripening, labor induction, and labor
Induction and Augmentation of Labor
The goal of labor induction and augmentation at term is to facilitate vaginal delivery of a healthy infant.2
A normal uterus is spontaneously contractile, but it changes during
pregnancy to maintain a quiescent state and a firm status to retain the
fetus.3 In the final 4 to 5 weeks of pregnancy, endogenous
prostaglandins are released to: 1) ripen the cervix, making it soft and
dilated, and 2) sensitize the uterus in preparation for labor.4
Pregnancies that go beyond term, pregnancies in which
premature rupture of the membranes occurs, or pregnancies in which there
are maternal or fetal indications for early delivery commonly require
induction of labor.3 The rate of induced labor ranges from 9.5% to 33.7% of all pregnancies annually.5
Various drugs can be used to induce and augment labor, but they are
commonly associated with either the inability to achieve effective labor
or uterine hyperstimulation.4 In some cases, women may be
offered sweeping of the membranes before drug therapy is considered, but
this can increase maternal discomfort, irregular contractions, and
Cervical ripening can be assessed using the Bishop score, a
measure that incorporates a number of factors including the position,
consistency, thickness, and dilation of the cervix as well as the
position of the fetus.5 As a rule of thumb, a patient with a
Bishop score of over 8 is likely to achieve a successful vaginal birth; a
patient with a Bishop score of less than 6 is likely to require a
cervical ripening agent.
Nonpharmacologic cervical ripening methods have been used
for centuries, although there are not many studies to prove their
efficacy. These include herbal compounds, castor oil, hot baths, enemas,
sexual intercourse, breast stimulation, acupuncture, acupressure,
transcutaneous nerve stimulation, and mechanical and surgical
Drug Therapy for Cervical Ripening
During cervical ripening, the collagen fiber alignment,
the collagen fiber strength, and the tensile strength of the
extracellular cervical matrix decrease and the cervical dermatan sulfate
proteoglycan 2 levels increase. The collagen fibers separate and the
cervix softens.6 These processes are targeted by
pharmacologic cervical ripening agents such as prostaglandins,
prostaglandin analogues, and oxytocin.
Prostaglandins: Prostaglandins are
released as a natural part of the cervical ripening processes. Both F-
and E-series prostaglandins allow for an increase in intracellular
calcium levels causing the contraction of myometrial muscle.7 Specifically, prostaglandin F2-alpha
causes an increase in the glycosaminoglycans. The E-series
prostaglandins tend to be more uteroselective and primarily cause7:
- Dilation of small vessels in the cervix
- Increase in collagen degradation
- Increase in hyaluronic acid, elastase, and dermatan sulfate5
- Increase in chemotaxis for leukocytes, which causes increased collagen degradation
- Increase in stimulation of interleukin (IL)-8 release.
A recent study has shown that the use of intravaginal
prostaglandins increases the likelihood that a vaginal delivery will
occur within 24 hours compared to placebo, which had no increase in
operative delivery rates.8 Intravenous prostaglandins, on the
other hand, do not show an advantage but produce increased maternal
side effects compared to other methods of induction.9,10 More
recently, researchers have studied the benefits of using a combination
of a mechanical method (i.e., the Foley catheter) and a pharmacologic
method (i.e., prostaglandins or “extra-amniotic prostaglandins”), but
there are insufficient data to recommend this method at present.9
Prostaglandins are associated with a number of risks including uterine
hyperstimulation and maternal nausea, vomiting, diarrhea, and fever.
Dinoprostone is the only prostaglandin currently available
for cervical ripening in the form of both a vaginal gel (Prepidil 0.5
mg) and a vaginal insert (Cervidil 10 mg). The gel needs be kept
refrigerated and brought to room temperature before use and should only
be administered with the patient near a delivery suite. Patients using
the gel need to be kept in the recumbent position for the first 30
minutes and should be monitored for a further 30 to 120 minutes.
Contractions typically appear within 60 minutes and peak within 4 hours.
The cervix is said to be ready when strong uterine contractions occur,
the Bishop score is 8 or more, or a change in maternal or fetal status
is noted.10 The inserts provide a lower constant release of
medication than the gel dose, with a similar efficacy. They do not
require refrigeration and are easier to remove in cases of
Prostaglandin Analogues: Misoprostol (Cytotec) is a synthetic prostaglandin (PGE1)
analogue that is a safe and inexpensive option for cervical ripening,
albeit an unlicensed indication. It can be administered orally at a dose
of 50 to 100 mcg that may be repeated up to every 4 hours. Peak
concentrations are achieved at 12 minutes following absorption and
de-esterification to the active free acid, with a half-life of 21
minutes. Vaginally, a 25-mcg insert can be given every 3 to 6 hours up
to a maximum of 50 mcg per dose. Misoprostol is three times more
bioavailable when administered vaginally than the oral formulation.10
While misoprostol is associated with an increased
incidence of tachysystole, current data show that the number of patients
requiring cesarean section because of fetal heart rate (FHR)
abnormalities, the need for terbutaline administration to arrest labor,
and the frequency of meconium aspiration syndrome is not significantly
different from patients given oxytocin or dinoprostone.10
Uncommon side effects of misoprostol use include hypertonus and
hyperstimulation syndrome, uterine rupture, fetal demise, nausea, and
Oxytocin: As a pregnancy progresses,
the number of oxytocin receptors increases, the phospholipase C–inositol
pathway is activated, and intracellular calcium levels increase,
stimulating contractions in myometrial smooth muscle. Used since the
1950s, oxytocin is still the preferred pharmacologic agent for cervical
ripening or inducing labor once the cervix is favorable.10 It can also be used for labor induction after misoprostol is administered for cervical ripening.
An infusion of no more than 4 mU per minute is effective
for cervical ripening and produces relatively few side effects.
Spontaneous labor normally occurs in 8 to 12 hours. One study found that
50 mcg of intravaginal misoprostol before an oxytocin infusion is more
effective than oxytocin alone for cervical ripening.11
Oxytocin has been shown to increase the chances of vaginal birth,
although it is generally less effective than prostaglandins in this
regard.12 It is potent but generally well tolerated, easy to
titrate, and has a short half-life of about 1 to 5 minutes. However,
dose-related adverse effects have been observed, including an
antidiuretic effect in high doses. Other side effects include uterine
hyperstimulation and uterine rupture. Continuous FHR monitoring is
required; if the FHR falls, the oxytocin dose can be lowered rather than
Other Agents: Relaxin, mifepristone,
corticosteroids, estrogens, hyaluronidase, and isosorbide mononitrate
are all currently under investigation for cervical ripening and inducing
While pain relief during labor is a well-documented
controversy, pharmacologic agents are widely used in obstetrics. A
painful labor may not only produce maternal physiological and
biochemical changes, but could also have adverse fetal effects.15
The pain may result in maternal anxiety, which is associated with an
increase in plasma catecholamines and cortisol and an increase in the
length of labor. The final result of these reactions has been associated
with maternal and fetal metabolic acidosis.15
Labor is generally divided into three stages, and the pain associated with each stage has its own source.16
Beginning from the start of regular uterine contractions until the
completion of cervical dilatation, the first stage is associated with
visceral pain and is due to the contractions and dilation of the uterine
segment and cervix. The second stage leads on from this point up to the
completion of delivery, and the pain is primarily somatic as a result
of the fetus in the birth canal, causing distention and tearing of the
vaginal and perineal tissues.17 The third stage of delivery is the postpartum stage.
Some women may choose to use breathing and mental
exercises to control the pain during labor. There is insufficient
evidence on the efficacy of these methods, and women may opt for
pharmacologic pain relievers, including nerve blocks and systemic
analgesia.17,18 In the last decade, the prescription use of
opioids and nonopioid analgesics for pain management during pregnancy
has increased by about 40%.19 The workforce survey conducted in 2001 showed an increase in the use of epidural analgesia.20
Both spinal analgesia and combined spinal analgesia were used in a
small number of maternity cases, and a slightly larger proportion of
patients used patient-controlled analgesia.
Nitric Oxide: Inhaled nitric oxide is a fairly effective and relatively safe option (for the mother and fetus) for analgesia.17
It does not interfere with the release and function of endogenous
oxytocin, and has no adverse effects on the normal physiology and
progress of labor.21 Patients may experience nausea, vomiting, and dizziness.18
Since nitric oxide is rapidly excreted by the lungs of the newborn, it
is relatively safe even though it crosses the placenta readily.15 Patients must be monitored for hypoxemia if nitric oxide is used together with systemic opioids.17
A recent survey, however, identified only two centers in the United
States where it is routinely available, and it was used by only about 1%
of women, perhaps because its efficacy has not been established.22
Opioid Agonists and Antagonists: All the drugs in this group share similar pharmacologic profiles but differ in potency, pharmacokinetics, and side effects (TABLE 1).23 Opioid agonists and antagonists provide systemic analgesia that is useful over neuraxial analgesia when17,24:
- Neuraxial analgesia is contraindicated, e.g., in
pre-existing coagulopathy, infection at puncture site, hemorrhage,
hypovolemia of other cause, untreated systemic infection,
preload-dependent disease states, and lumbar spinal pathology
- Neuraxial analgesia is refused, or not needed
- A skilled anesthesia provider is not available.
However, while systemic analgesia is widely used, it lacks
rigorous scientific evidence, and the analgesic effect achieved is
incomplete. Furthermore, the drugs in this group cross the placenta and
cause neonatal as well as maternal side effects.17
The common side effects of opioids include maternal
hypotension, increased maternal temperature, postdural puncture
headache, transient fetal heart deceleration, pruritus, and maternal
nausea, vomiting, and drowsiness.25,26 Upon delivery, the
newborn may experience neonatal depression and FHR abnormalities, as
well accumulation of the drug in its system.
Labor pain is transmitted through lower thoracic, lumbar,
and sacral roots that can be blocked by an epidural, a spinal, or a
combined spinal epidural (CSE). A spinal block is a single shot of a
long-acting anesthetic administered into the thecae of the spine with or
without an opioid. It is commonly used for the second stage of labor or
a cesarean. An epidural is a combination of a local anesthetic and an
opioid injected into the epidural space through a catheter to allow for
continuous infusion. Doses can be titrated through the entire labor, and
the same catheter can be used for labor, vaginal delivery, and a
cesarean. Block via an epidural is not usually initiated until active
labor is established. A CSE combines the rapid onset of spinal analgesia
with the continuous infusion of an epidural. CSEs are widely used to
provide immediate relief during the second stage of labor and can
convert to adequate analgesia if a cesarean is required.27
Neuraxial analgesia provides superior pain relief over systemic methods (TABLE 2).25,28
Neuraxial labor analgesia often combines opioids as well as local
anesthetics that work synergistically and allow the use of lower doses
of each agent, thereby minimizing side effects.17 The opioids
are useful for the visceral pain of early stage 1 labor, and the
anesthetics are useful for managing the somatic pain of late stage 1 and
stage 2 labor.17
Neuraxial analgesia is currently the gold standard for
pain management, and its use has increased significantly over the past
40 years.17,24 It has been observed that labor progress and outcomes are similar among women receiving either CSE or epidural analgesia.29
However, more research is required to establish whether neuraxial
anesthesia is associated with increased rates of instrumental vaginal
delivery.30 Side effects of neuraxial analgesia include
hypotension, pruritus, maternal headache, fever, fetal bradycardia, and
maternal hyperthermia.17 The patient’s ability to push may be
impaired if the motor block is too dense, and there is blunting of the
pressure sensation during the second stage. Neuraxial anesthesia
increases the risk for operative vaginal delivery (use of forceps or a
Bupivacaine is the drug of choice for spinal or dilute
epidural solutions for the initiation of anesthesia as well as
maintenance of labor analgesia.30 It provides favorable
sensory-motor differential block at low concentrations, resulting in
analgesia with motor sparing, thereby allowing ambulation.30
Bupivacaine has a long duration of action and does not produce
tachyphylaxis. It is highly protein bound and therefore does not cross
the placenta readily.17 Bupivacaine is effective in low
concentrations for early labor and in higher concentrations as the labor
progresses. For epidural or CSE analgesia, it is often combined with
sufentanil or fentanyl.
Lidocaine has less differential block, a shorter duration
of action, and a higher association of transient neurologic symptoms
than bupivacaine. It is usually reserved for the rapid extension of an
Ropivacaine is a newer amide local anesthetic and a homologue of bupivacaine.17 It is less cardiotoxic than bupivacaine but more so than lidocaine.31
Unlike bupivacaine, the cardiotoxicity of ropivacaine is not enhanced
by progesterone. Analogous to bupivacaine, ropivacaine has favorable
sensory-motor differential block at low concentrations, although when
compared in equal doses, it demonstrates greater separation between
sensory and motor blockade than bupivacaine.31 Ropivacaine is
60% as potent as bupivacaine when administered by the epidural route
and has a similar latency and duration of action to bupivacaine.17 It is associated with significantly fewer instrumental deliveries.31
The most common opioids used in neuraxial analgesia are
fentanyl and sufentanil. They both have a rapid onset of action but a
short duration that can be overcome by administering a continuous
Remifentanil is an ultra short-acting mu1-opioid receptor agonist that has a rapid onset and short half-life.24
It provides modest analgesia, particularly in the first stage of labor.
The amount of placental transfer is insignificant and does not seem to
affect the fetus.24 Maternal side effects include mild sedation, nausea, and vomiting.24 Patients require routine oxygen saturation monitoring, with oxygen supplementation as necessary.
Neuraxial Adjuvants: Adjuvants such
as epinephrine, clonidine, and neostigmine may be used to improve
analgesia and decrease complications associated with a high dose of a
Epinephrine binds to the spinal cord alpha-adrenergic
receptors, decreasing uptake of local anesthetics and opioids from the
epidural space as a result of vasoconstriction.17 It quickens
the onset of analgesia and increases the duration of action but cannot
be used for spinal analgesia. Anesthetics used in combination with
epinephrine are more likely to cause motor block.
Clonidine may be similarly used in other countries, but it
is not approved in the U.S. due to its sedative and hypotensive
Neostigmine has analgesic properties when administered
spinally, but its use is contraindicated in patients with
gastrointestinal problems.32 In an epidural combined with
sufentanil or clonidine, it initiates labor analgesia without side
effects and allows for a mobile epidural.
Collaboration between the obstetrician, neonatologist,
pharmacist, and other health care providers is essential to ensure the
safety of both the mother and the neonate. Misoprostol and oxytocin are
the most commonly used agents for cervical ripening and labor induction.
Analgesics for pain management are both systemic and neuraxial. While
the need for an analgesic that provides a complete effect with no side
effects particularly in the fetus is well recognized, the ideal agent is
yet to be found. Pharmacists can play a vital role in drug therapy
decisions and education of the patient, especially in determining pain
management options during labor and delivery.
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