In a prospective, randomized study, magnesium sulfate was superior to phenytoin
for the prevention of eclampsia in hypertensive pregnant women.
magnesium sulfate was more effective than nimodipine for seizure prophylaxis in
A regimen of magnesium sulfate 4 to 6 g IV as a loading dose followed by a
continuous infusion of 2 g/hour is the most commonly used regimen in the United
115 Lower dosages (e.g., 1 g/hour) have been associated with treatment
IV loading doses of 6 g followed by continuous infusions of 2 g/hour
maintain therapeutically effective magnesium serum concentrations between 4 and 8
115 Because magnesium is excreted by the kidneys and will accumulate in
cases of renal dysfunction, the continuous infusion rate must be lowered with oliguria
Because of the potential for infusion errors and significant patient morbidity and
even mortality with accidental overdoses of magnesium sulfate, the Institute of
Medicine has identified magnesium sulfate as a high-risk medication.
of magnesium sulfate must be given through a controlled pump designed to protect
against free flow. If such an infusion pump is not available, the intramuscular (IM)
route of administration should be used. Dispensing premixed IV bags from the central
pharmacy with a standardized concentration of magnesium sulfate and limiting the
total grams of magnesium sulfate in each dispensed IV bag also can help guard
against inadvertent overdose. Dispensing the loading dose in a separate small bag
(e.g., 4 g in 100 mL) from the maintenance bag (e.g., 20 g in 200 mL) also may be
Magnesium sulfate should be given to T.D. to prevent eclamptic seizures during
80 T.D. should be loaded with magnesium sulfate 4 g IV given for 30 minutes
and then started on a continuous infusion of 2 g/hour.
MONITORING MAGNESIUM SULFATE THERAPY
CASE 49-5, QUESTION 11: T.D. has been given magnesium sulfate 4 g IV for 30 minutes and was then
treatment of T.D. with magnesium?
Deep tendon reflexes (patellar reflex), respiratory rate, and urine output should be
monitored periodically during treatment with magnesium sulfate.
patellar reflexes, the first sign of magnesium toxicity, generally occurs at serum
8 to 12 mg/dL. The respiratory rate should be monitored hourly and should be
greater than 12 breaths/minute. Respiratory arrest can occur with serum
concentrations of greater than 13 mg/dL. Urine output should be carefully monitored
and should be at least 100 mL every 4 hours (or 25 mL/hour).
concentrations are not routinely measured unless renal dysfunction is evident with
oliguria or elevated SCr because magnesium is almost entirely excreted by the
106,109 Hypocalcemia and hypocalcemic tetany also can occur secondary to
elevated magnesium and can be reversed by calcium gluconate 1 g (10 mL of a 10%
solution) slow IV push for 3 minutes. Neuromuscular depression can occur in infants
whose mothers received magnesium sulfate.
38 Parenteral magnesium sulfate is safe
and rarely causes maternal or neonatal toxicity when administered properly but
requires stringent, built-in system safeguards to avoid unintended dosing errors.
CASE 49-5, QUESTION 12: How long should magnesium sulfate be continued in T.D.?
Depending on the severity of preeclampsia, magnesium sulfate therapy usually is
continued for 24 hours after delivery, which should be the same for T.D.
with severe preeclampsia or preeclampsia superimposed on chronic hypertension are
at greater risk for disease exacerbation when magnesium sulfate is discontinued too
CASE 49-5, QUESTION 13: T.D. delivers vaginally and her magnesium infusion was discontinued by
the magnesium is disconnected. What is appropriate drug therapy for eclampsia?
Lorazepam, diazepam, phenytoin, and magnesium sulfate have all been used to
treat eclampsia. The use of magnesium sulfate to treat these seizures results in less
maternal morbidity and mortality and less neonatal morbidity.
serum concentrations of magnesium sulfate are needed to treat than to prevent
eclamptic seizures. The same therapeutic range guides both prophylaxis and
114 Seizures unresponsive to magnesium sulfate treatment should
prompt an evaluation for other cerebrovascular events (e.g., cerebral hemorrhage or
115 Lorazepam 2 to 4 mg slow IV push stat should be given for seizure
cessation. T.D. should be reloaded with magnesium sulfate and continued on a
magnesium infusion for 24 to 48 hours.
DRUG THERAPY MANAGEMENT IN LABOR AND
In pregnancy, many hormones and peptides, including progesterone, prostacyclin,
relaxin, nitric oxide, and parathyroid hormone-related peptide, inhibit uterine smooth
muscle contractility. Labor at term occurs because the myometrium is released from
120 For example, as progesterone concentrations decrease near term
gestation, estrogen may stimulate uterine contractility.
Uterine activity is divided into four phases: quiescence (phase 0), activation
(phase 1), stimulation (phase 2), and involution (phase 3). Each of these phases is
stimulated or inhibited by several factors.
120 During activation, uterotropins such as
estrogen, and possibly others, stimulate a complex series of uterine changes (e.g.,
increased myometrial prostaglandin and oxytocin receptors and myometrial gap
junctions), which are important for the coordination of contractions. These changes
help prime the myometrium and cervix for stimulation by the uterotonins oxytocin and
prostaglandins E2 and F2α. The cervix softens, shortens, and dilates, a process
referred to as cervical ripening. Uterine stimulation is responsible for the change in
myometrial activity from irregular to regular contractions. During phase 3, involution
of the uterus occurs after delivery and is mediated mostly by oxytocin.
The exact stimulus of the biochemical scheme leading to labor in humans is
unknown. The fetus may help facilitate this process by affecting placental steroid
production through mechanical distension of the uterus and by activating the fetal
hypothalamic–pituitary–adrenal axis. Ultimately, these lead to increased production
of oxytocin and prostaglandins by the fetoplacental unit.
Labor is divided into three stages. Weak, irregular, rhythmic contractions
(Braxton-Hicks contractions or “false labor”) may happen for weeks before the onset
of true labor. The first stage begins with the start of regular uterine contractions and
ends with complete cervical dilation. Stage 1 is divided further into the latent phase,
active phase, and deceleration phase. During the latent phase, the cervix effaces
(thins) but dilates minimally. The contractions become progressively stronger and
longer, better coordinated, and more frequent. The duration of the latent phase is the
most varied and unpredictable of all aspects of labor, and can continue intermittently
for days. During the active phase, contractions are strong and regular, occurring
every 2 to 3 minutes. The cervix dilates from 3 to 4 cm to full dilation, usually 10 cm.
The second stage starts with complete cervical dilation and ends with the delivery of
the fetus. The third stage of labor is the time between the delivery of the fetus and the
INDICATIONS, CONTRAINDICATIONS, AND REQUIREMENTS
contraindications for labor induction in J.T.?
The induction of labor involves the artificial stimulation of uterine contractions
that lead to labor and delivery. Induction of labor is indicated when the benefits to
either the mother or fetus outweigh those of continuing the pregnancy. Examples may
include preeclampsia, chorioamnionitis (infection of the fetal membranes, see Case
49-7, Question 11), fetal demise, significant fetal growth restriction, maternal
medical problems, and post-term pregnancy.
121 Post-term pregnancy (≥42 weeks’
gestation), as in J.T.’s case, is one of the most common indications for induction of
121 Contraindications to labor induction are similar to those for spontaneous
labor and vaginal delivery and include, but are not limited to, active genital herpes
infection, placenta previa (placenta implanted over the internal cervical opening),
prior classic uterine incision, transverse fetal lie (laying longitudinally across the
uterus), and prolapsed umbilical cord. Maternal complications that are associated
with induction include increased rates of chorioamnionitis and uterine atony (loss of
tone in uterine musculature) (see Case 49-8, Question 4) resulting in hemorrhage, as
well as a twofold to threefold increased risk of cesarean delivery, particularly in
A complete assessment of both mother and fetus should be performed before
121,123 Gestational age must be
assessed accurately before the induction of labor to avoid the inadvertent delivery
121,122 When delivery is necessary before 34 weeks’ gestation with
intact membranes or before 32 weeks’ gestation with ruptured membranes, antenatal
corticosteroids should be administered (see Case 49-7, Question 7).
The degree of cervical ripeness and readiness for induction of labor should be
121,125 Success of labor induction is directly related to the favorability of the
126,127 The Bishop method of evaluating cervical ripeness assigns a score
based on the station of the fetal head relative to the maternal ischial spines and the
extent of cervical dilation, effacement (thinning of the cervix), consistency, and
122,125 Bishop scores of greater than 8 are associated with rates of vaginal
delivery similar to those after spontaneous labor.
121 Conversely, Bishop scores of 4
or less, as documented in J.T., are associated with a high likelihood of failed
induction and cesarean delivery. As a result, significant research has been directed
toward methods of improving the Bishop score and cervix ripeness before
stimulation of uterine contractions. However, women with low Bishop scores who
undergo cervical ripening before induction of labor still have higher rates of
cesarean delivery compared with spontaneous labor.
ripening appears to have some benefit in decreasing time to delivery, shortening
labor, and successfully improving Bishop score.
Cervical ripening can be accomplished pharmacologically or mechanically.
Pharmacologic methods include the administration of prostaglandins (E2 and E1
low-dose oxytocin. Mechanical methods include membrane sweeping (or membrane
stripping), and intracervical balloons.
121,123,125 Osmotic or hygroscopic dilators (e.g.,
Dilapan, Lamicel) work by absorbing cervical mucus and gradually swelling, thereby
In the setting of a favorable Bishop score, labor
induction is accomplished most commonly by amniotomy (artificial rupture of the
fetal membranes) and oxytocin administration.
Although labor induction is medically indicated in J.T. to decrease the risk of an
adverse fetal outcome with continuing a post-term pregnancy, such as macrosomia,
asphyxia, meconium aspiration, and intrauterine infection, her cervix is unfavorable
for induction and she is a candidate for cervix ripening.
CASE 49-6, QUESTION 2: What pharmacologic agents can be used for cervical ripening in J.T.?
Prostaglandins induce cervical ripening and enhance myometrial sensitivity to
oxytocin by promoting the breakdown of collagen and increasing the submucosal
hyaluronic acid and water content.
121,122,125 Misoprostol is a prostaglandin E1 analog
approved for use in the prevention of nonsteroidal anti-inflammatory drug-induced
peptic ulcer disease. It also has been used for cervical ripening and the induction of
labor in women despite the lack of approval by the FDA for these latter
In two large meta-analyses, misoprostol was more effective for
cervical ripening and labor induction than either placebo or treatment with
dinoprostone (prostaglandin E2
In comparisons, intravaginal misoprostol
produced labor more often during cervical ripening and resulted in reduced rate of
cesarean deliveries, shorter delivery times, and a greater incidence of vaginal
delivery within 24 hours but had a higher incidence of uterine contraction
abnormalities than either dinoprostone vaginal insert or dinoprostone endocervical
128–132 Uterine tachysystole, excessively frequent uterine contractions, without
fetal heart rate abnormalities was more common with misoprostol use. Maternal and
neonatal outcomes were similar in both groups. The need for oxytocin is decreased
significantly in women treated with misoprostol compared with women treated with
Oral misoprostol has also been studied for cervical ripening, but comparisons of
vaginal and oral misoprostol are complicated by wide variations in dose and dose
132 A meta-analysis of available studies concluded that the only consistent
finding was a reduction in low 5-minute Apgar scores with oral misoprostol but no
difference in neonatal intensive care unit admissions. When comparing all studies
with a wide range of doses, oral misoprostol resulted in similar rates of vaginal
delivery not achieved in 24 hours, uterine tachysystole with fetal heart rate changes,
and cesarean delivery compared with vaginal misoprostol.
Misoprostol 25 mcg (one-fourth of an unscored 100-mcg tablet) is inserted into the
posterior vaginal fornix and repeated as needed every 3 to 6 hours.
doses of 50 mcg are associated with increased uterine contractile abnormalities.
Continuous fetal heart rate and uterine monitoring is recommended throughout the
administration of misoprostol.
If oxytocin is indicated after cervical ripening,
administration should be delayed at least 4 hours from the last dose of misoprostol.
Misoprostol should not be used in women with previous uterine scars because of
121,130,132 Although misoprostol is a known teratogen in the
first trimester of pregnancy, particularly if used in an unsuccessful attempt at medical
abortion, there are no such reports with exposure beyond the first trimester.
Misoprostol’s low cost and ease of administration are advantages compared with
dinoprostone, and there is extensive clinical experience with this agent; however, its
lack of FDA approval for cervical ripening and induction of labor is a disadvantage.
Clinical trials of a controlled-release misoprostol vaginal insert are currently
There are two FDA-approved forms of dinoprostone available for cervical ripening.
Up to half of the women treated with dinoprostone experience labor and deliver
within 24 hours, some without oxytocin.
134,136 Dinoprostone cervical gel (Prepidil
Gel) contains dinoprostone contains 0.5 mg per 3-g syringe (2.5 mL gel) and is
administered endocervically. The dinoprostone cervical gel must be refrigerated, and
dinoprostone vaginal inserts must remain frozen until administration. Dinoprostone
slow-release insert (Cervidil) contains dinoprostone 10 mg and is inserted
137 Post-term women with unfavorable cervices who receive dinoprostone
have shorter durations of labor, and require lower doses of oxytocin, compared with
125,134–136 A large meta-analysis that included more than 10,000
women found that the use of vaginal prostaglandin E2 compared with no treatment or
placebo was associated with increased rates of vaginal delivery within 24 hours,
increased rates of cervix ripening, reduced need for oxytocin augmentation, and no
difference in cesarean section. The risk of uterine tachysystole with fetal heart rate
changes was increased, however.
Both dinoprostone products are effective for cervical ripening, leading to
successful induction of labor.
125,134–136 The two dinoprostone formulations differ in
139,141 The dinoprostone 10-mg vaginal insert slowly releases
dinoprostone 0.3 mg/hour for a 12-hour period.
137 The insert is contained within a
knitted pouch attached to a long tape. Advantages of the vaginal insert include that it
is easier for the clinician to place and less uncomfortable for the patient. In addition,
the insert can be removed with the onset of active labor or the development of uterine
tachysystole with concurrent fetal heart rate tracing abnormalities. It should be
removed within 12 hours of placement or after active labor develops, the membranes
rupture, or there is evidence of tachysystole with fetal heart rate changes.
dinoprostone cervical gel is used, the dose can be repeated in 6 to 12 hours if
there is inadequate change in the cervix and only minimal uterine activity, but no
more than three total doses are recommended.
141 The manufacturer of Prepidil
recommends a delay in initiation of oxytocin of 6 to 12 hours once the gel has been
placed compared with a shorter delay of only 30 to 60 minutes after the vaginal insert
has been removed. An initial period of uterine and fetal monitoring of up to 2 hours
should occur after placement of the intracervical gel, with continued monitoring
thereafter if regular uterine contractions develop and persist.
The most serious side effect associated with dinoprostone administration is uterine
hyperstimulation with or without an abnormal fetal heart rate tracing. The incidence
of uterine hyperstimulation associated with the use of dinoprostone intravaginal
insert is about 5%; the rate of occurrence for dinoprostone endocervical gel is about
121 Uterine hyperstimulation occurs more frequently if the Bishop score is greater
than 4 before administration of dinoprostone and can occur up to 9.5 hours after
placement of the intravaginal insert.
121,141 Use of the vaginal insert requires
continuous monitoring of fetal heart rate and uterine activity for as long as the insert
is in place and for at least 15 minutes after its removal because of possible uterine
hyperstimulation anytime during its administration.
hyperstimulation with the use of the vaginal insert occur during active labor and
resolve within a few minutes after removal of the insert.
abnormalities may be avoided if the insert is promptly removed at the onset of
128 Both dinoprostone formulations are associated with fever, nausea, vomiting,
and diarrhea, and neither are associated with adverse neonatal outcomes.
For J.T., misoprostol 25 mcg should be administered intravaginally every 3 to 6
hours for cervical ripening. Misoprostol is the most cost-effective option for cervical
CASE 49-6, QUESTION 3: Twelve hours after administration of two 25-mcg doses of misoprostol, J.T.’s
contractions. What drug therapy should be initiated at this point?
Synthetic oxytocin should be administered to J.T. to stimulate uterine contractions
for accomplishing delivery. Oxytocin increases the frequency, force, and duration of
142 The uterine response to oxytocin increases throughout
pregnancy beginning at approximately 20 weeks’ gestation and increases
considerably at 30 weeks’ gestation.
140 Oxytocin is indicated for both the induction
and augmentation of labor. A prolonged latent phase or dystocia (difficult labor)
caused by uterine hypocontractility in the active phase of labor is the indication for
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