CASE 49-6, QUESTION 4: How should oxytocin be administered to J.T.?
Oxytocin should be administered by continuous IV infusion using a controlled
infusion device. The goal of oxytocin administration is to induce uterine contractions
that dilate the cervix and aid in the descent of the fetus while avoiding uterine
hyperstimulation and fetal distress.
142 There are two opposing views about oxytocin
administration for the induction or augmentation of labor. One view is that oxytocin
infusions should mimic physiologic doses in the range of 2 to 6 milliunits/minute with
the goal being vaginal delivery with as little uterine hyperstimulation and fetal
121 The other view is that oxytocin should be used in
pharmacologic doses to cause strong uterine contractions with the goals being
shortened labor, timely correction of dysfunctional labor, decreased cesarean
deliveries, and reduced maternal morbidity.
Oxytocin plasma concentrations increase linearly with increasing doses, and
steady state is reached within 20 to 40 minutes. Oxytocin serum concentrations
correlate poorly with uterine activity, however.
143 Factors that may affect response to
oxytocin include parity, gestational age, and cervical dilation.
Despite many randomized, controlled trials and much experience with oxytocin,
the optimal starting doses, dosage increments, dosing intervals, and maximal doses
are different in the various protocols.
140,142,144 Starting doses range from 0.5 to 6
milliunits/minute, and dose increment intervals range from 15 to 60 minutes.
Waiting for 30 to 40 minutes between each dosage rate increase allows time to
assess the response at steady state. Most low-dose protocols usually start oxytocin 1
to 2 milliunits/minute and increase the rate of infusion by 1 to 2 milliunits/minute
142,145 High-dose protocols start oxytocin at 3 to 6
milliunits/minute with incremental increases of 3 to 6 milliunits/minute every 20 to
40 minutes. The maximal dose of oxytocin has not been established.
recommends that each hospital’s obstetrics departments develop guidelines for the
consistent preparation and administration of oxytocin.
Oxytocin protocols using higher doses or shorter dose adjustment intervals (15–20
minutes) for augmentation of labor generally result in fewer cesarean deliveries for
labor dystocia, which is an abnormally slow progress of labor.
of uterine hyperstimulation during labor induction is higher with high-dose protocols
(initial dose of 6 milliunits/minute with incremental increases of 6 milliunits/minute),
however, when compared with shorter dosing adjustment intervals of 20 minutes or
with longer dose adjustment intervals of 40 minutes.
induction with high-dose oxytocin have a higher incidence of uterine stimulation and
cesarean deliveries for fetal distress, but a reduced incidence of failed inductions
and neonatal sepsis compared with women treated with low-dose oxytocin.
general, lower maximal doses are needed for augmentation of labor than for
J.T. should be started on an infusion of oxytocin 10 units diluted in 1,000 mL of an
isotonic solution (concentration 10 milliunits/mL) at 1 milliunits/minute. She should
have continuous uterine and fetal heart rate monitoring throughout the infusion to
detect abnormal uterine contraction patterns or fetal heart rate patterns. The goal is to
establish a pattern of three to five uterine contractions of 60 to 90 seconds’ duration
146 The oxytocin infusion should be increased by 1 to 2
milliunits/minute every 30 to 40 minutes as needed for inadequate progression of
labor (cervical dilation rate of <1 cm/hour).
121,149 Fluid intake and urine output should
CASE 49-6, QUESTION 5: What are the adverse effects and complications of oxytocin for which J.T.
Uterine hyperstimulation, usually associated with excessive maternal dosing or
increased myometrial sensitivity to oxytocin, may result in uterine rupture, vaginal
and cervical lacerations, precipitous delivery, abruptio placentae, emergency
cesarean delivery for fetal distress, and postpartum hemorrhage secondary to uterine
atony. In general, neonatal outcomes associated with oxytocin use do not differ from
146 Although oxytocin has only weak antidiuretic properties, water
intoxication resulting in seizures, coma, and death has been reported.
structurally and functionally related to vasopressin, also known as antidiuretic
hormone. Administration of high concentrations of greater than 40 milliunits/minute
and for long periods is associated with hyponatremia, which can lead to lethargy,
drowsiness, generalized seizures, and potentially irreversible neurologic injury. IV
bolus administration may cause paradoxical relaxation of vascular smooth muscle
leading to hypotension and tachycardia. J.T. should be monitored for uterine
hyperstimulation with fetal heart rate deceleration because it is the most common
Preterm delivery occurred in 12.8% of births in the United States in 2006,
representing a 20% increase since 1990.
3 Approximately 55% of singleton preterm
births follow spontaneous preterm labor, and approximately 8% follow preterm
premature rupture of the chorioamniotic membranes.
150 Premature birth is the leading
cause of neonatal mortality (infant death <1 month of age), resulting in approximately
150 Prematurity is the second leading cause of infant mortality at
younger than 1 year of age, and resulted in 17% of such deaths in 2006.
the more inclusive classification of mortality as being “preterm related” was linked
to 36.1% of all infant deaths in 2006.
Spontaneous preterm labor is a heterogeneous syndrome, and several known
pathways can lead to preterm birth. These pathways include excessive uterine
distension, decidual hemorrhage, activation of the maternal and fetal hypothalamic–
pituitary system, and intrauterine infection leading to inflammation. These pathways
ultimately lead to a final common response with production of uterine and cervical
proteases and uterotonins, which result in progressive cervical ripening and dilation;
weakening of the chorioamniotic membranes, which leads to rupture; and uterine
contractions. Ultimately, delivery of the infant occurs. Infection, if present, triggers
an inflammatory response that results in the release of cytokines, prostaglandins, and
proteases, which stimulate uterine activity, induce cervix softening and dilation, and
weaken the chorioamniotic membranes.
152 Variations in maternal and fetal genes
coding for cytokines have been implicated in the apparent genetic predisposition to
preterm birth found in some families and racial groups.
uterotonic agent, which can cause uterine contractions, and has been implicated in
causing preterm labor associated with vaginal bleeding caused by placental
154 Studies have shown a relationship between increasing maternal
corticotropin-releasing hormone (CRH) and delivery timing.
stress can activate the hypothalamic–pituitary system and result in the rapid increase
of maternal CRH before premature birth. Infection can also activate the fetal
hypothalamic–pituitary system, increasing CRH, cortisol, and, ultimately,
152,154 Despite some progress in recent years, much remains unknown
about the etiology of preterm birth, and little is known about how preterm birth can
CLINICAL PRESENTATION AND EVALUATION
laboratory evidence support a diagnosis of preterm labor?
B.B. has backache and uterine contractions, which are symptoms of preterm labor.
Most women with preterm contractions are not in labor, however, which results in
frequent overdiagnosis. In addition, contractions during preterm labor are frequently
not painful, are not detected by the woman, and thus are not a sensitive marker for
preterm labor. Fibronectin, a protein that serves as an adhesive between the fetal
membranes and decidua, normally disappears from the cervical secretions after the
first half of pregnancy, reappearing only at term as labor approaches.
fibronectin test can exclude imminent preterm delivery in a woman at risk for preterm
delivery, between 24 and 34 weeks’ gestation with intact amniotic membranes, and
with cervical dilatation of less than 3 cm.
157 Because of fibronectin’s high negative
predictive value of greater than 95% for delivery in the next 1 to 2 weeks, it can be
used to avoid overdiagnosis of preterm labor. Although fibronectin testing will yield
false-positive results in the presence of blood, vaginal bleeding itself is
independently associated with preterm birth. B.B. has the criteria necessary to
establish a firm diagnosis of preterm labor. Not only is her fibronectin test positive,
but she has persistent contractions with a documented change in cervix dilatation.
CASE 49-7, QUESTION 2: What risk factors does B.B. have for spontaneous preterm labor?
B.B. has several risk factors for preterm delivery. The strongest predictor of
preterm birth is prior preterm birth. She has a twofold or higher increased risk of
preterm delivery because of one previous preterm delivery.
ends prematurely, her risk for a third preterm birth in her next pregnancy will be
sixfold higher than that in the normal population.
156 Recurrence risk rises as the
gestational age of the prior preterm birth decreases, especially for deliveries at less
than 32 weeks. Her young age may also be a risk factor. A maternal age younger than
18 or older than 35 years is associated with spontaneous preterm birth, although it is
difficult to separate age from the confounding factors associated with age.
likely does not contribute to her risk. Black race is an independent risk factor for
both preterm labor and lower neonatal birth weight. Other risk factors include low
maternal weight before pregnancy, smoking, second- or third-trimester bleeding,
multiple gestation, and uterine anomalies, which B.B. does not have.
cervix length by transvaginal ultrasound imaging have demonstrated that shorter
lengths are associated with greater risk for preterm delivery; however, the positive
predictive value varies widely.
156,157 Maternal infections, such as untreated urinary
tract infections and pneumonia, are associated with preterm delivery. In addition,
genital organisms such as Gardnerella vaginalis, C. trachomatis, N. gonorrhoeae,
Ureaplasma urealyticum, and T. vaginalis, are also associated with preterm births.
Although it is important to identify women at risk for spontaneous preterm delivery,
only half of all preterm deliveries occur in women with known risk factors.
CASE 49-7, QUESTION 3: What are the goals of tocolysis for B.B.?
Treatment of spontaneous preterm labor primarily has been directed at slowing or
stopping contractions (tocolysis), which are the obvious, although likely late, sign of
impending preterm birth. It has been presumed that if successful, this should prevent
or delay preterm birth. Few placebo-controlled trials have been conducted of agents
used to diminish contractions (tocolytics), and most data suggest delay of delivery by
158 This might be because of the heterogeneous causes of
spontaneous preterm birth and because tocolytic agents may not arrest the underlying
process that led to contractions. Most studies have been unable to demonstrate a
clear benefit of tocolysis on neonatal morbidity and mortality. Instead, they have
evaluated surrogate end points, such as pregnancy prolongation or number of preterm
births before various cut-off points.
159 The value of prolonging pregnancy will vary
by gestational age, and might be substantial if time is gained to administer
glucocorticoids to improve fetal lung maturation and decrease the risk of
intraventricular hemorrhage (see Case 49-7, Question 7). All women at risk for
preterm birth within 7 days and between 24 and 34 weeks’ gestation should be
considered for glucocorticoid therapy.
124,159,160 Delay of delivery can also allow
transport to a facility best equipped to care for both mother and premature newborn.
Numerous factors affect the decision to treat preterm labor with a tocolytic agent.
Fetal factors precluding tocolysis include nonreassuring fetal monitoring, significant
IUGR, and lethal congenital anomalies. Maternal factors include evidence of
chorioamnionitis, other significant maternal infections or illness, preeclampsia, and
156 Tocolysis is less likely to be effective in women with cervical
dilation of greater than 3 cm and is usually unsuccessful if the patient is in advanced
labor (cervical dilation >5 cm).
156 Because the etiology of preterm labor is
multifactorial, B.B. should be evaluated thoroughly and periodically for potential
causes of preterm labor and treated appropriately when diagnosed. For example,
urinary tract infections are associated with preterm labor, and they should be
diagnosed and treated if present.
156 Additionally, some would also perform
amniocentesis to exclude subclinical chorioamnionitis as a cause of preterm labor
before initiating or continuing tocolysis, and to evaluate lung maturity at later
160 B.B. has no evidence of overt infection or other complications,
and has no contraindications to tocolysis. Prolonging gestation, even for a few days,
would be beneficial because B.B. is only at 29 weeks’ gestation.
CASE 49-7, QUESTION 4: How should B.B.’s preterm labor be managed? Which tocolytic agent should be
Magnesium sulfate is the most frequently used parenteral tocolytic agent in the United
States and is also prescribed for the prevention and treatment of eclampsia.
Magnesium sulfate relaxes uterine smooth muscle at maternal serum levels of 5 to 8
156 The mechanism by which it exerts this effect is not understood completely,
but involves inhibition of myosin light-chain kinase activity by competition with
intracellular calcium, reducing myometrial contractility.
Despite its widespread use, the evidence for magnesium’s efficacy in prolonging
gestation is inadequate. In two published, randomized, placebo-controlled trials, no
benefit in mean prolongation of pregnancy or mean neonatal birth weight was
demonstrated. In meta-analyses of both placebo-controlled trials of magnesium for
tocolysis compared with other active drugs, no prolongation of pregnancy was seen
158,161 Several small randomized, controlled studies have directly
compared magnesium with parenteral β-adrenergic agonists, mostly ritodrine.
Three of the four showed no differences in birth outcomes. One of the four suggested
prolonged pregnancy with magnesium added to ritodrine compared with ritodrine
alone. Studies on the efficacy of β-adrenergic agonists (mostly ritodrine) versus
placebo have been mixed, but on balance suggest delay of delivery for 48 hours, but
equally effective. Magnesium is better tolerated than the β-adrenergic agonists, with
158 Magnesium is contraindicated in patients with
myasthenia gravis and must be used with caution in renal failure.
β-Adrenergic agonists are not the first-line choice for preterm labor because of high
costs and the significant potential for maternal adverse effects described
156,158 Both ritodrine, the only medication approved by the FDA for the
treatment of preterm labor, and terbutaline bind to β2
-adrenergic receptors in uterine
smooth muscle and ultimately inhibit smooth muscle cell contractility. Results of
randomized, controlled trials of ritodrine have been mixed; however, a meta-analysis
that included 1,320 women treated with β-agonists demonstrated fewer births at 48
hours but no change in number of births at 7 days. No benefit on neonatal morbidity
or mortality was seen; however, the studies are limited by sample size.
continued use of β-agonists can result in the development of tachyphylaxis to its
effects on the myometrium and may in part explain treatment failures with these
Terbutaline is available for IV, SC, and oral administration. One dose of
terbutaline 0.25 mg SC is often administered to women with mild contractions and
cervical dilation less than 2 cm. IV β-sympathomimetics are used in cases with more
severe and frequent contractions and cervical dilation greater than 2 cm. However,
because of potential adverse maternal side effects such as increased heart rate,
transient hyperglycemia, hypokalemia, cardiac arrhythmias, pulmonary edema, and
myocardial ischemia, the FDA issued a black box warning in 2011 against the use of
injectable terbutaline beyond 48 to 72 hours. The FDA also recommended against
any use of oral terbutaline for preterm labor owing to both lack of efficacy and the
potential for significant maternal side effects.
β-Adrenergic agonists are not selective for myometrial β2
pharmacologic doses, and this accounts for their high incidence of adverse effects.
Maternal adverse effects such as pulmonary edema, palpitations, tachycardia,
myocardial ischemia, hyperglycemia, hypokalemia, and hepatotoxicity result in
discontinuation of therapy in up to 10% of patients.
and, if not recognized promptly, can lead to ARDS and death.
should not be used in women with underlying cardiac disease or arrhythmias,
hypertension, diabetes mellitus, severe anemia, or thyrotoxicosis.
drugs should be avoided if there are signs of chorioamnionitis such as maternal
leukocytosis, fetal tachycardia, or maternal fever.
especially if the drug is being administered within hours of delivery.
hyperglycemia causing fetal hyperglycemia and hyperinsulinemia can lead
to neonatal hypoglycemia if not properly monitored postnatally. Fetal tachycardia
rarely leads to fetal myocardial ischemia or hypertrophy.
β-sympathomimetic drugs have been used commonly in the past, they are now used
much less frequently because of side effect profiles and safety concerns.
Prostaglandins F2a and especially E2 are important regulators of myometrial
contractility and cervical ripening.
120 Prostaglandin synthesis requires
cyclooxygenase (COX), also known as prostaglandin synthetase, to convert
arachidonic acid to prostaglandin G2
. COX inhibitors such as indomethacin decrease
prostaglandin production, which decreases contractions and inhibits cervical change.
As with other tocolytics, these drugs have not been adequately studied in multiple
randomized controlled trials. A review of available randomized trials of
indomethacin compared with placebo found significant reductions in women
delivering at less than 37 weeks’ gestation, an increase in gestational age at delivery,
and a trend toward fewer deliveries at 48 hours and 7 days.
comparing COX inhibitors with other tocolytics, a reduction in both delivery before
37 weeks’ gestation and maternal drug reactions was noted. Also, seen in these
studies was a trend toward a reduction in delivery within 48 hours.
is well tolerated, and GI upset can be mitigated by antacids when it occurs. The
available studies are inadequately powered to evaluate neonatal safety and outcomes,
Although well tolerated by the mother, concerns exist about the fetal and neonatal
effects of prostaglandin synthetase inhibition. Indomethacin crosses the placenta
rapidly, and fetal levels rapidly approach maternal levels.
indomethacin can decrease fetal urine output leading to oligohydramnios, the
amniotic fluid index should be followed and indomethacin discontinued if it falls
below 5 cm (normal range, 5–25 cm). Oligohydramnios generally resolves within 48
to 72 hours of the discontinuation of indomethacin. The fetal ductus arteriosus, which
is critical to allow blood from the right ventricle to bypass the fluid-filled lungs,
constricts in 25% to 50% of fetuses exposed to indomethacin in utero, but generally
156 Permanent closure of the ductus arteriosus, however, can lead to
fetal right heart failure and even intrauterine demise. The risk for neonatal adverse
effects is increased with drug exposure of longer than 48 hours, as well as use after
32 weeks’ gestation when premature closure of the ductus occurs more frequently.
An increased risk for maternal postpartum hemorrhage has also been reported with
indomethacin use but did not reach significance in a meta-analysis.
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