should not be used in the presence of oligohydramnios or suspected fetal renal or
cardiac anomaly (see Chapter 105, Neonatal Therapy).
More serious fetal and neonatal effects have been reported in some retrospective
and observational studies, including neonatal necrotizing enterocolitis,
intraventricular hemorrhage, and renal failure.
It is difficult, however, to discern
whether these complications are causally related to indomethacin or to the use of the
drug in cases of refractory preterm labor caused by subclinical intra-amniotic
166,169 An analysis of the risks and benefits of indomethacin suggested its
continued use as second-line treatment for preterm labor between 24 and 32 weeks’
gestation in women with contraindications to other tocolytics.
regimens include a loading dose of 50 to 100 mg either rectally or orally followed by
a maintenance dose of 25 mg orally every 4 to 6 hours for 24 to 48 hours.
The calcium-channel blockers nifedipine and nicardipine inhibit preterm contractions
by decreasing calcium influx into uterine smooth muscle and inhibiting myometrial
contractions. No placebo-controlled trials have been performed with nifedipine, the
most commonly used calcium-channel blocker. A meta-analysis of 12 randomized
trials including a total of 1,029 women found that calcium-channel blockers were
superior to other tocolytics (mostly β-mimetics) in reducing preterm births within 7
days and before 34 weeks’ gestation.
169 A more recent study of 192 women
comparing nifedipine with magnesium sulfate for preterm labor found no differences
in delivery in 48 hours, gestational age at delivery, or deliveries before 32 or 37
170 Maternal side effects were significantly fewer in patients
receiving calcium-channel blockers compared with other tocolytics.
Maternal side effects can include tachycardia, headache, flushing, dizziness,
nausea, and hypotension in the hypovolemic patient.
164 Nifedipine does not adversely
affect uteroplacental blood flow or fetal circulation. Concurrent use with magnesium
should be avoided because the combination may potentiate neuromuscular
106,160,164 The starting dose is usually 10 mg PO with repeated doses of 10
mg every 15 to 20 minutes for persistent contractions, up to a maximum of 40 mg in
172,173 Depending on the tocolytic effect, nifedipine is then maintained at
10 to 20 mg PO every 4 to 6 hours.
172 Overall, nifedipine appears to be an attractive
alternative for short-term tocolysis because the drug is usually well tolerated.
B.B. should be started on a magnesium sulfate 6-g IV loading dose for 30 minutes
followed by 2 g/hour continuous IV infusion through a controlled infusion pump. The
hourly rate of magnesium administration for B.B. may be increased until she has one
or fewer contractions per 10 minutes or a maximum of 4 g/hour is attained. B.B.’s
deep tendon reflexes, respiratory rate, and urine output should be monitored
regularly. Close monitoring of fluid balance is important because fluid overload has
been associated with pulmonary edema and the drug is renally excreted.
Magnesium serum concentrations are commonly evaluated every 6 to 12 hours in
an effort to minimize adverse effects.
175 The patellar reflex disappears with
magnesium serum concentrations between 9 and 10 mg/dL, and as long as deep
tendon reflexes are present, many practitioners will not measure concentrations. To
prevent inadvertent overdoses, a controlled infusion device should always be used to
deliver magnesium as a continuous infusion. Hypocalcemia and tetany can occur with
hypermagnesemia. Neuromuscular blockade and respiratory arrest develop with
magnesium serum concentrations of 15 to 17 mg/dL, and cardiac arrest develops with
greater concentrations. The toxic effects of magnesium can be rapidly reversed with
1 g of parenteral calcium gluconate, which should be readily available when patients
are receiving magnesium infusion.
The most common side effects of magnesium loading doses are transient
hypotension, flushing, a sense of warmth, headache, dizziness, lethargy, nystagmus,
156,172 Other adverse effects reported with magnesium are hypothermia,
paralytic ileus, and pulmonary edema, which may occur in 1% to 2% of patients
treated with magnesium sulfate.
172 Pulmonary edema occurs less frequently with
magnesium sulfate than with parenteral β-sympathomimetics but is more commonly
encountered with prolonged infusions, multifetal pregnancy, and the use of multiple
164 Treatment consists of discontinuing magnesium sulfate and
administration of the diuretic furosemide.
Fetal magnesium serum concentrations are similar to maternal concentrations.
The most common neonatal adverse effects are hypotonia and sleepiness. Hypotonia
may continue for 3 or 4 days in the neonate because of decreased renal elimination of
magnesium. Rarely, assisted mechanical ventilation for neuromuscular depression
CASE 49-7, QUESTION 5: B.B. has been maintained on magnesium sulfate continuous IV infusion for
B.B.’s contractions have completely stopped for 24 hours. Some protocols
maintain magnesium sulfate for 12 to 24 hours after successful tocolysis, or for the
time it takes to complete the course of corticosteroids. The weaning of magnesium
sulfate is unnecessary, and simple discontinuation of the magnesium infusion is an
easier and less costly option.
CASE 49-7, QUESTION 6: B.B. heard that preterm labor can return once stopped and asks whether she
should stay on medication. Should B.B. be started on chronic maintenance tocolytic therapy?
Maintenance tocolysis has been used in an attempt to prevent recurrence of
preterm labor and prolong gestation in women in whom preterm labor was
maintenance therapy after acute preterm labor showed no benefit in delay of delivery,
births at less than 34 or 37 weeks’ gestation, or neonatal complications.
increases in maternal adverse effects occurred, primarily tachycardia, hypotension,
and palpitations. Lastly, inadequate data exist to support the use of calcium-channel
blockers as maintenance therapy.
160 B.B. should not be started on chronic
maintenance tocolysis, because there is not compelling evidence that continued
suppression of contractions after acute tocolysis reduces the rate of preterm birth or
ANTENATAL GLUCOCORTICOID ADMINISTRATION
CASE 49-7, QUESTION 7: Given B.B. is in preterm labor at 29 weeks’ gestation, what medication can be
given to help facilitate fetal lung maturation?
B.B. should be given betamethasone 12 mg intramuscularly now and a second dose
24 hours later to facilitate fetal lung maturation by increasing production of fetal lung
surfactant, thereby reducing the incidence and severity of RDS.
corticosteroid administration (betamethasone and dexamethasone) also decreases the
incidence of intraventricular hemorrhage, necrotizing enterocolitis, and neonatal
124 The greatest reduction in RDS occurs when delivery can be delayed 24
hours up to 7 days after starting treatment. Repeated weekly corticosteroid courses
should not be given because of the association with decreased birth weight and head
circumference, hypothalamic–pituitary–adrenal axis suppression, deleterious effects
on cerebral myelination and lung growth, and neonatal death (particularly in neonates
born to mothers who received three or more courses).
clinical trial has now demonstrated a significant reduction in neonatal respiratory
morbidity and composite neonatal morbidity when women with preterm labor and
intact membranes who had received an initial course of steroids at less than 30
weeks’ gestation were treated again with a single rescue course of steroids
(betamethansone 12 mg IM × 2 doses, 24 hours apart) if more than 2 weeks had
passed and the gestational age was less than 33 weeks.
administered if there was judged to be a recurrent risk of preterm birth. Although
long-term outcome data are not yet available, the ACOG now recommends
consideration of a single rescue course of steroids under these specific
The National Institutes of Health (NIH) Consensus Panel and the ACOG
recommend a course of antenatal betamethasone or dexamethasone (dexamethasone 4
mg IM × every 12 hours, for 4 doses) for all women in preterm labor between 24 and
124,125 Betamethasone, however, might be the preferred agent
because fewer IM injections are needed and because in meta-analysis it was
associated with a greater reduction in RDS compared with dexamethasone.
conclusion, however, is not based on direct comparison of betamethasone with
dexamethasone and should be interpreted with caution. One study, although limited
by its retrospective nature, also suggested an advantage of betamethasone over
dexamethasone in the reduction of periventricular leukomalacia, a finding associated
with later risks for cerebral palsy.
In cases of PPROM, the NIH Consensus Panel
recommends that corticosteroids may be given up to 32 weeks’ gestation in the
124,125 Recent meta-analysis supports the efficacy of
corticosteroids in the reduction of neonatal death, RDS, duration of ventilator use,
and intraventricular hemorrhage in infants born after ruptured membranes.
at more than 32 weeks’ gestation can be considered for amniotic fluid testing for the
presence of phosphatidylglycerol or a lecithin to sphingomyelin ratio of greater than
2 because these are indicators of fetal lung maturation.
recommended for use in pregnant women who are at more than 34 weeks’ gestation
unless there is an indication of fetal lung immaturity (105, Neonatal Therapy).
Infectious Complications During Pregnancy and Labor
CASE 49-7, QUESTION 8: Preterm labor is often associated with an infectious etiology or source. Does
B.B. need to be started on any antibiotic therapy because she is in preterm labor?
PRETERM PREMATURE RUPTURE OF MEMBRANES
Increasing evidence associates preterm labor with intra-amniotic infections.
preterm births, 20% to 40% may be caused by an infectious or inflammatory
Intrauterine infection is associated with approximately 80% of early
154 Most of the bacteria found in amniotic fluid and the placenta
are believed to have ascended from the vagina.
It has been suggested that the
microbes responsible for preterm birth are already present in the endometrium before
conception or early in the pregnancy, causing a chronic, subclinical infection weeks
to months before eventually causing PPROM or labor.
When PPROM has occurred, spontaneous labor and delivery occurs on average
within 7 days, although longer intervals from PPROM to delivery occur with earlier
187 The use of a short course of antibiotics has been shown to prolong
the period between PPROM and delivery (the latency period) and decrease neonatal
In the largest and best-designed trial of antibiotic treatment of PPROM,
women between 24 and 32 weeks’ gestation treated with ampicillin and erythromycin
had both prolonged pregnancies and lower rates of chorioamnionitis.
newborns experienced decreased mortality, as well as decreased morbidity including
RDS and necrotizing enterocolitis. These effects were not owing to tocolytics or
corticosteroids because these were exclusionary factors. These results were
confirmed by the results of a large meta-analysis including more
than 6,000 women, although information on the best choice of antibiotics was less
189,190 Therefore, women with PPROM benefit from antibiotic therapy with a
broad-spectrum regimen, and IV ampicillin plus erythromycin for 48 hours followed
by 5 days of oral amoxicillin plus erythromycin for a total of 7 days treatment is a
B.B. should not be started on any PPROM antibiotic regimens because her
membranes are not ruptured. Antibiotics have not been proved to prevent premature
births in the setting of acute preterm labor.
158 There is currently no role for antibiotic
use to prolong pregnancy or reduce neonatal morbidity in preterm labor with intact
membranes, and it may be associated with long-term harm.
for treatment of bacterial vaginosis antenatally to reduce the risk of preterm birth in
women with a past history of spontaneous preterm birth.
Some, but not all, studies have demonstrated that screening and treating asymptomatic
women who are at high risk for preterm delivery for bacterial vaginosis (BV) may
reduce the risk of preterm birth.
158,160 A polymicrobial overgrowth of mostly
anaerobic bacteria, BV, is one of the most common genital infections in pregnancy,
and it is associated with an increased risk of preterm delivery.
women with BV who had a prior preterm delivery with oral metronidazole in
combination with erythromycin decreased the risk of recurrent preterm delivery in
one randomized clinical trial, but there was no difference for women without a
history of recurrent preterm birth.
In addition, a meta-analysis including 622
women with prior preterm birth found no reduction in the risk of preterm birth before
37 weeks’ gestation after treatment of BV with antibiotics, but did find a reduction in
PPROM. In addition, in women with BV who were treated with oral antibiotics
before 20 weeks’ gestation, there was a reduction in preterm birth at less than 37
198 B.B. does not have BV; therefore, treatment with metronidazole is
GROUP B STREPTOCOCCUS INTRAPARTUM PROPHYLAXIS
Antibiotics should be given to women if delivery is anticipated resulting either from
preterm labor with intact membranes or after PPROM to prevent group B
streptococcal (GBS) infection in the newborn. Other broad-spectrum antibiotic
therapy to prevent preterm delivery should not be given routinely to women in
preterm labor with intact membranes.
Approximately 10% to 30% of pregnant women are colonized with GBS or
Streptococcus agalactiae in the vagina or rectum, and 1% to 2% of neonates born to
colonized women experience early-onset invasive GBS disease in the absence of IV
intrapartum antibiotic prophylaxis.
199 One-fourth of all cases of neonatal GBS
infections occur in preterm newborns. B.B.’s fetus, therefore, is at risk for invasive
GBS infection from vertical transmission (mother to infant) of bacteria during labor
or delivery. The mortality rate for GBS is reported to be between 5% and 20%.
Fortunately, the incidence of GBS has declined to a rate of 0.34 to 0.37 cases per
1,000 live births in recent years owing to prevention efforts.
GBS infection can cause maternal urinary tract infection, amnionitis, endometritis,
and wound infection. Antibiotics given to the mother during preterm labor and
delivery help to prevent neonatal GBS disease, which may lead to sepsis,
pneumonia, and meningitis. In the past decade, the routine administration of
intrapartum antibiotic prophylaxis to certain subsets of pregnant women has led to a
70% reduction in the overall incidence of GBS disease.
women with intrapartum antibiotics has been based on either a positive vaginal and
rectal GBS culture routinely obtained at 35 to 37 weeks’ gestation or one or more of
the following risk factors without culture screening: (a) previous infant with invasive
GBS disease; (b) GBS bacteriuria during any trimester of the current pregnancy; (c)
unknown GBS status at onset of labor and any of the following: delivery at less than
37 weeks’ gestation, amniotic membrane rupture at 18 hours or more, intrapartum
temperature of 38°C (100.4°F) or greater.
Vaginal and rectal GBS cultures should be obtained from B.B., and she should be
given a loading dose of penicillin G injection 5 million units, followed by 2.5 to 3.0
million units IV every 4 hours until delivery, while awaiting success of tocolysis and
culture results. The Centers for Disease Control and Prevention guidelines
recommend that the benchmark for optimal prophylaxis should be antibiotics given at
least 4 or more hours before delivery. Penicillin G is preferred over ampicillin
because it has a narrower spectrum of antimicrobial activity. If B.B. had a severe
allergy to penicillin, sensitivities to clindamycin and erythromycin should be
requested at the time of culture in the event GBS is found because of increasing
resistance to these drugs. If the isolate is susceptible to both clindamycin and
erythromycin, then clindamycin 900 mg IV every 8 hours should be used until
delivery. Erythromycin is no longer recommended as an option for treatment because
it is often associated with inducible resistance to clindamycin. If the isolate is not
susceptible to both clindamycin and erythromycin or if sensitivities are not available,
penicillin-allergic women at high risk for anaphylaxis should receive vancomycin 1 g
IV every 12 hours until delivery. Penicillin-allergic women at low risk for
anaphylaxis should receive cefazolin 2 g IV initially, then 1 g IV every 8 hours until
192,193 Because B.B is only at 29 weeks’ gestation and is in preterm labor,
she has not yet had her GBS culture obtained, which normally occurs at 35 to 37
weeks. Until the results of her rapid testing for GBS culture returns, she should
receive penicillin G, 3 million units IV every 4 hours until delivery to prevent
imminent delivery. Should penicillin G administration be discontinued?
Penicillin should be discontinued at this time. Vaginal and rectal cultures need not
be repeated if B.B. delivers within the next 4 weeks. If tocolysis is successful and
delivery is delayed for more than 4 weeks, obtaining cultures and starting penicillin
G preemptively should be repeated at that time. Intrapartum prophylaxis is effective
only if antibiotics can be given immediately before and during delivery.
CASE 49-7, QUESTION 10: B.B.’s contractions are gone, and her cervical examination remains unchanged
another preterm delivery from occurring?
Recent studies have shown that progesterone supplementation can help to reduce
preterm births, but should only be used in women who have had a prior documented
history of a spontaneous preterm birth before 37 weeks’ gestation.
progesterone product is not known (vaginal suppositories, oral capsules, or IM
injectables). Progesterone should be offered to women like B.B. who have had a
prior history of spontaneous preterm delivery.
deliveries in these high-risk women with a prior documented history of preterm
195 The rate of preterm delivery in the treatment
group was 6.3% versus 54.9% in the placebo group.
injection prepared as 250 mg/mL once weekly. Therapy should be initiated at 16 to
20 weeks’ gestation and continued until 37 weeks’ gestation.
available from compounding pharmacies, and most recently, a commercially
marketed FDA-approved drug called Makena has been released into the market.
Although B.B. is already 29 weeks pregnant, she should be started on 17-OHP
therapy at 250 mg/mL injected IM once weekly until 37 weeks. She should be
counseled that progesterone should be started earlier at 16 weeks in her next
pregnancies. The compounded 17-OHP is more affordable, cost-effective, and
equally as effective as the marketed Makena product.
of 106/79 mm Hg, heart rate of 80 beats/minute, and respiratory rate of 12 breaths/minute with 99%
an elevated fever during labor, and how should B.B. be treated?
Chorioamnionitis is an infection of the amniotic fluid, membranes, and placenta
occurring before, during, or immediately after birth.
Intra-amniotic infections occur
in approximately 1% to 5% of term pregnancies and may complicate up to 15% of
204 Maternal fevers are usually the most common clinical
presentation in many patients. Diagnosis is based on the presence of fever, defined as
100.4°F (38°C) or greater measured twice at least 4 hours apart, or a temperature of
101°F (38.3°C) measured once. Patients may also present with maternal tachycardia
(>100 beats/minute), fetal tachycardia (160 beats/minute), uterine tenderness, foul
odor from amniotic fluid, and maternal leukocytosis.
197,198 The exclusion of other
ascending from vaginal flora causing polymicrobial intra-amniotic infections include
genital mycoplasmas such as U. urealyticum and Mycoplasma hominis, anaerobes
including G. vaginalis, enteric gram-negative bacilli, and GBS.
prominent risk factors of intra-amniotic infections are the number of digital
examinations and duration of labor.
Maternal complications from intra-amniotic infections include bacteremia,
suboptimal uterine contractility, and risk for postpartum hemorrhage.
rates of neonatal sepsis, pneumonia, meningitis, and mortality have been shown in
infants whose mothers had chorioamnionitis.
200 Furthermore, inflammation,
intrapartum fever, and infection increase the risk of long-term neurodevelopmental
delay and cerebral palsy in these neonates.
201 The risk of cerebral palsy is at least
twofold to fourfold higher in infants who were exposed to intra-amniotic infection in
Early administration of broad-spectrum antibiotics immediately after the diagnosis
of chorioamnionitis has been shown to have both maternal and neonatal benefit
versus postpartum antibiotic administration. A common regimen implemented is
ampicillin 2 g IV every 6 hours in addition to gentamicin dosed to a target peak of 8
mcg/mL and trough of 1 mcg/mL.
198 Standard dosing of gentamicin dosed every 8
hours is preferred over once-daily dosing to prevent elevated fetal serum peak
levels, although no adverse effects of high-dose therapy were noted.
900 mg IV every 8 hours may be added to the regimen to cover anaerobic organisms.
If fevers persist for longer than 24 hours on triple antibiotics with ampicillin,
gentamicin, and clindamycin, metronidazole can be substituted for clindamycin to
help broaden anaerobic coverage.
198 Other options for antibiotic coverage include
extended-spectrum penicillins (i.e., piperacillin–tazobactam, ampicillin–sulbactam)
or second-generation cephalosporins (i.e., cefoxitin and cefotetan).
antibiotics administered about 1 hour after infusion produce adequate bactericidal
concentrations in the fetus and placental membranes.
With a fever of 101.1°F, B.B. meets criteria for a clinical diagnosis of
chorioamnionitis. However, she does not exhibit any other symptoms of systemic
infection such as tachycardia, uterine tenderness, or fetal tachycardia, which is quite
common. Gentamicin and ampicillin should be started promptly after diagnosis to
decrease the risk of neonatal sepsis and to avoid possible neurodevelopment
sequelae. In addition, clindamycin can be added to cover anaerobic organisms.
B.B.’s risk for chorioamnionitis includes multiple digital examinations, preterm
labor, spontaneous labor, and long duration of labor. Antibiotics should be continued
until B.B. is afebrile for at least 24 to 48 hours or until delivery. Ultimately,
immediate antibiotic administration and delivery of the offending source is
paramount to ensure fetal health and safety.
Human Immunodeficiency Virus in Labor and BreastFeeding
minutes. Her last HIV RNA levels were undetectable, and her CD4 count was 400 cells/μL. Her current
must be started while she is in labor?
Current recommendations state that all HIV-infected pregnant women should
receive intrapartum AZT if the HIV RNA level is >1,000 copies/mL, and their infants
should receive neonatal AZT immediately after delivery for 6 weeks with a
consideration for a 4 week treatment plan if the mother has been maintained on a
cART regimen thought out the pregnancy.
203 Many factors must be taken into
consideration, including cost, ease of administration for compliance, individual ART
resistance patterns, and risks of side effects with the possibility of teratogenicity.
Generally, if a woman on cART becomes pregnant, she should continue on therapy
throughout the pregnancy, including the first trimester.
cART before becoming pregnant should start cART prophylaxis after the first
trimester but not later than 28 weeks of gestation.
preventing perinatal HIV transmission if it is started earlier, before 28 weeks’
gestation versus 36 weeks’ gestation.
203 All HIV-infected women should be
counseled and offered cART during pregnancy to prevent perinatal transmission
203 Avoid the use of stavudine and didanosine entry
and fusion inhibitors in women of childbearing age and during the first trimester, if
possible due to issues of toxicity and teratogenicity.
guidelines can be continued to be used if the women was on a efavirenz based
regimen. A fetal ultra sound is recommended. Further studies are needed to help
identify the effectiveness and safety of other cART regimens. Cesarean section
delivery is highly recommended.
S.L. should continue on her ART (AZT, lamivudine, and atazanavir/ritonavir)
during labor without missing any doses. Prophylactic neonatal AZT should be
administered to the infant at a dose of 4 mg/kg (actual weight) PO every 12 hours,
within 6 to 12 hours of birth, for a total duration of 6 weeks.
CASE 49-8, QUESTION 2: Should S.L. breast-feed her infant if her HIV RNA levels are undetectable and
her CD4 counts are 400 cells/μL?
Although S.L. is currently on effective cART to suppress her HIV RNA levels and
maintain her CD4 levels, she should not breast-feed. Breast-feeding is not
recommended for HIV-infected women in the United States because of safer and
affordable alternatives such as formula. Prophylactic cART in the infant and mother
does not entirely eliminate the risk of perinatal transmission through breast milk.
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