interim update

The American College of

Obstetricians and Gynecologists P R AC T I C E
BUL L E T I N
WOMEN’S HEALTH CARE PHYSICIANS

clinical management guidelines for obstetrician – gynecologists

Number 171, October 2016 (Replaces Practice Bulletin Number 159, January 2016)

INTERIM UPDATE: This Practice Bulletin is updated to reflect a limited, focused change in the gestational age at which
to consider antenatal corticosteroids, including administration during the late preterm period and rescue course timing.

Management of Preterm Labor

Preterm birth is the leading cause of neonatal mortality and the most common reason for antenatal hospitalization
(1–4). In the United States, approximately 12% of all live births occur before term, and preterm labor preceded
approximately 50% of these preterm births (5, 6). Although the causes of preterm labor are not well understood, the
burden of preterm births is clear—preterm births account for approximately 70% of neonatal deaths and 36% of infant
deaths as well as 25–50% of cases of long-term neurologic impairment in children (7–9). A 2006 report from the
Institute of Medicine estimated the annual cost of preterm birth in the United States to be $26.2 billion or more than
$51,000 per premature infant (10). However, identifying women who will give birth preterm is an inexact process.
The purpose of this document is to present the various methods proposed to manage preterm labor and to review the
evidence for the roles of these methods in clinical practice. Identification and management of risk factors for preterm
labor are not addressed in this document.

Background ventions to prolong pregnancy have included the use of

tocolytic drugs to inhibit uterine contractions as well as
Preterm birth is defined as birth between 20 0/7 weeks of antibiotics to treat intrauterine bacterial infection. The
gestation and 36 6/7 weeks of gestation. The diagnosis therapeutic agents currently thought to be clearly associ-
of preterm labor generally is based on clinical criteria of ated with improved neonatal outcomes include antenatal
regular uterine contractions accompanied by a change in corticosteroids for maturation of fetal lungs and other
cervical dilation, effacement, or both, or initial presenta- developing organ systems, and the targeted use of mag-
tion with regular contractions and cervical dilation of at nesium sulfate for fetal neuroprotection.
least 2 cm. Less than 10% of women with the clinical
diagnosis of preterm labor actually give birth within 7 days
of presentation (11). It is important to recognize that pre- Clinical Considerations and
term labor with intact membranes is not the only cause of
preterm birth; numerous preterm births are preceded by
Recommendations
either rupture of membranes or other medical problems Which tests can be used to stratify risk for
necessitating delivery (2, 6, 12). preterm delivery in patients who present with
Historically, nonpharmacologic treatments to pre- preterm contractions?
vent preterm births in women with preterm labor have
included bed rest, abstention from intercourse and Because the presence of fetal fibronectin or a short cer-
orgasm, and hydration. Evidence for the effectiveness of vix has been associated with preterm birth (17–19), the
these interventions is lacking, and adverse effects have utility of fetal fibronectin testing and the cervical length
been reported (13–16). Proposed pharmacologic inter- measurement, alone or in combination, to improve upon

Committee on Practice Bulletins—Obstetrics. This Practice Bulletin was developed by the American College of Obstetricians and Gynecologists’
Committee on Practice Bulletins—Obstetrics in collaboration with Hyagriv N. Simhan, MD, MS.
The information is designed to aid practitioners in making decisions about appropriate obstetric and gynecologic care. These guidelines should not be
construed as dictating an exclusive course of treatment or procedure. Variations in practice may be warranted based on the needs of the individual patient,
resources, and limitations unique to the institution or type of practice.

VOL. 128, NO. 4, OCTOBER 2016 OBSTETRICS & GYNECOLOGY e155

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Unauthorized reproduction of this article is prohibited.
the clinical ability to diagnose preterm labor and predict
preterm birth in symptomatic women were examined. Box 1. Contraindications to Tocolysis ^
Although the results of observational studies have sug- • Intrauterine fetal demise
gested that knowledge of fetal fibronectin status or
cervical length may help health care providers reduce • Lethal fetal anomaly
use of unnecessary resources (20, 21), these findings • Nonreassuring fetal status
have not been confirmed by randomized trials (22–24). • Severe preeclampsia or eclampsia
Further, the positive predictive value of a positive fetal • Maternal bleeding with hemodynamic instability
fibronectin test result or a short cervix alone is poor and
should not be used exclusively to direct management in • Chorioamnionitis
the setting of acute symptoms (25). • Preterm premature rupture of membranes*
• Maternal contraindications to tocolysis (agent
Which patients with preterm labor are appro- specific)
priate candidates for intervention?
*In the absence of maternal infection, tocolytics may be considered
Identifying women with preterm labor who ultimately for the purposes of maternal transport, steroid administration, or
will give birth preterm is difficult. Approximately both.
30% of preterm labor spontaneously resolves (26) and
50% of patients hospitalized for preterm labor actually
give birth at term (27–29). Interventions to reduce the
will have subsequent progressive cervical change (33).
likelihood of delivery should be reserved for women
In a study of 763 women who had unscheduled triage
with preterm labor at a gestational age at which a delay
visits for symptoms of preterm labor, only 18% gave
in delivery will provide benefit to the newborn. Because
birth before 37 weeks of gestation and only 3% gave birth
tocolytic therapy generally is effective for up to 48 hours
within 2 weeks of presenting with symptoms (17). No evi-
(30), only women with fetuses that would benefit from
a 48-hour delay in delivery should receive tocolytic dence exists to support the use of prophylactic tocolytic
treatment. therapy (34), home uterine activity monitoring, cerclage,
In general, tocolytics are not indicated for use before or narcotics to prevent preterm delivery in women with
neonatal viability. Regardless of interventions, perinatal contractions but no cervical change. Therefore, women
morbidity and mortality at that time are too high to jus- with preterm contractions without cervical change, espe-
tify the maternal risks associated with tocolytic therapy. cially those with a cervical dilation of less than 2 cm,
Similarly, no data exist regarding the efficacy of cortico- generally should not be treated with tocolytics.
steroid use before viability. However, there may be times
when it is appropriate to administer tocolytics before Does the administration of antenatal cortico-
viability. For example, inhibiting contractions in a patient steroids improve neonatal outcomes?
after an event known to cause preterm labor, such as The most beneficial intervention for improvement of
intra-abdominal surgery, may be reasonable even at pre- neonatal outcomes among patients who give birth pre-
viable gestational ages, although the efficacy of such an term is the administration of antenatal corticosteroids.
intervention remains unproved (31, 32). The upper limit A single course of corticosteroids is recommended for
for the use of tocolytic agents to prevent preterm birth pregnant women between 24 weeks and 34 weeks of
generally has been 34 weeks of gestation. Because of the gestation who are at risk of delivery within 7 days. For
possible risks associated with tocolytic and steroid thera- women with ruptured membranes or multiple gestations
pies, the use of these drugs should be limited to women who are at risk of delivery within 7 days, a single course
with preterm labor at high risk of spontaneous preterm
of corticosteroids is recommended between 24 weeks
birth. Tocolysis is contraindicated when the maternal and
and 34 weeks of gestation. A single course of corticoster-
fetal risks of prolonging pregnancy or the risks associated
oids may be considered starting at 23 weeks of gestation
with these drugs are greater than the risks associated with
for pregnant women who are at risk of preterm delivery
preterm birth (see Box 1).
within 7 days, irrespective of membrane status (35–37).
Recent data indicate that betamethasone decreases new-
Should women with preterm contractions but
born respiratory morbidity when given to women in the
without cervical change be treated?
late preterm period between 34 0/7 weeks and 36 6/7
Regular preterm contractions are common; however, weeks who are at risk of preterm delivery within 7 days
these contractions do not reliably predict which women and who have not previously received corticosteroids (38).

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Administration of corticosteroids for pregnant women consist of either two 12-mg doses of betamethasone given
during the periviable period who are at risk of preterm intramuscularly 24 hours apart or four 6-mg doses of
delivery within 7 days is linked to a family’s decision dexamethasone every 12 hours administered intramuscu-
regarding resuscitation and should be considered in that larly (45). Because treatment with corticosteroids for less
context. than 24 hours is still associated with significant reduc-
A Cochrane meta-analysis of corticosteroids tions in neonatal morbidity and mortality, a first dose of
therapy before 34 weeks of gestation reinforces the antenatal corticosteroids should be administered even if
beneficial effect of this therapy regardless of membrane the ability to give the second dose is unlikely, based on
status and concludes that a single course of antenatal the clinical scenario (36). However, no additional benefit
corticosteroids should be considered routine for all has been demonstrated for courses of antenatal steroids
preterm deliveries (39). The administration of antenatal with dosage intervals shorter than those outlined previ-
corticosteroids to the woman who is at risk of imminent ously, often referred to as accelerated dosing, even when
preterm birth is strongly associated with decreased neo- delivery appears imminent.
natal morbidity and mortality (39–41). Neonates whose
mothers receive antenatal corticosteroids have signifi- What is the role for magnesium sulfate for
cantly lower severity, frequency, or both of respiratory fetal neuroprotection?
distress syndrome (relative risk [RR], 0.66; 95% confi-
Early observational studies suggested an association
dence interval [CI], 0.59–0.73), intracranial hemorrhage
between prenatal exposure to magnesium sulfate and
(RR, 0.54; 95% CI, 0.43–0.69), necrotizing enterocolitis
the less frequent occurrence of subsequent neuro-
(RR, 0.46; 95% CI, 0.29–0.74), and death (RR, 0.69;
logic morbidities (46–48). Subsequently, several large
95% CI, 0.58–0.81), compared with neonates whose
clinical studies have evaluated the evidence regarding
mothers did not receive antenatal corticosteroids (39). magnesium sulfate, neuroprotection, and preterm births
One randomized trial demonstrated that additional (49–53). A 2009 meta-analysis synthesized the results
neonatal benefit could be derived from a single rescue of the clinical trials of magnesium sulfate for neuropro-
course of corticosteroids (42). The investigators reserved tection (54). Pooling the results of the available clinical
this intervention for patients with intact membranes, trials of magnesium sulfate for neuroprotection suggests
if the antecedent treatment had been given at least that predelivery administration of magnesium sulfate
2 weeks before the rescue course, the gestational age was reduces the occurrence of cerebral palsy when given with
less than 33 weeks, and the women were judged by the neuroprotective intent (RR, 0.71; 95% CI, 0.55–0.91)
clinician to be likely to give birth within the next week. A (55). Two subsequent meta-analyses of similar design
single repeat course of antenatal corticosteroids should, have confirmed these results (56, 57).
therefore, be considered in women who are less than None of the trials demonstrated significant preg-
34 weeks of gestation, who are at risk of preterm deliv- nancy prolongation when magnesium sulfate was given
ery within the next 7 days, and whose prior course of for neuroprotection. Although minor maternal complica-
antenatal corticosteroids was administered more than tions were more common with magnesium sulfate in the
14 days previously. Rescue course corticosteroids could three major trials, serious maternal complications (eg,
be provided as early as 7 days from the prior dose, if cardiac arrest, respiratory failure, and death) were not
indicated by the clinical scenario (38, 43). In the study seen more frequently in these studies or in the larger
of betamethasone in the late preterm period, patients meta-analyses (51–54).
who had received corticosteroids earlier in pregnancy Although the goal of each of the three major ran-
were excluded, and it is unclear whether there is benefit domized clinical trials was to evaluate the effect of
to a repeat course of betamethasone in those women magnesium sulfate treatment on neurodevelopmental
(38). Whether to administer a repeat or rescue course of outcomes and death, comparison between the trials is
corticosteroids with preterm premature rupture of mem- made difficult by differences in inclusion and exclusion
branes is controversial, and there is insufficient evidence criteria, populations studied, magnesium sulfate regimens,
to make a recommendation for or against. gestational age at treatment, and outcome variables
Betamethasone and dexamethasone are the most evaluated. However, accumulated available evidence
widely studied corticosteroids and have been the preferred suggests that magnesium sulfate reduces the severity
antenatal treatments to accelerate fetal organ maturation. and risk of cerebral palsy in surviving infants if adminis-
The administration of betamethasone or dexamethasone tered when birth is anticipated before 32 weeks of ges-
has been shown to decrease neonatal mortality (44, 45). tation. Hospitals that elect to use magnesium sulfate
Treatment, for either a primary or a rescue course, should for fetal neuroprotection should develop uniform and

VOL. 128, NO. 4, OCTOBER 2016 Practice Bulletin Management of Preterm Labor e157

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specific guidelines for their departments regarding inclu- Contractions are the most commonly recognized
sion criteria, treatment regimens, concurrent tocolysis, antecedent of preterm birth. For this reason, cessation
and monitoring in accordance with one of the larger trials of uterine contractions has been the primary focus of
(6, 51–53). therapeutic intervention. Many agents have been used to
inhibit myometrial contractions, including magnesium
Does tocolytic therapy improve neonatal sulfate, calcium channel blockers, oxytocin antagonists,
outcomes? nonsteroidal antiinflammatory drugs (NSAIDs), and
Tocolytic therapy may provide short-term prolongation beta-adrenergic receptor agonists (Table 1). Overall, the
of pregnancy, enabling the administration of antenatal evidence supports the use of first-line tocolytic treatment
corticosteroids and magnesium sulfate for neuroprotec- with beta-adrenergic receptor agonists, calcium channel
tion, as well as transport, if indicated, to a tertiary facil- blockers, or NSAIDs for short-term prolongation of
ity. However, no evidence exists that tocolytic therapy pregnancy (up to 48 hours) to allow for the admin-
has any direct favorable effect on neonatal outcomes istration of antenatal steroids (see Table 1) (30, 58,
or that any prolongation of pregnancy afforded by 59). One randomized trial suggested the potential role
tocolytics actually translates into statistically significant of transdermal nitroglycerine in short-term pregnancy
neonatal benefit. prolongation, particularly those pregnancies at less than

Table 1. Common Tocolytic Agents ^

Agent or Class Maternal Side Effects Fetal or Newborn Adverse Effects Contraindications
Calcium channel blockers Dizziness, flushing, and hypotension; No known adverse effects Hypotension and preload-dependent
suppression of heart rate, contractility, cardiac lesions, such as aortic
and left ventricular systolic pressure insufficiency
when used with magnesium sulfate;
and elevation of hepatic
transaminases
Nonsteroidal anti-
Nausea, esophageal reflux, gastritis, In utero constriction of ductus Platelet dysfunction or bleeding
inflammatory drugs
and emesis; platelet dysfunction is arteriosus*, oligohydramnios*, disorder, hepatic dysfunction,
rarely of clinical significance in necrotizing enterocolitis in preterm gastrointestinal ulcerative disease,
patients without underlying bleeding newborns, and patent ductus renal dysfunction, and asthma
disorder arteriosus in newborn† (in women with hypersensitivity
to aspirin)
Beta-adrenergic receptor Tachycardia, hypotension, tremor, Fetal tachycardia Tachycardia-sensitive maternal
agonists palpitations, shortness of breath, cardiac disease and poorly
chest discomfort, pulmonary edema, controlled diabetes mellitus
hypokalemia, and hyperglycemia
Magnesium sulfate Causes flushing, diaphoresis, nausea, Neonatal depression‡ Myasthenia gravis
loss of deep tendon reflexes,
respiratory depression, and cardiac
arrest; suppresses heart rate,
contractility and left ventricular
systolic pressure when used with
calcium channel blockers; and
produces neuromuscular blockade
when used with calcium-channel
blockers
*Greatest risk associated with use for longer than 48 hours.
Data are conflicting regarding this association.
†

‡
The use of magnesium sulfate in doses and duration for fetal neuroprotection alone does not appear to be associated with an increased risk of neonatal depression
when correlated with cord blood magnesium levels. (Johnson LH, Mapp DC, Rouse DJ, Spong CY, Mercer BM, Leveno KJ, et al. Association of cord blood magnesium
concentration and neonatal resuscitation. Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. J
Pediatr 2011;DOI: 10.1016/j.jpeds.2011.09.016.). [PubMed]
Modified from Hearne AE, Nagey DA. Therapeutic agents in preterm labor: tocolytic agents. Clin Obstet Gynecol 2000;43:787–801. [PubMed]

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28 weeks of gestation. However, its use was asso- inpatient, monitored setting but should not be used for
ciated with significant maternal side effects (60). longer than 48–72 hours (67). When compared with
Recommendations for its use would require additional placebo, maintenance tocolysis with nifedipine does not
data that demonstrate its efficacy and safety. appear to confer a reduction in preterm birth or improve-
The use of magnesium sulfate to inhibit acute pre- ment in neonatal outcomes (71). Atosiban is the only
term labor has similar limitations when used for preg- tocolytic that has demonstrated superiority as mainte-
nancy prolongation (34, 61). However, if magnesium nance therapy over placebo in prolonging pregnancy, but
sulfate is being used in the context of preterm labor for atosiban is not available in the United States (72).
fetal neuroprotection and the patient still is experienc-
ing preterm labor, a different agent could be considered Is there a role for antibiotics in preterm labor?
for short-term tocolysis. However, because of potential Intrauterine bacterial infection is an important cause of
serious maternal complications, beta-adrenergic receptor preterm labor, particularly at gestational ages less than
agonists and calcium-channel blockers should be used 32 weeks (73, 74). It has been theorized that infection
with caution in combination with magnesium sulfate for or inflammation is associated with contractions. Based
this indication. Before 32 weeks of gestation, indometh- on this concept, the utility of antibiotics to prolong preg-
acin is a potential option for use in conjunction with nancy and reduce neonatal morbidity in women with
magnesium sulfate. Several retrospective case–control preterm labor and intact membranes has been evaluated
studies and cohort studies evaluated neonatal outcomes, in numerous randomized clinical trials. However, most
including necrotizing enterocolitis, after short-term ante- have failed to demonstrate antibiotic benefit; a meta-
natal indomethacin therapy (62–66). They have shown analysis of eight randomized controlled trials that com-
conflicting results regarding duration of therapy, gesta- pared antibiotic treatment with placebo for patients with
tional age at exposure, and the interval between exposure documented preterm labor found no difference between
and delivery. As with all other tocolytics, indomethacin the antibiotic treatment and placebo for prolonging
for short-term treatment of preterm labor should be used pregnancy or preventing preterm delivery, respiratory
after carefully weighing the potential benefits and risks. distress syndrome, or neonatal sepsis (58). In fact, anti-
In 2011, the U.S. Food and Drug Administration biotic use may be associated with long-term harm (75).
(FDA) issued a warning regarding the use of terbutaline Thus, antibiotics should not be used to prolong gestation
to treat preterm labor because of reports of serious mater- or improve neonatal outcomes in women with preterm
nal side effects (67). Another review reported possible labor and intact membranes. This recommendation is
deleterious behavioral effects in offspring after in utero distinct from recommendations for antibiotic use for pre-
exposure to beta-adrenergic receptor agonists (68). These term premature rupture of membranes (76) and group B
data suggest that the use of terbutaline should be limited streptococci carrier status (77, 78).
to short-term inpatient use as a tocolytic or for the acute
antepartum therapy of uterine tachysystole. Is there a role for nonpharmacologic man-
agement of women with preterm contractions
Should tocolytics be used after acute therapy? or preterm labor?
Maintenance therapy with tocolytics is ineffective for The assessment of preterm delivery risk based on symp-
preventing preterm birth and improving neonatal out- toms and physical examination alone is inaccurate (17,
comes and is not recommended for this purpose. A 79, 80). Previously, when symptoms of possible preterm
meta-analysis has not shown any differences between labor were present, clinicians recommended reduced
magnesium sulfate maintenance therapy and either pla- maternal activity and hydration with or without seda-
cebo or beta-adrenergic receptor agonists in preventing tives, with the aim of reducing uterine activity. Most
preterm birth after an initial treated episode of threatened experts advocated awaiting cervical dilation or efface-
preterm labor (69). Likewise, maintenance beta-agonist ment before administering tocolytic drugs. However,
therapy has not been demonstrated to prolong pregnancy prophylactic therapy (tocolytic drugs, bed rest, hydra-
or prevent preterm birth and should not be used for this tion, and sedation) in asymptomatic women at increased
purpose (70). The FDA posted warnings specifically risk of preterm delivery has not been demonstrated to be
cautioning against the use of maintenance oral terbu- effective (41, 81). Although bed rest and hydration have
taline during pregnancy (67). Because of the lack of been recommended to women with symptoms of preterm
efficacy and potential maternal risk, the FDA states that labor to prevent preterm delivery, these measures have
oral terbutaline should not be used at all to treat preterm not been shown to be effective for the prevention of
labor. Injectable terbutaline may be used only in an preterm birth and should not be routinely recommended.

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Furthermore, the potential harm, including venous throm- Antibiotics should not be used to prolong gestation
boembolism, bone demineralization, and deconditioning, or improve neonatal outcomes in women with pre-
and the negative effects, such as loss of employment, term labor and intact membranes.
should not be underestimated (13–16, 82, 83).
The following recommendations and conclusions
Is preterm labor managed differently in are based on limited and inconsistent scientific
women with multiple gestations? evidence (Level B):
The use of tocolytics to inhibit preterm labor in multiple For women with ruptured membranes or multiple
gestations has been associated with a greater risk of gestations who are at risk of delivery within 7 days,
maternal complications, such as pulmonary edema (84, a single course of corticosteroids is recommended
85). In addition, prophylactic tocolytics have not been between 24 weeks and 34 weeks of gestation.
shown to reduce the risk of preterm birth or improve
A single course of corticosteroids may be considered
neonatal outcomes in women with multiple gestations
starting at 23 weeks of gestation for pregnant women
(86–89). Adequate data do not exist to specifically dem- who are at risk of preterm delivery within 7 days,
onstrate benefit from the use of antenatal corticosteroids irrespective of membrane status.
in multiple gestations. However, because of the clear
A single repeat course of antenatal corticosteroids
benefit attributable to the use of antenatal corticosteroids
should, therefore, be considered in women who are
in singleton gestations, most experts recommend their
less than 34 weeks of gestation, who are at risk of
use in preterm multiple gestations. Similar extrapolation
preterm delivery within the next 7 days, and whose
could also apply to the use of magnesium sulfate for fetal
prior course of antenatal corticosteroids was admin-
neuroprotection in multiple gestations.
istered more than 14 days previously. Rescue course
corticosteroids could be provided as early as 7 days
from the prior dose, if indicated by the clinical
Summary of scenario.
Recommendations Bed rest and hydration have not been shown to be
effective for the prevention of preterm birth and
The following recommendations and conclusions should not be routinely recommended.
are based on good and consistent scientific evi-
The positive predictive value of a positive fetal
dence (Level A): fibronectin test result or a short cervix alone is poor
A single course of corticosteroids is recommended and should not be used exclusively to direct manage-
for pregnant women between 24 weeks and ment in the setting of acute symptoms.
34 weeks of gestation who are at risk of delivery
within 7 days.
Proposed Performance
Accumulated available evidence suggests that magne-
sium sulfate reduces the severity and risk of cerebral Measure
palsy in surviving infants if administered when birth The proportion of women with preterm labor at less than
is anticipated before 32 weeks of gestation. Hospitals 34 weeks of gestation who receive corticosteroid therapy
that elect to use magnesium sulfate for fetal neuropro-
tection should develop uniform and specific guide-
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