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Preterm Labor
Preterm Labor
General Information
Description
regular uterine contractions occurring between 20 weeks and 36 weeks 6 days gestation and associated with cervical
changes(1, 2, 3)
most common cause of antenatal hospitalization(1)
resulting preterm birth is leading cause of perinatal morbidity and mortality(1, 3)
periviable birth refers to delivery occurring between 20 weeks and 25 weeks 6 days gestation(4)
Epidemiology
Who is most affected
black women(2, 3)
women with multiple gestations(2, 3)
women using assisted reproductive technologies(2)
women of advanced maternal age(2)
maternal age < 16 years associated with increased risk for preterm labor, and risk increased with young
gynecologic age (age ≤ 2 years from age at menarche)
based on cohort study
605 pregnant women evaluated
366 adolescents < 16 years old at time of last menstrual period
239 women aged 18-29 years at time of last menstrual period
36.3% of adolescents had young gynecologic age, defined as chronological age ≤ 2 years from age at menarche
factors associated with increased risk for preterm labor
age < 16 years (adjusted odds ratio [OR] 1.74, 95% CI 1.07-2.84)
age < 16 years with young gynecologic age (adjusted OR 2.64, 95% CI 1.23-5.65)
Reference - Ann Epidemiol 1997 Aug;7(6):400
Incidence/Prevalence
12.9 million preterm births estimated in 2005 (9.6% of all births worldwide), including
11.9% of births in Africa
10.6% of births in North America (excluding Mexico)
9.1% of births in Asia
8.1% of births in Latin American/Mexico and the Caribbean
6.4% of births in Australia/New Zealand
6.2% of births in Europe
Reference - Bull World Health Organ 2010 Jan;88(1):31 full-text
in United States(1, 2, 3)
about 12% of all births
percentage of births at < 34 weeks gestation decreased from 3.7% in 2006 to 3.4% in 2011
incidence varies by race in United States (data from 2005)(2)
about 18.4% for black women
about 12.1% for Hispanic women
about 11.7% for non-Hispanic white women
incidence increases with increasing number of fetuses(3)
about 50% of twin births reported to be preterm
about 90% of triplet births reported to be preterm
Associated conditions
group B streptococcal infection(2)
Etiology and Pathogenesis
Causes
often idiopathic - spontaneous preterm labor with intact membranes reported in about 50% of cases(2)
preterm premature rupture of membranes (PPROM) reported in about 25% of cases(2)
iatrogenic cause (elective induction of labor or cesarean delivery for medical indications) reported in about 25% of cases;
indications include(2, 3)
hypertensive disorders of pregnancy
intrauterine growth restriction (IUGR)
nonreassuring fetal status
placental abruption
Pathogenesis
decidual activation (paracrine signaling from fetus through amniotic fluid and across membranes to underlying maternal
decidua and myometrium) triggers contractions(3)
in term labor, decidual activation occurs in late pregnancy when fetal pituitary adrenal axis reaches maturity
in preterm labor, decidual activation may be triggered prematurely via genetic and/or environmental factors, such as
choriodecidual inflammation
decidual hemorrhage
membrane rupture
uterine trauma or stretching
fetal signals of compromise
persistent contractions lead to increased cervical dilation and thinning over a period of hours before birth, resulting in active
labor(3)
Risk factors
prior premature birth (strongest risk factor)
cervical risk factors
incompetent cervix
short cervix (commonly defined as < 25 mm before 24 weeks gestation)
excisional treatment of cervical dysplasia
infections
bacterial vaginosis
Chlamydia trachomatis
other infections
drugs and toxins
tobacco
alcohol
some medications (steroids, theophylline)
pollutants
other toxins (such as diethylstilbestrol [DES] exposure in utero)
psychological factors
depression
stress or anxiety
lower socioeconomic status
periodontal disease (but evidence inconsistent)
fetal risk factors
multiple gestation
congenital anomalies
early fetal growth restriction
uterine and placental factors
placental abruption
placenta previa
polyhydramnios
uterine anomalies
uterine leiomyoma
subchorionic hemorrhage
(first trimester)
vaginal bleeding
subchorionic hematoma
other possible risk factors
trauma
douching
autoimmune conditions
polycystic ovary syndrome
increased levels of inflammatory markers
hereditary factor
low fish intake
physically demanding work during pregnancy
maternal age < 20 years or > 40 years
low maternal prepregnancy weight
maternal weight gain < 0.27 kg (0.6 lbs)/week
infertility treatment
time interval between pregnancies < 18 months or > 59 months
ethnicity (black women)
factors not associated with increased risk of preterm labor
group B streptococcal (GBS) colonization
prior abortion
see Risk factors for preterm labor and premature birth for details
History and Physical
History
Chief concern (CC)
regular uterine contractions between 20 weeks and < 37 weeks gestation(1, 2, 3)
may be painful if contractions are sustained and precede clinically significant cervical preparation, such as contractions
occurring after decidual hemorrhage(3)
often present as uterine contractions (typical in women with short cervix), characterized by(3)
mild but persistent pelvic pressure
cramps
increased vaginal discharge/mucus
occasional spotting over several day or weeks
watery discharge and/or vaginal bleeding may indicate true labor(2)
History of present illness (HPI)
verify gestational age(2)
to determine likelihood of true labor, ask about characteristics of contractions, including(2)
strength
duration
frequency
associated vaginal bleeding or leaking of amniotic fluid
ask about recent uterine trauma(3)
Past medical history (PMH)
ask about history of(2)
previous preterm labor
previous preterm delivery or pregnancy loss
infection (bacterial vaginosis, chlamydia, nongenital infections)
multiple gestation
shortened cervix (< 3 cm)
uterine anomalies
intrauterine growth retardation
placental abruption or placenta previa
cervical conization or loop electrosurgical excision procedure of the cervix
maternal periodontal infection
maternal abdominal surgery
maternal medical conditions including diabetes mellitus, hypertension, thyroid disease
Social history (SH)
ask about history of(2)
smoking
substance abuse
stress
long work hours
Physical
General physical
assess fetal well-being(2)
assess for fever or other signs of infection(2,)
see Fetal monitoring during labor for details
Pelvic
assess for membrane rupture(2,)
may be indicated by fluid leakage from cervical os on sterile speculum exam
obtain sample for culture and fetal fibronectin analysis
nitrazine-positive reaction of fluid
ferning of fluid
may need to reexamine after periods of recumbency to look for pooling of fluids if high suspicion of rupture of membranes
avoid digital exam if suspected rupture of membranes
see Preterm premature rupture of membranes (PPROM) for additional information
asses for factors associated with increased likelihood of true labor, including(2,)
contractions accompanied by
descent of presenting fetal part
progressive dilation and effacement of cervix
vaginal bleeding
Diagnosis
Making the diagnosis
diagnosis of preterm labor made clinically based on(1, 2)
regular uterine contractions accompanied by descent of presenting fetal part
progressive dilation and cervical effacement
confirmation of estimated gestational age < 37 weeks
true labor likely if ≥ 6 contractions/hour, cervical dilation ≥ 3 cm, ≥ 80% effacement, membrane rupture, and/or vaginal
bleeding(2)
Differential diagnosis
incorrect dating of pregnancy
normal preterm uterine activity (Braxton Hicks contractions)
Testing overview
cervicovaginal fetal fibronectin (fFN)
positive fFN test results alone have low positive predictive value for preterm labor, and should not be used exclusively
to direct management in symptomatic women (ACOG Level B)
cervicovaginal fFN testing has limited ability to predict preterm birth within 7 days in symptomatic women (level 1 [likely
reliable] evidence)
negative fFN test may rule out delivery within 2 weeks in twin and singleton gestations in symptomatic women (level 2
[mid-level] evidence)
cervical ultrasound
short cervix on ultrasound alone has low positive predictive value for preterm labor, and should not be used exclusively
to direct management in symptomatic women (ACOG Level B)
cervical length > 15 mm on transvaginal ultrasound may not predict delivery within 1 week in women with signs of
preterm labor (level 2 [mid-level] evidence)
cervicovaginal and amniotic fluid biomarkers
amniotic fluid assay of interleukin-6 ≥ 13.4 ng/dL or proteomic biomarkers each associated with increased likelihood of
preterm birth in women with preterm labor but combination assay does not appear to be associated with improved
detection (level 2 [mid-level] evidence)
cervicovaginal interleukin-6 assay has lower sensitivity than fFN but similarly rules out preterm delivery within 14 days
in women in preterm labor with low rates of preterm delivery (level 1 [likely reliable] evidence)
tests for infection
in preterm labor improves outcomes
no evidence to suggest that routine amniocentesis to check for infection
perform urinalysis and culture to assess for infection
perform rectovaginal culture in unscreened patients to assess for group B Streptococcus, gonorrhea, and chlamydia
obtain vaginal samples in symptomatic patients to assess for bacterial vaginosis and trichomonas
Blood tests
white blood cell count > 12,000/mL before 28 weeks gestation and corticotrophin-releasing hormone > 684 pg/mL
after 28 weeks may predict preterm labor in next 48 hours (level 2 [mid-level] evidence)
based on analysis of retrospective data and prospective cohort of women in threatened preterm labor
white blood cell (WBC) > 12,000/mL at 22-27 weeks gestation more accurate predictor of delivery within 48 hours,
compared to corticotrophin-releasing hormone (CRH), cortisol, and maternal age
at 28-31 weeks gestation, CRH > 684 pg/mL more accurate predictor of delivery within 48 hours
Reference - Am J Obstet Gynecol 2008 Apr;198(4):468e1
Imaging studies
ultrasound-guided transabdominal amnioinfusion of indigo carmine (1 mL in 9 mL of normal saline) may confirm ruptured
membranes in women with high suspicion of ruptured membranes despite negative findings on speculum exam(2)
cervical ultrasound used to determine cervical length
ultrasound screening for short cervix may be indicated in women with persistent pelvic pressure, cramps, spotting, and
increased vaginal discharge(3)
short cervix on ultrasound alone has low positive predictive value for preterm labor, and should not be used exclusively
to direct management in symptomatic women (ACOG Level B)(1)
cervical length > 15 mm on transvaginal ultrasound may not predict delivery within 1 week in women with signs
of preterm labor (level 2 [mid-level] evidence)
based on systematic review limited by heterogeneity
systematic review of 28 cohort and case-control studies evaluating transvaginal ultrasound assessment of cervical
length for prediction of preterm birth in women with singleton pregnancy, intact membranes, and preterm labor
symptoms
7.1% of women delivered with 48 hours
11.1% of women delivered within 1 week from presentation
for prediction of preterm labor within 1 week, presentation < 34 weeks plus
cervical length > 15 mm associated with 96% pooled negative predictive value, results limited by significant
heterogeneity
cervical length < 15 mm associated with 63% pooled negative predictive value, results limited by significant
heterogeneity
Reference - Ultrasound Obstet Gynecol 2010 Jan;35(1):54 full-text
cervical length on ultrasound appears significantly associated with risk of preterm delivery, but predictive
accuracy appears low in women with threatened preterm labor (level 2 [mid-level] evidence)
based on retrospective prognostic cohort study
1,077 pregnant women with preterm labor at < 34 weeks gestation had ultrasound determination of cervical length
correlation between cervical length and time to delivery was significant but weak (each additional 2 mm associated
with 1 day increase in interval) (p < 0.001)
Reference - Obstet Gynecol 2013 Dec;122(6):1279
shortening of cervical length over repeated ultrasound measurements appears to have limited utility for
predicting preterm birth (level 2 [mid-level] evidence)
based on systematic review with clinical heterogeneity
systematic review of 14 studies evaluating transvaginal sonographic cervical length over time for prediction of
preterm birth in 4,398 pregnant women
7 studies provided data on women with singleton gestation and 8 studies provided data on women with twin
gestations
time intervals between cervical length measurements and definition of positive result for shortening in cervical length
between measurements varied across studies
pooled diagnostic performance of any cervical length shortening in singleton gestation
for preterm birth at < 37 weeks in analysis of 4 studies with 543 women
sensitivity 54% (95% CI 43%-65%)
specificity 84% (95% CI 80%-87%)
preterm birth at < 35 weeks in analysis of 5 studies with 2,979 women
sensitivity 65% (95% CI 57%-72%)
specificity 48% (95% CI 46%-50%)
pooled diagnostic performance of any cervical length shortening in twin gestation
for preterm birth at < 34 weeks in analysis of 7 studies with 852 women
sensitivity 47% (95% CI 39%-55%)
specificity 88% (95% CI 86%-91%)
for preterm birth at < 32 weeks in analysis of 4 studies with 644 women
sensitivity 61% (95% CI 49%-73%)
specificity 88% (95% CI 85%-91%)
consistent results for preterm birth < 30 weeks and at < 28 weeks in analysis of 3 studies with 454 women
Reference - Am J Obstet Gynecol 2015 Dec;213(6):789, commentary can be found in Evid Based Med 2016 Feb;21(1):40
fetal adrenal gland volume > 422 mm3 associated with increased likelihood of preterm birth within 5 days (level 2
[mid-level] evidence)
based on small prognostic cohort study without independent validation
126 women with singleton fetus had ultrasound evaluation of fetal adrenal gland volume
53 with signs or symptoms of preterm labor
73 controls
fetal adrenal gland volume successfully examined in 86.5%
diagnostic performance of corrected adrenal gland volume > 422 mm3/kg for predicting preterm birth within 5 days
sensitivity 92%
specificity 99%
positive likelihood ratio 93.5
negative likelihood ratio 0.08
Reference - Obstet Gynecol 2007 Apr;109(4):855, commentary can be found in Obstet Gynecol 2007 Jul;110(1):187
American College of Radiology (ACR) Appropriateness Criteria for assessment of gravid cervix can be found at ACR 2014
PDF, earlier version can be found at National Guideline Clearinghouse 2012 Apr 16:35156
Other diagnostic testing
Fetal fibronectin (fFN)
positive result on fetal fibronectin (fFN) test has low positive predictive value for preterm labor, and should not be used
exclusively to direct management in symptomatic women (ACOG Level B)(1)
negative results on fFN test may help determine which patients do not need tocolysis(1)
usual threshold indicating abnormal result for fFN test is > 50 ng/mL by enzyme-linked immunosorbent assay (BMJ 2002 Aug
10;325(7359):301 full-text)
possible causes of false-positive fFN test may include
sexual activity within 24 hours of sample collection
cervical examination within 24 hours of sample collection
cervical dilatation
uterine contractions
vaginal bleeding
preeclampsia
Reference - BMJ 2002 Aug 10;325(7359):301 full-text
cervicovaginal fFN testing has limited ability to predict preterm birth within 7 days in symptomatic women (level 1
[likely reliable] evidence)
based on systematic review
systematic review of 32 prognostic cohort studies evaluating fFN testing for predicting preterm birth within 7 days in
5,355 symptomatic patients
410 women (7.7%) delivered within 7 days of fFN testing
diagnostic performance of fFN testing for predicting preterm birth within 7 days
sensitivity 76.1%
specificity 81.9%
positive likelihood ratio 4.2
negative likelihood ratio 0.29
Reference - Obstet Gynecol 2009 Sep;114(3):631, commentary can be found in Obstet Gynecol 2010 Jan;115(1):186
negative fFN test may rule out delivery within 2 weeks in twin and singleton gestations in symptomatic women
(level 2 [mid-level] evidence)
based on retrospective prognostic cohort study
429 singleton and 87 twin gestations with complaints of preterm labor had fFN testing
3.5% singletons and 28.7% twin pregnancies delivered before 34 weeks gestation
Twins Singletons
Sensitivity 71% 82%
Specificity 74% 90%
Positive predictive value 19% 17%
Negative predictive value 97% 99%
Abbreviation: fFN, fetal fibronectin test.
Predictive Performance of fFN for Delivery within 14 days:
Reference - Obstet Gynecol 2007 May;109(5):1083
negative fFN may rule out delivery at < 30 weeks gestation in high-risk asymptomatic women with or without
cervical cerclage (level 2 [mid-level] evidence)
based on retrospective prognostic cohort study without blinding
910 asymptomatic women at high risk of preterm birth had fFN testing at 23-27 weeks gestation
clinicians were not blinded to fFN test results which may have influenced management
diagnostic performance of negative fetal fibronectin test for determining likelihood of delivery at < 30 weeks gestation in
women with vs. without cervical cerclage
specificity 77% vs. 90% (p < 0.0001)
sensitivity 60% vs. 78.6% (not significant)
negative predictive value > 98% in both groups (not significant)
Reference - BJOG 2009 May;116(6):799
positive fFN assay at 28 weeks (but not at 20-24 weeks) associated with increased risk of preterm birth in women
with HIV infection (level 2 [mid-level] evidence)
based on subgroup analysis of randomized trial
2,353 African women with HIV infection randomized to antibiotics vs. placebo to prevent chorioamnionitis and reduce
preterm birth and mother-to-child transmission of HIV had vaginal fluid collected prior to antibiotics (at 20-24 weeks) and
after treatment at (28 weeks)
gestational age calculated by uterine size from pubic symphysis to uterine fundus (ultrasound not available)
comparing positive fFN (≥ 50 ng/mL) vs. negative (fFN < 50 ng/mL) at 28 weeks
preterm birth at < 32 weeks gestation in 10.8% vs. 1.9% (odds ratio [OR] 6.3, 95% CI 3.2-12.3)
preterm birth at < 37 weeks gestation in 38.7% vs. 22% (OR 2.3, 95% CI 1.5-3.3)
positive fFN at 20-24 weeks not associated with increased risk of preterm birth compared to fFN < 50 ng/mL
antibiotic treatment did not influence fFN levels
Reference - Obstet Gynecol 2007 Feb;109(2 Pt 1):392, correction can be found in Obstet Gynecol 2007 Oct;110(4):936
management based on fFN testing might reduce risk of preterm birth in women with singleton pregnancies and
threatened preterm labor at 23-34 weeks gestation (level 2 [mid-level] evidence)
based on systematic review limited by clinical heterogeneity
systematic review of 6 randomized trials evaluating fFN testing in 546 women with singleton pregnancies and symptoms
of preterm labor at 23-34 weeks gestation
trials evaluating fFN testing combined with sonographic cervical length excluded
definition of preterm labor varied across studies
comparing management based on fFN testing to control (test results blinded or no testing)
management based on fFN testing associated with nonsignificant decrease in preterm birth at < 37 weeks gestation
(relative risk 0.72, 95% CI 0.52-1.01) in analysis of 5 trials with 434 women
no significant differences in
preterm birth at < 28, 32, or 34 weeks gestation in analyses of 4 trials with 357 women
delivery within 7 days in analysis of 4 days with 344 women
maternal hospitalization in analysis of 5 trials with 438 women
tocolysis in analysis of all trials
use of antenatal steroids in analysis of 5 trials with 438 women
neonatal respiratory distress syndrome in analysis of 2 trials with 148 neonates
neonatal intensive care admission in analysis of 2 trials with 129 neonates
Reference - Am J Obstet Gynecol 2016 Oct;215(4):431
similar results can be found in earlier Cochrane review evaluating fFN testing in 5 trials with 474 patients, including 4
trials in systematic review above (Cochrane Database Syst Rev 2008 Oct 8;(4):CD006843)
health technology assessment of rapid fetal fibronectin testing to predict preterm birth in women with symptoms of preterm
labor can be found in Health Technol Assess 2013 Sep;17(40):1 PDF
Cervicovaginal and amniotic fluid biomarkers
cervicovaginal interleukin-6 assay has lower sensitivity than fFN but similarly rules out preterm delivery within 14
days in women in preterm labor with low rates of preterm delivery (level 1 [likely reliable] evidence)
based on prognostic validation cohort study
660 cervicovaginal fluid samples from 552 women with singleton pregnancies at 24-34 weeks gestation were collected
for fetal fibronectin assay
559 samples from women with symptoms of preterm labor
61 samples were from women without symptoms of preterm labor at time of collection
prevalence of preterm delivery
2.1% < 7 days after sample collection
4.7% < 14 days after sample collection
Fetal Fibronectin > 50 mcg/LInterleukin-6 > 250 ng/L
Preterm delivery within 7 days
Sensitivity 93% 57%
Specificity 86% 91%
Positive predictive value 13% 12%
Negative predictive value 100% 99%
Preterm delivery within 14 days
Sensitivity 65% 35%
Specificity 87% 91%
Positive predictive value 19% 16%
Negative predictive value 98% 97%
Predictive Performance of Assays for Preterm Delivery:
interleukin-6 (IL-6) to albumin ratio had poorer performance than interleukin-6 assay
Reference - Clin Chem 2007 Aug;53(8):1534 full-text
combination of biomarkers
amniotic fluid assay of interleukin-6 ≥ 13.4 ng/dL or proteomic biomarkers each associated with increased
likelihood of preterm birth in women with preterm labor, but combination assay does not appear to be
associated with improved detection (level 2 [mid-level] evidence)
based on prognostic cohort study without independent validation
86 patients at 22-36 weeks gestation in preterm labor with intact membranes had assay of amniotic fluid interleukin-
6 and proteomic biomarkers (neutrophil defensins 1 and 2 and calgranulins A and C)
prevalence of intra-amniotic infection (defined as positive culture) 13.9%
interleukin-6 ≥ 13.4 ng/dL predicted preterm delivery < 37 weeks with
sensitivity 46%
specificity 93.8%
positive predictive value 92%
negative predictive value 52.6%
selected proteomic biomarkers predicted preterm delivery < 37 weeks with
sensitivity 30%
specificity 96.9%
positive predictive value 93.8%
negative predictive value 47%
combination assay did not improve prediction of preterm birth or neonatal morbidity
Reference - Am J Obstet Gynecol 2009 May;200(5):499e1
proteomic analysis of amniotic fluid may detect intra-amniotic inflammation and help determine time to delivery
(level 2 [mid-level] evidence)
based on diagnostic cohort study without independent reference standard
169 consecutive women with singleton pregnancies admitted with preterm labor or preterm premature rupture of
membranes had sample of amniotic fluid collected and analyzed
Mass Restricted (MR) score was calculated based on presence or absence of 4 protein biomarkers (neutrophil
defensins 1 and 2 and calgranulins A and C)
no antenatal clinical tests considered gold standard for diagnosis of inflammation, and concurrent placental biopsy
in utero not possible
amniocentesis-to-delivery interval mean 0.4 days for women with MR score 3-4 vs. 3.8 days for women with MR
score 1-2 vs. 17 days for women with MR score 0 (p < 0.001)
Reference - PLoS Med 2007 Jan 16;4(1):e18 full-text
amniotic fluid analysis to assess for intra-amniotic infection
strategies to identify and treat risk factors in early pregnancy (such as amniocentesis for intra-amniotic infection) have
not been shown to reduce rates of preterm birth(3)
low amniotic fluid glucose level does not appear to be a sensitive marker for detecting subclinical intrauterine
infections in patients with preterm labor and intact membranes (level 2 [mid-level] evidence)
based on diagnostic case-control study
55 women in preterm labor and 58 women matched for gestational age who were not in preterm labor had
assessment of amniotic fluid glucose levels, amniotic fluid cultures, and placental histologic characteristics
diagnostic performance of low amniotic fluid glucose level for detecting subclinical infection
sensitivity 41%-55%
specificity 94%-100%
Reference - Am J Obstet Gynecol 1994 Aug;171(2):365
amniotic fluid Gram stain may detect intra-amniotic infection in patients with preterm labor (level 2 [mid-level]
evidence)
based on diagnostic case-control study
127 patients with preterm labor and 26 patients with preterm premature rupture of the membranes had
amniocentesis and amniotic fluid culture
diagnostic performance of amniotic fluid Gram stain for detecting intra-amniotic infection
sensitivity 80%
specificity 91%
Reference - Am J Obstet Gynecol 1998 Sep;179(3 Pt 1):650
Other tests
vaginal fluid testing for assessment of rupture of membranes(2)
nitrazine test
tests fluid sample for alkalinity
false-positive nitrazine results may occur in presence of blood, semen, alkaline urine, or vaginal infection
ferning
obtain vaginal fluid sample, place on glass slide and allow to air dry 10 minutes
development of fern-like crystalline pattern suggests presence of amniotic fluid
cervical mucus may also cause ferning
absence of fetal breathing movements or cervical length ≤ 15 mm each associated with increased likelihood of
preterm birth within 2-7 days in pregnant women with labor symptoms (level 2 [mid-level] evidence)
based on systematic review of prognostic cohort studies with study-specific quality measures not reported
systematic review of 72 prognostic cohort studies evaluating fetal breathing movements (FBM),transvaginal sonographic
cervical length measurements (TVS CL), or cervicovaginal fetal fibronectin (fFN) for determining likelihood of preterm
birth within 2 or 7 days in 11,886 pregnant women with labor symptoms
pooled performance of tests for determining likelihood of preterm birth at 2 days and 7 days
2 Days 7 Days
Positive Positive
Likelihood Number of Likelihood Number of
Test Sensitivity Specificity Ratio studies Sensitivity Specificity Ratio studies
absence of 75% (95% CI 93% (95% CI 67% (95% CI 98% (95% CI
FBM 57%-87%) 75%-98%) 10.4 4 43%-84%) 83%-100%) 31.6 7
TVS CL
(cutoff ≤ 15 77% (95% CI 88% (95% CI 74% (95% CI 89% (95% CI
mm) 54%-90%) 84%-91%) 6.4 9 58%-85%) 85%-92%) 6.8 15
62% (95% CI 81% (95% CI 75% (95% CI 79% (95% CI
fFN 43%-78%) 74%-86%) 3.3 4 69%-80%) 76%-83%) 3.6 38
comparative performance for prediction of preterm birth
no significant differences among tests in sensitivity at 2 days and 7 days
FBM had significantly higher specificity than fFN and TVS CL at 2 days and 7 days
Reference - Am J Obstet Gynecol 2014 Jan;210(1):54.e1
ultrasound findings, amniotic fluid interleukin-6, and serum C-reactive protein may each be associated with
increased likelihood of birth within 2-7 days in women with threatened preterm labor (level 2 [mid-level] evidence)
based on systematic review of mostly poor-quality studies
systematic review of 22 tests determining risk of spontaneous preterm birth among asymptomatic women in early
pregnancy and symptomatic women with threatened preterm labor in later pregnancy
inadequate reporting of blinding in majority of trials
tests with likelihood ratio > 5 included
for predicting spontaneous preterm birth before 34 weeks gestation in asymptomatic women
cervical length measurement by ultrasound
cervicovaginal prolactin screening
fetal fibronectin screening
for predicting birth within 2-7 days in symptomatic women with threatened preterm labor
absence of fetal breathing movements
cervical length and funneling
amniotic fluid interleukin-6
serum C-reactive protein
for predicting birth before 34 or 37 weeks in symptomatic women with threatened preterm labor
matrix metalloprotease-9
amniotic fluid IL-6
cervicovaginal fetal fibronectin
cervicovaginal human chorionic gonadotrophin (hCG)
Reference - Health Technol Assess 2009 Sep;13(43):1
tests for infection(2)
perform urinalysis and culture to assess for infection
perform rectovaginal culture in unscreened patients to assess for group B Streptococcus, gonorrhea, and chlamydia
obtain vaginal samples in symptomatic patients to assess for bacterial vaginosis and trichomonas
Treatment
Treatment overview
reserve treatment for women with fetuses at a gestational age at which delaying delivery will benefit the neonate (Obstet
Gynecol 2016 Jan;127(1):190)
obstetric interventions for pregnancies at risk of periviable delivery should focus on delaying delivery and improving neonatal
outcomes should delivery occur (Obstet Gynecol 2015 Nov;126(5):e82)
medications to delay delivery
tocolytics
tocolytics may prolong gestation for up to 48 hours, which may permit enough time for steroids to improve fetal lung
maturity and for maternal transport to tertiary care facility
generally, tocolytics not indicated for use before neonatal viability but may be considered for previable pregnancy
to help inhibit contractions after an event known to cause preterm labor, such as intra-abdominal surgery
tocolytics not usually indicated in women with preterm contractions without cervical change, especially women with
cervical dilation < 2 cm
maintenance treatment with tocolytic drugs does not improve perinatal outcomes and is not routinely recommended
(ACOG Level A)
tocolytic drugs not associated with clear reduction in perinatal or neonatal mortality or neonatal morbidity (RCOG
Grade A)
nifedipine, atosiban, and cyclo-oxygenase (COX) inhibitors have fewer types of side effects and less frequent side
effects compared to beta agonists, but how they compare to one another is unclear (RCOG Grade A)
calcium channel blockers are more effective than beta-mimetics for tocolysis and result in lower rates of neonatal
morbidity (level 1 [likely reliable] evidence)
antibiotics
antibiotics indicated for specific infections if identified (such as group B Streptococcus), but no evidence of efficacy
for prolonging gestation in women with preterm labor and intact membranes (ACOG Level A)
antibiotics may prolong pregnancy in women with preterm premature rupture of membranes but not in women with
preterm labor and intact membranes (level 2 [mid-level] evidence)
in women in preterm labor with intact membranes, prophylactic antibiotics may reduce maternal infection but
associated with increased neonatal mortality and cerebral palsy (level 2 [mid-level] evidence) and do not reduce preterm
birth (level 1 [likely reliable] evidence)
medications to improve pediatric outcomes
corticosteroids
American College of Obstetricians and Gynecologists recommendations
single course of corticosteroids between 24 and 34 weeks gestation for women at risk of preterm delivery within
7 days
single course of corticosteroids before 32 weeks gestation in women with preterm premature rupture of
membranes
dosing options include betamethasone 12 mg intramuscularly every 24 hours for 2 doses, or dexamethasone 6
mg intramuscularly every 12 hours for 4 doses
antenatal steroids for women at risk of preterm birth associated with reduced neonatal mortality and respiratory
distress syndrome (RDS) (level 2 [mid-level] evidence)
repeat doses of prenatal corticosteroids reduce RDS in infants at risk of preterm birth, but no significant differences
in childhood outcomes at early childhood follow-up (18 months to 2 years corrected age) (level 1 [likely reliable] evidence)
prenatal dexamethasone might reduce risk of intraventricular hemorrhage compared to prenatal betamethasone
(level 3 [lacking direct] evidence), but no significant differences in neonatal mortality or most major neonatal morbidities
(level 2 [mid-level] evidence)
prenatal dexamethasone exposure may be associated with higher risk for neurodevelopmental abnormalities than
prenatal betamethasone exposure (level 2 [mid-level] evidence)
antenatal magnesium sulfate
if birth anticipated < 32 weeks, administer magnesium sulfate to reduce severity and risk of cerebral palsy in neonate
(ACOG Level A)
World Health Organization recommends magnesium sulfate in women at risk of imminent preterm birth < 32 weeks
gestational age for prevention of cerebral palsy (Strong recommendation based on moderate-quality evidence)
recommended dose 4-6 g IV bolus for 20 minutes followed by 1-2 g/hour (max 3 g/hour)
antenatal magnesium sulfate in women at risk for preterm birth decreases risk of cerebral palsy and substantial
gross motor dysfunction (level 1 [likely reliable] evidence)
addition of thyrotropin-releasing hormone to steroids in women at risk of very preterm delivery does not reduce mortality or
adverse fetal outcomes, and causes maternal side effects (level 1 [likely reliable] evidence)
IV hydration does not appear to reduce preterm delivery before 37 weeks for women in preterm labor
management in hospital or at home after initial treatment of preterm labor associated with similar preterm birth rates (level 2
[mid-level] evidence)
Treatment setting
antenatal transport to hospital with advanced neonatal and maternal care is recommended based on anticipated neonatal
or maternal complications associated with periviable birth (SMFM/ACOG Best practice)(4)
management in hospital or at home after initial treatment of preterm labor associated with similar preterm birth
rates (level 2 [mid-level] evidence)
based on randomized trial with incomplete blinding of caregivers
250 women > 18 years old at 20-35 weeks gestation experiencing first admission to hospital for first episode of preterm
labor were randomized to home care (early discharge with nurse home visits) vs. hospital care after treatment for acute
episode of premature labor
all women had cervical dilation of < 4 cm with < 80% effacement, lived within 50 km (31.1 miles) of hospital, and had no
prior preterm delivery
women in hospital group were discharged earlier than they might otherwise have been because their physicians were
aware that there were no major emergency readmissions or deliveries in the home group
no significant differences between groups in
mean gestational age at delivery
mean birth weight
preterm delivery rate
mean duration of neonatal hospital stay
mean duration of neonatal intensive care unit stay
Reference - CMAJ 2001 Apr 3;164(7):985 full-text
hospitalization may not be associated with reduced rate of preterm birth (level 2 [mid-level] evidence)
based on randomized trial with early termination and inadequate statistical power
101 women with arrested preterm labor and intact fetal membranes between 24 and 33 4/7 weeks gestation were
randomized to home or hospital management following course of dexamethasone
study terminated before planned interim analysis due to no apparent differences between groups after 6 years
sample size at study termination had 60% power to detect 30% relative reduction in delivery at ≥ 36 weeks
no significant differences between groups in delivery at ≥ 36 weeks gestation
hospitalization associated with higher rate of infants with respiratory distress requiring mechanical ventilation for at least
24 hours compared to home monitoring (13% vs. 2%, p = 0.04)
Reference - Obstet Gynecol 2005 Jul;106(1):14, editorial can be found in Obstet Gynecol 2005 Jul;106(1):3
delivery at hospital with high-level neonatal intensive care unit associated with fewer in-hospital deaths among
premature neonates (level 2 [mid-level] evidence)
based on retrospective cohort study
1,328,132 hospital deliveries of premature neonates delivered at 23-37 weeks gestation in hospitals in Pennsylvania,
California, and Missouri evaluated
high-level hospital defined as level III facility with mean annual delivery of ≥ 50 very-low-birth-weight infants
delivery at hospital with high-level neonatal intensive care unit associated with
7.8 fewer in-hospital deaths per 1,000 deliveries in Pennsylvania, United States
2.7 fewer in-hospital deaths per 1,000 deliveries in California, United States
12.6 fewer in-hospital deaths per 1,000 deliveries in Missouri, United States
Reference - Pediatrics 2012 Aug;130(2):270 full-text
Fluid and electrolytes
routine IV hydration has not been shown to reduce risk for preterm birth (ACOG Level B)(1)
IV hydration does not appear to reduce preterm delivery before 37 weeks for women in preterm labor (level 2 [mid-
level] evidence)
based on Cochrane review with limited evidence from trials that lacked blinding
systematic review of 2 randomized trials evaluating oral or IV hydration in 228 women with preterm labor
trials compared IV hydration (bolus of 500 mL of crystalloid over 20 minutes followed by continuous infusion of 200
mL/hour) vs. bed rest alone in 228 women meeting inclusion criteria
no significant differences in
preterm delivery before 37 weeks gestation in analysis of 2 trials with 228 women
neonatal intensive care unit admission in 1 trial with 118 patients
no trials evaluated oral hydration
Reference - Cochrane Database Syst Rev 2013 Nov 4;(11):CD003096
Counseling
for threatened and imminent periviable birth(4)
use best estimate of gestational age to guide counseling and decision making for periviable births
prenatal and postnatal counseling regarding anticipated short-term and long-term neonatal outcomes should consider
(SMFM/ACOG Best practice)
anticipated gestational age at delivery
other variables that may impact likelihood of survival and adverse outcomes, such as
fetal sex
multiple gestation
presences of suspected major malformations
antenatal corticosteroid administration
birth weight
response to initial resuscitation
formulate antenatal plan of care with parents focusing on optimizing chance of survival or minimizing suffering
Medications
Medications to delay delivery Tocolytics
reserve tocolytic therapy for women with fetuses that would benefit from 48-hour delay in delivery(1)
administer first-line tocolytic treatment with beta-adrenergic agonist therapy, calcium channel blockers, or nonsteroidal anti-
inflammatory drugs (NSAIDs) for short-term prolongation of pregnancy to allow time for administrations of steroids (ACOG
Level A)(1)
generally, tocolytics not indicated for use before neonatal viability but may be considered for previable pregnancy to help
inhibit contractions after an event known to cause preterm labor, such as intra-abdominal surgery(1)
recommendations for tocolytics in preterm labor for threatened and imminent periviable birth to allow for antenatal
corticosteroid administration based on best estimate of gestational age(4)
recommended for pregnancies ≥ 24 weeks gestation (SMFM/ACOG Grade 1B)
consider for pregnancies 23 weeks gestation (SMFM/ACOG Grade 2B)
not recommended for pregnancies > 20 weeks gestation but < 23 weeks gestation (SMFM/ACOG Grade 1A)
tocolytics not usually indicated in women with preterm contractions without cervical change, especially women with cervical
dilation < 2 cm(1)
prophylactic tocolytics may not reduce risk for preterm birth or improve neonatal outcomes in women with multiple gestations,
and may be associated with increased risk for maternal complications (such as pulmonary edema)(1)
American College of Obstetricians and Gynecologists (ACOG) recommendations on role of tocolysis
tocolytic agents may be used for short-term prolongation of pregnancy (up to 48 hours) to allow for administration of
antenatal steroids (ACOG Level A)
generally, tocolytics not indicated for use before neonatal viability but may be considered for previable pregnancy to
help inhibit contractions after an event known to cause preterm labor, such as intra-abdominal surgery
maintenance treatment with tocolytic drugs does not improve perinatal outcomes and is not routinely recommended
(ACOG Level A)
tocolytic drugs not associated with clear reduction in perinatal or neonatal mortality or neonatal morbidity (RCOG Grade A)
World Health Organization does not recommend tocolytic drugs to improve newborn outcomes in women at risk of imminent
preterm birth (WHO Conditional recommendation, Very low-quality evidence) (WHO 2015 PDF)
contraindications to tocolysis
tocolytics not usually indicated in women with preterm contractions without cervical change, especially women with
cervical dilation < 2 cm
other contraindications include
intrauterine fetal demise
lethal fetal anomaly
nonreassuring fetal status
severe preeclampsia or eclampsia
maternal bleeding with hemodynamic instability
chorioamnionitis
preterm premature rupture of membranes (PPROM) (tocolysis may be considered for purpose of maternal transport
and/or steroid administration)
medication-specific contraindications to tocolysis
choice of tocolytic agent
ACOG recommendations for choice of tocolytic agent
first-line agents include any of (ACOG Level A)
beta-adrenergic agonist therapy
calcium channel blockers (nifedipine)
nonsteroidal anti-inflammatory drugs (NSAIDs)
magnesium sulfate - The American College of Obstetricians and Gynecologists (ACOG) and The Society for Maternal-Fetal
Medicine support use of magnesium sulfate for short-term prolongation of pregnancy (up to 48 hours) to allow for
administration of antenatal steroids in pregnant women at risk of preterm delivery within 7 days
nifedipine, atosiban, and cyclooxygenase (COX) inhibitors have fewer types of side effects and less frequent side effects
compared to beta agonists, but how they compare to one another is unclear (RCOG Grade A)
calcium channel blockersmay decrease risk of preterm birth and admission to neonatal intensive care unit compared to beta-
mimetics in women with preterm labor (level 2 [mid-level] evidence)
NSAIDs appear to prevent preterm birth and appear more effective than beta-mimetics (level 2 [mid-level] evidence)
beta-mimetics delay delivery but do not decrease respiratory distress syndrome or mortality outcomes (level 3 [lacking direct]
evidence) and use limited by adverse effects
selected options include
nifedipine 20 mg orally, then 10-20 mg 3-4 times daily for up to 48 hours
NSAIDs (indomethacin)
50 mg rectal suppository or 50-100 mg orally as loading dose
25-50 mg orally every 4 hours for 48 hours subsequently
terbutaline 0.25 mg subcutaneously every 20 minutes to every 3 hours based on maternal uterine activity and pulse
ritodrine initially 0.1 mg/minute IV, increased 0.5 mg/minute every 10 minutes until labor controlled, maximum 0.35
mg/minute
once labor inhibited, reduce dose by 0.5 mg/minute every 30 minutes to lowest effective dose
duration of infusion arbitrary, but usually 12-14 hours
check potassium and glucose in 4 hours
atosiban 6.75 mg over 1 minute as initial bolus followed by 18 mg/hour for 3 hours, then 6 mg/hour for up to 45
hours (maximum total dose 330 mg)
magnesium sulfate 4-6 g IV bolus over 15-20 minutes, then 2 g/hour IV (may be increased to 4-5 g/hour as needed
if no significant adverse effects or oliguria)
see Tocolytics for treatment of preterm labor for details
Antibiotics
World Health Organization recommendations for antibiotics in women with preterm labor
does not give routine antibiotics if amniotic membranes are intact (WHO Strong recommendation, Moderate-quality evidence)
administer antibiotics if membranes have ruptured (WHO Strong recommendation, Moderate-quality evidence)
erythromycin is antibiotic of choice (WHO Conditional recommendation, Moderate-quality evidence)
do not use amoxicillin/clavulanic acid (WHO Strong recommendation, Moderate-quality evidence)
Reference - WHO 2015 PDF
antibiotics indicated for specific infections if identified (such as group B Streptococcus [GBS]), but no evidence of efficacy
for prolonging gestation in women with preterm labor and intact membranes (ACOG Level A)(1, 2)
indications for GBS prophylaxis
women with GBS bacteriuria at any time during current pregnancy
intrapartum prophylaxis for women with positive GBS colonization
women with prior infant with invasive GBS disease
women with culture results unknown if any of
< 37 weeks gestation
duration of membrane rupture ≥ 18 hours
temperature ≥ 100.4 degrees F (38 degrees C)
threatened preterm delivery until culture results known
see Group B streptococcal infection in infants less than 3 months old for details
periviable birth
recommendations for antibiotics to prolong latency during expectant management of preterm premature rupture of
membranes if delivery not imminent for threatened periviable birth based on best estimate of gestational age(4)
recommended for pregnancies ≥ 24 weeks gestation (SMFM/ACOG Grade 1B)
consider for pregnancies 23 weeks gestation (SMFM/ACOG Grade 2B)
consider for pregnancies > 20 weeks gestation but < 23 weeks gestation (SMFM/ACOG Grade 2C)
intrapartum antibiotics for GBS prophylaxis for threatened and imminent periviable birth based on best estimate of
gestational age(4)
recommended for pregnancies ≥ 24 weeks gestation (SMFM/ACOG Grade 1B)
consider for pregnancies 23 weeks gestation (SMFM/ACOG Grade 2B)
not recommended for pregnancies > 20 weeks gestation but < 23 weeks gestation (SMFM/ACOG Grade 1A)
evidence
antibiotics may prolong pregnancy in women with preterm premature rupture of membranes but not in women
with preterm labor and intact membranes (level 2 [mid-level] evidence)
based on systematic review without assessment of trial quality
systematic review of 22 randomized trials evaluating antibiotics for women at 22-34 weeks gestational age
presenting with preterm premature rupture of membrane (PPROM) or preterm labor
in women with PPROM antibiotics associated with
slightly increased latency period (weighted mean difference 0.33 days, 95% CI 0.17-0.5 days) in analysis of 5
trials with 4,435 women
reduced rate of delivery within 48 hours (odds ratio [OR] 0.65, 95% CI 0.57-0.74) in analysis of 5 trials with
4,974 women
reduced rate of delivery within 7 days (OR 0.67, 95% CI 0.59-0.76) in analysis of 5 trials with 5,001 women,
results limited by significant heterogeneity
reduced rate of clinical neonatal sepsis (OR 0.71, 95% CI 0.52-0.97) in analysis of 9 trials with 1,214 women
in women with preterm labor (intact membranes)
no significant difference in latency period (weighted mean difference 0.21 days, 95% CI -1.36 days to +1.78
days) in analysis of 6 trials with 6,204 women
no significant difference in rates of delivery within 48 hours (OR 1.07, 95% CI 0.88-1.3) in analysis of 2 trials
with 6,037 women
no significant difference in rates of delivery within 7 days (OR 1.03, 95% CI 0.88-1.21) in analysis of 5 trials with
6,267 women
no significant difference in neonatal mortality (OR 0.98, 95% CI 0.69-1.39) in analysis of 9 trials with 6,686
women
significant reduction in clinical neonatal sepsis (OR 0.43, 95% CI 0.27-0.68) in analysis of 9 trials with 1,004
women, but results limited by heterogeneity
Reference - Am J Obstet Gynecol 2008 Dec;199(6):620e1, editorial can be found in Am J Obstet Gynecol 2008 Dec;199(6):583
in women in preterm labor with intact membranes, prophylactic antibiotics may reduce maternal infection but
associated with increased neonatal mortality and cerebral palsy (level 2 [mid-level] evidence) and do not reduce
preterm birth (level 1 [likely reliable] evidence)
based on Cochrane review with wide confidence intervals or possible publication bias or small-study effects for
many outcomes
systematic review of 14 randomized trials comparing prophylactic antibiotics to placebo or no treatment in 7,837
women in preterm labor with intact membranes
most data came from 1 large trial (summarized below)
no significant differences in most outcomes in overall meta-analyses
preterm birth (relative risk [RR] 0.98, 95% CI 0.92-1.05)
perinatal mortality (combination of stillbirth and neonatal mortality) (RR 1.22, 95% CI 0.88-1.69)
stillbirth (RR 0.73, 95% CI 0.43-1.26)
infant mortality (RR 1.06, 95% CI 0.68-1.67)
birth weight (mean difference 58.38 g, 95% CI -26.24 g to +143 g)
admission to neonatal intensive care or special care (RR 0.82, 95% CI 0.62-1.1)
prophylactic antibiotics associated with reduced maternal infection in analysis of 10 trials with 7,371 women
RR 0.74 (95% CI 0.63-0.86)
NNT 25-65 with maternal infection in 11% of controls
asymmetrical funnel plot suggesting possible publication bias or small-study effects
increased neonatal mortality associated with
any prophylactic antibiotics in analysis of 9 trials with 7,248 infants
RR 1.57 (95% CI 1.03-2.4)
NNH 59-2,777 with neonatal mortality in 1.2% of controls
macrolide antibiotics in analysis of 3 trials with 6,684 infants (RR 1.52, 95% CI 1.05-2.19)
beta-lactam antibiotics in analysis of 7 trials with 7,053 infants (RR 1.51, 95% CI 1.06-2.15)
in single trial with 3,173 infants followed at age 7 years
macrolide antibiotics associated with increased risk of functional impairment (RR 1.11, 95% CI 1.01-1.2) and
cerebral palsy (RR 1.9, 95% CI 1.2-3.01)
beta-lactam antibiotics associated with increased risk of cerebral palsy (RR 1.67, 95% CI 1.06-2.61)
Reference - Cochrane Database Syst Rev 2013 Dec 5;(12):CD000246
antibiotics do not improve neonatal mortality or morbidity when taken by women in spontaneous preterm
labor without evidence of clinical infection (level 1 [likely reliable] evidence) and may be associated with
increased risk for cerebral palsy in children at age 7 years (level 2 [mid-level] evidence)
based on largest randomized trial included in Cochrane review above with limited follow-up at 7 years
6,295 women in spontaneous preterm labor with intact membranes and no evidence of clinical infection were
randomized to 1 of 4 treatments (orally 4 times daily for 10 days or until delivery)
erythromycin 250 mg
co-amoxiclav (amoxicillin 250 mg/clavulanic acid 125 mg)
erythromycin plus co-amoxiclav
placebo
comparing treatment groups, no significant differences in combined outcome (neonatal death, chronic lung
disease, or major cerebral abnormality on ultrasonography before hospital discharge)
Reference - ORACLE II trial (Lancet 2001 Mar 31;357(9261):989), editorial can be found in Lancet 2001 Mar 31;357(9261):973,
commentary can be found in ACP J Club 2001 Sep-Oct;135(2):70, Lancet 2001 Oct 6;358(9288):1184, Lancet 2001 Nov
17;358(9294):1728
in follow-up study of children born to 4,221 women completing ORACLE II trial with significant loss to follow-up
outcomes available for 3,196 children (71%)
cerebral palsy occurred in
3.3% with vs. 1.7% without erythromycin (p < 0.05, NNH 63)
3.2% with vs. 1.9% without co-amoxiclav (p < 0.05, NNH 77)
functional impairment occurred in
42.3% with vs. 38.3% without erythromycin (p < 0.05, NNH 25)
co-amoxiclav (with or without erythromycin) had no effect on functional impairment
no significant differences in
mortality
other medical conditions including fits/seizures, hydrocephalus with shunt, wheezing, diabetes, bowel
disorders, and attention deficit disorder
hospital admissions
medication for asthma
behavioral patterns
educational attainment compared to national curriculum test results
Reference - Lancet 2008 Oct 11;372(9646):1319, editorial can be found in Lancet 2008 Oct 11;372(9646):1276,
commentary can be found in Lancet 2009 Jan 3;373(9657):25
Heparin
limited evidence that heparin reduces preterm birth rates in women at risk of complications due to placental
dysfunction (level 2 [mid-level] evidence)
based on systematic review of low-quality trials
systematic review of 1 randomized trial and 1 cohort study evaluating heparin during pregnancy for women at risk of
complications including preterm birth < 37 weeks gestation
randomized trial had unclear reporting of blinding, randomization, and allocation concealment
in randomized trial with 107 women, heparin was not associated with reduction in preterm birth < 37 weeks gestation or
low birth weight
Reference - Acta Obstet Gynecol Scand 2008;87(8):804
Progesterones
reserve antenatal progesterone prophylaxis for women with previous spontaneous birth at < 37 weeks gestation(2, 3)
vaginal progesterone may not reduce preterm delivery in women with singleton pregnancies and threatened
preterm labor (level 2 [mid-level] evidence)
based on randomized trial with low compliance
385 women with singleton pregnancies and threatened preterm labor at 24-33 gestational weeks were treated with acute
tocolysis and randomized within 48 hours to self-administered progesterone 200 mg vaginally daily vs. placebo until 36 6/7
weeks gestation or preterm delivery
all women had intact membranes at baseline
trial had planned to recruit 626 women but was terminated early due to futility following prespecified interim analysis
42% in each group were noncompliant (defined as < 80% use of prescribed medication)
comparing progesterone vs. placebo
delivery at < 37 gestational weeks in 42.5% vs. 35.5% (not significant)
delivery at < 34 gestational weeks in 19.7% vs. 12.9% (p = 0.1, not significant)
delivery at < 32 gestational weeks in 12.9% vs. 9.7% (not significant)
neonatal morbidity in 22.8% vs. 18.8% (not significant)
no significant differences in duration of tocolysis, hospitalization, or recurrence of preterm labor
Reference - BJOG 2015 Jan;122(1):80
progesterone may reduce preterm delivery at < 37 gestational weeks for women with threatened preterm labor and
intact membranes (level 2 [mid-level] evidence)
based on Cochrane review with limited evidence
systematic review of 3 randomized trials and 1 quasi-randomized trial evaluating progestational agents for women with
threatened or established preterm labor with intact membranes in 307 patients
progesterone associated with reduced risk of preterm delivery at < 37 gestational weeks in analysis of 2 trials with 104
patients with threatened preterm labor
risk ratio 0.33 (95% CI 0.17-0.67)
NNT 3-7 with preterm delivery in 46.2% of controls
Reference - Cochrane Database Syst Rev 2010 Jan 20;(1):CD006770
Medications to improve pediatric outcomes Corticosteroids Corticosteroids for gestations up to 34 completed weeks
recommendations for antenatal steroids in pregnancies up to 34 completed weeks gestation
American College of Obstetricians and Gynecologists (ACOG) recommendations for antenatal corticosteroid
therapy for fetal maturation
single course of corticosteroids between 24 and 34 weeks gestation recommended for women at risk of preterm
delivery within 7 days (ACOG Level A)
consider single course of corticosteroids for pregnant women starting at 23 weeks gestation who are at increased
risk of preterm delivery within 7 days (ACOG Level A)
recommended corticosteroid regimen includes 1 of
betamethasone 12 mg intramuscularly every 24 hours for 2 doses, or
dexamethasone 6 mg intramuscularly every 12 hours for 4 doses
consider single rescue course if antecedent treatment given ≥ 7 days ago and woman remains at risk of preterm
birth before 34 weeks gestation (ACOG Level B)
regularly scheduled repeat courses or multiple courses (> 2) not recommended
References - Obstet Gynecol 2016 Jan;127(1):190
American College of Obstetricians and Gynecologists and Society for Maternal and Fetal Medicine consensus
guidelines on antenatal corticosteroids for threatened and imminent periviable birth based on best estimate of
gestational age
recommended for pregnancies ≥ 24 weeks gestation (SMFM/ACOG Grade 1B)
consider for pregnancies 23 weeks gestation (SMFM/ACOG Grade 2B)
not recommended for pregnancies > 20 weeks gestation but < 23 weeks gestation (SMFM/ACOG Grade 1A)
Reference - Obstet Gynecol 2015 Nov;126(5):e82
World Health Organization (WHO) recommendations on antenatal corticosteroid therapy for women at risk of
preterm birth from 24-34 weeks gestational age
indicated if (WHO Strong recommendation, Moderate-quality evidence for newborn outcomes; WHO Strong recommendation, Low-quality
evidence for maternal outcomes)
gestational age assessment can be done accurately
preterm birth is imminent (within 7 days of starting treatment, including within first 24 hours)
there is no clinical evidence of maternal infection, even if membranes have ruptured
adequate childbirth care is available (including capacity to recognize and safely manage preterm labour and
birth)
preterm neonate can receive adequate care if needed (including resuscitation, thermal care, feeding support,
infection treatment and safe oxygen use)
administer intramuscular dexamethasone or betamethasone 24 mg in divided doses (WHO Strong recommendation, Low-
quality evidence)
administer even if
single or multiple birth is anticipated. (WHO Strong recommendation, Low-quality evidence)
mother has hypertensive disorder (WHO Strong recommendation, Moderate-quality evidence for newborn outcomes; WHO
Strong recommendation, Low-quality evidence for maternal outcomes) or pre-gestational and gestational diabetes (WHO
Strong recommendation, Very low-quality evidence)
intrauterine growth restriction is present (WHO Strong recommendation, Very low-quality evidence)
do not administer if
chorioamnionitis is present (WHO Conditional recommendation, Very low-quality evidence)
planned cesarean section done at 34-36 weeks gestational age (WHO Conditional recommendation, Very low-quality
evidence)
if delivery has not occurred repeat dose in 7 days if clinical assessment demonstrates high risk of preterm birth
within 7 days. (WHO Conditional recommendation, Moderate-quality evidence for newborn outcomes: WHO Conditional recommendation,
low-quality evidence for maternal outcomes)
Reference - WHO 2015 PDF
European consensus guidelines on management of neonatal respiratory distress syndrome (RDS) in preterm
infants
prenatal steroids given to women with anticipated preterm delivery reduce risk of neonatal death
optimal treatment-to-delivery interval > 24 hours and < 7 days after starting steroid treatment
offer single course of prenatal corticosteroids to all women at risk of preterm delivery from about 23 weeks to 34
completed weeks gestation (European consensus Grade A)
consider short-term use of tocolytic drugs to allow completion of course of prenatal corticosteroids and/or in utero
transfer to perinatal center (European consensus Grade A)
second course of antenatal steroids may be appropriate if first course administered > 2-3 weeks earlier and infant
< 33 weeks gestation when additional obstetric indication occurs (European consensus Grade A)
Reference - Neonatology 2013;103(4):353 PDF
Royal College of Obstetricians and Gynaecologists (RCOG) guideline on antenatal corticosteroids to reduce neonatal
morbidity and mortality can be found at RCOG 2010 Oct PDF
single antenatal steroid course
antenatal steroids for women at risk of preterm birth associated with reduced neonatal mortality and RDS (level
2 [mid-level] evidence)
based on Cochrane review of trials with methodologic limitations, and subsequent randomized trial
Cochrane review
systematic review of 21 randomized trials comparing antenatal corticosteroids (betamethasone,
dexamethasone, hydrocortisone) vs. placebo or no treatment in 3,885 women (4,269 infants) with spontaneous
preterm labor, preterm premature rupture of membranes (PPROM), or elective preterm delivery
methodologic limitations included unclear or inadequate allocation concealment in 13 trials, no placebo control
in 8 trials, no intention-to-treat analysis in 11 trials; only 2 trials met all these quality criteria
search updated April 30, 2010 with 16 additional studies awaiting assessment
maternal outcomes comparing steroids vs. control (no significant differences)
maternal death in 0.53% vs. 0.56% (relative risk [RR] 0.98, 95% CI 0.06-15.5) in analysis of 3 trials with 365
women
chorioamnionitis in 7.4% vs. 8% (RR 0.91, 95% CI 0.7-1.18) in analysis of 12 trials with 2,485 women
puerperal sepsis in 11.5% vs. 8.7% (RR 1.35, 95% CI 0.93-1.95) in analysis of 8 trials with 1,003 women
for neonatal outcomes comparing steroids vs. control, steroids associated with reduced
combined fetal and neonatal death in analysis of 13 trials with 3,627 infants
RR 0.77 (95% CI 0.67-0.89)
NNT 16-49 assuming fetal and neonatal death in 18.8% of controls
neonatal death in analysis of 18 trials with 3,956 infants
RR 0.69 (95% CI 0.58-0.81)
NNT 16-36 assuming 14.8% neonatal death in controls
RDS in analysis of 21 trials with 4,038 infants, results limited by heterogeneity (p = 0.002)
RR 0.66 (95% CI 0.59-0.73)
NNT 4-15 assuming 26% RDS in controls
moderate-to-severe RDS in analysis of 6 trials with 1,686 infants, results may be limited by borderline
statistical heterogeneity (p = 0.06)
RR 0.55 (95% CI 0.43-0.71)
NNT 11-21 assuming 17% moderate-to-severe RDS in controls
cerebroventricular hemorrhage in analysis of 13 trials with 2,872 infants
RR 0.54 (95% CI 0.43-0.69)
NNT 16-30 assuming 10.9% cerebroventricular hemorrhage in controls
severe cerebroventricular hemorrhage 4.5% vs. 16.8% (p < 0.0001, NNT 9) in analysis of 5 trials with 572
infants
RR 0.28 (95% CI 0.16-0.5)
NNT 9-12 assuming 16.8% severe cerebroventricular hemorrhage in controls
necrotizing enterocolitis in analysis of 8 trials with 1,675 infants
RR 0.46 (95% CI 0.29-0.74)
NNT 23-61 assuming 6.3% necrotizing enterocolitis in controls
systemic infection in first 48 hours in analysis of 5 trials with 1,319 infants
RR 0.56 (95% CI 0.38-0.85)
NNT 19-78 assuming 8.6% systemic infection in controls
steroids associated with nonsignificant reduction in chronic lung disease (CLD) in analysis of 6 trials with 818
infants, results limited by heterogeneity
no significant difference in mean birth weight in analysis of 11 trials with 3,586 infants
child outcomes comparing steroids vs. control (no significant differences)
death in childhood 3% vs. 4.2% (RR 0.68, 95% CI 0.36-1.27) in analysis of 4 trials with 1,010 children
neurodevelopmental delay 6% vs. 9.4% (RR 0.64, 95% CI 0.14-2.98) in 1 trial with 82 children
Reference - Cochrane Database Syst Rev 2006 Jul 19;(3):CD004454 (review updated 2010 Apr 30), also published in Obstet
Gynecol 2007 Jan;109(1):189
in women at risk of preterm birth at < 24 weeks gestation, single course of antenatal corticosteroids may reduce
neonatal mortality before hospital discharge (level 2 [mid-level] evidence)
based on systematic review of observational studies
systematic review of 17 observational studies comparing single course of antenatal corticosteroids within 7 days
before birth vs. placebo or no treatment in women at risk of preterm birth at < 24 weeks gestation
all analyses included only neonates receiving active intensive treatment (resuscitation)
single course of antenatal corticosteroids associated with reduced risk of neonatal mortality before hospital
discharge (adjusted odds ratio 0.48, 95% CI 0.38-0.61) in analysis of 4 studies with 3,610 infants
no significant differences in
respiratory distress syndrome in analysis of 2 studies with 861 infants
severe intraventricular hemorrhage in analysis of 2 studies with 859 infants
necrotizing enterocolitis in analysis of 3 studies with 1,051 infants
chronic lung disease in analysis of 3 studies with 1,184 infants
neurologic impairment at 18-22 months in 1 study with 601 infants
Reference - Obstet Gynecol 2016 Apr;127(4):715
single course of antenatal corticosteroids in women at high risk for preterm birth associated with improved
neurodevelopmental outcomes in children born before 34 weeks gestation (level 2 [mid-level] evidence)
based on systematic review of mostly observational studies and with trial-specific quality measures not reported
systematic review of 14 randomized and nonrandomized clinical trials and observational studies evaluating
neurodevelopment outcomes in children born before 34 weeks gestation whose mothers received a single course
of betamethasone or dexamethasone (vs. placebo or no treatment) antenatally for threatened preterm birth
age range of offspring at follow-up 18 months to 31 years
single course of antenatal steroids associated with reduced risk of
cerebral palsy in analysis of 7 studies with 6,498 women
relative risk 0.678 (95% CI 0.564-0.815)
NNT 22-51 with cerebral palsy in 10.6% untreated children
psychomotor development index (PDI) < 70 in analysis of 2 studies with 4,018 women
relative risk 0.829 (95% CI 0.737-0.933)
NNT 14-56 with PDI < 70 in 26.6% untreated children
severe disability in analysis of 5 studies with 6,051 women
relative risk 0.787 (95% CI 0.729-0.850)
NNT 10-17 with severe disability in 39.2% untreated children
no significant differences in various scales of intelligence tests
Reference - Obstet Gynecol 2015 Jun;125(6):1385
single course of antenatal steroids not associated with adverse outcomes in long-term follow-up
based on 4 long-term follow-up studies
192 adult offspring (mean age 31 years) from 1,142 women participating in randomized trial of antenatal
betamethasone vs. placebo
no significant differences in cognitive functioning, working memory and attention, psychiatric morbidity,
handedness, or health-related quality of life
Reference - BMJ 2005 Sep 24;331(7518):665 full-text, editorial can be found in BMJ 2005 Sep 24;331(7518):645 full-text
81 adult offspring (aged 20-22 years) of 119 mothers at 26-32 weeks gestation (with threatened premature delivery)
participating in randomized trial of antenatal steroids vs. placebo
no significant differences in medical or psychological variables
Reference - Pediatrics 2000 Jun;105(6):e77
cohort study of 130 surviving children (aged 14 years) of birth weight < 1,501 g (3.3 lbs), 53% of whom had antenatal
corticosteroids
compared to offspring without antenatal corticosteroid exposure, steroid exposure had no obvious adverse
effects on growth or on sensorineural, cognitive, or lung function
Reference - Pediatrics 2000 Jul;106(1):e2
534 offspring of mothers from randomized trial were exposed to antenatal betamethasone vs. placebo 2 doses 24
hours apart intramuscularly
no significant differences in cardiovascular risk factors in offspring aged 30 years
Reference - Lancet 2005 May 28;365(9474):1856
12-hour dosing interval for antenatal betamethasone appears as effective as 24-hour dosing interval for
prevention of neonatal RDS, but may increase risk of necrotizing enterocolitis (level 2 [mid-level] evidence)
based on randomized trial without blinding
228 women pregnant with 260 singletons or twins at 23-34 weeks gestation and at risk for preterm delivery were
randomized to receive 2 doses of betamethasone given 12 vs. 24 hours apart
comparing 12-hour dosing interval vs. 24-hour dosing interval
neonatal RDS in 36.5% vs. 37.3% (not significant)
necrotizing enterocolitis in 6.2% vs. 0% (p = 0.03, NNH 16)
Reference - Am J Obstet Gynecol 2012 Mar;206(3):201.e1
repeat antenatal steroid courses
repeat doses of prenatal corticosteroids may reduce RDS in infants at risk of preterm birth, but no significant
differences in childhood outcomes at early childhood follow-up (18 months to 2 years corrected age) (level 2
[mid-level] evidence)
based on Cochrane review limited by clinical heterogeneity
systematic review of 10 randomized trials comparing repeat doses of corticosteroids vs. placebo or no treatment in
4,733 women and 5,700 infants who had already received corticosteroid at least 7 days previously and were still
considered at risk of preterm birth
results limited by heterogeneity in prenatal corticosteroid regimens evaluated
most patients received betamethasone for repeat antenatal corticosteroid dosing, 14% in 1 trial received
dexamethasone (6 mg intramuscularly every 12 hours up to 4 doses) due to unavailability of betamethasone
gestational age at enrollment typically was 25-33 weeks
betamethasone regimens included
betamethasone 12 mg/dose intramuscularly
for total of 2 doses 24 hours apart (2 trials, 1 trial summarized below)
for 2 doses 24 hours apart at weekly intervals until birth or 33-34 weeks gestation (5 trials)
for 2 doses 24 hours apart every 14 days until 33 weeks gestation or birth (1 trial)
betamethasone 12 mg intramuscularly for total of 1 dose (1 high-quality trial)
Celestone Chronodose 11.4 mg once weekly until delivery or 32 weeks gestation (1 high-quality trial,
ACTORDS)
repeat doses of corticosteroids associated with
lower risk of RDS in analysis of 8 trials with 3,206 infants
risk ratio 0.83 (95% CI 0.75-0.91)
NNT 17 (95% CI 11-32)
results in 2 high-quality trials suggest outcomes dependent on number of repeat corticosteroid injections
repeat doses of corticosteroids as multicourse regimen significantly decreased RDS in 1 trial with 1,144
women
no significant difference with single repeat dose of betamethasone 12 mg intramuscularly in 1 trial with
326 women
decreased mean birth weight in analysis of 9 trials with 5,626 infants
mean difference -76 g (-0.2 lbs) (95% CI -118 g to -34 g [-0.3 lbs to -.07 lbs])
when birth weight adjusted for gestational age, no significant difference found between groups in analysis
of 2 trials with 1,256 infants
nonsignificantly lower rate of vaginal birth (RR 0.93, 95% CI 0.87-1) and nonsignificantly higher rate of cesarean
section (RR 1.05, 95% CI 0.99-1.1) in analyses of 7 trials with 4,062 women
no significant differences in
perinatal or early postpartum outcomes including
severe lung disease in analysis of 6 trials with 4,826 infants, results limited by significant heterogeneity
fetal or neonatal mortality in analysis of 9 trials with 5,554 infants
chronic lung disease in analysis of 8 trials with 5,393 infants
intraventricular hemorrhage in analysis of 6 trials with 3,065 infants
chorioamnionitis in analysis of 6 trials with 4,261 women
puerperal sepsis in analysis of 5 trials with 3,091 women
early childhood outcomes (18 months to 2 years corrected age) including
total mortality in analysis of 4 trials with 4,370 children
survival free of any disability in analysis of 2 trials with 3,155 children
survival free of major neurosensory disability in analysis of 2 trials with 1,317 children, results limited by
significant heterogeneity
Reference - Cochrane Database Syst Rev 2015 Jul 5;(7):CD003935
DynaMed commentary -- 3 trials used single steroid course regimens which may have diminished effects in repeated
dose group
repeat doses of antenatal corticosteroids in women at risk for very preterm birth do not appear to affect
neurosensory, cognitive, or behavioral outcomes in children surviving to 6-8 years corrected age (level 2 [mid-
level] evidence)
based on post hoc follow-up analysis of ACTORDS trial
982 pregnant women at risk of very preterm birth who had corticosteroid injection ≥ 1 week before were randomized
to betamethasone (Celestone Chronodose 11.4 mg) intramuscularly vs. saline placebo with repeated injection
weekly if risk of preterm birth persisted
of 1,144 live births, 963 children who survived to 6-8 years corrected age were assessed
neurosensory disability-free survival in 78% with repeat betamethasone vs. 77% with placebo (not significant)
no significant difference in intellectual impairment, cognitive function, behavior, or general health including lung
function and blood pressure
Reference - Pediatrics 2016 Oct;138(4):e20160947
"rescue course" of antenatal corticosteroids associated with reduced RDS and ventilator and surfactant use
(level 2 [mid-level] evidence)
based on randomized trial with allocation concealment not stated
437 women with singletons or twins < 33 weeks gestation with recurring threat of preterm delivery in upcoming week
were randomized to single rescue course of betamethasone vs. placebo intramuscularly
all women had completed single course of antenatal corticosteroids before 30 weeks gestation and ≤ 14 days
before inclusion
betamethasone given as two 12 mg doses 24 hours apart ("rescue dose")
delivery at < 34 weeks gestation in 55% in each group
known outcomes in 97% of 577 delivered infants
comparing rescue steroid group vs. placebo
RDS (in infants born at < 34 weeks gestation) in 41.4% vs. 61.6% (p = 0.002, NNT 5)
RDS (in all infants) in 30.2% vs. 41.3% (p = 0.026, NNT 9)
surfactant use (in infants born at < 34 weeks gestation) in 37.7% vs. 55.5% (p = 0.004, NNT 6)
surfactant use (in all infants) in 25.6% vs. 35.4% (p = 0.038, NNT 11)
ventilator support (in infants born at < 34 weeks gestation) in 37.6% vs. 52.9% (p = 0.023, NNT 7)
ventilator support (in all infants) in 26.2% vs. 34.8% (p = 0.088)
no significant differences (in both infants born only at < 34 weeks gestation or in all infants) in
bronchopulmonary dysplasia (BPD)
severe intraventricular hemorrhage
periventricular leukomalacia
blood culture-proven sepsis
necrotizing enterocolitis
perinatal death (stillbirth or death before neonatal hospital discharge)
Reference - Am J Obstet Gynecol 2009 Mar;200(3):248.e1, editorial can be found in Am J Obstet Gynecol 2009 Mar;200(3):217
multiple courses of antenatal corticosteroids may not further reduce mortality or neurodevelopmental disability
compared to single course in children aged 5 years (level 2 [mid-level] evidence)
based on follow-up of randomized trial
1,858 pregnant women (2,318 fetuses) between 25 and 32 weeks gestation at risk of preterm birth were randomized
to antenatal betamethasone 12 mg intramuscularly 2 doses 1 day apart (multiple course) vs. betamethasone 12 mg
intramuscularly once (single course)
multiple course administered every 2 weeks until 33 weeks gestation or birth
single course group had placebo injections on same days as multiple course group after initial betamethasone
dose
in original trial
no significant differences in perinatal or neonatal mortality and morbidity (severe respiratory distress
syndrome, intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia, or necrotizing enterocolitis)
significant decrease in weight, length, and head circumference at birth comparing multiple-course vs. single-
course betamethasone
1,724 women (2,141 eligible children) completed follow-up at age 5 years
data from 1,719 children contributed to primary outcome (death or neurodevelopmental disability, defined as deficit
in neuromotor, neurosensory, or neurocognitive/neurobehavioral function)
at 5-year follow-up
primary outcome in 24.9% with multiple-course vs. 24.8% with single-course betamethasone (not significant)
no significant difference in weight, height, or head circumference
Reference - MACS-5 trial (JAMA Pediatr 2013 Dec;167(12):1102), commentary can be found in JAMA Pediatr 2014 Apr;168(4):389
multiple courses of antenatal corticosteroids associated with earlier birth and dose-dependent decrease in fetal
growth in women at high risk of preterm delivery (level 2 [mid-level] evidence)
based on secondary analysis of randomized trial
1,858 women at 25-33 weeks gestation who had not delivered 14-21 days after single course of antenatal
corticosteroids and remained at high risk of preterm delivery randomized to additional courses of antenatal
corticosteroids vs. placebo every 14 days until week 33 or delivery
additional antenatal corticosteroid course consisted of 2 doses betamethasone 12 mg intramuscularly given 24
hours apart
mean gestational age at birth 34.5 weeks for additional courses antenatal corticosteroids vs. 34.9 weeks for placebo
(p < 0.001)
after controlling for gestational age at birth and other confounding factors, each additional course of antenatal
corticosteroids associated with nonsignificant incremental decrease in birth weight, length, and head circumference
Reference - Obstet Gynecol 2012 May;119(5):917
comparative efficacy and safety among prenatal steroids
antenatal dexamethasone associated with reduced risk of intraventricular hemorrhage compared to antenatal
betamethasone (level 2 [mid-level] evidence)
based on Cochrane review of trials with methodologic limitations
systematic review of 12 randomized or quasi-randomized trials evaluating antenatal corticosteroids in 1,557 women
(1,661 infants) at risk of preterm birth
all trials had ≥ 1 limitation including
unclear or inadequate allocation concealment
lack of or unclear blinding
high loss to follow-up
comparing dexamethasone to betamethasone
dexamethasone associated with decreased intraventricular hemorrhage overall in analysis of 4 trials with 549
infants
risk ratio 0.44 (95% CI 0.21-0.92)
NNT 18-179 with intraventricular hemorrhage in 7% of betamethasone group
no significant differences in neonatal death, respiratory distress syndrome, bronchopulmonary dysplasia, severe
intraventricular hemorrhage, periventricular leukomalacia, and mean birth weight
no significant difference in neonatal intensive care unit (NICU) admission in 1 trial with 240 neonates, but
dexamethasone group had increased NICU admission in 1 trial with 105 neonates
for outcome of length of admission to birth in 1 trial with 240 women
antenatal dexamethasone group had significantly longer length of admission to birth in subgroup with intact
membranes
no significant difference in subgroup with ruptured membranes
Reference - Cochrane Database Syst Rev 2013 Aug 29;(8):CD006764
dexamethasone may reduce intraventricular hemorrhage compared to betamethasone (level 2 [mid-level]
evidence)
based on randomized trial without clear accounting for all neonates for some primary outcomes (largest trial in
Cochrane review)
299 women at risk of preterm delivery randomized to dexamethasone (6 mg at 0, 12, 24, and 36 hours) vs.
betamethasone (12 mg at 0 and 24 hours) intramuscularly
less than 70% had results for intraventricular hemorrhage
patients treated with betamethasone were given placebo injection at 12 and 36 hours to maintain blinding
comparing all 178 infants exposed to dexamethasone vs. all 181 infants exposed to betamethasone
no significant differences in neonatal death, RDS, BPD, necrotizing enterocolitis, retinopathy of prematurity,
patent ductus arteriosus (PDA), neonatal sepsis
comparing outcomes selectively reported in 105 infants exposed to dexamethasone vs. 100 infants exposed to
betamethasone
5.7% vs. 17% had intraventricular hemorrhage of any grade (p = 0.02, NNT 9)
1.9% vs. 7% had grade 3 or 4 intraventricular hemorrhage (p = 0.09)
6.7% vs. 18% had any brain lesion (p = 0.02, NNT 9)
1.9% vs. 4% had periventricular leukomalacia (not significant)
Reference - Betacode trial (Obstet Gynecol 2007 Jul;110(1):26), editorial can be found in Obstet Gynecol 2007 Jul;110(1):7,
commentary can be found in Obstet Gynecol 2007 Oct;110(4):930
prenatal dexamethasone exposure may be associated with higher risk for neurodevelopmental abnormalities
than prenatal betamethasone exposure (level 2 [mid-level] evidence)
based on 2 cohort studies
prenatal exposure to dexamethasone in extremely low-birth-weight infants may be associated with worse
neurodevelopmental outcomes at 18-22 months than prenatal betamethasone (level 2 [mid-level] evidence)
based on cohort study
1,124 extremely low-birth-weight infants born 2002-2003 had neurodevelopmental assessment at 18-22 months
corrected age
No SteroidDexamethasone Betamethasone
Cerebral palsy 13.1% 13.5% 9.9% (not significant)
PDI < 70 20% 24% 19% (not significant)
PDI ≥ 85 56% 51% 64% (p < 0.05)*
Deafness 3.3% 3.2% 0.9% (p < 0.05)*
Neurodevelopmental impairment45% 41% 34% (p < 0.05)*
Unimpaired 21% 26% 40% (p < 0.05)*
Abbreviation: PDI, Psychomotor Development Index.