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Original Article
A BS T R AC T
BACKGROUND
Infants who are born at 34 to 36 weeks of gestation (late preterm) are at greater
risk for adverse respiratory and other outcomes than those born at 37 weeks of
gestation or later. It is not known whether betamethasone administered to women
at risk for late preterm delivery decreases the risks of neonatal morbidities.
METHODS
The authors full names, academic degrees, and affiliations are listed in the Appendix. Address reprint requests to Dr.
Gyamfi-Bannerman at the Division of
MaternalFetal Medicine, Department
of Obstetrics and Gynecology, Columbia
University Medical Center, 622 W. 168th
St., PH-16, New York, NY 10032, or at
cg2231@cumc.columbia.edu.
*A complete list of the Eunice Kennedy
Shriver National Institute of Child Health
and Human Development (NICHD) MaternalFetal Medicine Units Network is
provided in the Supplementary Appendix, available at NEJM.org.
This article was published on February 4,
2016, at NEJM.org
DOI: 10.1056/NEJMoa1516783
Copyright 2016 Massachusetts Medical Society.
RESULTS
The primary outcome occurred in 165 of 1427 infants (11.6%) in the betamethasone group and 202 of 1400 (14.4%) in the placebo group (relative risk in the betamethasone group, 0.80; 95% confidence interval [CI], 0.66 to 0.97; P=0.02).
Severe respiratory complications, transient tachypnea of the newborn, surfactant
use, and bronchopulmonary dysplasia also occurred significantly less frequently in
the betamethasone group. There were no significant between-group differences in
the incidence of chorioamnionitis or neonatal sepsis. Neonatal hypoglycemia was
more common in the betamethasone group than in the placebo group (24.0% vs.
15.0%; relative risk, 1.60; 95% CI, 1.37 to 1.87; P<0.001).
CONCLUSIONS
Administration of betamethasone to women at risk for late preterm delivery significantly reduced the rate of neonatal respiratory complications. (Funded by the
National Heart, Lung, and Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT01222247.)
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Placebo
(N=1402)
400 (28.0)
392 (28.0)
Ruptured membranes
316 (22.1)
304 (21.7)
370 (25.9)
385 (27.5)
46 (3.2)
48 (3.4)
50 (3.5)
42 (3.0)
247 (17.3)
231 (16.5)
Characteristic
Indication for trial entry no. (%)
Preterm labor with intact membranes
369 (25.8)
399 (28.5)
35 wk 0 days to 35 wk 6 days
571 (40.0)
532 (37.9)
36 wk 0 days
489 (34.2)
471 (33.6)
28.66.3
27.86.1
Black
376 (26.3)
381 (27.2)
White
828 (57.9)
800 (57.1)
Asian
57 (4.0)
39 (2.8)
168 (11.8)
182 (13.0)
Hispanic
405 (28.3)
448 (32.0)
457 (32.0)
448 (32.0)
204 (14.3)
186 (13.3)
433 (30.3)
440 (31.4)
153 (10.7)
153 (10.9)
11 (0.8)
21 (1.5)
* There were no significant differences between the two groups except for maternal age (P=0.001) and Hispanic ethnic
group (P=0.03).
Race or ethnic group was self-reported. Patients of any race could report Hispanic background.
Although the presence of a major congenital anomaly was an exclusion criterion, these disorders were not discovered
until birth.
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Outcome
Placebo
(N=1400)
Relative Risk
(95% CI)
P Value
no. (%)
Primary outcome
165 (11.6)
202 (14.4)
0.80 (0.660.97)
0.02
145 (10.2)
184 (13.1)
0.77 (0.630.95)
0.01
48 (3.4)
61 (4.4)
0.77 (0.531.12)
0.17
Mechanical ventilation
0.78 (0.501.21)
0.26
34 (2.4)
43 (3.1)
ECMO
NA
NA
NA
NA
115 (8.1)
169 (12.1)
0.67 (0.530.84)
<0.001
93 (6.5)
147 (10.5)
0.62 (0.480.80)
<0.001
20 (1.4)
34 (2.4)
0.58 (0.331.00)
0.05
206 (14.5)
260 (18.7)
0.78 (0.660.92)
0.003
79 (5.5)
89 (6.4)
0.87 (0.651.17)
0.36
95 (6.7)
138 (9.9)
0.68 (0.530.87)
0.002
Apnea
33 (2.3)
37 (2.6)
0.88 (0.551.39)
0.57
Bronchopulmonary dysplasia
2 (0.1)
9 (0.6)
0.22 (0.020.92)
0.04
Pneumonia
6 (0.4)
13 (0.9)
0.45 (0.171.19)
0.10
Surfactant use
Composite of respiratory distress syndrome,
transient tachypnea of the newborn,
or apnea
Pulmonary air leak
26 (1.8)
43 (3.1)
0.59 (0.370.96)
0.03
198 (13.9)
249 (17.8)
0.78 (0.660.93)
0.004
5 (0.4)
6 (0.4)
0.82 (0.252.68)
0.74
* Two participants in each group were lost to follow-up for the analysis of neonatal respiratory outcomes. CI denotes
confidence interval, CPAP continuous positive airway pressure, ECMO extracorporeal membrane oxygenation, and NA
not applicable.
The primary outcome was defined as any of the following occurrences within 72 hours after birth: CPAP or high-flow
nasal cannula for at least 2 continuous hours, supplemental oxygen with a fraction of inspired oxygen of 0.30 or more
for at least 4 continuous hours, mechanical ventilation, stillbirth or neonatal death, or the need for ECMO.
A severe respiratory complication was defined as any of the following occurrences within 72 hours after birth: CPAP or
high-flow nasal cannula for at least 12 hours, supplemental oxygen with a fraction of inspired oxygen of 0.30 or more
for at least 24 hours, mechanical ventilation, stillbirth or neonatal death, or the need for ECMO. Except for the duration
of CPAP or high-flow nasal cannula and the duration of a fraction of inspired oxygen of 0.30 or more, the criteria for a
severe respiratory complication overlap with those of the primary outcome.
The need for resuscitation at birth was evaluated in 1422 infants in the betamethasone group and 1390 in the placebo
group.
Exact confidence limits are provided for the difference between two binomial proportions.15
Discussion
In this randomized, multicenter trial, we found
that antenatal administration of betamethasone
to women at risk for late preterm delivery decreased
the need for substantial respiratory support during the first 72 hours after birth. Betamethasone
administration also resulted in reduced rates of
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Betamethasone
(N=1427)
Placebo
(N=1400)
Relative Risk
(95% CI)
P Value
NA
0.50
2 (0.1)
2637480
2654484
255 (17.9)
220 (15.7)
0.32
1.14 (0.961.34)
0.10
34 wk 6 days
193 (13.5)
213 (15.2)
35 wk 0 days to 35 wk 6 days
394 (27.6)
386 (27.6)
36 wk 0 days to 36 wk 6 days
609 (42.7)
568 (40.6)
37 wk 0 days to 38 wk 6 days
202 (14.2)
185 (13.2)
29 (2.0)
48 (3.4)
1 (0.1)
9 (0.6)
11 (0.8)
2 (0.1)
81 (5.7)
39 wk 0 days
Necrotizing enterocolitis no. (%)
0.13
0.80 (0.331.93)
0.62
90 (6.4)
0.88 (0.661.18)
0.40
1.60 (1.371.87)
<0.001
343 (24.0)
210 (15.0)
5.5 (1.424.7)
9.9 (1.729.1)
0.004
211 (14.8)
223 (15.9)
0.93 (0.781.10)
0.40
167 (11.7)
140 (10.0)
1.17 (0.951.40)
0.15
132 (9.3)
112 (8.0)
1.16 (0.911.47)
0.24
Any duration
596 (41.8)
629 (44.9)
0.93 (0.851.01)
0.09
Duration 3 days
470 (32.9)
518 (37.0)
0.89 (0.800.98)
0.03
7 (412)
8 (413)
0.20
* Two participants in each group were lost to follow-up for the analysis of other secondary neonatal outcomes. IQR denotes interquartile range, and NICU neonatal intensive care unit.
Hypoglycemia was defined as a glucose level of less than 40 mg per deciliter (2.2 mmol per liter).
was a significant reduction in the rate of admission to neonatal intensive care units for respiratory complications in the betamethasone group
(relative risk, 0.46; 95% CI, 0.23 to 0.93).16 Treatment with betamethasone among patients undergoing a scheduled cesarean at term has since
become the standard of care in the United Kingdom. Two smaller randomized trials have specifically assessed the use of betamethasone in
the late preterm period to prevent adverse neonatal respiratory outcomes.17,18 However, these
studies were inconclusive, since they were underpowered,18 had substantial loss to follow-up,17
and had exclusions after randomization.18
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Placebo
(N=1400)
20 (1.4)
32 (2.3)
0.61 (0.351.07)
0.08
16 (1.1)
16 (1.1)
0.98 (0.491.95)
0.96
1.03 (0.931.15)
0.56
Outcome
Relative Risk
(95% CI)
P Value
454 (31.8)
431 (30.8)
33.0 (15.2111.6)
30.6 (14.6111.0)
0.57
3 (35)
3 (35)
0.11
* Two participants in each group were lost to follow-up for the analysis of maternal outcomes.
cin by 12 hours for women with ruptured membranes who had contractions or whose cervical
dilation was 3 cm or more, we did not find a
significant between-group difference in the rates
of maternal or neonatal infectious complications.
In conclusion, the administration of antenatal
betamethasone in women at risk for late preterm
delivery significantly decreased the rate of respiratory complications in newborns. Betamethasone
administration significantly increased the rate
of neonatal hypoglycemia but not the rates of
other maternal or neonatal complications.
The views expressed in this article are those of the authors
and do not necessarily represent the views of the NICHD or the
National Heart, Lung, and Blood Institute (NHLBI).
Supported by grants (HL098554 and HL098354) from the
NHLBI, by grants (HD21410, HD27915, HD27917, HD27869,
HD34116, HD34208, HD40485, HD40500, HD40512, HD40544,
HD40545, HD40560, HD53097, HD53118, HD68268, HD68258,
HD68282, and HD36801) from the NICHD, and by a grant (UL1
TR000040) from the National Center for Advancing Translational Sciences, National Institutes of Health.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Ronald Wapner, M.D., for his contributions to the
study design, protocol development, and central outcome review; Michelle DiVito, R.N., M.S.N., for her contributions to administrative management and central outcome review; Carol
Blaisdell, M.D., of the NHLBI for her advice, oversight, and support; Kathleen Jablonski, Ph.D., for study and data management
and statistical analysis; Catherine Spong, M.D., of the NICHD
for protocol development, central outcome review, and oversight; Felecia Ortiz, R.N., B.S.N., and Sabine Bousleiman,
R.N.C., M.S.N., M.P.H., for their coordination between the clinical research centers and central outcome review; Karin Kushniruk, R.N., Ashley Salazar, R.N., M.S.N., W.H.N.P., and Mary
Talucci, R.N., for their assistance in central outcome review; and
Rosemary Higgins, M.D., of the NICHD for her expert advice.
Appendix
The authors full names and academic degrees are as follows: Cynthia GyamfiBannerman, M.D., ElizabethA. Thom, Ph.D., SeanC.
Blackwell, M.D., AlanT.N. Tita, M.D., Ph.D., UmaM. Reddy, M.D., M.P.H., GeorgeR. Saade, M.D., DwightJ. Rouse, M.D., DavidS.
McKenna, M.D., ErinA.S. Clark, M.D., JohnM. Thorp, Jr., M.D., EdwardK. Chien, M.D., AlanM. Peaceman, M.D., RonaldS. Gibbs,
M.D., GeetaK. Swamy, M.D., MaryE. Norton, M.D., BrianM. Casey, M.D., SteveN. Caritis, M.D., JorgeE. Tolosa, M.D., M.S.C.E.,
Yoram Sorokin, M.D., J.Peter VanDorsten, M.D., and Lucky Jain, M.D., for the NICHD MaternalFetal Medicine Units Network.
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The authors affiliations are as follows: Columbia University, New York (C.G.-B.); the George Washington University Biostatistics
Center, Washington, DC (E.A.T.); the University of Texas Health Science Center at Childrens Memorial Hermann Hospital, Houston
(S.C.B.), the University of Texas Medical Branch, Galveston (G.R.S.), and the University of Texas Southwestern Medical Center, Dallas
(B.M.C.) all in Texas; the University of Alabama at Birmingham, Birmingham (A.T.N.T.); the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD (U.M.R.); Brown University, Providence, RI (D.J.R.); Ohio State University, Columbus (D.S.M.), and the MetroHealth Medical Center, Case Western Reserve University, Cleveland (E.K.C.) both in Ohio;
the University of Utah Health Sciences Center, Salt Lake City (E.A.S.C.); the University of North Carolina at Chapel Hill, Chapel Hill
(J.M.T.), and Duke University, Durham (G.K.S.) both in North Carolina; Northwestern University, Chicago (A.M.P.); the University
of Colorado School of Medicine, Anschutz Medical Campus, Aurora (R.S.G.); Stanford University, Stanford, CA (M.E.N.); University of
Pittsburgh, Pittsburgh (S.N.C.); Oregon Health and Science University, Portland (J.E.T.); Wayne State University, Detroit (Y.S.); the
Medical University of South Carolina, Charleston (J.P.V.); and Emory University, Atlanta (L.J.).
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