Antenatal Betamethasone for Women at Risk for Late Preterm Delivery 

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

We conducted a multicenter, randomized trial involving women with a singleton pregnancy at 34 weeks 0 days to 36 weeks 5 days of gestation who were at high risk for delivery during the late preterm period (up to 36 weeks 6 days). The par- ticipants were assigned to receive two injections of betamethasone or matching placebo 24 hours apart. The primary outcome was a neonatal composite of treat- ment in the first 72 hours (the use of continuous positive airway pressure or high-flow nasal cannula for at least 2 hours, supplemental oxygen with a frac- tion of inspired oxygen of at least 0.30 for at least 4 hours, extracorporeal mem- brane oxygenation, or mechanical ventilation) or stillbirth or neonatal death within 72 hours after delivery.

RESULTS

The primary outcome occurred in 165 of 1427 infants (11.6%) in the betametha- sone group and 202 of 1400 (14.4%) in the placebo group (relative risk in the be- tamethasone 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 sig- nificantly reduced the rate of neonatal respiratory complications. (Funded by the National Heart, Lung, and Blood Institute and the Eunice Kennedy Shriver Na- tional Institute of Child Health and Human Development; ClinicalTrials.gov num- ber, NCT01222247.) 

After administration of the study medication, the women were treated clinically according to local practice, including discharge home if deliv- ery did not occur and the patient’s condition was considered to be stable. For those enrolled because of an indication for preterm delivery, labor induc- tions were expected to start by 36 weeks 5 days, and cesarean deliveries were to be scheduled by 36 weeks 6 days and not before 24 hours after randomization. Trained and certified research staff members abstracted information from mater- nal and neonatal charts, including demographic information and outcome data, along with medi- cal, obstetrical, and social history. Follow-up was performed at 28 days after birth for all infants who were receiving oxygen at the time of discharge to determine whether there was a continuing need for oxygen supplementation.

Study Outcomes

The primary outcome was a composite end point describing the need for respiratory support within 72 hours after birth and consisting of one or more of the following: the use of continuous positive airway pressure (CPAP) or high-flow nasal can- nula for at least 2 consecutive hours, supplemen- tal oxygen with a fraction of inspired oxygen of at least 0.30 for at least 4 continuous hours, extra- corporeal membrane oxygenation (ECMO), or mechanical ventilation. A high flow of air or blended air and oxygen was defined as more than 1 liter per minute. Stillbirth and neonatal death within 72 hours after delivery were also included in the composite outcome as compet- ing events.

Prespecified subgroup analyses for the pri- mary outcome and severe respiratory complica- tions were a comparison of a gestational age of 34 to 35 weeks versus 36 weeks at randomization, the indication for trial entry (preterm labor, spon- taneous membrane rupture, or obstetrical or medical indication), a planned cesarean delivery versus a planned attempt at vaginal delivery at trial entry, infant sex, and race or ethnic group. Neonatal secondary outcomes included the following: severe respiratory complications (a com- posite outcome of CPAP or high-flow nasal can- nula for at least 12 continuous hours, supplemen- tal oxygen with a fraction of inspired oxygen of at least 0.30 for at least at least 24 continuous hours, ECMO or mechanical ventilation, stillbirth, or neonatal death within 72 hours after delivery), the respiratory distress syndrome, transient tachy- pnea of the newborn, apnea, bronchopulmonary dysplasia, surfactant administration, need for re- suscitation at birth, hypoglycemia, feeding diffi- culty, hypothermia, necrotizing enterocolitis, in- traventricular hemorrhage Papile grade 3 or 4,13 neonatal sepsis, pneumonia, and death before discharge. The respiratory distress syndrome was defined as the presence of clinical signs of respi- ratory distress (tachypnea, retractions, flaring, grunting, or cyanosis), with a requirement for supplemental oxygen with a fraction of inspired oxygen of more than 0.21 and a chest radio- graph showing hypoaeration and reticulogranu- lar infiltrates. Transient tachypnea of the new- born was diagnosed when tachypnea occurred in the absence of chest radiography or with a radio- graph that was normal or showed signs of in- creased perihilar interstitial markings and resolved within 72 hours. Bronchopulmonary dysplasia was defined as a requirement for supplemental oxygen with a fraction of inspired oxygen of more than 0.21 for the first 28 days of life. Hypoglycemia was defined as a glucose level of less than 40 mg per deciliter (2.2 mmol per liter) at any time.

Two composite outcomes were also prespeci- fied: one consisting of the respiratory distress syndrome, transient tachypnea of the newborn, or apnea; and the other, the respiratory distress syndrome, intraventricular hemorrhage, or necro- tizing enterocolitis. Maternal secondary outcomes included chorioamnionitis, endometritis, deliv- ery before completion of the course of glucocor- ticoids, and length of hospitalization. Defini- tions of all secondary outcomes are provided in the Supplementary Appendix.

Charts of all infants who were admitted to special care nurseries were centrally reviewed by a subgroup of the investigators and nurse coordi- nators to verify the respiratory outcomes. Discrep- ancies among the reviewers, or between local research staff members and reviewers, were ad judicated by an independent neonatal consultant who also reviewed all potential cases of broncho- pulmonary dysplasia. All the reviewers were un- aware of study-group assignments. 

Statistical Analysis

We estimated the expected rate of the primary outcome in the placebo group on the basis of the results of a pilot study of infants born at 34 to 36 weeks of gestation after adjustment to ac- count for women at risk for late preterm delivery who deliver at term. We estimated that 2800 women would provide a power of at least 85% to detect a relative decrease of 33% in the rate of the primary outcome, from 9.5% in the placebo group to 6.3% in the betamethasone group, with a two-sided type I error rate of 5%. Details re- garding the power analysis are provided in the Supplementary Appendix.

Analyses were performed according to the in- tention-to-treat principle. We compared continu- ous variables using the Wilcoxon test and cate- gorical variables using chi-square and Fisher’s exact tests. An independent data and safety moni- toring committee monitored the trial. We used a group sequential method to control the type I er- ror with the Lan–DeMets characterization of the O’Brien–Fleming boundary.14 Two interim analy- ses were performed; in the final analysis of the primary outcome, a two-tailed P value of less than 0.048 was considered to indicate statistical significance. Since the adjustment is minimal, we report the 95% confidence interval for the relative risk. For all secondary outcomes, a nominal P value of less than 0.05 was considered to indicate sta- tistical significance, without adjustment for mul- tiple comparisons; relative risks and 95% confi- dence intervals are reported. To determine whether there was a differential effect of betamethasone for the primary outcome and the composite outcome of severe respiratory complications within the pre- specified subgroups, we performed the Breslow– Day interaction test in which a nominal P value of less than 0.05 was considered to indicate statistical significance.

Results

Characteristics of the Participants

Recruitment began in October 2010 and con- cluded in February 2015. Of 24,133 women who underwent screening, 2831 eligible participants underwent randomization (with 1429 assigned to the betamethasone group and 1402 to the pla- cebo group) (Fig. 1). The most common reason for exclusion was the expectation that delivery would occur within 24 hours, which was deter- mined in 6203 of 19,587 women (31.7%) who did not meet the eligibility criteria. The betametha- sone and placebo groups were similar at base- line except for maternal age (mean, 28.6 vs. 27.8 years; P = 0.001) and the proportion of women of Hispanic ethnic background (28.3% vs. 32.0%, P=0.03) (Table 1). 

Compliance and Side Effects

A total of 860 of 1429 women (60.2%) in the betamethasone group and 826 of 1402 (58.9%) in the placebo group received the prespecified two doses of study medication. Of the 1145 women who did not receive a second dose, 1083 (94.6%) delivered before 24 hours; 6 women did not re- ceive any of the assigned study medication. (In the placebo group, 3 women who consented to participate in the trial subsequently declined the injection, 1 woman delivered after randomization but before the first dose, and 1 received open- label betamethasone. In the betamethasone group, 1 woman was in active labor with complete cervi- cal dilation at the time of randomization.)

Adverse events that were reported after both injections were less common in the betametha- sone group than in the placebo group (rate after first injection, 14.1% vs. 20.3%; P<0.001; rate after second injection, 5.5% vs. 9.5%; P<0.007). Almost all adverse events (95%) were local reac- tions at the injection site (Table S4 in the Supple- mentary Appendix).

Neonatal Outcomes

Two women in each study group were lost to follow-up, so outcome information was available for 2827 neonates. There were no stillbirths or neonatal deaths within 72 hours. The rate of the primary outcome was lower in the betametha- sone group than in the placebo group (11.6% vs. 14.4%; relative risk, 0.80; 95% confidence inter- val [CI], 0.66 to 0.97; P=0.02) (Table 2). We de- termined that 35 women (95% CI, 19 to 259) would need to be treated to prevent one case of the primary outcome. Results remained materi- ally unchanged in post hoc analyses after adjust- ment for maternal age and Hispanic ethnic group and with the exclusion of infants (11 in the betamethasone 

group and 21 in the placebo group) who had a major congenital anomaly that was not recognized until after delivery.

The rate of the composite outcome of severe respiratory complications was also significantly lower in the betamethasone group than in the placebo group (8.1% vs. 12.1%; relative risk, 0.67; 95% CI, 0.53 to 0.84; P<0.001). The number needed to treat to prevent one case was 25 (95% CI, 16 to 56). The rates of the respiratory distress syndrome, apnea, and pneumonia were similar in the two groups, but rates of several disorders were significantly lower in the betamethasone group than in the placebo group, including tran- sient tachypnea of the newborn (6.7% vs. 9.9%), bronchopulmonary dysplasia (0.1% vs. 0.6%), and the composite of the respiratory distress syn- drome, transient tachypnea of the newborn, or apnea (13.9% vs. 17.8%); there was also a signifi- cantly lower rate of resuscitation at birth (14.5% vs. 18.7%) and surfactant use (1.8% vs. 3.1%) (Table 2).

None of the subgroup interaction tests for the primary outcome were significant. There was one marginally significant interaction (P=0.05) between treatment group and planned delivery type for the secondary outcome of severe respi- ratory complications, with a significant reduc- tion in the betamethasone group among those for whom cesarean delivery was planned at trial 

entry but not among those planning to attempt a vaginal delivery (Tables S5 and S6 in the Sup- plementary Appendix).

Two infants (both in the betamethasone group) died before discharge: one death was due to septic shock and the other to a structural cardiac anomaly and arrhythmia. There were no significant between-group differences in the gestational age at delivery, the frequency of cat- egorization as small for gestational age, length of hospital stay, or rate of neonatal sepsis, nec- rotizing enterocolitis, intraventricular hemorrhage, hyperbilirubinemia, hypothermia, or a compos- ite of the respiratory distress syndrome, intra- ventricular hemorrhage, or necrotizing enterocolitis (Table 3). As compared with infants in the placebo group, infants in the betamethasone group were less likely to spend 3 or more days in the intensive or intermediate care nursery (P=0.03) and had a shorter time until the first feeding (P = 0.004) but had a higher incidence of neonatal hypoglycemia (24.0% vs. 15.0%; rela- tive risk, 1.60; 95% CI, 1.37 to 1.87; P<0.001).

Maternal Outcomes

There were no significant between-group differ- ences in the incidence of chorioamnionitis or endometritis. The rates of cesarean delivery, time to delivery, and length of stay were also similar in the two groups (Table 4). 

Serious Adverse Events

Serious maternal adverse events occurred in 10 women in the betamethasone group and 12 in the placebo group (Table S7 in the Supplemen- tary Appendix). Apart from the neonatal deaths, only one serious neonatal adverse event occurred (a case of thrombocytopenia in the betametha- sone group).

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 dur- ing the first 72 hours after birth. Betamethasone administration also resulted in reduced rates of 

severe respiratory complications, transient tachy- pnea of the newborn, and bronchopulmonary dysplasia, along with reduced rates of surfactant use, resuscitation, and a prolonged stay in a special care nursery. These benefits were found despite the challenges in predicting the timing of delivery, which resulted in the administration of two doses of the study drugs to only 60% of participants.

Our findings are consistent with the results of the Antenatal Steroids for Term Elective Cae- sarean Section (ASTECS) trial, in which women were randomly assigned to receive either antena- tal glucocorticoids or no glucocorticoids at the time of elective cesarean delivery at term. There was a significant reduction in the rate of admis- sion to neonatal intensive care units for respira- tory complications in the betamethasone group (relative risk, 0.46; 95% CI, 0.23 to 0.93).16 Treat- ment with betamethasone among patients un- dergoing a scheduled cesarean at term has since become the standard of care in the United King- dom. Two smaller randomized trials have spe- cifically assessed the use of betamethasone in the late preterm period to prevent adverse neo- natal respiratory outcomes.17,18 However, these studies were inconclusive, since they were under- powered,18 had substantial loss to follow-up,17 and had exclusions after randomization.18 

The administration of betamethasone did not significantly affect rates of peripartum maternal or neonatal infection but increased the rate of neonatal hypoglycemia, a common late preterm neonatal complication.19 We did not collect data on blood glucose levels over time. However, there were no reported adverse events related to hypoglycemia, which was not associated with an increased length of hospital stay. Infants with hypoglycemia were discharged on average 2 days earlier than those without hypoglycemia, which suggests that the condition was self-limiting. Few trials of antenatal glucocorticoids have in- cluded information on neonatal hypoglycemia.4 However, the original trial of antenatal gluco- corticoids showed no significant between-group difference in the rates of neonatal hypoglyce- mia.20 Nevertheless, our data support monitor- ing neonatal blood glucose after betamethasone exposure in the late preterm period.

It is possible that the reduction in the rate of bronchopulmonary dysplasia with betamethasone therapy could lead to benefit in long-term out- comes such as chronic lung disease. However, follow-up into childhood is needed to inform later outcomes of treatment.

Our study protocol did not allow the use of other prenatal interventions, such as tocolysis, so that we could determine whether the differ- ence in the primary outcome was due to the use of antenatal betamethasone. Although we de- layed augmentation of labor by means of oxytocin by 12 hours for women with ruptured mem- branes 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 respi- ratory 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 Transla- tional 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 re- view; Michelle DiVito, R.N., M.S.N., for her contributions to ad- ministrative management and central outcome review; Carol Blaisdell, M.D., of the NHLBI for her advice, oversight, and sup- port; 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 over- sight; Felecia Ortiz, R.N., B.S.N., and Sabine Bousleiman, R.N.C., M.S.N., M.P.H., for their coordination between the clin- ical research centers and central outcome review; Karin Kush- niruk, 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. 

The new england journal of medicine

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 Children’s 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 In- stitute of Child Health and Human Development, Bethesda, MD (U.M.R.); Brown University, Providence, RI (D.J.R.); Ohio State Uni- versity, 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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