Antenatal Betamethasone for Women at Risk for Late Preterm Delivery Reduces the Rate of Neonatal Respiratory Complications

MANUSCRIPT CITATION 

Gyamfi-Bannerman C, Thom EA, Blackwell SC, Tita ATN, Reddy UM, Saade GR, Rouse DJ, McKenna DS, Clark EAS, Thorp, Jr JM, Chien EK, Peaceman AM, Gibbs RS, Swamy GK, Norton ME, Casey BM, Caritis SN, Tolosa JE, Sorokin Y, VanDorsten JP, Jain L. Antenatal Betamethasone for Women at Risk for Late Preterm Delivery. N Engl J Med 2016; 374:1311-20. PMID 26842679.

REVIEWED BY

Hannah R Canty, MD
Pediatrics Resident
Oregon Health & Science University

Stephanie Dukhovny, MD
Assistant Professor of Obstetrics & Gynecology
Oregon Health & Science University

Jamie B Warren, MD, MPH
Assistant Professor of Pediatrics
Oregon Health & Science University

TYPE OF INVESTIGATION

Prevention

QUESTION

In women who are at risk for late preterm delivery between 34 weeks 0 days and 36 weeks 6 days, does administration of two doses of betamethasone compared to placebo decrease the rate of neonatal respiratory and other complications?

METHODS

  • Design: Randomized Clinical Trial
  • Allocation: Concealed – randomization was done by an independent data-coordinating center using a simple urn method and stratified by clinical site and gestational age category (34 to 35 weeks vs. 36 weeks).
  • Blinding: Study-group assignments were blinded to both the participants and the investigators.
  • Follow-up period: Infants who were discharged on supplemental oxygen were followed up 28 days after birth to determine if they still required supplemental oxygen. For babies not discharged home from the birth admission on supplemental oxygen, follow-up ended with discharge and trained research staff extracted outcome information from maternal and neonatal charts.
  • Setting: 17 university-based clinical centers who were involved in the Maternal Fetal Medicine Units Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
  • Patients: Women with singleton pregnancies between 34 weeks 0 days and 36 weeks 5 days of gestation who had a high probability of late preterm delivery (which extended to 36 weeks 6 days) were included in the study. High probability was defined as women with (1) preterm labor and intact membranes who were at least 3 cm dilated or 75% effaced, (2) spontaneous rupture of membranes, or (3) any other indication for delivery (either by induction or cesarean section) between 24 hours and 7 days after randomization. Women were ineligible if they had received antenatal glucocorticoids previously or if they were likely to deliver in less than 12 hours. Women were also excluded if they were without gestational-dating results on ultrasonography before 32 weeks gestation for those with a known last menstrual period date or before 24 weeks gestation for those with an unknown last menstrual period date, if there was a known major fetal anomaly, if they had multiple gestations, or if they had a diagnosis of pregestational diabetes.
  • Intervention: Women received two intramuscular injections, administered 24 hours apart, of either 12 mg of betamethasone or matching placebo. Women were randomly assigned in a 1:1 ratio to either betamethasone or placebo.
  • Primary outcome: The primary outcome was a composite end point that consisted of the need for respiratory support within 72 hours after birth, stillbirth, or neonatal death within 72 hours after birth. The need for respiratory support consisted of one or more of the following: continuous positive airway pressure (CPAP) or high-flow nasal cannula (HFNC) at more than 1 liter per minute for at least 2 consecutive hours, supplemental oxygen with a fraction of inspired oxygen of at least 0.30 for a minimum of 4 continuous hours, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Prespecified subgroup analyses for the primary outcome and severe respiratory complications (described below) included the indication for trial entry, a comparison of the gestational age at randomization (34 to 35 weeks vs. 36 weeks), planned vaginal attempt versus planned cesarean delivery at trial entry, race or ethnicity, and infant sex.
  • Secondary outcomes (neonatal): Severe respiratory complications (composite outcome of CPAP or HFNC for at least 12 continuous hours, supplemental oxygen with a fraction of inspired oxygen of at least 0.30 for a minimum of 24 continuous hours, mechanical ventilation, ECMO, stillbirth or neonatal death within 72 hours of delivery), respiratory distress syndrome, transient tachypnea of the newborn, apnea, surfactant administration, bronchopulmonary dysplasia, need for resuscitation at delivery, hypoglycemia, hypothermia, difficulty with feeding, necrotizing enterocolitis, Papile grade 3 or 4 intraventricular hemorrhage, pneumonia, neonatal sepsis, and death prior to discharge. Two prespecified composite secondary outcomes were (1) respiratory distress syndrome, transient tachypnea of the newborn, or apnea and (2) respiratory distress syndrome, necrotizing enterocolitis, or interventricular hemorrhage.
  • Secondary outcomes (maternal): Chorioamnionitis, endometritis, delivery before completion of the study medications, and length of hospitalization.
  • Analysis and Sample Size: Based on a pilot study of infants born at 34 to 36 weeks of gestation, an estimated 2800 participants were required to obtain a power of 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 of 5%. Analyses were performed using an intention-to-treat principle. An independent data and safety monitoring committee monitored the trial; two interim analyses were performed.
  • Patient follow-up: A total of 2831 women were randomized. Two women per study group were lost to follow-up; therefore, outcome information was available for 2827 neonates.

MAIN RESULTS

Of 24,133 women screened, 2831 women underwent randomization between October 2010 and February 2015. Of these, 1429 were assigned to the betamethasone group and 1402 to the placebo group. A total of 860 (60.2%) in the betamethasone group and 826 (58.9%) in the placebo group received the two doses of study medication. Of those who did not receive the second dose, the vast majority (94.6%) delivered before 24 hours. There were no stillbirths, neonatal deaths within 72 hours of delivery, or neonates that required ECMO. Two infants died before discharge from the hospital, both in the betamethasone group.

The rate of the primary outcome was lower in the betamethasone group than the placebo group [11.6% vs. 14.4%; relative risk of 0.80; 95% confidence interval (CI), 0.66 to 0.97; P=0.02; number needed to treat (NNT), 35 women; NNT 95% CI, 19 to 259].

The betamethasone group had lower rates of the composite outcome of severe respiratory complications in comparison to the placebo group (8.1% vs. 12.1%; relative risk, 0.67; 95% CI, 0.53 to 0.84; P<0.001; NNT, 25 women; NNT 95% CI, 16 to 56). This was mainly weighted by the CPAP or HFNC for at least 12 continuous hours subset. The rates of transient tachypnea of the newborn (6.7% vs. 9.9%; P=0.002); bronchopulmonary dysplasia (0.1% vs. 0.6%; P=0.04); the composite of transient tachypnea of the newborn, respiratory distress syndrome, or apnea (13.9% vs. 17.8%; P=0.004); resuscitation at birth (14.5% vs. 18.7%; P=0.003); and surfactant use (1.8% vs. 3.1%; P=0.03) were significantly lower in the betamethasone group than in the placebo group. There was no significant difference between the rates of respiratory distress syndrome, apnea, or pneumonia.

While none of the subgroup interaction tests for the primary outcome were significant, the interaction between treatment group and planned delivery type for the secondary composite outcome of severe respiratory complications had a P value of 0.05. For those with a planned attempt at vaginal delivery, 4.6% in the betamethasone group and 4.4% in the placebo group had the outcome of severe respiratory complications (relative risk, 1.06; 95% CI, 0.73-1.53). However, among those with a planned cesarean delivery, 10.3% in the betamethasone group and 17.6% in the placebo group had the outcome of severe respiratory complications (relative risk, 0.58; 95% CI, 0.36-0.94). This information is available in the Supplementary Appendix, Table S6.

There was no significant difference between the betamethasone group and placebo group for the following: small for gestational age, gestational age at delivery, length of hospital stay, or the rates of neonatal sepsis, intraventricular hemorrhage, necrotizing enterocolitis, hyperbilirubinemia, hypothermia, or the composite of respiratory distress syndrome, necrotizing enterocolitis, or intraventricular hemorrhage. Those infants that received betamethasone had a shorter time to first feeding (P=0.004) and a lower likelihood of spending 3 or more days in the intermediate care nursery or intensive care nursery (P=0.03). However, the incidence of neonatal hypoglycemia (defined as glucose level <40 mg/dL at any time) was higher in the betamethasone group (24.0% vs. 15.0%; relative risk, 1.60; 95% CI, 1.37 to 1.87; P<0.001).

There was no significant difference between groups regarding the following maternal outcomes: chorioamnionitis, endometritis, or rates of cesarean delivery, length of stay, or time to delivery.

CONCLUSION

Newborns of women at risk for late preterm delivery who received antenatal betamethasone had a significantly decreased rate of respiratory complications. While betamethasone significantly increased the rate of neonatal hypoglycemia, it did not affect the rates of other neonatal or maternal complications.

COMMENTARY

This study confirmed that provision of antenatal corticosteroids (ANCS) for threatened late preterm delivery decreases the rate of neonatal respiratory complications. Following this publication, the American Congress of Obstetricians and Gynecologists (ACOG) (1) and the Society for Maternal Fetal Medicine (SMFM) (2) published guidelines regarding use of ANCS in the late preterm period. Both groups recommend a single course of betamethasone for women with singleton pregnancies between 34 weeks 0 days and 36 weeks 6 days who are at risk for preterm delivery within 7 days but before 37 weeks. Both recommend against the delay of a medically indicated delivery or tocolysis in order to complete a betamethasone course, and both recommend against betamethasone in women who have previously received ANCS or who have a diagnosis of chorioamnionitis. Due to exclusion criteria, results cannot be generalized to populations who may be at higher risk of the outcomes studied (e.g., multiple gestations, congenital anomalies, pregestational diabetes), and SMFM does not recommend use of betamethasone in these excluded populations unless part of a research protocol or quality improvement project.

The outcome of concern is neonatal hypoglycemia. As 24% in the betamethasone group and 15% in the placebo group experienced hypoglycemia, the number needed to harm is 11. In general, hypoglycemia is a well-known complication in late preterm infants. In this study, there were no reported adverse events related to hypoglycemia and infants with hypoglycemia were discharged on average two days prior to those without, suggesting transient and/or easily treated hypoglycemia. As stated in the ACOG and SMFM guidelines, it is prudent to follow recommendations of the American Academy of Pediatrics (3) in terms of screening for hypoglycemia in this at-risk population, regardless of maternal medications.

From a respiratory standpoint, these findings have implications for public health. In 2014, 6.82% of the 3,998,076 births in the United States occurred in the late preterm period (almost 272,000 births) (4). While the NNT from this study cannot be directly applied to this total number of late preterm births (due to exclusion criteria), we can presume that implementation of this protocol would positively affect thousands of babies each year. While the intervention did not decrease length of stay, it did decrease the likelihood of spending three or more days in an intermediate care unit or intensive care unit, which could decrease overall cost of care. We must decide if these respiratory benefits outweigh the risks of increased blood glucose monitoring and treatment of hypoglycemia in this population.

Concerns have been raised about neonatal hypoglycemia (5) and exposure to ANCS (6) in the late preterm population and subsequent lack of data on neurodevelopmental and other health outcomes, such as hypertension or hormonal abnormalities (7). While these are valid concerns, we also know that respiratory conditions requiring mechanical ventilation, CPAP, or oxygen therapy, even in the late preterm population, also likely have long term consequences (8). By providing antenatal betamethasone to women at risk for delivering in the late preterm period, avoidance of these outcomes may be possible.

REFERENCES

  1. Committee Opinion No. 677: Antenatal Corticosteroid Therapy for Fetal Maturation. American College of Obstetricians and Gynecologists. Obstet Gynecol 2016; 128:e187-94. PMID: 27661658.
  2. Society for Maternal-Fetal Medicine (SMFM) Publications Committee. Implementation of the use of antenatal corticosteroids in the late preterm birth period in women at risk for preterm delivery. Am J Obstet and Gynecol 2016; 215:B13-5. PMID: 26992737.
  3. Adamkin DH and Committee on Fetus and Newborn. Clinical Report—Postnatal Glucose Homeostasis in Late-Preterm and Term Infants. Pediatrics 2011; 127:575-9. PMID: 21357346.
  4. Hamilton BE, Martin JA, Osterman MJK, Curtin SC, Mathews TJ. Births: Final Data for 2014. Natl Vital Stat Rep 2015; 64:1-64. PMID: 26727629.
  5. Redlich A, Bottger R, Costa SD. Antenatal Betamethasone for Women at Risk for Late Preterm Delivery. N Engl J Med 2016; 375:486. PMID: 27518671.
  6. Smith GC. Antenatal Betamethasone for Women at Risk for Late Preterm Delivery. N Engl J Med 2016; 375:486. PMID: 27518672.
  7. Kamath-Rayne BD, Rozance PJ, Goldenberg RL, Jobe AH. Antenatal corticosteroids beyond 34 weeks gestation: What do we do now? Am J Obstet and Gynecol 2016; 215:423-30. PMID: 27342043.
  8. Kotecha SJ, Dunstan FD, Kotecha S. Long term respiratory outcomes of late preterm-born infants. Semin Fetal Neonatal Med 2012; 17:77-81. PMID 22277112.

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