Antenatal Late Preterm Steroids (ALPS): A Randomized Placebo-Controlled Trial

• Sponsor: The George Washington University Biostatistics Center (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01222247
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
• Enrollment: 2,831
• Locations: 17
• Arms: 2
• Duration (Months): 141
• Patients Per Site: 166.5
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

This is a randomized placebo controlled trial to evaluate whether antenatal corticosteroids can decrease the rate of neonatal respiratory support, thus decreasing the rate of NICU admissions and improving short-term outcomes in the late preterm infant. The use of antenatal corticosteroids has been shown to be beneficial in women at risk for preterm delivery prior to 34 weeks but has not been evaluated in those likely to deliver in the late preterm period

Condition or Disease	Intervention/Treatment	Phase
Pregnancy; Respiratory Distress Syndrome; Pregnancy Outcomes; Preterm Birth	Drug: Betamethasone; Drug: Placebo	Phase 3

Detailed Description

The rate of preterm birth has steadily increased in the United States over the past 10 years. This increase is driven in part by the rising rate of late preterm birth, defined as those births occurring between 34 and 36 weeks. Late preterm infants experience a higher rate of readmission than their term counterparts, and these infants are more likely to suffer complications such as respiratory distress, kernicterus, feeding difficulties, and hypoglycemia. Late preterm infants also have a higher mortality for all causes when compared to term infants. The use of antenatal corticosteroids has been shown to be beneficial in women at risk for preterm delivery prior to 34 weeks but has not been evaluated in those likely to deliver in the late preterm period. If shown to reduce the need for respiratory support and thus to decrease the rate of special care nursery admissions and improve short-term outcomes, the public health and economic impact will be considerate.This protocol describes a randomized placebo controlled trial to evaluate whether antenatal corticosteroids can decrease the rate of neonatal respiratory support, thus decreasing the rate of neonatal intensive care unit (NICU) admissions and improving short-term outcomes in the late preterm infant.

Two follow-up studies will be conducted concurrently. The first follow-up study will examine if the positive effects of betamethasone on lung function will persist in children at 6 years of age of mothers randomized to betamethasone with an expected late preterm delivery. Neonatal respiratory morbidity is associated with an increased risk of adverse childhood respiratory disease. Thus it is quite plausible that the effect of betamethasone, in reducing neonatal morbidity, particularly TTN, will translate into improved respiratory morbidity in early childhood.The primary outcome is childhood respiratory disease defined by a composite outcome of abnormal pulmonary function test (PFT) measured by spirometry, physician diagnosis of asthma, or other respiratory illnesses with medication.

The second follow-up study will examine whether late preterm antenatal betamethasone treatment is associated with long-term neurocognitive functioning, and whether there are any long-term consequences of what is believed to be transient neonatal hypoglycemia. Cognitive function will be measured by the Differential Ability Scales 2nd Edition (DAS-II) core components of the general conceptual ability (GCA) that includes verbal ability, non-verbal reasoning ability and spatial ability. The primary outcome is defined as a GCA score of <85 (1 standard deviation below the mean) at 6 years of age or greater.

Study Design

• Study Type: Interventional
• Actual Enrollment: 2831 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: Antenatal Late Preterm Steroids (ALPS): A Randomized Placebo-Controlled Trial
• Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Mar 1, 2015
• Anticipated Study Completion Date: Jul 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Betamethasone A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	Drug: Betamethasone; The active study drug, betamethasone. 3 mg per ml betamethasone sodium phosphate 3 mg per milliliter betamethasone acetate The first dose of study drug medication will be administered at randomization as 2 ml injection; the next dose of 2 ml will be administered 24 hours later.; Other Names: Corticosteroid
Placebo Comparator: Placebo A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart	Drug: Placebo; Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.

Outcome Measures

Primary Outcome Measures

1. Neonatal Composite Outcome [72 hours of life]

   Need for respiratory support: Continuous positive airway pressure (CPAP) or humidified high-flow nasal cannula (HHFNC) for greater than or equal to 2 hours or more in the first 72 hours, or fraction of inspired oxygen (FiO2) greater than or equal to 0.30 for 4 hours or more in the first 72 hours, or mechanical ventilation in the first 72 hours, or Extracorporeal membrane oxygenation (ECMO) Stillbirth, or neonatal death less than 72 hours of age

Secondary Outcome Measures

1. Number of Neonates With Severe Respiratory Complication, [72 hours of life]

   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.

2. Neonates Needing Immediate Resuscitation After Birth [Within the first 30 minutes of birth]

   Need for resuscitation after birth: any intervention in the first 30 minutes other than blow-by oxygen

3. Number of Neonates With Respiratory Distress Syndrome [Delivery]

   Respiratory distress defined as the presence of clinical signs of respiratory distress (tachypnea, retractions, flaring, grunting, or cyanosis) with an oxygen requirement and a chest x-ray that shows hypoaeration and reticulogranular infiltrates

4. Number of Neonates With Transient Tachypnea of the Newborn [by 72 hours after delivery]

   TTN is defined as signs of respiratory distress, specifically tachypnea, that are resolved by 72 hours of age. TTN may be diagnosed in the absence of a chest X-ray or with a chest X-ray that is normal or shows signs of increased perihilar interstitial markings

5. Number of Infants With Neonatal Apnea [72 hours of life]

   Neonatal apnea with respiratory pauses of more than 20 seconds duration resulting in bradycardia or oxygen desaturation below baseline.

6. Number of Infants withChronic Lung Disease / Bronchopulmonary Dysplasia (BPD) Requiring Supplemental Oxygen [28 days of life]

   Infants requiring supplemental oxygen of more than 0.21 for the first 28 days of life

7. Neonates With Pneumonia [by 72 hours of life]

   Neonatal pneumonia

8. Number of Neonates Needing Surfactant Administration [Delivery]

   Administration of surfactant for neonatal respiratory treatment

9. Neonatal Outcome Composite [72 hours of life]

   Transient tachypnea of the newborn (TTN), respiratory distress syndrome (RDS), and apnea

10. Number of Neonates With Pulmonary Air Leak [72 hours post delivery]

    Neonatal pulmonary air leak syndrome

11. Neonatal Death After 72 Hours of Delivery [72 hours after delivery through hospital discharge up to 3 weeks]

    Neonatal death after 72 hours of life but before hospital discharge.

12. Birth Weight [Delivery]

    Weight in grams at delivery

13. Birth Weight Less Than 10th Percentile [Delivery]

    Neonates whose birth weight is less than the 10th percentile at delivery

14. Gestational Age at Delivery [Delivery]

    Number of neonates delivered at ≤ 34 weeks 6 days, between 35 weeks 0 days and 35 weeks 6 days, between 36 weeks 0 days and 36 weeks 6 days, between 37 weeks 0 days and 38 weeks 6 days, or on or after 39 weeks 0 days

15. Number of Neonates With Necrotizing Enterocolitic (NEC) [Delivery]

    Defined as modified Bell Stage 2 or 3. Stage 2: Clinical signs and symptoms with pneumatosis intestinalis on radiographs. Stage 3: Advanced clinical signs and symptoms, pneumatosis, impending or proven intestinal perforation.

16. Number of Infants With Neonatal Sepsis [Delivery]

    Clinical suspicion of systemic infection with a positive blood, cerebral spinal fluid, or catheterized/suprapubic urine culture; or, in the absence of positive cultures, clinical evience of cardiovascular collapse or an X-ray confirming infection.

17. Number of Neonates With Intraventricular Hemorrhage [Delivery]

    Grade 3 or 4 Intraventricular Hemorrhage

18. Neonatal Morbidity Composite [Delivery]

    A composite endpoint of morbidities known to be affected by steroid administration will also be evaluated. Specifically, this composite will include RDS, intraventricular hemorrhage (IVH), and NEC

19. Number of Neonates With Hypoglycemia [Delivery through hospital discharge up to 3 weeks]

    Glucose < 40 mg per deciliter (2.2 mmol per liter) at any time

20. Time Until First Neonatal Feeding [Delivery to 36 hours post delivery]

    Median length of time from delivery until the first neonatal feeding

21. Neonatal Feeding Difficulty [Delivery to 36 hours post delivery]

    Inability of the neonate to take all feeds (po), i.e. requiring gavage feeds or IV supplementation.

22. Neonatal Hyperbilirubinemia [Delivery]

    Peak total bilirubin of at least 15 mg% or the use of phototherapy.

23. Number of Neonates With Hypothermia [Delivery through discharge up to 3 weeks]

    Rectal temperature < 36 C at any time

24. Length of NICU or Nursery Stay [Delivery through hospital discharge up to 3 weeks]

    Includes need for NICU or intermediate care admission and length of stay if admitted. For analysis purposes, death before discharge is assigned maximum rank

25. Median Length of Hospital Stay [Duration of hospital stay following delivery up to 2 weeks]

    Median length of maternal hospital stay following delivery

26. Maternal Outcomes (Participant-based) [Labor and delivery through 72 hours post partum]

    Chorioamnionitis: clinical diagnosis and a body temperature of at least 100.4 degrees F., Endometritis: persistent postpartum temperature greater than 100.4 degrees F with uterine tenderness, cesarean delivery

27. Hours From Randomization to Delivery [Randomization through delivery]

    Median interval of hours from randomization to delivery

28. Median Length of Maternal Hospital Stay [Delivery through hospital discharge]

    Median length of maternal hospital stay in days

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

Singleton Pregnancy. A twin pregnancy reduced to singleton (either spontaneously or therapeutically) before 14,0 weeks by project gestational age is acceptable

Gestational age at randomization between 34,0 weeks and 36,5 weeks confirmed by study criteria

High probability of delivery in the late preterm period (any one of the following):

• Membrane rupture as defined by the occurrence of any two of the following: pooling of fluid in the vaginal vault, positive Nitrazine test, ferning of vaginal fluid, positive AmniSure test; or any one of the following: indigo carmine pooling in the vagina after amnioinfustion, visible leakage of amniotic fluid from the cervix

or

• Preterm labor with intact membranes. Preterm labor is defined as at least 6 regular uterine contractions in an observation period of no more than 60 minutes and at least one of the following: cervix greater than or equal to 3cm dilated or at least 75% effaced

or

• Planned delivery by induction of labor or cesarean section in no less than 24 hours and no more than 7 days, as deemed necessary by the provider. An induction must be scheduled to start by 36,5 weeks at the latest, whereas a cesarean delivery must be scheduled by 36,6 weeks at the latest. Therefore the latest gestational age for randomization is 36,4 weeks for a planned induction. The planned delivery may be for any indication, such as the following: prior myomectomy, prior classical cesarean, intrauterine growth restriction (IUGR), oligohydramnios, preeclampsia, nonreassuring fetal heart rate tracing warranting delivery, abruption, placenta previa

Exclusion Criteria:

1. Any prior antenatal corticosteroid course during the pregnancy because of potential contamination of the placebo group

2. Candidate for stress dose corticosteroids because of chronic steroid therapy to prevent suppression of adrenal gland, because of potential contamination of the placebo group

3. Twin gestation reduced to a singleton gestation at or after 14 weeks 0 days by project gestational age either spontaneously or therapeutically

4. Fetal demise, or known major fetal anomaly, including cardiac anomaly and hydrops

5. Maternal contraindication to betamethasone: hypersensitivity reaction to any components of the medication, idiopathic thromboycytopenic purpura, systemal fungal infection in case of exacerbation by betamethasone, use of amphotericin B due to the possibility of heart failure with concomitant betamethasone

6. Pre-gestational diabetes - exclude if the patient was on medication (insulin, glyburide) prior to pregnancy

7. Delivery expected within 12 hours of randomization, because of insufficient time of corticosteroids to confer benefit, including any of the following:

1. Rupture of Membranes (ROM) does not satisfy protocol criteria - exclude if the patient being evaluated for Preterm Premature Rupture of Membranes (pPROM), does not have preterm labor or planned delivery and does not satisfy the spontaneous membrane rupture criteria (any 2 of: positive Nitrazine test, pooling of fluid in the vaginal vault test or ferning of vaginal fluid; or indigo carmine pooling in the vagina after amnioinfusion; or visible leakage of amniotic fluid from the cervix) B. Rupture of the membranes in the presence of more than 6 contractions per hour or cervical dilation of 3 cm or more, unless oxytocin was withheld for at least 12 hours (other induction agents allowed) C. Chorioamnionitis - exclude if patient is diagnosed with chorioamnionitis D. Cervical dilation ≥ 8 cm E. Evidence of non-reassuring fetal status requiring immediate delivery

1. Participation in another interventional study that influences neonatal morbidity and mortality

2. Participation in this trial in a previous pregnancy

3. Delivery at a non-network hospital

4. At 36, 0 weeks to 36, 5 weeks and quota for 36 weeks already met. To ensure there is an adequate proportion of women presenting at 34 to 35 weeks of gestation, enrollment will be restricted so that no more than 50% of the women in the trial present at 36 weeks.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama - Birmingham	Birmingham	Alabama	United States	35233
2	Stanford University	Stanford	California	United States	94305
3	University of Colorado	Denver	Colorado	United States	80045
4	Northwestern University	Chicago	Illinois	United States	60611
5	Wayne State University	Detroit	Michigan	United States	48201
6	Columbia University	New York	New York	United States	10032
7	University of North Carolina - Chapel Hill	Chapel Hill	North Carolina	United States	27599
8	Duke University	Durham	North Carolina	United States	27710
9	Case Western Reserve University	Cleveland	Ohio	United States	44109
10	Ohio State University	Columbus	Ohio	United States	43210
11	Oregon Health & Science University	Portland	Oregon	United States	97239
12	University of Pittsburgh Magee Womens Hospital	Pittsburgh	Pennsylvania	United States	15213
13	Brown University	Providence	Rhode Island	United States	02905
14	University of Texas - Southwest	Dallas	Texas	United States	75235
15	University of Texas - Galveston	Galveston	Texas	United States	77555
16	University of Texas - Houston	Houston	Texas	United States	77030
17	University of Utah Medical Center	Salt Lake City	Utah	United States	84132

Sponsors and Collaborators

• The George Washington University Biostatistics Center
• National Heart, Lung, and Blood Institute (NHLBI)
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Study Director: Monica Longo, MD, NICHD Project Scientist
• Principal Investigator: Rebecca Clifton, PhD, George Washington University
• Study Chair: Cynthia Gyamfi Bannerman, MD, Columbia University

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• (The public website of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal Fetal Medicine Units (MFMU) Network)

Publications

• Bhutani VK, Johnson L. Kernicterus in late preterm infants cared for as term healthy infants. Semin Perinatol. 2006 Apr;30(2):89-97.
• Buus-Frank ME. The great imposter. Adv Neonatal Care. 2005 Oct;5(5):233-6.
• Clark RH. The epidemiology of respiratory failure in neonates born at an estimated gestational age of 34 weeks or more. J Perinatol. 2005 Apr;25(4):251-7.
• Davidoff MJ, Dias T, Damus K, Russell R, Bettegowda VR, Dolan S, Schwarz RH, Green NS, Petrini J. Changes in the gestational age distribution among U.S. singleton births: impact on rates of late preterm birth, 1992 to 2002. Semin Perinatol. 2006 Feb;30(1):8-15. Erratum in: Semin Perinatol. 2006 Oct;30(5):313.
• Dudell GG, Jain L. Hypoxic respiratory failure in the late preterm infant. Clin Perinatol. 2006 Dec;33(4):803-30; abstract viii-ix. Review.
• Escobar GJ, Clark RH, Greene JD. Short-term outcomes of infants born at 35 and 36 weeks gestation: we need to ask more questions. Semin Perinatol. 2006 Feb;30(1):28-33. Review.
• Gray RF, Indurkhya A, McCormick MC. Prevalence, stability, and predictors of clinically significant behavior problems in low birth weight children at 3, 5, and 8 years of age. Pediatrics. 2004 Sep;114(3):736-43.
• Hamilton BE, Martin JA, Ventura SJ, Sutton PD, Menacker F. Births: preliminary data for 2004. Natl Vital Stat Rep. 2005 Dec 29;54(8):1-17.
• Hoyert DL, Mathews TJ, Menacker F, Strobino DM, Guyer B. Annual summary of vital statistics: 2004. Pediatrics. 2006 Jan;117(1):168-83. Erratum in: Pediatrics. 2006 Jun;117(6):2338.
• Kramer MS, Demissie K, Yang H, Platt RW, Sauvé R, Liston R. The contribution of mild and moderate preterm birth to infant mortality. Fetal and Infant Health Study Group of the Canadian Perinatal Surveillance System. JAMA. 2000 Aug 16;284(7):843-9.
• Laptook A, Jackson GL. Cold stress and hypoglycemia in the late preterm ("near-term") infant: impact on nursery of admission. Semin Perinatol. 2006 Feb;30(1):24-7.
• Linnet KM, Wisborg K, Agerbo E, Secher NJ, Thomsen PH, Henriksen TB. Gestational age, birth weight, and the risk of hyperkinetic disorder. Arch Dis Child. 2006 Aug;91(8):655-60. Epub 2006 Jun 5.
• McIntire DD, Leveno KJ. Neonatal mortality and morbidity rates in late preterm births compared with births at term. Obstet Gynecol. 2008 Jan;111(1):35-41. doi: 10.1097/01.AOG.0000297311.33046.73.
• Moster D, Lie RT, Markestad T. Long-term medical and social consequences of preterm birth. N Engl J Med. 2008 Jul 17;359(3):262-73. doi: 10.1056/NEJMoa0706475.
• Neu J. Gastrointestinal maturation and feeding. Semin Perinatol. 2006 Apr;30(2):77-80. Review.
• Raju TN, Higgins RD, Stark AR, Leveno KJ. Optimizing care and outcome for late-preterm (near-term) infants: a summary of the workshop sponsored by the National Institute of Child Health and Human Development. Pediatrics. 2006 Sep;118(3):1207-14.
• Rubaltelli FF, Dani C, Reali MF, Bertini G, Wiechmann L, Tangucci M, Spagnolo A. Acute neonatal respiratory distress in Italy: a one-year prospective study. Italian Group of Neonatal Pneumology. Acta Paediatr. 1998 Dec;87(12):1261-8.
• Shapiro-Mendoza CK, Tomashek KM, Kotelchuck M, Barfield W, Weiss J, Evans S. Risk factors for neonatal morbidity and mortality among "healthy," late preterm newborns. Semin Perinatol. 2006 Apr;30(2):54-60.
• Stutchfield P, Whitaker R, Russell I; Antenatal Steroids for Term Elective Caesarean Section (ASTECS) Research Team. Antenatal betamethasone and incidence of neonatal respiratory distress after elective caesarean section: pragmatic randomised trial. BMJ. 2005 Sep 24;331(7518):662. Epub 2005 Aug 22.
• Tita AT, Landon MB, Spong CY, Lai Y, Leveno KJ, Varner MW, Moawad AH, Caritis SN, Meis PJ, Wapner RJ, Sorokin Y, Miodovnik M, Carpenter M, Peaceman AM, O'Sullivan MJ, Sibai BM, Langer O, Thorp JM, Ramin SM, Mercer BM; Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine Units Network. Timing of elective repeat cesarean delivery at term and neonatal outcomes. N Engl J Med. 2009 Jan 8;360(2):111-20. doi: 10.1056/NEJMoa0803267.
• Tomashek KM, Shapiro-Mendoza CK, Weiss J, Kotelchuck M, Barfield W, Evans S, Naninni A, Declercq E. Early discharge among late preterm and term newborns and risk of neonatal morbidity. Semin Perinatol. 2006 Apr;30(2):61-8.
• Wang ML, Dorer DJ, Fleming MP, Catlin EA. Clinical outcomes of near-term infants. Pediatrics. 2004 Aug;114(2):372-6.
• Yoder BA, Gordon MC, Barth WH Jr. Late-preterm birth: does the changing obstetric paradigm alter the epidemiology of respiratory complications? Obstet Gynecol. 2008 Apr;111(4):814-22. doi: 10.1097/AOG.0b013e31816499f4.

• Responsible Party: The George Washington University Biostatistics Center
• ClinicalTrials.gov Identifier: NCT01222247
• Other Study ID Numbers: HL98354-HD36801-ALPS; U10HD021410; U10HD027869; U10HD027917; U10HD053118; U10HD027915; U10HD034116; U10HD034208; U10HD053097; U10HD040500; U10HD040485; U10HD040544; U10HD040545; U10HD040560; U10HD040512; U10HD036801; U01HL098354; U01HL098554; U10HD068268; U10HD068258; U10HD068282
• First Posted: Oct 18, 2010
• Last Update Posted: Jul 6, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by The George Washington University Biostatistics Center: Betamethasone; Steroids; Perinatology; Late Preterm
• Additional relevant MeSH terms: Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Premature Birth; Betamethasone

Study Results

Participant Flow

Recruitment Details	Participants were recruited from October 2010 to February 2015 at 17 university-based clinical centers. Women with a singleton pregnancy at 34 weeks 0 days to 36 weeks 5 days of gestation and a high probability of delivery in the late preterm period were eligible to be enrolled.

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Period Title: Overall Study
STARTED	1429	1402
Received 2 Doses	860	826
Received 1 Dose	568	571
Did Not Receive Assigned Medication	1	5
COMPLETED	1427	1400
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	Betamethasone	Placebo	Total
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart Betamethasone: The active study drug, betamethasone. 3 mg per ml betamethasone sodium phosphate 3 mg per milliliter betamethasone acetate The first dose of study drug medication will be administered at randomization as 2 ml injection; the next dose of 2 ml will be administered 24 hours later.	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.	Total of all reporting groups
Overall Participants	1429	1402	2831
Age, Customized (years) [Mean (Standard Deviation) ]
Mean maternal age	28.6 (6.3)	27.8 (6.1)	28.2 (6.2)
Sex: Female, Male (Count of Participants)
Female	1429 100%	1402 100%	2831 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
Black	376 26.3%	381 27.2%	757 26.7%
White	828 57.9%	800 57.1%	1628 57.5%
Hispanic	168 11.8%	182 13%	350 12.4%
Other, unknown, more than one race	57 4%	39 2.8%	96 3.4%
Region of Enrollment (participants) [Number]
United States	1429 100%	1402 100%	2831 100%
Indication for trial entry (Count of Participants)
Preterm labor with intact membranes	400 28%	392 28%	792 28%
Ruptured membranes	316 22.1%	304 21.7%	620 21.9%
Exp delivery for gestational HTN or preeclampsia	370 25.9%	385 27.5%	755 26.7%
Expected delivery for fetal growth restriction	46 3.2%	48 3.4%	94 3.3%
Expected delivery for oligohydramnios	50 3.5%	42 3%	92 3.2%
Expected delivery for other indication	247 17.3%	231 16.5%	478 16.9%
Gestational age at trial entry (Count of Participants)
≤34 weeks 6 days	369 25.8%	399 28.5%	768 27.1%
35 weeks 0 days to 35 weeks 6 days	571 40%	532 37.9%	1103 39%
≥36 weeks 0 days	489 34.2%	471 33.6%	960 33.9%
Smoking during pregnancy (Count of Participants)
Count of Participants [Participants]	204 14.3%	186 13.3%	390 13.8%
Nulliparous (Count of Participants)
Count of Participants [Participants]	457 32%	448 32%	905 32%
Preeclampsia or gestational hypertension (Count of Participants)
Count of Participants [Participants]	433 30.3%	440 31.4%	873 30.8%
Gestational diabetes (Count of Participants)
Count of Participants [Participants]	153 10.7%	153 10.9%	306 10.8%
Major congenital anomaly in infant (Count of Participants)
Count of Participants [Participants]	11 0.8%	21 1.5%	32 1.1%

Outcome Measures

1. Primary Outcome

Title	Neonatal Composite Outcome
Description	Need for respiratory support: Continuous positive airway pressure (CPAP) or humidified high-flow nasal cannula (HHFNC) for greater than or equal to 2 hours or more in the first 72 hours, or fraction of inspired oxygen (FiO2) greater than or equal to 0.30 for 4 hours or more in the first 72 hours, or mechanical ventilation in the first 72 hours, or Extracorporeal membrane oxygenation (ECMO) Stillbirth, or neonatal death less than 72 hours of age
Time Frame	72 hours of life

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Primary Outcome Composite	165 11.5%	202 14.4%
CPAP or high-flow cannula ≥2 continuous hrs	145 10.1%	184 13.1%
Fraction of inspired O2 of ≥0.30 for ≥4 cont hrs	48 3.4%	61 4.4%
Mechanical ventilation	34 2.4%	43 3.1%
Extracorporeal membrane oxygenation (ECMO)	0 0%	0 0%
Stillbirth or neonatal death ≤72 hr after birth	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments	Analysis for Primary Outcome composite
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.66 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments	Analysis for CPAP or high-flow nasal cannula
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.63 to 0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments	Analysis for Fraction of inspired oxygen
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.17
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.53 to 1.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments	Analysis for mechanical ventilation
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.26
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; 0.50 to 1.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Neonates With Severe Respiratory Complication,
Description	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.
Time Frame	72 hours of life

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Severe Respiratory Complication Composite	114 8%	169 12.1%
CPAP or high-flow cannula ≥12 continuous hrs	93 6.5%	147 10.5%
Fraction of inspired 02 of ≥0.30 for ≥24 cont hrs	20 1.4%	34 2.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.53 to 0.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Neonates Needing Immediate Resuscitation After Birth
Description	Need for resuscitation after birth: any intervention in the first 30 minutes other than blow-by oxygen
Time Frame	Within the first 30 minutes of birth

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1422	1390
Count of Participants [Participants]	206 14.4%	260 18.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; 0.66 to 0.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Number of Neonates With Respiratory Distress Syndrome
Description	Respiratory distress defined as the presence of clinical signs of respiratory distress (tachypnea, retractions, flaring, grunting, or cyanosis) with an oxygen requirement and a chest x-ray that shows hypoaeration and reticulogranular infiltrates
Time Frame	Delivery

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Count of Participants [Participants]	79 5.5%	89 6.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.36
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.65 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Number of Neonates With Transient Tachypnea of the Newborn
Description	TTN is defined as signs of respiratory distress, specifically tachypnea, that are resolved by 72 hours of age. TTN may be diagnosed in the absence of a chest X-ray or with a chest X-ray that is normal or shows signs of increased perihilar interstitial markings
Time Frame	by 72 hours after delivery

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Count of Participants [Participants]	95 6.6%	138 9.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95%; 0.53 to 0.87
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Number of Infants With Neonatal Apnea
Description	Neonatal apnea with respiratory pauses of more than 20 seconds duration resulting in bradycardia or oxygen desaturation below baseline.
Time Frame	72 hours of life

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Count of Participants [Participants]	33 2.3%	37 2.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.57
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95%; 0.55 to 1.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Number of Infants withChronic Lung Disease / Bronchopulmonary Dysplasia (BPD) Requiring Supplemental Oxygen
Description	Infants requiring supplemental oxygen of more than 0.21 for the first 28 days of life
Time Frame	28 days of life

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Count of Participants [Participants]	2 0.1%	9 0.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.22
	Confidence Interval	(2-Sided) 95%; 0.02 to 0.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Neonates With Pneumonia
Description	Neonatal pneumonia
Time Frame	by 72 hours of life

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Count of Participants [Participants]	6 0.4%	13 0.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.10
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.45
	Confidence Interval	(2-Sided) 95%; 0.17 to 1.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Number of Neonates Needing Surfactant Administration
Description	Administration of surfactant for neonatal respiratory treatment
Time Frame	Delivery

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Count of Participants [Participants]	26 1.8%	43 3.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 95%; 0.37 to 0.96
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Neonatal Outcome Composite
Description	Transient tachypnea of the newborn (TTN), respiratory distress syndrome (RDS), and apnea
Time Frame	72 hours of life

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Count of Participants [Participants]	198 13.9%	249 17.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; 0.66 to 0.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Number of Neonates With Pulmonary Air Leak
Description	Neonatal pulmonary air leak syndrome
Time Frame	72 hours post delivery

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Count of Participants [Participants]	5 0.3%	6 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.74
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.25 to 2.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Neonatal Death After 72 Hours of Delivery
Description	Neonatal death after 72 hours of life but before hospital discharge.
Time Frame	72 hours after delivery through hospital discharge up to 3 weeks

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Count of Participants [Participants]	2 0.1%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.50
	Comments
	Method	Chi-squared
	Comments

13. Secondary Outcome

Title	Birth Weight
Description	Weight in grams at delivery
Time Frame	Delivery

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Mean (Standard Deviation) [grams]	2637 (480)	2654 (484)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.32
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

14. Secondary Outcome

Title	Birth Weight Less Than 10th Percentile
Description	Neonates whose birth weight is less than the 10th percentile at delivery
Time Frame	Delivery

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Count of Participants [Participants]	255 17.8%	220 15.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.13
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.96 to 1.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Gestational Age at Delivery
Description	Number of neonates delivered at ≤ 34 weeks 6 days, between 35 weeks 0 days and 35 weeks 6 days, between 36 weeks 0 days and 36 weeks 6 days, between 37 weeks 0 days and 38 weeks 6 days, or on or after 39 weeks 0 days
Time Frame	Delivery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
≤34 weeks 6 days	193 13.5%	213 15.2%
35 weeks 0 days to 35 weeks 6 days	394 27.6%	386 27.5%
36 weeks 0 days to 36 weeks 6 days	609 42.6%	568 40.5%
37 weeks 0 days to 38 weeks 6 days	202 14.1%	185 13.2%
≥39 weeks 0 days	29 2%	48 3.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.10
	Comments
	Method	Chi-squared
	Comments

16. Secondary Outcome

Title	Number of Neonates With Necrotizing Enterocolitic (NEC)
Description	Defined as modified Bell Stage 2 or 3. Stage 2: Clinical signs and symptoms with pneumatosis intestinalis on radiographs. Stage 3: Advanced clinical signs and symptoms, pneumatosis, impending or proven intestinal perforation.
Time Frame	Delivery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Count of Participants [Participants]	0 0%	1 0.1%

17. Secondary Outcome

Title	Number of Infants With Neonatal Sepsis
Description	Clinical suspicion of systemic infection with a positive blood, cerebral spinal fluid, or catheterized/suprapubic urine culture; or, in the absence of positive cultures, clinical evience of cardiovascular collapse or an X-ray confirming infection.
Time Frame	Delivery

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Count of Participants [Participants]	9 0.6%	11 0.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.62
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.33 to 1.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Secondary Outcome

Title	Number of Neonates With Intraventricular Hemorrhage
Description	Grade 3 or 4 Intraventricular Hemorrhage
Time Frame	Delivery

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Count of Participants [Participants]	2 0.1%	0 0%

19. Secondary Outcome

Title	Neonatal Morbidity Composite
Description	A composite endpoint of morbidities known to be affected by steroid administration will also be evaluated. Specifically, this composite will include RDS, intraventricular hemorrhage (IVH), and NEC
Time Frame	Delivery

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Count of Participants [Participants]	81 5.7%	90 6.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.40
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

20. Secondary Outcome

Title	Number of Neonates With Hypoglycemia
Description	Glucose < 40 mg per deciliter (2.2 mmol per liter) at any time
Time Frame	Delivery through hospital discharge up to 3 weeks

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Count of Participants [Participants]	343 24%	210 15%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.60
	Confidence Interval	(2-Sided) 95%; 1.37 to 1.87
	Parameter Dispersion	Type: Value:
	Estimation Comments

21. Secondary Outcome

Title	Time Until First Neonatal Feeding
Description	Median length of time from delivery until the first neonatal feeding
Time Frame	Delivery to 36 hours post delivery

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Median (Inter-Quartile Range) [hours]	5.5	9.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

22. Secondary Outcome

Title	Neonatal Feeding Difficulty
Description	Inability of the neonate to take all feeds (po), i.e. requiring gavage feeds or IV supplementation.
Time Frame	Delivery to 36 hours post delivery

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Count of Participants [Participants]	211 14.8%	223 15.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.40
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.78 to 1.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

23. Secondary Outcome

Title	Neonatal Hyperbilirubinemia
Description	Peak total bilirubin of at least 15 mg% or the use of phototherapy.
Time Frame	Delivery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Count of Participants [Participants]	167 11.7%	140 10%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.15
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.17
	Confidence Interval	(2-Sided) 95%; 0.95 to 1.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

24. Secondary Outcome

Title	Number of Neonates With Hypothermia
Description	Rectal temperature < 36 C at any time
Time Frame	Delivery through discharge up to 3 weeks

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Count of Participants [Participants]	132 9.2%	112 8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.24
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.16
	Confidence Interval	(2-Sided) 95%; 0.91 to 1.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

25. Secondary Outcome

Title	Length of NICU or Nursery Stay
Description	Includes need for NICU or intermediate care admission and length of stay if admitted. For analysis purposes, death before discharge is assigned maximum rank
Time Frame	Delivery through hospital discharge up to 3 weeks

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
NICU stay of any duration	596 41.7%	629 44.9%
NICU stay of ≥3 days	470 32.9%	518 36.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments	Analysis for NICU stay of any duration
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.09
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.85 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments	Analysis for duration greater than or equal to 3 days
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.80 to 0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

26. Secondary Outcome

Title	Median Length of Hospital Stay
Description	Median length of maternal hospital stay following delivery
Time Frame	Duration of hospital stay following delivery up to 2 weeks

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Median (Inter-Quartile Range) [days]	7	8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.20
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

27. Secondary Outcome

Title	Maternal Outcomes (Participant-based)
Description	Chorioamnionitis: clinical diagnosis and a body temperature of at least 100.4 degrees F., Endometritis: persistent postpartum temperature greater than 100.4 degrees F with uterine tenderness, cesarean delivery
Time Frame	Labor and delivery through 72 hours post partum

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Chorioamnionitis	20 1.4%	32 2.3%
Postpartum Endometritis	16 1.1%	16 1.1%
Cesarean Delivery	454 31.8%	431 30.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments	Statistical analysis for chorioamnionitis
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.08
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95%; 0.35 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments	Analysis for Postpartum Endometritis
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.96
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.49 to 1.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments	Statistical analysis for cesarean delivery
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.56
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; 0.93 to 1.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

28. Secondary Outcome

Title	Hours From Randomization to Delivery
Description	Median interval of hours from randomization to delivery
Time Frame	Randomization through delivery

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Median (Inter-Quartile Range) [Hours]	33.0	30.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments	Analysis for interval from randomization to delivery
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.57
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

29. Secondary Outcome

Title	Median Length of Maternal Hospital Stay
Description	Median length of maternal hospital stay in days
Time Frame	Delivery through hospital discharge

Outcome Measure Data

Analysis Population Description

The number of participants analyzed accounts for the 4 participants for which baseline measures were obtained but who were subsequently lost to follow-up (2 in each group).

Arm/Group Title	Betamethasone	Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart	A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Measure Participants	1427	1400
Median (Inter-Quartile Range) [days]	3	3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betamethasone, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	Adverse events were collected from the time of randomization into the study through 72 hours after delivery.
Adverse Event Reporting Description	Adverse events were documented by research nurse coordinators and principal investigators on standardized study protocol forms and reported to the study sponsor. Non-serious adverse events are reported for patients who received 1 or 2 doses of drug or placebo. Not all participants who were randomized received a study injection.
Arm/Group Title	Betamethasone		Placebo
Arm/Group Description	A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart		A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart Placebo: Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
All Cause Mortality
	Betamethasone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/1429 (0.1%)		0/1402 (0%)
Serious Adverse Events
	Betamethasone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/1429 (0.9%)		12/1402 (0.9%)
Blood and lymphatic system disorders
Neonatal Thrombocytopenia	1/1429 (0.1%)		0/1402 (0%)
Cardiac disorders
Aortic dissection type 1	0/1429 (0%)		1/1402 (0.1%)
Cardiomyopathy	0/1429 (0%)		2/1402 (0.1%)
Gastrointestinal disorders
Obstructed bowel	1/1429 (0.1%)		0/1402 (0%)
General disorders
Neonatal death	2/1429 (0.1%)		0/1402 (0%)
Musculoskeletal and connective tissue disorders
Lumbar plexus stretch injury	0/1429 (0%)		1/1402 (0.1%)
Pregnancy, puerperium and perinatal conditions
Postpartum Hemorrhage	7/1429 (0.5%)		5/1402 (0.4%)
Seizure	1/1429 (0.1%)		1/1402 (0.1%)
Uterine rupture	0/1429 (0%)		1/1402 (0.1%)
Delayed pre-eclampsia	1/1429 (0.1%)		0/1402 (0%)
Vascular disorders
Hypotension	0/1429 (0%)		1/1402 (0.1%)
Other (Not Including Serious) Adverse Events
	Betamethasone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	223/1428 (15.6%)		352/1397 (25.2%)
Skin and subcutaneous tissue disorders
Skin reaction at injecton site	223/1428 (15.6%)	223	352/1397 (25.2%)	352

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.