Pregnancy, Pregnancy Outcomes, Preterm Birth, Respiratory Distress Syndrome
Conditions
Keywords
Betamethasone, Steroids, Perinatology, Late Preterm
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
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.
Interventions
DRUGBetamethasone
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.
DRUGPlacebo
Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
The George Washington University Biostatistics Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
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: A. 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 8. Participation in another interventional study that influences neonatal morbidity and mortality 9. Participation in this trial in a previous pregnancy 10. Delivery at a non-network hospital 11. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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 |
| 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. |
| 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 |
| Neonates With Pneumonia | by 72 hours of life | Neonatal pneumonia |
| Number of Neonates Needing Surfactant Administration | Delivery | Administration of surfactant for neonatal respiratory treatment |
| Neonatal Outcome Composite | 72 hours of life | Transient tachypnea of the newborn (TTN), respiratory distress syndrome (RDS), and apnea |
| Number of Neonates With Pulmonary Air Leak | 72 hours post delivery | Neonatal pulmonary air leak syndrome |
| 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. |
| Birth Weight | Delivery | Weight in grams at delivery |
| Birth Weight Less Than 10th Percentile | Delivery | Neonates whose birth weight is less than the 10th percentile at delivery |
| 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 |
| 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. |
| 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. |
| Number of Neonates With Intraventricular Hemorrhage | Delivery | Grade 3 or 4 Intraventricular Hemorrhage |
| 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 |
| 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 |
| Time Until First Neonatal Feeding | Delivery to 36 hours post delivery | Median length of time from delivery until the first neonatal feeding |
| 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. |
| Neonatal Hyperbilirubinemia | Delivery | Peak total bilirubin of at least 15 mg% or the use of phototherapy. |
| Number of Neonates With Hypothermia | Delivery through discharge up to 3 weeks | Rectal temperature \< 36 C at any time |
| 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 |
| Median Length of Hospital Stay | Duration of hospital stay following delivery up to 2 weeks | Median length of maternal hospital stay following delivery |
| 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 |
| Hours From Randomization to Delivery | Randomization through delivery | Median interval of hours from randomization to delivery |
| Median Length of Maternal Hospital Stay | Delivery through hospital discharge | Median length of maternal hospital stay in days |
| 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. |
Countries
United States
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.
Participants by arm
| Arm | Count |
|---|---|
| Betamethasone 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. | 1,429 |
| Placebo 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. | 1,402 |
| Total | 2,831 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 2 |
Baseline characteristics
| Characteristic | Betamethasone | Placebo | Total |
|---|---|---|---|
| Age, Customized Mean maternal age | 28.6 years STANDARD_DEVIATION 6.3 | 27.8 years STANDARD_DEVIATION 6.1 | 28.2 years STANDARD_DEVIATION 6.2 |
| Gestational age at trial entry ≤34 weeks 6 days | 369 Participants | 399 Participants | 768 Participants |
| Gestational age at trial entry 35 weeks 0 days to 35 weeks 6 days | 571 Participants | 532 Participants | 1103 Participants |
| Gestational age at trial entry ≥36 weeks 0 days | 489 Participants | 471 Participants | 960 Participants |
| Gestational diabetes | 153 Participants | 153 Participants | 306 Participants |
| Indication for trial entry Exp delivery for gestational HTN or preeclampsia | 370 Participants | 385 Participants | 755 Participants |
| Indication for trial entry Expected delivery for fetal growth restriction | 46 Participants | 48 Participants | 94 Participants |
| Indication for trial entry Expected delivery for oligohydramnios | 50 Participants | 42 Participants | 92 Participants |
| Indication for trial entry Expected delivery for other indication | 247 Participants | 231 Participants | 478 Participants |
| Indication for trial entry Preterm labor with intact membranes | 400 Participants | 392 Participants | 792 Participants |
| Indication for trial entry Ruptured membranes | 316 Participants | 304 Participants | 620 Participants |
| Major congenital anomaly in infant | 11 Participants | 21 Participants | 32 Participants |
| Nulliparous | 457 Participants | 448 Participants | 905 Participants |
| Preeclampsia or gestational hypertension | 433 Participants | 440 Participants | 873 Participants |
| Race/Ethnicity, Customized Black | 376 Participants | 381 Participants | 757 Participants |
| Race/Ethnicity, Customized Hispanic | 168 Participants | 182 Participants | 350 Participants |
| Race/Ethnicity, Customized Other, unknown, more than one race | 57 Participants | 39 Participants | 96 Participants |
| Race/Ethnicity, Customized White | 828 Participants | 800 Participants | 1628 Participants |
| Region of Enrollment United States | 1429 participants | 1402 participants | 2831 participants |
| Sex: Female, Male Female | 1429 Participants | 1402 Participants | 2831 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Smoking during pregnancy | 204 Participants | 186 Participants | 390 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 1,429 | 0 / 1,402 |
| other Total, other adverse events | 223 / 1,428 | 352 / 1,397 |
| serious Total, serious adverse events | 13 / 1,429 | 12 / 1,402 |
Outcome results
Primary
Neonatal Composite Outcome
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
Population: 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 | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Betamethasone | Neonatal Composite Outcome | Extracorporeal membrane oxygenation (ECMO) | 0 Participants |
| Betamethasone | Neonatal Composite Outcome | Stillbirth or neonatal death ≤72 hr after birth | 0 Participants |
| Betamethasone | Neonatal Composite Outcome | Primary Outcome Composite | 165 Participants |
| Betamethasone | Neonatal Composite Outcome | CPAP or high-flow cannula ≥2 continuous hrs | 145 Participants |
| Betamethasone | Neonatal Composite Outcome | Fraction of inspired O2 of ≥0.30 for ≥4 cont hrs | 48 Participants |
| Betamethasone | Neonatal Composite Outcome | Mechanical ventilation | 34 Participants |
| Placebo | Neonatal Composite Outcome | Fraction of inspired O2 of ≥0.30 for ≥4 cont hrs | 61 Participants |
| Placebo | Neonatal Composite Outcome | Extracorporeal membrane oxygenation (ECMO) | 0 Participants |
| Placebo | Neonatal Composite Outcome | CPAP or high-flow cannula ≥2 continuous hrs | 184 Participants |
| Placebo | Neonatal Composite Outcome | Stillbirth or neonatal death ≤72 hr after birth | 0 Participants |
| Placebo | Neonatal Composite Outcome | Mechanical ventilation | 43 Participants |
| Placebo | Neonatal Composite Outcome | Primary Outcome Composite | 202 Participants |
Comparison: Analysis for Primary Outcome compositep-value: 0.0295% CI: [0.66, 0.97]Chi-squared
Comparison: Analysis for CPAP or high-flow nasal cannulap-value: 0.0195% CI: [0.63, 0.95]Chi-squared
Comparison: Analysis for Fraction of inspired oxygenp-value: 0.1795% CI: [0.53, 1.12]Chi-squared
Comparison: Analysis for mechanical ventilationp-value: 0.2695% CI: [0.5, 1.21]Chi-squared
Secondary
Birth Weight
Weight in grams at delivery
Time frame: Delivery
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Betamethasone | Birth Weight | 2637 grams | Standard Deviation 480 |
| Placebo | Birth Weight | 2654 grams | Standard Deviation 484 |
p-value: 0.32Wilcoxon (Mann-Whitney)
Secondary
Birth Weight Less Than 10th Percentile
Neonates whose birth weight is less than the 10th percentile at delivery
Time frame: Delivery
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Betamethasone | Birth Weight Less Than 10th Percentile | 255 Participants |
| Placebo | Birth Weight Less Than 10th Percentile | 220 Participants |
p-value: 0.1395% CI: [0.96, 1.34]Chi-squared
Secondary
Gestational Age at 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
Time frame: Delivery
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Betamethasone | Gestational Age at Delivery | 35 weeks 0 days to 35 weeks 6 days | 394 Participants |
| Betamethasone | Gestational Age at Delivery | 36 weeks 0 days to 36 weeks 6 days | 609 Participants |
| Betamethasone | Gestational Age at Delivery | ≥39 weeks 0 days | 29 Participants |
| Betamethasone | Gestational Age at Delivery | 37 weeks 0 days to 38 weeks 6 days | 202 Participants |
| Betamethasone | Gestational Age at Delivery | ≤34 weeks 6 days | 193 Participants |
| Placebo | Gestational Age at Delivery | 37 weeks 0 days to 38 weeks 6 days | 185 Participants |
| Placebo | Gestational Age at Delivery | ≤34 weeks 6 days | 213 Participants |
| Placebo | Gestational Age at Delivery | 35 weeks 0 days to 35 weeks 6 days | 386 Participants |
| Placebo | Gestational Age at Delivery | ≥39 weeks 0 days | 48 Participants |
| Placebo | Gestational Age at Delivery | 36 weeks 0 days to 36 weeks 6 days | 568 Participants |
p-value: 0.1Chi-squared
Secondary
Hours From Randomization to Delivery
Median interval of hours from randomization to delivery
Time frame: Randomization through delivery
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Betamethasone | Hours From Randomization to Delivery | 33.0 Hours |
| Placebo | Hours From Randomization to Delivery | 30.6 Hours |
Comparison: Analysis for interval from randomization to deliveryp-value: 0.57Wilcoxon (Mann-Whitney)
Secondary
Length of NICU or Nursery Stay
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
Population: 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 | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Betamethasone | Length of NICU or Nursery Stay | NICU stay of any duration | 596 Participants |
| Betamethasone | Length of NICU or Nursery Stay | NICU stay of ≥3 days | 470 Participants |
| Placebo | Length of NICU or Nursery Stay | NICU stay of any duration | 629 Participants |
| Placebo | Length of NICU or Nursery Stay | NICU stay of ≥3 days | 518 Participants |
Comparison: Analysis for NICU stay of any durationp-value: 0.0995% CI: [0.85, 1.01]Chi-squared
Comparison: Analysis for duration greater than or equal to 3 daysp-value: 0.0395% CI: [0.8, 0.98]Chi-squared
Secondary
Maternal Outcomes (Participant-based)
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
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Betamethasone | Maternal Outcomes (Participant-based) | Chorioamnionitis | 20 Participants |
| Betamethasone | Maternal Outcomes (Participant-based) | Postpartum Endometritis | 16 Participants |
| Betamethasone | Maternal Outcomes (Participant-based) | Cesarean Delivery | 454 Participants |
| Placebo | Maternal Outcomes (Participant-based) | Chorioamnionitis | 32 Participants |
| Placebo | Maternal Outcomes (Participant-based) | Postpartum Endometritis | 16 Participants |
| Placebo | Maternal Outcomes (Participant-based) | Cesarean Delivery | 431 Participants |
Comparison: Statistical analysis for chorioamnionitisp-value: 0.0895% CI: [0.35, 1.07]Chi-squared
Comparison: Analysis for Postpartum Endometritisp-value: 0.9695% CI: [0.49, 1.95]Chi-squared
Comparison: Statistical analysis for cesarean deliveryp-value: 0.5695% CI: [0.93, 1.15]Chi-squared
Secondary
Median Length of Hospital Stay
Median length of maternal hospital stay following delivery
Time frame: Duration of hospital stay following delivery up to 2 weeks
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Betamethasone | Median Length of Hospital Stay | 7 days |
| Placebo | Median Length of Hospital Stay | 8 days |
p-value: 0.2Wilcoxon (Mann-Whitney)
Secondary
Median Length of Maternal Hospital Stay
Median length of maternal hospital stay in days
Time frame: Delivery through hospital discharge
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Betamethasone | Median Length of Maternal Hospital Stay | 3 days |
| Placebo | Median Length of Maternal Hospital Stay | 3 days |
p-value: 0.11Wilcoxon (Mann-Whitney)
Secondary
Neonatal Death After 72 Hours of Delivery
Neonatal death after 72 hours of life but before hospital discharge.
Time frame: 72 hours after delivery through hospital discharge up to 3 weeks
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Betamethasone | Neonatal Death After 72 Hours of Delivery | 2 Participants |
| Placebo | Neonatal Death After 72 Hours of Delivery | 0 Participants |
p-value: 0.5Chi-squared
Secondary
Neonatal Feeding Difficulty
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
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Betamethasone | Neonatal Feeding Difficulty | 211 Participants |
| Placebo | Neonatal Feeding Difficulty | 223 Participants |
p-value: 0.495% CI: [0.78, 1.1]Chi-squared
Secondary
Neonatal Hyperbilirubinemia
Peak total bilirubin of at least 15 mg% or the use of phototherapy.
Time frame: Delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Betamethasone | Neonatal Hyperbilirubinemia | 167 Participants |
| Placebo | Neonatal Hyperbilirubinemia | 140 Participants |
p-value: 0.1595% CI: [0.95, 1.4]Chi-squared
Secondary
Neonatal Morbidity Composite
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
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Betamethasone | Neonatal Morbidity Composite | 81 Participants |
| Placebo | Neonatal Morbidity Composite | 90 Participants |
p-value: 0.495% CI: [0.66, 1.18]Chi-squared
Secondary
Neonatal Outcome Composite
Transient tachypnea of the newborn (TTN), respiratory distress syndrome (RDS), and apnea
Time frame: 72 hours of life
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Betamethasone | Neonatal Outcome Composite | 198 Participants |
| Placebo | Neonatal Outcome Composite | 249 Participants |
p-value: 0.00495% CI: [0.66, 0.93]Chi-squared
Secondary
Neonates Needing Immediate Resuscitation After Birth
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Betamethasone | Neonates Needing Immediate Resuscitation After Birth | 206 Participants |
| Placebo | Neonates Needing Immediate Resuscitation After Birth | 260 Participants |
p-value: 0.00395% CI: [0.66, 0.92]Chi-squared
Secondary
Neonates With Pneumonia
Neonatal pneumonia
Time frame: by 72 hours of life
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Betamethasone | Neonates With Pneumonia | 6 Participants |
| Placebo | Neonates With Pneumonia | 13 Participants |
p-value: 0.195% CI: [0.17, 1.19]Chi-squared
Secondary
Number of Infants withChronic Lung Disease / Bronchopulmonary Dysplasia (BPD) Requiring Supplemental Oxygen
Infants requiring supplemental oxygen of more than 0.21 for the first 28 days of life
Time frame: 28 days of life
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Betamethasone | Number of Infants withChronic Lung Disease / Bronchopulmonary Dysplasia (BPD) Requiring Supplemental Oxygen | 2 Participants |
| Placebo | Number of Infants withChronic Lung Disease / Bronchopulmonary Dysplasia (BPD) Requiring Supplemental Oxygen | 9 Participants |
p-value: 0.0495% CI: [0.02, 0.92]Chi-squared
Secondary
Number of Infants With Neonatal Apnea
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
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Betamethasone | Number of Infants With Neonatal Apnea | 33 Participants |
| Placebo | Number of Infants With Neonatal Apnea | 37 Participants |
p-value: 0.5795% CI: [0.55, 1.39]Chi-squared
Secondary
Number of Infants With Neonatal Sepsis
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
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Betamethasone | Number of Infants With Neonatal Sepsis | 9 Participants |
| Placebo | Number of Infants With Neonatal Sepsis | 11 Participants |
p-value: 0.6295% CI: [0.33, 1.93]Chi-squared
Secondary
Number of Neonates Needing Surfactant Administration
Administration of surfactant for neonatal respiratory treatment
Time frame: Delivery
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Betamethasone | Number of Neonates Needing Surfactant Administration | 26 Participants |
| Placebo | Number of Neonates Needing Surfactant Administration | 43 Participants |
p-value: 0.0395% CI: [0.37, 0.96]Chi-squared
Secondary
Number of Neonates With Hypoglycemia
Glucose \< 40 mg per deciliter (2.2 mmol per liter) at any time
Time frame: Delivery through hospital discharge up to 3 weeks
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Betamethasone | Number of Neonates With Hypoglycemia | 343 Participants |
| Placebo | Number of Neonates With Hypoglycemia | 210 Participants |
p-value: <0.00195% CI: [1.37, 1.87]Chi-squared
Secondary
Number of Neonates With Hypothermia
Rectal temperature \< 36 C at any time
Time frame: Delivery through discharge up to 3 weeks
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Betamethasone | Number of Neonates With Hypothermia | 132 Participants |
| Placebo | Number of Neonates With Hypothermia | 112 Participants |
p-value: 0.2495% CI: [0.91, 1.47]Chi-squared
Secondary
Number of Neonates With Intraventricular Hemorrhage
Grade 3 or 4 Intraventricular Hemorrhage
Time frame: Delivery
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Betamethasone | Number of Neonates With Intraventricular Hemorrhage | 2 Participants |
| Placebo | Number of Neonates With Intraventricular Hemorrhage | 0 Participants |
Secondary
Number of Neonates With Necrotizing Enterocolitic (NEC)
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Betamethasone | Number of Neonates With Necrotizing Enterocolitic (NEC) | 0 Participants |
| Placebo | Number of Neonates With Necrotizing Enterocolitic (NEC) | 1 Participants |
Secondary
Number of Neonates With Pulmonary Air Leak
Neonatal pulmonary air leak syndrome
Time frame: 72 hours post delivery
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Betamethasone | Number of Neonates With Pulmonary Air Leak | 5 Participants |
| Placebo | Number of Neonates With Pulmonary Air Leak | 6 Participants |
p-value: 0.7495% CI: [0.25, 2.68]Chi-squared
Secondary
Number of Neonates With Respiratory Distress Syndrome
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
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Betamethasone | Number of Neonates With Respiratory Distress Syndrome | 79 Participants |
| Placebo | Number of Neonates With Respiratory Distress Syndrome | 89 Participants |
p-value: 0.3695% CI: [0.65, 1.17]Chi-squared
Secondary
Number of Neonates With Severe Respiratory Complication,
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
Population: 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 | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Betamethasone | Number of Neonates With Severe Respiratory Complication, | Severe Respiratory Complication Composite | 114 Participants |
| Betamethasone | Number of Neonates With Severe Respiratory Complication, | CPAP or high-flow cannula ≥12 continuous hrs | 93 Participants |
| Betamethasone | Number of Neonates With Severe Respiratory Complication, | Fraction of inspired 02 of ≥0.30 for ≥24 cont hrs | 20 Participants |
| Placebo | Number of Neonates With Severe Respiratory Complication, | Severe Respiratory Complication Composite | 169 Participants |
| Placebo | Number of Neonates With Severe Respiratory Complication, | CPAP or high-flow cannula ≥12 continuous hrs | 147 Participants |
| Placebo | Number of Neonates With Severe Respiratory Complication, | Fraction of inspired 02 of ≥0.30 for ≥24 cont hrs | 34 Participants |
p-value: <0.00195% CI: [0.53, 0.84]Chi-squared
Secondary
Number of Neonates With Transient Tachypnea of the Newborn
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
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Betamethasone | Number of Neonates With Transient Tachypnea of the Newborn | 95 Participants |
| Placebo | Number of Neonates With Transient Tachypnea of the Newborn | 138 Participants |
p-value: 0.00295% CI: [0.53, 0.87]Chi-squared
Secondary
Time Until First Neonatal Feeding
Median length of time from delivery until the first neonatal feeding
Time frame: Delivery to 36 hours post delivery
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Betamethasone | Time Until First Neonatal Feeding | 5.5 hours |
| Placebo | Time Until First Neonatal Feeding | 9.9 hours |
p-value: 0.004Wilcoxon (Mann-Whitney)