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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Pregnancy, Respiratory Distress Syndrome, Pregnancy Outcomes, Preterm Birth

Intervention / Treatment
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* Drug: Betamethasone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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: Any prior antenatal corticosteroid course during the pregnancy because of potential contamination of the placebo group Candidate for stress dose corticosteroids because of chronic steroid therapy to prevent suppression of adrenal gland, because of potential contamination of the placebo group Twin gestation reduced to a singleton gestation at or after 14 weeks 0 days by project gestational age either spontaneously or therapeutically Fetal demise, or known major fetal anomaly, including cardiac anomaly and hydrops 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 Pre-gestational diabetes - exclude if the patient was on medication (insulin, glyburide) prior to pregnancy 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 Participation in another interventional study that influences neonatal morbidity and mortality Participation in this trial in a previous pregnancy Delivery at a non-network hospital 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.
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Betamethasone<br>A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart | Drug: Betamethasone<br>* 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.<br>* Other names: Corticosteroid;|
| Placebo Comparator: Placebo<br>A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart | Drug: Placebo<br>* Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 72 hours of life | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 72 hours of life | 
| Neonates Needing Immediate Resuscitation After Birth | Need for resuscitation after birth: any intervention in the first 30 minutes other than blow-by oxygen | Within the first 30 minutes of birth | 
| 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 | Delivery | 
| 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 | by 72 hours after delivery | 
| 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. | 72 hours of life | 
| 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 | 28 days of life | 
| Neonates With Pneumonia | Neonatal pneumonia | by 72 hours of life | 
| Number of Neonates Needing Surfactant Administration | Administration of surfactant for neonatal respiratory treatment | Delivery | 
| Neonatal Outcome Composite | Transient tachypnea of the newborn (TTN), respiratory distress syndrome (RDS), and apnea | 72 hours of life | 
| Number of Neonates With Pulmonary Air Leak | Neonatal pulmonary air leak syndrome | 72 hours post delivery | 
| Neonatal Death After 72 Hours of Delivery | Neonatal death after 72 hours of life but before hospital discharge. | 72 hours after delivery through hospital discharge up to 3 weeks | 
| Birth Weight | Weight in grams at delivery | Delivery | 
| Birth Weight Less Than 10th Percentile | Neonates whose birth weight is less than the 10th percentile at delivery | Delivery | 
| 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 | Delivery | 
| 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. | Delivery | 
| 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. | Delivery | 
| Number of Neonates With Intraventricular Hemorrhage | Grade 3 or 4 Intraventricular Hemorrhage | Delivery | 
| 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 | Delivery | 
| Number of Neonates With Hypoglycemia | Glucose < 40 mg per deciliter (2.2 mmol per liter) at any time | Delivery through hospital discharge up to 3 weeks | 
| Time Until First Neonatal Feeding | Median length of time from delivery until the first neonatal feeding | Delivery to 36 hours post delivery | 
| Neonatal Feeding Difficulty | Inability of the neonate to take all feeds (po), i.e. requiring gavage feeds or IV supplementation. | Delivery to 36 hours post delivery | 
| Neonatal Hyperbilirubinemia | Peak total bilirubin of at least 15 mg% or the use of phototherapy. | Delivery | 
| Number of Neonates With Hypothermia | Rectal temperature < 36 C at any time | Delivery through discharge up to 3 weeks | 
| 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 | Delivery through hospital discharge up to 3 weeks | 
| Median Length of Hospital Stay | Median length of maternal hospital stay following delivery | Duration of hospital stay following delivery up to 2 weeks | 
| 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 | Labor and delivery through 72 hours post partum | 
| Hours From Randomization to Delivery | Median interval of hours from randomization to delivery | Randomization through delivery | 
| Median Length of Maternal Hospital Stay | Median length of maternal hospital stay in days | Delivery through hospital discharge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Betamethasone, Steroids, Perinatology, Late Preterm