Antenatal Late Preterm Steroids (ALPS): A Randomized Placebo-Controlled Trial
Overview
- Phase
- Phase 3
- Intervention
- Betamethasone
- Conditions
- Pregnancy
- Sponsor
- The George Washington University Biostatistics Center
- Enrollment
- 2831
- Locations
- 17
- Primary Endpoint
- Neonatal Composite Outcome
- Status
- Completed
- Last Updated
- 3 years ago
Overview
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.
Investigators
Eligibility Criteria
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
- •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
- •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
Arms & Interventions
Betamethasone
A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart
Intervention: Betamethasone
Placebo
A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart
Intervention: Placebo
Outcomes
Primary Outcomes
Neonatal Composite Outcome
Time Frame: 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 Outcomes
- Birth Weight(Delivery)
- Number of Neonates With Severe Respiratory Complication,(72 hours of life)
- Number of Neonates Needing Surfactant Administration(Delivery)
- Number of Neonates With Pulmonary Air Leak(72 hours post delivery)
- Number of Infants With Neonatal Apnea(72 hours of life)
- Neonatal Outcome Composite(72 hours of life)
- Gestational Age at Delivery(Delivery)
- Median Length of Hospital Stay(Duration of hospital stay following delivery up to 2 weeks)
- Maternal Outcomes (Participant-based)(Labor and delivery through 72 hours post partum)
- Neonates Needing Immediate Resuscitation After Birth(Within the first 30 minutes of birth)
- Number of Neonates With Respiratory Distress Syndrome(Delivery)
- Number of Neonates With Transient Tachypnea of the Newborn(by 72 hours after delivery)
- Neonates With Pneumonia(by 72 hours of life)
- Neonatal Death After 72 Hours of Delivery(72 hours after delivery through hospital discharge up to 3 weeks)
- Birth Weight Less Than 10th Percentile(Delivery)
- Number of Neonates With Intraventricular Hemorrhage(Delivery)
- Number of Neonates With Hypothermia(Delivery through discharge up to 3 weeks)
- Length of NICU or Nursery Stay(Delivery through hospital discharge up to 3 weeks)
- Hours From Randomization to Delivery(Randomization through delivery)
- Median Length of Maternal Hospital Stay(Delivery through hospital discharge)
- Number of Infants withChronic Lung Disease / Bronchopulmonary Dysplasia (BPD) Requiring Supplemental Oxygen(28 days of life)
- Number of Neonates With Necrotizing Enterocolitic (NEC)(Delivery)
- Neonatal Feeding Difficulty(Delivery to 36 hours post delivery)
- Neonatal Hyperbilirubinemia(Delivery)
- Number of Infants With Neonatal Sepsis(Delivery)
- Neonatal Morbidity Composite(Delivery)
- Number of Neonates With Hypoglycemia(Delivery through hospital discharge up to 3 weeks)
- Time Until First Neonatal Feeding(Delivery to 36 hours post delivery)