Complication of Prematurity, Obstetric Labor, Premature, Pregnancy Complications, Premature Birth, Preterm Birth
Conditions
Keywords
Premature birth, Preterm birth, Obstetric labour, Betamethasone, Betamethasone Valerate, Betamethasone-17,21-dipropionate, Betamethasone benzoate, Betamethasone sodium phosphate, Anti-Inflammatory Agents, Glucocorticoids, Hormones, Hormones, Hormone Substitutes and Hormone Antagonists, Physiological Effect of Drugs, Anti-Asthmatic Agents, Respiratory System Agents
Brief summary
Antenatal corticosteroids (ACS) reduce the risks of neonatal death and morbidities in preterm infants, such as respiratory distress syndrome. The standard of care for pregnant people at risk of preterm birth includes 2 doses of Celestone (for a total of 24 mg in Canada, or 22.8 mg in Australia) to accelerate fetal lung maturity. The investigators plan to conduct a randomized controlled trial to determine whether half the usual dose (12 mg in Canada, or 11.4 mg in Australia) of Celestone is non-inferior to the standard double doses.
Detailed description
Preterm infants are at risk of mortality and morbidity. Antenatal corticosteroids (ACS) reduce the risks of neonatal death and morbidities, such as respiratory distress syndrome. The standard of care for pregnant people at risk of preterm birth includes 2 doses of Celestone to accelerate fetal lung maturity (total 24 mg in Canada, 22.8 mg in Australia). There are no published clinical trial data on the benefits or risks of a single dose of antenatal corticosteroid vs. standard double doses (Ninan et al JOGC 2020). Pregnant people at 22 weeks and 0 days to \< 34 weeks and 6 days' gestation at risk of preterm birth with a singleton or twin gestation who have received the first dose of Celestone and consented to the trial will be randomized to receive approximately 24 hours later either an experimental placebo injection (of normal saline) or the standard double dose of Celestone to determine whether the intervention is non-inferior for the primary outcome of a composite of perinatal mortality or substantial morbidity. Please note: Based on Health Canada's' guidance the study phase is 'Other: Off-Label use'. However, on the clincaltrial.gov record, 'Phase 4' is selected as this is the most relevant phase and there is no option to select 'Other'. Please note: McMaster University, Canada is the Canadian Regulatory Sponsor and Overall Sponsor, and the University of Adelaide Australia is the Australian Sponsor.
Interventions
DRUGCelestone + placebo
After the first intramuscular injection of Celestone, participants randomized to the Placebo Comparator group will receive 1 intramuscular injection of placebo.
DRUGCelestone + Celestone
After the first intramuscular injection of Celestone, participants randomized to the Active Comparator group will receive 1 intramuscular injection of Celestone.
Sponsors
Hamilton Health Sciences Corporation
Sunnybrook Research Institute
Women's and Children's Hospital, Australia
Canadian Institutes of Health Research (CIHR)
Medical Research Future Fund
University of Adelaide
McMaster University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Multicentre, blinded, pragmatic, 2 arm non-inferiority RCT
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Pregnant people, aged 18 to 55 years old, at risk of preterm birth with a singleton or twins between 22 weeks and 0 days and \<34 weeks and 6 days gestation who have received only a single dose of Celestone within 24 hours 2. Capable of giving informed, written consent.
Exclusion criteria
1. Contraindication to corticosteroids 2. Systemic corticosteroids for medical conditions during the pregnancy (e.g. lupus, severe asthma, Covid, etc). 3. Previous participation in this trial (in a previous pregnancy) 4. Known severe/life-threatening fetal or pregnant patient condition (e.g. fetal congenital/chromosomal abnormality) 5. Demise of one or more fetuses after 14 weeks and 0 days
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Perinatal Mortality or Substantial Neonatal Morbidity | approximately 1 month | Fetal death post-randomization or in hospital neonatal death OR =\> 1 of respiratory morbidity (requiring surfactant \<=48 hrs of life), severe intraventricular hemorrhage (distending/beyond the ventricles, i.e. Grade 3 or 4), or severe bowel problem (necrotizing enterocolitis, Stage 2 or 3) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Death or neurosensory/developmental impairment at 24 months | approximately 24 months | Death or neurosensory/developmental impairment at 24 months (+/- 6 months; accounting for gestation at birth), mood (anxiety/depression), behavior (aggression), etc as assessed by: 1. Ages and Stages Questionnaire-3 (ASQ) 2. Child Behavior Checklist: 4 subscales 3. Physician diagnosis of cerebral palsy (parent report). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of babies with respiratory distress after the initial resuscitation/stabilization and main cause | approximately 1 month | Number of babies with respiratory distress after the initial resuscitation/stabilization and main cause (such as respiratory distress syndrome, pneumothorax/pneumomediastinum, pneumonia, transient tachypnea of the newborn, meconium aspiration syndrome, persistent pulmonary hypertension of the newborn) |
| Number of babies with Respiratory distress after the initial resuscitation/stabilization and main cause | approximately at birth | Respiratory distress after the initial resuscitation/stabilization and main cause (such as respiratory distress syndrome, pneumothorax/pneumomediastinum, pneumonia, transient tachypnea of the newborn, meconium aspiration syndrome, persistent pulmonary hypertension of the newborn), |
| Number of babies with hypoglycemia | 48 hours | Number of babies with hypoglycemia (low plasma glucose \< 2.6 mmol/L between 30 minutes and 48 hours of life) |
| Number of babies with neonatal sepsis | 7 days | Number of babies with neonatal sepsis within 7 days of birth, defined as a positive (bacterial, viral or fungal): blood culture or cerebrospinal fluid culture (or gram stain) or urine culture by sterile collection. |
| Number of babies with severe retinopathy of prematurity needing treatment | approximately first few months of life | Number of babies with severe retinopathy of prematurity defined as requiring vascular endothelial growth factor (VEGF) or laser or cryotherapy per the local guidelines |
| Number of babies with patent ductus arteriosus (PDA) needing a closure procedure (surgery or device) | up to 12 weeks after birth | Number of babies with patent ductus arteriosus (PDA) needing a closure procedure (surgery or device) |
| Anthropometry at birth and at 24 months corrected age | at birth and at 24 months corrected age | Weight (in grams), length (in centimeters), and head circumference (in centimeters) for birth week as ACS can impact growth |
| Number of babies who received intubation and duration of invasive mechanical ventilation | approximately up to first 6 months of life | Number of babies who received intubation and duration of invasive mechanical ventilation |
| Number of babies with chronic lung disease | approximately up to first 6 months of life | Late respiratory morbidity, bronchopulmonary dysplasia (BPD), defined as requiring respiratory support or supplemental oxygen \> 36 completed weeks' corrected gestation. |
| Apgar score and cord blood pH | approximately at birth | Apgar score (at 1 and 5 min) and lowest cord blood pH, regardless of whether arterial or venous. |
| Length of stay in special care or an intensive care setting | approximately up to first 6 months of life | Length of stay in an intensive care setting such as the neonatal intensive care unit (NICU). |
| Use of postnatal corticosteroids | up to 20 weeks postnatal | Use of systemic (intravenous or oral) postnatal corticosteroids and type (e.g. hydrocortisone, dexamethasone). |
| Number of babies with longterm health care outcomes | approximately 5 -10 years | Number of babies with reported longterm health care outcomes after initial hospital, such as hospitalizations, and other health care use. |
| Number of babies with longterm education outcomes | approximately 5 -10 years | Number of babies with reported longterm education or non-health data outcomes, collected through database linkage where possible. |
| Number of participants with fetal death post-randomization or in hospital neonatal death OR => 1 of respiratory morbidity, severe intraventricular hemorrhage , or severe bowel problem | approximately 1 month | Fetal death post-randomization or in hospital neonatal death OR =\> 1 of respiratory morbidity (requiring surfactant \<=48 hrs of life), severe intraventricular hemorrhage (distending/beyond the ventricles, i.e. Grade 3 or 4), or severe bowel problem (necrotizing enterocolitis, Stage 2 or 3) |
| Number of babies with severe late brain injury | up to 20 weeks postnatal | Periventricular leukomalacia \[PVL\], i.e. cystic changes in white matter or porencephalic cysts or white matter changes diagnosed by ultrasound or MRI. |
| Number of babies who received, and duration of, supplemental oxygen (after resuscitation) and other ventilatory support | approximately up to first 6 months of life | Number of babies who received, and duration of, supplemental oxygen (after resuscitation) and other ventilatory support |
Countries
Canada
Contacts
Primary ContactSarah D McDonald, MD,MSc,FRCSC
Backup ContactSNACS Coordinating Centre
Outcome results
None listed