Anemia, Bronchopulmonary Dysplasia (BPD), Infant, Extremely Low Birth Weight, Infant, Newborn, Diseases, Infant, Small for Gestational Age
Conditions
Keywords
NICHD Neonatal Research Network, Very Low Birth Weight (VLBW), Extremely Low Birth Weight (ELBW), Transfusions
Brief summary
The objective of the TOP trial is to determine whether higher hemoglobin thresholds for transfusing ELBW infants resulting in higher hemoglobin levels lead to improvement in the primary outcome of survival and rates of neurodevelopmental impairment (NDI) at 22-26 months of age, using standardized assessments by Bayley.
Detailed description
Long-term outcomes of extremely low birth weight (ELBW) preterm infants, those weighing less than or equal to 1000 g at birth, are poor and pose a major health care burden. Virtually all of these infants are transfused, but at inconsistent hemoglobin (Hgb) thresholds. The investigators propose in TOP to randomize infants less than or equal to 1000 g BW and gestational age at least 22 weeks but less than 29 weeks to receive red blood cell (RBC) transfusions according to one of two strategies of Hgb thresholds, either a high Hgb (liberal transfusion) or a low Hgb (restrictive transfusion) algorithm. It is currently unknown which transfusion strategy is superior. TOP is powered to demonstrate which strategy reduces the primary outcome of death or neurodisability in survivors at 22-26 months. A secondary study entitled Effect of Blood Transfusion Practices on Cerebral and Somatic Oximetry, also known as the NIRS study, will determine differences in cerebral oxygenation and fractional tissue oxygen extraction with NIRS between high and low hemoglobin threshold groups during red blood cell transfusions. The investigators also propose to determine whether abnormal cerebral NIRS measures are a better predictor of NDI than hemoglobin alone and whether abnormal mesenteric NIRS measures are associated with the development of NEC within the 48 hours following a transfusion. A secondary study entitled Economic Evaluation Ancillary to the Transfusion of Prematures Randomized Controlled Trial will determine whether higher transfusion threshold will result in lower total costs to society over the first 22 to 26 corrected months of life and estimate the incremental cost-effectiveness ratio for survival without neurodevelopmental impairment, from the perspective of society, the third-party payer, and the family. Extended follow-up: Subjects will be seen for a follow-up visit at 5-6 years corrected age to assess neurological and functional outcomes at early school age based on neonatal transfusion threshold.
Interventions
PROCEDURELiberal Cell Transfusion
PROCEDURERestricted red cell transfusion
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
NICHD Neonatal Research Network
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 48 Hours
Healthy volunteers
No
Inclusion criteria
* Birth weight less than or equal to 1000 grams. * Gestational age at least 22 weeks but less than 29 weeks * Admitted to the NICU within 48 hours of life
Exclusion criteria
* Considered nonviable by the attending neonatologist * Cyanotic congenital heart disease * Parents opposed to the transfusion of blood * Parents with hemoglobinopathy or congenital anemia * In-utero fetal transfusion * Twin-to-twin transfusion syndrome * Isoimmune hemolytic disease * Lack of parental consent * Severe acute hemorrhage, acute shock, sepsis with coagulopathy, or need for perioperative transfusion. * Prior blood transfusion on clinical grounds beyond the first 6 hours of life * Infant has received erythropoietin prior to randomization, or is intended to receive erythropoietin through the neonatal course * Congenital condition, other than premature birth, that adversely affects life expectancy or neurodevelopment. * High probability that the family is socially disorganized to the point of being unable to attend follow-up at 22-26 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Death or Neurodevelopmental Impairment | Birth to 22-26 months corrected age | A composite outcome that measures the occurrence of death or neurodevelomental impairment between birth and 22-26 months corrected age. |
| Death | Birth to 22-26 months corrected age | This is measured as Yes if an infant died between birth and 22-26 months corrected age; Otherwise, No. |
| Neurodevelopmental Impairment | at 22-26 months corrected age | This is measured as Yes if any hearing impairment or visual impairment is noted, if severe or moderate cerebral palsy is noted, or if the cognitive score of the Bayley III score is more than 1 standard deviation below the average; Otherwise, No. |
| Cognitive Delay | at 22-26 months corrected age | This is measured as Yes if the Bayley Scale of Infant and Toddler Development (BSID)-III cognitive score is more than 1 standard deviation below the average; Otherwise, No. |
| Moderate or Severe Cerebral Palsy | at 22-26 months corrected age | This is measured as Yes if the Gross Motor Function Classification System (GMFCS) score is level II or higher; Otherwise, No. Higher values of the GMFCS are worse than lower values; a level of I denotes mild cerebral palsy (CP); level II or III moderate CP; level IV or V severe CP. |
| Severe Vision Impairment | at 22-26 months corrected age | This is measured as Yes if the corrected visual acuity in the better eye of less than 20/200; Otherwise, No. |
| Severe Hearing Impairment | at 22-26 months corrected age | This is measured as Yes if bilateral hearing loss occurred for which hearing aids or cochlear implants were warranted; Otherwise, No. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Length-for-age: Z-score | at 36 weeks postmenstrual age or initial hospital discharge, whichever occurs first | This is measured as the length-for-age Z-score at 36 weeks postmenstrual age or at initial hospital discharge, whichever occurs first. The Z-score is determined using Olsen percentile curves, and is derived from a normal distribution, where 0 designates average length-for-age, and negative scores denote less than average length-for-age. |
| Head Circumference-for-age: Z-score | at 36 weeks postmenstrual age or initial hospital discharge, whichever occurs first | This is measured as the head circumference-for-age Z-score at 36 weeks postmenstrual age or at initial hospital discharge, whichever occurs first. The Z-score is determined using Olsen percentile curves, and is derived from a normal distribution, where 0 designates average head circumference-for-age, and negative scores denote less than average head circumference-for-age. |
| Postmenstrual Age at Final Trachael Extubation | at final trachael extubation, assessed from birth up to the earliest of: death, hospital discharge, or 36 weeks postmenstrual age | This is measured as the average postmenstrual age (in weeks) at final tracheal extubation in infants who were intubated. |
| Postmenstrual Age at Final Caffeine Dose in Infants Who Received Caffeine Treatment | at final caffeine dose, assessed from birth up to the earliest of: death, hospital discharge, or 36 weeks postmenstrual age | This is measured as the average postmenstrual age (in weeks) at final caffeine dose in infants who received caffeine treatment. |
| Length of Stay | at initial hospital discharge or at death if it occurs earlier (a median of 97 days) | This is measured as the length of stay (in days) up to initial hospital discharge or death, whichever occurred first. |
| Time to Full Enteral Feeding | at first full enteral feeding, assessed from birth up to initial hospital discharge or to death if it occurs earlier (a median of 97 days) | This is measured as the amount of days it took for full enteral feeding to occur. |
| Severe Cerebral Palsy | at 22-26 months corrected age | This is measured as Yes if Gross Motor Function Classification System (GMFCS) is levels IV or V; Otherwise, No. Higher values of the GMFCS are worse than lower values; a level of I denotes mild cerebral palsy (CP); level II or III moderate CP; level IV or V severe CP. |
| Hydrocephalus Shunt | Initial hospital discharge to 22-26 months corrected age | This is measured as Yes if experienced Hydrocephalus shunt by follow-up; Otherwise, No. |
| Survival to Discharge Without Severe Complications | Birth to initial hospital discharge or to death if it occurs earlier (a median of 97 days) | This is measured as Yes if survived to discharge without severe morbidity, defined as bronchopulmonary dysplasia, retinopathy of prematurity (stage 3 or higher or requiring treatment), or serious brain abnormality; Otherwise, No. |
| Seizure Disorder | Initial hospital discharge to 22-26 months corrected age | This is measured as Yes if experienced one or more seizures since discharge or of regular use of anticonvulsants or seizure medications; Otherwise, No. |
| Respiratory Disease Necessitating Readmission Before Follow-up | Initial hospital discharge to 22-26 months corrected age | This is measured as Yes if obtained Respiratory disease necessitating readmission before follow-up; Otherwise, No. |
| Composite Language Score Less Than 85 | at 22-26 months corrected age | This is measured as Yes if scored less than 85 on the Bayley Scale of Infant and Toddler Development (BSID)-III composite language score; Otherwise, No. Higher scores indicate better performance. Composite BSID-III scores of less than 85 are less than 1 standard deviation below the mean of 100. |
| Composite Motor Score Less Than 85 | at 22-26 months corrected age | This is measured as Yes if scored less than 85 on the Bayley Scale of Infant and Toddler Development (BSID)-III composite motor score; Otherwise, No. Higher scores indicate better performance. Composite BSID-III scores of less than 85 are less than 1 standard deviation below the mean of 100. |
| Composite Cognitive Score Less Than 70 | at 22-26 months corrected age | This is measured as Yes if scored less than 85 on the Bayley Scale of Infant and Toddler Development (BSID)-III composite cognitive score; Otherwise, No. Higher scores indicate better performance. Composite BSID-III scores of less than 70 are less than 2 standard deviations below the mean of 100. |
| Composite Language Score Less Than 70 | at 22-26 months corrected age | This is measured as Yes if scored less than 85 on the Bayley Scale of Infant and Toddler Development (BSID)-III composite language score; Otherwise, No. Higher scores indicate better performance. Composite BSID-III scores of less than 70 are less than 2 standard deviations below the mean of 100. |
| Composite Motor Score Less Than 70 | at 22-26 months corrected age | This is measured as Yes if scored less than 85 on the Bayley Scale of Infant and Toddler Development (BSID)-III composite motor score; Otherwise, No. Higher scores indicate better performance. Composite BSID-III scores of less than 70 are less than 2 standard deviations below the mean of 100. |
| Microcephaly | at 22-26 months corrected age | This is measured as a head circumference-for-age Z-score of less than -2; Otherwise, No. The Z-score is determined using WHO percentile curves, and is derived from a normal distribution, where 0 designates average head circumference-for-age, and negative scores denote less than average head circumference-for-age. |
| Bronchopulmonary Dysplasia, Diagnosed on the Basis of the Need for Supplemental Oxygen After a Standardized Oxygen Reduction Test at 36 Weeks of Postmenstrual Age | at 36 weeks postmenstrual age | This is measured as Yes if experienced bronchopulmonary dysplasia, diagnosed on the basis of the need for supplemental oxygen after a standardized oxygen reduction test at 36 weeks of postmenstrual age; Otherwise, No. |
| Retinopathy of Prematurity Stage >=3 or Treatment for That Condition Received | Birth to initial hospital discharge or to death if it occurs earlier (a median of 97 days) | This is measured as Yes if experienced Retinopathy of Prematurity (ROP) Stage \>=3 or received treatment for that condition; Otherwise, No. Higher stages of ROP indicate a worse outcome; the stages range from 1 for mild disease, to 5 for severe disease. |
| Grade 3 or 4 Intraventricular Hemorrhage, Cystic Periventricular Leukomalacia, or Ventriculomegaly Diagnosed on Ultrasonographic Examination | Birth to initial hospital discharge or to death if it occurs earlier (a median of 97 days) | This is measured as Yes if experienced Grade 3 or 4 intraventricularhemorrhage, cystic periventricular leukomalacia, or ventriculomegaly diagnosed on ultrasonographic examination; Otherwise, No. |
| Necrotizing Enterocolitis, Bell's Stage >=2 | Birth to initial hospital discharge or to death if it occurs earlier (a median of 97 days) | This is measured as Yes if experienced necrotizing enterocolitis (NEC), Bell's stage \>=2; Otherwise, No. Higher scores of Bell's staging criteria denote a worse outcome, where 1 denotes suspect, 2 definite and 3 advanced NEC. |
| Number of Transfusions Per Infant | Birth, up to the earliest of: death, hospital discharge, or 36 weeks postmenstrual age (PMA) | This is measured as the number of protocol compliant transfusions, clinically justified non-protocol transfusions and unjustified non-protocol transfusions (violations) |
| Weight-for-age: Z-score | at 36 weeks postmenstrual age or initial hospital discharge, whichever occurs first | This is measured as the weight-for-age Z-score at 36 weeks postmenstrual age or at initial hospital discharge, whichever occurs first. The Z-score is determined using Olsen percentile curves, and is derived from a normal distribution, where 0 designates average weight-for-age, and negative scores denote less than average weight-for-age. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| High Transfusion Threshold Transfusions were administered using a higher threshold hemoglobin value. AKA 'Liberal Cell Transfusion' group. | 911 |
| Low Transfusion Threshold Transfusions were administered using a lower threshold hemoglobin value. The low threshold values reflect more common practice, so this is considered the 'usual treatment' group. AKA 'Restricted Red C | 913 |
| Total | 1,824 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Data withdrawn prior to hospital discharge | 3 | 7 |
| Overall Study | Incomplete Follow-up | 18 | 15 |
| Overall Study | Lost to Follow-up | 5 | 5 |
| Overall Study | Vital Status Assessment Only | 40 | 39 |
Baseline characteristics
| Characteristic | High Transfusion Threshold | Low Transfusion Threshold | Total |
|---|---|---|---|
| Age, Continuous | 25.9 weeks STANDARD_DEVIATION 1.5 | 25.9 weeks STANDARD_DEVIATION 1.5 | 25.9 weeks STANDARD_DEVIATION 1.5 |
| Maternal Race, Customized American Indian or Alaska Native | 8 Participants | 6 Participants | 14 Participants |
| Maternal Race, Customized Asian, Native Hawaiian, or Other Pacific Islander | 25 Participants | 35 Participants | 60 Participants |
| Maternal Race, Customized Black or African American | 423 Participants | 395 Participants | 818 Participants |
| Maternal Race, Customized More Than One Race | 20 Participants | 15 Participants | 35 Participants |
| Maternal Race, Customized Unknown or Not Reported | 16 Participants | 25 Participants | 41 Participants |
| Maternal Race, Customized White | 419 Participants | 437 Participants | 856 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 149 Participants | 150 Participants | 299 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 754 Participants | 753 Participants | 1507 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 8 Participants | 10 Participants | 18 Participants |
| Sex/Gender, Customized Female | 488 Participants | 462 Participants | 950 Participants |
| Sex/Gender, Customized Male | 423 Participants | 451 Participants | 874 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 146 / 903 | 135 / 901 |
| other Total, other adverse events | 184 / 908 | 164 / 906 |
| serious Total, serious adverse events | 206 / 908 | 197 / 906 |
Outcome results
Primary
Cognitive Delay
This is measured as Yes if the Bayley Scale of Infant and Toddler Development (BSID)-III cognitive score is more than 1 standard deviation below the average; Otherwise, No.
Time frame: at 22-26 months corrected age
Population: The analysis population includes all randomized infants with available data at the two-year followup.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Cognitive Delay | Cognitive Delay | 269 Participants |
| High Transfusion Threshold | Cognitive Delay | No Cognitive Delay | 426 Participants |
| Low Transfusion Threshold | Cognitive Delay | Cognitive Delay | 270 Participants |
| Low Transfusion Threshold | Cognitive Delay | No Cognitive Delay | 442 Participants |
Primary
Death
This is measured as Yes if an infant died between birth and 22-26 months corrected age; Otherwise, No.
Time frame: Birth to 22-26 months corrected age
Population: The analysis population includes all randomized infants with available vital status.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Death | Death | 146 Participants |
| High Transfusion Threshold | Death | No Death | 757 Participants |
| Low Transfusion Threshold | Death | Death | 135 Participants |
| Low Transfusion Threshold | Death | No Death | 766 Participants |
Primary
Death or Neurodevelopmental Impairment
A composite outcome that measures the occurrence of death or neurodevelomental impairment between birth and 22-26 months corrected age.
Time frame: Birth to 22-26 months corrected age
Population: The analysis population includes all randomized infants with available data for death and/or neurodevelopmental impairment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Death or Neurodevelopmental Impairment | Death or Neurodevelopmental Impairment | 423 Participants |
| High Transfusion Threshold | Death or Neurodevelopmental Impairment | No Death nor Neurodevelopmental Impairment | 422 Participants |
| Low Transfusion Threshold | Death or Neurodevelopmental Impairment | Death or Neurodevelopmental Impairment | 422 Participants |
| Low Transfusion Threshold | Death or Neurodevelopmental Impairment | No Death nor Neurodevelopmental Impairment | 425 Participants |
Comparison: Null hypothesis: A higher hemoglobin threshold for red-cell transfusions, as compared with a lower threshold, will not reduce nor increase the incidence of death or neurodevelopmental impairment in infants at 22 to 26 months of age corrected for prematurity.p-value: 0.9395% CI: [0.92, 1.1]Robust Poisson Regression
Primary
Moderate or Severe Cerebral Palsy
This is measured as Yes if the Gross Motor Function Classification System (GMFCS) score is level II or higher; Otherwise, No. Higher values of the GMFCS are worse than lower values; a level of I denotes mild cerebral palsy (CP); level II or III moderate CP; level IV or V severe CP.
Time frame: at 22-26 months corrected age
Population: The analysis population includes all randomized infants with available data at the two-year followup.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Moderate or Severe Cerebral Palsy | Moderate or Severe Cerebral Palsy | 48 Participants |
| High Transfusion Threshold | Moderate or Severe Cerebral Palsy | Mild or No Cerebral Palsy | 663 Participants |
| Low Transfusion Threshold | Moderate or Severe Cerebral Palsy | Moderate or Severe Cerebral Palsy | 55 Participants |
| Low Transfusion Threshold | Moderate or Severe Cerebral Palsy | Mild or No Cerebral Palsy | 665 Participants |
Primary
Neurodevelopmental Impairment
This is measured as Yes if any hearing impairment or visual impairment is noted, if severe or moderate cerebral palsy is noted, or if the cognitive score of the Bayley III score is more than 1 standard deviation below the average; Otherwise, No.
Time frame: at 22-26 months corrected age
Population: The analysis population includes all randomized infants with available data for neurodevelopmental impairment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Neurodevelopmental Impairment | Neurodevelopmental Impairment | 277 Participants |
| High Transfusion Threshold | Neurodevelopmental Impairment | No Neurodevelopmental Impairment | 422 Participants |
| Low Transfusion Threshold | Neurodevelopmental Impairment | Neurodevelopmental Impairment | 287 Participants |
| Low Transfusion Threshold | Neurodevelopmental Impairment | No Neurodevelopmental Impairment | 425 Participants |
Primary
Severe Hearing Impairment
This is measured as Yes if bilateral hearing loss occurred for which hearing aids or cochlear implants were warranted; Otherwise, No.
Time frame: at 22-26 months corrected age
Population: The analysis population includes all randomized infants with available data at the two-year followup.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Severe Hearing Impairment | No Severe Hearing Impairment | 696 Participants |
| High Transfusion Threshold | Severe Hearing Impairment | Severe Hearing Impairment | 14 Participants |
| Low Transfusion Threshold | Severe Hearing Impairment | No Severe Hearing Impairment | 690 Participants |
| Low Transfusion Threshold | Severe Hearing Impairment | Severe Hearing Impairment | 25 Participants |
Primary
Severe Vision Impairment
This is measured as Yes if the corrected visual acuity in the better eye of less than 20/200; Otherwise, No.
Time frame: at 22-26 months corrected age
Population: The analysis population includes all randomized infants with available data at the two-year followup.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Severe Vision Impairment | No Severe Vision Impairment | 708 Participants |
| High Transfusion Threshold | Severe Vision Impairment | Severe Vision Impairment | 5 Participants |
| Low Transfusion Threshold | Severe Vision Impairment | No Severe Vision Impairment | 714 Participants |
| Low Transfusion Threshold | Severe Vision Impairment | Severe Vision Impairment | 6 Participants |
Secondary
Bronchopulmonary Dysplasia, Diagnosed on the Basis of the Need for Supplemental Oxygen After a Standardized Oxygen Reduction Test at 36 Weeks of Postmenstrual Age
This is measured as Yes if experienced bronchopulmonary dysplasia, diagnosed on the basis of the need for supplemental oxygen after a standardized oxygen reduction test at 36 weeks of postmenstrual age; Otherwise, No.
Time frame: at 36 weeks postmenstrual age
Population: The analysis population includes all randomized infants with available data at 36 weeks postmenstrual age.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Bronchopulmonary Dysplasia, Diagnosed on the Basis of the Need for Supplemental Oxygen After a Standardized Oxygen Reduction Test at 36 Weeks of Postmenstrual Age | Bronchopulmonary Dysplasia at 36 Weeks Postmenstrual Age | 469 Participants |
| High Transfusion Threshold | Bronchopulmonary Dysplasia, Diagnosed on the Basis of the Need for Supplemental Oxygen After a Standardized Oxygen Reduction Test at 36 Weeks of Postmenstrual Age | No Bronchopulmonary Dysplasia at 36 Weeks Postmenstrual Age | 326 Participants |
| Low Transfusion Threshold | Bronchopulmonary Dysplasia, Diagnosed on the Basis of the Need for Supplemental Oxygen After a Standardized Oxygen Reduction Test at 36 Weeks of Postmenstrual Age | Bronchopulmonary Dysplasia at 36 Weeks Postmenstrual Age | 453 Participants |
| Low Transfusion Threshold | Bronchopulmonary Dysplasia, Diagnosed on the Basis of the Need for Supplemental Oxygen After a Standardized Oxygen Reduction Test at 36 Weeks of Postmenstrual Age | No Bronchopulmonary Dysplasia at 36 Weeks Postmenstrual Age | 352 Participants |
Secondary
Composite Cognitive Score Less Than 70
This is measured as Yes if scored less than 85 on the Bayley Scale of Infant and Toddler Development (BSID)-III composite cognitive score; Otherwise, No. Higher scores indicate better performance. Composite BSID-III scores of less than 70 are less than 2 standard deviations below the mean of 100.
Time frame: at 22-26 months corrected age
Population: The analysis population includes all randomized infants with available data at the two-year followup.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Composite Cognitive Score Less Than 70 | Composite cognitive score greater or equal to 70 | 607 Participants |
| High Transfusion Threshold | Composite Cognitive Score Less Than 70 | Composite cognitive score less than 70 | 88 Participants |
| Low Transfusion Threshold | Composite Cognitive Score Less Than 70 | Composite cognitive score greater or equal to 70 | 616 Participants |
| Low Transfusion Threshold | Composite Cognitive Score Less Than 70 | Composite cognitive score less than 70 | 96 Participants |
Secondary
Composite Language Score Less Than 70
This is measured as Yes if scored less than 85 on the Bayley Scale of Infant and Toddler Development (BSID)-III composite language score; Otherwise, No. Higher scores indicate better performance. Composite BSID-III scores of less than 70 are less than 2 standard deviations below the mean of 100.
Time frame: at 22-26 months corrected age
Population: The analysis population includes all randomized infants with available data at the two-year followup.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Composite Language Score Less Than 70 | Composite language score greater or equal to 70 | 507 Participants |
| High Transfusion Threshold | Composite Language Score Less Than 70 | Composite language score less than 70 | 164 Participants |
| Low Transfusion Threshold | Composite Language Score Less Than 70 | Composite language score greater or equal to 70 | 528 Participants |
| Low Transfusion Threshold | Composite Language Score Less Than 70 | Composite language score less than 70 | 163 Participants |
Secondary
Composite Language Score Less Than 85
This is measured as Yes if scored less than 85 on the Bayley Scale of Infant and Toddler Development (BSID)-III composite language score; Otherwise, No. Higher scores indicate better performance. Composite BSID-III scores of less than 85 are less than 1 standard deviation below the mean of 100.
Time frame: at 22-26 months corrected age
Population: The analysis population includes all randomized infants with available data at the two-year followup.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Composite Language Score Less Than 85 | Composite language score greater or equal to 85 | 316 Participants |
| High Transfusion Threshold | Composite Language Score Less Than 85 | Composite language score less than 85 | 355 Participants |
| Low Transfusion Threshold | Composite Language Score Less Than 85 | Composite language score greater or equal to 85 | 323 Participants |
| Low Transfusion Threshold | Composite Language Score Less Than 85 | Composite language score less than 85 | 368 Participants |
Secondary
Composite Motor Score Less Than 70
This is measured as Yes if scored less than 85 on the Bayley Scale of Infant and Toddler Development (BSID)-III composite motor score; Otherwise, No. Higher scores indicate better performance. Composite BSID-III scores of less than 70 are less than 2 standard deviations below the mean of 100.
Time frame: at 22-26 months corrected age
Population: The analysis population includes all randomized infants with available data at the two-year followup.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Composite Motor Score Less Than 70 | Composite motor score greater or equal to 70 | 591 Participants |
| High Transfusion Threshold | Composite Motor Score Less Than 70 | Composite motor score less than 70 | 87 Participants |
| Low Transfusion Threshold | Composite Motor Score Less Than 70 | Composite motor score greater or equal to 70 | 596 Participants |
| Low Transfusion Threshold | Composite Motor Score Less Than 70 | Composite motor score less than 70 | 99 Participants |
Secondary
Composite Motor Score Less Than 85
This is measured as Yes if scored less than 85 on the Bayley Scale of Infant and Toddler Development (BSID)-III composite motor score; Otherwise, No. Higher scores indicate better performance. Composite BSID-III scores of less than 85 are less than 1 standard deviation below the mean of 100.
Time frame: at 22-26 months corrected age
Population: The analysis population includes all randomized infants with available data at the two-year followup.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Composite Motor Score Less Than 85 | Composite motor score greater or equal to 85 | 423 Participants |
| High Transfusion Threshold | Composite Motor Score Less Than 85 | Composite motor score less than 85 | 255 Participants |
| Low Transfusion Threshold | Composite Motor Score Less Than 85 | Composite motor score greater or equal to 85 | 415 Participants |
| Low Transfusion Threshold | Composite Motor Score Less Than 85 | Composite motor score less than 85 | 280 Participants |
Secondary
Grade 3 or 4 Intraventricular Hemorrhage, Cystic Periventricular Leukomalacia, or Ventriculomegaly Diagnosed on Ultrasonographic Examination
This is measured as Yes if experienced Grade 3 or 4 intraventricularhemorrhage, cystic periventricular leukomalacia, or ventriculomegaly diagnosed on ultrasonographic examination; Otherwise, No.
Time frame: Birth to initial hospital discharge or to death if it occurs earlier (a median of 97 days)
Population: The analysis population includes all randomized infants with available data up to hospital discharge or death.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Grade 3 or 4 Intraventricular Hemorrhage, Cystic Periventricular Leukomalacia, or Ventriculomegaly Diagnosed on Ultrasonographic Examination | Grade 3 or 4 intraventricular hemorrhage, cystic periventricular leukomalacia, or ventriculomegaly | 146 Participants |
| High Transfusion Threshold | Grade 3 or 4 Intraventricular Hemorrhage, Cystic Periventricular Leukomalacia, or Ventriculomegaly Diagnosed on Ultrasonographic Examination | None of the stated head ultrasound diagnoses | 709 Participants |
| Low Transfusion Threshold | Grade 3 or 4 Intraventricular Hemorrhage, Cystic Periventricular Leukomalacia, or Ventriculomegaly Diagnosed on Ultrasonographic Examination | Grade 3 or 4 intraventricular hemorrhage, cystic periventricular leukomalacia, or ventriculomegaly | 154 Participants |
| Low Transfusion Threshold | Grade 3 or 4 Intraventricular Hemorrhage, Cystic Periventricular Leukomalacia, or Ventriculomegaly Diagnosed on Ultrasonographic Examination | None of the stated head ultrasound diagnoses | 705 Participants |
Secondary
Head Circumference-for-age: Z-score
This is measured as the head circumference-for-age Z-score at 36 weeks postmenstrual age or at initial hospital discharge, whichever occurs first. The Z-score is determined using Olsen percentile curves, and is derived from a normal distribution, where 0 designates average head circumference-for-age, and negative scores denote less than average head circumference-for-age.
Time frame: at 36 weeks postmenstrual age or initial hospital discharge, whichever occurs first
Population: The analysis population includes all randomized infants with available data at 36 weeks postmenstrual age or at initial hospital discharge, whichever occurs first.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Transfusion Threshold | Head Circumference-for-age: Z-score | -1.4 Z-score | Standard Deviation 1 |
| Low Transfusion Threshold | Head Circumference-for-age: Z-score | -1.4 Z-score | Standard Deviation 1 |
Secondary
Hydrocephalus Shunt
This is measured as Yes if experienced Hydrocephalus shunt by follow-up; Otherwise, No.
Time frame: Initial hospital discharge to 22-26 months corrected age
Population: The analysis population includes all randomized infants with available data at the two-year followup.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Hydrocephalus Shunt | Hydrocephalus Shunt | 20 Participants |
| High Transfusion Threshold | Hydrocephalus Shunt | No Hydrocephalus Shunt | 697 Participants |
| Low Transfusion Threshold | Hydrocephalus Shunt | Hydrocephalus Shunt | 22 Participants |
| Low Transfusion Threshold | Hydrocephalus Shunt | No Hydrocephalus Shunt | 706 Participants |
Secondary
Length-for-age: Z-score
This is measured as the length-for-age Z-score at 36 weeks postmenstrual age or at initial hospital discharge, whichever occurs first. The Z-score is determined using Olsen percentile curves, and is derived from a normal distribution, where 0 designates average length-for-age, and negative scores denote less than average length-for-age.
Time frame: at 36 weeks postmenstrual age or initial hospital discharge, whichever occurs first
Population: The analysis population includes all randomized infants with available data at 36 weeks postmenstrual age or initial hospital discharge, whichever occurs first.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Transfusion Threshold | Length-for-age: Z-score | -1.9 Z-score | Standard Deviation 1 |
| Low Transfusion Threshold | Length-for-age: Z-score | -1.9 Z-score | Standard Deviation 0.9 |
Secondary
Length of Stay
This is measured as the length of stay (in days) up to initial hospital discharge or death, whichever occurred first.
Time frame: at initial hospital discharge or at death if it occurs earlier (a median of 97 days)
Population: The analysis population includes all randomized infants with available data up to the initial hospital discharge or death, whichever occurs first.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| High Transfusion Threshold | Length of Stay | 96 Days |
| Low Transfusion Threshold | Length of Stay | 97 Days |
Secondary
Microcephaly
This is measured as a head circumference-for-age Z-score of less than -2; Otherwise, No. The Z-score is determined using WHO percentile curves, and is derived from a normal distribution, where 0 designates average head circumference-for-age, and negative scores denote less than average head circumference-for-age.
Time frame: at 22-26 months corrected age
Population: The analysis population includes all randomized infants with available data at the two-year followup.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Microcephaly | Microcephaly | 61 Participants |
| High Transfusion Threshold | Microcephaly | No Microcephaly | 639 Participants |
| Low Transfusion Threshold | Microcephaly | Microcephaly | 52 Participants |
| Low Transfusion Threshold | Microcephaly | No Microcephaly | 658 Participants |
Secondary
Necrotizing Enterocolitis, Bell's Stage >=2
This is measured as Yes if experienced necrotizing enterocolitis (NEC), Bell's stage \>=2; Otherwise, No. Higher scores of Bell's staging criteria denote a worse outcome, where 1 denotes suspect, 2 definite and 3 advanced NEC.
Time frame: Birth to initial hospital discharge or to death if it occurs earlier (a median of 97 days)
Population: The analysis population includes all randomized infants with available data up to hospital discharge or death.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Necrotizing Enterocolitis, Bell's Stage >=2 | NEC, Bell's Stage >= 2 | 91 Participants |
| High Transfusion Threshold | Necrotizing Enterocolitis, Bell's Stage >=2 | NEC, Bell's Stage = 1 or no NEC | 816 Participants |
| Low Transfusion Threshold | Necrotizing Enterocolitis, Bell's Stage >=2 | NEC, Bell's Stage >= 2 | 95 Participants |
| Low Transfusion Threshold | Necrotizing Enterocolitis, Bell's Stage >=2 | NEC, Bell's Stage = 1 or no NEC | 811 Participants |
Secondary
Number of Transfusions Per Infant
This is measured as the number of protocol compliant transfusions, clinically justified non-protocol transfusions and unjustified non-protocol transfusions (violations)
Time frame: Birth, up to the earliest of: death, hospital discharge, or 36 weeks postmenstrual age (PMA)
Population: The analysis population includes all randomized infants with available data up to death, hospital discharge, or 36 weeks PMA, whichever occurs first
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Transfusion Threshold | Number of Transfusions Per Infant | 6.2 Transfusions | Standard Deviation 4.3 |
| Low Transfusion Threshold | Number of Transfusions Per Infant | 4.4 Transfusions | Standard Deviation 4 |
Secondary
Postmenstrual Age at Final Caffeine Dose in Infants Who Received Caffeine Treatment
This is measured as the average postmenstrual age (in weeks) at final caffeine dose in infants who received caffeine treatment.
Time frame: at final caffeine dose, assessed from birth up to the earliest of: death, hospital discharge, or 36 weeks postmenstrual age
Population: The analysis population includes all randomized infants with available data on caffeine treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Transfusion Threshold | Postmenstrual Age at Final Caffeine Dose in Infants Who Received Caffeine Treatment | 33.8 Weeks | Standard Deviation 3 |
| Low Transfusion Threshold | Postmenstrual Age at Final Caffeine Dose in Infants Who Received Caffeine Treatment | 34.0 Weeks | Standard Deviation 2.8 |
Secondary
Postmenstrual Age at Final Trachael Extubation
This is measured as the average postmenstrual age (in weeks) at final tracheal extubation in infants who were intubated.
Time frame: at final trachael extubation, assessed from birth up to the earliest of: death, hospital discharge, or 36 weeks postmenstrual age
Population: The analysis population includes all randomized infants with available data on trachael extubation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Transfusion Threshold | Postmenstrual Age at Final Trachael Extubation | 30 Weeks | Standard Deviation 3.4 |
| Low Transfusion Threshold | Postmenstrual Age at Final Trachael Extubation | 30.2 Weeks | Standard Deviation 3.3 |
Secondary
Respiratory Disease Necessitating Readmission Before Follow-up
This is measured as Yes if obtained Respiratory disease necessitating readmission before follow-up; Otherwise, No.
Time frame: Initial hospital discharge to 22-26 months corrected age
Population: The analysis population includes all randomized infants with available data at the two-year followup.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Respiratory Disease Necessitating Readmission Before Follow-up | No Respiratory disease necessitating readmission before follow-up | 467 Participants |
| High Transfusion Threshold | Respiratory Disease Necessitating Readmission Before Follow-up | Respiratory disease necessitating readmission before follow-up | 248 Participants |
| Low Transfusion Threshold | Respiratory Disease Necessitating Readmission Before Follow-up | No Respiratory disease necessitating readmission before follow-up | 496 Participants |
| Low Transfusion Threshold | Respiratory Disease Necessitating Readmission Before Follow-up | Respiratory disease necessitating readmission before follow-up | 230 Participants |
Secondary
Retinopathy of Prematurity Stage >=3 or Treatment for That Condition Received
This is measured as Yes if experienced Retinopathy of Prematurity (ROP) Stage \>=3 or received treatment for that condition; Otherwise, No. Higher stages of ROP indicate a worse outcome; the stages range from 1 for mild disease, to 5 for severe disease.
Time frame: Birth to initial hospital discharge or to death if it occurs earlier (a median of 97 days)
Population: The analysis population includes all randomized infants with available data up to hospital discharge or death.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Retinopathy of Prematurity Stage >=3 or Treatment for That Condition Received | No Retinopathy of Prematurity at least Stage 3 and did not Receive Treatment for Such Condition | 640 Participants |
| High Transfusion Threshold | Retinopathy of Prematurity Stage >=3 or Treatment for That Condition Received | Retinopathy of Prematurity at least Stage 3 or Received Treatment for Such Condition | 157 Participants |
| Low Transfusion Threshold | Retinopathy of Prematurity Stage >=3 or Treatment for That Condition Received | No Retinopathy of Prematurity at least Stage 3 and did not Receive Treatment for Such Condition | 660 Participants |
| Low Transfusion Threshold | Retinopathy of Prematurity Stage >=3 or Treatment for That Condition Received | Retinopathy of Prematurity at least Stage 3 or Received Treatment for Such Condition | 137 Participants |
Secondary
Seizure Disorder
This is measured as Yes if experienced one or more seizures since discharge or of regular use of anticonvulsants or seizure medications; Otherwise, No.
Time frame: Initial hospital discharge to 22-26 months corrected age
Population: The analysis population includes all randomized infants with available data at the two-year followup.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Seizure Disorder | No Seizure disorder | 672 Participants |
| High Transfusion Threshold | Seizure Disorder | Seizure disorder | 42 Participants |
| Low Transfusion Threshold | Seizure Disorder | No Seizure disorder | 685 Participants |
| Low Transfusion Threshold | Seizure Disorder | Seizure disorder | 41 Participants |
Secondary
Severe Cerebral Palsy
This is measured as Yes if Gross Motor Function Classification System (GMFCS) is levels IV or V; Otherwise, No. Higher values of the GMFCS are worse than lower values; a level of I denotes mild cerebral palsy (CP); level II or III moderate CP; level IV or V severe CP.
Time frame: at 22-26 months corrected age
Population: The analysis population includes all randomized infants with available data at the two-year followup.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Severe Cerebral Palsy | No Severe Cerebral Palsy | 690 Participants |
| High Transfusion Threshold | Severe Cerebral Palsy | Severe Cerebral Palsy | 20 Participants |
| Low Transfusion Threshold | Severe Cerebral Palsy | No Severe Cerebral Palsy | 709 Participants |
| Low Transfusion Threshold | Severe Cerebral Palsy | Severe Cerebral Palsy | 11 Participants |
Secondary
Survival to Discharge Without Severe Complications
This is measured as Yes if survived to discharge without severe morbidity, defined as bronchopulmonary dysplasia, retinopathy of prematurity (stage 3 or higher or requiring treatment), or serious brain abnormality; Otherwise, No.
Time frame: Birth to initial hospital discharge or to death if it occurs earlier (a median of 97 days)
Population: The analysis population includes all randomized infants with available data up to hospital discharge or death.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Transfusion Threshold | Survival to Discharge Without Severe Complications | No Survival to Discharge Without Severe Complications | 644 Participants |
| High Transfusion Threshold | Survival to Discharge Without Severe Complications | Survival to Discharge Without Severe Complications | 257 Participants |
| Low Transfusion Threshold | Survival to Discharge Without Severe Complications | No Survival to Discharge Without Severe Complications | 614 Participants |
| Low Transfusion Threshold | Survival to Discharge Without Severe Complications | Survival to Discharge Without Severe Complications | 274 Participants |
Secondary
Time to Full Enteral Feeding
This is measured as the amount of days it took for full enteral feeding to occur.
Time frame: at first full enteral feeding, assessed from birth up to initial hospital discharge or to death if it occurs earlier (a median of 97 days)
Population: The analysis population includes all randomized infants with available data on enteral feeding.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| High Transfusion Threshold | Time to Full Enteral Feeding | 19.5 Days |
| Low Transfusion Threshold | Time to Full Enteral Feeding | 19.0 Days |
Secondary
Weight-for-age: Z-score
This is measured as the weight-for-age Z-score at 36 weeks postmenstrual age or at initial hospital discharge, whichever occurs first. The Z-score is determined using Olsen percentile curves, and is derived from a normal distribution, where 0 designates average weight-for-age, and negative scores denote less than average weight-for-age.
Time frame: at 36 weeks postmenstrual age or initial hospital discharge, whichever occurs first
Population: The analysis population includes all randomized infants with available data at 36 weeks postmenstrual age or at initial hospital discharge, whichever occurs first.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Transfusion Threshold | Weight-for-age: Z-score | -1.2 Z-score | Standard Deviation 0.8 |
| Low Transfusion Threshold | Weight-for-age: Z-score | -1.3 Z-score | Standard Deviation 0.8 |