Extremely Low Gestational Age Newborn, Premature Infant
Conditions
Brief summary
Colostrum is rich in cytokines and other immune agents that may provide immunomodulatory protection against nosocomial infection in extremely premature infants. However, most of them could not proceed enteral feedings due to clinical instability in the first few days. Recent studies supports oropharyngeal administration as a potentially safe and effective delivery method for immunologic benefits and only small amount of colostrum could be administrated for immune therapy for extremely premature babies. The purpose of this study is to determine the beneficial effects of oropharyngeal administration of colostrum for immunologic aspects in extremely low gestational age infants and evaluated the safety of this method to extremely premature infants in the first few days of life.
Interventions
application of 0.2 mL of colostrum to the infant's oropharyngeal mucosa every 3 hours for 3 days from the postnatal 48 to 96 hours.
application of 0.2 mL of sterile water to the infant's oropharyngeal mucosa every 3 hours for 3 days from the postnatal 48 to 96 hours.
Sponsors
Seoul National University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
48 Hours to 96 Hours
Healthy volunteers
Yes
Inclusion criteria
* premature infant with a gestational age less than 28 weeks born at Seoul National University Hospital and admit to the Seoul National University Children's Hospital NICU immediately after birth * parents of the infant signed to the informed consent form with voluntary agreement
Exclusion criteria
* infants with major congenital anomalies or chromosomal syndromes * infants of mothers not willing to provide colostrum in the first week of life * infants of mothers with known infectious diseases that may be transmitted through the breast milk such as HIV, hepatitis C or active TB
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Urinary Secretary IgA Concentration at 2 Weeks of Age | 2 weeks of age |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Salivary TGF-beta 1 Concentration at 2 Week of Age | 2 week of age | — |
| Salivary IL-8 Concentration at 2 Weeks of Age | 2 weeks of age | — |
| Concentration of Urinary Lactoferrin | 1 week of age | — |
| Concentration of Urinary IL-1 Beta | 2 weeks of age | — |
| Concentration of Salivary Lactoferrin, Lysozyme, Alpha-lactalbumin and Cytokines | 1 week of age | — |
| Time to Reach Full Feeding | up to 2 months of age | day of life when the baby reaches full enteral feeding, defined as a volume above 120\ 130mL/kg/day |
| Total Hospital Admission Duration | up to 4 months of age | days from admission to discharge from NICU |
| Urinary Secretary IgA Concentration at 1 Week of Age | 1 week of age | — |
| Episodes of Necrotizing Enterocolitis ≥ Bell's Stage 2 | from date of randomization up to 4 months of age | — |
| Episodes of Pneumonia | from date of randomization up to 4 months of age | numbers of documented pneumonia events those accompanied with increased tracheal secretion, increased ventilatory setting and treated with antibiotics |
| Development of Bronchopulmonary Dysplasia ≥ Moderate | up to 4 months of age | — |
| Development of Intraventricular Hemorrhage ≥ Grade 3 | up to 4 months of age | — |
| In-hospital Death | up to 4 months of age | — |
| Development of Adverse Effects | from the start date of oropharyngeal administration of colostrum or sterile water to 1 week of age | category of adverse effects 1. general - fever or hypothermia, rash 2. respiratory & cardiovascular - apnea, tachypnea, desaturation, hypotension, bradycardia, tachycardia 3. gastrointestinal - abdominal distension, bilious gastric remain, vomiting, bloody stool, necrotizing enterocolitis 4. renal - oliguria (urine output \< 1.0cc/kg/day) 5. laboratory - hypo-/hyper-natremia, acidosis, hypercarbia |
| Episodes of Culture Positive Sepsis | from date of randomization up to 4 months of age | numbers of documented sepsis events defined as isolation of the microorganism from ≥ 1 blood culture + ≥ 1 clinical symptoms or sign (fever, hypothermia, apnea, bradycardia, hypo-/hyperglycemia) |
Countries
South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Colostrum oropharyngeal administration of own mother's colostrum
oropharyngeal administration of own mother's colostrum: application of 0.2 mL of colostrum to the infant's oropharyngeal mucosa every 3 hours for 3 days from the postnatal 48 to 96 hours. | 21 |
| Placebo oropharyngeal administration of sterile water
oropharyngeal administration of sterile water: application of 0.2 mL of sterile water to the infant's oropharyngeal mucosa every 3 hours for 3 days from the postnatal 48 to 96 hours. | 21 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | absence of maternal colostrum | 2 | 0 |
| Overall Study | Death | 1 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Colostrum | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 26.1 weeks STANDARD_DEVIATION 1.4 | 26.0 weeks STANDARD_DEVIATION 1.4 | 26.1 weeks STANDARD_DEVIATION 1.4 |
| Birth weight | 862.2 g STANDARD_DEVIATION 234.8 | 842.4 g STANDARD_DEVIATION 250.4 | 849.3 g STANDARD_DEVIATION 239.8 |
| Sex: Female, Male Female | 10 Participants | 11 Participants | 21 Participants |
| Sex: Female, Male Male | 11 Participants | 10 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 21 | 0 / 21 |
| serious Total, serious adverse events | 0 / 21 | 0 / 21 |
Outcome results
Primary
Urinary Secretary IgA Concentration at 2 Weeks of Age
Time frame: 2 weeks of age
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colostrum | Urinary Secretary IgA Concentration at 2 Weeks of Age | 233.8 ng per g creatinine | Standard Deviation 37.4 |
| Placebo | Urinary Secretary IgA Concentration at 2 Weeks of Age | 48.3 ng per g creatinine | Standard Deviation 24.1 |
p-value: 0.006Wilcoxon (Mann-Whitney)
Secondary
Concentration of Salivary Lactoferrin, Lysozyme, Alpha-lactalbumin and Cytokines
Time frame: 2 weeks of age
Secondary
Concentration of Salivary Lactoferrin, Lysozyme, Alpha-lactalbumin and Cytokines
Time frame: 1 week of age
Secondary
Concentration of Urinary IL-1 Beta
Time frame: 2 weeks of age
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colostrum | Concentration of Urinary IL-1 Beta | 55.25 ug per g creatinine | Standard Deviation 7.12 |
| Placebo | Concentration of Urinary IL-1 Beta | 91.80 ug per g creatinine | Standard Deviation 11.86 |
p-value: 0.013Wilcoxon (Mann-Whitney)
Secondary
Concentration of Urinary Lactoferrin
Time frame: 1 week of age
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colostrum | Concentration of Urinary Lactoferrin | 3.51 ug per g creatinine | Standard Deviation 1.32 |
| Placebo | Concentration of Urinary Lactoferrin | 0.98 ug per g creatinine | Standard Deviation 0.28 |
p-value: 0.01Wilcoxon (Mann-Whitney)
Secondary
Development of Adverse Effects
category of adverse effects 1. general - fever or hypothermia, rash 2. respiratory & cardiovascular - apnea, tachypnea, desaturation, hypotension, bradycardia, tachycardia 3. gastrointestinal - abdominal distension, bilious gastric remain, vomiting, bloody stool, necrotizing enterocolitis 4. renal - oliguria (urine output \< 1.0cc/kg/day) 5. laboratory - hypo-/hyper-natremia, acidosis, hypercarbia
Time frame: from the start date of oropharyngeal administration of colostrum or sterile water to 1 week of age
Secondary
Development of Bronchopulmonary Dysplasia ≥ Moderate
Time frame: up to 4 months of age
Secondary
Development of Intraventricular Hemorrhage ≥ Grade 3
Time frame: up to 4 months of age
Secondary
Episodes of Culture Positive Sepsis
numbers of documented sepsis events defined as isolation of the microorganism from ≥ 1 blood culture + ≥ 1 clinical symptoms or sign (fever, hypothermia, apnea, bradycardia, hypo-/hyperglycemia)
Time frame: from date of randomization up to 4 months of age
Secondary
Episodes of Necrotizing Enterocolitis ≥ Bell's Stage 2
Time frame: from date of randomization up to 4 months of age
Secondary
Episodes of Pneumonia
numbers of documented pneumonia events those accompanied with increased tracheal secretion, increased ventilatory setting and treated with antibiotics
Time frame: from date of randomization up to 4 months of age
Secondary
In-hospital Death
Time frame: up to 4 months of age
Secondary
Salivary IL-8 Concentration at 2 Weeks of Age
Time frame: 2 weeks of age
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colostrum | Salivary IL-8 Concentration at 2 Weeks of Age | 2.58 ng/mL | Standard Deviation 1.01 |
| Placebo | Salivary IL-8 Concentration at 2 Weeks of Age | 4.90 ng/mL | Standard Deviation 1.19 |
p-value: 0.038Wilcoxon (Mann-Whitney)
Secondary
Salivary TGF-beta 1 Concentration at 2 Week of Age
Time frame: 2 week of age
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colostrum | Salivary TGF-beta 1 Concentration at 2 Week of Age | 39.2 ug/mL | Standard Deviation 6.3 |
| Placebo | Salivary TGF-beta 1 Concentration at 2 Week of Age | 69.7 ug/mL | Standard Deviation 12.7 |
p-value: 0.032Wilcoxon (Mann-Whitney)
Secondary
Time to Reach Full Feeding
day of life when the baby reaches full enteral feeding, defined as a volume above 120\ 130mL/kg/day
Time frame: up to 2 months of age
Secondary
Total Hospital Admission Duration
days from admission to discharge from NICU
Time frame: up to 4 months of age
Secondary
Urinary Secretary IgA Concentration at 1 Week of Age
Time frame: 1 week of age
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colostrum | Urinary Secretary IgA Concentration at 1 Week of Age | 71.4 ng per g creatinine | Standard Deviation 33.1 |
| Placebo | Urinary Secretary IgA Concentration at 1 Week of Age | 26.5 ng per g creatinine | Standard Deviation 6.7 |
p-value: 0.043Wilcoxon (Mann-Whitney)