Premature Birth of Newborn, Enterocolitis, Necrotizing
Conditions
Keywords
Microbiome, Antibiotics
Brief summary
The purpose of this study is to determine whether antibiotics given immediately after birth alter the development of the developing preterm infant's microbiome, which may further alter overall clinical outcomes.
Interventions
DRUGAmpicillin
Ampicillin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization.
DRUGGentamicins
Gentamicin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization.
DRUGPlacebo
Normal saline will be given as placebo for those in the placebo comparator group.
Sponsors
University of Chicago
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
No minimum to 6 Hours
Healthy volunteers
Yes
Inclusion criteria
for antibiotic randomization: 1. Infant must be born between the gestational ages of 28 0/7 weeks and 34 6/7 weeks -AND- 2. Infant must be born at investigator's home institution. -AND- 3. Infant must be considered to have a low risk of infection by one of the following criteria: 1. Delivered for maternal indications (Cesarean section or induction of labor for maternal health, including pre-eclampsia, placental abruption, history of intrauterine fetal demise (IUFD)/abruption, multiple gestation requiring preterm delivery, etc) -OR- 2. Delivered due to preterm labor to a mother without the diagnosis of chorioamnionitis/maternal fever or prolonged rupture of membranes \>18 hours
Exclusion criteria
for antibiotic randomization: 1. Signs of clinical illness within the first 3 hours of life: 1. 5-minute Apgar \<5 2. Requiring vasoactive drugs 3. Seizures 4. Significant respiratory distress requiring supplemental oxygen \>40% 2. Immature:Total (I:T) Ratio of \>0.2 on initial complete blood count (CBC) 3. Congenital anomalies, including renal anomalies requiring serum antibiotic level monitoring ANY infant born between the gestational ages of 28 0/7 weeks and 34 6/7 weeks who do not meet inclusion criteria, with parental consent, can participate in the stool analysis only arm of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Richness of the Preterm Infant Microbiome | 2 weeks | Number of 16S rRNA gene amplicon sequence variants (i.e., proxy for prokaryote species-like groupings) detected in each sample. A higher richness means that a higher number of species of archaea and bacteria was detected in a sample. |
| Shannon Diversity of the Preterm Infant Microbiome | 2 weeks | Function of richness and evenness of 16S rRNA gene amplicon sequence variants (i.e., proxy for prokaryote species-like groupings) within each sample. A higher Shannon diversity means that a sample had a combination of a higher number of species of archaea and bacteria, and/or a more even relative abundance of those species within a sample. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Retinopathy of Prematurity (ROP) | 4-12 weeks | Cases of ROP as diagnosed by the pediatric ophthalmologist |
| Chronic Lung Disease of Infancy (CLD) | 4-12 weeks | Premature infants who require \> 21% FiO2 for at least 28 days and/or at 36 weeks corrected gestation |
| Death | 18 months | — |
| Intraventricular Hemorrhage (IVH) | 4-12 weeks | Cases of IVH present on any head ultrasound obtained during patient's hospitalization |
| Necrotizing Enterocolitis (NEC) | 4-12 weeks | Any patient showing signs/symptoms of this acute neonatal gastrointestinal disease, including abdominal distension, bloody stools, systemic illness, and radiographic changes (pneumatosis intestinalis, portal venous gas, free intraperitoneal gas). |
Countries
United States
Participant flow
Recruitment details
Patients in the study were enrolled from The University of Chicago Comer Children's Hospital, a level IV NICU in Chicago, Illinois, as well as Northshore University HealthSystem Evanston Hospital, a level III NICU in Evanston, Illinois from 2015-2018.
Participants by arm
| Arm | Count |
|---|---|
| Randomized & Blinded - Receiving Antibiotics The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive routine ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life.
Ampicillin: Ampicillin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization.
Gentamicin: Gentamicin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization. | 12 |
| Randomized & Blinded - Receiving Placebo The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive placebo (saline) in place of ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life.
Placebo: Normal saline will be given as placebo for those in the placebo comparator group. | 15 |
| Total | 27 |
Baseline characteristics
| Characteristic | Randomized & Blinded - Receiving Placebo | Total | Randomized & Blinded - Receiving Antibiotics |
|---|---|---|---|
| Age, Customized Gestational Age | 31.9 weeks | 32.3 weeks | 32.6 weeks |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 25 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Female | 7 Participants | 12 Participants | 5 Participants |
| Sex: Female, Male Male | 8 Participants | 15 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 15 |
| other Total, other adverse events | 0 / 12 | 0 / 15 |
| serious Total, serious adverse events | 0 / 12 | 0 / 15 |
Outcome results
Primary
Richness of the Preterm Infant Microbiome
Number of 16S rRNA gene amplicon sequence variants (i.e., proxy for prokaryote species-like groupings) detected in each sample. A higher richness means that a higher number of species of archaea and bacteria was detected in a sample.
Time frame: 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized & Blinded - Receiving Antibiotics | Richness of the Preterm Infant Microbiome | 12.8 16S rRNA gene amplicon sequence variants | Standard Deviation 5.3 |
| Randomized & Blinded - Receiving Placebo | Richness of the Preterm Infant Microbiome | 11 16S rRNA gene amplicon sequence variants | Standard Deviation 6.9 |
Primary
Shannon Diversity of the Preterm Infant Microbiome
Function of richness and evenness of 16S rRNA gene amplicon sequence variants (i.e., proxy for prokaryote species-like groupings) within each sample. A higher Shannon diversity means that a sample had a combination of a higher number of species of archaea and bacteria, and/or a more even relative abundance of those species within a sample.
Time frame: 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized & Blinded - Receiving Antibiotics | Shannon Diversity of the Preterm Infant Microbiome | 5 Shannon diversity | Standard Deviation 3.6 |
| Randomized & Blinded - Receiving Placebo | Shannon Diversity of the Preterm Infant Microbiome | 3.8 Shannon diversity | Standard Deviation 3.3 |
Secondary
Chronic Lung Disease of Infancy (CLD)
Premature infants who require \> 21% FiO2 for at least 28 days and/or at 36 weeks corrected gestation
Time frame: 4-12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Randomized & Blinded - Receiving Antibiotics | Chronic Lung Disease of Infancy (CLD) | 0 Participants |
| Randomized & Blinded - Receiving Placebo | Chronic Lung Disease of Infancy (CLD) | 0 Participants |
Secondary
Death
Time frame: 18 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Randomized & Blinded - Receiving Antibiotics | Death | 0 Participants |
| Randomized & Blinded - Receiving Placebo | Death | 0 Participants |
Secondary
Intraventricular Hemorrhage (IVH)
Cases of IVH present on any head ultrasound obtained during patient's hospitalization
Time frame: 4-12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Randomized & Blinded - Receiving Antibiotics | Intraventricular Hemorrhage (IVH) | 0 Participants |
| Randomized & Blinded - Receiving Placebo | Intraventricular Hemorrhage (IVH) | 0 Participants |
Secondary
Necrotizing Enterocolitis (NEC)
Any patient showing signs/symptoms of this acute neonatal gastrointestinal disease, including abdominal distension, bloody stools, systemic illness, and radiographic changes (pneumatosis intestinalis, portal venous gas, free intraperitoneal gas).
Time frame: 4-12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Randomized & Blinded - Receiving Antibiotics | Necrotizing Enterocolitis (NEC) | 0 Participants |
| Randomized & Blinded - Receiving Placebo | Necrotizing Enterocolitis (NEC) | 0 Participants |
Secondary
Retinopathy of Prematurity (ROP)
Cases of ROP as diagnosed by the pediatric ophthalmologist
Time frame: 4-12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Randomized & Blinded - Receiving Antibiotics | Retinopathy of Prematurity (ROP) | 0 Participants |
| Randomized & Blinded - Receiving Placebo | Retinopathy of Prematurity (ROP) | 0 Participants |