Allergy, Wheezing
Conditions
Brief summary
The goal of this study is to identify a vitamin D supplementation strategy that best promotes the lung, immune, and overall health of black infants born preterm (28-36 weeks gestational age). This is a high risk population that seems to have unique vitamin D needs, and inappropriate supplementation may promote wheezing or allergy. The results of this study will help form nutritional recommendations for the approximately 100,000 black infants born at 30-36 weeks gestational age in the U.S. every year.
Detailed description
Black infants face the highest rates of prematurity in the U.S. (18%), have high rates of prematurity-associated wheezing illnesses, and tend to have lower vitamin D levels. The goal of this \[comparative effectiveness\] study is to identify a vit. D supplementation strategy that minimizes recurrent wheezing in infancy. Long recognized as important for bone health, a growing body of evidence suggests that vit. D may play a role in the regulation and development of many organ systems. The D pathway regulates lung inflammation and impacts morphogenesis, structure, and cell growth and survival in bronchial smooth muscle. Vit. D exposure has the potential to skew cytokine expression from a Th1 (less allergic) to a Th2 (more allergic) phenotype. Due to their developmental immaturity, preterm infants may be particularly vulnerable to any positive or negative effects of vit. D supplementation on the lung, airway, and immune system. Our preliminary data, supported by the literature, suggests that overly aggressive vit. D supplementation may inadvertently increase wheezing in infancy in black, but not white, preterm infants; however, vit. D deficiency could theoretically also increase wheezing via vulnerability to respiratory pathogens. The proposed study is a randomized clinical trial comparing the effect of two different enteral vitamin D supplementation strategies on recurrent wheezing in infancy in 300 black infants born preterm at 28 0/7-36 6/7 wks gestational age, a population for whom neither vit. D requirements nor optimal vit. D serum levels have been established. The investigators will test two strategies: (I) sustained supplementation until 6 mo. of age adjusted for prematurity, and (II) cessation of supplementation when a minimum dietary intake of 200 IU/day is reached. The specific aims are to characterize the effect of each strategy on (aim 1) recurrent wheezing and (aim 2) allergic sensitization and atopy. The investigators will (aim 3) explore the relationship between vit. D serum levels and recurrent wheezing. The investigators hypothesize that strategy II will be more effective in promoting pulmonary health by minimizing recurrent wheezing, allergic sensitization, and overall healthcare utilization, and will be sufficient to prevent clinical vit. D deficiency. The investigators also hypothesize that optimal vit. D serum levels will be lower than the norms for other populations.
Interventions
Once the dietary intake of vitamin D has exceeded 200 IU/Day, the infants will receive placebo until they are 6 months of age adjusted for prematurity
Sponsors
Study design
Eligibility
Inclusion criteria
1. 28 0/7-36 6/7 weeks gestational age (GA) at birth; 2. family identifies the child as black or African American; 3. \< 28 days of supplemental oxygen (subsequent oxygen therapy for \< 72 hrs for a brief subsequent illness or surgery will be allowed); 4. admitted to a participating site NICU, special care nursery, transitional care nursery, or well-baby nursery as a neonate; and 5. \< 40 weeks corrected GA at enrollment.
Exclusion criteria
1. BPD (\> 28 days of supplemental oxygen); 2. pre-existing diagnosis of moderate to severe osteopenia of prematurity and/or alkaline phosphatase \> 700; 3. history of fracture; 4. gastrointestinal surgery, including for NEC; 5. known gastrointestinal malabsorption; 6. major congenital anomaly; 7. congenital pulmonary or airway disorder (e.g., cystic fibrosis, tracheomalacia, swallowing disorder, bronchopulmonary sequestration); 8. documented wheezing or stridor prior to enrollment; 9. previous vit. D supplementation with \> 400 IU/day; 10. family plans to move more than 60 miles from CWRU or other pre-defined radius at other sites; 11. baseline hypo- or hypercalcemia, hypo- or hyperphosphatemia; and 12. baseline 25(OH) D level \< 10 ng/ml.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Infants With Recurrent Wheezing | up to 12 months adjusted age | Recurrent wheezing was defined as more than 1 episode of wheezing reported during the study period. Separate episodes were defined as occurring at least 2 weeks apart. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number With Infants With Allergic Sensitization as Measured by the PhadiaTop Infant Assay | Measured at the 12 month adjusted age visit | Measured using the Phadiatop Infant IgE panel |
| Bone Density | Measured at the 12 month adjusted age visit | Measured by bone speed of sound (ultrasound) |
Countries
United States
Participant flow
Recruitment details
Infants were recruited from participating NICUs, special care nurseries, and well-baby nurseries.
Pre-assignment details
If all eligibility labs were not available from routine clinical care, parents were consented prior to obtaining the remaining eligibility labs. If those post-consent laboratory results made the infant ineligible, they were not randomized.
Participants by arm
| Arm | Count |
|---|---|
| Sustained Infants will remain on 400 IU/day of cholecalciferol until 6 months of age adjusted for prematurity, regardless of dietary intake
Cholecalciferol: Infants will receive cholecalciferol 400 IU/day PO until they are 6 months of age adjusted for prematurity.
Exclusively breastfed infants receive 400 IU of vitamin D daily as needed beyond 6 months adjusted age for the duration of the study. | 153 |
| Diet-Limited Infants will receive placebo once their dietary intake of vitamin D has exceeded 200 IU/day
Cholecalciferol: Once the dietary intake of vitamin D has exceeded 200 IU/Day from formula or fortifiers, the infants will receive placebo until they are 6 months of age adjusted for prematurity.
Exclusively breastfed infants receive 400 IU of vitamin D daily as needed beyond 6 months adjusted age for the duration of the study. | 147 |
| Total | 300 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | Withdrawal by Subject | 11 | 7 |
Baseline characteristics
| Characteristic | Sustained | Diet-Limited | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 153 Participants | 147 Participants | 300 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Alkaline phosphatase (U/L) | 268 U/L | 257 U/L | 263 U/L |
| Antenatal steroids | 82 Participants | 78 Participants | 160 Participants |
| Birth weight | 1.84 kg | 1.96 kg | 1.87 kg |
| Calcium (mg/dl) | 9.5 mg/dl | 9.5 mg/dl | 9.5 mg/dl |
| Discharge season (Oct-March) | 69 Participants | 67 Participants | 136 Participants |
| Gestational age at birth | 33.00 weeks | 33.50 weeks | 33.14 weeks |
| History of oxygen administration | 66 Participants | 53 Participants | 119 Participants |
| History of ventilator support | 27 Participants | 26 Participants | 53 Participants |
| Multiple birth (twins and triplets) | 58 Participants | 38 Participants | 96 Participants |
| Phosphorus (mg/dl) | 7.0 mg/dl | 6.9 mg/dl | 7.0 mg/dl |
| 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 | 153 Participants | 147 Participants | 300 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 | 0 Participants | 0 Participants | 0 Participants |
| Receiving maternal breast milk at randomization | 107 Participants | 104 Participants | 211 Participants |
| Sex: Female, Male Female | 76 Participants | 57 Participants | 133 Participants |
| Sex: Female, Male Male | 77 Participants | 89 Participants | 166 Participants |
| Total circulating 25(OH)D (ng/ml) | 19.1 ng/ml | 21.0 ng/ml | 20.2 ng/ml |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 153 | 0 / 147 |
| other Total, other adverse events | 123 / 153 | 123 / 147 |
| serious Total, serious adverse events | 36 / 153 | 38 / 147 |
Outcome results
Number of Infants With Recurrent Wheezing
Recurrent wheezing was defined as more than 1 episode of wheezing reported during the study period. Separate episodes were defined as occurring at least 2 weeks apart.
Time frame: up to 12 months adjusted age
Population: Infants that were withdrawn, completely lost to follow-up, who died, or for whom recurrent wheezing status was indeterminate due to a missing 12 month visit (n=8) were not included in the primary analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sustained | Number of Infants With Recurrent Wheezing | 42 Participants |
| Diet-Limited | Number of Infants With Recurrent Wheezing | 56 Participants |
Bone Density
Measured by bone speed of sound (ultrasound)
Time frame: Measured at the 12 month adjusted age visit
Population: Bone density was not performed if (1) infant could not come to the clinic for their 12 month visit and the visit was done in the home (2) they missed their 12 month visit (3) the ultrasound was under repair, or (4) infant could not participate with the ultrasound to get a sufficient quality reading.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sustained | Bone Density | 3155 m/s |
| Diet-Limited | Bone Density | 3149 m/s |
Number With Infants With Allergic Sensitization as Measured by the PhadiaTop Infant Assay
Measured using the Phadiatop Infant IgE panel
Time frame: Measured at the 12 month adjusted age visit
Population: Positive result is \>0.35 U/L PAU/l
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sustained | Number With Infants With Allergic Sensitization as Measured by the PhadiaTop Infant Assay | 7 Participants |
| Diet-Limited | Number With Infants With Allergic Sensitization as Measured by the PhadiaTop Infant Assay | 3 Participants |