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Wheezing in Black Preterm Infants: Impact of Vitamin D Supplementation Strategy

Wheezing in Black Preterm Infants: Impact of Vitamin D Supplementation Strategy

Status
Completed
Phases
Phase 4
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT01601847
Acronym
D-Wheeze
Enrollment
300
Registered
2012-05-18
Start date
2013-01-31
Completion date
2017-03-12
Last updated
2018-06-08

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Allergy, Wheezing

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

DIETARY_SUPPLEMENTCholecalciferol

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

National Heart, Lung, and Blood Institute (NHLBI)
CollaboratorNIH
Office of Dietary Supplements (ODS)
CollaboratorNIH
Case Western Reserve University
Lead SponsorOTHER

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender
ALL
Age
No minimum to 1 Years
Healthy volunteers
No

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

MeasureTime frameDescription
Number of Infants With Recurrent Wheezingup to 12 months adjusted ageRecurrent 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

MeasureTime frameDescription
Number With Infants With Allergic Sensitization as Measured by the PhadiaTop Infant AssayMeasured at the 12 month adjusted age visitMeasured using the Phadiatop Infant IgE panel
Bone DensityMeasured at the 12 month adjusted age visitMeasured 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

ArmCount
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
Total300

Withdrawals & dropouts

PeriodReasonFG000FG001
Overall StudyDeath10
Overall StudyLost to Follow-up13
Overall StudyWithdrawal by Subject117

Baseline characteristics

CharacteristicSustainedDiet-LimitedTotal
Age, Categorical
<=18 years
153 Participants147 Participants300 Participants
Age, Categorical
>=65 years
0 Participants0 Participants0 Participants
Age, Categorical
Between 18 and 65 years
0 Participants0 Participants0 Participants
Alkaline phosphatase (U/L)268 U/L257 U/L263 U/L
Antenatal steroids82 Participants78 Participants160 Participants
Birth weight1.84 kg1.96 kg1.87 kg
Calcium (mg/dl)9.5 mg/dl9.5 mg/dl9.5 mg/dl
Discharge season (Oct-March)69 Participants67 Participants136 Participants
Gestational age at birth33.00 weeks33.50 weeks33.14 weeks
History of oxygen administration66 Participants53 Participants119 Participants
History of ventilator support27 Participants26 Participants53 Participants
Multiple birth (twins and triplets)58 Participants38 Participants96 Participants
Phosphorus (mg/dl)7.0 mg/dl6.9 mg/dl7.0 mg/dl
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Asian
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Black or African American
153 Participants147 Participants300 Participants
Race (NIH/OMB)
More than one race
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Unknown or Not Reported
0 Participants0 Participants0 Participants
Race (NIH/OMB)
White
0 Participants0 Participants0 Participants
Receiving maternal breast milk at randomization107 Participants104 Participants211 Participants
Sex: Female, Male
Female
76 Participants57 Participants133 Participants
Sex: Female, Male
Male
77 Participants89 Participants166 Participants
Total circulating 25(OH)D (ng/ml)19.1 ng/ml21.0 ng/ml20.2 ng/ml

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
deaths
Total, all-cause mortality
1 / 1530 / 147
other
Total, other adverse events
123 / 153123 / 147
serious
Total, serious adverse events
36 / 15338 / 147

Outcome results

Primary

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.

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
SustainedNumber of Infants With Recurrent Wheezing42 Participants
Diet-LimitedNumber of Infants With Recurrent Wheezing56 Participants
p-value: 0.0295% CI: [0.47, 0.94]Poisson
p-value: 0.018595% CI: [0.304, 0.897]logistic regression with GEE
Secondary

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.

ArmMeasureValue (MEDIAN)
SustainedBone Density3155 m/s
Diet-LimitedBone Density3149 m/s
p-value: 0.798Regression, Logistic
Secondary

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

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
SustainedNumber With Infants With Allergic Sensitization as Measured by the PhadiaTop Infant Assay7 Participants
Diet-LimitedNumber With Infants With Allergic Sensitization as Measured by the PhadiaTop Infant Assay3 Participants
Comparison: For secondary outcomes, GEE is used to assess randomization arm association.p-value: 0.228Regression, Logistic

Source: ClinicalTrials.gov · Data processed: Feb 26, 2026