Vitamin D Supplementation for Premature Infants

Overseen By Jordan Burdine, PharmD, MBA, BCPPS

Age: < 18

Sex: Any

Trial Phase: Academic

Sponsor: The University of Texas Health Science Center, Houston

Disqualifiers: Congenital anomaly, Nonbacterial infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The objective of the study is to compare supplementation with vitamin D at 800 IU/day to usual care for the first 28 days after birth with respect to 25 (OH) vitamin D levels and indicators of likely or plausible effects of vitamin D supplementation on the function or structure of the lung, bones, immune system, and brain in extremely premature (EP) infants who are \<28 weeks gestational age (GA) or \<1000 grams of birth weight (BW). The study results will be analyzed as intention to treat Bayesian analyses (Frequentist analyses will also be performed).

Will I have to stop taking my current medications?

The trial information does not specify whether participants must stop taking their current medications.

Is vitamin D supplementation safe for premature infants?

Vitamin D supplementation in premature infants is generally safe, but it should be monitored to avoid overdose. Some studies have shown that high doses can lead to potentially toxic levels, so careful monitoring is important to ensure safety. ^{1 2 3 4 5}

How does the drug Vitamin D3 supplementation for premature infants differ from other treatments?

The 800 IU/day vitamin D3 supplementation for premature infants is unique because it provides a higher dose than typically recommended, aiming to better support bone health and overall development in the first 28 days after birth, while the standard dose often ranges from 400 to 960 IU/day. ^{6 7 8 9 10}

What data supports the effectiveness of the drug 800 IU/day vitamin D supplementation for premature infants?

Research shows that early supplementation with 800 IU of vitamin D is effective and safe for very low birth weight infants, helping to improve their vitamin D levels. Another study found that even lower doses of vitamin D (500 IU) increased vitamin D levels in premature infants, suggesting that 800 IU could be even more effective. ^{1 3 11 12 13}

Who Is on the Research Team?

Sunil Jain, MD

Principal Investigator

The University of Texas Medical Branch

Are You a Good Fit for This Trial?

This trial is for very premature infants born at less than 28 weeks or weighing under 1000 grams. It's not for babies with conditions affecting vitamin D absorption, like cystic fibrosis, those too sick where intensive care isn't justified, with congenital infections, over 32 weeks gestation, or with major birth defects.

Inclusion Criteria

My condition is congenital.

Informed written consent in an Institutional Review Board (IRB)-approved manner

My baby was born before 28 weeks or weighed less than 1000 grams.

Exclusion Criteria

Any major congenital anomaly

Any known congenital nonbacterial infection

Such severe illness or immaturity that the attending neonatologist judges intensive care to be unjustified.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Infants receive either vitamin D supplementation or placebo for the first 28 days after birth

4 weeks

Daily administration

Follow-up

Participants are monitored for growth, neurodevelopment, and respiratory outcomes

2 years

Extended Follow-up

Monitoring of respiratory support and neurodevelopmental outcomes

22 to 26 months corrected age

What Are the Treatments Tested in This Trial?

Interventions

• 800 IU/day vitamin D supplementation with feedings in the first 28 days after birth
• Placebo
• Usual Care

Trial Overview The study tests if giving a high dose of vitamin D (800 IU/day) to extremely premature babies helps their bones, lungs, immune system and brain compared to usual care. Babies are randomly given either the vitamin D supplement or no extra vitamins in their first month.

How Is the Trial Designed?

Group I: Usual care plus vitamin D supplementation Experimental Treatment 2 Interventions

Infants will receive cholecalciferol 800 IU/day in the first 28 days after birth, given enterally four times per day (0.5mL per dose = 200 IU) until the infant is provided 400 IU/day. At that point the study cholecalciferol will be reduced to 400 IU/day for a total supplementation of 800 IU/day.

Group II: Usual care plus placebo Active Control 2 Interventions

Infants will receive placebo (normal saline) in the first 28 days after birth. Co-interventions will be unaffected and provided based on the judgment of the attending neonatal faculty and NICU policies and routine practices.

800 IU/day vitamin D supplementation with feedings in the first 28 days after birth is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Cholecalciferol for:

• Prevention and treatment of vitamin D deficiency
• Rickets
• Osteomalacia

Approved in United States as Vitamin D3 for:

• Prevention and treatment of vitamin D deficiency
• Rickets
• Osteomalacia

Approved in Canada as Cholecalciferol for:

• Prevention and treatment of vitamin D deficiency
• Rickets
• Osteomalacia

Who Is Running the Clinical Trial?

The University of Texas Health Science Center, Houston

Lead Sponsor

Trials

974

Recruited

361,000+

Published Research Related to This Trial

In a study of 66 very low birth weight (VLBW) infants, early supplementation with 800 IU of vitamin D starting at 2 weeks of age was found to be safe and effective, achieving an 88% probability of vitamin D sufficiency by 36 weeks for those with initial levels ≥10 ng/mL.

For infants with lower initial vitamin D levels (<10 ng/mL), the supplementation still showed promise, with a 65% probability of achieving sufficiency, indicating that vitamin D intake may significantly improve vitamin D status in vulnerable populations like VLBW infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of early supplementation with 800 IU of vitamin D in very preterm infants followed by underlying levels of vitamin D at birth. Cho, SY., Park, HK., Lee, HJ.[2022]

In a study of 25 healthy premature infants, daily supplementation of 500 IU of vitamin D2 significantly increased their plasma 25-hydroxyvitamin D levels from 30.6 nmol/l at birth to 65.3 nmol/l after 37 days, indicating effective absorption and metabolism of vitamin D2.

The increase in vitamin D levels was primarily due to the D2 fraction, while levels of vitamin D3 remained unchanged, suggesting that vitamin D2 supplementation is effective for rapidly achieving adequate vitamin D status in premature infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vitamin D nutritional status of premature infants supplemented with 500 IU vitamin D2 per day. Markestad, T., Aksnes, L., Finne, PH., et al.[2019]

In a study of 111 preterm babies, 12.6% were found to be vitamin D insufficient at birth, but this number rose dramatically to 52.2% at 6 weeks despite daily supplementation of 400 IU of vitamin D.

The findings suggest that the current recommended daily dose of 400 IU is insufficient to prevent vitamin D insufficiency in preterm infants, indicating a need for further research into higher supplementation doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vitamin D status and adequacy of standard supplementation in preterm neonates from South India. Tergestina, M., Jose, A., Sridhar, S., et al.[2018]

In a study of 120 preterm neonates, those receiving 1000 IU of vitamin D3 daily had a significantly lower prevalence of vitamin D insufficiency (2%) compared to those receiving 400 IU (64.6%) at 40 weeks of corrected gestational age.

While some infants on the higher dose experienced elevated vitamin D levels (9.8%), there were no signs of toxicity, suggesting that 1000 IU is a safe and effective supplementation level for reducing vitamin D insufficiency in preterm infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized double-blind controlled trial comparing two regimens of vitamin D supplementation in preterm neonates. Tergestina, M., Rebekah, G., Job, V., et al.[2022]

In a study of 83 very low birth weight infants, over half had low vitamin D levels at birth, but most achieved sufficient levels within 3 weeks with a daily intake of 120-400 IU.

Intakes above 600 IU/day were linked to a higher risk of vitamin D excess, indicating that careful monitoring of vitamin D intake is crucial for these infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vitamin D status in very low birth weight infants and response to vitamin D intake during their NICU stays: a prospective cohort study. Adnan, M., Wu, SY., Khilfeh, M., et al.[2022]

In a study of 109 preterm infants, monitored vitamin D supplementation (800-1000 IU) resulted in safer vitamin D levels compared to standard therapy, with a higher percentage of infants maintaining safe levels at 52 weeks of post-conceptional age.

Standard therapy led to a 23% discontinuation rate due to potentially toxic vitamin D levels, highlighting the importance of monitoring to prevent both deficiency and overdose in vitamin D supplementation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitored Supplementation of Vitamin D in Preterm Infants: A Randomized Controlled Trial. Kołodziejczyk-Nowotarska, A., Bokiniec, R., Seliga-Siwecka, J.[2021]

Vitamin D is essential for calcium absorption and bone health in infants, with a recommended daily intake of 400 IU for both preterm and full-term infants to prevent conditions like rickets, although rickets in premature infants is primarily due to calcium and phosphorus deficiency rather than vitamin D deficiency.

There is no strong evidence supporting routine testing of vitamin D levels or the need for high serum vitamin D levels in healthy infants, and while vitamin D toxicity is rare, care should be taken to avoid excessive doses from supplements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vitamin D in Preterm and Full-Term Infants. Abrams, SA.[2021]

In a study of 11 very low birth weight infants over 3 weeks, daily vitamin D intake of 380 to 480 IU maintained normal levels of plasma 25-hydroxyvitamin D and significantly increased 1,25-dihydroxyvitamin D concentrations.

The increase in 1,25-dihydroxyvitamin D was not linked to calcium or phosphorus absorption, suggesting that its levels are more closely related to the infants' maturity rather than their mineral absorption capabilities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vitamin D and mineral metabolism in the very low birth weight infant receiving 400 IU of vitamin D. Cooke, R., Hollis, B., Conner, C., et al.[2019]

In a study of 32 preterm infants receiving either 400 or 800 IU/day of vitamin D3 for 4 weeks, those on the higher dose showed a significant increase in serum 25(OH)D3 levels, indicating better vitamin D status.

Infants receiving 400 IU/day were more likely to have low bone density, suggesting that an 800 IU/day dose may be more beneficial for improving bone health and overall growth in preterm infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized trial of two doses of vitamin D3 in preterm infants Anderson-Berry, A., Thoene, M., Wagner, J., et al.[2018]

In a study of 301 preterm infants, about 80% had deficient or insufficient vitamin D levels at 4 weeks of age, highlighting a common issue among very low birth weight (VLBW) and extremely low birth weight (ELBW) infants.

Vitamin D supplementation significantly improved 25-hydroxy vitamin D levels in VLBW infants by 8 and 12 weeks, while ELBW infants showed slower improvement, indicating that while supplementation is effective, monitoring is essential to prevent excessively high vitamin D levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serum 25 Hydroxy Vitamin D Levels in Very Low Birth Weight Infants Receiving Oral Vitamin D Supplementation. Munshi, UK., Graziano, PD., Meunier, K., et al.[2019]

A study of 378 preterm infants in a neonatal intensive care unit showed that monitoring daily Vitamin D intake significantly improved the amount of Vitamin D these infants received.

The improvement in Vitamin D intake was observed in both extremely low birth weight infants (less than 1000 g) and very low birth weight infants (1000-1500 g), highlighting the importance of monitoring for ensuring adequate nutrient intake.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vitamin D Intake in Very Low Birth Weight Infants in Neonatal Intensive Care Unit. Munshi, UK., Graziano, PD., Meunier, K., et al.[2018]

A study involving 39 preterm infants showed that a lower vitamin D dose of 200 IU/kg (up to 400 IU/day) is effective in maintaining normal vitamin D levels and achieving similar bone mineral density as the higher recommended dose of 960 IU/day.

The results indicate that the lower dose is sufficient for bone health, suggesting that excessive vitamin D should be avoided in preterm infants due to potential risks, as both doses resulted in comparable bone mineral content and density.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomised controlled trial of vitamin D supplementation on bone density and biochemical indices in preterm infants. Backström, MC., Mäki, R., Kuusela, AL., et al.[2019]

In a study of 10 preterm infants, it was found that they can produce high levels of 1.25-dihydroxyvitamin D, with concentrations significantly higher than those in adults, indicating their ability to metabolize vitamin D effectively despite their premature birth.

No signs of rickets were observed in these infants, suggesting that the daily intake of about 400 I.U. of vitamin D3 through total parenteral nutrition and enteral feeding is sufficient to maintain healthy vitamin D levels during early development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plasma 1.25-dihydroxyvitamin D concentrations in preterm infants. Fetter, WP., Mettau, JW., Degenhart, HJ., et al.[2019]

Citations

1. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of early supplementation with 800 IU of vitamin D in very preterm infants followed by underlying levels of vitamin D at birth. [2022]

2. Sweden pubmed.ncbi.nlm.nih.gov

Vitamin D nutritional status of premature infants supplemented with 500 IU vitamin D2 per day. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Vitamin D status and adequacy of standard supplementation in preterm neonates from South India. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

A randomized double-blind controlled trial comparing two regimens of vitamin D supplementation in preterm neonates. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Vitamin D status in very low birth weight infants and response to vitamin D intake during their NICU stays: a prospective cohort study. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Monitored Supplementation of Vitamin D in Preterm Infants: A Randomized Controlled Trial. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Vitamin D in Preterm and Full-Term Infants. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Vitamin D and mineral metabolism in the very low birth weight infant receiving 400 IU of vitamin D. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Randomized trial of two doses of vitamin D3 in preterm infants [2018]

10. United States pubmed.ncbi.nlm.nih.gov

Serum 25 Hydroxy Vitamin D Levels in Very Low Birth Weight Infants Receiving Oral Vitamin D Supplementation. [2019]

11. United States pubmed.ncbi.nlm.nih.gov

Vitamin D Intake in Very Low Birth Weight Infants in Neonatal Intensive Care Unit. [2018]

12. England pubmed.ncbi.nlm.nih.gov

Randomised controlled trial of vitamin D supplementation on bone density and biochemical indices in preterm infants. [2019]

13. Sweden pubmed.ncbi.nlm.nih.gov

Plasma 1.25-dihydroxyvitamin D concentrations in preterm infants. [2019]