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?

This trial aims to determine if extra vitamin D improves lung, bone, immune system, and brain health in extremely premature infants (born before 28 weeks or weighing less than 1000 grams). One group of infants will receive vitamin D supplements with their feedings, while another group will receive a placebo. The researchers will compare these two groups to assess whether vitamin D significantly impacts their development. Infants born extremely early or with very low birth weight are ideal candidates for this study. As an unphased trial, this study provides a unique opportunity to enhance understanding of how vitamin D might benefit the health of extremely premature infants.

Will I have to stop taking my current medications?

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

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that giving preterm infants 800 IU of vitamin D daily is safe. Studies have found that this dosage can significantly improve vitamin D levels without causing harm. For instance, one study found that 800 IU/day safely increased vitamin D levels in very low birth weight infants. Another study noted benefits such as improved bone strength and growth with this higher dose of vitamin D in preterm infants. These findings suggest that the treatment is well-tolerated, with no serious side effects reported. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Unlike the standard of care for premature infants, which often involves routine supplementation with lower doses of vitamin D, this treatment uses a higher dosage of 800 IU/day of vitamin D. Researchers are excited about this approach because vitamin D plays a crucial role in bone health and immune function, and premature infants are at higher risk for deficiencies. By providing a higher dose early on, this method aims to better support the infants' rapid growth and development, potentially reducing complications associated with prematurity.

What evidence suggests that vitamin D supplementation might be an effective treatment for premature infants?

Research has shown that giving vitamin D to preterm infants can greatly improve their health. In this trial, some infants will receive a high dose of vitamin D (800 IU per day) to boost levels of a form of vitamin D crucial for strong bones, a healthy immune system, and overall growth. Studies have found that vitamin D supplements in preterm infants link to a drop in vitamin D deficiency rates from 83% at birth to as low as 40%. This supplementation also associates with better growth, such as increased weight and length. Overall, this amount of vitamin D is considered safe and effective for these small patients. ^{1 2 6 7 8}

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

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

My condition is congenital.

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

Exclusion Criteria

My baby was born after 32 weeks of pregnancy.

My unborn child has been diagnosed with a condition affecting vitamin D absorption.

Any major congenital anomaly

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

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]

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 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]

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]

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]

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 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 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]

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 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]

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 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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8537871/

Monitored Supplementation of Vitamin D in Preterm Infants Earlier studies reported an incidence of VDD in preterm infants between 64–83% at birth which was reduced by vitamin D supplementation to 40–66% [32,33].

2. nature.com nature.com/articles/s41372-025-02440-9

Short-term and long-term effects of vitamin D ... High-dose (≥800 IU/day) vitamin D supplementation for preterm infants was associated with positive short-term outcomes, encompassing ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40507157/

Improving Vitamin D Status in Preterm Newborns Vitamin D3 supplementation at 800 IU/day significantly improved vitamin D status and reduced hypovitaminosis D in preterm newborns, without observed toxicity.

4. nature.com nature.com/articles/s41598-024-75191-w

Effects of vitamin D supplementation on serum 25(OH)D3 ... The 25(OH)D3 levels of preterm infants at 42 days of age were positively correlated with VD supplementation during pregnancy, and before 42 days ...

5. publications.aap.org publications.aap.org/pediatrics/article/150/Supplement%201/e2022057092K/188647/Enteral-Vitamin-D-Supplementation-in-Preterm-or

Enteral Vitamin D Supplementation in Preterm or Low Birth ... Our systematic review found moderate certainty evidence of increase in weight, length, and reduction in vitamin D deficiency during first 6 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5634602/

Randomized trial of two doses of vitamin D3 in preterm ... Improvement in 25(OH)D3 levels at 4 weeks, bone density, and trends towards improvement in linear growth support consideration of a daily dose ...

7. ijponline.biomedcentral.com ijponline.biomedcentral.com/articles/10.1186/s13052-017-0361-0

Efficacy and safety of early supplementation with 800 IU of ... Vitamin D intake of 800 IU/day safely achieved an 88% probability of vitamin D sufficiency at 36 weeks postmenstrual age in VLBW infants with ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT02273843?term=AREA%5BBasicSearch%5D(CALCIUM%20AND%20CHOLECALCIFEROL%20AND%20PHOSPHORUS)&rank=9

A Trial on Different Dosages of Vitamin D in Preterm Infants ... This is a randomized controlled trial (RCT) to evaluate the influence of different doses of vitamin D3 (800 IU/d versus 400 IU/d), on serum levels of ...