DHA Supplementation for Premature Infants

Overseen By Ariel A Salas, MD, MSPH

Age: < 18

Sex: Any

Trial Phase: Academic

Sponsor: University of Alabama at Birmingham

Disqualifiers: Congenital anomalies, Terminal illness

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 3 weeks

152 Participants Needed

Trial Summary

What is the purpose of this trial?

Growth-restricted very preterm infants (VPT) are born without adequate fat mass (FM) deposits and low docosahexaenoic acid (DHA) concentrations. They often experience further declines in DHA concentrations during the initial three weeks post-birth while advancing enteral feeds and receiving lipid supplementation predominantly through parenteral nutrition. These suboptimal enteral and parenteral nutrition practices significantly heighten the risk of faltering postnatal growth. One promising approach to mitigate these issues is enteral DHA supplementation. However, it remains unclear whether the early administration of DHA through enteral supplementation could lead to a more substantial increase in head growth without affecting FM accretion in growth-restricted VPT infants. To address this question, we propose a masked randomized clinical trial involving 152 VPT infants.

Will I have to stop taking my current medications?

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

What data supports the effectiveness of the treatment DHA for premature infants?

Research shows that DHA supplementation in premature infants can improve visual development and help maintain healthy DHA levels, which are important for overall health and neurodevelopment. Additionally, DHA has been linked to better visual outcomes and growth in preterm infants. ^{1 2 3 4 5}

Is DHA supplementation safe for premature infants?

Research shows that DHA supplementation is generally safe for premature infants. Studies have evaluated its use in infant formulas and as a direct supplement, finding it well-tolerated without significant safety concerns. ^{4 6 7 8 9}

How is the treatment DHA supplementation unique for premature infants?

DHA supplementation is unique for premature infants because it directly addresses the DHA deficiency that these infants face, which is crucial for their neurodevelopment. Unlike other strategies that rely on increasing DHA in mother's milk or formula, this treatment provides a direct enteral (through the digestive tract) supplementation of DHA, ensuring that even extremely premature infants who cannot reach full feedings receive adequate DHA levels. ^{4 8 9 10 11}

Eligibility Criteria

This trial is for very preterm infants born smaller than usual (below the 25th percentile in birthweight) and between 22 to nearly 33 weeks of gestation. It's not open to babies with serious birth defects, chromosomal anomalies, or those with terminal illnesses where life support is limited.

Inclusion Criteria

Gestational ages between 22 0/7 - 32 6/7 weeks gestation

< 25th centile birthweight

Exclusion Criteria

I have a significant birth defect.

Terminal illness in which decisions to withhold or limit support have been made

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

DHA/ARA supplement is added to expressed human milk or donor human milk during the first 3 weeks after birth

3 weeks

Follow-up

Participants are monitored for head circumference and fat mass accretion until 36 weeks postmenstrual age or discharge

Up to 33 weeks

Long-term follow-up

Cognitive outcomes are assessed at 2 years of age using the Bayley assessment

2 years

Treatment Details

Interventions

• DHA

Trial Overview The study tests if giving DHA, an important fat, right after birth can help these tiny babies grow better, especially their heads. The trial randomly assigns them to receive DHA supplementation early on while monitoring growth without affecting body fat accumulation.

Participant Groups

Group I: Intervention Active Control 1 Intervention

A DHA/ARA supplement will be added to expressed human milk or donor human milk administered during the first 3 weeks after birth.

Group II: Control Active Control 1 Intervention

No DHA/ARA supplement will be added to expressed human milk or donor human milk administered during the first 3 weeks after birth.

DHA is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as DHA for:

• Pregnancy and lactation support
• Cardiovascular health
• Infant nutrition

Approved in European Union as DHA for:

• Pregnancy and lactation support
• Cardiovascular health
• Infant nutrition
• Cognitive function

Approved in Canada as DHA for:

• Pregnancy and lactation support
• Cardiovascular health
• Infant nutrition

Approved in Japan as DHA for:

• Infant nutrition
• Cardiovascular health

Who Is Running the Clinical Trial?

University of Alabama at Birmingham

Lead Sponsor

Trials

1,677

Recruited

2,458,000+

Mead Johnson Nutrition

Industry Sponsor

Trials

80

Recruited

15,900+

Findings from Research

Feeding preterm infants milk with three times the standard amount of docosahexaenoic acid (DHA) did not lead to significant improvements in language development or behavior by early childhood, as measured by various standardized assessments.

The study involved a double-blind randomized controlled trial with 127 preterm infants, and the results showed no clinically meaningful differences in language and behavioral outcomes between the higher-DHA group and the control group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feeding preterm infants milk with a higher dose of docosahexaenoic acid than that used in current practice does not influence language or behavior in early childhood: a follow-up study of a randomized controlled trial. Smithers, LG., Collins, CT., Simmonds, LA., et al.[2023]

Preterm infants fed a formula with 1% docosahexaenoic acid (DHA) showed improved visual acuity at 4 months corrected age compared to those fed a formula with approximately 0.3% DHA, indicating that higher DHA levels may enhance visual development.

The study suggests that the DHA needs of preterm infants may exceed current levels provided in standard formulas or human milk, highlighting the potential for optimizing nutritional interventions for better visual outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher dose of docosahexaenoic acid in the neonatal period improves visual acuity of preterm infants: results of a randomized controlled trial. Smithers, LG., Gibson, RA., McPhee, A., et al.[2023]

In a study involving 657 preterm infants, neonatal supplementation with high doses of docosahexaenoic acid (DHA) did not significantly reduce hospitalizations for lower respiratory tract (LRT) conditions compared to standard DHA supplementation.

While there was a trend suggesting that boys receiving high DHA had fewer hospitalizations for LRT issues, this finding was not statistically significant, indicating that higher DHA may not have a clear benefit in preventing respiratory-related hospitalizations in preterm infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Respiratory hospitalisation of infants supplemented with docosahexaenoic acid as preterm neonates. Atwell, K., Collins, CT., Sullivan, TR., et al.[2013]

A study involving 60 preterm infants (24-34 weeks gestational age) showed that daily enteral DHA supplementation (50 mg/day) significantly increased blood DHA levels over time, addressing the deficiency commonly seen in these infants.

The supplementation was found to be safe, with no differences in adverse events between the DHA and placebo groups, although preterm infants still had lower DHA levels compared to term peers at discharge.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daily Enteral DHA Supplementation Alleviates Deficiency in Premature Infants. Baack, ML., Puumala, SE., Messier, SE., et al.[2018]

Supplementation with DHA and ARA in formula-fed premature infants significantly improved weight gain compared to those on a control formula, with infants gaining 34.7 g/d versus 30.7 g/d.

There were no negative effects on visual acuity or adverse events associated with DHA or DHA+ARA supplementation, indicating it is a safe option for enhancing growth in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docosahexaenoic acid and arachidonic acid enhance growth with no adverse effects in preterm infants fed formula. Innis, SM., Adamkin, DH., Hall, RT., et al.[2013]

Preterm infants fed formulas containing docosahexaenoic acid (DHA) and arachidonic acid (ARA) showed significantly greater weight and length growth compared to those on unsupplemented formulas, with growth metrics comparable to term infants by 118 weeks postmenstrual age (PMA).

The supplemented groups also achieved higher mental and psychomotor development scores at 118 weeks PMA without an increase in adverse events, indicating that DHA and ARA supplementation is both safe and beneficial for developmental outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Growth and development of preterm infants fed infant formulas containing docosahexaenoic acid and arachidonic acid. Clandinin, MT., Van Aerde, JE., Merkel, KL., et al.[2013]

Preterm infants fed a formula enriched with low eicosapentaenoic fish oil showed significantly higher levels of docosahexaenoic acid (DHA) in their red blood cell phospholipids compared to those fed a standard formula, indicating improved DHA status essential for their development.

However, this enrichment also led to higher levels of eicosapentaenoic acid and lower levels of arachidonic acid, suggesting that while DHA status improves, the balance of n-6 fatty acids may be negatively affected, indicating a potential need for additional arachidonic acid in their diet.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of low-EPA fish oil for long-chain polyunsaturated fatty acid supplementation of preterm infants. Lapillonne, A., Picaud, JC., Chirouze, V., et al.[2013]

DHA supplementation after birth (ex utero) for preterm infants showed more significant improvements in neurodevelopmental outcomes compared to DHA supplementation during pregnancy (in utero).

The effectiveness of DHA supplementation varied based on the sex of the child and their birth weight, suggesting that these factors may influence how well infants respond to DHA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DHA supplementation during the perinatal period and neurodevelopment: Do some babies benefit more than others? Makrides, M.[2013]

The study will follow 194 very preterm infants who received high doses of DHA or a placebo to assess long-term neurodevelopmental outcomes at 5 years of age, focusing on aspects like executive functions and behavioral problems.

The primary goal is to confirm that at least 75% of eligible children will participate in the follow-up, which will help evaluate the effectiveness of DHA supplementation on neurodevelopment in preschool-aged children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of maternal docosahexaenoic acid supplementation on brain development and neurodevelopmental outcomes of breastfed preterm neonates: protocol for a follow-up at preschool age of a randomised clinical trial (MOBYDIckPS). Guillot, M., Robitaille, CA., Turner, L., et al.[2022]

Preterm infants receiving formula supplemented with DHA and AA showed significantly higher Mental Development Index (MDI) and Physical Development Index (PDI) scores at both 6 months and 1 year compared to those who did not receive supplementation, indicating potential benefits for neurodevelopment.

The study involved 27 preterm infants and found no adverse effects from the supplementation, suggesting that DHA and AA are safe for use in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of supplementation of docosahexaenoic acid and arachidonic acid on visual acuity and neurodevelopment in larger preterm infants. Fang, PC., Kuo, HK., Huang, CB., et al.[2013]

Preterm infants are at risk of a significant daily DHA deficit of 20 mg/kg, which is 44% less than the amount needed for optimal development, highlighting the inadequacy of current human milk and preterm formulas in meeting their DHA needs.

To address this deficit and support neurological development, it is recommended to increase the DHA content in human milk through maternal supplementation or direct addition, aiming for approximately 1.5% of total fatty acids as DHA, especially for infants with a birth weight below 1250 g.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reevaluation of the DHA requirement for the premature infant. Lapillonne, A., Jensen, CL.[2009]

References

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

Feeding preterm infants milk with a higher dose of docosahexaenoic acid than that used in current practice does not influence language or behavior in early childhood: a follow-up study of a randomized controlled trial. [2023]

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

Higher dose of docosahexaenoic acid in the neonatal period improves visual acuity of preterm infants: results of a randomized controlled trial. [2023]

3. Australia pubmed.ncbi.nlm.nih.gov

Respiratory hospitalisation of infants supplemented with docosahexaenoic acid as preterm neonates. [2013]

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

Daily Enteral DHA Supplementation Alleviates Deficiency in Premature Infants. [2018]

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

Docosahexaenoic acid and arachidonic acid enhance growth with no adverse effects in preterm infants fed formula. [2013]

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

Growth and development of preterm infants fed infant formulas containing docosahexaenoic acid and arachidonic acid. [2013]

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

The use of low-EPA fish oil for long-chain polyunsaturated fatty acid supplementation of preterm infants. [2013]

8. Scotland pubmed.ncbi.nlm.nih.gov

DHA supplementation during the perinatal period and neurodevelopment: Do some babies benefit more than others? [2013]

9. England pubmed.ncbi.nlm.nih.gov

Effects of maternal docosahexaenoic acid supplementation on brain development and neurodevelopmental outcomes of breastfed preterm neonates: protocol for a follow-up at preschool age of a randomised clinical trial (MOBYDIckPS). [2022]

10. China (Republic : 1949- ) pubmed.ncbi.nlm.nih.gov

The effect of supplementation of docosahexaenoic acid and arachidonic acid on visual acuity and neurodevelopment in larger preterm infants. [2013]

11. Scotland pubmed.ncbi.nlm.nih.gov

Reevaluation of the DHA requirement for the premature infant. [2009]