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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding DHA, a type of omega-3 fatty acid, to the milk of very preterm infants can improve head growth without affecting body fat gain. Many growth-restricted premature babies are born with low DHA levels, which may impact their growth. The trial compares two groups: one receiving milk with added DHA and one without. Babies born very early, between 22 and 32 weeks, and at a lower birth weight might be suitable for this study. As an unphased trial, this study offers a unique opportunity to contribute to understanding how DHA supplementation might benefit very preterm 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 DHA supplementation is likely to be safe for premature infants?

Research has shown that DHA, a type of omega-3 fatty acid, is generally safe for babies born prematurely. One study found that giving DHA by mouth until about 36 weeks of age was linked to better thinking skills at age 5. Another study showed that DHA did not affect growth or body composition when assessed at age 7. These findings suggest that DHA is well-tolerated.

Additionally, clinical trials indicate that DHA is safe and might even benefit very premature babies. However, one study noted that a high dose of DHA might not prevent certain conditions like BPD, a lung issue in newborns. Overall, DHA appears to be a safe choice for premature infants. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about DHA supplementation for premature infants because it offers a potentially vital boost to early brain and eye development. Unlike standard nutritional care that may not adequately provide these essential fatty acids, DHA directly supplements the diet with omega-3 fatty acids, which are crucial for neural and visual development. By adding DHA to human milk, there's hope for improved developmental outcomes during a critical time window, making this approach a promising enhancement over current nutritional options for preemies.

What evidence suggests that DHA supplementation might be an effective treatment for growth-restricted very preterm infants?

Research has shown that giving DHA (a type of fat) to very preterm infants can aid their development. Some studies suggest that adding DHA to a newborn's diet can enhance growth and brain development. In this trial, one group of participants will receive a DHA/ARA supplement added to expressed human milk or donor human milk during the first three weeks after birth. Preterm infants often have lower DHA levels, which can affect brain and cognitive skills. Increasing DHA levels early might improve growth and development. However, not all studies agree, and some have found no significant effects. Despite mixed evidence, DHA remains a promising option for supporting the growth of premature infants. ^{1 4 6 7 8}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

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 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]

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]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2206868

Neonatal Docosahexaenoic Acid in Preterm Infants and ... Preterm infants born before 30 weeks' gestation have reduced DHA concentrations in neural tissues, which may contribute to poorer cognitive ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2405457724013330

Maternal high-dose docosahexaenoic acid ... In very preterm infants, high-dose DHA supplementation did not improve behavioral functioning at 5 years.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6583023/

Effect of Docosahexaenoic Acid Supplementation vs ... In some trials, dietary DHA supplementation initiated in the neonatal period has improved global developmental outcomes in preterm infants.

4. sciencedirect.com sciencedirect.com/science/article/pii/S2352385915300219

The role of the omega-3 fatty acid docosahexaenoic acid The best evidence for the ability of DHA to improve respiratory outcomes in preterm infants comes from our “Docosahexaenoic acid for Improvement in ...

5. jamanetwork.com jamanetwork.com/journals/jama/fullarticle/2768134

Effect of Maternal Docosahexaenoic Acid Supplementation ... Supplementation with DHA in lactating mothers did not significantly improve bronchopulmonary dysplasia–free survival in preterm infants.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9867194/

Effect of Docosahexaenoic Acid (DHA) Supplementation ... DHA supplementation of premature infants did not affect growth, body composition, or blood pressure at 7-year CA overall by sex and birthweight strata.

7. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2802678

Association Between Enteral Supplementation With High- ... These results suggest that high-dose DHA enteral supplementation should not be recommended for prevention of BPD in very preterm infants.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12002185/

a collaborative individual participant data meta-analysis - PMC Neonatal supplementation with high-dose docosahexaenoic acid (DHA) omega-3 may benefit neurodevelopment in very preterm infants, ...