LCPUFA Supplementation in Pre-term Infants: Is it required?

Docosahexaenoic acid (DHA), a long chain polyunsaturated fatty acid (LCPUFA), is necessary for cognitive, visual, and immunity development of an infant. The maximum in utero accretion of LCPUFA occurs in the third trimester. As preterm infants are born prior to this accretion window, their DHA levels may remain persistently low. Despite receiving nutrition through human milk, fortified human milk or formula feed, their DHA deficit continues affecting overall physiological development. Present article discusses the need and benefits of providing DHA supplementation to the preterm infants and current provisions for overcoming this nutritional gap.

It is well known that DHA is necessary for cognitive, visual and immunity development in newborns. European Food Safety Authority (EFSA), US Department of Health & Human Services, and a Joint FAO/WHO Expert Consultation recommend that pregnant or lactating women should consume a minimum of 300mg/day of preformed DHA plus EPA (with at least 200mg/day of DHA)¹. After birth, neonates are solely dependent on the enteral sources, such as breast milk or supplemental milk formula to meet their nutritional (including DHA) requirement. However, maternal diet, gestational age, stage of lactation, obesity, FADS genotype etc. contribute to the varying content of the DHA in the human milk³. While DHA is important for the term infants, it is critical for preterm infants as they are born prior to the period of maximum DHA accretion in utero (last trimester).

DHA Deficit in Preterm Infants

Overall fetal DHA accretion has been estimated to be around 10g, most of which is deposited during last 10 weeks of pregnancy. The rate of deposition is around 42-67 mg/day during the third trimester. Preterm infants (25-32 weeks) miss in utero accretion window and thus DHA deficit begins right from the birth⁴. De Rooy et.al. evaluated the levels of DHA in extremely premature infants (≤ 28 weeks) receiving standard care and reported at the end of 6 weeks observation period that the infants received only 36.6% of DHA as compared to what they would have received in utero⁵. Additionally, this deficit persists due to the limited ability to convert precursor fatty acid (ALA) to DHA in adequate amounts and decreased adipose stores in extremely preterm infants. Filling this gap through the dietary intake is also challenging because even after several weeks of age, suckling reflexes remain underdeveloped in many cases. As these factors are unique with preterm infants, there is a critical need to provide direct DHA supplementation to preterm infants or to mothers for ensuring overall physiological, immunological & cognitive development.

Benefits of DHA Supplementation in Preterm Infants

1. Reduces the incidence of Inflammatory diseases

   Premature infants are at higher risk of inflammatory-mediated diseases which increase the risk of associated morbidity and mortality.

   • Necrotizing enterocolitis (NEC), an inflammatory disease, can affect the long-term health of 5-10% of VLBW infants. Preterm infants receiving an experimental formula with egg phospholipids showed significantly less stage II and III NEC compared to infants fed with control formula. Egg phospholipid formula provided 7-fold more AA, DHA and esterified choline compared to control formula⁷.
   • Another study revealed that maternal fish oil supplementation equivalent to LCPUFA of 1.5 g/day in lactating mothers resulted in increased IFN-gamma (indicative of faster maturation of immunity) production at 2-year follow-up in their children⁸.
   • A follow-up study of DINO trial evaluated the long-term respiratory and allergy outcomes at 18 months in 322 infants supplemented with high DHA diet. The study found statistically significant alleviation in the incidence of hay fever but no reductions in food allergies, eczema, or asthma⁹.
2. Cognitive and Visual Outcomes
   • A short-term (6-month follow up) study performed by Henriksen et.al. determined the effect of DHA (32 mg/d) and AA (31 mg/d) supplementation on the cognitive development at 6 months of age. Preterm infants fed with DHA and AA supplementation were noted to have better recognition memory and higher problem-solving scores¹⁰.
   • Preterm infants (<33 weeks' gestational age) receiving formulas containing DHA (0.26%) and AA (0.44%) for 12 months CA did not show significant development on the visual acuity at 2, 4, and 6 months of age but their Bayley Mental Development Index, Bayley Motor Development Index, and vocabulary comprehension were better than control infants at 12 months¹¹.
   • A small group of kids born preterm were followed up for 9 years to assess the effect of DHA supplementation on their overall cognitive development. The study pointed that the LCPUFA supplementation is a key factor in cognitive benefit and the children who were on LCPUFA supplementation had higher IQ (test done were Wechsler Abbreviated Scale of Intelligence, Neuropsychological Test for Children etc.), and memory score in comparison to the children who do not receive LCPUFA¹².
   • Another benefit was indicated by a randomized, double-blind clinical trial that provided high DHA (1% of total fatty acid) enteral feeds compared to standard (0.3% of total fatty acid) feeds. The study indicated that DHA dose in early life did not increase the MDI (mental development index) score of overall infant born (< 33 weeks) but improved the mental development of the girl infants. The study further concluded that higher DHA dose was able to improve mental development in girl infants¹³.
   • Clandinin et.al. fed preterm infants with formulas containing DHA (17 mg/day) and AA (34 mg/day) until 92 weeks noted enhanced growth, higher Bayley mental and psychomotor development scores at 118 weeks compared to infants who received non-supplemented formulas¹⁴.
3. Reducing the Severity of Retinopathy of Prematurity(ROP)

Retinopathy of prematurity (ROP) is caused due to abnormal development of retinal vasculature resulting in visual impairment and blindness in premature infants. Studies have observed the reduced risk of ROP by providing a fat emulsion containing fish oil compared to the standard emulsion. The authors also noted higher plasma and erythrocyte DHA levels after DHA supplementation suggesting long-term neurodevelopmental benefits^15,16.

Current Provisions for DHA Supplementation

Filling the gap of prematurity while ensuring adequate nutritious diet is extremely critical in preterm infants. The consensus group of the World Association of Perinatal Medicine, the Early Nutrition Academy, and the Child Health Foundation recommend that the supplemental milk formula should contain 0.2-0.5% of total FAs as DHA and equal or greater amount of AA to support infant growth¹⁷. Currently, human milk or formula feeds (without LCPUFAs) are provided to the preterm infants, but they may not overcome the preterm deficit. Hence, higher DHA dose (> 0.32%) may be necessary to achieve significant physiological benefits. However, the route of administration and the dose to 'normalize' the DHA levels in preterm infants is challenging because of the variability in the development of the gastrointestinal system of an infant. Additionally, infants are not fed by enteral route completely and available IV products may not contain preformed DHA. Several studies have considered DHA-rich oral emulsions (containing fish or soybean oil) through fetal or maternal DHA supplementation to address this issue^{8, 18}. These studies have supported DHA supplementation in premature infants.

Scientifically, clinically, and physiologically the need of DHA supplementation is clear. DHA deficit in preterm infants continues for an extended period due to multiple factors. Hence the provision for filling the gap of prematurity is necessary to reduce the morbidity, mortality, and to ensure overall physiological, immunological & cognitive development.

Would you consider higher than normal LCPUFA content for feeding preterm infants?