INTRODUCTION — Supplementation of enteral feedings with long-chain polyunsaturated fatty acids (LCPUFAs) has been proposed to improve outcomes in infants, particularly neurodevelopmental outcomes. Accumulating evidence suggests that supplementing feedings with dietary LCPUFAs is beneficial for preterm infants. It remains uncertain whether supplements have benefits for term infants.
This topic will review the evidence regarding whether or not dietary LCPUFA supplementation of enteral feedings is beneficial. The risk and benefits of maternal intake of LCPUFAs through fish intake during pregnancy and the potential benefits of LCPUFAs consumed as dietary seafood or fish oil in adults are discussed separately. (See "Fish consumption and marine omega-3 fatty acid supplementation in pregnancy" and "Fish oil: Physiologic effects and administration".)
Metabolism and function — LCPUFAs are configured as n-6 and n-3 structures (also referred to as omega-6 and omega-3 fatty acids, respectively). In an n-6 fatty acid, the first double bond from the methyl end is at the C6 position . In an n-3 fatty acid, the first double bond is at the C3 position .
The LCPUFAs are synthesized in the liver endoplasmic reticulum and peroxisomes by a series of desaturase and elongase enzymes, and the n-6 and n-3 LCPUFAs compete for these enzymes in their biosynthesis (figure 1) [3,4]. Biosynthesis depends on precursor availability and enzyme activity, which may be limiting in ill or preterm newborns [5,6].
Docosahexaenoic acid and other n-3 LCPUFAs — Docosahexaenoic acid (DHA) is the biologically active end product of alpha-linolenic acid, which is an essential fatty acid because it is exclusively attained from the diet. DHA is primarily derived from fish, especially oily fish such as herring, tuna, and salmon, as well as n-3-fed chickens and their eggs . Eicosapentaenoic acid is a precursor of DHA and is metabolized to DHA in the liver.
DHA is important for development of the nervous system because it is an integral component of the phospholipid membrane of brain and retinal cells. DHA and eicosapentaenoic acid also play a role in antiinflammatory eicosanoid/docosanoid synthesis, signaling events, gene expression, and cytokine expression. In one study, DHA supplements to lactating mothers decreased inflammatory markers and increased relative DHA concentrations in their preterm infants .
DHA is preferentially incorporated into the rapidly developing brain and retina during the last trimester of pregnancy and the first 24 months of life, with ongoing accumulation throughout childhood [9-12]. Autopsy analysis estimates that the fetus accumulates 50 to 60 mg/day of DHA during the third trimester of gestation . It is estimated that the store of DHA at term birth is approximately 1050 mg . Over the first six months of life, infants accumulate DHA at a rate of approximately 20 mg/day and approximately one-half of all dietary DHA is incorporated into the brain. As a result, women who are pregnant or breastfeeding need to consume sufficient n-3 LCPUFA to ensure adequate DHA accretion in the fetus and breast milk.
Arachidonic acid and other n-6 LCPUFAs — Arachidonic acid (ARA) is the biologically active end product of alpha-linoleic acid, which is an essential fatty acid because it is exclusively attained from the diet. ARA can be derived directly from animal foods or seed oils, which are rich in n-6 linoleic acid, the precursor for ARA. In the United States, the typical diet is high in seed oils and thus higher in n-6 compared with n-3 LCPUFA. Human milk generally contains more ARA than DHA, and the amount does not vary substantially with maternal dietary intake .
ARA is a major component of brain phosphoglycerides, generally in greater concentrations compared with DHA . In addition, ARA has a proinflammatory role in eicosanoid/docosanoid synthesis. Thus, the relative excess of n-6 LCPUFAs in the typical diet in the United States has a proinflammatory influence.
Suggested dietary requirements — The following are published suggested enteral intakes in infants, representing expert consensus based primarily on indirect evidence from intrauterine accretion rates in healthy fetuses:
●Infants 0 to 6 months
•Institute of Medicine in the United States :
-n-6 fatty acids 4.4 g/day
-n-3 fatty acids 0.5 g/day
•World Health Organization (WHO) :
-ARA 0.4 to 0.6 percent of fatty acids
-DHA 0.2 to 0.36 percent of fatty acids
●Infants 6 to 24 months
-Linoleic acid 3 to 4.5 percent of energy
-DHA 10 to 12 mg/kg body weight
•European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) :
-DHA 12 to 30 mg/kg
-ARA 18 to 42 mg/kg
-Alpha-linolenic acid (precursor for DHA) >55 mg/kg
-Linoleic acid (precursor for ARA) 385 to 1540 mg/kg
These ESPGHAN recommendations focus on infants weighing 1000 through 1800 g because this is the weight range in which most data are available .
LCPUFA content in milk
Human milk — LCPUFA content varies in human milk and depends on maternal diet and body stores [10,19,20]. Typical DHA concentration is 0.2 to 0.4 percent of total fatty acids (g per 100 g total fatty acids) but can be as low as 0.1 percent in the milk produced by a malnourished woman or as high as 2 percent in a woman who consumes fish as a main dietary source (a 20-fold increase) [21,22].
In the United States, the average amount of DHA in human milk is approximately 0.35 weight percent; a mother who consumes 100 mg/day of DHA will maintain this concentration in her breast milk . Term infants who consume 750 mL/day of human milk with a concentration of 0.35 weight percent have a daily DHA intake of 100 mg, which is consistent with the recommended intake outlined above. (See 'Suggested dietary requirements' above.)
Human milk sources with low DHA concentration are more concerning for preterm infants who are deprived of fetal DHA that normally accrues at an average rate of 50 to 60 mg/kg/day during the last trimester of pregnancy [9,24]. In the United States, DHA concentrations in maternal and donor human milk used in neonatal intensive care units are frequently low, with reported mean values between 0.1 and 0.32 weight percent, which may not meet the needs of premature infants [19,21,25,26]. As an example, a DHA milk concentration of 0.1 weight percent only provides a dietary intake of 12 mg/kg/day for the preterm infant fed 150 mL/kg enteral milk, whereas a milk concentration of 0.5 weight percent at the same volume would result in an intake of 60 mg/kg/day [4,27,28]. Thus, for some populations, human milk may be relatively low in DHA. In human milk-fed very low birth weight (VLBW) infants, enteral supplementation increases blood DHA concentrations and prevents the postnatal decline in levels that is seen without supplementation .
The concentration of DHA in breast milk rises with increased maternal fish consumption . The United States Dietary Guidelines for Americans recommends consuming a variety of seafood to achieve at least 250 mg/week n-3 LCPUFA intake. Mercury in seafood is a concern primarily for fish harvested from contaminated waters. As a result, we follow the United States Environmental Protection Agency guidelines that recommend that breastfeeding mothers consume one to three weekly servings of a variety of types of seafood to ensure adequate breast milk DHA content . These recommendations are intended to achieve a maternal dietary DHA intake of at least 200 to 300 mg/day. (See "Fish consumption and marine omega-3 fatty acid supplementation in pregnancy".)
Infant formula — In the 1980s and early 1990s, several studies demonstrated that n-3 LCPUFA concentration was lower in plasma and red blood cells of formula-fed infants compared with infants who received human milk [32-34]. Data were also being accumulated on DHA's role in brain and retinal cell structural development [9-12]. As a result, LCPUFAs, after obtaining the US Food and Drug Administration "GRAS" (Generally Recognized As Safe) status, were added in varying formulations and concentration to formulas for term and preterm infants. The vast majority of infant formula sold in the United States contains LCPUFAs, although the concentration varies between formulas, based on the manufacturer's decisions about targets for DHA intake. DHA-containing infant formulas generally provide DHA at concentrations of 0.15 to 0.32 weight percent (ie, percent of total fatty acids). This is intended to provide approximately the amount of DHA found in breast milk . However, whether LCPUFA (or DHA) supplementation has clinical benefits remains controversial, with the strongest evidence related to visual benefits. (See 'Clinical trials' below.)
RATIONALE FOR LCPUFA SUPPLEMENTATION — There is some, but inconsistent, evidence that breastfeeding compared with infant formula feeding is associated with improved cognition (ie, 3 to 5 points on cognitive tests) and with visual acuity in preterm infants. Although the mechanism of this effect is uncertain, it has been hypothesized that these results are due, at least in part, to differences in docosahexaenoic acid (DHA) content, which is present in human milk but not in bovine milk. (See "Infant benefits of breastfeeding", section on 'Neurodevelopmental outcomes'.)
LCPUFAs, and particularly DHA, are important components of the developing brain and retina, accumulating especially during the third trimester of gestation and the first six months of life. Breastfed infants have higher levels of LCPUFA in the cerebral cortex than those fed standard infant formula . In addition, the known antiinflammatory effects of omega-3 (n-3) LCPUFAs have led to hypotheses that DHA supplementation to premature infants might reduce risks for comorbid disease.
Together, these observations have led to the hypothesis that supplementation of bovine milk-based formula with LCPUFAs would improve cognition and visual acuity and possibly reduce comorbid disease in preterm infants. Addition of DHA to human milk via human milk fortifiers (HMFs) or supplements given to the lactating mother have also been suggested for preterm infants to compensate for the loss of accretion during the third trimester of pregnancy. However, clinical trials have not consistently shown that LCPUFA supplementation improves outcomes in preterm and term infants, as discussed below (see 'Clinical trials' below). Nonetheless, the overwhelming majority of infant formulas used in the United States and many other countries contain LCPUFA supplementation at varying levels.
CLINICAL TRIALS — More than 30 clinical trials have been conducted to evaluate the effect of supplementation of LCPUFAs. Most of the trials have focused on possible effects on cognition, visual acuity, and/or growth. The duration of omega-3 (n-3) LCPUFA feeding in infancy is consistently related to visual acuity at one year of age. Brain development as measured by the Bayley Scales of Infant and Toddler Development is not affected by LCPUFA feeding, though a few studies with specialized measures of problem-solving have been positive.
Term or preterm infants — Studies that analyzed the following outcomes focused on infants born at term or preterm. The study populations varied, but, when preterm infants were included, they were generally >1500 g birth weight:
●Visual acuity – Systematic reviews in preterm or term infants generally suggest that supplementation of infant formula with docosahexaenoic acid (DHA) has beneficial effects on visual acuity [14,37-39]. As an example, a systematic review noted modest effects of LCPUFA supplementation in infant formula on visual acuity (as measured by visual evoked potentials) at 2, 4, and 12 months of age . The effect was small, with weighted mean difference -0.11 (95% CI -0.02 to -0.03).
●Cognitive outcomes – Four systematic reviews failed to show any significant effect of LCPUFA supplementation in infant formula on cognitive development, which was, in most cases, measured by the Bayley Scales of Infant and Toddler Development [37,39,41,42]. One of these focused on preterm infants and found no significant effect on cognition as measured at 12 or 18 months post-term across seven studies . Another included a meta-analysis of 12 trials including 1802 term or preterm infants and also found no significant effect of LCPUFA overall or of LCPUFA dose or prematurity . Some studies compared different doses of LCPUFA in formula-fed infants, whereas others compared infants fed LCPUFA-supplemented formula with a human milk-fed control group. More data are needed to fully understand cognitive outcomes in supplemented human milk-fed preterm and full-term infants.
Very long-term data related to infant supplementation have begun to become available. In follow-up data from one study, infants who received LCPUFA-supplemented infant formula had long-term positive effects on brain structure, function, and neurochemical outcomes at 5.5 and 9 years of age compared with a control group fed a standard infant formula [43,44]. Of note, some of these effects of DHA and arachidonic acid (ARA) may be mediated by genetic polymorphisms regulating fatty acid metabolism .
●Growth – Although individual studies have reported either increased or decreased growth in infants with LCPUFA supplementation, meta-analyses showed no significant effect on growth overall [37-39]. Nonetheless, preliminary data have shown a relationship between red blood cell n-3 LCPUFA concentrations and neonatal body composition, such that higher red blood cell DHA levels were associated with lower fat mass . Further studies are needed to determine relationships between LCPUFA levels and long-term body composition outcomes.
Very low birth weight infants — Effects of LCPUFA supplementation have been examined separately in very low birth weight (VLBW) infants (<1500 g) because of the known deficiencies of LCPUFA in this population and their vulnerability to unique medical complications. The available clinical trial data on LCPUFA supplementation in VLBW infants are limited by considerable variability in study design, including differences in gestational ages and birth weights of the study participants, variability in the composition and dosing of supplements, differences in whether infants were fed human milk or formula, and variability in outcomes assessed.
Taken together, the data suggest that DHA supplementation (whether provided through a human milk fortifier [HMF], infant formula, standalone supplement, or maternal supplementation) is safe and may improve outcomes for retinopathy of prematurity (ROP), vision, cognition, and, possibly, necrotizing enterocolitis (NEC). It is uncertain whether DHA increases the risk of bronchopulmonary dysplasia (BPD); if there is an effect, it is likely small and would not outweigh the other possible benefits in most circumstances. Most trials used DHA doses that approximate in utero accretion (eg, 50 to 80 mg/kg/day), which is more than that provided in human milk fortified with standard HMFs available in the United States (which provide approximately 20 mg/kg/day). The role for concomitant supplementation with ARA is unclear, although it is generally recommended that ARA be included when DHA is provided .
The main evidence for each outcome is summarized below:
●ROP – In a randomized trial in infants <28 weeks gestation, combined supplements with ARA (100 mg/kg/day) and DHA (50 mg/kg/day) decreased the risk of ROP by 50 percent (15.8 versus 33.3 percent; relative risk [RR] 0.50, 95% CI 0.28-0.91) . This beneficial effect occurred despite only modest increases in the serum levels of ARA and DHA. This study found no effect on other comorbid diseases, including NEC. By contrast, other trials and a meta-analysis did not detect a reduction in ROP rates in infants who received DHA supplementation [48-50]. Many of these trials did not include ARA supplementation, and this may have contributed to lack of benefit. (See "Retinopathy of prematurity (ROP): Treatment and prognosis", section on 'Prevention'.)
●Cognitive outcomes – The benefit of LCPUFA supplementation on cognitive outcomes in VLBW infants is supported by several randomized trials [38,51-57]. Some studies have demonstrated improvements in mental development index (MDI) [51,54,55], while others did not detect a difference [56-58]. (See "Long-term neurodevelopmental impairment in infants born preterm: Epidemiology and risk factors", section on 'Differences in study design'.)
•In a 2016 meta-analysis of seven randomized trials involving preterm infants, supplementation with any n-3 LCPUFA modestly improved cognitive scores at 18 to 24 months (mean difference 2.2 points [95% CI 0.05-4.4] on the Bayley-II MDI) . However, there was considerable heterogeneity between the trials in the meta-analysis.
•The largest trial included in the meta-analysis was the DINO trial (DHA for the Improvement of Neurodevelopmental Outcome in preterm infants), in which 657 preterm infants (<33 weeks gestation, 45 percent <1200 g) were randomly assigned to high-DHA or standard-DHA enteral feeds (primarily achieved through supplements given to lactating mothers) . At 18 months corrected age, the rate of severe developmental delay (defined as MDI <70) was lower in the high-DHA group compared with the standard-DHA group (5.2 versus 10.5 percent, respectively; adjusted relative risk [aRR] 0.49, 95% CI 0.26-0.97). Mean MDI scores were not statistically different between the two groups (adjusted mean difference 1.6 points [95% CI -1.2 to 4.3]). In a follow-up study that included a subset of approximately 20 percent (n = 128) of the original DINO cohort, scores on standardized language and behavioral assessments at age two to five years were similar in both groups .
•Further support for the benefit of DHA supplementation on cognitive outcomes in preterm infants is provided from a study published after the meta-analysis, which reported long-term neurodevelopmental outcomes in a subset of infants who were enrolled in one of the neonatal DHA supplementation trials described above [48,54]. The original trial involved 1273 preterm infants (<29 weeks gestation) who were randomly assigned to DHA supplementation (60 mg/kg/day) or placebo (soy emulsion) started at the time of initiating enteral feeds and continued until 36 weeks of postmenstrual age or neonatal intensive care unit discharge . Approximately 70 percent of the surviving children from the original trial cohort (n = 457) underwent cognitive assessment at age five years. Scores on standardized tests were higher for the DHA-supplemented group compared with placebo (adjusted mean difference 3.5 points [95% CI 0.4-6.5] for full-scale intelligence quotient [IQ]) . This difference approaches the four-point IQ difference that has been considered clinically relevant for public policy. The rate of severe cognitive impairment (IQ <70) was lower in the DHA group compared with the control group (7 versus 12 percent), but the finding did not achieve statistical significance (aRR 0.6, 95% CI 0.33-1.08).
The effects of maternal n-3 LCPUFA consumption during pregnancy on neurodevelopment and other outcomes in the offspring are inconclusive, as discussed in a separate topic review. (See "Fish consumption and marine omega-3 fatty acid supplementation in pregnancy".)
●NEC – In a randomized trial in 226 VLBW infants, supplementation with DHA (75 mg/kg/day, without ARA, given during the first 14 days of enteral feeding) decreased the risk of NEC (RR 0.93, 95% CI 0.88-0.98) . In this study, most infants were fed formula rather than human milk. The study found no effect on other comorbid diseases, including ROP. By contrast, other trials and a meta-analysis did not detect a reduction in NEC rates in infants who received DHA supplementation [47,50]. The observed effects on NEC incidence may be modulated by the amount of human milk in the diet as well as other factors such as probiotic use.
●BPD – In a meta-analysis of 14 trials (3531 preterm infants), rates of BPD were similar in infants who received DHA supplementation compared with control (28.4 versus 28.9 percent, respectively; RR 0.99, 95% CI 0.84-1.18) . In the largest trial, which involved more than 1200 infants <29 weeks gestation, DHA supplementation (60 mg/kg/day without ARA supplementation) did not reduce the risk for BPD and, indeed, may have slightly increased this risk (RR 1.13, 95% CI 1.02-1.25) . Whether the lack of ARA supplementation in this study contributed to any adverse effect is uncertain. There was no significant effect on the incidence of other comorbidities, including ROP and NEC. The dose of supplemental DHA was intended to match the intrauterine accretion rate during the last trimester; enteral feeds supplied an additional 20 mg/kg/day DHA when full feeds were reached. Similarly, a large trial suggested that indirect supplementation (DHA given to lactating mothers) may have increased the infant's risk of BPD .
OUR APPROACH — Based on the above evidence, we suggest the following approach to LCPUFA nutrition for preterm and term infants:
●Maternal diet – Women who are pregnant or breastfeeding should include a source of omega-3 (n-3) LCPUFA in their diet, such as one to three weekly servings of seafood that is low in mercury (table 1), consistent with dietary guidelines in the United States . Women who are not able or willing to consume this amount and type of seafood should consume supplements or fortified foods to achieve docosahexaenoic acid (DHA) intake of at least 200 to 300 mg/day. This target is intended to provide sufficient amounts of n-3 LCPUFAs to ensure adequate accretion of n-3 LCPUFAs for the fetus and infant. This goal is particularly important for mothers of preterm infants because these infants miss the placental transfer of n-3 LCPUFAs during part of the third trimester. (See "Maternal nutrition during lactation", section on 'Fish intake' and "Fish consumption and marine omega-3 fatty acid supplementation in pregnancy" and 'Term or preterm infants' above.)
●DHA supplementation – For very low birth weight (VLBW) infants who are fed human milk, we suggest supplementation of DHA. DHA doses of 20 to 50 mg/day are supported by clinical evidence, but the optimal DHA dose and the role of concomitant supplementation with arachidonic acid (ARA) have not been established.
We achieve this supplementation using the combination of human milk with a standard human milk fortifier (HMF). The liquid HMFs available in the United States include DHA 15 to 20 mg/kg/day and ARA in approximately a 1:1.5 to 1:2 DHA:ARA (mg:mg) ratio . This is a safe and practical approach, although it supplies somewhat less DHA than was used in most clinical trials (50 to 80 mg/kg/day, with or without ARA), which found modest benefits of supplementation for some comorbidities of prematurity and for cognitive outcomes. In settings where the available HMFs do not contain DHA and ARA, it is reasonable to combine the available HMF with separate supplements to provide the target doses of DHA and ARA. (See 'Very low birth weight infants' above.)
●For formula-fed term and larger preterm infants (>1500 g birth weight), data are mostly inconclusive regarding benefits of n-3 LCPUFA provision, although there may be some modest positive effects on visual outcomes. There is good evidence that addition of LCPUFAs to infant formula is safe and does not have adverse effects on growth using the typical doses in commercially available formulas [23,37]. (See 'Term or preterm infants' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Breastfeeding and infant nutrition".)
SUMMARY AND RECOMMENDATIONS
●Biochemistry and physiology
•Docosahexaenoic acid (DHA) is an omega-3 (n-3) long-chain polyunsaturated fatty acid (LCPUFA) that is the biologically active end product of the essential fatty acid, alpha-linolenic acid. It is an integral component of the brain and retinal phospholipid membrane. It is preferentially incorporated into the rapidly developing brain and retina during the last trimester of pregnancy and the first two years of life, with ongoing accumulation through childhood. (See 'Docosahexaenoic acid and other n-3 LCPUFAs' above.)
•DHA is present in human milk but not in bovine milk. This is thought to be one possible mechanism for the beneficial effects of breastfeeding on neurocognitive and visual development compared with infant formula feeding. (See 'Rationale for LCPUFA supplementation' above and "Infant benefits of breastfeeding", section on 'Neurodevelopmental outcomes'.)
•Arachidonic acid (ARA) is an omega-6 (n-6) LCPUFA that is the biologically active end product of alpha-linoleic acid. It is a major component of brain phosphoglycerides (generally in greater concentrations compared with DHA) and also has a proinflammatory role in eicosanoid/docosanoid synthesis. The ratio of ARA to DHA in the diet or supplements may influence the net effects on inflammation. (See 'Arachidonic acid and other n-6 LCPUFAs' above.)
•Preterm infants miss some of the fetal accretion of n-3 LCPUFAs including DHA and ARA, which normally occurs during the third trimester of pregnancy. Human milk often provides less DHA than needed to mimic the intrauterine accretion values of 50 mg/day. (See 'Suggested dietary requirements' above and 'Human milk' above.)
●Approach to LCPUFA supplementation
•Pregnant and lactating women – Pregnant and lactating women should consume one to three weekly servings of a variety of types of seafood high in n-3 LCPUFAs or consume another source of n-3 LCPUFAs that provides at least 200 mg/day DHA. This recommendation and the supporting evidence are discussed separately. (See "Fish consumption and marine omega-3 fatty acid supplementation in pregnancy".)
•Breast milk-fed infants – We encourage human milk feeding for virtually all infants for a variety of health benefits, as discussed separately. (See "Infant benefits of breastfeeding".)
For most very low birth weight (VLBW) infants (<1500 g) who are fed human milk, we suggest supplementation of DHA and ARA (Grade 2C). Until further information is available, it is reasonable to provide these nutrients through the combination of human milk plus a standard human milk fortifier (HMF) that contains DHA and ARA. The HMFs available in the United States provide approximately the target doses of DHA and ARA that are recommended by expert consensus in Europe. However, it should be noted that substantially higher doses were used for some of the clinical trials of LCPUFA supplementation in this population. (See 'Our approach' above.)
Clinical trials investigating DHA (with or without ARA supplementation) in VLBW infants have reached variable conclusions, with some finding lower rates of retinopathy of prematurity (ROP), modest improvements in cognitive outcomes, and reduced risk of necrotizing enterocolitis (NEC), while other trials did not detect a benefit in these outcomes. It is uncertain if DHA supplementation impacts the risk of bronchopulmonary dysplasia (BPD); on balance, the available evidence suggests minimal to no effect on BPD (neither benefit nor harm). (See 'Very low birth weight infants' above.)
•Formula-fed infants – For formula-fed term and preterm infants, we suggest using a formula that includes LCPUFAs (Grade 2C). It is uncertain if including LCPUFAs in infant formula improves neurocognitive outcomes, but there may be some modest effects on visual outcomes and it appears to be safe. The vast majority of currently available infant formulas for term and preterm infants include LCPUFAs. Most provide DHA at concentrations of 0.15 to 0.32 weight percent (ie, percent of total fatty acids), which approximates the amount found in breast milk. However, the concentrations of DHA and ARA vary between formulas and the optimal concentrations remain uncertain. (See 'LCPUFA content in milk' above and 'Term or preterm infants' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Christina J Valentine, MD, MS, RD, who contributed to earlier versions of this topic review.
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