Why the DHA-ARA Balance Could Redefine Nutrition for Very Preterm Infants

Every year, roughly one in ten babies worldwide arrives before 37 completed weeks of gestation, the World Health Organization’s threshold for preterm birth. For the smallest and earliest of these infants, the weeks after delivery are a race against biology: organs that should still be developing inside the womb must now cope with the demands of the outside world. Among the many clinical battles fought in neonatal intensive care units, one of the most consequential and least visible concerns fat. Not just any fat, but two long-chain polyunsaturated fatty acids, docosahexaenoic acid and arachidonic acid, known to researchers as DHA and ARA. A new commentary published in Pediatric Research by Alessandra Mazzocchi, Veronica D’Oria and Carlo Agostoni of the University of Milan and Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico argues that the field’s focus on dosing DHA alone has missed a crucial point: what matters may be less the absolute amount of each fatty acid than the balance between them.

The scientific case for concern begins in the third trimester of pregnancy, a period of astonishing neural construction. During these final months, the fetal brain roughly quintuples in weight, and approximately 80 percent of the DHA and ARA that will accumulate in the brain over the entire course of development is deposited in this window. Both fatty acids are actively and selectively ferried across the placenta, a process that operates at peak intensity precisely when preterm infants are no longer connected to it. DHA, the dominant omega-3 fatty acid of the central nervous system, is a major structural component of neuronal membranes and of the photoreceptors in the retina. It participates in neurogenesis, synaptogenesis, myelination and neurovascular coupling, and it shapes visual development and cognitive function. Its influence extends beyond structure: DHA modulates membrane signalling pathways, alters gene expression through epigenetic mechanisms, and serves as the raw material for bioactive lipid mediators involved in neuroprotection and the control of inflammation.

ARA, its omega-6 counterpart, has long lived in DHA’s shadow in the public imagination, where omega-6 fats are often caricatured as harmful. In the developing brain, nothing could be further from the truth. ARA is an essential structural component of cell membranes, highly represented in the brain and many peripheral tissues, and it plays a key role in growth, brain development and immune function. Like DHA, it is a precursor of bioactive lipid mediators that regulate inflammation, vascular homeostasis and cellular signalling. Crucially, the two fatty acids are metabolically intertwined. They compete for the same elongation and desaturation enzymes and for incorporation sites in cell membranes, which means that flooding the system with one can crowd out the other. The consequence, the Milan authors emphasize, is that the relative ratio of DHA to ARA, and not merely the total supply, may determine neurodevelopmental and immunological outcomes.

Preterm birth derails this carefully choreographed transfer in two ways at once. First, it cuts off the placental supply before the third-trimester accretion is complete. Second, it prevents the infant from building the adipose tissue reserves that in term babies act as a buffer, slowly releasing fatty acids to support postnatal needs. The result is a paradox that has puzzled clinicians: circulating DHA and ARA concentrations at birth may look comparable to those of term infants, yet they plummet within the first days of life. The abrupt cessation of placental transfer, limited tissue stores and the difficulty of reproducing intrauterine fatty acid status through postnatal nutrition combine to produce a well-documented postnatal decline in blood and tissue levels of both fatty acids in very preterm infants.

The feeding regimen that replaces the placenta makes matters worse. Neonatal intensive care relies on parenteral lipid emulsions and enteral feeding sources whose fatty acid profiles differ substantially from what the fetus would have received in utero, typically delivering higher amounts of linoleic acid and lower amounts of DHA and ARA. This mismatch, the commentary notes, contributes directly to the postnatal LCPUFA deficit. The stakes are high, because such deficiencies have been associated with poorer neurodevelopmental outcomes, impaired visual function, attention deficits and other adverse health consequences that can extend into later life. Very preterm infants are already vulnerable to bronchopulmonary dysplasia, necrotizing enterocolitis, retinopathy of prematurity and long-term neurodevelopmental impairment; an uncorrected fatty acid deficit adds a modifiable risk factor to an already fragile picture.

Supplementation would seem to be the obvious fix, and both maternal and neonatal DHA supplementation strategies have indeed been explored in depth. Yet uncertainty persists about the optimal dose, the route of administration and, increasingly, the appropriate balance between DHA and ARA. Current guidance from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition, ESPGHAN, reflects this shift in thinking. The society recommends that DHA supplementation be accompanied by adequate ARA intake, with suggested doses of 30 to 65 milligrams per kilogram per day for DHA and 30 to 100 milligrams per kilogram per day for ARA, yielding an ARA-to-DHA ratio between 0.5 and 2. Those wide ranges are themselves a confession: the field knows that balance matters, but it does not yet know where within that range the optimum lies.

Recent trials are beginning to map the territory. A randomized controlled trial of early enteral ARA and DHA supplementation in very preterm infants, published in Frontiers in Pediatrics in 2022, and a double-blind randomized controlled trial published in Clinical Nutrition in 2024 that examined ARA and DHA supplementation and brain maturation both point toward measurable effects of combined provision. A secondary outcome analysis reported in 2026 in Archives of Disease in Childhood examined the effect of enteral ARA and DHA supplementation on brain volumes at term, while earlier work published in Pediatric Research in 2021 found that serum DHA levels in extremely preterm infants were associated with brain volumes. On the visual front, a randomized clinical trial published in JAMA Pediatrics in 2021 showed that an enteral lipid supplement reduced severe retinopathy of prematurity, one of the most feared complications of extreme prematurity. A systematic review and meta-analysis published in Translational Pediatrics in 2026 examined retinopathy of prematurity and cognitive development in enteral DHA-supplemented preterm infants, and a trial reported online ahead of print in Pediatric Research in 2026 tracked blood fatty acid changes during enteral DHA supplementation.

Taken together, this body of evidence supports the framing that the Milan commentary advances: DHA supplementation in preterm infants should be considered within the broader context of balanced LCPUFA provision rather than as a single-nutrient intervention. The biological logic is compelling. Because DHA and ARA share enzymatic pathways and membrane slots, giving large amounts of DHA without ARA risks distorting the very membrane composition that brain development depends on, while giving ARA without DHA could deprive neuronal and retinal membranes of their dominant omega-3 component. The developing immune system adds another layer of complexity, since ARA-derived mediators are central to inflammatory regulation and vascular homeostasis, processes implicated in conditions such as necrotizing enterocolitis and retinopathy of prematurity.

What would the next generation of studies need to settle? The commentary’s argument implies that trials should treat the ARA-to-DHA ratio as the primary experimental variable, rather than testing DHA dose alone, and should track outcomes that range from brain volumes and retinal health to immune function and long-term cognitive development. It also implies that the composition of parenteral lipid emulsions and enteral feeds deserves the same scrutiny as any supplement, since the postnatal fatty acid gap is created by the total diet, not by a single missing ingredient. The commentary was partially funded by a contribution from the Italian Ministry of Health through its Ricerca Corrente program, and the authors declare no competing interests, which lends weight to their call for a reframing of the field’s priorities.

For the families of the estimated 9 to 12 percent of infants born preterm worldwide, the fatty acid question may sound abstract next to the ventilators and incubators of the neonatal unit. But the third-trimester brain growth spurt happens whether or not the baby is still inside the womb, and the building materials for that growth must come from somewhere. If the balance of DHA and ARA proves to be as consequential as the commentary argues, then a modest adjustment to feeding protocols, informed by properly designed ratio-based trials, could quietly improve neurodevelopmental trajectories for hundreds of thousands of children each year. The next step in nutrition for very preterm infants, the authors suggest, is not more of one fat, but the right proportion of two.

Subject of Research: Balancing DHA and arachidonic acid supply in the nutrition of very preterm infants

Article Title: Balancing DHA and arachidonic acid: the next step in nutrition for very preterm infants. A commentary

Article References: Mazzocchi, A., D’Oria, V., & Agostoni, C. (2026). Balancing DHA and arachidonic acid: the next step in nutrition for very preterm infants. A commentary. Pediatric Research. https://doi.org/10.1038/s41390-026-05509-z

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05509-z

Keywords: DHA, arachidonic acid, preterm infants, LCPUFAs, neurodevelopment, ESPGHAN, retinopathy of prematurity, neonatal nutrition, third trimester, brain development, Pediatric Research, fatty acid ratio