Adding Nutrients to Breast Milk for Premature Babies: What the Biggest Review Yet Does and Doesn't Tell Us

A 2025 study combined 59 trials to compare ways of enriching milk for preterm infants — and found that mother's own milk matters most, but the evidence is thinner than many assume

When a baby is born many weeks early, breast milk is the best food a parent can give — but on its own it does not contain enough protein, calcium, and calories for a tiny baby who still needs to grow at the rapid pace of the womb. For decades, NICU teams have solved this by "fortifying" milk: adding a nutrient powder or liquid so each feed carries more nourishment. A large 2025 study pulled together 59 separate clinical trials to ask a simple question — does the type of milk-and-fortifier combination change how premature babies do? Its reassuring answer is that feeding built around the mother's own milk tends to give the best results; its honest answer is that, for most specific outcomes, the trials are too small and too few to prove that one recipe beats another [1].

Why This Question Matters, and How Families Faced It Before

For families, the choice of what goes into their baby's feeds can feel bewildering and high-stakes, and for good reason: nutrition in the first weeks of life shapes a premature baby's growth, brain development, and risk of serious complications. The most feared of these is necrotizing enterocolitis, or NEC — a sudden, dangerous inflammation of the bowel that is far more common in babies fed formula than in those fed human milk [2]. That single fact is why NICUs the world over try to give mother's own milk first, donor human milk from a milk bank when a mother's supply is not enough, and formula only as a last resort [3].

But a generation ago, and still in many places today, parents and clinicians faced a genuine dilemma once fortification entered the picture. The nutrient powders traditionally added to milk are made from cow's milk. In 2010, a widely discussed trial suggested that babies given an all-human-milk diet — including a fortifier made from human milk rather than cow's milk — had less NEC than babies whose diet included cow's-milk products [2]. This finding helped create a new generation of expensive human-milk-based fortifiers and left families wondering whether the cheaper, standard cow's-milk fortifier was putting their baby at risk. Yet when later researchers designed a cleaner trial that changed only the fortifier and kept everything else the same, the advantage vanished [4]. Major evidence reviews kept reaching the same frustrating conclusion: promising hints, but not enough solid proof to tell parents which choice was truly better [5]. This 2025 study was built to make the most of all those scattered trials at once.

How the Study Worked

The researchers, based in Halifax, Canada, did not run a new experiment on babies. Instead they gathered every high-quality trial they could find — 59 in total, published between 1980 and 2023 — in which premature babies received fortified feeds and at least one group got human milk [1]. They used a statistical technique called network meta-analysis, which is a way of comparing many different feeding recipes even when they were never tested directly against each other, by linking them through the trials that share a common comparison. Think of it as building a map of every road that connects a set of towns, then estimating the distance between two towns that no single road links directly. They sorted the many recipes into 10 broad groups and then ranked those groups for eight important outcomes, including survival, NEC, eye and lung complications of prematurity, bloodstream infection, brain-injury findings, how fast babies reached full feeds, and a developmental test score measured later in childhood.

One thing to understand about this kind of study is that its strength — combining decades of trials — is also its weakness. The trials stretch from 1980 to 2023, a span in which almost everything else about newborn intensive care changed, from the machines that help babies breathe to the way infections are prevented. Two babies fed the "same" recipe forty years apart were cared for in very different worlds, and that makes any single comparison harder to trust. The researchers were careful to build in statistical safeguards to keep a handful of small studies from dominating the results, and they were open about the fact that, for many of the recipes, only one or two small trials existed to draw on.

What They Found

Across most outcomes, the recipes containing more of the mother's own milk tended to rank at or near the top — a pattern that fits everything doctors already believe about the value of a mother's milk. For the two outcomes that matter most, survival and NEC, the highest-ranked recipe was mother's own milk topped up with donor milk and a human-milk-based fortifier. Feeding formula alone ranked at the bottom for NEC, and this was the one clear, statistically convincing result in the whole study: babies on all-human-milk recipes had meaningfully less bowel disease than those on formula [1]. That echoes the long-standing message that human milk protects the fragile newborn gut [6].

The important honesty of the study is in everything else. For eye disease, lung disease, infection, and the developmental score, the rankings were shaky and sometimes did not even make biological sense — for example, a mineral (phosphorus) fortifier came out on top for eye and lung outcomes, which the authors themselves treat as a fluke produced by having only a handful of small studies to work with. In plain terms, most of the comparisons had such wide margins of error that the study could not say with confidence whether one recipe was better or worse than another. A recent large trial comparing donor milk with formula reached a compatible conclusion: no difference in later development, but less NEC with donor milk [7].

What This Means for Families and Their Baby's Care

The practical takeaway is calm and clear. This study is a strong reminder that mother's own milk, supplemented with donor milk when needed, is the foundation of good nutrition for a premature baby — the strategy that ranked best for survival and NEC and the one that guideline groups already recommend [8]. Parents who are working hard to provide milk, or who are relying on donor milk, can be reassured that they are giving their baby the most protective foundation the evidence supports [9].

What the study does not do is tell families that a human-milk-based fortifier is worth insisting on over the standard cow's-milk-based one. Once the base diet is human milk, the trials simply do not show a clear winner between the two fortifier types [4], and because human-milk-based fortifiers are considerably more expensive, each NICU weighs that cost against its own situation. If your baby's team uses a standard fortifier, that is a reasonable, evidence-based choice, not a compromise. And if your baby seems to have trouble tolerating feeds, that is something the team judges baby-by-baby — the study could not even measure feeding tolerance, because the original trials reported it too inconsistently [10]. The best thing families can do is keep asking their team questions and, where possible, keep providing mother's milk, which remains the single most valuable ingredient in any recipe [11].

It can help to keep the big picture in view. Fortification is a small, technical adjustment layered on top of the far larger decision of what milk a baby receives, and it is that larger decision — human milk versus formula — where the evidence is clearest and most protective. Parents sometimes worry that they must fight for a particular brand of fortifier or a particular additive to give their baby the best chance. This study's most useful message is that such fine-grained choices are not where the important differences lie, at least not as far as the current evidence can show. Energy spent supporting a mother's milk supply, or ensuring donor milk is available when it is needed, is far more likely to matter than the choice between two fortifier types. Larger real-world studies that followed babies for years have pointed in the same direction, favouring human-milk-based diets, though they cannot rule out other explanations [12].

What Researchers Are Working On Next

The authors are refreshingly direct that they have reached the limit of what can be learned by combining published trial summaries. To finally settle which fortification recipe is best — and for which babies — they call for a different kind of research: studies that pool the detailed records of individual babies across many hospitals, so that differences in gestational age, era, and local care can be accounted for, and large database studies linked to long-term developmental follow-up [12]. Until those answers arrive, the guidance for families remains steady and hopeful: mother's own milk first, donor milk next, and a fortifier chosen sensibly by the care team.

References

  1. Campbell-Yeo M, Gullickson C, McCulloch H, Disher T, Hughes B. Effect of Multi-Nutrient Milk Fortification on Preterm Neonate Outcomes: A Network Meta-Analysis. Nutrients. 2025;17(10):1651. doi:10.3390/nu17101651 ↩
  2. Sullivan S, Schanler RJ, Kim JH, et al. An Exclusively Human Milk-Based Diet Is Associated with a Lower Rate of Necrotizing Enterocolitis than a Diet of Human Milk and Bovine Milk-Based Products. J Pediatr. 2010;156:562–567.e1. doi:10.1016/j.jpeds.2009.10.040 ↩
  3. Quigley M, Embleton ND, McGuire W. Formula versus Donor Breast Milk for Feeding Preterm or Low Birth Weight Infants. Cochrane Database Syst Rev. 2019;7:CD002971. doi:10.1002/14651858.CD002971.pub5 ↩
  4. O'Connor DL, Kiss A, Tomlinson C, et al. Nutrient Enrichment of Human Milk with Human and Bovine Milk-Based Fortifiers for Infants Born Weighing <1250 g: A Randomized Clinical Trial. Am J Clin Nutr. 2018;108:108–116. doi:10.1093/ajcn/nqy067 ↩
  5. Arslanoglu S, Boquien C-Y, King C, et al. Fortification of Human Milk for Preterm Infants: Update and Recommendations of the EMBA Working Group. Front Pediatr. 2019;7:76. doi:10.3389/fped.2019.00076 ↩
  6. Premkumar MH, Pammi M, Suresh G. Human Milk-Derived Fortifier versus Bovine Milk-Derived Fortifier for Prevention of Mortality and Morbidity in Preterm Neonates. Cochrane Database Syst Rev. 2019;11:CD013145. doi:10.1002/14651858.CD013145.pub2 ↩
  7. Colaizy TT, Poindexter BB, McDonald SA, et al. Neurodevelopmental Outcomes of Extremely Preterm Infants Fed Donor Milk or Preterm Infant Formula: A Randomized Clinical Trial. JAMA. 2024;331:582–591. doi:10.1001/jama.2023.27693 ↩
  8. Darmstadt GL, Al Jaifi NH, Arif S, et al. New WHO Recommendations for Care of Preterm or Low Birth Weight Infants. eClinicalMedicine. 2023;63:102155. doi:10.1016/j.eclinm.2023.102155 ↩
  9. Brown JVE, Embleton ND, Harding JE, McGuire W. Multi-nutrient Fortification of Human Milk for Preterm Infants. Cochrane Database Syst Rev. 2020;6:CD000343. doi:10.1002/14651858.CD000343.pub3 ↩
  10. Meiliana M, Alexander T, Bloomfield FH, et al. Nutrition Guidelines for Preterm Infants: A Systematic Review. JPEN J Parenter Enteral Nutr. 2024;48:11–26. doi:10.1002/jpen.2568 ↩
  11. Uthaya S, Jeffries S, Andrzejewska I, et al. Randomised Controlled Trial of Human Derived Breast Milk Fortifier versus Bovine Milk Fortifier on Body Composition in Very Preterm Babies. Early Hum Dev. 2022;171:105619. doi:10.1016/j.earlhumdev.2022.105619 ↩
  12. Hair AB, Patel AL, Kiechl-Kohlendorfer U, et al. Neurodevelopmental Outcomes of Extremely Preterm Infants Fed an Exclusive Human Milk-Based Diet versus a Mixed Diet. J Perinatol. 2022;42:1485–1488. doi:10.1038/s41372-022-01513-3 ↩