New findings in human milk fortification. Which fortifier, how, and when? [Session: Nutritional support in high risk infants]

Ann-Marie Brennan gave a clear tour of the human milk fortification evidence, built around three questions: which fortifier, how to fortify, and when to start. She ended with the Irish national experience of integrating fortification with parenteral nutrition.

Why fortify at all

• Unfortified human milk at 150–180 ml/kg/d provides only about 2–2.3 g/kg/d of protein. Even at very high volumes it covers only around 50–60% of the lower ESPGHAN limit for calcium and phosphorus.

• Multinutrient fortification (macronutrients plus minerals) improves in-hospital growth without increasing adverse effects.

• ESPGHAN 2022 recommends a multinutrient fortifier. Individualized strategies (adjustable or targeted) may be appropriate. There is insufficient evidence for routine human milk-derived fortifier. Fortification should start at enteral volumes of 40–100 ml/kg/d.

HOW: standard vs enhanced vs individualized

• Retrospective modelling study (2026), infants <33 weeks: with standard fortification, only 19% of maternal milk samples and 2% of donor milk samples reached 4 g/kg/d of protein, and none reached 4.5. Enhanced fortification brought all samples to 4 g/kg/d, and 74% of maternal and 35% of donor samples to 4.5. Donor milk clearly lags behind. Note that this study estimated delivery, not clinical outcomes.

• Double-blind RCT, n=130, 24–30 weeks: protein and fat supplementation guided by point-of-care milk analysis was compared with standard care, where supplements were added when clinically indicated. Both arms met or exceeded recommendations. There was no difference in weight, length or head growth, in body composition, or in brain MRI indices. Her reading: milk analysis adds little where standard care already reaches targets. That does not mean individualization never works.

• Meta-analysis of individualized vs standardized fortification (10 RCTs, 454 infants): individualized fortification increased weight gain by +2.87 g/kg/d, with gains in length and head growth, fat-free mass (+121 g) and fat mass (+69 g), all at low certainty. At 18 months there was no difference in weight, but only 69 infants contributed. The gains are short-term, not long-term.

WHICH: human vs bovine-derived fortifier

• AAP, BAPM and ESPGHAN do not recommend human milk-derived fortifier over bovine-derived fortifier.

• Jensen et al. RCT, n=228, 22–27 weeks, all on an exclusive human milk diet (maternal or donor): the only difference between arms was the fortifier. The composite primary outcome occurred in 35.7% with human milk-based fortifier vs 34.5% with bovine-based fortifier (OR 1.05). The trial was not powered for NEC alone.

• Systematic review and meta-analysis of 9 RCTs: the authors usefully separated trials by design.

  • Fortifier alone, same base diet: no significant NEC reduction (RR 0.83, wide CI, very low certainty).

  • Fortifier and base diet both differed (human fortifier plus donor milk vs bovine fortifier plus preterm formula): NEC risk was lower.

  • The same pattern held for mortality, ROP and BPD: any benefit appears only when the base diet changes.

• 👉 Take-home: the NEC benefit belongs to the human milk diet, not to the source of the fortifier.

WHEN: timing

• Recommendations vary:

  • ESPGHAN: 40–100 ml/kg/d.

  • European Milk Bank Association: 50–80 ml/kg/d in infants <1800 g.

  • AAP: no threshold.

• Early fortification RCT: very early fortification was compared with fortification at about 120 ml/kg/d. Early fortification reduced weight z-score loss in the first two postnatal weeks and improved linear and head growth (secondary outcomes). It did not reduce postnatal growth failure or change body composition at 36 weeks (the primary outcome).

• Swedish national cohorts, about a decade apart: fortification in the first week of life rose from 3.6% to 27%. NEC also rose (1.7% → 5.8%), but the authors could not attribute this to early fortification.

• Survey of 15 countries and 185 NICUs: large variation in fortifier practice.

• Overall: early fortification looks feasible and safe, with no increase in NEC in the trials, and growth results are encouraging. Practice still varies widely.

The overlooked transition phase: PN + enteral nutrition
Brennan’s key message was that early fortification usually happens while the infant is still on parenteral nutrition. We have precise targets for exclusive PN and for exclusive enteral nutrition, but no international targets or upper limits for combined intakes. Faster advances combined with earlier fortification could push infants into excessive intakes without anyone noticing.

The Cork / Irish solution: the “PremSmart” system

• A standardized system integrating parenteral and enteral nutrition: an aqueous standardized PN plus a standardized lipid infusion, with SPN dosed according to milk feed volume.

• Below 80 ml/kg/d of feeds parenteral targets apply; above 80, the higher enteral targets apply.

• Fortification starts at 80 ml/kg/d.

• The SPN was designed by modelling data from 59 infants. SPN complemented feeds well up to 80 ml/kg/d; beyond that it overshot.

• Clinical evaluation in 49 infants:

  • Intakes were consistently within target, with no excessive intakes, and actual intakes closely matched modelled ones.

  • The historical nutrient deficits during the transition phase disappeared.

  • Early postnatal weight loss was significantly reduced, and better growth was sustained to term-corrected age.

• PremSmart is now national. It accounts for about 95% of all preterm PN used in Ireland, and about 95% of staff use the protocol.

• A national survey (105 responses) found that the most frequent local adaptation was the timing of fortifier introduction. Some units hold back because of NEC experiences (“people are scared after a few babies who get NEC”). Even robust data doesn’t automatically overcome NEC anxiety.

Q&A highlights

• Duration: in Cork, fortification continues until discharge (anywhere from about 35 to 40 weeks), and to term-corrected age if the infant is still in the unit. Beyond growth, the fortifier supplies minerals (Ca, P, iron), so the unit gives no additional iron supplementation. They do not fortify beyond 40 weeks’ corrected age because of the calcium load and the risk of mineral disturbances.

• Discharge at about 36 weeks: decided case by case.

  • Poor growth: some expressed breast milk feeds are fortified until term-corrected age.

  • Good growth: fortification is stopped shortly before discharge to confirm that growth holds.

• Comment from a Swedish colleague: many units treat infants as “on PN” until they switch to “on enteral” and ignore the combination. Similar Swedish work also showed improved intakes and growth.

🎯 Take-home messages

1. Which: with the base diet held constant, the source of the fortifier makes no clear difference. The benefit comes from the human milk diet.

2. How: individualized or targeted fortification adds little when standard practice already reaches targets. Short-term growth gains in meta-analyses don’t persist to 18 months.

3. When: early fortification appears feasible and safe, but recommended thresholds range widely (40–100 ml/kg/d).

4. The gap: we need targets and upper limits for the PN + enteral transition phase, especially as feeds advance faster and fortification starts earlier.

Disclosure: This is an AI-assisted summary of the session, generated from a recording made by our team in attendance. We believe it is as accurate as our own notes would be, but please refer to the speakers’ original work before applying anything in clinical practice.