The dispute began with a letter from Drs. King and Malhotra, who raised concerns about nutritional confounding and reporting limitations in the trial. Their critique touched on issues that recur throughout neonatal nutrition research: the open-label design, the role of industry funding, and the fact that infants in the experimental arm received earlier fortification and additional caloric supplementation compared with those on the standard diet. In neonatal intensive care, feeding protocols, clinical practice, and nutrient delivery are inseparably intertwined, and critics argued that these connected factors muddy the interpretation of growth outcomes. The response, authored by Katsumi Mizuno of Showa Medical University in Tokyo, takes each objection in turn and reframes the entire interpretive exercise.

The first and perhaps most fundamental point concerns why JASMINE exists at all. According to the editorial, the trial was a multicenter, randomized, controlled phase III study conducted specifically to generate growth and safety data for Japan’s Pharmaceuticals and Medical Devices Agency, the PMDA, as part of the regulatory evaluation of human milk-based fortifiers as prescription drugs. This is a crucial distinction. JASMINE was not an academic curiosity designed to isolate a single biological variable; it was a regulatory trial, built to satisfy the requirements of a national agency that treats fortifiers as medicines subject to the same scrutiny as pharmaceuticals. The funding source, product supply, sponsor role, and open-label design were all transparently disclosed, and the study operated under strict Japanese Good Clinical Practice regulations, with regulatory authorities auditing the conduct, management, and analysis of the results.

On the question of industry involvement, the editorial’s position is direct: industry support is standard in studies required to evaluate regulated medical products, and when it is transparently reported and governed by prespecified methods, it does not by itself invalidate the findings. This argument carries weight in the regulatory context. Any company seeking approval for a fortifier product must sponsor the trials that demonstrate its safety and efficacy, and the alternative, leaving such products untested because of their commercial origin, would serve no one, least of all the fragile infants whose care depends on them. The GCP auditing framework adds a layer of independent oversight that goes beyond what many investigator-initiated studies undergo.

The statistical critique received an equally forceful rebuttal. King and Malhotra had suggested that the trial’s growth findings depended heavily on which infants were included in the per-protocol analysis set, implying that exclusions may have driven the result. The response counters this directly. Non-inferiority was assessed exactly as prespecified, followed by superiority testing, and the growth findings were not limited to the per-protocol set. In the intent-to-treat population, which includes all randomized infants regardless of protocol adherence, weight gain velocity was significantly higher in the exclusive human milk diet group than in the standard diet group. The same direction of effect appeared in the per-protocol set and in the Japanese subset analyses. In other words, the editorial argues, both analysis sets were strongly statistically significant, favoring not merely non-inferiority but superiority for growth in terms of weight gain velocity among the premature infants under study. The interpretation, on this account, does not rest on the fate of excluded patients.

The deepest disagreement, however, is conceptual, and it turns on the meaning of the word confounding. King and Malhotra characterized the differences in nutrient delivery between the two arms as confounders, variables that distort the true effect of the fortifier itself. Mizuno’s response rejects this framing entirely. JASMINE, the editorial explains, was never designed to isolate fortifier source under identical feeding advancement and caloric delivery, as other trials have attempted. Instead, it was designed to evaluate whether an exclusive human milk diet strategy could address a distinctly Japanese challenge in neonatal intensive care: supporting early growth in very low birth weight infants within the context of Japanese standard practice, where cow milk-based products are often delayed or limited because of gastrointestinal safety concerns.

This reframing transforms how the trial should be read. The conservative fortification approach in the standard diet arm was not an artificial protocol choice imposed by researchers; it reflected actual Japanese standard care, the real-world baseline against which the experimental strategy was being evaluated. Earlier fortification and the use of caloric fortifiers in the experimental arm were therefore not unplanned co-interventions that contaminated the result. They were prespecified, central features of the exclusive human milk diet protocol being tested. The unit of comparison was not a molecule of fortifier but a complete feeding strategy, evaluated as it would be deployed in Japanese nurseries. Critics who wish to isolate the fortifier alone are, on this view, asking a different question than the one the trial was built to answer.

Why does Japan need its own trial in the first place? The editorial situates the study within a national context that differs markedly from that of the United States and Europe. Japan has excellent survival outcomes for very low birth weight infants and very low baseline rates of necrotizing enterocolitis, the devastating intestinal disease that human milk diets are often promoted to prevent. A 2025 comparative analysis published in Scientific Reports examined necrotizing enterocolitis in preterm infants born in Japan and in infants of Japanese ethnicity born in California, underscoring how strikingly low the Japanese baseline rates are. This epidemiological reality changes the clinical calculus. The question facing Japanese neonatologists is not whether growth can be improved by providing more nutrition in the abstract, but whether adequate early fortification can be achieved without compromising the safety outcomes that Japanese intensive care units have worked so hard to preserve.

That framing explains the trial’s dual endpoints of growth and safety. In a system where necrotizing enterocolitis is already rare, an intervention that accelerates growth but carries even a small gastrointestinal risk could be net harmful, whereas the same intervention might be clearly beneficial in a setting with higher baseline disease rates. The JASMINE results, as summarized in the response, indicate that early fortification with an exclusive human milk diet strategy is feasible in Japanese very low birth weight infants and may improve growth without a statistically significant safety disadvantage. For regulators weighing approval, and for clinicians deciding whether to change entrenched feeding practices, that combination of feasibility, growth benefit, and preserved safety is precisely the evidence package they need.

The editorial closes on a note of measured openness rather than triumph. Mizuno agrees that longer follow-up and additional analyses of nutrient delivery and discharge growth would be valuable, acknowledging that the debate over how best to feed the smallest infants is far from settled. What the exchange ultimately demonstrates is that clinical trial evidence cannot be divorced from the systems in which it is generated. A trial designed to satisfy a national regulator, benchmarked against national practice, and conducted under national auditing standards produces answers calibrated to that nation’s needs. Whether the JASMINE findings will influence practice beyond Japan, or whether other countries will require their own system-specific trials, remains an open question, but the editorial makes a compelling case that interpreting any feeding trial requires asking first what question it was designed to answer, and for whom.

Subject of Research: Exclusive human milk-based diet fortification and growth outcomes in very low birth weight infants in Japanese neonatal intensive care

Article Title: Interpreting the JASMINE trial in the context of Japanese neonatal care

Article References: Mizuno, K. (2026). Interpreting the JASMINE trial in the context of Japanese neonatal care. Journal of Perinatology. https://doi.org/10.1038/s41372-026-02906-4

Image Credits: AI Generated

DOI: 10.1038/s41372-026-02906-4

Keywords: JASMINE trial, exclusive human milk diet, very low birth weight infants, neonatal nutrition, human milk fortifier, PMDA regulation, necrotizing enterocolitis, weight gain velocity, randomized controlled trial, Japanese NICU care, perinatology, clinical trial design