Letter to the Editor: Association between mixed fatty acid emulsion and parenteral nutrition–associated cholestasis in extremely low birthweight infants: A retrospective cohort study

We read with great interest the recent article “Association between mixed fatty acid emulsion and parenteral nutrition–associated cholestasis in extremely low-birth-weight infants: A retrospective cohort study.” The study investigates the comparative effects of mixed fatty acid emulsion (SMOF) and medium-chain triglyceride/long-chain triglyceride lipid emulsions on the incidence of parenteral nutrition–associated cholestasis (PNAC) in extremely low birthweight (ELBW) infants.1 We appreciate the authors’ exploration of the association between SMOF and PNAC in premature infants, but we would like to highlight some potential limitations that warrant further consideration. First, we would like to emphasize the standardization of nutrition practices. The study compares two cohorts separated by a time period (2016–2018 vs 2018–2022) during which SMOF was introduced as the sole lipid emulsion. Although the authors mention that nutrition practices were standardized, potential confounding factors exist in clinical practice—such as evolving sepsis management,2 evolving feeding protocols after 2018,3 or the introduction of donor breast milk in 2021.4 Failure to account for these factors may have affected the comprehensive assessment of the study. Second, the dosage and duration of lipid emulsion administration should be included in the overall assessment of clinical value. The study reports average lipid intakes but does not explore the potential impact of cumulative exposure or dosing intensity over time.5 Given that PNAC is a dose- and duration-dependent condition, a more granular analysis of lipid exposure (eg, cumulative grams per kilogram over the first 4 weeks) could provide deeper insight into the relationship between lipid emulsions and liver injury. Third, although the total sample size (N = 180) was adequate to detect the primary outcome, the subgroup analyses for high-risk infants (eg, those requiring PN >28 days or with necrotizing enterocolitis [NEC] at at least stage IIa) were underpowered. For instance, only 13 infants with NEC were included, limiting the ability to draw meaningful conclusions about the efficacy of SMOF in this particularly vulnerable subgroup. Fourth, the observed lower gamma-glutamyl transferase (GGT) levels in the SMOF group are intriguing but underdiscussed. GGT is a marker of cholestasis and oxidative stress, and its suppression may reflect a milder hepatic insult.6 However, the authors did not pursue this finding further, possibly missing an opportunity to explore the potential hepatoprotective effects of SMOF despite the lack of effect on bilirubin-based PNAC. In conclusion, this study offers a valuable contribution to understanding the association between mixed fatty acid emulsion and PNAC in ELBW infants and promotes continued advancements in optimizing PN strategies for this fragile population. Our comments are intended to further improve and strengthen this excellent work. None declared.