Comment on ‘Antenatal melatonin for cardiovascular deficits in fetal growth restriction’

Dear Editor, I read with great interest the article by Rock et al., which evaluates whether antenatal melatonin supplementation ameliorates cardiovascular dysfunction in a sheep model of placental insufficiency–induced fetal growth restriction (FGR). The authors report that melatonin crosses the placenta, reduces fetal oxidative stress, improves cardiac mitochondrial respiration and partially restores vascular reactivity (Figures 2–4, pp. 6–9). These findings provide important mechanistic insights into the potential role of melatonin as a therapy for FGR-associated cardiovascular impairment (Rock et al., 2025). A major strength of the study lies in its methodological rigour. The authors employ a well-established large-animal model that closely mirrors human fetal cardiovascular development. Their multimodal methodological framework, including continuous maternal melatonin infusion, repeated fetal blood sampling, isolated vessel myography and high-resolution mitochondrial respirometry enables an integrated evaluation of haemodynamics, vascular physiology and cellular bioenergetics. This alignment across levels of analysis strengthens causal inferences about oxidative stress and mitochondrial involvement in FGR pathophysiology. Furthermore the use of blinded outcome adjudication, strict tissue-processing protocols and standardized sampling intervals enhances internal validity. However several methodological limitations should be addressed in future work. First small sample sizes in individual experimental arms limit statistical power and precision, increasing susceptibility to type II error. Although mixed-effects modelling is appropriate, the study may not be fully powered to detect sex-specific or severity-dependent effects. Second Table 1 reveals notable variability in degrees of FGR between animals within a group. Without stratified analyses or covariate adjustment, this heterogeneity could confound the interpretation of treatment-associated effects. Third although cardiac oxidative stress and mitochondrial function are evaluated comprehensively, related assessments in placental or vascular tissues are limited, restricting the mechanistic scope of the findings. Pharmacokinetic sampling also merits further examination. The study relies on two fetal melatonin concentration measurements, which may not characterize circadian variation or steady-state dynamics, an important consideration given the inherently rhythmic biology of melatonin. Finally haemodynamic measurements were obtained during surgical instrumentation and anaesthesia, which may alter autonomic regulation. Including sham-operated controls or sensitivity analyses could strengthen the interpretation of cardiovascular endpoints. Placing these results in the context of existing literature, the human phase I pilot protocol by Alers et al. (2013) described antenatal melatonin as a plausible neuroprotective strategy in FGR, though outcomes remain unpublished. A recent systematic review by Fantasia et al. (2022) assessed melatonin in placental insufficiency pregnancies and highlighted the paucity of large-scale trials and methodological variability. The review by Rock et al. (2024) specifically emphasized melatonin's cardioprotective potential in FGR contexts. Compared to these studies, Rock et al.’s work offers one of the most comprehensive mechanistic investigations to date. Overall Rock et al. (2025) deliver an important methodologically robust contribution that advances our understanding of antenatal melatonin in FGR. Future work should aim for larger, sex-balanced cohorts, extended longitudinal follow-up into the post-natal period and detailed pharmacokinetic modelling to support clinical translation. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The authors declare no conflicts of interest. A.K.: Conceptualization, critical review. A.B.: Literature evaluation, content refinement. N.N.D.: Scientific review, manuscript editing. J.R.P.: Primary drafting of the manuscript, correspondence handling. S.P.: Literature support, manuscript revision. All authors contributed to the final manuscript and approved its submission. The authors declare that no external funding was received for this work. The authors acknowledge institutional academic support. No additional assistance was received.