Prematurity, the foremost risk factor for infant mortality and morbidity, poses a critical challenge to public health worldwide. According to the WHO, approximately 15 million babies – more than one in ten – are born prematurely each year over the past decade. The prevalence of preterm births varies substantially, even within developed regions⁽¹⁾. Prematurity is a major contributor to neonatal morbidity, affecting both minor and severe health outcomes. In a cohort comprising 8334 non-anomalous singleton preterm neonates with gestational ages ranging from 23 to 36·9 weeks, significant morbidities, including intraventricular haemorrhage grades III or IV, seizures, hypoxic-ischemic encephalopathy, necrotising enterocolitis stages II or III, bronchopulmonary dysplasia or persistent pulmonary hypertension, affected 7·9 % of the total cases. Additionally, minor morbidities such as hypotension requiring treatment, intraventricular haemorrhage grades I or II, necrotising enterocolitis stage I, respiratory distress syndrome and/or hyperbilirubinaemia requiring treatment during the initial hospitalisation, occurred in 37·6 % of the overall cases^{(Reference Manuck, Rice and Bailit2)}. These figures underscore the urgent need for comprehensive strategies to address prematurity and minimise its impact on infant health.

Several neurodevelopmental conditions are associated with prematurity, the main ones being cerebral palsy, intellectual disability, hearing loss and visual impairment. Notably, preterm birth appears to be linked to compromised sleep quality and disrupted bedtimes in school-age children when compared with term-born counterparts^{(Reference Visser, van Diemen and Kervezee3)}. Adequate sleep during critical developmental stages is crucial for normal brain development and supports healthy cognitive and psychosocial growth in full-term infants^{(Reference Alrousan, Hassan and Pillai4)}. Conversely, persistent sleep disruption or early-life sleep deprivation is believed to contribute to a range of mental health conditions, including anxiety disorders, depression and cognitive impairment^{(Reference Alrousan, Hassan and Pillai4)}, which may also be associated with preterm birth.

The importance of adequate sleep during infancy and its impact on neurodevelopmental outcomes is further highlighted by the role of melatonin. Produced by the pineal gland during the dark phase of the mammalian light/dark cycle, melatonin profoundly influences multiple biological pathways^{(Reference Cipolla-Neto and Amaral5)}. Melatonin acts in the synchronisation of sleep and body functions affected by circadian rhythms, including several physiological and neural functions in pregnancy, influencing fetal programming and development^{(Reference Cipolla-Neto and Amaral5)}. Studies in a mouse model demonstrated that melatonin treatment during gestation and lactation prevented adverse pancreatic beta-cell programming in male offspring induced by high-fat diet-induced obesity^{(Reference Nagagata, Ajackson and Ornellas6)}. Melatonin has also been proposed as a potential therapeutic intervention to mitigate fetal consequences arising from maternal morbidities during pregnancy, such as gestational diabetes, intrauterine growth restriction, preeclampsia and undernutrition^{(Reference Chen, Sheen and Tiao7)}.

Besides being produced by the maternal pineal gland, melatonin is also synthesised in the placenta during pregnancy, highlighting its importance for proper gestation development^{(Reference Ejaz, Figaro and Woolner8)}. Throughout gestation, the nocturnal peak of serum melatonin concentration slightly declines between the first and second trimesters, then rises after 24 weeks, reaching its peak towards the end of pregnancy. After birth, melatonin levels return to pre-pregnancy values by the second postpartum day. Therefore, special consideration should be given to prematurely born infants, as they miss the critical late-stage pregnancy period when maternal melatonin supply to the fetus is at its highest levels^{(Reference McCarthy, Jungheim and Fay9,Reference Nakamura, Tamura and Kashida10)} .

Biran et al. (2019) reported that plasma melatonin was undetectable at birth and on the third day of life in 78 % and 81 % of infants born before 34 gestational weeks, respectively (n 110, range 24–34 uncompleted weeks) and in 57 % and 34 % of infants born after 34 gestational weeks (n 99, range 34–42 uncompleted weeks), respectively^{(Reference Biran, Decobert and Bednarek11)}. Other researchers found that the rhythmic urinary excretion of 6-sulfatoxymelatonin, a melatonin metabolite, becomes detectable in term infants between 9 and 12 weeks of age^{(Reference Cipolla-Neto and Amaral5)}. Premature babies showed a 2–3-week delay in the rhythmic excretion of this melatonin metabolite, even after correction for gestational age. This delay is thought to be mainly due to environmental exposures in intensive care units, particularly light irregularity and intensity^{(Reference Cipolla-Neto and Amaral5)}, as melatonin production is confined to the dark phase and becomes compromised due to nocturnal light exposure. Clinical studies suggest that exposing preterm infants to a light–dark cycle, rather than constant dim lighting, is associated with distinct rest and activity patterns that emerge within a week after discharge. This exposure also correlates with improved growth rates, less fussing and crying, and shorter hospital stays^{(Reference Wong, Wright and Spencer12)}.

Building on the discussion of melatonin’s role in circadian rhythms and neurodevelopment, breast milk is crucial to providing the neonate chrono-nutrients, including melatonin, which coordinates the baby’s circadian rhythm until its internal clock becomes functional^{(Reference Gombert and Codoner-Franch13)}. The average melatonin concentration in breast milk is approximately 35 % of the maternal serum concentration^{(Reference Qin, Shi and Zhuang14)}. Melatonin in breast milk acts as a powerful antioxidant, indirectly diminishing the production of oxidant molecules while enhancing the body’s antioxidant capacity^{(Reference Gombert and Codoner-Franch13)}.

Beyond its antioxidant properties, melatonin in breast milk regulates inflammation and may influence the composition, diversity and dynamics of the developing intestinal microbiota, thereby modulating the absorption of specific molecules by the host^{(Reference Gombert and Codoner-Franch13)}. The circadian rhythm of melatonin concentrations in breast milk aligns with the rhythmicity observed in maternal serum^{(Reference Katzer, Pauli and Mueller15)}. However, premature birth affects both the production of breast milk and its melatonin concentration. While milk production is negatively affected, a higher concentration of melatonin in breast milk was found in mothers of preterm infants compared with mothers of full-term infants^{(Reference Qin, Shi and Zhuang14)}.

Exploring the relationship between prematurity and higher melatonin levels in breast milk and the potential advantages of increased melatonin intake for the development of premature infants could yield intriguing findings. Current guidelines for preterm nutrition recommend initiating early parenteral nutrition with amino acids and lipids, alongside early enteral nutrition incorporating breast milk^{(Reference Embleton, Moltu and Lapillonne16)}. Full enteral feeding with fortified raw own mother’s milk optimally promotes adequate growth and development in preterm infants^{(Reference de Halleux and Rigo17)}. Preterm nutrition with own mother’s milk decreases the risk of various complications, including necrotising enterocolitis^{(Reference Patel and Kim18)}, late neonatal sepsis^{(Reference Ronnestad, Abrahamsen and Medbo19)}, bronchopulmonary dysplasia^{(Reference Patel, Johnson and Robin20)} and retinopathy of prematurity^{(Reference Zhou, Shukla and John21)}. Donor milk (pasteurised) offers intermediate benefits, shielding preterm infants from complications, such as necrotising enterocolitis, bronchopulmonary dysplasia and retinopathy of prematurity compared with their own mother’s milk and preterm formula^{(Reference Kim, Lee and Chung22)}.

Our primary concern in the context of preterm infants is the potential impact of imbalanced melatonin availability related to different nutritional approaches. While some data indicate that melatonin levels in breast milk remain unaffected following freezing and defrosting^{(Reference Molad, Ashkenazi and Gover23)}, there is evidence of a significant decrease when comparing breast milk before and after pasteurisation^{(Reference Booker, Lenz and Spong24)}. Current data pointed that melatonin levels decrease by approximately 23·6 % after conventional pasteurisation^{(Reference Booker, Lenz and Spong24)}. Investigating alternative thermal and non-thermal methods applied to human milk preservation could also provide insights into how to best preserve melatonin concentrations in donor milk best^{(Reference Nunez-Delgado, Mizrachi-Chavez and Welti-Chanes25)}. Recently, the impact of alternative preservation methods on the composition of human milk was reviewed, but data on melatonin content were not presented in that work^{(Reference Conboy-Stephenson, Ross and Kelly26)}.

Given the critical role of melatonin as a physiological synchroniser and its importance in early development^{(Reference Cipolla-Neto and Amaral5)}, we propose that studies examining the effects of synchronising the collection and supply of expressed breast milk produced during the day and night would be highly valuable for the health of babies, especially premature babies. This is mainly due to the significant increase in melatonin concentration between these distinct time intervals^{(Reference Katzer, Pauli and Mueller15)}. Synchronised milk supply would commence when breast milk is introduced into the premature infant’s diet, as outlined in current guidelines. Recently, Booker et al. (2022) described an association between the mistiming of pasteurised maternal breast milk and delayed onset of infant sleep^{(Reference Booker, Spong and Deacon-Crouch27)}. As there are situations that prevent premature babies from being breastfed with their own mother’s milk, due to lack of milk production, infectious disease or death, it is essential to investigate postnatal melatonin supplementation for premature infants fed pasteurised breast milk or formula. Melatonin supplementation, whether given directly to preterm infants or indirectly through maternal supplementation to boost its levels in breast milk, offers promising potential for enhancing neonatal health outcomes. In fact, therapeutic administration of melatonin has already been proposed regarding neuroprotection for hypoxic-ischemic encephalopathy^{(Reference Paprocka, Kijonka and Rzepka28)}, in neonatal sepsis^{(Reference Henderson, Kim and Lee29)} and preclinically in necrotising enterocolitis^{(Reference Ma, Hao and Gao30)} and in retinopathy of prematurity^{(Reference Xu, Lu and Hu31)}.

In reproductive physiology, melatonin is involved in folliculogenesis, oocyte maturation, embryonic implantation, fetal development and parturition^{(Reference Carlomagno, Minini and Tilotta32)}. In reproductive medicine, melatonin supplementation has been investigated in male and female infertility management protocols with favourable preliminary results without considerable side effects^{(Reference Lucignani, Jannello and Fulgheri33,Reference Mejlhede, Jepsen and Knudsen34)} .

Although more robust data on the safety of maternal melatonin use during breast-feeding are lacking, and exogenous melatonin currently has no specific recommended use in this context, short-term, nighttime use of standard doses by a breast-feeding mother is unlikely to negatively affect either her or her infant’s health⁽³⁵⁾. However, due to the absence of robust data, some authors advise caution against its use during breast-feeding^{(Reference Andersen, Gogenur and Rosenberg36,Reference Vine, Brown and Frey37)} . Even higher-than-expected doses of melatonin in breast milk following maternal supplementation have been safely administered to infants^{(Reference Gitto, Aversa and Reiter38)}. Further research is essential to understand such interventions’ long-term safety and efficacy fully. Notably, the effect of prolonged melatonin supplementation on the maternal and premature infant haemostatic system deserves specific investigation, considering its observed dose-dependent inhibition of platelet activity^{(Reference Cardinali, Del Zar and Vacas39)}.

While the topic of melatonin supplementation is unresolved, a simple adjustment – labelling collected milk as either daytime (from 10.00 to 22.00) or nighttime (from 22.00 to 10.00)^{(Reference Katzer, Pauli and Mueller15)} and delivering milk with melatonin levels aligned with the appropriate time of day – offers a more immediately feasible and scientifically supported approach. In the hospital environment, the separate collection, labeling and processing of daytime and nighttime milk can be readily implemented with minor adjustments to milk receiving and processing logistics. For home collection and storage, whether for personal use or donation to milk banks, women should be instructed during prenatal and postpartum care to store daytime and nighttime milk in separate, clearly labelled containers and to use or donate them according to the time of collection. This practice could effectively support the circadian rhythm development of preterm infants and seamlessly integrate into existing neonatal care protocols without significant disruption. This proposal fits recent family-centred neonate care models.

The Neonatal Integrative Developmental Care Model, which outlines seven fundamental measures for neuroprotective, family-centred care of premature infants, guides clinical practice in many neonatal intensive care units worldwide^{(Reference Altimier and Phillips40)}. The model emphasises interventions that support optimal synaptic neural connections; promote normal neurological, physical and emotional development and prevent developmental deficiencies. Adherence to this model may incorporate synchronised melatonin delivery through breast-feeding and fosters an environment conducive to stimulating melatonin production in premature infants, as its two core pillars focus on safeguarding sleep and nutrition optimisation^{(Reference Altimier and Phillips40)}.

Despite the fact of our hypothesis is supported by existing studies on melatonin’s role in neonatal health and development, as well as by animal and human studies suggesting no risks associated with melatonin supplementation, a key limitation is the lack of direct clinical research explicitly examining the synchronisation of breast milk melatonin levels with circadian rhythms in preterm infants.

Future studies could employ randomised controlled trials to evaluate the effects of timed breast milk administration, with or without maternal melatonin supplementation, administered at a dosage sufficient to achieve plasma melatonin concentrations observed during the third trimester of pregnancy^{(Reference Ejaz, Figaro and Woolner8)}. Target populations – preterm infants weighing less than 1·5 kg – should receive supplementation starting from the third postnatal day (as no rhythmic pattern has been detected in melatonin concentrations in neonatal plasma during the first 72 h postpartum^{(Reference Munoz-Hoyos, Jaldo-Alba and Molina-Carballo41)}) and continuing for 16 weeks or until full breast-feeding is established. Key outcome measures should include sleep–wake cycling, neurodevelopmental progress and metabolic and inflammatory parameters. Long-term follow-up studies could also help determine whether early circadian alignment influences overall health trajectories in preterm infants. Studies show that oral melatonin supplementation in women leads to variable serum levels, with peaks of 1·1–2·6 mcg/l per 1 mg administered. This corresponds to an estimated increase in breast milk melatonin from 0·4 to 1 mcg/l per 1 mg, assuming milk concentrations average 35 % of maternal serum levels. Although higher than the typical physiologic peak of 0·02 mcg/l, these levels remain significantly lower than the 10 mg/kg doses safely used in neonatal clinical studies⁽³⁵⁾.

Ethically, the introduction of melatonin supplementation – whether administered directly to infants or indirectly through maternal milk in the context of prematurity – requires careful consideration. It is essential that mothers do not misinterpret this intervention as a sign of inadequate milk production or quality, as breast milk remains the gold standard for infant nutrition.

Human milk multi-nutrient fortification is the standard for enteral nutritional care for very low birth weight preterm infants^{(Reference Contreras Chova, Villanueva-Garcia and Gonzalez-Boyero42)}. Intriguingly, caregivers’ perceptions of fortification strategies and their effects on milk expression rates and preterm infant breast-feeding, both in the neonatal intensive care unit and after discharge, have not been adequately evaluated^{(Reference Palmer and Ericson43–Reference McLeish, Aloysius and Gale45)}. In this context, how mothers would respond to the proposition of melatonin supplementation in human milk remains unpredictable.

Enhanced health benefits, professional guidance, community support, ease of use and palatability are perceived as factors contributing to the high acceptability of nutritional interventions in children under 24 months of age, which can inform the implementation of any specific supplementation protocol^{(Reference Stelle, Kinshella and Moore46)}. Nonetheless, human milk collection, donation and supplementation are key activities in human milk banks worldwide, and these practices are associated with increased availability of mother’s milk during neonatal intensive care unit stays, as well with exclusive breast-feeding at discharge and beyond^{(Reference Quitadamo, Palumbo and Cianti47)}.

Clear and accessible communication of the scientific basis for the proposed intervention, close monitoring and evaluation of the preterm infant’s progress against established literature and informed consent are essential to ensure mothers understand that supplementation, when applicable, is meant to complement and not to replace their own milk. These informational and counselling practices appear to vary across Europe, raising concerns. Findings from a roundtable discussion with parent representatives of preterm infants in this country emphasise that best practice involves engaging parents, patients and the public at every stage of clinical research, from design to dissemination and implementation^{(Reference Moss, Lammons and Geiger48)}. A uniform approach would help in preserving maternal confidence while promoting optimal infant health without undermining breast-feeding practices.

In conclusion, we advocate comprehensive revisions to human milk collection and storage guidelines, emphasising the need for synchronised milk collection and supply periods. It is imperative to conduct well-designed clinical trials to assess the safety and efficacy of melatonin supplementation during the postpartum period in breast-feeding women with term and premature infants. By implementing these proposed revisions and conducting further research, the benefits of melatonin in infant health can be optimised, thereby improving their long-term outcomes.