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Open Access 24.04.2024 | Reviews

Melatonin in infants—physiology, pathophysiology and intervention options

verfasst von: Prof. Dr. med. Ekkehart Paditz

Erschienen in: Somnologie

Abstract

The effectiveness of melatonin in nonorganic sleep disorders in children and adolescents has been examined in 33 randomised controlled studies [1]. This review presents the current state of knowledge on the physiology, pharmacokinetics, pathophysiology and toxicity of melatonin in infancy based on well-documented studies. Up to the third month of life, premature and full-term babies cannot produce their own melatonin, so they are dependent on exogenous supply via their own mother’s breast milk, non-pooled breast milk or non-pooled formula. Non-pooled means that a distinction should be made between melatonin-rich night milk and melatonin-poor day milk. A number of intervention studies indicate that administration of melatonin to infants may have analgesic and antioxidant effects related to ophthalmological examinations, prevention of bronchopulmonary dysplasia, and the treatment of hypoxic ischaemic encephalopathies. Since melatonin concentrations in the mother’s blood, in breast milk and, e.g., also in cow’s milk show regular day–night fluctuations, and since breastfed infants have a more stable melatonin supply and fewer sleep disorders, infants who cannot be breastfed by their own mother should preferably have chrononutrition made from non-pooled human or cow’s milk. There has recently been evidence that infantile colic is a disorder with delayed development of chronobiological rhythms.

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Background

Historical development: from radical scavenger to sleep hormone

The neuroendocrine hormone melatonin (5-methoxy-N-acetyltryptamine) was discovered in 1958 by the American chemist and dermatologist Aaron B. Lerner (1920–2007) and described in more detail in 1959 [2, 3]. The Greek anatomist Herophilus of Alexandria (325–255 BC) is considered the first describer of the pineal gland. He viewed the organ referred to as Conarion as a sphincter for the flow of pneuma, while Galen (129–216 AD) already spoke of a gland that would support the venous networks of the brain. In 1543, Andreas Vesal (1514–1564) provided the first drawing of the pineal gland. Friedrich Tiedemann (1781–1861) assumed in 1816 that the foetal gland could be morphologically visualised from the fourth month of pregnancy onwards. René Descartes (1596–1650) referred to the pineal gland as the “right hand of the soul [4].” In 1717 and 1898, the first descriptions of pineal tumours by Charles Drelincourt and Otto Heubner followed, which contributed to the understanding of the pineal gland as an endocrine organ in the 20th century [5].

Nowadays, melatonin and vitamin D are considered the two fundamental hormones associated with night and day, as pineal melatonin synthesis and secretion are activated by sunset, while vitamin D is stimulated by UV light during the day [6]. The “timezyme” enzyme marks the rate-determining step of pulsatile melatonin synthesis in the pineal gland. Timezyme evolved more than 500 million years ago to establish a radical scavenger with the production of melatonin. Chronobiological time-keeping functions of melatonin emerged only in vertebrates and mammals [7]. Circadian fluctuations in melatonin concentration with a nighttime peak are detectable not only in blood but also in breast milk and cow’s milk [8, 9].

Objective

This work investigates the available data on the physiology and pathophysiology of melatonin in infancy, including the neonatal period, in breastfed and non-breastfed infants. Based on this, intervention effects related to melatonin in this age group are examined.

Methodology

PubMed searches were performed for the following features: ((melatonin[title/abstract]) AND (infant[title/abstract])). This generated 108 results, including 10 clinical studies. Of these, 2 studies were in pregnant women and those with cow’s milk intolerance, 2 were study protocols, and 2 animal experimental or cell biology studies, thus leaving 4 clinical studies [10‐13], the references of which were additionally evaluated. The results are presented in the form of thematic subject groups.

Results

In the first 3 months [14, 15] or up to the 5th–16th week of life (Fig. 1; [16]), infants cannot produce their own melatonin, as the maturation of the autonomic nervous system and circadian rhythms is not yet complete (Fig. 1); noradrenaline, as the essential biochemical stimulus for activation of pineal melatonin synthesis, is still absent during this time [1, 4]. This time interval is extended in premature infants and after neurological insults [14]. Optimal lighting in neonatal intensive care units, considering physiological day–night rhythms, can promote the development of chronobiological rhythms.

Therefore, in the first few months of life, infants depend on external melatonin intake, a) through melatonin contained in nocturnal breast milk, b) through non-pooled night milk from women’s milk or c) through appropriately adapted formula feeding in the form of chrononutrition made from non-pooled cow’s milk (Table 1; Fig. 2; [1, 17‐19]). Non-pooled means that melatonin-rich night milk is not mixed with melatonin-poor day milk [17, 20]. Several studies have shown that chronobiologically adapted chrononutrition in the form of “circadian-matched milk” [21] can significantly improve sleep parameters in infants [13, 18, 22] as well as food intake and growth (Fig. 3; [23]).

Table 1

Melatonin in breast milk

Author, year	Milk sample	Melatonin concentration
Aparici-Gonzalo S et al. 2020 [24]	One sample during the day 12–2 p.m. and one at night between midnight and 2 a.m. from colostrum (within 24 h after birth), transition milk (3–7 days), and mature follow-up milk (1 month after birth) from 21 and 17 women, respectively, with a mean age of 33 years, with epidural anaesthesia during normal delivery or elective caesarean section (healthy exclusively breastfed full-term infants born between 37–41 weeks without additional feeding, Apgar 9–10 at 1 min, birth weight 2900–3660 g)	Higher melatonin concentrations at night compared to daytime in colostrum, transition milk and mature follow-up milk (Fig. 2), daytime colostrum after normal delivery or caesarean section 14.7 vs. 30.3 pg/mL (p = 0.020)
Qin Y et al. 2019 [25]	Milk samples from 98 mothers on the 1st and 30th days of life of 66 full-term and 32 premature infants of 39th and 34th weeks	Significantly higher melatonin concentrations at night at 03:00 (23.5 pg/mL) compared to daytime at 09:00, 15:00 and 20:00 (3.27, 2.4 6.81 pg/mL) in colostrum, transition milk, and mature milk of mothers of premature and full-term infants
Illnerova H et al. 1993 [8]	Melatonin concentration in the blood and milk of 10 mothers 3–4 days after delivery	No measurable melatonin concentrations in the blood and milk during the day; at night, 280 ± 34 pmol/L in serum and 99 ± 26 pmol/L in breast milk
Katzer D et al. 2016 [26]	21 mothers: concentration of melatonin and glutathione peroxidase 3 (Gpx3) in serum and milk	“Nighttime” (22–10 h) significantly higher melatonin and Gpx3 concentrations in serum and milk compared to “daytime” (10–22 h): nighttime melatonin 7.3 pg/mL, Gpx3 1800 ng/mL, daytime 1.5 pg/mL and 1436 ng/mL ; i.e., 5.2 times higher melatonin concentrations in milk at night

The authors of different studies showed that unstable melatonin supply during this time with formula feeding instead of breastfeeding is associated with more fragmented sleep in infants or reduced sleep efficiency [13, 27].

Chronobiological fluctuations in terms of stable day–night rhythms of pulsatile melatonin synthesis cannot be detected in infants during the first months of life. This is because premature infants, compared to adults, have a significantly prolonged and interindividually variable elimination half-life of approximately 1.9–21 h in infants and < 1 h in adults after intravenous or oral melatonin administration. This prolonged half-life is associated with the immaturity of hepatic and renal pathways of metabolism and polymorphisms of hepatic enzymes (Table 2). Against this background, it is understandable that individual cases of infant deaths have been documented in connection with significant overdoses of melatonin, where very high accumulated melatonin concentrations were measured [4]. It remains unclear whether additional, as yet insufficiently investigated alternative metabolic pathways, play a role in infants [4].

Table 2

Pharmacokinetics of melatonin in premature infants compared to adults

Author, year	Sample	Elimination half-life t1/2	C_max and t_max (minutes)
Merchant NM et al., 2012 [14]	n = 18 premature infants (9 male, 9 female) at 27th week, birthweight 610–1430 g on days 1–6 of life, breastfed, no artificial nutrition; concurrent treatment with caffeine 12.5 mg/kg as a loading dose and 6 mg/kg/day	16.91 h and 21.02 h after intravenous administration^a of 0.1 μg/kg/h over 2 h (n = 4) or 6 h (n = 4) or 0.02 μg/kg/h over 2 h (n = 6) or 0.01 μg/kg/h over 2 h (n = 2), or 0.04 μg/kg/h over 30 min (n = 2)	C_max 393.3–554.5 pg/mL or 160–220 pg/mL at the end of the 6‑ or 2‑hour infusion
Carloni S et al., 2017 [28]	n = 15 premature infants (8 male, 7 female) at 26th–33rd week, birth weight 780–3200 g	6.20–15.51 h after 0.5 mg/kg melatonin via intragastric administration through nasogastric tube (n = 6) or 1.88–20.81 h after 1 mg/kg melatonin (n = 4) or 5.19–11.58 h after 5 mg/kg (n = 5)	C_max 0.44 to 7.04 μg/mL after 2.91 to 4.70 h (averages for these 3 groups)
Andersen LPH et al., 2016 [29]	n = 12 healthy male adults, aged 27.1 ± 5.2 years	53.7 ± 7.0 min after oral administration of 10 mg melatonin at 8:00 a.m. or 39.4 ± 3.6 min after intravenous administration at intervals of 3–9 months^b	Oral: C_max 2500.5–8057.5 pg/mL after 40.8 ± 17.8 min Intravenous: C_max 174775.0–440362.5 pg/mL after intravenous bolus

^a0.1 μg melatonin and 9 mg sodium chloride dissolved in 1 mL of water

^boral: gelatine capsule taken with 50 mL of water; intravenous: 10 mg melatonin in 23 mL of 0.9% saline solution and 2 mL of 99.9% ethanol as a short infusion at a rate of 2.5 mL/min over 10 min

Several studies have demonstrated the analgesic effects of melatonin in infants during ophthalmological examinations (Table 3; Fig. 4).

Table 3

Analgesic effects of melatonin in infants (see also Fig. 4)

Author, year	Study type and dosage	Participants	Effects
Behura SS et al., 2022 [10]	RCT n = 30 melatonin 4 mg/kg orally^a 20 min before retinopathy screening vs. n = 30 24% sucrose 0.5 mL orally 2 min before retinopathy screening	Premature infants, < 34 weeks or < 2000 g, with 7 mL/kg of breast milk per feed	Comparable moderate effects of both substances on a pain scale in addition to heart rate and SaO₂ (oxygen saturation) as well as apnoea, arrhythmia, vomiting or feeding problems within 24 h: severe pain in both groups during the examination (PIPP 14–17), moderate pain after 1 min (7–10), mild pain after 5 min (4–6)
Gitto E et al., 2012 [12], zit. bei Behura 2022 [10]	RCT n = 30 melatonin 10 mg/kg intravenously (cited in [31]) plus sedation and analgesia vs. n = 30 sedation and analgesia only (atropine, fentanyl, vecuronium)	Newborns during and after endotracheal intubation	Evidence of significant positive effects of melatonin administration (lower PIPP score, indicating less pain, and reduced release of pro-inflammatory and anti-inflammatory cytokines IL‑6, IL‑8, IL-10 and IL-12) during intubation and at 12, 24, 48 and 72 h under ventilation (p < 0.001)

PIPP premature infant pain profile score (score based on gestational age, behavioural state, maximum heart rate, reaction of eyebrows, eyes and nasolabial folds; score from 0 to a maximum of 21: < 6: no or mild pain; 6–12: moderate pain; > 12: severe pain) during 1 and 5 min after the procedure; administration of 10 mg/kg of oral paracetamol from PIPP 10

^aMelatonin syrup containing 3 mg/mL, 4 mg/kg = 6.6 mL/kg, with reference to intravenous dosages of 3–10 mg/kg in newborns, pharmacokinetic dose estimates after oral administration in premature infants [28] and reference to analgesic effects of intravenous melatonin administration in mechanically ventilated premature infants [12], as well as the 30-minute interval before venipuncture in children aged 1–14 years [32]

There is also evidence of chronobiological disturbances in infant colic (Table 4; [30]) as well as of the effects of melatonin in neonatal hypoxic ischaemic encephalopathy (HIE; Table 5) and the prevention of bronchopulmonary dysplasia (BPD) (Table 6).

Table 4

Melatonin and infant colic

Author, year	Study type	Participant characteristics	Results
Egeli TU et al., 2023 [30]	Prospective cohort study/comparison of n = 49 infants with colic^a aged 6–8 weeks vs. n = 46 control group without colic (no significant differences in terms of gestational age 39 weeks, birthweight 3424 vs. 3261 g, 43% vs. 50% female, maternal smoking 12% vs. 15%, breastfeeding 84% vs. 83%, breastfeeding plus formula feeding 16% vs. 17%)	Significant differences in the colic group regarding increased light sensitivity (61% vs. 20%), defecation problems (49% vs. 22%), shortened sleep duration (10 h with a range of 2–16 h vs. 13 h with a range of 7–20 h), frequency of nighttime awakenings 4.5 times with a range of 1–10 times per night vs. 2.5 times with a range of 1–5 times per night	Evidence of “circadian rhythm disruption and infantile colic”: significantly higher nocturnal melatonin concentrations in the control group (p = 0.014); significant differences in the day–night variability of H3f3b mRNA activity as a marker for central clock activity in the buccal mucosa (p = 0.002). Melatonin would be lacking as a serotonin antagonist in the intestine during the first 3 months of life, leading to painful intestinal cramps and evening crying

^aColic according to the criteria of Wessel

Table 5

Melatonin in neonatal hypoxic ischaemic encephalopathy (HIE)

Author, year	Study type, participants and dosage	Effects
Aly H et al., 2015 [34]	Prospective RCT n = 30 HIE (15 with hypothermia therapy for 72 h vs. 15 with hypothermia plus melatonin 10 mg/kg for 5 days) vs. n = 15 healthy newborns	Increased melatonin, superoxide dismutase (SOD) and nitric oxide (NO) concentrations in the HIE groups compared to controls. In the melatonin group, there was a stronger increase in melatonin on day 5 (p < 0.001) and reduced NO and SOD levels (p < 0.001 and 0.004, respectively). There were fewer seizures in the follow-up EEG and fewer lesions in the white matter (MRI), as well as improved survival without neurological or developmental deficits in the melatonin group (p < 0.001)
Ahmad QM et al., 2018 [35]	Prospective RCT Newborns with a mean gestational age of 36.81 ± 1.7 weeks: n = 40 HIE with a single dose of oral melatonin 10 mg via nasogastric tube vs. n = 40 HIE without melatonin administration	Survival rate higher in the melatonin group at 87% (35/40) vs. 65% (26/40)
Fulia F et al., 2001 [36]	Cohort study n = 10 newborns with asphyxia: melatonin 80 mg in 8 doses of 10 mg every 2 h orally, starting within the first 6 h of life vs. n = 10 with asphyxia without melatonin administration compared to laboratory findings of healthy controls	Significant reduction in nitrite/nitrate and malondialdehyde levels in the melatonin group within 12 and 24 h; mortality: 0 in the melatonin group, 3/10 in the asphyxia group without melatonin administration
Jerez-Calero A et al., 2020 [37]	RCT n = 13 hypothermia 33–34 °C for 72 h plus placebo term births at 39 weeks, birthweight 2974 g, umbilical cord pH 6.96 vs. n = 12 hypothermia for 72 h plus melatonin 5 mg/kg/day intravenously as a 2-hour infusion for the first 3 days of life, starting within the first 6 h^a in term births at 39 weeks, birthweight 3057 g, umbilical cord pH 6.98	Significantly better neurological development in the melatonin group at 18 months (Bayley III score, p < 0.05), but no significant improvement in language and motor skills after 6 and 18 months (p = 0.057). No stronger effects when considering the severity of the initial findings

^aMelatonin concentration 6.5 mg/mL in an infusion solution with macrogol and propylene glycol

Table 6

Melatonin in the prevention of bronchopulmonary dysplasia (BPD)

Author, year	Study type, participants and dosage	Effects
Gharehbaghi MM et al. 2022 [38]	RCT 40 premature infants of 28–29 weeks, administration of surfactant once endotracheally with or without melatonin 5 mg/kg/day for 3 days via nasogastric tube	Significant reduction in ventilation duration 5.3 vs. 7.6 days (p = 0.003), hospitalisation 6.4 vs. 10.7 days (p = 0.02), BPD rate 45 vs. 60% (p = 0.02), rate of intraventricular haemorrhage 30 vs. 40% (p = 0.04), and mortality 7.5 vs. 15% (p = 0.009)

Practical conclusion

Melatonin is an essential chronobiological and antioxidant hormone throughout infancy. Since melatonin cannot be synthesised by infants until the age of 3 months, infants rely on melatonin present in breast milk or non-pooled women’s or cow’s milk preparations.
Infant colic and non-organic sleep disturbances in infancy are associated with melatonin deficiency and delayed development of circadian rhythms.
Several studies have shown that melatonin administration can be effective in the prevention of bronchopulmonary dysplasia, for pain reduction and in treatment of neonatal hypoxic ischaemic encephalopathy.
Attention is drawn to the prolonged melatonin elimination half-life of up to approximately 20 h in infancy and recent reports of deaths associated with melatonin overdose.

Declarations

Conflict of interest

E. Paditz is the managing partner of kleanthes Verlag für Medizin und Prävention GmbH & Co. KG. He is the applicant and inventor of the family of patent applications cited in this article [17].

All human studies described were conducted with the approval of the respective ethics committees, in accordance with national law and in accordance with the Declaration of Helsinki of 1975 (in its current revised version). This article does not include any studies on animals, except for Eriksson’s [9] veterinary medicine contribution.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Titel: Melatonin in infants—physiology, pathophysiology and intervention options
verfasst von: Prof. Dr. med. Ekkehart Paditz
Publikationsdatum: 24.04.2024
Verlag: Springer Medizin
Erschienen in: Somnologie
Print ISSN: 1432-9123
Elektronische ISSN: 1439-054X
DOI: https://doi.org/10.1007/s11818-024-00456-5

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Historical development: from radical scavenger to sleep hormone

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