Chrononutrition in Preterm Infants: a Randomised Controlled Trial of Time-matched Breast Milk Feeding and Its Effects on Sleep and Circadian Development

This study investigates whether the timing of feeding expressed breast milk influences infant sleep and circadian (day-night) development in preterm infants.

In early life, infants produce very little of the hormone melatonin, which plays a key role in regulating sleep and circadian rhythms. Breast milk naturally contains melatonin, and its levels vary across the day, with higher concentrations at night. This variation may provide important biological signals that help infants develop healthy sleep-wake patterns.

However, expressed breast milk is often fed without considering the time it was expressed. This may disrupt the transfer of circadian signals from mother to infant.

The aim of this randomised controlled trial is to determine whether feeding expressed breast milk according to the time of expression (e.g. giving night-time milk at night) improves sleep consolidation and circadian development compared with usual feeding practices.

A total of 200 preterm infants born between 32+0 and 36+6 weeks' gestation who are receiving expressed breast milk will be enrolled and randomly assigned to one of two groups:

Intervention group: preterm infants receive expressed breast milk matched to the time of day it was expressed (day, evening or night)

Control group: preterm infants receive expressed breast milk without regard to timing (usual practice)

The main outcome is sleep consolidation at 6 months of age, measured objectively using actigraphy (a small wearable device that records sleep and activity). Additional outcomes include sleep patterns over time, circadian development, melatonin exposure, gut microbiota composition, and clinical outcomes such as infections and neurodevelopment.

The intervention does not involve any medication and uses the infant's usual nutrition. Risks are minimal and mainly relate to the additional effort required for milk labelling and timing.

This study will provide evidence on whether a simple, low-risk change in feeding practice can support infant sleep and early-life circadian development, with potential benefits for child health and family well-being.

Study Overview

• Status: Not yet recruiting
• Conditions: Circadian Rhythm; Neurodevelopment; Infant Sleep Problems
• Intervention / Treatment: Other: Chronobiologically Timed Feeding of Expressed Breast Milk; Other: Usual Feeding Practice (Untimed Expressed Breast Milk)

Detailed Description

This study investigates whether the timing of feeding expressed breast milk influences infant sleep and circadian (day-night) development in preterm infants.

In early life, infants produce very little of the hormone melatonin, which plays a key role in regulating sleep and circadian rhythms. Breast milk naturally contains melatonin, and its levels vary across the day, with higher concentrations at night. This variation may provide important biological signals that help infants develop healthy sleep-wake patterns.

However, expressed breast milk is often fed without considering the time it was expressed. This may disrupt the transfer of circadian signals from mother to infant.

The aim of this randomised controlled trial is to determine whether feeding expressed breast milk according to the time of expression (e.g. giving night-time milk at night) improves sleep consolidation and circadian development compared with usual feeding practices.

A total of 200 preterm infants born between 32+0 and 36+6 weeks' gestation who are receiving expressed breast milk will be enrolled and randomly assigned to one of two groups:

Intervention group: preterm infants receive expressed breast milk matched to the time of day it was expressed (day, evening or night) Control group: preterm infants receive expressed breast milk without regard to timing (usual practice)

The main outcome is sleep consolidation at 6 months of age, measured objectively using actigraphy (a small wearable device that records sleep and activity). Additional outcomes include sleep patterns over time, circadian development, melatonin exposure, gut microbiota composition, and clinical outcomes such as infections and neurodevelopment.

The intervention does not involve any medication and uses the infant's usual nutrition. Risks are minimal and mainly relate to the additional effort required for milk labelling and timing.

This study will provide evidence on whether a simple, low-risk change in feeding practice can support infant sleep and early-life circadian development, with potential benefits for child health and family well-being.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Petra Zimmermann, MD, PhD; Phone Number: +4141 205 82 69; Email: petra.zimmermann@luks.ch

Study Locations

• Switzerland
  • Lucerne, Switzerland
    • Kantonsspital Luzern, Universität Luzern

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Preterm infants born between 32+0 and 36+6 weeks' gestation
• Age ≤ 1 month at enrolment
• Infants routinely receiving expressed breast milk (fully or partially breastfed)
• Written informed consent obtained from parent(s) or legal representative(s)
• Ability of caregivers to comply with study procedures including milk labelling and feeding according to study allocation

Exclusion Criteria:

• Prenatal exposure to illicit drugs (e.g. cannabis, cocaine, heroin, opiates) or significant alcohol exposure
• Major congenital malformations or congenital infections
• Significant underlying disease (excluding transient neonatal conditions such as feeding difficulties, hyperbilirubinaemia, hypoglycaemia, anaemia, respiratory distress syndrome, or apnoea-bradycardia syndrome)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Chronobiologically Timed Feeding of Expressed Breast Milk; Infants receive expressed breast milk that is administered according to the time of expression (day, evening, or night), aligning feeding with circadian timing.	Other: Chronobiologically Timed Feeding of Expressed Breast Milk; Expressed breast milk is labelled at the time of expression and categorised into predefined time windows: Day milk: 06:00-17:59 Evening milk: 18:00-21:59 Night milk: 22:00-05:59 Infants are fed milk corresponding to the appropriate time-of-day window to align feeding with circadian rhythms. Caregivers receive standardised training, and adherence is monitored using feeding logs.
Active Comparator: Usual Feeding Practice (Untimed Expressed Breast Milk); Infants receive expressed breast milk without regard to the time of expression (standard care).	Other: Usual Feeding Practice (Untimed Expressed Breast Milk); Expressed breast milk is fed without consideration of the time of expression. Milk handling, storage, and preparation follow standard procedures. No modification of milk composition or additional substances are introduced.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sleep consolidation (longest nocturnal sleep bout)	Measured by actigraphy	At 6 months of age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sleep fragmentation	Assessed by actigraphy and sleep-wake diaries	At 2, 4, 6, 12, and 24 months
Circadian rhythm development (day-night activity ratios and circadian function index)	Assessed by actigraphy	At 2, 4, 6, 12, and 24 months
Parent-reported sleep outcomes	Assessed using the Brief Infant Sleep Questionnaire (BISQ)	At 2, 4, 6, 12, and 24 months
Melatonin circadian profiles	In breast milk and infant stool	At 2, 4, 6, 12, and 24 months
Intestinal microbiota composition	Assessed by shotgun metagenomic sequencing	At 2, 4, 6, 12, and 24 months
Infection rates	Clinically diagnosed infections (including otitis media and lower respiratory tract infections), assessed via medical records and parental report	At 2, 4, 6, 12, and 24 months
Neurodevelopmental outcomes	Bayley Scales of Infant and Toddler Development (Bayley-III)	24 months

Collaborators and Investigators

• Sponsor: Luzerner Kantonsspital

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): September 30, 2030
• Study Completion (Estimated): December 30, 2031

Study Registration Dates

• First Submitted: April 10, 2026
• First Submitted That Met QC Criteria: April 10, 2026
• First Posted (Actual): April 16, 2026

Study Record Updates

• Last Update Posted (Actual): April 16, 2026
• Last Update Submitted That Met QC Criteria: April 10, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Melatonin; Randomized Controlled Trial; Circadian Rhythm; Gut Microbiota; Sleep Consolidation; Actigraphy; Breast Milk; Infant Sleep; Chronobiology; Chrononutrition; Sleep-Wake Cycle; Circadian Development; Infant Microbiome
• Other Study ID Numbers: 2026-

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymised microbiome data will be made openly available in a recognised public repository (e.g. European Nucleotide Archive (ENA)).
• IPD Sharing Time Frame: Clinically diagnosed infections (including otitis media and lower respiratory tract infections), assessed via medical records and parental report.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No