Effect of early Restoration of CIRCADian rhythms in very preterm Infants via Environmental Modification on Infection in Early Life: The CIRCA DIEM Infection and Immunology Substudy

Very preterm infants (<32 w gestation) will be eligible for the CIRCA DIEM Infection and Immunology Substudy if they are enrolled in the parent CIRCA DIEM study. The parent CIRCA DIEM study involves randomisation of eligible enrolled infants to either standard environmental care (control) or a cycled environment (light and noise) from birth until discharge. The intervention group will receive cycled environmental light and noise to simulate day/night-time environments using a pragmatic 14 hour day (6 am – 8 pm), 10 hour night (8 pm – 6 am) cycle. Daytime intervention will include exposure to light including removal of cot-covers if present, to achieve lighting within the range of 300-600 lux, whilst avoiding direct bright light to the infant’s eyes. Nocturnal intervention will include repositioning of cot-covers, application of light-occlusive eye-masks; and silicone ear-plugs. Eye-masks and ear-plugs will remain in position during any medical procedures or overnight cares unless removal is necessary for medical reasons. Light meters positioned within the infant’s cot will be used to ensure daylight lux targets are achieved and maintained (intervention group) or level of ambient lighting recorded (control group). Lux/noise levels will be documented at 8 am, 4 pm and midnight, and audited frequently. Eye masks will continue to be used for phototherapy and ear protection for high-frequency ventilation as per normal nursery protocols (normally short-term). Respiratory stimulants (e.g. caffeine) will be regulated to 8 am dosing for all infants, when prescribed, to avoid pharmacologic confounding on circadian rhythm development. Similarly, if postnatal glucocorticoids are prescribed for severe lung disease, they will be given at 6 am/6 pm to reduce nocturnal disruption. Standardised eye masks and silicone earplugs will be supplied, and applied during each period by the nurse caring for the infant. Protocol adherence to the intervention in the parent CIRCA DIEM study will be monitored by inspection of hospital and clinical record form logs, direct observation by trials staff, and auditing of downloaded electronic recordings of environmental noise exposure (from sound monitors) Infants are eligible to be enrolled in the Infection and Immunology substudy if parental assent is provided for the collection of additional information and/or samples required. For most infants, involvement in the Infection and Immunology substudy involves provision of access to medical records detailing utilisation of health services (GP visits, hospitalisations for infections). For infants enrolled prospectively, parents will be invited to record their infant's general well-being on a custome designed mobile app (using the Vanderbuilt University MyCap platform) to facilitate recording of information pertaining to presence of symptoms of infection, visits to health care providers and hospitalisations. Parents will be prompted to enter this information at least weekly over the first 2 years of life. Reminders to complete the app will be sent if responses are not received within 24 hours of the due date for an entry. Biological samples (placental epithelial cells, nasal epithelial and microbiome, buccal cells, faeces, blood) collected at around the time of study entry (~ 7d age), at 36 w postmenstrual age, and at 2 years corrected postnatal age will be obtained from a subset of participants who are recruited to the Infection and Immunology substudy, are born in Western Australia and whose parents provide informed consent to the collection of these biological samples. Participation in this substudy will require parental assent to collection of the biological samples. We will aim to collect samples from up to 120 infants at each time point.