Immediate Parent -Infant Skin-to-Skin Study (IPISTOSS)

Continued randomization was questioned on ethical grounds after the WHO iKMC study reported mortality reduction in May 2021. The DSMB recommended to stop the trial after reviewing a preliminary data analysis because of benefit of the intervention.

The World Health Organization recommend all stable low birth weight neonates to have Skin-to-skin-Contact (SSC) after birth. Intermittent SSC is used in Sweden in neonatal units. Observations indicate that SSC makes neonates feel good. However, there is limited research done on SSC treatment on neonates born prior to week 33. The aim of this study is to investigate whether Skin-to-skin-Contact (SSC) leads to an improved physiological stabilization, altered epigenetic profile and improved longterm psychomotor outcome in neonates born in gestation age between week 28+0 - 32+6. This is a parallel, two-arm, multicentre, randomized controlled superiority trial. The two arms to be compared are a) immediate SSC with one parent/caregiver continous during the first 6 hours after birth and as much as possible during the first 72 hours, and b) conventional method of care during the same time.

Neonates in gestational age between 28+0 - 32+6 will get continuous Skin-to-skin contact with one parent/caregiver the first 6 hours after birth and as much as possible the first 72 hours after birth.

Neonates in gestational age between 28+0 - 32+6 will get Conventional care - incubators, warmers etc - the first 72 hours after birth.

Neonates will get Skin-to-skin Contact with parent/caregiver continuously the first 6 hours after birth and as much as possible the first 72 hours after birth.

Using the Stability of the CardioRespiratory system In the Preterm-score (SCRIP-score). A higher SCRIP score indicates greater physiological stability

Number of Days with antibiotic treatment from birth to discharge from hospital based on Medical records

Status of Breast-feeding according to a specific questionnaire: Breastfeeding Self efficacy Questionnaire (BSES)

Status of Breast-feeding according to a specific questionnaire: Infant Breastfeeding Assessment Tool (IBFAT).

Whole-genome methylation analysis and locus specific analysis of selected stress related genes, will be conducted to investigate early, intermediate and long-term epigenetic changes due to the intervention.

Whole-genome methylation analysis and locus specific analysis of selected stress related genes, will be conducted to investigate telomere length.

Whole-genome methylation analysis and locus specific analysis of selected stress related genes, will be conducted to investigate early, intermediate and long-term epigenetic changes due to the intervention.

Whole-genome methylation analysis and locus specific analysis of selected stress related genes, will be conducted to investigate telomere length

The child's colonization with bacteria is identified by DNA-analysis from stool samples, nasal and skin swabs, compared with parents (mother is tested by vaginal, rectal, nasal and skin swabs.

0-6 hours, 72 hours, 3-4 months, 12 and 24 months. Mother is tested at 0-6 hours and partner with skin swabs at 0-6 hours.

Magnetic Resonance Imaging scans will be performed with a 3 Tesla machine. Three-dimensional and diffusion sequences as well as functional MRI (fMRI) sequences will be performed in order to examine structural and functional maturation respectively. Structural sequences are used to study the different tissues of the brain; diffusion images give information about the connections of the brain (white matter) and fMRI gives information on how the brain integrates information to perform a specific function.

The maternal brain responses will be evaluated by using structural and functional magnetic resonance imaging to measure structural changes on social, emotional and behavioural networks as well as the cerebral response of mothers viewing neutral, happy and distress face images of their own infant, along with a matched unknown infant. We will use a 3 Tesla machine. We will study cortical and subcortical networks related with the emotional, social and behavioral responses involving the mother-child interactions and responses, such as the insula, the cingulate cortex, the precentral gyrus, the right orbital gyrus, the inferior, middle and superior frontal gyrus the fusiform gyrus, supramarginal gyrus, the superior parietal gyrus, the inferior temporal gyrus, and basal ganglia among others.

A videotaped mother-infant interaction session will be assessed through with the Parent-Child Early Relational Assessment (PCERA)

In the morning and in the evening at the day of discharge, At the day of discharge before and after diaper change, at 3-4 months, at the same day as Still Face-test before and after, at 12 months.

Inclusion Criteria: Born in gestation week plus days 28+0 - 32+6. Born at maternity ward at study center Consent from parents/caregivers Parent or caregiver or substitute are available to start skin-to-skin Contact during the first hour of life. Exclusion Criteria: Born outside the hospital Triplets or more Known malformation which will require immediate surgical action On-going resuscitation or intensive Medical care (mechanic ventilation or inotropy) after the first lifespan * Known congenital infection Parent/care giver can not communicate in Swedish/Norwegian or English Not suited for the study for other reasons (according to the principal investigator)

Linner A, Westrup B, Lode-Kolz K, Klemming S, Lillieskold S, Markhus Pike H, Morgan B, Bergman NJ, Rettedal S, Jonas W. Immediate parent-infant skin-to-skin study (IPISTOSS): study protocol of a randomised controlled trial on very preterm infants cared for in skin-to-skin contact immediately after birth and potential physiological, epigenetic, psychological and neurodevelopmental consequences. BMJ Open. 2020 Jul 6;10(7):e038938. doi: 10.1136/bmjopen-2020-038938.