Multimodal Approach to the Ontogenesis of Nociception in Very Preterm and Term Infants

The primary objective of this study is to evaluate the maturation of hemodynamic cortical responses in VPI at different postmenstrual ages (PMAs) and Full term neonates in response to a stimulation of nociceptive pathways (potentially associated with a venipuncture realized with recommended non pharmacological pain treatment and required for clinical purpose) and to a control non noxious stimulation (skin contact) and to a cold non noxious stimulation.

The secondary objectives of the study protocol are:

• To assess the maturation of neurophysiological, autonomic, and behavioral pain responses in VPI at different PMAs in response to the stimulation of nociceptive pathways
• To evaluate the impact at corrected term age of early neonatal experience (repeated nociceptive stimulations in VPIs compared to term neonate) on hemodynamic, neurophysiological, autonomic and behavioral responses to nociceptive stimulation
• To determine the existing correlations between cortical hemodynamic, neurophysiological, autonomic, and behavioral responses to pain in VPIs and term neonates.
• To evaluate the maturation of conduction velocities of small caliber nociceptive fibers in response to a non-painful cold stimulation of A delta and C fibers
• To evaluate the impact of the child's gender on the maturation of the nociceptive pathways and the pain behavior.
• To evaluate the impact of early maternal separation on the maturation of nociceptive pathways and pain behavior of the child.
• To evaluate the impact of an analgesic strategy using the mother's voice in addition to the usual non-pharmacological pain management strategies
• To evaluate the potential mechanisms of action of exposure to the maternal voice, in particular whether this exposure modifies oxytocin secretion in the newborn

We make several hypotheses. The first is that there is a progressive maturation of the nociceptive systems with a modification of the cerebral responses with advancing gestational age (partly related to a modification of the nociceptive conduction velocities). Furthermore, we hypothesize that there is a global correlation between measured nociceptive cortical activation (Near infra Red Spectroscopy and evoked potentials) indicative of a "conscious" perception of pain and other pain indicators (physiological-autonomic and behavioral) for stimuli encountered by VPI during routine care. However, the possibility of a discrepancy between the responses measured by these different indicators exists in the literature. In this case, the analysis of the differences observed with the cortical hemodynamic responses considered as reference, will allow a better understanding of the incidence and the mechanisms of these discordances.

We also hypothesize that early experiences of VPI, in particular early maternal separation, may alter the development and function of nociceptive pathways and make the neonate more sensitive to pain.

Finally, we hypothesize that live maternal voice delivery may have an additional analgesic effect compared to the non-pharmacological strategies usually used for the treatment of neonatal pain during venipuncture.

The expected results of this study are an improved knowledge of the development of nociception in VPI, the clinical relevance of pain indicators, and a better understanding of the environmental factors that may modulate it. They should allow a better evaluation of pain in VPIs and an improvement in the management of pain related to venipuncture. They should also allow a better understanding of the potential mechanisms of action of the antalgic use of the maternal voice during a painful procedure in the newborn.

Inclusion criteria

• Experimental group: VPIs of gestational age less than or equal to 33 weeks on the day of birth and hospitalized in the neonatal intermediate care unit or the neonatal intensive care unit of the Neonatal department of the Hautepierre Hospital (Strasbourg University Hospital)

• Control group: Healthy full-term babies (> 37 weeks gestational age) hospitalized in the maternity ward of Strasbourg University Hospital
• Consent obtained from both parents
• Subject affiliated to a social health insurance plan.

Exclusion criteria

• - Any malformation known before inclusion
• Cerebral lesions discovered on cerebral ultrasound performed as part of the standard management of newborns (Intra-Ventricular Hemorrhages of grade III or IV of the Papile classification, Periventricular Leucomalacia)
• Unstable clinical status according to the investigator's judgment
• Expected transfer of the child to another hospital before the term of 40 weeks PMAs.