Multimodal Approach to the Ontogenesis of Nociception in Very Preterm and Term Infants (NOCI-Prem)

The management of pain related to venipuncture remains insufficient in very preterm infants (VPI. The separation between the mother (father) and her(his) child can aggravate the short-term painful experience of the newborn. Accurate diagnosis and treatment of pain is necessary to preserve the well-being and brain development of VPI. A better understanding of the development of pain pathways and the cortical integration of nociceptive messages is essential to reach this goal.

Study Overview

• Status: Active, not recruiting
• Conditions: Procedural Pain; Pre-Term; Venipuncture
• Intervention / Treatment: Behavioral: Maternal vocal contact

Detailed Description

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:

1. To assess the maturation of neurophysiological, autonomic, and behavioral pain responses in VPI at different PMAs in response to the stimulation of nociceptive pathways
2. 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
3. To determine the existing correlations between cortical hemodynamic, neurophysiological, autonomic, and behavioral responses to pain in VPIs and term neonates.
4. 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
5. To evaluate the impact of the child's gender on the maturation of the nociceptive pathways and the pain behavior.
6. To evaluate the impact of early maternal separation on the maturation of nociceptive pathways and pain behavior of the child.
7. To evaluate the impact of an analgesic strategy using the mother's voice in addition to the usual non-pharmacological pain management strategies
8. 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.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Strasbourg, France, 67000
    • Service de Pédiatrie - Hôpital d'Hautepierre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Very preterm infant; Preterm infant below 33 weeks of GA	Behavioral: Maternal vocal contact; Two consecutive venipuncture (order randomly balanced) within a short period of time will be realized with and without the presence of the mother talking/singing to her VPI infant. In this intervention group, the mother will be supported to talk or to sing to her infants during before and during the venipuncture.
Active Comparator: Full term neonate; Term neonate from a gestational age of 37 weeks.	Behavioral: Maternal vocal contact; Two consecutive venipuncture (order randomly balanced) within a short period of time will be realized with and without the presence of the mother talking/singing to her VPI infant. In this intervention group, the mother will be supported to talk or to sing to her infants during before and during the venipuncture.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The cortical hemodynamic response profile(changes in oxyhemoglobin levels in the somato-sensory areas) in response to venipuncture performed with a recommended standard nonpharmacological analgesic treatment (non-nutritive sucking, and sweet solution)	The measurements will be performed using receiver and transmitter optodes to measure the variations of oxy and deoxyhemoglobin in the cerebral cortex below the optodes. The optodes will be placed in the primary and secondary somatosensory areas, and in other cortical areas (nociceptive pathway and control areas) using the EEG 10-20 classification. The data set will be collected over a basal period, a stimulation period and a post-stimulation period. Response patterns will be analyzed by mixed models and compared in VPIs in the different APM groups and with term neonates. A typical response associates an increase in oxyhemoglobin (Hb02) with a concomitant stability or decrease in deoxyhemoglobin (HHb).	During a venipuncture (needed for the standard care of the infants) and realized around 30 (+/- 2) weeks PMAs in VPI and at 2 to 3 days of life in term neonates.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of the hemodynamic response profiles and salivary oxytocin levels	Comparison of the hemodynamic response profiles and salivary oxytocin levels during 2 consecutive venipunctures, without and with the addition of the maternal voice as a supplementary non-pharmacological pain strategies	During a venipuncture (needed for the standard care of the infants) and realized around 30 (+/- 2) weeks PMAs in VPI
Comparison of the hemodynamic response profiles and salivary oxytocin levels	Comparison of the hemodynamic response profiles and salivary oxytocin levels during 2 consecutive venipunctures, without and with the addition of the maternal voice as a supplementary non-pharmacological pain strategies	During a venipuncture at 34 (+/-2) weeks PMAs in VPI
Comparison of the hemodynamic response profiles and salivary oxytocin levels	Comparison of the hemodynamic response profiles and salivary oxytocin levels during 2 consecutive venipunctures, without and with the addition of the maternal voice as a supplementary non-pharmacological pain strategies	During a venipuncture at 40 (+/-2) weeks PMAs in VPI
Comparison of the hemodynamic response profiles and salivary oxytocin levels	Comparison of the hemodynamic response profiles and salivary oxytocin levels during 2 consecutive venipunctures, without and with the addition of the maternal voice as a supplementary non-pharmacological pain strategies	During a venipuncture at 2 to 3 days of life in term neonates
Analysis of the impact on the responses of maternal separation	Analysis of the impact on the responses of maternal separation determined by the absence of early skin-to-skin contact (in the VPI < 3 days of life and in the term newborn < 2 hours of life).	During a venipuncture (needed for the standard care of the infants) and realized around 30 (+/- 2) weeks PMAs in VPI
Analysis of the impact on the responses of maternal separation	Analysis of the impact on the responses of maternal separation determined by the absence of early skin-to-skin contact (in the VPI < 3 days of life and in the term newborn < 2 hours of life).	During a venipuncture at 34 (+/-2) weeks PMAs in VPI
Analysis of the impact on the responses of maternal separation	Analysis of the impact on the responses of maternal separation determined by the absence of early skin-to-skin contact (in the VPI < 3 days of life and in the term newborn < 2 hours of life).	During a venipuncture at 40 (+/-2) weeks PMAs in VPI
Analysis of the impact on the responses of maternal separation	Analysis of the impact on the responses of maternal separation determined by the absence of early skin-to-skin contact (in the VPI < 3 days of life and in the term newborn < 2 hours of life).	During a venipuncture at 2 to 3 days of life in term neonates
Comparison of the response profiles according to the sex	Comparison of the response profiles obtained in females and males	During a venipuncture (needed for the standard care of the infants) and realized around 30 (+/- 2) weeks PMAs in VPI
Comparison of the response profiles according to the sex	Comparison of the response profiles obtained in females and males	During a venipuncture at 34 (+/-2) weeks PMAs in VPI
Comparison of the response profiles according to the sex	Comparison of the response profiles obtained in females and males	During a venipuncture at 40 (+/-2) weeks PMAs in VPI
Comparison of the response profiles according to the sex	Comparison of the response profiles obtained in females and males	During a venipuncture at 2 to 3 days of life in term neonates
Comparison of conduction velocities of small caliber nociceptive fibers	Comparison of conduction velocities of small caliber nociceptive fibers measured by evoked potentials, in response to non-painful cold stimulation in the VPIs of different APMs groups.	During a venipuncture (needed for the standard care of the infants) and realized around 30 (+/- 2) weeks PMAs in VPI
Comparison of conduction velocities of small caliber nociceptive fibers	Comparison of conduction velocities of small caliber nociceptive fibers measured by evoked potentials, in response to non-painful cold stimulation in the VPIs of different APMs groups.	During a venipuncture at 34 (+/-2) weeks PMAs in VPI
Comparison of conduction velocities of small caliber nociceptive fibers	Comparison of conduction velocities of small caliber nociceptive fibers measured by evoked potentials, in response to non-painful cold stimulation in the VPIs of different APMs groups.	During a venipuncture at 40 (+/-2) weeks PMAs in VPI
Comparison of conduction velocities of small caliber nociceptive fibers	Comparison of conduction velocities of small caliber nociceptive fibers measured by evoked potentials, in response to non-painful cold stimulation in the VPIs of different APMs groups.	During a venipuncture at 2 to 3 days of life in term neonates
Correlational analyses by APM group	Correlational analyses, by APM group, between the different pain indicators in response to stimulation	During a venipuncture (needed for the standard care of the infants) and realized around 30 (+/- 2) weeks PMAs in VPI
Correlational analyses by APM group	Correlational analyses, by APM group, between the different pain indicators in response to stimulation	During a venipuncture at 34 (+/-2) weeks PMAs in VPI
Correlational analyses by APM group	Correlational analyses, by APM group, between the different pain indicators in response to stimulation	During a venipuncture at 40 (+/-2) weeks PMAs in VPI
Correlational analyses by APM group	Correlational analyses, by APM group, between the different pain indicators in response to stimulation	During a venipuncture at 2 to 3 days of life in term neonates
Facial pain behavior	Facial pain behavior with the Neonatal Facial Coding System	During a venipuncture (needed for the standard care of the infants) and realized around 30 (+/- 2) weeks PMAs in VPI
Facial pain behavior	Facial pain behavior with the Neonatal Facial Coding System	During a venipuncture at 34 (+/-2) weeks PMAs in VPI
Facial pain behavior	Facial pain behavior with the Neonatal Facial Coding System	During a venipuncture at 40 (+/-2) weeks PMAs in VPI
Facial pain behavior	Facial pain behavior with the Neonatal Facial Coding System	During a venipuncture at 2 to 3 days of life in term neonates
Pain index	Pain index assessing the sympathetic and parasympathetic system	During a venipuncture (needed for the standard care of the infants) and realized around 30 (+/- 2) weeks PMAs in VPI
Pain index	Pain index assessing the sympathetic and parasympathetic system	During a venipuncture at 34 (+/-2) weeks PMAs in VPI
Pain index	Pain index assessing the sympathetic and parasympathetic system	During a venipuncture at 40 (+/-2) weeks PMAs in VPI
Pain index	Pain index assessing the sympathetic and parasympathetic system	During a venipuncture at 2 to 3 days of life in term neonates
Cortical evoked potentials	Cortical evoked potentials in Cz according to EEG 10:20 classification	During a venipuncture (needed for the standard care of the infants) and realized around 30 (+/- 2) weeks PMAs in VPI
Cortical evoked potentials	Cortical evoked potentials in Cz according to EEG 10:20 classification	During a venipuncture at 34 (+/-2) weeks PMAs in VPI
Cortical evoked potentials	Cortical evoked potentials in Cz according to EEG 10:20 classification	During a venipuncture at 40 (+/-2) weeks PMAs in VPI
Cortical evoked potentials	Cortical evoked potentials in Cz according to EEG 10:20 classification	During a venipuncture at 2 to 3 days of life in term neonates

Collaborators and Investigators

• Sponsor: University Hospital, Strasbourg, France

Study record dates

Study Major Dates

• Study Start (Actual): July 17, 2019
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: February 21, 2022
• First Submitted That Met QC Criteria: May 31, 2022
• First Posted (Actual): June 3, 2022

Study Record Updates

• Last Update Posted (Actual): August 25, 2026
• Last Update Submitted That Met QC Criteria: August 20, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: Oxytocin; Maternal voice; Gender; Very preterm infants; Development of nociception; Cortical hemodynamic responses; Pain indicators
• Additional Relevant MeSH Terms: Urogenital Diseases; Pain; Neurologic Manifestations; Female Urogenital Diseases and Pregnancy Complications; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Pathological Conditions, Signs and Symptoms; Behavior; Signs and Symptoms; Sexual Behavior; Pain, Procedural; Premature Birth; Coitus
• Other Study ID Numbers: 7256

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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