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. 2024 Mar 4;7(3):e242551.
doi: 10.1001/jamanetworkopen.2024.2551.

Pain Exposure and Brain Connectivity in Preterm Infants

Thiviya Selvanathan  1   2 , Steven Ufkes  1   3 , Ting Guo  2 , Vann Chau  2 , Helen M Branson  4 , George M Ibrahim  5 , Linh G Ly  2 , Edmond N Kelly  2   6 , Ruth E Grunau  1 , Steven P Miller  1   2
Affiliations

Pain Exposure and Brain Connectivity in Preterm Infants

Thiviya Selvanathan et al. JAMA Netw Open. .

Abstract

Importance: Early-life exposure to painful procedures has been associated with altered brain maturation and neurodevelopmental outcomes in preterm infants, although sex-specific differences are largely unknown.

Objective: To examine sex-specific associations among early-life pain exposure, alterations in neonatal structural connectivity, and 18-month neurodevelopment in preterm infants.

Design, setting, and participants: This prospective cohort study recruited 193 very preterm infants from April 1, 2015, to April 1, 2019, across 2 tertiary neonatal intensive care units in Toronto, Canada. Structural connectivity data were available for 150 infants; neurodevelopmental outcomes were available for 123 infants. Data were analyzed from January 1, 2022, to December 31, 2023.

Exposure: Pain was quantified in the initial weeks after birth as the total number of invasive procedures.

Main outcome and measure: Infants underwent early-life and/or term-equivalent-age magnetic resonance imaging with diffusion tensor imaging to quantify structural connectivity using graph theory measures and regional connection strength. Eighteen-month neurodevelopmental outcomes were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition. Stratifying by sex, generalized estimating equations were used to assess whether pain exposure modified the maturation of structural connectivity using an interaction term (early-life pain exposure × postmenstrual age [PMA] at scan). Generalized estimating equations were used to assess associations between structural connectivity and neurodevelopmental outcomes, adjusting for extreme prematurity and maternal education.

Results: A total of 150 infants (80 [53%] male; median [IQR] gestational age at birth, 27.1 [25.4-29.0] weeks) with structural connectivity data were analyzed. Sex-specific associations were found between early-life pain and neonatal brain connectivity in female infants only, with greater early-life pain exposure associated with slower maturation in global efficiency (pain × PMA at scan interaction P = .002) and local efficiency (pain × PMA at scan interaction P = .005). In the full cohort, greater pain exposure was associated with lower global efficiency (coefficient, -0.46; 95% CI, -0.78, to -0.15; P = .004) and local efficiency (coefficient, -0.57; 95% CI, -1.04 to -0.10; P = .02) and regional connection strength. Local efficiency (coefficient, 0.003; 95% CI, 0.001-0.004; P = .005) and regional connection strength in the striatum were associated with cognitive outcomes.

Conclusions and relevance: In this cohort study of very preterm infants, greater exposure to early-life pain was associated with altered maturation of neonatal structural connectivity, particularly in female infants. Alterations in structural connectivity were associated with neurodevelopmental outcomes, with potential regional specificities.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Selvanathan reported receiving financial support from the Canadian Institutes of Health Research Canada Graduate Scholarships–Master’s and Doctoral Awards, Ontario Ministry of Health–University of Toronto Clinician Investigator Program, and SickKids Research Institute Clinician Scientist Training Program. Prof Grunau reported receiving a salary award from the BC Children’s Hospital Research institute. Dr Ibrahim reported receiving personal fees from LivaNova Inc, Medtronic Inc, and Synergia Inc outside the submitted work. Dr Miller reported serving as the Paediatric Neuroscience Research Chair of the Bloorview Children’s Hospital, the Hudson Family Hospital Chair in Pediatric Medicine Academic, and the James & Annabel McCreary Chair in Pediatrics at the University of British Columbia during the conduct of the study and receiving personal fees from various law firms for expert consultation regarding neonatal brain injury outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Early-Life Pain × Postmenstrual Age (PMA) at Magnetic Resonance Imaging (MRI) Interaction, Stratified by Sex
A. Estimated values of global efficiency with 95% CIs (error bars) for a given number of invasive procedures and PMA at scan showing slower increase in global efficiency by PMA with greater exposure to early-life invasive procedures in female infants (P = .002 for interaction). B. Estimated values of global efficiency with 95% CIs for a given number of invasive procedures and PMA at scan showing no significant early-life pain × PMA interaction in male infants (P = .90). However, greater exposure to invasive procedures was associated with reduced global efficiency in male infants.
Figure 2.
Figure 2.. Significant Associations of Early-Life Invasive Procedures With Regional Connectivity Strength
Circle size indicates level of significance after correction for multiple comparisons. FDR indicates false discovery rate.
See this image and copyright information in PMC

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