Pain Exposure and Brain Connectivity in Preterm Infants

Abstract

ImportanceEarly-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.ObjectiveTo examine sex-specific associations among early-life pain exposure, alterations in neonatal structural connectivity, and 18-month neurodevelopment in preterm infants.Design, Setting, and ParticipantsThis 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.ExposurePain was quantified in the initial weeks after birth as the total number of invasive procedures.Main Outcome and MeasureInfants 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.ResultsA 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 RelevanceIn 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.

Terminology matters: is the International Association for the Study of Pain definition of pain fully satisfactory for fetuses, neonates, and infants?

“…Functional connectivity of the right thalamocortical pathway was related to negative neuromotor outcomes at 24 months ( P = 0.003). Early pain exposure is correlated with abnormal functional connectivity of developing networks involved in the modulation of noxious stimuli in preterm neonates, contributing to the neurodevelopmental consequence of preterm birth” ( 27 ); in this sense, this study was aligned with further research because an altered structural connectivity was associated with neurodevelopmental outcomes ( 28 ).…”