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- Title
Pain Exposure and Brain Connectivity in Preterm Infants.
- Authors
Selvanathan, Thiviya; Ufkes, Steven; Guo, Ting; Chau, Vann; Branson, Helen M.; Ibrahim, George M.; Ly, Linh G.; Kelly, Edmond N.; Grunau, Ruth E.; Miller, Steven P.
- Abstract
Key Points: Question: Are there sex-specific associations among early-life pain exposure, neonatal brain network maturation, and neurodevelopmental outcomes in preterm infants? Findings: In this prospective cohort study of 150 preterm infants, sex-specific associations were found between early-life pain exposure and maturation of neonatal brain structural connectivity, with a greater association with pain seen in female infants. Decreased brain structural connectivity was associated with poorer 18-month neurodevelopmental outcomes. Meaning: In this study, early-life pain exposure was associated with slower maturation of structural brain networks, particularly in female infants; clinical trials of neonatal analgesic strategies should consider this sex-specific vulnerability to early-life pain. This cohort study examines whether greater early-life pain is associated with slower maturation of neonatal connectivity in female vs male infants and whether reduced connectivity is associated with poorer neurodevelopmental outcomes. 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.
- Subjects
BRAIN physiology; FUNCTIONAL connectivity; DATA analysis; NEURAL development; KRUSKAL-Wallis Test; FISHER exact test; MAGNETIC resonance imaging; LONGITUDINAL method; PAIN; STATISTICS; CONFIDENCE intervals; DATA analysis software; CHILDREN
- Publication
JAMA Network Open, 2024, Vol 7, Issue 3, pe242551
- ISSN
2574-3805
- Publication type
Article
- DOI
10.1001/jamanetworkopen.2024.2551