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Neonatal pain… And afterwards?

Cláudia Maria Gaspardo, PhD, Beatriz Oliveira Valeri, MSc*, Maria Beatriz Martins Linhares, PhD*
*Department of Neurosciences and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil. Beatriz Oliveira Valeri is an international trainee member and Maria Beatriz Martins Linhares is a collaborator of the Canadian Institutes of Health Research (CIHR) Strategic Training Initiative in Health Research – Pain in Child Health (PICH).

The vulnerable preterm infants hospitalized in Neonatal Intensive Care Units (NICU) undergo many painful and stressful procedures, which cumulatively could affect early and later developmental outcomes. Early repeated exposure to pain and distress in the NICU can alter the neurological substrate and consequently lead to changes in somatosensory processing of pain and in neurobehavioral responses to painful events.¹ Moreover, repeated pain experiences in early development can have long-term effects on pain processing.²

Topical reviews highlighted the relevance of the relationship between neonatal pain and development.^3,4Therefore, a recent systematic review examined the association between early neonatal pain experiences of preterm infants and the subsequent developmental outcomes of these children across different ages.⁵ The 13 included studies showed that developmental outcomes were assessed during two different phases: early development outcomes during the neonatal period (from birth to term-equivalent age or 40 weeks post-conceptional age) and later development outcomes (4, 8, 12, 18, 24 and 26 months corrected chronological age for prematurity, and 7 years of age).

Concerning the early development of preterm infants, the neonatal pain experiences were associated with delayed early post-natal body and head growth, less attention and arousal, more lethargy, reduced suboptimal reflexes, reduced white matter and subcortical gray matter maturation, slower rise in fractional anisotropy of the corticospinal tract, and higher cortical activation in older preterm infants.⁵ Then, preterm infants who undergo early repeated painful procedures during NICU hospitalization are at risk for altered brain activation and development.

Regarding the later development of children born preterm, the findings demonstrated that neonatal pain predicted poorer cognitive and motor development at 8 months and 18 months of corrected chronological age.⁵ Moreover, the neonatal biobehavioral reactivity-recovery responses during acute painful procedures in NICU predicted the later temperament of toddlers born preterm, wherein very early pain reduced the ability to self-regulate after a painful event and may be part of the core of the surgency temperament factor during toddlerhood.⁶ Additionally, neonatal pain predicted the high negative affectivity in the temperament of preterm infants at 12 months and was associated with internalizing behavior in toddlers born very preterm at 18 months of corrected chronological age; both findings demonstrated associations between early neonatal pain and child emotional development, which are moderated by parenting factors.⁷ Finally, at school age, cumulative neonatal pain/stress was associated with changes in cortical rhythmicity, which was correlated with lower visual-perceptual abilities in the children.⁸

Despite the diversity of developmental outcomes measured, a number of key findings were elucidated in this systematic review study, which contributes to the literature regarding the significant relationship between neonatal pain and child development. Accordingly, the early, repeated, and cumulative pain had a negative impact beyond infancy, altering pain processing in the children’s development. Therefore, the neonatal pain in preterm infants should be accurately assessed and appropriately managed. Pain management strategies, such as non-pharmacological interventions for pain relief⁹, should be protective of adverse long-term effects. In addition, the findings reviewed have several clinical implications for developmental care in NICU setting10 and follow-up programs for preterm infants.

In conclusion, neonatal pain has a negative impact on development in the neonatal period and during infancy and toddlerhood through the middle childhood. However, notably few prospective longitudinal studies which analyzed the associations between neonatal pain and developmental outcomes in children born preterm both in the medium- and long-term were found. Since childhood is a period of both great opportunity and considerably risk, longitudinal studies including developmental assessments at different ages could further explore the effects of neonatal pain-related stress on the developmental pathway, as well as considering the pain history after neonatal discharge.⁵

References

¹Simons S, Tibboel D. Pain perception development and maturation. Semin Fetal Neonatal Med. 2006;11:227-231.
²Anand KJ. Effects of perinatal pain and stress. In: Mayer E, Saper C, eds. Progress in Brain Research. Amsterdam: Elsevier Science; 2000:117-129.
³Grunau, RE. Neonatal pain in very preterm infants: long-term effects on brain, neurodevelopment and pain reactivity. Rambam Maimonides Med J. 2013;4:e-0025.
⁴Vinall J, Grunau RE. Impact of repeated procedural pain-related stress in infants born very preterm. Pediatr Res. 2014;75(5):584-7.
⁵Valeri BO, Holsti L, Linhares, MBM. Neonatal pain and developmental outcomes in children born preterm: a systematic review. Clin J Pain. 2015;31:355-62.
⁶Klein V, Gaspardo CM, Martinez FE, Grunau RE, Linhares MBM. Pain and distress reactivity and recovery as early predictors of temperament in toddlers born preterm. Early Human Dev. 2009;85:569-576.
⁷Voigt B, Brandl A, Pietz J, Pauen S, Kliegel M, Reuner G. Negative reactivity in toddlers born prematurely: indirect and moderated pathways considering self-regulation, neonatal distress and parenting stress. Infant Behav Dev. 2013;36:124-138.
⁸Doesburg SM, Chau CM, Cheung TP, Moiseev A, Ribary U, Herdman AT et al. Neonatal pain-related stress, functional cortical activity and visual-perceptual abilities in school-age children born at extremely low gestational age. Pain. 2013;154:1946-1952.
⁹Bueno M, Yamada J, Harrison D, Khan S, Ohlsson A, Adams-Webber T et al. A systematic review and meta-analyses of nonsucrose sweet solutions for pain relief in neonates. Pain Res Manag. 2013;18;153-161.
¹⁰Als H, Duff F, Mcanulty G, et al. Early experience alters brain function and structure. Pediatrics. 2004;113:846-857.