Supplementary Material for: Prematurity, Opioid Exposure and Neonatal Pain: Do They Affect the Developing Brain?

Background: Traditionally, 10 years ago, children born preterm often routinely received morphine, especially during mechanical ventilation. Studies in neonatal rats, whose stage of brain development roughly corresponds to that of children born preterm, found negative long-term effects after pain and opioid exposure. Objectives: We studied possible effects of prematurity, procedural pain and opioids in humans 10 years later. We hypothesized that these factors would negatively influence neurobiological, neuropsychological and sensory development later in life. Methods: We included 19 children born preterm who as neonates participated in an RCT on the short-term effects of morphine administration and who previously participated in our follow-up studies at ages 5 and 8/9 years. We assessed associations between brain morphology (n = 11), neuropsychological functioning (n = 19) and thermal sensitivity (n = 17) and prematurity, opioid exposure and neonatal pain. Results: Significant correlations (coefficients 0.60-0.85) of gestational age, number of painful procedures and morphine exposure with brain volumes were observed. Significant correlations between these factors and thermal sensitivity were not established. Neuropsychological outcome was significantly moderately correlated with morphine exposure in only two subtests, and children performed in general ‘average' by Dutch norms. Conclusions: Although prematurity, opioid exposure and neonatal pain were significantly associated with brain volume, no major associations with neuropsychological functioning or thermal sensitivity were detected. Our findings suggest that morphine administration during neonatal life does not affect neurocognitive performance or thermal sensitivity during childhood in children born preterm without brain damage during early life. Future studies with larger sample sizes are needed to confirm these findings.

研究背景：十年前的传统临床实践中，早产新生儿常常规接受吗啡治疗，尤其是在机械通气期间。针对新生大鼠的研究显示，疼痛与阿片类药物暴露会带来长期负面影响——这类大鼠的脑发育阶段与早产新生儿大致相当。
研究目的：本研究旨在探究十年后，早产、操作相关疼痛以及阿片类药物暴露对人类个体的潜在影响，并提出假设：上述因素会对个体日后的神经生物学、神经心理学以及感觉发育产生负面影响。
研究方法：本研究纳入19名早产儿童，这些个体在新生儿期曾参与一项关于吗啡给药短期效应的随机对照试验（Randomized Controlled Trial，RCT），且此前已参与过本团队在其5岁、8/9岁时开展的随访研究。研究人员评估了脑形态学（样本量n=11）、神经心理学功能（样本量n=19）与热感觉敏感性（样本量n=17）分别与早产状态、阿片类药物暴露及新生儿期疼痛之间的关联。
研究结果：本研究观察到胎龄、疼痛操作次数与吗啡暴露量分别与脑容积存在显著相关性（相关系数区间为0.60~0.85）。但未发现上述因素与热感觉敏感性之间存在显著关联。仅在两项分测验中，神经心理学结局与吗啡暴露量存在显著中等程度相关；且按照荷兰常模来看，受试儿童的整体表现处于‘平均水平’。
研究结论：尽管早产、阿片类药物暴露与新生儿期疼痛均与脑容积存在显著相关性，但未检测到上述因素与神经心理学功能或热感觉敏感性之间存在显著关联。本研究结果提示：对于早期未出现脑损伤的早产儿童而言，新生儿期吗啡给药并不会影响其童年时期的神经认知表现与热感觉敏感性。未来需开展更大样本量的研究以验证本研究结论。