Very preterm infants may manifest neurodevelopmental impairments, even in the absence of brain lesions. Pathogenesis is complex and multifactorial. Evidence suggests a role of early adversities on neurodevelopmental outcomes, via epigenetic regulation and changes in brain architecture. In this context, we focused on cumulative pain exposure which preterm neonates experience in neonatal intensive care unit (NICU). We systematically searched for: i) evidence linking pain with brain development and exploring the potential pathogenetic role of epigenetics; ii) preclinical research supporting clinical observational studies. Nine clinical neuroimaging studies, during neonatal or school age, mostly from the same research group, revealed volume reduction of white and gray matter structures in association with postnatal pain exposure. Three controlled animal studies mimicking NICU settings found increased cell death or apoptosis; nevertheless, eligible groups were limited in size. Epigenetic modulation (SLC6A4 promoter methylation) was identified in only two clinical trials. We call for additional research and, although knowledge gaps, we also point out the urgent need of minimizing painful procedures in NICUs.

早产儿即使没有脑部病变也可能表现出神经发育障碍。发病机理是复杂的和多因素的。有证据表明，通过表观遗传调控和脑结构变化，早期逆境对神经发育结果具有重要作用。在这种情况下，我们集中于早产新生儿在新生儿重症监护病房（NICU）中所经历的累积疼痛暴露。我们系统地搜索：i）将疼痛与大脑发育联系起来并探索表观遗传学的潜在致病作用的证据；ii）临床前研究支持临床观察研究。在新生儿或学龄期的九项临床神经影像学研究中，大多数来自同一研究组，发现白和灰质结构的体积减少与产后疼痛暴露有关。模仿NICU设置的三项受控动物研究发现，细胞死亡或细胞凋亡增加。但是，合格的小组规模有限。仅在两项临床试验中发现了表观遗传调控（SLC6A4启动子甲基化）。我们要求进行更多的研究，尽管存在知识空白，但我们也指出了将NICU的痛苦手术最小化的迫切需求。