Review article
Cumulative procedural pain and brain development in very preterm infants: A systematic review of clinical and preclinical studies

https://doi.org/10.1016/j.neubiorev.2020.12.016Get rights and content

Highlights

  • Cumulative pain has been proven to influence brain development in preterm infants.

  • Translational animal studies show some harmful effects of pain on brain histology.

  • Evidence supporting epigenetics as potential underlying mechanism is still scarce.

  • The interplay among pain, epigenetics and brain development needs to be assessed.

  • Despite knowledge gaps, it is crucial to minimize pain exposure in neonatal units.

Abstract

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.

Introduction

Prematurity (birth before 37 weeks of gestational age) is associated with long-term neurodevelopmental impairments, with the youngest infants bearing the highest risk (Johnson and Marlow, 2011; Moore et al., 2013). Besides the major disabilities (cerebral palsy, mental retardation, blindness, and deafness) related to the occurrence of severe brain lesions, almost 25–50% of infants born before 32 weeks of gestation (very preterm, VPT) manifest neurodevelopmental disorders later in childhood, including learning and behavioral problems, even in the absence of overt brain damage in conventional neuroimaging studies (Aarnoudse-Moens et al., 2009; Aylward, 2005; Synnes et al., 2017). The pathogenesis of developmental disturbances related to VPT infants is multifactorial and includes dysmaturational events observed in their brains, which affect both white matter (WM) and neuroaxonal structures (Volpe, 2019). During the last trimester of pregnancy, the fetal brain undergoes relevant structural and molecular changes (Ouyang et al., 2019); in the case of premature birth, brain development occurs in the extra-uterine environment while exposed to potentially adverse insults that could alter the maturational process. These deviations from normal brain developmental trajectories have been clearly demonstrated by advanced neuroimaging studies —both during the neonatal period (Batalle et al., 2017; Gui et al., 2019; Inder et al., 2005; Smyser et al., 2016a) and later in childhood (Damaraju et al., 2010; Fischi-Gomez et al., 2016; Peterson et al., 2000; Zhang et al., 2015). The observed cerebral features of prematurity have been attributed to perinatal risk factors as well as the severity of postnatal morbidities (Boardman and Counsell, 2019; Gui et al., 2019; Inder et al., 2003). More recently, the effects of early life adverse events, such as stress and/or pain exposure, on VPT infants’ brain development have also been emphasized (Grunau, 2013; Smith et al., 2011).

Interestingly, pain in neonates was often unrecognized and undertreated in neonatal intensive care units (NICUs) until physiologic, emotional, and behavioral responses to painful stimuli were demonstrated in studies (Anand and Hickey, 1987; Grunau and Craig, 1987; Rodkey and Pillai Riddell, 2013). Afterwards, a large amount of literature was published regarding nociception, and assessment, management, and short- and long-term effects of pain in neonates (Fitzgerald, 2015; Fitzgerald and Walker, 2009; Goksan et al., 2015; Hartley et al., 2015; Relland et al., 2019; Schwaller and Fitzgerald, 2014).

Newborn infants admitted to NICUs experience repeated painful (defined as invading the bodily integrity) as well as stressful (causing physical uneasiness or annoyance) procedures for both diagnostic and therapeutic purposes (Carbajal et al., 2008). However, as stress and pain cannot be easily distinguished during the neonatal period, some authors consider them a single entity. It has been estimated that neonates, especially preterm infants, during the first 14 days of their stay in the NICU, undergo an average of 7.5–17.3 invasive procedures daily, including heel lance, suctioning, venipuncture, and the insertion of peripheral venous catheters (Cruz et al., 2016). The American Academy of Pediatrics (AAP) has highlighted the importance of preventing and managing neonatal procedural pain not only for ethical issues but also to reduce any potential detrimental consequences (AAP, 2016). Indeed, repetitive pain exposure in newborn infants has been proposed to play a role in their brain development, auxological growth, pain sensitivity, and stress response systems as well as in adverse neurodevelopmental, behavioral, and cognitive outcomes, which can persist later in life (Field, 2017; Grunau, 2013; Ranger and Grunau, 2014; Valeri et al., 2015; Walker, 2019). Hence, early adverse events in NICUs could contribute to explaining, at least in part, lifelong impairments in children born preterm; nevertheless, significant research gaps still remain as to the underlying mechanisms. Considering the burden of prematurity (worldwide about 15 million a year of all live births are preterm) (Blencowe et al., 2013) and the rate of neurodevelopmental deficits in VPT infants, this issue is of paramount importance.

The possible interplay between early life events and neurodevelopment has been explored in the last decade together with the growing amount of research on epigenetics, which investigates the molecular biological mechanisms (such as DNA methylation and histone acetylation) affecting gene expression without altering the DNA sequence. An ecobiodevelopmental framework has been proposed to better understand how the early environment, beginning prenatally, can modulate the expression of the genotype that shapes the brain architecture and affects long-term development (Shonkoff et al., 2012). The brain is a genomic mosaic due to environmentally regulated epigenetic variations of the neural genome (Bedrosian et al., 2018; Coufal et al., 2009) ultimately modulating the expression of neural functions (Karsten and Baram, 2013; Meaney, 2010). Preterm birth itself has been associated with alterations in the methylome of genes whose products influence neuronal and glial signaling, neurotransmission, apoptosis, and cellular energetics. Furthermore, DNA methylation (DNAm) was associated with WM tract tissue shape, suggesting that epigenetic variation may contribute to the cerebral phenotype of preterm infants (Sparrow et al., 2016). Notably, prematurity-related early life adversity exposure, including both repetitive stressful and painful experiences, has also been associated with altered epigenetic modulation (Casavant et al., 2019; Kantake et al., 2014; Provenzi et al., 2018). In this context, it has been hypothesized that epigenetic dysregulation, due to NICU-related stress, might be involved —either directly or through brain development alterations— in the pathogenesis of the neurobehavioral impairments observed in VPT infants (Fumagalli et al., 2018).

To better understand the mechanisms underlying the association between early exposure to painful experiences and neurodevelopment, we systematically review evidence focused on the potential influence of cumulative procedural pain on epigenetic regulation and/or brain development in infants born VPT according to the conceptual hypothesis outlined in Fig. 1. Since randomized controlled studies on the effects of early pain in children are not ethically feasible, studies using animal models mimicking NICU settings (Anand et al., 1999; Johnston et al., 2002; Walker, 2017) are also systematically reviewed for translational evidence supporting the human observational results (Ritskes-Hoitinga et al., 2014). Thus, the aims of this review are: 1) to assess evidence linking pain with brain development in VPT infants; 2) to explore the potential pathogenic role of epigenetics; and 3) to seek preclinical research supporting clinical observational studies.

Section snippets

Methods

The review was conducted and reported according to the AMSTAR 2 tool (Shea et al., 2017) and the PRISMA statement (Moher et al., 2009), respectively. The methods and inclusion criteria were specified in advance and documented in a protocol published in the PROSPERO database (registration number CRD42019139011).

Study characteristics

After removing duplicates, a total of 24,881 references remained from records identified through database searching and other sources. Of these, 24,787 studies were excluded on the basis of their titles and abstracts clearly being non-relevant. Ninety-four were judged to be potentially relevant and were thus acquired in full text for more detailed evaluation; 78 of these were then excluded for not meeting the inclusion criteria (see the exclusion reasons in Supplementary Material). A total of

Discussion

The dysmaturation events observed in the brain of preterm infants, potentially affecting their neurodevelopmental outcomes, have been partially attributed to early life adversity exposure —either directly or via epigenetic mechanisms (Korosi et al., 2012; Sparrow et al., 2016). With this systematic review, we focused on the available evidence on epigenetic modulation and brain architectural abnormalities associated with cumulative pain exposure that VPT infants experience during their NICU

Source of founding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest

The authors report no declarations of interest.

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