Preterm‐born individuals: a vulnerable population at risk of cardiovascular morbidity and mortality during thermal extremes?

Abstract Preterm‐born individuals are a uniquely vulnerable population. Preterm exposure to the extrauterine environment and the (mal)adaptations that occur during the transitional period can result in alterations to their macro‐ and micro‐physiological state. The physiological adaptations that increase survival in the short term may place those born preterm on a trajectory of lifelong dysfunction and later‐life decompensation. Cardiovascular compensation in children and adolescents, which masks this trajectory of dysfunction, is overcome under stress, such that the functional cardiovascular capacity is reduced and recovery impaired following physiological stress. This has implications for their response to thermal stress. As the Anthropocene introduces greater changes in our environment, thermal extremes will impact vulnerable populations as yet unidentified in the climate change context. Here, we present the hypothesis that individuals born preterm are a vulnerable population at an increased risk of cardiovascular morbidity and mortality during thermal extremes.

, with more than 50% of adverse health events during high-temperature days being of cardiovascular origin, whereas heat stroke and heat exhaustion contribute comparatively less (Campbell et al., 2018;Kang et al., 2016).Indeed, Danet et al. (1999) estimated as many as 10% of all myocardial infarctions may be due to fluctuations in the thermal environment.Given this tight association, the Intergovernmental Panel on Climate Change (IPCC) predicts that the main risk for morbidity across the first half of this century will be though climate-induced exacerbation of health conditions in vulnerable populations (K.R. Smith et al., 2014).
CVD is a leading cause of morbidity and mortality worldwide, but symptoms frequently remain concealed until the cardiovascular system is stressed, as commonly occurs during thermal extremes (Casas et al., 2016).This perhaps explains the dramatic increase in CVD-related hospital admissions during heat waves (Kim et al., 2017;Wang & Lin, 2014) and cold snaps (Hess et al., 2009;Shoraka et al., 2022), both acutely and in the days following exposure (Kang et al., 2016;Wang & Lin, 2014).Other factors, such as ageing (>60 years; Gravel et al., 2021;Holowatz & Kenney, 2010) and metabolic disease (Kenny et al., 2010;Wang & Lin, 2014) further enhance this cardiovascular risk in vulnerable populations.Among vulnerable population subgroups presenting with limited adaptive capacity, such as the elderly, heat-and cold-stress may favour the occurrence of disease with early death (Liu et al., 2015;Shoraka et al., 2022).For instance, excess mortality during the 2003 European heat wave exceeded 10% in most countries across Europe (Robine et al., 2008), and heat illness during the North American heat wave rose 69 times above the same period in 2019 (Philip et al., 2021).While not examined by Robine et al. (2008) or Philip et al. (2021), it is likely that vulnerable populations with comorbidities contributed to this excess mortality.
As cardiovascular dysfunction and disease is a leading comorbidity, cardiovascular events are likely the primary cause of excess mortality in these heat waves (Casas et al., 2016).However, when examining the effects of thermal extremes on excess morbidity and mortality, it is of interest not only to examine the response of vulnerable populations to temperature extremes, but also to understand the mechanisms that impair vulnerable subpopulations (Wang & Lin, 2014).
Those born preterm are one such vulnerable population.

Highlights
• What is the topic of this review?
Thermal extremes disproportionately affect populations with cardiovascular conditions.Preterm birth, across all gestational age ranges below 37 weeks, has been identified as a nonmodifiable risk factor for cardiovascular disease.
The hypothesis is presented that individuals born preterm are at an increased risk of cardiovascular morbidity and mortality during thermal extremes.
• What advances does it highlight?
Cardiovascular stress tests performed in preterm-born populations, from infancy through adulthood, highlight a progression of cardiovascular dysfunction accelerating through adolescence and adulthood.This dysfunction has many similarities with populations known to be at risk in thermal extremes.
The risk of climate change-induced exacerbation of health conditions in vulnerable populations highlights the need to understand the ways in which highly susceptible subpopulations are affected by extreme temperatures (Khraishah et al., 2022;Wang & Lin, 2014).As increasing numbers of preterm infants are surviving into adulthood it is of great importance that we understand how environmental temperature extremes may impact their lifelong health.The purpose of the current review is, therefore, twofold: first, to explore the mechanistic factors that make at-risk populations vulnerable to thermal extremes, and second, given the extensive evidence demonstrating a lifelong elevated pretermassociated CVD risk, to highlight those born preterm as a vulnerable population worth greater consideration in the climate change context.

COMORBIDITIES AND MODIFIERS OF THERMOREGULATION
While humans utilize a multi-organ approach to maintain homeothermy, the cardiovascular system is the 'linchpin' by which homeothermy is maintained.With deviations from thermoneutral conditions, thermoeffectors are recruited in a co-ordinated manner relative to their physiological cost.These consist of adjustments in vascular tone and thermal behaviours (e.g., seeking shade or shelter) followed by autonomic thermoeffectors (e.g., sweating or shivering/non-shivering thermogenesis) (Schlader et al., 2018;C. J. Smith & Johnson, 2016; Figure 2).Whereas recruited thermoeffectors (i.e., sweating or F I G U R E 1 Relative risk of cardiovascular morbidity and mortality with exposure to increasing global temperatures.Thresholds for compensable and uncompensable thermal tolerance are altered by the presence of disease and dysfunction, for example, elderly populations (orange line) or cardiovascular disease populations (purple line).With rising global temperatures and greater severity of thermal extremes, the proportion of vulnerable populations increases (dotted line and shaded area).This cardiovascular risk may extend to apparently healthy populations, such as those born preterm.Created with BioRender.com.shivering) may supersede the role of the cardiovascular system in terms of heat loss or heat conservation, they are accompanied by changes in vasomotor tone (Schlader et al., 2018).Schlader et al. (2018) demonstrated that even behavioural responses coincide with, but do not attenuate, changes in vasomotor tone.Cutaneous vasodilatation is important in thermoregulatory sweating, providing both the heat required for evaporation and the blood plasma necessary for sweat gland function (C.J. Smith & Johnson, 2016).Sweating further exacerbates cardiovascular strain under heat stress in its use of provided blood plasma.Indeed, it has been long established that a decrease in body weight of more than 2% as a result of sweating places severe demands on both the cardiovascular and thermoregulatory systems (Baker, 2019).
While lifestyle and environmental factors can modify this decline in function, they cannot completely alleviate or ameliorate it (Tochihara et al., 2021).Collectively, the reduced tolerable capacity of senescent systems in elderly individuals is ultimately borne out in their excess deaths during thermal extremes.
CVD demonstrably reduces the cardiovascular capacity to tolerate stressors.This cardiovascular impairment is worsened by cumulative years of disease burden and is readily observed in the cardiovascularrelated hospital admissions during heat waves and cold snaps, particularly in elderly individuals who may possess latent or overt cardiovascular dysfunction (Kang et al., 2016;Liu et al., 2015).
Moreover, societal factors, such as urbanisation (e.g., heat islands; Campbell et al., 2018) and pollution (Khraishah et al., 2022), enhance the severity of climatic events, further exacerbating the risk to vulnerable populations.As such, for those presenting with limited adaptive capacity, heat or cold stress may favour the onset of disease with early death (Liu et al., 2015).Indeed, those born preterm are one such sub-population that possess a life-long 'latent' risk -not the least of which is elevated BP -which may be uncovered by the stress of thermal extremes.In light of the indisputable rise in global temperatures, the preterm-born population is one sub-population that highlights our need to understand the health risk of climatic events.

PRETERM BIRTH AND CARDIOVASCULAR RISK ACROSS THE LIFESPAN
Events that alter the normal trajectory of early life development have profound implications for health and well-being extending throughout life (Crump, 2020).Of the 15 million live preterm births worldwide annually, ∼85% are moderate-to-late preterm deliveries (32-37 weeks), with very and extremely preterm deliveries (<32 weeks) accounting for ∼15% (Lewandowski et al., 2020).
Sufficient evidence now exists implicating preterm birth as an independent risk factor for CVD; while this cardiometabolic risk is inversely proportional to gestational age, it remains even for late preterm infants (Crump, 2020).Preterm-associated disease formation consistently occurs earlier than in the general population due in part to cessation of fetal maturation (Lewandowski et al., 2013;Schubert et al., 2011), systemic inflammation (Humberg et al., 2020) and accelerated ageing of systems (Prior & Modi, 2020).Some of these changes are observable from birth (Cohen et al., 2007(Cohen et al., , 2008;;Stark et al., 2008), whereas others become apparent across the lifespan.Dysfunction observed in childhood include pulmonary vascular disease (Naumburg & Soderstrom, 2019), arterial narrowing (Jiang et al., 2006;Schubert et al., 2011), and abnormal vascularisation (Bonamy et al., 2007;Hellström et al., 1998).In adulthood, higher rates of cardiometabolic dysfunction and disease have been widely observed (e.g., hypertension, diabetes mellitus, heart failure and ischaemic heart disease (Crump, 2020;Lewandowski et al., 2020).Despite efforts to reduce the harm of acute therapies on long-term health outcomes of preterm-born individuals (e.g., treatment of circulatory compromise, postnatal corticosteroids; McKinlay & Manley, 2019), treatments to address their long-term cardiovascular risk remain scarce (Lewandowski et al., 2020).As such, those born preterm are a burgeoning population who carry an increased risk of CVD throughout life (Crump, 2020; Figure 3).
While it is clear that at-risk populations experience the most detrimental effects during heat waves and cold snaps, the specific vulnerabilities of subpopulations require further attention in order to minimise excess morbidity and mortality (Wang & Lin, 2014).
The preterm risk of CVD is well established, though their functional cardiovascular capacity remains less well-known (Table 1).The risk of both age-and CVD-related morbidity and mortality from thermal extremes is also well established, as discussed above (K.R. Smith et al., 2014).Given that even apparently healthy elderly individuals carry this increased burden of risk, this then implicates preterm-born individuals, who despite appearing healthy in their early adulthood, carry underlying systemic cardiovascular dysfunction (Huckstep et al., 2018), and exhibit accelerated ageing (Prior & Modi, 2020).However, those born preterm have not been examined in relation to increased cardiovascular risk and thermal extremes.Here, we will attempt to connect the dots.

Cardiovascular (dys)function in preterm-born individuals
Preterm birth per se is the single most pervasive and lasting maternofetal insult to preterm infants (Bavineni et al., 2019;Crump, 2020).
Transition to extrauterine life is a period of an exceptionally dynamic and tightly coordinated physiological change, catalysed by changing materno-fetal hormonal profiles, parturition with separation from the placenta, and the first breaths.However, premature transition profoundly disrupts normal fetal maturation of cardiovascular, metabolic and neural systems (Lewandowski et al., 2020;Prior & Modi, 2020).In the cardiovascular system, this can be observed in abrupt maturation of cardiomyocytes, characterised by cessation of myocyte proliferation, reduced ventricular size and myocyte number, increased collagen deposition and smaller relative internal ventricular diameters -key cardiac structural elements which at the time of term birth are largely set for life (Lewandowski et al., 2013).Growth disruption also extends across the vasculature resulting in narrowed arteries (e.g., aortic, coronary, popliteal and brachial arteries), an anti-angiogenic state and disorganised microvasculature (Lewandowski et al., 2015;Schubert et al., 2011).Poor circulatory adaptation drives much of the clinical dysfunction observed in the preterm neonate (Knobel et al., 2009;Stark et al., 2008), but it remains a key driver of lifelong cardiovascular decompensation.
While the level of postnatal cardiovascular catch-up development, growth and functional recovery is unknown, the persistence of cardiovascular dysfunction in later life argues that it is limited.In childhood, this trajectory of cardiovascular dysfunction manifests in the form of elevated BP, heart rate and circulating catecholamines (Bonamy et al., 2007;Johansson et al., 2007), as well as reduced capillary density, and abnormal retinal and cutaneous vascularisation (Bonamy et al., 2007;Hellström et al., 1998).Indeed, many studies have reported the persistence, and further deterioration of, arterial dysfunction throughout infancy (Schubert et al., 2011;Tauzin et al., 2014), childhood (H.Martin et al., 2000), adolescence (Bonamy et al., 2005;Johansson et al., 2005) and adulthood (Hovi et al., 2011;Tauzin et al., 2014).
While the association between preterm-born individuals' arterial function and atherosclerosis formation remains uncertain, the effects on BP and afterload remain clear precursors to CVD.Indeed, elevated BP has both upstream (eccentric myocardial hypertrophy) and downstream effects.Both macro-and microvascular dysfunction contribute to elevated BP, with capillary rarefaction caused by, and further contributing to, sustained elevations in BP through their effect on systemic vascular resistance (Barnard et al., 2020;Lewandowski et al., 2015).Persistently elevated BP damages the endothelial lining, contributing to atherosclerotic plaque formation in major vessels and impairing eNOS throughout the vasculature (e.g., via oxidative stressmediated endothelial damage, and capillary rarefaction; Bavineni et al., 2019).Capillary rarefaction, and the associated antiangiogenic state demonstrated in preterm-born adolescents and adults, has been hypothesised to be a lasting effect from birth and causative in the preterm-risk of hypertension (Kistner et al., 2002;Lewandowski et al., 2015).
Systemic inflammation and sympathetic hyperactivity may also play a role in the persistence of cardiovascular dysfunction from infancy (Bavineni et al., 2019;Humberg et al., 2020).Preterm birth disrupts development of autonomic maturation, leaving the parasympathetic arm to mature postnatally (De Rogalski Landrot et al., 2007;Patural et al., 2008).A functional interdependence has been

TA B L E 1
The cardiovascular response to physiological stressors in preterm-born individuals across the lifespan.

Infancy
Cohen  hypothesised to form between the hyperadrenergic state and systemic inflammation, as preterm populations in the neonatal period 'collect' risk factors for chronic inflammation (e.g., respiratory inflammation, sepsis, enterocolitis), which alongside the NICU environment (e.g., bright lights, painful procedures, excess noise) may additionally interfere with maturation of autonomic control (Patural et al., 2008;Yiallourou et al., 2013).This relationship between systemic inflammation and sympathetic hyperactivity is causative in the aetiology of more traditional CVD (Buford, 2016;Humberg et al., 2020).In preterm infants, such factors may cement the autonomic imbalance beyond the neonatal period, as the immaturity of the descending modulating pathways appear to potentiate the neonatal stress response, both acutely and chronically, via neuroplastic mediators (Rodrigues & Guinsburg, 2013;van Ganzewinkel et al., 2017;Walker et al., 2009).This could further explain why maturation of parasympathetic nervous system (PNS) activity lags so far behind sympathetic maturation (PNS maturation suppressed in magnitude 2to 3-fold compared to term-born counterparts at 6 months; Yiallourou et al., 2013), and may further compromise heart rate recovery from stressors throughout life (tilt test in infancy, Yiallourou et al., 2013; exercise in adults, Haraldsdottir et al., 2019).
Importantly, any postnatal 'catch up' occurs on a background of structural deterioration of the vasculature and endothelium alongside excess circulating catecholamines (Bonamy et al., 2005;Johansson et al., 2005;Kistner et al., 2002), leading to increased shear stress, oxidative stress and inflammatory markers (Bavineni et al., 2019).
Systemic inflammation is further aggravated by the presence of other chronic preterm-specific dysfunction, including obesogenic factors and insulin resistance, which exacerbate and accelerate CVD formation (Humberg et al., 2020).This system-wide cardiovascular dysfunction associated with all abbreviated gestations (<37 weeks) necessarily affects the capacity to respond to stressors, such as psychosocial stress, exercise and thermal extremes even in the absence of overt disease.This is due to the cessation of fetal maturation, inflammation and accelerated ageing incurred as a result of preterm birth and early postnatal life.Early onset of CVD in those born preterm increases the cumulative years of disease burden, enhancing their risk in the face of thermal extremes.

Thermal resilience in preterm-born individuals
The response of preterm-born individuals to physiological stress has been examined in infancy, childhood, adolescence and adulthood (Table 1).Though much of this focus has been on respiratory capacity and exercise tolerance following extreme preterm birth (L.J. Smith et al., 2008), as well as orthostatic or CO 2 tolerance (Cohen et al., 2007(Cohen et al., , 2008) ) and potentiation of pain responses (Rodrigues & Guinsburg, 2013;van Ganzewinkel et al., 2017), inferences can be made regarding the response to environmental extremes.During the preterm perinatal period, cardiovascular and thermoregulatory instability (particularly of aberrant dilatation and deficient brown adipose tissue) have been well documented.Indeed, preterm infants are considered transiently poikilothermic, with this resolving in infancy (Knobel et al., 2009).The capacity of preterm-born individuals to adequately thermoregulate beyond the neonatal period has not been examined, and as such the level of postnatal catch up is unknown.However, troubling allusions include poor thermosensitivity across the entire thermal spectrum and altered pain sensitivity in childhood (Hermann et al., 2006;Walker et al., 2009), as well as system-wide cardiovascular dysfunction which is tightly interrelated with thermoregulatory capacity.
Cardiovascular responses to exercise stress appear to be reduced in healthy preterm-born children, adolescents and adults in comparison to their term counterparts (L.J. Smith et al., 2008;Welsh et al., 2010; Table 1).Exercise capacity is already significantly reduced in childhood (∼50% of term counterparts; L. J. Smith et al., 2008); 20% reduced VO 2 peak , (Clemm et al., 2014), and is further impaired by neonatal bronchopulmonary dysplasia (Welsh et al., 2010).In adulthood, this disparity in exercise capacity remains (10% reduced VO 2 peak in 18-25-year-olds; Clemm et al., 2014), with prematurity correlated with sedentary behaviour (Lowe et al., 2016).Huckstep et al. (2018), using an exercise stress test in young adults observed that while cardiac compensation in preterm-born adults occurred at rest, upon performing exercise at 60% capacity, ejection fraction reduced 6.7% from their term controls, and further declined to 7.3% by 80% of exercise capacity.This was matched by a significant ∼50% reduction in cardiac reserve from 40% of exercise capacity (Huckstep et al., 2018).Such findings are supported by evidence of increased aortic stiffness, and associated BP elevations, as well as attenuated stroke volume and cardiac output during exercise in preterm born adults (Barnard et al., 2020;Macdonald et al., 2021).In addition to poor performance, recovery from exercise stress may also be affected, with Haraldsdottir et al. (2019) reporting significantly lower VO 2 max and slower heart rate recovery from maximal effort.
Parallels can be drawn between exercise capacity and thermal risk (Wilson et al., 2014).Preterm-born individuals at all ages demonstrate reduced exercise capacity, altered cardiac response and impaired recovery.Cardiac stress remains the dominant cause of morbidity and mortality during thermal extremes in elderly and CVD populations (Campbell et al., 2018;Kang et al., 2016), and is likely of greatest risk in preterm populations.Elderly hearts exhibit attenuated changes in cardiac output and elevated cardiac strain during heat stress (Gravel et al., 2021).Similarly, impaired cardiac output and ventricular function are present in preterm-born adults under exercise stress (Huckstep et al., 2018;Macdonald et al., 2021).Like those with CVD, preterm populations exhibit persistent systemic inflammation and autonomic dysregulation.This has been shown in CVD populations to augment vasoconstriction and impair vasodilatory capacity (Ikaheimo, 2018;Kenny et al., 2010).Capillary rarefaction and fibrosis have been demonstrated in CVD to impair heat responses (Buford, 2016;Foëx & Sear, 2004); the prevalence of rarefaction, system-wide fibrosis and antiangiogenic factors in prematurity likely also impairs capillary recruitment and heat offload.Furthermore, sustained BP elevations and systemic inflammation damage the endothelial lining impairing nitric oxide release, and this may compound structural insufficiencies in prematurity.Finally, impaired thermosensitivity apparent in both elderly and preterm populations delays thermoregulatory action (Hermann et al., 2006;Walker et al., 2009), increasing the load of subsequent responses.It should be clear, then, that those born preterm share many characteristics that make elderly, and particularly those with CVD, vulnerable.More research is required to elucidate this educated speculation.
As perinatal medicine continues to evolve, enabling increasing numbers of even extremely preterm infants to survive, the focus must necessarily shift to accommodate consideration of long-term cardiometabolic wellbeing alongside innovation needed to improve neonatal survival.However, technological innovations are likely to mitigate only the worst life-course trajectory in those born preterm.Given this, the unknown long-term risk of morbidity and mortality from thermal extremes is of major concern and further studies are clearly needed.

DISCUSSION AND PERSPECTIVES
The IPCC predicts that the major risk for morbidity and mortality from climate change across the first half of this century will be through exacerbation of health conditions in vulnerable populations (K.R. Smith et al., 2014).Given rising global temperatures continually setting new temperature records, and a four-to five-fold increase in heat waves, the threshold for vulnerability is reducing (World Meteorological Organization, 2019).Excess hospital admissions and death due to climatic extremes are now routinely being documented (Kim et al., 2017;Robine et al., 2008;Shoraka et al., 2022;K. R. Smith et al., 2014).This necessitates wider investigation of potentially vulnerable populations, such as those born preterm, in the climate change context.
In this review, we have highlighted some of the common cardiovascular factors between elderly and CVD populations, and those born preterm.These include impaired thermosensitivity and impaired vasomotor reactivity with greater cardiac strain under physiological stress (Figure 2).While we are unable to draw direct comparisons in thermoregulatory capacity between these populations, the similarities in cardiovascular dysfunction are apparent.Those born preterm exhibit dysfunctional cardiovascular traits from an early age (Figure 3), and exhibit more cumulative years of disease burden than 'traditional' CVD populations who frequently manifest signs of CVD in mid-to-late adulthood.Overt cardiovascular dysfunction can be observed in preterm-born adolescents and young adults during exercise stress (Table 1).This includes progressive cardiac impairment, increased pulsatility of blood flow and elevated BP during graded exercise (Barnard et al., 2020;Huckstep et al., 2018;Macdonald et al., 2021).Similar limitations are observed in the progressive deterioration associated with 'traditional' CVD.
Those born preterm are, therefore, a population worthy of investigation in the climate change context.While the majority of those born preterm survive into adulthood without major comorbidities, the structural changes incurred at birth remain.This is true not just for those born at the limit of viability but all individuals born less than 37 weeks' gestation.Poor recognition of this risk in adulthood limits timely detection of dysfunctional traits that make this population at risk of CVD and of morbidity or mortality during thermal extremes.
Researchers, policymakers and public health officials would benefit from further examination of physiological responses to thermal stress in these vulnerable populations (Khraishah et al., 2022).

RECOMMENDATIONS FOR FUTURE RESEARCH
There remains much to learn regarding the response to heat and cold stress in vulnerable populations.This includes, but is certainly not limited to, the well-known CVD population.Those born preterm are uniquely at risk because of their early exposure to extrauterine life, which impacts nearly all bodily systems.Events that alter the trajectory of early life development and how this predisposes infants to increased risk of non-communicable disease in later life remain poorly recognised outside the field of developmental origins.However, preterm birth represents a relatively common and profound disruption to developmental physiological processes which can have far-reaching impacts.Due to this paucity of data, there is clearly a need for more research investigating the true risk in preterm-born populations.
As this is a heterogeneous group, with vast differences between gestational ages, all future studies must be couched in these terms.A list of future research avenues includes: • Are preterm populations present in the excess morbidity and mortality data of thermal extremes?Countries with adequate neonatal records should be capable of examining this question.
• What is the preterm response to heat and cold stress?Is this comparable to findings during exercise?And are these findings

F
Life course view of preterm CVD risk.Risk of CVD increases in a non-linear trajectory due to cumulative progression of dysfunction and disease from perinatal, lifestyle-induced or other challenges.Prematurity (grey region) elevates the starting trajectory for CVD away from term-born low-risk trajectory.Early interventions may lower this high-risk trajectory, whereas adult interventions of overt CVD have limited benefits.No treatment exists to lower preterm-born individuals to a low-risk trajectory.Figure adapted from Hanson and Gluckman (2014).Abbreviations: BP, blood pressure; CAD, coronary artery disease; CHF, congestive heart failure; CVD, cardiovascular disease; IHD, ischaemic heart disease; ISSI, intermittent or sustained systemic inflammation; NEC, necrotising enterocolitis; NOP, nephropathy of prematurity; PDA, patent ductus arteriosus; PPH, persistent pulmonary hypertension; ROP, retinopathy of prematurity; SNS, sympathetic nervous system.
present in moderate-to late-preterm born individuals?• Does thermal stress expose altered cardiac function as exercise appears to? • Could augmented systemic inflammation contribute to elevated risk in heat or cold?• What is the preterm vasomotor response to heat or cold exposure?What of thresholds for thermoeffector function?How effective is their sweat capacity?What of shivering and non-shivering thermogenesis?• Does vulnerability to stress coincide with cardiovascular dysfunction in adulthood, or are adolescents or even children at risk during thermal stress?Does any vulnerability correspond to that of known populations, or does their early life present a unique vulnerability?
The following studies during infancy, childhood, adolescence and adulthood are by no means an exhaustive list, but are representative of literature at these life stages.Abbreviations: AGA, average for gestational age; BIIP, behavioural indicators of infant pain; BPD, bronchopulmonary dysplasia; B/W, birth weight; CPET, cardiopulmonary exercise testing; DBP, diastolic blood pressure; EF, ejection fraction; f FRC, functional residual capacity; FVC, forced vital capacity; GA, gestational age; HF, high frequency domain of HRV analysis; HRV, heart rate variability; LF, low frequency domain of HRV analysis; LV, left ventricle; NICU, neonatal intensive care unit; NIPS, neonatal infant pain scale; PNA, postnatal age; PIPP, premature infant pain profile; P max , time to exhaustion; T sk , skin temperature; VLC, vital lung capacity; VO