Reduced Aerobic Exercise Capacity in Adults Born at Very Low Birth Weight: No Small Matter!

Preterm birth (<37 wk) and low birth weight (LBW; <2,500 g) accounts for ∼11% and ∼15%, respectively, of all live births worldwide (1, 2). There is a growing concern for this population as those born preterm have an increased risk of early mortality from noncommunicable diseases (3) but, surprisingly, not morbidity at ages 18–43 years (4). There is also evidence for an association between birthweight and risk of mortality (5). Thus, there is an urgent need to determine the reason(s) for the increased risk of mortality in this ever-growing population. Aerobic exercise capacity is an important predictor of all-cause morbidity and mortality in, presumably, term-born, normal birthweight men (6) and women (7). However, this has not yet been established in those born preterm with very LBW (VLBW). Interestingly, there are multiple reports demonstrating reduced aerobic exercise capacity in adults born preterm (8), which raises the possibility that the lower aerobic exercise capacity may be the link between preterm birth and the increased mortality risk. Therefore, gaining a better understanding of the underlying cause(s) of reduced aerobic exercise capacity in adults born preterm with VLBW remains a clinically relevant endeavor.

In this issue of the Journal, Yang and colleagues (pp. 88–98) provide compelling evidence in a population-based cohort that impaired respiratory and cardiovascular function is associated with reduced aerobic exercise capacity in those born preterm with VLBW (9). A clinically reduced peak o2, defined as <84% predicted, was found in 36% of VLBW adults compared with 17% of control subjects. Of those VLBW with a reduced peak o2, 49% had bronchopulmonary dysplasia (BPD) compared with 32% with no BPD. Multiple regression models revealed that in addition to physical activity with body mass index, lung function and cardiac structure/function contributed equally to the differences in cardiopulmonary exercise testing outcomes between the VLBW and control groups. Remarkably, prematurity-related perinatal factors (e.g., BPD, antenatal steroids, small for gestational age, extreme prematurity) were not associated with the reduced aerobic exercise capacity in the VLBW group. Similarly, desaturation measured by delta SpO (peak exercise–baseline oxygen saturation difference measured by pulse oximetry) was not associated with reduced aerobic exercise capacity despite VLBW adults having a significantly reduced diffusing capacity for the lung for carbon monoxide and rate constant for carbon monoxide with normal Va suggestive of pulmonary microvascular destruction/remodeling. These data support previous reports of normal pulmonary gas exchange in this population (8). This population-based study is an important advancement in the field by providing evidence for impaired lung structure and function and cardiac structure and function as equal contributors to impaired aerobic exercise capacity in adults born preterm with VLBW.

A limitation of the current study was that the authors were only able to quantify the association between impaired aerobic exercise capacity and the respiratory and cardiovascular physiology of adults born preterm with VLBW. Figure 1 provides a schematic representation of the relationship between altered heart and lung structure/function and exercise ability. Additional studies, particularly in large cohorts, are needed to determine whether a causative relationship exists between impaired cardiopulmonary function and reduced aerobic exercise capacity. For example, previous work in a small cohort has demonstrated that when adults born preterm breathe a helium–oxygen mixture (79% He, 21% O2) during exercise, expiratory flow limitation, presumably caused by small airways (10), is reduced and exercise endurance is “normalized” relative to term-born control subjects (11). This example of a late life intervention supports the idea that aerobic exercise capacity and/or exercise endurance can be improved in adults born preterm when respiratory limitations are minimized. Likewise, in animal models of preterm birth, complicated by BPD, human umbilical cord–derived stem cells delivered into the airways to prevent abnormal lung development improved treadmill running distance to values similar to control animals, regardless of whether they were delivered before or after hyperoxia-induced alveolar injury (12). This example of an early life intervention in a preclinical model also supports the idea that exercise capacity could possibly be rescued in this population when the negative respiratory consequences of preterm birth are minimized or prevented.

Figure 1.

Schematic representation of the impact of preterm birth and VLBW on lung structure/function and cardiac structure/function and, subsequently, reduced aerobic exercise capacity in adulthood. Likewise, the existent literature suggests that early and/or late life interventions can improve or rescue respiratory and cardiovascular structure/function. Early and late respiratory interventions have been shown to improve/normalize aerobic exercise capacity in preclinical and clinical models (11, 12). Early life cardiovascular interventions improve cardiac structure/function in adulthood (13), but whether or not this translates to improved/normalized aerobic exercise capacity remains unknown. It has been demonstrated that preterm birth and VLBW are associated with early mortality (3), but a definitive link between aerobic exercise capacity and early mortality has yet to be established. Blue = aspect that has been demonstrated; green = unknown/untested aspect. VLBW = very low birth weight.

Whether or not improving cardiac performance in adults born preterm with VLBW (i.e., a late life intervention) also improves exercise capacity is unknown. However, early life interventions such as maternal breast milk have demonstrated improved cardiac performance in adulthood (13). Thus, there is sufficient evidence that early life interventions have the potential for improving cardiac structure and function. If cardiovascular function is a limiting factor to aerobic exercise capacity, then improving function should improve aerobic exercise capacity in adults born preterm. One additional consideration for the cardiovascular contributions is competition for blood flow with respiratory muscle demand. In this population of preterm VLBW adults, it would be expected that the work of breathing would be greater given the greater magnitude of expiratory flow limitation during exercise (14). This would elicit the metaboreflex and result in more of the being diverted to the respiratory muscles and away from the exercising locomotor muscles. Although this would reduce exercise capacity in any population, this effect may be exacerbated in those born preterm because they have a reduced compared with term control subjects (15). Accordingly, any diversion of blood flow to the respiratory muscles would have a greater impact on those born preterm with VLBW. Although late life interventions for improved cardiac function are limited (e.g., left ventricular assist devices), late life respiratory interventions such as heliox may have a greater influence on improving exercise capacity than they would on populations without impaired cardiac structure and function.

The final frontier of this line of inquiry will be to determine whether or not early and/or late life interventions designed to improve respiratory and/or cardiovascular function will increase aerobic exercise capacity and subsequently reduce or normalize their risk of all-cause mortality. Doing so would be no small matter and could improve quality and longevity of life in a population that may be “prematurely” aged in adulthood.