Exercise Training Improves Exercise Capacity in Preterm-Born Adults: Lessons for Clinical Trials?

Approximately 10% of all births are considered preterm, or at less than 37 weeks of completed gestation. There is increasing recognition that preterm birth interrupts normal growth and development and has long-term cardiopulmonary consequences, particularly for those bornmoderately to extremely preterm. Althoughmost adults born mildly preterm present with heart and lung function within the range of normal, those born moderately to extremely pretermmore often present with overt airflow obstruction (1), smaller biventricular chamber size (2, 3), and/or pulmonary vascular disease (4) with a gestational age dose response. These differences impact exercise tolerance, with several studies reporting lower _ VO2, which may be a result of expiratory airflow limitation (5), impaired stroke volume reserve (4, 6), or multifactorial causes (7, 8). Importantly, exercise capacity is predictive of all-cause morbidity and mortality in the general population (9, 10). Thus, defining the mechanisms of exercise limitations in those born pretermmay provide specific targets for intervention, which has the potential to improve exercise capacity, quality of life, and overall mortality. In this issue of the Journal, Burchert and colleagues (pp. 1227–1236) present a subgroup analysis from the recent TEPHRA trial (Trial of Exercise to Prevent HypeRtension in young Adults) (11) comparing the intervention response between term (>37 weeks gestation) and preterm (,37 weeks gestation) participants (12). Fifty-two preterm and 151 term-born participants were randomized to a 16-week aerobic training program with wristworn physical activity monitoring and motivational coaching compared with educational materials alone. At baseline, the preterm group had an average gestational age of 32 weeks, normal body mass index, overall normal lung function (FEV1 97% predicted; FVC, 102% predicted in preterm exercise group), and baseline _ VO2 at peak exercise intensity ( _ VO2PEAK) percent predicted similar to the termborn exercise group (preterm 83% vs. term 81%). Overall, exercise was well tolerated among term and preterm groups and improved _ VO2PEAK and _ VO2 at ventilatory anaerobic threshold ( _ VO2AT). In termborn individuals in the exercise group, adjusted _ VO2PEAK increased significantly by 3.1 (95% confidence interval [CI], 1.7–4.4) ml/kg/min and adjusted _ VO2AT increased significantly by 2.3 (95% CI, 0.7–3.8) ml/kg/min. Among preterm-born individuals in the exercise group, adjusted _ VO2AT increased significantly by 2.3 (95% CI, 0.7–3.8) ml/kg/ min, whereas _ VO2PEAK increased nonsignificantly. There were no significant interaction effects for adjusted _ VO2PEAK or _ VO2AT to suggest that preterm-born adults respond differently to exercise intervention with respect to _ VO2. Several post hoc subgroup analyses were conducted. Both exercise intervention groups showed an increased estimated cardiac index at ventilatory threshold, although this appeared to be through greater increases in heart rate among preterm participants rather than greater increases in calculated stroke volume in term-born participants. Preterm participants also exhibited larger increases in minute ventilation at ventilatory threshold. The TEPHRA trial is the first to study exercise intervention in the preterm-born adult population. A previous 4-week aerobic intervention study in preterm children with bronchopulmonary dysplasia also demonstrated an improvement in exercise capacity measured by 6-minute-walk distance and incremental shuffle walk test (13). Collectively, these studies suggest that exercise is likely safe, at least in the short term, and leads to improved exercise capacity in the preterm population. By looking at changes in breathing (minute ventilation, breathing frequency, and tidal volume) as well as cardiac function (cardiac index, stroke volume index, and heart rate), the TEPHRA study explores the mechanisms regarding how this occurs. Although their subgroup analyses are likely underpowered, they begin to suggest that there may be unique adaptations to exercise training among preterm-born individuals. Specifically, gains in cardiac index are primarily through heart rate rather than stroke volume among preterm-born adults, which is opposite the expected augmentation in stroke volume with exercise training seen in term-born individuals. Although stroke volume was not directly measured, these data are consistent with a growing body of literature suggesting impaired stroke volume reserve and heart rate dependency in the preterm-born adult, likely as a result of overall smaller biventricular sizes (2–4, 6). Whether cardiac structural remodeling occurs with exercise in this preterm population is currently unknown but merits further evaluation. Additionally, whether improved exercise capacity leads to better overall health outcomes in these individuals remains unknown. It is important to note that the effects of preterm birth on cardiopulmonary outcomes are not uniform, and there are clear dose–response effects at lower gestational ages. As a result, studies in patients with an average gestational age of 28 weeks or less are much more likely to report significant differences in cardiopulmonary measures compared with term-born individuals. Similarly, the effects of preterm birth on aerobic exercise capacity also demonstrate a dose response, with lower workloads achieved by those born the most preterm (14). TEPHRA defined their preterm population as gestational age less than 37 weeks, with only 38.5% born at less than 32 weeks, which would be considered a higher-risk population. Future studies should focus on measures of respiratory and cardiovascular mechanics in those born moderately to extremely preterm, as these mechanistic studies are most likely to identify which cardiopulmonary adaptations to exercise are unique to the preterm population in the setting of significant cardiopulmonary developmental arrest. Considering that TEPHRA, as a primary study, was designed to assess the effect of exercise training on blood pressure, the authors are commended for conducting a well-performed exercise intervention study in which a subgroup of high-risk participants—namely those This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please e-mail Diane Gern (dgern@thoracic.org).