Study limitations

There was a large amount of heterogeneity in the included studies. Factors including different exercise protocols, differing populations, varying ages of the study participants at

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time of testing, different methods for reaching maximal exercise and variation in the neonatal management during different epochs are likely to explain the heterogeneity. The accuracy of the recording/measurement of gestational age at birth used by each study may not be reliable as the gold standard would be to assess using antenatal u/s scan and some studies were conducted prior to u/s dating scans. All the studies have excluded subjects with severe disabilities due to the coordination and physical strength needed to complete the exercise tests. Preterm-born subjects with physical disabilities may have severe CLD and their inclusion may have had a significant impact on the results, however many studies included in our review excluded all patients with physical disabilities. Also the definitions of CLD/BPD used by each included study varied and there were differences, which means the severity of CLD of the included participants ranged from mild to severe, which may have skewed the results of the data for the CLD groups. I comprehensively reviewed the literature and am confident of having included all major studies. There was little publication bias thus I am confident of the overall findings of this review. The quality of the studies included in our analysis was

reasonable. I was limited by the quality of the published information. One study with data from two separate cohorts, only presented results in graph format and the data were estimated, so this may have led to small errors, which are unlikely to substantially affect the main results (Clemm, Roksund et al. 2012).

There is considerable variation in the value of O2max(29-50 ml/kg/min) between studies possibly reflecting different exercise protocols used and the different populations studied (from 5 to 21 years old), however these values are within the normal range. Studies comparing the methods used to predict O2max have shown that a treadmill-running test gives higher results by 5-15% than the cycle ergometer test and the sensitivity analysis

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confirmed this finding (Keren, Magazanik et al. 1980, Grant, Corbett et al. 1995, LeMura, von Duvillard et al. 2001, Abrantes, Sampaio et al. 2012). The ability of preterm-born individuals to perform exercise capacity tests may be affected not only by their physical abilities but also the cognitive impairment associated with preterm birth (Bhutta, Cleves et al. 2002). This is especially for the shuttle run test which requires a higher degree of concentration and attention from participants, so preterm-born subjects maybe at a disadvantage, given they have been shown to have difficulties with their executive function and attention levels (Mulder, Pitchford et al. 2009). The shuttle run test was designed as a field test for athletes and so it is not recommended for research testing for a cohort of children or adults with possible physical difficulties, although it has been shown to be a reliable substitute for lab- based tests in children with developmental difficulties (Cairney, Hay et al. 2010). Also the results of tests are based on estimates and so is an indirect measure of the O2max . In my review only two studies used the shuttle run test and both identified a significant difference, but they are only included in the analysis for the first group (all preterm-subjects including CLD – therefore mixed cohorts) when the two studies are removed from the analysis this did not alter the message as the result continued to show a significant difference even with the two studies removed. Three studies from my systematic review assessed children younger than 8 years old using the cycle ergometry test and it has been suggested that cycle ergometry be avoided in younger children as they may have under developed knee extensors (Roitman 2001). It has been suggested that younger children may be better suited to doing the treadmill test, which may give more accurate results as shown by van der Cammen-van Zijp (van der Cammen-van Zijp, Ijsselstijn et al. 2010). However LeMura et al showed that both cycle ergometer and treadmill are effective tests for assessing exercise capacity in children aged 5-6 years (LeMura, von Duvillard et al. 2001).

132 3.5 Conclusion

Despite the limitations, the meta-analysis for O2maxshows that preterm-born subjects with or without CLD have marginally lower (<13%) exercise capacity than term-born control subjects. The differences in O2max are small (-2.20 ml/kg/min to -3.05 ml/kg/min; SMD - 0.33 to -0.44) and it would appear that despite the reduced lung function of preterm-born subjects with or without CLD, they are able to adapt and achieve near normal exercise capacity. However this may be at the expense of the preterm-born subjects, especially those with CLD, using more of their ventilatory reserve as shown by Joshi et al (Joshi, Powell et al. 2013). The follow up programs of preterm-born infants should aim to use similar exercise testing protocols with well-defined populations and clear criteria for maximal exercise testing. Future research needs to assess the longer-term impact of the slightly reduced deficit in exercise capacity. The physical activity of preterm-born children also requires further investigation, to review whether training can improve the exercise capacity and possibly the lung function of those born preterm. Finally it is important to assess the same cohorts of participants in later life to analyse for evidence of tracking. This would help to answer the research question: does a small difference in O2max in younger life equate to a much larger difference in later life and could this potentially be prevented?