This is the first study to report data on long-term neurodevelopmental follow-up at two years corrected age in very preterm infants treated with automated oxygen titration as standard of care compared with manual oxygen titration as standard of care. Implementation of automated oxygen titration did not lead to a change in mortality or neurodevelopmental outcome at 2 years. Although earlier studies[6–14] demonstrate an increase in time within target range when using automated oxygen titration, we were not able to demonstrate an effect on neurodevelopmental outcome in this large cohort.
To date, there is little data on clinically relevant outcome of infants receiving automated oxygen titration. There is no data available on neurodevelopmental outcome after usage of AOC, and data on follow-up of preterm infants from non-AOC studies are difficult to compare with, because they involved non-standard interventions[23, 24], infants born almost 15 years ago[25, 26], or had a study population that had markedly different characteristics[27, 28]. The outcomes of both groups in our study are similar to the outcome of a previous cohort study from our centre.
The reason for fewer readmissions after implementation of automated oxygen titration is not apparent from our data. Rates of BPD, ROP and other morbidity potentially requiring re-hospitalisation are similar, although we did find fewer ventilation days in our previous study for the post-AOC cohort.
A failure to demonstrate an impact on neurodevelopmental outcome after implementing automated titration can have several causes. In the previous study on achieved target range time in our NICU, we demonstrated that although infants spent more time within target range overall, this was mainly attributed to a reduction in time above the target range. In fact, using the CLiO2 controller led to a 6% increase of time spent under the SpO2 target range (90–95%). This increase was mainly just below (85–90%) target range while still having a similar proportion of hypoxaemia (< 80%). If indeed more time spent under the target range is where neurodevelopmental improvement can be gained, the lack of improvement in this area could explain the lack of impact on neurodevelopmental outcome. Furthermore, as reported before it could be that outcome is more largely influenced by the frequency and duration of hypoxia and hypoxic events, which were not investigated in our previous study nor in most other automated oxygen controller studies. Also, preterm infants can experience many potentially harmful stimuli and events before being tested at two years of corrected age, in particular during the neonatal phase. Oxygenation deviations during respiratory support may play only a minor role in the eventual neurodevelopmental outcome, meaning only very large randomised studies are able to demonstrate a statistically significant difference. Thirdly, neonatal care is a rapidly developing field with frequent changes to standard of care. Some of these unmeasured factors may influence the results in either direction. Finally, some of the adverse outcomes are relatively rare. If the effect of automated oxygen control is modest, a large clinical trial would be needed to observe an effect. Currently, the FiO2-C trial randomises between automated oxygen control or manual titration during the entire NICU stay, and will investigate the effect on clinical and neurodevelopmental outcome at 24 months of corrected age. The study is projected to run until December 2022.
A change in target range may influence the time spent in (mild) hypoxia. In our case one would expect that the 76% (223/293) infants in the pre-implementation group born before November 2014 spent more time in the 85% − 90% range, as the lower limit was changed from 85–90%. The achieved proportion of time in the 85% − 90% range based on 1 minute-values of the pre- and post-implementation data show no difference while infants received oxygen (pre-AOC 10.9 [8.6–13.5]%, post-AOC 10.4 [7.7–12.7]%, p = 0.09), and a 1.8% difference when considering the entire period of respiratory support (pre-AOC 5.5 [1.7–9.8]%, post-AOC 3.7 [1.6–7.6]%, p = 0.002; unpublished data). Van Zanten et al. reported before that the change of lower limit led to a reduction in achieved time within the 80%-90% range in our unit, but time spent in hypoxia (SpO2 < 80%) was not different.
One of the inherent limitations of a retrospective design is the rate of missing data (loss to follow-up in this study: pre-AOC 6.9%, post-AOC 10.6%), which is unfortunately frequently high in follow-up research. The majority of missing children were transferred to another university NICU in the neonatal phase and had subsequent follow-up there, therefore we expect them to be missing at random and not related to neurodevelopmental outcome. However, children lost to follow-up may be under treatment in a special care facility and therefore not missing at random. Parents may be less inclined to present their child for follow-up when they already receive regular tests in such a facility. To limit biased results due to missing such children, we requested data for all children tested elsewhere. Another strength of the study is that we have a relatively large cohort in which we had few exclusion criteria, meaning the results are generalisable to other NICUs in a similar setting. Furthermore children are tested by trained professionals as part of a standardized national follow-up programme, improving the repeatability and reliability of the assessment of neurodevelopmental outcome. Finally, most data was collected prospectively during standard follow-up, minimising recall bias.
Besides fewer parent-reported readmissions, no change in outcome occurred after implementation of automated oxygen control. It is reassuring that outcomes did not deteriorate, and that outcome of our follow-up is similar to earlier reported data. Our results show no signs children are affected negatively by using an automated oxygen controller, whereas there are benefits for staff workload.