• neonatology
• intensive care units
• neonatal

Bronchopulmonary dysplasia (BPD), the chronic lung disease of very preterm infants, is an important determinant of mortality and longer term morbidity. BPD is strongly associated with the duration of exposure to mechanical ventilation, and thus clinicians aim to support very preterm infants with ‘non-invasive’ ventilation (NIV) such as continuous positive airway pressure (CPAP), nasal intermittent positive pressure ventilation (NIPPV) or nasal high-flow (nHF) wherever possible. There is evidence from a systematic review of clinical trials that the use of CPAP in spontaneously breathing very preterm infants in the delivery room, instead of routine endotracheal intubation, may have a modest beneficial effect on rates of survival free of BPD.1 But does the increasing use of NIV actually reduce BPD in very preterm infants? Is LESS really MORE?

Two studies report the change over time in NIV use in very preterm infants, and associated outcomes. Let us state from the outset that both are non-randomised, observational cohort studies and thus causation between interventions and outcomes cannot be determined. Avila-Alvarez et al 2 compared the use of NIV and in-hospital outcomes in a total of almost 18 000 very preterm (<32 weeks’ gestation) or very low birthweight (<1500 g) infants born in two 5-year periods: 2010–2014 and 2015–2019. In the more recent epoch, survival increased in a subgroup of infants born at 29–31 weeks’ gestation, but did not change in extremely preterm infants. There was no increase in the overall rate of survival without BPD; in fact, there was a lower rate of survival without BPD in the subgroup of infants born <26 weeks’ gestation. This was despite greater exposure to all modes of NIV (CPAP, NIPPV and nHF), fewer infants being intubated in the delivery room and more infants avoiding mechanical ventilation altogether during their hospital admission. It should be noted that the database used in this study collects information on only about two-thirds of all very low birth weight infants born in Spain, and excludes outborn infants (in whom the risks of adverse outcomes may be higher) as well as infants who died in the delivery room.

Sand et al 3 report the change in patterns of respiratory support and outcomes over an 8-year period from 2010 to 2017 in England and Wales including over 56 000 very preterm infants. NIV use increased significantly over time: notably, the use of NIV as primary support on the day of birth increased for both CPAP (from 22% to 28%) and nHF (from 1% to 7%). The overall use of nHF at any time during the neonatal unit stay increased dramatically from 14% to 68%. The increasing use of nHF as primary (early) respiratory support for very preterm infants reported by Sand et al is interesting, given the findings of systematic reviews: nHF use as primary support for preterm infants results in a significantly higher rate of treatment failure than CPAP, although its use does not seem to be associated with increased mechanical ventilation.4 Very few extremely preterm infants have been included in randomised trials of nHF as primary respiratory support, so the effectiveness and safety of nHF in that population are unknown.

Sand et al reported that the use of nHF was associated with increased survival, but also with increases in neonatal morbidities including BPD. As the authors note, this is likely to be an example of ‘confounding by indication’: an exposure (eg, nHF use) appears to be associated with an outcome (eg, BPD), when the outcome is, in fact, related to the indication for the exposure. This is an interesting thought experiment: if we assume nHF is less efficacious than CPAP as early respiratory support, but more simple and comfortable to use in convalescing and stable infants, then (1) the sickest very preterm infants who die early may never receive nHF (so nHF use is associated with survival), and (2) the sickest very preterm infants who survive the neonatal period may ultimately be ‘weaned’ to nHF as their lung disease evolves (so nHF use is associated with BPD).

Our search for effective interventions against BPD is hampered by our own research culture and by changing clinical practice. We have historically used a dichotomous (yes/no) definition for BPD at 36 weeks’ postmenstrual age, based on whether the infants continue to receive respiratory support or oxygen, that does not account for a spectrum of severity or predict longer term outcomes as accurately as we would wish.5 As shown in the two studies in this edition, we are using more NIV for very preterm infants, for longer than we used to. If clinicians choose to continue treatment with NIV beyond 36 weeks’ postmenstrual age, where they previously might have ceased it earlier, then the diagnosis of BPD (due to the very nature of the definition) will of course be more common. It is possible this is a particular issue with nHF, as it is perceived as a gentle therapy that might be continued unnecessarily. Jensen et al 6 have tried to account for these changes in practice in their updated BPD definitions, that account for the increasing duration of exposure to NIV. Nevertheless, the facts are sobering: the rate of BPD (as currently defined) is not decreasing despite improvements in many aspects of neonatal intensive care.

Few interventions have been shown to significantly reduce the incidence of BPD, and the search continues for the BPD ‘holy grail’. Although, as Avila-Alvarez et al state, it is unlikely that a single strategy such as the avoidance of mechanical ventilation will be enough to have a meaningful effect on BPD rates. It is also becoming increasingly ludicrous to be conflating all very preterm infants born at <32 weeks’ gestation together in clinical trials of respiratory support with BPD as an outcome: infants born at <25 or <26 weeks’ gestation have very different needs and outcomes to infants born at 31 weeks’ gestation (or even at 27 weeks’ gestation for that matter). As daunting as it may seem, highly powered randomised trials of optimal respiratory support strategies in the highest risk (most immature) infants to improve survival, reduce severe BPD and improve longer term outcomes are required. These trials should include comparing ventilation strategies (both mechanical and non-invasive) in the delivery room and beyond, evaluating different postnatal corticosteroid regimens and exploring novel therapies to prevent severe BPD.