Association of Fluid Balance With Short- and Long-term Respiratory Outcomes in Extremely Premature Neonates A Secondary Analysis of a Randomized Clinical Trial.

JAMA Netw Open. 2022 Dec 1;5(12):e2248826. doi: 10.1001/jamanetworkopen.2022.48826

Michelle C Starr, Russell Griffin, Katja M Gist, Jeffrey L Segar, Rupesh Raina, Ronnie Guillet, Saudamini Nesargi, Shina Menon, Nekayla Anderson, David J Askenazi, David T Selewski; Neonatal Kidney Collaborative Research Committee. JAMA Network Open. Dec 2022

Reviewed by: Catherine Joseph


Fluid overload occurs commonly in preterm neonates and is associated with increased morbidity and mortality. Extremely low gestational age neonates (ELGANs) often develop multiorgan dysfunction, frequently accompanied by disordered fluid balance [FB]. There are only few studies that look at association between FB and respiratory outcomes in this population.


To describe FB patterns and evaluate the association of FB with respiratory outcomes in a cohort of ELGANS.

Study Design:

Secondary analysis of Preterm Erythropoietin Neuroprotection Trial (PENUT), a phase 3 placebo-controlled randomized clinical trial of erythropoietin in extremely premature neonates conducted in 30 neonatal intensive care units in the US from 2013 to 2016. This secondary analysis conducted in 2021 included 874 extremely premature neonates born at 24 to 27 weeks’ gestation who were enrolled in the PENUT study.


  • 874 neonates were included (449 [51.4%] male; mean [SD] birth weight [BW], 801 [188] g; 187 [21.4%] Hispanic, 676 [77.3%] non-Hispanic, and 11 [1.3%] of unknown ethnicity).
  • Of the cohort, 458 (52.4%) received mechanical ventilation on postnatal day 14.
  • Median peak positive FB was 11% (IQR, 4%-20%), occurring on postnatal day 13 (IQR, 9-14). Neonates requiring mechanical ventilation at postnatal day 14 had a higher peak FB compared with those who did not (15% above BW vs 8% above BW, P < .001). On postnatal day 3, neonates requiring mechanical ventilation were more likely to have a higher FB (5% below BW vs 8% below BW, P < .001).
  • After adjusting for confounding variables, for every 5% increase in peak FB during the first 14 postnatal days, there was 75% increased odds of receiving mechanical ventilation at postnatal day 14 (adjusted odds ratio, 1.75; 95% CI, 1.33-2.31).
  • The median time to return to BW was shorter in neonates who received mechanical ventilation (7 vs 8 days, P < .001) and those with severe BPD (7 vs 8 days, P < .001).


In this study, peak FB was associated with mechanical ventilation on postnatal day 14 and severe BPD or death.


Fluid balance in the first 3 days of life and time to return to BW could be possible targets to help guide management and improve outcomes.