Background <p>Time to regain birthweight (time-to-regain) includes subcomponents of time from birth to weight loss nadir (birth-to-nadir), time from weight loss nadir to regain birthweight (nadir-to-regain), and cumulative weight loss (CWL; sum of daily percent weight loss from birthweight until regain), yet relationship with in-hospital outcomes remains unknown.</p> Methods <p>We performed a secondary analysis of the multicenter Preterm Erythropoietin Neuroprotection (PENUT) Trial including extremely preterm (EP) newborns at 24w0d-27w6d gestation at birth evaluating time-to-regain and its subcomponents with in-hospital adverse outcomes.</p> Results <p>Among <i>n</i> = 876 EP newborns, time-to-regain was not significantly associated with in-hospital outcomes. CWL had a U-shaped distribution with &gt;2.5-fold increased odds of NEC for those without weight loss and moderate or severe CWL when compared with mild CWL (&gt;0 to −23 percent-days). Increasing birth-to-nadir was associated with increased odds of NEC (linear trend analysis aOR 1.33, 95% CI 1.05, 1.69). Total fluid intake and time-to-regain are directly related, with total fluid intake strongly associated with markers of severity of illness.</p> Conclusions <p>Among EP neonates, time-to-regain is not associated with in-hospital outcomes and is most associated with severity of illness metrics. CWL and birth-to-nadir appear to be more optimal nutritional and fluid status metrics.</p> Trial registration <p>This study is a post-hoc secondary analysis of pre-existing data from the PENUT Trial (NCT #01378273). PENUT Trial Registration: NCT01378273. <a href="https://clinicaltrials.gov/ct2/show/NCT01378273">https://clinicaltrials.gov/ct2/show/NCT01378273</a>.</p> Impact <p><UnorderedList Mark="Bullet"> <ItemContent> <p>Time to regain birthweight was not associated with in-hospital adverse outcomes, yet cumulative weight loss is significantly associated with necrotizing enterocolitis and is related to long-term neurodevelopmental outcomes.</p> </ItemContent> <ItemContent> <p>Time to regain birthweight does not appear to be an optimal metric of nutritional or hydration status among extremely preterm newborns.</p> </ItemContent> <ItemContent> <p>Cumulative weight loss’s relation to both in-hospital and long-term outcomes suggest it is a more promising indicator of optimal nutrition and hydration status.</p> </ItemContent> <ItemContent> <p>These findings point to the need to revisit current expert recommendations stating that prolonged time to regain birthweight among preterm neonates is a metric of malnutrition; instead, cumulative weight loss may be a more ideal metric.</p> </ItemContent> </UnorderedList></p>