Milk feed osmolality and adverse events in neonates: a systematic review

Title: Osmolality in the range of 300-500 mOsm/kg does not negatively impact gastrointestinal symptoms in neonates: A systematic review

Better neonatal care has improved short-term clinical outcomes of preterm born infants. However long-term health, in particular cognitive development, remains a concern. Poor postnatal growth of preterm is associated with adverse short- and long-term clinical outcomes.

Due to the high nutritional and caloric needs of preterm infants both fortified human milk and preterm formula has a higher osmolality than human milk alone.

Recent feeding guidelines for preterm infants do not include an upper recommended level of feed osmolality/osmolarity, however in 1976 the American Academy of Pediatrics recommended that formulae for all infants should have an osmolarity no greater than 400 mOsm/l (approximately 450 mOsm/kg). This recommendation remains without clear substantiation based on relevant trials, however they have led to high feed osmolality being considered to impact adverse events – particularly gastrointestinal dysfunctions and necrotising enterocolitis (NEC) – in preterm infants. Therefore this systematic review assessed there is a link between high milk feed osmolality and adverse gastrointestinal events, including feeding intolerance and NEC.

Based on 10 included human studies with 618 subjects no consistent evidence was found that feed osmolality is associated with any adverse gastrointestinal events except at very high levels.  Seven studies reported no differences in adverse events with varying feed osmolalities/osmolarities. One study reported delayed gastric emptying with feed osmolarity of 539 mOsm/l compared to lower levels, however significant compositional differences between the feeds limit the interpretation of this result. The most severe clinical manifestation of feeding intolerance is NEC, and no consistent evidence was found that higher milk feed osmolalities impact this. One study reported higher NEC incidence with feed of osmolarity of 650 mOsm/l compared to 359 mOsm/l, however again significant differences in formulae composition make it impossible to determine if this is attributable to increased osmolality. In addition, 1 study found higher NEC incidence with the lowest feed osmolality (326 mOsm/kg) compared to feeds with higher osmolality (385 mOsm/kg) with acidified vs non acidified products, highlighting the role of formulae composition. Of animal studies two reported delayed gastric emptying with feed osmolality >624 mOsm/l and none reported an increase in NEC incidence with differing feed osmolalities.  No clear mechanisms supporting a role of osmolality in feed intolerance were found.