Table 1

Characteristics of included human studies and overview of findings

Outcome measuresReferences*
(country)		Study designBirth weightGestational ageNumber of participantsType of feedOsmolality/
osmolarity†		Osmolality/
osmolarity measured		Outcomes
Gastric emptyingPascale (1978)13 (USA)RCT<2000 gNot reported8Intact protein formula (Isocal)204 mOsm/LNoGreater delay in gastric emptying in infants fed higher osmolarity formula.
6Intact protein formula (Portagen)211 mOsm/L
13Hydrolysed protein formula (Pregestimil)539 mOsm/L
Gastric emptyingRamirez (2006)14 (USA)Cross-over RCT<1570 g25–30 weeks10Half strength human milk or formula‡155 mOsm/kgYesNo change in gastric emptying with a higher diet osmolality.
Half strength human milk or formula‡310 mOsm/kg
Half strength human milk or formula‡310 mOsm/kg
Full strength human milk or formula‡310 mOsm/kg
7Full strength human milk or formula‡155 mOsm/kgYesAccelerated gastric emptying with decreased osmolality and increased feed volume.
Full strength human milk or formula‡310 mOsm/kg
Gastric emptyingSiegel (1982)15
(USA)		Cross-over RCTNot reported26–34 weeks10With sucrose (Neo-Mull-Soy)279±12 mOsm/kgYesNo significant difference in gastric emptying.
With glucose (Cho-Free with glucose)448±11 mOsm/kg
Gastric emptyingYigit (2008)16 (Turkey)Cross-over RCT600–1470 gMean 29.8 weeks20Human milk319±19 mOsm/§YesNo significant increase in gastric emptying time for full strength fortification.
Half strength HMF (Eoprotin)365±25 mOsm/L§
Full strength HMF (Eoprotin)440±44 mOsm/L§
Tolerance;
Gastric emptying		Kanmaz (2013)17 (Turkey)RCT≤1500 g≤32 weeks26Standard fortification (Eoprotin)340 mOsm/LNoNo significant difference in feeding intolerance, residuals and abdominal distension.
29Moderate fortification (Eoprotin)360 mOsm/L
29Aggressive fortification (Eoprotin)380 mOsm/L
Tolerance;
Overall morbidity		Kim (2015) 18
(USA)		RCT700–1500 g≤33 weeks63Powdered intact protein HMF (Similac)385 mOsm/kgNoNo significant differences in overall morbidity, and both fortifiers were well tolerated.
66New liquid hydrolysed protein HMF450 mOsm/kg
Tolerance;
NEC		Singh (2017)19
(India)		Prospective observational<1500 gNot reported15Higher carbohydrate HMF (Lactodex)378±34 mOsm/kgYesNo significant difference in episodes of feeding intolerance or NEC.
15Higher fat HMF (HIJAM)420±31 mOsm/kg
15Higher carbohydrate HMF (FM-85)451±39 mOsm/kg
Tolerance;
NEC		Rigo (2017)20 (France, Belgium, Germany, Switzerland and Italy)RCT≤1500 g≤32 weeks76New partially hydrolysed protein HMF (with higher protein and micronutrients)390 mOsm/kgYesNo significant difference in feeding tolerance and NEC.
74Extensively hydrolysed protein HMF
(FM-85)		441 mOsm/kg
NECBook (1975)21
(USA)		RCT<1200 g24–32 weeks8Cow milk formula (premature formula)359 mOsm/LNoSignificantly higher incidence of NEC in the elemental formula group (87.5%) compared with cow milk formula group (25%).
8Elemental formula (Pregestimil)650 mOsm/L
NECThoene (2016)22 (USA)Retrospective observational<2000 gNot reported23Acidified liquid hydrolysed protein HMF326 mOsm/kgNoSignificantly higher incidence of NEC in the feed group with lowest osmolality.
46Powdered intact protein HMF385 mOsm/kg
51Non-acidified liquid intact protein HMF385 mOsm/kg

  • *References indicated with first author and year.

  • † Osmolality/osmolarity values were rounded up.

  • ‡Formula used in Ramirez et al 14 were either Enfamil 24 or Neosure.

  • §Range of values also reported in Yigit et al 16 (275–371 mOsm/L, 310–411 mOsm/L and 344–576 mOsm/L).

  • HMF, human milk fortifier; NEC, necrotising enterocolitis.