Characteristics of included studies [ordered by study ID]

Methods  Randomised trial 

 Participants  14 very low birth weight infants (not defined). Dilute formula with double volume (half strength) group (n = 6; gestational age 29.2 ± 2 weeks; birth weight 1235 ± 243 grams); full strength group (n = 8; gestational age 29.5 ± 2 weeks; birth weight 1185 ± 286 grams). (Whether these statistics are means and standard deviations is not described in the abstract)
Day of life on which feeding was initiated did not differ between the groups. The ratio of male to female infants was not reported. The proportion of infants that were small for gestational age, or who had central venous catheters was not described 

 Interventions  Half versus full strength preterm formula. Dilute group received double volume, half strength 24 kcal Enfamil Premature formula. Full strength group received undiluted 24 kcal Enfamil Premature formula. Feeds were given as 3hourly bolus feeds. The 2 groups were compared until infants reached an enteral nutrient intake of 80 kcal per kilogram per day. No further details were provided on the feeding regimen 

 Outcomes  Feeding intolerance (abdominal girth increased by > 2 cm and/or residuals > 50% of previous feed), time to reach goal feeds of 80 kcal/kg/day 

 Notes  Location: Charleston, South Carolina, USA. Reported as a conference abstract only. The study was not published in full as trial investigators could not recruit enough babies who were being fed formula. (Personal communication) 

 Risk of bias 
 Bias  Authors' judgement  Support for judgement 
 Random sequence generation (selection bias)  Unclear risk  Comment: not described 
 Allocation concealment (selection bias)  Unclear risk  Comment: not described 
 Blinding of participants and personnel (performance bias) All outcomes  Unclear risk  Comment: blinding of study personnel or participants was not described but is unlikely given the nature of the trial 
 Blinding of outcome assessment (detection bias) Objective outcomes: enteral energy intake, objective measures of feeding intolerance  Unclear risk  Comment: not described but is unlikely given the nature of the trial 
 Blinding of outcome assessment (detection bias) Subjective outcomes: abdominal distention  Unclear risk  Comment: not described but is unlikely given the nature of the trial 
 Incomplete outcome data (attrition bias) All outcomes  Unclear risk  Comment: difficult to assess since trial reported as an abstract only 
 Selective reporting (reporting bias)  High risk  Comment: trial reported as an abstract only. Actual data not given for some outcomes even though outcomes narratively reported 
 Other bias  Unclear risk  Comment: not enough information to assess since trial reported as an abstract only  


Methods  Quasirandomised trial 

 Participants  50 preterm infants with birth weight less than 1500 grams. Dilute formula with double volume (half strength) group (n = 28; mean gestational age 30.2 weeks (SD 1.2); mean birth weight 1189 grams (SD 23.1)); full strength group (n = 22; mean gestational age 30.3 weeks (SD 1.3); mean birth weight 1269 grams (SD 45.4))
There were no significant differences between the full strength group and half strength group in terms of birth weight, gestational age or weight at the time of entry into the study. The ratio of male to female infants was also similar. The proportion of infants that were small for gestational age, or who had central venous catheters, was not described in the study 

 Interventions  The dilute formula with double volume (half strength) group received formula (Enfamil 20) diluted with water but fed in twice the volume (10 kcal/oz), thus maintaining the same enteral caloric and nutrient intake as the full strength group. During the initiation of the feeds, all infants received parenteral nutrition calculated to maintain adequate fluid and nutrient intake while the feeds were being advanced. The parenteral nutrition was progressively reduced as enteral feeds were tolerated and was finally discontinued after enteral feeds were fully established. The groups were compared until infants reached an enteral nutrient intake of 420 joules (100 kcal) per kilogram
Rate of feeding advancement varied with weight (< 1000 g, 1000 to 1250 g, 1250 to 1500 g) and followed an established pattern of introduction over 4 days ( ). Feeds were provided 2hourly. No further details on the feeding regimen were provided 

 Outcomes  Time to achieve full enteral feeding; gastric residuals; incidence of apnoea and/or bradycardia; episodes of vomiting; abdominal distension; guaiacpositive stools 

 Notes  Location: New York, USA 

 Risk of bias 
 Bias  Authors' judgement  Support for judgement 
 Random sequence generation (selection bias)  High risk  "... randomly assigned to one of two groups based on whether the last digit of their hospital identification number was odd or even." 
 Allocation concealment (selection bias)  High risk  Comment: it is unlikely that allocation was concealed due to odd/even number assignment. 
 Blinding of participants and personnel (performance bias) All outcomes  Unclear risk  Comment: blinding of study personnel or participants was not described but is unlikely given the nature of the trial. 
 Blinding of outcome assessment (detection bias) Objective outcomes: enteral energy intake, objective measures of feeding intolerance  Unclear risk  Comment: blinding of outcome was not described but is unlikely given the nature of the trial. 
 Blinding of outcome assessment (detection bias) Subjective outcomes: abdominal distention  Unclear risk  Comment: blinding of outcome assessor(s) not described, but is unlikely given the nature of the trial. 
 Incomplete outcome data (attrition bias) All outcomes  Low risk  Comment: outcome data were reported for all babies. 
 Selective reporting (reporting bias)  Unclear risk  Comment: There is no protocol to access so we do not know the original planned outcomes.  


Methods  Randomised trial 

 Participants  38 preterm infants with birth weight less than 1750 grams. Dilute formula with double volume (half strength) group (n = 20; mean gestational age 32.05 weeks (SD 2.08); mean birth weight 1420 grams (SD 200)); full strength group (n = 18; mean gestational age 32.5 weeks (SD 1.54); mean birth weight 1410 grams (SD 200))
The ratio of male to female infants was not significantly different. All infants in the 2 groups were between 1000 grams and 1750 grams except 2 infants who weighed less than 1000 grams. Gestational age of most infants was between 29 weeks and 34 weeks. The proportion of infants that were small for gestational age, or who had central venous catheters, was not described in the study 

 Interventions  Dilute formula with double volume (half strength) group received Lactogen infant formula (10 kcal/oz) but fed in twice the volume.
Infants in both groups received clear fluids for the first 12 hours followed by the dilute formula with double volume (half strength) formula or full strength formula. Infants were supplemented with intravenous fluids initially to maintain adequate fluid intake. The intravenous infusion was progressively reduced as enteral feeds were tolerated and was finally discontinued after enteral feeds were fully established. The groups were compared until infants reached an enteral nutrient intake of 420 joules (100 kcal) per kilogram.
Rate of feeding advancement varied with weight (< 1000 g, 1000 to 1250 g, 1250 to 1500 g, > 1500 g) and followed an established pattern of introduction over 4 days ( ). Feeds were provided 3hourly. No further details on the feeding regimen were provided 

 Outcomes  Time to achieve full enteral feeding; episodes of gastric aspirate; episodes of abdominal distension; weight gain 

 Notes  Location: New Delhi, India 

 Risk of bias 
 Bias  Authors' judgement  Support for judgement 
 Random sequence generation (selection bias)  Low risk  Quote: "The allocation of subjects to the two groups was through a simple randomisation. The random numbers were generated through the random numbers table." (personal communication with trialist) 
 Allocation concealment (selection bias)  Low risk  Quote: "The random number sequence was with one of the medical personnel not connected with the study. The numbers were made available to the PI (MS Sarna) at the time of enrolment of each subject." (personal communication with trialist) 
 Blinding of participants and personnel (performance bias) All outcomes  Unclear risk  Comment: blinding of study personnel or participants was not described but is unlikely given the nature of the trial 
 Blinding of outcome assessment (detection bias) Objective outcomes: enteral energy intake, objective measures of feeding intolerance  Unclear risk  Comment: blinding of outcome was not described but is unlikely given the nature of the trial 
 Blinding of outcome assessment (detection bias) Subjective outcomes: abdominal distention  Unclear risk  Comment: blinding of outcome assessor(s) not described, but is unlikely given the nature of the trial 
 Incomplete outcome data (attrition bias) All outcomes  Low risk  Comment: outcome data were reported for all babies 
 Selective reporting (reporting bias)  Unclear risk  Comment: there is no protocol to access so we do not know the original planned outcomes  

Characteristics of excluded studies [ordered by study ID]

Study  Reason for exclusion 

 Fewtrell 1997  Different overall nutrient density between groups 
 Postolow 2000  Compared half strength regular formula with full strength preterm formula. The overall nutrient density was different between the groups  

Comparison 1. Half strength formula versus full strength

Outcome or subgroup title  No. of studies  No. of participants  Statistical method  Effect size 

 1 Episodes of abdominal distention > 2 cm  2  88  Mean Difference (IV, Fixed, 95% CI)  0.16 [0.19, 0.13] 
 2 Episodes of gastric residuals  2   Mean Difference (IV, Fixed, 95% CI)  Totals not selected 
  1   Mean Difference (IV, Fixed, 95% CI)  0.0 [0.0, 0.0] 
  1   Mean Difference (IV, Fixed, 95% CI)  0.0 [0.0, 0.0] 
 3 Episodes of vomiting per day  1   Mean Difference (IV, Fixed, 95% CI)  Totals not selected 
 4 Weight gain one week after starting feeds (kg)  1  38  Mean Difference (IV, Fixed, 95% CI)  0.05 [0.06, 0.15] 
 5 Days until 420 joules per kilogram  2  88  Mean Difference (IV, Fixed, 95% CI)  2.26 [2.85, 1.67]  

Summary of findings for the main comparison. Half strength formula compared to full strength formula for exclusively formulafed preterm or low birth weight infants

Half strength formula compared to full strength formula for exclusively formulafed preterm or low birth weight infants 
 Patient or population: exclusively formulafed preterm or low birth weight infants
Settings: neonatal intensive care units (NICUs)
Intervention: half strength formula
Comparison: full strength formula 
 Outcomes  Illustrative comparative risks* (95% CI)  Relative effect (95% CI)  No of participants (studies)  Quality of the evidence (GRADE)  Comments 
 Assumed risk  Corresponding risk 
 Full strength formula  Half strength formula 
 Episodes of abdominal distention > 2 cm  The mean episodes of abdominal distention > 2 cm in the control groups was 0.83 episodes^{4}  The mean episodes of abdominal distention > 2 cm in the intervention groups was 0.16 lower (0.19 to 0.13 lower)^{4}   88 (2 studies)  ⊕⊕⊝⊝ low^{1,2}  
 Episodes of gastric residuals^{3} > 50% of last feed remaining  See comment  See comment  Not estimable^{3}  88 (2 studies)  ⊕⊕⊝⊝ low^{1,2}  Episodes of gastric residuals were lower in the half strength formula group in both studies (MD 1.20, 95% CI 2.20 to 0.20; and MD 0.80, 95% CI 1.32 to 0.28) 
 Days until 420 joules per kilogram days  The mean days until 420 joules per kilogram in the control groups was 10.3 days^{4}  The mean days until 420 joules per kilogram in the intervention groups was 2.26 lower (2.85 to 1.67 lower)^{4}   88 (2 studies)  ⊕⊕⊝⊝ low^{1,2}  
 Necrotising enterocolitis  Study population  Not estimable  0 (0)  See comment  Not reported 
 See comment  See comment 
 Medium risk population 
  
 Allcause mortality prior to hospital discharge  Study population  Not estimable  0 (0)  See comment  Not reported 





  See comment  See comment     
  Medium risk population     





       
 Incidence of invasive infection  Study population  Not estimable  0 (0)  See comment  Not reported 





  See comment  See comment     
  Medium risk population     





       
 *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RR: risk ratio 
 GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.  

^{1}Inadequate method of randomisation and allocation concealment unlikely in one study. Limited information to assess design in both studies. ^{2}We are aware of at least one study which was not published due to inability to recruit sufficient numbers of formulafed infants. ^{3}Studies used different units (residuals per baby per day and residuals per baby until attaining 100 kcal/day) and so could not be combined. ^{4}Assumed risk calculated from mean of control groups in both included studies.

Table 1. Feeding schedule for Currao 1988

Birth weight (< 1000 g)  Birth weight (1000 to 1250 g)  Birth weight (1250 to 1500 g) 


 Full strength formula  Diluted formula (double volume)  Full strength formula  Diluted formula (double volume)  Full strength formula  Diluted formula (double volume) 
 Day 1 
 2 mL 5% dextrose x 2  2 mL 5% dextrose x 2  3 mL 5% dextrose x 2  3 mL 5% dextrose x 2  5 mL 5% dextrose x 2  5 mL 5% dextrose x 2 
 2 mL ¼S x 3  2 mL ¼S x 3  3 mL ¼S x 3  3 mL ¼S x 3  5 mL ¼S x 3  5 mL ¼S x 3 
 2 mL ½S x 3  2 mL ½S x 7  3 mL ½S x 3  3 mL ½S x 7  5 mL ½S x 3  5 mL ½S x 7 
 2 mL ¾S x 3  [n/a]  3 mL ¾S x 4  [n/a]  5 mL ¾S x 4  [n/a] 
 Day 2 
 2 mL FS x 12  3 mL ½S x 6  3 mL FS x 12  5 mL ½S x 12  5 mL FS x 12  7 mL ½S x 6 
 4 mL ½S x 6  10 mL ½S x 6 
 Day 3 
 3 mL FS x 12  5 mL ½S x 6  4 mL FS x 12  6 mL ½S x 6  7 mL FS x 12  12 mL ½S x 6 
 6 mL ½S x 6  8 mL ½S x 6  14 mL ½S x 6 
 Day 4 
 4 mL FS x 12  7 mL ½S x 6  6 mL FS x 12  10 mL ½S x 6  9 mL FS x 12  16 mL ½S x 6 
 8 mL ½S x 6  12 mL ½S x 6  18 mL ½S x 6 
 Feeds were given every two hours. After day 4, the schedule remained the same.
S = strength; FS = full strength.
Multiplication factor indicates the number of feeds.  

Table 2. Feeding schedule for Sarna 1990

Schedule  Birth weight (< 1000 g)  Birth weight (1000 to 1250 g)  Birth weight (1250 to 1500 g)  Birth weight (> 1500 g) 




  Diluted formula (double volume)  Full strength formula  Diluted formula (double volume)  Full strength formula  Diluted formula (double volume)  Full strength formula  Diluted formula (double volume)  Full strength formula 
 First 24 hours  CF
1cc x 4  CF
1cc x 4  CF
2cc x 4  CF
2cc x 4  CF
3cc x 4  CF
3cc x 4  CF
4cc x 4  CF
4cc x 4 
  HSM
2cc x 4  FSM
1cc x 4  HSM
4cc x 4  FSM
2cc x 4  HSM
5cc x 4  FSM
3cc x 4  HSM
78cc x 4  FSM
4cc x 4 
 24 to 48 hours  3cc x 4  2cc x 4  6cc x 4  3cc x 4  8cc x 4  4cc x 4  12cc x 4  7cc x 4 
  4cc x 4  2cc x 4  8cc x 4  4cc x 4  10cc x 4  6cc x 4  16cc x 4  8cc x 4 
 Feeding continued until a volume of 150 mL/kg per day was reached. The end point of the study was achieved when the caloric intake became 100 kcal/kg/day. Then the strength in the dilute formula group was changed to full strength.
CF = clear fluid (5% dextrose)
HSM = half strength milk (double volume)
FSM = full strength milk
Multiplication factor indicates the number of feeds.  
