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Dilute versus full strength formula in exclusively formula-fed preterm or low birth weight infants

  1. Fauziah Basuki1,*,
  2. Diah R Hadiati2,
  3. Tari Turner3,
  4. Steve McDonald3,
  5. Mohammad Hakimi2

Editorial Group: Cochrane Neonatal Group

Published Online: 5 NOV 2013

Assessed as up-to-date: 1 FEB 2013

DOI: 10.1002/14651858.CD007263.pub2


How to Cite

Basuki F, Hadiati DR, Turner T, McDonald S, Hakimi M. Dilute versus full strength formula in exclusively formula-fed preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD007263. DOI: 10.1002/14651858.CD007263.pub2.

Author Information

  1. 1

    Sleman District Hospital, Child Health Department, Yogyakarta, Daerah Istimewa Yogyakarta, Indonesia

  2. 2

    Gadjah Mada University, Department of Obstetrics and Gynaecology, Faculty of Medicine, Yogyakarta, Daerah Istimewa Yogyakarta, Indonesia

  3. 3

    Monash University, School of Public Health & Preventive Medicine, Melbourne, Victoria, Australia

*Fauziah Basuki, Child Health Department, Sleman District Hospital, Jl Weling I no 107 G, CT VIII, Karang Gayam, Yogyakarta, Daerah Istimewa Yogyakarta, 55281, Indonesia. faunatsir@yahoo.com.

Publication History

  1. Publication Status: New
  2. Published Online: 5 NOV 2013

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Characteristics of included studies [ordered by study ID]
Anderson 1995

MethodsRandomised trial


Participants14 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


InterventionsHalf 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 3-hourly 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


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


NotesLocation: 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

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: not described

Allocation concealment (selection bias)Unclear riskComment: not described

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskComment: 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 riskComment: not described but is unlikely given the nature of the trial

Blinding of outcome assessment (detection bias)
Subjective outcomes: abdominal distention
Unclear riskComment: not described but is unlikely given the nature of the trial

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: difficult to assess since trial reported as an abstract only

Selective reporting (reporting bias)High riskComment: trial reported as an abstract only. Actual data not given for some outcomes even though outcomes narratively reported

Other biasUnclear riskComment: not enough information to assess since trial reported as an abstract only

Currao 1988

MethodsQuasi-randomised trial


Participants50 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


InterventionsThe 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 ( Table 1). Feeds were provided 2-hourly. No further details on the feeding regimen were provided


OutcomesTime to achieve full enteral feeding; gastric residuals; incidence of apnoea and/or bradycardia; episodes of vomiting; abdominal distension; guaiac-positive stools


NotesLocation: New York, USA


Risk of bias

BiasAuthors' judgementSupport 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 riskComment: it is unlikely that allocation was concealed due to odd/even number assignment.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskComment: 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 riskComment: 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 riskComment: blinding of outcome assessor(s) not described, but is unlikely given the nature of the trial.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: outcome data were reported for all babies.

Selective reporting (reporting bias)Unclear riskComment: There is no protocol to access so we do not know the original planned outcomes.

Sarna 1990

MethodsRandomised trial


Participants38 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


InterventionsDilute 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 ( Table 2). Feeds were provided 3-hourly. No further details on the feeding regimen were provided


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


NotesLocation: New Delhi, India


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "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 riskQuote: "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 riskComment: 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 riskComment: 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 riskComment: blinding of outcome assessor(s) not described, but is unlikely given the nature of the trial

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: outcome data were reported for all babies

Selective reporting (reporting bias)Unclear riskComment: there is no protocol to access so we do not know the original planned outcomes

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Fewtrell 1997Different overall nutrient density between groups

Postolow 2000Compared 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 titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Episodes of abdominal distention > 2 cm288Mean Difference (IV, Fixed, 95% CI)-0.16 [-0.19, -0.13]

 2 Episodes of gastric residuals2Mean Difference (IV, Fixed, 95% CI)Totals not selected

    2.1 Episodes of gastric residuals per baby per day
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.2 Episodes of gastric residuals per baby until attaining 100 kcal/kg
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Episodes of vomiting per day1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 4 Weight gain one week after starting feeds (kg)138Mean Difference (IV, Fixed, 95% CI)0.05 [-0.06, 0.15]

 5 Days until 420 joules per kilogram288Mean 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 formula-fed preterm or low birth weight infants

Half strength formula compared to full strength formula for exclusively formula-fed preterm or low birth weight infants

Patient or population: exclusively formula-fed preterm or low birth weight infants

Settings: neonatal intensive care units (NICUs)

Intervention: half strength formula

Comparison: full strength formula

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Full strength formulaHalf strength formula

Episodes of abdominal distention > 2 cmThe mean episodes of abdominal distention > 2 cm in the control groups was
0.83 episodes4
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)
⊕⊕⊝⊝
low1,2

Episodes of gastric residuals3
> 50% of last feed remaining
See commentSee commentNot estimable388
(2 studies)
⊕⊕⊝⊝
low1,2
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 days4
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)
⊕⊕⊝⊝
low1,2

Necrotising enterocolitisStudy populationNot estimable0
(0)
See commentNot reported

See commentSee comment

Medium risk population


All-cause mortality prior to hospital dischargeStudy populationNot estimable0
(0)
See commentNot reported






See commentSee comment

Medium risk population







Incidence of invasive infectionStudy populationNot estimable0
(0)
See commentNot reported






See commentSee 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.

 1Inadequate method of randomisation and allocation concealment unlikely in one study. Limited information to assess design in both studies.
2We are aware of at least one study which was not published due to inability to recruit sufficient numbers of formula-fed infants.
3Studies used different units (residuals per baby per day and residuals per baby until attaining 100 kcal/day) and so could not be combined.
4Assumed 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 formulaDiluted formula (double volume)Full strength formulaDiluted formula (double volume)Full strength formulaDiluted formula (double volume)

Day 1

2 mL 5% dextrose x 22 mL 5% dextrose x 23 mL 5% dextrose x 23 mL 5% dextrose x 25 mL 5% dextrose x 25 mL 5% dextrose x 2

2 mL ¼S x 32 mL ¼S x 33 mL ¼S x 33 mL ¼S x 35 mL ¼S x 35 mL ¼S x 3

2 mL ½S x 32 mL ½S x 73 mL ½S x 33 mL ½S x 75 mL ½S x 35 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 123 mL ½S x 63 mL FS x 125 mL ½S x 125 mL FS x 127 mL ½S x 6

4 mL ½S x 610 mL ½S x 6

Day 3

3 mL FS x 125 mL ½S x 64 mL FS x 126 mL ½S x 67 mL FS x 1212 mL ½S x 6

6 mL ½S x 68 mL ½S x 614 mL ½S x 6

Day 4

4 mL FS x 127 mL ½S x 66 mL FS x 1210 mL ½S x 69 mL FS x 1216 mL ½S x 6

8 mL ½S x 612 mL ½S x 618 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

ScheduleBirth 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 formulaDiluted formula (double volume)Full strength formulaDiluted formula (double volume)Full strength formulaDiluted formula (double volume)Full strength formula

First 24 hoursCF

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

7-8cc x 4
FSM

4cc x 4

24 to 48 hours3cc x 42cc x 46cc x 43cc x 48cc x 44cc x 412cc x 47cc x 4

4cc x 42cc x 48cc x 44cc x 410cc x 46cc x 416cc x 48cc 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.