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Nutrient-enriched formula versus standard term formula for preterm infants following hospital discharge

  1. Lauren Young1,
  2. Jessie Morgan1,
  3. Felicia M McCormick2,
  4. William McGuire1,*

Editorial Group: Cochrane Neonatal Group

Published Online: 14 MAR 2012

Assessed as up-to-date: 30 SEP 2011

DOI: 10.1002/14651858.CD004696.pub4


How to Cite

Young L, Morgan J, McCormick FM, McGuire W. Nutrient-enriched formula versus standard term formula for preterm infants following hospital discharge. Cochrane Database of Systematic Reviews 2012, Issue 3. Art. No.: CD004696. DOI: 10.1002/14651858.CD004696.pub4.

Author Information

  1. 1

    Hull York Medical School & Centre for Reviews and Dissemination, University of York, York, UK

  2. 2

    University of York, Mother and Infant Research Unit, Department of Health Sciences, York, UK

*William McGuire, Hull York Medical School & Centre for Reviews and Dissemination, University of York, York, Y010 5DD, UK. William.McGuire@hyms.ac.uk.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 14 MAR 2012

SEARCH

 
Characteristics of included studies [ordered by study ID]
Agosti 2003

MethodsRandomised controlled trial


Participants121 formula milk-fed VLBW (<1500 g) infants


InterventionsPreterm formula (energy content 80 kcal/100 ml, protein content 2.4 g/100ml, and calcium and phosphorus content 100 mg/100ml and 50 mg/100ml respectively) (N=69) or standard term formula (energy content 70 kcal/100ml, protein content 1.7 g/100ml) (N=52). The intention was for the allocated formula to be the only milk source from 40 weeks until 55 weeks postmenstrual age (PMA)


OutcomesGrowth parameters and "Griffiths Developmental Scale" at 40 weeks, 55 weeks PMA, and 6 and 12 months corrected age


NotesSetting: multicentre trial in Italy (2001)

Research supported by Milupa (formula milk manufacturing company)

Numerical growth data obtained from primary investigators (June 2011)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskReport simply states that infants were 'randomized' to study groups

Allocation concealment (selection bias)Unclear riskNo mention of randomisation method

Incomplete outcome data (attrition bias)
All outcomes
High riskLoss to follow-up was 34% at 6 months and 66% at 12 months

Blinding of participants and personnel (performance bias)
All outcomes
High riskFamilies and care givers were aware of which formula milk infants received

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes assessors are unlikely to have been aware of which formula milk infants received

Atkinson 1999

MethodsRandomised controlled trial


Participants70 formula milk-fed preterm infants of birth weight < 1800 g and 'appropriate for gestational age'


InterventionsPost-discharge formula (energy content 74 kcal/100ml, protein content 1.8 g/100ml) (N= 34) versus standard term formula (N=36) for 12 months post-discharge


OutcomesGrowth parameters at 6, 9 and 12 months corrected age


NotesPublished in abstract form only. Additional information and data courtesy of Dr Stephanie Atkinson


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskIndependent generation of random sequence

Allocation concealment (selection bias)Low riskAllocation drawn from sequential sealed opaque envelopes

Incomplete outcome data (attrition bias)
All outcomes
High riskGrowth outcomes data to 12 months were available for 24 (71%) intervention group and 29 (81%) control group infants

Blinding of participants and personnel (performance bias)
All outcomes
Low riskFamilies and care givers were unaware of which formula milk infants received

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes assessors not aware of which formula milk infants received

Atkinson 2004

MethodsRandomised controlled trial


Participants53 formula milk-fed preterm 'small for gestational age' infants


InterventionsPost-discharge formula (energy content 74 kcal/100ml, protein content 1.8 g/100ml (N=24) versus standard term formula (Ross Similac with Fe) (N=29) for 12 months post-discharge


OutcomesGrowth parameters at 6, 9 and 12 months corrected age


NotesPublished in abstract form only. Additional information and data courtesy of Dr Stephanie Atkinson


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskIndependent generation of random sequence

Allocation concealment (selection bias)Low riskAllocation drawn from sequential sealed opaque envelopes

Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up growth parameter outcome assessments were complete

Blinding of participants and personnel (performance bias)
All outcomes
Low riskFamilies and care givers were unaware of which formula milk infants received

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes assessors not aware of which formula milk infants received

Carver 2001

MethodsRandomised controlled trial


Participants125 preterm infants (birth weight <1800 g or gestation <37 weeks). Infants with severe bronchopulmonary dysplasia, cardiac, respiratory, gastrointestinal or other systemic diseases at time of discharge were not eligible to participate


InterventionsPost-discharge formula (energy content 74 kcal/100ml, protein content 1.9 g/100ml, and calcium and phosphorus content 78 mg/100ml and 46 mg/100ml respectively) (N=67) or standard term formula (energy content 68 kcal/100ml, protein content 1.5 g/100ml) (N=56). The intention was for the allocated formula to be the main milk source from hospital discharge until 12 months corrected age


OutcomesGrowth parameters at intervals until the end of the 12 months study period


NotesSetting: Multi-centre, six perinatal centres in North America


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskNo description of method used to generate random sequence

Allocation concealment (selection bias)Unclear riskNo information on randomisation method

Incomplete outcome data (attrition bias)
All outcomes
High risk31 of 67 in post-discharge formula group and 26 of 56 in standard term formula group left the study early (plus two other infants who were randomised but did not take part in the study). The total loss of follow-up at growth parameters assessment at 12 months was 60% in the intervention group and 52% in the controls.

Infants exited the study early (and did not have growth parameters measured) for a variety of reasons including study non-compliance (not defined or described), gastro-intestinal upset, and "illness unrelated to the study feedings" (not defined or described)

Blinding of participants and personnel (performance bias)
All outcomes
Low riskFamilies and care givers were unaware of which formula milk infants received

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes assessors not aware of which formula milk infants received

Cooke 2001

MethodsRandomised controlled trial


Participants103 preterm infants (birth weight < 1750 g or gestation < 35 weeks). Only infants who were "growing normally" (rate of weight gain more than 25 g/kg/day) at time of discharge were eligible to participate


InterventionsPreterm formula (energy content 80 kcal/100ml, protein content 2.2 g/100ml, and calcium and phosphorus content 108 mg/100ml and 54 mg/100ml respectively) (N=49) or a standard term formula (energy content 66 kcal/100ml, protein content 1.4 g/100ml) (N=54) from hospital discharge until six months corrected age


OutcomesAnthropometric and developmental parameters (including Bayley Scales of Infant Development II) and measures of bone mineralization


NotesSetting: Royal Victoria Hospital, Newcastle upon Tyne, UK

Research supported by Nutricia (formula milk manufacturer)
Article reported growth data for boys and girls separately. We combined the data for inclusion in this review


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom sequence centrally generated

Allocation concealment (selection bias)Low riskSealed opaque envelopes

Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up was near complete (> 80%)

Blinding of participants and personnel (performance bias)
All outcomes
Low riskFamilies and care givers were unaware of which formula milk infants received

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes assessors not aware of which formula milk infants received

De Curtis 2002

MethodsRandomised controlled trial


Participants33 formula milk-fed preterm infants (birth weight < 1750 grams or gestation < 35 weeks)


InterventionsPost-discharge formula (energy content 74 kcal/100ml, protein content 1.8 g/100ml, and calcium and phosphorus content 80 mg/100ml and 40 mg/100ml respectively) (N=16) or standard term formula (energy content 66 kcal/100ml, protein content 1.4 g/100ml) (N=17) from hospital discharge until two months corrected age


OutcomesGrowth parameters and bone mineralization measured using dual energy x-ray absorptiometry at the end of the 2 months study period


NotesSetting: Department of Pediatrics, University of Liege, Belgium


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo description of method used to generate random sequence

Allocation concealment (selection bias)Unclear riskNo information on randomisation method

Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up was near complete (> 80%)

Blinding of participants and personnel (performance bias)
All outcomes
Low riskFamilies and care givers were unaware of which formula milk infants received

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes assessors not aware of which formula milk infants received

Jeon 2011

MethodsRandomised controlled trial


Participants59 preterm very low birth weight infants


InterventionsPreterm formula (energy content 80 kcal/100ml, protein content 2.3 g/100ml, and calcium and phosphorus content 128 mg/100ml and 64 mg/100ml respectively) (N=34) or a standard term formula (energy content 67 kcal/100ml, protein content 1.6 g/100ml) (N=34) from hospital discharge until three months post term then both groups continuing with standard term formula until at least 6 months post term


OutcomesGrowth parameters at 3 monthly intervals until 18 months post term and Bayley Scales of Infant Development II at 18 months corrected age


NotesSetting: Multicentre trial in four hospitals in South Korea

Research supported by Maeli Dairy Industry Co. Ltd, (formula milk manufacturer)

Initially three groups were randomly allocated to receive either (1) standard term formula, (2) preterm formula for 3 months, or (3) preterm formula for 6 months. However, there were substantial and significant between-group differences in the baseline demographic characteristics, especially between group (3) and the other groups. Group (3) infants had statistically significantly lower birth weights and were more likely to be small for gestational age. We therefore chose to discard data from this arm and to restrict comparison of outcomes to group (1) versus group (3)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo description of method used to generate random sequence

Allocation concealment (selection bias)Unclear riskNo information on randomisation method

Incomplete outcome data (attrition bias)
All outcomes
Low riskGrowth outcomes data to 18 months were available for 30 (88%) intervention group and 29 (85%) control group infants

Blinding of participants and personnel (performance bias)
All outcomes
High riskFamilies and care givers were likely to have been aware of which formula milk infants received

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskOutcomes assessors may have been aware of which formula milk infants received

Koo 2006

MethodsRandomised controlled trial


Participants89 preterm infants ready for hospital discharge (gestational age at birth < 35 weeks). Infants with major congenital malformation, previous gastrointestinal surgery, or abnormal suck and swallow actions were not eligible to participate


InterventionsNutrient-enriched formula (energy content 74 kcal/100ml, protein content 1.9 g/100ml, and calcium and phosphorus content 78 mg/100ml and 46 mg/100ml respectively) (N=44) or standard term formula (energy content 67 kcal/100ml, protein content 1.5 g/100ml) (N=45). The intention was for the allocated formula to be fed ad libitum until 12 months after discharge


OutcomesGrowth parameters and bone mineral content at intervals until the end of the 12 months study period


NotesSetting: Department of Pediatrics, Wayne State University and Hutzel Hospital, Detroit, USA.

Research supported by Ross Products Division, Abbott Laboratories (formula milk manufacturer)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo description of method used to generate random sequence

Allocation concealment (selection bias)Low riskAllocation drawn from sequential sealed opaque envelopes

Incomplete outcome data (attrition bias)
All outcomes
High riskGrowth outcomes data to 12 months were available for 31 (70%) intervention group and 36 (80%) control group infants

Blinding of participants and personnel (performance bias)
All outcomes
Low riskFamilies and care givers were unaware of which formula milk infants received

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes assessors not aware of which formula milk infants received

Litmanovitz 2004

MethodsRandomised controlled trial


Participants20 healthy very low birth weight infants at hospital discharge


InterventionsNutrient-enriched formula (energy content 74 kcal/100ml, protein content 1.9 g/100ml (N=10) or a standard term formula (energy content 67 kcal/100ml, protein content 1.5 g/100ml) (N=10) following hospital discharge. The formulas were intended to provide the sole milk intake up to 6 months corrected age


OutcomesWeight, length, head circumference, and measures of bone mineralization at term and at 6 months corrected age


NotesSetting: Meir General Hospital, Kfar-saba, Israel


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo description of method used to generate random sequence

Allocation concealment (selection bias)Unclear riskNo information on randomisation method

Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up was near complete (> 80%)

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo information on whether families and care givers were aware of which formula milk infants received

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information on whether outcomes assessors were aware of which formula milk infants received

Lucas 1992

MethodsRandomised controlled trial


Participants32 exclusively formula milk-fed preterm infants, birth weight < 1850 g, and weight < 3000 g at hospital discharge


InterventionsNutrient-enriched formula (energy content 72 kcal/100ml, protein content 1.8 g/100ml, and calcium and phosphorus content 70 mg/100ml and 35 mg/100ml respectively) (N=16) or standard term formula (energy content 68 kcal/100ml, protein content 1.4 g/100ml) (N=16) following hospital discharge. The formulas were intended to provide the sole milk intake up to 9 months corrected age


OutcomesMeasures of growth (weight, crown-heel length and head circumference), feed tolerance, and bone mineralization during the trial period


NotesSetting: Department of Paediatrics, Rosie Maternity Hospital, Cambridge

Research supported by Farley Health Products (formula milk company)
One infant who was randomised to the standard term formula group was transferred to another hospital prior to the planned hospital discharge and could not be included in any follow-up assessments

Data were presented graphically. We extracted numerical data (mean and SD) from the graphs in order to calculate mean differences


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo description of method used to generate random sequence

Allocation concealment (selection bias)Unclear riskNo information on randomisation method

Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up was near complete (one infant from the standard term formula group was withdrawn)

Blinding of participants and personnel (performance bias)
All outcomes
Low riskIt is likely that families and care givers were unaware of which formula milk infants received

Blinding of outcome assessment (detection bias)
All outcomes
Low riskIt is likely that outcomes assessors were unaware of which formula milk infants received

Lucas 2001

MethodsRandomised controlled trial


Participants229 formula milk-fed preterm infants, birth weight <1750 g, and weight < 3000 g at hospital discharge


InterventionsNutrient-enriched formula (energy content 72 kcal/100ml, protein content 1.85 g/100ml, and calcium and phosphorus content 70 mg/100ml and 35 mg/100ml respectively) (N=113) or standard term formula (energy content 68 kcal/100ml, protein content 1.5 g/100ml) (N=116) from hospital-discharge until 9 months post-term


OutcomesGrowth parameters up to 18 months post term, and neurodevelopment (Bayley Scales) at 18 months corrected age


NotesSetting: Five neonatal centres in the UK (1993-5)

Research supported by Farley Health Products (formula milk company)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskA member of the clinical team not involved in the trial prepared the randomisation assignments

Allocation concealment (selection bias)Low riskAllocation drawn from sequential sealed opaque envelopes

Incomplete outcome data (attrition bias)
All outcomes
Low riskGrowth and developmental outcomes assessed in >80% of participating infants

Blinding of participants and personnel (performance bias)
All outcomes
Low riskFamilies and care givers were unaware of which formula milk infants received

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes assessors unaware of which formula milk infants received

Peng 2004

MethodsRandomised controlled trial


Participants34 preterm infants with a gestational age of < 35 weeks and birth weight < 1850 g


InterventionsNutrient-enriched formula (energy content 81 kcal/100ml, protein content 2.40 g/100ml, and calcium and phosphorus content 95 mg/100ml and 53 mg/100ml respectively) (N=19) or standard term formula (energy content 67.6 kcal/100ml, protein content 1.4 g/100ml) (N=15) from hospital-discharge until 6 months corrected age


OutcomesMeasures of growth (weight, crown-heel length and head circumference), feed tolerance, and bone mineralization during the trial period


NotesSetting: Mackay Memorial Hospital, Taipei, Taiwan

Research supported by Mead Johnson (formula milk company)

No differences were found between the two groups in weight, length, or head circumference at baseline or on follow-up. Infants fed premature formula had higher blood urea nitrogen and phosphorus at 3 months corrected age. Those on the premature formula also had higher energy intake at 1 month corrected age


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo description of method used to generate random sequence

Allocation concealment (selection bias)Unclear riskNo information on randomisation method

Incomplete outcome data (attrition bias)
All outcomes
High riskGrowth outcomes data to 6 months were available for 29 of the 40 infants initially enrolled (73%)

Blinding of participants and personnel (performance bias)
All outcomes
High riskFamilies and care givers were likely to have been aware of which formula milk infants received as parents were not blinded to the infants' assignment

Blinding of outcome assessment (detection bias)
All outcomes
High riskOutcomes assessors may have been aware of which formula milk infants received as physicians were not blinded to the infants' assignment

Picaud 2005

MethodsRandomised controlled trial


Participants49 formula milk-fed preterm infants, birth weight <1750 g or gestation at birth <33 weeks


InterventionsPreterm formula (energy content 81 kcal/100ml, protein content 2.3 g/100ml, and calcium and phosphorus content 100 mg/100ml and 53 mg/100ml respectively) (N=23) or a standard term formula (energy content 67 kcal/100ml, protein content 1.7 g/100ml) (N=26) from hospital discharge until 2 months post term


OutcomesGrowth parameters and measures of bone mineralization up to 4 months corrected age


NotesSetting: two tertiary care neonatal units in France (2001-04)

Research supported by Nestlé France (formula milk manufacturer)

From 2 months post-discharge both groups received standard term formula milk


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskClinical trials unit generated

Allocation concealment (selection bias)Low riskPharmacy coded

Incomplete outcome data (attrition bias)
All outcomes
High riskLoss to follow-up by 12 months in the control group was substantial (35%) and greater than that in the intervention group (9%)

Blinding of participants and personnel (performance bias)
All outcomes
Low riskFamilies and care givers were unaware of which formula milk infants received

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes assessors unaware of which formula milk infants received

Roggero 2011a

MethodsRandomised controlled trial


Participants84 formula milk-fed preterm infants born "small for gestational age" (<10th percentile)


InterventionsPost-discharge formula (energy content 75 kcal/100ml, protein content 2.0 g/100ml, and calcium and phosphorus content 100 mg/100ml and 56 mg/100ml respectively) (N=40) or a standard term formula (energy content 67 kcal/100ml, protein content 1.4 g/100ml) (N=44) from hospital discharge until 6 months corrected age


OutcomesGrowth parameters and fat mass up to 6 months corrected age


NotesSetting: Neonatal Intensive Care Unit, Department of Maternal and Paediatric Sciences, Milan, Italy (2008-10).
These trialists also conducted an RCT of nutrient-enriched versus standard formula in appropriate for gestational age infants (N= 123). These data are not yet published or available from the authors (referred to in conference abstract: Roggero 2011b)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up until 6 months post term was complete

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo information provided

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Taroni 2009

MethodsRandomised controlled trial


Participants27 formula milk-fed preterm infants, birth weight <1500 g or gestation at birth <33 weeks, and "small for gestational age" (<10th percentile)


InterventionsPost-discharge formula (energy content 75 kcal/100ml, protein content 2.0 g/100ml, and calcium and phosphorus content 100 mg/100ml and 56 mg/100ml respectively) (N= 14) or a standard term formula (energy content 67 kcal/100ml, protein content 1.4 g/100ml) (N= 13) from hospital discharge until 1 month corrected age


OutcomesGrowth parameters and fat mass up to 1 month corrected age


NotesSetting: Four Italian neonatal units (2008-9)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPre-prepared random sequence

Allocation concealment (selection bias)Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up until 1 month post term was complete

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo information provided

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Amesz 2010The protein content of both formula milks was <1.7 g/100ml

Bernbaum 1989The energy content of both formula milks was <70 kcal/100ml

Bhatia 1991The protein content of both formula milks was <1.7 g/100ml

Brunton 1998Both of the formula milks were calorie-enriched (90 kcal/100ml)

Chan 1994The energy content of both formula milks was <70 kcal/100ml

Cooper 1985The energy content of both formula milks was <70 kcal/100ml

Friel 1993The energy content of both formula milks was <70 kcal/100ml

Lapillonne 2004Both of the formula milks were calorie-enriched (81kcal/100ml) and protein-enriched (>2.0 grams/100ml

Wheeler 1996The energy content of both formula milks was <70 kcal/100ml

 
Characteristics of studies awaiting assessment [ordered by study ID]
Roggero 2011b

MethodsRandomised controlled trial

Participants123 formula fed preterm infants who were "appropriate (birth weight) for gestational age"

InterventionsPost-discharge formula (energy content 75 kcal/100ml, protein content 2.0 g/100ml, and calcium and phosphorus content 100 mg/100ml and 56 mg/100ml respectively) (N= 59) or a standard term formula (energy content 67 kcal/100ml, protein content 1.4 g/100ml) (N= 64) from hospital discharge until 6 months corrected age

OutcomesGrowth parameters and fat mass up to (at least) 12 months corrected age

NotesThis has been presented as an abstract at the European Society for Paediatric Research annual scientific meeting in Newcastle (October 2011). When published in full, or if sufficient data are available from the investigators, this trial is likely to be included in this Cochrane review

 
Comparison 1. POST-DISCHARGE FORMULA VERSUS STANDARD TERM FORMULA

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Growth rates during trial period1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    1.1 Weight gain (grams/kilogram/day)
133Mean Difference (IV, Fixed, 95% CI)0.0 [-1.37, 1.37]

    1.2 Linear growth (millimetres/week)
133Mean Difference (IV, Fixed, 95% CI)0.0 [-1.07, 1.07]

    1.3 Head circumference (millimetres/week)
133Mean Difference (IV, Fixed, 95% CI)0.0 [-0.68, 0.68]

 2 Weight (g)6Mean Difference (IV, Fixed, 95% CI)Subtotals only

    2.1 3-4 months post term
5408Mean Difference (IV, Fixed, 95% CI)-3.76 [-156.67, 149.15]

    2.2 6 months post term
6461Mean Difference (IV, Fixed, 95% CI)56.23 [-111.53, 223.98]

    2.3 9 months post term
4347Mean Difference (IV, Fixed, 95% CI)244.09 [16.95, 471.23]

    2.4 12 months post term
2120Mean Difference (IV, Fixed, 95% CI)71.53 [-344.06, 487.12]

    2.5 18 months post term
1192Mean Difference (IV, Fixed, 95% CI)100.0 [-246.90, 446.90]

 3 Crown heel length (mm)6Mean Difference (IV, Fixed, 95% CI)Subtotals only

    3.1 3- 4 months post term
5408Mean Difference (IV, Fixed, 95% CI)4.18 [-0.77, 9.13]

    3.2 6 months post term
6461Mean Difference (IV, Fixed, 95% CI)3.46 [-1.21, 8.13]

    3.3 9 months post term
4347Mean Difference (IV, Fixed, 95% CI)7.33 [1.80, 12.87]

    3.4 12 months post term
2120Mean Difference (IV, Fixed, 95% CI)-0.83 [-9.00, 9.34]

    3.5 18 months post term
1192Mean Difference (IV, Fixed, 95% CI)9.0 [0.32, 17.68]

 4 Head circumference (mm)6Mean Difference (IV, Fixed, 95% CI)Subtotals only

    4.1 3- 4 months post term
5408Mean Difference (IV, Fixed, 95% CI)-0.87 [-3.73, 1.99]

    4.2 6 months post term
6461Mean Difference (IV, Fixed, 95% CI)0.72 [-2.12, 3.56]

    4.3 9 months post-term
4347Mean Difference (IV, Fixed, 95% CI)0.16 [-3.21, 3.53]

    4.4 12 months post-term
2120Mean Difference (IV, Fixed, 95% CI)0.25 [-5.50, 6.01]

    4.5 18 months post-term
1192Mean Difference (IV, Fixed, 95% CI)-3.0 [-8.24, 2.24]

 5 Development1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    5.1 Bayley Scales of Infant Development II: Mental Development Index
1184Mean Difference (IV, Fixed, 95% CI)0.90 [-3.24, 5.04]

    5.2 Bayley Scales of Infant Development II: Psychomotor Development Index
1184Mean Difference (IV, Fixed, 95% CI)2.70 [-1.28, 6.68]

 6 Bone mineralization3Mean Difference (IV, Fixed, 95% CI)Subtotals only

    6.1 Bone area at 2 months post-term (cm2)
133Mean Difference (IV, Fixed, 95% CI)7.0 [-15.46, 29.46]

    6.2 Bone mineral content at 2 months post-term (g)
133Mean Difference (IV, Fixed, 95% CI)3.20 [-4.73, 11.13]

    6.3 Bone "speed of sound" assessed with ultrasound at 6 months post-term (mm/s)
120Mean Difference (IV, Fixed, 95% CI)45.0 [-18.48, 108.48]

    6.4 Bone specific serum alkaline phosphatase at 6 months post-term (units/L)
120Mean Difference (IV, Fixed, 95% CI)-9.0 [-42.01, 24.01]

    6.5 Bone width at 9 months post-term (cm)
131Mean Difference (IV, Fixed, 95% CI)0.05 [-0.01, 0.11]

    6.6 Bone mineral content at 9 months post-term (mg/cm)
131Mean Difference (IV, Fixed, 95% CI)20.60 [7.78, 33.42]

 
Comparison 2. PRETERM FORMULA VERSUS STANDARD TERM FORMULA

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Growth rates during trial period1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    1.1 Weight gain (grams/day)
142Mean Difference (IV, Fixed, 95% CI)3.70 [-0.16, 7.56]

    1.2 Linear growth (millimetres/week)
142Mean Difference (IV, Fixed, 95% CI)1.0 [0.09, 1.91]

    1.3 Head circumference (millimetres/week)
142Mean Difference (IV, Fixed, 95% CI)0.5 [-0.04, 1.04]

 2 Weight (g)5Mean Difference (IV, Fixed, 95% CI)Subtotals only

    2.1 3- 4 months post term
3130Mean Difference (IV, Fixed, 95% CI)74.41 [-267.10, 415.93]

    2.2 6 months post term
4273Mean Difference (IV, Fixed, 95% CI)74.60 [-164.73, 313.92]

    2.3 9 months post term
159Mean Difference (IV, Fixed, 95% CI)112.0 [-482.69, 706.69]

    2.4 12 months post term
4265Mean Difference (IV, Fixed, 95% CI)539.48 [255.03, 823.92]

    2.5 18 months post term
2162Mean Difference (IV, Fixed, 95% CI)490.81 [142.19, 839.44]

 3 Crown heel length (mm)5Mean Difference (IV, Fixed, 95% CI)Subtotals only

    3.1 3- 4 months post term
3130Mean Difference (IV, Fixed, 95% CI)-2.27 [-13.09, 8.56]

    3.2 6 months post term
3160Mean Difference (IV, Fixed, 95% CI)1.83 [-6.25, 9.92]

    3.3 9 months post term
159Mean Difference (IV, Fixed, 95% CI)-3.0 [-17.03, 11.03]

    3.4 12 months post term
3152Mean Difference (IV, Fixed, 95% CI)5.13 [-4.23, 14.49]

    3.5 18 months post term
2162Mean Difference (IV, Fixed, 95% CI)11.00 [1.89, 20.11]

 4 Head circumference (mm)5Mean Difference (IV, Fixed, 95% CI)Subtotals only

    4.1 3- 4 months post term
3130Mean Difference (IV, Fixed, 95% CI)3.61 [-2.09, 9.31]

    4.2 6 months post term
3160Mean Difference (IV, Fixed, 95% CI)5.82 [1.32, 10.32]

    4.3 9 months post term
159Mean Difference (IV, Fixed, 95% CI)8.0 [0.85, 15.15]

    4.4 12 months post term
3152Mean Difference (IV, Fixed, 95% CI)6.07 [1.07, 11.06]

    4.5 18 months post term
2162Mean Difference (IV, Fixed, 95% CI)5.42 [0.69, 10.14]

 5 Development2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    5.1 Bayley Scales of Infant Development II: Mental Development Index
2143Mean Difference (IV, Fixed, 95% CI)-1.44 [-6.22, 3.35]

    5.2 Bayley Scales of Infant Development II: Psychomotor Development Index
2143Mean Difference (IV, Fixed, 95% CI)-1.13 [-4.19, 1.93]