Methods

Randomised controlled trial

Participants

53 newborn infants: birth weight 500 ‐ 1250 g
Exclusions: major congenital abnormalities, high likelihood of transfer to a non‐study site after 48 hours
Seven neonatal intensive care units: six in US, one in Austria

(Probably) 2010‐12

Interventions

Preterm formula milk (N = 24) versus fortified (with human milk‐based fortifier), pasteurised donor breast milk (N = 29). Assigned until 91 days after birth, or discharge, or oral feeding at least 50% of feeds.

Outcomes

Duration of parenteral nutrition, growth, respiratory support, and NEC

Notes

Additional information on methods courtesy of Dr Cristafalo (April 2014)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random sequence generated centrally in permuted blocks stratified by investigational site

Allocation concealment (selection bias)

Low risk

Allocation outcome provided to an individual at each site who was not connected with the evaluation of outcomes for participants

Blinding (performance bias and detection bias)
All outcomes

Low risk

Investigators, caregivers, and families were blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

100% follow‐up

Methods

Randomised controlled trial

Participants

68 preterm infants: 28 to 36 weeks in 2 strata
Exclusions: multiple births, congenital abnormalities and chromosomal disorders, congenital infection. Growth‐restricted infants (< 5th percentile) may also have been excluded
Department of Child Health, University Hospital of Wales, Cardiff
1972‐1973

Interventions

Term formula milk (N = 34) versus unfortified, pasteurised donor breast milk (N = 34). Assigned from birth for 2 months

Outcomes

Rates of weight gain, increase in head circumference and length from birth until 1 month and from 1 month until 2 months

Notes

Infants of mothers who wished to breast‐feed were initially given expressed breast milk if unable to feed naturally. There were only 2 such infants, their feeding group was not specified and the results for these infants are not presented separately in the paper. Given that this applies to only 2 out of 68 infants, we have included this study in the review

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method not stated

Allocation concealment (selection bias)

Unclear risk

Method not stated

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

No information given

Incomplete outcome data (attrition bias)
All outcomes

Low risk

100% follow‐up

Methods

Randomised controlled trial

Participants

67 preterm infants (27 to 33 weeks)
Birth weight < 1600 g. Excluded if "congenital anomaly or major disease"
Department of Pediatrics, Duke University, USA
1980‐1982

Interventions

Term formula milk (N = 26) versus unfortified, pasteurised donor breast milk (N = 41). Feeds were assigned until the infant reached a weight of 1800 g or until withdrawn from the study because of feeding intolerance or NEC

Outcomes

Time to regain birth weight
Mean daily gain in weight, length and head circumference, from regaining birth weight until reaching 1800 g
Data on adverse events can be determined although these were not primary endpoints of the study

Notes

Although the report gave information on adverse outcomes, the 7 affected infants were withdrawn from the study and not included in the analyses of growth rates. Therefore, growth data are reported for 20 infants in each arm of the trial

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random number table

Allocation concealment (selection bias)

Unclear risk

Method not stated

"Any infant withdrawn from the study was replaced by the next one enrolled": implies lack of allocation concealment for these infants

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

No information given

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

7 out of 67 (10%) with adverse outcomes (NEC, mortality) were not assessed for growth outcomes. This included 6/26 (23%) in the formula group and 1/41 (2.4%) in the donor breast milk group, so potential bias

100% follow‐up and low risk of bias for mortality and NEC

Methods

Randomised controlled trial

Participants

159 infants of birth weight < 1850 g. Stratified by birth weight < 1200 g and 1201 g to 1850 g

Infants with congenital abnormalities excluded. Infants with intrauterine growth restriction not excluded
Study undertaken in the early 1980s in neonatal units in the Anglia region of the UK

Interventions

Preterm formula milk (N = 76) versus donor (mainly "drip") breast milk (N = 83)

The formula was intended to be delivered at 180 ml/kg/day versus the breast milk at 200 ml/kg/day

Feeds were assigned until the infant reached a weight of 2000 g or until discharge from the neonatal unit

Outcomes

Short term outcomes:
Time to regain birth weight (62 infants). Rates of change in weight (58 infants), crown‐heel length (26 infants) and head circumference (48 infants) from the point of regained birth weight until discharge from the neonatal unit or reaching a weight of 2000 g
Incidence of NEC ‐ suspected and confirmed reported on complete cohort of 159 infants

Longer‐term outcomes:
Validated neurological assessment at 18 months in 122 (85%) of surviving infants
Bayley Mental Development Index and Psychomotor Development Index at 18 months post‐term, in 114 (94%) of surviving infants suitable for the assessment
Growth performance in surviving infants (weight, length and head circumference) at 9 months (110 infants), 18 months (136 infants) and 7.5 to 8 years (130 infants) post‐term

Notes

The first "interim" report provided data on short‐term growth outcomes in a predefined subset of the total cohort recruited.
Follow‐up at 18 months was achieved for more than 80% of surviving infants. Developmental assessments (Bayley Psychomotor and Mental Development Indices) at 18 months post‐term were reported for 114 of the 159 children originally enrolled in the study. 16 children had died and 7 had been lost to follow‐up. 12 surviving children had cerebral palsy affecting fine motor skills and these children were not assessed. A further 10 children were not assessed due to severe visual or hearing impairment or because follow‐up data were obtained by telephone for geographical reasons

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Balanced randomisation sequence was prepared for each centre, within strata defined by birth weight (method of sequence generation not stated explicitly)

Allocation concealment (selection bias)

Low risk

Sealed, numbered envelopes

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

No information given

Incomplete outcome data (attrition bias)
All outcomes

Low risk

100% assessment of in‐hospital outcomes and > 80% follow‐up for long‐term outcomes (except for cognitive outcomes (verbal and performance intelligence quotient), which were assessed in about 20% of participants at ages 8 and 16 years)

Methods

Randomised controlled trial

Participants

343 infants of birth weight < 1850 g. Stratified by birth weight < 1200g and 1201 to 1850 g. Infants with congenital abnormalities excluded. Infants with intrauterine growth restriction not excluded
Study undertaken in the early 1980s in neonatal units in the Anglia region of the UK

Interventions

Preterm formula milk (N = 173) versus banked donor breast milk (N = 170) as a supplement to the mother's own breast milk

Outcomes

Short‐term outcomes: time to regain birth weight (132 infants). Rates of change in weight (115 infants), crown‐heel length (45 infants) and head circumference (97 infants) from the point of regained birth weight until discharge from the neonatal unit or reaching a weight of 2000 g
Incidence of NEC ‐ suspected and confirmed reported on complete cohort of 343 infants
Longer‐term outcomes:
Validated neurological assessment, at 18 months, in 278 (88%) of surviving infants
Bayley Mental Development Index and Psychomotor Development Index at 18 months, corrected for preterm gestation, in 273 (96%) of surviving infants suitable for the assessment
Growth performance in surviving infants (weight, length and head circumference) at 9 months (259 infants), 18 months (302 infants) and 7.5 to 8 years (290 infants) post‐term

Notes

The first "interim" report provided data on short‐term growth outcomes in a predefined subset of the total cohort recruited.
Developmental assessments (Bayley Psychomotor and Mental Development Indices) at 18 months post‐term were reported for 273 of 343 children originally enrolled in the study. 29 children had died and 12 had been lost to follow‐up. 24 surviving children had cerebral palsy affecting fine motor skills and these children were not assessed. A further 5 children were not assessed due to severe visual or hearing impairment or because follow‐up data were obtained by telephone for geographical reasons

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not stated

Allocation concealment (selection bias)

Low risk

Sealed, numbered envelopes

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

No information given

Incomplete outcome data (attrition bias)
All outcomes

Low risk

100% assessment of in‐hospital outcomes and > 80% follow‐up for long‐term outcomes (except for cognitive outcomes (verbal and performance intelligence quotient), which were assessed in about 20% of participants at ages 8 and 16 years)

Methods

Randomised controlled trial

Participants

106 preterm infants of birth weight < 2100 g, but between 10th and 90th centiles for birth weight. Infants excluded if evidence of "physical abnormality or obvious disease"

Premature Unit, Helsinki University Children's Hospital, 1972 to 1975

Interventions

Term formula milk (N = 84) versus unfortified donor breast milk (N = 22)

Feeds continued until a weight of 2.4 kg was attained or until infants were withdrawn from the study because of a "medical complication"

Outcomes

Time, from birth, to regain birth weight. Rate of weight change from birth and from point of regained birth weight

Notes

Donor breast milk was given at a 170 ml/kg/day, compared with formula at 150 ml/kg/day, "in order to achieve equivalent calorie inputs". Donor breast milk‐fed infants were also given supplemental vitamins

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Randomly selected permutations of 1, 2, 3, 4 were prepared in advance, which were used to allocate to the 4 formula arms. Every 5th infant was assigned to pooled breast milk. Hence, it was not strictly random. Also, no details of how the permutations were generated

Allocation concealment (selection bias)

High risk

Every 5th infant was assigned to pooled breast milk so allocation concealment may have been sub‐optimal

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

No information given

Incomplete outcome data (attrition bias)
All outcomes

Low risk

95% follow‐up (5/106 infants who were enrolled were dropped from the study for medical reasons)

Methods

Randomised controlled trial

Participants

173 infants of gestational age < 30 weeks, whose mothers intended to breast‐feed but whose own milk became insufficient from birth until 90 days of age or hospital discharge
North Shore University Hospital, New York, USA, 2000 to 2003

Interventions

Preterm formula (N = 81) versus unfortified donor breast milk (N = 92) given as a supplement to maternal breast milk

Outcomes

Incidence of late‐onset invasive infection and NEC, duration of hospitalisation and growth during the study period (weight gain, head circumference increment and length increment)

Notes

Participating infants received small quantities (20 ml/kg/day) of their own mother's milk during the first week after birth and continued for 3 to 5 days before the volume was advanced. Milk intake was increased by 20 to 100 ml/kg/day at which time human milk fortifier was added. Subsequently the volume of fortified human milk was advanced by 20 ml/kg/day until 160 ml/kg/day was achieved. If no mother's milk was available and the baby was assigned to donor breast milk then a similar advancement and fortification protocol was followed. For all infants, adjustments in milk intake between 160 and 200 ml/kg/day were recommended to ensure an average weekly weight gain of at least 15 g/kg per day
17 enrolled infants were switched from donor breast milk to preterm formula because of poor weight gain but all of these analyses were by intention‐to‐treat. However, 7 infants who were never fed (3 in the donor milk group, 4 in the formula group) were excluded from the analyses

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Method not stated explicitly but very likely to be computer‐generated since the random sequence was "an unbalanced blocked design, according to the stratification variables of gestational age and receipt of prenatal steroids"

Allocation concealment (selection bias)

Low risk

Allocation was "performed by the research nurse coordinator with sealed opaque envelopes"

Blinding (performance bias and detection bias)
All outcomes

High risk

Unblinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Complete follow‐up

Methods

Randomised controlled trial

Participants

20 preterm or LBW infants; all infants were "physically normal with no further signs of disease"
Department of Paediatrics, University Medical School, Pecs, Hungary, prior to 1980

Interventions

Term formula milk (N = 10) versus donor breast milk (N = 10) for at least 4 weeks from birth

Outcomes

Time, from birth, to regain birth weight (mean but no SD reported)
Mean weight change from birth and from regaining birth weight calculable from graph but no SD

Notes

—

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method not stated

Allocation concealment (selection bias)

Unclear risk

No information given

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

No information given

Incomplete outcome data (attrition bias)
All outcomes

Low risk

100% follow‐up

Methods

Randomised controlled trial

Participants

81 VLBW infants, excluding infants with "any significant illness" or those who required ventilatory support at day 10
Parklands Memorial Hospital, Dallas, USA, early 1980s

Interventions

Preterm formula milk (N = 44) versus donor breast milk (N = 37). The donor breast milk was not pasteurised. Feeds were allocated on the 10th day of life, and continued until the infant reached a weight of 2000 g or until withdrawn from the study because of "any illness requiring intravenous infusion of fat or protein"

Outcomes

Mean daily rates of change in weight, crown‐heel length and head circumference from the 10th until the 30th day of life were reported

Notes

The feeds were not allocated until the 10th day after birth in order to avoid the use of protein‐enriched formula "when active growth was unlikely". In the first 9 days of life the infants received a term formula or maternal expressed breast milk (if available). Although the report gave information on adverse outcomes, including NEC, the 5 affected infants were withdrawn from the study and not included in the analyses of growth rates

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Infants were stratified by birth weight and randomised, but how the sequence was generated is not stated

Allocation concealment (selection bias)

Low risk

Concealed envelope opened only after informed parental consent obtained

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

No information given

Incomplete outcome data (attrition bias)
All outcomes

Low risk

5 infants with adverse outcomes did not have growth data