1. Objectives

To compare the effects of nutrient-enriched formula to those of standard formula on growth and development of preterm infants following hospital discharge

2. How studies were identified

The following databases were searched in September 2016:

• PubMed
• CENTRAL (The Cochrane Library 2016, Issue 9)
• Embase
• CINAHL

Reference lists and conference proceedings were also searched

3. Criteria for including studies in the review

3.1 Study type

Randomized controlled trials, including cluster-randomized trials and quasi-randomized trials

3.2 Study participants

Preterm infants within one week of hospital discharge

3.3 Interventions

Nutrient-enriched preterm formula (>75 kcal/100 mL and protein content >2.0 g/100 mL) or post-discharge formula (>72 kcal/100 mL to ≤75 kcal/100 mL and protein content >1.7 g /100 mL) versus standard term formula (≤72 kcal/100 mL and protein content ≤1.7 g/100 mL)

(The intervention may have been initiated up to one week before planned discharge from hospital. The formula could have been provided as the sole diet or as a supplement to breast milk)

3.4 Primary outcomes

Growth

• Weight
• Length
• Head growth
• Skinfold thickness
• Body mass index (BMI), other measures of body composition (lean/fat mass)
• Growth restriction (proportion of infants who remain <10th centile for weight, length or head circumference in the index population)
• Long-term growth restriction (proportion of infants who remain below the 10th centile for weight, height or head circumference in the index population)

Development

• Neurodevelopmental outcomes at ≥12 months’ corrected age, assessed using validated instruments
• Classification of disability, including non-ambulant cerebral palsy, developmental delay, and auditory and visual impairment
• Cognitive and educational outcomes at ≥5 years, including intelligence quotient and/or validated measures of educational attainment

Secondary outcomes included feed intolerance (vomiting or diarrhoea) that requires cessation of the study formula, bone mineralization at long-term follow-up (serum alkaline phosphatase level, dual-energy X-ray absorptiometry (DEXA), clinical or radiological evidence of rickets), blood pressure at long-term follow-up, BMI or other measures of adiposity at long-term follow-up

4. Main results

4.1 Included studies

Sixteen randomized controlled trials, enrolling 1251 infants, were included in this review

• Twelve studies specified eligibility based on a maximum birth weight ranging from 1500 to 1850 g, while the remaining studies specified a gestational age of <37 weeks (3 trials) or <35 weeks (1 trial). Three studies also specifically recruited small-for-gestational age infants
• Eleven trials including 885 infants compared post-discharge formula to standard term formula
• Five trials involving 366 infants compared preterm formula to standard term formula
• Infants in all trials were fed ad libitum and the intervention period ranged from one to up to 12 months

4.2 Study settings

• Belgium, Canada (2 trials), France, Israel, Italy (4 trials), the Republic of Korea, the United Kingdom of Great Britain and Northern Ireland (3 trials), the United States of America (2 trials), and Taiwan, China
• Eight trials declared support from formula companies
• Trials were conducted in neonatal intensive care units or in paediatric departments of hospitals

4.3 Study settings

How the data were analysed
Two comparisons were made: post-discharge formula versus standard term formula and preterm formula versus standard term formula. Dichotomous data were summarized using risk ratios (RR), and continuous data were summarized using mean differences (MD), with corresponding 95% confidence intervals (CI). If substantial heterogeneity was detected (I²>50%), sensitivity analyses by differences in study design, participants or interventions, and completeness of outcome assessments were performed. In addition, the following subgroup analyses were conducted:

• Very preterm (<32 weeks’ gestation) or very low birth weight (<1500 g) infants versus infants born at 32 to 36 weeks’ gestation or with a birth weight 1500 to 2499 g
• Small-for-gestational age (<10^th centile for weight) at hospital discharge versus those ≥10^th centile for weight
• Infants with chronic lung disease receiving supplemental oxygen therapy at hospital discharge versus those without chronic lung disease

Results
Post-discharge formula versus standard term formula
Growth
Growth rates were measured in one trial of 33 infants in which no statistically significant differences between groups were found (weight gain: MD 0.0 g/kg/day, 95% CI [-1.37 to 1.37]; linear growth: MD 0.0 mm/week, 95% CI [-1.07 to 1.07]; head circumference: MD 0.0 mm/week, 95% CI [-0.68 to 0.68]). At three to four months post-term no statistically significant difference in weight was found between infants receiving post-discharge formula and those receiving term formula in pooled analysis (MD -7.45 g, 95% CI [-141.84 to 126.93], 6 trials/523 infants). At six, 12, and 18 to 24 months post-term there was also no evidence of a difference in weight between treatment groups (6 months: MD 35.54 g, 95% CI [-113.71 to 184.78], 7 trials/576 infants; 12 months: MD -14.87 g, 95% CI [-243.18 to 213.43], 4 trials/314 infants; 18 to 24 months: MD 100.00 g, 95% CI [-246.90 to 446.90], 1 trial/192 infants). However, at nine months post-term, infants who received post-discharge formula were on average 244.09 g heavier (95% CI [16.95 to 471.23 g], p=0.04; 4 trials/347 infants). At three to four months post-term no statistically significant difference in crown-heel length was found between infants receiving post-discharge formula and those receiving term formula (MD 2.45 mm, 95% CI [-2.01 to 6.90], 6 trials/523 infants). At six months and 12 months post-term there was also no evidence of a difference in length between treatment groups (MD 2.12 mm, 95% CI [-2.16 to 6.41], 7 trials/576 infants and MD -0.66 mm, 95% CI [-6.43 to 5.10], 4 trials/314 infants, respectively). At nine months and at 18 to 24 months post-term, infants who received post-discharge formula were greater in length (MD 7.33 mm, 95% CI [1.80 to 12.87], p=0.009; 4 trials/347 infants and MD 9.00 mm, 95% CI [0.32 to 17.68 mm], p=0.04; 1 trial/192 infants, respectively). For the outcome head circumference, no statistically significant differences between treatment groups were found in pooled analysis (3 to 4 months: MD -0.30 mm, 95% CI [-2.86 to 2.26], 6 trials/523 infants; 6 months: MD 2.28 mm, 95% CI [-0.28 to 4.83], 7 trials/576 infants; 9 months: MD 0.16 mm, 95% CI [-3.21 to 3.53], 4 trials/347 infants; 12 months: MD 2.11 mm, 95% CI [-1.52 to 5.75], 4 trials/314 infants; 18 to 24 months: MD -3.00 mm, 95% CI [-8.24 to 2.24], 1 trial/192 infants).

Development
In one trial involving 184 infants, no differences between groups in the Bayley Scales Mental Development Index (MD 0.90, 95% CI [-3.24 to 5.04]) or Psychomotor Development Index (MD 2.70, 95% CI [-1.28 to 6.68]) at 18 months’ corrected age were found.

Subgroup analyses
In two trials exclusively recruiting very low birth weight infants, no statistically significant differences between treatment groups were found for weight, length, head circumference or bone mineralisation up to six months’ corrected age. In the three trials recruiting infants who remained small-for-gestational age at hospital discharge, no statistically significant effect on weight up to 12 months’ corrected age was observed. However, pooled analysis of data at six months follow-up demonstrated statistically significant increases in crown-heel length (MD 8.88 mm, 95% CI [0.94 to 16.83], 2 trials/137 infants) and head circumference (MD 5.36, 95% CI [0.62 to 10.11], 2 trials/137 infants).

Additional outcomes
Bone mineral content at nine months post-term was statistically significantly greater among infants who received nutrient-enriched formula in one trial including 31 infants (MD 20.60 mg/cm, 95% CI [7.78 to 33.42], p=0.0016), while in another trial of 67 infants, bone mass as measured by DEXA at 12 months was significantly lower (data not shown). No differences in other measures of bone mineralization were found in other trials reporting on this outcome. In one trial reporting of feed intolerance, no difference was found between treatment and control groups. No trials reported on other pre-specified outcome measures.

Preterm formula versus standard term formula
Growth
Growth rates were measured in one trial of 42 infants. While no statistically significant differences were found for weight gain (MD 3.70 g/kg/day, 95% CI [-0.16 to 7.56]) or head circumference (MD 0.5 mm/week, 95% CI [-0.04 to 1.04]), linear growth was greater among the group receiving preterm formula (MD 1.0 mm/week, 95% CI [0.09 to 1.91], p=0.031). In pooled analysis, weight was not different between treatment groups at three to four months (MD 74.41 g, 95% CI [-267.10 to 415. 93], 3 trials/130 infants), six months (MD 74.60 g, 95% CI [-164.73 to 313. 92], 4 trials/273 infants), or nine months post-term (MD 112.0 g, 95% CI [-482.69 to 706. 69], 1 trial/59 infants). A clear effect in favour of preterm formula was found for weight at 12 months post-term (MD 539.48 g, 95% CI [255.03 to 823.92], p=0.0002; 4 trials/265 infants) and at 18 to 24 months post-term (MD 490.81 g, 95% CI [142.19 to 839.44], p=0.0058; 2 trials/162 infants). No statistically significant effect of preterm formula on crown-heel length was found at three to four months (MD -2.27 mm, 95% CI [-13.09 to 8.56], 3 trials/130 infants), six months (MD 1.83 mm, 95% CI [-6.25 to 9.92], 3 trials/160 infants), nine months (MD -3.0 mm, 95% CI [-17.03 to 11.03], 1 trial/59 infants) or 12 months (MD 5.13 mm, 95% CI [-4.23 to 14.49], 3 trials/152 infants). However, at 18 to 24 months’ corrected age, infants who received preterm formula were on average 11 mm greater in length (95% CI [1.89 to 20.11 mm], p=0.018; 2 trials/162 infants). Head circumference was statistically significantly greater with preterm formula among all age categories except three to four months (3 to 4 months: MD 3.61 mm, 95% CI [-2.09 to 9.31], 3 trials/130 infants; 6 months: MD 5.82 mm, 95% CI [1.32 to 10.32], p=0.011; 3 trials/160 infants; 9 months: MD 8.00 mm, 95% CI [0.85 to 15.15], p=0.028; 1 trial/59 participants; 12 months: MD 6.07 mm, 95% CI [1.07 to 11.06], p=0.017; 3 trials, 152 participants; 18 to 24 months: MD 5.42 mm, 95% CI [0.69 to 10.14], p=0.025; 2 trials/162 infants).

Development
In two trials involving 143 infants, no differences between groups in the Bayley Scales Mental Development Index (MD -1.44, 95% CI [-6.22 to 3.35]) or Psychomotor Development Index (MD -1.13, 95% CI [-4.19 to 1.93]) were found. At six, nine and 12 months’ corrected age, one trial involving 121 infants reported no statistically significant differences between treatment groups in Griffiths’ Developmental Scale assessments (data not available).

Additional outcomes
No effect of preterm formula on bone mineralization was found in one trial of 103 infants. No other pre-specified outcome measures were reported on.

5. Additional author observations*

All trials were conducted in high-income settings in Asia, Europe, the Middle East and North America, limiting the generalizability of the findings to other settings. In addition, all studies enrolled infants able to feed responsively (on demand), and thus findings may not be applicable to infants who cannot feed responsively. In nine trials, methods of allocation concealment were unclear, and in six trials, loss to follow-up was over 20%, with two of these trials having an attrition rate of over 50% at 12 months follow-up. GRADE quality of evidence assessment of growth outcomes was of moderate quality, while for the Bayley Scales Mental Development Index the GRADE rating was high quality.

Overall, there is little convincing evidence supporting the use of post-discharge formula over standard term formula for improving the growth and development of preterm infants following hospital discharge. However, in comparison with standard term formula, preterm formula appears to promote preterm infants’ growth. This is likely due to the higher mineral, protein, and energy content of preterm formula in comparison with post-discharge formula and standard term formula. Current consensus recommendations state that formula-fed preterm infants should receive a post-discharge formula for up to 12 months following discharge from hospital, a recommendation that is not supported by the evidence summarized in this review. However, preterm formula is generally only available for in-hospital use at present.

Further trials investigating the long-term effects of nutrient-enriched formula in comparison to standard formula on preterm infants’ growth and development are needed, as are trials investigating the effects of nutrient-enriched formula in infants who cannot demand feed. Determining the specific nutrients underlying the improvements in growth outcomes is also warranted.