1. Objectives

To assess the effect of multinutrient fortified human breast milk on growth and development in preterm infants following hospital discharge

2. How studies were identified

The following databases were searched in August 2012:

• CENTRAL (The Cochrane Library 2012, Issue 3)
• MEDLINE
• EMBASE
• CINAHL
• ClinicalTrials.gov
• Current Controlled Trials

Reference lists and conference proceedings were also searched

3. Criteria for including studies in the review

3.1 Study type

Randomized controlled trials, including quasi-randomized controlled trials

3.2 Study participants

Preterm (<37 weeks’ gestation) and low birth weight (<2500 g) infants fed with human breast milk following hospital discharge

3.3 Interventions

Human breast milk fortified with ≥1 nutrient (carbohydrate, fat, protein, calcium and/or phosphate) in comparison with unfortified human breast milk, initiated up to one week before hospital discharge and with a minimum follow-up of two weeks

(Micronutrients other than calcium or phosphate were not considered as multinutrient fortification for the purposes of this review)

(Infants in treatment and control groups should have received the same volume of breast milk and similar care)

3.4 Primary outcomes

Growth

• Weight
• Length
• Head circumference
• Skinfold thickness
• Body mass index and other measures of body composition
• Growth restriction (<10^th centile for the index population distribution of weight, length, or head circumference)

Development

• Neurodevelopmental outcomes assessed >12 months’ corrected age with validated tools
• Classifications of disability, including auditory and visual disability, non-ambulant cerebral palsy, and developmental delay
• Cognitive and educational outcomes at >5 years, including intelligence quotient and educational attainment measured with validated tools

Secondary outcomes included duration of breast milk feeding, proportion infants fed any breast milk at the end of the intervention period, feed intolerance resulting in the infant requiring treatment for dehydration, bone mineralization (as measured by dual energy X-ray absorptiometry, serum alkaline phosphatase concentrations, clinical or radiological evidence of rickets), and blood pressure at long-term follow-up

4. Main results

4.1 Included studies

Two randomized controlled trials, enrolling 246 infants, were included in this review

• In one trial, 39 breast milk-fed infants born at <33 weeks’ gestation with birth weight 750 to 1800 g were randomized to receive either unfortified breast milk or half of all feeds as expressed breast milk fortified with multinutrients. Multinutrient fortification was targeted to provide 74 kcal/100 mL and 1.8 g of protein per 100 mL of breast milk. The intervention began 3 days prior to hospital discharge and continued for a total of 12 weeks
• In the other included trial, 207 infants born at <33 weeks’ gestation were randomized to receive either unfortified milk or expressed breast milk fortified with commercially available fortifier providing an additional 17.5 kCal and 1.375 g of protein to 20 to 50 mL of breast milk given once daily. Fortified milk was fed by a bottle or cup and the intervention was initiated a few days before discharge and continued for four months post-discharge

4.2 Study settings

• Cananda and Denmark
• Both trials were supported by formula companies, and both trials were conducted between 2004 and 2007/2008

4.3 Study settings

How the data were analysed
The effects of multinutrient fortified human milk were compared to those of human breast milk without added nutrients in preterm infants following hospital discharge. For dichotomous data, risk ratios (RR) were calculated, while for continuous data, mean differences (MD) were produced. Corresponding 95% confidence intervals (CI) were also generated. Heterogeneity was deemed substantial if I² was greater than 50%. To investigate potential sources of heterogeneity, sensitivity analyses were undertaken, and the following subgroup analyses were planned:

• Very preterm (<32 weeks’ gestation) or very low birth weight (<1500 g) infants
• Small-for-gestational age infants (<10^th centile for the index populations distribution of weight) at hospital discharge
• Infants with chronic lung disease receiving supplemental oxygen therapy at hospital discharge
• Infants fed with donor breast milk

Results
Growth
Weight
At three to four months’ corrected age, no statistically significant effect of multinutrient fortified milk on weight was found (MD 138.26 g, 95% CI [-89.26 to 366.40], 2 trials/236 infants). Although the point estimate increased, no statistically significant effect was found at 12 months’ corrected age (MD 255.25 g, 95% CI [-93.40 to 603.90], 2 trials/211 infants).

Head circumference
In pooled analysis, no statistically significant effect of multinutrient fortified milk on head circumference was observed at three to four months’ corrected age (MD 0.22 cm, 95% CI [-0.15 to 0.58], 2 trials/235 infants) or at 12 months’ corrected age (MD 0.16, 95% CI [-0.27 to 0.60], 2 trials/197 infants).

Length
At three to four months’ corrected age, no statistically significant difference between treatment and control groups was found in length (MD 0.60 cm, 95% CI [-0.14 to 1.33], 2 trials/236 infants). However, at 12 months, infants who received multinutrient fortified milk were borderline statistically significantly greater in length than those who did not (MD 0.88 cm, 95% CI [0.01 to 1.74 cm], p=0.05; 2 trials/211 infants).

Neurodevelopment
In one trial of 39 infants, no statistically significant differences between treatment and control groups were found for Bayley II mental development index (100 versus 91 points) and psychomotor development index (94 versus 94 points) scores at 18 months’ corrected age. In the same trial, visual acuity assessed using sweep visual-evoked potential testing was improved among the multinutrient fortification group at both four months (MD 0.90 cycles/degree, 95% CI [0.03 to 1.77], 32 infants) and six months (MD 1.50 cycles/degree, 95% CI [0.62 to 2.38], 31 infants). However, visual acuity assessed using contrast sensitivity testing was not different between groups (4 months MD 0.10 log sensitivity, 95% CI [-0.12 to 0.32], 22 infants; 6 months MD 0.10 log sensitivity, 95% CI [-0.10 to 0.30], 26 infants).

Additional outcomes
In one trial, bone mineral content was statistically significantly greater by 20.6 g (95% CI [6.41 to 34.79 g], 34 infants) in the treatment group at four months’ corrected age and by 29.8 g (95% CI [3.63 to 55.97 g], 27 infants) at 12 months’ corrected age. In the same trial, bone mineral density was not different between groups at either four or 12 months’ corrected age. The duration of breast milk feeding did not differ significantly between groups in either trial. While the proportion of infants receiving any breast milk at the end of the intervention period did not differ between treatment groups in one trial, the proportion of infants being exclusively fed with breast milk was statistically significantly lower in the intervention group in the other trial (RR 0.48, 95% CI [0.30 to 0.76], 200 infants). No other pre-specified outcomes were reported on in the included trials.

5. Additional author observations*

The methodological quality of the two included trials was good, with both trials reporting adequate allocation concealment and having little attrition. However, the overall sample size was small and many pre-specified developmental and long-term growth outcomes were not assessed.

Current data on the effect of multinutrient fortified breast milk following hospital discharge on preterm infants’ growth and development are very limited, and do not provide any evidence that such interventions are beneficial. In addition, the effect on long-term growth is yet to be investigated. The increase in bone mineral density among the treatment group in one trial may have been due to the infants in the treatment group receiving a greater amount of dietary vitamin D (567 versus 380 IU/kg/day at 12 weeks).

Further research in this area is warranted given the potential benefits for preterm infants’ growth and development. However, maternal acceptability of multinutrient fortified breast milk interventions should first be investigated, as such interventions have a potential to disrupt breastfeeding. Further trials could focus on infants who require additional nutrition, such as those with a limited ability to breastfeed, those with poor growth, and those with increased metabolic requirements due to disease.