Abstract: This is an update of a 2001 review that identified no eligible trials. One trial including 40 infants met the inclusion criteria for this review. Using GRADE criteria, we judged the quality of the evidence as low owing to risk of bias (inadequate reporting of methods of randomisation, allocation concealment and/or blinding) and imprecision (wide confidence intervals and data from a single small trial). We found no evidence of a difference between calcium and phosphorus supplementation versus no supplementation for neonatal growth outcomes (weight, length, head circumference) at any time point reported (two, four or six weeks postnatal age). At six weeks postnatal age, supplementation with calcium/phosphorus was associated with a decrease in serum alkaline phosphatase concentration (MD -56.85 IU/L, 95% CI -101.27 to -12.43; one randomised controlled trial (RCT); n = 40 infants). Investigators provided no data on growth at 12 to 18 months, neonatal fractures, feed intolerance, breastfeeding or any of the prespecified childhood outcomes for this review (fractures, growth, neurodevelopmental outcomes). We identified one small trial including only 40 infants that compared supplementation of human milk with calcium and phosphorus versus no supplementation in hospitalised preterm infants. We judged the evidence to be of low quality and found no evidence of differences between groups for clinically important outcomes including growth and fractures. Although serum alkaline phosphatase concentration was reduced in the group receiving supplementation at six weeks postnatal age, this difference is unlikely to be of clinical significance. We conclude that evidence is insufficient to determine whether benefit or harm ensues when human milk is supplemented with calcium and/or phosphorus for the hospitalised preterm infant. We see no advantage of conducting further trials of this intervention because with the advent of multi-component human milk fortifier, supplementation of human milk with calcium and/or phosphorus alone is no longer common practice. Future trials should consider assessing effects of multi-component fortifiers with different mineral compositions on clinically important outcomes during the neonatal period and in later childhood.

Plain-language summary: We searched for evidence in April 2016 and identified one randomised controlled trial including 40 babies. Investigators reported a small decrease in the concentration of alkaline phosphatase (an enzyme involved in bone growth) among infants who had received calcium/phosphorus supplementation. We found no difference in growth between infants who had been given human milk supplemented with extra calcium and phosphorus and infants who had received no supplementation. One small trial provided the evidence, and we judged the evidence to be of low quality. Researchers reported no follow-up of these babies into childhood. Evidence is insufficient to allow a judgement as to whether extra calcium and/or phosphorus provided to preterm babies confers benefit for their bones and growth. It is no longer very common to give calcium and phosphorus supplements alone, as human milk fortifiers now available include many other components as well as minerals to support the growth and development of preterm babies. We therefore suggest that future trials conducted to examine effects of mineral supplements in preterm babies include them in multi-component human milk fortifiers and assess clinically important outcomes into childhood.