Background: Preterm infants have fewer nutrient reserves at birth than full-term infants and often receive artificial formula feeds in the absence of expressed breast milk. Although it is generally agreed that feeding must be initiated slowly and advanced with much greater deliberation than in a healthy, full-term infant, the way in which feeds are introduced and advanced in preterm infants varies widely. This review focuses on whether dilute or full-strength formula is the preferable mode of introducing feeds in preterm infants for whom expressed breast milk is unavailable.

Objectives: To assess the effects of dilute versus full-strength formula on the incidence of necrotising enterocolitis, feeding intolerance, weight gain, length of stay in hosptial and time to achieve full calorie intake in exclusively formula-fed preterm or low birth weight infants. A secondary objective was to assess the effects of different dilution strategies.

Search methods: We used the standard search strategy of Cochrane Neonatal to update the search in the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 9), MEDLINE via PubMed (1966 to 1 October 2018), Embase (1980 to 1 October 2018), and CINAHL (1982 to 1 October 2018).We searched clinical trials' registries for ongoing or recently completed trials (clinicaltrials.gov; the World Health Organization's International Trials Registry and Platform; and the ISRCTN Registry).

Selection criteria: Randomised or quasi-randomised trials comparing strengths of formula milk in exclusively formula-fed preterm or low birth weight infants. We excluded studies if infants received formula as a supplement to breast milk.

Data collection and analysis: We independently assessed studies for inclusion. We collected data using the standard methods of Cochrane Neonatal, with independent assessment of risk of bias and data extraction. We synthesised mean differences using a fixed-effect meta-analysis model. We used the GRADE approach to assess the certainty of evidence.

Main results: We included three studies involving 102 preterm or low birth weight infants in the review. The studies compared dilute (double-volume, half-strength) formula with full-strength (20 kcal/oz (˜ 68 to 70 kcal/100 mL)) formula. We assessed all three studies as having unclear risk of bias due to the likely absence of blinding of study personnel and the potential for selection bias in the largest trial. Data for the primary outcome of necrotising enterocolitis were not reported in any of the studies. We could combine two of the studies (88 infants) in the meta-analysis. The evidence suggests that dilute formula with double-volume (half-strength) may lead to fewer episodes of gastric residuals per day (one study; mean difference (MD) -1.20, 95% confidence interval (CI) -2.20 to -0.20; low-certainty evidence), fewer episodes of gastric residuals per baby until attaining 100 kcal/kg (one study; MD -0.80, 95% CI -1.32 to -0.28; low-certainty evidence), fewer episodes of vomiting per day (one study; MD -0.04, 95% CI -0.07 to -0.01; low-certainty evidence) and fewer occurrences of abdominal distension greater than 2 cm (two studies; MD -0.16, 95% CI -0.19 to -0.13; low-certainty evidence). For the secondary outcomes, data suggest that infants in the dilute formula with double-volume (half-strength) group may have attained an adequate energy intake earlier than infants in the full-strength group (two studies; MD -2.26, 95% CI -2.85 to -1.67; low-certainty evidence). There was no evidence of a difference between groups for weight gain one week after commencement of intragastric feeds (one study; MD 0.05 kg, 95% CI -0.06 to 0.15; low-certainty evidence). Data were not reported for length of hospital stay.

Authors' conclusions: There is low-certainty evidence from three small, old trials that use of dilute formula in preterm or low birth weight formula-fed infants may lead to an important reduction in the time taken for preterm infants to attain an adequate energy intake.However, our confidence in this result is limited due to uncertainty over risk of bias and sparsity of available data. Dilute formula may reduce incidence of feeding intolerance, but the clinical significance of the reduction is uncertain. The impact on serious gastrointestinal problems, including necrotising enterocolitis, was not reported in any of the trials. Further randomised trials are needed to confirm these results.

FB: none known

DH: none known

TT: none known

SM: none known

MH: none known

Core editorial and administrative support for this review has been provided by a grant from The Gerber Foundation. The Gerber Foundation is a separately endowed, private foundation, independent from the Gerber Products Company. The grantor has no input on the content of the review or the editorial process (see Declarations of interest).

• Wellcome Trust/United Kingdom