Abstract: 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. 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.

Plain-language summary: The evidence for this review is current as of 1 October 2018. We included three trials that compared dilute formula milk (half-strength, double-volume) with full-strength formula milk. The trials involved 102 preterm or low birth weight infants; two were conducted in the USA and one in India. The trials were small (14, 38 and 50 infants, respectively) and conducted between 25 and 30 years ago. The quality of two trials was judged to be poor due to insufficient information being provided in the trial publications, but judged to be moderate in the third trial (of 38 infants). None of the trials assessed necrotising enterocolitis as an outcome. Infants receiving dilute formula (half-strength, double-volume) experienced fewer episodes of feeding intolerance and achieved full energy intake earlier than infants receiving full-strength formula (20 kcal/oz (˜ 68 to 70 kcal/100 mL)). Feeding intolerance Two measures of feeding intolerance (abdominal distension and episodes of gastric residuals) were reported across the trials. Two trials (88 infants) provided data for abdominal distension and gastric residuals. Infants fed dilute formula experienced 19% (CI 16% to 23%) fewer episodes of abdominal distension (> 2 cm), equivalent to 0.67 episodes per infant in the half-strength group compared to 0.83 episodes in the full-strength group. It was not possible to combine data on gastric residuals but both trials reported fewer episodes of gastric residuals in the dilute formula group. The third trial (14 infants) only reported that there was no difference between the groups with respect to these two outcomes. Time to establish full enteral feeding In two trials (88 infants) infants receiving dilute formula experienced a 22% (CI 16% to 28%) reduction in the number of days required to reach an adequate energy intake (420 joules/kilogram), equivalent to 8 days in the half-strength group compared to 10.3 days in the full-strength group. In exclusively formula-fed preterm or low birth weight infants, low-certainty evidence shows that diluted formula may lead to an important reduction in the time taken to attain adequate enteral fluid and energy requirements, without increasing indicators of feeding intolerance. The clinical importance of the reduction in episodes of feeding intolerance is unclear. These findings are based on three small, old trials that may be of less relevance to current practice. A lack of data on other important outcomes, such as the incidence of necrotising enterocolitis and weight gain, limits the usefulness of the studies.