Dilute versus full-strength formula in exclusively formula-fed preterm or low birth weight infants

Review question
Is dilute formula milk (e.g. half the strength at double the volume) better tolerated than full-strength formula milk in the initial feeding of preterm babies for whom breast milk is not available? 

Background
Babies born preterm (at less than 37 weeks' gestation) or with a low birth weight (less than 2500 grams) have special feeding requirements. Expressed breast milk is preferred, but preterm babies are often fed with formula milk because breast milk is not always available. The provision of artificial feeds varies considerably in preterm babies and there is concern that introducing full-strength formulas too early may lead to the retention of feed in the stomach, which is associated with feeding intolerance and necrotising enterocolitis, a severe bowel disorder.

Study characteristics
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.

Key results
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.

Certainty of evidence
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.

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.

Read the full abstract...
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 strategy: 

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.

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