Review question: does individualized rather than standard, non-individualized addition of nutrients and calories to breast milk feeds safely improve growth and other outcomes in preterm infants?
Background: preterm infants are at risk for poor growth following birth. Breast milk reduces their risk of illness but does not meet their nutritional needs. Therefore, breast milk fed to preterm infants must be fortified with extra nutrients. Usual methods of fortifying breast milk treat all breast milk and all preterm infants the same. However, two methods are available for individualizing fortification for each preterm infant. Targeted fortification adds nutrients to breast milk based on the results of breast milk analysis. Adjustable fortification adds nutrients based on the results of preterm infant laboratory results. Individualized fortification may improve preterm infant growth or other outcomes. However, it is not known whether targeted or adjustable fortification is safe or improves outcomes for preterm infants compared with the standard method.
Study characteristics: through literature searches updated to September 2019, we found seven studies that tested the effects of targeted or adjustable fortification of breast milk feeds compared to standard fortification in preterm infants, yielding eight publications (521 total participants were enrolled in these studies). One study that was published after our literature search was completed is awaiting classification.
Key results: targeted or adjustable fortification improves short-term growth compared to standard fortification in preterm infants. Determining the best way to customize breast milk feeds is necessary, as is clarifying its safety and effects on other clinical outcomes.
Certainty of evidence: very low to moderate. Moderate certainty means that the true effect of individualized fortification on growth in preterm infants is likely to be close to the result of this review but there is a possibility that it is substantially different. Low certainty means that the true effect may be substantially different from the results of this review. Very low certainty means that the true effect of individualized fortification on growth in preterm infants is likely to be substantially different from the results of this review. Certainty of evidence was downgraded most often in this review due to small numbers of participants in included studies and significant differences in study design and outcome measures among included studies.
We found moderate- to low-certainty evidence suggesting that individualized (either targeted or adjustable) fortification of enteral feeds in very low birth weight infants increases growth velocity of weight, length, and head circumference during the intervention compared with standard non-individualized fortification. Evidence showing important in-hospital and post-discharge clinical outcomes was sparse and of very low certainty, precluding inferences regarding safety or clinical benefits beyond short-term growth.
Human milk as compared to formula reduces morbidity in preterm infants but requires fortification to meet their nutritional needs and to reduce the risk of extrauterine growth failure. Standard fortification methods are not individualized to the infant and assume that breast milk is uniform in nutritional content. Strategies for individualizing fortification are available; however it is not known whether these are safe, or if they improve outcomes in preterm infants.
To determine whether individualizing fortification of breast milk feeds in response to infant blood urea nitrogen (adjustable fortification) or to breast milk macronutrient content as measured with a milk analyzer (targeted fortification) reduces mortality and morbidity and promotes growth and development compared to standard, non-individualized fortification for preterm infants receiving human milk at < 37 weeks' gestation or at birth weight < 2500 grams.
We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 9), in the Cochrane Library; Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), on September 20, 2019. We also searched clinical trials databases and the reference lists of retrieved articles for pertinent randomized controlled trials (RCTs) and quasi-randomized trials.
We considered randomized, quasi-randomized, and cluster-randomized controlled trials of preterm infants fed exclusively breast milk that compared a standard non-individualized fortification strategy to individualized fortification using a targeted or adjustable strategy. We considered studies that examined any use of fortification in eligible infants for a minimum duration of two weeks, initiated at any time during enteral feeding, and providing any regimen of human milk feeding.
Data were collected using the standard methods of Cochrane Neonatal. Two review authors evaluated the quality of the studies and extracted data. We reported analyses of continuous data using mean differences (MDs), and dichotomous data using risk ratios (RRs). We used the GRADE approach to assess the certainty of evidence.
Data were extracted from seven RCTs, resulting in eight publications (521 total participants were enrolled among these studies), with duration of study interventions ranging from two to seven weeks. As compared to standard non-individualized fortification, individualized (targeted or adjustable) fortification of enteral feeds probably increased weight gain during the intervention (typical mean difference [MD] 1.88 g/kg/d, 95% confidence interval [CI] 1.26 to 2.50; 6 studies, 345 participants), may have increased length gain during the intervention (typical MD 0.43 mm/d, 95% CI 0.32 to 0.53; 5 studies, 242 participants), and may have increased head circumference gain during the intervention (typical MD 0.14 mm/d, 95% CI 0.06 to 0.23; 5 studies, 242 participants). Compared to standard non-individualized fortification, targeted fortification probably increased weight gain during the intervention (typical MD 1.87 g/kg/d, 95% CI 1.15 to 2.58; 4 studies, 269 participants) and may have increased length gain during the intervention (typical MD 0.45 mm/d, 95% CI 0.32 to 0.57; 3 studies, 166 participants). Adjustable fortification probably increased weight gain during the intervention (typical MD 2.86 g/kg/d, 95% CI 1.69 to 4.03; 3 studies, 96 participants), probably increased gain in length during the intervention (typical MD 0.54 mm/d, 95% CI 0.38 to 0.7; 3 studies, 96 participants), and increased gain in head circumference during the intervention (typical MD 0.36 mm/d, 95% CI 0.21 to 0.5; 3 studies, 96 participants). We are uncertain whether there are differences between individualized versus standard fortification strategies in the incidence of in-hospital mortality, bronchopulmonary dysplasia, necrotizing enterocolitis, culture-proven late-onset bacterial sepsis, retinopathy of prematurity, osteopenia, length of hospital stay, or post-hospital discharge growth. No study reported severe neurodevelopmental disability as an outcome. One study that was published after our literature search was completed is awaiting classification.