High versus low medium chain triglyceride content of formula for promoting short-term growth of preterm infants

Review question

How does high versus low medium chain triglyceride content of formula impact short-term growth of preterm infants?

Background

Triglycerides are the main constituents of body fat in humans. Fat provides about half of the energy source (calories) in human breast milk, mostly as long chain fatty acid triglycerides (LCTs). Nutrition is essential for growth, metabolism, and immunity.

Impaired weight gain and growth in preterm infants are significantly associated with adverse neurodevelopmental outcomes. Poor nutrition has been linked to inadequate head growth and thus poor psychomotor and mental skills, higher rates of cerebral palsy, and autism.

As a way of improving growth, fat can be added to formula used to feed preterm infants who cannot be fed maternal or donor breast milk or who may require supplementation. Fats in formula can contain triglycerides with long chain fatty acids or shorter medium chain fatty acids (MCTs). MCTs are more easily absorbed by the newborn infant with an immature digestive system. LCTs are still important for development of visual acuity and development of cell membranes and the brain.

Study characteristics

We included 10 small studies that compared the effects of feeding high versus low MCT formulas (for a minimum of 5 days) on short-term growth (weight, length, and head circumference gain) of preterm infants. These infants had a mean gestational age between 29 and 32 weeks, mean birth weight between 1 kg and 1.5 kg, and mean age of one to six weeks. The evidence is up to date as of September 2020.

Key results

The pattern of growth in infants fed high MCT versus low MCT formula shows little to no difference in any of the primary short-term growth outcomes. 

Certainty of evidence

We found little to no difference in short-term growth outcomes among premature infants fed either low MCT or high MCT formulas. The small number of trials (10), each containing a small study population, may be responsible for lack of evidence of a difference. We found evidence of very low to low certainty. Certainty is defined as low if confidence in the result is limited, meaning the true effect of individualized fortification on growth in preterm infants may be substantially different from the results of this review. Certainty is defined as very low if there is little confidence in the estimate of effect, which is likely to be substantially different from the results of this review. 

Authors' conclusions: 

We found evidence of very low to low certainty suggesting no differences among short-term growth data for infants fed low versus high MCT formulas. Due to lack of evidence and uncertainty, neither formula type could be concluded to improve short-term growth outcomes or have fewer adverse effects. Further studies are necessary because the results from included studies are imprecise due to small numbers and do not address important long-term outcomes. Additional research should aim to clarify effects on formula tolerance and on long-term growth and neurodevelopmental outcomes, and should include larger study populations to better evaluate effect on NEC incidence.

Read the full abstract...
Background: 

In-hospital growth of preterm infants remains a challenge in clinical practice. The high nutrient demands of preterm infants often lead to growth faltering. For preterm infants who cannot be fed maternal or donor breast milk or may require supplementation, preterm formulas with fat in the form of medium chain triglycerides (MCTs) or long chain triglycerides (LCTs) may be chosen to support nutrient utilization and to improve growth. MCTs are easily accessible to the preterm infant with an immature digestive system, and LCTs are beneficial for central nervous system development and visual function. Both have been incorporated into preterm formulas in varying amounts, but their effects on the preterm infant's short-term growth remain unclear. This is an update of a review originally published in 2002, then in 2007.

Objectives: 

To determine the effects of formula containing high as opposed to low MCTs on early growth in preterm infants fed a diet consisting primarily of formula. 

Search strategy: 

We used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 8), in the Cochrane Library; Ovid MEDLINE Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily, and Ovid MEDLINE(R); MEDLINE via PubMed for the previous year; and Cumulative Index to Nursing and Allied Health Literature (CINAHL), on 16 September 2020. We also searched clinical trials databases and the reference lists of retrieved articles for randomized controlled trials (RCTs) and quasi-RCTs.

Selection criteria: 

We included all randomized and quasi-randomized trials comparing the effects of feeding high versus low MCT formula (for a minimum of five days) on the short-term growth of preterm (< 37 weeks' gestation) infants. We defined high MCT formula as 30% or more by weight, and low MCT formula as less than 30% by weight. The infants must be on full enteral diets, and the allocated formula must be the predominant source of nutrition.

Data collection and analysis: 

The review authors assessed each study's quality and extracted data on growth parameters as well as adverse effects from included studies. All data used in analysis were continuous; therefore, mean differences with 95% confidence intervals were reported. We used the GRADE approach to assess the certainty of evidence.

Main results: 

We identified 10 eligible trials (253 infants) and extracted relevant growth data from 7 of these trials (136 infants). These studies were found to provide evidence of very low to low certainty. Risk of bias was noted, as few studies described specific methods for random sequence generation, allocation concealment, or blinding. We found no evidence of differences in short-term growth parameters when high and low MCT formulas were compared.

As compared to low MCT formula, preterm infants fed high MCT formula showed little to no difference in weight gain velocity (g/kg/d) during the intervention, with a typical mean difference (MD) of -0.21 g/kg/d (95% confidence interval (CI) -1.24 to 0.83; 6 studies, 118 infants; low-certainty evidence). The analysis for weight gain (g/d) did not show evidence of differences, with an MD of 0.00 g/d (95% CI -5.93 to 5.93; 1 study, 18 infants; very low-certainty evidence), finding an average weight gain of 20 ± 5.9 versus 20 ± 6.9 g/d for high and low MCT groups, respectively. We found that length gain showed no difference between low and high MCT formulas, with a typical MD of 0.10 cm/week (95% CI -0.09 to 0.29; 3 studies, 61 infants; very low-certainty evidence). Head circumference gain also showed little to no difference during the intervention period, with an MD of -0.04 cm/week (95% CI -0.17 to 0.09; 3 studies, 61 infants; low-certainty evidence). Two studies reported skinfold thickness with different measurement definitions, and evidence was insufficient to determine if there was a difference (2 studies, 32 infants; very low-certainty evidence). There are conflicting data (5 studies) as to formula tolerance, with 4 studies reporting narrative results of no observed clinical difference and 1 study reporting higher incidence of signs of gastrointestinal intolerance in high MCT formula groups. There is no evidence of effect on the incidence of necrotizing enterocolitis (NEC), based on small numbers in two trials. Review authors found no studies addressing long-term growth parameters or neurodevelopmental outcomes.

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