Intravenous protein: Impact on growth and development in extremely low birthweight babies

Abstract

Optimal early nutrition providing adequate amounts of all macronutrients and micronutrients is essential for normal brain development. Observational data suggest enhanced protein intake in the first weeks after birth may improve growth and neurodevelopment in extremely low birthweight (ELBW, <1,000 g) babies. However, the optimal intravenous nutrition solutions and electrolyte intakes remain unknown. Few randomised controlled trials (RCTs) have assessed whether higher protein intake in the first week after birth improves neurodevelopment and meta-analyses of RCTs investigating the effects of higher versus lower protein intake on growth and neurodevelopment are inconclusive. The ProVIDe trial, an international, multicentre, double-blind, RCT, randomised ELBW babies to receive either an amino acid solution (1 g.d-1 protein) or placebo for 5 days after birth, in addition to standard nutrition. The primary outcome is survival free from neurodevelopmental disability at 2 years’ corrected age (CA), available in 2021. Secondary cohort analyses aimed to investigate relationships between nutrient intakes in the 4 weeks after birth and plasma ammonia concentrations, growth from birth to 36 weeks’ CA, and the incidence of refeeding syndrome (RS). Relationships between nutrient intake, growth, RS and clinical outcomes were explored using chi-square tests and regression analysis adjusted for site, sex, gestation and birthweight z-score. Review of 22 studies on the effects of higher versus lower protein intake on growth revealed substantial variation in methods used to calculate and report nutritional intakes, and to assess growth, making metaanalysis unreliable. Standardised reporting of outcomes will aid future interpretation of research in this area and the StRoNNG (Standardised Reporting of Neonatal Nutrition and Growth) Checklist is proposed as a framework. The ProVIDe trial randomised 434 participants with median (range) birthweight 777 g (405, 998), and gestation 25.7 (22.7, 31.5) weeks across 8 sites in New Zealand and Australia. In week 1, median (IQR) total energy and protein intakes were 76 (70, 83) kcal.Kg⁻¹.d⁻¹ and 3.34 (2.86, 3.76) g.Kg⁻¹.d⁻¹. Ammonia concentrations were similar to those of term babies and only weakly correlated with protein intake. Sixty-eight babies (20%) developed RS, which was associated with a greater risk of mortality (34% vs. 11%, p<0.0001), but not sepsis, when compared with babies without RS. RS was associated with lower phosphate, calcium and sodium intake and higher amino acid intakes in the first week. The strongest associations between nutrient intakes and growth were for head circumference at 36 weeks’ CA with mean total protein in week 2 (ß 0.26 z-score change per 1 g.Kg⁻¹.d⁻¹ protein (CI 0.07-0.46) p=0.009). By week 3, babies with enteral protein intakes in the lowest quintile had 80% lower odds of achieving expected weight, length and head circumference growth than babies receiving enteral protein intakes in the middle quintile. Nutritional practices, change in z-score for growth parameters, incidence of RS and mortality differed widely amongst sites. Long-term follow-up of the ProVIDe trial participants will clarify the significance of these findings for neurodevelopment and long-term health. Optimised intravenous protein and electrolyte intake in the first two weeks after birth and enhanced enteral nutrition may reduce serious adverse outcomes and improve growth in this high-risk population.