Description of the condition

Three branched‐chain amino acids (BCAAs)—leucine, isoleucine and valine—are part of a group of essential amino acids (EAAs) that play a pivotal role in neonatal nutrition (De Groof 2011; Kashyap 2011; Suryawan 2011), and a range of key body functions (Ferrier 2013; Harper 1984). A significant amount of essential proteins for the human body comes from BCAAs, including 40% of total amino acids and approximately 35% of muscle protein (Harper 1984). Leucine in particular is of immense importance because it builds body protein and stimulates protein synthesis in the skeletal muscles (Fujita 2007; Suryawan 2011). During the neonatal period, leucine can promote protein synthesis and contribute to increasing skeletal muscle volume in animals (Escobar 2005; Suryawan 2011). It is associated with metabolism of glucose and stimulates insulin secretion (Layman 2006; Matthews 1997). Isoleucine might stimulate the innate immune system in the intestine, and has been shown to protect infants from various harmful microbes (Alam 2011). Additionally, BCAAs play an indispensable role in the brain by constantly nourishing neurons with glutamate (Fernstrom 2005), which is an important excitatory neurotransmitter (Yudkoff 2005). Furthermore, BCAAs act as indirect modulators to stimulate the synthesis of aromatic amino‐acid‐based neurotransmitters like serotonin, dopamine and norepinephrine (Fernstrom 2005).

As the human body is unable to synthesise these amino acids, EAAs should be consumed directly from food sources, such as egg yolk, soy bean and maize (WHO 2007). Approximately 20% of amino acids in human breast milk are BCAAs, and are important for optimal neonatal health (Zhang 2013). The appropriate BCAA intake for neonates is unclear, however, and remains a very challenging area of study (De Groof 2011). In term infants, insufficient supply of BCAAs from breast milk or formula milk may be caused by poor sucking ability due to perinatal asphyxia, perinatal infection or the relatively small body weight at birth. Even in healthy term neonates, BCAAs from breast milk or formula milk may be inadequate during the first few days of life as they are only able to suck a small amount of milk from the mother's breast (Neville 1988). Similarly, preterm neonates are at higher risk of nutrition deficits due to insufficient nutrient reserves at birth, delayed introduction of enteral milk feeding, and increased energy expenditure based on various complications, including respiratory distress syndrome, patent ductus arteriosus, and infections (Shah 2009). Preterm neonates therefore warrant close investigation as a crucial subgroup. There is, moreover, a paucity of data on the short‐term and long‐term effect of BCAA supplementation for improving clinical outcomes in human neonates.

Description of the intervention

Immediately after birth, administration of breast milk or formula milk is required to ensure an optimal supply of necessary nutrients in newborns. Based on the amino acid constituents of human breast milk, leucine, isoleucine and valine intake requirements for term neonates are defined as 165 mg/kg/day, 95 mg/kg/day and 95 mg/kg/day, respectively (WHO 2007; Zhang 2013). Estimates of amino acid intake requirements in term neonates based on a method involving stable isotopes led to optimum amounts of leucine, isoleucine and valine at 140 mg/kg/day, 105 mg/kg/day and 110 mg/kg/day, respectively (De Groof 2011), which differ from the dosage mentioned above. These recommendations are still insufficient to ensure newborns optimal dosages of BCAAs because breast milk nutrients vary among mothers, depending on the maternal nutritional status, duration of lactation, and geographical locations (Neville 1988; Wurtman 1979; Zhang 2013). For example, some amino acids such as isoleucine are significantly higher in Asia, whereas in North America mothers' breast milk is rich in glutamate (Zhang 2013). Besides, for neonates with chronic disease or a critical condition, enteral feeding requirements may differ (Mager 2006). BCAAs are therefore distinct from other amino acids in that they play a wide variety of key roles in body function: as a result, BCAAs may be added to daily nutrients of neonates who are at risk of BCAA deficits. Nevertheless, as multiple nutrients are required for a balanced nutrition state and body function, past studies did not just assess BCAA supplementation in neonates but a combination of other nutrients. Cochrane Neonatal suggested that compared to no supplementation, protein‐supplemented breast milk administered enterally resulted in statistically significant increases in short‐term outcomes such as weight gain, linear growth and head growth in relatively well preterm infants (Amissah 2018). Higher amino acid administration in preterm infants was found to be associated with improved postnatal growth, a reduction in hyperglycaemia, and an increased risk of abnormal blood urea nitrogen (Osborn 2018).

How the intervention might work

Administration of BCAA supplementation can be performed both parenterally and enterally. The foremost choice, however, is enteral feeding with breast milk whenever possible, otherwise parenteral feeding should be sought. Parenteral administration of necessary nutrients to very preterm neonates (< 32 weeks of gestation) during the initial postnatal period is practised widely in most developed countries (Embleton 2014). In particular, this method is considered a relatively safe way to ensure nutritional intake, especially for neonates with enteral feeding intolerance and necrotising enterocolitis showing gastrointestinal malfunction (Koletzko 2008).

Enteral administration of additional BCAAs to all neonates may provide benefits to decrease associated negative health outcomes especially in those with inadequate intake of recommended dosages. Although evidence of BCAA supplementation effect in human neonates is very limited, the possible beneficial and adverse effects have been suggested in other populations. For example, a systematic review suggested that BCAA supplementation (range 5.5 g/day to 30 g/day) might have a positive effect on the improvement of muscle strength, ascites and oedema in adults with chronic liver disease (Ooi 2018). In contrast, limited evidence showed potential favourable effects of BCAA supplementation on body weight and serum albumin level in paediatric patients with liver dysfunction (Ooi 2018). Another systematic review showed that leucine administration (range 1.2 g/day to 6 g/day) increased lean muscle‐mass content in sarcopaenic elderly individuals (Martinez‐Arnau 2019).

Conversely, excessive BCAA intake may lead to short‐term and long‐term adverse outcomes. For instance, excess ingestion of BCAA can be associated with nausea and fatigue in manic patients (Scarna 2003). Previous research suggests that high plasma concentrations of BCAAs could possibly develop from formula feeding and that might have a negative effect on neonates' carbohydrate and insulin metabolism (De Groof 2011; Jarvenpaa 1982). Interestingly, one meta‐analysis found that higher total BCAA intake could increase the risk of type 2 diabetes (odds ratio (OR) 1.32, 95% confidence interval (CI) 1.14 to 1.53), and could decrease obesity risk (OR 0.62, 95% CI 0.47 to 0.82) in adults (Okekunle 2019). Since diabetes and obesity are associated with increased probability of developing cardiovascular diseases in the long term, including ischaemic heart disease and stroke in adulthood, which are the two leading causes of death worldwide (WHO 2014), it is of utmost importance to examine the long‐term effects of BCAA supplementation on the progression of non‐communicable diseases in newborns. Such risk may even be higher for formula‐fed neonates, who have a higher likelihood of becoming overweight or obese (Koletzko 2009).

Why it is important to do this review

As BCAAs play an indispensable role in key body functions and growth, it is essential to gain a comprehensive understanding of the effect of BCAA supplementation in neonates including optimal dosages, duration of administration, and short‐ and long‐term clinical outcomes. Existing Cochrane Reviews have assessed the impact of additional amino acids on neonatal outcomes, that is glutamine supplementation on preterm neonates' morbidity and mortality (Moe‐Byrne 2016), as well as the effect of taurine supplementation on the growth and development of preterm or low birth weight (LBW) infants (Verner 2007). However, there is currently no synthesised evidence of the effectiveness of BCAA supplementation on positive or adverse outcomes for either term or preterm neonates. Although various nutrients are necessary for neonatal growth and development, BCAAs have distinctive importance considering their diverse body mechanisms beyond just nutritional metabolism (Nie 2018). Further research was therefore required to address this important literature gap in the field of neonatal health.