Early versus delayed fortification of human milk in Preterm Neonates-A Randomized Controlled Trial

Preterm birth places the infant at risk of nutritional emergency and results in interruption of growth. It is a challenge to sustain in-utero growth velocity in preterm infants due to difficulty in maintaining adequate protein‒energy supplementation and due to their catabolic state secondary to postnatal illnesses such as sepsis, necrotising enterocolitis (NEC), chronic lung disease, need for assisted ventilation, and exposure to postnatal steroids.

 Preterm infants are often deprived of in-utero nutrient accretion. This in-utero deprivation with additional nutrient deficit in postnatal life often results in postnatal growth failure.  The rate of extrauterine growth restriction (EUGR) at discharge is unacceptably high, ranging from 23% in infants born at 34 weeks’ gestation to 71% in those born at 23 weeks’ gestation.

Growth failure can continue even after discharge and has been associated with both short and long-term consequences including stunting, neurodevelopmental impairment, and early onset of adult diseases such as hypertension, diabetes, obesity, and hypercholesterolaemia.

 Early aggressive nutrition is the norm in the management of preterm infants. Total parenteral nutrition being quiet demanding in terms of logistic required and on contrary, each day without enteral nutrition increases the likelihood of EUGR. Human milk (HM) is the best enteral food for preterm infants. However, unfortified human milk may not provide adequate protein to support growth and lean body mass accretion in very low birth weight infants.

Hence, enteral feeds should be started early, and full enteral feeds should be achieved as soon as possible. However, the composition of human milk varies throughout the course of lactation, and the unfortified human milk does not provide sufficient amounts of protein, calcium, and phosphorus necessary to achieve adequate growth of preterm infants8,9leading to metabolic complications such as hypoproteinemia and osteopenia.

 On average, unfortified human milk provides 67 kcal and 1.1 g protein per 100 mL, while human milk with human milk fortifier (HMF) provides 80 kcal and 2 g protein per 100 mL. A recent Cochrane meta‐analysis showed that fortification of human milk with multi‐component HMF improved in‐hospital growth rates; however, there was no significant difference in other major clinical outcomes. However, there is no consensus on timing to introduce HMF in enterally fed preterm infants attributed to a ‘lack of evidence and a strong local tradition’.13As common practice most clinicians prefer adding HMF once the infant is on full enteral feeds generally defined as 150 ml/kg/day. Many units have preferred adding HMF at smaller feed volumes for the potential growth benefit to neonates. However, there are concerns relating to feed intolerance and increased hospital stay on adding early HMF in view of exposing an immature gut to high osmolarity.

Various eminent organisations including the European Milk Bank Association (EMBA) Working group and National Neonatology Forum India, 2022 guidelines have recommended the addition of HMF for preterm neonates with birth weight <1800g to as early as the feed volume of 50-80 ml/kg/day.

Extremely low birth weight (ELBW) infants take 16 ± 7 days to regain birth weight16. The first 2 postnatal weeks delineate a critical period for growth and development and provide an opportunity to prevent energy and protein deficits along with fat-free mass (FFM) accretion in critically ill preterm neonates..Adding the HMF in the enteral feeds early could mitigate this gap of protein and energy deficit and can avoid the consequences associated with poor postnatal growth, which may also have adverse neurodevelopment outcomes. However, this benefit needs to be balanced against the risk associated with exposing the immature gut to the high osmolarity of fortified feeds that in turn, increases the risk of feed intolerance and Necrotising enterocolitis (NEC).

Hence the randomised controlled trial is planned to assess the safety and effects on growth of early fortification of human milk versus late fortification in preterm infants.