Randomized controlled trial on Effect of early initiation of breast milk fortification on growth in preterm neonates.

Evidence indicates mother’s own milk is the best feeding source for premature infants because it is associated with both short- and longer-term health benefits. Human milk is especially beneficial for preterm infants because of its protective role on several comorbidities like NEC.

However nutritional requirements of preterm infants cannot be met with exclusive breast milk alone because the requirement of protein, energy, micronutrients, minerals etc are more when compare to healthy term new born. For the same reason we need to do “fortification of breast milk. Human breast milk alone does not satisfy the high nutritional requirement of VLBW, babies so fortification of both mother’s milk and donor human milk (DHM) is recommended to prevent extra uterine growth retardation and the associated poor neurodevelopmental outcome

However there are no univerdal recommendation or standard guidelines available for the timing of intiation of fortification of breast milk. According to current National neonatology Forum guidelines “multi nutrient fortification of breast milk can be begin in preterm LBW infants with birth weight <1800gm and receiving enteral feeds of at least 50-80 mL/kg/day”. (21)

“Latest ESPHGN guidelines of 2022, on feeding of low birth infants and fortification of breast recommends the use of multi-component fortifier products to enhance the nutrient Content of human milk and to promote growth in preterm infants and also recommends to start fortification once the enteral intakes reach 40 – 100 ml/kg/day

In our unit Currently preterm neonates are initiated on fortification of human milk if the growth remains inadequate inspite of adequate volume of milk intake, decided by the individual neonatologist. During this period, preterm neonates incur significant growth retardation which is difficult to catch up later.

Hence we would like to initiate the fortification early in neonates < 1250 grams neonates to prevent growth retardation as compared to clinician led timing of fortification which is delayed very frequently.

We shall be screening all neonates, weighing less than 1250 grams, admitted consecutively in the neonatal unit PGIMER and will be enrolled after meeting inclusion and exclusion criteria. For the calculation of gestational age, it will assigned as per LMP and postnatally will be confirmed by using New Ballard scoring (Annexure 4). By using Intergrowth -21 we will allocate the new born as SGA/AGA (Annexure 6) and  SES will be assessed by Modified Kuppuswamy SES scale (Annexure 5)Parental or guardian consent will be obtained after explaining the need for the study ( parent information sheet , annexure nos ) and wriiten PIS will be provided in local languages. , CTRI registration will be carried out as per guidelines. The study will be done in accordance with CONSORT standards (29)

Randomization : When the neonate reaches a feed volume of 150 ml/kg/day of expressed breast milk, neonate will be randomized to get either fortification with human milk fortifier (group A) or they will be initiated on HMF based on clinician’s decision (group B) as per unit’s criteria. Random numbers will be computer generated and placed in sealed, opaque envelopes

Outcome measures

1. Primary outcomes

i. Growth during hospital stay (weight as weekly in gm/kg/day. Length as cm/week, HC as cm/week, after enrolment)

ii. Growth at discharge or at 36 weeks PMA whichever is earlier

As measured by - weight, length and Head circumference

2. Secondary outcomes

i. Feed intolerance after starting fortification in fortification group and in control group (at similar feed volume)

ii. Osteopenia of prematurity at 4 weeks of life and at discharge (assessed by serum Ca, phosphate and alkaline phosphatase)

Study end point

36 weeks PMA or discharge whichever is earlier

approximately 100 cases will be enrolled (50 in each group).

STATISTICAL METHODS:

The statistical analysis will be performed using Statistical Package for Social Sciences (SPSS Inc., Chicago, IL version 25 for windows).

·                 Anthropometric data will be presented as continuous variables. - weight, length and OFC.

·                 Categorical data on feed intolerance, osteopenia of prematurity , various other morbidities will be  presented as n and %

·                 Incidence: The incidence of anemia and vitamin D deficiency and acute diarrheal illness will be expressed as proportion of total.

·                 Comparison: between the early fortification and control groups (clinician decision based) will be done by independent t test. And categorical variables as chi-square test. Skewed continuous data will be analyzed using non parametric tests like Mann Whitney test.

·                 Multiple logistic regression will be used to find out the predictors of poor growth outcome at discharge.

·                 An intention to treat analysis will be done.