Early total enteral feeding versus standard feeding practice in stable very low birth weight infants- A randomized controlled non-inferiority trial

Introduction-

Extra Uterine Growth Restriction (EUGR) is a condition that results in inadequate growth in a preterm infant that occurs during hospitalization. It is influenced by a number of factors such as impaired nutrition accretion, poor intestinal maturity, increased rate of infection, prolonged parenteral nutrition and delayed initiation of enteral feeding. In a study by Kim et al ,the incidence of EUGR in weight and length at discharge was found to be 28% and 34% respectively among preterm infants born at 23-34 weeks gestation. According to birthweight stratification, <1000g, 1000 to 1499g and >/=1500g birthweight infants showed EUGR rates of 65.9%, 43.4% and 23.8% respectively. (Lian Wang et al). Similar finding have been reported in very low birth weight (VLBW) neonates with incidences varying from 51-86%.(86% Gidi 2020, 51% Aloy 2020, 74% Peila 2020, 59% Radmacher 2003). Current definitions for EUGR are varied and can be classified as cross-sectional (weight at a given t-time <10th centile) or longitudinal (weight loss between birth and a given t-time >1SD), with no evidence for which definition is superior.  EUGR is a medical problem which influences the neurodevelopmental outcomes of ELBW neonates, with long-term health consequences into childhood and adulthood.( Ehrenkranz et al).

Factors that are associated with EUGR include prematurity, intrauterine growth restriction, necrotizing enterocolitis, bronchopulmonary dysplasia, anemia and others. For achieving optimal growth and weight gain in preterm infants, best-suggested practices include early enteral feeding with Mother’s own milk (MOM) as the first choice. Other practices include total parenteral nutrition, and human milk fortification. One of the recent practices for the prevention of EUGR included early total enteral feeding (ETEF).

In utero, the fetus swallows around 250 ml/kg per day of amniotic fluid, contributing 10–14% of fetal nutritional needs. This indicates clearly that the gastrointestinal tract of preterm infants can handle a significantly higher volume than what neonatologists feed these infants in the first few days of life .  Furthermore, osmolarity of human milk (290–300 mOsm/L) is just slightly higher than amniotic fluid (250–260 mOsm/L). Availability of donor human milk has made it possible to feed early preterm infants larger human milk volume until mother’s milk supply is sufficient. (Belal et al)

In current clinical practice, Stable low birth weight infants with gestational age 32-34 weeks and birth weight > 1250 g: ETEF with expressed breast milk (EBM) preferably or pasteurized donor human milk under careful monitoring is started. In case of non-availability of human milk, preterm formula is considered. However in stable LBW infants with less than 1250g partial parenteral nutrition soon after birth with minimal enteral feeds 10-15 ml/kg/day is started and then feed advanced by 20 ml/kg/day until full feeds of 150ml/kg/day are reached.

Uncertainty exists about ETEF in stable preterm infants with a birthweight between 1000-1250g. Implementation of ETEF is not without practical challenges. Concerns of necrotizing enterocolitis, feed intolerance and sepsis from early introduction of impose serious challenges to implement of ETEF  especially in resource limited settings.

Currently, 4 Randomized Controlled Trials have studied the effects of ETEF in premature infants born at gestation 28-32  weeks or birth weight 1000-1500g. Although these studies have not reported an improvement in short-term growth parameters, they have shown that ETEF  approach led to decreased time to regain birth weight, time to reach full feeds and decreased feed intolerance. All studies have shown that ETEF was well tolerated and did not increase the incidence of NEC suggesting the feasibility of this approach in infants 28-32 weeks and/or 1000-1500.g. However these studies had small sample sizes and there was use of preterm formula in addition to EBM or MOM. Hence, ETEF in 28-32 weeks and/or 1000-1500.g will require further validation and testing in future RCTs. None of these trials has considered EUGR as the primary objective and has not been studied.

A recent systematic review of ETEF in stable preterm infants  (<34 weeks of gestation) ETEF appeared to be safe and feasible in stable VLBW infants with birthweight 1000-1200g. However large RCT was needed to confirm the benefits.

Hence, we chose to conduct an RCT to assess the effect of ETEF in reducing EUGR prevalance in stable VLBW infants at 28-32 weeks and/or 1000-1250 g.

Aim- To evaluate effects of ETEF among stable VLBW infants at 28-32 weeks and/or 1000-1250 g.

Objective:

Primary objective:

To compare the rate of extrauterine growth restriction among stable VLBW infants at 28-32 weeks and/or 1000-1250g on ETEF.

Secondary objective:

1.Cumulative gain in weight during NICU stay (change in Z score)

2.Cumulative gain in length (cm/week) during NICU stay

3.Cumulative gain in head circumference(cm/week)

4.All-cause mortality

5.Total duration of hospital stay

6.Time to reach enteral feeds of 150ml/kg/day

7.Time to regain birth weight

8.Weekly enteral feed intake

11.Number of days of feed was interrupted

12.Neonatal morbidities-

      (A)Intra ventricular hemorrhage (Grade 3 or more) according to Papile’s classification

      (B)Patent Ductus Arteriosus requiring treatment,

      (C) Apnea requiring IPPV,

      (D) Hypoglycemia,

      (E) Early/Late onset sepsis (Blood and/or CSF culture positive within 72 hrs of age/>72 hours of age),

      (F) Necrotising Enterocolitis (stage 2 or higher as per Modified Bell’s staging),

      (G)Retinopathy of prematurity requiring intervention (laser or anti VEGF),

      (H)Bronchopulmonary dysplasia (according to Jensen’s criteria which defined bronchopulmonary dysplasia according to treatment with the following support at 36 weeks post menstrual age , regardless of prior or current oxygen therapy :

no bronchopulmonary dysplasia, no support;

Grade 1: nasal cannula

Grade 2: nasal cannula >2L/min or non invasive positive airway pressure;

Grade 3: Invasive mechanical ventilation )

      (I)Periventricular Leukomalacia

      (J) Duration of Mechanical Ventilation

      (K)Anemia of prematurity (Any Hemoglobin value of <10g/dl at 4 weeks of age in our study population)

       (L)Metabolic Bone Disease

Design- Open labelled, parallel-group non inferiority Randomized controlled trial with a 1:1 allocation ratio.

Setting- Level 3 NICU KEM hospital in Mumbai(Maharashtra).

Time period- From the day of approval from IEC a study duration of two years will be required to complete the recruitment.

Inclusion criteria:

Inborn infants 28-32 weeks and/or 1000-1250 g :

(A)Appropriate for Gestational Age (infants with birth weight >= 10th centile for gestational age on modified Fenton’s growth chart).

(B) Small for Gestational Age (infants with birth weight <10th centile for gestational age on modified Fenton’s growth chart) without any Doppler abnormalities.

Exclusion criteria:

1. Infants with serious congenital anomalies that are incompatible with life

2. Infants requiring major gastrointestinal surgeries in the first week of life.

3. Outborn infants admitted to the unit after initiation of feeds.

4. Infants with significant antenatal Doppler abnormalities.

5. Infants requiring resuscitation in the form of positive pressure ventilation/ intubation or medication.

6. Infants on invasive mechanical ventilation

7. Infants on non invasive mechanical ventilation with fio2 requirement more than 30% or CPAP more than 6

8. Infants on inotropic support

Sample size:

In our unit, the prevalence of EUGR in Inborn infants 28-32 weeks and/or 1000-1250 g. is 80%.  To reduce it to 60% with 95% confidence interval, power of 90% and a two-sided alpha of 5 % and non-inferiority margin of 5% the total is 110 with 55 neonates in each arm.

INTERVENTION TO BE DONE-

Randomization: Random sequences for this study will be computer generated by a statistician who will not be involved in the study. Variable permuted block randomization will be applied using block sizes of 2,4,6.

Allocation concealment: will be done using sequentially numbered sealed opaque envelopes.

At the time of feed initiation, the parents of eligible infants will be approached for consent to participate in the study. After informed consent, the sealed envelopes will be opened by the milk bank nurse, who will initiate the infants according to the group assignment.

Blinding: Blinding of the intervention from primary care providers is not feasible due to the study design. The data assessor and statistician will be blinded to the intervention.

Feed interruptions:

Feeds will be stopped (for atleast 24 hours or until resolution of the signs) in presence of 1 major or 2 minor criteria suggestive of feeding concerns. The criteria are as follows: -

Major criteria:

1) Haemorrhagic or dark green gastric aspirate

2) Hemodynamic instability (shock, hypotension requiring inotropes or >20% increase in respiratory support)

3) Presence of blood in stools.

Minor criteria:

1) Abdominal distension with increase in abdominal girth by 2cm at umbilicus level.

2) Abdominal discolouration

3) Altered vomitus

4) Significant apnea (3 or more requiring tactile stimulation OR 1 episode requiring IPPV over a 1-hour time period).

Feeding may be continued at 50% of the maximal achieved feeding in the presence of 1 minor criteria. Increased gastric residuals (aspirates greater than 50% of the preceding feed volume) in the absence of the a forementioned criteria for feeding concerns, will not be an indication to withhold feeds.

Presence of umbilical arterial line, switching over to invasive ventilation will not be contraindications to initiate or advance feeds.

Restarting feeding following feeding interruptions:

If feeding is interrupted before the achievement of full feeds, feeding will be restarted as assigned per study. If there is occurrence of feed intolerance again after restarting the feeds both groups will be managed as per standard unit protocol.

 If feeding is interrupted after achieving full feeds, feeding will be restarted at 150 ml/kg/day in both groups if cause of feed intolerance is unrelated to GI pathology. Rate of feed advancement will be at clinician’s discretion.

Feeding strategies:

In the control arm : Within 24 hours of life,  feeds would be initiated with 20ml/kg/day of human milk and will continue for a duration of 12-24 hrs. Advancement of feeds would be done at 20 ml/kg/day. Achievement of 150ml/kg/day of enteral feeds would be considered as full enteral feeds.

Parenteral nutrition will be administered to these infants as per standard protocols. Total fluid intake on day 1 will be targeted at 80ml/kg/day (including fluid and feeds) and increased by 20ml/kg every day to a maximum of 150ml/kg/day.

In the intervention arm:  Within 24 hours of life,, full total enteral feeds would be initiated with 80ml /kg/day of human milk and will be advancement at 20ml /kg/day. Achievement of 150ml/kg/day of enteral feeds would be considered as full enteral feeds.

Choice of milk and fortification :

All study infants would be exclusively provided human milk till 33 weeks postmenstrual age. Mother’s own milk (MOM) will be the first choice of feeding in these babies. If MOM is unavailable or insufficient, Pasteurized donor human milk(PDHM) from a human milk bank will be provided after taking parental consent.

Human milk fortifiers such as Lactodex (Raptakos, Brett and Co Ltd, Mumbai) and Hijam (Siroy Life Sciences, Delhi) will be introduced at 100 ml/kg/day of human milk feeds, and continued till discharge

Nutritional supplements:

Caffeine, iron, calcium and vitamin supplementation will be provided per standard recommendations for premature infants.

Unit protocol for discharge would be followed which includes: Infant weight 1.3kg, Postmenstrual age 34 weeks, with an infant on room air and on full oral feeds.

Maternal demographic details, maternal medical and obstetrical complications, and antenatal ultrasound/ Doppler reports will be collected. Details of birth events such as mode of delivery, delayed cord clamping and need of resuscitation will be noted. Gestational age will be determined from the last menstrual period and first trimester ultrasound (if available). In case of unreliability of dates, irregular cycles, or discrepancy of >2 weeks between the two methods, the first trimester scan will be taken for gestational age assignment.

The neonates will be assessed at birth for anthropometry such as weight, length, and head circumference (occipitofrontal circumference). Weight (without clothes/ diapers) will be measured in the delivery room using an electronic weighing scale with a sensitivity of 10 grams. The scale will be calibrated daily. Weight will be recorded in the similar manner in NICU on a daily basis. Weight changes (g/kg/day) will be calculated weekly till discharge. The nadir of weight and time taken to return to birth weight will also be noted. A Harpenden infantometer with a sensitivity of 5 millimeters will be used for the measurement of recumbent length. Head circumference will be assessed using a non-stretchable plastic tape with an accuracy of 1 millimeter. Length and head circumference will be measured weekly. Measurements of weight and head circumference will be classified based on Modified Fenton charts into 6 categories: 1 (<3rd percentile), 2 (3rd- 10th percentile), 3 (10th- 50th percentile), 4 (50th-90th percentile), 5 (90th- 97th percentile), and 6 (>97th percentile). Head circumference percentile at return to birth weight will also be recorded.

Nutritional data including energy (kcal/kg/d) and protein intake (g/kg/d) from parenteral and enteral sources will be calculated daily, and weekly average will be determined. Number of days on total parenteral nutrition, day of life (DOL) of initiation of enteral feeding, and DOL on which neonate reached 150ml/kg/day (full feeds) will be documented. Neonatal morbidities such as respiratory distress syndrome (RDS), need of surfactant, hemodynamically significant patent ductus arteriosus (PDA), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), sepsis, and the duration of mechanical ventilation will also be documented.

EUGR (defined as weight below the 10th percentile on sex-specific Modified Fenton chart) will be assessed cross sectionally at discharge. Longitudinal assessment of EUGR (reduction in z- score by >1SD compared to birth weight) will be assessed at DOL 14, 21, 28 and at discharge. For each infant in the study population, the z-score for the anthropometric parameter will be calculated electronically according to Fenton 2013 from software accessed from http://www.ucalgary.ca/fenton/2013chart.10

Statistical analysis: Data will be entered in MS Excel and analysed using SPSS software version 23. Categorical variables will be represented as percentages while continuous variables will be depicted as mean (standard deviation) and median (range). An independent t-test will be used for continuous data and chi-square and Fischer exact test for categorical data. A p value of <0.05 will be considered statistically significant.

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