Indian Pediatr 2019;56: 279-280
For a Change, May the Hare Defeat the
Division of Neonatology, Department of Pediatrics,
Postgraduate Institute of Medical Education and Research (PGIMER),
n this issue of Indian Pediatrics, Modi
and co-workers  have published an interesting open-label randomized
controlled trial in which they compared an early aggressive enteral
feeding strategy with a conservative enteral feeding strategy among
neonates weighing 750-1250 grams at birth, for its effect on all-cause
mortality during hospital stay. The authors initiated and advanced feeds
at 15 or 20 mL/kg/day in the conservative arm; and initiated and
advanced feeds at 30 or 40 mL/kg/day in the aggressive arm. They did not
detect statistically significant differences between the two groups with
respect to all-cause mortality, culture-positive sepsis, survival
without major morbidity, feed intolerance, or average daily weight gain
during hospital stay. However, the aggressive feeding regimen group
reached full feeds significantly earlier than the conservative feeding
This research group had published a somewhat similar
study  on neonates weighing <1250 g at birth, where they had compared
enteral feed advancement rates of 15 mL/kg/day and 30 mL/kg/day, with
the primary outcome being the time taken to achieve full feeds. Like in
their present study, the authors had demonstrated that the fast
advancement group had reached full feeds significantly earlier.
The present study population is a microcosm of India,
because it belonged to a lower middle- to lower social economic class,
which availed healthcare in a public hospital. Fifty-nine percent
participants had fetal growth restriction, 26% were born to mothers with
gestational hypertension, and 22% had absent or reversed end-diastolic
flow. While the need to safely reach full feeds early is felt world
over, it is particularly pressing in low- and middle-income countries
(LMIC) like India, because of the higher risk of nosocomial sepsis with
each extra hour of intravenous cannulation and the lack of parenteral
nutrition facilities in many centers. In LMIC, the risk of sepsis and
growth failure often overrides the competing risk (real or perceived) of
necrotizing enterocolitis (NEC). Sepsis, growth failure and NEC; all
contribute to mortality and/or neuro-developmental impairment.
Modi, et al.  did well to choose a
patient-centric outcome (all-cause mortality before discharge) as the
primary short-term outcome in this study, though it would have been
ideal to have a long-term patient-centric composite outcome such as
survival without neuro-developmental impairment by 18 months. There are
several other similar small clinical trials and meta-analyses, many of
which the authors have referenced in their article. In another study on
extremely low birth weight infants from Cape Town, South Africa, infants
receiving higher initial feed volumes and more rapid advancement had
more rapid weight gain, with no significant differences in the incidence
of NEC, feed intolerance and late-onset sepsis . An updated Cochrane
systematic review has been published after the ones referred to by Modi,
et al. in their article . In this meta-analysis of trials
typically comparing daily increments of 15-20 mL/kg/day versus 30-40 mL/kg/day
in very preterm or very low birth weight (VLBW) infants, there was no
overall effect on the risk of all-cause mortality or NEC, nor was there
any effect on the risk of these outcomes in subgroups of extremely low
birthweight or small for gestational age infants. In the rapid
advancement group, full enteral nutrition was established 1 to 5 days
earlier than the slow advancement group. The GRADE quality of evidence
of this meta-analysis was rated "moderate" because of the unavoidable
lack of blinding.
Modi, et al.  have administered a slightly
higher feed advancement rate (up to 40 mL/kg/day), compared to most
other authors, who have typically restricted the fast advancement to
30-35 mL/kg/day in VLBW infants. There are researchers who have gone a
step further and started full enteral feeds from the outset. Modi, et
al.  have referred to a feasibility study by Sanghvi, et al.
 in which they observed that it was possible to provide exclusive
enteral nutrition to preterm neonates weighing 1200-1500 g from day one,
without providing parenteral nutrition. In another randomized controlled
trial  conducted in Assam on neonates weighing 1000-1500 g, the
authors randomly allocated the neonates to receive either complete
enteral feeding (80 mL/kg/day) with expressed breast milk starting at 1
hour of life versus minimal enteral feeding. The authors found no
statistically significant differences in the incidence of feed
intolerance and NEC; however, time to regain birth weight, duration of
NICU stay and time to reach 180 kcal/kg/day was significantly shorter in
the complete enteral feeding group. Very recently, Nangia, et al.
 published a randomized controlled trial comparing early total
enteral feeding versus conventional feeding in stable infants who
weighed 1000-1500 grams. They too concluded that early total enteral
feeding resulted in earlier attainment of full feeds with a shorter
duration of hospital stay and no difference in the risk of NEC. All this
evidence suggests that it is possible to safely start larger feed
volumes upfront and advance faster than what we have been accustomed to
doing so far.
Modi, et al.  have correctly observed that
their study was underpowered to detect the desired difference in
all-cause mortality and other important outcomes. What is surprising is
that the authors had assumed an 80% mortality in the conservative
feeding strategy group, based on their pilot observation, a figure that
seems rather high in present era. Having assumed such a high mortality,
the authors hypothesized that an aggressive enteral feeding regimen
would reduce the mortality rate by almost one-third, which again seems
too ambitious. The observed mortality of 43% in the control arm also
seems high by today’s standards. The lack of data on the proportion of
usage of preterm formula is another shortcoming in the study.
Authors of a multicenter trial in the UK (the SIFT
trial) have planned to enrol 2800 very preterm or very low birth weight
infants and randomly allocate them to either a faster (30 mL/kg/day) or
slower (18 mL/kg/day) advancement of enteral feeds, with the intention
of comparing short-term morbidity, time to reach full feeds and
neurodevelopmental outcomes at 24 months of corrected age . The SIFT
study has finished recruiting subjects in January 2019, and the
follow-up part of the study is currently in progress. The results of the
UK-based SIFT study will throw light upon long-term outcomes but they
may not be generalizable to India and other developing countries, as the
initial volume and rate are still conservative by Indian standards. An
Indian multicenter trial on VLBW infants, which compares an aggressive
enteral feeding policy (based upon the local published experience of
early complete enteral feeding and/or rapid advancement) versus a
conservative policy, while assuming a more realistic baseline mortality
rate that reflects current-day pooled Indian data, is the need of the
The current study  focuses attention on this
pressing need. In this modern-day race between the hare and the
tortoise, one can only wish that it is the hare that wins.
Funding: None; Competing interest: None
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