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\begin{document}

\title{Commentary on ``Compatibility of rapid enteral feeding advances and
noninvasive ventilation in preterm infants -- an observational study''}



\author[1]{Catherine Buck}%
\author[1]{Sarah Taylor}%
\affil[1]{Yale School of Medicine}%


\vspace{-1em}



  
  \date{June 09, 2024}


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\selectlanguage{english}
\begin{abstract}
Nutritional support is essential in the critical care of the very
preterm infant, however, study of the potential role of nutrition in the
multifactorial pathogenesis of bronchopulmonary dysplasia (BPD) is
limited. Achievement of full enteral feeding faster has not been shown
to be harmful and may be of benefit in extremely preterm infants. This
commentary discusses the studied risk and potential benefits of more
rapid enteral feeding advancement in extremely preterm infants.%
\end{abstract}%



\sloppy


\textbf{Commentary on ``Compatibility of rapid enteral feeding advances
and noninvasive ventilation in preterm infants -- an observational
study''}

Catherine O. Buck, MD and Sarah N. Taylor, MD, MSCR

Yale School of Medicine, Department of Pediatrics

\emph{Corresponding Author:}

Sarah N. Taylor

Yale School of Medicine

Department of Pediatrics

333 Cedar Street

PO Box 208064

New Haven, CT 06520

Sarah.n.taylor@yale.edu

Phone: 203-688-2320

Fax: 203-688-5426

\emph{Funding:}

The authors received no financial support for the research, authorship,
and/or publication of this article.

\emph{Key words:}

extremely preterm infant, enteral feeding, faster feeding advancement

\emph{Running title:}

Benefits of faster feeding advancement in preterm infants

\emph{Abstract}

Nutritional support is essential in the critical care of the very
preterm infant, however, study of the potential role of nutrition in the
multifactorial pathogenesis of bronchopulmonary dysplasia (BPD) is
limited. Achievement of full enteral feeding faster has not been shown
to be harmful and may be of benefit in extremely preterm infants. This
commentary discusses the studied risk and potential benefits of more
rapid enteral feeding advancement in extremely preterm infants.

Attention to nutritional support is essential in the critical care of
the very preterm infant. Both individual nutritional exposures and
overall infant growth relate to infant health and neurodevelopmental
outcomes. Study of the potential role of nutrition in the multifactorial
pathogenesis of bronchopulmonary dysplasia (BPD) is limited. A potential
causal pathway is apparent as nutrition is required for both growth and
repair of the preterm infant lung which is halted at the saccular stage
of development. Observational studies have shown that infants with BPD
have suboptimal growth outcomes compared with preterm infants without
lung disease, both during the neonatal hospitalization and
beyond.(Davidson et al. 1990; Huysman et al. 2003; Vohr et al. 1982;
Wang et al. 2010) The directionality of these associations is not clear.
The study ``Compatibility of rapid enteral feeding advances and
noninvasive ventilation in preterm infants -- an observational study''
by Behnke et al focuses on early enteral feeding and its relation to
respiratory management in extremely low birthweight infants. The study
offers insight into the safety of faster feeding advancement,
specifically with the goal to avoid mechanical ventilation by promoting
the use of non-invasive ventilation in extremely preterm infants.

\textbf{Weighing the risks and benefits of faster feeding in preterm
infants}

Historically, enteral feeding advancement in the very preterm infant has
followed a conservative approach. Some observational studies have
reported an association between faster feeding and risk of both
necrotizing enterocolitis (NEC) and feeding intolerance. These
associations have not been replicated in randomized controlled trials.
The SIFT (Speed of Increasing Milk Feeds Trial) study, published in
2019, is the largest randomized multicenter trial of feeding advancement
in very preterm infants to date.(Dorling et al. 2019) Among infants born
\textless{} 32 weeks gestational age, faster feeding advancement (30
mL/kg/day versus 18 mL/kg/day) was not associated with differences in
survival without moderate or severe neurodevelopmental impairment at age
24 months. While the SIFT study did not specifically evaluate feeding
intolerance, a Cochrane review of 14 randomized trials of fast versus
slow feeding advancement found no significant differences in feeding
intolerance between groups.(Oddie et al. 2021) In that review, and in
the SIFT study, rapid feeding advancement was not associated with NEC,
and more importantly, slower feeding advancement did not prevent NEC or
neonatal mortality.

Achievement of full enteral feeds more rapidly likely equates to less
parenteral nutrition and less central line days.(Fenin et al. 2020)
Central line infections are an important risk factor for morbidity and
mortality in extremely preterm infants.(Stoll et al. 2002) Studies to
date, including the Behnke et al study in this issue, have not shown a
significant decrease in late onset sepsis when full enteral feeds are
achieved more quickly.(Dorling et al. 2019; Modi et al. 2019; Raban et
al. 2016) A recently-updated meta-analysis of 11 trials demonstrated
that slow advancement of feeds was associated with an 14\% increased
risk of invasive infection (RR 1.14, 95\% CI 0.99 to 1.31) in preterm
infants.(Oddie et al. 2021) Late onset sepsis, and more importantly the
inflammation associated with this condition, is associated with the
development of BPD.(Balany and Bhandari 2015; Jung and Lee 2019)
Additional studies are needed to specifically examine the association
between earlier enteral feeding achievement and risk of invasive
infections in preterm infants. To date, faster feed volume advancement
has not be associated with harm and may be associated with benefit.

\textbf{Preterm infant growth and neonatal lung development}

Preterm infants with BPD have slower growth compared with infants
without BPD. This may relate to difficulties with nutrient delivery or
with medical therapies, such as the use of steroids or diuretics.
Nutrient delivery in and of itself is associated with improved pulmonary
outcomes.(Wadhawan et al. 2007; Wemhoner et al. 2011) Previous studies
have shown that higher energy and caloric intakes in the first postnatal
weeks and avoidance of fluid overload are associated with decreased risk
of BPD in very preterm infants.(Klevebro et al. 2019; Oh et al. 2005)
Additionally, slower weight gain trajectories through 36-weeks corrected
gestational age have been associated with an increased incidence of the
diagnosis of BPD.(Ehrenkranz et al. 2011; Malikiwi et al. 2019)

Behnke et al found that more rapid feeding advancements (20-30 mL/kg/day
versus 10-15 mL/kg/day) were associated with improved growth parameters
at 36 weeks corrected gestational age, including among infants born
small-for-gestational age. These results differ from randomized trials
of fast versus slow feeding advancement which have not found more rapid
feeding advancement to be associated with improved growth
parameters.(Oddie et al. 2021) While infant growth was not the primary
outcome of these studies, inconsistencies in findings related to growth
may relate to the timing of the feeding intervention.

\textbf{Early feed initiation for very preterm infants}

The SIFT study began enteral feeding on day 4, after which full enteral
feeds were reached over an average of 7 days in the fast group and 11
days in the slow group.(Dorling et al. 2019) Behnke et al began enteral
feeds on the first day. Traditionally, neonatal enteral nutrition has
been guided by a ``fear of feeding''. Since enteral nutrition is a risk
factor for NEC, the historical clinical approach was to ensure each day
that a preterm infant was ``safe'' to be fed. However, this practice
leads to periods with no enteral intake which differs from the fetal
experience in which the gut is continuously exposed to amniotic fluid.
This lack of amniotic fluid for the preterm infant impacts gut and
immunoregulatory development, and this injury is at least partially
ameliorated by feeding human milk bioactives. The potential harm of not
feeding preterm infants in the first postnatal days suggests neonatal
care should consider a move from a ``fear of feeding'' to a ``fear of
not feeding'', and this evolution is supported by the feed tolerance
exhibited in the Behnke et al study and others.(Hamilton et al. 2014)
Longer duration of parenteral nutrition has also been associated with
altered body composition at term corrected age. (Alja'nini et al. 2021)
Regardless of the route of nutrient delivery in the early postnatal
days, adequate and balanced early nutritional support is key avoid
nutrient deficiencies and optimize neurodevelopmental outcomes.

\textbf{Nutritional therapies and BPD}

If early and rapid advancement of enteral nutrition relates to a
decrease in BPD, what might be the critical nutrient exposure? In a
systematic review, Huang et al demonstrated that exclusive and partial
human milk diets were associated with lower risk of BPD in preterm
infants.(Huang et al. 2019) Patel et al also demonstrated that each 10\%
increase in mother's own milk dose was associated with a decreased risk
of BPD at 36-week corrected age.(Patel et al. 2017) In the Behnke et al
study, in which feedings were initiated on the first postnatal day with
standard preterm formula and maternal milk as available, it would be
interesting to know the proportion of feeds which were maternal milk.

The specific components of human milk which may protect and/or support
lung development include long chain polyunsaturated fatty acids
(LC-PUFAs), which promote cell membrane function and surfactant
production. Additionally, LC-PUFAs have anti-inflammatory properties,
which may have benefits in the repair of neonatal lung injury. Postnatal
docosahexaenoic acid (DHA) concentrations were inversely associated with
BPD risk in one observational study of infants born \textless{} 30 weeks
gestational age.(Martin et al. 2011) Randomized trials of maternal and
preterm infant DHA and arachidonic acid supplementation are ongoing.
(Wendel et al. 2021) Studies specifically examining the role of PUFAs in
reducing risk of lung disease in extremely preterm infants are needed.

Vitamins such as vitamin A, or retinoic acid, and vitamin D also have
roles in respiratory outcomes.(Onwuneme et al. 2015; Tyson et al. 1999)
Intramuscular injections of vitamin A related to a 7\% reduction in BPD
or death in a clinical trial, but similar benefit is not yet shown with
enteral supplementation.(Tyson et al. 1999) Further investigation is
needed to identify the specific paths by which enteral nutrients may
mitigate BPD progression.

\textbf{Feeding tolerance with non-invasive ventilation}

Although the Behnke et al study raises interesting hypotheses as to how
achievement of enteral nutrition may relate to BPD, as described by the
authors, the most impactful result of this study is the tolerance of
enteral nutrition and greater growth trajectory in a very preterm infant
population in which 75\% received non-invasive ventilation. As a
single-site study, and with large neonatal practice variation in
site-specific diagnosis of feeding intolerance, support from further
observational studies or clinical trials will strengthen the authors'
conclusion. This study calls into question the practice of limiting
enteral nutrition advancement in infants receiving non-invasive
respiratory support.

\textbf{Conclusion}

While research continues to work toward determining the best therapies
for the prevention of BPD in extremely preterm infants, it remains clear
that early and adequate nutritional support in the first postnatal weeks
is critical to improve long-term outcomes and prevent harmful neonatal
morbidities. As neonatal medicine works toward improving outcomes in the
most premature infants, a multifaceted approach to the prevention and
treatment of pulmonary outcomes is warranted. In addition to the
investigation of the right ventilatory approach to limit injury and
oxidative stress to the preterm lung, research strategies which evaluate
the role of nutritional treatments aimed to prevent BPD are critical to
improving outcomes in extremely preterm infants.

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