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Available online at

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www.sciencedirect.com

Review article

Parenteral nutrition for preterm infants: Issues and strategy

D. Darmaun a,*, A. Lapillonne b, U. Simeoni c, J.-C. Picaud d, J.-C. Rozé a, E. Saliba e,
A. Bocquet f, J.-P. Chouraqui g, C. Dupont b, F. Feillet h, M.-L. Frelut i, J.-P. Girardet j, D. Turck k,
A. Briend l, Committee on Nutrition of the French Society of Pediatrics (CNSFP), and
French Society of Neonatology (SFN)
a
Université Nantes-Atlantique, 44300 Nantes, France
b
Université Paris Descartes, 75006 Paris, France
c
Université de Lausanne, CHUV, 1011 Lausanne, Suisse
d
Université Claude-Bernard-Lyon 1, 69008 Lyon, France
e
Université François-Rabelais, 37000 Tours, France
f
Université de Franche-Comté, 25000 Besançon, France
g
Université Joseph-Fourier, 38000 Grenoble, France
h
Université de Lorraine, 54000 Nancy, France
i
Université Paris-Sud, CHU de Bicêtre, 94270 Le Kremlin-Bicêtre, France
j
Université Pierre et Marie Curie-Paris 6, 75005 Paris, France
k
Université Lille 2, LIRIC-Inserm U995, 59037 Lille, France
l
Institut de recherche pour le développement, 13572 Marseille, France

A R T I C L E I N F O A B S T R A C T

Article history: Due to transient gut immaturity, most very preterm infants receive parenteral nutrition (PN) in the first
Received 18 November 2017 few weeks of life. Yet providing enough protein and energy to sustain optimal growth in such infants
Accepted 18 February 2018 remains a challenge. Extrauterine growth restriction is frequently observed in very preterm infants at the
Available online xxx
time of discharge from hospital, and has been found to be associated with later impaired
neurodevelopment. A few recent randomized trials suggest that intensified PN can improve early
Keywords: growth; whether or not such early PN improves long-term neurological outcome is still unclear. Several
Neonatology
other questions regarding what is optimal PN for very preterm infants remain unanswered. Amino acid
Extrauterine growth restriction
Intravenous nutrition
mixtures designed for infants contain large amounts of branched-chain amino acids and taurine, but
Nutritional imprinting there is no consensus on the need for some nonessential amino acids such as glutamine, arginine, and
cysteine. Whether excess growth in the first few weeks of life, at a time when very preterm infants
receive PN, has an imprinting effect, increasing the risk of metabolic or vascular disease at adulthood
continues to be debated. Even though uncertainty remains regarding the long-term effect of early PN, it
appears reasonable to propose intensified initial PN. The aim of the current position paper is to review
the evidence supporting such a strategy with regards to the early phase of nutrition, which is mainly
covered by parenteral nutrition. More randomized trials are, however, needed to further support this
type of approach and to demonstrate that this strategy improves short- and long-term outcome.
C 2018 Elsevier Masson SAS. All rights reserved.

1. What is at stake?
The incidence of preterm birth is on the rise: 7% of live births in
France [1] and 11% worldwide [2] occur before the 37th week of
gestation. Very preterm infants are defined by birth before the 32nd
week, extremely preterm infants by birth before the 28th week.
* Corresponding author.
E-mail address: ddarmaun@chu-nantes.fr (D. Darmaun).
Using birth weight instead of prematurity for defining nutritional
strategies is likely inadequate since three different trajectories can
result in low birth weight (LBW): (a) growth deceleration in utero
(intrauterine growth restriction, IUGR), (b) steady growth in utero
below normal range, or (c) preterm birth with a weight appropriate
for gestational age (AGA). The term ‘‘small for gestational age’’
(SGA) refers to the first two settings [3], and it should be borne in
mind that preterm infants can be born SGA as well. This paper only
addresses parenteral nutrition (PN) in preterm infants stricto sensu

https://doi.org/10.1016/j.arcped.2018.02.005
0929-693X/ C 2018 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Darmaun D, et al. Parenteral nutrition for preterm infants: Issues and strategy. Archives de Pédiatrie
(2018), https://doi.org/10.1016/j.arcped.2018.02.005
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since PN is rarely indicated in low-birth-weight infants born full
term and since nutritional requirements and metabolism differ
between preterm and LBW term infants.
1.1. Preterm nutrition, a challenge for neonatologists
Thanks to progress in neonatal intensive care, more than 90% of
very preterm infants survive the neonatal period [4], so that
nutrition has become a key determinant for their future health
outcome. In utero, bathed in a nearly sterile, isothermal, and
oxygen-poor milieu, the fetus receives continuous intravenous
feeding through the umbilical vein. Expelled at birth from this
cocoon, the premature infant confronts a cold environment that is
high in bacteria and oxygen. Its nutritional supply is cut off, its
nutrient stores scarce, and its needs are tremendous if this infant is
to triple its weight in 3 months as a normal fetus does over the
third trimester of gestation.
Due to gut immaturity during the first postnatal week(s),
feeding through the gastrointestinal route is at first insufficient to
cover such needs: intravenous nutrition (PN) is required during the
first few weeks. Despite a more rapid daily increase of feeds, full
enteral feeding was only achieved around the 22nd day of life in a
cohort of preterm infants weighing less than 1000 g [5]. PN takes
over from the maternal–fetal nutrient supply delivered via the
placenta, but is far from approaching the complex composition of
umbilical blood (e.g., regarding lactate, growth factors, etc.) and
should not necessarily mimic the fetal supply of nutrients in view
of the dramatic changes in metabolism occurring after birth. PN
may result in severe complications (e.g., sepsis, cholestasis,
thrombosis) and often falls short of covering needs. Lack of fine
tuning of the parenteral nutrient supply, combined with failure or
delay to provide adequate enteral nutrition often result in
extrauterine growth restriction (EUGR). Despite improvement in
nutritional care, EUGR remains common in premature infants. For
example, it was observed in 75% of very preterm infants in the early
2000s [6], and still concerns half of the very preterm infants in the
most recent studies [7,8]. EUGR may be, at least partly, preventable
in infants devoid of severe morbidities such as severe necrotizing
enterocolitis, by optimizing PN from birth onwards [9–13]. More-
over, suboptimal nutrition in the first few weeks of life was shown
to be associated with a higher risk of nosocomial infection,
necrotizing enterocolitis, and hospital admission [14].
1.2. Premature birth and the risk of suboptimal growth and
neurodevelopment
Premature birth is a well-known risk factor for suboptimal
neurodevelopment. At 8 years of age in the EPIPAGE 1 cohort, 77% of
infants born very preterm attended a classroom corresponding to
their postnatal age, 5% were in special classes, and 18% had repeated
a class (vs. 95, 1, and 5%, respectively, for children born full term)
[15]. In a landmark study, Ehrenkranz et al. showed that
neurodevelopment correlates with the initial growth rate: 600 very
preterm infants weighing between 500 and 1000 g at birth were
ranked in four growth rate quartiles during the hospital stay. Infants
in the 1st quartile gained an average of 12 g/kg/day vs. 21 g/kg/day
for those in the 4th quartile. At 18–22 months of age, the prevalence
of cerebral palsy was 21% in children in the 1st quartile vs. 6% in the
4th quartile [14]. This difference persisted after adjusting for
confounding variables affecting neurological outcome.
Many studies confirmed this observation. In the EPIPAGE
1 study, deficient postnatal growth was found to be associated
with poor neurologic outcome for both AGA and SGA preterm
infants. Specifically, risk of cerebral palsy was greater for those
born AGA and who lost more than 1 SD between birth and
6 months of age compared to those who grew adequately (aOR
Please cite this article in press as: Darmaun D, et al. Parenteral nutrition for preterm infants: Issues and strategy. Archives de Pédiatrie
(2018), https://doi.org/10.1016/j.arcped.2018.02.005
2.26 [95% CI, 1.37–3.72]) [16]. Interestingly, regardless of the
postnatal growth trajectory, SGA infants showed more frequent
behavioral problems and cognitive deficit at 5 years of age. The
association of slow growth in the first few weeks of life with poor
neurodevelopment is more pronounced in boys. In a cohort of
1221 boys and 1056 girls born preterm, the odds ratio for
suboptimal neurodevelopment at 2 years of age was 3.2 for boys
who experienced EUGR vs. those who did not, and the risk was 1.8
(95% CI, 0.7–4.2) and 0.95 (95% CI, 0.4–1.9), respectively, in girls
[17]. Most studies in the field, however, are observational. As such,
they cannot prove a causal relationship: premature infants who
grew slowly most likely were frailer or more severely ill, which
could have led to the prescription of less optimal nutrition during
their hospital stay.
1.3. Nutritional imprinting
The concept of nutritional imprinting emerged in the 1990s
when David Barker showed that infants born with a low birth
weight are exposed to a higher risk of developing obesity, type
2 diabetes, hypertension, high cholesterol, and coronary disease in
adulthood [18,19]. The first cohorts included children born SGA in
the 1900s, who were mostly term infants. More recent work shows
that adults born preterm are exposed to increased risk of
hypertension and insulin resistance in the long run [20–22]. In a
meta-analysis of 27 studies, collecting more than 17,000 adults born
preterm, LDL cholesterol and blood pressure were 0.14 mmol/L (95%
CI, 0.05–0.21) and 4.2 mmHg (95% CI, 2.8–5.7) higher for LDL and
blood pressure, respectively, in adults born preterm than in those
born full term [23]. Such differences, albeit small, are associated
with increased cardiovascular risk on a population scale. In contrast,
no significant difference was observed regarding corpulence, blood
glucose, or fasting serum insulin [23] nor insulin resistance [24].
Whether or not early markers of risk of hypertension and
insulin resistance can be found during childhood remains a matter
of debate. In a British cohort of 209 adults born preterm, the
growth rate in the upper quartile during the first 2 weeks of life
was associated with reduced flow-mediated arterial dilation at
adulthood [25]. In a French cohort, preterm birth was associated
with elevation of systolic blood pressure and arterial stiffness
(assessed by pulse wave velocity) at adulthood [26], but in another
study conducted earlier at 6 years of age, no such association was
found [27]. Factors other than nutrition obviously play a role as
well. Preterm babies undergo significant stress and stress-related
hormones may also play a major role in these outcomes.
1.4. Risk of disease at adulthood due to rapid catch-up growth
Several studies suggested a deleterious effect of excess growth
in infancy or childhood in preterm infants. In the study by Regan
et al., weight gain between 0 and 4 years was associated with
increased insulin resistance assessed at 10 years of age [28]. In a
more recent study, growth of preterm infants in early infancy did
not impact metabolic status in adolescence, in contrast to rapid
weight gain in childhood [29]. The most dangerous weight gain
may in fact be that occurring after 1 year of age. A recent review
showed that growth between birth and 12–18 months post-term
has no significant effect on later blood pressure and metabolic
syndrome in adulthood. In contrast, growth during late infancy and
childhood appears to be a major determinant of later metabolic
and cardiovascular well-being [29].
1.5. Impact of nutrition on body composition
Fetal weight triples over the 3rd trimester, with a weight
gain around 15 g/kg/day, consisting of 1.5–2.0 g/kg/day of fat,
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1.5–2.0 g/kg/day of protein, and 9–12 g/kg/day of water and
minerals. Fat mass gain is to be expected over the first 3 months of
extrauterine life in the preterm infant, but such accretion should be
much lower than the 4 g/kg/day observed in breastfed term
infants: the percent of fat mass in preterm infants at hospital
discharge is actually higher than in term neonates in several [30–
32] but not all studies [33–35]. Visceral fat mass was found
increased in one study [36], whereas a more recent study found no
evidence for abnormal fat distribution [35]. Of interest is the
finding that early body composition changes may be associated
with long-term neurological development: the greater the lean
body mass accretion, the better the neurodevelopment at 1 year
corrected age [37]. Finally, the respective roles of enteral and
parenteral feeding in later body composition are unclear, but most
recent randomized controlled trials suggest that manipulation of
parenteral nutrition has little effect on lean body mass accretion
[38].
It has long been felt that nutrition in preterm infants may alter
health outcomes. The ultimate goal is to avoid the occurrence of
EUGR, so that no subsequent catch-up growth is needed. The aim of
the current position paper is to review the evidence supporting this
strategy with regards to the early phase of nutrition, which is
mainly covered by parenteral nutrition. This narrative review
reflects the opinion of the Committee on Nutrition of the French
Society of Pediatrics (SFP) and the French Society of Neonatology
(SFN), taking into account recommendations from international
expert groups. Although vitamin and micronutrient intake may be
equally important and are obviously needed in any regimen of
parenteral nutrition, it should be remembered that the current
narrative review only addresses issues related to macronutrients,
water, electrolytes, and minerals.
2. What strategy should be adopted for parenteral amino acid
supply in preterm infants?
Amino acids, the building blocks of body protein, are the driving
force for growth. In the absence of nitrogen supply, premature
babies lose 1–2% of their protein stores per 24 h [39], and the
nitrogen balance increases as a function of amino acid intake [40].
2.1. What amount of amino acids is needed?
In the term fetus, the net transfer of amino acids from mother to
fetus (measured by infusing labeled leucine during elective
caesarean sections) ranges between 3.1 [41] and 4.5 g/kg fetal
weight/day [42].
Although carried out in enteral nutrition, the landmark study by
Lucas et al. deserves to be cited as one of the first randomized
artificial nutrition studies in preterm infants: increasing formula
protein content from 1.5 to 2.0 g/dL produced a 12-point benefit on
verbal IQ at 8 years, and 6 points on overall IQ, solely in boys [43];
this benefit was not confirmed by studies comparing neurodeve-
lopment before and after implementation of protocols designed to
increase protein intake in the 1st month [44,45].
Regarding PN, Thureen et al. randomly assigned 28 preterm
infants (with an average weight of 946 g) to PN, providing either
1 or 3 g/kg/day amino acids at 52 h of life. Protein gain was higher
in the high amino acid group, due to increased rates of protein
synthesis, measured using 13C-leucine infusion [46]. In 142 chil-
dren born before 29 weeks of gestational age, in a randomized trial
Tan et al. compared conventional PN to intensified PN, in an
attempt to approach the recommended intakes as closely as
possible. They observed a correlation between cumulative energy
and protein deficit and head circumference at 36 weeks post-
conceptional age, but no difference between groups [47]. Vlaar-
Please cite this article in press as: Darmaun D, et al. Parenteral nutrition for preterm infants: Issues and strategy. Archives de Pédiatrie
(2018), https://doi.org/10.1016/j.arcped.2018.02.005
3
dingerbroek et al. randomized preterm infants (mean weight,
862 g; mean gestational age, 27 weeks) into three groups: the
controls received from the 1st day of life 2.4 g of amino acids/kg/
day, and two other groups received either the same dose of amino
acids combined with 2–3 g lipid/kg/day or 3.6 g amino acids/kg/
day plus 2–3 g lipid/kg/day. The two intervention groups had a
better nitrogen balance, the intake at 3.6 g/kg/day from the outset
did not yield any additional benefit [48]. Morgan et al. compared
PN supplying 2.8 g/kg/day amino acids (and 2.8 g/kg/day lipid) vs.
3.8 g/kg/day amino acids (and 3.8 g/kg/day lipid) from 6 h of life in
premature infants under 1200 g and 29 weeks of gestational age
[49]. The growth of head circumference – an index of brain growth
[50] correlated with neurodevelopment [51] – between day 1 and
day 28 was higher (with a gain of 0.37 Z-score) with high amino
acid intake. However, this study does not allow us to delineate the
respective benefits of amino acid and lipid enrichment. Discrepant
results were obtained in a more recent study: 168 preterm infants
under 31 weeks of gestational age received PN supplying either
3.6 g/kg/day of amino acids from the 1st day (immediate group) or
1.7 g/kg/day on day 1 with a gradual increase up to 2.7 g/kg/day on
the 3rd day (gradual group), the lipids consisting either of soybean
oil (Intralipid1) or a mixture of oils (olive, soybean, medium-chain
triglyceride, fish oil, SMOF1). No difference was observed on
growth or body composition, as assessed by magnetic resonance
imaging (MRI), nor on liver fat accumulation, perhaps due to lack of
statistical power. A disturbing finding was the lesser gain in head
circumference in the immediate group [49]. It should be noted that
in most studies the intervention consists of a modification of amino
acid intakes rather than an overall strategy, and that the effect is
most often only assessed in the short term.
2.2. When should amino acid supply be initiated?
In the 1990s, amino acid supply was not started on the 1st day of
life, for fear of hyperammonia. There is in fact no increased risk of
acidosis with early amino acid intake [46]. In the retrospective
analysis of a cohort of more than 1000 preterm infants, those who
reached an amino acid intake of 3 g/kg/day prior to day 4 had a
twofold lower risk of having a head circumference under the 10th
percentile at discharge; this difference was significant only in boys
[52]. In a randomized prospective study, Van Goudoever et al.
demonstrated that starting amino acid intake in the early hours of life
does not result in hyperammonemia or acidosis, and improves the net
amino acid balance as measured by perfusion of 13C-leucine
[53]. Compared to PN glucose alone, the initiation of amino acids
(2.4 g/kg/day) in the first 2 h of life in 32 premature babies with an
average weight of 923 g improved not only protein synthesis and
nitrogen balance on the 2nd day of life [42], but the synthesis of
glutathione as well [54]. Preserving glutathione is relevant since that
tripeptide is the body’s first antioxidant defense system, and
glutathione deficiency is present at birth in premature infants [55],
even before they are confronted with high oxygen pressure, artificial
ventilation, or sepsis, which are all known to exacerbate oxidative
stress. Starting amino acids at 3.6 g/kg/day (rather than 2.4 g/kg/day)
did confer additional benefit, provided lipids were started early
[48]. The long-term benefit is less clear: the growth of children
observed at 2 years was no different, and boys who had earlier intakes
of amino acids were more likely to achieve optimal neurodevelop-
ment (odds ratio, 3.8; 95%CI, 1.3–11.4), but the development index
was lower for girls who had survived without disability [56].
2.3. What are the risks of an increase in early protein intake?
In the short term, increased protein intake exposes the infant to
the immediate risk of hypophosphatemia. In 154 preterm infants
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less than 33 weeks of gestational age, the incidence of hypo-
phosphatemia was 12.5% in those with an amino acid intake in the
upper tercile vs. 4.6% and 0% in the mid and lower terciles,
respectively [57]. Hypophosphoremia is thought to result from the
rise in phosphorus utilization for glucose conversion to glucose-6-
phosphate and higher ATP utilization for peptide bonds when
protein synthesis increases, a mechanism analogous to the
refeeding syndrome known to occur upon rapid nutritional
replenishment in severely undernourished patients [58]. Regarding
hypercalcemia, the incidence was 9.8%, 4.8%, and 1.9%, respectively
[57]. In the long run, the potential risks of excessive catch-up
growth promoted by an increase in early protein intake are still
being debated. It is not known whether the risk of premature
infants developing insulin resistance is related to premature birth
per se, EUGR during neonatal stay, or subsequent catch-up.
2.4. Is there a requirement for specific amino acids?
The composition of PN amino acid mixtures designed for
preterm infants differs from that for adults since (1) proteins differ
in amino acid composition between tissues, and the relative
proportion of the various organs differs widely between adults and
infants; (2) due to enzyme immaturity, amino acids deemed
nonessential for adults become conditionally essential in preterm
infants. The composition of the mixtures was chosen to mimic
either the profile of an ideal protein – human milk protein – in the
case of Vaminolact1 (Fresenius Kabi Bad Homburg, Germany) or
that of umbilical cord blood in term neonates as for Primene1
(Baxter, Guyancourt, France), while taking into account constraints
related to the solubility or stability of amino acids. When the
newborn is fed enterally, 50–75% of glutamine and glutamate, 70%
of threonine (synthesis of intestinal mucins) [59–61] are extracted
in the first pass in the splanchnic territory (intestine + liver). As the
latter territory is shunted when the child receives PN, amino acid
requirements may well differ between PN and enteral nutrition.
Glutamine, a nonessential amino acid synthesized in muscle, is a
prominent fuel for rapidly dividing cells such as those of intestinal
mucosa and the immune system, and becomes conditionally
essential under conditions of stress: glutamine stores are depleted,
at a time when splanchnic glutamine utilization increases [62] and
outstrips glutamine synthesis in skeletal muscle. Because of poor
heat stability, glutamine is not part of any of the PN mixtures, but
can be provided as alanyl-glutamine, a stable dipeptide precursor.
Glutamine supplementation is a grade A recommendation for PN in
critically ill adults [63]. Yet a recent study found an increase in
mortality in a group of septic and critically ill adults receiving
simultaneous intravenous and enteral glutamine supply [64]. Pre-
term infants appear likely candidates for glutamine supplementa-
tion since (1) fetal glutamine uptake exceeds that of all other
amino acids in utero, and the cutoff of umbilical supply results in
abrupt glutamine deprivation at birth; (2) although preterm
infants are able to synthesize glutamine [60], low muscle mass
limits glutamine synthesis capacity, at a time when the developing
gut avidly takes up glutamine; (3) the preterm infant is exposed to
major stress; and (4) in addition to its putative role in protein
homeostasis, glutamine plays multiple roles, e.g., in the replenish-
ment of substrates in the tricarboxylic acid (Krebs) cycle.
Supplementation of PN with glutamine (0.5 g/kg/day) inhibits
proteolysis [65,66] but did not reduce the risk of mortality or sepsis
in 1423 preterm infants [67]. In contrast, early life enteral
glutamine supplementation was reported to be associated with
improved brain growth [68]. No consensus has been reached to
date regarding glutamine supply in preterm infants.
Although arginine can be produced in part by the renal
conversion of citrulline, an amino acid synthesized in the gut from
Please cite this article in press as: Darmaun D, et al. Parenteral nutrition for preterm infants: Issues and strategy. Archives de Pédiatrie
(2018), https://doi.org/10.1016/j.arcped.2018.02.005
glutamine and proline, arginine depletion was observed in preterm
infants with necrotizing enterocolitis (NEC) [69]. In two studies,
arginine supplementation reduced the incidence of NEC to five
cases out of 76, vs. 21 out of 77 in controls in the first study [70],
and from 18.6 to 2.5% in the second one [71]. Such evidence is
unconvincing since: (1) arginine depletion could be not the cause,
but the consequence of NEC since gut ischemia may impair the
intestinal production of citrulline, and, consequently, arginine; (2)
in the trials, the incidence of NEC was unusually high in the control
groups.
Cysteine, a nonessential sulfur-containing amino acid synthe-
sized from methionine, serves as a precursor of glutathione (GSH,
tripeptide glutamyl-cysteinyl-glycine), the most abundant antiox-
idant in the body. Whether cysteine is essential for the PN-fed
preterm infants is unclear: (1) the activity of cystathionase, a key
enzyme for cysteine synthesis, is low in fetal liver; (2) methionine
is less well converted to cysteine when methionine is provided by
NP than enterally [72]; (3) premature infants experience major
oxidative stress and GSH deficiency; and (4) due to poor stability,
little cysteine is included in PN mixtures. However, cysteine
supplementation of PN failed to correct GSH deficiency [73]. Cys-
teine deficiency may in fact occur prior to birth, since it is observed
in the blood of mothers delivering preterm infants [55].
Taurine, a sulfo-amino acid not incorporated in proteins, is
essential to conjugate and excrete bile acids. In addition, taurine
deficiency alters retinal function, and neurodevelopment at 7 years
of age correlates with neonatal taurine supply [74]. Taurine
therefore is essential in preterm PN.
3. What strategy should be adopted regarding energy supply in
preterm PN?
3.1. What is the glucose requirement of preterm infants?
In the neonate, brain accounts for 90% of whole-body glucose
utilization [75]. Endogenous (hepatic) glucose production corre-
lates with brain volume across ages, and reaches 6 mg/kg/min
(8.6 g/kg/day) and 3–5 mg/kg/min in the preterm and term infant,
respectively, vs. 2.2 mg/kg/min (3 g/kg/day) in the adult [76]. This
high brain glucose requirement explains why hypoglycemia is
common in preterm infants, and why exposure to even mild or
asymptomatic hypoglycemia (< 45 mg/dL) in early life correlates
with impaired neurodevelopment at 18 months of age [77]. In
healthy adults who have fasted overnight, two-thirds of hepatic
glucose production arises from glycogenolysis and one-third from
gluconeogenesis. Gluconeogenesis does not operate in fetal life.
The physiological drop in blood glucose associated with birth
acutely elicits glucagon secretion, and inhibits insulin secretion,
resulting in the induction of PEPCK [78,79], which in turn initiates
gluconeogenesis from amino acids released by proteolysis in
skeletal muscle. Twenty-four hours after birth, glucose de novo
synthesis capacity is fully operational in very preterm infants [80].
The lipid supply is crucial for the maintenance of blood glucose
in preterm infants. Though the fat supply does not enhance glucose
production, the lipid supply decreases glucose utilization [81]. Con-
versely, over the course of intravenous nutrition delivering amino
acids, glucose, and fat, interrupting lipid supply impairs gluconeo-
genesis (mainly from glycerol), whereas interruption of the amino
acid supply does not [82].
In the adult, intravenous glucose infusion decreases liver
glucose production in a dose-dependent manner [83]. This brake
on endogenous glucose production does not operate in preterm
infants: residual glucose production arising from gluconeogenesis
persists despite exogenous glucose supply [84–86], even during PN
supplying all three macronutrients, including glucose [86]. Even
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though high rates of glucose delivery are required to meet energy
needs, such high rates are often poorly tolerated, resulting in
hyperglycemia. Hyperglycemia is associated with increased
mortality [87]. Glucose uptake does not require insulin in brain,
which is by far the main glucose user. Glucose utilization therefore
is poorly sensitive to insulin in preterm infants. In addition, in
preterm infants both insulin sensitivity and insulin secretion are
impaired, the latter due to insufficient conversion of proinsulin to
insulin [79].
Such relatively poor insulin sensitivity likely explains the lack
of benefit of insulin treatment in situations associated with
hyperglycemia in very preterm infants [88]. It remains a matter of
debate whether (i) initiating insulin treatment, (ii) reducing
glucose delivery to match brain glucose requirement (6 mg/kg/
min), or (iii) supplying medium-chain triglycerides is the best
option to tackle hyperglycemia in PN-fed preterm infants. The
early supply of amino acids may decrease the incidence of
hyperglycemia in PN-fed preterm infants [89] through as yet
unidentified mechanisms (enhanced insulin sensitivity or stimu-
lation of insulin secretion by amino acids).
3.2. Lipid delivery in PN-fed preterm infants: what is at stake?
In preterm infants, there is a clear rationale for parenteral lipid
supply: (1) delivering glucose as a sole source of non-protein
energy, even at a rate of 12 g/kg/day only supplies 48 kcal/kg/day,
less than half the overall energy need; adding lipid covers energy
needs, at a lesser cost in terms of osmolarity; (2) excess glucose
delivery exposes the infant to the risk of hyperglycemia (see above)
or steatosis; (3) a lipid supply is required for the physiological
accretion of body fat that normally occurs during the last trimester
of intrauterine life [90]; (4) linoleic acid (LA; C18:2n-6) and a-
linolenic acid (ALA; C18:3n-3), two 18-carbon fatty acids, are
indispensable regardless of age, since they are not synthesized in
the human body; (5) the synthesis of longer fatty acids from such
precursors is limited; and (6) the long-chain polyunsaturated fatty
acid docosahexaenoic acid (DHA) accounts for 56% of the lipid mass
of neuron membranes, which makes it essential for brain and
retina development.
3.3. When should parenteral lipid supply be started in preterm
infants?
When lipid supply is delayed, the concentration of essential
fatty acids (LA and ALA) declines by 0.75% per day, and deficiency
appears [91]. Starting lipid delivery before 48 h of life is well
tolerated, but is not associated with any growth benefit, regardless
of the emulsion used [92].
3.4. How much fat should be delivered?
A minimum lipid intake of 0.5–1 g/kg/day is theoretically
sufficient to cover the essential fatty acid requirement. A
retrospective study on 121 preterm infants nevertheless reports
an association between the amount of fat delivered during the 1st
week and growth at 28 days of age, and a negative correlation
between growth in the 1st month and the delay in introducing lipid
emulsions in preterm PN [93]. In a cohort of 48 very preterm
infants, neurodevelopment assessed by the Brunet-Lézine test at
1 year of age correlated with cumulative fat intake in the first
14 days, whereas it did not with amino acid supply [94]; of note,
protein intake (3 g/kg/day) was close to recommended intake in
the latter study.
Regarding protein anabolism, a 50/50 glucose/fat energy ratio
for non-protein energy supply was more efficient than supplying
100% as glucose [95], and a 66/33 ratio appears optimal [96].
Please cite this article in press as: Darmaun D, et al. Parenteral nutrition for preterm infants: Issues and strategy. Archives de Pédiatrie
(2018), https://doi.org/10.1016/j.arcped.2018.02.005
5
Conversely, although PN-induced liver disease clearly is
multifactorial, excess phospholipid and lipid intake is a contribut-
ing factor [97]. The mechanisms mediating intravenous lipid liver
toxicity are debated. Plasma phytosterol concentration is elevated
in children receiving long-term PN, and correlates with the severity
of cholestasis. The abundance of unsaturated n-6 fatty acids in soy
oil could also enhance inflammation given that n-6 PUFA are
precursors for the synthesis of pro-inflammatory prostaglandins.
Accordingly, elevated C-reactive protein, suspicion of sepsis, or
high bilirubin concentration were long considered contraindica-
tions for lipid supply.
The presumed toxicity of classic lipid admixtures led to the
development of emulsions enriched with medium-chain triglyc-
erides, thought to be less toxic for liver. Regarding protein gain,
medium-chain triglycerides, however, are less efficient than long-
chain triglycerides [98].
3.5. What specific lipid should be delivered?
LA (n-6) and ALA (n-3), the two fatty acids essential regardless
of age, probably are not the only essential fatty acids for preterm
infants.
Arachidonic (ARA; C20:4n-6) and docosahexaenoic acid (DHA;
C22:3n-3) are the most abundant PUFAs in neurons. In utero, the
fetal LC-PUFA supply is ensured through several mechanisms,
including preferential placental transfer [90]. Compelling evidence
suggests long-chain polyunsaturated fatty acids (LC-PUFAs), which
are synthesized in vivo from LA and ALA, are conditionally essential
in preterm infants:
 although preterm infants are able to synthesize LC-PUFAs from
their 18-carbon precursors (LA and ALA) [99], endogenous DHA
synthesis (13 mg/kg/day in preterm infants born at 32 weeks
gestational age) is much lower than fetal DHA accretion in the
3rd trimester of pregnancy (43 mg/kg/day) [100]; the preterm
infant is therefore dependent on an exogenous DHA supply;
 even though human milk covers the LC-PUFA requirement in
term infants, it likely is insufficient for preterm infants due to
their fast brain growth;
 even in preterm infants fed human milk or DHA-enriched
preterm formula, intravenous supply accounts for a larger
fraction of overall nutritional support than enteral nutrition over
the first few weeks of life, and most fat emulsions used in PN are
devoid of LC-PUFAs;
 in rodents and non-human primates, deficient DHA deposition
in retina and brain impairs vision and neuromotor development
[101–103].
Although the PUFA supply appears to be safe, the benefit of LC-
PUFA supplementation by intravenous lipids on neurodevelop-
ment has yet to be established [102].
Finally, supplementation with DHA alone without arachidonic
acid (C20:4;n-6) results in impaired growth in terms of weight
gain, length, and head circumference in the 1st year of life [103].
3.6. Can n-3 polyunsaturated fatty acids prevent PN-induced
cholestasis in preterm infants?
A meta-analysis of three studies including 93 subjects conclud-
ed that PN including fish oil is more effective than PN containing
standard lipid emulsion to treat cholestasis when the latter is
already present (OR, 6.14; 95% CI, 2.27–16.6; P <0.01) [104]. In a
meta-analysis of 17 studies conducted in preterm infants or
critically ill neonates with a short duration of intervention, no
differences in the rate of cholestasis or bilirubin levels were
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associated with short-term use of different intravenous lipid
emulsions [105]. Another meta-analysis concluded that all lipid
emulsions appeared to be safe in preterm infants, but found no
statistically significant differences in clinically important outco-
mes such as death, growth, and PN-associated liver disease with
the use of newer alternative emulsions vs. the pure soy oil-based
emulsion [106]. Pure soybean oil lipid emulsions are considered
less balanced (higher omega-6/omega-3 ratio, higher phytosterol
content, lower alpha-tocopherol content) than composite lipid
emulsions; composite lipid emulsions with or without fish oil
should therefore be the first choice in preterm infants.
Taken together, the literature data suggest that in the
pathophysiology of cholestasis, the omega-6/omega-3 ratio in
fatty acid supply could matter less than other factors such as
the glucose/fat energy ratio. In a prospective trial on
31 patients suffering from PN-induced liver disease, a simple
reduction of fat supply to 1 g/kg twice a week improved
cholestasis, compared with historical control patients who
had received the same emulsion at a rate of 3 g/kg/day, albeit
with a trend toward a rise in the triene/tetraene ratio, an
index of subclinical essential fatty acid deficiency [107]. It
should, however, be remembered that lipid reduction may
lead to energy shortage in preterm infants and should not be
promoted to a large extent.
4. What strategy is best for water and electrolyte supply?
4.1. What water intake is necessary?
Water and electrolyte balance of the preterm infant is
influenced by:
 substantial insensible, cutaneous, and respiratory water loss.
Cutaneous loss is very high during the first few days of life due to
cutaneous immaturity, particularly in case of extreme prema-
turity, warranting high water intakes. The infant’s environment,
designed to warm the infant, plays an important role: a relative
humidity of 80% or more must be sought, best obtained in an
enclosed incubator;
 the contraction of the extracellular compartment associated
with the transition to extrauterine life, implies that a
physiological weight loss should be allowed in the days
following birth, but must be strictly controlled;
 renal immaturity, responsible for a loss of sodium and water, in
fact facilitating the transition to extrauterine life in the first few
days, but requiring close monitoring, followed by high hydro-
sodium intakes;
 needs related to growth.
An excess of water and sodium intake increases the risk of
ductus arteriosus and bronchopulmonary dysplasia. Insufficient
water and sodium intake exposes the child to a risk of dehydration,
particularly in the case of carbohydrate intolerance, because
glycosuria increases water loss.
Water intake during the first few days of life is determined
according to an individualized progression, taking into account
changes in the infant’s weight, serum sodium, and to a lesser
extent urine output (which is difficult to interpret due to renal
immaturity). Most often, initial intakes of 70 mL/kg/24 h (50–
80 mL/kg/24 h, higher for lower gestational age) are proposed,
followed by a progression adapted depending on the infant’s
characteristics, thermal environment, sodium intakes, type of PN
solution used, and clinical and biological parameters, up to
approximately 140 mL/kg/day (100–200 mL/kg/24 h, depending
on the variables above) at the end of the 1st week.
Please cite this article in press as: Darmaun D, et al. Parenteral nutrition for preterm infants: Issues and strategy. Archives de Pédiatrie
(2018), https://doi.org/10.1016/j.arcped.2018.02.005
4.2. What sodium intake is required?
The sodium balance is an important issue in the extreme
premature infant. Wide variations in serum sodium are associated
with a worse prognosis at 2 years [108]. In the first few days, a
physiological contraction of extracellular volume takes place
[109]. Since sodium is the predominant cation in extracellular
medium, a physiological loss of sodium is therefore present in the
first few days of life. If sodium intake is lower than the excess loss
due to impaired sodium renal reabsorption, there is a risk of
hyponatremia due to sodium depletion. A randomized trial
showed a benefit of sodium intake from the first few days on
outcome at 10 years of age [110], even though this strategy is
associated with increased initial oxygen requirement [111].
After the first hours to days of life, which are characterized by
initial relative oliguria, a diuretic phase lasting a few days will
drive the sodium losses. All things considered, a restriction of Na
intake less than 2 mEq/kg/day should be considered from the first
day but followed by a rapid increase in sodium intake (4 mEq/Kg/
day or above adjusted to sodium losses) when sodium losses
increase because of increased urine output [110,112,113]. This
sodium intake must take into account the hidden sodium intake
associated with drugs. In the days following birth, preterm infants
are exposed to two contrasting risks: dilution hyponatremia due to
oligoanuria secondary to drug toxicity (antibiotics, ibuprofen) on
one hand, and hypernatremia through transcutaneous loss of
extracellular water due to extreme cutaneous immaturity [114].
4.3. What chlorine intake is required?
Chlorine intake is mostly not prescribed but passively
administered when potassium and phosphorus are prescribed in
the form of chlorides, which often leads to excess intake [115],
responsible for hyperchloremic metabolic acidosis [116]. Control-
ling this intake using other sodium, potassium, or phosphorus salts
reduces the risk of metabolic acidosis [117]. As a rule of thumb,
total chloride intake should be lower than the addition of sodium
and potassium intakes in order to avoid hyperchloremic metabolic
acidosis.
4.4. What potassium intake is needed?
Potassium is an intracellular cation: 98% of potassium stores are
intracellular. The intracellular concentration ranges between
100 and 150 mmol/L between tissues, whereas potassium
concentration in the extracellular compartment is 4.5 mmol/L.
Tissue catabolism representing 1% of body cell mass transfers
approximately 2.5 mmol of potassium to the extracellular sector.
Thus, kalemia reflects not only (1) potassium intake but also (2)
potassium flux from the intracellular to the extracellular
compartment (attrition, catabolism), which increases serum
potassium, (3) the passage of ions from the extracellular to the
intracellular compartment (anabolism), and (4) urinary potassium
loss and potassium secretion into intestinal lumen, which lower
serum potassium [118]. PN with higher and earlier amino acid and
energy intake will tend to lower serum potassium, avoid
nonoliguric hyperkalemia, and above all improve the potassium
balance [119]. Nevertheless, in a recent study, the increased intake
of amino acids did not lead to changes in serum electrolyte
concentrations [120]. The recommended intake of potassium is 2–
4 mEq/kg/day after urine output is well established [112].
4.5. What phosphorus and calcium intakes?
The phosphorus/calcium balance requires managing calcium
and phosphorus intake at the same time. Phosphorus is an
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D. Darmaun et al. / Archives de Pédiatrie xxx (2018) xxx–xxx
intracellular ion. High amino acid and energy intake from the 1st
day can lead to hypophosphatemia, hypercalcemia, and hyper-
calciuria [56]. The calcium balance therefore may become
negative, whereas most of the calcium accretion observed in the
fetus (30 g over the entire duration of pregnancy) occurs during the
3rd trimester [121]. Intakes of 1–2 mmol/kg/day for phosphorus
and 1–2 mmol/kg/day for calcium must be given to accommodate
the enhanced growth rate due to high amino acid intake, as early as
the first few days of life [112,113]. During the first days of life when
mineral intake is usually low and amino acid intake high, a molar
calcium-to-phosphorus ratio at 1 or below can be used to prevent
the occurrence of early hypophosphatemia.
5. Conclusions
For the very preterm infant, optimizing PN is a crucial issue,
since PN is the main source of nutrient intake for the first 2 weeks
of life. The ultimate goal of nutrition during hospitalization is to
ensure a rate of growth close to that of the fetus during the 3rd
trimester of pregnancy in order to ensure optimal brain growth.
This objective is often difficult to achieve, and a cumulative energy
and protein deficit during the hospital stay can lead to extrauterine
growth restriction (EUGR). Recent studies suggest that more
optimal nutrition through both enteral and intravenous routes
may prevent EUGR.
A striking association between growth rate in the first few
weeks and long-term neurodevelopment has been observed in
most retrospective observational studies. This correlation is, as
such, subjected to multiple sources of bias, and a correlation does
not necessarily imply a causal relationship, not to mention the
paucity of prospective, randomized trials.
Amino acid supply is the driver of growth, and should be started
from the time of birth, if possible at the rates recommended. There
appears to be room for improvement in the composition of
parenteral amino acid admixtures.
Attention should be paid to providing an adequate amount of
other nutrients, such as electrolytes and minerals, since inadequa-
cy of these nutrients may alter short- and long-term outcomes.
The non-protein energy supply should combine glucose and fat
from the time of birth, and primarily aims at covering brain
requirements for energy (glucose) and building materials (poly-
unsaturated fatty acids).
In children born preterm, it remains to be elucidated whether
the risk of developing chronic disease at adulthood is linked to
catch-up growth occurring after EUGR or poor quality of growth
(suboptimal fat/lean body mass accretion). Optimized, personal-
ized – rather than aggressive – intravenous nutrition may help
prevent both EUGR and suboptimal lean/fat mass accretion, and
may in turn improve long-term health outcomes.
Even though uncertainty remains regarding the long-term
effect of early nutrition, it appears reasonable to propose more
optimal initial PN and to follow the recommended intakes. More
randomized trials are needed, however, to further support this
approach and to more firmly demonstrate that this type of strategy
improves short-term and long-term outcomes.
Disclosure of interest
D.D.: occasional conferences: invitation as speaker for Baxter
SA, B Braun, Bledina, Danone, Fresenius Kabi, Nestlé, Novartis,
Nutricia, Novartis SA; occasional consultancies: expert reports for
Baxter SA, B Braun, Bledina, Danone, Fresenius Kabi, Nestlé,
Novartis, Nutricia, Novartis SA.
D.D.: substantial contribution to research grants from: Baxter
SA, B Braun, Bledina, Danone, Fresenius Kabi, Nestlé, Novartis,
Nutricia, Novartis SA.
Please cite this article in press as: Darmaun D, et al. Parenteral nutrition for preterm infants: Issues and strategy. Archives de Pédiatrie
(2018), https://doi.org/10.1016/j.arcped.2018.02.005
7
A.L.: occasional conferences: invitation as speaker for Baxter SA,
Fresenius Kabi; occasional consultancies: expert reports for Baxter
SA, Fresenius Kabi.
U.S.: occasional conference as invited speaker for Baxter SA.
A.Bo., A.Br., D.T., E.S., F.F., J.-C.R., J.-P.C., J.-P.G., M.L.F., R.H.
declare that they have no competing interest.
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