Clinical Outcome of Low Birthweight, Long-Term Consequences

Bhatia J, Bhutta ZA, Kalhan SC (eds): Maternal and Child Nutrition: The First 1,000 Days.
Nestlé Nutr Inst Workshop Ser, vol 74, pp 211–221, (DOI: 10.1159/000348775)
Nestec Ltd., Vevey/S. Karger AG., Basel, © 2013

Improving the Neurodevelopmental

Outcomes of Low-Birthweight Infants
Maria Makrides a, b  ·   Amanda Anderson a  ·   Robert A. Gibson a, c  ·  
     

Carmel T. Collins a, b  

a Women’s
and Children’s Health Research Institute, North Adelaide, SA, b School of Paediatrics
 

and Reproductive Health and c School of Agriculture, Food and Wine, The University of Adelaide,
 

Adelaide, SA, Australia

Abstract
Infants born with low birthweight (LBW) have poorer neurodevelopmental outcomes
compared with their term counterparts with appropriate weight for gestational age. The
perinatal period is a time of high energy and high nutrient needs, and any process, such
as preterm birth, poor nutrition or placental insufficiency, that interrupts the concen-
trated flow of nutrients to the fetus may result in babies with LBW. Therefore, it makes
logical sense that at least part of the cognitive deficits may be explained by nutritional
deprivation. The nutrients commonly deficient in LBW infants include protein and en-
ergy and micronutrients such as iron, zinc and long chain polyunsaturated fatty acids. In
this review, we aimed to determine the effect of nutrient supplementation on neurode-
velopment in LBW infants. While few trials have supported the hypothesis that nutri-
tional supplementation improves neurodevelopment, many studies are limited by sam-
ple size and methodological shortcomings. Further large-scale rigorously designed
intervention trials, with long-term neurodevelopment follow-up, are required to deter-
mine the optimal nutritional supplements and the timing of their administration to LBW
infants. Copyright © 2013 Nestec Ltd., Vevey/S. Karger AG, Basel

The trajectory of growth is greatest during the perinatal period, which is the
time that includes late pregnancy and early postnatal life. During the last tri-
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mester of pregnancy the normal fetus will grow from approximately 900 to
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3,400 g, more than tripling in weight. The newborn term baby will double
birthweight in the first 4 months of life and will again nearly double in size over
the next 24 months, but will not achieve adult size until late adolescence. The
brain, on the other hand, will achieve adult size (approximately 1,200 g) by
about 2 years of age. In the last trimester of pregnancy, brain weight will in-
crease from approximately 150 to 400 g, and between term birth and 6 months
of age the brain will again double in size, reaching approximately two thirds of
adult brain weight [1]. The composition and structure of the brain also chang-
es dramatically during this time [2], and these changes continue well into
childhood.
The perinatal period is characterized by high energy and high nutrient re-
quirements necessary to sustain the high growth rates. It is therefore not sur-
prising that any process, such as preterm birth, poor nutrition or placental
insufficiency, that interrupts the concentrated flow of nutrients to the fetus
will result in babies with low birthweight (LBW). The brain appears particu-
larly sensitive to the nutrient deprivation associated with LBW, as infants
who are born with LBW are more likely to have lower scores on neurodevel-
opmental tasks into childhood compared with term, normal-birthweight in-
fants [3]. Preterm infants are at particular risk for long-term cognitive and
educational problems directly proportional to their degree of prematurity,
with those most preterm demonstrating a mean intelligence quotient (IQ) of
0.8–1.5 standard deviations (SD) lower than children who were born at term
[4]. Recent evidence also suggests there are even higher rates of developmen-
tal delay in preterm infants born growth restricted compared with appropri-
ately grown preterm infants [5, 6]. Children born at term and with LBW are
twice as likely to have an IQ that is 2 SD lower than term-born appropriately
grown infants [7].
Strategies to improve the neurodevelopmental outcome of children born
with LBW are important, and many interventions have focused on nutrition-
al approaches applied during the period immediately after birth, especially for
preterm infants who are born before the last trimester of pregnancy is com-
plete and the concentrated nutrient supply delivered across the placenta is
prematurely ceased. The nutrients that are commonly deficient in LBW in-
fants include protein and energy as well as micronutrients such as iron, zinc
and long-chain polyunsaturated fatty acids (LC-PUFA) [2]. The focus of this
review, therefore, is to determine the effect of nutrient supplementation on
neurodevelopment in LBW infants. The review is limited to randomized
­controlled trials (RCTs) designed to assess the effects of enteral nutrition
­interventions during the postnatal period. Other study designs have not
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been  considered because complex neurodevelopmental outcomes are influ-

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212 Makrides · Anderson · Gibson · Collins

Bhatia J, Bhutta ZA, Kalhan SC (eds): Maternal and Child Nutrition: The First 1,000 Days.
Nestlé Nutr Inst Workshop Ser, vol 74, pp 211–221, (DOI: 10.1159/000348775) Nestec Ltd., Vevey/S. Karger AG., Basel, © 2013
enced by many factors including sex, perinatal morbidity as well as social and
environmental influences [4], and RCTs remain the gold standard methodol-
ogy to minimize the biases of these other factors and show cause and effect
relationships.
A comprehensive literature search was undertaken to identify systematic re-
views of RCTs or RCTs including postnatal protein-energy, micronutrient or
LC-PUFA supplementation in LBW infants and reported neurodevelopmental
outcomes.

Protein-Energy Supplementation of Preterm Infants

The effect of protein-energy enrichment in the postnatal period on neurodevel-

opment of preterm infants has been summarized in five Cochrane Systematic
Reviews [8–12] involving 9 RCTs conducted between mid-1960 to mid-2000
[13–21]. The early trials compared differing concentrations of protein in for-
mula or breast milk while in hospital [13–18], and the more recent trials inves-
tigated the effect of providing protein-energy-enriched formula or breast milk
after discharge [19–21].

In-Hospital Supplementation of Formula Compared with Donor

Human Milk

In a systematic review of formula versus donor human milk (either as the sole
diet or as a supplement to mother’s own milk) only one trial was included [9].
This seminal study conducted by Lucas et al. [15, 22, 23] in the 1980s compared
preterm formula (2 g protein and 80 kcal/dl; 2.5 g protein/100 kcal) with donor
breast milk (1.07 g protein and 46 kcal/dl; 2.3 g protein/100 kcal). In this paral-
lel RCT, women who chose not to breastfeed were randomized to preterm for-
mula or donor breast milk as the sole diet (trial 1), and women who chose to
breastfeed were randomized to receive preterm formula or donor breast milk as
a supplement to breast milk (trial 2) [15]. At 9 months of age, on combining tri-
als 1 and 2, a significant benefit was found in developmental quotients (DQ)
with the preterm formula (preterm formula 100.4, SD 10.7, versus banked donor
human milk 97.9, SD 9.6; 95% CI: 0.4–4.6) [23]. At 18 months’ corrected age, no
benefit to mental development was found in either trial 1 or trial 2 or on meta-
analysis of both trials (n = 387, weighted mean difference, WMD, 1.24, 95%
CI: –2.62 to 5.09) [9].
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Low Birthweight Infant Nutrition and Developmental Outcome 213

Bhatia J, Bhutta ZA, Kalhan SC (eds): Maternal and Child Nutrition: The First 1,000 Days.
Nestlé Nutr Inst Workshop Ser, vol 74, pp 211–221, (DOI: 10.1159/000348775) Nestec Ltd., Vevey/S. Karger AG., Basel, © 2013
In-Hospital Supplementation with Protein and Energy Using Human Milk
Fortifiers

While human milk is the preferred base feed for preterm infants because of its
immunological properties, it is well recognized that protein, energy and micro-
nutrient supplementation is needed to achieve appropriate growth rates. How-
ever, in a systematic review of multicomponent fortification of human milk ver-
sus no fortification, there was only one trial that assessed neurodevelopment
[10]. In this trial, 275 infants born weighing <1,850 g whose mothers chose to
breastfeed were randomized to receive 0.7 g protein and 14 kcal added to 100 ml
of breast milk or no additional protein-energy supplement [18]. Neurodevelop-
ment was assessed at 18 months’ corrected age with no significant difference
found (MD 2.2, 95% CI: –3.35 to 7.75) [10].

In-Hospital Supplementation with Protein and Energy Using Infant

Formulas

Lucas et al. [16] in another well-known study compared term formula vs. pre-
term formula in preterm infants. This study included two parallel trials in which
infants born weighing <1,850 g were randomly allocated to receive a protein-
energy-enriched formula containing 2.0 g protein and 80 kcal/dl (2.5 g pro-
tein/100 kcal) or standard formula of 1.45 g protein and 68 kcal/dl (2.1 g pro-
tein/100 kcal) [16]. The first trial (trial A) included infants who were not receiv-
ing any breast milk, so the test formulas were the sole diets, and the second trial
(trial B) included infants who were receiving some breast milk so that the test
diets were a supplement to mother’s milk. In trial A, psychomotor development,
but not mental development, at 18 months’ corrected age was higher with pro-
tein energy enrichment (mean difference, MD, 14.7, 95% CI: 8.7–20.7) [16].
There were no neurodevelopmental differences found in trial B. When trials A
and B were combined at 18 months, there were no differences found in mental
development, but the improvement in psychomotor development remained
(MD 6.2, 95% CI: 2.4–10.0) [16], and there was a significant sex by diet interac-
tion such that boys fed the protein-energy-enriched formula had an 8-point gain
in mental development (95% CI: 2–13) [16].
When the same cohort was assessed at 7.5–8 years of age (84% follow-up rate)
no differences in any IQ measures were found in either trial A or trial B or when
trials A and B were combined [24]. However, the verbal IQ of children who were
fed the protein-enriched formula in trial A was higher compared with control but
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did not reach statistical significance (MD 4.8, 95% CI: –0.6 to 10.02) [24]. Al-
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214 Makrides · Anderson · Gibson · Collins

Bhatia J, Bhutta ZA, Kalhan SC (eds): Maternal and Child Nutrition: The First 1,000 Days.
Nestlé Nutr Inst Workshop Ser, vol 74, pp 211–221, (DOI: 10.1159/000348775) Nestec Ltd., Vevey/S. Karger AG., Basel, © 2013
though no sex by diet interaction was reported, post hoc analyses indicated that
boys in trial A who had protein-energy-enriched formula as the sole diet had a
12.2 increase in verbal IQ (95% CI: 3.7–20.6) compared to boys who had standard
formula [24]. We have excluded from this review results for a subset (n = 95) of
the children assessed as neurologically normal at 7.5–8 years of age and who were
assessed again at 16 years of age. This highly selected population now constitutes
an exploratory analysis with a high risk of bias [25]. Although the neurodevelop-
mental data are not strong with trial A including the smallest numbers and ex-
tensive exploratory analyses, nutrient-enriched preterm formulas are now com-
mon practice for all preterm infants who require formula complements.
Nevertheless, there is significant interest in further enriching protein concen-
tration based on growth and other metabolic studies. A systematic review of the
effects of higher versus lower protein intakes in exclusively formula-fed infants
included three trials reporting developmental outcome [8]. These trials, begin-
ning early in the postnatal period in LBW infants, have yielded mixed results on
neurodevelopmental outcomes [8]. The earliest and largest trial included in the
review was conducted in the 1960s and included infants <2,000 g (n = 304) [13].
This study reported no difference in overall IQ at 3 and 5–7 years of age between
infants fed very high protein content formula (5 g protein/100 kcal providing
6.0–7.2 g/kg per day) compared with lower protein content formula (2.5 g pro-
tein/100 kcal, providing 3.0–3.6 g/kg per day). However, in infants with birth-
weights <1,300 g, the infants fed the higher protein formula had a significantly
increased incidence of IQ <90 at 3 (RR 0.30, 95% CI: 0.14–0.64) and 5–7 years
of age (RR 0.31, 95% CI: 0.15–0.66) when compared to infants fed lower protein
formula [8]. The formula was isocaloric; however, the very high protein formu-
la had 17% more minerals. Results of this early study have led to a cautious ap-
proach to increasing protein concentration and the recommendation from the
Cochrane Systematic Review that protein intakes greater than 4 g/kg per day
should be considered experimental [8].
The two remaining trials included in the review were limited primarily by
small sample sizes and by either inadequate description of trial details/proce-
dures or large loss to follow-up. One trial (n = 48), fed very LBW preterm infants
isocaloric formula of 3.0 g protein/100 kcal to provide 3.2 g/kg per day protein
compared with 2.3 g/100 kcal providing 2.6 g/kg per day from 3 weeks of age
[14]. No difference in neurodevelopmental assessments (tests not specified)
were reported at 6 months, 1 or 2 years of age [8]. The remaining trial (n = 26)
fed isocaloric formula yielding 2.6 g/kg per day (2.2 g protein/100 kcal) of pro-
tein compared with 3.1 and 3.8 g/kg per day (2.7 and 3.2 g/100 kcal) of protein
to very LBW infants [17]. Infants receiving the higher protein performed sig-
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nificantly better on orientation (p = 0.0003), habituation (p = 0.003) and auto-

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Low Birthweight Infant Nutrition and Developmental Outcome 215

Bhatia J, Bhutta ZA, Kalhan SC (eds): Maternal and Child Nutrition: The First 1,000 Days.
Nestlé Nutr Inst Workshop Ser, vol 74, pp 211–221, (DOI: 10.1159/000348775) Nestec Ltd., Vevey/S. Karger AG., Basel, © 2013
nomic stability (p = 0.01) clusters of the Neonatal Behavior Assessment Scale
when assessed at approximately 36–37 weeks’ postmenstrual age [8].

Postdischarge Supplementation with Protein and Energy for Breast Milk and
Formula

As almost all of the in-hospital studies did not continue supplementation be-
yond discharge, it is possible that the intervention period was too short to ‘catch
up’ the nutrient deprivation associated with prematurity and hence see consis-
tent neurodevelopmental advantages. With this rationale, postdischarge protein
and energy supplementation has been investigated for preterm infants. The key
trials are summarized in two systematic reviews, one comparing term formula
versus preterm formula [11] and one comparing fortified with unfortified hu-
man milk [12]. Only two trials of preterm versus term formula have assessed
neurodevelopment at 18 months’ corrected age [11]. The trials included preterm
infants with birthweight <1,750 g. In one trial, only infants who were growing
normally with a rate of weight gain ≥25 g/day at time of discharge were eligible
to participate [19]; in the other trial, infants had to weigh <3,000 g at time of
discharge [20]. Infants were randomized to receive nutrient-enriched formula
(72–80 kcal and 1.85–2.2 g protein/dl) or standard term formula from discharge
to 6 [19] or 9 [20] months after term. A meta-analysis of data from both trials
(n = 299) showed no significant difference in mental (WMD 0.23, 95% CI: –2.99
to 3.45) or psychomotor development (WMD 0.55, 95% CI: –1.95 to 3.05) [11].
Only one small trial (with a high loss to follow-up) of postdischarge fortification
of human milk was found for inclusion in a systematic review [12]. Thirty-nine
preterm infants born at <33 weeks’ gestation, with birthweight 750–1,800 g were
included in the trial [26]. Infants were randomized to have half of the daily breast
milk intake fortified to achieve an approximate protein and energy content of
2.2 g and 81 kcal/100 ml or no fortification (1.3 g protein and 68 kcal/100 ml)
for 12 weeks. No significant difference in developmental outcome was found at
18 months’ corrected age [intervention mental development index (MDI) 100
(1st to 3rd centile; 72–102.5) versus control 91 (1st to 3rd centile; 77–107)] [12].

Protein-Energy Supplementation of Term Growth-Restricted Infants

Limited data exist for term-born infants who are born small for gestational age
(SGA). The benefits of a nutrient-enriched formula compared with standard
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formula for SGA term infants (>37 weeks and birthweight <10th percentile for
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216 Makrides · Anderson · Gibson · Collins

Bhatia J, Bhutta ZA, Kalhan SC (eds): Maternal and Child Nutrition: The First 1,000 Days.
Nestlé Nutr Inst Workshop Ser, vol 74, pp 211–221, (DOI: 10.1159/000348775) Nestec Ltd., Vevey/S. Karger AG., Basel, © 2013
sex/age) also require more clarification. At 9 months of age, infants fed the nu-
trient-enriched formula from week 1 after birth until 9 months of age, had a
significant disadvantage (MD –2.5, 95% CI: –4.6 to 0.4) in overall DQ as assessed
with the Knobloch Developmental Screening Inventory. There was a significant
sex by treatment interaction with girls fed the nutrient-enriched formula per-
forming significantly poorer (MD –5.1, 95% CI: –7.8 to –2.4) compared to boys
(MD 0.9, 95% CI: –2.4, 4.2). At 18 months, however, the same cohort of infants
assessed using the Bayley Scales of Infant Development (BSID) showed that the
enriched formula had no significant effect on mental or psychomotor develop-
ment compared with standard formula [27].
Although protein-energy supplementation for LBW infants has been widely
studied, there are surprisingly few well-conducted trials with neurodevelop-
mental outcomes that have adequate sample sizes to draw robust conclusions
regarding the direct effect of protein-energy supplementation on cognitive and
psychomotor outcomes.

Micronutrient Supplementation

Individual micronutrient building blocks, which do not contribute energy, are

also considered important for brain development, and a number of studies
have specifically investigated individual nutrient supplementation for LBW
infants, although LC-PUFA have been the most widely studied in relation to
neurodevelopment.

Zinc and Iron

Zinc supplementation and neurodevelopment has been investigated in two tri-

als of LBW term infants in low-income families in Brazil and India [28, 29]. In
one trial in an impoverished community in India, 1,250 infants were random-
ized to receive a daily supplement of: (1) 5 mg of zinc sulfate, in a micronutrient
mix of riboflavin, calcium, phosphorus, folate and iron supplement, or (2) the
same micronutrient mix without zinc, or (3) 5 mg of zinc sulfate with riboflavin
or (4) riboflavin only [29]. Treatment was given from 30 days of age to 9 months.
200 infants were randomly selected from groups 1 and 2 for neurodevelopmen-
tal assessment at 6 and 10 months of age. No significant difference in mental
development was found at either time point (MDI intervention 83, SD 9 vs.
control 82, SD 9; intervention 86, SD 5 vs. control 86, SD 5, at 6 and 10 months,
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respectively) [29].
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Bhatia J, Bhutta ZA, Kalhan SC (eds): Maternal and Child Nutrition: The First 1,000 Days.
Nestlé Nutr Inst Workshop Ser, vol 74, pp 211–221, (DOI: 10.1159/000348775) Nestec Ltd., Vevey/S. Karger AG., Basel, © 2013
 In the only other trial of zinc supplementation where neurodevelopment was
measured, the intent was to randomize 250 infants to receive a 5-mg oral solution
of zinc compared with no supplementation form birth to 8 weeks of age [28].
There was an error in the manufacture of the solution such that it only contained
1 mg of zinc rather than 5 mg. At this stage, 134 infants had been randomized.
The study continued with a further 71 infants enrolled to receive 5 mg of zinc,
i.e. not randomized, to give a total sample size of 134. No significant difference
in either mental or psychomotor development was found at 6 or 12 months of
age between placebo, 1 mg of zinc and 5 mg of zinc supplement (12 months MDI:
1 mg zinc 107, SD 11; 5 mg zinc 107, SD 12; placebo 109, SD 12; p = 0.6) [28].
Iron supplementation has been investigated in a small trial of LBW infants
born weighing <2,500 g. Fifty-eight infants were randomized to receive a high-
iron-containing formula (21 mg/l) compared with formula containing 13.4 mg/l
[30]. The infants’ neurodevelopment was assessed using the Griffiths Develop-
mental Assessment at 3, 6, 9 and 12 months of age, with no significant difference
found at any time point (12 months DQ higher iron 118, SD 11 vs. control 118,
SD 10, n = 42).

Long-Chain Polyunsaturated Fatty Acids

Supplementation of infant formula with LC-PUFA for preterm infants has been
the focus of two recent systematic reviews [31, 32]. Both reviews found that
supplemented formula had no significant effect on DQ compared with no sup-
plementation. At 12 months’ corrected age in a meta-analysis of 4 trials includ-
ing 364 preterm infants, the WMD in BSID MDI was 0.96 (95% CI: –1.42 to
3.34) [31]. At 18 months’ corrected age, a 2.4-point improvement in DQ was
found, but again this was not significant (95% CI: –0.33 to 5.12) [31].
Different versions of the BSID were used in the included trials, and because
of this, Smithers et al. [32] conducted a subgroup analysis according to BSID ver-
sion. The second version of the BSID included more language and problem solv-
ing items for 12- to 18-month-old children. This, along with differences in scor-
ing and administration, may have introduced systematic differences in assessing
neurodevelopment [32]. Accordingly, when trials using the same version of the
BSID were considered as a separate subgroup, the cognitive DQ of LC-PUFA-
supplemented infants assessed using version II of the Bayley Scales was signifi-
cantly higher than control [32]. The meta-analysis included 5 trials of 879 infants
and demonstrated a mean difference in MDI of 3.4 points (95% CI: 0.56–6.31).
Beyond 18 months, only one study has followed children into early childhood
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to determine cognitive effects of LC-PUFA supplementation in infancy [33]. This

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Bhatia J, Bhutta ZA, Kalhan SC (eds): Maternal and Child Nutrition: The First 1,000 Days.
Nestlé Nutr Inst Workshop Ser, vol 74, pp 211–221, (DOI: 10.1159/000348775) Nestec Ltd., Vevey/S. Karger AG., Basel, © 2013
trial of 238 infants randomized to formula supplemented with 0.5% DHA as total
fatty acids versus unsupplemented, given from enrolment to 9 months of age as-
sessed children when 10 years of age. They found no difference in IQ but did find
suggestions of sex-specific and diet-specific effects, i.e. girls who received supple-
mented formula performed significantly better at single word reading accuracy
and spelling than girls who received unsupplemented formula. In infants who did
not receive any breast milk, those who were fed supplemented formula per-
formed significantly better on a number of cognitive outcomes including IQ than
infants who received unsupplemented formula [33]. However, given the very
large losses to follow-up (55%), interpretation and generalization is difficult.
Most preterm formula has been supplemented with LC-PUFA since early
2000. Of more current clinical relevance are two recent trials in which DHA dos-
es reflective of the estimated in utero accretion rate were used [34, 35]. These tri-
als also included infants fed human milk. Both trials reported improvements in
neurodevelopment. Henriksen et al. [34] studied 141 very LBW infants (<1,500 g)
and demonstrated an improvement in problem solving at 6 months’ corrected
age (intervention 53.4, SD 7.0 vs. control 49.5, SD 9.5; p = 0.02; n = 105). In a
further follow-up at 20 months of age, they showed no difference in MDI (inter-
vention 103, SD 10 vs. control 101, SD 13, p = 0.4; n = 92) but reported a signifi-
cant improvement in sustained attention in free play activities [36]. The small
sample size and large losses to follow-up make interpretation difficult.
The best evidence comes from the largest trial [35]. Although there were no
significant differences in overall cognitive DQ at 18 months’ corrected age (MD
1.9; 95% CI: –1.0 to 4.7), girls had a significant 4.5-point (≈0.3 SD) improvement
in cognitive DQ (95% CI: 0.5–8.5) [35]. In post hoc analyses, significant mental
delay (MDI <70) was reduced from 10.5% in the control group to 5% in the high-
er DHA group (RR 0.50; 95% CI: 0.26–0.93). These children are currently being
followed at 7 years’ corrected age to determine the effect of early LC-PUFA sup-
plementation on cognitive outcome in early childhood. While suggestion of ben-
efit is evident for LC-PUFA supplementation at 18 months of age, the long-term
benefits of LC-PUFA supplementation in preterm children remain unclear.

Conclusion

LBW infants have well-documented cognitive deficits compared with their term,
normal-birthweight counterparts. While it makes logical sense that at least part of
these cognitive deficits may be explained by nutritional deprivation and that nu-
tritional enrichment may improve the longer term neurodevelopmental outcomes
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of LBW children, few studies have been able to support this hypothesis. However,
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Nestlé Nutr Inst Workshop Ser, vol 74, pp 211–221, (DOI: 10.1159/000348775) Nestec Ltd., Vevey/S. Karger AG., Basel, © 2013
the lack of support for the hypothesis linking nutritional supplementation and
neurodevelopmental outcome is largely because the available studies were too
small or had methodological shortcomings, limiting their ability to draw robust
conclusions. Further large-scale rigorously designed intervention trials, with
long-term neurodevelopment follow-up, are required to determine the optimal
nutritional supplements and the timing of their administration to LBW infants.

Disclosure Statement

Maria Makrides serves on advisory boards for the Nestlé Nutrition Institute, Fonterra
and Danone, and associated honoraria are paid to her institution to support the continu-
ing education of early and mid-career researchers. Robert Gibson serves on advisory
boards for Fonterra, and associated honoraria are paid to his institution to support the
continuing education of early and mid-career researchers. For Carmel Collins and
Amanda Anderson, there are no financial or other conflicts to report.

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Nestlé Nutr Inst Workshop Ser, vol 74, pp 211–221, (DOI: 10.1159/000348775) Nestec Ltd., Vevey/S. Karger AG., Basel, © 2013