Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set
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formulas specially designed for preterm infants, the
carbohydrate content is enriched by the addition of
glucose polymers. Preterm infants are able to digest
glucose polymers, apparently through the action of
salivary amylase and mucosal a-glycosidase.
0003 Protein is required for the formation of new tissues
and is therefore essential for growth and repair.
Because of the immaturity of the amino acid meta-
bolic pathways, preterm infants are not able to
completely metabolize several amino acids. Hence,
excessive protein intake might lead to incomplete
amino acid catabolism resulting in elevation of
plasma concentration of amino acids, hydrogen ion,
and ammonia. Also, because of the immature amino
acid metabolism, preterm infants are not able to syn-
thesize some amino acids that are nonessential in
older subjects. These amino acids, notably cysteine,
taurine, and glycine, must be provided in the diet.
0004 The fat component of milk consists mainly of tri-
glycerides. The digestion of fat begins in the intestinal
lumen when the triglycerides are solubilized and
hydrolyzed into fatty acids by the combined action
of bile sat and lipase. In the preterm infants, pancre-
atic lipase and intraluminal bile salts are relatively
deficient, and triglyceride hydrolysis is carried out
mainly by the action of endogenous lingual lipase
and gastric lipase, and also the lipase present in
human milk. Infants with gestation less than 26
weeks might have impaired fat digestion owing to a
deficiency of gastric lipase. The second phase of fat
digestion takes place in the intestinal mucosa, where
fatty acids are reesterified to form chylomicron,
which is secreted into the lymphatics. Some of the
fatty acids remain unesterified and are directly
absorbed into the portal venous system.
0005 Medium chain triglycerides (MCT) are incorpor-
ated into the intestinal mucosal cells without the need
for intraluminal lipase or bile salt. In the intestinal
mucosa, MCT are hydrolyzed by mucosal lipase, and
absorbed directly into the portal venous system. Thus
the addition of MCT to preterm infant formulas
should theoretically enhance fat absorption. A
number of studies showed that MCT increase energy
absorption and better weight gain in preterm infants,
but others failed to demonstrate any benefit of MCT
in energy or nitrogen balance.
0006 Besides being a concentrated source of calories,
fat is also an important component of phospho-
lipids, which are essential for cellular functions and
the formation of a large variety of bioactive metab-
olites including surfactant and the prostaglandins.
Some fatty acids, including linoeic acid and linolenic
acid, cannot be synthesized by the body, and are
known as essential fatty acids. Deficiency in these
fatty acids in animal fetus has been associated with
long-term impairment in learning and visual func-
tion. Linoleic acid and linolenic acid are metabolized
to arachidonic acid and docosahexaenoic acid,
respectively, both of which are essential for growth
and development, especially of the central nervous
system. In the preterms, the formation of arachido-
nic acid and docosahexaenoic acid is relatively in-
sufficient, especially when the supply of calories is
suboptimal.
0007Arachidonic acid (20:4n-6) and docosahexaenoic
acid (22:6n-3) belong to the n-3 and n-6 long-chain
polyunsaturated fatty acids (LCPUFA) with double
bonds at the six and third position, respectively.
LCPUFA are present in human milk but absent from
formula milk. In a randomized control trial in 447
full-term infants, supplementation with n-3 and n-6
LCPUFA did not seem to have any beneficial or
adverse effect. In another randomized control trial
on 56 healthy full-term infants, supplementation of
infant formulas with 0.35% DHA or with 0.36%
DHA and 0.72% arachidonic acid results in an in-
crease of 7 points on mental development index at 18
months of age.
Nutritional Requirements of Preterm
Infants
Energy
0008Energy intake from food is required to maintain the
resting metabolism, normal body temperature, and
growth. A small amount of energy is excreted in the
feces and urine. Normally, a very low birth-weight
infant can retain up to 85–95% of the energy intake
starting at 2–3 weeks of age. The resting metabolic
rate of a preterm infant is around 40 kcal kg
1
day
1
in the first week, increasing to 50 kcal kg
1
day
1
by
2–3 weeks of age, and is higher in small for gesta-
tional age infants. The energy expenditure due to
activity is highly variable, and the reported values
range from 3.6 to 19 kcal kg
1
day
1
. Energy spent
on thermoregulation should be negligible in infants
being nursed in a thermal neutral environment. Pub-
lished data on the energy of growth vary greatly as the
amount of energy varies with the composition of the
tissues synthesized. A reasonable estimate is approxi-
mately 3–4.5 kcal per gram weight gain, or an average
of 10 kcal kg
1
day
1
. The total energy requirement,
including that for the basal metabolic need, growth,
stored energy, energy excreted, and energy stored,
activity, is approximately 90–120 kcal kg
1
day
1
.
Infants who have suffered from intrauterine growth
retardation require a higher energy intake. Infants
with medical or surgical complications also have
significantly greater demands for energy.
PRETERM INFANTS – NUTRITIONAL REQUIREMENTS AND MANAGEMENT 4785
Carbohydrate
0009 Carbohydrate is an important and readily usable
source of energy. An adequate supply of glucose also
serves to prevent catabolism of body tissues. During
the early days of life when the infant is sick from the
complications of prematurity, glucose is often given
via the intravenous route to maintain a normoglyce-
mic state. Any shortage of exogenous glucose supply
at this stage will result in hypoglycemia, which may
cause injury to the brain and potentially other organs
since glucose is the major, if not the only, source of
energy for the metabolism of the nervous system, red
blood cells, the renal medulla, and the retina. Exces-
sive glucose supply, however, results in hypergly-
cemia, which causes glycosuria and osmotic diuresis,
and stimulation of pancreatic islet cells resulting in
rebound hypoglycemia when the glucose supply is
interrupted. In most preterm infants, the glucose
infusion rate should be 4–6mgkg
1
min
1
. The ex-
tremely preterm infants may develop hyperglycemia,
even at this rate of glucose infusion, because of
inadequate insulin secretion, or peripheral insulin
resistance. These infants may require a reduction of
glucose intake or insulin therapy. When the infant
becomes stable and is taking enteral milk feeding,
carbohydrate should contribute to about 40–50% of
the total caloric intake (10–14 g per kilogram of body
weight), which is the proportion of carbohydrate
content in human milk.
Protein
0010 The estimation of protein requirement and the
requirements of most other nutrients were based on
the need of the growing fetus of the same gestation.
Daily protein requirements appeared to be 2–4g
kg
1
. In extremely low birth-weight infants, the
amount could be increased in stepwise fashion over
a span of 2 weeks. This should be accompanied by
a concomitant increase in calories intake, since pro-
tein synthesis requires energy. For each gram of
protein deposited, the body spends about 10 kcal of
energy. A deficient energy intake will result in the
breakdown of endogenous protein and a negative
nitrogen balance.
Fat
0011 Fat provides a concentrated source of energy and is
also required to provide the essential fatty acids. As
recommended by the European Society of Paediatric
Gastroenterology and Nutrition Committee on Nu-
trition, the fat intake of enterally fed preterm infants
should be 40–55% of the total calories intake, or 4.4–
6.0 g per 100 kcal. The Committee also recommended
a linoleic acid content of 4.5–10.8% of the total
energy content of infant formulas, and a linoleic
acid: a-linolenic acid ratio of 5:1 to 15:1.
0012Carnitine facilitates the transport of long-chain
fatty acids through the mitochondrial membrane
and is therefore essential for the oxidation of fatty
acids for energy production in the heart and skeletal
muscle. The European Society of Paediatric Gastro-
enterology and Nutrition Committee on Nutrition
recommended that infant formulas contain at least
7.5 mmol of carnitine per 100 kcal. This amount
should be available in human milk. Carnitine is now
added to some of the commercial parenteral nutrition
fluid. There is, however, no clinical evidence that
supplementation of carnitine to the parenteral lipid
infusion has any physiological benefit.
Vitamins and Minerals
0013Vitamin A Vitamin A is important for the growth
and differentiation of epithelial cells, and its defi-
ciency results in pathological changes of the epithe-
lium, including that of the airways and lungs. The
vitamin is transferred to the fetus from the mother
mainly during late gestation, and therefore the vita-
min content is significantly lower in the preterm
infants than in the term infants. Several studies have
demonstrated a protective effect of vitamin A supple-
mentation against bronchopulmonary dysplasia in
preterm infants. Excessive vitamin A intake results
in intoxication manifesting with increased intracra-
nial pressure, bone and joint damage, mucocutaneous
lesions, liver damage, and hematological changes.
0014The dietary intake of vitamin A, as recommended
by the World Health Organization, is 333 IU
kg
1
day
1
. This amount may not be sufficient for
preterm infants, and a daily intake of 1500 IU kg
1
,
700–1500 IU kg
1
, and 700 IU kg
1
has been recom-
mended for infants weighing less than 1000 g, 1000–
1750 g, and 1751–2500 g, respectively. Infants at risk
of developing BPD, namely the extremely preterm
infants with respiratory distress requiring supplemen-
tal oxygen and mechanical ventilation, might be
protected from BPD by additional vitamin A intake.
It has been demonstrated that, in these infants,
biochemical vitamin A deficiency could be corrected
with intramuscular administration of 5000 IU of vita-
min A given three times per week for 4 weeks, which
was associated with a slight reduction in the risk of
chronic lung disease.
0015Vitamin E Vitamin E is a biologic antioxidant
important for the integrity of the lipid layers of
cell membranes. Its deficiency in preterm infants
has been associated with hemolytic anemia, and
impaired phagocytosis. Clinical trials have been
carried out to evaluate its protective effects
4786 PRETERM INFANTS – NUTRITIONAL REQUIREMENTS AND MANAGEMENT
against bronchopulmonary dysplasia, retinopathy
of prematurity, and intraventricular hemorrhage.
However, there is no convincing evidence that vita-
min E protects preterm infants from any of these
conditions.
0016 Because of the limited tissue store and poor dietary
absorption of vitamin E, and the rapid growth of the
preterm infants, The American Academy of Pediatrics
Committee on Nutrition recommended that preterm
infants should receive 5–25 IU supplemental oral
vitamin E per day.
0017 Vitamin K Vitamin K is a cofactor in the metabolic
conversion of intracellular precursors of vitamin
K-dependent clotting factors 2, 7, 9, and 10. Vitamin
K deficiency results in hemorrhagic disease of new-
born. Purely breast fed infants are particularly prone
to develop vitamin K deficiency, since the concentra-
tion of the vitamin is very low in human milk. The
current recommended daily intake of vitamin K for
newborn infants is the same as that for children and
adults, namely 1 mg kg
1
day
1
.
0018 Vitamin D Vitamin D is obtained from the diet or
produced endogenously in the skin after exposure to
ultraviolet light. The vitamin is hydroxylated to 25-
hydroxyvitamin in the liver, which is further hydro-
xylated to its most active ingredient, 1,25-dihydroxy
vitamin D in the kidney. The process is stimulated by
parathyroid hormone and deficiency in calcium and
phosphate. Vitamin D increases intestinal calcium
and phosphorus absorption; 1,25-dihdroxy vitamin
D also maintains normal circulating calcium concen-
tration by its direct action on mobilization of bone
calcium and phosphorus to the extracellular fluid.
The role of vitamin D in the cause of osteopenia and
ricket of the newborn is not clear. It appears that
mineral (calcium and phosphorus) intake is the most
important factor affecting bone mineralization, since
infants with low mineral intake developed ricket des-
pite supplementation of vitamin D of up to 2000 IU
day
1
, whereas ricket could be prevented by high
mineral intake and moderate vitamin D (400 IU
day
1
) supplementation. Thus, a daily enteral intake
of vitamin D of 400 IU should be sufficient for the
preterm infants. For infants on parenteral nutrition, a
daily intake of 40–160 IU kg
1
has been recom-
mended, with a maximum intake not exceeding
400 IU day
1
.
0019 Water-soluble vitamins The water-soluble vitamins,
vitamin C, vitamin B
1
(thiamin), vitamin B
2
(ribofla-
vin), vitamin B
3
(niacin), vitamin B
6
(pyridoxine),
pantothenic acid, and biotin, are cofactors for several
important enzymatic reactions, and deficiencies can
result in abnormal substrate utilization. The exact
requirements for these vitamins by preterm infants
are not clear. The vitamins are water-soluble, and
therefore, excessive intake will be excreted in the
urine. The current recommended dietary allowance
(RDA) for the term neonate is: vitamin C 30
mg day
1
, vitamin B
1
300 mg day
1
, vitamin B
2
400 mg day
1
, vitamin B
6
300 mg day
1
, niacin
5 mg day
1
. The RDA of biotin and pantothenic
acid has not been established, but doses of
10 mg day
1
and 2 mg day
1
mg have been suggested
for biotin and pantothenic acid, respectively. For pre-
term infants, it has been suggested that those
weighing > 1500 g should receive the RDA, whereas
smaller infants can be supplemented with half the oral
doses. Very low birth-weight infants on total paren-
teral nutrition should be supplemented with 25–
30 mg of vitamin C per kilogram per day, 35 mg
of vitamin B
1
per kilogram per day, 150–200 mgof
vitamin B
2
per kilogram per day, 150–200 mg of vita-
min B
6
per kilogram per day, 4–6 mg of niacin per
kilogram per day, 5–8 mg of biotin per kilogram
per day, and 1–2 mg of pantothenic acid per kilo-
gram per day.
0020Folic acid is a water-soluble vitamin that is import-
ant for DNA synthesis and cell division, especially in
tissues with high rates of cell multiplication, such as
the bone marrow and intestine. Preterm infants are
predisposed to folic acid deficiency because of limited
intrauterine hepatic stores and because of their rapid
postnatal growth. The American Academy of Paedi-
atrics Committee on Nutrition for Preterm Infants
recommended that preterm infants < 2000 g should
receive 50 mg of folic acid daily, with a minimum
intake of no less than 4 mg per 100 kcal, which is the
same as that for term infants. Preterm infants on total
parenteral nutrition should be given folic acid supple-
ment at a dose of 56 mgkg
1
day
1
(140 mgkg
1
day
1
for full term) usually in the form of a multi-
vitamin preparation.
0021Vitamin B
12
is a water-soluble vitamin. Its defi-
ciency may result in megaloblastic anemia and neuro-
logical changes during late infancy. The minimal
dietary intake for preterm infants, as recommended
by the American Academy of Pediatrics Committee
on Nutrition, is 0.15 mg per 100 kcal, which is the
same as that for term infants. Preterm infants on
total parenteral nutrition should be given vitamin
B
12
supplement at a dose of 0.3 mgkg
1
day
1
(1 mg
kg
1
day
1
for full term).
Minerals
0022Calcium, phosphorus, and magnesium Calcium
and phosphorus are the major constituents of bone.
Magnesium is also an important constituent of
PRETERM INFANTS – NUTRITIONAL REQUIREMENTS AND MANAGEMENT 4787
bone, but a large amount is also found in the muscle
and intracellular fluid. About 80% of these minerals
accrue in the fetus from 25 weeks of gestation to
term. The peak accretion rate occurs between 36
and 38 weeks of gestation. The amount of minerals
present in human milk and ordinary infant formulas,
especially that of calcium and phosphorus, is not
sufficient to cope with this rate of mineral accumula-
tion. Osteopenia and rickets are common among
the extremely preterm infants, and the condition
can be prevented by high calcium and phosphorus
intake. The recommended daily intakes of calcium,
phosphorus, and magnesium for preterm infants
are 210 mg kg
1
(5.25 mmol kg
1
), 140 mg kg
1
(4.52 mmol kg
1
) and 10 mg kg
1
(0.42 mmol kg
1
),
respectively.
0023 Sodium and potassium Preterm infants, particularly
those with a birth weight less than 1500 g, have sig-
nificant urinary sodium loss during the first 10–14
days of life because of high fractional excretion rates
of sodium. During this time when the infants are sick
and unstable, serum sodium and potassium values are
affected by a number of factors including the amount
of fluid intake, the rate of evaporative fluid loss,
which is affected by environmental temperature and
humidity, and therapeutic interventions such as
mechanical ventilation. These infants are normally
given only parenteral fluid. Restriction of parenteral
sodium intake during the first 2 days of life is a
common practice in neonatal intensive care units
and may prevent the development of hypernatremia.
Additional potassium intake is also not necessary
during this period. Subsequently, the daily require-
ment is 2–3mmolkg
1
for each of sodium and potas-
sium. The amount of supplementation has to be
adjusted according to the serum sodium and potas-
sium levels, which should be monitored frequently for
as long as the infant is on intravenous feed. Preterm
infants on enteral feeding also require 2–3mmolof
sodium per kilogram per day, which is greater than
that required by term infants. The sodium content in
term human milk and commercial infant formulas
designed for the feeding of term infants is too low
to meet the requirement of very low birth-weight
preterm infants and may lead to hyponatremia
when given to these infants as the sole source
of sodium. Special formulas for preterm infants
provide 2.5–3.5 mmol of sodium per kilogram
per day at full feeding. During the stable and
growing period, sodium requirements are usually
met with a daily intake of 2–3 mmol kg
1
day
1
.
The potassium requirement of preterm infants seem
to be the same as that of term infants (2–3 mmol
kg
1
day
1
).
0024Trace minerals Eight trace minerals are nutrition-
ally essential for the human: iron, zinc, copper,
selenium, chromium, molybdenum, manganese, and
iodine.
0025Preterm infants have low iron stores because iron
accumulation occurs mainly at the third trimester at a
rate of 1.6–2.0 mg kg
1
day
1
. This, together with the
rapid growth rate of preterm infants, and the frequent
blood sampling during the early postnatal days,
results in a high incidence of iron deficiency anemia
after age 4 months. The incidence has been decreased
with iron supplementation. At the same time, these
infants are also often given multiple transfusions,
which may restore the iron load and impair intestinal
absorption of iron.
0026The American Academy of Pediatrics Committee
on Nutrition recommended that iron should be
started no later than 2 months of age in very low
birth-weight preterm infants and should be continued
for at least the remainder of the first year. The recom-
mended dose is 2 mg kg
1
day
1
up to a maximum of
15 mg day
1
. Others have suggested that iron should
be started at 2 weeks of age or when the body weight
doubles the birth weight. Iron supplementation is
particularly important when the infant is being
treated with erythropoietin because of increased
erythropoiesis.
0027Zinc is important for protein metabolism and cell
growth. Fetal accretion of zinc takes place mainly
during the third trimester of pregnancy, and preterm
infants have a lower total store at birth than term
infants. The daily enteral intake of zinc, as recom-
mended by the American Academy of Paediatrics and
the European Society of Paediatric Gastroenterology
and Nutrition, is 600 mgkg
1
day
1
and 720–1400 mg
kg
1
day
1
respectively.
0028Copper is an essential component of many oxida-
tive enzymes and is important for the integrity of cell
membranes. Its deficiency presents clinically with
anemia, neutropenia, osteoporosis, decreased pig-
mentation of the skin and hair, dermatitis, failure to
thrive, diarrhea, hypotonia, and psychomotor
retardation. The recommended daily enteral intake
of copper for preterm infants is 100–150 mgkg
1
.
For infants on long-term parenteral nutrition, the
recommended daily intake is 20 mgkg
1
. Copper sup-
plementation is not necessary for those on only short-
term TPN. As copper is primarily metabolized in the
liver, and reduced hepatic excretion may cause liver
cirrhosis, it should be withheld from infants with
cholestasis.
0029Iodine is essential for the manufacturing of thyroid
hormones. Transient hypothyroidism has been
reported in preterm infants taking 10–30 mgkg
1
day
1
of iodine. Excessive intake of iodine, however,
4788 PRETERM INFANTS – NUTRITIONAL REQUIREMENTS AND MANAGEMENT
also suppresses the thyroid gland. The recommended
daily intake of iodine for stable growing preterm
infants is 30–60 mgkg
1
day
1
. For infants on total
parenteral nutrition (TPN), a daily intake of 1 mgkg
1
is recommended.
0030 Selenium is an essential constituent of the enzyme
glutathione peroxidase. Its deficiency results in car-
diomyopathy affecting children and adults. Clinical
selenium deficiency has, however, not been reported
in preterm infants. The recommended daily enteral
intake of selenium for stable and growing preterm
infants is 1.3–3 mgkg
1
. Infants on parenteral nutri-
tion should be supplemented with selenium at a dose
of 2 mgkg
1
day
1
.
0031 Chromium is a cofactor involved in glucose
homeostasis. Chromium deficiency has not been de-
scribed in newborns. The daily recommended intake
for stable and growing preterm infants is 0.1–0.5 mg
kg
1
. The recommended daily parenteral intake for
infants on TPN is 0.2 mgkg
1
.
0032 Molybdenum is required for the function of certain
enzymes, including xanthine oxidase. Its deficiency
has not been described in the newborns. The recom-
mended daily enteral intake for stable preterm infants
is 0.3 mgkg
1
. The recommended intake for infants
on total parenteral nutrition is 0.25 mgkg
1
day
1
.
0033 Manganese is required for the function of pyruvate
carboxylase, superoxide dismutase, and glycosyl
transferase. Manganese deficiency has not been
reported in the newborns. The recommended intake
for stable growing preterms is 0.75–7.5 mgkg
1
day
1
. The recommended parenteral intake for
infants on total parenteral nutrition is 1 mgkg
1
day
1
. Since manganese is metabolized in the liver,
and its accumulation has been implicated as a cause
of cholestasis and damage to the central nervous
system, the element should be withheld from infants
with cholestasis or impaired liver function.
Dietary Sources of Nutrients
Carbohydrate
0034 The lactose content of mature human milk is 7.4–
9.9 g dl
1
. The lactose content of preterm milk is
6.99 g dl
1
after 26–31 weeks of gestation and
6.24 g dl
1
after 32–36 weeks of gestation. In preterm
formulas, the carbohydrate content is about 8.5 g
dl
1
and consists of lactose and glucose polymers in
equal amounts. Compared with lactose, the addition
of glucose polymers to formulas adds fewer osmotic
particles per unit weight. Its use has allowed a
substantial increase in the carbohydrate content
of formulas without any significant increase in
osmolality.
0035In infants receiving parenteral nutrition, carbohy-
drate is usually given in the form of intravenous glu-
cose. As described above, the glucose infusion rate
should be sufficient to maintain a normoglycemic
state, and most preterm infants will require a glucose
infusion rate of 4–6mg kg
1
min
1
. The extremely
preterm infants may not be able to tolerate glucose
load and may require a reduction in the infusion rate
or insulin therapy.
Protein
0036Mature human milk cannot provide sufficient protein
for preterm infants since its protein content is only
1.2 g dl
1
. To obtain a daily amount of protein of 3 g
kg
1
, the infant has to consume 250 ml of milk per
kilogram per day. The milk produced by the preterm
baby’s own mother contains significantly more pro-
tein, especially during the first few weeks of life, and
is more suitable for the infant. However, as the pro-
tein content of the preterm milk declines rapidly after
delivery, and becomes quite similar to that of term
milk after 2 weeks, it is now common practice to
enrich the protein content of expressed breast milk
with human milk fortifier. Such supplementation has
resulted in a greater weight gain and nitrogen reten-
tion.
0037Formulas specially designed for preterm infants
have a higher protein content than breast milk –
ranging from 1.8 to 2.4 g dl
1
and providing about
2.2–3.2 g of protein per 100 kcal.
0038Infants on parenteral nutrition are given protein in
the form of amino acid mixture. Currently available
amino acid mixtures provide up to 3 g kg
1
day
1
of
protein intake, and are able to meet the requirements
for growth and nitrogen retention.
Fat
0039The fat content of mature expressed human milk is
around 3.5–4.5 g dl
1
. The fat content of premature
milk is lower, and its content and composition vary,
depending on the mother’s dietary fat intake. The fat
content in the milk obtained by manual expression
(expressed breast milk) is higher than drip breast
milk. During tube feeding, substantial reduction in
fat intake may result from the deposition of fat on
the wall of the gastric tube.
0040Preterm formulas often contain 20–50% MCT.
MCT are absorbed directly into the portal venous
system without the need for intraluminal bile salts,
which are relatively deficient in the preterms. The
benefit of adding MCT oils to preterm formulas is
controversial.
0041Several commercially available premature formu-
las are now supplemented with LCPUFAs.
PRETERM INFANTS – NUTRITIONAL REQUIREMENTS AND MANAGEMENT 4789
0042 Preterm infants on parenteral nutrition are given
intravenous lipid, which contains about 45–55%
linoleic acid and 6–9% linolenic acid. Normally, in-
fusion of 0.5–1 g of lipid per kilogram per day of lipid
will prevent essential fatty acid deficiency. More lipid
can be given to provide more energy but should not
exceed the rate of lipid clearance from the plasma.
Most infants over 28 weeks of gestation can clear
from the plasma up to 2 g of lipid per kilogram per
day, and most infants more than 32 weeks of gesta-
tion can clear up to 3 g kg
1
day
1
. Infants less than
28 weeks of gestation are less able to clear lipid and
have a high chance of hyperlipidemia when receiving
intravenous lipid.
0043 Intravenous lipid is hydrolyzed by endogenous
lipoprotein lipase. The use of MCT in the lipid prep-
aration results in more rapid clearance of lipid from
the blood. There is, however, no clinical evidence that
MCT preparation offers any physiological or meta-
bolic advantage to the preterm infants.
Vitamins and minerals
0044 Vitamin A The concentration of vitamin A in
preterm milk is approximately 300 IU dl
1
, which is
lower than that in term milk. The concentration is,
however, variable. Preterm formulas are fortified
with a vitamin A concentration of 250–1000 IU
dl
1
. Multivitamin preparations usually contain
about 1500 IU of vitamin A per milliliter.
0045 Vitamin E The vitamin E content of preterm human
milk is sufficient to satisfy the requirement of the
preterm infant. The American Academy of Pediatrics
Committee on Nutrition recommended that formulas
designed for preterm infants should meet the min-
imum requirement of 0.7 IU per 100 kcal and 1.0 IU
of linoleic acid per gram. The currently available
preterm formulas are fortified with vitamin E well in
excess of this amount. The requirement of vitamin E
by preterm infants receiving parenteral nutrition is
not clear. It has been recommended that infants
weighting < 1000 g at birth should receive supplemen-
tal vitamin E of 3.5 IU day
1
, and those weighting
1000–1500 g should receive 4.7 IU day
1
.
0046 Vitamin K The American Academy of Pediatrics
recommended that in order to prevent hemorrhagic
disease of newborns, vitamin K should be given to
term infants at birth in the form of vitamin K
1
admin-
istered intramuscularly at a dose of 1 mg. Oral vita-
min K can be used, but at a dose of 2 mg at birth, and
should be repeated at 1–2 weeks and 4 weeks after
birth. For preterm infants, an intramuscular dose of
0.3 mg is sufficient. It has been reported in one study
that intramuscular vitamin K is associated with a
higher incidence of childhood leukemia and suggested
that it should be replaced by oral vitamin K. This
recommendation was not supported, however, by
other studies, and intramuscular injection remains
the most certain way of vitamin K administration.
Formulas designed for preterms are fortified with
vitamin K well in excess of the daily requirement of
the infants.
0047Preterm infants on TPN should be supplemented
with vitamin K in the form of a multivitamin prepar-
ation. The amount provided usually exceeds the daily
requirement of 10 mgkg
1
.
0048Vitamin D Preterm infants are often deficient in
their mineral (calcium and phosphate) intake but the
quantity of vitamin D in both human milk and for-
mulas is sufficient. Infants on parenteral nutrition
should be supplemented with vitamin D in form of a
multivitamin preparation. Care is required to ensure
that the dose is not excessive.
0049Water-soluble vitamins Human milk produced by
healthy mothers on a balanced diet is a good source
of the water-soluble vitamins vitamin C, vitamin B
1
(thiamin), vitamin B
2
(riboflavin), vitamin B
3
(niacin), vitamin B
6
(pyridoxine), pantothenic acid,
biotin, folic acid, and vitamin B
12
. Infant formulas
are now all fortified with a sufficient quantity of these
vitamins to meet the infant’s requirements.
Minerals
0050Sodium and potassium Mature human milk con-
tains 0.7–0.9 mmol per 100 ml, which is inadequate
to meet the requirement of the preterm infants. Pre-
term milk has a higher sodium content during the
first 3 weeks postpartum (1.3–1.7 mmol per 100 ml),
which declines to 0.8 mmol per 100 ml by the 4th
postpartum week. Formulas designed for preterm
infants have a higher sodium content of 1.4 mmol -
per 100 ml and are able to provide 2.5–3.5 mmol of
sodium per kilogram per day to infants receiving a
full feed of 200 ml kg
1
day
1
. The potassium content
in preterm formulas, and also in term and preterm
human milk, contain is sufficient to meet the require-
ment of 2–3mmolkg
1
day
1
in preterm infants.
0051Calcium, phosphorus, and magnesium Preterm
human milk contains only 40 mg of calcium per
100 kcal and 20 mg of phosphorus per 100 kcal,
which are insufficient to satisfy the need of the pre-
term infants. The mineral content of the milk can be
enriched by the addition of a human milk fortifier, the
use of which has been associated with improved bone
mineral content of the infants. Ordinary infant
4790 PRETERM INFANTS – NUTRITIONAL REQUIREMENTS AND MANAGEMENT
formulas also cannot provide the necessary amount of
calcium and phosphorus. Formulas designed for pre-
term infants contain 94–183 mg of calcium per
100 kcal and 50–70 mg of phosphorus per 100 kcal.
Consumption of these formulas has been associated
with improved bone mineral content of the preterm
infants. The magnesium content of both human and
formula milk is adequate for preterm infants.
0052 Preterm infants, especially very low birth-weight
infants, often have a transient period of hypocalcemia
during the first few days of life, and require intraven-
ous calcium supplement. In these infants, hypocalce-
mia can be prevented or treated with calcium infusion
in the form of 10% calcium gluconate at a rate of
1.25–1.88 mmol (50–75 mg) of elemental calcium per
kilogram per day in the first 2–3 days of life.
0053 When the minerals are being delivered to infants on
TPN, it is important that the concentrations of calcium
and phosphorus do not exceed the solubility product, or
else the minerals will precipitate. A calcium:phosphorus
ratio of 1:1 to 1.3:1 by molar ratio, or 1.3:1 to 1.7:1 by
weight, results in the highest calcium and phosphorus
retention. It has been recommended that the TPN
solution should contain 12.5–15 mmol (500–600 mg)
of calcium per liter, 12.5–15 mmol (390–470 mg) of
phosphorus per liter, and 1.5–2 mmol (36–48 mg)
of magnesium per liter. This would provide the infant
with 1.5–2.5 mmol (60–90 mg) of calcium per kilogram
per day, 1.5–2.25 mmol (47–70 mg) of phosphorus per
kilogram per day and 0.18–0.3 mmol (4.3–7.2 mg) of
magnesium per kilogram per day.
0054 Iron Human milk contains very little iron. Infants
fed on breast milk should be supplemented with fer-
rous sulfate, which provides 2–4 mg of elemental iron
per kilogram per day. Preterm formulas are fortified
with 1.33 mg of iron per 100 ml or 1.67 mg of iron
per 100 kcal, which should be sufficient for a fully fed
infant.
0055 For babies on prolonged TPN, 0.1–0.2 mg of par-
enteral iron per kilogram per day should be adminis-
tered together with the TPN solution.
0056 Trace minerals The zinc content in human milk
declines rapidly during the first few postpartum
months, and might not be sufficient to meet the
need of the growing preterm infant. Preterm formulas
contain sufficient zinc to provide the recommended
daily intake in fully enterally fed infants. It has been
suggested that preterm infants on human milk should
be supplemented with 500 mgkg
1
day
1
until 6
months of age. For infants on parenteral nutrition, it
has been suggested that the TPN solution should be
supplemented with 150 mg of zinc per kilogram per
day during the transitional period after birth.
0057The copper content in human milk and preterm
formulas is sufficient to meet the need of preterm
infants. The iodine content of human milk varies
with the dietary intake and geographic location of
the mother. In most developed countries, human
milk contains sufficient iodine to meet the need of
the preterm infants. Preterm formulas are also forti-
fied with an adequate amount of iodine. The amounts
of other trace minerals (selenium, chromium, molyb-
denum, and manganese) in both human and formula
milk are also adequate for the preterm infants.
See also: Energy: Intake and Energy Requirements; Fats:
Requirements; Folic Acid: Physiology; Magnesium;
Minerals – Dietary Importance; Phosphorus:
Physiology; Potassium: Physiology; Protein: Food
Sources; Requirements; Selenium: Physiology; Sodium:
Physiology; Thiamin: Physiology; Tocopherols:
Physiology; Vitamin K: Physiology; Zinc: Physiology
Further Reading
Birch EE, Garfield S, Hoffman DR, Uauy R and Birch DG
(2000) A randomized controlled trial of early dietary
supply of long-chain polyunsaturated fatty acids and
mental development in term infants. Developmental
Medicine and Child Neurology 42(3): 174–181.
Catzeflis C, Schutz Y, Micheli JL et al. (1985) Whole body
protein synthesis and energy expenditure in very low
birth weight infants. Pediatric Research 19(7): 679–687.
Evans JR, Allen AC, Stinson DA et al. (1989) Effect of high-
dose vitamin D supplementation on radiographically
detectable bone disease of very low birth weight infants.
Journal of Pediatrics 115(5 Part 1): 779–786.
Freymond D, Schutz Y, Decombaz J, Micheli JL and Jequier
E (1986) Energy balance, physical activity, and thermo-
genic effect of feeding in premature infants. Pediatric
Research 20(7): 638–645.
Greene HL, Hambidge KM, Schanler R and Tsang RC
(1988) Guidelines for the use of vitamins, trace elements,
calcium, magnesium, and phosphorus in infants and
children receiving total parenteral nutrition: report of
the Subcommittee on Pediatric Parenteral Nutrient Re-
quirements from the Committee on Clinical Practice
Issues of the American Society for Clinical Nutrition
[published errata appear in American Journal of Clinical
Nutrition 1989; 49(6): 1332 and 1989; 50(3): 560].
American Journal of Clinical Nutrition 48(5): 1324–
1342.
Gross SJ (1983) Growth and biochemical response of pre-
term infants fed human milk or modified infant formula.
New England Journal of Medicine 308(5): 237–241.
Hanning RM and Zlotkin SH (1989) Amino acid and pro-
tein needs of the neonate: effects of excess and defi-
ciency. Seminars in Perinatology 13(2): 131–141.
Kashyap S, Schulze KF, Forsyth M et al. (1990) Growth,
nutrient retention, and metabolic response of low-birth-
weight infants fed supplemented and unsupplemented
PRETERM INFANTS – NUTRITIONAL REQUIREMENTS AND MANAGEMENT 4791
preterm human milk. American Journal of Clinical Nu-
trition 52(2): 254–262.
Lucas A, Stafford M, Morley R et al. (1999) Efficacy and
safety of long-chain polyunsaturated fatty acid supple-
mentation of infant-formula milk: a randomised trial
[see comments]. Lancet 354(9194): 1948–1954.
Lundstrom U, Siimes MA and Dallman PR (1977) At what
age does iron supplementation become necessary in low-
birth-weight infants? Journal of Pediatrics 91(6): 878–
883.
Putet G (1993) Energy. In: Tsang RC, Lucas A, Uauy R and
Zlotkin S (eds) Nutritional Needs of the Preterm Infant.
Scientific Basis and Practical Guidelines, pp. 15–28.Cin-
cinnati, OH: Digital Educational Publishing.
Reifen RM and Zlotkin S (1993) Microminerals. In: Tsang
RC, Lucas A, Uauy R and Zlotkin S (eds) Nutritional
Needs of the Preterm Infant. Scientific Basis and Prac-
tical Guidelines, pp. 195–207. Cincinnati, OH: Digital
Educational Publishing.
Schulze KF, Stefanski M, Masterson J et al. (1987) Energy
expenditure, energy balance, and composition of weight
gain in low birth weight infants fed diets of different
protein and energy content. Journal of Pediatrics
110(5): 753–759.
Tyson JE, Wright LL, Oh W et al. (1999) Vitamin A supple-
mentation for extremely-low-birth-weight infants.
National Institute of Child Health and Human
Development Neonatal Research Network [see com-
ments]. New England Journal of Medicine 340(25):
1962–1968.
Vileisis RA (1987) Effect of phosphorus intake in total
parenteral nutrition infusates in premature neonates.
Journal of Pediatrics 110(4): 586–590.
PROBIOTICS
S E Gilliland, Oklahoma State University, Stillwater,
OK, USA
Copyright 2003, Elsevier Science Ltd. All Rights Reserved.
Background
0001 Probiotics may be defined as selected viable micro-
organisms that, following consumption in a food or
feed, have potential for improving health or nutrition
of man or animal. Bacteria in this group may be used
to ferment food or are added to food as dietary sup-
plements. Foods for human consumption containing
these organisms are sometimes referred to as func-
tional foods. A number of different bacterial species
have been suggested as probiotics (Table 1). The
major species that have been considered over the
years, however, are Lactobacillus acidophilus, Lacto-
bacillus casei, and Bifidobacterium species, and Bifi-
dobacterium longum.
0002Dairy products provide an excellent carrier for
these probiotic bacteria especially Lactobacillus acid-
ophilus, Lactobacillus casei,andBifidobacterium
species. Most of these can readily utilize lactose as
an energy source for growth; thus, an important re-
quirement for their growth in the intestinal tract is
provided by the milk. Additionally, many of them
have been used for centuries in the manufacture of
cultured dairy products and thus are generally
regarded as safe. This means that there should be no
objection to their being used as dietary adjuncts in
milk products. In the early 1900s, Eli Metchnikoff
advocated that man should consume, on a daily basis,
milk fermented by Lactobacillus species to displace
microorganisms in the intestinal tract that produce
toxic substances that could shorten man’s life. Thus,
he felt that consumption of such fermented milk
would prolong life. This theory was the beginning of
what we refer to today as foods containing probiotic
bacteria.
0003Several dairy products containing probiotic bac-
teria are marketed today, and the most widely en-
countered product is yogurt. It is not uncommon to
read on the label of a yogurt product that it was
made with a culture including Lactobacillus acid-
ophilus and/or Bifidobacterium species. These are
not the bacteria that have traditionally been used to
manufacture yogurt. The traditional yogurt starter
cultures are Streptococcus salivarius ssp. thermophi-
lus and Lactobacillus delbrueckii ssp. bulgaricus.
Neither of these two organisms is traditionally listed
as a probiotic, because they are not expected to
survive and grow in the intestinal tract, whereas
tbl0001 Table 1 Bacteria used as probiotics
Major bacteria
Lactobacillus acidophilus
Lactobacillus casei
Bifidobacterium longum
Bifidobacterium bifidum
Others
Lactobacillus ruterii
Lactobacillus johnsonii
Bifidobacterium lactis
Lactobacillus plantarum
4792 PROBIOTICS
probiotics do. In the USA, nonfermented milk prod-
ucts are available that contain added cells of Lacto-
bacillus acidophilus and/or bifidobacteria. Following
supplementation of the pasteurized milk with these
two organisms, it is stored under refrigeration so
that the probiotic bacteria do not grow in the milk.
In this case, milk serves as a carrier for the organ-
isms, and the product, of course, does not have
the sour or tart taste normally associated with fer-
mented dairy products. This provides a product con-
taining the probiotics for those people who do not
desire the taste and flavor associated with fermented
products.
Potential Benefits
0004 When Eli Metchnikoff proposed his theory to pro-
long life, the primary benefit he proposed from the
consumption of the fermented milk product was to
control the intestinal microflora. Since the interest
in probiotics was renewed some 20–30 years ago,
several other potential benefits have come to light
(Table 2). While these potential health and nutritional
benefits appear to be very important to mankind,
most of them have not been thoroughly proven. In
order to firmly establish whether or not the benefits
can actually be produced, relatively large clinical
trials will be required, especially in the case of
humans. A large number of factors must be con-
sidered when undertaking such a monumental task.
A very important aspect is the selection of the probio-
tic bacteria to be utilized. This will be discussed in a
later section of this chapter. Most of the possible
benefits listed in Table 2 have to do with human
health and nutrition. However, with the pending
ban on the use of subtherapeutic levels of antibiotics
in livestock feed, there is tremendous interest in the
role of probiotics as supplements for animal feed. The
primary interest here focuses on controlling intestinal
pathogens as well as improving nutrient utilization.
The subtherapeutic antibiotics, which have been used
for years as livestock feed supplements, have been
shown in many cases to improve the growth and
performance of livestock. While this may be due in
part to control of undesirable microorganisms in the
digestive tract, other mechanisms are also likely. Pro-
biotic bacteria offer very good opportunities for use
as livestock feed supplements to achieve these goals.
Control of Intestinal Infections
0005In the literature, there are many studies on the use of
Lactobacillus species to control intestinal infections.
Unfortunately, many of these earlier studies were not
well designed. In most cases, the probiotics, primarily
Lactobacillus species, were used as a therapeutic
rather than a preventative agent. In many cases,
proper controls were not included in the studies, so
valid observations as to the effectiveness of the pro-
biotic could not be made. Additionally, in many of
these studies, there was very little information con-
cerning the particular culture of probiotic involved,
especially with regard to origin or characteristics
giving it the potential for producing the desired effect.
0006While it is possible that they may function in a
therapeutic manner, it is more reasonable to consider
probiotics as a prophylactic treatment for intestinal
infections. This has been shown in a well-designed
study involving germ-free chickens. In this study,
germ-free chickens were fed a culture of Lactobacillus
acidophilus and 2 days later were challenged with
either Salmonella typhimurium or Staphylococcus
aureus. In the same study, another series of germ-
free chickens were fed the pathogenic organisms ini-
tially and then fed Lactobacillus acidophilus (as a
therapeutic treatment). In the therapeutic experi-
ments, the Lactobacillus acidophilus had minimal
effect, but those animals fed the Lactobacillus acid-
ophilus initially (prior to challenge with the patho-
gen) survived much better than did those animals that
were challenged with the pathogen first. These results
suggest that it is important to have the Lactobacillus
acidophilus initially (i.e., as a prophylactic treatment)
to ward off intestinal pathogens. The scientists con-
ducting this study also indicated that it was desirable
to provide the probiotic organism on a continuing
basis in a diet for best control of the pathogens.
Other studies involving animal models have con-
firmed these types of results. It is difficult to perform
such studies in humans, since it is very difficult, if not
impossible, in a university setting to obtain approval
for doing challenge studies with intestinal pathogens
using human test subjects. However, there have been
some well-designed studies in which feeding products
containing selected probiotic bacteria have been
shown to be effective in helping control naturally
occurring intestinal disorders brought on by intestinal
pathogens, especially in young children. Based
on what is known about the variation among
strains and species of this group of bacteria, it is
tbl0002 Table 2 Potential health and/or nutritional benefits from
probiotics in the diet
. Control of intestinal pathogens
. Modulation of the immune system
. Control lactose maldigestion
. Hypocholesterolemic action
. Control of colon cancer
. Improved utilization of nutrients
PROBIOTICS 4793
very important to properly select a strain or culture
for use as a probiotic to control intestinal infections.
0007 Several mechanisms have been suggested to be re-
sponsible for the control of intestinal pathogens by
probiotic bacteria (Table 3). Probiotic bacteria can
produce several types of antimicrobial agents, includ-
ing acid, bacteriocins, and hydrogen peroxide. How-
ever, because of the proteolytic enzymes in the
intestine, the role of bacteriocins (most of which are
easily inactivated by proteolysis) may be very limited.
Because of the low levels of oxygen, peroxide forma-
tion should be minimal. Acid (especially acetic acid) is
likely the most involved of these antimicrobial agents.
Some have suggested competition for nutrients as a
mechanism, although this is unlikely. Competitive
exclusion, where probiotic bacteria occupy the
binding sights on the intestinal wall, thus preventing
attachment of pathogenic organisms, may be a
main factor in some cases. Stimulation or modu-
lation of the body’s immune system, which is dis-
cussed in the next section, appears to be a very
likely mechanism.
Modulation of the Immune System
0008 Stimulation or modulation of the body’s immune
system by probiotic bacteria can have health benefits.
Probiotic bacteria can cause the body to secrete anti-
microbial substances into the intestines. These
antimicrobial substances then in turn inhibit the
growth of undesirable microorganisms. This is a
very interesting and challenging area of research and
is currently receiving considerable attention through-
out the world. While most of the research on modu-
lation of the immune system has involved animal
studies, several studies have focused on the influence
of feeding cells of Lactobacillus acidophilus on the
immune system of humans. In these studies, an in-
crease in the secretion of substances, which are
considered inhibitory for certain intestinal patho-
gens, into the intestine was observed. The ability
to modulate the body’s immune system through
the consumption of probiotic bacteria provides a
great opportunity to control intestinal pathogens
as well as potentially to have other benefits for the
consumer.
Lactose Maldigestion
0009A number of terms, including ‘lactose malabsorption‘
and ‘lactose intolerance,‘ have been used to describe
the inability of a person to digest lactose adequately.
‘Lactose maldigestion‘ seems to be a more accurate
term to describe this condition in humans, since it
refers to the inability of a person to digest lactose
adequately. This is primarily due to the absence of
sufficient amounts of the enzyme b -galactosidase in
the small intestine.
0010Microorganisms in the intestinal tract can influ-
ence the ability to digest lactose. For instance, dietary
lactose is highly toxic to germ-free chicks, whereas
chicks with a normal intestinal flora, are able to
digest the lactose. This difference has been attributed
to the lactose-hydrolyzing enzymes provided by the
microorganisms in the intestinal tract of conventional
chicks.
0011Some cultured or culture-containing milk products
have been shown to be beneficial. For instance, the
consumption of milk containing cells of Lactobacillus
acidophilus has been shown to improve the utiliza-
tion of lactose by lactose maldigestors. A similar phe-
nomenon can be observed by the consumption of
cultured yogurt containing viable starter bacteria.
The primary requirement for these probiotic and
yogurt bacteria to provide this benefit is that they
contain adequate levels of the enzyme b-galactosidase
(Figure 1). The traditional bacteria used to manufac-
ture yogurt, Lactobacillus delbrueckii ssp. bulgaricus
and Streptococcus salivarius ssp. thermophilus, are
not expected to survive and grow in the intestinal
tract, because they lack bile tolerance. However,
when they interact with bile in the intestinal tract,
their permeability is altered, permitting lactose to
enter the cells to be hydrolyzed. This results in the
organisms being able to hydrolyze lactose at a more
rapid rate than they would in milk in the absence of
bile. Thus, without growing in the intestinal tract,
these two species of bacteria can provide a benefit
for those people unable to digest lactose adequately.
Research has shown that, while the permeability of
these cells was altered in the presence of bile, it was
not sufficient to completely rupture the cells. The
b-galactosidase remains in the cell having the in-
creased permeability.
0012Bile has a similar effect on Lactobacillus acido-
philus in that the permeability of the cells increases
tbl0003 Table 3 Suggested mechanisms through which probiotics
might control intestinal infections
. Production of antimicrobial substances
. Competition for nutrients (not likely)
. Competitive exclusion
. Stimulation or modulation of the body’s immune system
LACTOSE GLUCOSE + GALACTOSE
β-galactosidase
fig0001Figure 1 Action required by probiotics to provide benefit for
lactose maldigestion.
4794 PROBIOTICS