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Praveen S. Goday and Timothy S. Sentongo
Nutritional Deficiencies During Normal Growth
David L. Suskind
Nutritional deficiencies have always been a major consideration in pediat-
rics. Although the classic forms of many of the well-documented nutritional
deficiencies are memorized during training as a physician, nutritional defi-
ciencies that can occur in otherwise asymptomatic normally growing chil-
dren are often overlooked. The two most common deficiencies seen in
children who are growing normally are iron and vitamin D deficiencies.
These deficiencies are surprisingly common and can have a significant im-
pact on the overall health of a child. This article reviews these nutritional
deficiencies and other less commonly seen deficiencies in children who
are otherwise growing normally.
Protein Energy Malnutrition
Zubin Grover and Looi C. Ee
Protein energy malnutrition (PEM) is a common problem worldwide and
occurs in both developing and industrialized nations. In the developing
world, it is frequently a result of socioeconomic, political, or environmental
factors. In contrast, protein energy malnutrition in the developed world
usually occurs in the context of chronic disease. There remains much var-
iation in the criteria used to define malnutrition, with each method having
its own limitations. Early recognition, prompt management, and robust fol-
low up are critical for best outcomes in preventing and treating PEM.
Nutrient Deficiencies in the Premature Infant
Malika D. Shah and Shilpa R. Shah
Premature infants are a population prone to nutrient deficiencies. Because
the early diet of these infants is entirely amenable to intervention, under-
standing the pathophysiology behind these deficiencies is important for
both the neonatologists who care for them acutely and for pediatricians
who are responsible for their care through childhood. This article reviews
the normal accretion of nutrients in the fetus, discusses specific nutrient
deficiencies that are exacerbated in the postnatal period, and identifies
key areas for future research.
Nutritional Deficiencies in Children on Restricted Diets
Midge Kirby and Elaine Danner
Pediatric nutritional deficiencies are associated not only with poverty and
developing countries, but also in children in the developed world who
adhere to restricted diets. At times, these diets are medically necessary,
such as the gluten-free diet for management of celiac disease or exclusion
diets in children with food allergies. At other times, the diets are self-se-
lected by children with behavioral disorders, or parent-selected because
of nutrition misinformation, cultural preferences, alternative nutrition ther-
apies, or misconceptions regarding food tolerance. Health care providers
must be vigilant in monitoring both growth and feeding patterns to identify
inappropriate dietary changes that may result in nutritional deficiencies.
Nutritional Deficiencies in Obesity and After Bariatric Surgery
Stavra A. Xanthakos
The presence of nutritional deficiencies in overweight and obesity may
seem paradoxical in light of excess caloric intake, but several micronu-
trient deficiencies appear to be higher in prevalence in overweight and
obese adults and children. Causes are multifactorial and include de-
creased consumption of fruits and vegetables, increased intake of high-
calorie, but nutritionally poor-quality foods, and increased adiposity, which
may influence the storage and availability of some nutrients. As the obesity
epidemic continues unabated and the popularity of bariatric surgery rises
for severely obese adults and adolescents, medical practitioners must be
aware of pre-existing nutritional deficiencies in overweight and obese pa-
tients and appropriately recognize and treat common and rare nutritional
deficiencies that may arise or worsen following bariatric surgery. This
article reviews current knowledge of nutritional deficits in obese and
overweight individuals and those that commonly present after bariatric
surgery and summarizes current recommendations for screening and
Nutrition Management of Pediatric Patients Who Have Cystic Fibrosis
Suzanne H. Michel, Asim Maqbool, Maria D. Hanna,
and Maria Mascarenhas
Since the identification of cystic fibrosis (CF) in the 1940s, nutrition care of
patients whohave CF has been a challenge. Through optimal caloric intake
and careful management of malabsorption, patients are expected to meet
genetic potential for growth. Yet factors beyond malabsorption, including
nutrient activity at the cellular level, may influence growth and health. This
article reviews nutrition topics frequently discussed in relationship to CF
and presents intriguing new information describing nutrients currently be-
ing studied for their impact on overall health of patients who have CF.
Nutritional Deficiencies During Critical Illness
Nilesh M. Mehta and Christopher P. Duggan
A significant proportion of critically ill children admitted to the pediatric in-
tensive care unit (PICU) present with nutritional deficiencies. Malnourished
hospitalized patients have a higher rate of complications, increased mor-
tality, longer length of hospital stay, and increased hospital costs. Critical
illness may further contribute to nutritional deteriorate with poor outcomes.
Younger age, longer duration of PICU stay, congenital heart disease, burn
injury, and need for mechanical ventilation support are some of the factors
that are associated with worse nutritional deficiencies. Failure to estimate
energy requirements accurately, barriers to bedside delivery of nutrients,
and reluctance to perform regular nutritional assessments are responsible
for the persistence and delayed detection of malnutrition in this cohort.
Optimizing Nutritional Management in Children with Chronic Liver Disease
Scott Nightingale and Vicky Lee Ng
Malnutrition is common in infants and children with chronic liver disease
(CLD) and may easily be underestimated by clinical appearance alone.
The cause of malnutrition in CLD is multifactorial, although insufficient di-
etary intake is probably the most important factor and is correctable. Fat
malabsorption occurs in cholestatic disorders, and one must also consider
any accompanying fat-soluble vitamin and essential fatty acid defi-
ciencies. The clinician should proactively evaluate, treat, and re-evaluate
response to treatment of nutritional deficiencies. Because a better nutri-
tional state is associated with better survival before and after liver trans-
plantation, aggressive nutritional management is an important part of the
care of these children.
Nutritional Deficiencies in Intestinal Failure
Charmaine H. Mziray-Andrew and Timothy A. Sentongo
Intestinal failure (IF) is the ultimate malabsorption state, with multiple
causes, requiring long-term therapy with enteral or intravenous fluids
and nutrient supplements. The primary goal during management of chil-
dren with potentially reversible IF is to promote intestinal autonomy while
supporting normal growth, nutrient status, and preventing complications
from parenteral nutrition therapy. This article presents how an improved
understanding of digestive pathophysiology is essential for diagnosis, suc-
cessful management, and prevention of nutrient deficiencies in children
Judy Fuentebella and John A. Kerner
Refeeding syndrome (RFS) is the result of aggressive enteral or parenteral
feeding in a malnourished patient, with hypophosphatemia being the hall-
mark of this phenomenon. Other metabolic abnormalities, such as hypoka-
lemia and hypomagnesemia, may also occur, along with sodium and fluid
retention. The metabolic changes that occur in RFS can be severe enough
to cause cardiorespiratory failure and death. This article reviews the path-
ophysiology, the clinical manifestations, and the management of RFS. The
key to prevention is identifying patients at risk and being aware of the po-
tential complications involved in rapidly reintroducing feeds to a malnour-
Drug-Induced Nutrient Deficiencies
Lina Felı ´pez and Timothy A. Sentongo
Good clinical care extends beyond mere diagnosis and treatment of dis-
ease to appreciation that nutrient deficiencies can be the price of effective
drug therapy. The major risk factors for developing drug-induced nutrient
deficiencies are lack of awareness by the prescribing physician and long
duration of drug therapy. The field of pharmacogenomics has potential
to improve clinical care by detecting patients at risk for complications
from drug therapy. Further improvements in patient safety rely on physi-
cians voluntarily reporting serious suspected adverse drug reactions.
Praveen S. Goday, MBBS, CNSP Timothy S. Sentongo, MD
We are honored to edit this issue on ‘‘Nutritional Deficiencies’’ in the Pediatric Clinics of
North America. The last issue of Pediatric Clinics of North America addressing
nutritional problems was published 7 years ago. We have highlighted a spectrum of
nutritional deficiencies ranging from those occurring despite normal health to those
associated with a variety of disease states. Our aim is to provide pediatric practitioners
and trainees across the globe with a comprehensive and practical clinical review that
links pathophysiology with clinical manifestations and management strategies.
The first part of this issue discusses nutrient deficiencies associated with growth in
normal children, premature infants, children with protein-energy malnutrition, children
on restricted diets, and adolescents who have undergone bariatric surgery. Despite
increased knowledge about growth and nutrient requirements, protein-energy malnu-
trition and nutrient deficiencies remain globally pervasive problems. Preventable
childhood illness and decreased access to food due to geopolitical factors are the
main causes of malnutrition in less-developed countries. In contrast, chronic disease
and excess calories are major risk factors for malnutrition in more-developed
countries. The forced maldigestion and malabsorption of nutrients induced by bariatric
surgery have been responsible for the re-emergence of nutrient deficiencies previously
consigned to textbooks. Restricted diets used during therapy for food allergies and
intolerances, and, sometimes, empirically in children with autism are also associated
with increased risk for nutrient deficiencies.
Nutrient deficiencies may manifest differently based on disease and medical
therapy; therefore, the second part of this issue discusses pathophysiology, diagnosis,
and management of nutrient deficiencies encountered in critically ill children and
chronic disease states, including cystic fibrosis, chronic liver disease, and intestinal
failure. These are representative conditions that have a unique impact on nutrient
intake, digestion, absorption, and use. We have also included a sobering reminder
that regardless of the cause of malnutrition, nutritional intervention should proceed
cautiously because of risk of precipitating refeeding syndrome. Finally, this issue is
rounded off by a discussion about the nutritional implications of drug therapy and an
Pediatr Clin N Am 56 (2009) xiii–xiv
0031-3955/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
introduction to the role of pharmacogenomics in avoidance of adverse drug-nutrient
We are proud of a global cast of authors—authors from the United Kingdom,
Canada, and Australia joined authors from all over the United States in this
venture—whose contributions made this issue possible. We also thank Carla
Holloway, Peggy Ennis, and the editorial team at Elsevier for their invaluable help
in assembling this issue. Finally, we would like to dedicate this issue to our
families—Thangam, Arvind, and Tara Goday and Mirika, David, Samuel, and Joanna
Sentongo—and extend appreciation for their continued love, understanding, and
Praveen S. Goday, MBBS, CNSP
Pediatric Gastroenterology and Nutrition
Medical College of Wisconsin
8701 Watertown Plank Road
Milwaukee, WI 53226
Timothy S. Sentongo, MD
Hepatology & Nutrition
The University of Chicago Medical Center
5839 South Maryland Avenue, MC 4065 WP C-474
Chicago, IL 60637
email@example.com (P.S. Goday)
firstname.lastname@example.org (T.S. Sentongo)
DavidL. Suskind, MD
Nutritional deficiencies have always been a major consideration in pediatrics.
Although the classic forms of many of the well-documented nutritional deficiencies
are memorized during training as a physician, nutritional deficiencies that can occur
in otherwise asymptomatic normally growing children are often overlooked. The two
most common deficiencies seen in children who are growing normally are iron and
vitamin D deficiencies. These deficiencies are surprisingly common and can have
a significant impact on the overall health of a child. This article reviews these nutritional
deficiencies and other less commonly seen deficiencies in children who are otherwise
Iron deficiency (ID) is the most common nutritional deficiency in children. The usual
presentation of ID anemia is an otherwise asymptomatic, well-nourished infant with
a mild-to-moderate microcytic, hypochromic anemia. In some developing countries,
up to 50% of preschool children and pregnant mothers have ID anemia (IDA).1
Although the prevalence of ID among 1-year-old infants in the United States has
declined as a result of improved iron supplementation during the first year of life,2,3
the rate of ID in older children and toddlers has remained relatively unchanged over
the last 4 decades. National Health and Nutrition Examination Surveys (NHANES) II
and IV revealed that 8% of children aged 12 to 36 months between 1999 and 2002
were iron deficient.4ID is higher among children living at or below the poverty level,
among premature and low-birth-weight infants, among black and Hispanic toddlers,
and among infants fed only non-iron fortified formulas.4–6Other risk factors for
Department of Pediatrics, Division of Pediatric Gastroenterology Hepatology and Nutrition,
Seattle Children’s Hospital, University of Washington, 4800 Sand Point Way NE, Seattle, WA
E-mail address: email@example.com
? Growth ? Pediatric mineral ? Vitamin deficiency
?Micronutrient deficiency development ?Pediatric
? Iron deficiency ? Vitamin D deficiency
Pediatr Clin N Am 56 (2009) 1035–1053
0031-3955/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
developing IDA in children 1 to 3 years of age include obesity, being of Hispanic origin,
and not attending day care.4Immigrant populations are also at higher risk for IDA.7
Infants born to mothers with ID or who are breast-fed by iron-deficient mothers are
also at risk. A decreased hemoglobin concentration at birth directly affects nonstorage
iron and increases the risk of IDA during the first 3 to 6 months of life. Prematurity,
fetal-maternal hemorrhage, twin-twin transfusion syndrome and insufficient dietary
intake can all lead to the early development of IDA.
Dietary issues contribute significantly to the evolution of ID anemia in infancy and
early childhood. Common factors leading to IDA include insufficient iron intake or
poor dietary sources of iron (eg, vegetarian/vegan diet), early introduction of whole
cow’s milk,8–10occult blood loss secondary to cow’s milk intolerance, medications
(eg, nonsteroidal antiinflammatory drugs), and malabsorptive states.11
The early introduction of whole cow’s milk in infants increases intestinal blood loss.
In one study, infants 5 to 6 months of age consuming cow’s milk had a higher rate of
heme-positive stools (up to 30%) during the first 28 days, whereas only 5% of infants
maintained onformula hadheme-positive stools.12There isalsoan increased riskof ID
with continued bottle-feeding compared with cup feeding in the second and third year
of life, most likely also because of greater consumption of cow’s milk.13
ID in industrialized countries presents most commonly as a mild-to-moderate
microcytic, hypochromic anemia in an asymptomatic, well-nourished infant.
Uncommon but also reported are infants with severe anemia who present with pallor,
lethargy, irritability, poor feeding, and cardiomegaly. Although typically presenting as
a nutritional anemia, IDA may present secondary to other diseases including celiac
disease,14Helicobacter pylori infections,15and the anemia of chronic disease.
Pica (the craving for substances largely non-nutritive such as clay or paper prod-
ucts) and pagophagia (craving for ice) are common features associated with ID. It
may be present in children who are not anemic and will respond rapidly to treatment
with iron, often before any increase is noted in the hemoglobin concentration.16
Despite several well-documented studies, there is still debate about the effect of ID
on the neurodevelopment of infants and children. Impaired psychomotor or mental
development has been described in iron-deficient infants and cognitive impairment
has been noted in iron-deficient adolescents.17,18ID may also negatively affect the
infant’s social-emotional behavior.19,20It may be a risk factor for children with atten-
tion-deficit/hyperactivity disorder.21,22Decreased iron, even in the absence of anemia,
is associated with decreased exercise performance in laboratory animals and chil-
dren, particularly in adolescent athletes. ID has been associated with altered immunity
and with cerebral vein thrombosis in children.23
Diagnosing ID in a healthy-appearing infant/child can be challenging. Analysis of
the NHANES III database demonstrated that anemia (hemoglobin level <11 g/dL) is
neither a sensitive nor a specific screen for ID.24Only one-third of iron-deficient chil-
dren have evidence of IDA. A careful dietary history is an important screening tool in
determining whether a child is iron deficient.25Dietary ID can be suspected from
one or more of the following: less than five servings each of meat, grains, vegetables,
and fruit per week; more than 480 mL of milk per day; or daily intake of fatty snacks,
sweets, or more than 480 mL of soft drinks. Other studies have not shown dietary
history to be useful.26
For infants/children presenting with a mild microcytic, hypochromic anemia with
apresumptive diagnosis of ID anemia, the most cost-effective strategy isa therapeutic
trial of iron.27Several laboratory tests can be helpful in confirming the diagnosis of ID
anemia. Although an elevated red cell distribution width is the earliest hematologic
manifestation of ID,27ID in infants and young children is usually identified by a serum
ferritin concentration of less than 12 ng/mL. IDA is diagnosed by a low hemoglobin
concentration in conjunction with a low serum ferritin. The major drawback with using
serum ferritin as an indicator of ID is that ferritin is an acute phase reactant, with serum
levels increasing with inflammatory and infectious processes.28A more complete eval-
uation for IDA would also include a serum iron, total iron-binding capacity, and trans-
ferrin saturation. Other laboratory tests, although not routinely used, such as
erythrocyte protoporphyrin, serum transferrin receptor, and reticulocyte hemoglobin
content, may prove useful tools for measuring ID.29,30
Once the diagnosis of ID anemia is established, every child should have a careful
dietary history, be screened for lead poisoning and have three separate stools
screened for occult blood. Among older children and adolescents with moderate-
to-severe IDA, more detailed investigations for gastrointestinal blood loss should be
considered unless the menstrual history in an adolescent girl is thought to be the
cause of the deficiency.
For infants with confirmed IDA, ferrous sulfate (3–4 mg/kg of elemental iron, in
divided doses, between meals with a citrus juice) is the standard of care.27Ferrous
sulfate at 3 mg/kg should produce an increase of greater than 1 g/dL per week in
patients with ID. Iron absorption is increased if the ferrous sulfate is given with juice
rather than milk. Iron should be continued in responders for 2 to 3 months after
normalization of hemoglobin values to replace iron stores. If the patient fails to
respond after 4 weeks of therapy, a review of the patient’s history should take place
for medication dosing and administration errors, appropriate dietary modifications, or
history of a recent illness. Other laboratory studies, including a serum ferritin level,
should be obtained to evaluate the anemia further and to rule out conditions
simulating (ie, thalassemias and the anemia of chronic disease) or complicating
(eg, concomitant vitamin B12or folic acid deficiency) ID anemia. Close follow-up
should occur after appropriate treatment to ensure the patient’s response to iron
VITAMIN D DEFICIENCY
Vitamin D is a prohormone that is essential for the normal absorption of calcium in the
gastrointestinal tract. Deficiency in vitamin D leads to hypocalcemia and hypophos-
phatemia with resultant rickets in children and osteomalacia in adults. In adults,
vitamin D deficiency has been linked to cardiovascular disease, insulin resistance,
In addition to a number of large case studies, NHANES III has emphasized the high
prevalence of vitamin D deficiency in industrialized nations, with up to 14% in the
United States.31,32In NHANES III, children aged 1 to 5 years had the highest mean
serum vitamin D concentrations followed by children aged 6 to 11 years, with adoles-
cents having the lowest mean vitamin D levels. The resurgence of vitamin D deficiency
is likely a result of several dietary and environmental factors, including body mass
index, milk ingestion, and sun exposure.33In nonindustrialized nations vitamin D defi-
ciency remains a major public health problem.
Vitamin D deficiency causes nutritional rickets. The primary abnormality may be die-
tary deficiency or decreased vitamin D activity, which leads to a decrease in intestinal
absorption of calcium. Although the majority of pediatric patients with low vitamin D
level are asymptomatic, some may develop secondary hyperparathyroidism and char-
acteristic changes in the growth plates and metaphyseal bones.
Rickets due to vitamin D deficiency has three stages of increasing severity.34Stage
one arises from impaired intestinal calcium absorption, resulting in hypocalcemia.
Nutritional Deficiencies During Normal Growth
Hyperaminoaciduria and hyperphosphaturia are absent and serum inorganic phos-
phorus is normal. Hypophosphatemia develops in stages two and three. Serum
calcium is normal in stage two, but low in stage three, when the clinical and radiolog-
ical findings of rickets are most striking. Serum parathyroid hormone concentrations
are elevated in all three stages.
The vitamin D status of an infant depends upon the amount of vitamin D transferred
from the mother prenatally and on the amount of vitamin D ingested or produced by
the skin during exposure to ultraviolet light postnatally.35Maternal-fetal transfer of
vitamin D is mostly in the form of calcidiol (25-OH vitamin D), which readily crosses
the placenta.35The half-life of calcidiol is approximately 3 to 4 weeks.36Thus, the
serum concentration of vitamin D falls rapidly after birth unless additional sources
In North America, infant formula, cow’s milk, and cereals are fortified with vitamin D.
All infant formulas in the United States contain at least 400 IU/L of vitamin D. Nonethe-
less, the diet of most breast-fed infants and many formula-fed infants does not provide
the recommended intake of vitamin D. Vitamin D deficiency rickets commonly pres-
ents between 3 months and 3 years of age, when growth rates (and calcium needs)
are high, and exposure to sunlight may be limited.37–39The main reasons for inade-
quate vitamin D supply in infants from Western countries are prolonged breast-feeding
without vitamin D supplementation, and concomitant avoidance of sun exposure.39,40
The recommended intake of vitamin D to prevent deficiency in normal infants and
young children is 200 to 400 IU/day.41Human milk typically contains less than 25 IU
of vitamin D per liter.42Dark skin is an additional risk factor for developing rickets in
breast-fed infants as dark-skinned individuals produce less vitamin D in response to
sunlight.39The vitamin D concentration of the breast milk of dark-skinned mothers
is less than that of lighter-skinned individuals.43In high-risk populations, most mothers
of breast-fed infants with rickets are deficient in vitamin D. Consequently, all at-risk
mothers should be evaluated for vitamin D deficiency.38
Other causes of vitamin D deficiency caused by diminished absorption are gastrec-
tomy, celiac disease, malabsorption, extensive bowel surgery, inflammatory bowel
disease, and advanced cystic fibrosis.
Although vitamin D deficiency is often asymptomatic, skeletal findings can occur
with advanced disease. The classic findings of advanced rickets include delay in
the closure of the fontanels, frontal bossing, craniotabes (soft skull bones), enlarge-
ment of the costochondral junction visible as beading along the anterolateral aspects
of the chest (the ‘‘rachitic rosary’’), Harrison groove caused by the muscular pull of the
diaphragm on the ‘‘softened’’ lower ribs, enlargement of the wrist, bowing of the distal
radius and ulna, and progressive lateral bowing of the femur and tibia.
The most widely used treatment for vitamin D deficiency is vitamin D2(ergocalci-
ferol). Infants younger than 1 month with vitamin D deficient rickets should receive
1000 IU daily, infants aged 1 to 12 months should receive between 1000 and 5000
IU daily, and children older than 1 year should receive 5000 IU daily. Treatment is
continued at these doses until radiographic evidence of healing is observed. The
dose of vitamin D is then reduced to 400 IU daily. Radiographic evidence of healing
usually occurs after 3 months of treatment.41Calcium intake should be maintained at
approximately 1000 mg per day to avoid the so-called hungry bone syndrome (wors-
ening hypocalcemia after the start of vitamin D therapy). This is usually accomplished
by administering supplements of 30 to 75 mg/kg of elemental calcium per day in
three divided doses.41
Nutritional management should lead to resolution of biochemical and radiological
abnormalities within 3 months. A key signal that this is occurring is the increase in
urinary calcium excretion. If after appropriate nutritional treatment for 3 months the
patient still has no detectable urinary calcium, continuation of the same treatment
regimen for an additional 3 months is recommended. Serum calcium, phosphorus,
alkaline phosphatase, and urinary calcium/creatinine ratio should be measured
4 weeks after the initiation of therapy in children who are being treated for vitamin D
deficiency. These studies should be repeated after 3 months of therapy, at which point
radiographs should be obtained to document healing of rachitic lesions.
An alternative treatment protocol is the so-called stosstherapy, which consists of
a high dose of oral vitamin D (600,000 IU) given on a single day.44This amount of
vitamin D approximately corresponds to a 3-month course of 5000 IU per day and
should be sufficient to induce healing within 3 months. Stosstherapy may be advanta-
geous when compliance with therapy or follow-up is a problem.45However, such high
doses of vitamin D can lead to hypercalcemia. Doses of 150,000 or 300,000 IU appear
to be equally effective, but with less risk of hypercalcemia.46
Nutritional rickets remains prevalent in many parts of the world. Because ample
sunlight exists in many of the countries where the incidence of rickets is high,
researchers have suggested that insufficient calcium intake rather than primary
vitamin D deficiency may be the main causative factor.47Most of the children in these
studies had normal serum 25-OH vitamin D concentrations and high serum 1,25-OH2
vitamin D concentrations, indicating adequate intake of vitamin D. A randomized,
double-blind, controlled trial of 123 Nigerian children with rickets showed that baseline
intake of calcium was very low (about 200 mg/d).48These children responded better to
treatment with calcium alone or in combination with vitamin D than to treatment with
vitamin D alone. However, other factors in addition to calcium intake may play a role
because control children without rickets had similarly low calcium intake. Although
most of the studies on calcium deficiency rickets have been performed in Africa,
similar dietary deficiencies occur in North America.49
Although vitamin D and iron are the most common nutritional deficiencies in nor-
mally growing infants and children, an array of other nutritional deficiencies can occur
in specific clinical scenarios. These occur in certain diseases and in special diets, such
as vegetarian/vegan diets. Less common causes of nutritional deficiencies in normal-
growing infants and children are reviewed in the following sections.
WATER-SOLUBLE VITAMIN DEFICIENCIES
Thiamine deficiency has been associated with three disorders: beriberi (infantile and
adult), Wernicke-Korsakoff syndrome, and Leigh syndrome. Although these patients
usually present with severe malnutrition, there have been case reports of thiamine
deficiency in well-nourished patients.50Thiamine is found in larger quantities in food
products such as yeast, legumes, pork, rice, and cereals, whereas milk products,
fruits, and vegetables are poor sources of thiamine. The thiamine molecule is dena-
tured at high pH and high temperatures. Hence, cooking, baking, and canning of
some foods and pasteurization can destroy thiamine.
Beriberi in infants becomes clinically apparent between the ages of 2 and 3 months.
The clinical features are variable and may include a fulminant cardiac syndrome with
cardiomegaly, tachycardia, a loud piercing cry, cyanosis, dyspnea, and vomiting.51
A form of aseptic meningitis has also been described, in which the affected infants
Nutritional Deficiencies During Normal Growth
cerebrospinal fluid.52Wernicke disease is a triad of nystagmus, ophthalmoplegia, and
ataxia, along with confusion. Korsakoff psychosis is impaired short-term memory and
confabulation with otherwise grossly normal cognition.
Beriberi has been reported as a complication of weight loss surgery, presenting as
a polyneuropathy with a burning sensation in the extremities, weakness, and falls.53,54
Thiamine deficiency can occur as a complication of total parenteral nutrition if
adequate thiamine supplements are not provided.55Although a number of adult
studies have suggested that patients on chronic loop diuretics can develop thiamine
deficiency, pediatric data on cardiac patients suggest the cause of the thiamine defi-
ciency is multifactorial.56
Vitamin B2, or riboflavin, is one of a group of naturally occurring compounds known as
flavins. Flavoproteins are catalysts in several mitochondrial oxidative and reductive
reactions, and function as electron transporters. Although riboflavin is supplied in
many foods, including meats, fish, eggs, milk, green vegetables, yeast, and enriched
foods, riboflavin deficiency may be more common than generally appreciated. One
of riboflavin deficiency of 26.6% among those not on vitamin supplements. Deficiency
was determined from estimation of erythrocyte glutathione reductase activity, an
accurate reflector of riboflavin nutritional status. The prevalence was neither sex nor
age dependent. Prevalence was highest among those consuming less than 1 cup of
milk/week and least among those taking 3 or more cups of milk a day.57The same
group found riboflavin deficiency in 11% of children from the same socioeconomic
background.58In the United Kingdom, the National Diet and Nutrition Survey reported
a high prevalence of poor riboflavin status in adolescent girls (15–18 years) and young
women (19–24 years). It has been reported that 95% of adolescent girls (15–18 years)
and 75% of young women (19–24 years) in the United Kingdom have poor riboflavin
status as measured by the erythrocyte glutathione reductase activation coefficient
Most cases of riboflavin deficiency go undetected because of the mild nature and
nonspecific signs and symptoms of the deficiency. Significant deficiency is character-
ized by sore throat, hyperemia of pharyngeal mucous membranes, edema of mucous
membranes, cheilitis, stomatitis, glossitis, normocytic-normochromic anemia, and
Pellagra (meaning ‘‘raw skin’’) is characterized by a photosensitive-pigmented derma-
titis (typically located in sun-exposed areas), diarrhea, dementia, and death. Pellagra
was epidemic in the southeastern part of the United States during the early 20th
century secondary to malnutrition and the consumption of tryptophan-deficient
corn, because tryptophan is a precursor of niacin. Currently, pellagra is uncommon
in the industrialized world except as a complication of alcoholism, anorexia nervosa,
and malabsorptive diseases. Primary nutritional deficiencies secondary to inadequate
niacin intake are uncommon, because niacin is widely distributed in plant and animal
foods, with the exception of cereal, corn, or sorghum.
The most characteristic finding is the presence of a symmetrical hyperpigmented
rash in sun-exposed areas. Other clinical findings are a red tongue and several
nonspecific symptoms, such as diarrhea and vomiting. Neurologic symptoms include
insomnia, anxiety, disorientation, delusions, dementia, encephalopathy, and death.
Subclinical niacin deficiency has been reported in an adult patient with carcinoid
syndrome in which the conversion of tryptophan is to 5-OH tryptophan and serotonin
rather than to nicotinic acid.60These patients can also develop full-blown pellagra.
Niacin deficiency has not been identified in normal-growing children.
Pyridoxine deficiency is seen classically in one of six pyridoxine-dependent
syndromes: pyridoxine-dependent seizures, B6responsive anemia, xanthurenic acid-
emia, cystathionemia, homocystinuria, and type 2 hyperprolinemia.61Unusual as an
isolated nutritional deficiency, pyridoxine deficiency has been associated with isoni-
azid treatment and in exclusively breast-fed infants older than 6 months.62–64Pyri-
doxine deficiency has also been associated with low-income pregnant adolescents.
Although low vitamin B6in pregnancy has been associated with low Apgar scores,
the true benefit of supplementation is unclear.65In adults, vitamin B6deficiency has
been associated with increased risk of venous thromboembolism.66
VITAMIN B12DEFICIENCY/FOLATE-ASSOCIATED MEGALOBLASTIC ANEMIA
Nutritional megaloblastic anemia features macrocytic red cells and mean corpuscular
volumes greater than 100 fL. The megaloblast, the morphologic hallmark of the
syndrome, is a result of impaired DNA formation secondary to deficiencies of vitamin
B12(cobalamin, Cbl) or folic acid.67
Animal products (meat and dairy products) provide the only dietary source of vitamin
B12for humans. Although the true prevalence of vitamin B12deficiency is unknown in
the United States, the NHANES III (1991–1994) estimated a frequency of 1 in 200 chil-
dren aged 4 to 19 years with decreased vitamin B12levels (<200 pg/mL).68
Clinically evident vitamin B12deficiency is uncommon in infants and children without
predisposing factors. In infancy, cobalamin deficiency is usually secondary to
maternal deficiency in breast-feeding mothers who follow strict vegan diets or are
moderate vegetarians.69In addition, reported cases of cobalamin deficiency during
infancy include breast-feeding mothers with a history of gastric bypass, malabsorptive
syndromes, and pernicious anemia.69,70Depending on the age of presentation, these
infants often present with poor growth, movement disorders, developmental delays,
and hematologic abnormalities. If identified early, however, the infants may have no
physical stigmata of cobalamin deficiency, emphasizing the importance of pre- and
In older children and adolescents, cobalamin deficiency is often associated with
autoimmune diseases. There are case reports of pediatric patients with polyglandular
autoimmune disease, Hashimoto thyroiditis, and pernicious anemia.70–72Cobalamin
deficiency in pernicious anemia is thought to occur as a result of an autoimmune
attack on gastric intrinsic factor.73Other reported causes include H pylori infection,
intestinal bacterial overgrowth, ileal disease including Crohn disease, long-term use
of biguanides, antacids, H2receptor antagonists/proton pump inhibitors,74bariatric
surgery,75pancreatic insufficiency, and Sjo ¨gren syndrome.
Vitamin B12can cause not only megaloblastic anemia but also neurologic changes.
Because vitamin B12stores are so large in relation to daily requirements, years of inad-
equate intake or absorption are required before the onset of symptoms. The classic
picture of a patient with vitamin B12deficiency (ie, an elderly Caucasian woman with
anemia, icterus, and atrophic glossitis, who has a shuffling gait and is mentally
Nutritional Deficiencies During Normal Growth
sluggish) is less common and has been replaced by more subtle presentations, espe-
cially in pediatrics. Children may present with hard-to-characterize neuropsychiatric
problems consisting of paresthesias, numbness, weakness, loss of dexterity, impaired
memory, and personality changes.76It is clinically important to note that not all
patients with neurologic abnormalities secondary to vitamin B12deficiency are either
anemic or have macrocytic red cell indices.77
Folate occurs in animal products and in leafy vegetables.78Normal daily requirements
are from 200 to 400 mg/d; this increases to 500 to 800 mg/d in pregnancy and lactation.
Folate at physiologic levels enters cells by binding to a folate receptor. Once inside the
cell, Folic acid is polyglutamated, a form that is biologically active and cannot rediffuse
into the plasma.78Folic acid deficiency in pediatrics is generally secondary to an inad-
equate dietary intake or to drug interference. Since 1998, the US Food and Drug
Administration has required the fortification of enriched cereal-grain products with
folic acid. As a result there has been an increase in serum folate levels in the United
States across all ages, sexes, and ethnicities. Adolescents have experienced the
biggest relative increase, with children aged 5 years or younger having the smallest
The most common cause of folate deficiency is a lack of dietary intake. Although
folate is plentiful in liver, greens, and yeast, it is easily destroyed by heat during cook-
ing. Body stores are small (5–10 mg) and individuals on a folate-deficient diet can
develop a megaloblastic anemia within 4 to 5 months. Individuals with increased
requirements (ie, patients with hemolytic anemias, exfoliative skin diseases, and
drug-induced interference with folate metabolism) are at higher risk for developing
folate deficiency. Medications that interfere with folic acid metabolism include pyri-
methamine (an antimalarial agent) and methotrexate, both of which cause a megalo-
blastic anemia by inhibiting dihydrofolate reductase. Phenytoin blocks folic acid
absorption and increases use of folic acid by an unknown mechanism.80
The classic presentation of folate deficiency differs from vitamin B12deficiency in
two important ways. Although the hematologic manifestations of folate deficiency
are similar, neurologic abnormalities do not occur with folate deficiency. In addition,
symptoms of folate deficiency can occur within a few months of a decreased intake,
in contrast with vitamin B12.
Diagnosis of vitamin B12or folate deficiency requires an examination of red blood
cell histology. Macrocytosis (mean cell volume >100) is not specific for vitamin B12
or folate deficiency, and hypersegmented neutrophils can also occur in renal failure,
ID, or as a familial trait. However, the combination of macrocytosis and hyperseg-
mented neutrophils is pathognomonic of a megaloblastic anemia.
Other hematologic abnormalities that occur in vitamin B12and folate deficiencies
include decreased reticulocyte count, increased serum iron, evidence of mild hemo-
lysis, decreased serum haptoglobin, elevated lactate dehydrogenase , and slightly
When the anemia is severe, there may also be thrombocytopenia and neutropenia
(ie, pancytopenia), suggesting diagnoses such as myelodysplastic syndrome/acute
myeloid leukemia, or aplastic anemia, all of which may present with macrocytosis,
a reduced reticulocyte count, and pancytopenia. Assays of serum or red cell folate,
serum B12, methylmalonate, and homocysteine will confirm the diagnosis of folic
acid or vitamin B12deficiency.
marrowis typicallyhypercellular and
Vitamin C (Ascorbic Acid)
Ascorbic acid deficiency presents with the clinical manifestations of scurvy. In all
primates, ascorbic acid is an essential nutrient derived from the diet. In industrialized
countries vitamin C deficiency has often been thought of as a disease of the past or to
deficiency, based on data from NHANES III, is not uncommon: 14% of males and 10%
of females were vitamin C deficient as determined by serum vitamin C levels; the
percentage of 12- to 17-year-old males and females was 5% to 6%. Smoking, not
taking vitamin supplements, and being male were all associated with an increased
risk of vitamin C deficiency.81
Although ascorbic acid has a number of biologic actions, the clinical symptoms of
ascorbic acid deficiency are largely due to impaired collagen synthesis. Symptoms,
which occur as early as 3 months after the initiation of a deficient intake, include
bleeding gums, ecchymoses, petechiae, coiled hairs, hyperkeratosis, arthralgias,
andimpaired wound healing. Two cases of well-nourished children with vitamin Cdefi-
ciency presented solely with painful limp secondary to a periosteal hematoma.82,83As
deficiency progresses, patients may develop generalized systemic symptoms,
including weakness, malaise, joint swelling, edema, depression, and vasomotor
The incidence of vitamin C deficiency in normal-growing infants is unknown, but
likely low since breast milk and infant formulas provide an adequate source of ascor-
bic acid. Although vitamin C deficiency is not uncommon in industrialized countries,
overt scurvy has only been noted in case reports. It occurs in children with restricted
or low dietary vitamin C. These children are usually growing normally without evidence
of protein energy malnutrition.84Vitamin C deficiency has been described in normal-
growing infants fed exclusively cow’s milk formula and in children with neurodevelop-
mental disabilities.85Resolution of symptoms occurs with pharmacologic dosing of
Biotin is an essential component of several enzyme complexes in mammals, all of
which are involved in carbohydrate and lipid metabolism. Because of its role in lipid
metabolism, biotin deficiency can lead to defects in the metabolism of long-chain fatty
acids. The resulting deficiency of essential fatty acids is often manifested by derma-
tologic changes, including seborrheic dermatitis and alopecia.
The clinical significance of biotin deficiency was first demonstrated in humans by
Sydenstricker in 1942 in an experiment in which he gave human volunteers a diet
deficient solely in biotin. He ensured biotin deficiency by feeding participants raw
eggs, which contain avidin, which binds to biotin. Volunteers developed nonpruritic,
scaly dermatitis, atrophic glossitis, anorexia and nausea, pallor, muscle pains and
localized paresthesia, lassitude, somnolence, depression, anemia, and electrocardio-
graphic abnormalities. With administration of biotin all symptoms reversed within
5 days.86In pediatrics, biotin deficiency is best characterized by biotinidase defi-
ciency, a genetic disorder characterized by a patient’s inability to reutilize biotin.
Clinical features include hypotonia, ataxia, hearing loss, optic atrophy, skin rash,
Although primary nutritional biotin deficiency is unusual, case reports have been
described. In Japan, where biotin was not a required supplement in infant formulas,
cases of biotin deficiency presented primarily with an exfoliative rash and lethargy.87
Cases of biotin deficiency have also been associated with parenteral nutrition without
Nutritional Deficiencies During Normal Growth
biotin supplementation.88Although presenting with associated protein calorie malnu-
trition, reports of patients consuming diets high in raw eggs, in which avidin binds to
biotin and affects absorption, have also produced biotin deficiency.89As in the Syden-
stricker study, dietary biotin supplementation reversed the primary clinical symptoms
associated with biotin deficiency.
OTHER FAT-SOLUBLE VITAMIN DEFICIENCIES
Vitamin A deficiency, a common nutrient deficiency in developing countries, causes
primarily ophthalmologic disease.90Vitamin A is essential for maintaining the integrity
of epithelial tissues, particularly the surface linings of the eye, respiratory, urinary, and
intestinal tracts. The first clinical signs of vitamin A deficiency are drying of the
conjunctiva, the development of Bitot spots and drying of the cornea (xerophthalmia);
the patient also complains of an inability to see in dim light (night blindness).91As the
disease progresses, vitamin A deficiency leads to a breakdown of the cornea (kerato-
malacia) and permanent blindness. Vitamin A deficient children often have evidence of
protein energy malnutrition and other complicating nutritional deficiencies.92,93The
World Health Organization (WHO) estimates that 70 to 80 million children worldwide
suffer from subclinical vitamin A deficiency without overt clinical signs or symptoms.94
Subclinical vitamin A deficiency has also been identified in the pediatric age group
within the United States.95
Subclinical vitamin A deficiency increases the child’s susceptibility to infection,
reduces physical growth, and decreases the possibility of survival from serious
illness.96Recent epidemiologic studies in developing countries have identified a rela-
tionship between subclinical vitamin A deficiency and higher rates of morbidity and
mortality from common infectious diseases such as respiratory and diarrheal infec-
tions.97In nonindustrialized nations, vitamin A deficiency has been associated with
measles. This association, and increasing morbidity associated with measles, has
also been identified in the United States.98As a result, WHO, the United Nations Chil-
dren’s Fund (UNICEF), and the American Academy of Pediatrics have all issued
recommendations regarding supplementation of vitamin A in children with measles.95
Tocopherol (Vitamin E) Deficiency
Vitamin E is a generic term for a group of fat-soluble compounds, of which a-tocoph-
erol is most important. These compounds function as free radical scavengers at the
cellular level. Vitamin E provides protective effects against free radical damage, which
fosters chronic disease. Data suggest it may help prevent ischemic heart disease,
atherosclerosis, diabetes, cataracts, Parkinson disease and Alzheimer disease. It
may also have a protective effect against cancer.99Clinically evident vitamin E defi-
ciency is uncommon in humans except in unusual circumstances secondary to the
abundance of tocopherols in our diet. Vitamin E deficiency can occur in patients
with fat malabsorption and in certain genetic disorders, including abetalipoproteine-
mia and Friedreich ataxia.
The major features of vitamin E deficiency are myopathy, ataxia, and pigmented reti-
nopathy with loss of vision.100Sensory-motor neuropathy occurs late in the course of
vitamin E deficiency and is manifested by loss of vibration and position sense, loss of
reflexes, and generalized weakness. The progressive course of the neurologic
disorder in vitamin E deficiency was described in a series of children with chronic
forms of intrahepatic neonatal cholestasis or extrahepatic biliary atresia.
Data on the adequacy of vitamin E levels in healthy normal-growing children are
primarily based upon serum a-tocopherol levels. Reports of less than adequate
vitamin E levels have been reported in preschool children and adolescents within
the United States, but the clinical significance of these lower levels based upon serum
a-tocopheral levels have not been validated.101,102
Vitamin K deficiency causes a coagulation disorder as shown by an elevated
prothrombin time and international normalization ratio (INR) in the presence of normal
platelets and fibrinogen. Vitamin K deficiency in the neonate, previously named
hemorrhagic disease of the newborn, manifests itself in three ways.
Early vitamin K deficiency at birth (VKDB) presents within 24 hours of birth. Infants
affected by early VKDB are usually born to mothers taking medications that inhibit
vitamin K, including vitamin K antagonists such as warfarin, anticonvulsants such as
carbamazepine, phenytoin, and barbiturates, and antibiotics such as cephalosporins,
isoniazid, and rifampicin. At-risk infants have a 6% to 12% chance of developing
VKDB if vitamin K is not administered at birth.
Classic VKDB occurs between the second and seventh day of life and is usually
associated with a delay in feeding or insufficient feeding. Clinical presentation is
usually mild, with bruising or minimal bleeding from the gastrointestinal tract/umbi-
licus. Rarely has significant blood loss or intracranial bleeding been described.
Without vitamin K supplementation the incidence of classic VKDB is 0.01% to
Late VKDB is associated with exclusive breast-feeding and occurs between 8 days
and 6 months. Clinical presentation is usually severe, with mortality as high as 20%
and intracranial hemorrhage occurring in 50% of infants. Infants with cholestasis or
malabsorptive syndrome are at greatest risk, although the disease has been described
in normal-growing infants. The cholestasis associated with late VKDB may be mild and
self-limiting.104In fully breast-fed infants who did not receive vitamin K at birth, the
incidence is 1 per 15,000 to 20,000 live births.105
Vitamin K given after birth prevents development of VKDB. There have been
a number of epidemiologic studies and reviews examining the efficacy of different
administration rates and dosing.106Both intramuscular and oral administration of
1 mg protects against classic VKDB. A single dose of intramuscular vitamin K at birth
in exclusively breast-fed infants appears to be effective in preventing late VKDB, but
oral administration should be repeated to prevent late VKDB.107
OTHER MINERAL DEFICIENCIES
Zinc is an essential micronutrient for human growth, development, and immune func-
tion. Zinc intake is closely related to protein intake. Moderate-to-severe symptoms
attributable to zinc deficiency include growth failure, primary hypogonadism, skin
lesions including alopecia, impaired taste/smell, impaired immunity, and resistance
to infection. Primary dietary sources of zinc include animal products such as meat,
seafood, and milk. Sufficient dietary zinc sources are available in a typical mixed
diet, but lacto-ovovegetarians require additional milk, eggs, grains, legumes, nuts,
and seeds to achieve an adequate intake. Zinc absorption is inhibited by the presence
of dietary phytates and fiber, which bind zinc and inhibit its absorption.108
Although nutritional zinc deficiency has often been associated with protein energy
malnutrition, Crohn disease,109sickle cell anemia,110and nephrotic syndrome, mild
Nutritional Deficiencies During Normal Growth
zinc deficiencies can occur in vegan/vegetarian diets high in phytates,111and in
healthy adolescent gymnasts.112The true prevalence of mild zinc deficiency is
unknown because of the nonspecific nature of deficiency symptoms and imprecise
diagnostic methods. Experimental zinc deficiency hasbeen produced innormal volun-
teers and leads to a decreased immune response, as shown by a decrease in lympho-
cyte and natural killer cell activity, and endocrine changes, including primary
hypogonadism with a decrease in serum androgens, an increase in serum gonadotro-
pins, and oligospermia.113,114
Iodine is an essential component of thyroxin (T4) and triiodothyronine (T3). It is
acquired solely from the diet. Although mention of iodine deficiency suggests
cretinism and severe developmental delay, it presents as a spectrum of diseases
dependent on the degree of iodine deficiency. Since 1985, the International Council
for the Control of Iodine Deficiency Disorders (http://www.iccidd.org), supported by
WHO and UNICEF, has focused on the elimination of iodine deficiency disorders.115
Despite significant progress with the introduction of iodinated salt, iodine deficiency
is still a significant public health problem in many developing and industrialized coun-
tries.116Based on urinary iodine data collected from 1993 to 2003, WHO estimates the
prevalence of iodine deficiency in school-aged children to be 36.4% worldwide.
The lowest prevalence of iodine deficiency is found in the Americas (10.1%), where
the proportion of households consuming iodized salt is the highest in the world
(90%). The prevalence of iodine deficiency in Europe is much higher (59.9%), where
the proportion of households consuming iodized salt is the lowest (27%).117
Iodine deficiency disorders include goiter, hypothyroidism, mental retardation,
cretinism, and increased neonatal and infant mortality. Iodine deficiency goiter is often
only a cosmetic problem for many individuals, who have no other clinical features of
the disease. Decreased iodine intake leads to decreased T4 and T3 production.
This in turn causes an increase in thyrotropin (TSH) secretion, which is an attempt
by the body to restore T4 and T3 levels. TSH also stimulates thyroid growth; thus,
goiter occurs as part of the compensatory response to iodine deficiency.118,119
Mild-to-moderate iodine deficiency during pregnancy can lead to minor neuropsycho-
logical defects in offspring.120Smoking reduces iodine in breast milk. Mothers who
smoke have reduced iodine levels in their breast milk (26 mg /L vs 54 mg /L in
nonsmokers despite identical urine iodine concentrations), and their infants have
reduced urinary iodine concentrations (33 mg /L vs 40 mg /L in nonsmokers).121,122
Iodine supplementation should be considered in smokers. In infants and children,
the effects of iodine deficiency on growth and development are well documented,
but children may present with subclinical manifestations of mild iodine deficiency
with only mild-to-moderate neurologic and neuropsychological deficits123
Selenium is an essential nutrient that acts as a cofactor in several enzymatic reactions
important in redox function, production of active thyroid hormone, and immune func-
tion. Selenium is a component of selenoproteins, including glutathione peroxidase, se-
lenoprotein-P, and thioredoxin reductase. Nutritional selenium deficiency occurs in
areas with low selenium content in the soil. In industrialized nations, which have soils
rich in selenium, deficiencies are seen in infants and children with dietary restrictions
and prolonged parenteral nutrition. Severe endemic selenium deficiency can result in
Keshan disease (an endemic cardiomyopathy) and Kashin-Bek disease (a deforming
arthritis). The effects of selenium deficiency can also be less overt. Selenium
deficiency has been shown to negatively affect immunocompetency, spermatogen-
esis, mood, thyroid function, and cardiovascular disease.124,125
Copper deficiency is best characterized by Menkes syndrome, an X-linked recessive
disorder characterized by generalized copper deficiency leading to early growth retar-
dation, peculiar hair, and focal cerebral and cerebellar degeneration. Nutritional
copper deficiency in children can occur in burn patients,126patients with short bowel
syndrome, and patients dependent on total parenteral nutrition,127and has been iden-
tified in normally growing individuals.128In a cohort of children from low-income fami-
lies in the United States, despite identification of other nutritional deficiencies, copper
deficiency was not identified, making the true prevalence of nutritional copper defi-
ciency most likely very low in normal-growing children.129
Health care providers often focus their attention on overt disease processes and fail to
recognize deficiencies. This is especially true for nutritional deficiencies. It is evident
from the medical literature that children, even when growing normally, are at risk for
nutritional deficiencies. These deficiencies are common and can have significant
negative short-term and long-term effects on their lives. Health care providers should
continue to stress the importance of proper diet and nutrition to their patients,
colleagues, and the wider community.
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Nutritional Deficiencies During Normal Growth
ZubinGrover, MBBS, MD*, LooiC. Ee, MBBS, FRACP
The World Health Organization (WHO) defines malnutrition as ‘‘the cellular imbalance
between the supply of nutrients and energy and the body’s demand for them to
ensure growth, maintenance, and specific functions.’’1Although malnutrition is
a state of deficiency or excess of energy, protein, and other nutrients, this article
deals with undernutrition and specifically protein energy malnutrition (PEM). Children
with primary PEM generally are found in developing countries as a result of inade-
quate food supply caused by socioeconomic, political, and occasionally environ-
mental factors such as natural disasters. Among the four principal causes of
mortality in young children worldwide, undernutrition has been ascribed to be the
cause of death in 60.7% of children with diarrheal diseases, 52.3% of those with
pneumonia, 44.8% of measles cases, and 57.3% of children with malaria.2More
than 50% of all the childhood deaths are attributable to undernutrition, with relative
risks of mortality being 8.4 for severe malnutrition, 4.6 for moderate malnutrition, and
2.5 for mild malnutrition as estimated by analyses of 28 epidemiologic studies done
across 53 countries.3–5Most of the deaths (> 80%) occur among those with mild or
moderate malnutrition (weight for age 60% to 80%). This is explained by the fact that
although the risk of death is greatest for those with severe malnutrition, these
extreme cases only make up a small fraction of total number of children with
Malnutrition in the developed world is not rare, but its prevalence and importance
often are underappreciated. Several studies using various measures of malnutrition
have reported a prevalence of between 6% and 51% of hospitalized children in devel-
oped nations.6–9The genesis of secondary malnutrition in the developed world may be
attributed to abnormal nutrient loss, increased energy expenditure, or decreased food
intake, frequently in the context of associated chronic diseases like cystic fibrosis,
chronic renal failure, childhood malignancies, congenital heart disease, and neuro-
Department of Gastroenterology, Royal Children’s Hospital, Herston Road, Brisbane,
Queensland 4029, Australia
* Corresponding author.
E-mail address: firstname.lastname@example.org (Z. Grover).
? Protein energy malnutrition ? Pediatrics
Pediatr Clin N Am 56 (2009) 1055–1068
0031-3955/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
According to the United Nations Children’s Fund (UNICEF), PEM is an invisible emer-
gency much like the tip of an iceberg, where its deadly consequences are hidden from
view. In 2005, 20% of children younger than 5 years in low-to-middle income countries
were estimated to be underweight (weight for age z-score <?2), while 32% (178
million) children younger than 5 years in developing countries were estimated to be
stunted (height for age z score <?2).10The highest prevalence of stunting was in
central Africa and south-central Asia, although the largest numbers of children, 74
million, live in southern Asia.10Worldwide, only 36 countries account for 90% of all
stunted children when countries with stunting prevalence of at least 20% were consid-
ered.10India alone has 34% of the world’s stunted children because of its large pop-
ulation, although there issignificant variation between itsstates. The global estimate of
wasting (weight for height z score <?2) is 10%, with south-central Asia estimated to
have the highest prevalence and total number affected, 16% and 29 million respec-
tively. Sub-Saharan Africa has about 25% of the world’s underweight children younger
than 5 years of age, with Congo, Ethiopia, and Nigeria being the nations affected
In 1990, the World Summit for Children announced key requirements for improving
child health and nutrition. Subsequently, the United Nations incorporated this into its
first Millennium Goal in September 2000. A key target for MDG1 (Millennium Develop-
ment Goal 1) is to halve the proportion of people who suffer from hunger between 1990
and 2015. Unfortunately, despite progress in reducing the prevalence of undernutri-
tion, the current rate of decline is not fast enough to reach this target for most of
the world except for Latin America and the Caribbean, Pacific, and eastern Asia. In
Africa, the number of underweight children was forecasted to increase because of
political and social instability and the acquired immunodeficiency syndrome (AIDS)
MALNUTRITION IN THE DEVELOPED WORLD
Several reports from Germany, the United Kingdom, the United States, and France as
recently as the last decade reported the prevalence of acute malnutrition in hospital-
ized pediatric patients to be between 6.1% and 24%.6,7,9In 2008, Pawellek and
colleagues,7using Waterlow’s criteria, reported 24.1% of patients in a tertiary pedi-
atric hospital in Germany to be malnourished (<90th percentile weight for height), of
which 17.9% were mild, 4.4% moderate, and 1.7% severely malnourished. The prev-
alence of malnutrition varied depending on their underlying medical conditions and
ranged from 40% in patients with neurologic diseases, to 34.5% in those with infec-
tious disease, 33.3% in those with cystic fibrosis, 28.6% in those with cardiovascular
disease, 27.3% in oncology patients, and 23.6% in those with gastrointestinal
diseases.7Patients with multiple diagnoses were most likely to be malnourished
(43.8%). The prevalence and degree of acute PEM in hospitalized pediatric patients
are similar to those observed by Hendricks and colleagues9almost a decade ago
using the same criteria.
Secker and colleagues8used subjective global nutritional assessment in children
admitted for elective surgery in a tertiary referral pediatric hospital in Toronto and
found that 51% of children were malnourished (36% had moderate malnutrition,
and 15% had severe malnutrition). Despite differences in methods of assessing
malnutrition, these studies clearly document a significant prevalence of malnutrition
even in the developed world, particularly in hospitalized pediatric patients. These
results may be skewed, because most of the reports have been from tertiary centers
Grover & Ee
with relatively larger proportions of patients with chronic and severe disorders.
A cross-sectional study on patients attending outpatient clinics in Brazil, however,
reported an overall prevalence of underweight, stunting, and wasting as 14.3%,
17.3%, and 4.4%, respectively, with reference to National Center for Health Statistics
(NCHS) growth curves.13
One of the difficulties in being able to compare prevalence between studies and
centers is the lack of consensus on a uniform definition of malnutrition and its grades
of severity. A recent review highlighted the issues of lack of uniform screening tools,
poor nutritional data collection, and early identification of those at risk of developing
assessing and defining malnutrition. In 1956, Gomez introduced a classification based
on weight below a specified percentage of median weight for age.14Seoane and Lath-
guish between wasting and stunting.15Wasting, where weight for height is reduced, is
indicative of acute growth disturbance from malnutrition, whereas stunting, where
height for age is reduced is more suggestive of chronic malnutrition with faltering of
long-term growth.16In 1977, Waterlow recommended the use of z-scores and SDs
below the median to define underweight, wasting, and stunting.17,18These definitions
continue to be used widely with subsequent WHO modifications. WHO adopted the
US National Center for Health Statistics (NCHS) classification in 1983 as the interna-
usingNCHS criteria asthe population standard are the extrapolation from an ethnically
homogenous population, which likely does not represent developing world countries,
inclusion of bottle-fed infants, and the assumption that all children of a given height
will have the same average weight regardless of age. In 2006, a new population stan-
dard was adopted by WHO based on an international multicenter study using exclu-
sively breast-fed children of diverse ethnic backgrounds.22Subsequent studies have
highlighted that these new WHO growth reference curves will result in a higher
measured prevalence of malnutrition when compared with NCHS standards.23,24
An alternative proposed approach to assessing malnutrition is to measure mid-
upper arm circumference (MUAC) as a proxy for weight, and head circumference as
a proxy for height.25This may be useful when accurate measures of height and weight
are unavailable, particularly in children younger than 3 years and also in small regional
centers. The degree of malnutrition is calculated by dividing the MUAC by occipito-
frontal head circumference. The use of MUAC and presence of edema have been re-
ported to be better indicators than weight for height (either NCHS or WHO) for case
definition of severe acute malnutrition.26There is significant evidence indicating that
using MUAC less than 110 mm as a definition for severe malnutrition may be the
best method to assess nutrition in terms of age independence, simplicity, accuracy,
specificity, and sensitivity. Additionally, it is a good anthropometric predictor of
mortality related to malnutrition.26–31Although the evidence favors use of MUAC for
estimating malnutrition and for admission to therapeutic feeding programs, moreinfor-
mation is needed on the use of MUAC as a discharge and follow-up tool.
More recently, a new definition of thinness has been proposed by Cole,32who
performed meta-analyses on population studies from six high- and middle-income
countries, with a total of 192,727 subjects, whose ages ranged from 0 to 25 years.
Protein Energy Malnutrition
He proposed using body mass index for age to grade thinness according to age as
a method of assessing malnutrition. This methodology, however, has not been tested
in population studies, and its validity in predicting morbidity is unknown.
A summary of the several different methods of assessing malnutrition is shown in
The two main clinical syndromes of the extreme forms of PEM are marasmus and
kwashiorkor, although a mixed picture also is seen frequently. These are differentiated
on the basis of clinical findings, with the primary distinction between kwashiorkor and
marasmus being the presence edema in kwashiorkor.
Marasmus, the more common syndrome, is characterized clinically by depletion of
subcutaneous fat stores, muscle wasting, and absence of edema. It results from the
body’s physiologic adaptation to starvation in response to severe deprivation of calo-
ries and all nutrients. It most commonly occurs in children younger than 5 years
because of their increased caloric requirements and increased susceptibility to infec-
tions. These children often appear emaciated, are weak and lethargic, and have asso-
ciated bradycardia, hypotension, and hypothermia. Their skin is xerotic, wrinkled, and
loose because of the loss of subcutaneous fat but is not characterized by any specific
dermatosis. Muscle wasting often starts in the axilla and groin, then thigh and
buttocks, followed by chest and abdomen, and finally the facial muscles, which are
metabolically less active. The loss of buccal fat pads commonly gives the child an
appearance of monkey-like or aged facies in severe cases (Fig. 1). Severely affected
Definitions of malnutrition
Weight below %
Mild (grade 1)
Moderate (grade 2)
Severe (grade 3)
Waterlowz-scores (SD) below
?3% z-score <?2
?3% z-score <?2
WHO (wasting)z-scores (SD) below
WHO (stunting)z-scores (SD) below
KanawatiMUAC divided by
Colez-scores of BMI for ageGrade 1
BMI for age z-score <?1
BMI for age z-score <?2
BMI for age z-score <?3
Abbreviations: BMI, body mass index; HFA, height for age; MUAC, mid-upper arm circumference;
NCHS, US National Center for Health Statistics; SD, standard deviation; WFA, weight for age; WFH,
weight for height; WHO, World Health Organization.
Grover & Ee
children are often apathetic but become irritable and difficult to console when
The term kwashiorkor, which first was introduced by Cicely D. Williams in 1935,33is
taken from the Ga language of Ghana and means the sickness of the weaning. Kwash-
iorkor tends to occur mainly in older infants and young children, and results from a diet
with inadequate protein but reasonably normal caloric intake, often exacerbated by
superimposed infection. A common scenario is when the older infant or toddler is
displaced from breastfeeding by the birth of a younger sibling and has to wean rapidly
but is unable to increase protein intake adequately. The clinical picture is character-
ized by almost normal weight for age, marked generalized edema, dermatoses, hypo-
pigmented hair, distended abdomen, and hepatomegaly (see Fig. 2). The term sugar
baby also has been used to describe these children, as their typical diet is low in
protein but high in carbohydrate. Edema usually results from a combination of low
serum albumin, increased cortisol, and inability to activate antidiuretic hormone.
Hair is usually dry, sparse, brittle, and depigmented, appearing reddish yellow. With
adequate protein intake, hair color is restored and may result in alternating bands of
pale and normal-colored hair, also known as the flag sign, reflecting periods of poor
and good nutrition. Cutaneous manifestations are characteristic and progress over
days from dry atrophic skin with confluent areas of hyperkeratosis and hyperpigmen-
tation, which then splits when stretched, resulting in erosions and underlying paler,
erythematous skin. These patchy areas of dark and pale skin give the impression of
crazy paving or flaky paint, particularly over limbs and buttocks. Various skin changes
in children with kwashiorkor include: shiny, varnished-looking skin (64%), dark
Fig. 1. Marasmus with wasting, loss of subcutaneous tissue, and old man’s facies. Courtesy of
Tom D. Thacher, MD, Rochester, MN.
Protein Energy Malnutrition
erythematous pigmented macules (48%), xerotic crazy paving skin (28%), residual
hypopigmentation (18%), and hyperpigmentation and erythema (11%).34
A child with marasmic kwashiorkor presents with a mixed picture with features of both
marasmus and kwashiorkor. Characteristically, these children have concurrent gross
wasting and edema and frequently are stunted. They usually have mild hair and skin
changes and an enlarged palpable fatty liver.
Inadequate energy intake leads to various physiologic adaptations, including growth
restriction; loss of fat, muscle, and visceral mass; reduced basal metabolic rate,
and reduced total energy expenditure. The biochemical changes in prolonged starva-
tion involve complex metabolic, hormonal, and glucoregulatory mechanisms. Meta-
bolic changes progress from the early phase, where there is rapid gluconeogenesis
with resultant loss of skeletal muscle caused by use of amino acids, pyruvate and
lactate, to the later protein conservation phase, with fat mobilization leading to
lipolysis and ketogenesis. Major electrolyte changes including sodium retention and
intracellular potassium depletion can be explained by decreased activity of glyco-
side-sensitive energy-dependent sodium pump to increased permeability of cell
membranes in kwashiorkor.35
Some studies suggest that marasmus represents an adaptive response to starva-
tion, while kwashiorkor is a maladaptive response. Aflatoxins have been proposed
to have a role in the pathogenesis of kwashiorkor.36Reactive oxygen species also
Fig.2. Kwashiorkor with edema and abdominal distension. Courtesy of Tom D. Thacher, MD,
Grover & Ee
have been postulated to have a role in its pathogenesis.37This is supported by the
observation that supplementation with N-acetylcysteine, a free radical scavenger,
leads to more rapid resolution of signs and symptoms and improved erythrocyte gluta-
ALTERATIONS IN ORGAN SYSTEMS
The main hormones affected are the thyroid hormones, insulin, and growth hormone.
Changes include reduced levels of tri-iodothyroxine (T3), insulin, insulin-like growth
factor-1 (IGF-1), and raised levels of growth hormone and cortisol. Glucose levels
are often initially low, with depletion of glycogen stores. Patients frequently also
develop some degree of glucose intolerance of unclear etiology and are at risk of
profound hypoglycemia during the renourishment phase.
Cellular immunity is affected most because of atrophy of the thymus, lymph nodes,
and tonsils. Changes include reduced CD4 but relatively preserved CD8-T lympho-
cytes, loss of delayed hypersensitivity, impaired phagocytosis, and reduced secretory
immunoglobulin A (IgA). These changes increase the susceptibility of malnourished
children to invasive infections.
Villous atrophy with resultant loss of disaccharidases, crypt hypoplasia, and altered
intestinal permeability results in malabsorption, but losses often rapidly recover
once nutrition is improved. Bacterial overgrowth is common with reduced gastric
acid secretion. Pancreatic atrophy is also common and results in fat malabsorption.
Although fatty infiltration of the liver is common, synthetic function usually is
preserved. Protein synthesis, gluconeogenesis, and drug metabolism are decreased.
Cardiac myofibrils are thinned with impaired contractility. Cardiac output is reduced
proportionate to weight loss. Bradycardia and hypotension are also common in the
severely affected. Intravascular volume frequently is decreased. The combination of
bradycardia, impaired cardiac contractility, and electrolyte imbalances predispose
these children to arrhythmias.
Reduced thoracic muscle mass, decreased metabolic rate, and electrolyte imbal-
ances (hypokalemia and hypophosphatemia) may result in decreased minute ventila-
tion, leading to impaired ventilatory response to hypoxia.
Specific neurodevelopmental sequelae attributable to just PEM are difficult to ascer-
tain, as PEM frequently coexists with other nutritional deficiencies. Malnutrition has
been recognized to cause reductions in the numbers of neurons, synapses, dendritic
arborizations, and myelinations, all of which result in decreased brain size.39The cere-
bral cortex is thinned and brain growth slowed. Delays in global function, motor func-
tion, and memory have been associated with PEM, with neonates and infants being
most susceptible despite the plasticity of the infant’s brain.39
Protein Energy Malnutrition
Normochromic anemia is often present but can be exacerbated by other nutrient (iron
and folate) deficiencies and infections such as malaria or other parasitic infections.
Blood clotting usually is preserved.
Malnutrition has the potential to affect all organ systems in the body. Initially, clinical
findings include lack of adiposity and subcutaneous tissue, poor muscle bulk, irrita-
bility, and edema. As malnutrition progresses, growth is delayed, leading to stunting,
and other systems become involved, with changes in hair, skin, nails, mucous
membranes, and other organs. Micronutrient deficiencies, particularly deficiencies
of vitamins and minerals, are common in malnourished patients, so many patients
also will exhibit signs of these deficiencies. The most commonly reported micronu-
trient deficiencies are of iron, zinc, iodine, and vitamin A.40Deficiencies of other micro-
nutrients, however, including calcium, vitamin D, vitamin C, folic acid, thiamine, and
riboflavin are increasingly being recognized. A summary of the clinical findings in
PEM is shown in Table 2.
Laboratory investigations can be useful to identify deficiencies before clinical symp-
toms develop, confirm deficiencies associated with specific disease states, and
monitor recovery from malnutrition. The most useful tests in assessing nutritional state
are hemoglobin and red cell indices, and serum albumin. Electrolytes, specifically
potassium, magnesium, and phosphate, should be monitored closely in the early
treatment phase to avoid refeeding syndrome. WHO recommends performing the
following tests in malnourished children: blood glucose, hemoglobin and blood smear,
electrolytes, serum albumin, urine microscopy and culture, stool microscopy and
culture including for parasites, and human immunodeficiency virus testing.41Specific
testing should be directed by the history and physical examination.
Complete blood cell count measuring hemoglobin, red cell indices, and blood film is
helpful to demonstrate anemia, which is usually normochromic but can be microcytic
from iron deficiency. Blood film can identify malarial parasites, if appropriate. Addi-
tional testing including iron studies, vitamin B12, and folic acid measurements are
also useful when assessing for deficiencies.
Biochemical testing is useful in determining hypoglycemia; electrolyte imbalances,
particularly of sodium, potassium, phosphate, magnesium, and protein stores with
serum albumin and prealbumin levels. Fat-soluble vitamin measurement may be indi-
cated if there is evidence of malabsorption.
Culture and microscopy of urine and stool are important, as concurrent infections
are common in malnourished children. If clinically indicated, blood cultures and
lumbar puncture also may be necessary. Other additional tests such as QuantiFERON
testing for tuberculosis, celiac serology, sweat test, and thyroid function testing also
may be warranted depending on history and physical examination.
Radiology and other imaging studies are often unnecessary but may be performed if
clinically indicated. Skeletal radiographs maybe useful in assessing bone age and de-
tecting early evidence of scurvy or rickets. Body composition testing, including air
displacement plethysmography, bioimpedance analysis, dual energy x-ray absorpti-
ometry (DEXA), and total body potassium are potentially helpful in identifying lean
Grover & Ee
mass or lack of it in malnourished patients. These investigations, however, are
expensive, require highly specialized equipment, and are done in the research setting.
WHO has developed guidelines for managing severe malnutrition.41These guidelines,
with some adaptation to local conditions, have been demonstrated to reduce case
fatality rates when administered in Bangladesh, Africa, and South America.42–48Infec-
tion and sepsis continue to be the main causes of death in severe acute malnutrition,
although other causes include dehydration, electrolyte imbalances, and heart
failure.42,47,49Death also can occur once treatment is instituted because of refeeding
syndrome with its associated electrolyte and metabolic changes. The decision as to
whether to treat in the hospital or community depends on the patient’s clinical condi-
tion and availability of resources. Controlled trials show that community- or home-
based management for children with uncomplicated acute severe malnutrition results
in equivalent or superior outcomes to hospital care.50,51The authors have adopted
algorithm suggested by Collins and colleagues to help clinicians decide whether the
malnourished child can be managed at home or in the hospital (Fig. 3).52
WHO has formulated a three-phase management approach, where the patient
initially is resuscitated and stabilized (phase 1), before starting nutritional rehabilitation
(phase 2), and eventual follow-up and recurrence prevention (phase 3).
Phase 1: Resuscitate and Stabilize
The main aim during this phase is to resuscitate, rehydrate, treat infections, prevent
sepsis, and monitor closely to avoid developing complications of treatment. Patients
Clinical signs of malnutrition
Moon face (kwashiorkor), simian facies (marasmus)
Eye Dry eyes, pale conjunctiva, Bitot’s spots (vitamin A), periorbital edema
Mouth Angular stomatitis, cheilitis, glossitis, spongy bleeding gums (vitamin C),
TeethEnamel mottling, delayed eruption
Hair Dull, sparse, brittle hair, hypopigmentation, flag sign (alternating bands
of light and normal color), broomstick eyelashes, alopecia.
Skin Loose and wrinkled (marasmus), shiny and edematous (kwashiorkor), dry,
follicular hyperkeratosis, patchy hyper- and hypopigmentation (crazy
paving or flaky paint dermatoses), erosions, poor wound healing
NailKoilonychia, thin and soft nail plates, fissures or ridges
Musculature Muscle wasting particularly buttocks and thighs. Chvostek or Trousseau
Skeletal Deformities usually aresult of calcium, vitamin D or vitamin C deficiencies
AbdomenDistended—hepatomegaly with fatty liver; ascites may be present
Cardiovascular Bradycardia, hypotension, reduced cardiac output, small vessel
Neurologic Global developmental delay, loss of knee and ankle reflexes, impaired
HematologicalPallor, petechiae, bleeding diathesis
BehaviorLethargic, apathetic, irritable on handling
Protein Energy Malnutrition
are most vulnerable during this period, which usually lasts about 1 week. Feeding
should be instituted carefully and slowly, with restriction of caloric intake to 60% to
80% of caloric requirement for age. This is to avoid refeeding syndrome, but many
severely malnourished children also have some degree of malabsorption because of
disaccharidase deficiencies, villous atrophy, and relative pancreatic insufficiency.
Continuous nasogastric feeding or small frequent meals including at night may be
necessary to avoid hypoglycemia. Vitamins, especially thiamine and oral phosphate,
also are administered, in addition to supplemental feeds to prevent the potentially fatal
hypophosphatemia with refeeding.
Refeeding syndrome is thought to be explained by the sudden availability of
glucose, leading to inhibition of gluconeogenesis and an insulin surge. This causes
rapid influx of potassium, magnesium, and phosphate intracellularly and thus low
serum levels and poor myocardial contractility. This clinical syndrome, which can
manifest with excessive sweatiness, muscle weakness, tachycardia, and heart failure,
may be prevented by avoiding rapid carbohydrate feeding, supplementing phosphate
and thiamine during the initial increase in nutritional intake, and monitoring the patient
carefully for alterations in serum phosphate, potassium, and magnesium.53–55
Initial Triage in the Community
Presence of edema
WFH z-score < -3,
or MUAC < 110 mm*
and any one of:
respiratory distress, high
fever, cardiac failure,
WFH z-score < -3,
or MUAC < 110 mm
-2 < WFH z-score < -3
or MUAC >110 mm
Fig. 3. Algorithm to help clinicians decide whether the malnourished child needs hospitali-
zation. Abbreviations: MUAC, mid-upper arm circumference; WFH, weight-for-height. WFH
z-score based on WHO criteria. *For children between 6 and 59 months or length/height 65
to 110 cm as a proxy for age.
Grover & Ee
During this phase, patients also should be kept warm, as they are often hypothermic
and may need restriction of physical activities because of decreased cardiac output.
Antibiotics additionally may be necessary even in the absence of fever if infection is
Phase 2: Nutritional Rehabilitation
The rehabilitation phase starts once acute complications have been addressed
adequately with gradual return of appetite, resolution of diarrhea and sepsis, and
correction of electrolyte imbalances. The main goals of this phase are to increase die-
tary caloric intake, treat occult infections, complete vaccination, improve family
involvement, and stimulate psychomotor activity. Weight loss is common initially in
children with kwashiorkor as their edema resolves. Most children will need 120% to
140% of their estimated caloric requirements to achieve desired weight gain and
maintain catch-up growth. This phase usually lasts between 2 to 6 weeks. WHO
recommends delaying iron therapy until rehabilitation occurs because of concerns
about increased infection risk, although a recent review does not support this prac-
tice.56,57Elemental iron 2 to 6 mg/kg should be prescribed for 3 months.
Phase 3: Follow-up and Recurrence Prevention
Discharge planning and follow-up are recommended, as these patients have tendency
to relapse. Interventions that have been reported to be helpful in preventing undernu-
trition in children include promoting breast-feeding, complementary and supplemental
feeding, zinc and vitamin A supplementation, universal salt iodization, and hand-
washing and other hygiene measures.58Universal provision of iodized salt could
reduce stunting by 36% and mortality for children younger than 3 years by 25%.58–60
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factors in children attending outpatient clinics in the city of Manaus, Amazonas,
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14. Gomez F, Ramos-Galvan R, Frenk S, et al. Mortality in second- and third-degree
malnutrition. J Trop Pediatr 1956;2:77–83.
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tion in childhood. J Trop Pediatr Environ Child Health 1971;17:1271–4.
16. Bear MT, Harris AB. Pediatric nutrition assessment: identifying children at risk.
J Am Diet Assoc 1997;97(10S2):107–15.
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18. Waterlow JC, Buzina R, Keller W, et al. The presentation and use of height and
weight data for comparing the nutritional status of groups of children under the
age of 10years. Bull World Health Organ 1977;55:489–98.
19. Hamill PW, Drizd TA, Johnson CL, et al. NCHS growth curves for children birth–
18years. Washington, DC: National Center for Health Statistics; 1977.
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Guidelines for assessing the nutritional impact of supplementary feeding pro-
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21. World Health Organization. Physical status: the use and interpretation of anthro-
pometry. Geneva (Switzerland): World Health Organization; 1995.
22. WHO Multicentre Growth Reference Study Group. WHO child growth standards
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23. Seal A, Kerac M. Operational implications of using 2006 World Health Organiza-
tion growth standards in nutrition programmes: secondary data analysis. BMJ
24. Prost MA, Jahn A, Floyd S, et al. Implication of new WHO growth standards on
identification of risk factors and estimated prevalence of malnutrition in rural Ma-
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25. Kanawati AA, McLaren DS. Assessment of marginal malnutrition. Nature 1970;
26. Myatt M, Khara T, Collins S. A review of methods to detect cases of severely
malnourished children in the community for their admission into community-
based therapeutic care programs. Food Nutr Bull 2006;27:S7–23.
27. Briend A, Zimicki S. Validation of arm circumference as an indicator of risk of
death in one to four year old children. Nutr Res 1986;6:249–61.
28. Briend A, Dykewicz C, Graven K, et al. Usefulness of nutritional indices and clas-
sifications in predicting death of malnourished children. Br Med J (Clin Res Ed)
29. Briend A, Wojtyniak B, Rowland MGM. Arm circumference and other factors in
children at heightened risk of death in rural Bangladesh. Lancet 1987;26:
30. Chen LC, Chowdhury MK, Huffman SL. Anthropometric assessment of energy
protein malnutrition and subsequent risk of mortality among preschool children.
Am J Clin Nutr 1980;33:1836–45.
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31. Alam N, Wojtyniak B, Rahaman MM. Anthropometric indicators and risk of death.
Am J Clin Nutr 1989;49:884–8.
32. Cole TJ, Flegal KM, Nicholls D, et al. Body mass index cutoff to define thinness in
children and adolescents: international survey. BMJ 2007;335:194–202.
33. Williams CD. Kwashiorkor: a nutritional disease of children associated with
a maize diet. Lancet 1935;229:1151–2.
34. Lowy G, Meilman I. Kwashiorkor. Dermatological and clinical aspects. Analysis of
100 cases. Med Cutan Ibero Lat Am 1975;3(3):181–9.
35. Patrick J, Golden M. Leukocyte electrolytes and sodium transport in protein
energy malnutrition. Am J Clin Nutr 1977;30:1478–81.
36. Lamplugh SM, Hendrickse RG. Aflatoxins in the livers of children with kwashi-
orkor. Ann Trop Paediatr 1982;2:101–4.
37. Golden MH, Ramdath D. Free radicals in the pathogenesis of kwashiorkor. Proc
Nutr Soc 1987;46:53–68.
38. Badaloo A, Reid M, Forrester T, et al. Cysteine supplementation improves the
erythrocyte glutathione synthesis rate in children with severe edematous malnu-
trition. Am J Clin Nutr 2002;76:646–52.
39. Georgieff MK. Nutrition and the developing brain: nutrient priorities and measure-
ment. Am J Clin Nutr 2007;85:614S–20S.
40. Bhutta ZA. Micronutrient needs of malnourished children. Curr Opin Clin Nutr
Metab Care 2008;11:309–14.
41. World Health Organization. Management of severe malnutrition: a manual for
physicians and other senior health workers. Geneva (Switzerland): World Health
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severe malnutrition in rural South African hospitals: effect on case fatality and
the influence of operational factors. Lancet 2004;363(9415):1110–5.
43. Ahmed T, Ali M, Ullah MM, et al. Mortality in severely malnourished children with diar-
rhea and use of standard management protocol. Lancet 1999;353(9168):1919–22.
44. Deen JL, Funk M, Guevera VC, et al. Implementation of WHO guidelines on
management of severe malnutrition in hospitals in Africa. Bull World Health Organ
45. Briend A. Management of severe malnutrition: efficacious or effective? J Pediatr
Gastroenterol Nutr 2001;32:521–2.
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simple solutions to a common problem. Trop Doct 1998;28:95–7.
47. Bernal C, Velasquez C, Alcaraz G, et al. Treatment of severe malnutrition in chil-
dren: experience in implementing the World Health Organisation guidelines in
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48. Falbo AR, Alves JG, Filho MB, et al. Decline in hospital mortality rate after the use
of the World Health Organization protocol for management of severe malnutrition.
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severely malnourished children in Kampala, Uganda. BMC Pediatr 2006;6:7–16.
50. Ciliberto MA, Sandige H, Ndekha MJ, et al. A comparison of home-based therapy
with ready-to-use therapeutic food with standard therapy in the treatment of
malnourished Malawian children: a controlled clinical effectiveness trial. Am J
Clin Nutr 2005;81:864–70.
51. Linneman Z, Matilsky D, Ndekha M, et al. A large-scale operation study of home-
based therapy with ready-to-use therapeutic food in childhood malnutrition in
Malawi. Matern Child Nutr 2007;3:206–15.
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52. Collins S, Yates R. The need to update the classification of acute malnutrition.
53. Crook MA, Hally V, Panteli JV. The importance of the refeeding syndrome.
54. Stanga Z, Brunner A, Leuenberger M, et al. Nutrition in clinical practice—the
refeeding syndrome: illustrative cases and guidelines for prevention and
treatment. Eur J Clin Nutr 2008;62:687–94.
55. Manary MJ, Hart CA, Whyte MP. Severe hypophosphatemia in children with
kwashiorkor is associated with increased mortality. J Pediatr 1998;133:789–91.
56. Smith IF, Taiwo O, Golden MH. Plant protein rehabilitation diets and iron supple-
mentation of protein energy malnourished child. Eur J Clin Nutr 1989;43:763–8.
57. Gera T, Sachdev HP. Effect of iron supplementation on incidence of infectious
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58. Bhutta ZA, Ahmed T, Black RE, et al. What works? Interventions for maternal and
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Grover & Ee
in the Premature Infant
Malika D.Shah, MD, FAAPa,*, Shilpa R. Shah, MBBS, MD, MRCPCHb
Premature infants are a population prone to nutrient deficiencies. Because the early
diet of these infants isentirely amenable to intervention, understanding the pathophys-
iology behind these deficiencies is important for both the neonatologists who care for
them acutely and for pediatricians who are responsible for their care through
childhood. This article reviews the normal accretion of nutrients in the fetus, discusses
specific nutrient deficiencies that are exacerbated in the postnatal period, and
identifies key areas for future research.
IN UTEROACCRETION OF NUTRIENTS
The potential for adverse effects of inadequate or excess intake of any nutrient on any
organ system is based on the timing, dose, and duration of exposure.1The lungs,
gastrointestinal system, immune system, and brain undergo rapid growth and matu-
ration during the last two trimesters and throughout the first year of life. Growth rates
mirroring intrauterine growth are presumed to result in optimal postnatal development.
Although this strategy has come under scrutiny because premature infants who show
greater catch-up growth seem to be at increased risk for metabolic disease in later
years,2–7the known positive effects of catch-up growth on neurodevelopment seem
to outweigh these concerns and most published studies on premature infant growth
patterns continue to use the intrauterine growth standard.8–10
The fetus is ideally adapted for survival, taking most nutrients it needs irrespective of
the nutritional status of the mother. Except in extreme situations of nutrient depriva-
tion, most vital nutrients are transported in a fashion that ensures proper substrate
delivery to the fetus for growth. Placental transfer of several macronutrients and
important micronutrients has been well studied (Table 1).
aDepartment of Pediatrics, Division of Neonatology, Northwestern University’s Feinberg
School of Medicine, 250 East Superior Street, Suite 05-2146, Chicago, IL 60611
bDepartment of Paediatric, Royal Belfast Hospital for Sick Children, 180 Falls Road, Belfast BT
12 6BE, Northern Ireland, UK
* Corresponding author.
E-mail address: email@example.com (M.D. Shah).
? Premature ? Nutrition ? Fetus ? Accretion
Pediatr Clin N Am 56 (2009) 1069–1083
0031-3955/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
In 1976, in a landmark paper published in Growth, Ziegler and colleagues11
described the body of the reference fetus using reports of whole-body chemical anal-
ysis of infants born prematurely who were stillborn or passed away within 48 hours. He
found fetal body composition to be dynamic: although percentages of body water,
extracellular water, sodium, and chloride decrease during gestation, percentages of
intracellular water, protein, fat, calcium, iron, and magnesium increase. Between 24
and 40 weeks gestation, water content declines from approximately 87% to 71%,
protein rises from 8.8% to 12%, and fat from 1% to 13.1%. Early gestation is charac-
terized by accumulation of lean tissue, whereas late gestation is characterized by
accumulation of fat.11Current recommended intake levels for premature infants are
based on fetal accretion rates of specific nutrients during the third trimester and do
not compensate for additional needs for sick infants.
As a result, the more premature an infant, the more nutrient deficient he or she is at
birth. Umbilical cord blood samples confirm that premature infants have lower plasma
levels of certain nutrients. These results likely underestimate the deficiencies, because
plasma levels can be in a normal range at the expense of tissue deficits (Table 2).
Placental transferof keynutrients
Mode of Transport
1% throughout gestation11
3 g adipose tissue/kg11
552 mg/d N-6100
67 mg/d N-3100
Fatty acidsSimple and receptor-mediated
diffusion (ARA and DHA
Abbreviations: ARA, arachidonic acid; DHA, docohexanoic acid.
Umbilical cord blood levels of nutrients in preterm infants
Age if Preterm
Ferritin (mg/dL) 23
Cord Blood (SD)
Siddappa et al,
24–29 31 (27–35)
Sweet et al,
Selenium (mg/dL)23 45.85 (15.4)68.4 (26.6) Makhoul et al,
Total protein (g/dL)
Elizabeth et al,
Shah & Shah
Hospital Course Predisposes to Nutrient Deficiencies
At birth, clamping of the cord immediately disrupts all nutrient delivery from the
placenta. Premature infants are then abruptly exposed to an environment that exacer-
bates virtually every existing nutrient deficiency. Although incubators and mechanical
ventilators are used to minimize energy expenditure in preterm infants, other factors
including enteral feeding, respiratory distress, chronic lung disease, and therapy
with methylxanthines result in higher energy needs than in utero.12Management of
respiratory distress syndrome, chronic lung disease, patent ductus arteriosus, intra-
ventricular hemorrhage, and feeding intolerance frequently involves restriction of fluids
and delayed advancement of enteral feeds. To support optimal growth, energy
delivery must surpass energy requirements and this can be difficult to achieve with
such restrictions in place.
Parenteral and enteral nutrition do not achieve the same nutrient delivery as the
placenta. As a result, premature infants accrue protein and energy deficits rather
quickly. Embleton and colleagues13studied preterm infants less than 34 weeks and
found that nutrient intakes meeting current recommended dietary intakes were rarely
achieved during early life. Despite initiation of parenteral nutrition by day of life 2,
enteral feeds by day of life 4, and over 80% of participants receiving full enteral feeds
by 12 days of life, cumulative energy and protein deficits were 400 kcal/kg in infants
less than30 weeksgestation in the firstweek oflife. Bythe end ofthe fifth week, cumu-
lative energy and protein deficits were over 813 kcal/kg for such infants. Variation in
dietary intake accounted for 45% of the variation in changes in z score suggesting
that the growth restriction may be partially amenable to intervention.13
Breast milk is always preferred for its immune properties, tolerance, and protective
effect against necrotizing enterocolitis.14The nutrient content of unfortified breast milk
is insufficient to meet the requirements in preterm infants. Approximately 30% to 50%
of very low birth weight (VLBW) infants who are fed unfortified human milk or term
infant formulas have decreased bone mineral content compared with a fetus of
comparable weight or gestational age.15–17VLBW infants fed unfortified milk achieve
only a third of the intrauterine calcium-phosphorous accrual rates when consuming
180 to 200 mL/kg/d.18As a consequence, preterm and VLBW infants fed unfortified
milk have abnormalities in calcium-phosphorous balance and increase in serum alka-
line phosphatase activity compared with infants fed fortified preterm formula.16
It is the combined responsibility of all members of the heath care team to ensure
increased opportunities for the availability of maternal breast milk. Furman and
coworkers19conducted a prospective observational study of 119 mothers of singleton
VLBW infants. Over 70% intended to breastfeed, but only 34% continued lactating
beyond 40 weeks corrected gestational age. Significant correlates of lactation beyond
40 weeks corrected age included initiating milk expression within 6 hours of delivery,
expressing milk greater than or equal to five times per day, and kangaroo care. These
correlates remained significant after controlling for maternal age, race, marital status,
and education beyond high school. Education on lactation for pregnant mothers at
risk for premature delivery should begin in the antenatal period.19For infants unable to
receive breast milk, formula enriched with additional phosphorus, calcium, and protein
and used during the early neonatal period hasbeen shown to improve bone mineraliza-
tion at discharge over standard formula, even when caloric composition is the same.20
Postdischarge Nutritional Deficiencies
Postdischarge nutritional deficiencies in premature infants represent a grossly under-
studied area. Greater awareness of the long-term nutritional, metabolic, immune, and
Nutrient Deficiencies in the Premature Infant
neurocognitive benefits of breast milk and has prompted increased advocacy for pro-
longed breastfeeding. The recently published World Health Organization Multicenter
Growth Reference Study international growth charts used breastfed full-term infants
as the standard for growth during the first year.21For premature infants, it is unclear
what should be the optimal postdischarge growth standard. The commonly used
Infant Health and Development Program growth charts have limited use because
they used data from the 1980s and only followed 867 infants.22Although the updated
Fenton growth chart includes several large meta-analyses, growth data for 40 weeks
onward was collected in term, not premature, infants.23Premature infants differ signif-
icantly from term infants even after correcting for gestation age. Approximately 90% of
preterm infants are less than the tenth percentile for corrected gestation age at the
time of discharge.9
Nutritional status at discharge remains an uncontrolled variable in virtually every
long-term study of premature infants. Data on how to feed these premature infants
postdischarge are conflicting. Some studies suggest, whereas others do not, more
favorable growth profiles and rates of bone mineralization with the use of enriched
formula postdischarge.24–27A common misperception is that infants fed enriched
formula are getting more calories. The relatively few studies examining caloric intake
suggest that infants fed regular formulas ad libitum generally consume more
calories.28,29For example, Koo and Hockman30in a randomized, double-blind
comparison study involving 89 preterm infants found that those fed formula for term
infants (20 kcal/oz) had greater weight gain and accrued more lean mass, fat mass,
and bone mineral density during the first year than those who were fed a nutrient-
enriched formula (22 kcal/oz). Although there is a paucity of data, small studies
done on premature infants fed exclusively unfortified human milk postdischarge
suggest they may be a population particularly vulnerable to nutrient deficiencies. Wau-
ben and colleagues31found premature infants exclusively fed breast milk to have
decreased bone mineral content at 6 months corrected age when compared with
formula-fed infants. These differences correlated with lower calcium, phosphorus,
and protein intakes in postbreastfed compared with post–formula-fed infants. Fortifi-
cation of at least half of the milk for 12 weeks after hospital discharge may be an effec-
tive strategy in addressing early discharge nutrient deficits and poor growth
without unduly influencing human milk feeding when intensive support is provided.32
Schanler33evaluated preterm infants fed unfortified formula and found decreased
bone mineral content 1 year postdischarge that later improved by 2 years.34,35Infant
iron deficiency anemia and clinically significant zinc deficiency has also been reported
in small studies.34,35Infants consuming lower volumes benefit the most from nutrient-
enriched formula postdischarge.36,37
SPECIFIC NUTRIENT DEFICIENCIES
This section discusses specific nutrient deficiencies that the premature infant can
develop and also other nutrients whose supplementation may be beneficial to prema-
ture infants. These nutrients include minerals, trace elements, vitamins, long-chain
polyunsaturated fatty acids (LCPUFAs), and carnitine.
Calcium and Phosphorus
Preterm infants have increased calcium requirements compared with term infants
because they miss part or all of the third trimester, which is an important period for
fetal accretion of calcium. Nonsupplemented human milk cannot meet the calcium
needs of a preterm infant.16,18To account for these higher requirements preterm infant
Shah & Shah
formulas contain more calcium and phosphorous than term infants formulas. The
calcium content of human milk can be increased by supplementing with human milk
The calcium/phosphorus ratio in infant formulas may be an important determinant of
calcium absorption and retention. In human milk, the calcium/phosphorus ratio is
approximately 2.38Based on the American Academy of Pediatrics Committee on
Nutrition recommendations (2003), the recommended calcium/phosphorus ratio is
1.9.36The Committee on Nutrition of the Preterm Infant of the European Society of
Pediatric Gastroenterology and Nutrition (1987) recommended that preterm formulas
have a calcium/phosphorus ratio between 1.4 and 2.39
Adequate intake of calcium, phosphorus, and vitamin D is required to prevent
osteopenia of prematurity. Osteopenia of prematurity tends to remain asymptomatic
but severely affected infants may develop rickets, difficulty in weaning from the venti-
lator, poor linear growth, and hypotonia.38Osteopenia of prematurity is common in
VLBW infants and gestation age less than 28 weeks. The major risk factors are
extreme prematurity, prolonged feeding intolerance, parenteral nutrition, inadequate
calcium and phosphate intake,40chronic lung disease, and prolonged immobility.38
Screening for osteopenia of prematurity should begin at about 6 weeks postnatal
age in at-risk infants and should continue at 1- to 2-week intervals to allow early iden-
tification of the biochemical changes.38The biochemical screening tools are serum
concentrations of calcium, inorganic phosphate, and alkaline phosphatase. None of
these measurements by themselves, however, is adequately sensitive for diagnostic
purposes. One study showed that a combination of serum alkaline phosphatase
greater than 900 IU/L and inorganic phosphate less than 1.8 mmol/L in a group of
preterm infants yielded a sensitivity of 100% and a specificity of 70% in detecting
low bone mineral density at 3 months corrected gestational age.41
The major goal in the treatment of osteopenia of prematurity is to provide sufficient
calcium, phosphate, and vitamin D42to achieve intrauterine rates of bone mineraliza-
tion. This requires 200 mg/kg/d of calcium and 90 mg/kg/d of phosphorus enterally.
Early trophic enteral feeding significantly enhances achievement of full-volume feeds,
calcium/phosphate intake, and retention. In addition to the use of preterm infant
formulas and human milk fortifiers, extremely preterm infants may need additional
calcium and phosphorus after discharge until they reach 3.5 to 4 kg.38Infants with
osteopenia, rickets, and fractures require additional therapy with calcium and phos-
phorus supplements until normalization of serum alkaline phosphatase concentration
or at least 6 months postnatal age.38
Premature infants have limited iron stores, which are prone to rapidly being depleted
within the first few weeks of postnatal growth. The risk factors for developing iron
deficiency include inadequate intake and frequent phlebotomy.43Increased erythro-
poiesis, rapid catch-up growth, and use of erythropoietin further deplete iron
stores.44–46The hemoglobin nadir is lower and occurs earlier in preterm and VLBW
infants.47As the body preferentially distributes iron to red blood cells, decreased
hemoglobin is a late finding of iron deficiency.48Supplementing preterm and VLBW
infants tolerating 100 mL/kg/d of enteral feeds with iron was found to be safe, feasible,
and reduced the incidence of iron deficiency and late blood transfusions.49
Because iron deficiency seems particularly amenable to intervention, several
groups have studied iron status of premature infants postdischarge over the last
few decades. Catch-up growth is associated with increased iron requirements.
Studies done in the 1960s and 1970s showed that supplementing preterm infants
Nutrient Deficiencies in the Premature Infant
with iron 2 mg/kg/d prevented iron deficiency anemia in premature infants at 6 to
12 months corrected gestational age.46,50,51More recently, Schiza and colleagues52
found over 10% of predominantly formula-fed premature infants (32–36 weeks
gestation) had decreased iron stores (ferritin <12 mg/L) between 3 and 12 months
postdischarge. Anemia is a late finding of iron deficiency, a point at which brain iron
stores may already be severely depleted and the effects on development may be
irreversible.48,53The earlier studies suggesting efficacy of supplemental iron of
2 mg/kg/d in preventing iron deficiency anemia in preterm infants for the entire first
year of life must be interpreted with caution because iron deficiency may exist without
anemia. In addition, recommendations based on studies conducted during postdi-
scharge follow-up of larger preterm infants fed iron-fortified formula may not be appli-
cable to VLBW at greater risk for iron deficiency because of limited reserves at birth
and inadequate iron in breast milk.
Zinc is perhaps the most widely studied microelement in infant feeding because it is
a component of several enzymes involved in intermediary metabolism ranging from
growth to cell differentiation and metabolism of proteins, carbohydrates, and lipids.54
The clinical features of zinc deficiency include anorexia, failure to thrive, irritability,
periorificial and extensor dermatitis, stomatitis, glossitis, nail dystrophy, diarrhea,
and increased susceptibility to infection.55Many ex-preterm infants have subtle zinc
deficiency, which may benefit from extra zinc.56Zinc deficiency has been described
in breastfed preterm infants (gestation <34 weeks).55This may be explained by the
relative inability of breast milk to supply the zinc needs of the preterm infant. Affected
infants tend to be boys usually presenting at about 3 months postnatal age, which
coincides with the nadir for plasma zinc concentrations (6–12 weeks).55Male infants
may disproportionately be more affected because of more rapid weight gain. Current
recommended intakes for enterally fed infants are from 500 to 1000 mg/kg/d. Recom-
mended zinc intakes for the parenterally fed neonate range from 150 to 400 mg/kg/d.57
Copper is an essential trace mineral that functions as a cofactor in many important
enzymes, such as ceruloplasmin, elastase, cytochrome oxidase, and superoxide
dismutase.58Copper deficiency is associated with hypochromic anemia resistant to
iron supplementation, neutropenia, osteoporosis, and difficulty in gaining weight.54
Preterm infants have decreased serum copper and hepatic stores compared with
full-term infants.59The serum copper concentrations in full-term infants rapidly
increase to reach adult levels. Preterm infants continue to have serum low serum
copper, however, during the first 4 to 6 postnatal months.60This difference in serum
copper concentrations is dependent on the rate of growth (ie, infants growing rapidly
have relatively decreased serum copper concentrations compared with infants with
slower growth).61Copper requirements increase during phases when there is rapid
The World Health Organization has recommended a minimum intake of 60 mg/kg/d
for infants,62whereas the new recommended daily allowance for copper is 200 mg/d.63
The copper content in breast milk, preterm infant formulas, and formula for full-term
infants is 0.2 to 0.4 mg/L, 1 to 2 mg/dL, and 0.4 to 0.6 mg/L, respectively. In compar-
ison, breast milk has the least amount of copper; however, it is more bioavailable than
Shah & Shah
Selenium is a constituent part of selenoenzymes, including glutathione peroxidase,
which has a role in protecting against oxidative damage. Glutathione peroxidase
participates in antioxidant defense and helps scavenge free radicals and protect the
body against oxidative insult.66Serum glutathione peroxidase levels have been
used to assess short-term selenium status, whereas erythrocyte glutathione peroxi-
dase levels have been used as an indicator of longer-term status. Serum selenium
levels are also used frequently to assess selenium status.
Premature infants have lower tissue and plasma selenium concentrations than term
infants.67No data exist on the fetal concentrations of selenium, but a selenium intake
of at least 1 mg/kg/d is recommended to achieve intrauterine tissue accretion.54The
evaluation of selenium status in preterm infants is difficult. In one study preterm infants
were fed either human milk (24 ng selenium/mL); preterm formula (7.8 ng selenium/
mL); or preterm formula supplemented with selenium (34.8 ng selenium/mL). Although
selenium intakes of infants fed the selenium-supplemented formula were greater than
those of infants in the other two groups, there were no differences found in plasma or
erythrocyte selenium or glutathione peroxidase.67Risk for developing selenium
deficiency may be increased, however, in disorders associated with oxidative stress.
Preterm infants with respiratory distress syndrome receiving parenteral nutrition
without selenium had decreased serum concentrations of selenium compared with
infants supplemented with 3 mg/kg of selenium in parenteral fluids and prevented
the fall in the concentration seen in nonsupplemented infants.68
Darlow and colleagues69assessed the effects of selenium supplementation in
a multicenter, randomized, double-blind study of VLBW infants. Supplementation
was associated with increased serum concentrations of selenium at postnatal age
28 days and 36 weeks corrected gestation age. These observations have been
confirmed by most studies on selenium with preterm infants. Itis still unclear, however,
whether selenium is effective in preventing or ameliorating respiratory distress
syndrome, bronchopulmonary dysplasia, retinopathy of prematurity, and other disor-
ders associated with oxidative stress. In a meta-analysis that included three studies,
selenium supplementation of very preterm infants was associated with a reduction in
one or more episodes of sepsis.70Supplementation was not associated, however,
with improved survival, a reduction in chronic lung disease, or retinopathy of prema-
turity. Because these data were dominated by data from a large trial conducted in New
Zealand (a country with low selenium concentrations), the findings may not apply to
preterm infants in geographic areas with higher selenium concentrations.70
The amount of selenium recommended for supplementation in preterm infants is
variable. In the United States, 2 mg/kg/d given parenterally is recommended. A large
clinical trial conducted in New Zealand, however, suggested 3 mg/kg/d to maintain
concentrations at the umbilical cord blood levels.69To increase the concentrations
above umbilical cord blood levels and closer to range in breastfed full-term infants,
5 to 7 mg/kg/d is recommended.54An expert panel organized by the Food and Drug
Administration and American Society for Nutritional Sciences71recommended
a minimum selenium concentration of 1.8 mg/100 kcal and a maximum of 5 mg/100
kcal in preterm formulas.
The iodine content of breast milk is dependent on maternal intake of iodine, which in
turn is related to geographic location.72Transient hypothyroidism has been reported in
preterm infants obtaining less than 30 mg/kg/d of iodine.72The recommended intake of
Nutrient Deficiencies in the Premature Infant
iodine is 30 to 60 mg/kg/d.73In healthy preterm infants fed human milk, deficiencies of
chromium, manganese, or molybdenum have not been reported.73
Like in all humans, the preterm infant has a limited reserve of water-soluble vitamins
and needs a constant supply to avoid deficiencies. Preterms have higher recommen-
ded intakes based on reduced vitamin stores and increased protein requirements.73
These increased requirements can be met in two ways. Preterm formulas contain
larger amounts of water-soluble vitamins than term formulas and meet the increased
needs for these vitamins. Breastfed preterm infants can have these needs met by
using a vitamin-containing human milk fortifier.73It is important to note that standard
infant multivitamin supplements do not contain all of these water-soluble vitamins.73
Vitamin A promotes normal growth and differentiation of epithelial tissues. In the
developing world, supplementing newborn infants with vitamin A within 48 hours of
birth significantly reduces infant mortality, with the greatest benefit to those of low
The preterm infant is born with lower stores of vitamin A than term infants. Term
infants absorb vitamin A when it is provided enterally.75In VLBW infants, vitamin
A given orally in conjunction with early feeds can achieve comparable plasma concen-
trations of retinol as vitamin A given intramuscularly.75Extremely low birth weight
(<1000 g) infants do not absorb vitamin A to significantly increase plasma concentra-
tions even when large doses are provided.75These infants may benefit from three-
times-a-week intramuscular injections of vitamin A with a reduction in death or oxygen
requirement at 1 month of age.76This relatively small benefit needs to be balanced
with the need to give frequent intramuscular injections to these infants.
Overt vitamin D deficiency is rare in the preterm infant in the United States. The main
cause of metabolic bone disease of prematurity is a deficiency of calcium and phos-
phorus and not vitamin D.42All preterm formulas and human milk fortifiers provide
between 200 and 400 IU/day of vitamin D.73
Vitamin E is an antioxidant vitamin whose requirement increases with the level of
LCPUFA in the diet. Vitamin E deficiency has induced hemolytic anemia among
preterm infants. This has occurred with the use of formulas that contained high quan-
tities of LCPUFA with inadequate vitamin E.77These formulas also contained supple-
mental iron, which functioned as a pro-oxidant.77Today’s formulas are designed to
provide a minimum of 0.7 IU of vitamin/100 kcal at least of vitamin E and 1 IU/g of
linoleic acid.73The use of large doses of vitamin E to prevent retinopathy of prematu-
rity or bronchopulmonary dysplasia is not recommended.73
Hemorrhagic disease of the newborn is most commonly seen in exclusively
breastfed infants, and is a manifestation of vitamin K deficiency. A preventive intra-
muscular injection of vitamin K (1 mg for children >1 kg and 0.3 mg/kg for children
<1 kg) is recommended.73Breast milk has a low vitamin K content, which can be sup-
plemented by the use of vitamin-containing human milk fortifiers. Preterm formulas
contain adequate vitamin K to meet the daily needs of the infant.
Preterm infants exhibit poorer developmental outcomes in a wide range of domains
than infants born at term.78–82LCPUFAs, such as docosahexaenoic acid and arach-
idonic acid, are rapidly accumulated into the tissues of the central nervous system
during the third trimester and early postnatal life. Biochemical studies have shown
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that term infants who receive a full complement of all LCPUFAs through breast milk
have higher concentrations of LCPUFAs in their blood cells and higher concentra-
tions of docosahexaenoic acid in the brain than do infants fed formulas that do not
contain LCPUFAs.83Several randomized controlled trials have reported that
preterm infants fed LCPUFA-enriched formulas have enhanced visual development,
including improved retinal sensitivity and visual acuity, compared with those fed un-
supplemented formulas.84–88Such data have led to many intervention trials
involving LCPUFA-enriched formulas for preterm infants with developmental end
points. The addition of LCPUFAs to preterm formulas has shown conflicting results
with regard to neurodevelopment. Some studies have suggested strong benefits of
LCPUFA supplementation,89,90whereas other studies have shown no effect.88,91,92
A more recent study that had an adequate sample size showed benefit in prema-
ture girls but not in boys who were supplemented with high-dose docosahexaenoic
These formulas seem to be safe. Further studies are needed to determine the extent
of the benefit of supplemental LCPUFAs on the neurodevelopment and health
outcomes of infants born preterm.
Carnitine plays an important role in fatty acid oxidation by facilitating the transport of
long-chain fatty acids into the mitochondria.94,95Preterm infants have very low stores
of skeletal muscle carnitine and are considered at high risk of carnitine deficiency.
Infants on full feeds with breast milk or infant formula receive adequate amounts of
carnitine. The risk for developing carnitine deficiency is increased in infants receiving
parenteral nutrition without carnitine supplements. Studies have shown that parenteral
supplementation of carnitine may increase serum carnitine concentrations96–98and
improve lipid tolerance,95,97weight gain, and nitrogen retention96in preterm infants
who received 10 to 20 mg/kg/d of carnitine. One study that used a higher dose of
carnitine (48 mg/kg/d) showed slower growth rates in preterm infants compared
with those receiving lower amounts.98A Cochrane database review that included all
randomized trials involving parenteral supplementation of carnitine in neonates for
improvements in growth or lipid tolerance found no evidence supporting routine
supplementation with carnitine.99This review is limited by the fact that most of the
studies included were short-term studies. Carnitine supplementation may be impor-
tant for infants requiring long-term parenteral nutrition with minimal or no enteral
Infants born prematurely are prone to nutrient deficiencies at birth that are exacer-
bated by the time of discharge from the neonatal intensive care unit, and understudied
thereafter. General guidelines are available for postdischarge feeding practices and
follow-up.36More comprehensive nutritional care should be provided depending on
the risk and specific needs of each infant.
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