CLINICAL PRACTICE
Abstract
Parents and health care providers often
incorrectly use the term milk intoler-
ance to describe a wide spectrum of
symptoms seen in infants who have
problems digesting cow’s milk. The most
common reasons for milk intolerance
are the negative reactions to lactose or
cow’s milk protein. Identification and
correct diagnosis of lactose intolerance
or cow’s milk protein allergy is imper-
ative to correctly recommend altera-
tions in feeding practices or suggest
formula changes.
n 2005 Elsevier Inc. All rights
reserved.
From the Mercy Medical Center, Department of
Pediatrics, Division of Neonatology, Baltimore, MD.
Address reprint requests to Janice Wilson, MS,
CRNP, PO Box 748, 126 Main Street, New Windsor,
MD 21776.
n 2005 Elsevier Inc. All rights reserved.
1527-3369/05/0504-0111$30.00/0
doi:10.1053/j.nainr.2005.08.004
Milk
Intolerance:
Lactose
Intolerance and
Cow’s Milk
Protein Allergy
By Janice Wilson, MS, CRNP
B
oth health care providers and parents frequently use milk intolerance
to describe a whole host of symptoms most commonly seen in infants
who are fed commercially prepared formulas. In actuality, milk
intolerance is a broad and generic term that includes the more specific
maladies of lactose intolerance, cow’s milk protein intolerance (CMPI), and
cow’s milk allergy (CMA).
Negative reactions to cow’s milk have been documented for centuries.
Hippocrates noted gastrointestinal (GI) upset and skin reactions in some
individuals exposed to cow’s milk.1 Galen also gave a description of a patient
with suspected cow’s milk allergy.2
Before the 1950s, milk intolerance—although reported—was a rare event.
As commercially prepared formulas became more readily available, a
concomitant decrease in breast-feeding was seen. This may explain, in part,
the documentation of increased frequency of reactions to cow’s milk from the
1950s until today.3
To assist patients and their families attain a successful feeding regimen for
their infants, whether it be breast feeding, formula feeding, or a combination
of the two feeding options, health care providers need a thorough under-
standing of the physiological conditions that are included under the umbrella of
milk intolerance.
Lactose Intolerance
L actose intolerance is a result of lactase deficiency and is a form of
carbohydrate malabsorption. Lactose is hydrolyzed by lactase in the
intestinal mucosa. Lactase is one of many b-galactosidases seen in the small
bowel and is most active in the jejunum.4 The by-products of lactose
hydrolysis are the monosaccharides: (1) glucose and (2) galactose. When
lactase is absent or deficient, hydrolysis of the sugar lactose is incomplete.
Because it is osmotically active, the undigested sugar will pull fluid into the
intestine. Hydrogen and lactic acid, in addition to other organic acids, are
produced when colonic bacteria act on the undigested sugar. The combined
osmotic effect of the undigested sugar and organic acids results in the passage
Newborn and Infant Nursing Reviews, Vol 5, No 4 (December), 2005: pp 203–207 203
204 Janice Wilson
of acidic diarrheal stools. These stools can produce
significant skin irritation and breakdown.5 Infants with
lactose intolerance may also present with abdominal
distension and vomiting.5 In its most severe form, lactose
intolerance can lead to dehydration, electrolyte abnor-
malities, and failure to thrive.
Lactase deficiency has been described as primary,
secondary, or congenital.6 Congenital lactase deficiency
is a rare hereditary disorder in which lactase activity is
absent.5,6 Primary lactase deficiency is the normal gradual
reduction in lactase production seen as an individual
matures from infancy into adulthood and is expressed
variably across populations.6 Lactase deficiency may also
be a secondary occurrence because of gastroenteritis,
bowel surgery, cystic fibrosis, or immune disorders. It
has also been seen transiently in infants exposed to
phototherapy and antibiotic therapy.6
Cow’s Milk Protein Allergy/Cow’s Milk
Protein Intolerance
I ntolerance or allergy to cow’s milk is more complex and
less well understood.3,7 Sensitivity and allergic reaction
to cow’s milk protein is said to be the most common
allergy seen in infancy.8 The incidence has been reported
to be anywhere between 1.8% and 7.5%.3,9–13 The
variability in incidence reporting has been attributed to
the differences in diagnostic criteria used to identify
infants with the disorder, as well as differences in the
design of studies used to evaluate the disease.9
Proteins in cow’s milk are processed in the gut via
gastric and pancreatic proteolytic enzymes.7 This process
can be impacted by intestinal epithelial function, hormonal
controls, and genetic factors.7 As the proteins are broken
down, macromolecules are formed. These high-molecular-
weight food proteins are then absorbed via the intestinal
mucosa. This results in the development of antibodies
against cow’s milk protein and is thought to be a normal
physiological response.3 Macromolecular absorption, in
combination with changes in intestinal mucosa and
genetic allergic predisposition, most likely plays a part
in any given infant’s allergic response when exposed
to cow’s milk.3 Other factors that may influence the
development of cow’s milk allergy are timing of the
exposure, the magnitude and frequency of the exposure,
as well as the allergenicity of the protein itself.3,14 Casein,
a-lactoglobulin, b-lactoglobulin, bovine serum albumin,
and c-globulin are the compounds in cow’s milk that
are postulated to be allergenic.15
The terms cow’s milk protein allergy and CMA are
often used interchangeably in the literature. The same is
true of the terms CMPI and cow’s milk intolerance (CMI).
Cow’s milk protein allergy/cows’ milk allergy can be best
defined as adverse reactions to cow’s milk that can be
reproduced and are immune-mediated.3 The most common
immune responses are immunoglobulin E (IgE)-mediated,
cell-mediated (non-IgE), or the combination of the
two.16,17 Cow’s milk protein intolerance/cow’s milk
intolerance is not immune-mediated. It is said to be
undefined because an immune component is not clearly
identifiable. The definition of CMPI/CMI does not include
the symptoms of lactose intolerance or the presence of
incidental isolated GI tract infections.3
Children with CMA or CMI can present with a variety
of signs that are cutaneous, GI, or respiratory in origin. The
most common cutaneous reactions are urticaria, atopic
dermatitis, angioedema, and contact rashes.3,8,16,18,19
Infants with GI reactions can present with nausea,
vomiting (including hematemesis), colic, diarrhea, (includ-
ing occult and frank blood), enterocolitis, colitis, consti-
pation, and transient enteropathies.3,8,14,16,18,19 Respiratory
reactions include rhinoconjuctivitis, asthma, wheezing,
laryngeal edema, otitis media, and anaphylaxis.3,8,16,18,19
Breast-feeding is thought to protect against or prolong
the onset of CMA/CMI. Secretory immunoglobulin A in
breast milk may block the absorption of the macro-
molecules derived from protein breakdown.20 The inci-
dence of CMA/CMI in infants who were exclusively
breast-fed for more that 1 month has been reported to be
up to 1%.7 Reproducible reactions to cow’s milk protein
in human milk has been reported in about 0.5% of
infants.9,13 These infants may be reacting to cow’s milk
protein ingested by their mothers.9 Small amounts of
b-lactoglobulin have been measured in the breast milk of
lactating women.9 Cord blood IgE specific to cow’s milk
protein has been seen in several infants who go on to
develop CMA/CMI, but the link is unclear.9 It does
raise the possibility of intrauterine sensitivity to cow’s
milk protein.
Most cases of CMA/CMI present within the first month
of life and within the first week of exposure to cow’s
milk.9 Symptoms tend to disappear by age 2 to 3 years but
some evidence suggests that symptoms may persist up to
4 years of age.21
To diagnose either lactose intolerance or CMA/CMI,
the health care provider must obtain an accurate history
and perform a thorough physical exam. The history must
include all types of formulas and any other foods that are
in the infant’s diet. Timing of the symptoms to any
changes in diet could be crucial. If the infant is breast-
fed exclusively, a detailed history of familial allergies
should be explored. Children who have one or both
parents or an older sibling with a history of CMA or
other allergic reactions are most at risk for development
of CMA.8,16,22,23

Lactose Intolerance Diagnosis and
Management
T he symptoms of lactose intolerance tend to be
primarily GI in origin. If a bout of gastroenteritis or
use of antibiotics occurs around the time of the GI
symptoms, a secondary lactose deficiency should be
suspected. In the intestinal insult that often occurs with
secondary lactose intolerance, lactase is the first enzyme to
be negatively impacted and the last to recover as the insult
resolves.5 Testing for reducing substances in the stools is
not always helpful. Infants with positive reducing sub-
stances may have sufficient lactase activity. Because
lactase breaks down lactose into glucose and galactose,
the presence of 20 –25 milligrams per deciliter of glucose
above fasting levels indicates sufficient levels of lactase.5
When colonic bacteria act upon undigested lactose,
hydrogen is formed. Breath hydrogen analysis may be
useful in the diagnosis of lactose intolerance.6
The treatment of documented lactose intolerance is
removal of lactose from the diet in the form of lactose-free
formulas (see Table 1). The American Academy of
Pediatrics, in its 1998 policy statement, recommends the
use of soy-based formulas in the management of primary
lactose deficiency. In cases of secondary lactose intoler-
ance when infants have recovered from the offending
insult, refeeding with breast milk or cow’s milk formula
should be well tolerated.24 Soy-based formulas, however,
are not nutritionally adequate for the preterm infant less
than 1800 grams.24 Routine use of soy-based formulas to
treat or prevent colic is not recommended.24 Health care
providers and parents often request a change to soy
formulas when signs of colic become apparent, without
documentation of lactose intolerance or CMA.
Cows’ Milk Protein Allergy/Intolerance
Diagnosis and Management
T here is no single one test that can be used to identify
all children with CMA.16,19,25 Total serum IgE levels
Table 1. Formulas Used in the Treatment of Lactose Intolerance and Cow’s Milk Protein Allergy
Partially Hydrolyzed Extensively Hydrolyzed
Soy Formulas Lactose-Free Formulas
Isomil (Ross/Abott Laboratories, Lactofree
Columbus, OH) (Meade Johnson) (Meade Johnson)
Prosobee (Meade Johnson, Soy formulas Good Start Supreme
Evansville, IN)
Alsoy (Carnation/Nestle, Hydrolyzed formulas
Glendale, CA)
Nursoy (Gerber Productions,
Freemont, M I)
Milk Intolerance 205
are not helpful by themselves. Infants with normal IgE
levels can still have CMA. Skin or prick tests specific for
cow’s milk protein can be used but have high rates of
false positives and false negatives.19,26 The radioallergo-
sorbent test can be done to detect specific IgE to cow’s
milk but may be negative in children who are truly
allergic.19 Scratch and radioallergosorbent tests when
used together may be more useful.19 A complete blood
count should be requested to evaluate eosinophilia and to
identify anemia secondary to GI blood loss. Stool
cultures and stool for ova and parasites should be sent
to help rule out intestinal infection.
Children and infants with CMA/CMI also tend to
present with symptoms from two or more organ systems.9
There is some evidence to suggest that patients who have
immediate reactions (within minutes) to cow’s milk may
be more likely to develop acute rashes, perioral erythema,
facial angioedema, and widespread urticaria (with or
without anaphylaxis). These children have higher
levels of cow’s milk specific IgE antibodies.14 Intermedi-
ate reactors may show mainly GI symptoms within
1–24 hours after exposure. They do not have the same
IgE response as the immediate reactors.14 The late group
of reactors can demonstrate symptoms from 24 hours up to
5 days after cow’s milk exposure. They typically present
with atopic dermatitis flares or cough and wheeze.14,27–30
The Gold Standard in the diagnosis of cow’s milk
allergy is the double-blind placebo-controlled food chal-
lenge.9,14,31 The double-blind placebo-controlled food
challenge is difficult to administer and time consum-
ing.16,17,25 If CMA/CMI is suspected, most health care
providers will remove cow’s milk entirely from the diet for
a period. The patient will be observed for cessation of
symptoms, and cow’s milk will be carefully reintroduced.
If symptoms reappear after reintroduction of cow’s milk, it
is said to be highly suspicious of CMA. If the patient is
exclusively breast-fed and there is suspicion of CMA, the
removal of cow’s milk protein from the mother’s diet may
help reduce or eliminate symptoms.32
Free Amino Acid
Formulas Formulas Formulas
Gentlease Nutramigen Lipil Neocate (SHS America,
(Meade Johnson) Gaithersburg, MD)
Pregestimil Elecare (Ross)
(Carnation) (Meade Johnson)
Alimentum (Ross)
206 Janice Wilson
A Cochrane Database Review published in 2004
recommends that infants with a strong family history of
CMA (one or more parents or older sibling with
documented CMA) and other allergies be exclusively
breast-fed. If exclusive breast-feeding is not possible or if
breast-feeding must be supplemented, these high-risk
infants might have fewer symptoms if fed hydrolyzed
formulas instead of standard cow’s milk formulas (see
Table 1). The use of soy-based formulas in patients with
high risk of CMA may not be advisable because of the
concern for the potential allergenicity of soy protein.33
There is insufficient evidence that soy formulas reduce the
development of asthma or wheezing in the first year of life
in those children most at risk.33
The American Academy of Pediatrics published a
policy statement in 2000 with a list of recommendations
for the feeding of infants with CMA or at a high risk for
developing symptoms of CMA. Breast milk is strongly
recommended as the best choice for infant feeding through
the first year of life. If exclusively breast-fed infants
develop CMA, the reduction of cow’s milk in the mother’s
diet (in addition to other commonly allergenic foods) may
reduce or eliminate symptoms. When amendments in the
mother’s diet are unsuccessful, or if supplementation to
breast feeding is required, the recommendation is to use
extensively hydrolyzed formulas or free amino acid–based
formulas. Partially hydrolyzed formulas are not recom-
mended. Hydrolyzed formulas are treated so that the
proteins are predigested. Partially hydrolyzed formulas
have a higher percentage of intact cow’s milk proteins that
may continue to produce allergic reactions.
Extensively hydrolyzed formulas have a lower percent-
age of proteins that are intact. They may also induce
allergic reactions, but most infants fed these formulas
(90%) tolerate them well.32 Free amino acid or elemental
formulas have protein that is even further broken down
and are also well tolerated by infants. Soy formulas may be
of benefit only in those children who have IgE symptoms
of CMA (urticaria, atopic dermatitis, angioedema, rhino-
conjunctivitis, laryngeal edema, cough, or wheeze) but not
with non-IgE symptoms such as enterocolitis, proctocoli-
tis, malabsorption, or esophagitis. It is suggested that in
those infants who are at highest risk for cow’s milk protein
allergies, solid food introduction be delayed until at least
6 months of age with a delay of adding dairy until 1 year,
eggs at 2 years, and peanuts, nuts, and fish at 3 years.32
Infants with severe colic may benefit from the use of
hypoallergenic formulas (extensively hydrolyzed or free
amino acid formulas) for 1 to 2 weeks before the
reintroduction of cow’s milk.32
Understanding and diagnosing lactose intolerance and
cow’s milk protein allergy is paramount in being able to
assist parents make logical choices in feeding their
infants. Exclusive breast-feeding for the first 6 months
to 1 year of life should be supported and strongly
recommended for all infants but, most particularly, for
those infants at highest risk for the development of cow’s
milk allergy. If breast-feeding is not an option or must be
supplemented with formula, most infants will do well
with standard cow’s milk formulas. Extensively hydro-
lyzed or free amino acid formulas are best designed to fit
the needs of the cow’s milk protein–intolerant child and
should be the first formula of choice in those situations.
Lactose-free formulas should be used in instances of
documented lactose intolerance. Soy formulas may be
used in children with IgE-mediated allergic reactions.
Careful attention to history and physical examination
with a basic understanding of lactose intolerance and
cow’s milk allergy will hopefully avoid unnecessary or
inappropriate feeding changes.
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