Insomnia
and Cow’s
Milk Allergy
in Infants
A. Kahn, MD, M. J. Mozin, G. Casimir, MD, L. Montauk, and
D. Blum, MD
From the Pediatric Sleep Laboratory and Department of Pediatrics, Free University of
Brussels, Brussels, Belgium
ABSTRACT. A group of eight infants (six boys and two girls, 7 to 46 weeks of age) is reported, in whom a causal relationship between cow’s milk allergy and chronic sleeplessness was suspected. They were referred because of waking and crying episodes that had occurred since
the early days of life during sleep hours. During an
average night, they slept about 4.5 hours and woke their parents about five times. They cried a lot during the day and were described as fussy. Two infants had been treated
with phenothiazine without improvement. No cause for
chronic insomnia was found during a standard medical
and psychologic workup. An all-night polygraphic record-ing confirmed the disrupted sleep pattern ofthese infants, as compared with that of normal infants, and excluded further causes of arousals. Due to a clinical suspicion of atopy, the infants were further subjected to a series of allergy tests. IgE levels were shown to be elevated in each
child, and radioallergosorbent tests were positive for
cow’s milk protein. The infants were than fed exclusively with a hydrolyzed milk protein mixture for 4 weeks. Sleep normalized within 2 weeks in every infant: night sleep increased to a median of 10 hours, and the awakenings
only occurred occasionally. In four infants less than 6
months of age, cow’s milk was reintroduced in the diet, and within 1 week all four became severely sleepless.
Cow’s milk was again excluded from the diet and the
babies’ sleep behaviors were again normalized. It is con-cluded that, when no evident cause for sleeplessness can
be found in an infant, the possibility of milk allergy
should be given serious consideration. Pediatrics
1985;76:880-884; insomnia, allergy, cow’s milk, phenothi-azine, sleep.
Spontaneous awakenings during the night have
been shown to occur normally in more than 84% of
infants younger than 1 year of age.’ They are
sel-dom a source of concern, except for parents poorly
Received for publication Oct 24, 1984; accepted Jan 22, 1985. Reprint requests to (A.K.) Pediatric Sleep Laboratory, Depart-ment of Pediatrics, Free University of Brussels, Rue Haute, 320, 1000 Bruxelles, Belgium.
PEDIATRICS (ISSN 0031 4005). Copyright © 1985 by the American Academy of Pediatrics.
informed about normal infant sleep behavior.”2
Persistent settling and waking difficulties,
associ-ated with disturbing behavior such as restlessness
and intense crying, are encountered in 10%2 to 20%
of children less than 1 year of age. These symptoms
can be found early in life, sometimes from birth.46
Such chronic insomnia in a child disrupts family
life and is a real challenge to the pediatrician.3’6’7
Persistent restlessness and crying during the
night have been attributed to a variety of external
causes: they may be indicative of family problems
such as excessive parental anxiety, resulting in
oversolicitousness and inappropriate behavior2’7;
they can also be explained by adverse
environmen-tal conditions such as changed sleeping
arrange-ments, family separations, or minor trauma,
espe-cially during the second half of the first year.2
Some cases of persistent insomnia have been
attributed to causes within the child, such as a
constitutional sensitiveness,2’7 a low sensory
threshold,8 a possible imbalance of the autonomic
nervous system,9 the delayed effects of neonatal
asphyxia,2’4”#{176} and brain malformation or
chromo-somal abnormalities.” Recurrent episodes of upper
airway obstruction,6 chronic physical discomfort, or
gastroesophageal reflux” have also been shown to
induce waking during the night.
We report a group of eight infants in whom a
causal relationship between cow’s milk allergy and
chronic insomnia was suspected.
PATIENTS AND INVESTIGATIONS
From January 1983 to June 1984, eight infants
with histories or physical examination findings
suggestive of atopy were selected from an
out-pa-tient sleep clinic. They had been referred by their
pediatricians for chronic waking and crying during
sleep hours. On the first visit, a standardized
inter-view was conducted with the parents to determine
main behavioral characteristics. A standard
medi-cal examination of the child was performed. For
seven days the parents were asked to fill in a log
describing the child’s sleep schedule. On the second
visit, a standard medical and psychologic protocol
was followed to rule out the most frequently
ne-ported causes for chronic insomnia in infants.3’4’6 It
was completed by an all-night polygraphic
record-ing, which excluded further causes of anousals (such
as obstructive apneas, esophageal reflux), and
eval-uated the child’s sleep, albeit in laboratory
condi-tions.
Due to the suspicion of atopy, the eight children were further subjected to a series of allergy tests.
All cow’s milk was then removed from the diet by
feeding the infants exclusively with a hydrolyzed
milk protein mixture (Alfane, Nestle Nutrition) for
4 weeks. Follow-up interviews and home visits were
carried out by nurses to evaluate the child’s
prog-ness. For ethical reasons, no control of the
polysom-nographies was done after reported improvement
of the children’s sleep. Informed parental consent
was obtained in each case.
ALLERGY TEST
Prior to blood collection, information pertaining
to allergies in the child and the family was obtained
by interviewing the parents. The presence in the
child of clinical signs of atopy (digestive, cutaneous,
or respiratory) was noted. Assay kits for IgE (Pnist,
Phadebas) were used to determine serum IgE levels. According to local control values, a test was consid-ened positive if a value was greaten than 5 U/mL
for an infant younger than 3 months of age and if
a value was greaten than 10 U/mL for an infant 3
to 12 months of age. In vitro radioallengosorbent
tests (RAST, Pharmacia Fine Chemicals) were
con-ducted to identify specific IgE against fl-lactoglob-ulin.
MONITORING PROCEDURE
Each child’s night sleep was recorded for 12 hours under standard sleep laboratory conditions.
Moni-toning was carried out in a quiet and darkened room,
at a temperature ranging between 23#{176}and 25#{176}C.
The infants were observed continuously during
re-cordings, and awakenings (defined as opening of
the eyes), behavior, vocalizations, and nursing
in-terventions were charted. The data were recorded
on a 16-channel Alvar model polygraph (paper
speed 10 mm/s). The following variables were
si-multaneously recorded: scalp EEG, electrooculo-gram, digastnic electromyogram, and ECG. Respi-ratony characteristics were measured by a thoracic and an abdominal strain gauge and air flow was
measured by thermistors taped under the infant’s
nostrils and on the side of the mouth. Esophageal
pH was continuously recorded from a pH meter
(Digital-pH-meter, Knick), with a flexible glass pH
probe radiographically located 3 cm above the car-dia. Every 30-second period of the recording was
scored for sleep stage and central and obstructive
apneas, according to usual definitions.’2 Esophageal
reflux was defined as a decrease in pH to less than
4#{149}o#{149}3
The results obtained from the recordings were compared with values obtained from 20 normal
infants (ten boys and ten girls) matched for age and
recorded under similar conditions during a sleep
research project.12 Statistical analysis was
pen-formed using the Wilcoxon rank test.
RESULTS
The general characteristics of the infants are reported in Table 1. There were no premature on
no small-for-date infants. There were six boys and
two girls, 7 to 46 weeks of age. Four were first-born
and four were second-bonn infants. They were all
from middle class Belgian families. A history of
atopy (hay fever and eczema) was found in four of
the families. Five infants were bottle-fed since
birth, and three were breast-fed and bottle-fed for
3 weeks; on hospital admission all infants were on
a diet containing cow’s milk. Although no infant had previously been considered ill or had been
TABLE 1. Characteristics Study Infants*
and Laboratory Results of
Characteristic Result P
Value
No. of patients 8
Gestational age (wk) 39.4 ± 1.2
Age on admission (wk)
Median 14.8
Range 7-46
Wt
At birth (percentile) 73.4 ± 16.7
On admission (percentile) 39.1 ± 14.2 .05
Ht
At birth (percentile) 65.9 ± 33.5
On admission (percentile) 38.8 ± 29.9 NS Laboratory tests
IgE (U/mL) [range] 118.8 ± 66.9
[7-175J Radioallergosorbentt
Positive for 3-lactoglobulin 4
Negative 1
Not done 3
* Results are reported as means and SD, median, or
absolute values. Statistical analysis to compare weight or height at birth with that on admission was performed with the use of Wilcoxon rank test.
TABLE 2. Sleep Characteristics Before and After Exclusion Regimen*
Characteristic Before
Treatment
P1 After
Treatment
P2
Sleep time during the night (min/12 h)
Reported by parents 266.3 ± 68.9 588.4 ± 120.0 .01
Recorded in sleep lab 305.3 ± 123.1
Controls in sleep lab 509.9 ± 37.7 .01
Total sleep time/24 h (h)
Median 4.5 11.75
Range 3.5-6.5 9-14 .01
No. of arousals during the night/12 h
Reported by parents 5.4 ± 1.9 0.5 ± 0.1 .01
Recorded in sleep lab 4.8 ± 2.6
Controls in sleep lab 0.9 ± 0.1 .01
Duration of arousals (mm)
Reported by parents 35.5 ± 8.0 10.5 ± 5.0 .01
Recorded in sleep lab 27.4 ± 8.7
Controls in sleep lab 10.2 ±5.2 .01
* Results are expressed as means ± SD. Controls were 20 normal infants studiedunder similar conditions. Statistical
analysis (Wilcoxon rank test) compared the infants’ sleep recorded in the laboratory with that of controls (P1) and
the infants’s sleep, as described by the parents, before and after treatment (P2).
hospitalized, five had a history of chronic eczema
on the face and trunk, and three had at least two
episodes of wheezing and bronchitis. Seven also had
frequent episodes ofloose stools, vomiting, and poor
appetite; these infants had gained weight poorly, as
shown by plotting their weight for age on a local percentile growth curve.’4 The same trend appeared
for the height growth curves but was not shown to
be statistically significant.
On admission to the hospital, seven infants were pale and seemed tired; none had any infection or malformation disclosed by chest and skull x-ray film evaluation.
Disruption of sleep by prolonged crying had been
noted since the early days of life in all infants. Two
infants had been treated with phenothiazine syrups
for at least 2 weeks without any improvement.
According to the parents’ records, the children’s median duration of sleep was 4.5 hours per night (range 2.5 to 5.5 hours) (Table 2). An additional
0.25 to 3 hours were spent sleeping during the day.
The infants were reported to awaken about five
times pen night (range 3.5 to nine) and to remain
crying for a median duration of 30 minutes (range
20 to 40 minutes). They were all described as fussy,
difficult to pacify, and tired on waking up.
Short and disrupted sleep patterns were also
observed during the laboratory recordings: sleep duration and the number of awakenings signifi-cantly distinguished these patients from local standards (Table 2). No cause for arousal was seen
in any child (no prolonged central apnea,
obstruc-tive apnea, esophageal reflux, or heart rate disturb-ance).
Laboratory tests revealed that IgE levels were
elevated in all children. RASTs were also conducted
to identify IgE against 3-globu1in in five infants: in
four the RAST test was positive and in one the RAST was negative. Two children also had positive RASTs to egg. Three infants had no RAST pen-formed for technical reasons.
All infants tolerated the artificial diet well. Within 2 weeks (range 1 to 4 weeks), every parent reported that their infant’s sleep schedule was non-ma! (Table 2). During the night, the infants slept for a median of ten hours (range 6.5 to 12 hours). Awakenings only occurred occasionally, and the parents had no difficulty putting the baby back to
sleep. During the day, the babies’ sleep increased
by a median duration of 1.5 hours (range 0.5 to 2.0
hours); their behavior was considered normal in
four and clearly improved in the others. On physical examination, none looked pale on tired. The
cuta-neous and respiratory symptoms had completely
cleaned in five infants and improved in three. Until now, the follow-up period has lasted a median of 8 months (range 4 to 13 months) during which the exclusion diet was continued in four
infants without any relapse of the initial symptoms.
Cow’s milk was reintroduced in the diet of four infants aged less than 6 months. Within 1 week all four demonstrated sleeplessness, agitated behavior, and eczema. Bronchospasm and vomiting was ob-served in one baby. The symptoms were reported to be more severe than before treatment. During
the night, sleep time was reduced to a median of
four hours (range two to 5.5 hours); arousals and
crying occurred from four to 12 times pen night (Table 3). During the day, two babies slept less than one hour, and the two others were not sleeping at all. Cow’s milk was excluded again from the diet and an improvement of these manifestations was obtained within five days and the sleep behavior
TABLE 3. Main Characteristics of Sleep for Four Infants After Cow’s Milk Reintroduced in Diet and After Its Second Exclusion*
Characteristic After Milk
Challenge
After Second Milk Elimination
P Value
Sleep time during the night (min/12 h) 240.0 ± 71.0 574.5 ± 73.3 .01
Total sleep time/24 h (h)
Median 4.3 11.8
Range 2-6.5 10-13.3 .01
No. of arousals during the night/12 h 8.1 ± 3.4 0
Duration of arousals (mm) 52.5 ± 10.2 0
* Statistical analysis was done with Wilcoxon rank test.
DISCUSSION
Allergy to cow’s milk is mainly a disease of
in-fancy. It is usually manifested during the first 3
months of life, and its prevalence declines
signifi-cantly after the age of 3 years.’5 No age, however,
is exempt, and milk allergy may be first detected
during adolescence or adulthood.’5 In the general
population of Western countries, its prevalence is
between 0.5%16 and 3%#{149}15 The child with milk
a!-lergy is usually brought to a physician because of
gastrointestinal upset, wheezing, or eczema that
started in the neonatal period shortly after
formula-feeding was begun.’5 The diagnosis is based on a
positive clinical history and exclusion of other
con-ditions that may cause similar manifestations.
Im-provements in symptoms after milk has been
strictly avoided, a recurrence of symptoms on
chal-lenge with milk, and a clearing again on a second
trial of milk elimination confirm the diagnosis.
Laboratory tests may be contributive by revealing
immunologic reactions to milk.’5 The eight infants
reported in the present study shared these
charac-tenistics, including the response to a dietary
chal-lenge test in four infants.
In the apparently healthy infant, hypersensitivity
reactions are largely attributed to the protein
com-ponents of milk. Still, intolerance to cow’s milk can
also result from a rare autosomal recessive disorder,
lactase deficiency. Profuse diarrhea after the first
feeding of breast milk can be the initiating
symp-tom. Acute malabsorption syndrome in affected
infants may lead to severe weight loss and
dehydra-tion.’7 Although this etiology was not excluded in
our infants through a lactose-free milk diet, the
reported clinical and laboratory findings do not
point to such a congenital anomaly.
That allergic reactions may affect the CNS was
postulated in 1916.18 Food allergy in children has
been alleged to induce a variety of motor and
be-havior disorders,’9’2#{176} and restlessness during sleep
has been reported,’8’2’23 leading to what has been
referred to as the “allergic tension-fatigue syn-dnome.”23 The subjectivity and nonspecificity of the
behavioral symptoms attributed to food allergy
have led to skepticism in the medical profession’5
and no reference to cow’s milk allergy is found in
most studies dealing with sleepless infants.21#{176}
Like-wise, recent surveys on food allergy in children
mention sleeplessness not at all’6’24’25 or only
mci-dentally.’5
Explanations that relate milk allergy to
sleep-lessness are not yet available. Chronic allergic
re-sponses in various systems could lead to abdominal
discomfort or musculoskeletal pain severe enough
to awaken the child during the night.’5 Likewise,
the respiratory manifestations or itching skin could
lead to repeated anousals.’8
Chronic sleeplessness or sleep fragmentation
could also be related to imbalance in the
metabo-lism of some neurotransmitter, either released
ex-cessively during the hypersensitivity state, eg,
his-tamine,’5 or reduced through a depressed
absorp-tion of its precursors, eg, serotonin.26
Because repeated anousals disturb the baby’s
family, there is pressure from the parents for active
intervention. Sedatives such as phenothiazines are
used widely.3’4’7’27 As in two of the infants reported
in the present study, these drugs usually do not
improve the condition3’5’7’2’ but have been reported
to favor insomnia through drug dependency6 and to
increase the risk for sudden infant death syndrome
in some susceptible infants.27 Once its cause is
identified, this type of insomnia can easily be cured
without any medication by temporarily excluding
all cow’s milk protein from the diet.
It is not known yet how many sleepless infants
would benefit from such an exclusion regimen
be-cause the condition may be underdiagnosed.
Nei-then is it known whether such a treatment for
these restless infants could prevent their eventual
development of “childhood-onset insomnia” as
128
In conclusion, we suspect that a number of
in-fants with intractable insomnia suffer from
undi-agnosed cow’s milk allergy. When trying to solve
the problem of a chronically sleepless infant, when
no indication can be found of faulty adjustment in
for the restlessness can be found, the possibility of an allergic etiology, and particularly of milk allergy,
should be given serious consideration. A proper
history, physical examination, and laboratory
work-up, followed by a dramatic response to a
con-rect elimination diet, will ascertain the diagnosis
and relieve both the patient and family.
ACKNOWLEDGMENTS
This work was supported by the Fonds de la Recherche Scientifique M#{233}dicale(grant 3.4543.83).
We thank Professor H. L. Vis for his encouragement.
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