Posted by: Indonesian Children | April 6, 2010

Insomnia and Cow’s Milk Allergy in Infants

Insomnia and Cow’s Milk Allergy in Infants

A. Kahn MD1, M. J. Mozin 1, G. Casimir MD1, L. Montauk 1, and D. Blum MD1

PEDIATRICS Vol. 76 No. 6 December 1985, pp. 880-884

1 From the Pediatric Sleep Laboratory and Department of Pediatrics, Free University of Brussels, Brussels, Belgium

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 recording confirmed the disrupted sleep pattern of these 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 concluded that, when no evident cause for sleeplessness can be found in an infant, the possibility of milk allergy should be given serious consideration.

Key Words: insomnia • allergy • cow’s milk • phenothiazine • sleep

 

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 record­ing confirmed the disrupted sleep pattern of these 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 con­cluded 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, phenothi­azine, sleep.

Spontaneous awakenings during the night have been shown to occur normally in more than 84% of infants younger than 1 year of age.1 They are sel­dom 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, Depart­ment 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.1,2 Persistent settling and waking difficulties, associ­ated with disturbing behavior such as restlessness and intense crying, are encountered in 10%2 to 20%3 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.3,67

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 environmen­tal conditions such as changed sleeping arrange­ments, family separations, or minor trauma, espe­cially 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,2,4,10 and brain malformation or chromo­somal abnormalities.11 Recurrent episodes of upper airway obstruction,6 chronic physical discomfort, or gastroesophageal reflux11 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-pa­tient sleep clinic. They had been referred by their pediatricians for chronic waking and crying during sleep hours. On the first visit, a standardized inter­view was conducted with the parents to determine the duration of the child’s day and night sleep and

880      PEDIATRICS Vol. 76 No. 6 December 1985

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main behavioral characteristics. A standard medi­cal 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 re­ported causes for chronic insomnia in infants.34,6 It was completed by an all-night polygraphic record­ing, which excluded further causes of arousals (such as obstructive apneas, esophageal reflux), and eval­uated the child’s sleep, albeit in laboratory condi­tions.

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 (Alfare, Nestle Nutrition) for 4 weeks. Follow-up interviews and home visits were carried out by nurses to evaluate the child’s prog­ress. 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 (Prist, Phadebas) were used to determine serum IgE levels. According to local control values, a test was consid­ered positive if a value was greater than 5 U/mL for an infant younger than 3 months of age and if a value was greater than 10 U/mL for an infant 3 to 12 months of age. In vitro radioallergosorbent tests (RAST, Pharmacia Fine Chemicals) were con­ducted to identify specific IgE against 0-lactoglob-ulin.

MONITORING PROCEDURE

Each child’s night sleep was recorded for 12 hours under standard sleep laboratory conditions. Moni­toring was carried out in a quiet and darkened room, at a temperature ranging between 23° and 25°C. The infants were observed continuously during re­cordings, and awakenings (defined as opening of the eyes), behavior, vocalizations, and nursing in­terventions were charted. The data were recorded on a 16-channel Alvar model polygraph (paper speed 10 mm/s). The following variables were si­multaneously recorded: scalp EEG, electrooculo-gram, digastric electromyogram, and ECG. Respi­ratory 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.12 Esophageal reflux was defined as a decrease in pH to less than 4.O.13

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 per­formed using the Wilcoxon rank test.

RESULTS

The general characteristics of the infants are reported in Table 1. There were no premature or 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-born 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 and Laboratory Results of Study Infants*

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 [7-175]  
Radioallergosorbentt    
Positive for /Mactoglobulin 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. t Test performed on five infants.

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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 of loose 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.14 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 per 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 signifi­cantly distinguished these patients from local standards (Table 2). No cause for arousal was seen in any child (no prolonged central apnea, obstruc­tive apnea, esophageal reflux, or heart rate disturb­ance).

Laboratory tests revealed that IgE levels were elevated in all children. RASTs were also conducted to identify IgE against /^-globulin 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 per­formed 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 nor­mal (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 or tired. The cuta­neous and respiratory symptoms had completely cleared 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 ob­served 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 per 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 was normalized in the four infants (Table 3).

TABLE 2.   Sleep Characteristics Before and After Exclusion Regimen*

Characteristic   Before Treatment PI 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 ni ght/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 (min)          
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 studied under similar conditions. Statistical analysis (Wilcoxon rank test) compared the infants’ sleep recorded in the laboratory with that of controls (PI) and the infants’s sleep, as described by the parents, before and after treatment (P2).

882       COWS MILK ALLERGY

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TABLE 3.    Main Characteristics of Sleep for Four Infants After Cow’s Milk Reintroduced in Diet and After Its Second Exclusion*

Characteristic After Milk After Second Milk P Value
  Challenge Elimination  
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 (min) 52.5 ± 10.2 0  

* Statistical analysis was done with Wilcoxon rank test.

DISCUSSION

Allergy to cow’s milk is mainly a disease of in­fancy. It is usually manifested during the first 3 months of life, and its prevalence declines signifi­cantly after the age of 3 years.15 No age, however, is exempt, and milk allergy may be first detected during adolescence or adulthood.15 In the general population of Western countries, its prevalence is between 0.5%16 and 3%.15 The child with milk al­lergy 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.15 The diagnosis is based on a positive clinical history and exclusion of other con­ditions that may cause similar manifestations. Im­provements in symptoms after milk has been strictly avoided, a recurrence of symptoms on chal­lenge 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.15 The eight infants reported in the present study shared these charac­teristics, including the response to a dietary chal­lenge test in four infants.

In the apparently healthy infant, hypersensitivity reactions are largely attributed to the protein com­ponents 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 symp­tom. Acute malabsorption syndrome in affected infants may lead to severe weight loss and dehydra­tion.17 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 be­havior disorders,19,20 and restlessness during sleep has been reported,182123 leading to what has been referred to as the “allergic tension-fatigue syn­drome.”23 The subjectivity and nonspecificity of the behavioral symptoms attributed to food allergy

have led to skepticism in the medical profession15 and no reference to cow’s milk allergy is found in most studies dealing with sleepless infants.210 Like­wise, recent surveys on food allergy in children mention sleeplessness not at all16,24,25 or only inci­dentally.15

Explanations that relate milk allergy to sleep­lessness are not yet available. Chronic allergic re­sponses in various systems could lead to abdominal discomfort or musculoskeletal pain severe enough to awaken the child during the night.15 Likewise, the respiratory manifestations or itching skin could lead to repeated arousals.18

Chronic sleeplessness or sleep fragmentation could also be related to imbalance in the metabo­lism of some neurotransmitter, either released ex­cessively during the hypersensitivity state, eg, his-tamine,15 or reduced through a depressed absorp­tion of its precursors, eg, serotonin.26

Because repeated arousals disturb the baby’s family, there is pressure from the parents for active intervention. Sedatives such as phenothiazines are used widely.347,27 As in two of the infants reported in the present study, these drugs usually do not improve the condition35,7,21 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 be­cause the condition may be underdiagnosed. Nei­ther is it known whether such a treatment for these restless infants could prevent their eventual development of “childhood-onset insomnia” as adults.5,11,28

In conclusion, we suspect that a number of in­fants 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 the infant or family, and no evident medical cause

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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 cor­rect 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 Medicale (grant 3.4543.83).

We thank Professor H. L. Vis for his encouragement.

REFERENCES

  1. 1.       Anders TF: Night-waking in infants during the first year of life. Pediatrics 1979;63:860-864
  2. 2.   Moore T, Ucko LE: Night waking in early infancy: Part I. Arch Dis Child 1957;32:333-342
  3. 3.   Bax MCO: Sleep disturbance in the young child. Br Med J 1980;5:1177-1179
  4. 4.   Bernal JF: Night waking in infants during the first 14 months. Dev Med Child Neurol 1973;15:760-769
  5. 5.   Dixon KN, Monroe LJ, Jakim S: Insomnia children. Sleep 1981;4:313-318
  6. 6.   Guilleminault C, Anders TF: Sleep disorders in children. Adv Pediatr 1976;22:151-175
  7. 7.   Largo RH, Hunziker UA: A developmental approach to the management of children with sleep disturbances in the first three years of life. Eur J Pediatr 1984;142:170-173
  8. 8.   Carey WB: Night waking and temperament in infancy. J Pediatr 1974;84:756-758
  9. 9.   Wender EH, Palmer FB, Herbst JJ, et al: Behavioral char­acteristics of children with chronic nonspecific diarrhea. Am J Psychiatry 1976;133:20-25

 

  1. 10.      Jones NB, Ferreira MCR, Brown MF, et al: The association between perinatal factors and later night waking. Dev Med Child Neurol 1978;20:427-434

11.  Association of Sleep Disorders Centers and the Association for the Psychophysiological Study of Sleep: Diagnostic clas-


sification of sleep and arousal disorders;  Roffwarg HP (chairman). Sleep 1979;2:21-57

12.  Kahn A, Blum D, Waterschoot P, et al: Effects of obstructive sleep apneas on transcutaneous oxygen pressure in control infants, siblings of sudden infant death syndrome victims, and near miss infants: Comparison with the effects of central sleep apneas. Pediatrics 1982;70:852-857

13.  Sondheimer JM: Continuous monitoring of distal esophageal pH: A diagnostic test for gastroesophageal reflux in infants. J Pediatr 1980;96:804-807

14.  Wachholder A, Graffar M: La croissance et le developpement de Venfant normal Paris, Centre International de l’Enfance, 1976, 104

15.  Bahna SL (ed): Allergies to Milk. New York, Grune and Stratton, 1980

16.  Stintzing G, Zetterstrom R: Cow’s milk allergy, incidence and pathogenetic role of early exposure to cow’s milk for­mula. Acta Pediatr Scand 1979;68:383-387 

17.  Savilahti E, Launiala K, Kuitunen P: Congenital lactase deficiency. Arch Dis Child 1983;58:246-252

18.  Hoobler BR: Some early symptoms suggesting protein sen-sitization in infancy. Am J Dis Child 1916;12:129-135

19.  Dees SC: Neurologic allergy in childhood. Pediatric Clin North Am 1954;5:1017-1025

20.  Tryphonas H, Trites R: Food allergy in children with hy-peractivity, learning disabilities and/or minimal brain dys­function. Ann Allergy 1979;42:22-27

21.  Randolph TG: Allergy as a causative factor of fatigue, irrit­ability, and behavior problems of children. J Pediatr 1947;31:560-572

22.  Davison HM: Allergy of the nervous system. Q Rev Allergy Appl Immun 1952;6:157-188

23.  Speer F: The allergic tension-fatigue syndrome. Pediatr Clin North Am 1954;1:1029-1037

24.  Weinberg EG,Tuchinda M: Allergic tension-fatigue syn­drome. Ann Allergy 1973;31:209-211

25.  Jackobsson I, Lindberg T: Cow’s milk protein intolerance in infants in a Swedish urban community—A prospective study. Acta Pediatr Belg 1979;32:224

26.  Hartmann E: L-Tryptophan: A rational hypnotic with clin­ical potential. Am J Psychiatry 1977;134:366-370

27.  Kahn A, Blum D: Phenothiazines and sudden infant death syndrome. Pediatrics 1982;70:75-78

28.  Salzarulo P, Chevalier A: Sleep problems in children and their relationship with early disturbances of the waking-sleeping rhythms. Sleep 1983;6:47-51

 

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Responses

  1. My goodness. I am surprised that most doctors do not know more about this allergy in infants. My boy is 11 and still has a hard time sleeping. I only realized he had a milk allergy a few days ago and had to figure it out on my own by doing research on Internet.

    He was put on Ritalin … mistakenly in my opinion. I wonder how many children are being misdiagnosed?

    I find it very frustrating that most professionals tend to blame parents for behavioral problems instead of digging deeper to make sure there are no physical causes. Because of their attitude, many children continue to suffer.

    Thank you for sharing this article.

  2. This is amazing information, I am so glad to find this. My son is a year old and still waking up 5 – 15 times every single night. He is also allergic to cows milk.. we have done all the tests to make sure.. Thank you..


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