| Iacono et al. Intolerance of cow's milk and chronic constipation in children. 1998. New England Journal of Medicine 339[16], 1100-1104United States. | Study Type:
Cross over randomised controlled trial
Evidence level:
1+ | 65 patients
33 patients received cow's milk and 32 soy milk during the first study period
32 patients received cow's milk and 33 soy milk during the second study period
Inclusion criteria:
consecutive children referred by family paediatricians to a paediatric gastroenterology clinic diagnosed with chronic constipation. Chronic constipation defined as chronic faecal retention (one bowel movement every 3 to 15 days) often associated with abdominal symptoms (abdominal pain, painful defecation and so forth)
Exclusion criteria:
Anatomical causes (Hirschsprung's disease, spinal disease) another disorder (hypothyroidism, psychomotor retardation), prior anal surgery, medication that can cause constipation (chlorpromazine) and referral for other reasons | Age (mo)
34.6+-17.1
Sex M/F 29/36 | Intervention:
Excluding cow's milk and its derivatives from the diet of children with constipation
Comparison:
Cow's milk vs. soy milk
Weeks 1-2:
observation period all medication stopped
Weeks 3-4: one group received cow's milk and unrestricted diet and the other had cow's milk and its derivatives excluded from diet and received soy milk instead
Week 5: washout period for both groups, unrestricted diet and intake of soy or cow's milk and its derivatives
Week 6-7:
patients switched to the other type of milk
Total amount of milk given to the patient during the two weeks: 5-10 litres
Bottles coded A or B by hospital dispensary Infants < 15 months age: formula based on cow's milk (Transilat, Plasmon, Milan, Italy) or formula based on soy (Plasmonsoy, Plasmon). Children > 15 months age: commercially available whole cow's milk or soy milk
After the two study periods children with a response to cow's-milk free diet were given the soy-milk diet for another month and then underwent a 2-week double-blind challenge with cow's milk at hospital. Children were randomly assigned to receive cow's milk or a placebo containing soy milk. If no clinical reactions were observed within 12 hours, patients were discharged and the challenge continued at home with bottles coded A or B by the hospital dispensary. Challenge was stopped when a clinical reaction occurred, in particular when there were not bowel movements for 72 hours and the patient had abdominal pain, perianal lessons or both. | Follow-up period:
Mean:
10 months (range 3 to 20)
Outcome Measures:
Number of bowels movements Children with eight or more bowel movements during a treatment period were considered to have a response
Qualitative faecal score
1: mushy or liquid stool
2: soft faeces and no pain in passing stools
3: hard faeces and difficulty and pain on passing stools
Both Number of bowels movements and qualitative faecal score were recorded by parents | Observation period (n=65)
Weeks 3-4 and 6-7
- -
Cow's milk group: - -
Soy milk group:
p values were < 0.001 for all variables
Challenge with cow's milk (n=44)
- -
Placebo group (soy milk): 0 clinical reactions - -
Cow's milk group: 0 acute reaction, but in all patients constipation associated with hard stools and discomfort on defecation reappeared after 5-10 days on the diet. Cow's-milk-free diet was recommenced, with a consequent normalisation of bowel movements in all patients
Follow-up:
0 children with response had constipation
Cow's milk reintroduced into the diets of 15 children after 8-12 of cow's milk-free diet and in all cases constipation returned within 5-10 days
Children with no response to soy-milk diet were treated with high doses of laxatives, with subsequent improvement in stool frequency. In all cases symptoms returned once treatment with laxatives was stopped | The order of treatment was randomly assigned by a computer-generated method with the individual patient as the unit of randomisation. The researchers were unaware of the order of the treatment.
At baseline and end of two study periods children were examined by a researcher who was unaware of laboratory test results and histological findings
To ensure that children did not receive any other kind of milk-containing food during the study periods parents were given a list of most common milk-containing food to be avoided
6 patients were withdrawn from the study during the cow's-milk study period (on days 9-12) because of the reappearance of constipation and other related disorders. For these children the number of bowel movements per period was prorated. Intention to treat analysis was used
The mean (±SD) daily consumption was 450±120 ml of soy milk and 470±135 ml of cow's milk. Analysis of the main constituents of the diet (proteins, carbohydrates and fibres) did not show any qualitative or quantitative variation during the study period (data not shown).
Patients were highly selected and this might have led to overestimate the frequency of cow's milk intolerance as a cause of constipation. Paediatricians who referred the patients may have preselected them having being the centre where the study was conducted experience in the treatment of food allergies. The inclusion of patients with no response to laxatives may have also contributed to this issue. |
| Carroccio et al. Chronic constipation and food intolerance: A model of proctitis causing constipation. 2005. Scandinavian Journal of Gastroenterology 40[1], 33-42Norway. | Study Type:
Case series and embedded randomised controlled challenge
Evidence level:
3 | 52 consecutive infants and children with chronic constipation unresponsive to previous treatments examined at the outpatients clinic of a hospital. Chronic constipation defined as chronic faecal retention (one bowel movement every 3 days or more) with painful elimination of hard stools associated with abdominal pain
Inclusion criteria:
- -
a history of chronic constipation lasting at least 6 months - -
lack of response to a previous increase in dietary fibre intake and/or to laxative treatment (milk of magnesia 1-2 ml per kg bodyweight, polyethylene glycol 4000 mean dose 0.75 g per kg daily) attempted for at least one month - -
regular dietary intake of cow's milk and derivatives
Exclusion criteria:
- -
prior anal surgery - -
use of medication that can cause constipation - -
referral for reasons other than chronic constipation - -
anatomical /neurological causes of constipation (Hirschsprung's disease, spinal disease, psychomotor retardation) - -
another disease causing constipation (hypothyroidism, coeliac disease)
| Age (months) :
51.2±18
Sex (M/F):
22/30 | Intervention:
Cow's milk-free diet, with the exclusion of cow's milk and all its derivatives
Comparisons:
Cow's milk-free diet vs. soy milk Cow's milk vs. ass's milk
Cow's milk-free diet vs. soy milk - -
2 weeks observation period: all medications stopped and at the end a clean-out with single dose of polyethyleneglycol 4000 (0.75g/kg). Normal diet, no restrictions - -
4 weeks of cow's milk free diet (without cow's milk derivatives too)
Infants < 15 months age: soy-based (Nutrilon-soya, Nutricia, Milan, Italy) Children > 15 months age: commercially available soy milk Patients unresponsive to CM-free diet placed on oligoantigenic diet 4 weeks (also excluding cow's milk): exclusively rice, lamb, carrots, ass's milk, olive oil and sugar Cow's milk vs. ass's milk Double-blind placebo-controlled challenge with cow's milk, after 12 weeks, to all patients cured on CM-free or oligoantigenic diet. Placebo: ass's milk If no clinical reactions after 12 hours, patients were discharged and challenge continued at home with bottles coded A or B. Challenge was stopped when a clinical reaction occurred
| Follow-up period:
None reported
Outcome Measures:
Number of bowels movements/week
Qualitative faecal score
1: mushy or liquid stool
2: soft faeces and no pain in passing stools
3: hard faeces and difficulty and pain on passing stools
both number of bowels movements/week
and qualitative faecal score were recorded by parents
Children with eight or more bowel movements during a treatment period were considered to have a response
Normalised stools habits: bowel frequency of at least five evacuations/week with the elimination of soft stools, without painful defecation | Observation period:
- -
Patients with food intolerance (n=30) - -
Patients with constipation unrelated to food intolerance (n=22):
Elimination diet period:
- -
Patients with food intolerance (n=30) - -
Patients with constipation unrelated to food intolerance (n=22):
Cow's milk challenge:
No specific data are reported apart from saying that in all cases cow's milk readministration caused the reappearance of constipation within 5 days after commencing the challenge (median 2 days, range 1-5 days) | Qualitative faecal score previously validated according to authors
Randomisation method used during the cow's milk challenge not described
To ensure that children did not receive any other kind of milk-containing food during the study periods parents were given a list of most common milk-containing food to be avoided. Furthermore, they were asked to record the amount and type of food their children had eaten every day. Frequent telephone contacts helped to ensure adherence to the diet
Patients with chronic constipation caused by food intolerance showed at baseline a higher frequency of a personal history of previous food intolerance (p=0.02) and concomitant signs of food intolerance (bronchospasm five cases, rhinitis four cases, dermatitis two cases) (p=0.03) than patients with constipation unrelated to food intolerance.
No difference was observed between the 24 patients with CM intolerance and the 6 patients with multiple food intolerance for outcome measures considered (number of bowel movements and qualitative faecal score), either at baseline or on elimination diet. However in comparison with patients intolerant to CM alone, patients suffering from multiple food intolerance were older (p=0/04) and had a higher frequency of family history of atopic disease (p=0.03)
Analysis of the main constituents of the diet (proteins, carbohydrates and fibres) did not show any qualitative or quantitative variation during the study period (data not shown)
Patients with food intolerance (to CM only or multiple) were treated as a group for the purpose of analysing the data, therefore it is not possible to offer specific data for the CM group only
The high frequency of chronic constipation owing to food intolerance likely due to a selection bias, as mainly food-intolerant patients are treated at the centre where study was conducted.
Funding source:
partly supported by a grant from MURST and from the MiPAF (progetto “ALICE”, D.D. n 86 dated 30.01.2002) |
| Iacono et al. Chronic constipation as a symptom of cow milk allergy. 1995. Journal of Pediatrics 126[1], 34-39 | Study Type:
Case series
Evidence level: 3 | 27 infants
Inclusion criteria:
referred to a paediatric gastroenterology clinic during the 12 months preceding the study and considered to have idiopathic constipation. Diagnosis of constipation made on the basis of a history of reduced frequency of stools (one evacuation every 3 to 7 days- and on pain in the passage of hard stools. In all patients the frequency of stools per day was lower than the 3rd percentile of the values observed in a large
population of healthy subject participating in an Italian multicentre study
Exclusion criteria:
Hirschsprung's disease, mental retardation | 15 boys
Mean age: 20.6 +- 13.4 months (range 5 to 36 months) | Intervention:
Mean age: 20.6 +- 13.4 months (range 5 to 36 months) Excluding cow's milk and its derivatives from the diet of children with chronic constipation
Comparisons:
Cow's milk-free diet vs. soy milk/ ass's milk Cow's milk vs. ass's milk
Cow's milk-free diet vs. soy milk/ ass's milk - -
First 7 days: All patients were being fed the same diet as at the time of diagnosis: various form of commercial formula derived from cow milk or whole cow milk and its derivatives - -
For the next month: all patients started a cow's milk protein-free diet. Three patients aged < 12 months were fed a formula containing soy protein and the others received soy milk or ass's milk (eight cases) and all milk derivatives were excluded After a month: - -
Patients whose symptoms abated: cow milk challenge. Cow milk given for a maximum of 10 days, again an exclusion diet for 1 month and then a second cow milk challenge. All challenges were performed in hospital. Before the challenge a prick test was performed with CMP. In patients with a negative result, the challenge was performed by giving whole cow milk in a singles feeding; if there were no clinical reactions, the same food was given the following days. In patients with a positive test result, the challenge was performed by giving a formula containing CMP, beginning with an initial quantity of 10 ml and gradually increasing the amount to reach the dose equivalent to a full feeding after 48 hours. No other change in diet was made.
Reintroduction of cow milk cautiously attempted in 16 children 6-9 months after the diagnosis of CMPA-dependant constipation - -
Patients with no abatement in symptoms: permanently given an unrestricted diet, except for one infant who had episodes of recurrent bronchospasm related to ingestion of cow milk
| Follow-up period:
monthly for a mean period of 18 months (range 10 to 30 months)
Outcome Measures:
- -
Number of stools/day - -
Description of stools + Difficulty in passing them = Qualitative score
Qualitative score:
3: hard faeces, difficulty and pain in passing stools
2: soft faeces, no pain 1: mushy or liquid stool During the various study periods ( as recorded by parents): | Mean number (+-SD) of stools per day during unrestricted diet (UD) and during CMP-free diet
Stools from patients on CMP-free diet
- -
Cured (n=21) UD: 0.24+-0.10 1rst CMP-free diet: 1.04+-0.12 1rst CMP challenge: 031+-0.14 2nd CMP-free diet: 1.05+-0.11
Significance: b and d vs. a and c, p<0.0005 - -
Unimproved (n=6) UD: 0.18+-0.12 1rst CMP-free diet: 0.20+-0.13 CMP challenge: - CMP-free diet: -
Qualitative score:
- -
Cured (n=21) UD: 2.85+-0.05 1rst CMP-free diet: 1.90+-0.08 1rst CMP challenge: 2.75+-0.11 2nd CMP-free diet: 1.85+-0.10
(p<0.001) - -
Unimproved (n=6) UD: 3 1rst CMP-free diet: 3 CMP challenge: - CMP-free diet: -
Difficulty in passing stools: - -
Cured (n=21) - a.
UD: - B.
1rst CMP-free diet: none had difficulty - c.
1rst CMP challenge: Painful - d.
2nd CMP-free diet: none had difficulty
During the second challenge symptoms reappeared within 24 to 48 h: all 21 patients had painful passage of stools and for this reason challenge was suspended on the third day - -
Unimproved (n=6) Control: ? 1rst CMP-free diet: no CMP challenge: - CMP-free diet: -
Follow-up period:
Reintroduction of cow milk was cautiously attempted in 16 children 6-9 months after the diagnosis of CMPA-dependant constipation. In eight children CMP did not cause the onset of any problems and it was reintroduced on a permanent basis; in eight patients CMP led to the reappearance of constipation within 2 to 3 days after introduction, and these infants were still following CMP-free diet at the time the paper was written. | Analysis of the patient's dietary diaries did not show any significant variations in daily fibre and liquid intake during the various study periods
It is not reported whether any medication was stopped at the beginning of the study
Funding: not reported |
| Iacono et al. Food intolerance and chronic constipation: manometry and histology study. 2006. European Journal of Gastroenterology and Hepatology 18[2], 143-150 | Study Type:
Case series and embedded randomised controlled challenge
Evidence level:
3 | 36 consecutive infants and children with chronic constipation unresponsive to previous treatments, examined at the outpatient clinic of a hospital Paediatric Gastroenterology Division. Chronic constipation defined as less than 3 bowel movements/r week with painful elimination of hard stools
Inclusion criteria:
- -
a history of chronic constipation lasting at least 3 months - -
lack of response to a previous increase in dietary fibre intake or to laxative treatment (milk of magnesia 1-2 ml/ kg of body weight) - -
a regular dietary intake of cow's milk and derivatives
Exclusion criteria:
- -
previous evaluation for chronic constipation - -
anatomical /neurological causes (Hirschsprung's disease, psychomotor retardation) - -
another disease (coeliac disease, hypothyroidism) - -
previous anal surgery - -
use of medication that causes constipation - -
referral for reasons other than constipation
| 20 females
Aged 9 months to 10 years (median 3.6 years) | Intervention:
Cow's milk-free diet, with the exclusion of cow's milk and all its derivatives
Comparisons:
Cow's milk-free diet vs. soy milk Cow's milk vs. ass's milk
Cow's milk-free diet vs. soy milk: 2-week observation period: all medications stopped 4 weeks: all patients on cow's milk free diet. Infants < 15 months old received a formula based on soy (Nutrilon-soya, Nutricia, Milan, Italy), children>15 months old a commercially available soy milk. Patients unresponsive to CM-free diet placed on oligoantigenic diet 4 weeks (also excluding cow's milk): exclusively rice, lamb, carrots, ass's milk, olive oil and sugar
Cow's milk vs. ass's milk: After 12 weeks: patients cured on cow's milk-free diet and oligoantigenic underwent a 2-week double-blind placebo-controlled challenge with cow's milk. Asses' milk was used as placebo. If no clinical reactions after 12 hours, patients were discharged and challenge continued at home with bottles coded A or B. Challenge was stopped when a clinical reaction occurred
| Follow-up period:
Not reported
Outcome Measures:
Number of bowel movements/week
Appearance of stools + child's degree of difficulty in passing stools = Qualitative faecal score:
1. Mushy or liquid stools
2. Soft faeces and no pain in passing stools
3. Hard stools and difficulty and pain on passing stools
(All outcomes measures were recorded by parents)
Normalised stool habits:
a bowel frequency of at least three evacuations per week, with the elimination of soft stools, without painful defecation | Observation period:
- -
Patients with food intolerance (n=17) - -
Patients with constipation unrelated to food intolerance (n=19):
Elimination diet period:
- -
Patients with food intolerance (n=17) - -
Patients with constipation unrelated to food intolerance (n=19):
Cow's milk challenge period
Reappearance of constipation in all cases (n=17), very often associated with painful defecation, within 5 days after the commencement of the challenge (median 2 days, range 1-5 days). | To ensure that all children observed a correct elimination diet, parents were asked to record the amount and type of food their children had eaten each day. These diaries were analysed at the end of the study to evaluate adherence to the diet and the quantity of milk consumed
Neither the parents nor the children were able to distinguish whether the bottles contained asses' or cows' milk.
According to the authors the qualitative faecal score had been previously validated
Randomisation method used during the cow's milk challenge not described
Specific data related to number of bowel movements and qualitative faecal score were not reported for the challenge period.
Analysis of the main constituents of the diet (proteins, carbohydrates and fibres) did not show any qualitative or quantitative variation during the study period (data not shown)
Patients with food intolerance (to CM only or multiple) were treated as a group for the purpose of analysing the data, therefore it is not possible to offer specific data for the CM group only
Funding:
partly supported by a grant from MIUR and MiPAF: project “Alimetazione e celiachia (ALICE)”, D.D. n 86 dated 30.01.2002) |
