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Lactose avoidance for young children with acute diarrhoea

  1. Stephen MacGillivray1,*,
  2. Tom Fahey2,
  3. William McGuire3

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 31 OCT 2013

DOI: 10.1002/14651858.CD005433.pub2


How to Cite

MacGillivray S, Fahey T, McGuire W. Lactose avoidance for young children with acute diarrhoea. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD005433. DOI: 10.1002/14651858.CD005433.pub2.

Author Information

  1. 1

    University of Dundee, Social Dimensions of Health Institute, Dundee, Tayside, UK

  2. 2

    Royal College of Surgeons in Ireland Medical School, Department of Family Medicine and General Practice, Dublin, Ireland

  3. 3

    Hull York Medical School & Centre for Reviews and Dissemination, University of York, York, Y010 5DD, UK

*Stephen MacGillivray, Social Dimensions of Health Institute, University of Dundee, Airlie Place, Dundee, Tayside, DD1 4HN, UK. s.a.macgillivray@dundee.ac.uk.

Publication History

  1. Publication Status: New
  2. Published Online: 31 OCT 2013

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Characteristics of included studies [ordered by study ID]

MethodsRCT


ParticipantsFormula-fed infants (2 months to 12 months) with acute non-bloody diarrhoea < 7 days duration, with mild or moderate dehydration.

Exclusion criteria: Being breast-fed, intolerant to trial formulae, malnourished infants (height or weight below 3rd percentile).


Interventions1. Soy-based formula (Isomil®): N = 39

2. Lactose-containing formula (SMA®): N = 34


OutcomesDuration of diarrhoea (until last abnormal stool when subsequent stools were normal for 24 hr period)
Treatment failure

Weight gain
Formula intake
Duration of hospital admission (inpatients only)

Follow-up period: 14 days


NotesSetting: Tertiary care hospital, Toronta, Canada. Included hospitalized (N = 13) and non-hospitalized (N = 20) infants.

Infants were initially rehydrated using an oral electrolyte solution or intravenous dextrose sodium solution.

Stool pathogens: Rotavirus (14%); adenovirus (3%): Salmonella spp. (3%); not identified (80%).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Infants were consecutively assigned...according to a table of random numbers."

Allocation concealment (selection bias)Unclear riskNo details given in trial report.

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"In order to maintain blinding the bottles containing formula were coded and given to parents without informing them of the content"

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNurses performed telephone assessment of outcomes.

"Investigators and study participants were kept blinded to the study formula received, even after treatment failure"

Incomplete outcome data (attrition bias)
All outcomes
Low riskData for all outcomes were available for 73 of 76 enrolled infants (three infants were removed from the trial within one day of enrolment because of non-compliance).


MethodsRCT


ParticipantsFormula-fed infants (< 9 months) with acute diarrhoea or vomiting or both < 7 days, with mild dehydration.

Exclusion criteria: Breast fed babies, babies previously treated for acute diarrhoea elsewhere, and babies with chronic diarrhoea, cow's milk protein intolerance, or drug induced diarrhoea.


Interventions1. Whey hydrolysate, low lactose-free formula (Alfare®): N = 24

2. Diluted standard (usual) formula (¼ strength for 24 hrs, ½ strength for 24 hrs, ¾ strength for 24 hrs, then full strength): N = 22

3. Full strength formula: N = 22

COMPARISON 1. Group 1 versus Group 3

COMPARISON 2. Group 2 versus Group 3


OutcomesStool frequency

Percentage change in weight
Duration of hospital stay (inpatients)

Relapse

Refusal of feeding

Follow-up period: 14 days


NotesSetting: Tertiary care hospital, London, UK.

Included hospitalized (57%) and non-hospitalized (outpatient) (43%) infants.

Infants were rehydrated using an oral electrolyte solution for 24 hrs prior to trial entry.

Stool pathogens: Viral (34%); bacterial (16%); not identified (50%).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details given in trial report.

Allocation concealment (selection bias)Unclear riskNo details given in trial report.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo details given in trial report.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details given in trial report.

Incomplete outcome data (attrition bias)
All outcomes
High riskOutcome data were not reported for 22 of 68 (32%) enrolled infants (Six of 24 infants allocated to Group 1 refused the whey hydrolysate formula).


MethodsRCT


ParticipantsChildren (3 months to 24 months) with acute diarrhoea < 7 days, with mild dehydration.

Exclusion criteria: Prior antibiotic therapy; milk elimination during concurrent illness; concurrent non-gastrointestinal infections; blood in stools; clinical signs of moderate to severe dehydration.


Interventions1. Non-milk based (lactose-free) locally prepared formula (rice, lentil, sugar, and coconut oil): N = 30.

2. Cow's milk formula (Lactogen full protein, Nestle: lactose 4.6 g/100 mL, with 2.5 g/100 mL sugar added): N = 30.


OutcomesDuration of diarrhoea

Treatment failure (worsening diarrhoea leading to change of nutritional management)
Weight gain
Energy intake

Follow-up period: "until recovery" (patients reviewed at home)


NotesLocation: Community-care (outpatient) facility, New Delhi, India.
Infants were initially rehydrated using an oral rehydration solution (50 mL/kg) and mothers were advised to continue oral rehydration therapy at home (10mL/kg for each liquid stool passed).

Stool pathogens: Rotavirus (28%); bacterial, mainly E. coli (42%): not identified (30%).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomization was achieved using permutation blocks of fixed length".

Allocation concealment (selection bias)Low riskAllocation concealment was achieved "with the help of sealed envelopes".

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo details given in trial report but unlikely that they were blinded.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details given in trial report.

Incomplete outcome data (attrition bias)
All outcomes
Low riskThree participants with treatment failure were excluded from the final analyses.


MethodsRCT


ParticipantsBoys* (3 months to 24 months) with acute diarrhoea < 4 days.

(*Only male to facilitate separation of urine and stool for microbiological analyses)

Exclusion criteria: Prior antibiotic therapy; severe systemic infections; receiving > two breast feeds per day; another episode of diarrhoea < two weeks previously; "poor nutritional status"; presence of oedema.


Interventions1. Lactase treated (low lactose) 95% hydrolysed milk: N = 30

2. Cow's milk formula: N = 28


OutcomesDuration of diarrhoea (time after admission until excretion of the last liquid or semi-liquid stool not followed by another liquid or semi-liquid stool within 24 hrs).

Treatment failure defined as:
a) Recurrent dehydration if after successful initial rehydration clinical evidence of > 5% dehydration or electrolyte disorders

b) Severe diarrhoea if faecal excretion was greater > 350 g/kg/day for one day or > 250 g/kg/day for two consecutive days

c) Severe prolonged diarrhoea if faecal output was still > 100 g/kg/day during the sixth day of treatment

Follow-up period: 6 days


NotesSetting: Inpatient specialist hospital clinic, Lima, Peru.

This trial include two further groups (data not included in this review):

3. Wheat noodles and 95% lactose-hydrolysed milk: N = 29

4. Wheat noodles and diluted (50%) cow's milk formula: N = 29 (not included in diluted versus not diluted comparison because of wheat noodle co-intervention)

Stool pathogens: Rotavirus (22%); bacterial, mainly E. coli (62%); mixed (32%); not identified (25%).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were assigned "using a fixed-interval, blocked randomization procedure."

Allocation concealment (selection bias)Unclear riskNo details given as to how this was achieved.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDescribed as "double-masked" study but no details given.

"Clinical personnel responsible for patient management were unaware of treatment assignments."

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details given in trial report.

Incomplete outcome data (attrition bias)
All outcomes
Low riskOne (of 59) participant was withdrawn within two days and not included in the final analyses.


MethodsRCT


ParticipantsBoys (< 6 months) with acute diarrhoea < 120 hrs, without clinical signs of severe dehydration.

Exclusion criteria: Breast-fed, severe malnutrition, systemic infections, or other diseases requiring additional treatments.


Interventions1. Full strength milk formula: N = 80

2. Diluted milk formula (½ strength for 24 hrs, ¾ strength for 24 hrs, then full strength): N = 79


OutcomesDuration of diarrhoea

Treatment failure
Total stool output

Number of stools (over 5 days)*

Weight gain by discharge

Follow-up period: 5 days

*(reported number of stools divided by 5 to give daily mean number)


NotesSetting: Hospital inpatients, Guatemala and Brazil.

Oral rehydration solution and plain water could be given according to WHO recommendations.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"One randomization list per centre was established...with random permuted blocks of variable length (6 to 12 subjects per block)."

Allocation concealment (selection bias)Low risk"Master randomization lists were then placed in sealed serially numbered envelopes."

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"The different formulae, which were similar in appearance, were administered through opaque feeding bottles."

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Staff and investigators did not know which formula was being given."

Incomplete outcome data (attrition bias)
All outcomes
Low risk16 participants (10%) did not complete the trial and were not included in the final analyses, mainly (N = 14) because they had severe infection requiring antibiotic treatment.


MethodsRCT


ParticipantsFormula-fed infants (1 to 12 months) with acute diarrhoea < 7 days duration.

Exclusion criteria: None stated.


Interventions1. Cow's milk (lactose-containing) formula: N = 32

2. Lactose-free formula: N = 28


OutcomesDuration of diarrhoea
Treatment failure

Weight change
Stool volume

Follow-up period: not stated


NotesSetting: Hospital (inpatients); Hospital Severo Ochoa, Madrid, Spain.

Stool pathogens: Not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were randomly allocated using a random numbers table.

Allocation concealment (selection bias)Unclear riskNo allocation concealment described.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo blinding described.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo blinding described.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete outcome assessment.


MethodsRCT


ParticipantsFormula-fed infants (6 weeks to 12 months) with acute gastroenteritis < 14 days duration, with mild or moderate dehydration.

Exclusion criteria: Malnourished infants


Interventions1. Standard cow's milk formula graded re-feeding (24 hrs oral rehydration solution; 24 hrs ½ strength; 24 hrs ¾ strength formula): N = 50

2. Lactose-free cow's milk from time of admission until 2 days after stools returned to normal: N = 50

3. Standard cow's milk formula: N = 50

4. Lactose-free soy-based formula: N = 50

COMPARISON 1. Group 2 + 4 versus Group 3

Subgroup comparison "of trials in which only difference between feeds was the presence or absence of lactose": Group 2 versus Group 3.

COMPARISON 2. Group1 versus Group 3.


OutcomesWeight change
Duration of diarrhoea
Duration of hospitalization
Treatment failure (continued or increased severity of diarrhoea with weight loss, or deteriorating fluid-electrolyte imbalance, or both)

Follow-up period: Until hospital discharge


NotesLocation: Seacroft Hospital, Leeds, UK.

Dehydrated infants were given oral rehydration solution or intravenous fluids.

Stool pathogens: Rotavirus (23%); bacterial, mainly Salmonella spp., E. coli (12%); not identified (65%).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details given in trial report.

Allocation concealment (selection bias)Unclear riskNo details given in trial report.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo details given in trial report.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details given in trial report.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll trial participants were available for analysis.


MethodsQuasi-RCT


ParticipantsInfants (1 month to 12 months) with acute diarrhoea < 7 days duration which resulted in weight loss, with mild, moderate, or severe dehydration.

Exclusion criteria: None stated.


Interventions1. Full strength cow's milk formula (with 5% glucose added): N = 35

2. Soy-based formula (Hyprovit®): N = 40


OutcomesDuration of diarrhoea
Changes in body weight

Length of hospital stay
Number of days requiring intravenous fluids
Treatment failure (persistence of dehydration or vomiting and diarrhoea)

Follow-up period: Until hospital discharge


NotesSetting: Hospital inpatients, Israel.

Infants in one general paediatric service given one intervention and infants in a second service given other intervention.

Oral and intravenous rehydration therapies available.

Stool pathogens (only bacteria reported): E. coli (40%); Shigella spp. (5%); not detected (55%).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskQuasi-randomized.

Allocation concealment (selection bias)High riskQuasi-randomized.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo details given in trial report.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details given in trial report.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll trial participants were available for analysis.


MethodsRCT


ParticipantsChildren (6 months to 59 months) with acute gastroenteritis < 7 days, without "other major illness".

Exclusion criteria: Not stated.


Interventions1. Diluted milk (½ strength for 24 hrs, then full strength): N = 32

2. Full strength milk: N = 28


OutcomesTreatment failure
Weight change (in first 24 hrs only)
Duration of hospital admission

Follow-up period: Not stated, but included post-discharge assessment


NotesSetting: Inpatient service at Mater Children's Hospital, Brisbane, Australia.

Oral and intravenous rehydration therapies available.

Stool pathogens: Not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported.

Allocation concealment (selection bias)Unclear riskNot reported.

Blinding of participants and personnel (performance bias)
All outcomes
High riskUnblinded.

Blinding of outcome assessment (detection bias)
All outcomes
High riskUnblinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskChildren aged > 5 years recruited were not included in any analyses.


MethodsRCT


ParticipantsFormula-fed boys (3 months to 18 months) with acute watery diarrhoea < 7 days, without blood visible in the stool. Most (99%) of participants were mildly or moderately dehydrated.

Exclusion criteria: Breast-fed, severe malnutrition, systemic infections, or other diseases requiring additional treatments.


Interventions1. Soy-based formula with lactose (69 g/L): N = 100

2. Soy-based formula with sucrose: N = 100


OutcomesDuration of diarrhoea

Treatment failure
Weight gain
Stool output

Follow-up period: Until cessation of diarrhoea or hospital discharge, whichever came sooner.


NotesSetting: Inpatient service at Cairo University Children's Hospital, Egypt.

Oral and intravenous rehydration therapies available.

Stool pathogens: Not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"The randomization list was established at Wyeth Nutritionals International with random permuted blocks of variable lengths."

Allocation concealment (selection bias)Unclear riskNo details given in trial report.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo details given in trial report.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details given in trial report.

Incomplete outcome data (attrition bias)
All outcomes
Low risk16 (of 200) enrolled participants were withdrawn and excluded before beginning the treatment phase; eight participants because dehydration could not be corrected, and eight because diarrhoea stopped during the rehydration phase. An intention-to-treat analysis could not be performed.


MethodsRCT


ParticipantsFormula-fed infants (< 12 months) with acute diarrhoea < 7 days, without evidence of dehydration.

Exclusion criteria: Breast-fed, receiving antibiotics.


Interventions1. Soy-based formula with lactose: N = 20

2. Soy-based formula with sucrose: N = 22

3. Soy-based formula with polycose: N = 20

4. Soy-based formula with polycose-sucrose: N = 21


OutcomesStool output
Weight gain

Hospitalization

Follow-up period: Two weeks.


NotesLocation: Outpatient clinic, Colorado, USA.

All infants were fed with clear liquids for 24 hrs, half strength formula for an additional 24 hrs, and full strength trial formula on the third day.

Parents were asked to limit feeding of solids for the intervention period.

Five infants ware admitted to hospital: one for suspected sepsis, and the remaining four had developed more diarrhoea and had become dehydrated.

Stool pathogens: Rotavirus (24%); bacterial (7%); not identified (69%).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details given in trial report.

Allocation concealment (selection bias)Low risk"...opaque packaging units that were coded by the hospital pharmacists".

Blinding of participants and personnel (performance bias)
All outcomes
Low riskInterventions were "pre-measured in identical opaque packaging units that were coded by the hospital pharmacists, who retained the random coded table until completion of the study".

Blinding of outcome assessment (detection bias)
All outcomes
Low riskInterventions were "pre-measured in identical opaque packaging units that were coded by the hospital pharmacists, who retained the random coded table until completion of the study".

Incomplete outcome data (attrition bias)
All outcomes
Low riskTwo participants lost to follow-up but no intention-to treat analysis performed.


MethodsRCT


ParticipantsFormula fed children (< 28 months) with acute diarrhoea < 7 days, without evidence of dehydration.

Exclusion criteria: Breast-fed. Receipt of oral rehydration therapy, antibiotics, or antidiarrhoeal preparations during the 5 days prior to admission; or any dietary modification, restriction of lactose intake, or withholding of food during this period; patients unable to tolerate oral feeds and those (mainly older children) who were receiving formula feeds before onset of diarrhoea.


Interventions1. Cow's milk formula: N = 124

2. Lactose-free soy-based formula N = 77


OutcomesDuration of diarrhoea

Follow-up period: 14 days


NotesLocation: Hospital inpatient ward, Durban, South Africa.

Oral and intravenous rehydration therapies available.

Stool pathogens (only rotavirus reported): Rotavirus (56%).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details given in trial report.

Allocation concealment (selection bias)Low risk"Randomization was achieved by opening a sealed envelope containing a previously determined feeding schedule".

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo details given in trial report.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details given in trial report.

Incomplete outcome data (attrition bias)
All outcomes
Low riskDuration of diarrhoea not reported for 6 withdrawn participants: two infants died in acute stage (one in each group), and four infants developed chronic (> 14 days) diarrhoea (three in cow's milk group and one in soy group).


MethodsRCT


ParticipantsChildren (1 to 24 months) with acute diarrhoea and mild, moderate, or severe dehydration.

Exclusion criteria: None stated.


InterventionsClear fluids for 6 to 24 hrs then either:

1. Diluted milk formula (¼ strength for 24 hrs, ½ strength for 24 hrs, then full strength): N = 52

2. Full strength milk formula: N = 46

(Third group allocated to immediate milk feeding without clear fluids, not included in this analysis)


OutcomesDuration of diarrhoea
Changes in body weight

Length of hospital stay

Follow-up period: Until hospital discharge


NotesSetting: Inpatient (hospital), Saudi Arabia.

Oral and intravenous rehydration therapies available.

Stool pathogens: Not stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot stated.

Allocation concealment (selection bias)Unclear riskNot stated.

Blinding of participants and personnel (performance bias)
All outcomes
High riskUnblinded.

Blinding of outcome assessment (detection bias)
All outcomes
High riskUnblinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up.


MethodsRCT


ParticipantsChildren (6 to 34 months) with acute diarrhoea.

Exclusion criteria: None stated.


Interventions1. Mixed diet with milk and milk products eliminated: N = 27

2. Mixed diet with usual milk and milk products retained: N = 38


OutcomesDuration of diarrhoea and vomiting
Duration of hospital admission
Weight gain
Recurrence of diarrhoea within one month

Follow-up period: Up to one month


NotesSetting: Hospital inpatient ward, Finland.

All children in both groups received ordinary mixed diet appropriate for age.

Stool pathogens (only rotavirus reported): Rotavirus (71%).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details given in trial report.

Allocation concealment (selection bias)Unclear riskNo details given in trial report.

Blinding of participants and personnel (performance bias)
All outcomes
High risk"Parents were aware of the type of diet".

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details given in trial report.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo participants were lost to follow-up.


MethodsRCT


ParticipantsFormula-fed infants (1 week to 8 months) with acute severe diarrhoea < 7 days duration.

Exclusion criteria: None stated.

Lost to follow-up: 1 (from group 2 due to severe intolerance to soy and milk formulas)


Interventions1. Soy-based (lactose-free) formula (Isomil®): N = 11

2. Cow's milk formula: N = 11


OutcomesTreatment failure (> 5 watery stools per day for 3 consecutive days).

Follow-up period: Not stated.


NotesSetting: Hospital inpatient department, California, USA.

Oral rehydration therapy was available when required prior to randomization to feed.

Stool pathogens: Not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"the patient was assigned to one of two groups by a table of random numbers."

Allocation concealment (selection bias)Unclear riskNo details given in trial report.

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"All formulas were kept in coded sterile bottles. The formula codes were broken at the end of the study."

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"All formulas were kept in coded sterile bottles. The formula codes were broken at the end of the study."

Incomplete outcome data (attrition bias)
All outcomes
Low riskOne participant was lost to follow-up but not accounted for in analysis.


MethodsRCT


ParticipantsFormula-fed boys (< 12 months) with acute severe diarrhoea < 7 days, and clinical signs of > 5% dehydration.

Exclusion criteria: Systemic infections treated with antibiotics. Breast fed in the month before admission.


Interventions1. Diluted (2/3) cow's milk: N = 10

2. Cow's milk formula (Nanon®): N = 10

3. Lactose-free milk formula (Portagen®): N = 10

4. Lactose-free milk formula (Pregestimil®): N = 10

5. Lactose-free milk formula (Prosobee®): N = 10

COMPARISON 1. Group 1 + 2 versus Group 3 + 4 + 5

(COMPARISON 2. Not eligible since Group 1 dilution < 50%)


OutcomesRecovery by 72 hrs

Volume of diarrhoea
Need for oral or intravenous rehydration
Treatment failure

Follow-up period: 72 hrs.


NotesSetting: Hospital metabolic inpatient unit, San Paulo, Brazil.

Stool pathogens: E. coli (50%); "others" (14%); not detected (36%).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details given in trial report.

Allocation concealment (selection bias)Unclear riskNo details given in trial report.

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"The physicians in charge of the patients were unaware of feeding selection given throughout the study."

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details given in trial report.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up assessment.


MethodsRCT


ParticipantsChildren (1 to 24 months) with acute diarrhoea < 7 days, and evidence of dehydration.

Exclusion criteria: Receiving > 50% of daily milk as breast milk, not receiving lactose or milk formula prior to illness, antibiotic therapy < 48 hrs prior to admission, chronic malabsorption syndrome.


Interventions1. Lactose-free formula (AL-110®): N = 29

2. Cow's milk (lactose-containing) formula (NAN1® or NAN2®): N = 28


OutcomesDuration of diarrhoea
Weight change
Treatment failure

Follow-up period: Until discharge


NotesSetting: Hospital (inpatients), Bogota, Colombia.

Stool pathogens: (only rotavirus reported): Rotavirus (44%).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"allocated to intervention or control group...using block randomization".

Allocation concealment (selection bias)Unclear riskNo details given in trial report.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo details given in trial report.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details given in trial report.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo details given in trial report.


MethodsRCT


ParticipantsChildren (mean age 1 year) with "mild" gastroenteritis.


Interventions1. "Graduated" re-feeding with milk or cow's milk formula: ¼ strength for 24 hrs, ½ strength for further 24 hrs, then full strength: N = 86

2. Immediate re-feeding with full strength milk or cow's milk formula: N = 89


OutcomesDuration of hospital admission

Stool frequency (until 96 hrs)

Weight change (until 96 hrs)

Follow-up period: Not stated, presumed until discharge.


NotesSetting: Hospital (inpatients) ward, St. George's Hospital, London, UK.

Stool pathogens: Rotavirus (about 30%); others not specified or not detected.

Note: Duration of diarrhoea reported in Brown 1994; unclear where these data came from, so not included in this review.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported.

Allocation concealment (selection bias)Unclear riskNot reported.

Blinding of participants and personnel (performance bias)
All outcomes
High riskUnblinded.

Blinding of outcome assessment (detection bias)
All outcomes
High riskUnblinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskData not reported for 6 (of 181) recruited children.


MethodsRCT


ParticipantsChildren (3 months to 18 months) with acute diarrhoea (gastroenteritis) < 5 days, with any severity of dehydration.

Exclusion criteria: Need for intravenous rehydration.


Interventions1. Immediate full-strength cow's milk formula: N = 47

2. Diluted formula: ¼ strength for 12 hrs; ½ strength for 12 hrs; ¾ strength for 12 hrs; then full strength: N = 46


OutcomesTreatment failure

Duration of hospital admission

Follow-up period: Until discharge


NotesSetting: Hospital (inpatient) ward, Countess of Chester Hospital, Chester, UK.

Oral rehydration therapy was available when required prior to randomization to feed.

Stool pathogens: Pathogens detected in 50% ( mix of rotavirus, adenovirus, E. coli, Salmonella spp. and Giardia lamblia).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported.

Allocation concealment (selection bias)Unclear riskNot reported.

Blinding of participants and personnel (performance bias)
All outcomes
High riskUnblinded.

Blinding of outcome assessment (detection bias)
All outcomes
High riskUnblinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up.


MethodsRCT


ParticipantsInfants (< 12 months) with severe diarrhoea < 48 hrs, and evidence of dehydration.

Exclusion criteria: None stated.

All infants were dehydrated on admission and most had electrolyte imbalance requiring I/V fluid therapy.


Interventions1. Lactose-free soy-based formula (Isomil®): N = 56

2. Standard (lactose-containing) cow's milk formula: N = 56


OutcomesTreatment failure (infant required another period of fasting or intravenous fluid, or > 5 watery stools/day for 3 consecutive days)

Number of stools/day
Readmission to hospital

Follow-up period: Not stated


NotesSetting: Hospital (inpatient), Durban, South Africa.

Stool pathogens: Not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details given in trial report - only states that child was: "assigned at random".

Allocation concealment (selection bias)Unclear riskNo details given in trial report.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo details given in trial report.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details given in trial report.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up.


MethodsRCT


ParticipantsInfants (< 12 months) with acute liquid or watery diarrhoea < 5 days, and evidence of dehydration.

Exclusion criteria: None stated.

Infants were dehydrated on admission and most had electrolyte imbalance requiring intravenous fluid therapy.


InterventionsDiluted formula (50%), for 24 hrs: N = 20

Full strength formula: N = 20


OutcomesTreatment failure

Stool frequency (48 hrs)

Duration of hospitalization

Follow-up period: Not stated


NotesRatchasima Hospital (in patients), Maharaj Nakhon, Thailand.

Stool pathogens: Rotavirus (about 50%); one case of Vibrio parahaemolyticus, one case of E. coli infection.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported.

Allocation concealment (selection bias)High riskCards selected ("pulled out") that indicated diluted or full strength formula.

Blinding of participants and personnel (performance bias)
All outcomes
High riskUnblinded.

Blinding of outcome assessment (detection bias)
All outcomes
High riskUnblinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up.


MethodsQuasi-RCT


ParticipantsChildren (< 18 months) with acute gastroenteritis < 5 days, and > 5% dehydration.

Exclusion criteria: Breast fed, "not thriving".


Interventions1. "Graduated" re-feeding with milk or cow's milk formula: ¼ strength for 24 hrs, ½ strength for 24 hrs, ¾ strength for 24 hrs, then full strength: N = 25

2. Immediate re-feeding with full strength cow's milk formula: N = 23


OutcomesTreatment failure (1/25 versus 7/23)

Stool frequency on day 3

Weight change (until 96 hrs)

Duration of hospital stay

Oral or intravenous rehydration therapy was given as required

Follow-up period: Until discharge


NotesSetting: Hospital (inpatient) ward, Queen Elizabeth Hospital for Children, London, UK.

Stool pathogens: Rotavirus (about 30%); other enterovirus (about 20%); E. coli (about 10%); mixed (6%); not detected (44%).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskAlternate allocation.

Allocation concealment (selection bias)High riskAlternate allocation.

Blinding of participants and personnel (performance bias)
All outcomes
High riskUnblinded.

Blinding of outcome assessment (detection bias)
All outcomes
High riskUnblinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up.


MethodsRCT


ParticipantsInfants (1 month to 12 months) with acute diarrhoea < 7 days duration and evidence of dehydration.

Exclusion criteria: Breast fed, chronic diarrhoea, neurological disturbances, immune deficiencies, or uncontrollable vomiting.


Interventions1. Soy-based formula (lactose-free): N = 44

2. Lactose-containing cow's milk formula: N = 45


OutcomesDuration of diarrhoea

Treatment failure

Follow-up period: Not stated


NotesSetting: Inpatient facility, Brazil.

Stool pathogens: Rotavirus (10%); "parasites" (5%); bacterial (16%); not identified (69%).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomly assigned to two groups – no further information.

Allocation concealment (selection bias)Unclear riskNo information.

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen label.

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen label.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up.


MethodsRCT


ParticipantsChildren (3 months to 36 months) with acute gastroenteritis requiring intravenous therapy.

Exclusion criteria: Severe malnutrition (marasmus or kwashiorkor), and absence of lactose in the stools.


Interventions1. Full strength cow's milk formula: N = 37

2. "Graduated" cow's milk formula: ½ strength for 24 hrs, 2/3 strength for further 48 hrs, then full strength on fourth day: N = 37


OutcomesDuration of diarrhoea

Treatment failure (withdrawn due to lactose malabsorption)

Follow-up period: Not stated.


NotesSetting: Hospital (inpatient) ward, Johannesburg, South Africa.

Stool pathogens: Not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details given in trial report.

Allocation concealment (selection bias)Unclear riskNo details given in trial report.

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"The milk room attendant was the only person who knew the formulation of the two milks until the trial was over".

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details given in trial report.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up.

Duration of diarrhoea not reported for children with "treatment failure" (18%).


MethodsRCT


ParticipantsBoys (3 months to 14 months) with acute diarrhoea < 4 days, with signs of dehydration,

Exclusion criteria: Shock, severe malnutrition, underlying disease, breast-fed (> 2 breast milk feeds daily), treated with antibiotics during the previous 2 weeks.


Interventions1. Lactose-free mixed diet (soup based on chicken, plantain, and coconut oil): N = 36

2. Diet with cow's milk at normal concentration for age (8.8% for 3-6 months; 13.5% for over 6 months): N = 37


OutcomesDuration of diarrhoea
Weight change

Treatment failure

Follow-up period: Until discharge


NotesSetting: Hospital (inpatient) facility, Caracas, Venezuela.

WHO oral rehydration solution (WHO-ORS) available for both groups on admission.

Stool pathogens: (only rotavirus reported): Rotavirus (44%).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"...the study was carried out by blocked randomization".

Allocation concealment (selection bias)Low risk"An envelope corresponding to each patient was only opened when he was given WHO-ORS".

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo details given in trial report.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details given in trial report.

Incomplete outcome data (attrition bias)
All outcomes
High risk17 of 76 participants (22%) were excluded and not included in any analyses.


MethodsQuasi-RCT


ParticipantsFormula-fed children (1 month to 24 months) with acute non-bloody diarrhoea, < 14 days.

Exclusion criteria: Bloody stools, major systemic illness, severe malnutrition (weight for age <60% or weight for height <70%), severe dehydration requiring intravenous infusion, severe vomiting, or history of antibiotic therapy.


Interventions1. Lactose-free formula: N = 37

2. Lactose-containing formula: N = 37

(No further description of formula reported)


OutcomesDuration of diarrhoea (only defined as "time to diarrhoea relief")
Weight change

Follow-up period: 7 days


NotesSetting: Outpatient facility; University Hospitals in Isfahan, Iran (

community-based intervention).

Oral rehydration therapy administered at first assessment for dehydrated children.

Stool pathogens: Not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskAlternate allocation.

Allocation concealment (selection bias)High riskAlternate allocation.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo details given in trial report.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details given in trial report.

Incomplete outcome data (attrition bias)
All outcomes
Low riskThree participants (all controls) were lost to follow-up.


MethodsRCT


ParticipantsFormula fed boys (3 months to 24 months) with acute watery diarrhoea < 7 days, with mild or moderate dehydration.

Exclusion criteria: Children with mucous bloody stools, major systemic illness, or severe malnutrition.


Interventions1. Lactose-free formula (Dumex®): N = 40

2. Lactose-containing formula (Dumex®): N = 40


OutcomesDuration of diarrhoea

Treatment failure
Weight change

Follow-up period: 7 days


NotesSetting: Hospital (inpatient) facility: Maharat Nakhon Ratchasima Hospital, Thailand.

Oral rehydration fluids administered as required during first 4 hrs of admission.

Stool pathogens: Rotavirus (53%); bacterial "entero-pathogens" (19%); not identified (28%).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomisation [was in] blocks of four".

Allocation concealment (selection bias)Low risk"[randomisation blocks contained] 2 lactose-free and 2 lactose containing...numerically coded".

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"[intervention] could not be distinguished from [comparator]".

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDescribed as "double blind". Not explicitly stated if assessors were also blind to treatment assignment but given that the intervention could not be distinguished and codes were applied it is highly likely.

Incomplete outcome data (attrition bias)
All outcomes
Low risk"no participants were lost to follow-up".


MethodsRCT


ParticipantsChildren (< 24 months) hospitalized with acute gastroenteritis, < 73 days.

Exclusion criteria: Chronic disease, received antibiotics < 48 hrs before trial entry.


Interventions1. Lactose-free formula (glucose 6.4%): N = 48

2. Lactose-containing formula (lactose 6.4%): N = 49

Both formulae were given in increased concentrations over first few days to full strength.


OutcomesDuration of diarrhoea
Treatment failure (defined as persisting profuse diarrhoea after a second fast)
Number of stools per day

Follow-up period: Until discharge


NotesSetting: Hospital (inpatient), Ontario, Canada.

Stool pathogens: Not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details given in trial report.

Allocation concealment (selection bias)Unclear riskNo details given in trial report.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo details given in trial report.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details given in trial report.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo participants lost to follow-up.


MethodsRCT


Participants"Well nourished and weaned" infants (< 9 months) with acute diarrhoea.

Exclusion criteria: Breast-fed.


Interventions1. Full strength cow's milk formula: N = 40

2. "Graduated" cow's milk formula: ½ strength for 24 hrs, then full strength: N = 40


OutcomesDuration of diarrhoea

Treatment failure

Oral rehydration therapy given as required on admission prior to randomization

Follow-up period: Until discharge


NotesSetting: l'Unité de Recherche "Mère-Enfant", Institut des Sciences Médicale Oran, Algeria.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported.

Allocation concealment (selection bias)Unclear riskNot reported.

Blinding of participants and personnel (performance bias)
All outcomes
High riskUnblinded.

Blinding of outcome assessment (detection bias)
All outcomes
High riskUnblinded.

Incomplete outcome data (attrition bias)
All outcomes
Low risk86% follow-up: 5 infants in each group withdrawn by parents, and 1 infant in intervention group withdrawn because of a "complication".


MethodsRCT


ParticipantsChildren (< 24 months) with acute gastroenteritis, < 5 days, with or without vomiting.

Exclusion criteria: Extra-intestinal infection.


Interventions1. Lactose-free corn syrup-based milk formula (O-LAC®): N = 29

2. Low lactose (95% hydrolysed) milk formula (De-Lact®): N = 29

3. Standard 100% lactose-containing cow's milk formula (Enfalac®): N = 33

COMPARISON 1. Group 1 + 2 versus Group 3

Subgroup comparison "of trials in which only difference between feeds was the presence or absence of lactose": Group 2 versus Group 3.


OutcomesDuration of diarrhoea (reported as median/range)
Treatment failure (continued or increased severity of diarrhoea with weight loss or deteriorating fluid and electrolyte balance)
Weight change

Follow-up period: 48 hrs


NotesSetting: Hospital (inpatient) wards, Brisbane and Adelaide, Australia.

Prior to randomization, dehydrated infants received oral or Iintravenouse fluids.

Stool pathogens: Rotavirus (38%); adenovirus (3%); E. coli (3%); Salmonella spp. (2%); G. lamblia (1%); not identified (53%).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details given in trial report.

Allocation concealment (selection bias)Unclear riskNo details given in trial report.

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"The formulae were supplied and packaged so as to blind caregivers and investigators".

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details given in trial report.

Incomplete outcome data (attrition bias)
All outcomes
High risk21 of 91 participants (23%) dropped out and were not accounted for in any analyses.


MethodsRCT


ParticipantsFormula-fed infants (< 60 days) admitted to hospital with acute diarrhoea.

Exclusion criteria: None stated


Interventions1. Lactose-containing formula: N = 14

2. Lactose-free (hydrolysed) formula (Alfare): N = 14


OutcomesTreatment failure

Weight gain

Follow-up period: Not stated


NotesSetting: University Children's Hospital, Ulm, Germany.

Stool pathogens: Not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomized. No further details.

Allocation concealment (selection bias)Unclear riskNone described.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNone described.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNone described.

Incomplete outcome data (attrition bias)
All outcomes
Low risk5 of 28 (18%) participants were lost to follow-up.


MethodsRCT


ParticipantsFormula-fed infants (< 12 months) with acute diarrhoea.

Exclusion criteria: None stated


Interventions1. Lactose-containing cow's milk formula: N = 63

2. Lactose-free cow's milk formula: N = 63


OutcomesDuration of diarrhoea

Treatment failure

Follow-up period: Not stated


NotesInpatients and outpatients departments, Children's Hospital of Fudan University, Shanghai, China.

Stool pathogens: Not identified.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described.

Allocation concealment (selection bias)Unclear riskNone described.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDescribed as "double blind".

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDescribed as "double blind".

Incomplete outcome data (attrition bias)
All outcomes
Low riskData for six infants (three in each group) withdrawn because of formula intolerance (parental request) or worsening vomiting were not reported for "duration of diarrhoea" (but were included in "treatment failure").

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Agustina 2007Both control and intervention groups received formulas with low levels of lactose.

Alarcon 1991Comparison of lactose-free milk with very low lactose-containing milk (1.5% lactose).

Binns 2007Both control and intervention groups contained the same level of lactose.

Brand 1977Included children both with and without diarrhoea.

Brunster 1990Not a RCT or quasi-RCT.

Dagan 1980Reports findings from a study already included (Dagan 1984).

Dewit 1987Participants had chronic (not acute) diarrhoea.

Donovan 1987Participants had chronic (not acute) diarrhoea.

Eichenberger 1984Some participants had sub-acute diarrhoea.

Ferrari 1987Neither formula contains sufficient lactose.

Fox 1990Comparison of full strength cow's milk with rapid regrade (within 24 hrs) to full strength cow's milk.

Herrera-Anaya 1987Participants had chronic (not acute) diarrhoea.

Hoghton 1996Study of immediate modified feeding with no group receiving any lactose-containing milk or food.

Hohenauer 1983No lactose-containing intervention.

Ibanez 1986Unclear if study is a comparison between lactose-containing and lactose-free feeds.

Kukuruzovic 2002Comparison of lactose-free formula with a formula containing only a trace of lactose (Alfare).

Loredo-Adala 1984Unclear as to the content of lactose in either the control or intervention group.

Mahalanabis 1993No lactose-containing intervention.

Margolis 1990Compared patients assigned to any treatment diet (some lactose-containing some non-lactose) with those who continued to receive their usual diet.

McClean 1990Only compares a dilute lactose intervention with either a very low lactose-containing intervention or a lactose-free intervention.

Mitchell 1977Participants both with and without diarrhoea were included.

Ooi 1989Compared graduated feeding with cow's milk versus immediate full feeding with soy-based formula.

Palma 1997Not comparing lactose against non-lactose.

Rajah 1988Participants had prolonged (not acute) diarrhoea.

Rees 1979Compared continuing on full-strength milk with taking clear fluids until the diarrhoea settled before full-strength milk was reintroduced either immediately, or gradually in quarter-strength steps.

Rothman 1980Participants suffered from kwashiorkor and not necessarily diarrhoea.

Sagaro 1991Participants suffered from persistent diarrhoea.

Schmidt 1990Not a RCT and all participants did not have acute diarrhoea.

Silveira 1989Participants had prolonged (not acute) diarrhoea.

Sperotto 1998Not a RCT.

Suthutvoravut 1983Participants had prolonged (not acute) diarrhoea.

Ubaldo 1998Not described as randomized.

Wehba 1989Comparison of lactose-free milk with very low lactose-containing milk.

Wemmer 1977Unclear if participants had acute diarrhoea. Unclear about lactose content in intervention and comparison group.

 
Characteristics of studies awaiting assessment [ordered by study ID]

MethodsInformation not available.

ParticipantsInformation not available.

InterventionsInformation not available.

OutcomesInformation not available.

NotesCited in Brown 1994.

Article not available from British Library.


MethodsInformation not available.

ParticipantsInformation not available.

InterventionsInformation not available.

OutcomesInformation not available.

NotesCited in Brown 1994.

Article not available from the British Library.

 
Comparison 1. Lactose-free versus lactose-containing milk, milk products, or foodstuffs

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Duration of diarrhoea (hours)161467Mean Difference (IV, Random, 95% CI)-17.77 [-25.32, -10.21]

 2 Treatment failure181470Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.39, 0.68]

 3 Need for hospitalization183Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.09, 6.65]

 4 Duration of hospital stay (days)5246Mean Difference (IV, Random, 95% CI)-0.31 [-0.83, 0.21]

 5 Stool volume (g/kg body weight/day)3194Mean Difference (IV, Random, 95% CI)-9.23 [-32.61, 14.14]

 6 Weight change (at discharge or recovery)2228Mean Difference (IV, Fixed, 95% CI)-0.25 [-0.92, 0.42]

 
Comparison 2. Subgroup analyses (other differences in feed type): Lactose-free versus lactose-containing

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Duration of diarrhoea (feed type)161417Mean Difference (IV, Random, 95% CI)-17.94 [-25.61, -10.26]

   1.1 Only difference between trial groups is presence or absence of lactose
9810Mean Difference (IV, Random, 95% CI)-20.20 [-24.71, -15.69]

   1.2 Treatment groups differ in types of feed as well as presence or absence of lactose
7607Mean Difference (IV, Random, 95% CI)-14.38 [-30.15, 1.39]

 2 Treatment failure (feed type)181391Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.40, 0.69]

   2.1 Only difference between trial groups is presence or absence of lactose
11894Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.42, 0.85]

   2.2 Treatment groups differ in types of feed as well as presence or absence of lactose
7497Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.28, 0.66]

 
Comparison 3. Sensitivity analyses (low risk of bias): Lactose-free versus lactose-containing

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Duration of diarrhoea (sequence generation)8605Mean Difference (IV, Fixed, 95% CI)-17.85 [-23.87, -11.82]

 2 Duration of diarrhoea (allocation concealment)4385Mean Difference (IV, Random, 95% CI)-16.89 [-31.43, -2.36]

 3 Duration of diarrhoea (blinding of participants and personnel)3273Mean Difference (IV, Random, 95% CI)-31.53 [-46.25, -16.82]

 4 Duration of diarrhoea (blinding of outcome assessment)3273Mean Difference (IV, Random, 95% CI)-31.53 [-46.25, -16.82]

 5 Duration of diarrhoea (complete outcome assessment)131164Mean Difference (IV, Random, 95% CI)-17.75 [-26.62, -8.89]

 6 Treatment failure (sequence generation)9657Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.37, 0.84]

 7 Treatment failure (allocation concealment)3207Risk Ratio (M-H, Fixed, 95% CI)0.47 [0.16, 1.41]

 8 Treatment failure (blinding of participants and personnel)5305Risk Ratio (M-H, Fixed, 95% CI)0.54 [0.36, 0.81]

 9 Treatment failure (blinding of outcome assessment)3174Risk Ratio (M-H, Fixed, 95% CI)0.47 [0.28, 0.79]

 10 Treatment failure (complete outcome assessment)141116Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.37, 0.72]

 
Comparison 4. Diluted versus undiluted lactose-containing milk, milk products, or foodstuffs

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Duration of diarrhoea (hrs)5471Mean Difference (IV, Fixed, 95% CI)-2.01 [-9.71, 5.68]

 2 Treatment failure9687Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.45, 0.94]

 3 Duration of hospital stay (days)9804Mean Difference (IV, Fixed, 95% CI)-0.17 [-0.50, 0.16]

 4 Stool volume (g/kg/day or g/day)2Mean Difference (IV, Fixed, 95% CI)Totals not selected

 5 Number of stools per day4417Mean Difference (IV, Fixed, 95% CI)-0.21 [-0.99, 0.57]

 6 Weight change (at discharge or recovery)2187Mean Difference (IV, Fixed, 95% CI)-0.75 [-1.81, 0.32]

 
Summary of findings for the main comparison. Lactose-free versus lactose-containing milk, milk products, or foodstuffs for young children with acute diarrhoea

Lactose-free versus lactose-containing milk, milk products, or foodstuffs for young children with acute diarrhoea.

Patient or population: Young children with acute diarrhoea
Settings: Inpatient and outpatient
Intervention: Lactose-free milk, milk products, or foodstuffs
Control: Lactose-containing milk, milk products, or foodstuffs

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)

Assumed riskCorresponding risk

Lactose-containingLactose-free

Duration of diarrhoea (hours)The mean duration of diarrhoea in the control groups ranged from 28.8 to 230 hoursThe mean duration in the intervention groups was 17.77 hours shorter
(25.32 to 10.21 shorter)
-1467
(16 trials)
⊕⊕⊝⊝
low1,2,3,4

Treatment failure164 per 100085 per 1000
(64 to 112)
RR 0.52
(0.39 to 0.68)
1470
(18 trials)
⊕⊕⊕⊝
moderate5,6,3,4

Need for hospitalization63 per 100050 per 1000
(6 to 422)
RR 0.79
(0.09 to 6.65)
83
(1 trials)
⊕⊝⊝⊝
very low7,8

*The assumed risk is taken from the control group risk in the meta-analysis. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk Ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Downgraded by 1 for serious risk of bias: Almost all trials were at high or unclear risk of bias for more than one of the risk of bias criteria, and only two studies were adequately blinded.
2 Downgraded by 1 for serious inconsistency: A high level of heterogeneity between trials was found which could not be fully explained through subgroup analyses by age, setting, or income level of the country.
3 No serious indirectness: The included trials were mainly conducted in inpatient settings, but came from a mix of high- and low-income countries. Subgroup analyses did not find any significant differences in estimate size based on age, setting, income level of the country, or differences in feed type apart from the lactose content.
4 No serious imprecision: The result is a statistically significant effect in favour of lactose-free, with a narrow CI.
5 Downgraded by 1 for serious risk of bias: Many of the trials were at high or unclear risk of selection, performance, and attrition bias. In a sensitivity analysis limited to the three trials at low risk of selection bias, no statistically significant effect was seen.
6 No serious inconsistency: Statistical heterogeneity was low.
7 Downgraded by 1 for serious indirectness: Only a single trial from a single setting evaluated this outcome.
8 Downgraded by 2 for very serious imprecision: There were few participants and few events. The CIs were very wide for this outcome and the 95% CIs around the pooled effect estimate included both significant benefit and harm of intervention.
 
Summary of findings 2. Diluted (by at least 50%) versus undiluted lactose-containing milk, milk products, or foodstuffs for young children with acute diarrhoea

Diluted versus undiluted lactose-containing milk, milk products, or foodstuffs for young children with acute diarrhoea.

Patient or population: Young children with acute diarrhoea
Settings: Inpatient and outpatient
Intervention: Diluted lactose-containing milk, milk products, or foodstuffs
Control: Undiluted lactose-containing milk, milk products, or foodstuffs

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)

Assumed riskCorresponding risk

UndilutedDiluted

Duration of diarrhoea (hours)The mean duration of diarrhoea in the control groups ranged from 47 to 92 hoursThe mean duration of diarrhoea in the intervention groups was
2.01 hours shorter
(9.71 lower to 5.68 higher)
-471
(5 trials)
⊕⊕⊝⊝
low1,2,3,4

Treatment failure173 per 1000112 per 1000
(78 to 163)
RR 0.65
(0.45 to 0.94)
687
(9 trials)
⊕⊕⊝⊝
low1,2,3,5

Need for hospitalization---(0 trials)-

*The assumed risk is taken from the control group risk in the meta-analysis. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk Ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Downgraded by 1 for serious risk of bias: Only one of these trials adequately described a method of allocation concealment to be considered at low risk of selection bias, and only two conducted any form of blinding.
2 No serious inconsistency: Statistical heterogeneity was low.
3 No serious indirectness: These trials were from a mix of high-, middle-, and low-income settings, and included children up to three years of age. All were conducted in inpatient settings.
4 Downgraded by 1 for serious imprecision: The 95% CIs around the pooled effect estimate included both significant benefit and harm of intervention.
5 Downgraded by 1 for serious imprecision: The result was statistically significant, but the meta-analysis remained underpowered to have full confidence in this effect.
 
Table 1. Detailed search strategies

Search setCIDG SR*CENTRALMEDLINE**EMBASE**LILACS**

1diarrheadiarrheadiarrheadiarrheadiarrhea

2gastroenteritisgastroenteritisdiarrhoeaDIARRHEAlactose

3lactose1 or 2DIARRHEA, INFANTILEgastroenteritissoy

4milklactose intolerancegastroenteritis1 or 2 or 3infant formula

5formulaLACTOSE INTOLERANCE1 or 2 or 3 or 4lactose intolerance2 or 3 or 4

6soyamilklactose intoleranceLACTOSE-INTOLERANCE1 and 5

71 or 2soyLACTOSE INTOLERANCEsoy--

83 or 4 or 5 or 6formulaSOY MILKsoya--

97 and 84 or 5 or 6 or 7 or 8MILK SUBSTITUTESARTIFICIAL MILK--

10--3 and 9INFANT FORMULAmilk substitute--

11----6 or 7 or 8 or 9 or 10infant formula--

12----5 and 115 or 6 or 7 or 8 or 9 or 10 or 11--

13------4 and 12--

 * Cochrane Infectious Diseases Group Specialized Register.
** Search terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Lefebvre 2011) ; Upper case: MeSH or EMTREE heading; Lower case: free text term.
 
Table 2. Subgroup analyses of duration of diarrhoea (lactose-free versus lactose-containing)

Duration of diarrhoea Trials (participants)MD (95% CI) hours

(random-effects)
Tau²Chi² (df)

1. Age

All participants 12 months of age or less6 (567)-25.23 (-45.01, -5.45)404.8819.00 (5)

P = 0.002
74%

Some of participants older than 12 months10 (900)-16.08 (-24.21, -7.94)90.1926.57 (9)

P = 0.0001
66%

2. Setting

Inpatient14 (1342)-17.94 (-26.28, -9.59)139.7339.82 (13)

 P = 0.0001
67%

Outpatient2 (143)7.59 (-83.51, 98.69)2996.572.29 (1)

P = 0.13
56%

3. Income level

Low- or middle-income country10 (947)-15.77 (-22.64, -8.90)42.0915.59 (9)

P = 0.08
42%

High-income country6 (520)-24.88 (-44.18, -5.57)417.6128.14 (5)

P < 0.0001
82%

 df = degrees of freedom
 
Table 3. Subgroup analyses of treatment failure (lactose-free versus lactose-containing)

Treatment failure Trials (participants)RR (95% CI)

(fixed-effect)
Chi² (df)

1. Age

All participants 12 months of age or less10 (779)0.51 (0.37, 0.69)9.15 (9)

P = 0.0001
0%

Some of participants older than 12 months10 (900)-16.08 (-24.21, -7.94)7.37 (7)

P = 0.02
5%

2. Setting

Inpatient17 (1416)0.50 (0.38, 0.66)15.63 (16)

P = 0.00001
0%

Outpatient1 (54 )___

3. Income level

Low- or middle-income country10 (880)0.50 (0.34, 0.72)6.69 (9)

P = 0.0001
0%

High-income country8 (590)0.54 (0.36, 0.80)9.64 (7)

P = 0.002
27%