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Zinc supplementation for the prevention of pneumonia in children aged 2 months to 59 months

  1. Zohra S Lassi1,
  2. Batool A Haider2,
  3. Zulfiqar A Bhutta1,*

Editorial Group: Cochrane Acute Respiratory Infections Group

Published Online: 8 DEC 2010

Assessed as up-to-date: 26 JAN 2010

DOI: 10.1002/14651858.CD005978.pub2


How to Cite

Lassi ZS, Haider BA, Bhutta ZA. Zinc supplementation for the prevention of pneumonia in children aged 2 months to 59 months. Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD005978. DOI: 10.1002/14651858.CD005978.pub2.

Author Information

  1. 1

    Aga Khan University Hospital, Division of Women and Child Health, Karachi, Pakistan

  2. 2

    Harvard School of Public Health, Departments of Epidemiology and Nutrition, Boston, MA, USA

*Zulfiqar A Bhutta, Division of Women and Child Health, Aga Khan University Hospital, Stadium Road, PO Box 3500, Karachi, 74800, Pakistan. zulfiqar.bhutta@aku.edu.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 8 DEC 2010

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This is not the most recent version of the article. View current version (04 DEC 2016)

 
Characteristics of included studies [ordered by study ID]
Bhandari 2002a

MethodsRCT in which the children were individually randomised by a computer generated simple randomisation scheme in blocks of 8. Zinc or placebo bottles were labelled with a unique child identification number according to the randomisation scheme. 6 bottles, one for each month and 2 extra, for each child were produced and labelled before enrolment commenced. The supplies for each child were kept separately in labelled plastic bags. The zinc and placebo syrups were similar in appearance, taste, and packaging. Masking was maintained during analyses by coding the groups as A or B


ParticipantsThe study included children aged 6 to 30 months. There were 1241 children in each group and after drop outs the number reduced to 1093 in the zinc and 1133 in the placebo group. Children were excluded if consent was refused, were likely to move out of the study area within the next four months, needed urgent admission to hospital on the enrolment day or had received a massive dose of vitamin A (100,000 IU for infants and 200,000 IU for older children) within the two months before enrolment


InterventionsDoses of elemental zinc were 10 mg for infants and 20 mg for older children (twice the recommended daily dosage) as zinc gluconate. Zinc or placebo was taken daily for four months. Both groups received single massive doses of vitamin A (100,000 IU for infants and 200,000 IU for older children) at enrolment. Immunisations and treatment for acute illnesses were provided as per World Health Organization (WHO) guidelines. Children with acute lower respiratory tract infections received co­trimoxazole. Amoxicillin was substituted if the child did not respond within three days. Children were sent to hospital if they had signs and symptoms that warranted referral according to WHO guidelines


OutcomesNumber of incidence of ALRI. ALRIs were defined by cough and fast-breathing or lower chest indrawing as assessed by the physician; other clinical signs were not taken into account. Fast breathing was defined as 2 counts of > 50 breaths/min for infants and > 40 breaths/min for older children


NotesThe study took place in the urban slum of Dakshinpuri in New Delhi, India. For episodes to be counted as individual, there had to be at least 14 intervening days. The children in the two groups were comparable for age, anthropometry, child feeding practices, morbidity in the previous 24 hours, socioeconomic characteristics and plasma zinc concentration


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "children were individually randomised by a simple randomisation scheme in blocks of eight. The randomisation scheme was generated by a statistician at Statens Serum Institut, not otherwise involved with this study, using the SAS software"

Comment: adequately done

Allocation concealment (selection bias)Low riskQuote: "zinc or placebo syrups were prepared and packaged in unbreakable bottles by GK Pharma ApS Koge, Denmark, who also labelled bottles with a unique child identification number according to the randomisation scheme. The supplies of each child were kept separately in labelled plastic bags. The Zinc and placebo were similar in appearances, taste and packaging. Masking was maintained during the analysis by coding the groups as A and B"

Comment: adequately done

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "the supplies for each child were kept separately in labelled plastic bags". "Masking was maintained during analyses by coding the groups as A or B"

Comment: participants and outcome assessors were blinded to the treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Low riskExclusion (35%) with their reasons documented. Attrition was 12% in the zinc group and 8.7% in the control group

Selective reporting (reporting bias)Low riskThe study appears to be free of selective reporting

Bhandari 2002b

MethodsSame as Bhandari 2002a


ParticipantsSame as Bhandari 2002a


InterventionsSame as Bhandari 2002a


OutcomesPneumonia was diagnosed either by a combination of cough with crepitations or bronchial breathing by auscultation or as an episode of acute lower respiratory tract infection associated with at least one of lower chest indrawing, convulsions, not able to drink or feed, extreme lethargy, restlessness or irritability, nasal flaring, or abnormal sleepiness


NotesSame as Bhandari 2002a


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "children were individually randomised by a simple randomisation scheme in blocks of eight. the randomisation scheme was generated by a statistician at Statens Serum Institut, not otherwise involved with this study, using the SAS software"

Comment: adequately done

Allocation concealment (selection bias)Low riskQuote: "zinc or placebo syrups were prepared and packaged in unbreakable bottles by GK Pharma ApS Koge, Denmark, who also labelled bottles with a unique child identification number according to the randomisation scheme. The supplies of each child were kept separately in labelled plastic bags. The Zinc and placebo were similar in appearances, taste and packaging. Masking was maintained during the analysis by coding the groups as A and B

Comment: adequately done

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "the supplies for each child were kept separately in labelled plastic bags". "Masking was maintained during analyses by coding the groups as A or B"

Comment: participants and outcome assessors were blinded to the treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Low riskExclusion (35%) with their reasons documented. Attrition was 12% in the zinc group and 8.7% in the control group

Selective reporting (reporting bias)Low riskThe study appears to be free of selective reporting

Bobat 2005

MethodsThis was a randomised, double-blind controlled placebo controlled trial conducted in Grey's Hospital in Pietermaritxburg, South Africa. Baseline measurements of plasma HIV-1 viral load and the percentage of CD4T lymphocytes were established at two study visits before randomisation, and measurements were repeated 3, 6, and 9 months after the start of supplementation


Participants96 children with HIV-1 infection between the ages of 6 months to 60 months, being cared for as outpatients at Grey’s Hospital, and not receiving anti-retroviral therapy were recruited. Pneumonia was diagnosed by history and physical examination, including chest auscultation, and confirmed by chest radiograph


InterventionsChildren either received 10 mg of elemental zinc as sulphate or placebo every day for 6 months. The child’s parent or guardian was given 1 packet at the first 2 visits and two packets at each monthly follow-up visit thereafter, and was instructed on how to give the tablet


OutcomesThe primary outcome measure was plasma HIV-1 viral load


NotesOutpatient management of children with HIV-1 infection is provided by a team of paediatricians, medical officers, and nurses who care for about 20 to 30 children per week. After starting zinc or placebo, children were assessed at Grey’s Hospital every 2 weeks for the first month, monthly for 5 months, and a final visit 9 months after zinc or placebo supplementation started. Pneumonia was diagnosed by history and physical examination, including chest auscultation, and confirmed by chest radiograph


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Children were block–randomised in three age strata (6 to 23, 24 to 41, and 42 to 60 months)"; "Randomisation lists were computer generated at the WHO in a fixed block size of eight"

Comment: adequately done

Allocation concealment (selection bias)Unclear riskQuote: "Tablets of zinc sulphate or placebo were produced by the same manufacturer (Nutriset, Bierne, France) and supplied in blister packets of 14 dispersible tablets"; "An investigator at Grey’s Hospital assigned children to the treatment groups. The investigators were unaware of the treatment allocation until follow up was completed"

Comment: insufficient information to permit judgement

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "double-blind"; tablets of zinc sulphate or placebo were produced by the same manufacturer (Nutriset, Bierne, France) and supplied in blister packets of 14 dispersible tablets." An investigator at Grey’s Hospital assigned children to the treatment groups. The investigators were unaware of the treatment allocation until follow up was completed."

Comment: participants and the care givers were blinded to the treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Low risk9/105 (8.6%) were excluded. 2/46 (4.4%) and 9/50 (18%) did not complete trial in zinc and placebo groups, respectively. The reasons for lost to follow-up were given

Selective reporting (reporting bias)Low riskThe study appears to be free of selective reporting

Brooks 2005

MethodsIt is a randomised controlled trial in which random assignment to zinc or placebo was done with permuted blocks of variable length between 2 and 8. Placebo was designed to be identical to the zinc syrup in colour, odour, and taste


ParticipantsChildren aged 60 days to 12 months at the time of enrolment and excluded those with known or suspected tuberculosis, chronic respiratory or congenital heart disease, or severe malnutrition requiring hospital admission. Pneumonia was diagnosed if crepitations were heard on inspiration with a respiratory rate greater than 50 breaths per minute; severe pneumonia was diagnosed if there was also chest indrawing, or at least one other danger sign. Children with wheezing or rhonchi with crepitations were also diagnosed with pneumonia. 809 children were randomly assigned to zinc and 812 to placebo. There were no significant differences between groups at baseline, except for a slightly higher proportion of boys in the zinc group. There was no difference between the groups in serum zinc values at baseline


InterventionsZinc was given orally as a syrup (35 mg zinc acetate per 5 mL). The placebo was non-nutritious and vitamin-free. Compliance required intake of two teaspoons of syrup (10 mL). Children with pneumonia were treated with co-trimoxazole (10 mg/kg trimethoprim, twice daily for 5 days) for pneumonia. Children on antibiotics were assessed within 72 hours of starting treatment; those who did not improve (i.e., the respiratory rate did not change by more than 5 breaths/min from baseline) were switched to treatment with amoxicillin (40 mg/kg, three times daily for 5 days). If oral treatment failed, or if they had severe pneumonia, children were referred to hospital for parenteral treatment (ceftriaxone 75 mg/kg intramuscularly per day). Children with only expiratory wheezes or rhonchi were managed with salbutamol syrup (0·3 mg/kg, three times daily), or referred to hospital for danger signs


OutcomesThe main outcome was to find out the incidence of pneumonia in both groups. Other outcomes included frequency of other illnesses and mortality


NotesThe study was conducted at Kamalapur, southeastern Dhaka, Bangladesh. The medical officer diagnosed pneumonia if crepitations were heard on inspiration with a respiratory rate greater than 50 breaths per minute; severe pneumonia was diagnosed if there was also chest indrawing, or at least one other danger sign


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Random assignment to zinc or placebo was done with permuted blocks of variable length between two and eight"

Comment: adequately done

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "ACME Laboratories (Dhaka) prepared, labelled and masked the identity of both preparations. Both placebo and treatment were designed to be identical in colour, odour, and taste"; "identity of both the preparations were masked"

Comment: participants and care givers were blinded to the treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe loss to follow up was 9.1% for the whole study

Selective reporting (reporting bias)Low riskThe study appears to be free of selective reporting

Luabeya 2007

MethodsThe study was conducted in northern KwaZulu-Natal Province, South Africa. Children were enrolled into the study by nurses at five government primary health care clinics


ParticipantsChildren eligible for study were 4 to 6 months old. Children were excluded from the study if they were: less than 60% of median weight-for-age using United States National Center for Health Statistics standards; had nutritional oedema; had received vitamin or micronutrient supplements in the previous month; had diarrhoea for more than seven days at the time of study enrolment; or were enrolled in another study of a clinical intervention. Confirmed pneumonia was defined as an elevated respiratory rate at rest measured by the fieldworker using WHO/UNICEF Integrated Management of Childhood Illness guidelines


InterventionsThe 3 treatment arms were: vitamin A alone; vitamin A plus zinc; and vitamin A, zinc and multiple micronutrients. All supplements were given daily at home from entry into the study until 24 months of age


OutcomesDiarrhoea, pneumonia


NotesPneumonia by maternal report was considered to have occurred if there was a history of either fast breathing or chest in-drawing. Confirmed pneumonia was defined as an elevated respiratory rate at rest measured by the fieldworker using WHO/UNICEF Integrated Management of Childhood Illness guidelines


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "An allocation list was prepared using computer-generated random numbers and a block size of six"; assignment to the three treatment arms was done separately for three cohorts of children stratified by HIV status of child and mother: HIV-infected children and mothers; HIV-uninfected children of HIV-infected mothers; and HIV-uninfected children of HIV-uninfected mothers

Comment: adequately done

Allocation concealment (selection bias)Low riskQuote: "The manufacturer prepared numbered packs of tablets corresponding to the allocation list. Children enrolled in the study were assigned by a study physician to one of the three study cohorts after results of the HIV tests became available. The physician then allocated the next pack of tablets from the blocks assigned to that cohort to the participant"

Comment: adequately done

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Investigators, study staff and participants were blind to the treatment assignments"

Comment: participants, care givers and outcome assessors were blinded to the treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Low riskExclusion (12.7%) and attrition (8.1% in vitamin A + zinc and 8.9% in vitamin A group) data were reported along with their reasons

Selective reporting (reporting bias)Low riskThe study appears to be free of selective reporting

Penny 2004

MethodsThis randomised, double-masked, placebo-controlled, community-based trial was carried out in Canto Grande, a shanty town on the outskirts of Lima, Peru. The study was carried out in 2 phases. During the first phase they evaluated the effect of zinc or multiple micronutrient supplementation on the recovery from persistent diarrhoea. During the second phase they assessed the effect of continued supplementation on morbidity from new infections during the following 6 months


Participants412 children aged 6 to 36 months with diarrhoea for 14 days were randomly assigned, after being stratified for breastfeeding status, to receive 2 weeks of daily supplementation with 1 of 3 indistinguishable supplements: placebo; 20 mg Zn/d as zinc gluconate (Zn group); or 20 mg Zn/d as zinc gluconate plus a mixture of other micronutrients, i.e., vitamins and minerals (ZnVM group). A subset of children consisting of the first 246 children enrolled who intended to remain in the study area subsequently received the same assigned supplement at one-half the initial daily dose (10 mgZn/d) and continued under observation for a total of 6 months


InterventionsThe supplements were supplied as individual doses of a dry micronutrient mixture with added sugar, colorings, and flavouring agents, which were dissolved in clean water in the participants’ homes and provided as a liquid beverage under the supervision of study personnel on Monday through Friday and by parents or other caregivers during the weekends. There were two intervention arms, zinc plus vitamins and minerals who were given 10 mg of zinc supplementation along with different combinations of mineral and vitamins. Another interventional arm was given zinc 10 mg and the control group was not given any supplementation


OutcomesChanges in plasma zinc, hematocrit, hemoglobin, plasma ferritin. Children with dysentery, diarrhoea and pneumonia


NotesIn this review, groups with zinc and placebo are included for analysis. Examination always included assessment of hydration status, measurement of rectal temperature and monitoring of respiratory rate, which was counted for 1 min and repeated if the rate was greater than age-specific upper limits (50/min for children aged 6 to 11 mo and 40/min for children
aged 11 mo). Children were referred to the study physician for diagnosis and treatment when the fieldworker or caregiver was concerned about the child’s health status or if the child had any one of several predefined signs of illness, including fever, presentation or worsening of cough with elevated respiratory rate (i.e., fieldworker-defined acute lower respiratory infection), persistent diarrhoea, diarrhoea with signs of dehydration, or vomiting or skin conditions requiring diagnosis


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information to permit judgement

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "double-masked"

Comment: participants and treatment assigners were blinded to the treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Low risk14/81 (17.3%) in zinc and 13/83 (15.7%) placebo groups lost to follow-up with reasons reported

Selective reporting (reporting bias)Low riskThe study appears to be free of selective reporting

Sazawal 1998a

MethodsIt is a double-blind RCT in which the loss of follow up was less than 2%


ParticipantsChildren, 6 to 35 months of age, presenting to a community based clinic for acute diarrhoea and before enrolment, a parent of the child was given an explanation of the study and written informed consent was obtained. The baseline characteristics for the child-periods included in the analysis were similar between the two groups. The zinc group had 298 participants and the placebo one had 311


InterventionsChildren were randomised to receive either zinc or placebo in a liquid preparation containing vitamins A (800 units), B1 (0.6 mg), B2 (0.5 mg), B6 (0.5 mg), D3 (100 IU), and E (3 mg) and niacinamide (10 mg); the zinc preparation contained zinc gluconate (10 mg elemental zinc). The liquid preparation 5 ml was given daily for 6 months to all enrolled children; during diarrhoeal illness this was increased to 10 mL to provide for excess zinc losses


OutcomesIncidence and prevalence of ALRI. ALRI was diagnosed as using WHO criteria for respiratory disease episodes based on fast breathing alone


NotesThe study was conducted in a low socioeconomic population of urban India


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Randomisation schedules with permuted blocks of 10 were used for children"

Comment: adequately done

Allocation concealment (selection bias)Low riskQuote: "Supplements were prepared and coded by Sandoz India Ltd (Mumbai). Both formulation were liquid preparations, similar in colour and taste"

Comment: adequately done

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "double-blind"; "The Code, which was kept by WHO personnel, was not available to the investigator until the end of the study; "both formulation were liquid preparations, similar in colour and taste"

Comment: participants, care givers and outcome assessors were blinded to the treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskExclusion and attrition rates with their reasons were not described in the study

Selective reporting (reporting bias)Low riskThe study appears to be free of selective reporting

Sazawal 1998b

MethodsSame as Sazawal 1998a


ParticipantsSame as Sazawal 1998a


InterventionsSame as Sazawal 1998a


OutcomesALRI defined as child having cough and at least one assessment documenting: a) an elevated respiratory rate more than the age-specific value on both 1-minute estimations; and b) a recorded temperature of more than 101°F or lower chest indrawing (LCI)


NotesSame as Sazawal 1998a


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Randomisations schedules with permuted blocks of 10 were used for children"

Comment: adequately done

Allocation concealment (selection bias)Low riskQuote: "Supplements were prepared and coded by Sandoz India Ltd (Mumbai). Both formulation were liquid preparations, similar in colour and taste"

Comment: adequately done

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "double-blind"; "The Code, which was kept by WHO personnel, was not available to the investigator until the end of the study"

Comment: participants, care givers and outcome assessors were blinded to the treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskExclusion and attrition rates with their reasons were not described in the study

Selective reporting (reporting bias)Low riskThe study appears to be free of selective reporting

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Baqui 2002Zinc supplementation was given for 2 weeks

Baqui 2003ALRI was diagnosed if the child had reported symptoms of cough or difficulty in breathing with rapid breathing with or without chest indrawing

Bates 1993Zinc supplement was delivered in a fortified drink form

Castillo-Duran 1987Zinc supplementation period too short (60 d); did not study effects on diarrhoea or respiratory illnesses

Lind 2004Considered ‘cough and fever’ as ALRI outcome

Lira 1998Infants were recruited and supplemented from birth; short-course supplementation was provided; only cough was reported

Long 2006Respiratory tract infection outcomes were defined as the occurrence of cough alone, cough and fever, or cough and rapid respiratory rate as reported by the mother

Ninh 1996Respiratory outcome was cough and fever

Osendarp 2002Infants were recruited and supplemented from 4 weeks of age

Rahman 2001Supplementation was given for 2 weeks only

Reul 1997Respiratory infections were defined as the presence of at least two of the following symptoms: runny nose, cough, wheezing, difficulty breathing, or fever

Richard 2006An ALRI was parent defined by the presence of cough and rapid respiration

Rosado 1997Their respiratory illness was presence of runny nose, common cold, sore throat or cough

Roy 1999Zinc supplementation period was 2 weeks

Sempértegui 1996Zinc supplementation period was 60 days

Sur 2003Infants were recruited and supplemented from within 7 days of birth

Taneja 2009Zinc supplementation was given to infants between 2 to 4 wk and 12 mo of age

Tielsch 2007Trial was on children aged 1 to 35 months

Umeta 2000Cough was only reported respiratory outcome

 
Comparison 1. Zinc supplementation vs placebo

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

 1 Pneumonia incidence87850Risk Ratio (Fixed, 95% CI)0.87 [0.81, 0.94]

    1.1 Diagnosis based on age-specific fast breathing with or without lower chest indrawing
43259Risk Ratio (Fixed, 95% CI)0.95 [0.86, 1.06]

    1.2 Diagnosis based age-specific fast breathing AND confirmed by chest examination or chest radiograph
44591Risk Ratio (Fixed, 95% CI)0.79 [0.71, 0.88]

 2 Pneumonia prevalence13296Risk Ratio (Fixed, 95% CI)0.59 [0.35, 0.99]

 
Table 1. Zinc supplement schedule and duration

StudySupplementScheduleDurationSurveillance

ZincControl

Bhandari 2002a

Bhandari 2002b
Zinc gluconate

10 mg
Both groups vitamin ADaily4 monthsOnce weekly

Bobat 2005Zinc sulphate

10 mg
PlaceboDaily6 monthsEvery 2 weeks

Brooks 2005Zinc acetate 35 mg to infants

70 mg to children > 12 months
PlaceboWeekly12 monthsOnce weekly

Luabeya 2007Zinc gluconate

10 mg
Both groups vitamin ADaily(Continued until 24 months of age)Once weekly

Penny 2004Zinc gluconate

10 mg
PlaceboDaily6 monthsOnce weekly

Sazawal 1998a

Sazawal 1998b
Zinc gluconate

10 mg
PlaceboDaily4 monthsEvery 5th day