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Vitamin A supplementation for the prevention of morbidity and mortality in infants six months of age or less

  1. Siddhartha Gogia1,*,
  2. Harshpal S Sachdev2

Editorial Group: Cochrane Neonatal Group

Published Online: 5 OCT 2011

Assessed as up-to-date: 29 NOV 2010

DOI: 10.1002/14651858.CD007480.pub2


How to Cite

Gogia S, Sachdev HS. Vitamin A supplementation for the prevention of morbidity and mortality in infants six months of age or less. Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD007480. DOI: 10.1002/14651858.CD007480.pub2.

Author Information

  1. 1

    Max Hospital, Pediatrics, Gurgaon, Haryana, India

  2. 2

    Sitaram Bhartia Institute of Science and Research, Pediatrics and Clinical Epidemiology, New Delhi, India

*Siddhartha Gogia, Pediatrics, Max Hospital, Gurgaon, Haryana, India. gogiasiddhartha@gmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 5 OCT 2011

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This is not the most recent version of the article. View current version (28 SEP 2016)

 
Characteristics of included studies [ordered by study ID]
Ayah 2007

MethodsRandomised, placebo-controlled, double-blind, 2 x 2 factorial trial

Data collection: July 1999 to November 2001


ParticipantsNumber: 564

Inclusion criteria: recently delivered women with live singleton neonate

Exclusion criteria: none


Interventions(Aa group) Maternal vitamin A, infant vitamin A (mother received 400,000 IU vitamin A within 24 hours of delivery; infant received 100,000 IU vitamin A at 14 weeks age with DPT and OPV vaccines; n=142)

(Pa group) Maternal placebo, infant vitamin A (mother received placebo within 24 hours of delivery; infant received 100,000 IU vitamin A at 14 weeks age with DPT and OPV vaccines; n=143)

(Ap group) Maternal vitamin A, infant placebo (mother received 400,000 IU vitamin A within 24 hours of delivery; infant received placebo at 14 weeks age with DPT and OPV vaccines; n=140)

(Pp group) Maternal placebo, infant placebo (mother received placebo within 24 hours of delivery; infant received placebo at 14 weeks age with DPT and OPV vaccines; n=139)

All pregnant women received presumptive malarial treatment in their second and third trimesters.


OutcomesMaternal supplementation: mortality; morbidity and adverse effects not reported; follow-up at 14 weeks

Infant supplementation: adverse effects; mortality and morbidity not reported; follow-up after infant dosing at 14 and 26 weeks


NotesLocation: Bondo District, rural western Kenya (Africa)

HIV status: earlier HIV prevalence reported as 28% among antenatal clinic attendees; however, the trial was conducted before to the availability of HIV testing and antiretroviral prophylaxis for antenatal women in public sector facilities in western Kenya

Maternal supplementation:

  • Mortality extracted until 14 weeks only; differential mortality in the 4 groups not depicted after 14 weeks when infant intervention commenced
  • Adverse effect of bulging fontanel is recorded as a comparison of infants receiving vitamin A or placebo; the stratification according to factorial design is not available, and thus adverse effects cannot be extracted for the intervention and comparison groups as specified


Infant supplementation:

  • Mortality given as a composite from 0 to 6 months; data not extractable after starting intervention in infants (14 weeks to 6 months) in the 4 treatment arms
  • Adverse effect of bulging fontanel is recorded as a comparison of infants receiving vitamin A or placebo irrespective of maternal vitamin A supplementation


In our analyses for the effects of maternal supplementation, we have combined group Aa and group Ap for the vitamin A group, and we have combined group Pa and group Pp for the placebo group.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Two random sequences of X and Y were prepared, one for the mothers and one for the infants. Identification numbers from 1 to 700 were assigned consecutively to each of the two lists and mother–infant pairs of capsules were packaged in zip-lock bags numbered from 1 to 700 and kept in batches of ten."

Allocation concealment (selection bias)Low risk"The randomisation codes were concealed for the entire trial duration and only revealed
after completion of data analysis."

Blinding (performance bias and detection bias)
All outcomes
Low risk"...prepared and supplied the vitamin A and identical-looking placebo supplements as oily capsules in brown bottles coded as X or Y."

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll analyses were by intention-to-treat

Selective reporting (reporting bias)High riskNot all relevant outcomes reported

Other biasHigh riskSample size calculation reported, but a protocol was not reported a priori

Supported by Hoffmann-La Roche Ltd (Basel, Switzerland)

Baqui 1995

MethodsRandomised, double-blind, placebo-controlled trial

Data collection: 1993


ParticipantsNumber: 167

Inclusion criteria: infants registered in local demographic surveillance system aged between 6 to 7 weeks

Exclusion criteria: severe malnutrition (defined as weight/age < 60% of the National Center for Health Statistics reference median); clinical vitamin A deficiency (any signs or symptoms)


InterventionsVitamin A (25,000 IU palmitate in peanut oil and transport media, given at 6, 10, and 14 weeks of age; n=86)

Control (soybean oil and the same transport media given at 6, 10, and 14 weeks of age; n=81)


Outcomes
  • Mortality: not recorded
  • Morbidity: not recorded
  • Adverse effects


Follow-up on days 1, 2 ,3, and 8


NotesLocation: Slum population, Dhaka city, Bangladesh (Asia)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"5 different numbers between 1 to 10 were randomly assigned to bottle A and rest 5 were assigned to bottle B. The last digit of the serial number assigned to the infant determined the bottle from which the infant received the supplement, each infant received all doses from bottle with the same code"

Allocation concealment (selection bias)Low risk"The randomisation code was supplied in a sealed envelope to a committee of two paediatricians and a statistician who were not involved in the study. The code was made available after data analysis was completed."

Blinding (performance bias and detection bias)
All outcomes
Low risk"Vitamin A and placebo were supplied by a local pharmaceutical company as 1 ml of fluid in small, dark bottles, which were marked "A" or "B"."

Incomplete outcome data (attrition bias)
All outcomes
High risk9.7% of infants lost to follow up and not accounted for in the analysis

Selective reporting (reporting bias)High riskNot all relevant outcomes reported

Other biasUnclear riskNo a priori research protocol reported

Study funded by the US Agency for International Development (USAID) under grant No. DPE-5986-A-00-1009-00 with the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B)

Benn 2008

MethodsRandomised, double-blind, placebo-controlled trial


ParticipantsNumber: 4345

Inclusion criteria: infants weighing at least 2500 g at birth with no signs of overt illness or malformations; infants were recruited at the time of Bacillus Calmette-Guérin (BCG) vaccination.

Exclusion criteria: birth weight < 2500 g; signs of illness


Interventions
  1. Vitamin A (0.5 mL vegetable oil containing 50,000 IU of vitamin A as retinyl palmitate and 10 IU vitamin E, 1 dose at the time of BCG vaccination; n=2145)
  2. Control (10 IU of vitamin E was given into the mouth of child at the time of BCG vaccination; n=2200)


Other: BCG vaccine was given as co-intervention in both groups


Outcomes
  • Mortality at 12 months of age
  • Cause-specific mortality at 12 months of age
  • Retinol-binding protein (RBP) concentration at 6 weeks and 4 months of age (low RBP defined as serum retinol < 0.70 μ/L)
  • Adverse effects (bulging fontanelle, hospitalizations, irritability, fever, frequent stools, vomiting, mother thinks the child is not well)
  • Morbidity (cough and running nose)


Follow-up every 3 months until 1 year of age


NotesLocation: Guinea-Bissau (Africa)

Setting: 6 urban districts in capital of Guinea-Bissau which is classified as an area of subclinical vitamin A deficiency and high infant mortality; HIV prevalence among women in the study area was 3% to 5%

Since the trial authors did not have information about the gestational age at delivery and the inclusion criteria was infants with birth weight of at least 2500g, we included data as such assuming that none were preterm infants

The adverse effects and morbidity components were reported in Nante 2007. For this outcome, attrition was 4.66%. The intervention group had 1086 participants and the placebo group had 1059 participants. The follow-up was done daily for first 3 days following supplementation and then weekly follow-up during the first month following supplementation. In this report in  Table 1 captioned for adverse effects, the outcomes diarrhoea and vomiting are considered as adverse effects whereas cough and running nose were considered as morbidity as these have not been reported as adverse effects in the literature


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"The mother drew a lot from an envelope prepared by the study supervisor. Each envelope contained 100 lots—50 marked “1” and 50 marked “2”—indicating from which
of two numbered bottles, “1” or “2,” the child should receive the supplement.The lots were folded, making it impossible to tell what was written on them before they were opened."

Allocation concealment (selection bias)Low risk"The code was kept at the pharmacy until 12 months after the last child was included."

Blinding (performance bias and detection bias)
All outcomes
Low risk"Apart from the randomisation number, the bottles looked alike". Small differences in taste and colour of the contents were judged as "unimportant owing to the recipients’ age."

"blinding of mothers and assistants was successful" and "assistants of the registration system and the special team were unaware........vaccination card and follow up forms"

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition was 1.6%; reasons for attrition and distribution in the 2 groups are provided

Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Other biasHigh riskA protocol was provided but post hoc analyses were conducted after assuming that vitamin A might be more beneficial to boys

The study was funded by the EU (ICA4-CT-2002-10053), the Danish Medical Research Council, University of Copenhagen, March of Dimes, and the Ville Heise Foundation

Benn 2010

MethodsRandomised, placebo controlled, 2 x 2 factorial trial


ParticipantsNumber: 1717

Inclusion criteria: low birthweight (< 2.5 kg) children born at the national hospital about to be discharged; medical officer ascertained that they were sufficiently well to be discharged

Exclusion criteria: severe malformations


Interventions
  1. Vitamin A (25,000 IU vitamin A as retinyl palmitate and 10 IU vitamin E per 0.5 mL oil; n=854)
  2. Control (10 IU vitamin E per 0.5 mL oil; n=863)


Other: all infants were also assigned to early Bacillus Calmette-Guérin (BCG) vaccine or the usual late BCG vaccine


Outcomes
  • Infant mortality and cause-specific infant mortality at 12 months
  • Morbidity
  • Adverse effects


Follow-up at home within the first 3 days and at 2, 6, and 12 months of age


NotesLocation: Guinea Bissau, Africa

Detailed data on RR and 95% CI for cause-specific mortality received through a personal communication (depicted only as a graph in report). Authors intend to report the morbidity and adverse effects data separately and do not wish to share the unpublished information for this review

The morbidity data on diarrhoea was reported in Diness 2010 for a sub-sample of 287 infants during annual rotavirus epidemic from Januray through March 2005.

No evidence of an interaction between BCG and vitamin A supplementation in neonates (P value = 0.73)

Vitamin A was administered within the first 48 h of life to 878 (51%) of the 1717 children


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Low birth weight infants were randomly allocated in a two by two factorial design to early BCG vaccination or the usual delayed BCG vaccination and to 25,000 IU vitamin A or placebo....... ... the mother drew an envelope from a bag. Each bag was prepared by the study
supervisor and contained 48 envelopes; each envelope contained a lot name. Within each bag were 12 envelopes with lots marked "BCG 6", 12 marked "BCG 7", and 12 marked "no BCG 7". The numbers "6" and "7" indicated from which of the two numbered bottles, "6" or "7", the child should receive treatment (that is, either 25,000 IU vitamin A or placebo). Twins were allocated the same treatment to prevent confusion regarding who had been vaccinated and supplemented".

Allocation concealment (selection bias)Low risk"The envelopes were closed and non-transparent, making it impossible to identify the allocation before the envelopes were opened"

Blinding (performance bias and detection bias)
All outcomes
Low risk"Apart from the bottle number, the vitamin A and placebo bottles looked alike. Small differences in the taste and colour of the contents were judged as unimportant owing to the recipients’ age. The assistant and the nurse who were responsible for the randomisation procedure had no idea which bottles contained vitamin A or which had placebo when asked. The follow-up assistants were unaware of the allocated treatment, "6" or "7", because they were not present during enrolment and the information was not transferred to the children's vaccination card or follow up forms."

Incomplete outcome data (attrition bias)
All outcomes
Low riskExclusions and attrition were 18.72%; reasons and distribution in the 2 groups are provided

Selective reporting (reporting bias)Low riskAll expected outcomes, as per protocol are reported or are under preparation (personal communication from the author)

Other biasHigh riskA protocol was provided but post hoc analyses were conducted after assuming that vitamin A might be more beneficial to boys

The study was funded by the EU (ICA4-CT-2002-10053), the Danish Medical Research Council, University of Copenhagen, March of Dimes, and the Ville Heise Foundation

Bhaskaram 1998

MethodsRandomised, double-blind, placebo-controlled trial


ParticipantsNumber: 102

Inclusion criteria: recently delivered mothers with neonates born at the end of a healthy term pregnancy

Exclusion criteria: complicated full term deliveries


Interventions
  1. Vitamin A (mother received 200,000 IU vitamin A as retinyl palmitate within 24 h after delivery; n=50)
  2. Control (mother received placebo; n=52)


Other: all infants given oral polio vaccine within 72 h after birth; all infants breast fed, followed up at 6 months


Outcomes
  • Infant serum retinol concentration
  • Breast milk retinol concentration
  • Corneal lesions


Follow-up for first 5 days of life


NotesLocation: Hyderabad, India (Asia)

100% followed up until 6 weeks, 87% followed up until 3 months, and 46% followed up until 6 months


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"The mothers were randomly allocated into two groups"

Allocation concealment (selection bias)Unclear riskInformation not provided

Blinding (performance bias and detection bias)
All outcomes
High riskInformation not provided

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInformation not provided

Selective reporting (reporting bias)High riskMost clinically relevant outcomes are not reported

Other biasHigh riskStudy protocol not provided, small sample size

Source of funding not provided

de Francisco 1993

MethodsRandomised, double-blind, placebo-controlled trial


ParticipantsNumber: 191

Inclusion criteria: neonates

Exclusion criteria: none


Interventions
  1. Vitamin A (50,000 IU vitamin A (palmitate in peanut oil and transport media) at 1.5, 2.5, and 3.5 months of age)
  2. Control group (soybean oil and the same transport media as above at 1.5, 2.5, and 3.5 months of age)


Infants were examined on days 1, 2, 3, and 8 after supplementation.


Outcomes
  • Mortality: not recorded
  • Morbidity: not recorded
  • Adverse effects


Follow-up on days 1, 2, 3, and 8


NotesLocation: rural Bangladesh (Asia)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"A computerised randomisation procedure had been used to assign a bottle code to each infant."

Allocation concealment (selection bias)High risk"The first 42 infants (22%) were given the first dose and then monitored for 24 h. These infants were randomised to receive either an A or B bottle according to their order of arrival at the hospital."

Blinding (performance bias and detection bias)
All outcomes
Low risk"Vitamin A (50,000 IU palmitate in peanut oil and transport media) and a placebo (soybean oil and the same transport media) were supplied as 1 mL liquid in dark small, bottles, which were marked A or B." Outcome assessors were unaware of the bottle code.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk“Losses of follow up were minimal and equally distributed in the vitamin A and placebo groups”

Selective reporting (reporting bias)Unclear riskNot all clinically relevant outcomes reported

Other biasUnclear riskNo a priori research protocol reported

Study funded by the US Agency for International Development (USAID) under grant No. DPE-5986-A-00-1009-00 with the International Centre for Diarrhoea1 Disease Research, Bangladesh (ICDDR,B)

Humphrey 1996

MethodsRandomised, placebo-controlled trial

Data collection: 18 June 1992 to 3 June 1993


ParticipantsNumber: 2067

Inclusion criteria: all neonates within 24 h of birth

Exclusion criteria: birth weight < 1500 g; severe respiratory distress syndrome; major congenital anomalies; paralysis; sepsis; hypoglycaemia; hypocalcaemia; and hypoxia


Interventions
  1. Vitamin A (1 oral dose of 52 µmol vitamin A (as retinyl palmitate) plus 23 µmoL vitamin E on day 1 of life; n=1034)
  2. Control (<0.10 µmoL vitamin A + 23 µmoL vitamin E; n=1033)


Outcomes
  • Mortality at 4, 6, and 12 months in 1 subgroup (n=470) and at 12 months in other subgroup (n=1597); follow up in per 1000 child year


  • Morbidity at 4, 6, and 12 months in 1 subgroup (n=470)


  • Adverse effects (bulging fontanelle, vomiting, fever, loose stool, irritability, intracranial haemorrhage, resistive index)


Adverse effects reported in Agoestina 1994.


NotesLocation: Bandung, Indonesia (Asia)

The adverse effects are recorded in Agoestina 1994 by follow-up until 48 h of life; attrition for this outcome was 0.5%

Treatment groups were comparable at baseline


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"by simple randomisation, blocked within the birth weight strata"

Allocation concealment (selection bias)Low risk"The randomisation scheme and coded supplement packets were prepared by a team in Baltimore, none of whom was involved in recruitment or follow-up of infants in Indonesia."

Blinding (performance bias and detection bias)
All outcomes
Low riskSupplements were individually coded, odourless, and identical in appearance

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition was 11% and reasons for it are provided. Missing outcome data for mortality unlikely to be affected as there were no significant differences in baseline factors between the treatment groups among those who were lost to follow up

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement

Adverse events were reported in a separate publication (Agoestina 1994)

Other biasHigh riskAgoestina 1994 mentioned a protocol, but no further details were provided

Supported by a grant from Johns Hopkins University and assistance from Hoffmann-LaRoche industry (Basel, Switzerland), a manufacturer of Vitamin A.

Several unplanned subgroup analyses reported including gender, birth weight, ponderal index). In Discussion, it is stated "Although the study was not designed to investigate subgroups......".

Unclear as to how the mortality rates for all subjects were derived between 1 and 4 months of age when the majority were to be followed-up only at one year of age.

Katz 2000

MethodsRandomised, cluster, placebo-controlled trial

Data collection: July 1994 to October 1997


ParticipantsNumber: 10,785

Inclusion criteria: women of child-bearing age

Exclusion criteria: families moving into the study area


Interventions
  1. Vitamin A (23,300 IU vitamin A weekly to the women of childbearing age until 24 weeks postpartum; n=5583 infants born alive)
  2. Control group (peanut oil to women; n=5202 infants born alive)


All capsules contained 5 mg dl-alpha-tocopherol (Roche, Basel, Switzerland)


Outcomes
  • Mortality
  • Morbidity: not recorded
  • Adverse effects: not recorded


Follow-up at 3 and 6 months postpartum


NotesLocation: Sarlahi district, Nepal (Asia)

Setting: 270 wards in 30 subdistricts (9 wards each) with total population of around 176,000

Generalized-estimating-equations logistic regression model with exchangeable correlation structure in which survival as modelled as a function of the treatment assignment, adjusted for the correlation within the units of randomisation (the ward) and stratification (by village development community)

Miscarriages and stillbirths included in mortality data, maternal deaths not included


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"30 subdistrict areas (village development communities), each composed of 9 wards, were enrolled in the study. Within each subdistrict, each of the 9 wards were randomly assigned to receive 1 of the 3 treatments, resulting in 90 wards assigned to
each treatment group."

Allocation concealment (selection bias)Low risk"All capsules ..... were shipped to Nepal in opaque plastic bottles labelled with 1 of 3 masked, numeric codes. The bottles were relabeled with individual ward numbers that had been assigned to the specific codes."

Blinding (performance bias and detection bias)
All outcomes
Low risk"gelatin capsules of identical appearance"; "This committee and the data analysts were unmasked to the treatment codes, but the codes were made available to study investigators only at the end of the trial"

Comment: participants and outcome assessors were blinded; people responsible for analysing data were not blinded

Incomplete outcome data (attrition bias)
All outcomes
Low risk8.1% of attrition, however intention-to-treat analysis was conducted

Selective reporting (reporting bias)High riskNot all relevant outcomes for infants were provided

Other biasUnclear riskSupported by the Johns Hopkins University, Baltimore; the Office of Health and Nutrition, USAgency for International Development (USAID); the Task Force Sight and Life, Roche, Basel, Switzerland; and the Sushil Kedia Foundation, Hariaun, Sarlahi, Nepal, under cooperative agreement DAN 0045-A-005094-00

Unclear if study protocol was published a priori

Kirkwood 2010

MethodsRandomised, cluster, placebo-controlled trial

Data collection: December 2000 to October 2008


ParticipantsNumber: 73,752

Inclusion criteria: women of reproductive age (15 to 45 years) who gave informed consent and who planned to remain in the area for at least 3 months

Exclusion criteria: families moving into the study area


Interventions
  1. Vitamin A (25,000 IU vitamin A weekly; n=37,042)
  2. Control (placebo; n=36,710)


Outcomes
  • Mortality
  • Morbidity: not recorded
  • Adverse effects: not recorded


Follow-up monthly


NotesLocation: Ghana (Africa)

Setting: 1086 small geographical clusters of compounds with fieldwork areas consisting of 4 contiguous clusters

Intention-to-treat analyses to compare treatment groups with random-effects regression to account for the cluster-randomised design was used

Trial registration: ClinicalTrials.gov, number NCT00211341.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomisation was blocked and based on an independent, computer-generated list with two clusters in each fieldwork area allocated to vitamin A supplementation and two to placebo."

Allocation concealment (selection bias)Low risk"A computer-generated randomisation list was prepared for the capsule manufacturers by an independent statistician on the data monitoring and ethics committee. The capsules were packaged in labelled jars, for each cluster for each week of the trial. Trial personnel had no access to the randomisation list or to any information that would allow them to deduce or change the cluster allocation."

Blinding (performance bias and detection bias)
All outcomes
Low risk"Placebo capsules were identical in taste and appearance to the vitamin A capsules."

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants enrolled were accounted for in the analysis

Selective reporting (reporting bias)Low riskAll planned outcomes on the published protocol were subsequently reported in the main publication

Other biasLow riskA protocol was published a priori with details of sample size calculation and outcomes

Funded by the UK Department for International Development, and USAID, and Roche (Basel, Switzerland) donated vitamin A palmitate

Klemm 2008

MethodsDouble-masked, cluster-randomised, placebo-controlled trial


ParticipantsNumber: 5349 mothers, 10585 infants (see details under Interventions below)

Inclusion criteria: infants born to consenting mothers participating in the parent trial

Exclusion criteria: infants of consenting mothers who had died before they could be supplemented by staff, those who were born outside the study area, and infants who were not supplemented after repeated staff visits during the first 30 days following birth


Interventions
  1. (Group=Aa) Maternal vitamin A (vitamin A 23,300 IU weekly during pregnancy until 12 weeks postpartum) and newborn vitamin A (vitamin A 50,000 IU after birth) (n=2531)
  2. (Group=Ap) Maternal vitamin A (vitamin A 23,300 IU weekly during pregnancy until 12 weeks postpartum) and newborn placebo (placebo after birth) (n=2717)
  3. (Group=Ba) Maternal beta carotene (beta carotene weekly during pregnancy until 12 weeks postpartum) and newborn vitamin A (vitamin A 50,000 IU after birth) (n=2700)
  4. (Group=Bp) Maternal beta carotene (beta carotene weekly during pregnancy until 12 weeks postpartum) and newborn placebo (placebo after birth) (n=2635)
  5. (Group=Pa) Maternal placebo (placebo weekly during pregnancy until 12 weeks postpartum) and newborn vitamin A (vitamin A 50,000 IU after birth) (n=2722)
  6. (Group=Pp) Maternal placebo (placebo weekly during pregnancy until 12 weeks postpartum) and newborn placebo (after birth) (n=2632)


The numbers refer to infants whose vital status was known at 24 weeks of life; only 3 of the 7956 infants were lost to follow-up in the vitamin A supplemented infants and 8 of the 7992 infants were lost to follow up in the placebo supplemented infants. The number randomised in each of the six groups above cannot be depicted as loss to follow-up stratified by groups is not reported

Maternal supplementation

Mortality outcome:

Intervention - (Group=Ap) Maternal vitamin A (vitamin A 23,300 IU weekly during pregnancy until 12 weeks postpartum) and newborn placebo (placebo after birth) (n=2717)

Control - (Group=Pp) Maternal placebo (placebo weekly during pregnancy until 12 weeks postpartum) and newborn placebo (after birth) (n=2632)

Infant supplementation

Mortality outcome:

Intervention - (Groups Aa, Ba and Pa) Newborn vitamin A (vitamin A 50,000 IU after birth) irrespective of maternal supplementation status (n=7953)

Control - (Group=Pp) Maternal placebo (placebo weekly during pregnancy until 12 weeks postpartum) and newborn placebo (after birth) (n=2632)

Adverse effects:

Intervention - (Groups Aa, Ba and Pa) Newborn vitamin A (vitamin A 50,000 IU after birth) irrespective of maternal supplementation status (n=7953)

Control - (Groups Ap, Bp and Pp) Newborn placebo (placebo after birth) irrespective of maternal supplementation status (n=7984). The control group could not be the same as for mortality outcome because the adverse effects were not reported for each subgroup of newborn placebo intake


OutcomesMaternal supplementation:

  • Mortality
  • Morbidity: not recorded
  • Adverse effects: not recorded


Infant supplementation:

  • Mortality
  • Morbidity: not recorded
  • Adverse effects


Follow-up weekly at home for the first 12 weeks of life by field staff and then again at 24 weeks of age


NotesLocation: districts of Gaibandha and Rangpur, Bangladesh (Asia)

Setting: community-based

The trial was nested into and balanced across the treatment arms of an ongoing placebo-controlled, weekly, low-dose vitamin A or beta carotene supplementation trial among pregnant women, underway since August 2001 to evaluate effects on pregnancy-related mortality; risk ratio and 95% confidence intervals adjusted for design effect by generalised estimating equation logistic regression model with log link and exchangeable correlation to adjust for the design effect

Randomisation of sectors was done in a manner to produce 2 infant supplementation groups that were balanced across the maternal supplementation trial arms

An expected 6 month infant mortality rate 64 deaths per 1000 live birth

Approximately 84% infants supplemented within the first 48 h after birth

Treatment groups were comparable at baseline

Analysis was adjusted for cluster design


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"The study area was divided into 596 smaller community groups of comparable size, each with a median number of households of 228 (interquartile range [IQR]: 200–263), called “sectors,” which served as units of randomisation. Sectors were listed in geographically contiguous order and were randomised in blocks of 4 within each of 3 previously randomised maternal supplementation trial treatment arms (i.e., vitamin A,-carotene, and placebo, each 200 sectors) for newborns to receive 50 000 IU of vitamin A or placebo in oil as soon as possible after birth."

However, in the description, the method used to generate the randomisation sequence is not described in sufficient detail to permit judgement.

Allocation concealment (selection bias)Unclear risk"administered a sector-coded supplement containing either 50 000 IU of vitamin A or placebo"

Blinding (performance bias and detection bias)
All outcomes
Low risk"The supplements for both groups were opaque gelatinous capsules identical in shape, size, and colour containing edible oil."

Incomplete outcome data (attrition bias)
All outcomes
Low riskExclusions and attrition was 7%. Reasons for attrition and exclusions; and numbers in each intervention group are reported. Attrition and reasons for attrition were balanced across the treatment groups.

Selective reporting (reporting bias)Low riskComment: results of all outcomes mentioned in the methods section of the published paper and trial registration document were presented in the paper

Other biasHigh riskAn independent data safety and monitoring board (DSMB) halted the study "for reasons of efficacy of the intervention in reducing infant mortality"

Results adjusted by cluster effect. Source of funding: Johns Hopkins University (GHS-A-00-03-00019-00), Bill and Melinda Gates Foundation

Malaba 2005

MethodsRandomised, placebo-controlled, 2 x 2 factorial design trial

Data collection: 25 November 1997 to 29 January 2000


ParticipantsNumber: 4639 women, 6908 infants

Inclusion criteria: newly delivered mother and her infant

Exclusion criteria: birth weight < 1500 g; severe congenital anomalies; life-threatening illness; families intending to move out of study area


Interventions(Aa group) Maternal vitamin A, infant vitamin A (mother received 400,000 IU vitamin A, infant received 50,000 IU vitamin A within 96 hours of delivery; n=2319)

(Pa group) Maternal placebo, infant vitamin A (mother received placebo, infant received 50,000 IU vitamin A within 96 hours of delivery; n=2280)

(Ap group) Maternal vitamin A, infant placebo (mother received 400,000 IU vitamin A, infant received placebo within 96 hours of delivery; n=2300)

(Pp group) Maternal placebo, infant placebo (mother received placebo, infant received placebo within 96 hours of delivery; n=2309)

  • Maternal supplementation vitamin A group (vitamin A 400,000 IU, 1 dose, within 96 h of delivery; n=2300)
  • Maternal comparison group (placebo; n=2309)
  • Infant supplementation vitamin A group (50,000 IU vitamin A, 1 dose within 96 h of birth; n=4599)
  • Infant comparison group (placebo; n=2309)


Outcomes
  • Mortality
  • Morbidity: not recorded
  • Adverse effects


Follow up at 6 weeks, 3 months, and then 3 monthly until 1 year

For maternal supplementation review only mortality


NotesLocation: Harare, Zimbabwe (Africa)

HIV-negative mothers (Zimbabwe is categorized by the World Health Organization as a high-risk area for vitamin A deficiency. HIV is endemic in Zimbabwe nearly 25% are HIV-positive.)

Infants were randomly assigned within 96 h of delivery to 1 of the 4 treatment groups: mothers and infants received vitamin A; mothers received vitamin A and infants received placebo; mothers received placebo and infants received vitamin A; and both mothers and infants received placebo. The vitamin A dose in the mothers was 400,000 IU and in the infants was 50,000 IU

The adverse effects were documented in Iliff 1999 with follow-up for 2 days after supplementation. The attrition was 6%. In the intervention vitamin A group (n=398), infant received 50,000 IU vitamin A within 24 h of life and the mother received 400,000 IU vitamin A within 24 h following delivery. In the control group (n=390) placebo was given to the infant and mother. The HIV status of mothers is not stated

The trial included multiple intervention groups employing a factorial design. Data were abstracted and pooled for comparison of vitamin A-supplemented infants (irrespective of maternal vitamin A supplementation status) with controls receiving placebo (mothers received no intervention or placebo). If comparison with a "pure" placebo group (infants receiving placebo with mothers receiving no intervention or placebo) was not possible from the available data, comparisons were performed with infants receiving placebo whose mothers had received supplementation analogous to the infant intervention group(s).

Strictly speaking, a subsequent report (Humphrey 2006) from this trial presenting data on HIV positive women (an exclusion criteria for this review) should have been classified along with this study. However, to prevent confusion in an already long review with different comparisons, we have preferred to show the Humphrey 2006 report as an excluded study under the various headings in this review. The description in this table pertains only to the HIV negative mothers (one of the inclusion criteria for this review).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"A separate team at Johns Hopkins University prepared the study capsule packets. Study identification numbers were randomly allocated to the treatment groups by computer in blocks of 12. The numbers were printed on adhesive labels and affixed to amber-coloured zip-lock plastic bags that were packed with the assigned capsules. Capsule packets were prepared separately for each of the 4 treatment groups and were then merged into numeric order before shipping to Zimbabwe, where a series of packets were distributed to each recruitment site. As each mother- infant pair was recruited, the capsules in the next sequential bag were administered, and the associated study number was assigned to the pair.

Allocation concealment (selection bias)Low risk"Lists linking the study number to the treatment were kept in sealed envelopes and encrypted computer files."

Blinding (performance bias and detection bias)
All outcomes
Low risk"Treatment and placebo capsules appeared identical"

"separate team at Johns Hopkins University prepared the study capsule packets" and "neither participants nor nurses who administered the capsules or assessed outcomes were aware of treatment group assignment"

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk"Only infants of mothers who remained HIV-negative to 12 mo postpartum were included in the current analysis."

Attrition was 11.5%

It is unclear, in the absence of a trial protocol, as to why the entire trial data on HIV negative and HIV positive mothers was not reported as a single publication.

Selective reporting (reporting bias)Unclear riskIt is unclear, in the absence of a trial protocol, whether all the pre-specified outcomes were reported.

Adverse effects reported only in a subset (irrespective of HIV status) early in the course of trial (Illif 1999).

Iliff 1999 states "The main hypotheses of this study (the ZVITAMBO Project) are that vitamin A supplementation of mothers and/or babies will reduce (i) infant mortality, (ii) vertical transmission of HIV through breast milk and (iii) HIV infection, during the first year postpartum, of mothers seronegative at delivery." A later report (Humphrey 2006) presents HIV infection data but this was not done for HIV negative women in Malaba 2005.

Other biasLow risk"The ZVITAMBO Project was primarily supported by the Canadian International Development Agency (R/C Project 690/M3688), the US Agency for International Development (cooperative agreement no. HRN-A-00-97-00015-00 between Johns Hopkins University and the Office of Health and Nutrition of the USAID), and a grant from the Bill and Melinda Gates Foundation (Seattle); additional support was provided by the Rockefeller Foundation (New York) and BASF (Ludwigshafen, Germany)."

Newton 2005

MethodsRandomised, placebo-controlled, 2 x 2 factorial design trial

Data collection: November 1996 to January 1999


ParticipantsNumber: 470 women, 816 infants

Inclusion criteria: newly delivered mother and her infant

Exclusion criteria: families intending to move out of the study area


Interventions(Aa group) Maternal vitamin A, infant vitamin A (mother received 200,000 IU vitamin A within 24 hours of delivery; infant received 25,000 IU vitamin A at 6,10 and 14 weeks age with DPT and OPV vaccines; n=274)

(Pa group) Maternal placebo, infant vitamin A (mother received placebo within 24 hours of delivery; infant received 25,000 IU vitamin A at 6,10 and 14 weeks age with DPT and OPV vaccines; n=265)

(Ap group) Maternal vitamin A, infant placebo (mother received 200,000 IU vitamin A within 24 hours of delivery; infant received placebo at 6,10 and 14 weeks age with DPT and OPV vaccines; n=269

(Pp group) Maternal placebo, infant placebo (mother received 200,000 IU vitamin A within 24 hours of delivery; infant received 25,000 IU vitamin A at 6,10 and 14 weeks age with DPT and OPV vaccines; n=277)

  • Maternal supplementation vitamin A group (vitamin A 2,00,000 IU, 1 dose, 3 to 4 weeks postpartum; n=269)
  • Maternal comparison group (placebo; n=277)
  • Infant supplementation vitamin A group (vitamin A 25,000 IU at 6, 10, and 14 weeks; n=539)
  • Infant comparison group (placebo; n=277)


OutcomesMaternal supplementation:

  • Mortality
  • Morbidity: not recorded
  • Adverse effects: not recorded


Infant supplementation:

  • Mortality
  • Morbidity: not recorded
  • Adverse effects


Follow-up at 6 months


NotesLocation: Kintampo, Ghana (Africa)

Breast feeding rate was almost 100% and 51% of children aged < 5 years in the area had serum retinol concentrations less than 0.70 micromol/L

3 vitamin A supplementation strategies were investigated: (1) supplementation of breast-feeding mothers with 60 mg retinol equivalent (RE) vitamin A within 4 wk of delivery; (2) Expanded Program on Immunization (EPI)-linked supplementation of infants with 7.5 mg RE vitamin A at 6, 10, and 14 wk; and (3) combined mother and child supplementations. A fourth group in which mother and child were given placebos served as controls


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Mothers and infants were allocated to 1 of 4 treatment groups, using a blocked randomisation scheme."

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low risk"The test and placebo capsules were identical in size colour and shape."

Incomplete outcome data (attrition bias)
All outcomes
High riskOnly infants of mothers for which blood sample was obtained in the end of the study were included in the analysis; attrition was 34.6%

Selective reporting (reporting bias)High riskNot all clinically relevant outcomes were reported

Other biasUnclear riskEnrolment of participants was extended to higher than planned lost to follow up; sample size calculation provided, but unclear whether a protocol was published a priori

Supported by a grant from the Wellcome Trust

Rahmathullah 2003

MethodsRandomised, placebo-controlled, community-based trial

Data collection: June 1998 and March 2001


ParticipantsNumber: Pregnant mothers 13294. Of these, only 11,619 newborns received the intervention in the village (excluding migrations, stillbirths, early infant deaths and refusals). These newborns were enrolled and followed up.

Inclusion criteria: infants born to pregnant females residing in the study area

Exclusion criteria: miscarriages/stillbirths; delivery 20 km outside the study area; or infants who died before the study team reached


Interventions
  1. Vitamin A (vitamin A 24,000 IU on days 1 and 2 of life; n=5786)
  2. Control (placebo; n=5833)


Outcomes
  • Mortality and cause specific mortality
  • Morbidity
  • Adverse effects


Follow-up fortnightly for 6 months


NotesLocation: 2 rural districts of Tamil Nadu, India (Asia)

Miscarriages and still births not included in mortality data

No bulging fontanelle (adverse effect) in either group

Tielsch 2007 had recorded case fatality following common morbidities


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Randomisation was at the individual level, stratified by geographical area in blocks of four."

Allocation concealment (selection bias)Unclear risk"Investigators, study staff, and mothers were masked to the assigned treatment. Treatment codes were kept in a sealed envelope in a locked filing cabinet in Baltimore."

Blinding (performance bias and detection bias)
All outcomes
Low risk"treatment doses were in an edible oil solution packaged in identical gelatin capsules" and "investigators, study staff, and mothers were masked to the assigned treatment"

Incomplete outcome data (attrition bias)
All outcomes
Low riskExclusions and attrition was 18.9%; reasons for attrition and exclusions, and numbers in each intervention group are reported

Selective reporting (reporting bias)Low riskAll planned outcomes reported on the main study

Other biasUnclear riskSupported by a grant from Johns Hopkins University and the Bill and Melinda Gates Foundation

No information about the protocol provided

Semba 2001

MethodsRandomised, double-blind, placebo-controlled clinical trial


ParticipantsNumber: 467

Inclusion criteria: infants < 6 weeks of age

Exclusion criteria: none


Interventions
  1. Vitamin A group 1 (25,000 IU vitamin A at 6, 10, and 14 weeks of life; n=156)
  2. Vitamin A group 2 (50,000 IU vitamin A at 6, 10, and 14 weeks of life; n=155)
  3. Control group (placebo; n=156)


Co-intervention with oral polio vaccine (OPV) and diphtheria, pertussis (whooping cough), and tetanus (DPT) vaccine at each visit


Outcomes
  • Mortality: not recorded
  • Morbidity
  • Adverse effects


Follow-up within 24 h of first visit at 6 weeks in 293 infants; follow-up at 10 and 14 weeks and at 9, 10, and 15 months


NotesLocation: Indonesia (Asia)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Randomly allocated by number table in blocks of ten"

Allocation concealment (selection bias)Unclear risk"Infants received identification numbers as they were enrolled into the study, and each
identification number had an envelope with an identical capsule containing either vitamin A or placebo. At the time of treatment allocation, both paediatrician and study nurse were required to verify the identification number of the infant."

Blinding (performance bias and detection bias)
All outcomes
Low risk"Identical capsules containing either vitamin A or placebo"

Incomplete outcome data (attrition bias)
All outcomes
High riskExclusions and attrition was 8.4%; reasons for attrition and exclusions not reported

Selective reporting (reporting bias)High riskNot all clinically relevant outcomes were reported

Other biasUnclear riskSupported by grants from the National Institutes of Health (AI35143, HD30042), the Thrasher Research Fund, the WHO Expanded Programme on Immunization, and the Office of Nutrition, Bureau for Science and Technology, US Agency for International Development (Cooperative Agreement DAN-0045-A-5094-00).”

Protocol mentioned but no details given

Stabell 1995

MethodsDouble-blind, placebo-controlled trial


ParticipantsNumber: 68

Inclusion criteria: infants 6 month of age

Exclusion criteria: none


Interventions
  1. Vitamin A (vitamin A 100,000 IU 1 dose; n=32)
  2. Control (placebo; n=36)


Co-administration of vitamin A and measles vaccine


Outcomes
  1. Mortality: not recorded
  2. Morbidity: not recorded
  3. Adverse effects


Daily follow-up for first 2 days following supplementation


NotesLocation: Guinea-Bissau (Africa)

No episodes of bulging fontanelle recorded in either group

Compliance monitoring not recorded

Attrition = 10.3%

Intention-to-treat data unknown


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDetails not provided

Allocation concealment (selection bias)Unclear riskDetails not provided

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble-blind; details not provided

Incomplete outcome data (attrition bias)
All outcomes
High riskReasons for attrition and exclusions not reported

Selective reporting (reporting bias)High riskNot all clinically relevant outcomes reported

Other biasUnclear riskSource of funding not mentioned

No mention of any research protocol published a priori

Venkatarao 1996

MethodsRandomised, double-blind, placebo-controlled trial


ParticipantsInclusion criteria: newly delivered mother and her infant

Exclusion criteria: none


Interventions
  1. Maternal vitamin A, infant vitamin A (vitamin A 300,000 IU to the mother, 1 dose, 7 to 14 days postpartum; vitamin A 200,000 IU to the infant, 1 dose, at 6 months of age; n=311)
  2. Maternal vitamin A, infant placebo (vitamin A 300,000 IU to the mother, 1 dose, 7 to 14 days postpartum; placebo to the infant, 1 dose, at 6 months of age; n=301)
  3. Maternal placebo, infant placebo (placebo to the mother, 1 dose, 7 to14 days postpartum; placebo to the infant, 1 dose, at 6 months of age; n=297


OutcomesMaternal supplementation:

  • Mortality
  • Morbidity
  • Adverse effects follow-up at least fortnightly for 6 months


Infant supplementation:

  • Mortality: not recorded
  • Morbidity
  • Adverse effects follow-up at least fortnightly for 6 months


NotesLocation: India (Asia)

For the maternal supplementation comparison, the data on mortality outcome pertains to Ap and Pp groups only as the mortality after 6 months of age cannot be ascertained according to the different treatment arms. For the infant supplementation comparison, the data on mortality after initiating vitamin A supplementation (mortality after 6 months) cannot be extracted, and hence this outcome could not be included. For recalculating for the morbidity analyses, for Ap + Aa groups versus Pp for 0 to 6 months, Ap versus Pp for 6 to 12 months, and Aa versus Pp for 6 to 12 months, the total number of person years was taken from the number stated by the author (denominator) in  Table 2 (page 283)

No adverse effects were observed in any of the 3 groups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"...randomly allocated"; no further details given

Allocation concealment (selection bias)Unclear risk"the Medical Officer...administered the appropriate capsules to the mother from the sealed envelope supplied by the Statistical Section at the Camp Office"

Blinding (performance bias and detection bias)
All outcomes
Low risk"...capsules that were similar in colour and consistency"

Incomplete outcome data (attrition bias)
All outcomes
High riskExclusions and attrition were 23%; intention-to-treat analyses not performed

Selective reporting (reporting bias)Low riskAll key expected outcomes reported

Other biasUnclear riskSource of funding not provided

No mention of research protocol

West 1995

MethodsCluster-randomised, double-masked, placebo-controlled

Data collection: September 1989 to December 1991


ParticipantsNumber:11918

Inclusion criteria: infants < 6 months

Exclusion criteria: none


Interventions
  1. Vitamin A (1 oral dose 50,000 IU vitamin A (3 drops of oil) for neonates, 100,000 IU (6 drops of oil) for 1 to 5 months of age; n= 6086)
  2. Control group (1 oral dose of placebo, 75 RE (250 IU) for neonates or 150 RE (500 IU) for 1 to 5 months of age; n= 5832)


All supplements also contained ˜3.3 IU vitamin E per drop, added as an antioxidant


Outcomes
  1. Mortality
  2. Morbidity: not recorded
  3. Adverse effects


Follow-up 4 monthly until 6 months of age


NotesLocation: Sarlahi, Nepal (Asia)

Setting: community trial (261 wards in 29 village development areas (33,000 households))

Variance inflated by 22% for cluster adjustment

1621 infants enrolled before 1 month of age (830 in intervention group and 791 in control group)

Adverse effects recorded in West 1992 by follow-up at 24 h after supplementation then daily until bulging fontanel subsided. Intervention group (n=1461) and placebo (n=1379). No irritability (adverse effect) recorded in either group


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Two hundred sixty-one wards in 29 contiguous village development areas (VDAs) in the District of Sanlahi were mapped and 33,000 households were numbered. After a random start, wards were systematically assigned, blocked on VDAs, for infants to receive an oral dose of vitamin A."

However, in the description, the method used to generate the randomisation sequence is not described in sufficient detail to permit judgement.

Allocation concealment (selection bias)Unclear riskThe method used for allocation concealment is not described in sufficient detail to permit judgement.

Blinding (performance bias and detection bias)
All outcomes
Low risk"The supplements were given as single-dose gelatin capsules of identical taste and appearance." "Capsule codes were broken" after the study was over.

Incomplete outcome data (attrition bias)
All outcomes
Low risk“All analyses were performed on an intention-to-treat basis, that is, by randomised treatment group irrespective of individual compliance to the dosing regimen.”

Selective reporting (reporting bias)Unclear riskIn the absence of trial protocol it is unclear if all pre-specified outcomes were reported

Other biasUnclear riskSupported by a grant from Johns Hopkins University and assistance from Hoffmann-LaRoche industry (Basel, Switzerland)

A protocol is described but no details are provided

WHO 1998

MethodsRandomised, double-blind, multi-centre trial


ParticipantsNumber: 9424

Inclusion criteria: pregnant women and those with newborn babies

Exclusion criteria: families intending to leave study site


InterventionsVitamin A (mothers 21 to 42 days postpartum in Ghana and 18 to 28 days postpartum in India and Peru received 200,000 IU vitamin A at enrolment; infants received 25,000 IU at 6, 10, and 14 weeks in India and Ghana and at 2, 3, and 4 months in Peru; n=4716)

Control (placebo to both mothers and infants at the same time as the vitamin A group; n=4708)

At 9 months, with measles immunisation, infants in the vitamin A group were given 25,000 IU vitamin A, whereas those in control group received 100,000 IU vitamin A. Vitamin A was provided as retinol palmitate with minute amounts of vitamin E; placebo was soy bean oil.


Outcomes
  1. Mortality
  2. Morbidity
  3. Adverse effects


Follow-up: 4 weekly until 9 months of age


NotesLocation: Ghana, India, Peru

Compliance monitoring: direct

Attrition: 2.6%

Intention-to-treat data: yes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Identification numbers were generated by computer at the data management centre at John Hopkins University in Baltimore, and assigned as random permuted blocks of size eight."

Allocation concealment (selection bias)Low risk"Three sealed copies of study codes were prepared and kept at WHO in Geneva, with the ethics committee of the All India Institute of Medical Sciences in New Delhi, and at the data management centre in Baltimore. Access was limited to one data manager, who had no direct involvement in the data analysis, and who prepared information requested by the treatment effects monitoring committee."

Blinding (performance bias and detection bias)
All outcomes
Low risk"The supplements and placebo, in identical opaque gelatin capsules, were packaged in individually coded blister packs in Baltimore."

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll analyses were intention to treat; reasons and distributions in the two groups are provided

Selective reporting (reporting bias)Low riskAll clinically relevant outcomes reported

Other biasLow riskSample size calculation reported; protocol and study SOP available in the World Health Organization, Geneva on request

Supported by Child Health and Development Division, WHO (Geneva), Indian Council of Medical Research and John Hopkins Family Health and Child Survival Co-operative agreement with USAID

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Basu 2003Not placebo controlled

Benn 2000Relevant outcomes not reported

Bhaskaram 1997Relevant outcomes not reported

Coles 2001Relevant outcomes not reported

Coutsoudis 1999Trial conducted on HIV positive women

Dimenstein 2007Relevant outcomes not reported

Fawzi 2002Trial conducted on HIV positive women

Humphrey 2006Trial reports data only on HIV positive women

Kumwenda 2002Trial conducted on HIV positive women

Mahalanabis 1997Trial done on infants treated for diarrhoea (before discharge from hospital)

Miller 2006Trial predominantly (81.1%) on infants born to HIV positive mothers

Newton 2007Relevant outcomes not reported

Rahman 1995Trial done on infants treated for diarrhoea (before discharge from hospital)

Rahman 1996Relevant outcomes not reported

Rahman 1997Relevant outcomes not reported

Rahman 1998Relevant outcomes not reported

Rahman 1999Relevant outcomes not reported

Rao 1976Relevant outcomes not reported

Rice 1999Relevant outcomes not reported

Rice 2000Relevant outcomes not reported

Roy 1997Not placebo controlled

Schmidt 2002Maternal supplementation only in the antenatal period

Stoltzfus 1993Relevant outcomes not reported

Vinutha 2000Not placebo controlled

 
Characteristics of ongoing studies [ordered by study ID]
Bhandari 2010

Trial name or titleBhandari N, et al. Efficacy of neonatal vitamin A supplementation in improving child survival in Haryana, India: generation of evidence necessary for informing global policy - NeoVitA Trial

MethodsIndividually randomised double blind placebo controlled trials

Location: Faridabad and Palwal Districts of Haryana, India

ParticipantsEstimated number: 40,200

Inclusion Criteria: Consent to participate; All births in the study area that are contacted by enrolment team within the eligible age window (on the day of birth or in the next 2 days keeping a minimum period of 2 hours between birth and dosing)

Exclusion Criteria: Unable to feed on offering feeds, as reported by the mother; mother does not intend to stay in the study area for at least 6 months

InterventionsVitamin A Capsules: Retinol Palmitate (50,000 IU) and minute amounts of Vitamin E in Soybean Oil orally as a single dose to neonates (on the day of birth or in the next 2 days keeping a minimum period of 2 hours between birth and dosing)

Control: Placebo capsules containing minute amounts of Vitamin E in Soybean Oil orally as a single dose to neonates (on the day of birth or in the next 2 days keeping a minimum period of 2 hours between birth and dosing)

OutcomesPrimary: Risk of death in the period between receiving the intervention/placebo and six months of age

Secondary: Risk of death in the neonatal period (dosing to-28 days age); risk of death in infancy (dosing to 365 days age), risk of hospital admissions in the follow up period, adverse events in a 3-day period following supplementation, and vitamin A status of a random sample of neonates in the intervention and placebo groups at 2 weeks and 3 months of age.

Starting dateJune 2010

Contact informationDr. Nita Bhandari, 45 Kalu Sarai, New Delhi 110016. E-mail: CHRD@sas.org.in

Notes

Bhutta 2010

Trial name or titleBhutta ZA, et al. Newborn Vitamin A (VA) Supplementation Pilot Project, Pakistan

MethodsCommunity based, cluster randomised, double blinded, placebo controlled trial

Estimated completion date: December 2009

Location: Rural area, Karachi, Pakistan

ParticipantsEstimated number: 7400

Inclusion criteria: Live born infants from all pregnancies within participating villages

Exclusion criteria: Child born with congenital malformation, serious birth injury, neonate with birth asphyxia and serious infections, gestational age less than 32 weeks, birth weight less than 1500 gms, refuse to participate

InterventionsRoutine Post-partum Care and Vitamin A supplementation (50,000 IU) to the Newborn (within 48 hours of birth; maximum of 15 days after birth)

Control: Routine Post-partum Care with Placebo to the Newborn (within 48 hours of birth; maximum of 15 days after birth)

OutcomesMortality and morbidity until six months of age

Starting dateJanuary 2007

Contact informationProf. Zulfiqar A. Bhutta, Aga Khan University, Karachi, Pakistan. E-Mail: zulfiqar.bhutta@aku.edu

Notes

Edmond 2010

Trial name or titleEdmond K, et al. Efficacy of newborn vitamin A supplementation in improving child survival in rural Ghana: generation of evidence necessary for informing global policy - - NeoVitA

MethodsIndividually randomised double blind placebo controlled trials

Location: Rural areas Ghana

ParticipantsEstimated number: 28000

Inclusion Criteria:Consent to participate; all births in the study area that are contacted by enrolment team within the eligible age window (on the day of birth or in the next 2 days keeping a minimum period of 2 hours between birth and dosing)

Exclusion Criteria: Unable to feed on offering feeds, as reported by the mother; mother does not intend to stay in the study area for at least 6 months

InterventionsVitamin A Capsules: Retinol Palmitate (50,000 IU) and minute amounts of Vitamin E in Soybean Oil orally as a single dose to neonates (on the day of birth or in the next 2 days keeping a minimum period of 2 hours between birth and dosing)

Control: Placebo capsules containing minute amounts of Vitamin E in Soybean Oil orally as a single dose to neonates (on the day of birth or in the next 2 days keeping a minimum period of 2 hours between birth and dosing)

OutcomesPrimary: Risk of death in the period between receiving the intervention/placebo and six months of age

Secondary: Risk of death in the neonatal period (dosing to-28 days age); risk of death in infancy (dosing to 365 days age), risk of hospital admissions in the follow up period, adverse events in a 3-day period following supplementation, and vitamin A status of a random sample of neonates in the intervention and placebo groups at 2 weeks and 3 months of age.

Starting dateAugust 2010

Contact informationDr Karen Edmond, London School of Hygiene and Tropical Medicine, Keppel St London, WC1E7HT, United Kingdom. Email: karen.edmond@lshtm.ac.uk

Notes

Fawzi 2010

Trial name or titleFawzi W, et al. Efficacy of newborn vitamin A supplementation in improving child survival in Tanzania: generation of evidence necessary for informing global policy - Neovita

MethodsIndividually randomised double blind placebo controlled trials

Location: Rural areas Tanzania

ParticipantsEstimated number: 32000

Inclusion Criteria:Consent to participate; All births in the study area that are contacted by enrolment team within the eligible age window (on the day of birth or in the next 2 days keeping a minimum period of 2 hours between birth and dosing)

Exclusion Criteria:Unable to feed on offering feeds, as reported by the mother; mother does not intend to stay in the study area for at least 6 months

InterventionsVitamin A Capsules: Retinol Palmitate (50,000 IU) and minute amounts of Vitamin E in Soybean Oil orally as a single dose to neonates (on the day of birth or in the next 2 days keeping a minimum period of 2 hours between birth and dosing)

Control: Placebo capsules containing minute amounts of Vitamin E in Soybean Oil orally as a single dose to neonates (on the day of birth or in the next 2 days keeping a minimum period of 2 hours between birth and dosing)

OutcomesPrimary: Risk of death in the period between receiving the intervention/placebo and six months of age

Secondary: Risk of death in the neonatal period (dosing to-28 days age); risk of death in infancy (dosing to 365 days age), risk of hospital admissions in the follow up period, adverse events in a 3-day period following supplementation, and vitamin A status of a random sample of neonates in the intervention and placebo groups at 2 weeks and 3 months of age.

Starting dateAugust 2010

Contact informationDr. Honorati Masanja, Ifakara Health Institute P. O. Box 78373 Dar es Salaam, Tanzania, United Republic Of. Tel: +255 22 2150503. E-mail: hmasanja@ihi.or.tz

Notes

 
Comparison 1. Maternal vitamin A supplementation versus placebo

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

 1 Mortality in the first year of life7Risk Ratio (Random, 95% CI)Subtotals only

    1.1 Postpartum vitamin A supplementation
7Risk Ratio (Random, 95% CI)1.00 [0.94, 1.06]

    1.2 Maternal nightblindness prevalence <5%
2Risk Ratio (Random, 95% CI)1.02 [0.85, 1.22]

    1.3 Maternal nightblindness prevalence >5%
1Risk Ratio (Random, 95% CI)1.02 [0.79, 1.32]

    1.4 Cumulative vitamin A dose<200000 IU
1Risk Ratio (Random, 95% CI)1.54 [0.31, 7.63]

    1.5 Cumulative vitamin A dose>200000 IU
6Risk Ratio (Random, 95% CI)1.00 [0.93, 1.06]

    1.6 Maternal serum retinol ≤1.1 µmol/l
2Risk Ratio (Random, 95% CI)1.04 [0.88, 1.23]

    1.7 Maternal serum retinol>1.1µmol/l
3Risk Ratio (Random, 95% CI)0.99 [0.92, 1.06]

 2 Mortality in the first month of life2Risk Ratio (Random, 95% CI)0.98 [0.87, 1.11]

 3 Cause specific mortality in the first year of life2Risk Ratio (Random, 95% CI)Subtotals only

    3.1 ARI
2Risk Ratio (Random, 95% CI)1.59 [0.84, 2.99]

    3.2 Diarrhoea
2Risk Ratio (Random, 95% CI)2.57 [0.72, 9.12]

    3.3 Others
2Risk Ratio (Random, 95% CI)0.62 [0.09, 4.09]

 
Comparison 2. Young infant vitamin A supplementation versus placebo

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

 1 Mortality in the first year of life9Risk Ratio (Random, 95% CI)Subtotals only

    1.1 Vitamin A supplementation in first 6 months of life
9Risk Ratio (Random, 95% CI)0.97 [0.83, 1.12]

    1.2 Neonatal vitamin A supplementation
7Risk Ratio (Random, 95% CI)0.94 [0.79, 1.12]

    1.3 Post neonatal Vitamin A supplementation
3Risk Ratio (Random, 95% CI)1.05 [0.84, 1.32]

    1.4 Cumulative vitamin A dose received <=50,000 IU
7Risk Ratio (Random, 95% CI)0.94 [0.79, 1.12]

    1.5 Cumulative vitamin A dose received >50,000 IU
3Risk Ratio (Random, 95% CI)1.05 [0.84, 1.32]

    1.6 With concomitant maternal vitamin A supplementation
4Risk Ratio (Random, 95% CI)1.00 [0.81, 1.23]

    1.7 Without concomitant maternal vitamin A supplementation
5Risk Ratio (Random, 95% CI)0.93 [0.74, 1.17]

    1.8 Low birthweight
4Risk Ratio (Random, 95% CI)0.84 [0.65, 1.07]

    1.9 Normal birthweight
3Risk Ratio (Random, 95% CI)0.78 [0.43, 1.40]

    1.10 Maternal nightblindness prevalence <5%
2Risk Ratio (Random, 95% CI)1.06 [0.83, 1.34]

    1.11 Maternal nightblindness prevalence>5%
2Risk Ratio (Random, 95% CI)0.83 [0.71, 0.96]

 2 Mortality in the first month of life3Risk Ratio (Random, 95% CI)0.90 [0.75, 1.08]

 3 Cause specific mortality in the first year of life7Risk Ratio (Random, 95% CI)Subtotals only

    3.1 Diarrhoea
7Risk Ratio (Random, 95% CI)1.01 [0.72, 1.41]

    3.2 ARI
7Risk Ratio (Random, 95% CI)1.12 [0.91, 1.39]

    3.3 Others
7Risk Ratio (Random, 95% CI)0.81 [0.64, 1.02]

 4 Morbidity in the first year of life7Risk Ratio (Random, 95% CI)Subtotals only

    4.1 Diarrhoea
6Risk Ratio (Random, 95% CI)1.02 [0.99, 1.06]

    4.2 Acute respiratory infection or respiratory difficulty
4Risk Ratio (Random, 95% CI)1.04 [0.95, 1.15]

    4.3 Cough or running nose
3Risk Ratio (Random, 95% CI)0.98 [0.85, 1.13]

   4.4 Ear infection
0Risk Ratio (Random, 95% CI)0.0 [0.0, 0.0]

    4.5 Fever
3Risk Ratio (Random, 95% CI)0.92 [0.76, 1.11]

   4.6 Vomiting
0Risk Ratio (Random, 95% CI)0.0 [0.0, 0.0]

 5 Adverse effects of vitamin A supplementation10Risk Ratio (Random, 95% CI)Subtotals only

    5.1 Bulging fontanelle following any dose of vitamin A
10Risk Ratio (Random, 95% CI)1.55 [1.05, 2.28]

    5.2 Bulging fontanelle following first dose of vitamin A
7Risk Ratio (Random, 95% CI)1.37 [0.98, 1.91]

    5.3 Bulging fontanelle following second dose of vitamin A
2Risk Ratio (Random, 95% CI)3.60 [1.65, 7.87]

    5.4 Bulging fontanelle following third dose of vitamin A
2Risk Ratio (Random, 95% CI)3.14 [1.72, 5.74]

    5.5 Vomiting
4Risk Ratio (Random, 95% CI)0.81 [0.58, 1.12]

    5.6 Irritability
4Risk Ratio (Random, 95% CI)0.98 [0.87, 1.11]

    5.7 Diarrhoea
3Risk Ratio (Random, 95% CI)0.99 [0.75, 1.31]

    5.8 Fever
5Risk Ratio (Random, 95% CI)1.07 [0.96, 1.20]

 
Summary of findings for the main comparison. Maternal vitamin A supplementation compared to placebo for the prevention of morbidity and mortality in infants up to six weeks of age

Maternal Vitamin A Supplementation compared to Placebo for the prevention of morbidity and mortality in infants up to six weeks of age

Patient or population: patients with the prevention of morbidity and mortality in infants up to six weeks of age
Settings: Low and middle income countries
Intervention: Maternal Vitamin A Supplementation
Comparison: Placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

PlaceboMaternal Vitamin A Supplementation

All-cause mortality in the first year of life
Follow-up: 6-12 months
Low risk population1RR 1
(0.94 to 1.06)
96203
(7 studies)
⊕⊕⊕⊕
high2
Trials gave vitamin A to mothers in developing countries, reflecting the main question of the review. CER from external sources.

41 per 100041 per 1000
(39 to 43)

Medium risk population1

62 per 100062 per 1000
(58 to 66)

High risk population1

81 per 100081 per 1000
(76 to 86)

All-cause mortality at 1 month
Follow-up: 1 months
Medium risk population3RR 0.98
(0.87 to 1.11)
84537
(2 studies)
⊕⊕⊕⊝
moderate4
Data analysed as risk ratios. Cumulative risk and incidence ratios from studies were combined to generate a pooled risk ratio. CER from external sources.

30 per 100029 per 1000
(26 to 33)

ARI-related mortality in the first year of life
verbal autopsy or lay reporting
Follow-up: 12 months
Low risk population5RR 1.59
(0.84 to 2.99)
5207
(2 studies)
⊕⊝⊝⊝
very low6,7,8
The studies reported risk ratios and 95% confidence intervals. In the absence of dichotomous data CERs were calculated based on external data.

9 per 100015 per 1000
(8 to 28)

High risk population5

11 per 100018 per 1000
(9 to 33)

Diarrhoea-related mortality in the first year of life
verbal autopsy or lay reporting
Follow-up: 12 months
Low risk population9RR 2.57
(0.72 to 9.12)
5207
(2 studies)
⊕⊝⊝⊝
very low6,8,10
The studies reported risk ratios and 95% confidence intervals. In the absence of dichotomous data CERs were calculated based on external data.<BR/>

8 per 100020 per 1000
(6 to 71)

High risk population9

9 per 100024 per 1000
(7 to 85)

Morbidity due to acute respiratory infections11
Follow-up: mean 12 months
Study populationRate ratio 0.96
(0.85 to 1.08)
598
(1 study)
⊕⊝⊝⊝
very low11,12
Data were analysed as ratios of rates. No estimates of cumulative risk available. Estimates of morbidity not available from external sources.

See commentSee comment

Medium risk population


Morbidity due to diarrhoea11
Follow-up: mean 12 months
Study populationRR 1.10
(0.99 to 1.23)
598
(1 study)
⊕⊝⊝⊝
very low11,12
Data were analysed as ratios of rates. No estimates of cumulative risk available. Estimates of morbidity not available from external sources.

See commentSee comment

Medium risk population


Adverse effectsStudy populationRR 0
(0 to 0)
700
(2 studies)
See commentNo adverse events were reported in two trials providing this information (Bhaskaram 1998, Venkatarao 1996).

See commentSee comment

Medium risk population


*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) 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 Control group risk taken from the World Health Statistics 2010 (http://www.who.int/whosis/whostat/2010/en/index.html) for mortality before 1 year of age recorded in 2008 in the countries where included studies were conducted (Bangladesh, Ghana, India, Kenya, Nepal, Zimbabwe). The lowest, medium and highest mortality rates were entered for these countries.
2 Trial design was adequately reported in all but three trials that accounted for 6.6% of the weight in the pooled analysis (Klemm 2008, Newton 2005, Venkatarao 1996). Three trials were cluster randomised with adjustment for the design effect (Katz 2000, Kirkwood 2010, Klemm 2008). The cumulative vitamin A dose received by the postpartum mothers was similar in all but one study (Newton 2005).
3 Control group risk taken from the World Health Statistics 2010 (http://www.who.int/whosis/whostat/2010/en/index.html) for neonatal mortality rate. Estimates of neonatal mortality were based on rates of 30/1000 live births for Ghana (Kirkwood 2010) and Nepal (Katz 2000) recorded in 2008.
4 Two out of seven studies reporting mortality. Both studies had very large sample sizes.
5 Information taken from two sources. The World Health Statistics 2010 (http://www.who.int/whosis/whostat/2010/en/index.html) provided the low and high mortality rates at 1 year of age in the countries of the included studies (India and Zimbabwe). Based on the proportion of global all cause mortality attributed to pneumonia (18%, reported in Black 2010), the CERs entered represent 18% of the national rates of mortality.
6 Venkatarao 1996 had inadequate concealment of allocation. Both studies failed to address missing data appropriately.
7 The confidence intervals include a 16% reduction and 300% increase (appreciable harm) in the risk of ARI related death
8 Only two trials reported this outcome, and the meta-analysis may be affected by the non-disclosure of cause-specific mortality in the remaining studies.
9 Information taken from two sources. The World Health Statistics 2010 (http://www.who.int/whosis/whostat/2010/en/index.html) provided the low and high mortality rates at 1 year of age in the countries of the included studies for 2008(India and Zimbabwe). Based on the proportion of global all cause mortality attributed to diarrhoea (15% reported in Black 2010), the events entered represent 15% of the national rates of mortality.
10 The confidence intervals include a 28% reduction (appreciable benefit) and 900% increase (appreciable harm) in the risk of diarrhoea-related death.
11 Single study (Venkatarao 1996) on which randomisation procedure and method of allocation concealment were not described, and incomplete outcome data was not addressed.
12 A single small trial reported this outcome.
 
Summary of findings 2. Young infant vitamin A supplementation compared to placebo for the prevention of morbidity and mortality in infants six months of age or less

Young Infant Vitamin A Supplementation compared to placebo for the prevention of morbidity and mortality in infants six months of age or less

Patient or population: patients with the prevention of morbidity and mortality in infants six months of age or less
Settings: Low middle income countries
Intervention: Young Infant Vitamin A Supplementation
Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

placeboYoung Infant Vitamin A Supplementation

All-cause mortality in the first year of life
Follow-up: 6-12 months
Low risk population1RR 0.97
(0.83 to 1.12)
59402
(9 studies)
⊕⊕⊕⊝
moderate2,3
Data analysed as risk ratios. Cumulative risk and incidence ratios from studies were combined to generate a pooled risk ratio. CER from external source.

22 per 100021 per 1000
(18 to 25)

Medium risk population1

51 per 100049 per 1000
(42 to 57)

High risk population1

117 per 1000113 per 1000
(97 to 131)

All-cause mortality at 1 month
Follow-up: 1 months
Low risk population4RR 0.90
(0.75 to 1.08)
17000
(3 studies)
⊕⊝⊝⊝
very low5,6,7
Data analysed as risk ratios. Cumulative risk and incidence ratios from studies were combined to generate a pooled risk ratio. CERs from external source.

19 per 100017 per 1000
(14 to 21)

High risk population4

45 per 100040 per 1000
(34 to 49)

Diarrhoea-related mortality in the first year of life
verbal autopsy or lay reporting
Low risk population8RR 1.01
(0.72 to 1.41)
47998
(7 studies)
⊕⊕⊝⊝
low9,10
Data analysed as risk ratios. Cumulative risk and incidence ratios from studies were combined to generate a pooled risk ratio. CER from external sources.

3 per 10003 per 1000
(2 to 5)

Medium risk population8

8 per 10008 per 1000
(6 to 11)

High risk population8

18 per 100018 per 1000
(13 to 25)

ARI-related mortality in the first year of life
verbal autopsy or lay reporting
Low risk population11RR 1.12
(0.91 to 1.39)
47998
(7 studies)
⊕⊕⊕⊝
moderate6,9
Data analysed as risk ratios. Cumulative risk and incidence ratios from studies were combined to generate a pooled risk ratio. CER from included studies.

4 per 10004 per 1000
(4 to 6)

Medium risk population11

9 per 100010 per 1000
(8 to 13)

High risk population11

21 per 100024 per 1000
(19 to 29)

Morbidity in the first year of life - Diarrhoea
Follow-up: 2-12 months
Medium risk population12RR 1.02
(0.99 to 1.06)
24802
(6 studies)
⊕⊕⊝⊝
low13,14
Data were analysed from ratios of rates and risk. Estimate of cumulative risk comes from an included study (WHO 1998).

100 per 1000102 per 1000
(99 to 106)

Morbidity in the first year of life - Acute respiratory infection or respiratory difficulty
Follow-up: 4-12 months
Medium risk population12RR 1.04
(0.95 to 1.15)
24019
(4 studies)
⊕⊕⊝⊝
low15,16
Data were analysed from ratios of rates and risk. Estimate of cumulative risk comes from an included study (WHO 1998).

34 per 100035 per 1000
(32 to 39)

Adverse effects of vitamin A supplementation - Bulging fontanelle following any dose of vitamin A18 per 100028 per 1000
(19 to 41)
RR 1.55
(1.05 to 2.28)
32978
(10 studies)
⊕⊕⊝⊝
low17,18
We believe that further research is unlikely to affect the direction of effect, but that it may improve the precision of the estimated increase in risk.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) 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 Information taken from the World Health Statistics 2010 (http://www.who.int/whosis/whostat/2010/en/index.html) based on the lowest, medium and highest mortality rates at 1 year of age recorded in 2008 in the countries of the included studies (Bangladesh, Ghana, Guinea-Bissau, India, Indonesia, Nepal, Peru, Zimbabwe).
2 Five studies were at an unclear risk of selection bias due to insufficient reporting (Humphrey 1996: allocation generation; Klemm 2008, Newton 2005, Rahmathullah 2003, West 1995: allocation generation and concealment). However, this was not considered to pose a serious bias for this outcome (unlikely risk of high bias - lack of clarity primarily due to inadequate reporting with intervention and control arms being reasonably balanced for confounders likely to influence mortality estimates). All trials had a low risk of bias for blinding. One small trial (Newton 2005) was at high risk of bias for incomplete outcome data reporting. Selective outcome reporting was not considered to pose a risk of bias for this outcome. Three trials (Benn 2008, Benn 2010, Humphrey 1996) at high risk of bias for depicting post hoc sub-group comparisons were not considered to pose a bias for this outcome. Partial funding from Vitamin A manufacturer was not considered to pose a risk of bias (Humphrey 1996). One trial terminated early was considered to pose a high risk of bias (Klemm 2008). The weighting of the two trials (Klemm 2008, Newton 2005) with a high risk of bias on one or more key domains was 17.6%. Thus overall, the data was not considered to have serious limitations of design.
3 A moderate to high level of heterogeneity (I squared: 49%, p = 0.05) was observed between the results of the studies. This variation could not be fully explained by supplementation age, maternal postpartum vitamin A supplementation, total dose received, maternal night blindness and birth weight at baseline. Humphrey 1996 and Rahmathullah 2003 were the only studies to find a statistically significant benefit for vitamin A.
4 Information taken from the World Health Statistics 2010 (http://www.who.int/whosis/whostat/2010/en/index.html) based on the lowest, medium and highest mortality rates at 1 month of age in the countries of the included studies (Bangladesh, Guinea-Bissau, Indonesia).
5 Two studies were at an unclear risk of selection bias due to insufficient reporting (Humphrey 1996: allocation generation; Klemm 2008: allocation generation and concealment). However, this was not considered to pose a serious bias for this outcome (unlikely risk of bias - lack of clarity primarily due to aspects of reporting, with intervention and control arms reasonably balanced for confounders likely to influence mortality estimates). Blinding, incomplete data and selective reporting were not considered to significantly bias the results. Two trials (Benn 2008, Humphrey 1996) at high risk of bias for depicting post hoc sub-group comparisons were not considered to pose a bias for this outcome. Partial funding from Vitamin A manufacturer was not considered to pose a risk of bias (Humphrey 1996). Reporting on neonatal mortality with most (˜75%) of the participants being followed-up only at one year of age after intervention within 48 hours of birth was considered to pose a high risk of bias (Humphrey 1996). One trial with terminated early was considered to pose a high risk of bias (Klemm 2008). The weighting of the two trials (Humphrey 1996, Klemm 2008) with a high risk of bias on one or more key domains was 95.4%. Thus overall, the data was considered to have serious limitations of design.
6 The 95% confidence intervals around the pooled effect estimate include both (i) no effect and (ii) appreciable benefit or appreciable harm.
7 Only three studies reported this outcome. Selective reporting bias cannot be excluded.
8 Information taken from two sources. World Health Statistics 2010 (http://www.who.int/whosis/whostat/2010/en/index.html) provided the lowest, medium and highest mortality rates at 1 year of age from the countries where the included studies were performed (Ghana, Guinea-Bissau, India, Indonesia, Nepal, Peru, Zimbabwe). Based on the proportion of global all cause mortality attributed to diarrhoea (15% reported in Black 2010), the events entered represent 15% of each of the national rates of mortality.
9 Three studies were at an unclear risk of selection bias due to insufficient reporting (Humphrey 1996: allocation generation; Rahmathullah 2003, West 1995: allocation generation and concealment). However, this was not considered to pose a serious bias for this outcome (unlikely risk of high bias - lack of clarity primarily due to aspects of reporting, with intervention and control arms being reasonably balanced for confounders likely to influence mortality estimates). All trials had a low risk of bias for blinding. Selective outcome reporting was not considered to pose a risk of bias for this outcome. Three trials (Benn 2008, Benn 2010, Humphrey 1996) at high risk of bias for depicting post hoc sub-group comparisons were not considered to pose a bias for this outcome. Partial funding from Vitamin A manufacturer was not considered to pose a risk of bias (Humphrey 1996). Thus overall, the data was not considered to have serious limitations of design.
10 The 95% confidence intervals around the pooled effect estimate include both appreciable benefit and appreciable harm.
11 Information taken from two sources. World Health Statistics 2010 (http://www.who.int/whosis/whostat/2010/en/index.html) provided the lowest, medium and highest mortality rates at 1 year of age from the countries where the included studies were performed (Ghana, Guinea-Bissau, India, Indonesia, Nepal, Peru, Zimbabwe). Based on the proportion of global all cause mortality attributed to pneumonia (18% reported in Black 2010), the events entered represent 18% of each of the national rates of mortality.
12 Derived from multi-country trial (WHO 1998).
13 Only one study (WHO 1998) described an adequate sequence generation, and two studies had adequate allocation concealment (Humphrey 1996, WHO 1998). For the remaining studies there was a high risk of selection bias. Blinding was adequately reported in all studies. Two studies (Semba 2001, Venkatarao 1996) were at high risk of attrition bias, and two studies (Humphrey 1996, Semba 2001) were at risk of selective reporting. Only WHO 1998 was considered to be free of other sources of bias.
14 Only six of the studies contributing data were included. Selective reporting bias cannot be excluded.
15 Only one study (WHO 1998) described an adequate sequence generation, and two studies had adequate allocation concealment (Humphrey 1996, WHO 1998). For the remaining studies there was a high risk of selection bias. Blinding was adequately reported in all studies. Venkatarao 1996 was at high risk of attrition bias, and one study (Humphrey 1996) was at risk of selective reporting bias. Only WHO 1998 was considered to be free of other sources of bias.
16 Only four of the studies contributing data were included. Selective reporting bias cannot be excluded.
17 Five studies had unclear sequence generation (de Francisco 1993, Humphrey 1996, Klemm 2008; Semba 2001; West 1995), and four studies had unclear or inappropriate allocation concealment (de Francisco 1993, Klemm 2008, Semba 2001, West 1995). For the remaining studies there was a low risk of selection bias. Blinding was adequately reported in all studies. Three studies (Baqui 1995; de Francisco 1993, Semba 2001) were at high risk of attrition bias, and only three studies (Benn 2008, Klemm 2008, WHO 1998) were free of selective reporting bias. Only Malaba 2005 and WHO 1998 were judged to be free of other biases.
18 A high level of statistical heterogeneity was observed between the results of the studies (I squared: 68%, P = 0.0009). Three studies (de Francisco 1993, Humphrey 1996 and WHO 1998) found a statistically significant increase in the risk of bulging fontanelle after vitamin A supplementation when compared to placebo.
 
Summary of findings 3. Young infant vitamin A supplementation compared to placebo for the prevention of morbidity and mortality in infants six months of age or less

Young Infant Vitamin A Supplementation compared to Placebo for the prevention of morbidity and mortality in infants six months of age or less

Patient or population: patients with the prevention of morbidity and mortality in infants six months of age or less
Settings: Low middle income countries
Intervention: Young Infant Vitamin A Supplementation
Comparison: Placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

PlaceboYoung Infant Vitamin A Supplementation

Mortality in the first year of life - Neonatal vitamin A supplementation
Follow-up: 6-12 months
Low risk population1RR 0.94
(0.79 to 1.12)
38865
(7 studies)
⊕⊕⊕⊝
moderate2,3
This was a subgroup estimate. Meta-regression gave a non-significant Ratio of the subgroup RRs of 1.13, 95% CI 0.76 to 1.68.

22 per 100021 per 1000
(17 to 25)

Medium risk population1

51 per 100048 per 1000
(40 to 57)

High risk population1

117 per 1000110 per 1000
(92 to 131)

Mortality in the first year of life - Post neonatal Vitamin A supplementation
Follow-up: 6-9 months
Low risk population1RR 1.05
(0.84 to 1.32)
20537
(3 studies)
⊕⊕⊕⊝
moderate4,5
This was a subgroup estimate. Meta-regression gave a non-significant Ratio of the subgroup RRs of 1.13, 95% CI 0.76 to 1.68.

22 per 100023 per 1000
(18 to 29)

Medium risk population1

41 per 100043 per 1000
(34 to 54)

High risk population1

52 per 100055 per 1000
(44 to 69)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) 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 Information taken from the World Health Statistics 2010 (http://www.who.int/whosis/whostat/2010/en/index.html) based on the lowest, medium and highest mortality rates at 1 year of age recorded in 2008 in the countries of the included studies
2 Four studies were at an unclear risk of selection bias due to insufficient reporting (Humphrey 1996: allocation generation; Klemm 2008, Rahmathullah 2003, West 1995: allocation generation and concealment). However, this was not considered to pose a serious bias for this outcome (unlikely risk of high bias - lack of clarity primarily due to reporting aspects with intervention and control arms being reasonably balanced for confounders likely to influence mortality estimates). All trials had a low risk of bias for blinding. Selective outcome reporting was not considered to pose a risk of bias for this outcome. Three trials (Benn 2008, Benn 2010, Humphrey 1996) were at a high risk of bias for depicting post-hoc subgroup comparisons were not considered to pose a bias for this outcome. Partial funding from Vitamin A manufacturer was not considered to pose a risk of bias (Humphrey 1996). One trial terminated prematurely was considered to pose a high risk of bias (Klemm 2008); and contributed 22% weight of the estimated effect. Thus overall, the data were not considered to have serious limitations of design.
3 I square for the subgroup estimate in neonatal children was moderately high (50%, P = 0.06).
4 Two studies were at an unclear risk of selection bias due to insufficient reporting (Newton 2005, West 1995: allocation generation and concealment). However, this was not considered to pose a serious bias for this outcome (unlikely risk of high bias - lack of clarity primarily due to reporting aspects with intervention and control arms being reasonably balanced for confounders likely to influence mortality estimates). All trials had a low risk of bias for blinding. One small trial (Newton 2005) was at high risk of bias for incomplete outcome data reporting. Selective outcome reporting was not considered to pose a risk of bias for this outcome. The weighting of the trial (Newton 2005) with a high risk of bias on one or more key domains was only 2.2%. Thus overall, the data was not considered to have serious limitations of design.
5 The confidence intervals include both a reduction in the risk of all cause mortality of 16% and an appreciable increase in the risk of mortality of 32%.
 
Table 1. Details of vital events for the mortality analysis in the maternal supplementation review

AuthorVitamin APlaceboSource of RR used in meta-analysis


Number randomisedNumber deadNumber aliveNumber lostVital status knownFollow up duration (child yrs)Number randomisedNumber deadNumber aliveNumber lostVital status knownFollow up duration (child yrs)

Venkatarao 1996301822865236NM297922860237NMCalculated

Katz 2000 558338247824195164NM520233443854834719NMStated

Malaba 2005^230048201323920612119230938202824320662120Calculated^

Newton 2005269319868201NM277220471206NMCalculated

Ayah 2007  2822322732250NM2822321445237NMCalculated

Klemm 2008  NC1212596NC2717NMNC1152517NC2632NMCalculated

Kirkwood 2010370421948NMNMNM30858367101963NMNMNM30544Stated

 NM Not mentioned; NC Not calculable
 ^ The deaths also include those due to injuries and congenital defects (2 in Vitamin A and 2 in placebo), and RR calculated from child year denominator.
 
Table 2. Meta-regression analyses of all- cause infant mortality following maternal postpartum vitamin A supplementation

Study characteristicUnivariate analysis

Ratio of RRs* (95% CI); I2     
P Value

Total vitamin A dose (units) received by mother

(Per unit change) (7 trials)
 

 

1.00 (1.00, 1.00); 0.0
 

 

0.496

Mean maternal serum retinol (micromoles/L) (5 trials)

(Per unit change)
 

 

0.81 (0.17, 3.99); 0.0
 

 

0.706

 * When the study characteristic is a binary variable, the estimate of effect size is the ratio of relative risks for infant mortality (treated/control) in the two groups.  When the study characteristic is continuous, the estimate of effect size is the ratio of relative risks for infant mortality multiplicatively per unit change in the characteristic.
 
 
Table 3. Details of vital events for the mortality analysis in the infant supplementation review

StudyVitamin APlaceboSource of RR used in meta-analysis



Number randomisedNumber deadNumber aliveNumber lostVital status knownFollow up duration

(child yrs)
Number randomisedNumber deadNumber aliveNumber lostVital status knownFollow up duration (child yrs)

West (0-1 mo) 1995  8303878111819268.4791347516785256.9Stated

West (1-6 mo) 1995525611250618351732356.950419648529349482260.2Calculated*

Humphrey 1996  1034  7918109925969.6103319895119914957.1Stated

WHO 1998  47169743882314485NM47089943962134495NMStated

Rahmathullah 20035786146521742353632713.05833188522042554082719.1Stated

Malaba 2005^459993NMNMNM4195230938NMNMNM2120Calculated^

Newton 2005  53910397132407NM277220471206NMCalculated

Benn 20082145912015392106NM2200882081312169NMStated

Klemm 2008#7956306764737953NMNC1152517NC2632NMCalculated #

Benn 201085483701707847578637871075788762Stated

 NM Not mentioned; NC Not calculable
* Values derived from Tables 1 and 2 of publication and RR calculated with child year denominator.
^ The deaths also include those due to injuries and congenital defects (5 in Vitamin A and 2 in placebo), and RR calculated from child year denominator.
# In the placebo group for this comparison, both mothers and newborns had received placebos. The RRs have been adjusted for the calculated design effect of 1.01769.
 
Table 4. Meta-regression analyses of all cause infant mortality following vitamin A supplementation in the first six months of life

Study characteristicUnivariate analysis

Ratio of RRs* (95% CI); I2
P value

Vitamin A supplementation age

  (Post-neonatal versus neonatal)
 

1.13 (0.76, 1.68); 0.44
 

0.50

Maternal post-partum vitamin A supplementation

  (Yes versus no)
 

 

 

1.05 (0.72, 1.53); 0.48
 

 

 

0.77

Total vitamin A dose (units) received by infant

 (Per unit change)
 

 

1.00 (1.00, 1.00); 0.41
 

 

0.39

Maternal night blindness

 (>5% versus <5%) (components=5)
 

0.78 (0.53, 1.14); 0.00
 

0.13

Birthweight

(<2500 grams versus >=2500 grams)

(components = 4 for <2500 grams and 3 for >=2500 grams)
1.02 (0.49, 2.15);

0.61
0.94

 * When the study characteristic is a binary variable, the estimate of effect size is the ratio of relative risks for infant mortality (treated/control) in the two groups.  When the study characteristic is continuous, the estimate of effect size is the ratio of relative risks for infant mortality multiplicatively per unit change in the characteristic.