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Neonatal vitamin A supplementation for the prevention of mortality and morbidity in term neonates in developing countries

  1. Batool A Haider2,
  2. Zulfiqar A Bhutta1,*

Editorial Group: Cochrane Neonatal Group

Published Online: 5 OCT 2011

Assessed as up-to-date: 29 NOV 2010

DOI: 10.1002/14651858.CD006980.pub2


How to Cite

Haider BA, Bhutta ZA. Neonatal vitamin A supplementation for the prevention of mortality and morbidity in term neonates in developing countries. Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD006980. DOI: 10.1002/14651858.CD006980.pub2.

Author Information

  1. 1

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

  2. 2

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

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

Publication History

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

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Characteristics of included studies [ordered by study ID]
Benn 2008

MethodsRandomised, double blind placebo controlled trial.


ParticipantsInclusion criteria were infants weighing at least 2500 g at birth with no signs of overt illness or malformations. Infants were recruited at the time of BCG vaccination. Number of participants in vitamin A group was 2145 and that in the placebo was 2200.


Interventions0.5 ml vegetable oil, either containing 50,000 IU of vitamin A as retinyl palmitate and 10 IU vitamin E, or only 10 IU of vitamin E was given into the mouth of child at the time of BCG vaccination.


OutcomesMortality at 12 month of age, cause specific mortality at 12 months of age, scar, in vivo and ex vivo PPD response to BCG, retinol binding protein (RBP) concentration at 6 weeks and 4 months of age (low RBP defined as serum retinol <0.70 micromol/L) and adverse effects (bulging fontanelle, hospitalizations, irritability, fever, frequent stools, vomiting, mother thinks the child is not well).


NotesStudy was conducted in 6 urban districts in capital of Guinea-Bissau which is classified as an area of subclinical vitamin A deficiency (by UNICEF) and high infant mortality. The HIV prevalence among women in the study area was 3-5%.

Since the authors did not have information about the gestational age at delivery and the inclusion criteria was infants with birth weight of at least 2500 g, we included data as such in the term neonate analysis assuming that a greater proportion of these were term infants.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "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".

Comment: probably done

Allocation concealment (selection bias)Low riskQuote: "lots were folded, making it impossible to tell what was written on them before they were opened. A new envelope was not taken into use before the previous envelope had been completely emptied. The result of the randomisation was noted on the inclusion form and the lot was stapled to the inclusion form.", "The dark glass bottles were prepared at Skanderborg Pharmacy" and "The code was kept at the pharmacy until 12 months after the last child was included".

Comment: probably done

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "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" and "Apart from the randomisation number, the bottles looked alike; we judged small differences in taste and colour of the contents as unimportant owing to the recipients".

Comment: blinding of participants, study personnel and outcome assessors probably done

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition was 1.6%. Reasons for attrition and distribution in the two groups were provided. Infant lost to follow up were similar to those who were followed in baseline anthropometric characteristics.

Selective reporting (reporting bias)Low riskComment: results of all expected outcomes were presented in several publications of the study

Other biasHigh riskA protocol was provided but post hoc analyses were conducted after assuming that Vit 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, two by two factorial trial.


ParticipantsInclusion criteria were infants weighing < 2500 g at birth with no severe malformations. Number of participants in vitamin A group was 864 and that in the placebo was 872.


InterventionsNeonates < 2500 g at birth were assigned to 25,000 IU vitamin A as retinyl palmitate and 10 IU vitamin E per 0.5ml oil or placebo which contained only 10 IU vitamin E per 0.5ml oil, as well as to early BCG vaccine or the usual late BCG vaccine.


OutcomesInfant mortality and cause-specific infant mortality at 12 months


Notes
  • Study was conducted in 6 urban districts in capital of Guinea-Bissau which is classified as an area having moderate to severe vitamin A deficiency (by WHO) and high infant mortality.
  • No evidence of an interaction between BCG and vitamin A supplementation in neonates (P=0.73).
  • Vitamin A was administered within the first 48 hours of life to 878 (51%) of the 1717 children.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "randomly allocated in a two by two factorial design" and"mother drew an envelope
from a bag. Each bag was prepared... 12 marked "no BCG 6," and 12 marked "no BCG 7", "The numbers 6 and 7 indicated from which of two numbered bottles, 6 or 7, the child should receive treatment (that is, either 25 000 IU vitamin A or placebo)."

Comment: probably done

Allocation concealment (selection bias)Low riskQuote: "The envelopes were closed and non-transparent, making it impossible to identify the allocation before the envelopes were opened.", "The result of the randomisation was noted on the inclusion form and, furthermore, the lot name was stapled on the form." and "The code of which treatment was in which bottle was kept at the pharmacy until 12 months after the last child was included."

Comment: probably done

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "numbers "6" and "7" indicated from which of two numbered bottles, “6” or “7,” the child should receive treatment", "vitamin A and placebo bottles looked alike" and "assistant and the nurse who were responsible for the randomisation procedures had no idea which bottles contained vitamin A or which had placebo" and "follow-up assistants were unaware of the allocated treatment,

Comment: blinding of participants, study personnel and outcome assessors probably done

Incomplete outcome data (attrition bias)
All outcomes
Low riskExclusions and attrition were 18.72%. Reasons and distribution in the two groups were provided. Numbers were balanced across the treatment groups.

Selective reporting (reporting bias)Low riskComment: All expected outcomes, as per protocol were 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 Vit 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.

Humphrey 1996

MethodsRandomised placebo controlled trial.


ParticipantsAll neonates within 24 hours of birth were eligible for inclusion. Very low birthweight babies (<1500 gm) and those with life threatening illnesses such as severe respiratory distress syndrome, major congenital anomalies, paralysis, hypoglycaemia, hypocalcaemia, clinical evidence of ischaemic hypoxia, or sepsis were excluded. A total of 2067 were enrolled within the 24-hour inclusion period.


InterventionsOne oral dose of 52 µmol vitamin A (as retinyl palmitate) plus 23 µmol vitamin E in the treatment group. Placebo (<0.10 µmol vitamin A + 23 µmol vitamin E) in the control group. Intervention n=1034 and placebo n=1033.


OutcomesMortality at 6 and 12 months of age, cause specific mortality at 12 month of age, morbidity at 4 months of age, adverse effects of  VAS (bulging fontanelle, vomiting, fever, loose stool, irritability, intracranial haemorrhage, resistive index), development at 3 years of age.


Notes
  • Infants born at Hasan Sadikin Hospital in Bandung, Indonesia, from June 18,1992 to June 3, 1993 were considered.
  • Mean age of dosing was 16.2 (SD=8.2) hours, 88.2% were dosed in first 24 hours of life birth.
  • Treatment groups were comparable at baseline.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "simple randomisation blocked within the birth weight strata".

Comment: method used to generate the randomisation sequence is not described in sufficient detail to permit judgement

Allocation concealment (selection bias)Low riskQuote: "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".

Comment: probably done

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "supplements were individually coded, odourless......follow-up of infants in Indonesia".

Comment: blinding of participants, study personnel and outcome assessors probably done.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition was 11% and reasons for it were provided. Distribution was balanced in the two groups. Infants lost to follow up were not significantly different from those who were followed.

Selective reporting (reporting bias)Unclear riskComment: Insufficient information to permit judgement

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

Other biasUnclear riskAgoestina 1994 mentioned a protocol, but no further details were provided. Supported by a grant from John HopkinsUniversity and assistance from Hoffmann-LaRoche industry (Basel, Switzerland).

Klemm 2008

MethodsCommunity based double masked, cluster randomised, placebo controlled trial.


ParticipantsInfants born to consenting mothers who were participating in the parent trial were eligible for inclusion in the study.

Vitamin A group infants whose mothers consented=8525               

Placebo group infants whose mothers consented=8591

Infants of consenting mothers who had died before they could be supplemented by staff, those who were born outside of the study area, and infants who could not be reached to receive a supplement after repeated staff visits during the first 30 days after birth were excluded


InterventionsIntervention= 50,000 IU of vitamin A or a placebo in oil given as soon as possible after birth.


OutcomesInfant mortality at 6 months of age and adverse effects


Notes
  • The trial was nested into 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. The present study began in January 2004 in districts of Gaibandha and Rangpur, Bangladesh.
  • Randomisation of sectors was done in a manner to produce 2 infant supplementation groups that were balanced across the maternal supplementation trial arms. Interaction between maternal and vitamin A supplementation was non-significant.
  • Approx 84% supplemented within the first 48 hours 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 riskQuote: "cluster randomised" and "sectors were listed in geographically contiguous order and were randomised in blocks of 4".

Comment: method used to generate the randomisation sequence is not described in sufficient detail to permit judgement.

Allocation concealment (selection bias)Unclear riskComment: insufficient detail to permit judgement.

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "sector-coded supplement", "supplements for both groups were opaque gelatinous capsules identical in shape, size, and colour containing edible oil"; "double-masked"

Comment: blinding of participants, study personnel and outcome assessors probably done

Incomplete outcome data (attrition bias)
All outcomes
Low riskExclusions and attrition was 7%. Reasons and distribution in the two groups were provided. Attrition and reasons for attrition were balanced across the treatment groups.

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

Other biasHigh riskStudy halted before conclusion because mortality on the placebo group was significantly higher than intervention group after 2/3 of infants were randomised. Results adjusted by cluster effect. Source of funding: John Hopkins University (GHS-A-00-03-00019-00), Bill and Melinda Gates Foundation

Malaba 2005

MethodsRandomised placebo controlled two by two factorial design trial.


ParticipantsMother and infant pairs enrolled within 96 hrs of delivery. Pairs were eligible if neither of the pairs have an acutely life threatening condition, the infant was a singleton with birthweight >1500gms, and the mother planned to stay in Harare after delivery.

Mothers and infants were assigned into the following 4 groups

  1. Mothers received 400,000 IU vitamin A and infants received 50 000 IU vitamin A  (Aa group)=3529
  2. Mothers received 400,000 IU vitamin A and infants received placebo                    (Ap group)=3529
  3. Mothers received placebo and infants received 50,000 IU vitamin A                      (Pa group)=3530
  4. Both mothers and infants received placebo                                                            (Pp group)=3522


InterventionsMothers received 400,000 IU vitamin A and infants received 50,000 IU vitamin A. Both treatment and placebo contained a soy oil base with vitamin E (50 IU per maternal capsule; 10 IU per infant capsule).  


OutcomesInfant mortality at 6 and 12 months, cause-specific infant mortality at 12 months, anaemia and haemoglobin in infants and MTCT of HIV in infants born to HIV positive mothers


Notes
  • Zimbabwe is categorized by WHO as a high risk area for vitamin A deficiency. HIV is endemic in Zimbabwe nearly 25% are HIV infected.
  • From 25 November 1997 to 29 January 2000 in Harare, Zimbabwe. 
  • Three-quarters of the pairs received their treatment dose within 24 hours, and 94% received it within 48 hours of delivery.
  • Interaction between maternal and infant vitamin A supplementation was not significant (P=0.60).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "study identification numbers were randomly allocated to the treatment groups by computer in blocks of 12", "A separate team at Johns Hopkins University prepared the study capsule packets" and "Lists linking the study number to the treatment were kept in sealed envelopes and encrypted computer files."

Comment: probably done.

Allocation concealment (selection bias)Low riskQuote: "numbers were printed on adhesive labels and affixed to amber-coloured zip-lock plastic bags" and "capsules in the next sequential bag were administered...... files".

Comment: probably done.

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

Comment: blinding of participants, study personnel and outcome assessors probably done

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskExclusions and attrition were 41.8%. Reasons for exclusion included being HIV-positive or HIV-indeterminate at baseline or those who seroconverted. Reasons for attrition were not provided.

Selective reporting (reporting bias)Low riskComment: results of all expected outcomes were presented in various publications.

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)."

Rahmathullah 2003

MethodsRandomised, placebo controlled, community based trial.


ParticipantsLive born infants that resulted from all pregnancies within participating villages were eligible for participation. Pregnant women (>12 weeks) were identified for recruitment from a variety of sources. The infants were randomly assigned to receive either the intervention, or placebo.

Exclusions after randomisation were stillbirths, miscarriages, delivery more than 20 km outside the study area, and infants, who died before the study team reached.


InterventionsInfants received 24,000 IU of vitamin A twice within a 24 hour interval, beginning within 48 hours of birth, or placebo.


OutcomesInfant mortality at 6 months, cause-specific mortality at 6 months, incidence of common morbidities and pneumococcal colonization


Notes
  • Conducted between June 1998 and March 2001 in two rural districts of Tamil Nadu, southern India. 
  • These areas are characterized by endemic vitamin A deficiency.
  • An expected infant mortality at 6 months of age of 52.5 per 1000 live births.
  • Approximately 80% of participants were supplemented within 48 hours of birth.
  • Treatment groups were comparable at baseline.


Risk of bias

BiasAuthors' judgementSupport for judgement

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

Comment: method used to generate the randomisation sequence is not described in sufficient detail to permit judgement.

Allocation concealment (selection bias)Unclear riskQuote: "For twins, the first born received the assigned treatment and the second born the other treatment. For triplets, the first two born infants were handled as twins and the third born received the originally assigned treatment."

Comment: insufficient information provided to judge allocation concealment for singleton births. However, for triplets (only 2 in the data set), allocation concealment did not hold.

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "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".

Comment: blinding of participants, study personnel and outcome assessors was probably done.

Incomplete outcome data (attrition bias)
All outcomes
Low riskExclusions and attrition was 18.9%. Reasons and distributions in the two treatment groups were reported. Mortality in infants born alive but not enrolled was similar in treatment groups.

Selective reporting (reporting bias)Low riskComment: outcomes mentioned in the methods section were reported. All expected outcomes were presented in published reports.

Other biasUnclear riskSupported by a grant from John Hopkins Universityand the Bill and Melinda Gates Foundation.

West 1995

MethodsThis trial was part of a large, cluster randomised, double masked, placebo controlled community trial in Nepal.


ParticipantsInfants ≤5 months of age were eligible for inclusion. No exclusion criteria given.


InterventionsIntervention group received an oral dose of vitamin A [15,000 RE (50,000 IU) in 3 drops of oil for neonates (< 1 mo of age) and 30,000 RE (100 000 IU) in 6 drops of oil for infants 1-5 mo of age or placebo [75 RE (250 IU) or 150 RE (500 IU), respectively]. A total of 11,918 infants (infants ≤5 months: intervention= 6086, control= 5832) were enrolled. Among these, the distribution of neonates was: intervention=791, control= 830.


Outcomes4 month mortality, cause specific mortality and adverse effect noted after 24 hours of dosing (vomiting, loose stools, fever, irritability, bulging fontanelles).


Notes
  • Was conducted in district of Sarlahi, Nepal between September 1989 and December 1991.
  • Evaluated the effect of VAS every 4 month on preschool child mortality.
  • No information about gestational age and birth weight recorded and almost all neonates were supplemented after the first week of life (Keith West; personnel communication 2008)
  • Treatment groups were comparable at baseline.
  • The 4-month mortality estimates have been included in the 6 month mortality analysis
  • This trial measured adverse effects approximately 24 hours after supplementation whereas 2 other trials reported adverse effects 48-72 hours after supplementation. Because of the difference in the timing of measurement of adverse effects, we did not include the 24 hour measurements from this trial in the analysis. This trial found no difference in the incidence of various adverse effects after 24 hours of supplementation in the two groups of neonates.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "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."

Comment: method used for the first random assignment is not described in sufficient detail to permit judgement.

Allocation concealment (selection bias)Unclear riskComment: It is unclear as the wards were assigned systematically

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "gelatinous capsules of identical appearance, size (8*16mm), and taste" and "double-masked" and "capsule codes were broken" (noted from methods section of the larger trial paper).

Comment: blinding of participants, study personnel and outcome assessors was probably done.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition among neonates was 1.04% reasons for which were not provided. All analyses 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)Low riskComment: published reports included all expected outcomes.

Other biasUnclear riskSupported by a grant from John Hopkins University and assistance from Hoffmann-LaRoche industry (Basel, Switzerland). A protocol is described but no details are provided.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Bezzera 2009This study included supplementation of mothers only with vitamin A supplements in the immediate postpartum period and there was no supplementation of neonates with vitamin A.

Bhaskaram 1998This study included supplementation of mothers only with vitamin A supplements within 24 hours of delivery while all neonates were given oral poliovirus vaccine (OPV) between 48 and 72 hours after birth.

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

Trial name or titleEfficacy of newborn vitamin A supplementation in improving child survival in rural Ghana: generation of evidence necessary for informing global policy (Neovita)

MethodsDouble blind, randomised, placebo controlled trial in 7 contiguous districts (Kintampo North, Kintampo South, Wenchi, Tain, Techiman, Nkoranza North and Nkoranza South) in the Brong Ahafo region of central rural Ghana.

ParticipantsInclusion criteria is all births in the study area that are contacted by the study team on the day of birth or in the next 2 days. Both singleton and multiple births are eligible for inclusion in this study and each infant will be provided with their own unique study identification number. Infants will be included even if they were not identified during pregnancy surveillance.

Exclusion criteria is if the neonate is unable to feed on offering feeds, as reported by the mother or the mother does not intend to stay in the study area for at least 6 months.

InterventionsIntervention includes vitamin A 50,000 International Units (IU) once orally within the first 3 days of life keeping a minimum period of 2 hours between the birth and the dosing.

Placebo capsule of soy bean oil once orally within the first 3 days of life.

OutcomesAll cause early infant mortality (0-5 months) assessed at 6 months of age, all cause neonatal mortality (0-1 month) assessed at 1 month, incidence of severe morbidity defined as hospitalisations due to any illness in the first 6 months of infancy, potential adverse effects of vitamin A such as bulging fontanelle, vomiting, irritability, fever, diarrhoea, inability to suck or feed, convulsions or any other condition that caused parents to be concerned, in the 3 days period following administration of the supplement, and vitamin A and C reactive protein (CRP) status of a subsample of infants at 2 weeks and 3 months of age.

Starting dateAnticipated date of first participant enrolment: Aug 16, 2010

Contact informationKaren Edmond

London School of Hygiene and Tropical Medicine, Keppel St London, WC1E7HT, UK

Email: karen.edmond@lshtm.ac.uk

NotesTarget sample size: 28000

India 2010

Trial name or titleEfficacy of Neonatal Vitamin A Supplementation in Improving Child Survival in Haryana, India: Generation of Evidence Necessary for Informing Global Policy (NeoVitA Trial)

MethodsDouble blind, randomised, placebo controlled trial in two districts in the state of Haryana, India.

ParticipantsInclusion criteria is all births in the study area that are contacted by the enrolment team within the eligible age window (up to 60 hours of birth) and parent's consent to participate.

Exclusion criteria is neonate unable to feed on offering feeds, as reported by the mother or mother does not intend to stay in the study area for at least 6 months.

InterventionsIntervention includes 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 of birth keeping a minimum period of 2 hours between the birth and the dosing.

Placebo capsules will contain minute amounts of vitamin E in soybean oil.

OutcomesInfant mortality at 6 months, mortality in the neonatal period (first month of life), incidence of severe morbidity defined as hospitalizations due to any illness in the first 6 months of infancy; bulging fontanelle, vomiting, irritability, fever, diarrhea, inability to suck or feed, convulsions or any other conditions that caused parents to be concerned, in the 3 day period following administration of the supplement; and vitamin A status in a subgroup of newborns and caregivers.

Starting dateJune 2010

Contact informationNita Bhandari

Society for Applied Studies

New Delhi, Delhi, India, 110016

00 91 11 46043751-55 ext 201    

Email: CHRD@sas.org.in  

NotesEstimated enrolment: 40200

Estimated study completion date: November 2013

Pakistan 2008

Trial name or titleFeasibility study of delivering a neonatal dose of vitamin A through the Lady Health Workers (LHWs) program in Pakistan

MethodsCluster randomised, double blind, placebo controlled trial in Sukkhur and Jehlum districts in Pakistan.

ParticipantsInclusion criteria is live born infants from all pregnancies within participating villages.

Exclusion criteria is a child born with congenital malformation, serious birth injury, birth asphyxia, serious infections, gestational age less than 32 weeks, birthweight less than 1500 gms and refuse to participate.

InterventionsIntervention includes routine postpartum care and vitamin A supplementation (50,000 IU) to the newborn within 48-72 hours of birth.

Control group receives routine postpartum care and placebo.

OutcomesAll cause infant mortality at 6 months, cause-specific infant mortality at 6 months of age, serum retinol values, rates of breastfeeding and incidence of serious infections (sepsis, pneumonia and diarrhoea).

Starting dateJanuary 2007

Contact informationZulfiqar A Bhutta

Division of Women & Child Health

The Aga Khan University, Karachi 74800, Pakistan

Email : zulfiqar.bhutta@aku.edu

NotesEstimated enrolment: 7400

Expected completion date: April 2010

Tanzania 2010

Trial name or titleEfficacy of newborn vitamin A supplementation in improving child survival in Tanzania: generation of evidence necessary for informing global policy

MethodsDouble blind, randomised, placebo controlled trial in Dar-es-Salaam, and Kilombero and Ulanga districts in Ifakara, Tanzania.

ParticipantsInclusion criteria is all births in the study area that are between two hours and two days of age, whose caretakers confirm of intention to remain in the study areas for a minimum of six months thereafter. Both singleton and multiple births are eligible for inclusion in this study and each infant will be provided with their own unique study identification number. Infants will be included even if they were not identified during pregnancy surveillance.

Exclusion criteria is if the neonate is unable to feed on offering feeds, the mother does not intend to stay in the study area for at least 6 months and women younger than 18 years old.

InterventionsIntervention includes vitamin A 50,000 International Units (IU) as retinol palmitate and minute amounts of vitamin E in soybean oil, once orally within the first 3 days of life keeping a minimum period of 2 hours between the birth and the dosing.

Placebo capsule with minute amounts of vitamin E in soybean oil once orally within the first 3 days of life.

OutcomesInfant mortality assessed at 6 months of age, neonatal mortality (0-1 month) assessed at 1 month, incidence of severe morbidity defined as hospitalizations due to any illness in the first 6 months of infancy, potential adverse effects of vitamin A such as bulging fontanelle, vomiting, irritability, fever, diarrhoea, inability to suck or feed, convulsions or any other condition that caused parents to be concerned, in the 3 days period following administration of the supplement, and vitamin A and C reactive protein (CRP) status of a subsample of infants at 2 weeks and 3 months of age.

Starting dateAnticipated date of first participant enrolment: July 1, 2010

Contact informationHonorati Masanja

Ifakara Health Institute, PO Box 78373, Dar-es-Salaam,

Tanzania

Email: hmasanja@ihi.or.tz

NotesTarget sample size: 32,000

 
Comparison 1. Neonatal vitamin A supplementation versus control

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

 1 All-cause infant mortality at 6 months: risk ratios based on cumulative risk (%, adjusted for clustering)5Risk Ratio (Fixed, 95% CI)Subtotals only

    1.1 Term infants
322721Risk Ratio (Fixed, 95% CI)0.82 [0.68, 0.99]

    1.2 All infants
539040Risk Ratio (Fixed, 95% CI)0.86 [0.77, 0.97]

 2 All-cause infant mortality at 6 months: rate ratios (per years of follow-up)4Rate Ratio (Fixed, 95% CI)Subtotals only

    2.1 Term infants
2Rate Ratio (Fixed, 95% CI)0.91 [0.73, 1.13]

    2.2 All infants
4Rate Ratio (Fixed, 95% CI)0.91 [0.77, 1.06]

 3 All-cause infant mortality at 12 months (all infants): risk ratios based on cumulative risk (%)415731Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.87, 1.20]

 4 All-cause infant mortality at 12 months: rate ratios (per years of follow-up)4Rate Ratio (Fixed, 95% CI)Subtotals only

    4.1 Term infants
2Rate Ratio (Fixed, 95% CI)0.95 [0.72, 1.26]

    4.2 All infants
4Rate Ratio (Fixed, 95% CI)1.03 [0.87, 1.23]

 5 Cause-specific infant mortality at 6 months (all infants): Diarrhea2 (Fixed, 95% CI)Totals not selected

    5.1 Risk ratio
1 (Fixed, 95% CI)0.0 [0.0, 0.0]

    5.2 Rate ratio
1 (Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Cause-specific infant mortality at 6 months (all infants): Respiratory infections2 (Fixed, 95% CI)Totals not selected

    6.1 Risk ratio
1 (Fixed, 95% CI)0.0 [0.0, 0.0]

    6.2 Rate ratio
1 (Fixed, 95% CI)0.0 [0.0, 0.0]

 7 Cause-specific infant mortality at 12 months (all infants): Diarrhoea3 (Fixed, 95% CI)Subtotals only

    7.1 Risk ratios
1 (Fixed, 95% CI)0.40 [0.08, 2.03]

    7.2 Rate ratios
2 (Fixed, 95% CI)1.32 [0.80, 2.16]

 8 Cause-speciifc infant mortality at 12 months (all infants): Respiratory infections3 (Fixed, 95% CI)Subtotals only

    8.1 Risk ratios
1 (Fixed, 95% CI)0.66 [0.11, 3.95]

    8.2 Rate ratios
2 (Fixed, 95% CI)0.97 [0.67, 1.42]

 9 Infant morbidity at 6 months (rate ratio): Diarrhoea2Rate ratio (Fixed, 95% CI)1.05 [0.99, 1.10]

 10 Infant morbidity at 6 months (rate ratio): Respiratory infections2Rate ratio (Fixed, 95% CI)1.01 [0.96, 1.05]

 11 Vitamin A deficient (serum retinol <0.70 micromol/L) at 6 weeks of age1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 12 Vitamin A deficient (serum retinol <0.70 micromol/L) at 4 months of age1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 13 Anaemia (haemoglobin <105g/L) at 8-14 months of age1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 14 Adverse events during the first 48-72 hours post supplementation2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    14.1 Bulging fontanelle
23158Risk Ratio (M-H, Fixed, 95% CI)1.38 [1.04, 1.82]

    14.2 Diarrhoea
23159Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.77, 1.09]

    14.3 Vomiting
23159Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.74, 1.05]

 15 Adverse events during the first month post supplementation1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    15.1 Diarrhoea
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    15.2 Vomiting
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Summary of findings for the main comparison. Neonatal vitamin A supplementation versus control for the prevention of mortality and morbidity in term neonates in developing countries

Neonatal vitamin A supplementation versus control for the prevention of mortality and morbidity in term neonates in developing countries

Patient or population: mortality and morbidity in term neonates
Settings: low and middle income countries
Intervention: neonatal vitamin A supplementation

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

Assumed riskCorresponding risk

Controlneonatal vitamin A supplementation

All cause infant mortality at 6 months
Follow-up: 6 months
Low risk populationRR 0.82
(0.68 to 0.99)
22721
(3 studies)
⊕⊕⊝⊝
low1,2,3

13 per 100011 per 1000
(9 to 13)

Medium risk population

15 per 100012 per 1000
(10 to 15)

High risk population

28 per 100023 per 1000
(19 to 28)

All cause infant mortality at 12 months
child years of follow-up
Follow-up: 12 months
Low risk population4Rate ratio 0.95
(0.72 to 1.26)
5732
(2 studies)
⊕⊕⊝⊝
low3,5,6

13 per 100012 per 1000
(9 to 16)

High risk population4

46 per 100043 per 1000
(33 to 58)

Adverse events: Bulging fontanelle
Follow-up: 3 days
Low risk populationRR 1.38
(1.04 to 1.82)
3158
(2 studies)
⊕⊕⊕⊕
high3,7,8

25 per 100035 per 1000
(26 to 46)

High risk population

94 per 1000130 per 1000
(98 to 171)

Adverse events: Vomiting
Follow-up: 3 days
145 per 1000128 per 1000
(107 to 152)
RR 0.88
(0.74 to 1.05)
3159
(2 studies)
⊕⊕⊕⊝
moderate7,8,9

Adverse events: Diarrhoea
Follow-up: 3 days
51 per 100047 per 1000
(39 to 56)
RR 0.92
(0.77 to 1.09)
3159
(2 studies)
⊕⊕⊕⊝
moderate7,8,10

*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 The risk of bias assessment identified a possible issue over the stopping procedure in Klemm 2008. A higher rate of mortality was observed in the placebo group after 2/3 participants had been randomised. This study dominated the analysis (65% weight).
2 The level of statistical heterogeneity between the results of the studies was moderate (I square 63%). The variation between the studies may have been related to differences between the study populations and settings in terms of infant mortality rates and baseline prevalence of vitamin A deficiency.
3 It should be noted that there are a number of ongoing studies. The funnel plots did not indicate substantial asymmetry. The review concluded that firm policy recommendations could not be made until the studies are complete and contribute to the review.
4 The rate reflects the number of events per 1000 years of child follow-up.
5 Very high levels of statistical heterogeneity (I square 82%).
6 The 95% confidence intervals include a substantial reduction in rate of mortality by 28% (translating to a reduction of 4 and 13 events/1000 child years in low and high risk populations), as well as a substantial increase in the mortality rate of 26% (translating to an increase of 3 and 12 events/1000 child years in low and high risk populations).
7 The population for these outcomes includes all infants (i.e. term and pre-term).
8 Only two of the included studies reported this outcome. The authors note that data reported on this outcome specified different timepoints and could not be formally used in the meta-analysis.
9 In view of the high event rates for this outcome, the width of the confidence intervals lead to substantial variation in the absolute effect from a protective effect of vitamin A to an increase in the risk of vomiting.
10 There was a high level of statistical heterogeneity (I square 80%).
 
Table 1. Data type and source: all-cause infant mortality at 6 months

Study IDAnalyzed as Rate/Risk ratioData source (term/all infants)InfantsVitamin A group:

Deaths
Vitamin A group:

Child-years of follow-up
Vitamin A group:

N
Control group:

Deaths
Control group:

Child-years of follow-up
Control group:

N

Benn 2008Rate ratioCorrespondence with study investigatorsAll infants55964-501003-

Benn 2010Rate ratioCorrespondence with study investigatorsAll infants62393-62397-

Humphrey 1996Risk ratioCorrespondence with study investigators (denominators are number of neonates randomised)All infants7-103418-1033

Term infants6-101115-1007

Klemm 2008Risk ratioKlemm at al, Pediatrics 2008;122(1):e242-50.All infants306-7953360-7984

Term infants129-6109171-6061

Malaba 2005Risk ratioCorrespondence with study investigators. Data aggregated for the four treatment groups: Maternal vitamin A and infant vitamin A + maternal placebo and infant vitamin A versus maternal placebo and infant placebo + maternal vitamin A and infant placebo (For term infants, denominators are number of HIV negative mothers with term deliveries)All infants73-430966-4352

Term infants62-425357-4280

Rahmathullah 2003Rate ratio/Risk ratioRahmathullah et al, BMJ 2003;327(7409):254.All infants146271353631882719.15408

Correspondence with study investigatorsTerm infants1062348.7-1302346.7-

West 1995Rate ratio/Risk ratioWest et al, American Journal of Clinical Nutrition 1995;62(1):143-8. Data were extracted for infants under 1 month old who had been allocated to treatment.All infants38268.481934256.9785

 Klemm 2008 was a cluster randomised study. The study authors reported that observed design effect was 0.9%.
West 1995 was a cluster randomised study. The study authors reported that the 95% confidence intervals of the effect estimates were inflated by 10% to account for the impact of the design on the study. We estimated that the 10% increase in the 95% CIs gave an ICC of 0.04 for the cohort of infants administered Vitamin A.
 
Table 2. Data type and source: all-cause infant mortality at 12 months

Study IDAnalyzed as Rate/Risk ratioData sourceInfantsVitamin A group:

Deaths
Vitamin A group:

Child-years of follow-up
Vitamin A group:

N
Control group:

Deaths
Control group:

Child-years of follow-up
Control group:

N

Benn 2008Rate ratio/risk ratioBenn et al, BMJ 2008;336(7658):1416-20.All infants88179521068618842169

Benn 2010Rate ratio/risk ratioBenn et al, BMJ 2010;340:c1101.All infants8375770178762710

Humphrey 1996Rate ratio/risk ratioHumphrey et al, Journal of Pediatrics 1996;128(4):489-96.All infants (includes 6% preterms)7969.692519957.1914

Klemm 2008---------

Malaba 2005Rate ratio/risk ratioMalaba et al, The American Journal of Clinical Nutrition 2005;81(2):454-60. Data aggregated for the four treatment groups: Maternal vitamin A and infant vitamin A + maternal placebo and infant vitamin A versus maternal placebo and infant placebo + maternal vitamin A and infant placebo.All infants88419540798242394127

Rahmathullah 2003---------

West 1995---------