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Neonatal vitamin A supplementation for the prevention of mortality and morbidity in term neonates in low and middle income countries

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Authors

Batool A Haider1,,Renee Sharma2, Zulfiqar A Bhutta2

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Department of Global Health and Population, Harvard School of Public Health, Boston, MA, USA [top]
2Centre for Global Child Health, Hospital for Sick Children, Toronto, Canada [top]

Citation example: Haider BA, Sharma R, Bhutta ZA. Neonatal vitamin A supplementation for the prevention of mortality and morbidity in term neonates in low and middle income countries. Cochrane Database of Systematic Reviews 2017, Issue 2. Art. No.: CD006980. DOI: 10.1002/14651858.CD006980.pub3.

Contact person

Zulfiqar A Bhutta

Centre for Global Child Health
Hospital for Sick Children
Toronto ON M5G A04
Canada

E-mail: Zulfiqar.bhutta@sickkids.ca
E-mail 2: zulfiqar.bhutta@aku.edu

Dates

Assessed as Up-to-date: 13 March 2016
Date of Search: 13 March 2016
Next Stage Expected: 13 March 2018
Protocol First Published: Issue 1, 2008
Review First Published: Issue 10, 2011
Last Citation Issue: Issue 2, 2017

What's new

Date / Event Description
18 July 2016
Updated

We found 5 new studies during the updated literature search in March 2016. We added a new subgroup for sex of the neonate, along with a new outcome of all-cause neonatal mortality.

18 July 2016
New citation: conclusions changed

We added to this update new outcomes and new studies that have altered conclusions.

History

Date / Event Description
13 March 2012
Amended

We corrected a minor typographical error.

14 May 2008
Amended

We made a needed reference correction.

08 May 2008
Amended

We converted this review to new review format.

12 October 2007
New citation: major change

We made substantive amendments to this review.

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Abstract

Background

Vitamin A deficiency is a major public health problem in low and middle income countries. Vitamin A supplementation in children six months of age and older has been found to be beneficial, but no effect of supplementation has been noted for children between one and five months of age. Supplementation during the neonatal period has been suggested to have an impact by increasing body stores in early infancy.

Objectives

To evaluate the role of vitamin A supplementation for term neonates in low and middle income countries with respect to prevention of mortality and morbidity.

Search methods

We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2), MEDLINE via PubMed (1966 to 13 March 2016), Embase (1980 to 13 March 2016) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 13 March 2016). We also searched clinical trials databases, conference proceedings and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.

Selection criteria

Randomised and quasi-randomised controlled trials. Also trials with a factorial design.

Data collection and analysis

Two review authors independently assessed trial quality and extracted study data. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence.

Main results

We included 12 trials (168,460 neonates) in this review, with only a few trials reporting disaggregated data for term infants. Therefore, we analysed data and presented estimates for term infants (when specified) and for all infants.

Data for term neonates from three studies did not show a statistically significant effect on the risk of infant mortality at six months in the vitamin A group compared with the control group (typical risk ratio (RR) 0.80; 95% confidence interval (CI) 0.54 to 1.18; I2 = 63%). Analysis of data for all infants from 11 studies revealed no evidence of a significant reduction in the risk of infant mortality at six months among neonates supplemented with vitamin A compared with control neonates (typical RR 0.98, 95% CI 0.89 to 1.07; I2 = 47%). We observed similar results for infant mortality at 12 months of age with no significant effect of vitamin A compared with control (typical RR 1.04, 95% CI 0.94 to 1.15; I2 = 47%). Limited data were available for the outcomes of cause-specific mortality and morbidity, vitamin A deficiency, anaemia and adverse events.

Authors' conclusions

Given the high burden of death among children younger than five years of age in low and middle income countries, and the fact that mortality in infancy is a major contributory cause, it is critical to obtain sound scientific evidence of the effect of vitamin A supplementation during the neonatal period on infant mortality and morbidity. Evidence provided in this review does not indicate a potential beneficial effect of vitamin A supplementation among neonates at birth in reducing mortality during the first six months or 12 months of life. Given this finding and the absence of a clear indication of the biological mechanism through which vitamin A could affect mortality, along with substantial conflicting findings from individual studies conducted in settings with potentially varying levels of maternal vitamin A deficiency and infant mortality, absence of follow-up studies assessing any long-term impact of a bulging fontanelle after supplementation and the finding of a potentially harmful effect among female infants, additional research is warranted before a decision can be reached regarding policy recommendations for this intervention.

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Plain language summary

Neonatal vitamin A supplementation for prevention of mortality and morbidity among term neonates in low and middle income countries

 

Review question: Does vitamin A supplementation among term neonates in low and middle income countries prevent mortality and morbidity?

Background: Vitamin A is an important micronutrient that is required for maintenance of normal functioning of the human body. In the developing world, many pregnant women are vitamin A deficient. During pregnancy, additional vitamin A is required to promote growth of the baby and to provide stores in the baby's liver. Deficiency of this micronutrient in the mother may lead to its deficiency in the baby and may result in adverse effects on the baby's health. The benefits of giving vitamin A to children older than six months of age for reducing death and adverse effects on health have been established, but no available evidence shows this beneficial effect among infants one to five months of age. Potential benefits of vitamin A supplementation during the newborn period (during the first month of life) are under investigation.

Study characteristics: The present review identified 12 studies including 168,460 newborns in which the intervention group was supplemented with vitamin A during the newborn period.

Key results: Analysis of data for all infants shows no significant reduction in infant deaths at six months of age with the intervention and similar findings for infant deaths at 12 months of age.

Quality of evidence: We judged the quality of evidence as high for the most important clinical outcomes, with the exception of two outcomes that we scored as having low and very low quality: ‘diarrhoeal events during the first 48-72 hours post supplementation’ and ‘all-cause infant mortality at 6 months in term infants’, respectively.

Background

Description of the condition

Vitamin A deficiency is considered a major public health problem in low and middle income countries (WHO 2009). Globally, 9.8 million pregnant women are affected by night blindness, and more than 19 million have low serum retinol concentrations (< 0.70 µmol/L). Night blindness affects 5.2 million preschool children, and an estimated 190 million have low serum retinol concentrations. The prevalence of low serum retinol concentrations among pregnant women is highest in South-East Asia (17.3%), followed by Africa (13.5%), whereas the prevalence of night blindness is approximately the same in the two regions (9.9% in South-East Asia vs 9.8% in Africa) (WHO 2009).

Deficiency of vitamin A may be secondary to decreased ingestion, defective absorption and altered metabolism or increased requirements. Factors such as low dietary fat intake or intestinal infection may also interfere with absorption of vitamin A. Vitamin A deficiency is the most important cause of childhood blindness and contributes significantly to morbidity and mortality from common childhood infections (WHO 2016).

Description of the intervention

Vitamin A is an essential micronutrient that is required for maintenance of normal functioning of the human body. It was the first fat-soluble vitamin to be discovered and for nearly a century has been known to be an important dietary constituent (Hopkins 1912; McCollum 1915). Vitamin A is part of a family of compounds called retinoids; naturally occurring retinoids include retinol, retinal and retinoic acid. For human physiology, retinol is the predominant form and 11-cis-retinol is the active form. Inactive retinoids, also known as provitamin A, are produced as plant pigments and are called carotenoids. Although many carotenoids are found in foods, only about 50% can be metabolised into active retinoid forms. Beta-carotene, a retinol dimer, has the most significant provitamin A activity. Vitamin A is stored in the liver as retinyl esters and, when needed, is transported into blood, where it is carried by retinol binding protein (RBP) for delivery to other tissues (Bowman 2001).

Vitamin A is important for normal functioning of the visual system, as well as for immune response, gene expression, reproduction, embryogenesis and hematopoiesis. It is essential for maintenance of normal epithelial tissues throughout the body (Bowman 2001). Preformed vitamin A is found only in animal foods such as liver, fish and dairy products (such as milk, cheese and butter); it constitutes 65% to 75% of dietary vitamin A intake. Remaining dietary vitamin A is obtained from carotenoids present in plant sources such as carrots, dark green leafy vegetables, red and orange fruits and red palm oil. Recommended Dietary Allowances (RDAs) for vitamin A vary with age. For healthy breast-fed infants up to six months of age, the average RDA is 400 µg/d, and for infants seven to 12 months of age, the RDA is 500 µg/d. For children one to three years and four to eight years old, the RDA is 300 µg/d and 400 µg/d, respectively (DRI 2001).

Routine consumption of large amounts of vitamin A over time can result in toxic symptoms, which include liver damage, headaches, vomiting, skin desquamation, bone abnormalities, joint pain and alopecia (Bowman 2001). Hypervitaminosis A appears to be due to abnormal transport and distribution of vitamin A and retinoids that is caused by overloading of plasma transport mechanisms. A very high single dose can also cause transient acute toxic symptoms that may include a bulging fontanelle in infants; headaches in older children and adults; and vomiting, diarrhoea, loss of appetite and irritability in all age groups. Toxicity from ingestion of food sources of preformed vitamin A is rare (Hathcock 1997).

How the intervention might work

During pregnancy, women need additional vitamin A (an additional increment of 100 µg/d above basal requirements during the full gestation period) to sustain growth of the foetus and to provide a limited reserve in the foetal liver, as well as to maintain the woman's own tissue growth. Because therapeutic levels of vitamin A are generally higher than preventive levels, the safe intake level recommended during pregnancy is 800 µg retinol equivalents (RE)/d. Women who are or who might become pregnant should carefully limit their total daily vitamin A intake to a maximum of 3000 µg RE (10,000 IU) to minimise risk of foetal toxicity (WHO/NUT 1998). Infants have very low levels of vitamin A stored in the liver at birth and are dependent on breast milk as a source of vitamin A during the first few months of life. Thus, maternal vitamin A deficiency during lactation, early weaning or artificial feeding may result in vitamin A deficiency among infants (Underwood 1994). The physiological vitamin A needs of infants born to vitamin A-adequate mothers and fed breast milk with adequate vitamin A (in excess of 30 µg/dL, or 1.05 µmol/L) are met for at least the first six months of life (Underwood 1994). Because of the need for vitamin A to promote growth in infancy, the rate of which can vary considerably, a requirement estimate of 180 µg RE/d seems appropriate. Average consumption of human milk by such infants is about 750 mL/d during the first six months (WHO/NUT/98.1 1998). If an average concentration of vitamin A in human milk of about 1.75 mmol/L is assumed, mean daily intake would have to be about 375 µg RE, which is therefore the recommended safe level.

Why it is important to do this review

The role of vitamin A supplementation for children older than six months of age is well established (Beaton 1993; Imdad 2010; Rice 2004). Beaton and colleagues in their meta-analysis showed that vitamin A supplementation in children six months to five years of age significantly reduced mortality by 23% (Beaton 1993). A recent Cochrane review concluded that two oral doses of 200,000 IU of vitamin A given on consecutive days to children younger than two years of age with measles were associated with reduced risk of overall mortality (risk ratio (RR) 0.18, 95% confidence interval (CI) 0.03 to 0.61) and pneumonia-specific mortality (RR 0.33, 95% CI 0.08 to 0.92) (Huiming 2005). The World Health Organization (WHO) recommends administration of vitamin A during vaccination contacts to prevent vitamin A deficiency (WHO 1998). The policy of WHO has been to supplement vitamin A by providing 100,000 IU at the earliest possible opportunity after six months of age. However, it is now recommended that an additional 50,000 IU of vitamin A be administered with each of the diphtheria-tetanus-pertussis (DTP) and polio vaccinations, which usually are given at six, 10 and 14 weeks of age (Sommer 2002). National and regional programmes of vitamin A supplementation, which are in place in more than 60 countries worldwide, target children older than six months of age (Fawzi 2006). Not only are these programmes highly effective in reducing mortality and morbidity, but in countries in which vitamin A deficiency constitutes a public health problem, they appear to be among the most cost-effective public health interventions available. Such programmes seek to maximise child survival among children older than six months - the group that accounts for a quarter of deaths in children younger than five years of age. To address the major proportion of deaths in children younger than five, programmes should target children younger than six months of age. Supplementation with vitamin A between one and five months of age has been found to have no beneficial effect (Daulaire 1992; Rahman 1995; WHO/CHD 1998). Supplementation of neonates has been suggested as a feasible approach to bolstering body stores of vitamin A during early infancy, thereby having an impact on mortality and morbidity (Sommer 1995). Several randomised clinical trials and systematic reviews have evaluated this approach (Benn 2008; Benn 2010; Benn 2014; Bhutta 2016; Edmond 2015; Haider 2011; Haider 2015; Humphrey 1996; Klemm 2008; Malaba 2005; Masanja 2015; Mazumder 2015; Rahmathullah 2003; West 1995). This review updates the previous Cochrance review on this topic, which was published in 2011 (Haider 2011), and includes trials published since the time of the previous publication.

Objectives

To evaluate the role of vitamin A supplementation for term neonates in low and middle income countries with respect to prevention of mortality and morbidity.

Methods

Criteria for considering studies for this review

Types of studies

We included in this review all randomised controlled trials (RCTs), both individually randomised and cluster-randomised, irrespective of publication status and language, conducted to evaluate effects of vitamin A supplementation for term neonates in low and middle income countries. We also included studies using a factorial design and quasi-randomised trials.

Types of participants

We included all term neonates (born between 37 and 42 weeks' gestational age) up to 28 days after birth.

Types of interventions

Studies compared supplementation with vitamin A within the first 28 days of life against a control (placebo or no supplementation). We excluded from the review any trial with continued supplementation beyond the first 28 days of life. Co-interventions, if any, should have been identical in the two groups.

Types of outcome measures

Primary outcomes
  • All-cause infant mortality at six months and 12 months
Secondary outcomes
  • Cause-specific infant mortality associated with acute respiratory infection and diarrhoea at six months and 12 months
  • Infant morbidity at six months of age, associated with acute respiratory infection and diarrhoea, measured as at least one episode of morbidity
  • Biochemical indicator values of vitamin A deficiency (vitamin A deficiency measured as serum retinol < 0.70 µmol/L)
  • Blindness and signs of xerophthalmia (Bitot's spots and corneal lesions)
  • Mean haemoglobin level or anaemia defined as haemoglobin less than the age-specific cut-off value as stated by study authors
  • Adverse events reported in trials due to vitamin A toxicity such as bulging fontanelles, vomiting and diarrhoea
  • All-cause neonatal mortality (between supplementation and 28 days of age)

Search methods for identification of studies

For the March 2016 update:

  • We conducted a comprehensive search including Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2) in the Cochrane Library; MEDLINE via PubMed (1966 to 13 March 2016); Embase (1980 to 13 March 2016); and Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 13 March 2016) using the following search terms: (vitamin A OR retinol OR retinoid OR retinoic OR vitamin A [MeSH]), plus database-specific limiters for RCTs and neonates (see Appendix 1 for full search strategies for each database). We applied no language or date restrictions.
  • We searched clinical trials registries for ongoing and recently completed trials (clinicaltrials.gov; World Health Organization’s International Trials Registry and Platform - www.who.int/ictrp/search/en/ External Web Site Policy and the ISRCTN Registry External Web Site Policy).

For prior searches:

  • We used the standard search strategy of the Cochrane Neonatal Review Group. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 14 June 2010) in the Cochrane Library; and Embase and MEDLINE (1966 to May 2010) via PubMed using the following search terms: (Newborn OR infan* OR neonat*) AND (vitamin A OR retino*). We limited our search to the clinical trial publication type.
  • We limited searches to human studies and applied no language restrictions. We also searched related conference proceedings for relevant abstracts. We contacted organisations and researchers in the field for information on unpublished and ongoing trials and searched reference lists of all trials identified by the above methods. For further identification of ongoing trials, we searched the websites www.clinicaltrials.gov and http://www.anzctr.org.au/ External Web Site Policy.

Data collection and analysis

Selection of studies

Two review authors independently assessed for inclusion all potential studies identified as a result of the search strategy. We resolved disagreements through discussion.

Data extraction and management

We designed a form on which to record extracted data. For eligible studies, two review authors extracted data using the agreed form. We resolved discrepancies through discussion. We entered data into Review Manager software (RevMan 2008) and checked them for accuracy.

Assessment of risk of bias in included studies

Two review authors independently assessed risk of bias (low, high or unclear) of all included trials using the Cochrane ‘Risk of bias’ tool (Higgins 2011) for the following domains.

  • Selection bias.
  • Performance bias.
  • Attrition bias.
  • Reporting bias.
  • Any other bias.

We resolved disagreements by discussion or by consultation with a third assessor. See Appendix 2 for a more detailed description of risk of bias for each domain.

Measures of treatment effect

Dichotomous data

For dichotomous data, we presented results as summary risk ratios or rate ratios with 95% confidence intervals (CIs). 

Continuous data

We included no continuous outcomes in this review.

Unit of analysis issues

We included in this review three cluster-randomised trials (Bhutta 2016; Klemm 2008; West 1995). For Bhutta 2016, study investigators reported that the observed design effect and intracluster correlation coefficient (ICC) for neonatal mortality were 1.29 and 0.01, respectively. For infant mortality at six months, the observed design effect and ICC were 1.27 and 0.01. Klemm 2008 reported that the observed design effect was 0.9%. For West 1995, 95% CIs of effect estimates were inflated by 10% to account for the impact of design on study findings. We estimated that the 10% increase in 95% CIs yielded an ICC of 0.04 for the cohort of infants administered vitamin A.

Data synthesis

We analysed the data using a generic inverse variance approach to meta-analysis via Review Manager software (RevMan 2008) and generated risk ratio or rate ratio estimates with 95% CIs for dichotomous outcomes. For this approach, we entered data as natural logarithms (as log risk ratios and log rate ratios and standard error (SE) of log risk ratios and SE of log rate ratios) for each individual study, using data extracted from published papers or obtained from study authors if not presented in papers. We have presented data used for infant mortality analyses along with their sources in 'Additional tables'. We used the fixed-effect method for combining data when trials were examining the same intervention, and when we judged trial populations and methods as sufficiently similar.

The review objective was to evaluate the effect of vitamin A supplementation in term neonates. Studies included in this review had enrolled all births identified in their study settings without restriction for gestational age of < 37 or greater than/or equal to 37 weeks, which would have allowed us to use only term data. Three studies used birth weight as a criterion: Benn 2008 and Benn 2014 enrolled normal birth weight neonates (birth weight greater than/or equal to 2500 grams), and Benn 2010 recruited only low birth weight neonates (birth weight < 2500 grams). One study presented data for term neonates separately only in the published paper for the infant mortality outcome at six months (Klemm 2008). West 1995 (Keith West; personal communication, 2008) did not provide information about gestational age. Given the small number of studies included in the review and limited available data for primary outcomes, we analysed data for term neonates, when available, then performed analyses of data for all infants. For all secondary outcomes, investigators presented data for all infants together in published papers, and we analysed these data as such. As the inclusion criterion for both Benn 2008 and Benn 2014 was birth weight of at least 2500 grams, we assumed that a greater proportion of neonates would be term babies and analysed their data as such in our term neonate analysis. We used the term 'all infants' to refer to aggregated term and preterm infant data throughout this review.

Two studies provided maternal supplementation with vitamin A in the postpartum period (Malaba 2005) or during pregnancy (Klemm 2008). Malaba and colleagues randomised mother-infant pairs to four treatment arms (described in detail in the Characteristics of included studies table), whereas Klemm and associates randomised neonates within each of three previously randomised treatment arms of a maternal supplementation trial of vitamin A. This resulted in two neonatal treatment arms in Klemm 2008, which were balanced across maternal supplementation arms. Both studies reported no significant interaction between maternal and neonatal supplementation with vitamin A, and we included data for all neonates provided by these studies on the basis of their randomisation to the neonatal vitamin A intervention or control group.

Quality of evidence

We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, as outlined in the GRADE Handbook (Schünemann 2013), to assess the quality of evidence for the following (clinically relevant) outcomes.

  • All-cause infant mortality at six months.
  • All-cause neonatal mortality (between supplementation and 28 days of age).
  • Blindness and signs of xerophthalmia (Bitot's spots and corneal lesions).
  • Adverse events reported in trials due to vitamin A toxicity: bulging fontanelles.
  • Adverse events reported in trials due to vitamin A toxicity: vomiting.
  • Adverse events reported in trials due to vitamin A toxicity: diarrhoea.
  • Biochemical indicator values of vitamin A deficiency (vitamin A deficiency measured as serum retinol < 0.70 µmol/L).

Two review authors independently assessed the quality of evidence for each of the outcomes above. We considered evidence from RCTs as high quality but downgraded the evidence one level for serious (or two levels for very serious) limitations on the basis of the following: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates and presence of publication bias. We used the GRADEpro GDT Guideline Development Tool to create Summary of findings table 1 to report the quality of the evidence.

The GRADE approach results in an assessment of the quality of a body of evidence according to one of four grades.

  • High: We are very confident that the true effect lies close to the estimate of effect.
  • Moderate: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of effect but may be substantially different.
  • Low: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of effect.
  • Very low: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

Subgroup analysis and investigation of heterogeneity

We prespecified the following subgroups to investigate heterogeneity.

  • Maternal vitamin A supplementation.
  • Birth weight of neonates.
  • HIV status of mother and infant.
  • Dose and frequency of vitamin A used.
  • High baseline infant mortality.
  • Comorbidities.
  • Timing of vitamin A supplementation (within the first 48 to 72 hours or later).
  • Sex of the neonate.
  • Geographic region.

We measured heterogeneity among trials by calculating the I2 statistic. We considered values of the I2 statistic greater than 50% to represent substantial heterogeneity, in which case we planned to explore heterogeneity by undertaking prespecified subgroup analysis. However, the small number of studies included in the review precluded evaluation of heterogeneity, when identified. We conducted subgroup analysis by geographic region and sex of the infant for mortality outcomes for all infants in response to the special interest of the scientific community in evaluating this differential effect.

We planned to investigate publication bias for outcomes if we identified more than 10 studies for inclusion. However, we did not investigate this bias as the number of studies included was small.

Results

Description of studies

Included studies

We included in this review 12 studies including 168,460 neonates (Figure 1).

Humphrey 1996 was conducted in a single tertiary care hospital in Indonesia as a safety trial for vitamin A supplementation at the time of birth. In this randomised double-blind placebo-controlled trial of 2067 infants with birth weight > 1500 grams and without critical illness, researchers randomly assigned infants to receive a single oral dose of vitamin A (50,000 IU) or placebo within 24 hours of delivery. Maternal, infant and household characteristics were similar in the two groups at baseline.

West 1995 was part of a large cluster-randomised, double-blind, placebo-controlled trial of vitamin A supplementation for preschool children conducted in Nepal. Investigators enrolled a total of 11,918 infants younger than six months, of whom 1621 were neonates, and administered vitamin A (50,000 IU to infants < one month old and 100,000 IU to infants one to less than/or equal to five months old) or placebo. Baseline characteristics of the two groups were similar.

Rahmathullah 2003 was also a randomised, double-blind, placebo-controlled trial conducted in India in which all live-born infants within participating villages were eligible for inclusion. Investigators enrolled a total of 11,619 newborn infants born to consenting mothers who were residing in the study area and administered two doses of vitamin A or placebo - the first dose within the first 48 hours of delivery and the second dose within 24 hours of the first dose. Baseline characteristics of families, mothers and infants were similar between treatment groups.

Malaba 2005 was a randomised, double-bind, placebo-controlled trial conducted in Zimbabwe in which investigators used a two-by-two factorial design. Mother-infant pairs were eligible for inclusion if the mother planned to reside in the study area after delivery; if neither of the two had a life-threatening illness; and if the infant's birth weight was > 1500 grams. Researchers enrolled around 14,110 infant-mother pairs within 96 hours of delivery and assigned them to one of the following groups: Aa (vitamin A supplementation for both mother and infant), Ap (vitamin A for mother and placebo for infant), pa (placebo for mother and vitamin A for infant) and pp (placebo for both mother and infant). The vitamin A dose for mothers was 400,000 IU, and for infants 50,000 IU. All treatment groups were similar at baseline in terms of maternal, household and other related variables.

Klemm 2008 was a cluster-randomised, double-bind, placebo-controlled trial conducted in Bangladesh that was nested within an ongoing parent trial of vitamin A supplementation for pregnant women. All infants born to consenting mothers from the original trial were included in the current trial. A total of 15,948 infants received vitamin A (50,000 IU) or placebo at home as soon as possible after birth. Baseline characteristics of mothers and infants in this study were comparable at baseline.

Benn et al conducted three studies in Guinea Bissau. Benn 2008 was a randomised, double-blind, placebo-controlled trial that included 4345 normal birth weight infants (birth weight greater than/or equal to 2500 grams). For births occurring at the national hospital or at local health centres, researchers invited mothers to participate in the study at the time of Bacille Calmette-Guérin (BCG) vaccination. For home births, they invited mothers to participate at the time of their visit to the local health centre for BCG vaccination. Study investigators randomised all infants with birth weight at least 2500 grams, with no serious medical condition or malformation and for whom parental consent was available, to oral drops of vitamin A (50,000 IU) or to placebo. Treatment groups were similar at baseline in terms of various characteristics. Conducted in parallel with Benn 2008, Benn 2010 was a two-by-two factorial, randomised, double-blind, placebo-controlled trial in low birth weight neonates (birth weight < 2500 grams) that included 1736 neonates randomised to 25,000 IU vitamin A or to placebo, as well as to early BCG vaccine or the usual late BCG vaccine. Investigators in Benn 2014, a double-blind, placebo-controlled randomised trial that included 6048 healthy normal birth weight neonates (> 2500 grams), randomly assigned infants in a 1:1:1 ratio to three different treatment groups: 50,000 IU of vitamin A; 25,000 IU of vitamin A; or placebo, concurrent with BCG vaccination.

Recent studies conducted in Ghana, Tanzania, India and Pakistan aimed to evaluate the effect of neonatal supplementation of 50,000 IU of vitamin A against control. All four studies were randomised, double-blind, placebo-controlled trials; the study conducted in Pakistan used a cluster-randomised design.

Edmond 2015, Masanja 2015 and Mazumder 2015 recruited participants who were at least two hours old; were identified at home or in facilities on the day of birth or over the next two days; were able to feed orally; were likely to stay in the study area for at least six months; and had received parental consent to participate. In all three studies, infant and maternal baseline characteristics were similar between intervention and control groups. Investigators conducted Edmond 2015 in seven contiguous districts in the Brong Ahafo region of central rural Ghana, with a sample size of 22,955 neonates; Masanja 2015, in the Morogoro and Dar es Salaam regions of Tanzania, with a sample size of 31,999 neonates; and Mazumder 2015, in two districts (Faridabad and Palwal) in the state of Haryana, India, with a sample size of 44,984 neonates. Masanja 2015 and Mazumder 2015 considered infants from both singleton and multiple births as eligible for enrolment.

Soofi and colleagues conducted a community-based, cluster-randomised, placebo-controlled trial in two districts (Sukkhur and Jehlum) of rural Pakistan (Bhutta 2016). All live-born infants within participating villages were potentially eligible for inclusion, and infants with obvious congenital malformations and birth weight less than 1500 grams were ineligible. Investigators randomised a total of 11,028 consecutively delivered neonates to receive vitamin A or placebo. Baseline characteristics of the two study arms were comparable.

See the Characteristics of included studies table for additional details.

Ongoing studies

McDonald 2014 is a double-blind, randomised, placebo-controlled trial conducted in a peri-urban area of The Gambia. Researchers recruited two hundred mother-infant pairs at the Sukuta Health Centre, a government health clinic in the Western coastal region of The Gambia. Inclusion criteria were singleton birth, birth weight greater than/or equal to 1500 grams, mothers over 18 years of age, residency within the study area and administration of birth vaccinations and vitamin A supplementation within 48 hours of birth. Exclusion criteria were infants with a congenital disease, a serious infection at birth or inability to feed, and mothers who were seriously ill at the time of enrolment, were participating in other studies and/or were HIV positive. Within 48 hours of birth, investigators randomised neonates to receive an oral dose of 50,000 IU vitamin A or placebo. The primary outcome is frequency of circulating T regulatory (Treg) cells expressing gut homing receptors in infants at 17 weeks post supplementation. Secondary outcomes are differences in thymus size, B cell immune responses and improved mucosal barrier function in infant participants. Recruitment and follow-up for this study are complete and data analysis is in progress.

See the Characteristics of ongoing studies table for additional details.

Excluded studies

We excluded five studies from the review (Ahmad 2014; Bezzera 2009; Bhaskaram 1998; Mathew 2015; Schmiedchen 2016). Bezzera 2009 provided vitamin A supplementation to mothers only in the immediate postpartum period and did not supplement neonates. Bhaskaram 1998 supplemented only mothers with vitamin A within 24 hours of delivery and gave all neonates oral poliovirus vaccine (OPV) between 48 and 72 hours after birth. Ahmad 2014 reported no relevant outcomes. Mathew 2015 was a commentary on an included study (Mazumder 2015). Schmiedchen 2016 included infants with birth weight < 1500 grams and gestational age < 33 weeks.

Risk of bias in included studies

Allocation (selection bias)

Eight studies adequately randomised neonates to treatment groups (Benn 2008; Benn 2010; Benn 2014; Bhutta 2016; Edmond 2015; Malaba 2005; Masanja 2015; Mazumder 2015) and provided a clear description of the method used to generate the randomisation sequence. Four studies did not provide sufficient details to allow judgement of the adequacy of study methods (Humphrey 1996; Klemm 2008; Rahmathullah 2003; West 1995). Nine studies clearly described the method of allocation concealment (Benn 2008; Benn 2010; Benn 2014; Bhutta 2016; Edmond 2015; Humphrey 1996; Malaba 2005; Masanja 2015; Mazumder 2015), whereas Klemm 2008, Rahmathullah 2003 and West 1995 did not provide sufficient details.

Blinding (performance bias and detection bias)

All included studies clearly described and achieved blinding of participants, study personnel and outcome assessors.

Incomplete outcome data (attrition bias)

Rates of postrandomisation attrition and exclusion of participants were as follows: 1.6% (Benn 2008), 18.7% (Benn 2010), 1.87% (Benn 2014), 6.7% (Bhutta 2016), 1.1% (Edmond 2015), 11% (Humphrey 1996), 7% (Klemm 2008), 41.8% (Malaba 2005), 3.5% (Masanja 2015), 0.1% (Mazumder 2015) and 18.9% (Rahmathullah 2003); papers described reasons for attrition and exclusion of participants. West 1995 reported exclusion and attrition of 1.04% and provided no details.

Selective reporting (reporting bias)

Evaluation of selective outcome reporting by review of trial registration documents, if available, or of methods presented in published papers revealed that all trials had reported findings for prespecified or expected outcomes, except for Humphrey 1996, for which reporting was unclear.

Other potential sources of bias

We identified three trials with potentially high risk of other bias: Benn 2008 and Benn 2010 conducted post hoc analyses after assuming that vitamin A might be more beneficial to boys, whereas Klemm 2008 was terminated after randomisation of two-thirds of the planned number of infants owing to significantly higher mortality in the control group. We found Malaba 2005 to be free of other bias and determined that risk of other bias was uncertain in the remaining eight trials owing to insufficient information (Benn 2014; Bhutta 2016; Edmond 2015; Humphrey 1996; Masanja 2015; Mazumder 2015; Rahmathullah 2003; West 1995).

See the Characteristics of included studies table for additional details on risk of bias in included studies. We have provided in Figure 2 a graphical presentation of our individual judgements per item per study and a summary graph in Figure 3.

Effects of interventions

We have included in this review Summary of findings table 1 based on outcomes in term neonates, which was prepared in accordance with the method recommended by GRADE (Summary of findings table 1).

Neonatal vitamin A supplementation versus placebo

Primary outcomes
All-cause infant mortality at six months of age

We have presented in Table 1 an overview of the type and source of data for this outcome.

Ten included studies (Benn 2008; Benn 2010; Bhutta 2016; Edmond 2015; Humphrey 1996; Klemm 2008; Malaba 2005; Masanja 2015; Mazumder 2015; Rahmathullah 2003) measured infant mortality at six months of age. West 1995 measured mortality at four months of age, and we have included these data in the six-month mortality analysis.

All-cause infant mortality at six months of age: risk ratios based on cumulative risk (%) (Outcome 1.1)

Eleven studies measured data as risk ratios based on cumulative risk.

The pooled estimate of data for term infants from three studies (Humphrey 1996; Klemm 2008; Malaba 2005) suggests that risk of death from any cause at six months of age for neonates supplemented with vitamin A is 20% lower than for control infants and was not statistically significant (pooled risk ratio 0.80, 95% CI 0.54 to 1.18; Analysis 1.1.1). The level of statistical heterogeneity in this analysis was 63%. As the number of studies included was small, we considered a subgroup analysis to investigate heterogeneity as not reliable. Given substantial statistical heterogeneity and the small number of included studies, the reader should interpret these findings with caution.

The pooled estimate of data for all infants from 11 studies (Benn 2008; Benn 2010; Bhutta 2016; Edmond 2015; Humphrey 1996; Klemm 2008; Malaba 2005; Masanja 2015; Mazumder 2015; Rahmathullah 2003; West 1995) showed no evidence of a significant effect on risk of death from any cause for neonates supplemented with vitamin A as compared with control neonates (typical risk ratio 0.98, 95% CI 0.89 to 1.07). The level of statistical heterogeneity for this analysis was 47% (Analysis 1.1.2).

For gender-specific subanalyses, the pooled estimate of data for all male infants from five studies (Bhutta 2016; Edmond 2015; Klemm 2008; Masanja 2015; Mazumder 2015) showed no evidence of a significant effect (typical risk ratio 1.01, 95% CI 0.92 to 1.12). The level of statistical heterogeneity for this analysis was less than 50% (I2 = 11%; Analysis 1.1.3). Likewise, analysis of data for all female infants from five studies (Bhutta 2016; Edmond 2015; Klemm 2008; Masanja 2015; Mazumder 2015) did not reach statistical significance (typical risk ratio 0.95, 95% CI 0.84 to 1.08; I2 = 41%; Analysis 1.1.4).

For the analysis based on geographic region, the pooled estimate from studies conducted in Asia showed a statistically significant reduction in risk of mortality at six months (typical risk ratio 0.89, 95% CI 0.80, 0.99; I2 = 29%), whereas the pooled estimate from studies conducted in Africa indicated higher risk of mortality at six months (P = 0.05; typical risk ratio 1.10, 95% CI 1.00 to 1.21; I2 = 0%).

All-cause infant mortality at six months of age: rate ratios (per years of follow-up) (Outcome 1.2)

We analysed data from five studies as rate ratios (per year of follow-up).

Pooled estimates for term neonates from Benn 2008 and Rahmathullah 2003 showed no evidence of a significant effect on the rate of death from any cause at six months of age in those given vitamin A as compared with control neonates (typical rate ratio 0.93, 95% CI 0.67 to 1.30; Analysis 1.2.1). Analysis of data for all infants from five studies (Benn 2008; Benn 2010; Masanja 2015; Rahmathullah 2003; West 1995) did not show statistical significance (typical rate ratio 0.99, 95% CI 0.84 to 1.17; Analysis 1.2.2). Levels of statistical heterogeneity were as follows: I2 = 51% and 46% for analyses of term and all infants, respectively.

For gender-specific subanalyses, the pooled estimate of data for all male infants from two studies (Masanja 2015; Rahmathullah 2003) showed no evidence of a significant effect on the rate of death from any cause at six months of age in those who received vitamin A as compared with control infants (typical rate ratio 0.88, 95% CI 0.58 to 1.35; Analysis 1.2.3). Analysis of data for all female infants from two studies (Masanja 2015; Rahmathullah 2003) also did not show statistical significance (typical rate ratio 1.01, 95% CI 0.79 to 1.30; Analysis 1.2.4). Levels of statistical heterogeneity were as follows: 12 = 82% and 46% for analyses of all male infants and all female infants, respectively.

For geography-specific subanalyses, the pooled estimate from two studies conducted in Asia showed a non-significant effect on the rate of mortality at six months (typical rate ratio 0.85, 95% CI 0.64 to 1.13; I2 = 33%). Similarly, a pooled estimate from three studies conducted in Africa showed no significant impact on mortality at six months (typical rate ratio 1.09, 95% CI 0.96 to 1.23; I2 = 0%).

All-cause infant mortality at 12 months of age

We have presented in Table 2 an overview of the type and source of data for this outcome.

Eight included studies (Benn 2008; Benn 2010; Benn 2014; Edmond 2015; Humphrey 1996; Malaba 2005; Masanja 2015; Mazumder 2015) measured infant mortality at 12 months of age.

All-cause infant mortality at 12 months of age: risk ratios based on cumulative risk (%) (Outcome 1.3)

Eight studies measured data as risk ratios based on cumulative risk. The pooled estimate of data for all infants from the eight studies (Benn 2008; Benn 2010; Edmond 2015; Humphrey 1996; Malaba 2005; Masanja 2015; Mazumder 2015) showed no evidence of a significant effect on risk of death from any cause at 12 months of age for neonates supplemented with vitamin A as compared with control neonates (typical risk ratio 1.04, 95% CI 0.94 to 1.15). The level of statistical heterogeneity for this analysis was less than 50% (I2 = 47%; Analysis 1.3.1).

For gender-specific subanalyses, the pooled estimate of data for all male infants from three studies (Edmond 2015; Masanja 2015; Mazumder 2015) showed no evidence of a significant effect on risk of death from any cause at 12 months of age for neonates supplemented with vitamin A as compared with control neonates (typical risk ratio 1.00, 95% CI 0.88 to 1.14). The level of statistical heterogeneity for this analysis was less than 50% (I2 = 46%; Analysis 1.3.2). Analysis of the data for all female infants from three studies (Edmond 2015; Masanja 2015; Mazumder 2015) also did not show statistical significance (typical risk ratio 1.04, 95% CI 0.90 to 1.20). The level of statistical heterogeneity for this analysis was 56% (Analysis 1.3.3).

For geography-specific analyses, the pooled estimate of data from studies conducted in Asia showed no evidence of a significant effect on risk of death from any cause at 12 months of age (typical risk ratio 0.65, 95% CI 0.26 to 1.60; I2 = 78%). The pooled estimate for studies conducted in Africa showed an indication of higher risk of mortality at 12 months of age (typical risk ratio 1.08, 95% CI 1.00 to 1.17; I2 = 0%).

All-cause infant mortality at 12 months of age: rate ratios (per years of follow up) (Outcome 1.4)

We analysed data from six studies as rate ratios (per year of follow-up).

Analysis of term neonate data from three studies expressed as rate ratios (Benn 2008; Benn 2014; Humphrey 1996) showed no evidence of a significant effect on infant mortality from any cause at 12 months of age among neonates supplemented with vitamin A as compared with control infants, with statistical heterogeneity of 72% (typical rate ratio 0.94, 95% CI 0.59 to 1.50; Analysis 1.4.1). The pooled estimate of data for all infants from six studies (Benn 2008; Benn 2010; Benn 2014; Humphrey 1996; Malaba 2005; Masanja 2015) also did not reach statistical significance (typical rate ratio 1.06, 95% CI 0.92 to 1.22; Analysis 1.4.2). The level of statistical heterogeneity was lower than 50% (I2 = 31%).

Analysis of data for all male infants from five studies (Benn 2008; Benn 2010; Benn 2014; Humphrey 1996; Masanja 2015) showed no evidence of a significant effect of supplementation of neonates with vitamin A on infant mortality at 12 months of age compared with control (typical rate ratio 0.89, 95% CI 0.66 to 1.19; Analysis 1.4.3). In contrast, the pooled estimate for all female infants from five studies (Benn 2008; Benn 2010; Benn 2014; Humphrey 1996; Masanja 2015) did reach statistical significance (typical rate ratio 1.21, 95% CI 1.05 to 1.41; Analysis 1.4.3). However, differences between subgroups were not statistically significant (P = 0.06). Levels of statistical heterogeneity included the following: 12 = 58% and 0% for analyses of all male infants and all female infants, respectively.

For geography-specific analyses, the pooled estimate of data from three studies conducted in Asia showed no evidence of a significant effect on risk of death from any cause at 12 months of age (typical rate ratio 0.94, 95% CI 0.69 to 1.29; I2 = 65%). Similarly, the estimate for three studies conducted in Africa showed no impact on mortality at 12 months of age (typical rate ratio 1.13, 95% CI 0.94 to 1.36; I2 = 0%).

Secondary outcomes
Cause-specific infant mortality at six months of age: diarrhoea and acute respiratory infection (Outcomes 1.5 and 1.6)

Two studies (Humphrey 1996; Rahmathullah 2003) measured infant mortality related to diarrhoea and acute respiratory infection at six months of age. Investigators in Humphrey 1996 provided data for all infants as risk ratios based on cumulative risk, which showed no significant effect of vitamin A supplementation on diarrhoea and respiratory infection as compared with control (diarrhoea-specific infant mortality: risk ratio 0.20, 95% CI 0.02 to 1.68; acute respiratory infection-specific infant mortality: risk ratio 0.66, 95% CI 0.11 to 3.91). Rahmathullah 2003 presented data for all infants as rate ratios (per years of follow-up) and showed a similar non-significant effect of vitamin A on rates of diarrhoea-specific and acute respiratory infection-specific infant mortality at six months of age as compared with control (diarrhoea-specific infant mortality: rate ratio 0.67, 95% CI 0.32 to 1.39; acute respiratory infection-specific infant mortality: rate ratio 1.00, 95% CI 0.56 to 1.79).

Cause-specific infant mortality at 12 months of age: diarrhoea and acute respiratory infection (Outcomes 1.7 and 1.8)

Three studies (Benn 2008; Humphrey 1996; Malaba 2005) measured infant mortality related to diarrhoea and acute respiratory infection at 12 months of age.

Humphrey 1996 provided data for all infants as risk ratios based on cumulative risk and showed no evidence of a significant effect of vitamin A on death due to diarrhoea and acute respiratory infection as compared with control (diarrhoea-specific infant mortality: risk ratio 0.40, 95% CI 0.08 to 2.03; acute respiratory infection-specific infant mortality: risk ratio 0.66, 95% CI 0.11 to 3.95). Benn 2008 and Malaba 2005 analysed data for all infants as rate ratios. Pooled data provided no evidence of a significant effect of vitamin A on diarrhoea-specific and acute respiratory infection-specific infant mortality at 12 months of age as compared with control (typical rate ratio 1.32, 95% CI 0.80 to 2.16; I2 = 0%; and rate ratio 0.97, 95% CI 0.67 to 1.42; I2 = 0%, respectively).

Cause-specific infant morbidity at six months of age: diarrhoea and acute respiratory infection (Outcomes 1.9 and 1.10)

Three trials (Benn 2008; Malaba 2005; Rahmathullah 2003) measured infant morbidity at six months of age as rate ratios (per year of follow-up). Pooled estimates showed no significant effect of vitamin A as compared with control on rates of diarrhoea and acute respiratory infection among infants at six months of age (typical rate ratio 0.89, 95% CI 0.69 to 1.14; I2 = 89%; and rate ratio 1.05, 95% CI 0.91 to 1.21; I2 = 85%, respectively). We did not consider performing a subgroup analysis to investigate heterogeneity because of the small number of studies contributing data to this analysis.

Vitamin A deficiency (Outcomes 1.11 and 1.12)

One study only (Benn 2008) reported vitamin A deficiency defined as serum retinol value < 0.70 µmol/L for all infants and showed no evidence of a significant effect of vitamin A supplementation on vitamin A deficiency as compared with control (at six weeks: risk ratio 0.94, 95% CI 0.75 to 1.19; at four months: risk ratio 1.02, 95% CI 0.64 to 1.62).

Anaemia (Outcome 1.13)

Only one study (Malaba 2005) measured the impact of the intervention on anaemia for all infants born to both HIV-positive and HIV-negative women. Vitamin A supplementation in neonates did not lead to a significant impact on anaemia (haemoglobin (Hb) < 105 g/L) at eight to 14 months of age (risk ratio 0.97, 95% CI 0.87 to 1.07) compared with control.

Adverse events (Outcomes 1.14 and 1.15)

We were able to pool data from five studies (Benn 2008; Edmond 2015; Humphrey 1996; Masanja 2015; Mazumder 2015) for adverse events in all infants during the first 48 to 72 hours, and only one study (Benn 2008) presented adverse events at one month of age (Analysis 1.14 and Analysis 1.15). Risk of a bulging fontanelle during the first 48 to 72 hours for neonates supplemented with vitamin A was 53% higher than for control neonates, and this finding is statistically significant (typical risk ratio 1.53, 95% CI 1.11 to 2.11; I2 = 71%). Pooled estimates from the five studies provided no evidence of a significant increase in diarrhoea (typical risk ratio 0.96, 95% CI 0.81 to 1.13) or vomiting (typical risk ratio 1.00, 95% CI 0.93 to 1.07) in the vitamin A group versus the control group. Likewise, analyses from three studies (Edmond 2015; Masanja 2015; Mazumder 2015) indicated no significant increase in fever (typical risk ratio 1.04, 95% CI 0.98 to 1.09), inability to suck or feed (typical risk ratio 1.00, 95% CI 0.81 to 1.23) and convulsions (typical risk ratio 1.12, 95% CI 0.66 to 1.88). Estimates from one study (Mazumder 2015) showed no statistically significant differences in excessive crying (typical risk ratio 0.99, 95% CI 0.93 to 1.05), jaundice (typical risk ratio 1.07, 95% CI 0.96 to 1.19), eye infection (typical risk ratio 0.99, 95% CI 0.88 to 1.12), skin infection (typical risk ratio 0.94, 95% CI 0.82 to 1.09), umbilical infection (typical risk ratio 0.97, 95% 0.81 to 1.15), respiratory infection (typical risk ratio 1.08, 95% 0.94 to 1.24), feeding problems (typical risk ratio 1.01, 95% 0.88 to 1.16) or other adverse events during the first 48 to 72 hours (typical risk ratio 0.93, 95% 0.84 to 1.02). Benn 2008 showed no evidence of a significant increase in adverse events during the first month post supplementation (diarrhoea: risk ratio 1.07, 95% CI 0.46 to 2.51; vomiting: risk ratio 1.22, 95% CI 0.57 to 2.58).

All-cause neonatal mortality (Outcomes 1.16 and 1.17)

We have presented in Table 3 an overview of the type and source of data for this outcome.

Five included studies measured neonatal mortality in the first month of life (Bhutta 2016; Edmond 2015; Klemm 2008; Masanja 2015; Mazumder 2015). Investigators measured data for these five studies as risk ratios based on cumulative risk. The pooled estimate of data for all infants showed no evidence of a significant effect on risk of death from any cause at one month of age for neonates supplemented with vitamin A as compared with control neonates (typical risk ratio 0.99, 95% CI 0.90 to 1.08). Analyses for all male infants and for all female infants also did not reach statistical significance (male: typical risk ratio 1.01, 95% CI 0.87 to 1.17; female: typical risk ratio 1.03, 95% CI 0.89 to 1.19). The level of statistical heterogeneity for all three analyses was 0%.

Masanja 2015 analysed data as rate ratios (per year of follow-up) and showed no significant effect on neonatal mortality for all infants (typical rate ratio 1.04, 95% CI 0.86 to 1.25), all male infants (typical rate ratio 0.99, 95% CI 0.77 to 1.27) or all female infants (typical rate ratio 1.10, 95% CI 0.82 to 1.49) supplemented with vitamin A as compared with control infants.

Other outcomes

Included studies did not measure the impact of neonatal vitamin A supplementation on blindness and xerophthalmia.

Discussion

Summary of main results

We conducted this review to compare the effect of supplementing term neonates with vitamin A as compared with not providing vitamin A supplementation. As term neonatal outcome data were available for only a small number of studies, and then for infant mortality outcomes only, we analysed and presented estimates for both term neonates (when specified) and all infants for various prespecified outcomes. Our analysis of data provided for all infants provided evidence of a non-significant reduction in risk of death at six months of age in the vitamin A supplemented group as compared with the control group. Analysis of term neonatal outcomes included data from a subset of studies included in the all-infant analysis and revealed a non-significant reduction in risk of death in the first six months or 12 months of life. The reader should interpret these findings with caution because of the small number of studies contributing data to these analyses, statistical heterogeneity and wide confidence intervals that are close to the null effect. In addition to these results, our analysis of data from Asia on all infants based on geographical region showed a significant reduction in risk of death at six months as a result of vitamin A (reduction 11%; 95% confidence interval (CI) 1% to 20%). On the contrary, studies from Africa showed an effect that ranged from no impact to a 21% increase in risk of mortality. Overall, our review findings do not suggest a potential effect of this intervention on infant mortality.

Overall completeness and applicability of evidence

This review included a total of 12 trials conducted to evaluate the effect of vitamin A supplementation for neonates. These include all trials conducted to date to assess this intervention. Inclusion of these studies, which we identified through extensive searches of the literature and of additional data obtained by contacting study authors, represents the overall completeness of evidence.

Deficiency of vitamin A is a major nutritional concern in many countries of the world. All studies included in this review were conducted in low and middle income countries with varying levels of vitamin A deficiency and infant mortality. These studies have demonstrated a mix of effects on infant mortality resulting from supplementation with vitamin A, and studies conducted in areas with vitamin A deficiency indicate a potential beneficial effect of supplementation; however, studies conducted in regions with less deficiency suggest no benefit of supplementation and potential for harm.

Reasons for these conflicting findings are unclear, and data show no clear indication of the biological mechanisms through which vitamin A could lower risk of death when given during the neonatal period. Investigators have proposed various mechanisms. Newborns have marginal reserves of vitamin A in their liver, and they depend on breast milk as a source of this vitamin during the first few months of life. Hence, low maternal vitamin A levels translate into vitamin A deficiency among newborns (Underwood 1994). Deficiency of vitamin A could begin very early in life if colostrum is discarded or breastfeeding is inadequate. Colostrum and early breast milk have been found to be very rich sources of vitamin A that can significantly augment vitamin A stores among neonates (Wallingford 1986). Along with inadequate breastfeeding, introduction of artificial feeds hinders establishment of good breastfeeding practices, thereby denying infants this critical source of vitamin A throughout the breastfeeding period (Haskell 1999). Artificial feeds early in life also increase the risk of gastrointestinal infection among these infants. It has been proposed that vitamin A supplementation may have an impact on infant mortality through development and maintenance of the integrity of intestinal and respiratory epithelia, and by provision of enhanced local and systemic immunity (Sommer 1996; Tielsch 2008 - a report on Rahmathullah 2003). These pathways may provide an explanation for the effect of supplementation in settings where the practice of discarding colostrum, the presence of inadequate breastfeeding or reports of artificial feeds and infections are common. Alternatively, early initiation of feeding of colostrum and exclusive breastfeeding could explain absence of a beneficial effect of vitamin A received as a supplement. However, in this review, we could not study these proposed mechanisms, as only a few included studies presented limited information on breastfeeding practices and the use of artificial feeds.

Limited data were available for the outcomes of cause-specific mortality and morbidity and vitamin A deficiency, measured as serum retinol values in infants. Data on adverse events, specifically bulging fontanelle, vomiting or diarrhoea, were also limited and showed no significant increase within the first 48 to 72 hours of supplementation.

Quality of the evidence

We graded the evidence for most outcomes as high quality, with the exception of two outcomes that we scored as having low and very low quality: ‘diarrhoeal events during the first 48-72 hours post supplementation’ and ‘all-cause infant mortality at six months in term infants’, respectively (Summary of findings table 1). We downgraded the former outcome for inconsistency and imprecision, a moderate level of statistical heterogeneity (I2 = 58%) and wide confidence intervals, with the lower confidence limit indicating a 19% reduction in diarrhoeal events and the upper limit indicating a 13% increase. We downgraded the latter outcome, 'all-cause infant mortality at six months in term infants', to very low quality, although the previous review judged this outcome as low quality. This change reflected adoption of a random-effects model; the estimate changed from a risk ratio (RR) of 0.82 (95% CI 0.68 to 0.99) to an RR of 0.80 (95% CI 0.54 to 1.18), with the wider confidence interval indicating less precision. It should be noted that we considered the evidence for all-cause infant mortality at six months in all infants as high quality, despite inclusion of three studies with the outcome for term infants. With the introduction of eight new studies into the analysis of data for all infants, the relative influence of the three previously included studies decreased. Unclear risk of bias from Klemm 2008 was no longer a reason to downgrade the quality of the entire analysis because it had little effect on the overall risk ratio. Likewise, heterogeneity was lower (I2 = 47%), and imprecision was not indicated as serious.

Potential biases in the review process

This update of the review includes additional data published since the time of the last update. We conducted an extensive literature search to identify new studies or new publications of previously included studies available since the last search was conducted. Two review authors independently screened the updated search for identification of studies, eligibility assessment, risk of bias evaluation and extraction of data from selected studies. Given that we applied the Cochrane methods described above, the findings of this review are unlikely to be affected by biases in the review process.

Agreements and disagreements with other studies or reviews

Considerable debate has surrounded the issue of supplementing neonates with vitamin A owing to conflicting study findings and variability in the results of pooled analyses (Abrams 2008; Bhutta 2008; Gogia 2009; Haider 2015; Sachdev 2008; Tielsch 2008). The current review includes most of the up-to-date data available on neonatal vitamin A supplementation and additional data provided when we contacted study authors.

Two of the included trials, one conducted in India (Rahmathullah 2003) and one in Bangladesh (Klemm 2008), examined a population characterised by high infant mortality and vitamin A deficiency. The trial in India showed a reduction of 22% in risk of infant mortality at six months, whereas the trial in Bangladesh showed a 15% reduction in risk of infant mortality in the vitamin A group compared with the control group. In the Indian setting, 5% to 6% of included women reported a history of night blindness, which is a clinical manifestation of vitamin A deficiency, and this event was not significantly different between the two groups (P = 0.26). Study authors noted that the impact of vitamin A supplementation on mortality was evident from two weeks of age and continued until three months, after which no further effect was apparent. The Bangladesh trial reported similar observations, including a difference in mortality among infants as early as after the first week of life that persisted until four months of age. Approximately 9.5% of pregnant women in each group reported night blindness during their most recent pregnancy. Investigators measured a subsample of this study population for serum retinol in the first trimester and showed suboptimal vitamin A status (defined as serum retinol < 1.05 µmol/L) in approximately 41% of women in the vitamin A group and 36% of those in the control group. These findings of an effect of vitamin A on risk of mortality between the early weeks of life until four months do indicate a common biological mechanism of vitamin A. Of the three large recent trials funded by the World Health Organization (WHO), the trial conducted in India by Mazumder et al examined a population with moderate vitamin A deficiency (about 40% of mothers in this setting had low vitamin A status). Researchers reported a significant reduction of 10% in risk of infant mortality at six months of age with vitamin A supplementation for neonates. This beneficial effect was evident in survival curves after a few weeks of supplementation and was sustained until 12 months of age. This study observed no significant interaction between the intervention effect and sex of the infant in terms of mortality at six months. Humphrey 1996, an Indonesian trial, was the first trial of vitamin A supplementation in neonates that was conducted as a safety trial. Although this trial had reported significant benefit for survival that was notable after the first month and became consistent after four months of birth, trial authors had noted that the mother included in the study had little vitamin A deficiency (based on serum retinol levels for a subset of the study population). The infant mortality rate in the control group (7.2 per 1000 child-years) was well below that reported for families included in this study, which were relatively privileged (Humphrey 1996). Although serum retinol levels were adequate, these findings provide no information on hepatic reserves, which may have been low in this study group (Tielsch 2008).

Studies conducted in Nepal, Zimbabwe, Guinea Bissau, Ghana and Tanzania reported conflicting results. West 1995, the Nepal trial, was part of a larger vitamin A supplementation trial in preschool children. Infants supplemented during the neonatal period did not show a significant effect on infant mortality, which investigators evaluated at four months of age. Of note, this study setting was characterised by endemic vitamin A deficiency and high infant mortality. This finding contrasted with findings from other studies conducted in similar settings. Studies conducted in Zimbabwe (Malaba 2005) and Guinea Bissau (Benn 2008) reported non-significant effects of vitamin A on both six-month and 12-month infant mortality outcomes. Benn and associates (Benn 2010) measured infant mortality in a study conducted in Guinea Bissau at 12 months and reported no effect on this outcome. The vitamin A status of mothers provided evidence of minimal deficiency in these study settings, with mean (± standard deviation (SD)) serum retinol values in a subset of Zimbabwean women in the control group of 1.09 (± 0.29) and 1.19 (± 0.42) µmol/L at six weeks postpartum. In Guinea Bissau, less than 1% of women had low retinol binding proteins (retinol binding proteins < 1.11 µmol/L). This study also measured serum retinol values among infants at six weeks and four months of age and found no evidence of an effect of vitamin A supplementation on vitamin A deficiency. An important feature of this trial is that all eligible children were provided free consultations and essential drugs for any illness during the first year of life. The mechanism through which vitamin A supplementation in children older than six months of age improves survival has been explained in part by a reduction in severity rather than the incidence of infection (Sommer 1996). We believe that provision of free consultations and essential drugs for illnesses in the Guinea Bissau trial masked any beneficial effect of vitamin A supplementation that might have occurred by reducing episodes of severe illness. Recent large trials in Ghana (Edmond 2015) and Tanzania (Masanja 2015) also reported no significant beneficial effect of vitamin A supplementation on infant mortality at six months. Results of these trials indicated potential for harm. Study sites for these recent studies included districts with long-running demographic surveillance programmes for supplementation of women to address the problem of micronutrient deficiencies. As a result, less than 3% of women in Ghana and 5% to 8% of those in Tanzania had biochemical vitamin A deficiency.

This update also found differences in the effect of vitamin A supplementation for neonates on infant mortality at six months by geographic region, with studies conducted in Asia showing a beneficial effect of supplementation and those in Africa indicating potential for harm. Haider 2015 noted this in another pooled analysis of data. The reasons for possible differences in results of trials conducted in different geographic regions are uncertain. However, these findings could represent genuine differences in population-attributable risks of micronutrient deficiencies. As noted above, studies included neonates of mothers with varying levels of baseline vitamin A deficiency, both low birth weight and normal birth weight neonates and varying rates of baseline infant mortality. These factors could affect the generalisability of study findings. It should be noted that in contrast to observed benefits of vitamin A supplementation among mothers in Nepal (West 1999), a large trial of maternal vitamin A supplementation in Ghana (Kirkwood 2010) reported no benefit.

Another concern raised by some trial authors is the presence of a differential effect of vitamin A supplementation for neonates on infant mortality by sex (Benn 2014). In the current review, we conducted a subgroup analysis by sex of the infant, when data were available. Although results showed no significant difference in infant mortality at six months of age, findings were statistically significantly different for infant mortality at 12 months, with significantly higher risk noted in the subgroup of female infants (RR 1.21, 95% CI 1.05 to 1.41). Benn 2014 reported similar findings in an assessment and pooled analysis of infant mortality among children six to 12 months of age; however, recent trials did not observe significant interaction of effects of interventions on infant mortality at six months by sex. Given these differences in study findings, additional research is warranted to further study this effect.

Authors' conclusions

Implications for practice

Evidence provided in this review does not indicate a potential beneficial effect of vitamin A supplementation for neonates at birth in reducing mortality during the first six months or 12 months of life. Analyses based on geographical region, however, demonstrated a beneficial effect of supplementation in studies from Asia and potential for harm in studies from Africa. Given this finding and the absence of a clear indication of the biological mechanism through which vitamin A could affect mortality during early infancy, along with substantial conflicting findings from individual studies conducted in settings with potentially varying levels of maternal vitamin A deficiency and infant mortality; the absence of follow-up studies assessing the long-term impact of a bulging fontanelle after supplementation; and the finding of a potentially harmful effect among female infants, additional research is warranted before a decision can be reached regarding any policy recommendations for this intervention.

Implications for research

Future research should seek to identify biological mechanisms and indicators for vitamin A in reducing risk of death, and to explain the differences observed in vitamin A supplementation trials conducted in different geographical settings with varying levels of baseline vitamin A deficiency. Longer follow-up studies should evaluate neurodevelopmental outcomes for neonates supplemented with vitamin A at birth to ensure the safety of this intervention. Future investigators should make every effort to stratify effects by sex of the infant, age after birth of vitamin A administration, prematurity and intrauterine growth retardation.

Acknowledgements

We would like to thank the trial authors who provided additional data for this review; the Cochrane Editorial Unit, particularly Toby Lasserson, who provided statistical advice and drafted the 'Summary of findings' tables; Karla Soares-Weiser and Harriet MacLehose for comments on the 'Risk of bias' tables; Furqan Bin Irfan, who assisted in writing the protocol; Fahad Javaid Siddiqui for assistance with the GRADE assessment; and Shannon Harding, Azza ElBakry, Tyler Vaivada and Michelle Gaffey from the Centre for Global Child Health at the Hospital for Sick Children for their support with screening and data extraction. In addition, we would like to thank the staff at the editorial office of the Neonatal Cochrane Review Group for their support in preparation of this review and, in particular, the Co-ordinating Editor Dr Roger Soll and Managing Editor Diane Haughton. We also would like to thank the peer reviewers, who provided helpful feedback on the review.

Contributions of authors

Batool A Haider (BAH) wrote the review protocol under the guidance of Zulfiqar A Bhutta (ZAB). BAH and Renee Sharma (RS) extracted data. BAH and RS entered data, created comparisons, analysed data and wrote the text of the review. ZAB provided supervision and contributed to the writing process for the review. BAH was at the Harvard School of Public Health at the time of this review.

Declarations of interest

Zulfiqar A Bhutta is a principal investigator of a neonatal vitamin A supplementation trial in Pakistan (Bhutta 2016).

Batool A Haider: none.

Renee Sharma: none.

Differences between protocol and review

For the 2017 update, we added neonatal mortality as a secondary outcome. We added the methods and the plan for 'Summary of findings' tables and GRADE recommendations, which we did not include in the original protocol.

Published notes

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Characteristics of studies

Characteristics of included studies

Benn 2008

Methods

Randomised, double-blind, placebo controlled trial

Participants

Inclusion criteria: infants weighing greater than/or equal to 2500 grams at birth with no signs of overt illness or malformation. Infants were recruited at the time of BCG vaccination. Number of participants in vitamin A group: 2145. Number in the placebo group: 2200

Interventions

0.5 mL vegetable oil, 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 child's mouth at the time of BCG vaccination

Outcomes

Mortality at 12 months 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), adverse effects (bulging fontanelle, hospitalisations, irritability, fever, frequent stools, vomiting, mother thinks the child is not well)

Notes

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

Given that study authors did not provide information about gestational age at delivery and that inclusion criteria included infants with birth weight greater than/or equal to 2500 grams, we included such data in the term neonate analysis while assuming that a greater proportion of these were term infants

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Quote: "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 risk

Quote: "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) Low risk

Quote: "blinding of mothers and assistants was successful"; "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) Low risk

Attrition was 1.6%. Reasons for attrition and distribution in the 2 groups were provided. Infants lost to follow-up were similar to those followed in terms of baseline anthropometric characteristics

Selective reporting (reporting bias) Low risk

Comment: Results of all expected outcomes were presented in several publications of the study

Other bias High risk

A protocol was provided but post hoc analyses were conducted after it was assumed that vitamin A might be more beneficial for boys. The study was funded by the EU (ICA4-CT-2002-10053), the Danish Medical Research Council, the University of Copenhagen, the March of Dimes and the Ville Heise Foundation

Benn 2010

Methods

Randomised, placebo-controlled, 2-by-2 factorial trial

Participants

Inclusion criteria: infants weighing < 2500 grams at birth with no severe malformations. Number of participants in vitamin A group: 864. Number in placebo group: 872

Interventions

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

Outcomes

Infant mortality and cause-specific infant mortality at 12 months

Notes
  • Study was conducted in 6 urban districts in the 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 table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Quote: "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 risk

Quote: "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) Low risk

Quote: "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"; "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) Low risk

Exclusions and attrition were 18.72%. Reasons and distribution in the 2 groups were provided. Numbers were balanced across treatment groups

Selective reporting (reporting bias) Low risk

Comment: All expected outcomes, as per protocol, were reported or are under preparation (personal communication from study author)

Other bias High risk

A protocol was provided, but post hoc analyses were conducted after it was assumed that vitamin A might be more beneficial for boys. The study was funded by the EU (ICA4-CT-2002-10053), the Danish Medical Research Council, the University of Copenhagen, the March of Dimes and the Ville Heise Foundation

Benn 2014

Methods

Randomised, double-blind, placebo-controlled trial in Guinea-Bissau

Participants

Eligible participants: healthy normal birth weight neonates who were due to be administered bacille Calmette-Guérin (BCG) vaccine. Exclusion criteria: weight < 2500 grams at presentation or overt illness/malformations

Interventions

Infants were randomly assigned in a 1:1:1 ratio to 3 different treatment groups: 50,000 IU of vitamin A; 25,000 IU of vitamin A; or placebo; concurrent with BCG vaccination

Outcomes

Infant mortality

Notes
  • The Bandim Health Project has a demographic surveillance system in 6 suburban districts of the capital of Guinea-Bissau covering ~102,000 inhabitants
  • Enrolment into the trial took place between 29 November 2004, and 31 May 2007
  • Of 6053 infants invited to participate, 6048 were randomly allocated to each of the 3 treatment groups (50,000 IU vitamin A, 25,000 IU vitamin A, placebo)
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Quote: "At each inclusion site, the randomization procedure was carried out by 1 carefully trained assistant every day except during short vacations. After providing consent, the mother drew a lot from an envelope"; and "the result of the randomization was noted on the inclusion form and the lot was also stapled on the inclusion form"

Comment: probably done

Allocation concealment (selection bias) Low risk

Quote: "Each envelope was prepared by the data manager, who did not take part in the enrollment procedures, and contained 48 folded lots indicating from which of 3 numbered bottles—'3', '4', or '5'—the child should receive his or her supplement"; and "the code was kept at the pharmacy until follow-up had ended"

Comment: probably done

Blinding (performance bias and detection bias) Low risk

Quote: "Apart from the randomization number the bottles looked alike, and small differences in taste and color of the contents were judged as being unimportant due to the recipients' age"; and "registration system assistants and the special team were unaware of the allocated treatment, because they were not present during enrollment, and the information was not transferred to the children's vaccination card or follow-up forms"

Comment: probably done

Incomplete outcome data (attrition bias) Low risk

Quote: "Of 6053 children invited to participate, 6048 were randomly allocated to each of the 3 groups (50,000 IU vitamin A, 25,000 IU vitamin A, or placebo) (Fig. 1). The 3 randomly assigned groups were similar in terms of their background characteristics (Table 1). A total of 176 deaths occurred; 2 of these were due to accidents and were censored. Fourteen deaths occurred after the child had been eligible for a national vitamin A campaign. Hence, censoring for accidents and subsequent VAS, the cohort had 160 deaths during 4125 person-years of risk, corresponding to an MR of 39 per 1000 person-years"

Selective reporting (reporting bias) Low risk

Comment: The published study reported on expected outcomes

Other bias Unclear risk

Quote: "We had based our sample size calculations on an infant mortality rate of 70, but in this trial it declined to 39. Although this clearly is a very positive development, it decreased our power to detect any differences between the randomly assigned groups. With the current MR, we only would have been able to show a difference of > 40% between the 2 doses. Because there was minimal difference between the 2 doses, we used the data to test findings made in our previous NVAS trial. All of these analyses were not a priori analyses prespecified in the protocol but were formulated before we initiated the data analysis of the present trial. The trial was not sized to test these findings, and the results should be interpreted with appropriate caution"

The Bandim Health Project receives support from the Danish International Development Agency. The Research Center for Vitamins and Vaccines (CVIVA) is funded by the Danish National Research Foundation (DNRF108). The funding agencies had no role in study design, data collection, data analysis, data interpretation or writing of the report

Bhutta 2016

Methods

A community-based, cluster-randomised, placebo-controlled trial in 2 districts (Sukkhur and Jehlum) of rural Pakistan

Participants

All live-born infants within participating villages were potentially eligible for inclusion in the study. Infants with obvious congenital malformations and birth weight less than 1500 grams were excluded

Interventions

Intervention was vitamin A capsule containing (50,000 units) retinol palmitate in soybean oil. Placebo contained minute amounts of vitamin E (10 IU) in soybean oil

Outcomes

Primary outcome was all-cause mortality within the first six months of life. Secondary outcomes were common morbidities (febrile illness, diarrhoea or pneumonia)

Notes
  • Trial was conducted between January 2007 and October 2010
  • A total of 11,028 consecutively delivered newborns participated in the study; 5380 (49%) received VAS, and 5648 (51%) placebo
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Quote: "This was a cluster randomized, placebo-controlled trial"; and "an external consultant generated the computerized allocation sequence of clusters to each study intervention to either group using Epi Info 3.5.3 with restricted randomization based on population size, expected births and LHW presence"

Comment: probably done

Allocation concealment (selection bias) Low risk

Quote: "An external consultant generated the computerized allocation sequence of clusters to each study intervention to either group using Epi Info 3.5.3 with restricted randomization based on population size, expected births and LHW presence"

Comment: probably done

Blinding (performance bias and detection bias) Low risk

Quote: "The capsules were identical in appearance (Banner Pharmacaps, Canada) and supplied through the courtesy of the Micronutrient Initiative (Ottawa, Canada).The capsules were packaged in containers labeled as A & B. The content of the capsules were masked from field staff and supervisors, and the codes were only known to the external consultant responsible for cluster randomization and the chair of the DSMB. The masking was maintained until the completion of the study"

Comment: probably done

Incomplete outcome data (attrition bias) Low risk

Quote: "We were able to follow 10,286 (93%) infants until death or 6 months of age"

Selective reporting (reporting bias) Low risk

Comment: The published study reported on all expected outcomes

Other bias Unclear risk

Protocol was not mentioned. This study was funded by PAIMAN (Pakistan Initiative for Mothers and Newborns)/John Snow Inc. via a grant funded by USAID, Award Number: Subagreement #36098-01 (USAID Co-operative Agreement #391-A-00-05-01037-00). The funding body provided clearance for the project design but, apart from field visits to review progress, did not influence the field trial or data analysis procedures

Edmond 2015

Methods

Randomised, double-blind, 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

Participants

Trial participants were at least 2 hours old, were identified at home or at facilities on the day of birth or in the next 2 days, were able to feed orally, and were likely to stay in the study area for at least 6 months; at least 1 parent provided written informed consent for participation

Interventions

Intervention was retinol palmitate (50,000 IU) and minute amounts of vitamin E in soybean oil, given orally as a single dose to neonates on the day of birth or in the next 2 days after birth, with a minimum period of 2 hours between birth and dosing. Placebo capsules contained minute amounts of vitamin E (9.5–12.6 IU) in soybean oil

Outcomes

All-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, over 3 days following administration of the supplement; vitamin A and C-reactive protein (CRP) status of a subsample of infants at 2 weeks and 3 months of age

Notes
  • Study population was estimated at 600,000 and included about 120,000 women of reproductive age. This area had low HIV prevalence (2.0% in 2011)
  • Infants born between 16 August 2010, and 7 November 2011, were considered
  • 16,792 (73.2%) infants were dosed within 24 hours of birth
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Quote: "The computerised block randomisation scheme was done with a block size of 20, so that in each block ten infants received vitamin A and ten received placebo"

Comment: probably done

Allocation concealment (selection bias) Low risk

Quote: "An independent statistician who was not part of the trial prepared the randomisation code at the WHO offices in Geneva, Switzerland. The code was available only to the Data Safety and Monitoring Board (DSMB) and their statistician"

Comment: probably done

Blinding (performance bias and detection bias) Low risk

Quote: "The research team and parents were fully unaware of the content of the capsules, which were only labelled with the infant number. A manufacturer (Strides Arcolab Limited, Bangalore, India) supplied the capsules. Separate staff, who were not part of the trial, labelled all capsules"

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

Incomplete outcome data (attrition bias) Low risk

Quote: "Our loss to follow-up was only 1.1% at the time of ascertainment of our primary outcome at 6 months and only 2.9% at 12 months"

Comment: Mortality and attrition distribution in the 2 groups was provided and appeared balanced

Selective reporting (reporting bias) Low risk

Comment: The published study reported on all expected outcomes

Other bias Unclear risk

75 protocol violations occurred, and all protocol violations were included in the analyses. The published protocol is available. The trial was funded by a grant from the Bill & Melinda Gates Foundation to WHO

Humphrey 1996

Methods

Randomised, placebo-controlled trial

Participants

Eligible for inclusion: all neonates within 24 hours of birth. Exclusion criteria: very low birth weight babies (< 1500 grams); those with life-threatening illness such as severe respiratory distress syndrome, major congenital anomalies, paralysis, hypoglycaemia and hypocalcaemia; clinical evidence of ischaemic hypoxia or sepsis. A total of 2067 were enrolled within the 24-hour inclusion period

Interventions

One 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; placebo, n = 1033

Outcomes

Mortality at 6 months and 12 months of age, cause-specific mortality at 12 months 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 18 June 1992, to 3 June 1993, were considered
  • Mean age of dosing was 16.2 (SD 8.2) hours; 88.2% were dosed in first 24 hours of life after birth
  • Treatment groups were comparable at baseline
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Quote: "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 risk

Quote: "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) Low risk

Quote: "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) Low risk

Attrition was 11% and reasons for it were provided. Distribution was balanced in the 2 groups. Infants lost to follow-up were not significantly different from those who were followed

Selective reporting (reporting bias) Unclear risk

Comment: insufficient information to permit judgement

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

Other bias Unclear risk

Agoestina 1994 mentioned a protocol but provided no details. Supported by a grant from John Hopkins University and assistance from Hoffmann-LaRoche industry (Basel, Switzerland)

Klemm 2008

Methods

Community-based, double-masked, cluster-randomised, placebo-controlled trial

Participants

Eligible for inclusion in the study: infants born to consenting mothers who were participating in the parent trial

Vitamin A group infants whose mothers consented = 8525               

Placebo group infants whose mothers consented = 8591

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

Interventions

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

Outcomes

Infant mortality at 6 months of age, adverse effects

Notes
  • Trial was nested into an ongoing, placebo-controlled, weekly, low-dose vitamin A or beta-carotene supplementation trial among pregnant women, which was under way 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 maternal supplementation trial arms. Interaction between maternal and vitamin A supplementation was non-significant
  • Approximately 84% were supplemented within the first 48 hours after birth
  • Treatment groups were comparable at baseline
  • Analysis was adjusted for cluster design
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Quote: "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 risk

Comment: insufficient detail to permit judgement

Blinding (performance bias and detection bias) Low risk

Quote: "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) Low risk

Exclusions and attrition were 7%. Reasons and distribution in the 2 groups were provided. Attrition and reasons for attrition were balanced across treatment groups

Selective reporting (reporting bias) Low risk

Comment: Results of all outcomes mentioned in Methods section of the published paper and those in trial registration document were presented in the paper

Other bias High risk

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

Malaba 2005

Methods

Randomised, placebo-controlled, 2-by-2 factorial design trial

Participants

Mother and infant pairs were enrolled within 96 hours of delivery. Pairs were eligible if neither member of the pair had an acutely life-threatening condition, the infant was a singleton with birth weight > 1500 grams and the mother planned to stay in Harare after delivery

Mothers and infants were assigned to the following 4 groups

  • Mothers received 400,000 IU vitamin A and infants received 50 000 IU vitamin A  (Aa group) = 3529
  • Mothers received 400,000 IU vitamin A and infants received placebo                    (Ap group) = 3529
  • Mothers received placebo and infants received 50,000 IU vitamin A                      (Pa group) = 3530
  • Both mothers and infants received placebo                                                            (Pp group) = 3522
Interventions

Mothers 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)  

Outcomes

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

Notes
  • Zimbabwe is categorised 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 treatment dose within 24 hours; 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 table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Quote: "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 risk

Quote: "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) Low risk

Quote: "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) Unclear risk

Exclusions and attrition were 41.8%. Reasons for exclusion included HIV positive or HIV indeterminate at baseline or seroconverted. Reasons for attrition were not provided

Selective reporting (reporting bias) Low risk

Comment: Results of all expected outcomes were presented in various publications

Other bias Low 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)"

Masanja 2015

Methods

Randomised, double-blind, placebo-controlled trial of infants born in the Morogoro and Dar es Salaam regions of Tanzania

Participants

Eligible participants: neonates whose parents consented to participate, were likely to stay in the study area until at least 6 months of age and were able to feed orally at the time of enrolment Both singleton and multiple births were eligible for enrolment. Excluded were babies who were enrolled in other trials

Interventions

Intervention was retinol palmitate (50,000 IU) and minute amounts of vitamin E in soybean oil, given orally as a single dose to neonates on the day of birth or over the next 2 days after birth with a minimum period of 2 hours between birth and dosing. Placebo capsules contained minute amounts of vitamin E (9.5–12.6 IU) in soybean oil

Outcomes

Primary outcome was death between supplementation and 180 days of age (6 months). Secondary outcomes were defined as death between supplementation and 28 days of age, death between supplementation and 365 days of age and hospital admission during the first 6 months of life, which was defined as admission to hospital as an inpatient as reported by the mother. In the case of more than 1 hospital admission; each infant contributed only the first admission to the analysis. Adverse events were defined as any harmful or undesired effects reported by the family within 3 days of supplementation. These included death, presence of bulging fontanelle confirmed by research team through physical examination of the infant, vomiting, fever, diarrhoea, inability to suck or feed and convulsions

Notes
  • In Dar es Salaam, mothers and newborn babies were enrolled from 10 large antenatal clinics and labour wards in catchment areas, and in the Morogoro region, the study was nested within the Ifakara Health Institute’s health and demographic surveillance system (HDSS)
  • All births that occurred as part of the HDSS or at designated labour wards were eligible for screening
  • 34,133 live births between 26 August 2010, and 3 March 2013, were identified and were assessed for eligibility
  • Most (24,888; 78%) infants received vitamin A or placebo within 24 hours
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Quote: "Block randomisation was done at WHO (Geneva, Switzerland) in block sizes of 20 (ten infants received vitamin A and ten received placebo)"

Comment: probably done

Allocation concealment (selection bias) Low risk

Quote: "Codes for the experimental regimens were kept with the data and safety monitoring board and broken during the analysis after a cleaned and locked database for the study was submitted to WHO"

Comment: probably done

Blinding (performance bias and detection bias) Low risk

Quote: "The vitamin A and placebo capsules were identical in taste and appearance. Capsules were individually packed in blister packs of two capsules each; one for the dose and the second for the backup dose. Labels for the capsules were printed at WHO with country and infant study number in sequential order. Labels were first fixed on blister packs containing vitamin A capsules. The capsules were then packed in sealed boxes and removed from the packing room before the next treatment group was brought in. Investigators had no access to the randomisation list or to any information that would allow them to deduce the allocation. Participants’ families, and trial personnel (including those distributing capsules and collecting, processing, and analysing data) were masked to treatment assignment for the duration of the trial"

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

Incomplete outcome data (attrition bias) Low risk

Quote: "Our study had high ascertainment of the outcomes of interest, as shown by the low loss to follow-up rates both at 6 months (3.5%) and at 12 months of age (4.8%), despite many challenges throughout the implementation of the study"

Comment: Mortality and attrition distribution in the 2 groups was provided and appeared balanced

Selective reporting (reporting bias) Low risk

Comment: The published study reported on all expected outcomes

Other bias Unclear risk

This trial was funded by a grant from the Bill & Melinda Gates Foundation to WHO. The published protocol is available. Study authors stated differences from the protocol and lack of power to detect differences between randomly assigned groups

Mazumder 2015

Methods

Double-blind, randomised, placebo-controlled trial in 2 districts (Faridabad and Palwal) in the state of Haryana, India

Participants

Eligible participants: neonates whose parents consented to participate, were likely to stay in the study area until at least 6 months of age and were able to feed orally at the time of enrolment Both singleton and multiple births were eligible for enrolment

Interventions

Intervention was retinol palmitate (50,000 IU) and minute amounts of vitamin E in soybean oil, given orally as a single dose to neonates on the day of birth or over the next 2 days after birth with a minimum period of 2 hours between birth and dosing. Placebo capsules contained minute amounts of vitamin E (9.5–12.6 IU) in soybean oil

Outcomes

Primary outcome was death between supplementation and 180 days of age (6 months). Secondary outcomes were deaths between supplementation and 28 days of age (neonatal period), deaths between supplementation and 365 days of age (12 months), admission of an infant to hospital 1 or more times because of any illness between supplementation and 180 days of age, potential adverse events during the 3-day period after supplementation and vitamin A status in a subsample of infants at 2 weeks and 3 months of age

Notes
  • Neonates were screened between 24 June 2010, and 1 July 2012
  • 44,984 neonates were randomly assigned to receive vitamin A (22,493) or placebo (22,491)
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Quote: "We randomly assigned infants using a block randomisation scheme with a block size of 20, so that in each block ten infants received vitamin A and ten received placebo"

Comment: probably done

Allocation concealment (selection bias) Low risk

Quote: "The randomisation list was prepared offsite at WHO (Geneva, Switzerland) by a statistician not otherwise involved with the trial. After preparation of the supplements, the code was available only to the data safety monitoring board until trial termination"

Comment: probably done

Blinding (performance bias and detection bias) Low risk

Quote: "The vitamin A and placebo capsules were identical in colour, shape, and size. Capsules were individually packaged in identical blister packs with two capsules, one for the dose and the other as a backup. Labels with a unique infant number based on the randomisation list were printed at WHO and under WHO staff supervision affixed on the appropriate capsule strips of vitamin A or placebo, which were then sent to the study site. The research team, parents, data analysis team, and safety board were unaware of the content of the capsules in the strip"

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

Incomplete outcome data (attrition bias) Low risk

Loss to follow-up was extremely low (47/44,984; 0.1%) at 12 months. Mortality and attrition distribution in the 2 groups was provided and appeared balanced

Selective reporting (reporting bias) Low risk

Comment: The published study reported on all expected outcomes

Other bias Unclear risk

Quote: "The capsule could not be given to one infant randomly assigned to the vitamin A group. 4715 (21.6%) infants in the vitamin A group and 4552 (20.9%) in the placebo group received vitamin A supplementation not given by study investigators during follow-up"

The trial was funded by a grant from the Bill & Melinda Gates Foundation to WHO. The published protocol is available

Rahmathullah 2003

Methods

Randomised, placebo-controlled, community-based trial

Participants

Eligible for participation: live-born infants who resulted from all pregnancies within participating villages. Pregnant women (> 12 weeks) were identified for recruitment from a variety of sources. Infants were randomly assigned to receive the intervention or placebo

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

Interventions

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

Outcomes

Infant mortality at 6 months, cause-specific mortality at 6 months, incidence of common morbidities and pneumococcal colonisation

Notes
  • Conducted between June 1998 and March 2001 in 2 rural districts of Tamil Nadu, southern India 
  • These areas are characterised by endemic vitamin A deficiency
  • Expected infant mortality at 6 months of age: 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 table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Quote: "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 risk

Quote: "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 was provided to allow judgement of 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) Low risk

Quote: "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) Low risk

Exclusions and attrition were 18.9%. Reasons and distributions in the 2 treatment groups were reported. Mortality in infants born alive but not enrolled was similar across treatment groups

Selective reporting (reporting bias) Low risk

Comment: Outcomes mentioned in the Methods section were reported. All expected outcomes were presented in published reports

Other bias Unclear risk

Supported by a grant from John Hopkins University and the Bill and Melinda Gates Foundation

West 1995

Methods

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

Participants

Infants less than/or equal to 5 months of age were eligible for inclusion. No exclusion criteria were given

Interventions

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

Outcomes

4-Month mortality, cause-specific mortality, adverse effects noted after 24 hours of dosing (vomiting, loose stools, fever, irritability, bulging fontanelles)

Notes
  • Conducted in district of Sarlahi, Nepal, between September 1989 and December 1991
  • Evaluated effect of VAS every 4 months on preschool child mortality
  • No information about gestational age and birth weight recorded, and almost all neonates supplemented after the first week of life (Keith West, personnel communication, 2008)
  • Treatment groups were comparable at baseline
  • 4-Month mortality estimates 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 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 2 groups of neonates
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Quote: "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 first random assignment is not described in sufficient detail to permit judgement

Allocation concealment (selection bias) Unclear risk

Comment: It is unclear, as the wards were assigned systematically

Blinding (performance bias and detection bias) Low risk

Quote: "gelatinous capsules of identical appearance, size (8*16mm), and taste"; "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 probably done

Incomplete outcome data (attrition bias) Low risk

Attrition among neonates was 1.04%; reasons were not provided. All analyses were performed on an intention-to-treat basis, that is, by randomised treatment group, irrespective of individual compliance with dosing regimen

Selective reporting (reporting bias) Low risk

Comment: Published reports included all expected outcomes

Other bias Unclear risk

Supported by a grant from Johns Hopkins University with assistance from Hoffmann-LaRoche industry (Basel, Switzerland). A protocol is described, but no details are provided

Footnotes

BCG: Bacille Calmette-Guérin
CRP: C-reactive protein
HIV: human immunodeficiency virus
MTCT: mother-to-child transmission
PPD: purified protein derivative
RBP: retinol binding protein
VAS: visual analogue scale
WHO: World Health Organization

Characteristics of excluded studies

Ahmad 2014

Reason for exclusion

This study reported no relevant outcomes

Bezzera 2009

Reason for exclusion

This study included supplementation of mothers only with vitamin A supplements during the immediate postpartum period and no vitamin A supplementation of neonates

Bhaskaram 1998

Reason for exclusion

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

Mathew 2015

Reason for exclusion

This paper was a commentary on an included study (Mazumder 2014)

Schmiedchen 2016

Reason for exclusion

Study participants were infants with birth weight below 1500 grams and gestational age less than 33 weeks

Characteristics of ongoing studies

McDonald 2014

Study name

A Double Blind Randomized Controlled Trial in Neonates to Determine the Effect of Vitamin A Supplementation on Immune Responses

Methods

Double-blind, randomised, placebo-controlled trial in a peri-urban area of The Gambia

Participants

Two hundred mother-infant pairs were recruited at the Sukuta Health Centre, a government health clinic in the Western coastal region of The Gambia. Inclusion criteria: singleton birth, birth weight greater than/or equal to 1500 grams, mothers over 18 years of age, residency within the study area and administration of birth vaccinations and vitamin A supplementation within 48 hours of birth. Exclusion criteria: infants with a congenital disease, a serious infection at birth or inability to feed; mothers who were seriously ill at the time of enrolment, mothers participating in other studies and/or mothers who were HIV positive

Interventions

Within 48 hours of birth, neonates were randomised to receive an oral dose of 50,000 IU vitamin A or placebo

Outcomes

Primary outcome is the frequency of circulating T regulatory (Treg) cells expressing gut homing receptors in infants at 17 weeks post supplementation. Secondary outcomes are differences in thymus size (assessed at 1, 6, 12 and 17 weeks), differences in B cell immune responses after routine vaccination (assessed at 6 and 17 weeks) and improved mucosal barrier function (assessed at 6 and 17 weeks) in infant participants

Starting date

November 2011

Contact information

Suzanna McDonald

Medical Research Council (MRC) International Nutrition Group (ING), London School of Hygiene & Tropical Medicine (LSHTM), Keppel Street, WC1E 7HT, United Kingdom & MRC Keneba, London, The Gambia

Suzanna.McDonald@lshtm.ac.uk

Notes
  • Recruitment commenced in December 2011 and was completed in October 2012
  • The last study participant reached the 17th week of life in February 2013 and graduated from the trial in October 2013

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Summary of findings tables

1 Neonatal vitamin A supplementation versus control for prevention of mortality and morbidity in term neonates in low and middle income countries

Neonatal vitamin A supplementation versus control for prevention of mortality and morbidity in term neonates in low and middle income countries

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

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Neonatal

vitamin A supplementation

All-cause infant mortality at 6 months: risk ratios based on cumulative risk (%, adjusted for clustering) - term infants

Low-risk population

RR 0.80
(0.54 to 1.18)

Risk ratios based on cumulative risk (%)

22,721
(3 studies)

⊕⊝⊝⊝
Very low a,b,c

The pooled estimate of data for term infants from 3 studies ( Humphrey 1996; Klemm 2008; Malaba 2005) suggests that risk of death from any cause at 6 months of age for neonates who were supplemented with vitamin A was 20% lower than control and was not statistically significant (pooled RR 0.80, 95% CI 0.54 to 1.18; Analysis 1.1.1)

The level of statistical heterogeneity in this analysis was 63%. As the number of studies included was small, a subgroup analysis to investigate heterogeneity was not considered reliable. Given substantial statistical heterogeneity and the small number of included studies, these findings should be interpreted with caution

13 per 1000

10 per 1000
(7 to 15)

Medium-risk population

15 per 1000

12 per 1000
(8 to 18)

High-risk population

28 per 1000

22 per 1000
(15 to 33)

All-cause infant mortality at 6 months: risk ratios based on cumulative risk (%, adjusted for clustering) - all infants

Low-risk population

RR 0.98

(0.89 to 1.07)

Risk ratios based on cumulative risk (%)

154,634

(11 studies)

⊕⊕⊕⊕
High

The pooled estimate of data for all infants from 11 studies ( Benn 2008; Benn 2010; Bhutta 2016; Edmond 2015; Humphrey 1996; Klemm 2008; Malaba 2005; Masanja 2015; Mazumder 2015; Rahmathullah 2003; West 1995) showed no evidence of a significant effect on risk of death from any cause for neonates supplemented with vitamin A as compared with controls (typical RR 0.98, 95% CI 0.89 to 1.07). The level of statistical heterogeneity for this analysis was 47% ( Analysis 1.1.2)

13 per 1000

13 per 1000
(12 to 15)

Medium-risk population

15 per 1000

15 per 1000
(13 to 16)

High-risk population

28 per 1000

27 per 1000
(25 to 30)

All-cause neonatal mortality: risk ratios based on cumulative risk (%, adjusted for clustering) - all infants

Low-risk population

RR 0.99

(0.90 to 1.08)

Risk ratios based on cumulative risk (%)

126,242

(5 studies)

⊕⊕⊕⊕
High

Five included studies measured neonatal mortality in the first month of life ( Bhutta 2016; Edmond 2015; Klemm 2008; Masanja 2015; Mazumder 2015). Data from these 5 studies were measured as risk ratios based on cumulative risk. The pooled estimate of data for all infants showed no evidence of a significant effect on risk of death from any cause at 1 month of age for neonates supplemented with vitamin A as compared with controls (typical RR 0.99. 95% CI 0.90 to 1.08)

   

Medium-risk population

   

High-risk population

   

Adverse events during first 48-72 hours post supplementation - bulging fontanelle

7 per 1000

11 per 1000
(8 to 14)

RR 1.53
(1.11 to 2.11)

100,256
(5 studies)

⊕⊕⊕⊕
High d

Data for adverse events in all infants during the first 48 to 72 hours could be pooled from 5 studies ( Benn 2008; Edmond 2015; Humphrey 1996; Masanja 2015; Mazumder 2015 ), and only 1 study ( Benn 2008) presented adverse events at 1 month of age ( Analysis 1.14 and Analysis 1.15)

The risk of a bulging fontanelle during the first 48 to 72 hours for neonates supplemented with vitamin A was 53% higher than for controls, which is statistically significant (typical RR 1.53, 95% CI 1.11 to 2.11; I 2 = 71%)

Adverse events during first 48-72 hours post supplementation - vomiting

34 per 1000

34 per 1000
(31 to 36)

RR 1.00
(0.93 to 1.07)

99,582
(5 studies)

⊕⊕⊕⊕
High

Typical RR 1.00 (95% CI 0.93 to 1.07) in vitamin A group vs control group

Adverse events during first 48-72 hours post supplementation - diarrhoea

43 per 1000

41 per 1000
(35 to 49)

RR 0.96
(0.81 to 1.13)

102,638
(5 studies)

⊕⊕⊝⊝
Low e,f

Pooled estimates from the 5 studies provided no evidence of a significant increase in diarrhoea (typical RR 0.96, 95% CI 0.81 to 1.13)

Vitamin A deficiency (serum retinol < 0.70 micromol/L) at 6 weeks of age

331 per 1000

311 per 1000
(248 to 394)

RR 0.94

(0.75 to 1.19) at 6 weeks

612
(1 study)

⊕⊕⊕⊕
High g

Vitamin A deficiency defined as serum retinol value < 0.70 µmol/L was available for all infants from 1 study only ( Benn 2008), which showed no evidence of a significant effect of vitamin A supplementation on vitamin A deficiency as compared with control at 6 weeks (RR 0.94, 95% CI 0.75 to 1.19)

Vitamin A deficiency (serum retinol < 0.70 micromol/L) at 4 months of age

158 per 1000

162 per 1000
(101 to 257)

RR 1.02

(0.64 to 1.62) at 4 months

369
(1 study)

⊕⊕⊕⊕
High h

Vitamin A deficiency defined as serum retinol value < 0.70 µmol/L was available for all infants from 1 study only ( Benn 2008), which provided no evidence of a significant effect of vitamin A supplementation on vitamin A deficiency as compared with control at 4 months (RR 1.02, 95% CI 0.64 to 1.62)

*The basis for the assumed risk (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on 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

Footnotes

aRisk 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

bThe lower confidence limit indicates a 46% reduction in mortality at 6 months, whereas the upper limit indicates an 18% increase

cThe level of statistical heterogeneity between study results was moderate (I2 = 63%). Variation between studies may have been related to differences between study populations and settings in terms of infant mortality rates and baseline prevalence of vitamin A deficiency

dAlthough level of statistical heterogeneity was substantial (I2 = 71%), all included studies indicated potential harm. Heterogeneity was caused by differences in strength of association among the included studies

eModerate level of statistical heterogeneity (I2 = 58%)

fThe lower confidence limit indicates a 19% reduction in diarrhoea, whereas the upper limit indicates a 13% increase

gOnly one of the included studies reported this outcome at 6 weeks of age. Review authors noted that data reported on this outcome specified different time points and could not be formally used in the meta-analysis

hOnly 1 of the included studies reported this outcome at 4 months of age. Review authors noted that data reported on this outcome specified different time points and could not be formally used in the meta-analysis

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Additional tables

1 Data type and source: all-cause infant mortality at 6 months

Study ID

Analyzed as rate/risk ratio

Data source (term/all infants)

Infants

Vitamin 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 2008

Rate ratio/ risk ratio

Correspondence with study investigators; published paper

All infants

55

964

2106

50

1003

2169

Benn 2010

Rate ratio/risk ratio

Correspondence with study investigators; published paper

All infants

62

393

854

62

397

863

Benn 2014

-

-

-

-

-

-

-

-

-

Bhutta 2016a

Risk ratio

Soofi et al (unpublished data)

All infants

128

-

5648

115

-

5380

All infants - male

58

-

2966

49

-

2774

All infants - female

70

-

2682

66

-

2606

Edmond 2015

Risk ratio

Edmond et al (Lancet 2015;385:1315–23)

All infants

278

-

11,345

248

-

11,353

All infants - male

150

-

5802

124

-

5715

All infants - female

128

-

5543

124

-

5638

Humphrey 1996

Risk ratio

Correspondence with study investigators (denominators are numbers of neonates randomised)

All infants

7

-

1034

18

-

1033

Term infants

6

-

1011

15

-

1007

Klemm 2008b

Risk ratio

Klemm et al (Pediatrics 2008;122:e242-50)

All infants

306

-

7953

360

-

7984

Term infants

129

-

6109

171

-

6061

All infants - male

169

-

4117

185

-

4020

All infants - female

137

-

3836

175

-

3964

Malaba 2005

Risk ratio

Correspondence with study investigators. Data aggregated for the 4 treatment groups: maternal vitamin A and infant vitamin A + maternal placebo and infant vitamin A vs maternal placebo and infant placebo + maternal vitamin A and infant placebo (for term infants, denominators are numbers of HIV-negative mothers with term deliveries)

All infants

73

-

4309

66

-

4352

Term infants

62

-

4253

57

-

4280

Masanja 2015

Rate ratio/ risk ratio

Masanja et al (Lancet 2015;385:1324-32)

All infants

407

7521

15,428

372

7542

15,464

All infants - male

233

3960

8135

215

3927

8070

All infants - female

174

3559

7291

157

3614

7392

Mazumder 2015

Risk ratio

Muzumder et al (Lancet 2015;385:1333–42)

All infants

656

-

22,493

726

-

22,491

All infants - male

293

-

11,689

310

-

11,729

All infants - female

363

-

10,804

416

-

10,762

Rahmathullah 2003

Rate ratio/ risk ratio

Rahmathullah et al (BMJ 2003;327(7409):254)

All infants

146

2713

5363

188

2719.1

5408

Correspondence with study investigators

Term infants

106

2348.7

-

130

2346.7

-

Rahmathullah et al (BMJ 2003;327(7409):254)

All infants - male

68

1378.2

-

100

1412.3

-

Rahmathullah et al (BMJ 2003;327(7409):254)

All infants - female

78

1334.8

-

88

1306.7

-

West 1995c

Rate ratio/ risk ratio

West et al (American Journal of Clinical Nutrition 1995;62:143-8). Data were extracted for infants under 1 month old who had been allocated to treatment

All infants

38

268.4

819

34

256.9

785

Footnotes

aBhutta 2016 was a cluster-randomised study. Study investigators reported that observed design effect and intracluster coefficient (ICC) for infant mortality at 6 months were 1.26666 and 0.00978
bKlemm 2008 was a cluster-randomised study. Study authors reported that observed design effect was 0.9%
cWest 1995 was a cluster-randomised study. Study authors reported that 95% confidence intervals of effect estimates were inflated by 10% to account for the impact of the design on the study. We estimated that the 10% increase in 95% CIs gave an ICC of 0.04 for the cohort of infants administered vitamin A

2 Data type and source: all-cause infant mortality at 12 months

Study ID

Analyzed as rate/risk ratio

Data source

Infants

Vitamin 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 2008

Rate ratio/risk ratio

Benn et al (BMJ 2008;336(7658):1416-20)

All infants

88

1795

2106

86

1884

2169

Benn 2010

Rate ratio/risk ratio

Benn et al (BMJ 2010;340:c1101)

All infants

83

757

701

78

762

710

Benn 2014

Rate ratio/risk ratio

Benn et al (Journal of Nutrition 2014;144:1474-9)

All infants

115

2744

3948

45

1377

1987

All infants - male

63

1406

-

24

724

-

All infants - female

52

1339

-

21

653

-

Bhutta 2016

-

-

-

-

-

-

-

-

-

Edmond 2015

Risk ratio

Edmond et al (Lancet 2015;385:1315–23)

All infants

371

-

11,133

328

-

11,158

All infants - male

199

-

5676

166

-

5612

All infants - female

172

-

5457

162

-

5546

Humphrey 1996

Rate ratio/risk ratio

Humphrey et al (Journal of Pediatrics 1996;128:489-96)

All infants (include 6% preterms)

7

969.6

925

19

957.1

914

All infants - male

2

505.8

-

13

492.1

-

All infants - female

5

463.9

-

6

465

-

Klemm 2008

-

-

-

-

-

-

-

-

-

Malaba 2005

Rate ratio/ Risk ratio

Malaba et al (American Journal of Clinical Nutrition 2005;81:454-60). Data aggregated for the 4 treatment groups: maternal vitamin A and infant vitamin A + maternal placebo and infant vitamin A vs maternal placebo and infant placebo + maternal vitamin A and infant placebo

All infants

88

4195

4079

82

4239

4127

Masanja 2015

Rate ratio/ Risk ratio

Masanja et al (Lancet 2015;385:1324-32)

All infants

566

15,010

14,686

546

15,059

14,749

All infants - male

312

7899

7745

324

7833

7713

All infants - female

254

7108

6939

222

7223

7034

Mazumder 2015

Risk ratio

Muzumder et al (Lancet 2015;385:1333–42)

All infants

879

-

22,493

939

-

22,491

All infants - male

371

-

11,689

396

-

11,729

All infants - female

508

-

10,804

543

-

10,762

Rahmathullah 2003

-

-

-

-

-

-

-

-

-

West 1995

-

-

-

-

-

-

-

-

-

3 Data type and source: all-cause neonatal mortality

Study ID

Analyzed as rate/risk ratio

Data source

Infants

Vitamin 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 2008

-

-

-

-

-

-

-

-

-

Benn 2010

-

-

-

-

-

-

-

-

-

Benn 2014

-

-

-

-

-

-

-

-

-

Bhutta 2016

Risk ratio

Soofi et al (unpublished data)

All

infants

57

-

5648

48

-

5380

All infants - male

26

-

2966

21

-

2774

All infants - female

31

-

2682

27

-

2606

Edmond 2015

Risk ratio

Edmond et al (Lancet 2015;385:1315–23)

All infants

147

-

11,447

130

-

11,459

All infants - male

79

-

5857

69

-

5768

All infants - female

68

-

5590

61

-

5691

Humphrey 1996

-

-

-

-

-

-

-

-

-

Klemm 2008

Risk ratio

Klemm at al (Pediatrics 2008;122:e242-50)

All

infants

222

-

7953

250

-

7984

Malaba 2005

-

-

-

-

-

-

-

-

-

Masanja 2015

Rate ratio/risk ratio

Masanja et al (Lancet 2015;385:1324-32)

All infants

213

1192

15,677

206

1194

15,710

All infants - male

124

628

8273

124

622

8198

All infants - female

89

563

7402

82

572

7510

Mazumder 2015

Risk ratio

Mazumder et al (Lancet 2015;385:1333–42)

All

infants

281

-

22,493

298

-

22,491

All infants - male

124

-

11,689

132

-

11,729

All infants - female

157

-

10,804

166

-

10,762

Rahmathullah 2003

-

-

-

-

-

-

-

-

-

West 1995

-

-

-

-

-

-

-

-

-

[top]

References to studies

Included studies

Benn 2008

[CRSSTD: 2743316]

Aage S, Kiraly N, Da Costa K, Byberg S, Bjerregaard-Andersen M, Fisker AB, et al. Neonatal vitamin A supplementation associated with increased atopy in girls. Allergy 2015;70(8):985-94. [CRSREF: 5282289; DOI: 10.1111/all.12641]

* Benn CS, Diness BR, Roth A, Nante E, Fisker AB, Lisse IM, et al. Effect of 50,000 IU vitamin A given with BCG vaccine on mortality in infants in Guinea-Bissau: randomised placebo controlled trial. BMJ 2008;336(7658):1416-20. [CRSREF: 2743317; DOI: 10.1136/bmj.39542.509444.AE]

Diness BR, Christoffersen D, Pedersen UB, Rodrigues A, Fischer TK, Andersen A, et al. The effect of high-dose vitamin A supplementation given with bacille Calmette-Guerin vaccine at birth on infant rotavirus infection and diarrhea: a randomized prospective study from Guinea-Bissau. The Journal of Infectious Diseases 2010;202(Suppl 1):S243-251. [CRSREF: 4291680; DOI: 10.1086/653569]

Diness BR, Fisker AB, Roth A, Yazdanbakhsh M, Sartono E, Whittle H, et al. Effect of high-dose vitamin A supplementation on the immune response to Bacille Calmette-Guerin vaccine. The American Journal of Clinical Nutrition 2007;86(4):1152-9. [CRSREF: 2743318; PubMed: 17921396]

Fisker AB, Aaby P, Rodrigues A, Frydenberg M, Bibby BM, Benn CS. Vitamin A supplementation at birth might prime the response to subsequent vitamin A supplements in girls. Three year follow-up of a randomized trial. PloS One 2011;6(8):e23265. [CRSREF: 5282290]

Fisker AB, Benn CS, Diness BR, Martins C, Rodrigues A, Aaby P, et al. The effect of 50000IU vitamin A with BCG vaccine at birth on growth in the first year of life. Journal of Tropical Medicine 2011;2011:Article Number: 570170. [CRSREF: 5282291]

Fisker AB, Lisse IM, Aaby P, Erhardt JG, Rodrigues A, Bibby BM, et al. Effect of vitamin A supplementation with BCG vaccine at birth on vitamin A status at 6 wk and 4 mo of age. The American Journal of Clinical Nutrition 2007;86(4):1032-9. [CRSREF: 2743319; PubMed: 17921381]

Jorgensen MJ, Fisker AB, Sartono E, Andersen A, Erikstrup C, Lisse IM, et al. The effect of at-birth vitamin A supplementation on differential leucocyte counts and in vitro cytokine production: an immunological study nested within a randomised trial in Guinea-Bissau. The British Journal of Nutrition 2013;109(3):467-77. [CRSREF: 5282292; DOI: 10.1017/S0007114512001304]

Nante JE, Diness BR, Ravn H, Roth A, Aaby P, Benn CS. No adverse events after simultaneous administration of 50 000 IU vitamin A and Bacille Calmette-Guerin vaccination to normal-birth-weight newborns in Guinea-Bissau. European Journal of Clinical Nutrition 2008;62(7):842-8. [CRSREF: 2743320; DOI: 10.1038/sj.ejcn.1602796]

Benn 2010

[CRSSTD: 2743321]

* Benn CS, Fisker AB, Napirna BM, Roth A, Diness BR, Lausch KR, et al. Vitamin A supplementation and BCG vaccination at birth in low birthweight neonates: two by two factorial randomised controlled trial. BMJ 2010;340:c1101. [CRSREF: 4291682; DOI: 10.1136/bmj.c1101]

Biering-Sørensen S, Fisker AB, Ravn H, Camala L, Monteiro I, Aaby P, et al. The effect of neonatal vitamin A supplementation on growth in the first year of life among low-birth-weight infants in Guinea-Bissau: two by two factorial randomised controlled trial. BMC Pediatrics 2013;13:87. [CRSREF: 5282293; DOI: 10.1186/1471-2431-13-87]

Kiraly N, Benn CS, Biering-Sorensen S, Rodrigues A, Jensen KJ, Ravn H, et al. Vitamin A supplementation and BCG vaccination at birth may affect atopy in childhood: long-term follow-up of a randomized controlled trial. Allergy 2013;68(9):1168-76. [CRSREF: 5282294; DOI: 10.1111/all.12216]

Benn 2014

[CRSSTD: 2743345]

Benn CS, Diness BR, Balde I, Rodrigues A, Lausch KR, Martins CL, et al. Two different doses of supplemental vitamin A did not affect mortality of normal-birth-weight neonates in Guinea-Bissau in a randomized controlled trial. The Journal of Nutrition 2014;144(9):1474-9. [CRSREF: 4291683]

Bhutta 2016

Unpublished data only [CRSSTD: 4291684]

Bhutta Z, Soofi S, Ariff S, Sadiq K, Habib A, Ahmad I, et al. Evaluation of the uptake and impact of neonatal vitamin A supplementation delivered through the Lady Health Worker Program on neonatal and infant morbidity and mortality in rural Pakistan; an effectiveness trial. [CRSREF: 4291685]

Edmond 2015

[CRSSTD: 4291686]

Bahl R, Bhandari N, Dube B, Edmond K, Fawzi W, Fontaine O, et al; NEOVITA Study Author Group. Efficacy of early neonatal vitamin A supplementation in reducing mortality during infancy in Ghana, India and Tanzania: study protocol for a randomized controlled trial. Trials 2012;13:22. [CRSREF: 5282295; DOI: 10.1186/1745-6215-13-22]

* Edmond KM, Newton S, Shannon C, O'Leary M, Hurt L, Thomas G, et al. Effect of early neonatal vitamin A supplementation on mortality during infancy in Ghana (Neovita): a randomised, double-blind, placebo-controlled trial. Lancet 2015;385(9975):1315–23. [CRSREF: 4291687; DOI: 10.1016/S0140-6736(14)60880-1]

Humphrey 1996

[CRSSTD: 2743323]

Agoestina T, Humphrey JH, Taylor GA, Usman A, Subardja D, Hidayat S, et al. Safety of one 52-mumol (50,000 IU) oral dose of vitamin A administered to neonates. Bulletin of the World Health Organization 1994;72(6):859-68. [CRSREF: 2743324; PubMed: 7867131]

Humphrey JH, Agoestina T, Juliana A, Septiana S, Widjaja H, Cerreto MC, et al. Neonatal vitamin A supplementation: effect on development and growth at 3 y of age. The American Journal of Clinical Nutrition 1998;68(1):109-17. [CRSREF: 2743325; PubMed: 9665104]

* Humphrey JH, Agoestina T, Wu L, Usman A, Nurachim M, Subardja D, et al. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. The Journal of Pediatrics 1996;128(4):489-96. [CRSREF: 2743326; PubMed: 8618182]

Klemm 2008

[CRSSTD: 2743327]

Coles CL, Labrique A, Saha SK, Ali H, Al-Emran H, Rashid M, et al. Newborn vitamin A supplementation does not affect nasopharyngeal carriage of Streptococcus pneumoniae in Bangladeshi infants at age 3 months. Journal of Nutlrition 2011;141(10):1907-11. [CRSREF: 5282296; DOI: 10.3945/jn.111.141622]

Klemm RD, Labrique AB, Christian P, Rashid M, Shamim AA, Katz J, et al. Newborn vitamin A supplementation reduced infant mortality in rural Bangladesh. Pediatrics 2008;122(1):e242-50. [CRSREF: 2743328; DOI: 10.1542/peds.2007-3448]

Malaba 2005

Published and unpublished data [CRSSTD: 2743329; Other: Both maternal and neonatal supplementation]

Humphrey JH, Iliff PJ, Marinda ET, Mutasa K, Moulton LH, Chidawanyika H, et al. Effects of a single large dose of vitamin A, given during the postpartum period to HIV-positive women and their infants, on child HIV infection, HIV-free survival, and mortality. The Journal of Infectious Diseases 2006;193(6):860-71. [CRSREF: 2743330; DOI: 10.1086/500366]

* Malaba LC, Iliff PJ, Nathoo KJ, Marinda E, Moulton LH, Zijenah LS, et al. Effect of postpartum maternal or neonatal vitamin A supplementation on infant mortality among infants born to HIV-negative mothers in Zimbabwe. The American Journal of Clinical Nutrition 2005;81(2):454-60. [CRSREF: 2743331; PubMed: 15699235]

Miller MF, Stoltzfus RJ, Iliff PJ, Malaba LC, Mbuya NV, Humphrey JH; Zimbabwe Vitamin A for Mothers and Babies Project (ZVITAMBO) Study Group. Effect of maternal and neonatal vitamin A supplementation and other postnatal factors on anemia in Zimbabwean infants: a prospective, randomized study. The American Journal of Clinical Nutrition 2006;84(1):212-22. [CRSREF: 2743332; PubMed: 16825698]

Masanja 2015

[CRSSTD: 4291688]

Bahl R, Bhandari N, Dube B, Edmond K, Fawzi W, Fontaine O, et al; NEOVITA Study Author Group. Efficacy of early neonatal vitamin A supplementation in reducing mortality during infancy in Ghana, India and Tanzania: study protocol for a randomized controlled trial. Trials 2012;13(22). [CRSREF: 5282297; DOI: 10.1186/1745-6215-13-22]

* Masanja H, Smith ER, Muhihi A, et al, for the Neovita Tanzania Study Group. Effect of neonatal vitamin A supplementation on mortality in infants in Tanzania: a randomised, double-blind, placebo-controlled trial. Lancet 2015;385:1324-32. [CRSREF: 4291689]

Mazumder 2015

[CRSSTD: 4291690]

Bahl R, Bhandari N, Dube B, Edmond K, Fawzi W, Fontaine O, et al. Efficacy of early neonatal vitamin A supplementation in reducing mortality during infancy in Ghana, India and Tanzania: study protocol for a randomized controlled trial. Trials 2012;13(22). [CRSREF: 5282298]

* Mazumder S, Taneja S, Bhatia K, Yoshida S, Kaur J, Dube B, et al; Neovita India Study Group. Efficacy of early neonatal supplementation with vitamin A to reduce mortality in infancy in Haryana, India (Neovita): a randomised, double-blind, placebo-controlled trial. Lancet 2015;385(9975):1333–42. [CRSREF: 4291691; DOI: 10.1016/S0140-6736(14)60891-6]

Rahmathullah 2003

[CRSSTD: 2743333]

Coles CL, Rahmathullah L, Kanungo R, Thulasiraj RD, Katz J, Santhosham M, et al. Vitamin A supplementation at birth delays pneumococcal colonization in South Indian infants. Journal of Nutrition 2001;131(2):255-61. [CRSREF: 2743334; PubMed: 11160543]

* Rahmathullah L, Tielsch JM, Thulasiraj RD, Katz J, Coles C, Devi S, et al. Impact of supplementing newborn infants with vitamin A on early infant mortality: community based randomised trial in southern India. BMJ 2003;327(7409):254. [CRSREF: 2743335; DOI: 10.1136/bmj.327.7409.254]

Tielsch JM, Rahmathullah L, Thulasiraj RD, Katz J, Coles C, Sheeladevi S, et al. Newborn vitamin A dosing reduces the case fatality but not incidence of common childhood morbidities in South India. Journal of Nutrition 2007;137(11):2470-4. [CRSREF: 2743336; PubMed: 17951487]

West 1995

[CRSSTD: 2743337]

Katz J, West KP, Khatry SK, Thapa MD, LeClerq SC, Pradhan EK, et al. Impact of vitamin A supplementation on prevalence and incidence of xerophthalmia in Nepal. Investigative Ophthalmology and Visual Science 1995;36(13):2577-83. [CRSREF: 2743338; PubMed: 7499080]

* West KP Jr, Katz J, Shrestha SR, LeClerq SC, KhatrY SK, Pradhan EK, et al. Mortality of infants <6 mo of age supplemented with vitamin A: a randomized, double-masked trial in Nepal. The American Journal of Clinical Nutrition 1995;62(1):143-8. [CRSREF: 2743339; PubMed: 7598058]

West KP, Khatry SK, LeClerq SC, Adhikari R, See L, Katz J, et al. Tolerance of young infants to a single, large dose of vitamin A: a randomized community trial in Nepal. Bulletin of the World Health Organization 1992;70(6):733-9. [CRSREF: 2743340; PubMed: 1486669]

Excluded studies

Ahmad 2014

[CRSSTD: 4291694]

Ahmad SM, Raqib R, Qadri F, Stephensen CB. The effect of newborn vitamin A supplementation on infant immune functions: trial design, interventions, and baseline data. Contemporary Clinical Trials 2014;39(2):269-79. [CRSREF: 4291695; DOI: 10.1016/j.cct.2014.09.004]

Bezzera 2009

[CRSSTD: 2743341]

Bezerra DS, Araújo KF, Azevêdo GM, Dimenstein R. Maternal supplementation with retinyl palmitate during immediate postpartum period: potential consumption by infants. Revista de Saude Publica 2009;43(4):572-9. [CRSREF: 2743342; PubMed: 19547802]

Bhaskaram 1998

[CRSSTD: 2743343]

Bhaskaram P, Balakrishna N. Effect of administration of 200,000 IU of vitamin A to women within 24 hrs after delivery on response to PPV administered to the newborn. Indian Pediatrics 1998;35(3):217-22. [CRSREF: 2743344; PubMed: 9707874]

Mathew 2015

[CRSSTD: 4291710]

Mathew JL. Does early neonatal vitamin A supplementation reduce infant mortality? Indian Pediatrics 2015;52(4):329-32. [CRSREF: 4291711; PubMed: 25929632]

Schmiedchen 2016

[CRSSTD: 4291714]

Schmiedchen B, Longardt AC, Loui A, Buhrer C, Raila J, Schweigert FJ. Effect of vitamin A supplementation on the urinary retinol excretion in very low birth weight infants. European Journal of Pediatrics 2016;175(3):365-72. [CRSREF: 4291715; DOI: 10.1007/s00431-015-2647-9]

Studies awaiting classification

None noted.

Ongoing studies

McDonald 2014

[CRSSTD: 4291712]

McDonald SLR, Savy M, Fulford AJC, Kendall L, Flanagan KL, Prentice AM. A double blind randomized controlled trial in neonates to determine the effect of vitamin A supplementation on immune responses: the Gambia protocol. BMC Pediatrics 2014;14:92. [CRSREF: 4291713; DOI: 10.1186/1471-2431-14-92]

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Other references

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Abrams SA, Hilmers DC. Postnatal vitamin A supplementation in developing countries: an intervention whose time has come? Pediatrics 2008;122(1):180-1. [DOI: 10.1542/peds.2008-0455]

Beaton 1993

Beaton GH, Martorell R, Aronson KJ, Edmonston B, McCabe G, Ross AC, et al. Effectiveness of vitamin A supplementation in the control of young child morbidity and mortality in developing countries. ACC/SCN State-of-the-Art Series policy discussion paper no. 13. Geneva, Switzerland: World Health Organization, 1993.

Bhutta 2008

Bhutta ZA, Ahmed T, Black RE, Cousens S, Dewey K, Giugliani E, et al; Maternal and Child Undernutrition Study Group. What works? Interventions for maternal and child undernutrition and survival. Lancet 2008;371(9610):417-40. [Other: 10.1016/S0140-6736(07)61693-6]

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Solomons NW. Vitamin A and carotenoids. In: Bowman BA, Russell RM, editor(s). Present Knowledge in Nutrition. 8th edition. Washington, DC: ILSI Press, 2001.

Daulaire 1992

Daulaire NM, Starbuck ES, Houston RM, Church MS, Stukel TA, Pandey MR. Childhood mortality after a high dose of vitamin A in a high risk population. BMJ 1992;304(6821):207-10. [PubMed: 1739794]

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Institute of Medicine (US) Panel on Micronutrients. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academies Press, 2001. [DOI: 10.17226/10026 ]

Fawzi 2006

Fawzi WW. The benefits and concerns related to vitamin A supplementation. Journal of Infectious Diseases 2006;193(6):756–9. [DOI: 10.1086/500369]

Gogia 2009

Gogia S, Sachdev HS. Neonatal vitamin A supplementation for prevention of mortality and morbidity in infancy: systematic review of randomised controlled trials. BMJ 2009;338:b919. [DOI: 10.1136/bmj.b919]

GRADEpro GDT

GRADEpro [www.gradepro.org] [Computer program]. Version 14, September 2016. Hamilton (ON): Grade Working Group, McMaster University, 2014.

Haider 2015

Haider BA, Bhutta ZA. Neonatal vitamin A supplementation: time to move on. Lancet 2015;385(9975):1268–71. [DOI: 10.1016/S0140-6736(14)62342-4]

Haskell 1999

Haskell MJ, Brown KH. Maternal vitamin A nutriture and the vitamin A content of human milk. Journal of Mammary Gland Biology and Neoplasia 1999;4(3):243–57. [PubMed: 10527467]

Hathcock 1997

Hathcock JN. Vitamins and minerals: efficacy and safety. The American Journal of Clinical Nutrition 1997;66(2):427-37. [PubMed: 9250127]

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Huiming 2005

Huiming Y, Chaomin W, Meng M. Vitamin A for treating measles in children. Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD001479. DOI: 10.1002/14651858.CD001479.pub3.

Imdad 2010

Imdad A, Herzer K, Mayo-Wilson E, Yakoob MY, Bhutta ZA. Vitamin A supplementation for preventing morbidity and mortality in children from 6 months to 5 years of age. Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD008524. DOI: 10.1002/14651858.CD008524.pub2.

Kirkwood 2010

Kirkwood BR, Hurt L, Amenga-Etego S, Tawiah C, Zandoh C, Danso S, et al; ObaapaVitA Trial Team. Effect of vitamin A supplementation in women of reproductive age on maternal survival in Ghana (ObaapaVitA): a cluster-randomised, placebo-controlled trial. Lancet 2010;375(9726):1640-9. [DOI: 10.1016/S0140-6736(10)60311-X]

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Rahman MM, Mahalanabis D, Wahed MA, Islam MA, Habte D. Administration of 25,000 IU vitamin A doses at routine immunisation in young infants. European Journal of Clinical Nutrition 1995;49(6):439-45. [PubMed: 7656887]

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Rice AL, West KP Jr, Black RE. Vitamin A deficiency. In: Ezzati M, Lopez AD, Rodgers A, Murray CJL, editor(s). Global and Regional Burden of Disease Attributable to Selected Major Risk Factors. Vol. 1. Geneva: World Health Organization, 2004:211-56.

Sachdev 2008

Sachdev HP. Neonatal vitamin A supplementation and infant survival in Asia. Lancet 2008;371(9626):1746; author reply 1746-8. [DOI: 10.1016/S0140-6736(08)60750-3]

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Schünemann H, Brożek J, Guyatt G, Oxman A, editors; GRADE Working Group. GRADE Handbook for Grading Quality of Evidence and Strength of Recommendations. www.guidelinedevelopment.org/handbook. Updated October 2013.

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Sommer A. Vitamin A Deficiency and Its Consequences: A Field Guide to Their Detection and Control. 3rd ed. Geneva: World Health Organization, 1995.

Sommer 1996

Sommer A, West KP Jr. Vitamin A Deficiency: Health, Survival, and Vision. New York: Oxford University Press, 1996.

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Tielsch JM. Vitamin A supplements in newborns and child survival. BMJ 2008;336(7658):1385-6. [DOI: 10.1136/bmj.39575.486609.80]

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Underwood BA. Maternal vitamin A status and its importance in infancy and early childhood. The American Journal of Clinical Nutrition 1994;59(2 Suppl):517S-24S. [PubMed: 8304290]

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Wallingford JC, Underwood BA. Vitamin A deficiency in pregnancy, lactation, and the nursing child. In: Bauernfeind CJ, editor(s). Vitamin A Deficiency and Its Control. New York: Academic Press, 1986:101-52.

West 1999

West KP Jr, Katz J, Khatry SK, LeClerq SC, Pradhan EK, Shrestha SR, et al. Double blind, cluster randomised trial of low dose supplementation with vitamin A or beta carotene on mortality related to pregnancy in Nepal. The NNIPS-2 Study Group. BMJ 1999;318(7183):570-5. [PubMed: 10037634 ]

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Other published versions of this review

Haider 2011

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.

Classification pending references

None noted.

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Data and analyses

1 Neonatal vitamin A supplementation versus control

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 All-cause infant mortality at 6 months: risk ratios based on cumulative risk (%, adjusted for clustering) 11 Risk Ratio (IV, Random, 95% CI) Subtotals only
  1.1.1 Term infants 3 22721 Risk Ratio (IV, Random, 95% CI) 0.80 [0.54, 1.18]
  1.1.2 All infants 11 154634 Risk Ratio (IV, Random, 95% CI) 0.98 [0.89, 1.07]
  1.1.3 All infants - male 5 65017 Risk Ratio (IV, Random, 95% CI) 1.01 [0.92, 1.12]
  1.1.4 All infants - female 5 60518 Risk Ratio (IV, Random, 95% CI) 0.95 [0.84, 1.08]
  1.1.5 All infants - Asia 6 86391 Risk Ratio (IV, Random, 95% CI) 0.89 [0.80, 0.99]
  1.1.6 All infants - Africa 5 68243 Risk Ratio (IV, Random, 95% CI) 1.10 [1.00, 1.21]
1.2 All-cause infant mortality at 6 months: rate ratios (per years of follow-up) 5 Rate Ratio (IV, Random, 95% CI) Subtotals only
  1.2.1 Term infants 2 Rate Ratio (IV, Random, 95% CI) 0.93 [0.67, 1.30]
  1.2.2 All infants 5 Rate Ratio (IV, Random, 95% CI) 0.99 [0.84, 1.17]
  1.2.3 All infants - male 2 Rate Ratio (IV, Random, 95% CI) 0.88 [0.58, 1.35]
  1.2.4 All infants - female 2 Rate Ratio (IV, Random, 95% CI) 1.01 [0.79, 1.30]
  1.2.5 All infants - Asia 2 Rate Ratio (IV, Random, 95% CI) 0.85 [0.64, 1.13]
  1.2.6 All infants - Africa 3 Rate Ratio (IV, Random, 95% CI) 1.09 [0.96, 1.23]
1.3 All-cause infant mortality at 12 months: risk ratios based on cumulative risk (%) 8 Risk Ratio (M-H, Random, 95% CI) Subtotals only
  1.3.1 All infants 8 118376 Risk Ratio (M-H, Random, 95% CI) 1.04 [0.94, 1.15]
  1.3.2 All infants - male 3 50164 Risk Ratio (M-H, Random, 95% CI) 1.00 [0.88, 1.14]
  1.3.3 All infants - female 3 46542 Risk Ratio (M-H, Random, 95% CI) 1.04 [0.90, 1.20]
  1.3.4 All infants - Asia 2 46823 Risk Ratio (M-H, Random, 95% CI) 0.65 [0.26, 1.60]
  1.3.5 All infants - Africa 6 71553 Risk Ratio (M-H, Random, 95% CI) 1.08 [1.00, 1.17]
1.4 All-cause infant mortality at 12 months: rate ratios (per years of follow-up) 6 Rate Ratio (IV, Random, 95% CI) Subtotals only
  1.4.1 Term infants 3 Rate Ratio (IV, Random, 95% CI) 0.94 [0.59, 1.50]
  1.4.2 All infants 6 Rate Ratio (IV, Random, 95% CI) 1.06 [0.92, 1.22]
  1.4.3 All infants - male 5 Rate Ratio (IV, Random, 95% CI) 0.89 [0.66, 1.19]
  1.4.4 All infants - female 5 Rate Ratio (IV, Random, 95% CI) 1.21 [1.05, 1.41]
  1.4.5 All infants - Asia 3 Rate Ratio (IV, Random, 95% CI) 0.94 [0.69, 1.29]
  1.4.6 All infants - Africa 3 Rate Ratio (IV, Random, 95% CI) 1.13 [0.94, 1.36]
1.5 Cause-specific infant mortality at 6 months (all infants): diarrhoea 2 (IV, Fixed, 95% CI) No totals
  1.5.1 Risk ratio 1 (IV, Fixed, 95% CI) No totals
  1.5.2 Rate ratio 1 (IV, Fixed, 95% CI) No totals
1.6 Cause-specific infant mortality at 6 months (all infants): respiratory infection 2 (IV, Fixed, 95% CI) No totals
  1.6.1 Risk ratio 1 (IV, Fixed, 95% CI) No totals
  1.6.2 Rate ratio 1 (IV, Fixed, 95% CI) No totals
1.7 Cause-specific infant mortality at 12 months (all infants): diarrhoea 3 (IV, Fixed, 95% CI) Subtotals only
  1.7.1 Risk ratios 1 (IV, Fixed, 95% CI) 0.40 [0.08, 2.03]
  1.7.2 Rate ratios 2 (IV, Fixed, 95% CI) 1.32 [0.80, 2.16]
1.8 Cause-speciifc infant mortality at 12 months (all infants): respiratory infection 3 (IV, Fixed, 95% CI) Subtotals only
  1.8.1 Risk ratios 1 (IV, Fixed, 95% CI) 0.66 [0.11, 3.95]
  1.8.2 Rate ratios 2 (IV, Fixed, 95% CI) 0.97 [0.67, 1.42]
1.9 Infant morbidity at 6 months (rate ratio): diarrhoea 3 Rate ratio (IV, Random, 95% CI) 0.89 [0.69, 1.14]
  1.9.1 All Diarrhoea 3 Rate ratio (IV, Random, 95% CI) 0.89 [0.69, 1.14]
1.10 Infant morbidity at 6 months (rate ratio): respiratory infection 2 Rate ratio (IV, Random, 95% CI) 1.05 [0.91, 1.21]
1.11 Vitamin A deficiency (serum retinol < 0.70 micromol/L) at 6 weeks of age 1 Risk Ratio (M-H, Fixed, 95% CI) No totals
1.12 Vitamin A deficiency (serum retinol < 0.70 micromol/L) at 4 months of age 1 Risk Ratio (M-H, Fixed, 95% CI) No totals
1.13 Anaemia (haemoglobin < 105 g/L) at 8-14 months of age 1 Risk Ratio (M-H, Fixed, 95% CI) No totals
1.14 Adverse events during the first 48-72 hours post supplementation 5 Risk Ratio (M-H, Random, 95% CI) Subtotals only
  1.14.1 Bulging fontanelle 5 100256 Risk Ratio (M-H, Random, 95% CI) 1.53 [1.11, 2.11]
  1.14.2 Diarrhoea 5 102638 Risk Ratio (M-H, Random, 95% CI) 0.96 [0.81, 1.13]
  1.14.3 Vomiting 5 99582 Risk Ratio (M-H, Random, 95% CI) 1.00 [0.93, 1.07]
  1.14.4 Fever 3 96865 Risk Ratio (M-H, Random, 95% CI) 1.04 [0.98, 1.09]
  1.14.5 Inability to suck or feed 3 96598 Risk Ratio (M-H, Random, 95% CI) 1.00 [0.81, 1.23]
  1.14.6 Convulsions 3 96853 Risk Ratio (M-H, Random, 95% CI) 1.12 [0.66, 1.88]
  1.14.7 Excessive crying 1 44961 Risk Ratio (M-H, Random, 95% CI) 0.99 [0.93, 1.05]
  1.14.8 Jaundice 1 44961 Risk Ratio (M-H, Random, 95% CI) 1.07 [0.96, 1.19]
  1.14.9 Eye infection 1 44961 Risk Ratio (M-H, Random, 95% CI) 0.99 [0.88, 1.12]
  1.14.10 Skin infection 1 44961 Risk Ratio (M-H, Random, 95% CI) 0.94 [0.82, 1.09]
  1.14.11 Umbilical infection 1 44961 Risk Ratio (M-H, Random, 95% CI) 0.97 [0.81, 1.15]
  1.14.12 Respiratory infection 1 44961 Risk Ratio (M-H, Random, 95% CI) 1.08 [0.94, 1.24]
  1.14.13 Feeding problems 1 44961 Risk Ratio (M-H, Random, 95% CI) 1.01 [0.88, 1.16]
  1.14.14 Others 1 44961 Risk Ratio (M-H, Random, 95% CI) 0.93 [0.84, 1.02]
1.15 Adverse events during the first month post supplementation 1 Risk Ratio (M-H, Fixed, 95% CI) No totals
  1.15.1 Diarrhoea 1 Risk Ratio (M-H, Fixed, 95% CI) No totals
  1.15.2 Vomiting 1 Risk Ratio (M-H, Fixed, 95% CI) No totals
1.16 All-cause neonatal mortality: risk ratios based on cumulative risk (%, adjusted for clustering) 5 Risk Ratio (IV, Fixed, 95% CI) Subtotals only
  1.16.1 All infants 5 126242 Risk Ratio (IV, Fixed, 95% CI) 0.99 [0.90, 1.08]
  1.16.2 All infants - male 4 57254 Risk Ratio (IV, Fixed, 95% CI) 1.01 [0.87, 1.17]
  1.16.3 All infants - female 4 53047 Risk Ratio (IV, Fixed, 95% CI) 1.03 [0.89, 1.19]
1.17 All-cause neonatal mortality: rate ratios (person-years of follow-up) 1 Rate Ratio (IV, Fixed, 95% CI) Subtotals only
  1.17.1 All infants 1 Rate Ratio (IV, Fixed, 95% CI) 1.04 [0.86, 1.25]
  1.17.2 All male infants 1 Rate Ratio (IV, Fixed, 95% CI) 0.99 [0.77, 1.27]
  1.17.3 All female infants 1 Rate Ratio (IV, Fixed, 95% CI) 1.10 [0.82, 1.49]
 

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Figures

Figure 1

Refer to Figure 1 caption below.

Study flow diagram: review update (Figure 1).

Figure 2

Refer to Figure 2 caption below.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study (Figure 2).

Figure 3

Refer to Figure 3 caption below.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies (Figure 3).

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Sources of support

Internal sources

  • Centre for Global Child Health, The Hospital for Sick Children, Canada

External sources

  • Evidence and Programme Guidance, Department of Nutrition for Health and Development, World Health Organization, Switzerland

    A grant was provided by the WHO to fund the completion of this Cochrane Review.

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, USA

    Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C

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Appendices

1 Standard search methods

PubMed: ((infant, newborn[MeSH] OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or infan* or neonat*) AND (randomized controlled trial [pt] OR controlled clinical trial [pt] OR Clinical Trial[ptyp] OR randomized [tiab] OR placebo [tiab] OR clinical trials as topic [mesh: noexp] OR randomly [tiab] OR trial [ti]) NOT (animals [mh] NOT humans [mh]))

Embase: (infant, newborn or newborn or neonate or neonatal or premature or very low birth weight or low birth weight or VLBW or LBW or Newborn or infan* or neonat*) AND (human not animal) AND (randomized controlled trial or controlled clinical trial or randomized or placebo or clinical trials as topic or randomly or trial or clinical trial)

CINAHL: (infant, newborn OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or Newborn or infan* or neonat*) AND (randomized controlled trial OR controlled clinical trial OR randomized OR placebo OR clinical trials as topic OR randomly OR trial OR PT clinical trial)

Cochrane Library: (infant or newborn or neonate or neonatal or premature or very low birth weight or low birth weight or VLBW or LBW)

2 Risk of bias tool

The following issues were evaluated and entered into the risk of bias table:

  1. Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated?

    For each included study, we categorised the method used to generate the allocation sequence as:
    1. low risk (any truly random process e.g. random number table; computer random number generator);
    2. high risk (any non-random process e.g. odd or even date of birth; hospital or clinic record number);
    3. unclear risk.

  2. Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?

    For each included study, we categorised the method used to conceal the allocation sequence as:
    1. low risk (e.g. telephone or central randomization; consecutively numbered sealed opaque envelopes);
    2. high risk (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
    3. unclear risk.

  3. Blinding (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment?

    For each included study, we categorised the methods used to blind study participants and personnel from knowledge of which intervention a participant received. Blinding was assessed separately for different outcomes or classes of outcomes. We categorised the methods as:
    1. low risk, high risk or unclear risk for participants;
    2. low risk, high risk or unclear risk for personnel;
    3. low risk, high risk or unclear risk for outcome assessors.

  4. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). Were incomplete outcome data adequately addressed?

    For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion, when reported, and whether missing data were balanced across groups or were related to outcomes. When sufficient information was reported or supplied by trial authors, we re-included missing data in analyses. We categorised the methods as:
    1. low risk (< 20% missing data);
    2. high risk (greater than/or equal to 20% missing data);
    3. unclear risk.

  5. Selective reporting bias. Are reports of the study free of suggestion of selective outcome reporting?

    For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. We assessed the methods as:
    1. low risk (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);
    2. high risk (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
    3. unclear risk.

  6. Other sources of bias. Was the study apparently free of other problems that could put it at a high risk of bias?

    For each included study, we described any important concerns we had about other possible sources of bias (e.g. whether a potential source of bias was related to the specific study design, whether the trial was stopped early owing to some data-dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as:
    1. low risk;
    2. high risk;
    3. unclear risk.

If needed, we planned to explore the impact of the level of bias by undertaking sensitivity analyses.


This review is published as a Cochrane review in The Cochrane Library, Issue 2, 2017 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent recent version of the review.