Summary of findings
Description of the condition
Importance of vitamin A
Vitamin A is a generic term for a group of fat-soluble substances that carry out similar biological activity in human metabolism. It plays an important role in normal vision, gene expression, growth and physical development, maintenance and proliferation of epithelial cells, and immune function, at all stages of life, particularly during pregnancy and lactation, given maternal, fetal and newborn requirements (Butte 2002; FNB 2000; WHO 1996; WHO 1998). The dietary sources of pro-vitamin A (alfa- and beta-carotene, alfa-cryptoxanthin) are vegetables such as carrot, pumpkin, papaya, buriti, and red palm oil; and animal foods rich in pre-formed vitamin A, such as dairy products (whole milk, yogurt, cheese), liver, fish oils and human milk (FAO/WHO 2001; FNB 2000). In most cultures, young infants depend on breast milk to obtain adequate amounts of vitamin A (WHO 1998), which is highly dependent upon maternal diet and nutritional status. In well-nourished populations the breast milk amounts of vitamin A are adequate to meet the infants' requirements during the first six months of life. In populations deficient in vitamin A, the amount in breast milk will be suboptimal and insufficient to build or maintain stores of this micronutrient in nursing infants (Butte 2002; WHO 1998).
Specific biological indicators of vitamin A deficiency (VAD) can be divided into two types: clinical and subclinical. Among the clinical indicators is xerophthalmia, which includes all ocular manifestations of VAD from night blindness to corneal ulceration, and resultant blindness (Sommer 1993). Subclinical indicators can include measurement of serum retinol (less than 0.7 µmol/L), breast milk retinol (less than 1.05 µmol/L or 0.28 µmol/g milk fat), relative dose response (RDR), and modified relative dose response (MRDR) (WHO 1996). Although there is not consensus, serum retinol less than 1.05 μmol/l has been proposed to reflect low vitamin A status among pregnant and lactating women (WHO 2009, West 2002). RDR and MRDR are indirect methods to assess the level of vitamin A in the liver. Other non-specific symptoms, such as increased maternal and infant morbidity and mortality, increased risk of anaemia, slowed infant growth and development can be related to VAD (FAO/WHO 2001, WHO 2009). RDR and MRDR are indirect methods to assess the level of vitamin A in the liver. Other non-specific symptoms, such as increased maternal and infant morbidity and mortality, increased risk of anaemia, slowed infant growth and development can be related to VAD (FAO/WHO 2001).
Vitamin A and adverse effects
There are limited human data on the potential teratogenicity of high doses of vitamin A in women exposed during early pregnancy. However, teratogenic effects from natural metabolites of vitamin A (like trans retinoic acids and 13-cis retinoic acids) are well documented from case studies of women exposed to high doses of retinoic acid derivatives within the first six weeks of pregnancy. Extensive epidemiologic studies have produced no evidence of teratogenicity in the human fetus after six weeks of pregnancy (Rasmussen 1998). Maternal or infant supplementation with high doses of vitamin A (more than 50,000 IU) can produce adverse effects including nausea, headache, fever, vomiting, transient diarrhoea, increased cerebrospinal fluid pressure, blurred vision and lack of muscular co-ordination (Allen 2002).
Vitamin A interaction with other micronutrients
It is believed that zinc status may influence vitamin A metabolism, including its absorption, transport and utilisation, probably through regulation of vitamin A transport and oxidative conversion of retinol to retinal. However, randomised trials have failed to show a consistent effect of zinc supplementation on vitamin A status (Christian 1998).
There is evidence that VAD impairs iron mobilisation from stores and its transportation, resulting in anaemia (Lynch 1997). The role of vitamin A in iron absorption is unconfirmed; according to Garcia-Casal 1998, vitamin A forms a complex with iron, increasing its absorption, but Walczyk 2003 found a slightly negative effect of this vitamin.
Some studies have shown that iron deficiency may influence vitamin A metabolism (Oliveira 2008a), decreasing liver mobilisation and serum retinol concentration (Rosales 1999; Jang 2000; Strube 2002). Munoz 2000 conducted a clinical trial and found that iron supplementation improved the indicators of vitamin A status in preschoolers from Mexico.
Vitamin A deficiency around the world
The global distribution of VAD, presented by the World Health Organization (WHO) (WHO 1995), classifies countries by the significance of VAD as a public health problem, based on clinical and subclinical (serum retinol) indicators. The most widely affected areas are in Africa, Asia and Latin America. The recent prevalence presented by WHO (WHO 2009), including data from 1995 to 2005, indicates that Africa and South-East Asia have the highest burden of VAD. Although these estimations were produced by different methodologies, there is some indication that the prevalence of xerophthalmia among pre-school children decreased, but the subclinical VAD (serum retinol concentration) in pre-school children and pregnant women increased, possibly due to improved methods of assessing, and a wider population being assessed (WHO 2009). Results relating to lactating women were not considered in these publications. A study carried out in Nepal showed that 27% of postpartum women were vitamin A deficient (West 1997). Another study in Bangladesh found that 13.3% of lactating women presented with VAD (Ahmed 2003).
Vitamin A supplementation during pregnancy
A Cochrane systematic review (Van den Broek 2002) of five trials with a total of 23,426 pregnant women, mostly from countries with significant levels of VAD, noted a possible beneficial effect on maternal mortality after weekly supplementation, a reduction in maternal night-blindness and a reduction in maternal anaemia in some, but not all studies.
Breastfeeding around the world
According to the WHO (WHO 2010), 36% of infants are exclusively breast fed for the first six months of life. South-East Asia presents the highest prevalence (48%) and Europe the lowest (23%). The prevalence in Africa and America is the same (31%). Considering income, the low and lower middle income groups showed the highest proportion (around 38%). In Bangladesh, India, Indonesia and Nepal 43%, 46%, 32% and 53% of infants are exclusively breast fed during the first six months. The prevalences in Africa vary by the specific country. In Ghana the proportion is 63%, followed by Gambia (41%), Tanzania (41%), Kenya (32%), and Zimbabwe (22%). In South America these differences are also observed. For example, in Brazil the prevalence is 40% and in Peru 73%.
Maternal mortality around the world
In Africa and South-East Asia the maternal mortality ratios (MMR) average 900/100,000 and 450/100,000 live births, respectively. Although these areas present the highest maternal mortality around the world, the ratios are not homogenous when considering different countries within continents. The MMR is higher in Nepal (830/100,000) than in Bangladesh (570/100,000), India (450/100,000) or Indonesia (420/100,000). The differences among African countries are also evident. In Tanzania the MMR is 950/100,000; followed by Zimbabwe (880/100,000); Gambia (690/100,000); Ghana and Kenya (both 560/100,000 live births). In North America and Europe, these ratios are below 100/100,000 live births, but the rates are relatively high in Brazil (110/100,000) and Peru (240/100,000 live births) (WHO 2010).
Description of the intervention
Vitamin A supplementation for postpartum mothers
Vitamin A supplementation may take a number of forms: for example, as Vitamin A, measured in international units (IU) of Retinyl palmitate (3.33 IU or 0.003491 micromol of retinol = 1 microgram or 1 Retinol Equivalent (RE) (IVACG 2004), water miscible formulation, or as beta-carotene. Synthetic beta-carotene supplements result in improved breast milk vitamin A concentrations compared with dietary sources of beta-carotene (De Pee 1995).
WHO, UNICEF and the International Vitamin A Consultative Group recommend that in areas of endemic VAD, high doses of supplementary vitamin A should be given to breastfeeding women during the postpartum period (to six weeks after childbirth), as a strategy to improve mothers' and infants' stores of this micronutrient (Ross 2002; WHO 1996).
Four scenarios in which vitamin A supplements could be given in VAD countries, considering safe dosage and frequency of administration, are: (1) maternal supplementation during pregnancy; (2) supplementation for mothers in the first six months postpartum; (3) supplementation of infants before six months of age; and (4) supplementation of both the mothers during the safe infertile postpartum period and infants under six months of age (WHO 1998).
At the population level, for mothers from VAD countries who are not breastfeeding, a high dose of vitamin A (over 25,000 IU and usually 200,000 IU) during the first four weeks after delivery could be beneficial. Beyond six months, for these mothers no more than 10,000 IU daily should be given. Non-breast-fed infants (less than six months of age) could receive a single high dose of 50,000 IU of vitamin A or two doses of 25,000 IU approximately a month apart, to meet their needs if they are not receiving a fortified breast-milk substitute. However, for mothers who are breastfeeding, a high dose given up until 60 days postpartum could be beneficial for them and as well as for their infants through higher concentration of vitamin A in breast milk (WHO 1998).
According to WHO's recommendations (WHO 1998), research that considers the supplementation of mothers up to eight weeks postpartum should include an evaluation of maternal outcomes, such as morbidity, mortality, serum retinol and breast milk retinol and its metabolites; long-term effects on morbidity, mortality and vitamin A status in infancy up to three years of age; as well as effects on partial weaning/cessation of breastfeeding on morbidity, mortality, vitamin A status and return to fertility.
Other integrated approaches to control VAD are the improvement of dietary quality, quantity and food fortification (WHO 1998).
Why it is important to do this review
Numerous studies and programs have involved postpartum supplementation that aims to improve women's and infants' health in regions of vitamin A deficiency. However, there are no consistent practices or recommendations. A systematic review of the relevant randomised controlled trials is therefore warranted.
To assess the effects of vitamin A supplementation, alone or in combination with other micronutrients (e.g. iron, folic acid, vitamin E), in mothers during the postpartum period, on maternal and infant health.
Criteria for considering studies for this review
Types of studies
Randomised controlled trials evaluating the effects of vitamin A supplementation in mothers during the postpartum period, including cluster-randomised studies and excluding quasi-randomised studies.
Types of participants
Mothers in the postpartum period, breastfeeding or not, from vitamin A deficiency areas, without confirmed chronic diseases (e.g. HIV). We included maternal data from studies conducted in areas with high prevalence of HIV without individual diagnostics at baseline. We considered only data of HIV-negative mothers in studies conducted with both HIV-positive and -negative mothers.
Types of interventions
Maternal vitamin A supplementation (beta-carotene or retinyl palmitate or water miscible formulation) alone or in combination with other micronutrients (examples: iron, folic acid, vitamin E) compared with placebo, no intervention, other micronutrient, or a lower dose of vitamin A, commenced at any time during the postpartum period, that is, within 24 hours of birthing until six weeks after giving birth.
Studies included maternal administration of high doses (given as a single dose of 200,000, 300,000, or 400,000 IU) or two doses (for a total of 400,000 IU), daily (7.8 mg or 4,327 IU) doses or a combination of high or lower doses.
Studies that involved continuous daily/weekly supplementation for mothers during reproductive age (pre-pregnancy or during pregnancy) are addressed in a separate systematic review (Van den Broek 2002).
Several studies included infant supplementation, in addition to maternal postpartum supplementation. We considered maternal outcomes from these studies. We included infant outcomes only when they had been measured prior to commencement of infant supplementation.
Types of outcome measures
When studies involved both maternal and infant supplementation, we reviewed them for maternal outcomes and limited the infant outcomes to those measured prior to commencement of infant supplementation. In this way, we only included results related to a comparison of maternal supplementation or no treatment/placebo; or different maternal supplementation regimens. With the exception of adverse effects of vitamin supplementation, we reviewed outcomes for up to 12 months postpartum.
Primary maternal outcomes
- morbidity (febrile illness, respiratory tract infection, diarrhoea);
- adverse effects of vitamin A within three days after receiving supplement.
Primary infant outcomes
- morbidity episodes (febrile illness, respiratory tract infection, diarrhoea, and others);
- adverse effects of vitamin A supplementation within three days after receiving supplement.
Secondary maternal outcomes
- Serum retinol concentration;
- vitamin A hepatic stores (MRDR or RDR);
- breast milk retinol concentration;
- vitamin A deficiency (clinical: impaired visual adaptation to darkness, night blindness, xerophthalmia; and subclinical: abnormal conjunctival impression cytology);
Secondary infant outcomes
- Serum retinol concentration;
- vitamin A hepatic stores (RDR or MRDR);
- clinical vitamin A deficiency.
Search methods for identification of studies
We contacted the Trials Search Co-ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register (31 July 2010).
The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from:
- quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
- weekly searches of MEDLINE;
- handsearches of 30 journals and the proceedings of major conferences;
- weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL and MEDLINE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co-ordinator searches the register for each review using the topic list rather than keywords.
In addition, we searched LILACS - Latin American and Caribbean Health Sciences by Bireme (1982 to July 2010), Web of Science (1945 to July 2010), Biological Abstracts (1998 to July 2010) using the search strategies detailed in Appendix 1.
We also searched Human Nutrition (1982 to October 2007), Food Sciences & Tech Abstracts (1969 to November 2008), Food and Human Nutrition (1975 to October 2007), and AGRIS (1975 to October 2007). See Appendix 1 for details.
We did not apply any language restrictions.
Data collection and analysis
Selection of studies
At least two review authors (JM Oliveira-Menegozzo, DP Bergamaschi, CE East, P Middleton) assessed potentially eligible trials identified by the literature search to determine if they met the inclusion criteria for the review. We made decisions regarding inclusion independently and compared results. We resolved any disagreement through discussion.
Data extraction and management
For eligible studies, at least two authors (JM Oliveira-Menegozzo, CE East, P Middleton) independently extracted data and compared the results. We resolved discrepancies through discussion. We double-checked data against printouts of data entered into Review Manager software (RevMan 2008).
We carried out the meta-analysis using the Review Manager software (RevMan 2008).
Assessment of risk of bias in included studies
At least two authors independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009). We resolved any disagreements by discussion.
(1) Sequence generation (checking for possible selection bias)
We described for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.
We assessed the method as:
- adequate (any truly random process, e.g. random number table; computer random number generator),
- inadequate (any non-random process, e.g. odd or even date of birth; hospital or clinic record number) or,
(2) Allocation concealment (checking for possible selection bias)
We described for each included study the method used to conceal the allocation sequence and determine whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.
We assessed the methods as:
- adequate (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
- inadequate (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
(3) Blinding (checking for possible performance bias)
We described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We considered that studies are at low risk of bias if they were blinded, or if we judged that the lack of blinding could not have affected the results. We assessed blinding separately for different outcomes or classes of outcomes.
We assessed the methods as:
- adequate, inadequate or unclear for participants;
- adequate, inadequate or unclear for personnel;
- adequate, inadequate or unclear for outcome assessors.
(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)
We described for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We stated 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 where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported, or could be supplied by the trial authors, we would have re-included missing data in the analyses which we undertook. However, this did not apply to any of the included studies. We did not specify a level of missing data to assess that a study was adequate. We assessed methods as:
(5) Selective reporting bias
We described for each included study how we investigated the possibility of selective outcome reporting bias and what we found.
We assessed the methods as:
- adequate (where it was clear that all of the study's pre-specified outcomes and all expected outcomes of interest to the review had been reported);
- inadequate (where not all the study's pre-specified outcomes had been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest were reported incompletely and so cannot be used; study failed to include results of a key outcome that would have been expected to have been reported);
(6) Other sources of bias
We described for each included study any important concerns we have about other possible sources of bias.
We assessed whether each study was free of other problems that could put it at risk of bias:
(7) Overall risk of bias
We made explicit judgements about whether studies were at high risk of bias, according to the criteria given in the Handbook (Higgins 2009). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we considered it was likely to impact on the findings. We planned to explore the impact of the level of bias through undertaking sensitivity analyses - see 'Sensitivity analysis'.
Measures of treatment effect
For dichotomous data, we presented results as summary risk ratio (RR) with 95% confidence intervals.
For continuous data, we used the mean difference if outcomes were measured in the same way between trials.
Where data were reported in a format that did not allow for entry into the RevMan software, we have reported the published results in tables or in text.
Unit of analysis issues
We planned to include cluster-randomised trials in the analyses along with individually randomised trials. If we had identified cluster trials, we planned to adjust their sample sizes using the methods described in the Handbook (Secion 16.3.4) using an estimate of the intracluster correlation co-efficient (ICC) derived from the trial (if possible), from a similar trial or from a study of a similar population.
If cluster studies are in included in future review updates, we will use ICCs from other sources; we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster-randomised trials and individually-randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely.
We will also acknowledge heterogeneity in the randomisation unit and perform a sensitivity analysis to investigate the effects of the randomisation unit.
Dealing with missing data
For included studies, we noted levels of attrition. We planned to explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis if we identified such studies.
Although not ultimately required for the included studies, for all outcomes, we planned to carry out analyses, as far as possible, on an intention-to-treat basis, i.e. we planned to attempt to include all participants randomised to each group in the analyses, and all participants would have been analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. If studies requiring this are identified in future review updates, the denominator for each outcome in each trial will be the number randomised minus any participants whose outcomes are known to be missing.
Assessment of heterogeneity
We assessed statistical heterogeneity in each meta-analysis using the T², I² and Chi² statistics. We regarded heterogeneity as substantial if T² was greater than zero and either I² was greater than 30% or there was a low P-value (less than 0.10) in the Chi² test for heterogeneity.
Assessment of reporting biases
If 10 or more studies were meta-analysed we would have investigated reporting biases (such as publication bias) using funnel plots. However, no outcomes had results from 10 or more studies. If this becomes necessary in future review updates, we will assess funnel plot asymmetry visually, and use formal tests for funnel plot asymmetry. For continuous outcomes we will use the test proposed by Egger 1997, and for dichotomous outcomes we will use the test proposed by Harbord 2006. If we detect asymmetry in any of these tests or by a visual assessment, we will perform exploratory analyses to investigate it.
We carried out statistical analysis using RevMan software (RevMan 2008). We use fixed-effect meta-analysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect: i.e. where trials were examining the same intervention, and the trials' populations and methods were judged sufficiently similar. If there was clinical heterogeneity sufficient to expect that the underlying treatment effects differed between trials, or if substantial statistical heterogeneity was detected, we used random-effects meta-analysis to produce an overall summary if an average treatment effect across trials was considered clinically meaningful. We treated the random-effects summary as the average range of possible treatment effects and we discussed the clinical implications of treatment effects differing between trials. If the average treatment effect was not clinically meaningful, we did not combine trials.
If we used random-effects analyses, we presented the results as the average treatment effect with its 95% confidence interval, and the estimates of T² and I
Subgroup analysis and investigation of heterogeneity
If we identified substantial heterogeneity, we investigated it using subgroup analyses. We considered whether an overall summary was meaningful, and it was, we used random-effects analysis to produce it.
We planned to conduct the following sub-groups analyses of primary outcomes, if sufficient data were available:
- type of supplement (vitamin A (retinyl palmitate or water miscible formulation) or beta-carotene);
- duration of supplementation (daily, single or double dose);
- dose of supplement (200,000-300,000 IU or 400,000 IU);
- type of control group (supplementation versus placebo/no supplement, or higher versus lower supplementation dose);
- duration of breastfeeding.
If we identified substantial heterogeneity, we investigated it using sensitivity analyses.
Description of studies
We included 12 studies enrolling 25,465 mother-baby pairs residing in low-income settings in India, Bangladesh, Indonesia, Tanzania, Gambia, Zimbabwe, Kenya, Ghana and Peru, countries in which women in the studies were likely to have low vitamin A levels and low nutritional status. The 'Characteristics of included studies' table provides further information on these trials. Although all studies reported or implied that postpartum women breastfed their infants, the available details made it impractical to perform subgroup analysis by duration of breastfeeding. Moreover, there were insufficient data to perform sensitivity analyses.
Dosage and duration of vitamin A supplementation
Nine studies (Ayah 2007; Bhaskaram 2000; Newton 2005; Roy 1997; Stoltzfus 1993a; Venkatarao 1996; Vinutha 2000; WHO/CHD IVASSG; ZVITAMBO Study Group) administered a single dose of vitamin A in the form of retinyl palmitate or water miscible formulation (200,000; 300,000 or 400,000 IU) supplementation for mothers within the first days or weeks postpartum. Eight of the trials compared vitamin A supplementation with placebo (Ayah 2007; Bhaskaram 2000; RETIBETA Project; Stoltzfus 1993a; Venkatarao 1996; ZVITAMBO Study Group; WHO/CHD IVASSG; Newton 2005). In two studies, women in the control group received no intervention (Vinutha 2000) or were given iron supplementation (as were those in that study's intervention group) (Roy 1997). The RETIBETA Project used a three-group approach of single postpartum dose of vitamin A (as retinyl palmitate) followed by placebo for nine months, placebo at enrolment followed by daily beta-carotene supplementation for nine months, or placebo at enrolment and daily for nine months. Two trials compared a lower dose of vitamin A (200,000 IU) with a higher dose (400,000 IU) (Darboe 2007; Idindili 2007).
The studies reported the dosage in a variety of units: for the purpose of this review, dosages have generally been presented as international units (IU), based on the calculation of 3.33 IU or 0.003491 micromol of retinol = 1 microgram or 1 Retinol Equivalent (RE).
Eight of the included studies reported that women breastfed their infants, with several studies noting that infants were exclusively breastfed (Vinutha 2000 for the duration of the study and Idindili 2007 for the first month) and others indicating that infants were at least partially breast fed to six months (Bhaskaram 2000; RETIBETA Project; Roy 1997; Venkatarao 1996; WHO/CHD IVASSG; ZVITAMBO Study Group). All four studies that did not specify details of breastfeeding provided strong surrogate evidence to support the likelihood of at least partial breastfeeding. The studies by Ayah 2007 and Darboe 2007 reported breast milk retinol levels at six months postpartum, whilst the study title, background and/or discussion material suggested that the reports from Newton 2005 and Stoltzfus 1993a related to breastfeeding, although the duration or extent cannot be estimated.
We excluded four trials because they used alternate, rather than randomised allocation (Ala-Houhala 1988; Basu 2003, Bezerra 2010; Tchum 2006). We excluded eight trials that involved provision of vitamin A rich foods, rather than vitamin A supplementation (Canfield 2001; De Pee 1995; Filteau 1999; Gossage 2000; Khan 2007; Lietz 2001; Lietz 2006; Ncube 2001). We also excluded two studies involving long-term supplementation for women of reproductive age (NNIPS-2; ObaapaVitA). (See 'Characteristics of excluded studies').
Risk of bias in included studies
|Figure 1. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.|
|Figure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.|
In the WHO CHD Immunization Linked Vitamin A supplementation multi-centre trial (WHO/CHD IVASSG), mother and infant pairs were individually randomised to one of four treatment groups. Randomisation was carried out by identification numbers generated by computer and assigned as random permuted blocks of size eight. The codes were kept by WHO in Geneva.
Participants in the RETIBETA Project were individually randomised. Before beginning the study, treatment codes and follow-up schedules were assigned to a sequence of identification numbers in blocks of 18 using a random number table. During enrolment, the women were randomly allocated to one of three treatment groups and to a follow-up schedule.
In the Ayah 2007 trial, two random sequences were prepared for mothers and infants. The randomisation code was concealed for the entire trial duration and only revealed after completion of data analysis. In the ZVITAMBO trial (ZVITAMBO Study Group) randomisation was done by computer generation of identification numbers in blocks of 12.
Subjects from the Gambia trial (Darboe 2007) were randomised by a senior scientist, who then packed and labelled the supplements, by blocks (16 per block) to allow for possible effects of season of birth. In the Idindili 2007 trial, individual randomisation was achieved by using a list of study numbers that had been randomly assigned to an intervention arm in blocks of ten, generated by the Data and Safety Monitoring Board. The Stoltzfus 1993a trial used individual randomisation to treatment codes in blocks of eight.
For most studies, the vitamin A and placebo capsules were identical in appearance (see Risk of bias tables in Characteristics of included studies. In one study (RETIBETA Project) the capsules differed slightly in colour, but they were individually wrapped in foil, making the direct comparisons between groups unlikely.
In the study by Idindili 2007, there was not enough detail to judge whether participants were blinded, while the Vinutha 2000 study did not provide detail on blinding. Stoltzfus 1993a noted that all investigators, field, and laboratory staff were blinded to the randomisation code until field work was completed.
Incomplete outcome data
In the Venkatarao 1996 trial study there was a 24.2% overall loss of follow-up, distributed similarly between the three groups and attributed to post-randomisation exclusions for medical reasons such as congenital abnormalities or jaundice, migration and miscellaneous. In the study by Roy et al (Roy 1997) no losses to follow-up were discussed, but data from the tables indicate 100% of follow-up. In the Vinutha et al (Vinutha 2000) clinical trial the loss of follow-up rate was 22.9%. In the trial by Bhaskaram et al (Bhaskaram 2000) the rates of loss to follow-up were 13% and 54% until three and six months postpartum, respectively. Ayah 2007 reported a 12.6% loss to follow-up by 14 weeks' postpartum and a 22.9% loss by six months. In the trial from Gambia (Darboe 2007) 89.5% of mothers and infants were followed up until 12 months. Idindili 2007 reported 19%, 20.5%, 22.8% of loss by three, six, and nine months, respectively. Attrition was 11.3% (in both the vitamin A and placebo groups) for HIV-negative women (985/9562) in the report from the ZVITAMBO Study Group.
Twenty-three of the total 220 women in the RETIBETA Project missed one or more visits, resulting in follow-up rates of 98%, 95%, and 92% at three, six, and nine months postpartum, respectively, with data reported for these participants in most outcomes. The exception was for maternal hepatic stores of vitamin A and serum retinol concentrations, for which approximately 50% of women were sampled: the report does not specify why all women were not tested. The study by Stoltzfus 1993a had a 9% loss to follow-up in each group by three months and 13% and 5% losses in the vitamin A and control groups respectively by six months.
Loss of follow-up at nine months for the WHO/CHD IVASSG study was 783 (17%) in the intervention group and 770 (16%) in the placebo group. This increased to 25% and 24.5% in the intervention and control groups respectively by 12 months. Infant death was the only outcome of interest for this review at this time, therefore it was recorded in this review for the nine month follow-up time, rather than at 12 months. Biochemical markers had been measured in a subgroup of approximately 100 mothers and their infants from each of the three participating countries: the exact number sampled increased from the first to the second timeframe, which meant we were unable to determine loss to follow up from the report.
We judged all but one trial to be at risk of selective reporting; for example only five of the 12 trials reported infant mortality and only two reported maternal mortality.
Other potential sources of bias
We judged most trials as unclear for risk of other bias, mostly due to a lack of clarity about any influence of funding bodies.
Effects of interventions
Primary maternal outcomes
Two studies evaluated maternal mortality for a total of 9126 women (Ayah 2007; ZVITAMBO Study Group). The study by Ayah 2007 reported no statistically significant difference in maternal mortality to six months (n = 564, RR 0.50, 95% CI 0.09 to 2.71) - Analysis 1.1. There were no reported differences in maternal deaths following vitamin A supplementation or placebo in HIV-negative women (n = 8562) followed to six months (Hazard Ratio (HR) 1.40, 95% CI 0.4, 5.0) or 12 months (HR 1.11, 95% CI 0.81, 1.51) in the report by Zvandasara (ZVITAMBO Study Group): we report here the adjusted HR and confidence intervals for maternal mortality, as there was insufficient detail to re-analyse using RevMan software (RevMan 2008).
Adverse effects of vitamin A supplementation
In a subset of 788 mother-infant pairs in the ZVITAMBO Study Group, no statistically significant differences were seen in adverse effects within 30 hours of supplementation, including headache, blurred vision, drowsiness, vomiting, poor appetite or abdominal pain following a single dose of 400,000 IU vitamin A or placebo - Analysis 1.5.
Secondary maternal outcomes
Maternal serum retinol
Six studies reported maternal serum retinol values, measured between six weeks and nine months after birth, for a total of 1418 women ( Analysis 1.6; Analysis 1.7; Analysis 1.8; Analysis 1.9). Few analyses included meta-analysis of more than three of these studies at a time, due to the clinical and statistical heterogeneity of reported data.
Maternal serum retinol concentrations were not enhanced by the largest single dose (400,000 IU), when measured at one and a half months (260 HIV-negative women, mean difference (MD) 0.09 µmol/L, 95% CI -0.02 to 0.20) (ZVITAMBO Study Group); nor at three and a half months (n = 402, MD 0.04 µmol/L, 95% CI -0.01 to 0.09) or six months postpartum (n = 291, MD -0.02 µmol/L, 95% CI -0.08 to 0.04) in a study that had substantial losses to follow-up (Ayah 2007). However, other smaller studies that administered a single dose (200,000-300,000 IU) within three weeks postpartum reported a statistically significant improvement in serum retinol at three months compared with placebo (three studies, n = 258, MD 0.17 µmol/L, 95% CI 0.06 to 0.28), but not at six months (three studies, n = 260, MD 0.10 µmol/L, 95% CI -0.02 to 0.23). Daily postpartum administration of 7.8 mg beta-carotene did not improve maternal serum retinol concentrations three, six or nine months after delivery in one small study (n = 71, RETIBETA Project).
Vitamin A hepatic stores
Three studies analysed low vitamin A hepatic stores (reported as relative dose response (RDR) greater than 20% or modified relative dose response (MRDR) > 0.06) at three, six, and nine months postpartum (n = 315) - Analysis 1.10, Analysis 1.11, Analysis 1.12, Analysis 1.13, Analysis 1.14. The RETIBETA Project reported an improvement in the proportion of women with low hepatic stores at three months (n = 69, MRDR > 0.06; RR 0.33, 95% CI 0.15 to 0.71) following a single 200,000 IU dose of vitamin A, compared with placebo. In contrast, another small study (Stoltzfus 1993a) did not report any difference in RDR greater than 20% three months postpartum (n = 139, RR 1.15, 95% CI 0.41, 3.25). Neither study reported statistically significant differences when measuring at six or months postpartum. No differences were reported in the RETIBETA Project for this outcome between daily beta-carotene supplementation (for nine months) and placebo at any times, for example, when measured at nine months (n = 66, RR 0.61, 95% CI 0.30,1.23).
Breast milk retinol
Breast milk retinol levels were reported in several formats (retinol concentration, proportion of milk retinol <1.05µmol/L or <0.28 µmol/gram of fat) in seven studies for a total of 1075 women ( Analysis 1.15 to Analysis 1.23 and Analysis 2.3). Vitamin A supplementation (200,000-300,000 IU) was associated with an increased breast milk retinol concentration at three to three and a half months (four studies, n = 390, MD 0.27µmol/L, 95% CI 0.11 to 0.43) but this improvement was not sustained by six to six and a half months postpartum. Supplementation with a single dose of vitamin A (200,000-300,000 IU) significantly reduced the proportion of women with low retinol concentration (<1.05µmol/L) in human milk at three months (three studies, n = 373, RR 0.42, 95% CI 0.19 to 0.91), but not at six months after delivery (two studies, n = 275, RR 0.65, 95% CI 0.23 to 1.90), compared with placebo. Daily doses of beta-carotene to nine months postpartum did not improve breast milk retinol at three or six months but did demonstrate improvement for this outcome by nine months postpartum (n=135, MD 0.21µmol/L, 95% CI 0.04 to 0.38) in the RETIBETA Project, compared with placebo.
Two studies (RETIBETA Project; WHO/CHD IVASSG) reported the proportion of women with low breast milk retinol levels (< 0.28 µmol/gram of fat; n = 479). Supplementation with a single dose of vitamin A (200,000 IU) or daily beta-carotene 7.8mg daily for nine months did not improve this measure at three months postpartum. Following supplementation with 200,000 IU demonstrated an improvement (two studies, n = 813, RR 0.84, 95% CI 0.71 to 0.99) at six months, which did not persist to nine months (two studies, n = 699, RR 0.87, 95% 0.74 to 1.02). Although no improvements were noted at three and six months following daily administration of beta-carotene, an improvement was noted by nine months (n = 134, RR 0.76, 95% CI 0.62 to 0.95).
Clinical and subclinical vitamin A deficiency
Stoltzfus 1993a measured abnormal conjunctival impression cytology (CIC) in one or both eyes as the criterion for vitamin A deficiency. There was no significant difference in the proportion of women with abnormal CIC at six months postpartum, following supplementation with vitamin A or placebo (n = 148, RR 0.56, 95% CI 0.27 to 1.17). However, they did reported a decline in abnormal CIC from baseline (32.5%) to six months postpartum (23.3%) following vitamin A supplementation (P < 0.006). No such decline was recorded in the placebo group (27.6% at baseline; 23.3% at six months) - Analysis 1.24, Analysis 1.25.
No studies addressed maternal anaemia.
Primary infant outcomes
Infant mortality was assessed in four trials (Ayah 2007; Newton 2005; Venkatarao 1996; ZVITAMBO Study Group), with no differences for vitamin A compared with placebo (RR 1.14 95% CI 0.84 to 1.57; 6170 infants - Analysis 1.26) or between different dosing regimens ( Analysis 2.1).
None of the three studies that considered diarrhoea or gastroenteritis reported any significant differences between the vitamin A supplementation or control groups (Roy 1997 (n = 50, diarrhoea episodes, P = 0.59), Venkatarao 1996 (n = 456, RR 1.02, 95% CI 0.98 to 1.06) and Vinutha 2000 (n = 84, RR 8.44, 95% CI 0.45, 158.4).
The reduction in observed reduced mean duration of acute respiratory tract infection (n = 50, 3.1 versus 3.7; P < 0.03) in the treatment group reported by Roy 1997 was not noted in the larger study by Venkatarao 1996, which reported no significant statistical difference in overall incidence of one or more episodes to 12 months of age of acute respiratory infection (n = 456, RR 1.00, 95% CI 0.96 to 1.03) between the supplemented and placebo groups.
One small study (Roy 1997) reported a lower mean number of febrile illness episodes (n = 50, 0.1 versus 0.3, P < 0.002) in the vitamin A group compared to the control group.
Adverse effects of vitamin A supplementation
No statistically significant differences were detected in the potential for developing the adverse effect of bulging fontanelle following vitamin A supplementation, including bulging fontanelle (200,000 or 400,000 IU; n = 9622; RR 2.22 95% CI 1.01, 4.86) - Analysis 1.34.
Secondary infant outcomes
Infant serum retinol
Four studies reported infant serum retinol between two and three and a half months after birth (n = 454), with none demonstrating a beneficial effect from any of the variety of dosing regimens used - Analysis 1.35, Analysis 1.36. For example, the use of 400,000 IU versus placebo resulted in a MD of 0.02 µmol/L (n = 164, 95% CI -0.03 to 0.07) (Ayah 2007); or 400,000 versus 200,000 IU resulted in MD -0.02µmol/L (n = 134, 95% CI -0.05 to 0.09) (Darboe 2007). There were no differences at five to six months by any of the four studies that reported this outcome ( Analysis 1.36, n = 604), for example, the subgroup analysis of 200,000-300,000 IU versus placebo yielded a MD 0.04µmol/L (three studies, n = 324, 95% CI -0.01 to 0.09).
Vitamin A hepatic stores
Vitamin A hepatic stores analysed at six weeks, or five to six months of infancy were not enhanced by any vitamin A dosing regimens, compared with placebo, for example, 200,000 IU versus placebo, measured at six weeks of age (n = 600, RR 1.11, 95% CI 1.02 to1.21) (WHO/CHD IVASSG).
Clinical vitamin A deficiency
No studies addressed infant clinical vitamin A deficiency.
Summary of main results
Maternal mortality was not influenced by single high-dose vitamin A supplementation (400,000 IU) in two studies (Ayah 2007; ZVITAMBO Study Group) conducted in areas of high maternal mortality ratios (MMR): Zimbabwe (880/100,000) and Kenya (560/100,000 live births). In contrast to our findings, one large study carried out in Nepal that evaluated weekly long-term low-dose supplementation with vitamin A or beta carotene (23,300 IU) for women during pregnancy and postpartum period demonstrated a protective effect of vitamin A for maternal mortality (NNIPS-2). However, more recently, other large studies from Bangladesh (JivitA-1 Trial) and Ghana (ObaapaVitA) have not been able to replicate this effect, which may relate to the different maternal mortality ratios in these countries (Nepal 830/100,000; Bangladesh 570/100,000 and Ghana 560/100,000 live births).
Several maternal morbidities are more prevalent in populations known to be vitamin A deficient than in industrialised countries. However, we did not observe a reduction in maternal morbidity after supplementation. Only a protective effect of vitamin A (300,000 IU) supplementation was observed in the prevalence of abnormal conjunctival impression cytology, a measure that is useful when there is restricted access to laboratory estimation of vitamin A status, although not an ideal stand-alone indicator of vitamin A deficiency (VAD) (Stoltzfus 1993b).
Maternal supplementation with a single postpartum dose of 200,000 IU vitamin A improved the proportion of women with breast milk retinol content < 0.28 µmol/g of fat, compared with placebo at six months after giving birth. This protective effect was not observed in the pooled analysis including studies of mean breast milk retinol (µmol/L).
Methodological studies suggest that the breast milk vitamin A content expressed per gram of fat is a more responsive indicator compared with serum retinol (Rice 2000; Stoltzfus 1993c). Moreover, serum retinol has some limitations as an indicator of vitamin A status, because retinol binding protein is a negative acute phase reactant protein (Filteau 1993; WHO 1996). Dancheck 2005 investigated the influence of acute phase reaction in breast milk retinol concentration in women from Malawi. The authors observed no significant differences in retinol breast milk concentration between lactating women with or without signs of inflammation. Thus, the meta-analysis results for breast milk retinol in this review were probably more informative than serum retinol in assessing the impact of vitamin A supplementation.
Although serum retinol concentration has some limitations as an indicator, the Global WHO database on Vitamin A Deficiency, a part of the Vitamin and Mineral Nutrition Information System (VMNIS), compiles data on the prevalence of clinical VAD (night blindness and ocular manifestation) and blood retinol concentration regularly from scientific literature and collaborators to estimates the prevalence of VAD around the world. These estimates provide valuable information for monitoring global progress and for evaluating current strategies to reduce VAD (WHO 2009). The pooled analysis of the reviewed studies showed that maternal supplementation (200,000-300,000 IU) is associated with reduced proportions of low vitamin A hepatic stores and significantly higher serum retinol concentration only until three months postpartum.
There is a concern that maternal administration of 400,000 IU within a single day might result in transient increases in breast milk retinoic acids to toxic levels. For this reason, the International Vitamin A Consultative Group (Ross 2002) recommends an interval of at least 24 hours between the two doses (200,000 IU each) for a total 400,000 IU vitamin A. Despite this recommendation, the full 400,000 IU was administered as one dose in two studies (ZVITAMBO Study Group; Ayah 2007), with no reports of breast milk retinoic acid concentration immediately after supplementation. Although Darboe 2007 and Idindili 2007 supplemented the mothers with two doses of 200,000 IU with an interval of 24 hours or one month, respectively, no data regarding breast milk retinoic acid concentration were described. Studies of VAD populations included in this review reported no increase in signs and symptoms likely to be associated with raised intracranial pressure among lactating women supplemented with high doses of vitamin A, compared with placebo, including headaches, drowsiness, nausea, vomiting or blurred vision.
This review did not find evidence of a protective effect in respect of infant mortality. Only one small study reviewed observed significant impact on infant morbidity (duration of acute respiratory illness, number of febrile illnesses) (Roy 1997). In spite of the lack of impact observed in this current review, other published meta-analyses provide evidence that vitamin A supplementation in children over six months of age may be associated with reduced risk of mortality from measles (Fawzi 1993; Yang 2005) and diarrhoea (Glasziou 1993). The coexistence of multiple micronutrient deficiencies could also be a factor that influenced the results. According to Rahman 2001, supplementation with zinc and vitamin A is more effective than vitamin A supplementation alone in reduction of persistent diarrhoea and dysentery in children (one to three years). Multiple-micronutrient supplementation to women during pregnancy may improve outcomes such as fetal growth, but infant outcomes including neurodevelopmental delay had not been reported at the time of a systematic review by Haider 2006. Further studies that consider fetal/neonatal/infant outcomes following maternal multiple-micronutrient supplementation during pregnancy, breastfeeding, or both, may therefore be of interest.
A case-control study by Rondó 1997 conducted with Brazilian infants observed that cord blood retinol concentration was higher in infants with adequate growth for gestational age at delivery compared with infants with intrauterine growth restriction. According to the authors, one possible explanation for this result is maternal VAD. In our review, we included one study (Ayah 2007) that investigated the interaction of birthweight in the response to the vitamin A supplementation, but the authors found no significant effect. The studies included in this present systematic review did not provide data in a format that would allow us to perform subgroup analysis considering birthweight, although future studies may consider this.
Co-existing vitamin A, iron and zinc deficiencies are important and common nutritional problems. There is evidence that zinc status influences several aspects of vitamin A metabolism, including absorption, transport and use (Christian 1998). Studies conducted in rats noted that vitamin A metabolism is also altered with iron deficiency, characterised by low serum retinol concentration and increased vitamin A hepatic stores, probably associated with reduced retinyl ester hydrolase's activity (Jang 2000; Oliveira 2008a; Rosales 1999; Strube 2002). Clinical trials that combine two or more micronutrients may be more effective in improving the nutritional parameters compared to studies that use only one micronutrient (Dijkhuizen 2004; Rahman 2001; Suharno 1993). In the present review, one trial supplemented the postpartum women with vitamin A plus iron, compared to iron alone. In the vitamin A plus iron group, the improvement on vitamin A status was evident only until three months postpartum. Although the maternal serum retinol and breast milk concentration demonstrated a trend toward improvement in the iron alone group at nine months, it did not reach statistical significance (Roy 1997). In the trial by Ayah 2007 a significant interaction between vitamin A supplementation and serum ferritin was found. The authors observed higher serum retinol among women with serum ferritin above 12 µg/L, suggesting that an improved iron status could influence the response to vitamin A supplementation.
Regarding the infant hepatic vitamin A estimated stores, no protective effect of maternal vitamin A supplementation (200,000-400,000 IU) was observed (Ayah 2007, RETIBETA Project; Stoltzfus 1993a; WHO/CHD IVASSG).
Concern has been expressed about adverse effects from infant supplementation with high doses of vitamin A (more than 50,000 IU; Allen 2002). Studies included in this review did not report increased adverse signs and symptoms among infants supplemented with doses ranging from 25,000-200,000 IU vitamin A, or whose mothers received supplements. The lack of adverse effects in women and babies following maternal vitamin A supplementation is reassuring in the VAD populations studied. Such reassurance cannot be assumed for other populations, including many industrialised nations, where adequate vitamin A dietary intake is achieved.
Only one study monitored the vitamin A content in the capsules during the trial and demonstrated that the vitamin content was stable in the capsules administered to the women. However, the lower dose capsules administered to infants (results not included in this review) were subject to deterioration over time by up to 32% of expected content (Idindili 2007). Thus, the stability of vitamin A capsules should be considered in further studies and routine supplementation programmes (Idindili 2007; Newton 2008).
Four studies (Ayah 2007; Darboe 2007; Idindili 2007; ZVITAMBO Study Group) assessed the effects of a higher dose of vitamin A (400,000 IU). Two of them evaluated the effects of two high doses of 200,000 IU vitamin A (400,000 IU) versus one dose (200,000 IU) and no improvement in maternal and infant health were observed. The remaining studies compared the higher dose (400,000 IU) with placebo and did not report a significant impact on maternal health.
Overall completeness and applicability of evidence
Although included studies were conducted in areas of VAD (WHO 2009), in most of the studies the baseline mean maternal serum concentrations were above the cutoff point proposed by WHO (WHO 1996). Despite this, our findings may be interpreted to represent chronic inadequate vitamin A stores for mothers' health needs, which translated to infants born with inadequate stores. This sub-optimal 'starting point' could not be corrected by postpartum administration of vitamin A to mothers, specifically when breastfeeding. Other systematic reviews of long-term supplementation to women during their reproductive years (including the postpartum period) and of infant supplementation may examine whether long-term preventive supplementation confers greater benefits than postpartum supplementation, that is, after the time when the infant has already received inadequate provision of vitamin A during pregnancy (Haider 2006; Van den Broek 2002).
Quality of the evidence
We judged the included trials to have an overall moderate risk of bias. However we also judged that any bias was unlikely to have obscured a true effect of vitamin A (should it have existed).
Potential biases in the review process
We used several approaches in an attempt to minimise bias. The search strategy incorporated both the trials register of the Cochrane Pregnancy and Childbirth Group and other databases that were likely to included publications from less well developed countries that may not be identified through standard searches. The review authors independently assessed eligibility for conclusion, conducted data extraction and negotiated on areas of concern or uncertainty. Considering the high number of meta-analyses, there is a risk of spuriously significant results.
Implications for practice
In countries with widespread breastfeeding practices and high prevalences of vitamin A deficiency, the transient improvement in maternal serum retinol concentration and milk retinol represent at least a limited benefit of vitamin A supplementation for postpartum women. These findings need to be considered in the context of the potential for follow up with longer term supplementation to ultimately improve maternal and infant health outcomes.
No vitamin A supplementation regimens report adverse effects for infants or their mothers, in regions of vitamin A deficiency.
This review has not evaluated vitamin A supplementation in non-deficient populations.
Implications for research
This review's focus on postpartum supplementation needs to be considered as part of a wider focus on vitamin A status during infancy and for women, across their reproductive years, including the ideal dosing regimen to achieve improved maternal and infant health for those residing in countries of vitamin A deficiency, where there are also high rates of maternal and infant mortality. Moreover, the stability of vitamin A content in capsules needs consideration.
Further research may consider the potential interaction between vitamin A and other micronutrients, including iron and zinc. Other sustainable long-term strategies to achieve food security, as increased access to local vitamin A rich foods and nutritional education, are also recommended.
Staff at the Cochrane Editorial Unit who helped finalise the review.
As part of the pre-publication editorial process, this review has been commented on by three peers (an editor and two referees who are external to the editorial team), a member of the Pregnancy and Childbirth Group's international panel of consumers and the Group's Statistical Adviser.
Data and analyses
- Top of page
- Summary of findings [Explanations]
- Authors' conclusions
- Data and analyses
- Contributions of authors
- Declarations of interest
- Sources of support
- Differences between protocol and review
- Index terms
Appendix 1. Additional search strategies
LILACS - Latin American and Caribbean Health Sciences by Bireme (1982 to July 2010)
#1: ((Pt ENSAIO CONTROLADO ALEATORIO OR Pt ENSAIO CLINICO CONTROLADO OR Mh ENSAIOS CONTROLADOS ALEATORIOS OR Mh DISTRIBUICAO ALEATORIA OR Mh MÉTODO DUPLO-CEGO OR Mh MÉTODO SIMPLES-CEGO) AND NOT (Ct ANIMAIS AND NOT (Ct HUMANO AND Ct ANIMAIS)) OR (Pt ENSAIO CLÍNICO OR Ex E05.318.760.535$) OR (Tw clin$ AND (Tw trial$ OR Tw ensa$ OR Tw estud$ OR Tw experim$ OR Tw investiga$)) OR ((Tw singl$ OR Tw simple$ OR Tw doubl$ OR Tw doble$ OR Tw duplo$ OR Tw trebl$ OR Tw trip$) AND (Tw blind$ OR Tw cego$ OR Tw ciego$ OR Tw mask$ OR Tw mascar$)) OR Mh PLACEBOS OR Tw placebo$ OR (Tw random$ OR Tw randon$ OR Tw casual$ OR Tw acaso$ OR Tw azar OR Tw aleator$) OR (Mh PROJETOS DE PESQUISA) AND NOT (Ct ANIMAIS AND NOT (Ct HUMANO AND Ct ANIMAIS)) OR (Ct ESTUDO COMPARATIVO OR Ex E05.337$ OR Mh SEGUIMENTOS OR Mh ESTUDOS PROSPECTIVOS OR Tw control$ OR Tw prospectiv$ OR Tw volunt$ OR Tw volunteer$) AND NOT (Ct ANIMAIS AND NOT (Ct HUMANO AND Ct ANIMAIS))) AND NOT Mh ANIMAIS [Palavras]
#2: retinol or "vitamin A" or caroten$ [Palavras]
#3: #1 AND #2
WEB OF SCIENCE by ISI (1945 to July 2010)
#1: TS=(randomised controlled trial) OR TS=(controlled clinical trial) OR TS=(randomised controlled trials) OR TS=(random allocation) OR TS=(double-blind method) OR TS=(single-blind method) OR TS=(clinical trial) OR TS=(clinical trials) OR TS=(clinical trial) OR ((TS=singl* OR TS=doubl* OR TS=trebl* OR TS=tripl*) AND (TS=mask* OR TS=blind*)) OR (TS=(latin square) OR TS=placebo* OR TS=random* OR TS=(research design) or TS=(comparative study) OR TS=(evaluation studies) OR TS=(follow-up studies) OR TS=(prospective studies) OR TS=(cross-over studies) OR TS=control* OR TS=prospectiv* OR TS=volunteer*)
#2: TS=puerp* or TS=matern* or TS=lacta* or TS=breastfe* or TS=(breast fee*) or TS=breast-fee* or TS=(human milk) or TS=postnatal or TS=postpart* or TS=newborn* or TS=infant* or TS=newborn
#3: TS=retinol* or TS=(vitamin A) or TS=caroten*
#4: #3 AND #2 AND #1
BIOLOGICAL ABSTRACTS (1998 to July 2010), HUMAN NUTRITION (1982 to October 2007), FOOD SCIENCES & TECH ABSTRACTS (1969 to November 2008), FOOD AND HUMAN NUTRITION (1975 to October 2007), AGRIS (1975 to October 2007) (By ERL - Electronic Reference Library): the latter database searches were not updated due to lack of access to them.
#1: (RANDOMIZED-CONTROLLED-TRIAL) or (CONTROLLED-CLINICAL-TRIAL) or RANDOMIZED-CONTROLLED-TRIALS or RANDOM-ALLOCATION or DOUBLE-BLIND-METHOD or SINGLE-BLIND-METHOD or (CLINICAL-TRIAL) or (CLINICAL-TRIALS) or ((clin* near trial*) in TI) or ((clin* near trial*) in AB) or ((singl* or doubl* or trebl* or tripl*) near (blind* or mask*)) or ((singl* or doubl* or trebl* or tripl*) near ((blind* or mask*) in TI)) or ((singl* or doubl* or trebl* or tripl*) near ((blind* or mask*) in AB)) or PLACEBOS or (placebo* in TI) or (placebo* in AB) or (random* in TI) or (random* in AB) or RESEARCH-DESIGN \
#2: (('POSTPARTUM PERIOD' or 'MATERNAL-CHILD NURSING' or 'MATERNAL NUTRITION' or 'LACTATION' or 'BREAST FEEDING' or 'MILK, HUMAN' or 'POSTNATAL CARE' or 'INFANT, NEWBORN' or 'INFANT') in DE) or PUERP* or MATERN* or LACTA* or BREASTFE* or 'BREAST FE*' or BREAST-FE* or 'HUMAN MILK' or MILK-HUMAN or POSTNATAL or POSTPART* or INFANT-NEWBORN* or NEWBORN* or INFANT*
#3: ('Vitamin A' in DE) or ('Vitamin A Deficiency' in DE) or ('Carotenoids' in DE) or caroten* or retinol* or 'vitamin A'
#4: #1 AND #2 AND #3
Protocol first published: Issue 2, 2006
Review first published: Issue 10, 2010
Contributions of authors
JM Oliveira-Menegozzo, CE East and P Middleton wrote the review with input from DP Bergamaschi.
Declarations of interest
Sources of support
- Brazilian Cochrane Center, Brazil.
- Coordenadoria de Aperfeiçoamento do Ensino Superior - CAPES, Brazil.
- Fundação de Amparo à Pesquisa do Estado de SP - FAPESP, Brazil.
- Pró-reitoria de Pesquisa da USP, Brazil.
- Department of Nutrition for Health and Development, World Health Organization, Switzerland.Provided funding for the preparation of this review.
Differences between protocol and review
Considerable collaborative input from referees, authors and other Cochrane personnel resulted in a focus specifically on postpartum supplementation, rather than widening to include long-term supplementation during women's reproductive years.
Criteria for considering studies in this review: we added the potential for including cluster-randomised trials, which were considered important for the purpose of the review, although none were ultimately included.
Medical Subject Headings (MeSH)
*Postpartum Period; Infant Mortality; Infant, Newborn; Maternal Mortality; Milk, Human [chemistry]; Randomized Controlled Trials as Topic; Vitamin A [*administration & dosage; analysis]; Vitamin A Deficiency [drug therapy]; Vitamins [*administration & dosage]
MeSH check words
Female; Humans; Infant; Pregnancy
* Indicates the major publication for the study