EAL

H/A: Micronutrient Supplementation (2009)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

The objectives of the study were to determine the association between maternal multi-vitamin supplementation and the mental and psycho-motor development of children who are born to HIV-1-infected mothers in Tanzania, as secondary endpoints in a randomized trial that investigated the effects of maternal multi-vitamin supplementation on HIV-1 vertical transmission and progression.

Inclusion Criteria:

Children in this study were born to mothers who were part of a randomized double-blind, placebo-controlled trial of vitamin supplements (multi-vitamins and vitamin A in a 2x2 factorial design) among HIV-1-infected pregnant women in Dar es Salaam, Tanzania.

Exclusion Criteria:

None specifically mentioned.

Description of Study Protocol:

Recruitment

Recruitment methods not described.

Design

Enrolled women were followed-up at the study clinic at Muhimbili National Hospital monthly during pregnancy and with their infants after delivery for a minimum of 18 months
Women received a daily dose during pregnancy and continued after delivery, throughout follow-up one of the following regimens:
- Vitamin A (30mg of beta carotene plus 5,000 IU of pre-formed vitamin A)
- Multi-vitamins excluding vitamin A (20mg of B_1,20mg of B₂, 25mg of B₆, 100mg of niacin, 50mcg of B₁₂, 500mg of C, 30mg of E and 0.8mg of folic acid)
- Multi-vitamins including vitamin A, all formulated in two tablets
- Two tablets of placebo.

Blinding Used

Double-blind.

Intervention

The Bayley Scales of Infant Development (Mental Development Index and Pyschomotor Development Index portions), Second Edition, was used to assess the current developmental functioning of children aged six to 18 months in this study.

Statistical Analysis

For longitudinal analysis, linear regression models were fitted for each of the outcomes seperately, using all available data
Cox proportional hazards regression models were used to investigate the effect of maternal supplementation on time to an index score under 70.

Data Collection Summary:

Timing of Measurements

The BSID-II was administered at six, 12 and 18 months, to a subset of the infants who were born from the first-study pregnancies, attended clinic on Mondays or Fridays and had an identification number that ended in an uneven digit.

Dependent Variables

Mental Development Index (MDI) and raw mental scores
Psychomotor Development Index (PDI) and raw motor scores.

Independent Variables

Multi-vitamin or placebo supplementation in mothers during pregnancy.

Control Variables

HIV status.

Description of Actual Data Sample:

Initial N: 327 infants
Attrition (final N): 681 assessments (158 in placebo group; 169 in multi-vitamins group; 147 in multi-vitamins plus vitamin A group; 180 in vitamin A-only group)
Age: Ages six, 12 and 18 months
Ethnicity: Not mentioned.

Other Relevant Demographics

Children whose mothers received multi-vitamin supplements were signficantly less likely to have low birth weight (under 2,500g; P=0.02)
Mothers who received vitamin A supplementation tended to be slightly older than the other women (P=0.03)
Otherwise, there were no significant differences between maternal groups factors regarding HIV state at baseline, CD4 count, marital status, educational level, quintiles of money spent or ESR.

Anthropometrics

There were no signficant differences between child groups with regards to

Gender
Fewer than 37 weeks' gestation
Small for gestational age
Number of child deaths.

Location

Muhimbili National Hospital, Dar es Salaam, Tanzania.

Summary of Results:

Other Findings

Multivariate PDI score was increased by 2.6 points (95% CI, 0.1 to 5.1, P=0.04) on average over the period of six to 18 months, in the group which received multi-vitamin supplementation, compared to those without supplementation. The raw score was also increased by 0.8 items (95% CI, 0.02 to 1.6, P=0.04). Multi-vitamin supplementation did not signficantly affect mental scores.
Vitamin A supplementation was not signficantly associated with a change in either mental or psycho-motor function
The results of multivariate analyses indicated that multi-vitamin supplements were signficantly protective against the risk for developmental delay on the motor scale (relative risk, 0.4; 95% CI, 0.2 to 0.7; P=0.004), but not on the mental scale. Vitamin A supplementation was not protective against the risk for developmental delay on either scale.
Women with lower ESR at baseline in the multi-vitamin-supplemented group had a difference in 0.3 items (95% CI, - 0.7 to 1.2; P=0.004 for interaction) on the motor scores compared to those in the non-supplemented group.
Among children whose mothers' CD4 count at baseline was at least 200 cells per mm³, vitamin A supplementation was associated with a 0.5-point (95% CI, -1.6 to 2.5; P=0.0009 for interaction) increase in MDI and a 1.0-point (95% CI, -1.6 to 3.6; P=0.009 for interaction) increase in PDI, compared with the group which did not receive vitamin A supplementation. The same pattern of effect modification by maternal CD4 count at baseline was observed when the raw mental (P=0.004 for interaction) and motor scores (P=0.05 for interaction) were considered.

Author Conclusion:

Maternal multi-vitamin supplments provide a low-cost intervention to reduce the risk for developmental delays among infants who are born to HIV-positive mothers in developing countries.

Funding Source:

Government:	NIH; NICHD; Fogarty International Center
University/Hospital:	Harvard School of Public Health;Children's Hospital, Boston MA;Muhimbili University College of Health Sciences

Reviewer Comments:

This study was part of a larger study examining the effect of various multi-vitamins on mother-to-child HIV-1 transmission and disease progression. It had a large sample size and was well designed. Authors note:

The study design does not permit the effects of pre-natal and post-natal multi-vitamin supplementation to be distinguished because of all of the women received the supplements throughout
Neither is it possible to know which nutrient produced the beneficial effect observed because they were all in the same tablet.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	???
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	N/A
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	N/A
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.6.	Were extra or unplanned treatments described?	???
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes