EAL

H/A: Micronutrient Supplementation (2009)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

The purpose of this study was to investigate the relationship between multivitamin and vitamin A supplementation and hypertension in pregnant women.

Inclusion Criteria:

Pregnant women between 12 and 27 weeks' gestation who were HIV-1 infected without WHO-defined Stage IV disease
Resident of Dar es Salaam
Intending to remain in the city for the duration of the pregnancy and one year after
At least one blood pressure assessment at baseline and one between randomization and 90 days post-partum.

Exclusion Criteria:

None specifically mentioned.

Description of Study Protocol:

Recruitment

Recruitment was for a randomized, controlled trial evaluating the effects of vitamin supplements and pregnancy outcomes in HIV-1 infected women in Tanzania from April, 1995 to 1997.

Design

Randomized controlled trial. Women who were part of the study on the effects of vitamin supplements and pregnancy outcomes were evaluated for hypertension during pregnancy. Blood pressure measurements were taken at least monthly at pre-natal visits, at delivery and at post-natal visits.

Blinding Used

Supplementation with the multivitamins, multivitamins and vitamin A, vitamin A and beta-carotene, and placebo were done in a double-blind manner. All tablets were similar in appearance, identically packaged and labeled. The participant, dispenser and study physicians were unaware of their contents.

Intervention

Subjects were randomized into one of the following intervention groups:
- Vitamin A and beta-carotene alone (30mg beta-carotene and 5,000 IU preformed vitamin A)
- Multivitamins (excluding vitamin A and beta-carotene) that included 20mg thiamine (vitamin B₁), 20mg riboflavin (vitamin B₂), 25mg vitamin B₆, 100mg niacin, 50mcg cobalamin (vitamin B₁₂), 500mg vitamin C, 30mg vitamin E and 0.8mg folic acid
- Vitamins provided in same doses as above
- Placebo.
All women were given 400mg ferrous sulfate, 5.0mg folate, and 500mg cloroquine phosphate. At delivery, all women taking vitamin A were administered a single oral dose of 200,000 IU vitamin A; the others were given an extra dose of placebo.

Statistical Analysis

Women with hypertension at the time of randomization were excluded from the statistical analysis
In the intention-to-treat analyses, the Kaplan-Meier estimator was used to obtain cumulative rates and the Cox proportional hazards model to estimate relative risks and the 95% confidence interval for the effect of vitamins on hypertension
The alpha level was set at 5%
To assess the predictors of hypertension during pregnancy, the researchers included all potential predictors in a forward stepwise Cox proportional hazards model with entry and staying criteria for the variables set at 0.20.

Data Collection Summary:

Timing of Measurements

Blood pressure measurements were taken at least monthly at pre-natal visits, at delivery and at post-natal visits
Height, weight and mid-upper arm circumference was measured at baseline and at monthly visits.

Dependent Variables

Hypertension (defined as systolic blood pressure 140mg Hg or higher, or diastolic blood pressure of 90mm Hg or higher at any time during pregnancy
Height, weight and mid-upper arm circumference.

Independent Variables

Subjects were randomized into one of the following intervention groups:

Vitamin A and beta-carotene alone (30mg beta-carotene and 5,000 IU preformed vitamin A)
Multivitamins (excluding vitamin A and beta-carotene) that included 20mg thiamine (vitamin B₁), 20mg riboflavin (vitamin B₂), 25mg vitamin B₆, 100mg niacin, 50mcg cobalamin (vitamin B₁₂), 500mg vitamin C, 30mg vitamin E and 0.8mg folic acid
Vitamins provided in same doses as above
Placebo.

Description of Actual Data Sample:

Initial N: 1,078 women. 1,073 had baseline blood pressure measurements and 41 had hypertension. 999 had follow-up visits.
Attrition (final N): 955 were included in the analysis. 485 administered multivitamins, 470 administered placebos
Age: 113 were less than 20 years of age, 726 were 20 to 29 years of age and 116 were 30 years of age or older
Ethnicity: Tanzanian.

Other Relevant Demographics

Mean CD4 cell count:

Multivitamins: 422±202 cells per mm³
Placebo: 411±209 cells per mm³
Vitamin A: 412±204 cells per mm³
Placebo: 421±207 cells per mm³.

Anthropometrics

The multivitamin and vitamin A groups did not differ from their respective placebo groups for any of the variables.

Location

Dar es Salaam, Tanzania.

Summary of Results:

Other Findings

Mean compliance with the regimen was 91% (median 96%)
Women who received the multivitamins were less likely to develop incident hypertension during pregnancy than those who did not
Multivitamins reduced the risk of hypertension during pregnancy by 38% (RR=0.62; 95% CI, 0.4 to 0.94; P=0.03)
Vitamin A did not affect hypertension during pregnancy (RR=1.00; 95% CI, 0.66 to 1.51; P=0.98)
Wome with systolic blood pressure higher than 120mm Hg at baseline were six times more likely to have hypertension during pregnancy than women with systolic blood pressure 120mm Hg or lower (RR=6.02; 95% CI, 2.59 to 13.97; P<0.001).

Author Conclusion:

Those who received multivitamins were 38% less likely to develop hypertension during pregnancy than those who did not. There was no overall effect of Vitamin A on hypertension during pregnancy. Hypertension during pregnancy was more likely in women with high baseline systolic blood pressure and those with higher mid-upper arm circumference.Taking multivitamins containing vitamins B, C and E during pregnancy may be an inexpensive and effective strategy to improve the health of the mother and baby.

Funding Source:

Government:

National Istitute of Child Health and Human Development; Fogarty International Center, National Institutes of Health

Industry:

Reviewer Comments:

Secondary outcome analysis from a large, double-blind, placebo-controlled, randomized clinical trial in HIV-positive pregnant Tanzanian women.

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.)	Yes
	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?	Yes
	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?	Yes
	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?	???
	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