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,2
,,
* Population Health Research Institute and McMaster University, Hamilton ON, Canada;
Department of Oral Health Policy and Epidemiology, Harvard School of Dental Medicine, Boston, MA 02115;
** Muhimbili University, Department of Community Health, Muhimbili University College of Sciences, Dar-es-Salaam, Tanzania; and Departments of
Nutrition and
Epidemiology, Harvard School of Public Health, Boston, MA 02115
2To whom correspondence should be addressed. E-mail: anwar.merchant{at}post.harvard.edu.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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140 mm Hg or diastolic blood pressure 90 mm Hg at any time during pregnancy). In a double-blind, placebo-controlled, randomized, clinical trial, conducted among 1078 HIV-positive pregnant Tanzanian women, those who received multivitamins were 38% less likely to develop hypertension during pregnancy than those who did not [relative risk (RR) = 0.62, 95% CI 0.40–0.94, P = 0.03]. There was no overall effect of vitamin A on hypertension during pregnancy (RR = 1.00, 95% CI 0.66–1.51, P = 0.98). Hypertension during pregnancy was more likely in women with high baseline systolic blood pressure (>120 vs. 
120 mm Hg) (RR = 6.02, 95%CI 2.59–13.97, P < 0.001), and those with higher mid-upper arm circumference (RR = 1.12, 95% CI 1.04–1.19, P = 0.002). 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.
KEY WORDS: • multivitamins • hypertension during pregnancy • randomized controlled trial
Hypertension during pregnancy increases fetal growth retardation, preterm deliveries, and perinatal deaths, and yet its causes remain unclear (1). Even though improvements in postnatal care reduced perinatal deaths rates in developed countries, preeclampsia rates remained constant at between 3 and 10% of all births (2), and preterm birth rates have increased (3). The worldwide prevalence of hypertensive disorders during pregnancy is 15% (4). In developing countries, 
25% of newborns have growth retardation (5), and perinatal mortality ranges from 150 to 400/1000 live births (6); 10% of perinatal deaths in Africa are related to hypertension during pregnancy (7). In HIV-infected women, preterm birth additionally increases the risk of HIV transmission to the infant (8).
There are few interventions known to prevent hypertension during pregnancy (9). Aspirin was shown to reduce the risk of preeclampsia in women with underlying risk factors (10). The results of calcium supplementation to prevent hypertension during pregnancy were inconsistent (9). Large doses of vitamin C (1000 mg/d) and vitamin E (400 IU/d) given to high-risk British women reduced preeclampsia but there was no effect on gestational hypertension (11). Folate alone or in combination with iron did not protect against hypertension during pregnancy (9). Other B vitamins, carotenoids, or multivitamin supplements have not been evaluated in relation to preeclampsia or other hypertensive disorders during pregnancy (9).
Oxidative stress and endothelial cell dysfunction of the placenta have been implicated in the development of clinical preeclampsia (2). Low serum antioxidant levels were associated with increased oxidative stress and endothelial cell dysfunction (12); high serum homocysteine was related to increased risk of preeclampsia, preterm birth, and low birthweight (13). B vitamin intake reduces serum homocysteine (14) and improves endothelial function (15). Dietary antioxidants quench reactive oxygen species, reduce oxidative stress, and improve endothelial function (16). It is plausible, therefore, that multivitamin supplements may reduce the risk of hypertension during pregnancy, particularly in populations at risk of nutritional deficiencies. Vitamin supplementation is affordable, safe, and can be easily implemented. We enrolled 1078 HIV-infected pregnant Tanzanian women in a double-blind, factorial, randomized, placebo-controlled trial to examine the effect of prenatal multivitamin (vitamins B, C, and E) and vitamin A supplements on HIV mother-to-child transmission and HIV progression. The results of these studies were reported earlier (17,18). In this investigation, we examined the relation between multivitamin and vitamin A supplementation and hypertension in pregnant women.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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For these analyses, we followed up women from recruitment to 3 mo postpartum, consistent with other studies evaluating maternal outcomes (20). Pregnant women between 12 and 27 wk gestation who were HIV-1 infected without WHO-defined Stage IV disease (21), resident of Dar-es-Salaam, intending to remain in the city for the duration of the pregnancy and 1 y thereafter were eligible (details are described elsewhere) (17).
We included women for whom we had at least 1 blood pressure assessment at baseline and 1 between randomization and 90 d postpartum. Of the 1078 women who were randomized in the trial, 1073 had baseline blood pressure measurements and 41 had hypertension; 999 had follow-up visits leaving 955 women in this analysis. The study protocol was approved by the respective ethics committees of Muhimbili University of Health Sciences, Dar-es-Salaam, Tanzania and Harvard School of Public Health, Boston, MA. We obtained written consent from all participants.
Intervention. Randomization followed a 2 x 2 factorial design. Women in group A3 (n = 238) were given vitamin A (30 mg ß-carotene plus 5000 IU preformed vitamin A); those in group MV (n = 243) were given multivitamins excluding vitamin A (20 mg thiamine, 20 mg riboflavin, 25 mg B-6, 50 µg B-12, 500 mg C, 30 mg E, and 0.8 mg folic acid); those in group MV+A (n = 242) were given all vitamins, and those in group P (n = 232) were given placebo. All regimen tablets were similar in appearance, identically packaged and labeled; the participant, dispenser, and study physicians were unaware of their contents. All women were given 400 mg ferrous sulfate, 5 mg folate, and 500 mg chloroquine 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.
At every visit, we exchanged old regimen bottles containing any leftover pills for new bottles. To check compliance, we subtracted the number of pills returned from the total number administered to calculate the percentage of pills taken and compared plasma vitamin A levels at baseline to that at delivery for a subgroup of 100 women.
Outcome assessment.
A woman was considered hypertensive if her systolic blood pressure was 140 mm Hg or diastolic blood pressure was 90 mm Hg at any time during pregnancy. The nurse measured the blood pressure using a mercury sphygmomanometer with the woman sitting rested on a chair, and recorded single values for systolic and diastolic blood pressure. Measurements were made at least monthly at prenatal visits, at delivery, and at postnatal visits.
Data collections for other covariates. Information on sociodemographic characteristics was collected at baseline and all routine laboratory tests were conducted as described elsewhere (19). A study physician examined the patient; a nurse obtained the history and measured height, weight, and mid-upper arm circumference at baseline and every subsequent month. Gestational age was determined by the physician using the date of the last menstrual period.
Statistical analysis.
In the analysis for treatment effect of vitamins on hypertension during pregnancy, we excluded women with hypertension at the time of randomization, and considered the first event of hypertension between randomization and 3 mo postpartum. We calculated person time from randomization to the first diagnosis of hypertension during pregnancy, loss to follow-up, or 90 d postpartum, whichever came first. In intention-to-treat analyses, we used the Kaplan-Meier estimator to obtain cumulative rates and the Cox proportional hazards model to estimate relative risks (RR) and the 95% CI for the effect of vitamins on hypertension. The 
level was set at 5%. We analyzed the main effects of vitamin A, multivitamins, and their interactions. We explored effect modification by CD4 cell count, lymphocyte count, erythrocyte sedimentation rate (ESR), hemoglobin, age, baseline BMI, history of diabetes, nulliparity, literacy level, and plasma vitamins A and E by comparing full and reduced Cox models using the likelihood ratio test. All of the analyses in Figure 1, and Tables 2, and 3 were unadjusted for any covariates. To assess the predictors of hypertension during pregnancy, we included all potential predictors in a forward stepwise Cox proportional hazards model with entry and staying criteria for the variables set at 0.20.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Women who received multivitamins were less likely to develop incident hypertension during pregnancy than those who did not (Fig. 1). The difference between the 2 groups was apparent shortly after the first month following randomization and remained until the end of the study. Overall, multivitamins reduced the hypertension risk during pregnancy by 38% (RR = 0.62, 95% CI 0.40–0.94, P = 0.03) (Table 2). The effect of multivitamins on hypertension during pregnancy remained inverse and significant when we restricted the analyses to cases not detected until delivery, and when we included baseline cases of hypertension and those detected at the first contact after delivery (data not shown).
Vitamin A did not affect hypertension during pregnancy; the Kaplan-Meier graphs of the vitamin A and no vitamin A groups overlapped over the entire course of follow-up (Fig. 1), (RR = 1.00, 95% CI 0.66–1.51, P = 0.98) (Table 2).
This study was not designed to evaluate effect modification of the relation between multivitamin intake and hypertension risk; thus, data were sparse in some of the categories. The effect of multivitamins on hypertension during pregnancy did not differ between women who did and did not receive vitamin A (P-value for interaction = 0.97). The effect of multivitamins on hypertension was not modified by any of the factors we evaluated (Table 3).
In the analysis of predictors of hypertension during pregnancy, systolic blood pressure at baseline > 120 mm Hg (after excluding women with systolic blood pressure 140 mm Hg) and mid-upper arm circumference at baseline were related to hypertension risk during pregnancy after adjustment for age. Women with systolic blood pressure > 120 mm Hg at baseline were 6 times more likely to have hypertension during pregnancy than women with systolic blood pressure 120 mm Hg (RR = 6.02, 95% CI 2.59–13.97, P = 0.002). There was a 12% increased risk of hypertension during pregnancy for every centimeter increase in mid-upper arm circumference at baseline (RR = 1.12, 95% CI 1.04–1.19, P < 0.001).
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Dyslipidemia, i.e., increased serum triglycerides, LDL cholesterol, and free fatty acids, precedes preeclampsia, increasing lipid peroxidation, oxidative stress (22), and endothelial dysfunction (23). Oxidative stress is hypothesized to induce endothelial dysfunction of the placental blood vessels (2) and to impair uteroplacental blood flow, increase placental free radical synthesis (24), deplete serum antioxidants (25), and raise preeclampsia risk.
Vitamins C and E can act as scavengers of free radicals (11), decrease oxidative stress, and improve endothelial dysfunction. Habitual vitamin E intake was negatively correlated with diastolic blood pressure among HIV-infected subjects (26). A combination of vitamin C and E supplements reduced preeclampsia by 61% in high-risk women (RR = 0.39, 95% CI0.17–0.90) (11). It is plausible, therefore, that the antioxidant content of the multivitamin contributed to the reduction in hypertension.
High serum homocysteine was also hypothesized to induce oxidative stress and endothelial dysfunction (27) and is positively associated with preeclampsia risk (28) and adverse pregnancy outcomes (13). Low intakes of vitamins B-6, vitamin B-12, and folate are related to high plasma homocysteine concentration (14). All women in this study received folate and iron, but folate and iron alone were not shown to affect preeclampsia (9). It is possible that the reduction of hypertension risk was through reduction in homocysteine in women who received folate, vitamin B-6, and vitamin B-12.
Carotenoid supplementation has not been evaluated in relation to preeclampsia, but low-dose vitamin A and ß-carotene supplementation in Nepal caused a reduction in maternal mortality. Moreover, the proportion of women dying as a result of eclampsia and preeclampsia was similar in the intervention and placebo groups (9). These results suggest that vitamin A and carotenoids probably do not have a direct effect on eclampsia and preeclampsia. The lack of association between vitamin A intake and hypertension during pregnancy in our study is consistent with those findings.
Antiretroviral protease inhibitors induce insulin resistance and dyslipidemia (29), 2 factors associated with eclampsia (1). HIV-positive women administered antiretroviral treatment had higher preeclampsia prevalence than HIV-positive women not given antiretroviral treatment; the latter had a prevalence of preeclampsia similar to that of HIV-negative women (30). The women in our study did not receive antiretroviral treatment; therefore, the hypertension observed in this population could not be attributed to the effects of antiretroviral treatment.
The strongest predictor of hypertension during pregnancy in the current study was modestly elevated blood pressure at baseline, consistent with the literature (24). We observed a positive association between mid-upper arm circumference and the risk of hypertension during pregnancy. We used mid-upper arm circumference instead of BMI as a measure of adiposity because women entered the study at different stages of gestation and we did not have information about their prepregnancy BMIs. Obesity is associated with increased risk of preeclampsia (31) and insulin resistance during pregnancy (32). Hyperinsulinemia is associated with increased blood cholesterol, triglycerides, free fatty acids, and oxidized lipids (32), which might contribute to endothelial dysfunction and increased hypertension risk during pregnancy.
A limitation of this study was that we measured hypertension in a clinical setting using a single recording; this did not follow international guidelines, which recommend 2 readings 4 h apart (33). However, the nurses were trained in measuring blood pressures and followed a defined clinical protocol. Because blood pressure was measured in the same way in all of the women and this was a double-blind study, any misclassification of hypertensive status would most likely be random. This would result in an attenuation of effect, but would not create spurious relations. Another limitation was that we did not have data on proteinuria; thus, we could not classify the cases as eclampsia or preeclampsia. Our definition of hypertension was therefore a composite of preeclampsia, eclampsia, and chronic hypertension. Because it included chronic hypertension (in which blood pressure may be raised for several weeks postpartum), we included women with hypertension at their first postpartum visit because we did not have blood pressure measurements made just before delivery. Confounding is not likely to contribute to our results because randomization ensured that the comparison groups were similar. In generalizing the results, we must consider that this study was conducted among Tanzanian women with HIV in whom nutritional status was compromised. There is a need to evaluate this relation in HIV-negative women as well.
Prenatal multivitamin intake during pregnancy reduced the incidence of hypertension during pregnancy in this group of HIV-infected women. Taking multivitamins during pregnancy may be an inexpensive and effective strategy to improve the health of the mother and baby.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: ESR, erythrocyte sedimentation rate; group A, 30 mg ß-carotene plus 5000 IU preformed vitamin A; group MV, multivitamins excluding vitamin A; group MV+A, all vitamins; group P, placebo; RR, relative risk.
Manuscript received 11 March 2005. Initial review completed 26 March 2005. Revision accepted 15 April 2005.
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LITERATURE CITED |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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