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Randomized, double-blind, placebo-controlled trial of seleniumsupplements among HIV-infected pregnant women in Tanzania:effects on maternal and child outcomes13

Roland Kupka, Ferdinand Mugusi, Said Aboud, Gernard I Msamanga, Julia L Finkelstein, Donna Spiegelman, andWafaie W Fawzi

ABSTRACT

Background: In observational studies, adequate selenium statushas

been associated with better pregnancy outcomes and slowed HIV

disease progression.

Objective: We investigated the effects of daily selenium supple-

ments on CD4 cell counts, viral load, pregnancy outcomes, and

maternal and infant mortality among 913 HIV-infected pregnant

women.

Design: In this randomized, double-blind, placebo-controlled trial,

eligible women between 12 and 27 wk of gestation were given daily

selenium (200 g as selenomethionine) or placebo as supplements

from recruitment until 6 mo after delivery. All women received

prenatal iron, folic acid, and multivitamin supplements irrespective

of experimental assignment.

Results: Theseleniumregimen hadno significant effecton maternal

CD4 cell counts or viral load. Selenium was marginally associated

with a reduced risk of low birth weight [relative risk (RR) 0.71;

95% CI: 0.49, 1.05; P 0.09] and increased risk of fetal death (RR

1.58; 95% CI 0.95, 2.63; P 0.08), but had no effect on risk of

prematurity or small-for-gestational age birth. The regimen had nosignificant effect on maternal mortality (RR 1.02; 95%CI 0.51,

2.04; P 0.96). There was no significant effect on neonatal or

overall child mortality, but selenium reduced the risk of child mor-

tality after 6 wk (RR 0.43; 95% CI 0.19, 0.99; P 0.048).

Conclusion: Among HIV-infected women from Dar es Salaam,

Tanzania, selenium supplements given during and after pregnancy

did not improve HIV disease progression or pregnancy outcomes,

but may improve child survival. This trial was registered at clinical-

trials.gov as NCT00197561. Am J Clin Nutr2008;87:18028.

INTRODUCTION

HIV infection is a serious global public health problem, and33 million persons are currently living with the infection (1).

Sub-Saharan Africa is the geographic region most heavily af-

fected by the HIV epidemic and accounts for about two-thirds of

the global total of infections. Despite the progress toward in-

creasing access to highly active antiretroviral therapy (HAART)

in sub-Saharan Africa, only one-quarter of those in need receive

it (2). Therefore, treatment modalities that prolong the need for

HAART may be of great benefit in sub-Saharan Africa.

The trace element selenium has been proposed as a key nutri-

ent among persons living with HIV (3). Biochemical selenium

deficiency has been associated with increased mortality among

those infected with HIV (47) and with accelerated HIV disease

progression through increased viral load (8). Seleniums role in

antioxidant defense (9) and immunity (10)may be the underlying

mechanism. Because advanced HIV disease is a risk factor for

adverse pregnancy outcomes (11, 12), maternal selenium defi-

ciency may also worsen pregnancy outcomes (13).

The interpretation of observational studies that used plasma

selenium concentrations to determine selenium deficiency may

be limited by confounding dueto predictors of adverse outcomes

that may also affect selenium concentrations, such as the acute-

phase response to infection (14). The role of selenium status,

especially among those experiencing infections, should thus

preferably be assessed by using randomized, placebo-controlled

supplementation trials. Trials conducted among HIV-infected

populations from the United States showed that selenium sup-

plements decreased hospital admissions (15) and suppressed vi-

ral load (8). The effect of selenium supplements among HIV-

infected populations in sub-Saharan Africa is unclear.

We therefore conducted a randomized, double-blind,placebo-

controlled trial of selenium among HIV-infected women en-rolled during pregnancy to examine the effect of selenium sup-

plementation on maternal HIV disease progression, pregnancy

outcomes, and maternal and child survival.

SUBJECTS AND METHODS

Study design, study population, and setting

Pregnant women seeking care at antenatal clinics in Dar es

Salaam, Tanzania, were offered HIV-1 testing as part of the

prevalent standard of care. Women who tested positive for HIV

were referred to a study clinic located at Muhimbili National

1 From theDepartments ofNutrition(RK,JLF, andWWF),Epidemiology

(WWF and DS), and Biostatistics (DS), Harvard School of Public Health,

Boston, MA,and the Departments of Internal Medicine (FM), Microbiology

and Immunology (SA), and Community Health (GIM), Muhimbili Univer-

sity of Health and Allied Sciences, Dar es Salaam, Tanzania.2 Supported by the National Institute of Child Health and Human Devel-

opment (NICHD R24 043555-05).3 Address reprint requests to R Kupka, Department of Nutrition, Harvard

School of Public Health, 1633 Tremont Street, Boston, MA 02120. E-mail:

[email protected] January 18, 2008.

Accepted for publication February 13, 2008.

1802 Am J Clin Nutr 2008;87:18028. Printed in USA. 2008 American Society for Nutrition

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with use of the Roche Amplicor version 1.5 assay (Roche Diag-

nostics Corporation, Indianapolis, IN), and hemoglobin concen-

trations with use of the CBC5 Coulter Counter (Coulter Corpo-

ration, Miami, FL).

Statistical analyses

The intention-to-treat principle was used for statistical analy-

ses. For pregnancy outcomes, generalized estimating equations

were used to account for the correlations owing to twinning (n

22 pairs oftwins) (23). Binaryendpoints were modeled with a log

link and binomial variance function to yield relative risks,

whereas the identity link and the Gaussian variance function

were used for continuous endpoints to yield comparisons of

means (24). Mean differences in maternal T-cellcounts andviral

load between treatment groups were estimated with general lin-

ear models for repeated measurements (PROC MIXED; SAS

InstituteInc, Cary, NC). In these models, a compound symmetry

working correlation matrix with the empirical variance was used

(23). Point estimates of postrandomization change in values and

95% CIs directly modeled the difference between repeated mea-

sures. P values were obtained through a parallel groups analysis,

adjusted for baseline. For infant (singletons only) and adult mor-

tality endpoints, Cox proportional hazards models were used to

obtain hazard ratios and 95% CIs.

Compliance with the study regimen was calculated as the

number of tablets absent from the returned bottles divided by the

total numberof tablets the participant should have taken. Breast-

feeding status was determined at each postpartum visit by inter-

view. All P values reportedare two-sided; statistical significance

was defined as P 0.05. No adjustments for multiple compar-

isons or interim analyses were done. Statistical analyses were

carried out by using SAS system version 9.1 (SAS Institute Inc).

Unless otherwise noted, values are means SDs or percentages.

RESULTS

Of the 915 women randomly assigned, 1 woman had a gesta-

tional age at entry outside the allowable range of 1227 wk and

1 woman was found to not be pregnant; both of these women

were excluded from the final analyses (Figure 1). A total of 3

women died before delivery, and data on birth outcomes (mis-

carriage,stillbirth,or live birth)were notavailable for18 women

(13 in the selenium group and 5 in the placebo group; P 0.06).

Among women with live births, birth weightwas unavailable for

14 women (7 in the selenium group and 7 in the placebo group;

P 0.99).

At the time of random assignment, women had a mean gesta-

tionalage of 21.63.4 wkand wereon average 27.54.9yold.

The intervals from the time of random assignment to delivery

(4.0 1.0 mo) and to 6 wk postpartum (5.4 1.0 mo) did not

differ significantly between treatment groups (P 0.72 and P

0.78,respectively).The proportion of participantswith randomly

selected viral load measurements was similar in each treatment

group (P 0.92). There were no relevant differences in baseline

characteristics (Table 1). Mean compliance with the study reg-

imen by 6 mo in the selenium (91.2 6.3%) and placebo (91.7

6.3%) groupsdid notdiffer significantly between groups(P

0.10).

FIGURE 1. Trial design. Numbers represent the number of subjects at each stage. For children, data on both twin and singleton births are presented. For

the child death endpoint, numbers in parentheses indicate the number of deaths among singleton births.

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Selenium hadno significant effecton absolute CD4, CD8, and

CD3cellcounts or on viral load over thefollow-up period(Table

2).Themean( SD)birth weightin theselenium (3008543g)

and placebo (2982588g) groupsdid notdiffer significantly (P

0.76; Table 3). Selenium supplements had no significant

effecton risks oflow birth weight(P 0.09), preterm birth (P

0.93), and small for gestational age (P 0.54).

Among the 913 women, 32 (3.5%) died during follow-up.

Mortality rates were not significantly different between treat-

ment groups (P 0.96). There were 58 fetal deaths in the study;

among them, there were 50 stillbirths and 8 miscarriages (Table

4). Selenium supplements tended to increase the risk of fetal

death, but the results were not statistically significant (P 0.08).

Among singleton live births, 50/815 (6.1%) died during follow-

up. The risk of infant death did not differ significantly by treat-

ment group (RR 0.64; 95% CI 0.36, 1.13; P 0.12).

However, seleniumsupplements resultedin a lower riskof infant

death after 6 wk (RR 0.43; 95% CI 0.19, 0.99; P 0.048).

The prevalence of breastfeeding in this cohort was 90%, and the

median duration among those who breastfed was 16 wk (inter-

quartile range: 1223). These estimates did not differ signifi-

cantly by treatment group.

DISCUSSION

In this randomized, double-blind, placebo-controlled trial, se-

lenium supplements given during the antenatal and postpartum

periods to HIV-infected Tanzanian women did not have signif-

icant effects on HIV-1 viral load, CD4 cell counts, pregnancy

outcomes, or maternal and overall infant mortality. Several lines

of laboratory evidence suggested beneficial effects of selenium

in HIV infection. Selenium status may influence both the hu-

moral and cell-mediated arms of immune function (25). Supple-

mental selenium increases expression of the T-cell high-affinity

interleukin-2 receptor (26), up-regulates the activity of natural

killer and cytotoxic T-cells (27), and increases interferon-pro-

duction and T-helper cell counts (28).

TABLE 1

Baseline characteristics by treatment group

Characteristic

Selenium group Placebo group

n Value n Value

Gestational age (wk) 457 21.4 3.51 456 21.7 3.4

Age (y) 457 27.4 4.8 27.6 4.9

Level of education (%) 454 452

None or adult education 9.5 9.1

14 y 4.6 5.1

58 y 63.2 66.6

8 y 22.7 19.3

Prior pregnancies (%) 452 452

0 27.2 23.0

13 64.2 68.6

3 8.6 8.4

Previous stillbirth or miscarriage (%)2 329 7.3 348 6.9

Midupper arm circumference (cm) 444 26.3 3.5 439 26.2 3.1

Hemoglobin (g/L) 316 97 13 311 96 14

CD4 count (/mm3) 306 375 238 300 376 213

CD3 count (/mm3) 306 1144 445 300 1191 480

CD8 count (/mm3) 306 726 348 300 761 631

Viral load (log)3

222 3.94 0.94 223 3.95 0.961x SD (all such values).2 Among n 677 with a previous pregnancy.3 From a random subsample of participants with complete data for viral load and other primary trial endpoints.

TABLE 2T-cell measurements and HIV RNA viral load among women who received selenium compared with those who received placebo

Endpoint

Mean value in

placebo group1

Selenium group

Mean difference

(95% CI)2 P3

CD4 cell count (/mm3) 486 278 1 (22, 19) 0.72

CD3 cell count (/mm3) 1635 630 10 (38, 58) 0.86

CD8 cell count (/mm3) 1048 439 12 (21, 44) 0.91

Viral load (log) 4.12 1.03 0.02 (0.11, 0.06) 0.71

1 Baseline measurements were excluded. Placebo means are based on n 739 measurements for T-cells and n 438 for viral load.2 Based on general linear models for repeated measurements. Point estimates and 95% CIs directly modeled the differences between repeated measures.3 P obtained from a robust parallel groups analysis with adjustment for baseline.

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Furthermore, selenium functions in oxidative defense, such as

in the glutathione peroxidase (GSH-Px) enzyme system (9).Poor

seleniumstatus lowers GSH-Px activity(29, 30),which maylead

to oxidative stress followed by apoptosis of T lymphocytes (27)

and increased HIV replication rates (31, 32). During embryonic

and fetal development, oxidative stress may damage DNA and

cell membranes (33, 34).

Seleniumsupplementshad no significant effects on pregnancy

outcomes, yet marginally decreased the risk of low birth weight

and marginally increased the risk of fetal death. The role of

selenium status for pregnancyoutcomeshas only been examined

in a few epidemiologic studies and remains unclear. In those

studies, low maternal serum selenium concentrations were re-

lated to adverse pregnancy outcomes such as fetal death (13),

neural tube defects (35), miscarriage (33), and poor weight gain

during pregnancy (36).

Among HIV-infected adults, low plasma selenium concentra-

tions are related to decreasedsurvival(4, 5, 7). However, there is

TABLE 3

Relative risks of adverse pregnancy outcomes by treatment group1

Endpoint Women Children

Selenium

group

Placebo

group

Mean difference or

relative risk (95%

CI)2 P2

n n

Birth weight

Mean value (g) 823 842 3008 5433 2982 588 11 (63, 86) 0.76

2500 g [n(%)] 823 842 42 (10.3) 66 (15.2) 0.71 (0.49, 1.05) 0.09

2000 g [n(%)] 823 842 15 (3.7) 27 (6.2) 0.67 (0.34, 1.34) 0.26

Gestational age (wk)4 837 39.3 3.1 39.4 3.2 0.0 (0.5, 0.4) 0.87

Preterm birth (wk)4

37 wk [n(%)] 837 66 (16.1) 70 (16.4) 0.99 (0.73, 1.34) 0.93

34 wk [n(%)] 837 22 (5.4) 22 (5.1) 1.05 (0.59, 1.86) 0.88

Low birth weight and preterm birth [n (%)]5 823 842 25 (6.1) 34 (7.8) 0.83 (0.48, 1.44) 0.52

Low birth weight and term birth [n(%)]6 693 700 17 (5.0) 32 (8.9) 0.61 (0.34, 1.08) 0.09

Small for gestational age [n(%)]7 789 808 72 (18.4) 73 (17.5) 1.10 (0.81, 1.49) 0.54

Length (cm) 756 774 48.2 4.5 47.7 4.9 0.33 (0.29, 1.02) 0.28

Head circumference (cm) 761 779 34.6 3.1 34.4 3.1 0.18 (0.26, 0.61) 0.42

1 Data were available from 870 singleton pregnancy and 22 twin pregnancy outcomes. 837 pregnancies resulted in live births; among those, birth weight

was not available for 14 pregnancies.2 From generalized estimatingequationswith a compound symmetry working correlation matrix. Forbinary endpoints, thelog link andbinomial variance

function was used, whereas the identity link with Gaussian variance function was used for continuous endpoints.3x SD (all such values).4 Considered to be an outcome for women.5 Defined as birth weight 2500 g and gestational age 37 wk.6 Defined as birth weight 2500 g and gestational age 37 wk.7 Defined as birth weight below 10th percentile of weight for gestational age by the standards of Brenner et al (17).

TABLE 4

Relative risks of perinatal, infant, and adult mortality by treatment group

Endpoint Time of death Women Children

Selenium

group

Placebo

group

Relative risk or hazard

ratio (95% CI)1 P1

n n n (%) n (%)

Perinatal

Miscarriage2 Before 28 wk gestation 892 6 (0.7) 2 (0.2) 3.05 (0.62, 15.05) 0.17

Stillbirth Between 28 wk gestation and delivery 884 906 29 (6.5) 21 (4.5) 1.45 (0.84, 2.50) 0.18

Fetal loss Any time before delivery 892 914 35 (7.8) 23 (4.9) 1.58 (0.95, 2.63) 0.08Perinatal death Between 28 wk gestation and 1 wk after

delivery

859 881 38 (8.9) 30 (6.6) 1.36 (0.86, 2.15) 0.19

Infant3

Neonatal death During the first 42 d after delivery 815 815 11 (2.7) 12 (2.9) 0.96 (0.42, 2.17) 0.91

Infant death Between 42 and 180 d after delivery 750 750 8 (2.2) 19 (5.0) 0.43 (0.19, 0.99) 0.048

Neonatal or infant

death

During the first 180 d after delivery 815 815 19 (4.7) 31 (7.5) 0.64 (0.36, 1.13) 0.12

Adult death Any time between randomization and 180 d

after delivery

913 16 (3.5) 16 (3.5) 1.02 (0.51, 2.04) 0.96

1 Relative risks,95% CI, and corresponding P were obtained fromgeneralizedestimating equations withcompound symmetry working correlationmatrix,

log link, and binomial variance function. Hazard ratios, 95% CI, and corresponding P were obtained from Cox proportional hazards models.2 Considered to be an outcome for women.3 Singletons births only. Neonatal and infant deaths were evaluated among live births.

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concern that these associations were confounded by the acute

phase response to infection (14, 37, 38). A randomized, placebo-

controlled trial from Miami, FL, examined the effect of 200 g

selenium given daily for 9 mo in primarily symptomatic HIV-

infected adult menand women (8). Elevations in serum selenium

concentrations related to selenium supplementation were asso-

ciated with decreases in HIV-1 viral load, which in turn were

related to improved CD4 cell counts. Selenium responders (de-

fined as those withmean serum selenium3SDsabovethemeanchange in the placebo group) had lower HIV-1 viral loads and

higher CD4 counts than did the selenium nonresponder or pla-

cebo groups. However, interpretation of these findings is diffi-

cult, because extraneous factors that are related to both supple-

ment use or response and outcome may have biased these

findings. For instance, the beneficial effects of improvements in

serum selenium concentrations, indicative of high supplement

adherence, may have been confounded by higher than normal

adherence to antiretroviral therapy (39, 40). In another trial from

Miami, FL, 200 g selenium decreased the number of hospital-

izations among 186 HIV-infected participants over a 12-mo

follow-up period (25). The supplements had no effect on mean

CD4 cell counts over time, but reduced the risk of a CD4 cellcount decline50 cells/mm3.

Similar to evidence from adults, low plasma selenium con-

centrations are related to poorsurvivalamong HIV-infectedchil-

dren (6, 41). In this study, selenium reduced the risk of child

mortalityafter 6 wk.Thisreduction may bedue toimproved child

selenium status as a result of increased supply through the pla-

centa, umbilical cord (42), and breast milk (43).

Several explanations are possible for the lack of effect of

selenium on maternal and pregnancy outcomes. All participants

received supplements containing B-complex vitamins, vitamin

C, and vitamin E at multiples of the RDAs, which may have

limited the effect of selenium. The intervention may only be

effective among patients with advanced HIV disease or thosereceiving HAART; in our study, participants were primarily

asymptomatic at baseline and HAART use was uncommon.

Findings from a previous study in Dar es Salaam among HIV-

infected pregnant women (13) showed that only 2% of partici-

pants had low plasma selenium concentrations (85 g/L). De-

spite uncertainty about selenium requirements (44), selenium

deficiency is thus likely to be uncommon in oursetting. This may

be due to adequate intake of selenium-rich foods, such as plant

foods grown in selenium-containing soils, or animal foods such

as seafood (16).

Our study is the largest selenium supplementation trial con-

ducted to date and included rigorous design and analysis meth-

ods. Even thoughthere maybe some benefits forchildren, we didnot find benefits of selenium supplements on maternal disease

progression and mortality. Therefore, there is no support for

providing selenium supplements to HIV-infected populations

nave to HAART, who receive high-dose multivitamin supple-

ments, and who live in areas where selenium deficiency is likely

to be rare.

We thank themothers andchildren andthe members of theresearch team,

including physicians, nurses, midwives, supervisors, laboratory staff, and

administrative staff, whomade the study possible. We greatlyappreciatethe

input of the following colleagues: Illuminata Ballonzi, Juliana Mghamba,

Megan OBrien, Antje Hebestreit,Paul Petraro, Ellen Hertzmark,and Heav-

engton Mshiu. We thank the Permanent Secretary, Ministry of Health, and

the officials at Muhimbili University of Healthand Allied Sciences, Muhim-

bili National Hospital, the City of Dar es Salaam Regional Health Authority,

and the National AIDS Control Program for their support.

The contributions of the authors were as followsRK: analyzed and

interpreted the data and wrote the initial draft of the manuscript; FM and

WWF: are principal investigators of the trial and contributed to the study

designand itsimplementation; GIM: assisted in thetrial designand with JLF

in data interpretation; SA: supervised the laboratory analysis; DS: provided

statistical guidance in the design of the study and in data analyses. All

coauthors participated in the manuscript preparation. The authors did not

have a conflict of interest.

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