1. family and parenting
2. motherhood
3. pregnancy

Effect of multivitamin and vitamin A supplements on weight gain
during pregnancy among HIV-1-infected women1–3
Eduardo Villamor, Gernard Msamanga, Donna Spiegelman, Gretchen Antelman, Karen E Peterson, David J Hunter,
and Wafaie W Fawzi
Maternal HIV infection also contributes to LBW resulting from
preterm delivery and intrauterine growth retardation (IUGR) (13),
particularly in sub-Saharan Africa, where > 13 million women of
childbearing age are infected (14). Progression of HIV disease is
usually accompanied by opportunistic infections (15), diminished
dietary intake (16), nutrient malabsorption (17), and metabolic and
hormonal alterations (18–21) that lead to depletion of both body
fat and fat-free compartments (22–25), resulting in weight loss. A
part of the adverse effect of HIV disease on pregnancy outcomes
is most likely mediated through the changes in maternal body
composition and the weight loss induced by the infection. However, the magnitude and determinants of these changes remain virtually unknown.
It was shown that daily consumption of multivitamin supplements by HIV-infected pregnant women resulted in significant
reductions in the risk of LBW [relative risk (RR): 0.56; 95% CI:
0.38, 0.82], severe preterm birth (RR: 0.61; 95% CI: 0.38,
0.96), IUGR (RR: 0.57; 95% CI: 0.39, 0.82), and fetal loss (RR:
0.61; 95% CI: 0.39, 0.94) and also improved the immunologic
profile of the mothers and increased their hemoglobin concentrations (26). In another study, vitamin A supplementation during
pregnancy was found to reduce the risk of preterm delivery among
HIV-infected women (27). If a positive effect of vitamin supplementation on gestational weight gain is also found, this could constitute a mechanistic explanation for the reduced risk of adverse
pregnancy outcomes. We examined this question in the context of
a randomized trial of multivitamin and vitamin A supplementation among HIV-infected pregnant women in Tanzania.
KEY WORDS
Weight gain, pregnancy, HIV infection, AIDS,
multivitamins, vitamin A, sub-Saharan Africa, maternal health,
prenatal nutrition
1
From the Departments of Nutrition (EV, GA, KEP, DJH, and WWF), Epidemiology (DS, DJH, and WWF), Biostatistics (DS), and Maternal and Child
Health (KEP), Harvard School of Public Health, Boston, and the Department
of Community Health, Muhimbili University College of Health Sciences, Dar
es Salaam, Tanzania (GM).
2
Supported by the National Institute of Child Health and Human Development (NICHD R01 32257) and the Fogarty International Center (NIH D43
TW00004). The National University of Colombia, the Fulbright Program, and
the Colombian National Science Foundation “Colciencias” provided partial
support to EV.
3
Address reprint requests to E Villamor, Department of Nutrition, Harvard
School of Public Health, 665 Huntington Avenue, Boston, MA 02115. E-mail:
[email protected].
Received July 23, 2001.
Accepted for publication December 7, 2001.
INTRODUCTION
Maternal nutritional status before and during gestation is one
of the strongest determinants of pregnancy outcomes. Gestational
weight gains below recommended amounts are common in developing countries (1–6) and account for a significant proportion of
the risk of low birth weight (LBW) (7–9) and preterm delivery
(10–12). Identifying potential interventions for improving gestational weight gain may be important in reducing the incidence of
adverse pregnancy outcomes.
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Am J Clin Nutr 2002;76:1082–90. Printed in USA. © 2002 American Society for Clinical Nutrition
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ABSTRACT
Background: The pattern of weight gain during pregnancy among
HIV-infected women is largely unknown. Multivitamin supplementation was shown to be effective in preventing adverse pregnancy outcomes among HIV-positive women. These protective
effects could be mediated in part by an improvement in the pattern of gestational weight gain.
Objective: We examined the effects of multivitamin and vitamin A
supplements on weight gain during the second and third trimesters
of pregnancy among HIV-infected women.
Design: We enrolled 1075 pregnant, HIV-1-positive women from
Dar es Salaam, Tanzania, in a randomized, placebo-controlled
trial. Using a 2-by-2 factorial design, we assigned each woman
to 1 of 4 regimens: multivitamins (thiamine, riboflavin, niacin,
folic acid, and vitamins B-6, B-12, C, and E), vitamin A, multivitamins including vitamin A, or placebo. The women took these
oral supplements daily and were weighed monthly until the end of
pregnancy.
Results: The mean rate of weight gain was 306 g/wk during the
second trimester and 247 g/wk during the third trimester. During
the third trimester, average weight gain was significantly greater
(by 304 g; 95% CI: 17, 590; P = 0.04) and the risk of low rate of
weight gain (≤ 100 g/wk) was significantly lower (relative risk:
0.73; 95% CI: 0.58, 0.93) in women who received multivitamins
than in women who did not. Multivitamins including vitamin A
were protective against low weight gain during the second
trimester compared with multivitamins alone.
Conclusion: Multivitamin supplementation during pregnancy
improves the pattern of weight gain among HIV-infected
women.
Am J Clin Nutr 2002;76:1082–90.
VITAMINS AND PREGNANCY WEIGHT GAIN IN HIV INFECTION
SUBJECTS AND METHODS
Study design and population
Laboratory investigations
Baseline tests were carried out to obtain a complete blood profile and routine urine and stool examinations and to test for malaria
and sexually transmitted diseases. Hemoglobin was measured by
using the CBC5 Coulter Counter (Coulter Corporation, Miami) or
the cyanmethemoglobin colorimetric method (Corning Inc, Corning, NY). Absolute counts of CD3+, CD4+, and CD8+ T lymphocyte
subsets were obtained with the FACS count system (Becton Dickinson, San Jose, CA). Serum retinol and vitamin E concentrations
were measured with HPLC, and serum selenium was measured with
atomic absorption analysis. Active syphilis was diagnosed if the
subject had positive results for sera antibodies on 2 tests: the VDRL
(Murex Diagnostic, Dartford, United Kingdom) and Treponema
Pallidum Hemagglutination (Fujirebio, Tokyo). Infections caused
by Neisseria gonorrhea, Candida albicans, and Trichomonas vaginalis were identified from vaginal and cervical swabs. The presence
of malaria parasites was ascertained from giemsa-stained thick- and
thin-smear blood films. Virtually all malaria infections were caused
by Plasmodium falciparum. Parasite density per cubic millimeter
was calculated from the number of malaria parasites identified per
200 leukocytes and each subject’s total leukocyte count/mm3 in
peripheral blood. Stool specimens were examined for the presence
of helminths (Ascaris lumbricoides, hookworm, Trichuris trichiura,
Strongyloides stercoralis, and Schistosoma mansoni) and protozoans (Giardia lamblia, Entamoeba histolytica, and Cryptosporidium parvum). Samples were examined macroscopically for worms
and microscopically for eggs, larvae, trophozoites, and cysts by
using saline and iodine wet mount and the formalin-ether concentration technique. A urine sample was examined for the presence of
Schistosoma haematobium.
Data analyses
Analyses of weight gain during pregnancy were limited to
women who had: 1) a singleton pregnancy, 2) a known date of
pregnancy outcome, and 3) ≥ 2 weight measurements between
enrollment and the end of gestation. Data from women with
adverse outcomes, such as abortion or stillbirth, were not excluded
from the analyses.
The distribution of baseline characteristics was compared across
treatment groups by using the Wilcoxon rank sum and KruskalWallis tests for continuous variables and 2 tests for proportions.
Intent-to-treat analyses were carried out to examine treatment
effects on both continuous and categorical weight gain outcomes. We examined the overall effect of multivitamin supplements by comparing women who received multivitamins alone
or in combination with vitamin A with women who did not
receive multivitamins, ie, those who received only vitamin A or
placebo. Similarly, to assess the overall effect of vitamin A supplements, we compared women who received vitamin A alone
or in combination with multivitamins with women who did not
receive vitamin A, ie, those who received only multivitamins or
placebo. We assessed the joint effect of multivitamins and vitamin A according to the methods described below.
Continuous outcomes
The continuous outcomes included overall and trimester-specific total weight gain and the rate of weight gain at various points
during pregnancy. We calculated overall total weight gain as the
arithmetic difference between the last weight recorded before the
end of pregnancy and weight at randomization. Trimester-specific
total weight gain was estimated separately for the subset of
women contributing ≥ 2 weight measurements between weeks 12
and 26 (second trimester) and for those with ≥ 2 weight measurements after week 26 (third trimester), as the difference between
the last and first weight measurements available during the interval. The effect of the supplements was then calculated as the difference in average weight change between treatment arms, overall and by trimesters. The 95% CI for the treatment effect was
estimated from a two-way analysis of variance model with robust
estimators of variance (30).
We also examined the effect of the supplements on the weekly
rate of weight gain by using a mixed-effects regression model for
repeated measures (PROC MIXED; SAS Institute Inc, Cary, NC):
WT ij = (0 + b i0) + 1MV i + 2VA i + (3 + b i1) GA ij +
4GA 2ij + 5MV i GA ij + 6VA i GA ij + 7MV i GA 2ij + 8VA i GA 2ij + 9MV i VA i + 10MV i VA i GA ij + 11MV i VA i GA 2ij + e ij
(1)
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Between April 1995 and July 1997, pregnant women who were
receiving prenatal care and tested positive for HIV infection at 1
of 4 clinics in Tanzania were invited to participate in a randomized clinical trial. The study aim was to test the effect of micronutrient supplements on vertical transmission and various health and
pregnancy outcomes. Detailed descriptions of the trial design were
published previously (26, 28). In brief, women eligible for enrollment were between 12 and 27 wk gestation according to the date
of the last menstrual period; they resided in Dar es Salaam and
intended to stay in the city until delivery and for ≥ 1 y thereafter.
As part of the prenatal screening, consent was sought for HIV-1
testing. Pretest and posttest counseling sessions were provided. We
tested HIV-1 serostatus by using an enzyme-linked immunosorbent
assay (Wellcozyme; Murex Biotech Ltd, Dartford, United Kingdom) and confirmed positive results with Western blot (Bio-Rad
Laboratories Ltd, Hertfordshire, United Kingdom). HIV-1-infected
women who consented to participate in the trial were randomly
assigned in a 2-by-2 factorial design to receive a daily oral dose of
1 of 4 regimens. The 4 regimens were as follows: multivitamins
(20 mg thiamine, 20 mg riboflavin, 25 mg vitamin B-6, 100 mg
niacin, 50 g vitamin B-12, 500 mg vitamin C, 30 mg vitamin E,
and 0.8 mg folic acid), vitamin A alone (30 mg -carotene plus
5000 IU preformed vitamin A), multivitamins including vitamin A,
and placebo. Subjects consumed the supplements or placebo from
enrollment until the end of the study (after delivery). The supplement and placebo tablets were indistinguishable. In addition, all
subjects received 120 mg ferrous iron and 5 mg folate daily. Weekly
malaria prophylaxis was also provided in accordance with the standard of prenatal care in Tanzania. Prenatal care and counseling were
provided throughout the study period. Antiretroviral medications
were unavailable in this setting at the time of the study.
Information on subject age, education, socioeconomic and marital status, and obstetric history was obtained at the first study visit
by trained personnel. Study physicians performed a complete
medical examination and collected blood, urine, stool, and vaginal specimens. Height, weight, and midupper arm circumference
were measured in light clothing by trained personnel using standardized methods and calibrated instruments (29). At every
monthly visit after enrollment, study personnel conducted a physical examination and obtained anthropometric measurements.
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VILLAMOR ET AL
Mixed effects models allow the use of all available measurements during follow-up ( j) for every subject ( i), adjusting
for the within-person correlation of measurements in the estimation of the variance (31). The effect of multivitamins (MV)
at any given week of gestation (GA) was estimated as the difference ( 5 + 7 ) in the rate of weight (WT) gain between
women who received multivitamins and those who did not.
The effect of vitamin A (VA) was estimated as ( 6 + 8 ),
whereas a potential joint effect of multivitamins and vitamin A
was assessed from a three-way interaction term between multivitamins, vitamin A, and gestational age. A quadratic term
for time (GA 2) has been found appropriate to describe nonlinear patterns of weight gain during pregnancy (32), and was
statistically significant in this population. CIs for the treatment effect were computed by using robust estimates of variance. Average weight gain curves were fitted by using
restricted cubic splines (33).
Categorical outcomes
We considered the effect of supplements on 1) the risk of low
total weight gain, 2) the risk of low rate of weight gain, and 3) the
risk of weight loss. Low total weight gain, overall and by
trimesters, was defined as a weight difference between the last and
first measurements that was below the 25th percentile of the distribution for total or trimester-specific weight gain, respectively.
For the definitions of low rate of weight gain and weight loss as
categorical outcomes, the rate of weight gain was estimated separately for the second and third trimesters as the regression slope
of every individual’s set of weight measurements on week of gestation during the trimester-specific interval. Low rate of weight
gain was defined as a regression slope below the 25th percentile
of the trimester-specific distribution, and weight loss was defined
as a slope ≤ 0. To test the effect of supplements on these categorical outcomes, we calculated RRs with 95% CIs from 2 n tables,
and we used the chi-square test.
We also assessed whether the effect of supplements was
modified by baseline characteristics, including midupper arm
circumference, CD4+ and CD8+ T cell counts, clinical stage of
HIV disease according to World Health Organization criteria
(34), hemoglobin concentration, malaria infection, intestinal
parasitoses, sexually transmitted diseases, season at conception, and serum retinol, vitamin E, and selenium concentrations. The statistical significance of all interactions was tested
with the likelihood ratio test. Analyses were carried out with
Statistical Analyses System software, version 8 (SAS Institute
Inc, Cary, NC).
The study protocol was approved by the Research and Publications Committee of Muhimbili University College of
Health Sciences, the Ethical Committee of the National AIDS
Control Program of the Tanzanian Ministry of Health, and the
Institutional Review Board of the Harvard School of Public
Health. All subjects gave their informed consent to participate in the study.
RESULTS
A total of 1075 HIV-infected, pregnant women were randomly
assigned to a treatment group; 6 of the women died before delivery. Twin pregnancies (n = 24), women with unknown date of
pregnancy outcome (n = 42), and mothers with < 2 weight measurements during pregnancy (n = 46) were excluded from the
analyses of weight gain; thus, results are shown for 957 women
(Figure 1). The distribution of baseline covariates, including
sociodemographic characteristics of the mother, indicators of
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FIGURE 1. Profile of the study population in the Tanzania Trial of Vitamins.
VITAMINS AND PREGNANCY WEIGHT GAIN IN HIV INFECTION
1085
TABLE 1
Maternal characteristics at baseline according to treatment assignment1
Characteristic
Vitamin A only
(n = 239)
Multivitamins only
(n = 237)
20.4 ± 3.4
24.8 ± 4.8
85.9 [201]
90.2 [211]
25.4 [59]
30.6 [71]
517 ± 260
20.4 ± 3.4
24.6 ± 5.0
87.9 [210]
86.2 [206]
25.2 [60]
37.2 [89]
581 ± 324
20.8 ± 3.1
24.6 ± 4.7
83.6 [198]
88.6 [210]
26.6 [63]
36.0 [85]
495 ± 243
20.4 ± 3.2
24.9 ± 4.6
88.7 [219]
88.3 [218]
24.1 [60]
31.3 [77]
510 ± 250
9.4 [22]
20.5 [48]
56.8 [133]
13.3 [31]
156.4 ± 5.9
56.3 ± 8.7
25.4 ± 2.9
0.90 ± 0.41
9.8 ± 3.0
0.130 ± 0.03
449 ± 263
767 ± 366
97 ± 17
23.1 [54]
13.0 [31]
16.7 [40]
53.1 [127]
17.2 [41]
156.7 ± 6.2
57.6 ± 9.7
25.7 ± 3.0
0.85 ± 0.33
9.8 ± 3.2
0.127 ± 0.02
440 ± 273
751 ± 343
96 ± 18
28.4 [68]
13.5 [32]
16.0 [38]
54.0 [128]
16.5 [39]
156.8 ± 5.4
58.2 ± 9.5
25.8 ± 2.9
0.84 ± 0.33
9.7 ± 3.0
0.125 ± 0.02
451 ± 255
723 ± 324
95 ± 17
20.7 [49]
13.8 [34]
17.4 [43]
56.3 [139]
12.6 [31]
156.5 ± 5.9
57.3 ± 8.4)
25.6 ± 2.7
0.86 ± 0.29
10.4 ± 3.2
0.126 ± 0.02
438 ± 242
764 ± 330
94 ± 17
24.7 [61]
15.8 [37]
4.3 [9]
11.5 [24]
5.3 [11]
6.2 [14]
25.9 [60]
18.5 [44]
4.3 [9]
9.3 [19]
3.9 [8]
4.7 [11]
21.0 [50]
17.8 [42]
5.7 [12]
12.5 [26]
4.8 [10]
8.8 [20]
27.5 [65]
22.7 [56]
7.9 [17]
13.0 [28]
4.2 [9]
5.0 [12]
25.2 [62]
Completed ≥ 8 y of formal schooling.
Mothers who provided part or all of the houshold income; those who did not were solely supported by the partner or another person.
4
Average household income spent on food per person per day, estimated by dividing the total amount of money spent on food by the number of household members. The exchange rate for 500 shillings was US$0.62 at the time of data collection. The difference in median household income spent on food
per person per day between treatments was significant, P = 0.05 (Wilcoxon rank-sum test).
5
The month at conception was estimated from the reported date of the last menstrual period plus 14 d.
6
Women in stages 2 or 3 at recruitment according to the World Health Organization staging system of HIV disease.
2
3
nutritional and immunologic status, stage of HIV disease, and
presence of selected infectious diseases did not differ significantly
across treatment regimens (Table 1). For each treatment arm,
mean gestational age at randomization was 20 wk, and the last
visit occurred at week 36, on average. The mean number of weight
measurements per woman was 4.7, independent of treatment
assignment, and 94% of the mothers had ≥ 3 measurements. We
reported previously that compliance with treatment during pregnancy was high, as assessed by pill count (median: 90% by the
time of delivery) (26). In addition, in a subset of 125 women, evidence of high compliance was reported. In the group that received
vitamin A, the plasma -carotene concentration increased significantly from 0.23 mol/L at baseline to 1.71 mol/L at delivery,
whereas the values were 0.22 mol/L at baseline and 0.25 mol/L
at delivery in the group not given vitamin A (28).
Total weight gain from randomization to the last visit during
pregnancy was 4.0 ± 3.2 kg. The estimated average rate of
weight gain during the second trimester, 306 g/wk (95% CI: 283,
329), was significantly higher than that during the third
trimester, 247 g/wk (95% CI: 230, 263). This indicates that the
pattern of weight gain in this population did not follow a linear
trend. The incidence of weight loss was 14.2% (n = 94) during
the second trimester and 15.7% (n = 131) during the third
trimester. The subsets of women with ≥ 2 weight measurements
in the second and third trimesters were comparable to each other
with respect to baseline characteristics.
Supplementation with multivitamins significantly increased
weight gain during the third trimester (Table 2). The average
total effect was 304 g (95% CI: 17, 590; P = 0.04). We also
observed a positive effect on the rate of weight gain, particularly after week 26 of gestation (Figure 2A). By week 36, mothers receiving multivitamins were gaining an average of 39 g/wk
more than women not receiving multivitamins. During the third
trimester, multivitamin supplements resulted in significantly
reduced risks of low total weight gain (RR: 0.70; 95% CI: 0.55,
0.90; P = 0.005), weight loss (RR: 0.69; 95% CI: 0.50, 0.95;
P = 0.02), and low rate of weight gain (RR: 0.73; 95% CI: 0.58,
0.93; P = 0.01).
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Gestational age at recruitment (wk)
Age (y)
Completed primary school (%)2
Lives with partner (%)
Contributes to household income (%)3
Nulliparous (%)
Money spent on food (Tanzanian shillings)4
Season at conception (%)5
January–February (Dry)
March–May (Long rains)
June–October (Dry)
November–December (Short rains)
Height (cm)
Weight (kg)
Midupper arm circumference (cm)
Serum retinol (mol/L)
Serum vitamin E (mol/L)
Serum selenium (ppm)
CD4+ cell count (cells/mm3)
CD8+ cell count (cells/mm3)
Hemoglobin (g/L)
Symptomatic HIV disease (%)6
Infectious diseases (%)
Malaria
Ascaris
Hookworm
Cryptosporidium
Syphilis
Trichomonas vaginalis
1–
x ± SD; n in brackets.
Multivitamins
and vitamin A
(n = 247)
Placebo
(n = 234)
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VILLAMOR ET AL
TABLE 2
Effects of multivitamins and vitamin A supplements on gestational weight gain outcomes
Outcome
Vitamin A
only
3914 ± 3474 3962 ± 3134
1953 ± 1886 1793 ± 1766
1855 ± 2187 1939 ± 2021
Multivitamins Multivitamins
only
and vitamin A
Difference,
MV vs no MV1
Difference,
VA vs no VA2
4041 ± 2975 4048 ± 3221 107 (299, 512)
1613 ± 1961 1802 ± 1697 161 (117, 438)
2272 ± 1954 2131 ± 2302 304 (17, 590)
28 (434, 377)
13 (292, 266)
31 (256, 319)
295 ± 31
320 ± 30
309 ± 30
283 ± 28
13 (71, 46)
3 (62, 55)
254 ± 14
198 ± 21
260 ± 12
216 ± 20
266 ± 12
247 ± 19
262 ± 12
245 ± 21
7 (17, 32)
39 (1, 79)
1 (25, 24)
9 (49, 31)
28.6 [67]8
20.9 [34]
29.2 [59]
25.1 [60]
26.1 [42]
28.5 [59]
22.8 [54]
29.6 [47]
18.9 [40]
25.9 [64]
21.1 [38]
21.8 [47]
0.91 (0.73, 1.13)
1.07 (0.82, 1.40)
0.70 (0.55, 0.90)
0.99 (0.80, 1.23)
0.93 (0.71, 1.22)
1.05 (0.83, 1.33)
11.7 [19]
18.8 [38]
15.5 [25]
18.4 [38]
19.5 [31]
9.4 [20]
10.6 [19]
16.2 [35]
1.09 (0.75, 1.58)
0.69 (0.50, 0.95)
0.83 (0.57, 1.21)
1.23 (0.90, 1.69)
22.7 [37]
28.7 [58]
24.8 [40]
30.0 [62]
30.2 [48]
20.3 [43]
22.2 [40]
22.7 [49]
1.09 (0.84, 1.42)
0.73 (0.58, 0.93)
0.89 (0.68, 1.16)
1.08 (0.85, 1.36)
1
Mean difference between women receiving multivitamins (MV; multivitamins only or multivitamins plus vitamin A) and women not receiving multivitamins (vitamin A only or placebo); 95% CI in parentheses.
2
Mean difference between women receiving vitamin A (VA; vitamin A only or multivitamins plus vitamin A) and women not receiving vitamin A (multivitamins only or placebo); 95% CI in parentheses.
3–
x ± SD.
4
From 20 to 36 wk of gestation, on average.
5
From a repeated-measures mixed-effects model that included weight as the dependent variable and time, treatment, and their interaction term as predictors. A quadratic term for week of gestation was included to account for the nonlinearity of the weight gain pattern.
6–
x ± SE.
7
Defined as below the 25th percentile of the weight change distribution.
8
n in brackets.
9
Subject-specific slope of the regression of weight on gestational age ≤ 0.
10
Subject-specific slope of the regression of weight on gestational age < 25th percentile of the trimester-specific distribution of slopes.
Vitamin A supplements did not have a significant effect on
weight gain outcomes overall or during the third trimester (Figure 2B). However, there was a positive, significant interaction
between vitamin A supplements and multivitamins during the second trimester (P = 0.04). Women receiving both vitamin A and
multivitamins had a 29% lower risk of low total weight gain than
did women who received multivitamins alone (RR: 0.71; 95% CI:
0.49, 1.03). There was no effect of vitamin A alone compared with
placebo (RR: 1.25; 95% CI: 0.84, 1.86).
We also examined whether the protective effect of multivitamins during the third trimester differed between strata of certain
baseline characteristics that were potential effect modifiers (eg,
stage of HIV disease; Table 3). The protective effect tended to
be greater among women in stage 1 of HIV disease compared
with women in stage 2 or higher (P for interaction = 0.12). The
protective effect also tended to be greater when the approximate
date of conception coincided with the first dry season of the year
(P for interaction = 0.11). During the second trimester, vitamin A
supplementation was associated with a significant reduction in
the risk of low rate of weight gain among mothers with hemoglobin concentration ≥ 110 g/L (RR: 0.31; 95% CI: 0.14, 0.68)
but not among mothers with hemoglobin < 110 g/L (RR: 1.08;
95% CI: 0.81, 1.45) (P for interaction = 0.001). There were no
significant interactions between the treatments and other potential effect modifiers including the mother’s level of education,
CD4+ or CD8+ cell counts, malaria infection, intestinal parasites,
sexually transmitted diseases, and plasma concentrations of vitamin A, vitamin E, or selenium.
DISCUSSION
We described the pattern of weight gain during pregnancy
among HIV-infected women in Tanzania within the context of a
randomized clinical trial. Multivitamin supplementation resulted
in a small increase in maternal weight gain during the third
trimester of pregnancy (304 g; 95% CI: 17, 590). Multivitamins
were also associated with a significant 30% reduction in the risk
of weight loss or low weight gain after week 27 of gestation. It is
not likely that these results are attributable to either chance or confounding, given the large sample size and the randomized nature
of the trial, respectively. The distribution of baseline covariates in
each trimester subset was homogeneous across treatment arms,
implying an absence of selection bias.
Little information is available on the relation between the
micronutrient status of the mother and weight gain during pregnancy, especially among HIV-infected women. Some evidence of
a beneficial association has been reported from an observational
study conducted in the United States (35) and from trials performed in Greece (36) and Chile (37), all presumably among HIVnegative women. In the US study of prenatal micronutrient supplements, the proportion of mothers with inadequate weight gain
was significantly higher among women who did not take prenatal
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Total weight gain (g)3
Overall: from baseline to last visit4
Second trimester: weeks 12 to 26
Third trimester: week 27 to delivery
Estimated rate of weight gain (g/wk)5,6
Second trimester (week 17)
Third trimester
Week 27
Week 36
Risk of low total weight gain (%)7
Overall: from baseline to last visit (< 1.8 kg)4
Second trimester: weeks 12 to 26 (< 0.7 kg)
Third trimester: week 27 to delivery (< 0.7 kg)
Risk of weight loss (%)9
During second trimester
During third trimester
Risk of low rate of weight gain (%)10
During second trimester (≤ 130 g/wk)
During third trimester (≤ 100 g/wk)
Placebo
VITAMINS AND PREGNANCY WEIGHT GAIN IN HIV INFECTION
supplements (28.7%) than among those who did (22.0%) (35). The
mean rate of weight gain increased monotonically and significantly according to the total amount of folate consumed during
pregnancy (38). In a trial conducted in Greece, pregnant women
assigned to receive biweekly counseling about selecting foods
with high nutrient value and using techniques for reducing nutrient loss during preparation had higher total weight gain than did
the control subjects (11.3 and 10.3 kg, respectively; P < 0.05) (36).
This coincided with increases in serum -carotene concentrations
during late pregnancy and serum vitamin C during early and late
pregnancy in the intervention group. In a supplementation trial
conducted in Santiago, Chile, mothers were randomly assigned to
receive a milk-based product fortified with thiamine, pyridoxine,
niacin, folate, zinc, iron, copper, iodine, and vitamins A, C, E,
and D or a nonfortified supplement of powdered milk (37). Total
weight gain during pregnancy was significantly greater for mothers receiving the fortified product than for those receiving unfortified powdered milk (12.3 compared with 11.3 kg; P < 0.05). The
authors suggested that this effect could be attributable to the
micronutrients in the fortified product, because the total energy,
fat, and protein contents were higher in the unfortified powered
milk. However, none of these 3 studies were designed to specifically address the effect of micronutrient supplementation on
weight gain. Regarding the trials, one cannot conclude that the
vitamins definitely had a causal effect, and in the observational
study, only unadjusted associations were presented, opening the
possibility of confounding by intakes of other nutrients or total
energy, socioeconomic status, or other variables.
In our study, the effect of multivitamins on maternal weight
gain was limited to the third trimester and was relatively modest
(300 g between week 27 and term). Although this overall effect
may have limited clinical relevance, our data suggest that multivitamin supplements may be particularly efficacious in preventing severe impairments in the weight-gain patterns of HIVinfected women, including weight loss and very low weight gain.
Some studies among presumably HIV-negative women have
linked low weight gain or weight loss during the third trimester
of pregnancy with adverse pregnancy outcomes that include low
birth weight and premature birth. In the Dutch Famine Birth
Cohort Study, low weight gain (< 0.5 kg/wk) or weight loss during the third trimester were related to lower birth weight, length,
and ponderal index (39). In women from rural Malawi, the rate of
weight gain during late pregnancy (defined as after week 32) was
more strongly predictive of birth weight and length than was the
weight-gain rate during early to mid pregnancy (40). In the same
population, lower birth weight and length were observed among
the offspring of women exposed to seasonal nutritional stress during the third trimester, but not during the second trimester (41).
In a group of low-income women in the United States, the risk of
preterm delivery was found to be higher in those with low weight
gain during the third trimester (after week 27) but not during the
first or second trimester (42).
The observed protective effect of multivitamins against low
maternal weight gain in our study population could be a mechanistic explanation for a protective effect of multivitamins against
adverse pregnancy outcomes reported previously in this same group
of mothers (26). Also, an effect of vitamin supplements on weight
gain during the second trimester of pregnancy cannot be ruled out.
In our study, the limitation of the beneficial effect to the third
trimester suggests that it may take weeks for the correction of baseline deficiencies and the activation of regulatory mechanisms to
occur; therefore, supplementation should be implemented as early
as possible during pregnancy. Improvement of second trimester
weight gain could also have a positive effect on birth outcomes, as
was shown in various cohorts in the United States (43–45).
The trimester-specific rates of weight gain in this group of
HIV-infected mothers were generally below the average reported
in presumably HIV-negative populations in developed countries
(8, 46, 47) but were comparable to those documented in undernourished women of undetermined HIV status in developing
countries (5, 6). HIV infection may be related to poor patterns of
gestational weight gain in many present-day populations,
although the evidence is limited. One small study performed in
Rwanda showed that total weight gain between the first visit and
the last visit before delivery was lower for HIV-positive women
Downloaded from ajcn.nutrition.org by guest on June 11, 2014
FIGURE 2. Effect of multivitamin (A) and vitamin A (B) supplements
on weight gain during the third trimester of pregnancy. The average trends
of weight gain were estimated by using cubic splines (33). The multivitamin group (n = 473) included those subjects assigned to receive multivitamins only or multivitamins plus vitamin A. In this group, the rate of
weight gain became progressively higher over time (P = 0.06 for the rate
difference at week 36 according to the Wald test). The “no multivitamins”
group included those subjects assigned to receive placebo or vitamin A
only (n = 484). The vitamin A group (n = 471) included those subjects
assigned to receive vitamin A only or vitamin A plus multivitamins. The
“no vitamin A” group included those subjects assigned to receive placebo
or multivitamins only (n = 486). No significant effect was observed.
1087
1088
VILLAMOR ET AL
TABLE 3
Effects of multivitamins (MV) on the risk of low rate of weight gain (≤ 100 g/wk) during the third trimester of pregnancy, by strata of potential effect
modifiers at baseline1
Modifier
Relative risk3
P for interaction4
0.11
13/44
22/77
71/228
14/60
5/62
19/69
57/234
11/63
0.27 (0.10, 0.71)
0.96 (0.57, 1.62)
0.78 (0.58, 1.05)
0.75 (0.37, 1.52)
88/310
32/99
63/337
29/91
0.66 (0.50, 0.87)
0.99 (0.65, 1.49)
24/51
95/354
14/54
78/370
0.55 (0.32, 0.94)
0.79 (0.51, 1.02)
62/218
28/108
53/232
24/117
0.80 (0.59, 1.10)
0.79 (0.49, 1.28)
41/152
50/175
43/187
34/162
0.85 (0.59, 1.23)
0.73 (0.50, 1.07)
20/80
100/327
8/65
84/362
0.49 (0.23, 1.04)
0.76 (0.59, 0.97)
98/336
22/72
69/346
23/82
0.68 (0.52, 0.89)
0.92 (0.56, 1.50)
0.12
0.24
0.96
0.70
0.27
0.30
1
Cutoffs for CD4+ cell counts, serum retinol, and hemoglobin were established according to commonly used references. The median of the distribution
was used to determine the cutoff for serum vitamin E. WHO, World Health Organization.
2
No MV includes women assigned to vitamin A only or placebo. MV includes women assigned to multivitamins plus vitamin A or multivitamins only.
3
95% CI in parentheses.
4
Likelihood ratio test for interaction.
5
Malaria parasites were present in peripheral blood at prenatal visit.
than for HIV-negative women, but the slope of weight gain was
not significantly different (48). In a study conducted in Italy, total
weight gain among opiate addicts was slightly higher for HIVpositive women than for HIV-negative women, but among nonaddicts, HIV-negative women gained significantly more weight
than did HIV-positive women (49).
Poor gestational weight gain among HIV-infected women
could be explained by an HIV-related impairment of fetal and
placental growth (13, 50) or by an effect of the infection on
maternal body composition (51). Multivitamin supplements
could ameliorate these adverse effects through several mechanisms. Regular use of multivitamins or B vitamins and higher
dietary intakes of riboflavin, thiamin, and niacin were linked to
slower progression of HIV disease (52–54). This effect may be
mediated by an improvement in immune status, as documented
in the Tanzania trial (26), which would in turn reduce the incidence and severity of secondary infections. In animal and human
studies, vitamin B-6 deficiency was associated with alterations
in the differentiation of lymphocytes, decreased antibody production, and delayed hypersensitivity responses (55), and serum
concentrations correlated well with natural killer cell cytotoxicity (56). In animals, riboflavin and vitamin B-12 deficiencies
are related to impaired production of antibodies, and low vitamin B-12 concentrations are associated with diminished expression of T cells and decreased neutrophil function (55, 57).
Administration of vitamins C and E reduced HIV viral load and
oxidative stress in a supplementation trial (58). Secondary infections among HIV-infected patients may lead to wasting through
various mechanisms including increased secretion of cytokines,
faster viral replication, decreased intake and absorption of nutrients, and increased nutrient losses and utilization (59). Enhancement of immune function mediated by micronutrient supplementation might lessen the burden of this cascade by improving
the immune response against opportunistic infections.
In conclusion, HIV infection is likely to impair the pattern of
weight gain during pregnancy in women from sub-Saharan Africa.
Multivitamin supplementation could be a useful method of ameliorating this effect and, consequently, improving pregnancy outcomes. Additional research is needed to investigate the effects that
HIV-induced changes in body composition may have on fetal loss,
prematurity, intrauterine growth retardation, vertical transmission,
and infant and maternal mortality. Also, the ways that pregnancy
may affect HIV-related wasting deserve further examination. Studies should also investigate the effect of reducing weight loss on
the postpartum health and survival of HIV-infected women.
Finally, the potential beneficial effects of micronutrient supplementation on gestational weight gain should be examined in
women who are not infected with HIV.
We thank the women who participated in this project; the study coordinator,
Illuminata Ballonzi; the study physicians, Heavington Mshiu, Josephine Ballat,
and Vensesla Sakwari; and the research assistants, laboratory technicians,
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Season at conception
January–February (Dry)
March–May (Long rains)
June–October (Dry)
November–December (Short rains)
WHO stage of HIV disease
Asymptomatic (stage 1)
Symptomatic (stage ≥ 2)
CD4+ cell count
0–199 cells/mm3
≥ 200 cells/mm3
Serum retinol
≥ 0.70 mol/L
< 0.70 mol/L
Serum vitamin E
≥ 9.7 mol/L
< 9.7 mol/L
Hemoglobin
≥ 110 g/L
< 110 g/L
Malaria
No
Yes5
No. of subjects with low rate of
weight gain/total subjects at risk
No MV2
MV2
VITAMINS AND PREGNANCY WEIGHT GAIN IN HIV INFECTION
nurses, midwives, and administrative staff who made the study possible. We
also acknowledge the valuable input from various colleagues including Ellen
Hertzmark, Michele Dreyfuss, and Miguel Hernán.
22.
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