Effect of Providing Vitamin Supplements to Human Immunodeficiency Virus-Infected, Lactating Mothers on the Child's Morbidity and CD4+ Cell Counts
Identifieur interne : 001031 ( Istex/Corpus ); précédent : 001030; suivant : 001032Effect of Providing Vitamin Supplements to Human Immunodeficiency Virus-Infected, Lactating Mothers on the Child's Morbidity and CD4+ Cell Counts
Auteurs : Wafaie W. Fawzi ; Gernard I. Msamanga ; Ruilan Wei ; Donna Spiegelman ; Gretchen Antelman ; Eduardo Villamor ; Karim Manji ; David HunterSource :
- Clinical Infectious Diseases [ 1058-4838 ] ; 2003-04-15.
Abstract
A total of 1078 human immunodeficiency virus (HIV) type 1-infected women from Tanzania were randomized in a placebo-controlled trial using a factorial design to examine the effects of supplementation with vitamin A (preformed vitamin A and beta carotene) and/or multivitamins (vitamins B, C, and E). Supplements were given during pregnancy and lactation. Children of women in the multivitamin arms had a significantly lower risk of diarrhea than did those in the no-multivitamin arm (P = .03). The mean CD4+ cell count was 151 cells/μL higher among children in the multivitamin arms than among those in the no-multivitamin arm (P = .0006). HIV-positive children experienced a benefit apparently similar to that in HIV-negative children (P = .34, by test for interaction). Maternal receipt of vitamin A significantly reduced the risk that the child would have cough with a rapid respiratory rate, a proxy for pneumonia (P = .03), but receipt of vitamin A had no effect on diarrhea or CD4+ cell count. Provision of multivitamin supplements (including those with vitamins B, C, and E) to HIV-infected, lactating women may be a low-cost intervention to improve their children's health.
Url:
DOI: 10.1086/374223
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ISTEX:33032B8BCAEEB16E237F77AF24216D8FE4F907E3Le document en format XML
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Supplements were given during pregnancy and lactation. Children of women in the multivitamin arms had a significantly lower risk of diarrhea than did those in the no-multivitamin arm (P = .03). The mean CD4+ cell count was 151 cells/μL higher among children in the multivitamin arms than among those in the no-multivitamin arm (P = .0006). HIV-positive children experienced a benefit apparently similar to that in HIV-negative children (P = .34, by test for interaction). Maternal receipt of vitamin A significantly reduced the risk that the child would have cough with a rapid respiratory rate, a proxy for pneumonia (P = .03), but receipt of vitamin A had no effect on diarrhea or CD4+ cell count. Provision of multivitamin supplements (including those with vitamins B, C, and E) to HIV-infected, lactating women may be a low-cost intervention to improve their children's health.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Wafaie W. 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W.</forename><surname>Fawzi</surname></persName><email>mina@hsph.harvard.edu</email><email>mina@hsph.harvard.edu</email><affiliation>Department of Nutrition, Boston, Massachusetts</affiliation><affiliation>Department of Epidemiology, Boston, Massachusetts</affiliation><affiliation>Reprints or correspondence: Dr. Wafaie Fawzi, Dept. of Nutrition, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Gernard I.</forename><surname>Msamanga</surname></persName><affiliation>Department of Community Health, Tanzania</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Ruilan</forename><surname>Wei</surname></persName><affiliation>Department of Nutrition, Boston, Massachusetts</affiliation></author><author xml:id="author-0003"><persName><forename type="first">Donna</forename><surname>Spiegelman</surname></persName><affiliation>Department of Epidemiology, Boston, Massachusetts</affiliation><affiliation>Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts</affiliation></author><author xml:id="author-0004"><persName><forename type="first">Gretchen</forename><surname>Antelman</surname></persName><affiliation>Department of Nutrition, Boston, Massachusetts</affiliation><affiliation>Department of Community Health, Tanzania</affiliation></author><author xml:id="author-0005"><persName><forename type="first">Eduardo</forename><surname>Villamor</surname></persName><affiliation>Department of Nutrition, Boston, Massachusetts</affiliation><affiliation>Department of Community Health, Tanzania</affiliation></author><author xml:id="author-0006"><persName><forename type="first">Karim</forename><surname>Manji</surname></persName><affiliation>Department of Paediatrics and Child Health, Muhimbili University College of Health Sciences, Dar es Salaam, Tanzania</affiliation></author><author xml:id="author-0007"><persName><forename 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Supplements were given during pregnancy and lactation. Children of women in the multivitamin arms had a significantly lower risk of diarrhea than did those in the no-multivitamin arm (P = .03). The mean CD4+ cell count was 151 cells/μL higher among children in the multivitamin arms than among those in the no-multivitamin arm (P = .0006). HIV-positive children experienced a benefit apparently similar to that in HIV-negative children (P = .34, by test for interaction). Maternal receipt of vitamin A significantly reduced the risk that the child would have cough with a rapid respiratory rate, a proxy for pneumonia (P = .03), but receipt of vitamin A had no effect on diarrhea or CD4+ cell count. Provision of multivitamin supplements (including those with vitamins B, C, and E) to HIV-infected, lactating women may be a low-cost intervention to improve their children's health.</p></abstract></profileDesc><revisionDesc><change when="2003-04-15">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/33032B8BCAEEB16E237F77AF24216D8FE4F907E3/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup, element #text not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article">
<front>
<journal-meta>
<journal-id journal-id-type="hwp">cid</journal-id>
<journal-id journal-id-type="publisher-id">cid</journal-id>
<journal-title>Clinical Infectious Diseases</journal-title>
<abbrev-journal-title>Clinical Infectious Diseases</abbrev-journal-title>
<issn pub-type="ppub">1058-4838</issn>
<issn pub-type="epub">1537-6591</issn>
<publisher>
<publisher-name>The University of Chicago Press</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.1086/374223</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>HIV/AIDS</subject>
<subj-group subj-group-type="heading">
<subject>Major Articles</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Effect of Providing Vitamin Supplements to Human Immunodeficiency Virus-Infected, Lactating Mothers on the Child's Morbidity and CD4<sup>+</sup> Cell Counts</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Fawzi</surname>
<given-names>Wafaie W.</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
<xref rid="aff2" ref-type="aff">2</xref>
<xref rid="cor1" ref-type="corresp"></xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Msamanga</surname>
<given-names>Gernard I.</given-names>
</name>
<xref rid="aff4" ref-type="aff">4</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Wei</surname>
<given-names>Ruilan</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Spiegelman</surname>
<given-names>Donna</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
<xref rid="aff3" ref-type="aff">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Antelman</surname>
<given-names>Gretchen</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
<xref rid="aff4" ref-type="aff">4</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Villamor</surname>
<given-names>Eduardo</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
<xref rid="aff4" ref-type="aff">4</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Manji</surname>
<given-names>Karim</given-names>
</name>
<xref rid="aff5" ref-type="aff">5</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Hunter</surname>
<given-names>David</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<aff id="aff1"><label>1</label><institution>Department of Nutrition</institution>, <addr-line>Boston, Massachusetts</addr-line></aff>
<aff id="aff2"><label>2</label><institution>Department of Epidemiology</institution>, <addr-line>Boston, Massachusetts</addr-line></aff>
<aff id="aff3"><label>3</label><institution>Department of Biostatistics, Harvard School of Public Health</institution>, <addr-line>Boston, Massachusetts</addr-line></aff>
<aff id="aff4"><label>4</label><institution>Department of Community Health</institution>, <addr-line>Tanzania</addr-line></aff>
<aff id="aff5"><label>5</label><institution>Department of Paediatrics and Child Health, Muhimbili University College of Health Sciences, Dar es Salaam</institution>, <addr-line>Tanzania</addr-line></aff>
</contrib-group>
<author-notes>
<corresp id="cor1">Reprints or correspondence: Dr. Wafaie Fawzi, Dept. of Nutrition, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115 (<email>mina@hsph.harvard.edu</email>).</corresp>
</author-notes>
<pub-date pub-type="ppub">
<day>15</day>
<month>4</month>
<year>2003</year>
</pub-date>
<volume>36</volume>
<issue>8</issue>
<fpage>1053</fpage>
<lpage>1062</lpage>
<history>
<date date-type="received">
<day>28</day>
<month>10</month>
<year>2002</year>
</date>
<date date-type="accepted">
<day>10</day>
<month>1</month>
<year>2003</year>
</date>
</history>
<copyright-statement>© 2003 by the Infectious Diseases Society of America</copyright-statement>
<copyright-year>2003</copyright-year>
<abstract>
<p>A total of 1078 human immunodeficiency virus (HIV) type 1-infected women from Tanzania were randomized in a placebo-controlled trial using a factorial design to examine the effects of supplementation with vitamin A (preformed vitamin A and beta carotene) and/or multivitamins (vitamins B, C, and E). Supplements were given during pregnancy and lactation. Children of women in the multivitamin arms had a significantly lower risk of diarrhea than did those in the no-multivitamin arm (<italic>P</italic> = .03). The mean CD4<sup>+</sup> cell count was 151 cells/μL higher among children in the multivitamin arms than among those in the no-multivitamin arm (<italic>P</italic> = .0006). HIV-positive children experienced a benefit apparently similar to that in HIV-negative children (<italic>P</italic> = .34, by test for interaction). Maternal receipt of vitamin A significantly reduced the risk that the child would have cough with a rapid respiratory rate, a proxy for pneumonia (<italic>P</italic> = .03), but receipt of vitamin A had no effect on diarrhea or CD4<sup>+</sup> cell count. Provision of multivitamin supplements (including those with vitamins B, C, and E) to HIV-infected, lactating women may be a low-cost intervention to improve their children's health.</p>
</abstract>
</article-meta>
</front>
<body>
<p>As of the end of 2001, ∼40 million people worldwide were living with HIV infection or AIDS [<xref rid="ref1" ref-type="bibr">1</xref>]. New infections totaled 5 million in 2001, and there were 1.8 million newly infected women and 800,000 newly infected children. The great majority of new infections and concomitant morbidities occur among populations in sub-Saharan Africa and south and Southeast Asia. Infant and child mortality and morbidity are major public health problems in these countries, with diarrheal and respiratory diseases being important causes [<xref rid="ref2" ref-type="bibr">2</xref>]. In addition, these children are at risk for micronutrient deficiencies [<xref rid="ref3" ref-type="bibr">3</xref>, <xref rid="ref4" ref-type="bibr">4</xref>]. Particularly vulnerable are children born to HIV-infected women, regardless of whether the children are themselves infected.</p>
<p>Periodic vitamin A supplementation reduced child mortality rates in community-based, placebo-controlled trials involving children aged >6 months who were presumed to be HIV negative [<xref rid="ref5" ref-type="bibr">5</xref>, <xref rid="ref6" ref-type="bibr">6</xref>]. Vitamin A supplementation was also beneficial in reducing mortality and morbidity among HIV-infected children in Tanzania and South Africa [<xref rid="ref7" ref-type="bibr">7</xref>–<xref rid="ref9" ref-type="bibr">9</xref>]. However, the effects of use of other vitamins on child morbidity and mortality have not been previously examined, although deficiencies in these nutrients are associated with impaired immunity [<xref rid="ref10" ref-type="bibr">10</xref>, <xref rid="ref11" ref-type="bibr">11</xref>] and are probably associated with adverse health outcomes in children.</p>
<p>We conducted a randomized, double-blind, placebo-controlled trial involving HIV-infected pregnant women in Tanzania to examine the effects of administering supplementation with vitamin A and/or multivitamins (excluding vitamin A) on vertical transmission of HIV-1 and other health outcomes among women and children. We have previously reported that use of multivitamin supplements resulted in significant reductions in the risks of adverse pregnancy outcomes (i.e., fetal death, low birth weight, and severe prematurity) [<xref rid="ref12" ref-type="bibr">12</xref>], in transmission of the virus through breast-feeding, and in the mortality rate among children born to mothers who were nutritionally and immunologically compromised [<xref rid="ref13" ref-type="bibr">13</xref>]. In this article, we examine the efficacy of the supplements on the risks of diarrhea and respiratory infections and on CD4<sup>+</sup> cell counts in the first 2 years of life among children from the same study population.</p>
<sec sec-type="patients|materials|methods" id="sec1">
<title>Patients, Materials, and Methods</title>
<p>Starting in April 1995 and during the subsequent 2 years, we enrolled HIV-infected pregnant women who were at 12–27 weeks' gestation, who resided in Dar es Salaam, Tanzania, and who intended to stay in the city until after delivery and for ⩾1 year thereafter. Details about the trial were published elsewhere [<xref rid="ref12" ref-type="bibr">12</xref>–<xref rid="ref14" ref-type="bibr">14</xref>]. In brief, women were randomly assigned, in a 2 × 2 factorial design, to receive, from enrollment and throughout the pregnancy and lactation periods, a daily oral dose of 1 of 4 regimens: (1) vitamin A alone (30 mg of beta carotene plus 5000 IU of preformed vitamin A), (2) multivitamins that did not include vitamin A (20 mg of vitamin B<sub>1</sub>, 20 mg of vitamin B<sub>2</sub>, 25 mg of vitamin B<sub>6</sub>, 100 mg of niacin, 50 μg of vitamin B<sub>12</sub>, 500 mg of vitamin C, 30 mg of vitamin E, and 0.8 mg of folic acid), (3) multivitamins that included vitamin A (same doses as above), or (4) placebo. At delivery, women in groups 1 and 3 received an additional oral dose of vitamin A (200,000 IU), whereas women in groups 2 and 4 were given a placebo. Active tablets and placebo were identical in size and color. We previously reported that compliance with the experimental regimens, assessed using pill counts and biochemical analysis (determination of plasma levels of vitamin A over time), was high [<xref rid="ref14" ref-type="bibr">14</xref>]. Women and children, regardless of experimental group, were provided with standard prenatal and child care services in Tanzania, including distribution of 100,000 IU of vitamin A to infants at 6 months of age and twice that amount every 6 months thereafter.</p>
<p>Information on sociodemographic characteristics was collected at baseline. At monthly visits, a study physician examined the study participants, and study nurses measured their weight, height, and mid-upper arm circumference. A research midwife measured the weight of the baby immediately after birth. In accordance with the guidelines of the World Health Organization and the Tanzanian Ministry of Health, HIV-infected women were provided with information about the benefits and risks associated with infant feeding options; however, the decision on whether to breast-feed was ultimately made by the mother. Breast-feeding was almost universally adopted in this population. Among children who were observed for ⩾24 months, the mean duration (±SD) of breast-feeding was 20.3 ± 4.4 months (median, 20.5 months).</p>
<p>Morbidity surveillance of children was performed at monthly clinic visits. For women who did not attend the clinic with their children or who traveled outside of Dar es Salaam, a home visit was made, and neighbors or relatives in the area were contacted to collect information on the vital status of the mother and her child, but no morbidity data were collected at these visits. At each clinic visit, mothers were asked about the number of days, if any, on which the child had diarrheal or respiratory signs during the previous month. Diarrhea was defined as ⩾3 watery stools in the prior 24 h, and we inquired whether blood or mucus was seen in stool. Respiratory signs studied were fever, cough, difficulty breathing, chest retractions, and difficulties with eating, drinking, or breast-feeding. A child's respiratory rate was measured using a stopwatch on the day of the monthly visit, and rapid respiratory rate was defined as ⩾50 breaths/min, for infants, and ⩾40 breaths/min, for children aged >1 year.</p>
<p>Episodes of diarrhea during each monthly interval were defined as follows: “acute diarrhea” included all periods with ⩾1 day but <14 days of diarrhea. Acute diarrhea was classified as dysentery, which included all episodes of diarrhea with mucus or blood, or as watery diarrhea, which included all other episodes (with neither mucus nor blood). Only a small number of periods included persistent diarrhea (defined as ⩾14 days of diarrhea), so this end point was not examined in our analysis. “Respiratory infection” was defined in 4 ways: the occurrence of cough alone; cough and fever; “cough plus” (defined as cough with ⩾1 of the following events: difficult breathing, chest retractions, and refusal to eat, drink, or breast-feed); or cough with rapid respiratory rate on the day of visit.</p>
<p>At baseline, maternal complete blood count and absolute counts of T cell subsets (CD4<sup>+</sup> and CD8<sup>+</sup> ) were measured. Infant CD4<sup>+</sup> cell counts were also measured at birth and at 6-month intervals thereafter. CD4<sup>+</sup> cell counts were measured using the FACScount system (Becton Dickinson). In 13% of cases, the system flagged the specimen (especially for children with CD4<sup>+</sup> cell counts of >2000 cells/μL), and the specimen was analyzed using FACScan system; there was no difference in the type of machine used across experimental groups. Details of the assessment of HIV infection status in infants have been published elsewhere [<xref rid="ref13" ref-type="bibr">13</xref>, <xref rid="ref14" ref-type="bibr">14</xref>]. For diagnosis of HIV infection in infants, we attempted to obtain whole-blood samples at birth, at the age of 6 weeks, and at 3-month intervals thereafter. A child was determined to be HIV-1 infected if either a peripheral blood mononuclear cell specimen tested positive by PCR at any point or a plasma specimen obtained at ⩾18 months of age tested positive by ELISA (and if positivity was confirmed by a Western blot test). A child was determined to be uninfected if a blood sample obtained at the last visit had a negative HIV-1 PCR test result or, for children aged ⩾18 months, if a plasma specimen obtained at the last visit had a negative ELISA test result. Baseline maternal plasma specimens were analyzed for vitamin A and E levels using high-pressure liquid chromatography.</p>
<p><bold><italic>Data analyses</italic></bold>. We previously reported that 1083 HIV-positive women were enrolled in the trial. We retested specimens obtained from all randomized women as part of a quality-control procedure and found that 5 women were HIV negative; a mechanism for counseling these 5 women was instituted immediately. Of the remaining 1078 women, 3 were eventually found not to be pregnant, 6 died before delivery, and pregnancy outcome was not known for 28. Pregnancy outcome was known for 1041 women. Of the latter group, 1016 had singleton newborns (938 live births and 78 fetal deaths) and 25 had twins (21 pairs of twins were both born live, and 1 of the twins was stillborn for 4 pairs). Overall, 984 children were born alive, of whom 838 were known to be alive by 6 weeks of age, and, of these, 50 had no morbidity data. Morbidity data from 6 weeks to 24 months of age from the remaining 788 children were used in the analyses in this paper. Among the 788 children, 400 had mothers randomized to receive multivitamins, whereas the mothers of the remaining 388 children did not receive multivitamins; similarly, 397 and 391 mothers were in the vitamin A and no-vitamin A groups, respectively. By 6 weeks of age, 108 infants were determined to be HIV positive, and 680 were either HIV negative at 6 weeks or were not known to be HIV positive. Among the 788 children, 664 had CD4<sup>+</sup> cell count measurements obtained during the period from 6 weeks to 24 months of age. Of these, 342 had mothers who received multivitamins, 322 had mothers who did not receive multivitamins, and 339 and 325 had mothers who did and did not receive vitamin A, respectively.</p>
<p>The mean number of episodes per child per year (±SD) was calculated for each outcome. To assess the effects of supplementation on the incidence of disease and CD4<sup>+</sup> cell counts, data were analyzed using generalized estimating equations (GEE) with the Genmod procedure of SAS software (SAS Institute) [<xref rid="ref15" ref-type="bibr">15</xref>]. Follow-up data (6 weeks to 24 months) for each child were grouped into 4 half-year periods. A GEE model with exchangeable working covariance structure was used. A working binomial distribution was specified for diarrhea and respiratory infections, and a working normal distribution was used for CD4<sup>+</sup> cell counts.</p>
<p>We examined the effect of the supplements on the children's diarrhea, respiratory infections, and CD4<sup>+</sup> cell counts, both overall and within the strata of HIV infection status of infants by 6 weeks of age. The overall results were adjusted for baseline maternal age, education level, CD4<sup>+</sup> and CD8<sup>+</sup> cell counts, erythrocyte sedimentation rate (ESR), hemoglobin level, and plasma concentrations of vitamin A and E. The results were essentially similar to those obtained from the univariate models; thus, only the latter are reported. We further examined the effect of use of the supplements on various outcomes among children who were uninfected by 6 weeks of age, stratifying by maternal and child characteristics. Given the factorial design of the trial, we compared the effect of multivitamins with that of no multivitamins; the efficacy in the vitamin A group was similarly compared to the that in no-vitamin A group. We also examined for the interaction between the effects of multivitamins and vitamin A.</p>
<p>The effects of vitamin A or multivitamins that excluded A on watery diarrhea and “cough plus” are reported within the strata of the child characteristics birth weight (<2500 g or ⩾2500 g) and gestational age at birth (<37 weeks and ⩾37 weeks), as well as within categories of the following baseline maternal characteristics (dichotomization level): CD4<sup>+</sup> cell count (350 cells/μL), hemoglobin concentration (8.5 g/dL), plasma vitamin A concentration (20 μg/dL), plasma vitamin E concentration (9.7 μmol/dL), and ESR (81 mm/h). Conventional cutoff points were used to dichotomize continuous variables when available (CD4<sup>+</sup> cell count, hemoglobin level, and plasma concentration of vitamin A); otherwise, cutoff points that had been selected a priori were used: the median (vitamin E) or highest quartile (ESR) values.</p>
<p>A data safety and monitoring board (DSMB) reviewed the study progress and interim analyses of primary end points. In September 2000, the DSMB recommended that the vitamin A treatment arms be dropped from the study because of an observed increase in the occurrence of transmission of HIV-1 to children in these arms, compared with children whose mothers did not receive vitamin A [<xref rid="ref13" ref-type="bibr">13</xref>]. Although all children of index pregnancies had stopped breast-feeding by that time, there was a concern about subsequent pregnancies in women were still randomized to receive vitamin A. The study protocol was approved by the Research and Publications Committee of Muhimbili University College of Health Sciences (Dar es Salaam), the Ethical Committee of the National AIDS Control Program of the Tanzanian Ministry of Health (Dar es Salaam), and the Institutional Review Board of the Harvard School of Public Health (Boston, MA).</p>
</sec>
<sec sec-type="Results" id="sec2">
<title>Results</title>
<p>Women assigned to the various treatment groups were similar with respect to baseline characteristics, including age, education level, CD4<sup>+</sup> and CD8<sup>+</sup> cell counts, ESR, hemoglobin level, and plasma vitamin A and E levels (<xref rid="tab1" ref-type="fig">table 1</xref>). The duration of breast-feeding was not different among treatment arms (<italic>P</italic> = .37); the mean durations (±SD) were 16.4 ± 7.3 months among women who received multivitamins that included vitamin A, 16.2 ± 7.0 months among those who received multivitamins that did not include vitamin A, 16.1 ± 7.5 months among those who received vitamin A only, and 15.2 ± 7.7 months among placebo recipients.</p>
<p>We examined the effect of receipt of supplements on diarrhea and respiratory infection during the first 2 years of life (<xref rid="tab2" ref-type="fig">table 2</xref>). Children born to women who were assigned to receive multivitamins (with vitamins B, C, and E) had a 17% significantly lower risk of diarrhea, compared with children whose mothers received no multivitamins (relative risk [RR], 0.83; 95% CI, 0.71–0.98; <italic>P</italic> = 0.03). Receipt of vitamin A, on the other hand, had no significant effect on this outcome (RR, 0.95; 95% CI, 0.81–1.12; <italic>P</italic> = .52). Receipt of multivitamins that did not include vitamin A, but not receipt of vitamin A alone, also resulted in reductions in the risks of acute diarrhea, watery diarrhea, and dysentery. We repeated all the analyses shown in <xref rid="tab2" ref-type="fig">table 2</xref> with adjustment for baseline maternal age, education, CD4<sup>+</sup> and CD8<sup>+</sup> cell counts, ESR, hemoglobin level, and plasma concentrations of vitamins A and E. The results were virtually the same as those obtained from univariate models.</p>
<p>In secondary analyses, we examined the interaction between the effects of the 2 regimens (i.e., vitamin A alone and with other vitamins) on the incidence of diarrhea-associated end points. Significant interactions were detected for acute diarrhea and watery diarrhea (<italic>P</italic> = .04 and .008, respectively, by test for interaction). Compared with children of mothers who received placebo, children whose mothers received both vitamin A and other vitamins had a significantly lower risk, nearly 30% lower, of acute diarrhea (<italic>P</italic> = .02). However, those whose mothers received vitamin A alone (RR, 1.08; <italic>P</italic> = .50) or multivitamins excluding vitamin A (RR, 0.99; <italic>P</italic> = .92) had a risk of developing acute diarrhea similar to that for children of mothers in the placebo group.</p>
<p>Receipt of vitamin A alone by the mother resulted in a significant reduction in the risk of cough with rapid respiratory rate in the children (RR, 0.69; 95% CI, 0.49–0.96; <italic>P</italic> = .03; <xref rid="tab2" ref-type="fig">table 2</xref>). However, we found no effect for receipt of other vitamins by the mother on the risks of respiratory infection in the children, and no interactions were observed between the 2 regimens with regard to respiratory outcomes.</p>
<p>We then examined the efficacy of the supplements on these outcomes within the strata of HIV infection status of the child by 6 weeks of age (<xref rid="tab3" ref-type="fig">table 3</xref>). Multivitamins appeared to have a larger protective effect on the risk of diarrhea during the first 2 years of life among children who were not known to be HIV positive at 6 weeks of age. However, <italic>P</italic> values determined with tests for interaction between maternal receipt of multivitamins and the child's HIV infection status did not denote statistical significance for all diarrhea end points (<italic>P</italic> > .1). The childrens' HIV infection status did not modify the efficacy of vitamin A alone on any of the definitions of diarrhea either. The effects of receipt of vitamin A and of multivitamins excluding vitamin A on the risk of respiratory infection were also not modified by HIV infection status (<xref rid="tab3" ref-type="fig">table 3</xref>).</p>
<p>In <xref rid="tab4" ref-type="fig">table 4</xref>, we present findings on the efficacy of receipt of multivitamins or vitamin A on watery diarrhea during the first 2 years of life among HIV-uninfected children within the strata of child or maternal characteristics. Multivitamins were apparently more protective against watery diarrhea among children who were born prematurely (RR, 0.53; 95% CI, 0.33–0.84; <italic>P</italic> = .007), compared with those who were born at term (RR, 0.86; 95% CI, 0.67–1.10; <italic>P</italic> = .22; <italic>P</italic> = .07, by test for interaction). The efficacy of vitamin A alone was stronger among children born to mothers with a low baseline CD4<sup>+</sup> cell count (<italic>P</italic> = .08, by test for interaction) or a high ESR (<italic>P</italic> = .01, by test for interaction). The effects of receipt of multivitamins as well as vitamin A on respiratory infection were similar among children within the strata of child and maternal characteristics (data not shown).</p>
<p>We examined the effects of the supplements on CD4<sup>+</sup> cell count during the first 2 years of life. Overall, CD4<sup>+</sup> cell count among children in the multivitamin arms was 151 cells/μL higher than the count among those in the no-multivitamin arms (95% CI, 64–237 cells/μL; <italic>P</italic> = .0006; <xref rid="fig1" ref-type="fig">figure 1</xref>). The effect of multivitamins was not different within strata of vitamin A supplementation (<italic>P</italic> = .14, by test for interaction). At 6 months of age, children of mothers who received multivitamins had significantly higher CD4<sup>+</sup> cell counts (mean ± SD, 1711 ± 646 cells/μL; median, 1645 cells/μL) than did children in the no-multivitamin arms (mean ± SD, 1558 ± 576 cells/μL; median, 1541 cells/μL; <italic>P</italic> = .0001). The effect of vitamin A on the childrens' CD4<sup>+</sup> cell counts was not statistically significant.</p>
<p>Within the strata of HIV infection status at 6 weeks of age, HIV-infected children experienced an apparently similar benefit (mean CD4<sup>+</sup> cell difference, 265 cells/μL; 95% CI, 38–493 cells/μL; <italic>P</italic> = .02), compared with HIV-negative children (mean CD4<sup>+</sup> cell difference, 155 cells/μL; 95% CI, 65–245 cells/μL; <italic>P</italic> = .0007; <italic>P</italic> = 0.34, by test for interaction). We repeated the analysis in the HIV-negative stratum by excluding children who became infected by 12 months of age, and the results were stronger (mean CD4<sup>+</sup> cell difference, 198 cells/μL; 95% CI, 105–291 cells/μL; <italic>P</italic> < .0001). We examined the effects of maternal receipt of the supplements on CD4<sup>+</sup> cell counts among children who were uninfected at 6 weeks of age by stratifying by characteristics of the mothers and children (<xref rid="tab5" ref-type="fig">table 5</xref>). The beneficial effect of multivitamins may have been greater among children who were born prematurely (<italic>P</italic> = 0.07, by test for interaction) and those born to mothers who had low plasma concentrations of vitamin E (<italic>P</italic> = 0.06, by test for interaction).</p>
</sec>
<sec sec-type="Discussion" id="sec3">
<title>Discussion</title>
<p>Relatively little information is available on the potential effects of multiple deficiencies of vitamins in mothers on infant and child health. In this article, we report that providing HIV-infected women with supplements including vitamins B, C, and E during lactation resulted in significant reductions in the overall risks for diarrhea among the children and in a pronounced improvement in the childrens' CD4<sup>+</sup> cell counts during the first 2 years of life. To our knowledge, this is the first randomized study that has examined the effect of maternal multimicronutrient supplements on infant health. We have previously reported that providing multivitamins (including vitamins B, C, and E) to the same study population resulted in significant reductions in the risks of HIV transmission through breast-feeding and in mortality during the first 2 years of life among children born to mothers who were immunologically or nutritionally compromised [<xref rid="ref13" ref-type="bibr">13</xref>].</p>
<p>Maternal micronutrient deficiencies are associated with poor nutritional quality of breast milk and with concurrent deficiencies in infants. Therefore, maternal multivitamin supplementation may lead to improved quality of breast milk that is reflected in better nutritional and health status of the child [<xref rid="ref16" ref-type="bibr">16</xref>–<xref rid="ref18" ref-type="bibr">18</xref>]. Multiple micronutrient deficiencies have been reported during early childhood. In a cohort of children from Mexico, 10% of subjects were deficient in vitamin B<sub>12</sub>, 30% were deficient in vitamin A, and 70% were deficient in vitamin E [<xref rid="ref19" ref-type="bibr">19</xref>]. Data from the Human Nutrition Collaborative Research Support Program in Kenya and Egypt indicated that vitamin B<sub>12</sub> intake in these populations was extremely low, and even the modest amounts available in supplementary foods provided to infants were associated positively with linear growth [<xref rid="ref20" ref-type="bibr">20</xref>].</p>
<p>Data from randomized trials on the efficacy of providing multivitamin supplements to children are very scanty. In a trial involving school children from Tanzania aged 6–11 years, a placebo beverage was compared with an “active” beverage that contained vitamins A, B<sub>2</sub>, B<sub>6</sub>, B<sub>12</sub>, C, and E and folic acid, among other nutrients [<xref rid="ref21" ref-type="bibr">21</xref>]. Children who received the active beverage daily for 6 months experienced significant increases in hemoglobin level, plasma vitamin A level, and weight and height, compared with placebo recipients. A recent trial from Mexico reported better growth for infants aged <12 months who received a multiple-micronutrient supplement, compared with placebo recipients [<xref rid="ref22" ref-type="bibr">22</xref>]. None of the latter trials has assessed the effect of multivitamins on clinical outcomes, such as mortality and morbidity associated with infectious diseases.</p>
<p>We also found that providing supplements of vitamins B, C, and E to lactating mothers resulted in higher CD4<sup>+</sup> cell counts among children during the first 2 years of life, providing a potential mechanism by which the supplements may have improved health outcomes. In addition to the beneficial effects of the supplements on the CD4<sup>+</sup> cell count, the relationships between various micronutrients and immune cell functions has been examined in a number of studies involving animals and humans. For example, vitamin B<sub>6</sub> deficiency affects cellular immune function, including the total number of lymphocytes, lymphocyte proliferation, and IL-2 production in response to cell mitogens, whereas riboflavin (vitamin B<sub>2</sub>) deficiency was shown to impair the ability to generate humoral antibodies in response to test antigens [<xref rid="ref10" ref-type="bibr">10</xref>]. Vitamin B<sub>12</sub> deficiency is associated with impaired neutrophil function, and supplementation is associated with enhanced antibody function and mitogenic responses. T and B lymphocyte proliferative responses were noted to have increased after receipt of vitamin C supplementation in some studies of human subjects [<xref rid="ref11" ref-type="bibr">11</xref>], and enhanced vitamin C status was associated with a lower rate of infection [<xref rid="ref23" ref-type="bibr">23</xref>]. Vitamin E deficiency has been reported to impair T cell-mediated function, and receipt of supplements may significantly improve lymphocyte proliferation, IL-2 production, delayed-type hypersensitivity, and response to T cell-dependent vaccines and to reduce the incidence of self-reported infection [<xref rid="ref24" ref-type="bibr">24</xref>].</p>
<p>Multivitamins appeared to be similarly beneficial among children who were already HIV infected. The beneficial effects of maternal supplements on infant health and CD4<sup>+</sup> cell count may therefore slow the progression of HIV disease in these children. A number of epidemiologic studies have examined the relationships between vitamin status and HIV disease progression [<xref rid="ref25" ref-type="bibr">25</xref>]. In longitudinal studies involving homosexual and bisexual men, higher intakes of micronutrients (vitamins B, C, and E) and higher plasma levels of vitamins B<sub>12</sub> and E were associated with slower progression to AIDS and a lower risk of mortality [<xref rid="ref26" ref-type="bibr">26</xref>–<xref rid="ref31" ref-type="bibr">31</xref>]. In a study from Canada, large daily doses of vitamins C and E resulted in significant reductions in virus load [<xref rid="ref32" ref-type="bibr">32</xref>]. The aforementioned studies on micronutrients and HIV disease progression involved adults in developed countries and were mostly observational in design. In several of them, the results were adjusted for potential confounding by baseline signs and symptoms and immunological surrogates, such as CD4<sup>+</sup> cell count. However, residual confounding is still a possible explanation for the findings, especially that associated with the effects of HIV infection on blood markers of nutritional status, access to health care, and socioeconomic status, among other variables.</p>
<p>In addition to a direct effect of supplementation on infant health through enhanced breast milk quality, the observed beneficial effects of receipt of multivitamins may have been mediated through improved maternal health and immune status. Multivitamin supplementation of mothers may enhance their own systemic immunity and possibly reduce the rate of clinical, immunological, or virological progression, as noted above. We reported elsewhere that receipt of multivitamin supplements substantially reduced the risk of adverse pregnancy outcomes and resulted in increased levels of maternal CD4<sup>+</sup> cell subsets during pregnancy and during the first 6 months postpartum [<xref rid="ref12" ref-type="bibr">12</xref>]. Healthier mothers are likely to be better able to care for their children. However, the long-term clinical relevance of these findings on maternal CD4<sup>+</sup>cell count has yet to be determined.</p>
<p>Maternal vitamin A supplementation resulted in a significant reduction in the risk of developing cough with rapid respiratory rate, a proxy for acute lower respiratory infection. Although it had no overall effect on diarrhea-associated outcomes, maternal supplements were protective within subgroups of children who were born to sicker mothers, as defined by lower baseline CD4<sup>+</sup> cell counts and higher ESRs, and among children born to mothers who also received other multivitamins (including vitamins B, C, and E). The effect of maternal vitamin A supplementation in this study may have been attenuated, given that all children in the trial, regardless of the group to which their mothers were assigned, received large doses of vitamin A every 6 months, in accordance with the standard of care in Tanzania. Our findings suggest that, at least in certain subgroups, additional vitamin A provided through relatively higher concentrations of the vitamin in breast milk may be beneficial over and above the large dose that was provided to all children every 6 months. These findings are in accordance with results from a meta-analysis of 8 large, community-based trials involving vitamin A [<xref rid="ref6" ref-type="bibr">6</xref>], in which data from 3 studies that used a large dose every 6 months (the current standard of care in Tanzania) were pooled; the meta-analysis revealed a small and nonsignificant protective association against all-cause mortality (OR, 0.90; <italic>P</italic> = .46), whereas the protective relationship was apparently stronger in trials that used small frequent doses in the form of weekly doses of vitamin A or dietary fortification (OR, 0.58; <italic>P</italic> = .02).</p>
<p>In the same study population, providing mothers with vitamin A supplements resulted in an overall significantly higher risk of mother-to-child transmission of HIV-1, including transmission through the breast-feeding period among children who were not known to be infected at 6 weeks of age [<xref rid="ref13" ref-type="bibr">13</xref>]. The possible increased risk of HIV-1 infection may mean that individuals offered vitamin A also need to receive counseling about and testing for HIV-1 infection so that supplementation is limited to HIV-negative women. This may not be a cost-effective intervention to pursue, unless such a counseling program is already in place as part of a strategy to reduce mother-to-child transmission of HIV-1. A more realistic approach would be to strengthen programs that provide direct periodic supplementation to children starting at 6 months of age. The risk of the latter approach with respect to transmission is unknown, but it can be minimized in situations in which early weaning (e.g., at 6 months) is encouraged to reduce the risk of late postnatal transmission [<xref rid="ref33" ref-type="bibr">33</xref>]. The adequacy of providing a large dose of vitamin A at and after 6 months of age to weaned children needs to be further examined. More-frequent dosing may be necessary. In a trial that involved HIV-positive and HIV-negative Tanzanian children aged ⩾6 months, providing vitamin A supplements every 4 months resulted in significantly lower mortality rates, compared with placebo [<xref rid="ref7" ref-type="bibr">7</xref>].</p>
<p>Multivitamin supplements (i.e., supplements that include vitamins B, C, and E) are recommended for HIV-infected pregnant women in Tanzania and in other countries, in light of the protective effects on adverse pregnancy outcomes. Continued provision of these supplements during lactation resulted in significant improvements in CD4<sup>+</sup> cell counts and reductions in the rate of childhood diarrhea during the first 2 years of life. In light of these effects, the previously reported benefits of these supplements on mortality and breast-feeding transmission of HIV-1 in subgroups of children at risk, and the relatively low cost of this intervention, provision of these supplements during lactation ought to be considered.</p>
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<ack>
<title>Acknowledgments</title>
<p>We are grateful to Hoffmann-La Roche for donating the raw material that was used for preparing the vitamin and placebo tablets. We thank the mothers and children, field teams (including nurses, midwives, supervisors, and laboratory staff), and the administrative staff who made the study possible. We greatly appreciate input from the colleagues Illuminata Ballonzi, Beth Chaplin, Jenny Coley, Max Essex, Ellen Hertzmark, Heavengton Mshiu, Davis Mwakagile, Boris Renjifo, Willy Urassa, Walter Willett, and all other members of the Harvard-Tanzania collaboration, and we also greatly appreciate the assistance of members of the Data Safety and Monitoring Board: Graham Colditz, Nicholas Horton, Valerian Kimati, Kenneth McIntosh, Marcello Pagano (Chair), and Abby Shevitz. We also thanks Anne Willoughby (National Institutes of Child Health and Human Development [Bethesda, MD]) and Ken Bridbord (Fogarty International Center, National Institutes of Health [Bethesda]) for their valuable support. Finally, we thank Muhimbili Medical Centre, Muhimbili University College of Health Sciences, and the National AIDS Control Program in Dar es Salaam, Tanzania, for their institutional support.</p>
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<sec sec-type="display-objects">
<title>Figures and Tables</title>
<fig position="float" id="fig1">
<label>Figure 1</label>
<caption>
<p>CD4<sup>+</sup> cell counts among children of HIV-infected mothers, who were not known to be HIV infected at 6 weeks of age, according to maternal multivitamin group.</p>
</caption>
<graphic mimetype="image" xlink:href="36-8-1053-fig001.tif"></graphic>
</fig>
<fig position="float" id="tab1">
<label>Table 1</label>
<caption>
<p>Baseline characteristics of mothers in intervention and control groups.</p>
</caption>
<graphic mimetype="image" xlink:href="36-8-1053-tbl001.tif"></graphic>
</fig>
<fig position="float" id="tab2">
<label>Table 2</label>
<caption>
<p>Effects of maternal receipt of multivitamins and vitamin A supplements on the incidence of diarrhea and respiratory infection in 788 children.</p>
</caption>
<graphic mimetype="image" xlink:href="36-8-1053-tbl002.tif"></graphic>
</fig>
<fig position="float" id="tab3">
<label>Table 3</label>
<caption>
<p>Effects of maternal receipt of multivitamins and vitamin A supplements on the incidence of diarrhea and respiratory infections in 108 HIV-infected and 680 HIV-uninfected children, stratified by HIV infection status, by 6 weeks of age.</p>
</caption>
<graphic mimetype="image" xlink:href="36-8-1053-tbl003.tif"></graphic>
</fig>
<fig position="float" id="tab4">
<label>Table 4</label>
<caption>
<p>Effects of maternal receipt of multivitamins and vitamin A supplements on the incidence of watery diarrhea in children, within the strata of maternal and child characteristics.</p>
</caption>
<graphic mimetype="image" xlink:href="36-8-1053-tbl004.tif"></graphic>
</fig>
<fig position="float" id="tab5">
<label>Table 5</label>
<caption>
<p>Effects of maternal receipt of multivitamins and vitamin A supplements on the children's CD4<sup>+</sup> cell counts.</p>
</caption>
<graphic mimetype="image" xlink:href="36-8-1053-tbl005.tif"></graphic>
</fig>
</sec>
<fn-group>
<fn fn-type="financial-disclosure"><p>Financial support: National Institute of Child Health and Human Development (grant R01 32257) and Fogarty International Center, National Institutes of Health (grant D43 TW00004).</p></fn>
</fn-group>
</back>
</article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Effect of Providing Vitamin Supplements to Human Immunodeficiency Virus-Infected, Lactating Mothers on the Child's Morbidity and CD4+ Cell Counts</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Effect of Providing Vitamin Supplements to Human Immunodeficiency Virus-Infected, Lactating Mothers on the Child's Morbidity and CD4+ Cell Counts</title></titleInfo><name type="personal" displayLabel="corresp"><namePart type="given">Wafaie W.</namePart><namePart type="family">Fawzi</namePart><affiliation>Department of Nutrition, Boston, Massachusetts</affiliation><affiliation>Department of Epidemiology, Boston, Massachusetts</affiliation><affiliation>E-mail: mina@hsph.harvard.edu</affiliation><affiliation>Reprints or correspondence: Dr. Wafaie Fawzi, Dept. of Nutrition, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115</affiliation><affiliation>E-mail: mina@hsph.harvard.edu</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Gernard I.</namePart><namePart type="family">Msamanga</namePart><affiliation>Department of Community Health, Tanzania</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ruilan</namePart><namePart type="family">Wei</namePart><affiliation>Department of Nutrition, Boston, Massachusetts</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Donna</namePart><namePart type="family">Spiegelman</namePart><affiliation>Department of Epidemiology, Boston, Massachusetts</affiliation><affiliation>Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Gretchen</namePart><namePart type="family">Antelman</namePart><affiliation>Department of Nutrition, Boston, Massachusetts</affiliation><affiliation>Department of Community Health, Tanzania</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Eduardo</namePart><namePart type="family">Villamor</namePart><affiliation>Department of Nutrition, Boston, Massachusetts</affiliation><affiliation>Department of Community Health, Tanzania</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Karim</namePart><namePart type="family">Manji</namePart><affiliation>Department of Paediatrics and Child Health, Muhimbili University College of Health Sciences, Dar es Salaam, Tanzania</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">David</namePart><namePart type="family">Hunter</namePart><affiliation>Department of Nutrition, Boston, Massachusetts</affiliation><affiliation>Department of Epidemiology, Boston, Massachusetts</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>The University of Chicago Press</publisher><dateIssued encoding="w3cdtf">2003-04-15</dateIssued><copyrightDate encoding="w3cdtf">2003</copyrightDate></originInfo><abstract>A total of 1078 human immunodeficiency virus (HIV) type 1-infected women from Tanzania were randomized in a placebo-controlled trial using a factorial design to examine the effects of supplementation with vitamin A (preformed vitamin A and beta carotene) and/or multivitamins (vitamins B, C, and E). Supplements were given during pregnancy and lactation. Children of women in the multivitamin arms had a significantly lower risk of diarrhea than did those in the no-multivitamin arm (P = .03). The mean CD4+ cell count was 151 cells/μL higher among children in the multivitamin arms than among those in the no-multivitamin arm (P = .0006). HIV-positive children experienced a benefit apparently similar to that in HIV-negative children (P = .34, by test for interaction). Maternal receipt of vitamin A significantly reduced the risk that the child would have cough with a rapid respiratory rate, a proxy for pneumonia (P = .03), but receipt of vitamin A had no effect on diarrhea or CD4+ cell count. Provision of multivitamin supplements (including those with vitamins B, C, and E) to HIV-infected, lactating women may be a low-cost intervention to improve their children's health.</abstract><relatedItem type="host"><titleInfo><title>Clinical Infectious Diseases</title></titleInfo><titleInfo type="abbreviated"><title>Clinical Infectious Diseases</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><identifier type="ISSN">1058-4838</identifier><identifier type="eISSN">1537-6591</identifier><identifier type="PublisherID">cid</identifier><identifier type="PublisherID-hwp">cid</identifier><part><date>2003</date><detail type="volume"><caption>vol.</caption><number>36</number></detail><detail type="issue"><caption>no.</caption><number>8</number></detail><extent unit="pages"><start>1053</start><end>1062</end></extent></part></relatedItem><identifier type="istex">33032B8BCAEEB16E237F77AF24216D8FE4F907E3</identifier><identifier type="DOI">10.1086/374223</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2003 by the Infectious Diseases Society of America</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-GTWS0RDP-M">oup</recordContentSource><recordOrigin>© 2003 by the Infectious Diseases Society of America</recordOrigin></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/document/33032B8BCAEEB16E237F77AF24216D8FE4F907E3/metadata/json</uri></json:item></metadata><covers><json:item><extension>tiff</extension><original>true</original><mimetype>image/tiff</mimetype><uri>https://api.istex.fr/document/33032B8BCAEEB16E237F77AF24216D8FE4F907E3/covers/tiff</uri></json:item><json:item><extension>html</extension><original>true</original><mimetype>text/html</mimetype><uri>https://api.istex.fr/document/33032B8BCAEEB16E237F77AF24216D8FE4F907E3/covers/html</uri></json:item></covers><annexes><json:item><extension>jpeg</extension><original>true</original><mimetype>image/jpeg</mimetype><uri>https://api.istex.fr/document/33032B8BCAEEB16E237F77AF24216D8FE4F907E3/annexes/jpeg</uri></json:item><json:item><extension>gif</extension><original>true</original><mimetype>image/gif</mimetype><uri>https://api.istex.fr/document/33032B8BCAEEB16E237F77AF24216D8FE4F907E3/annexes/gif</uri></json:item><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/33032B8BCAEEB16E237F77AF24216D8FE4F907E3/annexes/pdf</uri></json:item></annexes><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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