• 1

    Moore JM, Ayisi J, Nahlen BL, Misore A, Lal AA, Udhayakumar V, 2000. Immunity to placental malaria. II. Placental antigen-specific cytokine responses are impaired in human immunodeficiency virus-infected women. J Infect Dis 182 :960–964.

    • Search Google Scholar
    • Export Citation
  • 2

    Chaisavaneeyakorn S, Moore JM, Otieno J, Chaiyaroj SC, Perkins DJ, Shi YP, Nahlen BL, Lal AA, Udhayakumar V, 2002. Immunity to placental malaria. III. Impairment of interleukin(IL)-12, not IL-18, and interferon-inducible protein-10 responses in the placental intervillous blood of human immunodeficiency virus/malaria-coinfected women. J Infect Dis 185 :127–131.

    • Search Google Scholar
    • Export Citation
  • 3

    Ayisi JG, van Eijk AM, ter Kuile FO, Kolczak MS, Otieno JA, Misore AO, Kager PA, Steketee RW, Nahlen BL, 2003. The effect of dual infection with HIV and malaria on pregnancy outcome in western Kenya. AIDS 17 :585–594.

    • Search Google Scholar
    • Export Citation
  • 4

    Mount AM, Mwapasa V, Elliott SR, Beeson JG, Tadesse E, Lema VM, Molyneux ME, Meshnick SR, Rogerson SJ, 2004. Impairment of humoral immunity to Plasmodium falciparum malaria in pregnancy by HIV infection. Lancet 363 :1860–1867.

    • Search Google Scholar
    • Export Citation
  • 5

    Steketee RW, Wirima JJ, Bloland PB, Chilima B, Mermin JH, Chitsulo L, Breman JG, 1996. Impairment of a pregnant woman’s acquired ability to limit Plasmodium falciparum by infection with human immunodeficiency virus type-1. Am J Trop Med Hyg 55 :42–49.

    • Search Google Scholar
    • Export Citation
  • 6

    van Eijk AM, Ayisi JG, ter Kuile FO, Misore AO, Otieno JA, Rosen DH, Kager PA, Steketee RW, Nahlen BL, 2003. HIV increases the risk of malaria in women of all gravidities in Kisumu, Kenya. AIDS 17 :595–603.

    • Search Google Scholar
    • Export Citation
  • 7

    van Eijk AM, Ayisi JG, ter Kuile FO, Misore A, Otieno JA, Kolczak MS, Kager PA, Steketee RW, Nahlen BL, 2001. Human immunodeficiency virus seropositivity and malaria as risk factors for third-trimester anemia in asymptomatic pregnant women in western Kenya. Am J Trop Med Hyg 65 :623–630.

    • Search Google Scholar
    • Export Citation
  • 8

    Ticconi C, Mapfumo M, Dorrucci M, Naha N, Tarira E, Pietropolli A, Rezza G, 2003. Effect of maternal HIV and malaria infection on pregnancy and perinatal outcome in Zimbabwe. J Acquir Immune Defic Syndr 34 :289–294.

    • Search Google Scholar
    • Export Citation
  • 9

    Steketee RW, Wirima JJ, Hightower AW, Slutsker L, Heymann DL, Breman JG, 1996. The effect of malaria and malaria prevention in pregnancy on offspring birthweight, prematurity, and intrauterine growth retardation in rural Malawi. Am J Trop Med Hyg 55 :S33–S41.

    • Search Google Scholar
    • Export Citation
  • 10

    Leroy V, Ladner J, Nyiraziraje M, De Clercq A, Bazubagira A, Van de Perre P, Karita E, Dabis F, 1998. Effect of HIV-1 infection on pregnancy outcome in women in Kigali, Rwanda, 1992–1994. Pregnancy and HIV Study Group. AIDS 12 :643–650.

    • Search Google Scholar
    • Export Citation
  • 11

    Fawzi WW, Villamor E, Msamanga GI, Antelman G, Aboud S, Urassa W, Hunter D, 2005. Trial of zinc supplements in relation to pregnancy outcomes, hematologic indicators, and T cell counts among HIV-1-infected women in Tanzania. Am J Clin Nutr 81 :161–167.

    • Search Google Scholar
    • Export Citation
  • 12

    Guay LA, Musoke P, Fleming T, Bagenda D, Allen M, Nakabiito C, Sherman J, Bakaki P, Ducar C, Deseyve M, Emel L, Mirochnick M, Fowler MG, Mofenson L, Miotti P, Dransfield K, Bray D, Mmiro F, Jackson JB, 1999. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 354 :795–802.

    • Search Google Scholar
    • Export Citation
  • 13

    World Health Organization, 1991. Basic Laboratory Methods in Medical Parasitology. Geneva: WHO.

  • 14

    Fawzi WW, Msamanga G, Hunter D, Urassa E, Rengifo B, Mwakagile D, Hertzmark E, Coley J, Garland M, Kapiga S, Antelman G, Essex M, Spiegelman D, 2000. Randomized trial of vitamin supplements in relation to vertical transmission of HIV-1 in Tanzania. J Acquir Immune Defic Syndr 23 :246–254.

    • Search Google Scholar
    • Export Citation
  • 15

    Brenner WE, Edelman DA, Hendricks CH, 1976. A standard of fetal growth for the United States of America. Am J Obstet Gynecol 126 :555–564.

    • Search Google Scholar
    • Export Citation
  • 16

    Nyirjesy P, Kavasya T, Axelrod P, Fischer PR, 1993. Malaria during pregnancy: neonatal morbidity and mortality and the efficacy of chloroquine chemoprophylaxis. Clin Infect Dis 16 :127–132.

    • Search Google Scholar
    • Export Citation
  • 17

    Redd SC, Wirima JJ, Steketee RW, Breman JG, Heymann DL, 1996. Transplacental transmission of Plasmodium falciparum in rural Malawi. Am J Trop Med Hyg 55 :57–60.

    • Search Google Scholar
    • Export Citation
  • 18

    Kariuki SK, ter Kuile FO, Wannemuehler K, Terlouw DJ, Kolczak MS, Hawley WA, Phillips-Howard PA, Orago AS, Nahlen BL, Lal AA, Shi YP, 2003. Effects of permethrin-treated bed nets on immunity to malaria in western Kenya I. Antibody responses in pregnant women and cord blood in an area of intense malaria transmission. Am J Trop Med Hyg 68 :61–67.

    • Search Google Scholar
    • Export Citation
  • 19

    Bloland PB, Wirima JJ, Steketee RW, Chilima B, Hightower A, Breman JG, 1995. Maternal HIV infection and infant mortality in Malawi: evidence for increased mortality due to placental malaria infection. AIDS 9 :721–726.

    • Search Google Scholar
    • Export Citation
  • 20

    Premji Z, Makwaya C, Minjas JN, 1999. Current clinical efficacy of chloroquine for the treatment of Plasmodium falciparum infections in urban Dar es Salaam, United Republic of Tanzania. Bull World Health Organ 77 :740–744.

    • Search Google Scholar
    • Export Citation
  • 21

    Wolfe EB, Parise ME, Haddix AC, Nahlen BL, Ayisi JG, Misore A, Steketee RW, 2001. Cost-effectiveness of sulfadoxine-pyrimethamine for the prevention of malaria-associated low birth weight. Am J Trop Med Hyg 64 :178–186.

    • Search Google Scholar
    • Export Citation
  • 22

    Shankar AH, Prasad AS, 1998. Zinc and immune function: the biological basis of altered resistance to infection. Am J Clin Nutr 68 :447S–463S.

    • Search Google Scholar
    • Export Citation
  • 23

    Shankar AH, Genton B, Baisor M, Paino J, Tamja S, Adiguma T, Wu L, Rare L, Bannon D, Tielsch JM, West KP Jr, Alpers MP, 2000. The influence of zinc supplementation on morbidity due to Plasmodium falciparum: a randomized trial in preschool children in Papua New Guinea. Am J Trop Med Hyg 62 :663–669.

    • Search Google Scholar
    • Export Citation
  • 24

    Gibson RS, Huddle JM, 1998. Suboptimal zinc status in pregnant Malawian women: its association with low intakes of poorly available zinc, frequent reproductive cycling, and malaria. Am J Clin Nutr 67 :702–709.

    • Search Google Scholar
    • Export Citation
  • 25

    Nacher M, McGready R, Stepniewska K, Cho T, Looareesuwan S, White NJ, Nosten F, 2003. Haematinic treatment of anaemia increases the risk of Plasmodium vivax malaria in pregnancy. Trans R Soc Trop Med Hyg 97 :273–276.

    • Search Google Scholar
    • Export Citation
  • 26

    Fiske DN, McCoy HE 3rd, Kitchens CS, 1994. Zinc-induced si-deroblastic anemia: report of a case, review of the literature, and description of the hematologic syndrome. Am J Hematol 46 :147–150.

    • Search Google Scholar
    • Export Citation

 

 

 

 

ADVERSE PERINATAL OUTCOMES OF HIV-1–INFECTED WOMEN IN RELATION TO MALARIA PARASITEMIA IN MATERNAL AND UMBILICAL CORD BLOOD

View More View Less
  • 1 Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts; Departments of Community Health and Microbiology and Immunology, Muhimbili University College of Health Sciences, Dar es Salaam, Tanzania; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts

Malaria infection during pregnancy increases the risk of adverse birth outcomes among HIV-infected women. The role of umbilical cord parasitemia is not well characterized. We examined the risk of adverse perinatal outcomes in relation to maternal or umbilical cord Plasmodium falciparum parasitemia among 275 HIV-infected women from Tanzania, who participated in a randomized trial of zinc supplementation during pregnancy. Maternal parasitemia (≥1/μL) at the first antenatal visit was associated with increased risk of low birth weight < 2,500 g (adjusted relative risk [ARR] = 2.66; P = 0.01) and preterm delivery < 37 weeks (ARR = 1.87; P = 0.06). Maternal parasitemia at delivery was associated with preterm delivery (ARR = 2.27; P = 0.008), intrauterine growth retardation (ARR = 1.92; P = 0.03), and neonatal death (ARR = 3.22; P = 0.07). Cord parasitemia was associated with a large and significant increase in the risk of neonatal death (ARR = 8.75; P = 0.003). Maternal parasitemia at the first antenatal visit was strongly related to parasitemia at delivery, and the latter was associated with cord blood parasitemia. CD4 cell counts, parity, or assignment to the zinc arm (25 mg daily) were not associated with parasitemia in maternal or cord blood at delivery. Successful treatment of HIV-infected women who present to the first prenatal visit with malaria parasitemia and avoidance of reinfection are likely to decrease the risk of adverse outcomes during pregnancy and the early postpartum period. Cord blood parasitemia is a strong predictor of neonatal death. The potential effect of zinc supplementation on clinical malaria outcomes deserves future investigation.

INTRODUCTION

HIV infection has the potential to impair both cellular1,2 and humoral3,4 immune responses to malaria. In consequence, coinfection with HIV and malaria during pregnancy often results in increased parasitemia,5 high incidence of clinical malaria,6 maternal anemia,3,7 and adverse perinatal outcomes.3,810 Previous studies documented increased risks of low birth weight (LBW), intrauterine growth retardation (IUGR), preterm delivery, and early infant deaths associated with maternal or placental malaria. However, little information is available on the magnitude and consequences of umbilical cord parasitemia, an indicator of transplacental passage of parasites, among HIV-infected women.

We examined the associations between maternal and umbilical cord blood Plasmodium falciparum parasitemia and perinatal outcomes in a group of HIV-infected women who participated in a zinc supplementation trial during pregnancy. We also studied potential risk factors for maternal and cord parasitemia in this group.

MATERIALS AND METHODS

The trial was conducted between 2000 and 2002, in Dar es Salaam, Tanzania, among 400 HIV-infected pregnant women. The aim of the trial was to examine the effect of daily oral doses of 25 mg zinc sulfate on maternal and perinatal outcomes. As detailed previously,11 consenting women who were between 12 and 27 weeks of gestation according to the last menstrual period date were randomly assigned to receive a daily oral dose of 25 mg zinc as zinc sulfate or an indistinguishable placebo from enrollment until the end of the study, 6 weeks after delivery. Sociodemographic characteristics, complete blood and T-cell subset counts, and malaria parasitemia were assessed at the first visit. Women were followed during monthly visits to Muhimbili National Hospital, where all the study procedures took place after enrollment. As part of the standard of prenatal care, all women received multivitamin (B-complex, C, and E), iron and folate supplements daily, and prophylactic chloroquine phosphate (500 mg, equivalent to 300 mg of chloroquine base) weekly. Prophylactic nevirapine was offered to all women and their babies as a measure to prevent mother-to-child transmission of HIV.12 At delivery, attending midwives weighed the newborns and the placentas after removing clots and obtained venous blood samples from the mothers through finger pricks and from the newborns’ side of the umbilical cord veins by venipuncture. The presence of malaria parasites in peripheral or cord blood was assessed by thick and thin smears stained with Giemsa. One trained laboratory technician carried out readings of each blood smear in three different fields of the slide. Parasite density per cubic millimeter was estimated from the number of parasites per 200 leukocytes and a leukocyte count of 8,000/mm3.13 HIV status of the baby was assessed through PCR analyses of samples obtained at birth and at the last study visit, 6 weeks postdelivery, using the Amplicor HIV-1 detection kit (Roche Diagnostic System, Branchburg, NJ). We defined HIV infection at birth using data from live births whose HIV status was known at birth or who did not have a birth sample but had a specimen tested at 6 weeks according to published criteria.14 An assessment of neonatal survival was done at the postpartum visit.

Peripheral malaria parasitemia at delivery was assessed in 275 of the 400 women originally enrolled. This subset did not differ significantly from women without malaria assessment in terms of treatment assignment or baseline characteristics including age, level of education, marital status, parity, malaria parasitemia, and CD4 cell counts. Umbilical cord samples were available in 69% (N = 191) of these 275 women.

Using the χ2 test, we tested the associations between maternal or cord parasitemia and neonatal binary outcomes that included low birth weight (< 2,500 g), preterm delivery (< 37 weeks), intrauterine growth retardation (< 10th percentile of weight for gestational age according to the Brenner reference15), HIV status at birth, and neonatal mortality (between birth and 28 days postpartum). Adjusted relative risks were obtained from multivariate binomial regression models that controlled for maternal CD4 cell counts and parity. We also examined whether the prevalence of parasitemia at delivery varied according to baseline characteristics including maternal age, parity, CD4 cell count, history of fetal loss, parasitemia at first visit, and treatment assignment after the intent-to-treat principle.

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.

RESULTS

On average, the group of 275 women included in these analyses attended the first prenatal care visit at week 23 of gestation (SD = 3.4), were 26.9 years old (SD = 5.0), and had completed primary schooling (91%). Twenty-seven percent were primigravidae, 17% had malaria parasitemia at recruitment, 73% were anemic (hemoglobin < 11 g/dL), and 18% had CD4 cell counts < 200/mm3. One hundred forty (51%) were in the zinc arm and 135 (49%) received placebo. Seventeen percent and 16% of the women had malaria parasitemia in peripheral blood at baseline and delivery, respectively; the proportion of positive slides from umbilical cord samples was 15%. The median (interquartile range) parasite loads/μL in positive slides were 680 (500–840) and 660 (480–770) for maternal peripheral blood at baseline and delivery, respectively, and 700 (560–1010) for cord blood. Virtually all infections were by P. falciparum.

Maternal parasitemia at baseline was related to increased risk of LBW (adjusted relative risk [ARR] = 2.66; 95% CI = 1.24, 5.71; P = 0.01) and preterm delivery (ARR = 1.87; 95% CI = 0.98, 3.57; P = 0.06), and non-significantly to IUGR (Table 1). Maternal parasitemia at delivery was associated with preterm delivery (ARR = 2.27; 95% CI = 1.23, 4.16; P = 0.008), IUGR (ARR = 1.92; 95% CI = 1.08, 3.44; P = 0.03), and neonatal death (ARR = 3.22; 95% CI = 0.89, 11.6; P = 0.07). Cord parasitemia was associated with a large and significant increase in the risk of neonatal death (ARR = 8.75; 95% CI = 2.14, 35.9; P = 0.003). It was also related, albeit not significantly, to higher risk of LBW, IUGR, and HIV-infection of the baby. Neither maternal nor cord parasitemia were related to placental weight.

We next examined potential risk factors for parasitemia at delivery (Table 2). For maternal malaria parasitemia at delivery, significant predictors included parasitemia at the first antenatal visit (ARR = 1.96; 95% CI = 1.03, 3.71; P = 0.04) and a history of involuntary fetal loss (ARR = 1.89; 95% CI = 1.06, 3.35; P = 0.03). For cord parasitemia, the strongest predictor was the presence of parasites in maternal peripheral blood at delivery (ARR = 5.63; 95% CI = 2.97, 10.7; P < 0.0001). Zinc supplements had no significant effects on the proportion of maternal or umbilical cord samples with parasitemia at delivery. Also, there were no significant differences in the distribution of parasite density by treatment arm in specimens from women or cord blood with positive slides; the average effects of zinc were −165/μL (P = 0.19) and −172/μL (P = 0.38), respectively. Maternal age, CD4 cell counts, and parity were not significant predictors of maternal or cord parasitemia in this group.

DISCUSSION

In this group of HIV-infected women, maternal malaria parasitemia was associated with increased risk of adverse birth outcomes, in agreement with previous studies.3,810 In addition, we found that umbilical cord parasitemia was a strong risk factor for neonatal death. The prevalence of cord parasitemia in babies born to HIV-infected women from our study, 15%, was lower than that reported for HIV-positive Malawian women, 26%5 but higher than that in children born to presumably HIV-negative women: 9% in Zaire,16 7% in Malawi,17 and 2% in Kenya.18 In the Zaire study, an association was noted between neonatal parasitemia and early mortality, and in Malawi cord parasitemia was found to be associated with preterm delivery. The strong association between cord parasitemia and neonatal mortality that we found could indicate that, among HIV-infected women, the transplacental passage of P. falciparum is not only more frequent compared with HIV-uninfected but is also more detrimental for survival. In children born to HIV-infected women, asymptomatic congenital malaria could mediate in part the previously reported relationships between placental or maternal peripheral parasitemia and perinatal death8 or early post-neonatal mortality.19

The strongest risk factor for umbilical cord parasitemia was maternal parasitemia at delivery, while the latter was strongly correlated with parasitemia at the first prenatal visit. This chain of associations suggests that avoiding treatment failure and reinfection specifically in women who present with malaria parasitemia at the first prenatal visit could decrease the burden of adverse pregnancy and early postpartum outcomes including preterm delivery, congenital malaria, and neonatal death. Prophylaxis with periodic chloroquine did not appear to be effective in reducing the burden of malaria in this population, as the rates of parasitemia at the first visit were similar to those at delivery. This is unfortunately not surprising as widespread P. falciparum resistance to chloroquine has been reported in Tanzania.20 Intermittent presumptive treatment with sulfadoxine–pyrimethamine during pregnancy at monthly doses has been found to be the most cost-effective strategy to decrease the risk of placental malaria in populations with HIV prevalence > 10%, such as Tanzania.21

Zinc is essential to sustain adequate cellular and humoral immune functions in humans22 and supplementation to children has shown benefits on malaria-related clinical outcomes.23 We did not find significant effects of zinc supplementation during pregnancy on malaria parasitemia at delivery in this group of HIV-infected women. The trial was not primarily designed to study the impact of zinc on malaria and, consequently, statistical power to examine this question was very low. With a prevalence of parasitemia at delivery equal to 19%, as observed in the placebo arm, we would have needed 660 women per arm to detect a treatment effect of 30% at P < 0.05 with 80% statistical power. In addition, even in the absence of an effect on parasitemia, zinc could have an effect on clinical episodes of malaria, which we did not measure. Zinc deficiency has been related to malaria during pregnancy in observational studies,24 and the effect of supplementation on gestational malaria remains an open question that needs to be addressed in randomized trials including both HIV-infected and -uninfected women. These trials should take into account potential negative interactions between zinc and other micronutrients, saliently iron, which has been shown to increase the risk of P. vivax malaria among pregnant women,25 and copper, which could be decreased by very high doses of zinc (300–600 mg per day).26

In conclusion, umbilical cord blood parasitemia is frequent among HIV-infected women and is strongly associated with neonatal death. The effect of zinc supplementation on malaria outcomes during pregnancy requires further evaluation in clinical trials.

Table 1

Perinatal outcomes in relation to maternal or cord P. falciparum malaria parasitemia* among HIV-infected women from Tanzania

Maternal parasitemia at first visitMaternal parasitemia at deliveryCord blood parasitemia
Outcomes†No N = 224Yes N = 45No N = 230Yes N = 45No N = 162Yes N = 29
* Defined as ≥ 1 parasite/μL
P values are from χ2 test.
‡ Intrauterine growth retardation: < 10th percentile of weight for gestational age according to the Brenner reference.
§ Child death within the first 28 days postpartum.
Low birth weight (< 2,500 g)
    % with outcome (N at risk)7.0 (215)20.9 (43)8.7 (219)13.3 (45)8.7 (161)14.3 (28)
    P value0.0040.330.35
Preterm delivery (< 37 weeks)
    % with outcome (N at risk)12.6 (215)23.3 (43)12.8 (219)26.7 (45)15.5 (161)14.3 (28)
    P value0.070.020.87
Intrauterine growth retardation‡
    % with outcome (N at risk)15.8 (215)23.3 (43)15.5 (219)26.7 (45)18.0 (161)28.6 (28)
    P value0.240.070.19
HIV-positive at birth
    % with outcome (N = risk)5.1 (175)6.7 (30)5.2 (174)5.7 (35)4.0 (125)9.1 (22)
    P value0.730.900.30
Neonatal death§
    % with outcome (N at risk)3.7 (215)2.3 (43)2.3 (219)8.9 (45)1.9 (161)14.3 (28)
    P value0.730.030.001
Table 2

Predictors of maternal and cord malaria parasitemia at delivery among HIV-infected women from Tanzania

Maternal parasitemiaCord parasitemia
Correlates% with outcome* (N at risk)P value†% with outcome* (N at risk)P value†
* Defined as ≥ 1 parasite/μL.
† From χ2 test.
Maternal parasitemia at delivery
    No8.1 (160)< 0.0001
    Yes51.6 (31)
Parasitemia at first antenatal visit
    No13.8 (224)0.0112.8 (156)0.06
    Yes28.9 (45)25.8 (31)
Previous fetal loss
    No14.3 (224)0.0411.3 (151)0.003
    Yes26.0 (50)30.0 (40)
Mother is primigravidae
    No15.9 (201)0.7116.3 (141)0.47
    Yes17.8 (73)12.0 (50)
CD4 at recruitment
    ≥ 200/mm311.3 (159)0.5811.2 (116)0.32
    < 200/mm314.7 (34)19.1 (21)
Treatment assignment
    Placebo18.5 (135)0.3411.5 (96)0.15
    Zinc14.3 (140)19.0 (95)

*

Address correspondence to Eduardo Villamor, Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115. E-mail: evillamo@hsph.harvard.edu.

Authors’ addresses: Eduardo Villamor, Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115, E-mail: evillamo@hsph.harvard.edu. Gernard Msamanga, Department of Community Health, Muhimbili University College of Health Sciences, Dar es Salaam, Tanzania, E-mail: gmsamanga@muchs.ac.tz. Said Aboud, Department of Microbiology and Immunology, Muhimbili University College of Health Sciences, Dar es Salaam, Tanzania, E-mail: saboud@muchs.ac.tz. Willy Urassa, Department of Microbiology and Immunology, Muhimbili University College of Health Sciences, Dar es Salaam, Tanzania, E-mail: wurassa@muchs.ac.tz. David J. Hunter, Department of Epidemiology, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115, E-mail: nhdjh@channing.harvard.edu. Wafaie W. Fawzi, Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115, E-mail: mina@hsph.harvard.edu.

Acknowledgments: We are grateful to the women and children who participated in the study. The authors thank the field teams including nurses, physicians, midwives, supervisors, lab staff, and the administrative staff who made the study possible. The authors thank the authorities at Muhimbili University College of Health Sciences, Muhimbili National Hospital, the City of Dar es Salaam Regional Health Authority, and the Tanzanian National AIDS Control Program for their institutional support.

Financial support: This study was supported by the National Institute of Child Health and Human Development (NICHD R01 32257).

REFERENCES

  • 1

    Moore JM, Ayisi J, Nahlen BL, Misore A, Lal AA, Udhayakumar V, 2000. Immunity to placental malaria. II. Placental antigen-specific cytokine responses are impaired in human immunodeficiency virus-infected women. J Infect Dis 182 :960–964.

    • Search Google Scholar
    • Export Citation
  • 2

    Chaisavaneeyakorn S, Moore JM, Otieno J, Chaiyaroj SC, Perkins DJ, Shi YP, Nahlen BL, Lal AA, Udhayakumar V, 2002. Immunity to placental malaria. III. Impairment of interleukin(IL)-12, not IL-18, and interferon-inducible protein-10 responses in the placental intervillous blood of human immunodeficiency virus/malaria-coinfected women. J Infect Dis 185 :127–131.

    • Search Google Scholar
    • Export Citation
  • 3

    Ayisi JG, van Eijk AM, ter Kuile FO, Kolczak MS, Otieno JA, Misore AO, Kager PA, Steketee RW, Nahlen BL, 2003. The effect of dual infection with HIV and malaria on pregnancy outcome in western Kenya. AIDS 17 :585–594.

    • Search Google Scholar
    • Export Citation
  • 4

    Mount AM, Mwapasa V, Elliott SR, Beeson JG, Tadesse E, Lema VM, Molyneux ME, Meshnick SR, Rogerson SJ, 2004. Impairment of humoral immunity to Plasmodium falciparum malaria in pregnancy by HIV infection. Lancet 363 :1860–1867.

    • Search Google Scholar
    • Export Citation
  • 5

    Steketee RW, Wirima JJ, Bloland PB, Chilima B, Mermin JH, Chitsulo L, Breman JG, 1996. Impairment of a pregnant woman’s acquired ability to limit Plasmodium falciparum by infection with human immunodeficiency virus type-1. Am J Trop Med Hyg 55 :42–49.

    • Search Google Scholar
    • Export Citation
  • 6

    van Eijk AM, Ayisi JG, ter Kuile FO, Misore AO, Otieno JA, Rosen DH, Kager PA, Steketee RW, Nahlen BL, 2003. HIV increases the risk of malaria in women of all gravidities in Kisumu, Kenya. AIDS 17 :595–603.

    • Search Google Scholar
    • Export Citation
  • 7

    van Eijk AM, Ayisi JG, ter Kuile FO, Misore A, Otieno JA, Kolczak MS, Kager PA, Steketee RW, Nahlen BL, 2001. Human immunodeficiency virus seropositivity and malaria as risk factors for third-trimester anemia in asymptomatic pregnant women in western Kenya. Am J Trop Med Hyg 65 :623–630.

    • Search Google Scholar
    • Export Citation
  • 8

    Ticconi C, Mapfumo M, Dorrucci M, Naha N, Tarira E, Pietropolli A, Rezza G, 2003. Effect of maternal HIV and malaria infection on pregnancy and perinatal outcome in Zimbabwe. J Acquir Immune Defic Syndr 34 :289–294.

    • Search Google Scholar
    • Export Citation
  • 9

    Steketee RW, Wirima JJ, Hightower AW, Slutsker L, Heymann DL, Breman JG, 1996. The effect of malaria and malaria prevention in pregnancy on offspring birthweight, prematurity, and intrauterine growth retardation in rural Malawi. Am J Trop Med Hyg 55 :S33–S41.

    • Search Google Scholar
    • Export Citation
  • 10

    Leroy V, Ladner J, Nyiraziraje M, De Clercq A, Bazubagira A, Van de Perre P, Karita E, Dabis F, 1998. Effect of HIV-1 infection on pregnancy outcome in women in Kigali, Rwanda, 1992–1994. Pregnancy and HIV Study Group. AIDS 12 :643–650.

    • Search Google Scholar
    • Export Citation
  • 11

    Fawzi WW, Villamor E, Msamanga GI, Antelman G, Aboud S, Urassa W, Hunter D, 2005. Trial of zinc supplements in relation to pregnancy outcomes, hematologic indicators, and T cell counts among HIV-1-infected women in Tanzania. Am J Clin Nutr 81 :161–167.

    • Search Google Scholar
    • Export Citation
  • 12

    Guay LA, Musoke P, Fleming T, Bagenda D, Allen M, Nakabiito C, Sherman J, Bakaki P, Ducar C, Deseyve M, Emel L, Mirochnick M, Fowler MG, Mofenson L, Miotti P, Dransfield K, Bray D, Mmiro F, Jackson JB, 1999. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 354 :795–802.

    • Search Google Scholar
    • Export Citation
  • 13

    World Health Organization, 1991. Basic Laboratory Methods in Medical Parasitology. Geneva: WHO.

  • 14

    Fawzi WW, Msamanga G, Hunter D, Urassa E, Rengifo B, Mwakagile D, Hertzmark E, Coley J, Garland M, Kapiga S, Antelman G, Essex M, Spiegelman D, 2000. Randomized trial of vitamin supplements in relation to vertical transmission of HIV-1 in Tanzania. J Acquir Immune Defic Syndr 23 :246–254.

    • Search Google Scholar
    • Export Citation
  • 15

    Brenner WE, Edelman DA, Hendricks CH, 1976. A standard of fetal growth for the United States of America. Am J Obstet Gynecol 126 :555–564.

    • Search Google Scholar
    • Export Citation
  • 16

    Nyirjesy P, Kavasya T, Axelrod P, Fischer PR, 1993. Malaria during pregnancy: neonatal morbidity and mortality and the efficacy of chloroquine chemoprophylaxis. Clin Infect Dis 16 :127–132.

    • Search Google Scholar
    • Export Citation
  • 17

    Redd SC, Wirima JJ, Steketee RW, Breman JG, Heymann DL, 1996. Transplacental transmission of Plasmodium falciparum in rural Malawi. Am J Trop Med Hyg 55 :57–60.

    • Search Google Scholar
    • Export Citation
  • 18

    Kariuki SK, ter Kuile FO, Wannemuehler K, Terlouw DJ, Kolczak MS, Hawley WA, Phillips-Howard PA, Orago AS, Nahlen BL, Lal AA, Shi YP, 2003. Effects of permethrin-treated bed nets on immunity to malaria in western Kenya I. Antibody responses in pregnant women and cord blood in an area of intense malaria transmission. Am J Trop Med Hyg 68 :61–67.

    • Search Google Scholar
    • Export Citation
  • 19

    Bloland PB, Wirima JJ, Steketee RW, Chilima B, Hightower A, Breman JG, 1995. Maternal HIV infection and infant mortality in Malawi: evidence for increased mortality due to placental malaria infection. AIDS 9 :721–726.

    • Search Google Scholar
    • Export Citation
  • 20

    Premji Z, Makwaya C, Minjas JN, 1999. Current clinical efficacy of chloroquine for the treatment of Plasmodium falciparum infections in urban Dar es Salaam, United Republic of Tanzania. Bull World Health Organ 77 :740–744.

    • Search Google Scholar
    • Export Citation
  • 21

    Wolfe EB, Parise ME, Haddix AC, Nahlen BL, Ayisi JG, Misore A, Steketee RW, 2001. Cost-effectiveness of sulfadoxine-pyrimethamine for the prevention of malaria-associated low birth weight. Am J Trop Med Hyg 64 :178–186.

    • Search Google Scholar
    • Export Citation
  • 22

    Shankar AH, Prasad AS, 1998. Zinc and immune function: the biological basis of altered resistance to infection. Am J Clin Nutr 68 :447S–463S.

    • Search Google Scholar
    • Export Citation
  • 23

    Shankar AH, Genton B, Baisor M, Paino J, Tamja S, Adiguma T, Wu L, Rare L, Bannon D, Tielsch JM, West KP Jr, Alpers MP, 2000. The influence of zinc supplementation on morbidity due to Plasmodium falciparum: a randomized trial in preschool children in Papua New Guinea. Am J Trop Med Hyg 62 :663–669.

    • Search Google Scholar
    • Export Citation
  • 24

    Gibson RS, Huddle JM, 1998. Suboptimal zinc status in pregnant Malawian women: its association with low intakes of poorly available zinc, frequent reproductive cycling, and malaria. Am J Clin Nutr 67 :702–709.

    • Search Google Scholar
    • Export Citation
  • 25

    Nacher M, McGready R, Stepniewska K, Cho T, Looareesuwan S, White NJ, Nosten F, 2003. Haematinic treatment of anaemia increases the risk of Plasmodium vivax malaria in pregnancy. Trans R Soc Trop Med Hyg 97 :273–276.

    • Search Google Scholar
    • Export Citation
  • 26

    Fiske DN, McCoy HE 3rd, Kitchens CS, 1994. Zinc-induced si-deroblastic anemia: report of a case, review of the literature, and description of the hematologic syndrome. Am J Hematol 46 :147–150.

    • Search Google Scholar
    • Export Citation

Author Notes

Reprint requests: Eduardo Villamor, Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave., SPH2, Boston, MA 02115. E-mail: evillamo@hsph.harvard.edu.
Save