Anemia and Micronutrient Status during Pregnancy, and Their Associations with Obstetric and Infant Outcomes among HIV-Infected Ugandan Women Receiving Antiretroviral Therapy

Julia L Finkelstein, Heather S Herman, Albert Plenty, Saurabh Mehta, Paul Natureeba, Tamara D Clark, Moses R Kamya, Theodore Ruel, Edwin D Charlebois, Deborah Cohan, Diane Havlir, Sera L Young, Julia L Finkelstein, Heather S Herman, Albert Plenty, Saurabh Mehta, Paul Natureeba, Tamara D Clark, Moses R Kamya, Theodore Ruel, Edwin D Charlebois, Deborah Cohan, Diane Havlir, Sera L Young

Abstract

Background: Women living with HIV (WLHIV) are at higher risk of micronutrient deficiencies and adverse health outcomes. There are limited data on the burden or sequelae of micronutrient deficiencies among pregnant WLHIV receiving antiretroviral therapy (ART).

Objectives: We aimed to examine anemia and vitamin B-12, folate, and vitamin D deficiencies, and their associations with obstetric and infant outcomes, among pregnant WLHIV initiating combination antiretroviral therapy (cART) in rural Uganda.

Methods: This was a prospective analysis among pregnant WLHIV (12-28 weeks of gestation) in PROMOTE-Pregnant Women and Infants (PIs), a randomized trial comparing the effects of protease inhibitor (PI)-based ART with those of a non-PI-based ART on placental malaria risk. We conducted a substudy on the burden of anemia [trimester 1/3: hemoglobin (Hb) <11.0 g/dL; trimester 2: Hb <10.5 g/dL; n = 367] and micronutrient deficiencies (n = 127) in pregnant WLHIV and their associations with obstetric and infant outcomes. Hb was measured by cyanmethemoglobin, vitamin B-12 and folate were measured via electrochemiluminescence, and vitamin D was measured by ELISA. Linear and binomial regression were used to evaluate associations between micronutrient status during pregnancy and perinatal outcomes.

Results: 26.8% women were anemic, 30.2% were vitamin B-12 insufficient (<221.0 pmol/L), 66.1% were folate insufficient (<13.5 nmol/L), and 65.4% were vitamin D insufficient (<30.0 ng/mL) at enrollment. Anemia during pregnancy was associated with a greater risk of small for gestational age (SGA) (RR: 1.88; 95% CI: 1.28, 2.77; P = 0.001); each 1-g/dL decrease in Hb was associated with greater risk of SGA (RR: 0.76; 95% CI: 0.65, 0.90; P = 0.001). Multivariate models showed that increased vitamin D concentrations predicted lower risk of infant wasting (WLZ < -2; RR: 0.94; 95% CI: 0.89, 0.99; P = 0.04). Multivariate models also indicated that maternal vitamin B-12 and folate concentrations at enrollment predicted maternal (P < 0.001) and infant (P = 0.02) concentrations postpartum.

Conclusions: Anemia and micronutrient deficiencies are associated with a variety of adverse obstetric and infant outcomes and are an important public health concern in perinatal WLHIV on cART and their children.This trial was registered at clinicaltrials.gov as NCT00993031.

Keywords: AIDS; anemia; folate; micronutrient; postpartum; pregnant; sub-Saharan Africa; vitamin B-12; vitamin D.

Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.

References

    1. Finkelstein JL, Aribindi H, Herman HS, Mehta S. Micronutrients and HIV in pediatric populations. In: Mehta S, Finkelstein JL, editors. Nutrition and HIV: epidemiological evidence to public health practice. Boca Raton (FL): CRC Press; 2018. pp. 275–306.
    1. Khondakar NR, Finkelstein JL. Iron and HIV/AIDS. In: Mehta S, Finkelstein JL, editors. Nutrition and HIV: epidemiological evidence to public health practice. Boca Raton (FL): CRC Press; 2018. pp. 89–152.
    1. Redig AJ, Berliner N. Pathogenesis and clinical implications of HIV-related anemia in 2013. Hematology Am Soc Hematol Educ Program. 2013:377–81.
    1. Visser ME, Durao S, Sinclair D, Irlam JH, Siegfried N. Micronutrient supplementation in adults with HIV infection. Cochrane Database Syst Rev. 2017;5:CD003650.
    1. Finkelstein JL, Mehta S. Micronutrients and perinatal outcomes in HIV-infected pregnant women. In: Mehta S, Finkelstein JL, editors. Nutrition and HIV: epidemiological evidence to public health practice. Boca Raton (FL): CRC Press; 2018. pp. 207–42.
    1. Finkelstein JL, Mehta S, Duggan CP, Spiegelman D, Aboud S, Kupka R, Msamanga GI, Fawzi WW. Predictors of anaemia and iron deficiency in HIV-infected pregnant women in Tanzania: a potential role for vitamin D and parasitic infections. Public Health Nutr. 2012;15(5):928–37.
    1. Mehta S, Giovannucci E, Mugusi FM, Spiegelman D, Aboud S, Hertzmark E, Msamanga GI, Hunter D, Fawzi WW. Vitamin D status of HIV-infected women and its association with HIV disease progression, anemia, and mortality. PLoS One. 2010;5(1):e8770.
    1. Layden AJ, Finkelstein JL. B-vitamins and HIV/AIDS. In: Mehta S, Finkelstein JL, editors. Nutrition and HIV: epidemiological evidence to public health practice. Boca Raton (FL): CRC Press; 2018. pp. 27–88.
    1. Tang AM, Graham NM, Chandra RK, Saah AJ. Low serum vitamin B-12 concentrations are associated with faster human immunodeficiency virus type 1 (HIV-1) disease progression. J Nutr. 1997;127(2):345–51.
    1. Villamor E, Saathoff E, Manji K, Msamanga G, Hunter DJ, Fawzi WW. Vitamin supplements, socioeconomic status, and morbidity events as predictors of wasting in HIV-infected women from Tanzania. Am J Clin Nutr. 2005;82(4):857–65.
    1. Fawzi WW, Msamanga GI, Kupka R, Spiegelman D, Villamor E, Mugusi F, Wei R, Hunter D. Multivitamin supplementation improves hematologic status in HIV-infected women and their children in Tanzania. Am J Clin Nutr. 2007;85(5):1335–43.
    1. Villamor E, Mugusi F, Urassa W, Bosch RJ, Saathoff E, Matsumoto K, Meydani SN, Fawzi WW. A trial of the effect of micronutrient supplementation on treatment outcome, T cell counts, morbidity, and mortality in adults with pulmonary tuberculosis. J Infect Dis. 2008;197(11):1499–505.
    1. Olofin IO, Spiegelman D, Aboud S, Duggan C, Danaei G, Fawzi WW. Supplementation with multivitamins and vitamin A and incidence of malaria among HIV-infected Tanzanian women. J Acquir Immune Defic Syndr. 2014;67(Suppl 4):S173–8.
    1. Deluca HF, Cantorna MT. Vitamin D: its role and uses in immunology. FASEB J. 2001;15(14):2579–85.
    1. Yu EA, Mehta S. Vitamin D and HIV. In: Mehta S, Finkelstein JL, editors. Nutrition and HIV: epidemiological evidence to public health practice. Boca Raton (FL): CRC Press; 2018. pp. 153–90.
    1. Allavena C, Delpierre C, Cuzin L, Rey D, Viget N, Bernard J, Guillot P, Duvivier C, Billaud E, Raffi F. High frequency of vitamin D deficiency in HIV-infected patients: effects of HIV-related factors and antiretroviral drugs. J Antimicrob Chemother. 2012;67(9):2222–30.
    1. Rwebembera A, Sudfeld CR, Manji KP, Duggan C, Aboud S, Fawzi WW. Prevalence and risk factors for vitamin D deficiency among Tanzanian HIV-exposed uninfected infants. J Trop Pediatr. 2013;59(5):426–9.
    1. Mehta S, Manji KP, Young AM, Brown ER, Chasela C, Taha TE, Read JS, Goldenberg RL, Fawzi WW. Nutritional indicators of adverse pregnancy outcomes and mother-to-child transmission of HIV among HIV-infected women. Am J Clin Nutr. 2008;87(6):1639–49.
    1. Castetbon K, Ladner J, Leroy V, Chauliac M, Karita E, De Clercq A, Van de Perre P, Dabis F; Pregnancy and HIV Study Group (EGE). Low birthweight in infants born to African HIV-infected women: relationship with maternal body weight during pregnancy. J Tropical Pediatr. 1999;45(3):152–7.
    1. Villamor E, Dreyfuss ML, Baylin A, Msamanga G, Fawzi WW. Weight loss during pregnancy is associated with adverse pregnancy outcomes among HIV-1 infected women. J Nutr. 2004;134(6):1424–31.
    1. Coutsoudis A, Bobat RA, Coovadia HM, Kuhn L, Tsai WY, Stein ZA. The effects of vitamin A supplementation on the morbidity of children born to HIV-infected women. Am J Public Health. 1995;85(8 Pt 1):1076–81.
    1. Kupka R, Manji KP, Bosch RJ, Aboud S, Kisenge R, Okuma J, Fawzi WW, Duggan C. Multivitamin supplements have no effect on growth of Tanzanian children born to HIV-infected mothers. J Nutr. 2013;143(5):722–7.
    1. Duggan C, Manji KP, Kupka R, Bosch RJ, Aboud S, Kisenge R, Okuma J, Fawzi WW. Multiple micronutrient supplementation in Tanzanian infants born to HIV-infected mothers: a randomized, double-blind, placebo-controlled clinical trial. Am J Clin Nutr. 2012;96(6):1437–46.
    1. Luabeya KK, Mpontshane N, Mackay M, Ward H, Elson I, Chhagan M, Tomkins A, Van den Broeck J, Bennish ML. Zinc or multiple micronutrient supplementation to reduce diarrhea and respiratory disease in South African children: a randomized controlled trial. PLoS One. 2007;2(6):e541.
    1. Liu E, Duggan C, Manji KP, Kupka R, Aboud S, Bosch RJ, Kisenge RR, Okuma J, Fawzi WW. Multivitamin supplementation improves haematologic status in children born to HIV-positive women in Tanzania. J Int AIDS Soc. 2013;16:18022.
    1. Manji KP, McDonald CM, Kupka R, Bosch RJ, Kisenge R, Aboud S, Bellinger DC, Fawzi WW, Duggan CP. Effect of multivitamin supplementation on the neurodevelopment of HIV-exposed Tanzanian infants: a randomized, double-blind, placebo-controlled clinical trial. J Trop Pediatr. 2014;60(4):279–86.
    1. Familiar I, Collins SM, Sikorskii A, Ruisenor-Escudero H, Natamba B, Bangirana P, Widen EM, Achidri D, Achola H, Onen D et al. .. Quality of caregiving is positively associated with neurodevelopment during the first year of life among HIV-exposed uninfected children in Uganda. J Acquir Immune Defic Syndr. 2018;77(3):235–42.
    1. Wedderburn CJ, Evans C, Yeung S, Gibb DM, Donald KA, Prendergast AJ. Growth and neurodevelopment of HIV-exposed uninfected children: a conceptual framework. Curr HIV/AIDS Rep. 2019;16(6):501–13.
    1. Jacobson DL, Patel K, Williams PL, Geffner ME, Siberry GK, DiMeglio LA, Crain MJ, Mirza A, Chen JS, McFarland E et al. .. Growth at 2 years of age in HIV-exposed uninfected children in the United States by trimester of maternal antiretroviral initiation. Pediatric Infect Dis J. 2017;36(2):189–97.
    1. le Roux SM, Abrams EJ, Donald KA, Brittain K, Phillips TK, Zerbe A, le Roux DM, Kroon M, Myer L. Infectious morbidity of breastfed, HIV-exposed uninfected infants under conditions of universal antiretroviral therapy in South Africa: a prospective cohort study. Lancet Child Adolesc Health. 2020;4(3):220–31.
    1. Young S, Murray K, Mwesigwa J, Natureeba P, Osterbauer B, Achan J, Arinaitwe E, Clark T, Ades V, Plenty A et al. .. Maternal nutritional status predicts adverse birth outcomes among HIV-infected rural Ugandan women receiving combination antiretroviral therapy. PLoS One. 2012;7(8):e41934.
    1. World Health Organization. Micronutrient supplementation in HIV-infected women during pregnancy. [Internet] Geneva: WHO; 2019; [cited 2019 Jan 15] Available from:.
    1. Siegfried N, Irlam JH, Visser ME, Rollins NN. Micronutrient supplementation in pregnant women with HIV infection. Cochrane Database Syst Rev. 2012(3):CD009755.
    1. Cohan D, Natureeba P, Koss CA, Plenty A, Luwedde F, Mwesigwa J, Ades V, Charlebois ED, Gandhi M, Clark TD et al. .. Efficacy and safety of lopinavir/ritonavir versus efavirenz-based antiretroviral therapy in HIV-infected pregnant Ugandan women. AIDS. 2015;29(2):183–91.
    1. Natureeba P, Ades V, Luwedde F, Mwesigwa J, Plenty A, Okong P, Charlebois ED, Clark TD, Nzarubara B, Havlir DV et al. .. Lopinavir/ritonavir-based antiretroviral treatment (ART) versus efavirenz-based ART for the prevention of malaria among HIV-infected pregnant women. J Infect Dis. 2014;210(12):1938–45.
    1. Young S, Natamba B, Luwedde F, Nyafwono D, Okia B, Osterbauer B, Natureeba P, Johnson L, Michel C, Zheng A et al. .. “I have remained strong because of that food”: acceptability and use of lipid-based nutrient supplements among pregnant HIV-infected Ugandan women receiving combination antiretroviral therapy. AIDS Behav. 2015;19(8):1535–47.
    1. Esiru G. The New National Guidelines (2010) for PMTCT and infant feeding in the context of HIV. Kampala (Uganda): Ministry of Health; 2010.
    1. WHO. WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIV-related disease in adults and children. Geneva: World Health Organization; 2007.
    1. Sanchez MA, Bowen DJ, Hart A Jr, Spigner C. Factors influencing prostate cancer screening decisions among African American men. Ethn Dis. 2007;17(2):374–80.
    1. WHO. Technical meeting: use and interpretation of haemoglobin concentrations for assessing anaemia status in individuals and populations. Geneva: World Health Organization; 2017.
    1. Bailey LB, Stover PJ, McNulty H, Fenech MF, Gregory JF 3rd, Mills JL, Pfeiffer CM, Fazili Z, Zhang M, Ueland PM et al. .. Biomarkers of Nutrition for Development—folate review. J Nutr. 2015;145(7):1636S–80S.
    1. Yetley EA, Pfeiffer CM, Phinney KW, Fazili Z, Lacher DA, Bailey RL, Blackmore S, Bock JL, Brody LC, Carmel R et al. .. Biomarkers of folate status in NHANES: a roundtable summary. Am J Clin Nutr. 2011;94(1):303S–12S.
    1. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM; Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911–30.
    1. Villar J, Cheikh Ismail L, Victora CG, Ohuma EO, Bertino E, Altman DG, Lambert A, Papageorghiou AT, Carvalho M, Jaffer YA et al. .. International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project. Lancet. 2014;384(9946):857–68.
    1. de Onis M, Blössner M. The World Health Organization Global Database on Child Growth and Malnutrition: methodology and applications. Int J Epidemiol. 2003;32(4):518–26.
    1. Durrleman S, Simon R. Flexible regression models with cubic splines. Stat Med. 1989;8(5):551–61.
    1. Govindarajulu US, Spiegelman D, Thurston SW, Ganguli B, Eisen EA. Comparing smoothing techniques in Cox models for exposure-response relationships. Stat Med. 2007;26(20):3735–52.
    1. Greenland S. Modeling and variable selection in epidemiologic analysis. Am J Public Health. 1989;79(3):340–9.
    1. Miettinen O. Theoretical epidemiology. New York: John Wiley & Sons; 1985.
    1. Finkelstein JL, Guillet R, Pressman EK, Fothergill A, Guetterman HM, Kent TR, O'Brien KO. Vitamin B12 status in pregnant adolescents and their infants. Nutrients. 2019;11(2):397.
    1. Bora R, Sable C, Wolfson J, Boro K, Rao R. Prevalence of anemia in pregnant women and its effect on neonatal outcomes in northeast India. J Matern Fetal Neonatal Med. 2014;27(9):887–91.
    1. Breymann C. Iron deficiency anemia in pregnancy. Semin Hematol. 2015;52(4):339–47.
    1. Haider BA, Olofin I, Wang M, Spiegelman D, Ezzati M, Fawzi WW. Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis. BMJ. 2013;346:f3443.
    1. Jwa SC, Fujiwara T, Yamanobe Y, Kozuka K, Sago H. Changes in maternal hemoglobin during pregnancy and birth outcomes. BMC Pregnancy Childbirth. 2015;15:80.
    1. Rahman MM, Abe SK, Rahman MS, Kanda M, Narita S, Bilano V, Ota E, Gilmour S, Shibuya K. Maternal anemia and risk of adverse birth and health outcomes in low- and middle-income countries: systematic review and meta-analysis. Am J Clin Nutr. 2016;103(2):495–504.
    1. Olagbuji BN, Ezeanochie MC, Ande AB, Oboro VO. Obstetric and perinatal outcome in HIV positive women receiving HAART in urban Nigeria. Arch Gynecol Obstet. 2010;281(6):991–4.
    1. Evans C, Chasekwa B, Ntozini R, Majo FD, Mutasa K, Tavengwa N, Mutasa B, Mbuya MNN, Smith LE, Stoltzfus RJ et al. .. Mortality, HIV transmission and growth in children exposed to HIV in rural Zimbabwe. Clin Infect Dis. 2020; (Epub ahead of print; DOI: 10.1093/cid/ciaa076), Available from: .
    1. Lassi ZS, Salam RA, Haider BA, Bhutta ZA. Folic acid supplementation during pregnancy for maternal health and pregnancy outcomes. Cochrane Database Syst Rev. 2013(3):CD006896.
    1. Finkelstein JL, Layden AJ, Stover PJ. Vitamin B-12 and perinatal health. Adv Nutr. 2015;6(5):552–63.
    1. Rogne T, Tielemans MJ, Chong MF-F, Yajnik CS, Krishnaveni GV, Poston L, Jaddoe VWV, Steegers EAP, Joshi S, Chong Y-S et al. .. Associations of maternal vitamin B12 concentration in pregnancy with the risks of preterm birth and low birth weight: a systematic review and meta-analysis of individual participant data. Am J Epidemiol. 2017;185(3):212–23.
    1. Finkelstein JL, Fothergill A, Qi YP, Crider KS. Vitamin B12 supplementation during pregnancy for maternal and child health outcomes. Cochrane Database Syst Rev. In press.
    1. Eckard AR, Leong T, Avery A, Castillo MD, Bonilla H, Storer N, Labbato D, Khaitan A, Tangpricha V, McComsey GA. Short communication: high prevalence of vitamin D deficiency in HIV-infected and HIV-uninfected pregnant women. AIDS Res Hum Retroviruses. 2013;29(9):1224–8.
    1. Finkelstein JL, Mehta S, Duggan C, Manji KP, Mugusi FM, Aboud S, Spiegelman D, Msamanga GI, Fawzi WW. Maternal vitamin D status and child morbidity, anemia, and growth in human immunodeficiency virus-exposed children in Tanzania. Pediatr Infect Dis J. 2012;31(2):171–5.
    1. Jao J, Freimanis L, Mussi-Pinhata MM, Cohen RA, Monteiro JP, Cruz ML, Branch A, Sperling RS, Siberry GK. Severe vitamin D deficiency in human immunodeficiency virus-infected pregnant women is associated with preterm birth. Am J Perinatol. 2017;34(5):486–92.
    1. Sudfeld CR, Jacobson DL, Rueda NM, Neri D, Mendez AJ, Butler L, Siminski S, Hendricks KM, Mellins CA, Duggan CP et al. .. Third trimester vitamin D status is associated with birth outcomes and linear growth of HIV-exposed uninfected infants in the United States. J Acquir Immune Defic Syndr. 2019;81(3):336–44.
    1. Mehta S, Hunter DJ, Mugusi FM, Spiegelman D, Manji KP, Giovannucci EL, Hertzmark E, Msamanga GI, Fawzi WW. Perinatal outcomes, including mother-to-child transmission of HIV, and child mortality and their association with maternal vitamin D status in Tanzania. J Infect Dis. 2009;200(7):1022–30.
    1. Powis K, Lockman S, Smeaton L, Hughes MD, Fawzi W, Ogwu A, Moyo S, van Widenfelt E, von Oettingen J, Makhema J et al. .. Vitamin D insufficiency in HIV-infected pregnant women receiving antiretroviral therapy is not associated with morbidity, mortality or growth impairment in their uninfected infants in Botswana. Pediatr Infect Dis J. 2014;33(11):1141–7.
    1. Sudfeld CR, Manji KP, Duggan CP, Aboud S, Muhihi A, Sando DM, Al-Beity FMA, Wang M, Fawzi WW. Effect of maternal vitamin D3 supplementation on maternal health, birth outcomes, and infant growth among HIV-infected Tanzanian pregnant women: study protocol for a randomized controlled trial. Trials. 2017;18(1):411.
    1. Evans C, Jones CE, Prendergast AJ. HIV-exposed, uninfected infants: new global challenges in the era of paediatric HIV elimination. Lancet Infect Dis. 2016;16(6):e92–e107.
    1. Afran L, Garcia Knight M, Nduati E, Urban BC, Heyderman RS, Rowland-Jones SL. HIV-exposed uninfected children: a growing population with a vulnerable immune system?. Clin Exp Immunol. 2014;176(1):11–22.
    1. Miller MF, Stoltzfus RJ, Iliff PJ, Malaba LC, Mbuya NV, Humphrey JH. Effect of maternal and neonatal vitamin A supplementation and other postnatal factors on anemia in Zimbabwean infants: a prospective, randomized study. Am J Clin Nutr. 2006;84(1):212–22.
    1. Humphrey JH, Iliff PJ, Marinda ET, Mutasa K, Moulton LH, Chidawanyika H, Ward BJ, Nathoo KJ, Malaba LC, Zijenah LS et al. .. Effects of a single large dose of vitamin A, given during the postpartum period to HIV-positive women and their infants, on child HIV infection, HIV-free survival, and mortality. J Infect Dis. 2006;193(6):860–71.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner