Multivariate longitudinal analysis showed that after adjusting for age, the weight-for-age Z score was lower in ENIC than in UEC (difference between means: −0.27; 95% CI: −0.53 to 0.00; P = 0.049). The proportions of moderate and severe wasting, stunting, and underweight were similar among ENIC and UEC (data not shown).
The findings of this study show that compared with UE infants, HIV ENI infants had an increased frequency of anemia, poorer nutritional status, and alterations in some immunologic profiles. In addition, although the risk of outpatient attendances was lower in ENIC, the risk of severe pneumonia was increased in these children compared with UE infants.
Reduced hematocrit and hemoglobin and increased anemia have previously been described in ENIC.34 It has been suggested that these changes might be associated with exposure to antiretrovirals for PMTCT35 or because of a direct impact of the virus on fetal erythropoiesis.36 This type of anemia is mainly macrocytic and usually resolves within the first 3 months of life.35,37–39 In this study, ENIC were more frequently anemic than UEC at all times, especially at 9 months of age, and in many, the anemia was microcytic, thus arguing against zidovudine as the main cause of anemia. It could be speculated that the anemia in these children may be associated with inadequate nutrition in ENIC, as suggested by the early weaning in the HIV-exposed group or to increased exposure of ENIC to infectious diseases.2 CTXP exposure may also result in anemia as a secondary effect of this drug.40 However, in this study, the lower level of hematocrit was already present at 1 month, before initiation of CTXP. Additionally, CTXP-associated anemia is characteristically megaloblastic,41 which was not the case in this study. In addition, it has been observed that HIV-infected children taking CTXP have significantly higher hemoglobin levels than children with placebo.42 Although it is known that anemia in children is associated with increased morbidity and mortality,43 the clinical impact of reduced hematocrit levels in ENIC is still unclear. As previously reported, we found an imbalance in T-cell populations with higher CD8 levels and lower CD4 levels in ENIC compared with UEC.16,18,44 The clinical implications of these findings are not well understood.
Children born to HIV-positive mothers with CD4 <200 cells per microliter are more likely to have a poor birth outcome and increased infant morbidity and mortality.7,11,15,45,46 In this study, the prevalence of LBW and prematurity in ENIC was not significantly higher than in UEC. This is probably because of the few HIV-positive women with CD4 counts below 200 cells per microliter in this study.
Interestingly, ENIC had a significantly lower risk of OPD visits than did UEC, mainly because of a decreased risk of diarrhea and AURI episodes. This lower OPD attendance is probably related to the antibacterial effect of CTXP that ENIC routinely receive through a special clinic at the MDH. Alternatively, this additional clinical follow-up might have affected the health-seeking behavior of mothers of ENIC reducing their attendance to the OPD. It is important to note that previous studies documenting an increased morbidity in ENIC were performed in contexts where CTXP was not available.3,9,11 Contrary to the other reports suggesting a nonsignificant increased risk of diarrhea with CTXP,47–49 the findings of this study showed a significant effect of CTXP in decreasing the risk of AURI (by 30%) and diarrhea (by 50%). This was observed even in the presence of high levels of bacterial resistance to CTX in this setting.50 The contribution of CTXP to these findings is also supported by the lack of difference in the incidence of OPD visits between the 2 groups of infants in the first month of life before the initiation of CTXP. Discrepancies between this and other reports regarding the effect of CTXP on morbidity in ENIC might be explained by the differences in age, feeding modes, duration of CTXP, or follow-up. It has been shown that CTXP confers protection against malaria.49,51 However, we were unable to assess the effect of CTXP on malaria incidence because of the small number of malaria episodes registered during the follow-up. We did, however, observe a borderline significant increased incidence of hospital admissions for CSP in ENIC. This could be explained by a misdiagnosis of tuberculosis.12 Tuberculosis is frequent among infants born to HIV-positive mothers,2 but it is difficult to diagnose in small children in poor resource settings,52 and it is not preventable by CTXP. Alternatively, it may be possible that CTXP is less effective in preventing CSP than mild respiratory infections53 or that those ENIC with CSP were poor compliers for CTX. Larger studies will be necessary to elucidate CSP risk in ENIC.
CTXP for ENIC is being reconsidered because of the concerns regarding the development of bacterial resistance.24,25 In the current study, despite an established PMTCT program, the rate of vertical transmission at 12 months of age was 27%, which illustrates the shortcomings of the health-care system. It might be premature to discontinue the CTXP in ENIC in the current context of continued breast-feeding up to 12 months of age and poor uptake of antiretrovirals.1 More information is needed on the impact of CTXP on infant health and uptake of PMTCT interventions before changing the current policy.
In conclusion, the findings of this study have shown that ENIC have more anemia, are nutritionally disadvantaged, and have immunologic alterations, which may all have clinical consequences that need to be studied in larger prospective studies. We have also shown that CTXP may have a role in reducing morbidity in ENIC. This information is crucial to assist in tailoring public health policies for the management of this group of vulnerable infants in sub-Saharan Africa.
The authors are grateful to all the mothers and their infants who participated in the study, also to the dedicated staff of the Manhiça District Hospital, and to the field, clinic, and data management staff at the Manhiça Health Research Centre, Mozambique.
2. Filteau S. The HIV-exposed, uninfected African child. Trop Med Int Health. 2009;14:276–287.
3. Thea DM, St Louis ME, Atido U, et al.. A prospective study of diarrhea and HIV-1 infection among 429 Zairian infants. N Engl J Med. 1993;329:1696–1702.
4. Spira R, Lepage P, Msellati P, et al.. Natural history of human immunodeficiency virus type 1 infection in children: a five-year prospective study in Rwanda. Mother-to-Child HIV-1 Transmission Study Group. Pediatrics. 1999;104:e56.
5. Venkatesh KK, de Bruyn G, Marinda E, et al.. Morbidity and mortality among infants born to HIV-infected women in South Africa: implications for child health in resource-limited settings. J Trop Pediatr. 2011;57:109–119.
6. Brahmbhatt H, Kigozi G, Wabwire-Mangen F, et al.. Mortality in HIV-infected and uninfected children of HIV-infected and uninfected mothers in rural Uganda. J Acquir Immune Defic Syndr. 2006;41:504–508.
7. Marinda E, Humphrey JH, Iliff PJ, et al.. Child mortality according to maternal and infant HIV status in Zimbabwe. Pediatr Infect Dis J. 2007;26:519–526.
8. Mugwaneza P, Umutoni NW, Ruton H, et al.. Under-two child mortality according to maternal HIV status in Rwanda: assessing outcomes within the National PMTCT Program. Pan Afr Med J. 2011;9:37.
9. Shapiro RL, Lockman S, Kim S, et al.. Infant morbidity, mortality, and breast milk immunologic profiles among breast-feeding HIV-infected and HIV-uninfected women in Botswana. J Infect Dis. 2007;196:562–569.
10. Newell ML, Coovadia H, Cortina-Borja M, et al.. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet. 2004;364:1236–1243.
11. Koyanagi A, Humphrey JH, Ntozini R, et al.. Morbidity among human immunodeficiency virus-exposed but uninfected, human immunodeficiency virus-infected, and human immunodeficiency virus-unexposed infants in Zimbabwe before availability of highly active antiretroviral therapy. Pediatr Infect Dis J. 2011;30:45–51.
12. McNally LM, Jeena PM, Gajee K, et al.. Effect of age, polymicrobial disease, and maternal HIV status on treatment response and cause of severe pneumonia in South African children: a prospective descriptive study. Lancet. 2007;369:1440–1451.
13. Lepage P, Dabis F, Hitimana DG, et al.. Perinatal transmission of HIV-1: lack of impact of maternal HIV infection on characteristics of livebirths and on neonatal mortality in Kigali, Rwanda. AIDS. 1991;5:295–300.
14. Taha TE, Graham SM, Kumwenda NI, et al.. Morbidity among human immunodeficiency virus-1-infected and -uninfected African children. Pediatrics. 2000;106:E77.
15. Rollins NC, Coovadia HM, Bland RM, et al.. Pregnancy outcomes in HIV-infected and uninfected women in rural and urban South Africa. J Acquir Immune Defic Syndr. 2007;44:321–328.
16. Clerici M, Saresella M, Colombo F, et al.. T-lymphocyte maturation abnormalities in uninfected newborns and children with vertical exposure to HIV. Blood. 2000;96:3866–3871.
17. Nielsen SD, Jeppesen DL, Kolte L, et al.. Impaired progenitor cell function in HIV-negative infants of HIV-positive mothers results in decreased thymic output and low CD4 counts. Blood. 2001;98:398–404.
18. Miyamoto M, Pessoa SD, Ono E, et al.. Low CD4+ T-cell levels and B-cell apoptosis in vertically HIV-exposed noninfected children and adolescents. J Trop Pediatr. 2010;56:427–432.
19. Mussi-Pinhata MM, Motta F, Freimanis-Hance L, et al.. Lower respiratory tract infections among human immunodeficiency virus-exposed, uninfected infants. Int JInfect Dis. 2010;14(suppl 3):e176–182.
20. Sutcliffe CG, Scott S, Mugala N, et al.. Survival from 9 months of age among HIV-infected and uninfected Zambian children prior to the availability of antiretroviral therapy. Clin Infect Dis. 2008;47:837–844.
21. Chintu C, Bhat GJ, Walker AS, et al.. Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): a double-blind randomised placebo-controlled trial. Lancet. 2004;364:1865–1871.
22. Mermin J, Lule J, Ekwaru JP, et al.. Cotrimoxazole prophylaxis by HIV-infected persons in Uganda reduces morbidity and mortality among HIV-uninfected family members. AIDS. 2005;19:1035–1042.
23. Provisional WHO/UNAIDS recommendations on the use of contrimoxazole prophylaxis in adults and children living with HIV/AIDS in Africa. Afr Health Sci. 2001;1:30–31.
24. Gill CJ, Sabin LL, Tham J, et al.. Reconsidering empirical cotrimoxazole prophylaxis for infants exposed to HIV infection. Bull World Health Organ. 2004;82:290–297.
25. Coutsoudis A, Coovadia HM, Kindra G. Time for new recommendations on cotrimoxazole prophylaxis for HIV-exposed infants in developing countries? Bull World Health Organ. 2010;88:949–950.
26. Guinovart C, Bassat Q, Sigauque B, et al.. Malaria in rural Mozambique. Part I: children attending the outpatient clinic. Malar J. 2008;7:36.
27. Gonzalez R, Munguambe K, Aponte J, et al.. High HIV prevalence in a southern semi-rural area of Mozambique: a community-based survey. HIV Med. 2012;13:581–588.
30. Dubowitz LM, Dubowitz V, Goldberg C. Clinical assessment of gestational age in the newborn infant. J Pediatr. 1970;77:1–10.
33. Burns DN, Landesman S, Wright DJ, et al.. Influence of other maternal variables on the relationship between maternal virus load and mother-to-infant transmission of human immunodeficiency virus type 1. J Infect Dis. 1997;175:1206–1210.
34. Mwinga K, Vermund SH, Chen YQ, et al.. Selected hematologic and biochemical measurements in African HIV-infected and uninfected pregnant women and their infants: the HIV Prevention Trials Network 024 protocol. BMC Pediatr. 2009;9:49.
35. Le Chenadec J, Mayaux MJ, Guihenneuc-Jouyaux C, et al.. Perinatal antiretroviral treatment and hematopoiesis in HIV-uninfected infants. AIDS. 2003;17:2053–2061.
36. Burstein Y, Rashbaum WK, Hatch WC, et al.. Alterations in human fetal hematopoiesis are associated with maternal HIV infection. Pediatr Res. 1992;32:155–159.
37. Connor EM, Sperling RS, Gelber R, et al.. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994;331:1173–1180.
38. Fernandez Ibieta M, Ramos Amador JT, Gonzalez Tome MI, et al.. Anaemia and neutropenia in a cohort of non-infected children of HIV-positive mothers [in Spanish]. An Pediatr (Barc). 2008;69:533–543.
39. Lahoz R, Noguera A, Rovira N, et al.. Antiretroviral-related hematologic short-term toxicity in healthy infants: implications of the new neonatal 4-week zidovudine regimen. Pediatr Infect Dis J. 2010;29:376–379.
40. Rieder MJ, King SM, Read S. Adverse reactions to trimethoprim-sulfamethoxazole among children with human immunodeficiency virus infection. Pediatr Infect Dis J. 1997;16:1028–1031.
41. Watkins D, Whitehead MV, Rosenblatt DS. Megaloblastic anemia. In: Orkin SH, Nathan DG, Ginsburg D, et al., eds. Nathan and Oski's Hematology of Infancy and Childhood. Philadelphia, PA: Saunders Elsevier. 2009;chap 11.
42. Prendergast A, Walker AS, Mulenga V, et al.. Improved growth and anemia in HIV-infected African children taking cotrimoxazole prophylaxis. Clin Infect Dis. 2011;52:953–956. doi: 910.1093/cid/cir1029.
43. Brabin BJ, Premji Z, Verhoeff F. An analysis of anemia and child mortality. J Nutr. 2001;131(2S-2):636S–645S; discussion 646S-648S.
44. Embree J, Bwayo J, Nagelkerke N, et al.. Lymphocyte subsets in human immunodeficiency virus type 1-infected and uninfected children in Nairobi. Pediatr Infect Dis J. 2001;20:397–403.
45. Kuhn L, Kasonde P, Sinkala M, et al.. Does severity of HIV disease in HIV-infected mothers affect mortality and morbidity among their uninfected infants? Clin Infect Dis. 2005;41:1654–1661.
46. Chilongozi D, Wang L, Brown L, et al.. Morbidity and mortality among a cohort of human immunodeficiency virus type 1-infected and uninfected pregnant women and their infants from Malawi, Zambia, and Tanzania. Pediatr Infect Dis J. 2008;27:808–814.
47. Coutsoudis A, Pillay K, Spooner E, et al.. Routinely available cotrimoxazole prophylaxis and occurrence of respiratory and diarrhoeal morbidity in infants born to HIV-infected mothers in South Africa. S Afr Med J. 2005;95:339–345.
48. Coutsoudis A, Kindra G, Esterhuizen T. Impact of cotrimoxazole prophylaxis on the health of breast-fed, HIV-exposed, HIV-negative infants in a resource-limited setting. AIDS. 2011;25:1797–1799.
49. Sandison TG, Homsy J, Arinaitwe E, et al.. Protective efficacy of co-trimoxazole prophylaxis against malaria in HIV exposed children in rural Uganda: a randomised clinical trial. BMJ. 2011;342:d1617.
50. Mandomando IM, Macete EV, Ruiz J, et al.. Etiology of diarrhea in children younger than 5 years of age admitted in a rural hospital of southern Mozambique. Am J Trop Med Hyg. 2007;76:522–527.
51. Thera MA, Sehdev PS, Coulibaly D, et al.. Impact of trimethoprim-sulfamethoxazole prophylaxis on falciparum malaria infection and disease. J Infect Dis. 2005;192:1823–1829.
52. Marais BJ, Gie RP, Schaaf HS, et al.. Childhood pulmonary tuberculosis: old wisdom and new challenges. Am J Respir Crit Care Med. 2006;173:1078–1090.
53. Straus WL, Qazi SA, Kundi Z, et al.. Antimicrobial resistance and clinical effectiveness of co-trimoxazole versus amoxycillin for pneumonia among children in Pakistan: randomised controlled trial. Pakistan Co-trimoxazole Study Group. Lancet. 1998;352:270–274.