Immune Activation Markers in Peripartum Women in Botswana: Association with Feeding Strategy and Maternal Morbidity

PLOS ONE, Dec 2019

Hormone levels shift the immune state in HIV-uninfected pregnant and breastfeeding women away from Th1 responses and toward regulation to permit fetal tolerance. Limited data exist on inflammation during pregnancy or postpartum in HIV-infected women, though certain inflammatory markers are associated with adverse health outcomes among HIV-infected persons. We measured hsCRP, D-dimer, IFN-γ, IL-6, IL-10 and TNF-α at 34 weeks gestation and six months postpartum in HIV-infected women from the Botswana Mashi PMTCT trial who were randomized to breastfeeding or formula-feeding. Differences in inflammatory markers between gestation and postpartum periods, and by randomized feeding method, were estimated using generalized estimating equations, adjusting for baseline plasma HIV-1 viral load, CD4 count, calendar time, and antiretroviral treatment status. Additionally, we studied the association between marker concentrations at six months postpartum and major adverse clinical events over the following 4.5 years, using case-cohort sampling and adjusted Cox proportional hazards models. In 86 breastfeeding and 75 formula-feeding women, hsCRP and D-dimer decreased significantly between 34 weeks gestation and six months postpartum, while IFN-γ increased. There was no significant association between inflammatory marker change and randomized feeding method after adjusting for multiple comparisons and removing outliers. In univariate analysis, TNF-α, D-dimer, and IFN-γ concentrations at six months postpartum were significant predictors of subsequent clinical events, and TNF-α remained significant in multivariate analysis (HR = 4.16, p = 0.001). In young HIV-infected women in Botswana inflammatory marker concentrations did not differ significantly between women who breast- vs. formula-fed. However, postpartum TNF-α level was predictive of subsequent adverse clinical event.

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Immune Activation Markers in Peripartum Women in Botswana: Association with Feeding Strategy and Maternal Morbidity

et al. (2014) Immune Activation Markers in Peripartum Women in Botswana: Association with Feeding Strategy and Maternal Morbidity. PLoS ONE 9(3): e89928. doi:10.1371/journal.pone.0089928 Immune Activation Markers in Peripartum Women in Botswana: Association with Feeding Strategy and Maternal Morbidity Elizabeth S. Russell 0 Terence Mohammed 0 Laura Smeaton 0 Baitshepi Jorowe 0 Iain J. MacLeod 0 Risa M. Hoffman 0 Judith S. Currier 0 Sikhulile Moyo 0 Max Essex 0 Shahin Lockman 0 Aftab A. Ansari, Emory University School of Medicine, United States of America 0 1 Harvard AIDS Initiative, Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America, 2 Botswana-Harvard AIDS Institute, Gaborone, Botswana, 3 Center for Biostatistics in AIDS Research, Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America, 4 David Geffen School of Medicine, University of California Los Angeles , Los Angeles , California, United States of America, 5 Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital , Boston, Massachusetts , United States of America Hormone levels shift the immune state in HIV-uninfected pregnant and breastfeeding women away from Th1 responses and toward regulation to permit fetal tolerance. Limited data exist on inflammation during pregnancy or postpartum in HIVinfected women, though certain inflammatory markers are associated with adverse health outcomes among HIV-infected persons. We measured hsCRP, D-dimer, IFN-c, IL-6, IL-10 and TNF-a at 34 weeks gestation and six months postpartum in HIV-infected women from the Botswana Mashi PMTCT trial who were randomized to breastfeeding or formula-feeding. Differences in inflammatory markers between gestation and postpartum periods, and by randomized feeding method, were estimated using generalized estimating equations, adjusting for baseline plasma HIV-1 viral load, CD4 count, calendar time, and antiretroviral treatment status. Additionally, we studied the association between marker concentrations at six months postpartum and major adverse clinical events over the following 4.5 years, using case-cohort sampling and adjusted Cox proportional hazards models. In 86 breastfeeding and 75 formula-feeding women, hsCRP and D-dimer decreased significantly between 34 weeks gestation and six months postpartum, while IFN-c increased. There was no significant association between inflammatory marker change and randomized feeding method after adjusting for multiple comparisons and removing outliers. In univariate analysis, TNF-a, D-dimer, and IFN-c concentrations at six months postpartum were significant predictors of subsequent clinical events, and TNF-a remained significant in multivariate analysis (HR = 4.16, p = 0.001). In young HIV-infected women in Botswana inflammatory marker concentrations did not differ significantly between women who breast- vs. formula-fed. However, postpartum TNF-a level was predictive of subsequent adverse clinical event. - Funding: This study was funded by National Institutes of Health National Institute of Child Health and Human Development Grants: R01 HD37793 and R01 HD44391. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Pregnancy and breastfeeding are associated with modulation of the immune system toward immune regulation and reduced Th1 responses [1,2]. Hormonal changes during pregnancy, which persist in part during breastfeeding, are one cause of this immune shift [3]; breastfeeding and the hormone prolactin have been shown to be associated with B-cell production and reduced inflammatory responses [4,5]. Such data support a hypothesis that breastfeeding could, at least transiently, influence HIV-1 disease progression through regulation of the immune response. Some, but not all [6,7,8], studies suggest that breastfeeding is associated with more rapid CD4 count decline or adverse health outcomes among HIV-infected women [9]. In one trial conducted in Kenya among HIV-infected women without access to antiretroviral treatment (ART), women randomized to breastfeeding had a higher mortality at two-years postpartum compared with those randomized to formula-feeding (10.5% vs. 3.8%, respectively) [10]. Similarly, a trend toward more rapid progression to AIDS or death was observed at six months postpartum in women randomized to breastfeeding in the Botswana Mashi trial, possibly as a result of higher maternal inflammation as suggested by CRP level, despite similar micronutrient level [11]. The cause of this potentially higher rate of HIV disease progression and adverse clinical outcomes associated with breastfeeding among HIVinfected women is unknown, and to our knowledge there are no published data on the association between inflammation an (...truncated)


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Elizabeth S. Russell, Terence Mohammed, Laura Smeaton, Baitshepi Jorowe, Iain J. MacLeod, Risa M. Hoffman, Judith S. Currier, Sikhulile Moyo, Max Essex, Shahin Lockman. Immune Activation Markers in Peripartum Women in Botswana: Association with Feeding Strategy and Maternal Morbidity, PLOS ONE, 2014, 3, DOI: 10.1371/journal.pone.0089928