Immune activation markers in peripartum women in Botswana: association with feeding strategy and maternal morbidity

Abstract

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.

Figure 1. Selection of subcohorts.

For Aim 1, we selected at random 86 women from the breastfeeding and 75 women from the formula-feeding arms of the Mashi Study. For Aim 2, a case was defined as a woman who had a six-month postpartum sample available, and experienced a major adverse clinical event after, but not before, eight months postpartum. Women randomly selected for Aim 1 who did not experience any adverse clinical events comprised the controls for Aim 2.

Figure 2. Association of viral load and CD4 count with cytokine expression.

Viral load (red) is shown on the left y axis, and CD4 count (blue) on the right y axis. (a) association with cytokine expression at enrollment; (b) association with cytokine expression at six months postpartum.

Figure 3. Changes in inflammatory marker concentrations between the third trimester and six months postpartum.

The effect of time between enrolment (antepartum) and six months postpartum on inflammatory marker levels – either as absolute concentrations or percentage of women with detectable marker expression – was tested using generalized estimating equations (GEEs). Time and time*group interaction terms are reported, adjusted for CD4 and viral load at enrolment, and whether HAART was initiated between sampling times.