Low Immune Activation in Early Pregnancy Is Associated With Preterm But Not Small-for-gestational-age Delivery in Women Infected With Human Immunodeficiency Virus Initiating Antiretroviral Therapy in Pregnancy: A Prematurity Immunology in HIV-infected Mothers and their Infants Study (PIMS) Case-control Study in Cape Town, South Africa

Abstract

Background Mechanisms underlying an association between HIV or antiretroviral therapy (ART) during pregnancy with risk of preterm delivery (PTD) and small-for-gestational-age (SGA) remain unclear. We explored the association between cellular immune activation and PTD or SGA in HIV-infected women initiating ART during or before pregnancy. Methods HIV infected women enrolled at median 15 weeks gestation; were analyzed for immune markers, matched on ART initiation timing (15 women initiated pre- and 15 during pregnancy). There were 30 PTD (delivery <37 weeks), 30 SGA (weight for age ≤10 th centile) cases and 30 controls (term, weight for gestational age >25 th centile) as outcomes. Lymphocytes, monocytes and dendritic cell populations, their activation status or functionality were enumerated by flow cytometry. Results PTD cases initiating ART in pregnancy showed decreased CD8 + T cell, monocyte and dendritic cell activation, increased classical (CD14 +CD16 -) and intermediate (CD14 +CD16 +) monocyte frequencies, and decreased inflammatory monocytes (CD14 dimCD16 +) compared to SGA cases and term controls (all p<0.05). Allowing for baseline viral load, the immune markers remained significantly associated with PTD but only in women initiating ART in pregnancy. Lower monocyte activation was predictive of PTD. TLR ligand-induced IFN-α and MIP-1β levels in monocytes were significantly lower in PTD women initiating ART in pregnancy. Conclusion Low immune activation, skewing towards anti-inflammatory monocytes and lower monocyte cytokine production in response to TLR ligand stimulation were associated with PTD but not SGA among women initiating ART in, but not before, pregnancy suggesting immune anergy to microbial stimulation as a possible underlying mechanism for PTD in women initiating ART in pregnancy.

Pregnancy outcomes in women living with HIV and HIV‐negative women in South Africa: Cohort analysis based on bias‐corrected gestational age

“…A key confounder in the relationship between ART initiation timing and adverse outcomes is maternal disease stage; previously women initiating ART preconception initiated treatment because of advanced HIV disease status. In the era of our cohort, ART had become common from before or early pregnancy; we showed in a case‐control subset of women in our PIMS cohort that early and prolonged ART use may lead to correction of the immediate immunological response following ART initiation 36 …”

“…In the era of our cohort, ART had become common from before or early pregnancy; we showed in a case-control subset of women in our PIMS cohort that early and prolonged ART use may lead to correction of the immediate immunological response following ART initiation. 36…”

Association between maternal HIV infection and the risks of preterm birth and low birth weight in Chengdu, China: a propensity score matching approach

“…Another study found that immunosuppression and a decrease in CD4+T cells in HIV-infected pregnancies may be attributed to LBW. In comparison to women with greater CD4+ cell counts, those with CD4+ cell counts <350 cells/mm 3 had a higher chance of having LBW infants (RR 1.57, 95 % CI 1.16 to 2.12) 28. Second, abnormal placenta and altered placental angiogenesis: lower placenta weight and smaller placenta area were examined in the HIV-infective mothers, both of which were significantly associated with lower infant birth weight 29.…”

“…In comparison to women with greater CD4+ cell counts, those with CD4+ cell counts <350 cells/mm 3 had a higher chance of having LBW infants (RR 1.57, 95 % CI 1.16 to 2.12). 28 Second, abnormal placenta and altered placental angiogenesis: lower placenta weight and smaller placenta area were examined in the HIV-infective mothers, both of which were significantly associated with lower infant birth weight. 29 Placental angiogenic processes are critical for birth outcomes, and aberrant levels of two angiogenic factors throughout gestation were linked to APOs.…”

Predictors of adverse pregnancy outcomes among Kenyan women with HIV on antiretroviral treatment in pregnancy

“…This may be due to immune activation or immune compromise with resultant vulnerability to other infections [15]. Dysregulation of inflammatory cytokine production at the maternal-fetal interface may also contribute to APOs, and this may differ by ART regimen and timing [16][17][18][19][20]. Other HIV-related factors, including clinical stage of disease and CD4 þ cell count, have been associated with APOs [10,13,[21][22][23].…”