Low immune activation in early pregnancy is associated with preterm but not small-for-gestational age delivery in HIV infected women initiating antiretroviral therapy in pregnancy: a PIMS case-control study in Cape Town, South Africa.

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 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.