Preterm Birth in Women With HIV: The Role of the Placenta

Abstract

Maternal HIV infection is associated with an increased risk of preterm birth (PTB). However, the mechanisms underlying this increased risk in women with HIV remain poorly understood. In this regard, it is well-established that labor is an inflammatory process and premature activation of the pro-inflammatory signals (associated with labor) can result in preterm labor which can subsequently lead to PTB. HIV infection is known to cause severe immune dysregulation within its host characterized by altered immune profiles, chronic inflammation and eventually, the progressive failure of the immune system. The human placenta comprises different immune cell subsets, some of which play an important role during pregnancy including participating in the inflammatory processes that accompany labor. It is therefore plausible that HIV/antiretroviral therapy (ART)-associated immune dysregulation within the placental microenvironment may underlie the increased risk of PTB reported in women with HIV. Here, we review evidence from studies that point toward the placental origin of spontaneous PTB and discuss possible ways maternal HIV infection and/or ART could increase this risk. We focus on key cellular players in the maternal decidua including natural killer cells, CD4+ T cells including CD4+ regulatory T cells, CD8+ T cells as well as macrophages.

Markers of intestinal immune activation and inflammation are not associated with preterm birth among women with low level HIV viremia

“…It should be noted that biomarker associations with PTB may not be entirely generalizable and may differ by both biological and non‐biological variables such as race; plasma IL‐1β at the time of delivery was significantly elevated among African American women delivering prematurely compared to those delivering at term 32 . Interferon‐gamma is a pro‐inflammatory cytokine elaborated as part of the Th1 immune response, which plays a role in pregnancy and parturition, particularly in the first and third trimesters 33 . CD4 + T cell count loss and dysregulation are hallmarks of HIV infection and, in the case of PTB, may affect the timing of inflammatory cytokine elaboration and thus PTB risk.…”

“…32 Interferon-gamma is a pro-inflammatory cytokine elaborated as part of the Th1 immune response, which plays a role in pregnancy and parturition, particularly in the first and third trimesters. 33 CD4 + T cell count loss and dysregulation are hallmarks of HIV infection and, in the case of PTB, may affect the timing of inflammatory cytokine elaboration and thus PTB risk. Pro-inflammatory cytokine levels may have been reduced by supplemental progesterone among women with prior PTB.…”

Does Precision-Based Medicine Hold the Promise of a New Approach to Predicting and Treating Spontaneous Preterm Birth?

“…Even with treatment and subsequent immune reconstitution of CD4 T cells, the effects of chronic viral infection potentiate the proinflammatory environment, and some elements of immune dysregulation persist. Specifically, in pregnancy, the result is an upregulation of cytotoxic decidual NK cells and both decidual and peripheral CD8 T cells and an Increase in the proinflammatory subsets of (M1) monocytes and macrophages with cytokine (IL-6, TNFα and IL-1b) and phagocytic immune functions [41,42]. Moreover, both decidual and peripheral T helper subsets are altered, but specifically, at the maternal-fetal interface, there is a skewed T helper cell profile that results in further proinflammatory cytokine release [41].…”

“…The ProSPAR study, a multicenter randomized controlled trial investigating progesterone supplementation in HIV-positive pregnant women on protease inhibitor-based regimens, has been designed to explore the use of progesterone to counteract the potential increased risk of spontaneous PTB in these women, but is not yet underway [51]. Impaired vascular placental development and poor perfusion and placental insufficiency have also been observed in pregnant women with HIV [41]. Moreover, patients on anti-retroviral treatment have been shown to have lower serum progesterone levels, and this is a possible contributor to placental pathology and cause for protease inhibitor-associated PTB [52,53].…”

Systemic inflammation in pregnant women with HIV: relationship with HIV treatment regimen and preterm delivery

“…Data from various settings show that pregnant women with HIV (WHIV) have higher rates of preterm delivery (PTD) than mothers without HIV [2,3]. Although various risk factors such as low CD4 þ T-cell count, high viral load, co-infections, and comorbidities likely contribute to this relationship [4][5][6], higher systemic inflammation is thought to be another contributing factor [7].…”