Differential impact of antiretroviral therapy initiated before or during pregnancy on placenta pathology in HIV-positive women

Abstract

a,d , for the PIMS Study Group Objective: To examine the association between timing of antiretroviral treatment (ART) initiation in HIV-infected women and placental histopathology. Design: A nested substudy in a larger cohort of HIV-infected women which examined the association between ART status and birth outcomes. Methods: Placentas (n ¼ 130) were examined for histopathology from two ART groups: stable (n ¼ 53), who initiated ART before conception and initiating (n ¼ 77), who started ART during pregnancy [median (interquartile range) 15 weeks gestation (11)(12)(13)(14)(15)(16)(17)(18)]. Using binomial regression we quantified associations between ART initiation timing with placental histopathology and pregnancy outcomes. Results: One-third of all placentas were less than 10th percentile weight-for-gestation and there was no significant difference between ART groups. Placental diameter, thickness, cord insertion position and foetal-placental weight ratio were also similar by group. However, placentas from the stable group showed increased maternal vascular malperfusion (MVM) (39.6 vs. 19.4%), and decreased weight (392 vs. 422 g, P ¼ 0.09). MVM risk was twice as high [risk ratios 2.03 (95% confidence interval: 1.16-3.57); P ¼ 0.01] in the stable group; the increased risk remaining significant when adjusting for maternal age [risk ratios 2.04 (95% confidence interval: 1.12-3.72); P ¼ 0.02]. Furthermore, MVM was significantly associated with preterm delivery and low birth weight (P ¼ 0.002 and <0.0001, respectively). Conclusion: Preconception initiation of ART was associated with an increased MVM risk, and may contribute to placental dysfunction. The association between MVM with preterm delivery and low birth weight suggests that a placenta-mediated mechanism likely links the putative association between long-term use of ART and adverse birth outcomes.

T cell Homeostatic Imbalance in Placentae from Women with HIV in the absence of Vertical Transmission

“…Interestingly, all cases of maternal vascular malperfusion (MVM) were reported in placentae from PWH and possibly reflects placental injury affecting maternal vasculature and perfusion and increasing the risk of an adverse birth outcome [42]. We have previously reported on MVM in placentae from PWH on long-term ART, an incidence of about 27% overall, similar to Kalk et al [6,21]. It is likely that HIV and/or ART exposure alters factors involved in vascular development, resulting in placental insufficiency and increased risk of adverse birth outcomes [8,9,43].…”

“…Specimens were macroscopically examined and samples from the umbilical cord, placental membranes and placental disk were obtained based on the Amsterdam Placental Workshop Group Consensus Statement [20]. Briefly, four blocks were prepared from each placenta; including a roll of the placental membranes, two cross sections of the umbilical cord; and full-thickness sections of the placental parenchyma and examined in detail as previously described [21].…”

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

“…The mechanisms underlying the increased risk of PTB in women who initiate ART before pregnancy are not well-understood. However, in a recent study on pregnant women initiating ART either before or during pregnancy, we found that women who initiated ART before pregnancy were more likely to have maternal vascular malperfusion (MVM) ( 13 ). Furthermore, MVM was significantly increased in placentae from women who delivered preterm ( 13 ).…”

“…However, in a recent study on pregnant women initiating ART either before or during pregnancy, we found that women who initiated ART before pregnancy were more likely to have maternal vascular malperfusion (MVM) ( 13 ). Furthermore, MVM was significantly increased in placentae from women who delivered preterm ( 13 ). MVM refers to a constellation of gross and histologic findings that represent injury affecting maternal vasculature and circulation in the placenta and is linked to adverse birth outcomes including but not limited to PTB ( 28 ).…”

“…Placentae from women with HIV have been shown to have increased features of placental insufficiency including maternal vascular malperfusion in addition to acute and chronic inflammation ( 12 ). These patterns of injury have further been associated with adverse birth outcomes such as PTB and available evidence links poor placental function to compromised fetal development ( 13 , 14 ). Women with HIV manifest an altered placental T cell profile where the decidua appears to mirror the systemic circulation during HIV infection characterized by a dysregulated CD4:CD8 T cell ratio and this dysregulation positively correlates with maternal viral load ( 15 ).…”