Provision of combined antiretroviral therapy in HIV-positive pregnant women and the increased risk of apoptosis-related intra-uterine growth restriction

Human immunodeficiency virus (HIV) infection during pregnancy is still a major problem worldwide, especially in developing countries. Although administration of anti-retroviral drugs has succeeded in reducing mother-to-child transmission, poor obstetric outcomes such as intrauterine growth restriction (IUGR) and preterm labor still significantly affect this population. IUGR and preterm labor are associated with many short-term and long-term adverse outcomes such as low APGAR score, longer neonatal intensive care unit (NICU) stay, and increased neonatal morbidity and mortality. These conditions are thought to be related to pathologic apoptosis in the placenta, induced either by the presence of viral antigens or by the effect of combined antiretroviral therapy (ART). Some viral antigens are thought to be involved in apoptosis by mediating bystander apoptosis and increasing reactive oxygen species (ROS) production. These viral antigens such as the glycoprotein Env and gp120 and gp41 subunits may trigger caspase-dependent and caspase-independent apoptotic pathways. In some studies, combined ART has been reported to exert mitochondrial DNA toxicity, causing DNA dysfunction. The toxicity of antiretroviral therapy was first described in 1988 through observations of damaged muscle fibers which are characteristic of myopathy, in patients who consume zidovudine. Thus, it is suggested that both viral antigens and combined ART may activate apoptosis cascades, ultimately disturbing placental functions.