The Impact of Infection in Pregnancy on Placental Vascular Development and Adverse Birth Outcomes

Abstract

Healthy fetal development is dependent on nutrient and oxygen transfer via the placenta. Optimal growth and function of placental vasculature is therefore essential to support in utero development. Vasculogenesis, the de novo formation of blood vessels, and angiogenesis, the branching and remodeling of existing vasculature, mediate the development and maturation of placental villi, which form the materno-fetal interface. Several lines of evidence indicate that systemic maternal infection and consequent inflammation can disrupt placental vasculogenesis and angiogenesis. The resulting alterations in placental hemodynamics impact fetal growth and contribute to poor birth outcomes including preterm delivery, small-for-gestational age (SGA), stillbirth, and low birth weight (LBW). Furthermore, pathways involved in maternal immune activation and placental vascularization parallel those involved in normal fetal development, notably neurovascular development. Therefore, immune-mediated disruption of angiogenic pathways at the materno-fetal interface may also have long-term neurological consequences for offspring. Here, we review current literature evaluating the influence of maternal infection and immune activation at the materno-fetal interface and the subsequent impact on placental vascular function and birth outcome. Immunomodulatory pathways, including chemokines and cytokines released in response to maternal infection, interact closely with the principal pathways regulating placental vascular development, including the angiopoietin-Tie-2, vascular endothelial growth factor (VEGF), and placental growth factor (PlGF) pathways. A detailed mechanistic understanding of how maternal infections impact placental and fetal development is critical to the design of effective interventions to promote placental growth and function and thereby reduce adverse birth outcomes.

Keywords: adverse birth outcomes; infection; placenta; pregnancy; vascular development.

Figure 1

Overview of key angiogenic and vasculogenic factors mediating placental function and how they may be disrupted in the context of maternal infection. Placental vasculogenesis and angiogenesis are processes that are vital for placental vascular development and function. These processes depend on a fine balance between pro-angiogenic and anti-angiogenic pathways. The vascular endothelial growth factor (VEGF) family of proteins (including PlGF – placental growth factor) are pro-angiogenic mediators. VEGF and PlGF bind VEGF receptor 1 [fms-like tyrosine kinase (Flt-1)] to induce vessel proliferation and sprouting. Alternative splicing of Flt-1 results in soluble Flt-1 (sFlt-1) that is anti-angiogenic. Angiopoietin-1 (Ang-1) binds its tyrosine-kinase receptor Tie2 inducing vessel maturation, whereas angiopoietin-2 (Ang-2) promotes vessel destabilization and angiogenesis. Tight control of these pathways is essential for proper vascular development, remodeling, robust placental function, and healthy birth outcomes. Maternal infection (e.g., malaria, HIV-1) can result in immune activation and inflammation which dysregulates these tightly regulated processes, contributing to poor birth outcomes.

Figure 2

Malaria in pregnancy as a model for infection-driven dysregulation of placental vascular development as a common mechanism underlying adverse birth outcomes. During malaria in pregnancy, parasitized erythrocytes (PE) activate the maternal complement cascade. Complement component C5a acts synergistically with circulating parasite-associated bioactive molecules (i.e., Plasmodium falciparum glycosylphosphatidylinositol anchor molecules; PfGPI) to trigger an inflammatory response at the materno-fetal interface. This inflammatory host response dysregulates the tight balance of angiogenic factors required for placental vascular development leading to aberrant placental vascularization, placental dysfunction, and adverse birth outcomes. Existing evidence for other infections during pregnancy supports this model as a common mechanism underlying adverse birth outcomes in maternal infection [reproduced from Conroy et al., 2009].