Influence of infection during pregnancy on fetal development

Abstract

Infection by bacteria, viruses, and parasites may lead to fetal death, organ injury, or limited sequelae depending on the pathogen. Here, we consider the role of infection during pregnancy in fetal development including placental development and function, which can lead to fetal growth restriction. The classical group of teratogenic pathogens is referred to as 'TORCH' (Toxoplasma gondii, others like Treponema pallidum, rubella virus, cytomegalovirus, and herpes simplex virus) but should include a much broader group of pathogens including Parvovirus B19, Varicella zoster virus, and Plasmodium falciparum to name a few. In this review, we describe the influence of different infections in utero on fetal development and the short- and long-term outcomes for the neonate. In some cases, the mechanisms used by these pathogens to disrupt fetal development are well known. Bacterial infection of the developing fetal lungs and brain begins with an inflammatory cascade resulting in cytokine injury and oxidative stress. For some pathogens like P. falciparum, the mechanisms involve oxidative stress and apoptosis to disrupt placental and fetal growth. An in utero infection may also affect the long-term health of the infant; in many cases, a viral infection in utero increases the risk of developing type 1 diabetes in childhood. Understanding the varied mechanisms employed by these pathogens may enable therapies to attenuate changes in fetal development, decrease preterm birth, and improve survival.

Figure 1

Bacteria, viruses and parasites known to influence fetal development

Figure 2

Our conceptual model of events leading to fetal lung injury in utero. First, bacteria from the vagina traffics into the choriodecidual space. Inflammation (e.g. IL-8 and IL-6) is produced by the decidua and/or membranes, which diffuses into the amniotic fluid and fetal lung. Fetal lung injury is induced by inflammatory mediators with significant genes shown involved in inflammation, cellular growth, and angiogenesis. IL, Interleukin; AF, amniotic fluid.

Figure 3

Our conceptual model of events leading to fetal brain injury in utero. Bacteria traffic from the lower genital tract into the uterus. Inflammatory mediators (e.g., IL-6 or IL-1β) and/or bacteria may reach the fetal circulation directly through placental transmission into the umbilical cord or indirectly through the amniotic fluid and subsequent spread to the fetal lungs and pulmonary circulation by amniotic fluid exchange. Once bacteria or cytokines enter the blood, inflammation may result in disruption of tight and adherens junctions in the blood-brain or blood-CSF barrier leading to pathogen or cytokine trafficking across disrupted tight junctions with subsequent activation of astrocytes and microglia. The degree of gray and white matter injury depend on the extent of microglial and astrocyte activation as well as the infectious source, duration, and degree of inflammation.