Question

Why is it so important to be knowledgeable about teratogens?

What are the "critical factors" that can also affect development? How do they influence prenatal development? How do they compare to teratogens?

Answer 1

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.The prevalence of viral infection during pregnancy has been hypothesized to contribute to some cases of intra-amniotic inflammation associated with preterm birth. Several studies using quantitative real-time PCR to test amniotic fluid in the second trimester have determined that between 2.2 and 8.4% of low-risk women with normal fetuses on ultrasound have detectable genome sequences from at least one of eight viruses: adenoviruses, herpes simplex virus, Varicella zostervirus (VZV), human herpes virus 6 (HHV6), human cytomegalovirus (HCMV), Epstein–Barr virus (EBV), parvovirus B19, and enteroviruses (Gervasi et al. 2012). HHV6 was the most common virus detected in amniotic fluid at 1.0%. Viral invasion of the amniotic cavity was not associated with a significant change in the amniotic fluid white blood cell count, glucose, or IL6 level; however, CXCL10 correlated with HCMV viral load. Fetal involvement appears rare with in uteroinfection by these viruses. Exploring mechanisms of disease for the viruses with the greatest potential to cause fetal morbidity and mortality require further discussion of rubella virus, HCMV, and VZV. A focus on human immunodeficiency virus (HIV) is also appropriate based on its global impact.

The devastating teratogenic effects of the rubella virus were first reported in 1941 by Dr Norman Gregg, who recognized congenital cataracts and other deformities following rubella (German measles) infection in the mother during pregnancy (Gregg 1941). The first and early second trimesters appear to be the most vulnerable periods in pregnancy for developing CRS secondary to a maternal infection. CRS occurs in nearly all fetuses affected before 8 weeks and there are few defects if maternal rubella is acquired after 17 weeks (Lee & Bowden 2000). Manifestations of CRS are numerous (Table 1) with deafness being most common. Pathological analysis of tissues from aborted fetuses infected with rubella reveal widespread non-inflammatory necrotic damage of the eyes (lens, iris, and retina), heart (myocardium, endothelial cells in cardiac vessels), brain (vascular necrotic lesions in cerebral blood vessels), and ears (epithelium of cochlear duct) (Tondury & Smith 1966). The teratogenicity of rubella is likely due to several mechanisms including a direct cytopathic effect of the virus, which may trigger apoptosis, and inhibition of mitosis through cytoskeletal derangements resulting in a partial arrest of organ development (Lee & Bowden 2000). A teratogenic mechanism that may be shared between rubella and HCMV is the interaction of viral products with the host retinoblastoma (Rb) gene, which regulates fetal cell growth (Atreya et al. 1998). In the case of rubella virus, the binding of the putative replicase (NSP90; critical for virus replication) to the Rb protein in vivo facilitates rubella virus replication, yet alters the normal function of Rb in cellular growth leading to teratogenesis. HCMV produces an immediate-early gene product (IE2 86), which interacts with Rb and has been hypothesized to partially explain the teratogenicity of HCMV (Fortunato et al. 1997).

The observation of an increased risk of type 1 diabetes following a congenital rubella infection prompted further study of the risk of neonatal or childhood viral infections on acquisition of type 1 diabetes (Menser et al. 1978). Epidemiological studies have also associated other perinatal viral infections with an increased risk of acquiring type 1 diabetes; these viruses include enteroviruses, coxsackie B viruses, HCMV, or mumps virus (Ramondetti et al. 2012). Type 1 diabetes is thought to occur as the result of molecular mimicry between viral pathogens (e.g., HCMV peptides) and pancreatic islet β-cell proteins in these cases. According to this theory, neonatal T cells reactive to viral peptides become cross-reactive to an antigen in the insulin-producing pancreatic β islet cells resulting in an autoimmune destruction of the islet cells and type 1 diabetes. Evidence for this theory remains controversial and difficult to study given the inaccessibility of the pancreas and long latency between viral infections and disease onset.