**3.4 Cytomegalovirus (CMV)**

*Congenital Anomalies in Newborn Infants - Clinical and Etiopathological Perspectives*

Despite the availability of an effective vaccine, over 100,000 cases of congenital rubella syndrome are reported every year. Congenital rubella infection occurs via transplacental transmission of the RNA virus to the fetus during maternal viremia [104]. The infection may be asymptomatic, present with mild common cold-like symptoms, or devastating. Clinical features such as fetal-neonatal cataract and glaucoma, microphthalmia; patent ductus arteriosus, cardiac septal defects, pulmonary vascular stenosis, sensorineural deafness, fetal growth restriction, thrombocytopenia, anemia, hepatosplenomegaly, hepatitis, direct hyperbilirubinemia, chronic diffuse interstitial pneumonia, osseous changes, and even chromosomal abnormalities are grouped in congenital rubella syndrome. Fetal infection is found to cause necrosis, apoptosis, and division errors of cells involved in organogenesis, resulting in malformations. The mitotic activity is noted to be reduced in rubellainfected cells. Another potential mechanism is that of a direct viral invasion into vasculatures causing tissue necrosis without inflammation (**Figure 5**) [105]. The capsid of the rubella virion (RV) plays an important role in mitochondrial damage and viral replication complexes, as evidenced by immunogold electron microscopy and indirect immunofluorescence studies. Cardiolipin is a phospholipid associated exclusively with mitochondria, and its presence in rubella virions suggests the involvement of the internal mitochondrial membrane of cells in viral proliferation. Both the mitochondrial distribution and morphology are abnormal in RV-infected cells, and the mitochondria tend to cluster in the perinuclear region along with viral replication complexes. In advanced infection electron-dense plaques between opposing mitochondria are formed, and the mitochondrial cristae may be lost in RV-infected cells [106]. The risk of congenital malformation is low after 17 weeks of IU life. It is thought that the immune response mechanisms (immunoglobulins like IgM, IgG, and IgA, T cells, natural killer cells, and interferons) appear during the second half of pregnancy and are not sufficiently mounted against the infection

Parvovirus, a non-enveloped single-stranded DNA virus, is the only member of the *Parvoviridae* family known to cause human disease. Failure to produce the virus in cell culture has made it difficult to elucidate the pathophysiology. The symptoms of parvovirus B19-related infection are usually related to the host's immunological and hematological status. Since the immunological functions of the fetus are not optimum, parvovirus B19 infection may cause intrauterine infection, presenting as fetal anemia, hydrops fetalis, congenital malformations, and at times fetal-neonatal

*Chorioretinitis, cataract, and blueberry muffin skin rash due to congenital rubella.*

**3.2 Rubella**

during the first trimester [107].

**3.3 Parvovirus**

death [108].

**28**

**Figure 5.**

CMV is the most common organism causing congenital infection around the world. The frequency is reported as 5–12/1000 live births. The risk of transmission increases with increasing gestational age, but the severity of fetal disease decreases. Approximately 10–15% of the fetuses infected in early pregnancy are symptomatic at birth, and in those cases severe systemic invasive disease marked by intrauterine growth restriction, hepatosplenomegaly, cholestasis, transaminitis, abnormal liver function tests, pneumonia, pancytopenia, hemolytic anemia, petechia, purpura, and central nervous system anomalies is noted [112]. Central nervous system findings in congenital CMV infection are quite diverse. Microcephaly, sensorineural hearing loss, chorioretinitis, and convulsion are the most common presentations. Abnormal neuroradiological findings, including ventriculomegaly-hydrocephalus, increased periventricular echogenicity and calcification, white matter involvement, and lenticulostriate vasculopathy, are detected in 70% of the cases. Neuronal migration anomalies, temporal cystic periventricular leukomalacia, occipital intraventricular septa, cerebral atrophy, corpus callosum dysgenesis, and cerebellar hypoplasia are other relatively uncommon findings [113].

The inflammation process in the placenta infected with CMV is characterized by ICAM-1 expression on the membranes of placental trophoblasts, with enhancement in the adhesion of maternal blood cells [114]. During the mother's primary infection, virus-bearing infectious leukocytes transmit CMV infection to the trophoblasts, and through the trophoblasts, the CMV reaches the stromal fibroblasts and fetal endothelial capillary cells [115]. Further in the process the virus is directed toward and proliferates in the major target fetal organs, namely, the brain, liver, inner ear, spinal cord, kidney, and the vascular epithelium. Viral DNA replication takes place in the infected organs with the production of infectious viral progeny. Neurons, oligodendroglia, microglia/macrophages, and neural progenitor/ stem cells, especially astrocytes, are particularly predisposed to CMV infections and may act as hosts in the replication and assist in the spread of the virus. The activated apoptosis during organogenesis is the important mechanism that leads

**Figure 6.**

*Congenital CMV-induced chorioretinitis, intracerebral calcifications, and blueberry muffin skin rash.*

to malformations [114, 116]. The sensitivity of CMV IgM test, which is frequently used for the diagnosis of congenital CMV infection, is low, and the false positivity rate is high. Urine and saliva cultures for the virus are the recommended investigations for the identification of infection (**Figure 6**) [113, 116].

The Infectious Diseases Committee and the American Academy of Pediatrics recommend that ganciclovir treatment be considered in patients with congenital CMV infection with symptomatic central nervous system involvement (microcephaly, intracranial calcification, hearing impairment, and retinitis). Ganciclovir is a deoxyguanosine analogue and the first antiviral drug shown to be effective in the treatment of CMV infection in humans. It is first phosphorylated to ganciclovir monophosphate by a viral kinase encoded by the CMV gene UL97 during infection. Then cellular kinases catalyze the formation of ganciclovir diphosphate, and ganciclovir triphosphate is a competitive inhibitor of deoxyguanosine triphosphate incorporation into DNA and preferentially inhibits viral DNA polymerases. Ganciclovir triphosphate inhibits the binding of deoxyguanosine triphosphate to viral DNA, slows viral DNA chain construction, and forms noninfectious viral DNA fragments. The concentration of ganciclovir triphosphate in infected cells is 10 times that of uninfected cells with a half-life in the cell longer than 24 hours [117]. Ganciclovir triphosphate also serves as a poor substrate for chain elongation, thereby disrupting viral DNA synthesis via a second route. However, clinically, ganciclovir treatment remains controversial in congenital CMV infection due to the need of long-term intravenous therapy, frequency of side effects, and limited healing from the infection. The use of valganciclovir, the L-valyl ester of ganciclovir, which is rapidly metabolized to ganciclovir in the body after oral administration, is increasing as with this treatment the need of parenteral therapy, hospitalization, and the risk of catheterrelated infection are eliminated. The antiviral therapy may reduce the risk and duration of hospitalization in infants and is also reported to have a positive long-term effect on hearing [117, 118].

#### **3.5 Varicella-zoster**

The incidence of varicella infection in pregnancy is approximately 0.4–2.4/1000. The infection can result in severe fetomaternal complications. Spontaneous abortion with varicella infection is observed in the first trimester [119]. Congenital varicella syndrome occurs secondary to infection in the first two trimesters, and the infection is thought to result from the reactivation of varicella and invasion of the placenta, similar to the mechanism of herpes zoster. The syndrome generally presents with an abnormal development of musculoskeletal system, dermatomal pattern of skin lesions, and segmental dysfunction of somatic

**31**

*The Pathogenesis of Congenital Anomalies: Roles of Teratogens and Infections*

and autonomic nervous systems [120]. About 2% of fetuses exposed to the virus during the first 20 weeks of pregnancy (particularly during the 6th–20th week of gestation) may develop congenital varicella syndrome if the mother had no prior exposure to varicella. If varicella-zoster virus (VZV) infection occurs later during pregnancy (i.e., in the middle of the second or in the third trimester), the fetal immune system may be able to mount a response to the invading organism, typically resulting in a benign course. Embryopathy is not reported after 28 weeks. In one study, the incidence of varicella syndrome due to varicella infection during the first 20 weeks of pregnancy was reported as 0.91%, and the syndrome was not observed after 28 weeks [121]. In congenital varicella syndrome, the frequencies of occurrences of various systemic anomalies are as follows: skin lesions approximately 70%; limb hypoplasia 46–72%; nervous system abnormalities, such as cortical atrophy, microcephaly, and mental retardation, 48–62%; eye anomalies such as microphthalmia, cataract, and chorioretinitis 44–52%; and muscle hypoplasia, gastrointestinal, genitourinary, and cardiovascular system abnormalities,

In 2016, the US Centers for Disease Control and Prevention pronounced Zika virus infection as a risk for severe CNS defects in the fetuses of infected mothers. After crossing the placenta, the virus proliferates in the fetal brain tissues and infects the progenitor neural cells, leading to the growth failure and death of neural cells [123]. Although very few cases of Zika embryopathy are reported, the Zika virus-related CNS abnormalities are noted to be as follows: microcephaly, ventriculomegaly, cerebral calcifications, absent corpus callosum, and atrophy of the

Congenital anomalies present with significant financial, social, and moral issues

and questions to the family and society and are difficult to rehabilitate. In utero exposure to teratogenic agents and infection are the two most important causes of nongenetic, acquired anomalies presenting at birth. Teratogens are environmental and other agents that can cause structural or functional anomalies, or even demise in the embryo or fetus. TORCH (toxoplasmosis, others, rubella, cytomegalovirus, herpes) and other more recently identified infections during pregnancy may present with embryo-fetal systemic lesions of varying severity and result in significant morbidity and mortality. Most of the teratogen-induced and several infectionassociated anomalies are preventable. Multiple factors determine the occurrence, presentation, and severity of congenital malformations in neonates who are exposed in utero to teratogens or infections. The individual response to teratogens is very diverse and depends on the genetic sensitivity of the product of conception

*DOI: http://dx.doi.org/10.5772/intechopen.92580*

and developmental delay 7–24% [122].

**3.6 Zika virus**

**4. Summary**

cerebellum and brainstem.

and the severity of exposure.

*The Pathogenesis of Congenital Anomalies: Roles of Teratogens and Infections DOI: http://dx.doi.org/10.5772/intechopen.92580*

and autonomic nervous systems [120]. About 2% of fetuses exposed to the virus during the first 20 weeks of pregnancy (particularly during the 6th–20th week of gestation) may develop congenital varicella syndrome if the mother had no prior exposure to varicella. If varicella-zoster virus (VZV) infection occurs later during pregnancy (i.e., in the middle of the second or in the third trimester), the fetal immune system may be able to mount a response to the invading organism, typically resulting in a benign course. Embryopathy is not reported after 28 weeks. In one study, the incidence of varicella syndrome due to varicella infection during the first 20 weeks of pregnancy was reported as 0.91%, and the syndrome was not observed after 28 weeks [121]. In congenital varicella syndrome, the frequencies of occurrences of various systemic anomalies are as follows: skin lesions approximately 70%; limb hypoplasia 46–72%; nervous system abnormalities, such as cortical atrophy, microcephaly, and mental retardation, 48–62%; eye anomalies such as microphthalmia, cataract, and chorioretinitis 44–52%; and muscle hypoplasia, gastrointestinal, genitourinary, and cardiovascular system abnormalities, and developmental delay 7–24% [122].

#### **3.6 Zika virus**

*Congenital Anomalies in Newborn Infants - Clinical and Etiopathological Perspectives*

*Congenital CMV-induced chorioretinitis, intracerebral calcifications, and blueberry muffin skin rash.*

recommend that ganciclovir treatment be considered in patients with congenital CMV infection with symptomatic central nervous system involvement (microcephaly, intracranial calcification, hearing impairment, and retinitis). Ganciclovir is a deoxyguanosine analogue and the first antiviral drug shown to be effective in the treatment of CMV infection in humans. It is first phosphorylated to ganciclovir monophosphate by a viral kinase encoded by the CMV gene UL97 during infection. Then cellular kinases catalyze the formation of ganciclovir diphosphate, and ganciclovir triphosphate is a competitive inhibitor of deoxyguanosine triphosphate incorporation into DNA and preferentially inhibits viral DNA polymerases. Ganciclovir triphosphate inhibits the binding of deoxyguanosine triphosphate to viral DNA, slows viral DNA chain construction, and forms noninfectious viral DNA fragments. The concentration of ganciclovir triphosphate in infected cells is 10 times that of uninfected cells with a half-life in the cell longer than 24 hours [117]. Ganciclovir triphosphate also serves as a poor substrate for chain elongation, thereby disrupting viral DNA synthesis via a second route. However, clinically, ganciclovir treatment remains controversial in congenital CMV infection due to the need of long-term intravenous therapy, frequency of side effects, and limited healing from the infection. The use of valganciclovir, the L-valyl ester of ganciclovir, which is rapidly metabolized to ganciclovir in the body after oral administration, is increasing as with this treatment the need of parenteral therapy, hospitalization, and the risk of catheterrelated infection are eliminated. The antiviral therapy may reduce the risk and duration of hospitalization in infants and is also reported to have a positive

The incidence of varicella infection in pregnancy is approximately 0.4–2.4/1000. The infection can result in severe fetomaternal complications. Spontaneous abortion with varicella infection is observed in the first trimester [119]. Congenital varicella syndrome occurs secondary to infection in the first two trimesters, and the infection is thought to result from the reactivation of varicella and invasion of the placenta, similar to the mechanism of herpes zoster. The syndrome generally presents with an abnormal development of musculoskeletal system, dermatomal pattern of skin lesions, and segmental dysfunction of somatic

tions for the identification of infection (**Figure 6**) [113, 116].

long-term effect on hearing [117, 118].

**3.5 Varicella-zoster**

to malformations [114, 116]. The sensitivity of CMV IgM test, which is frequently used for the diagnosis of congenital CMV infection, is low, and the false positivity rate is high. Urine and saliva cultures for the virus are the recommended investiga-

The Infectious Diseases Committee and the American Academy of Pediatrics

**30**

**Figure 6.**

In 2016, the US Centers for Disease Control and Prevention pronounced Zika virus infection as a risk for severe CNS defects in the fetuses of infected mothers. After crossing the placenta, the virus proliferates in the fetal brain tissues and infects the progenitor neural cells, leading to the growth failure and death of neural cells [123]. Although very few cases of Zika embryopathy are reported, the Zika virus-related CNS abnormalities are noted to be as follows: microcephaly, ventriculomegaly, cerebral calcifications, absent corpus callosum, and atrophy of the cerebellum and brainstem.

#### **4. Summary**

Congenital anomalies present with significant financial, social, and moral issues and questions to the family and society and are difficult to rehabilitate. In utero exposure to teratogenic agents and infection are the two most important causes of nongenetic, acquired anomalies presenting at birth. Teratogens are environmental and other agents that can cause structural or functional anomalies, or even demise in the embryo or fetus. TORCH (toxoplasmosis, others, rubella, cytomegalovirus, herpes) and other more recently identified infections during pregnancy may present with embryo-fetal systemic lesions of varying severity and result in significant morbidity and mortality. Most of the teratogen-induced and several infectionassociated anomalies are preventable. Multiple factors determine the occurrence, presentation, and severity of congenital malformations in neonates who are exposed in utero to teratogens or infections. The individual response to teratogens is very diverse and depends on the genetic sensitivity of the product of conception and the severity of exposure.

*Congenital Anomalies in Newborn Infants - Clinical and Etiopathological Perspectives*
