**3. Maternal infections**

Congenital anomalies caused by intrauterine exposure to infectious pathogens, especially certain viruses, continue to be a significant clinical problem around the world, despite the availability of vaccines (effective against rubella, varicella-zoster, and hepatitis B viruses), drugs (against herpes, toxoplasma, and HIV), and specific and sensitive immunological diagnostic tests for the majority of them. With the help of highly sensitive diagnostic procedures, the incidence of intrauterine infections during pregnancy is estimated to be about 12–20%. These infections cause a wide range of major anomalies and dysfunctions, including deafness, blindness, neurodevelopmental aberrations, growth failure, and congenital cardiac defects [92]. These diseases have been traditionally dealt with under the title of TORCH complex [93] representing toxoplasmosis; other (syphilis, parvovirus); R, rubella (German measles); C, cytomegalovirus; H, herpes simplex virus (**Table 5**).

The fetus and embryo are highly susceptible to infections, especially during the organogenesis period, while those encountered earlier may end in abortion. The fetus does not synthesize IgG and cannot adequately synthesize IgM and IgA until the second half of pregnancy. It has a very poor cellular immunity and the production of the necessary cytokines is suboptimal [94]. Some pathogens may infect the mother and the placenta without showing any clinical symptoms in mother and lead to miscarriage, congenital anomalies, preterm birth, fetal hydrops, and premature rupture of the membrane.

#### **3.1 Toxoplasmosis**

Congenital toxoplasmosis occurs due to the transplacental passage of acute maternal infection with the protozoan organism *Toxoplasma gondii* to the fetus. In neonates, it presents with a wide spectrum of clinicopathological features. It may be clinically asymptomatic and present in a serologically detected form only, at times, to manifest clinically only in later years. On the other end, it may display severe multisystem involvement with debilitating features, such as chorioretinitis, hydrocephalus, and intracranial calcifications [95]. The severity of fetal infection depends on the gestational age during the parasitemia. In early pregnancy, the placenta is an effective barrier to the parasite. The risk of congenital infection increases with increasing gestational age, the incidence being 15–17% in the first, 25% in the second, and 65% in the third trimester [96]. However, the severity and sequelae of the infection are much higher if encountered during early pregnancy. The incidence


#### **Table 5.**

*Some strains of infection causing congonse to teratogens are very diverse and depend on the genetic sensitivity and severity of exposure.*

**27**

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

serological to be due to toxoplasma by age as late as 20 years.

of organ anomalies is 75% with the fetal infection in the first trimester and 5% if the infection happens during the third trimester. Overall, organ anomalies in congenital toxoplasmosis can be detected in 10–20% of infected fetuses. Preterm birth and intrauterine growth retardation are other complications of intrauterine toxoplasmosis [97]. Fetal infection during the first trimester of pregnancy may result in miscarriage or otherwise present as congenital infection with organ abnormalities specific to toxoplasmosis. Fetal infection occurring in the third trimester of pregnancy is often mild and asymptomatic depending upon the maturation of the fetal immune system and may at times only be serologically detected [98]. In addition, clinical symptoms may appear months or even years after birth. In a prospective study, it was reported that visual disturbances developed and detected during the regular well-child visit examinations of newborns asymptomatic at birth were diagnosed by

*Hydrocephalus, chorioretinitis, and intracerebral calcification findings in congenital toxoplasmosis.*

Other features of congenital toxoplasmosis are hydrocephalus, corpus callosum agenesis, cerebral calcification, microcephaly, intrauterine growth retardation, and nonimmune hydrops fetalis (**Figure 4**) [96, 99]. Pathologically, the placenta becomes first infected and appears to be pale, sludge-like, and edematous. Placental vasculitis along with granulomatous inflammatory lesions characterized by polymorphonuclear and lymphocyte infiltration in chorionic villi is specific for the disease. Following fetal transmission, fetal vasculitis develops [100], and the spreading

trophozoites tend to settle in the brain and eyes. They form a granulomatous

development. Vision and hearing disorders may occur in later life [103].

infectious lesion in the brain and its membranes. Eventually tissue necrosis happens around the parasite followed by fibrosis. These pathological processes cause congenital toxoplasmosis-specific microcephaly, cerebral calcifications, hydrocephalus, and chorioretinitis. It is reported that brain damage is more prominent in fetal infection before the 18th week of gestation. Eyes are the most commonly involved organ in congenital toxoplasmosis in which melanin pigment distribution disorder in the uvea and yellow-white edematous retinitis in the retina can be detected [101]. Microphthalmia and optic nerve atrophy may develop in infection encountered during early pregnancy. Deafness may develop in infants due to internal ear involvement. Skeletal muscles and myocardial infections are frequently involved. Moderate pneumonitis emulating viral pneumonia can be detected in the lungs. The liver usually enlarges and may present with pathological changes such as bile stasis, extramedullary hematopoiesis, dystrophic calcification, and portal fibrosis, while the pancreas, genital organs, urinary system, and gastrointestinal organs are generally not affected by the organism. The lymphoid tissue is affected and splenomegaly and adenopathy are commonly seen [102]. Clinically, fever, jaundice, espy direct, respiratory distress due to lung involvement, cardiovascular compromise due to myocarditis, hydrocephalus, and at times convulsions may be seen during neonatal period and in later life. In childhood, retardation is evident in mental and physical

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

**Figure 4.**

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

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

blood phenylalanine levels to safe levels [91].

**3. Maternal infections**

rupture of the membrane.

**3.1 Toxoplasmosis**

• Cytomegalovirus

• Zika virus

*and severity of exposure.*

• Human immunodeficiency virus (HIV)

• *Toxoplasma gondii* (Cong. toxoplasmosis)

• Herpes simplex virus (HSV)

(LNAA) treatment, which is one of the other dietary alternatives used in patients with phenylketonuria, is contraindicated in pregnancy because it does not reduce

Congenital anomalies caused by intrauterine exposure to infectious pathogens, especially certain viruses, continue to be a significant clinical problem around the world, despite the availability of vaccines (effective against rubella, varicella-zoster, and hepatitis B viruses), drugs (against herpes, toxoplasma, and HIV), and specific and sensitive immunological diagnostic tests for the majority of them. With the help of highly sensitive diagnostic procedures, the incidence of intrauterine infections during pregnancy is estimated to be about 12–20%. These infections cause a wide range of major anomalies and dysfunctions, including deafness, blindness, neurodevelopmental aberrations, growth failure, and congenital cardiac defects [92]. These diseases have been traditionally dealt with under the title of TORCH complex [93] representing toxoplasmosis; other (syphilis, parvovirus); R, rubella (German measles); C, cytomegalovirus; H, herpes simplex virus (**Table 5**).

The fetus and embryo are highly susceptible to infections, especially during the organogenesis period, while those encountered earlier may end in abortion. The fetus does not synthesize IgG and cannot adequately synthesize IgM and IgA until the second half of pregnancy. It has a very poor cellular immunity and the production of the necessary cytokines is suboptimal [94]. Some pathogens may infect the mother and the placenta without showing any clinical symptoms in mother and lead to miscarriage, congenital anomalies, preterm birth, fetal hydrops, and premature

Congenital toxoplasmosis occurs due to the transplacental passage of acute maternal infection with the protozoan organism *Toxoplasma gondii* to the fetus. In neonates, it presents with a wide spectrum of clinicopathological features. It may be clinically asymptomatic and present in a serologically detected form only, at times, to manifest clinically only in later years. On the other end, it may display severe multisystem involvement with debilitating features, such as chorioretinitis, hydrocephalus, and intracranial calcifications [95]. The severity of fetal infection depends on the gestational age during the parasitemia. In early pregnancy, the placenta is an effective barrier to the parasite. The risk of congenital infection increases with increasing gestational age, the incidence being 15–17% in the first, 25% in the second, and 65% in the third trimester [96]. However, the severity and sequelae of the infection are much higher if encountered during early pregnancy. The incidence

*Some strains of infection causing congonse to teratogens are very diverse and depend on the genetic sensitivity* 

• Varicella-zoster virus (VZV)

• Parvovirus • Rubella

• *Trypanosoma cruzi* (Cong. Chagas disease)

• *Treponema pallidum* (Cong. syphilis)

**26**

**Table 5.**

**Figure 4.** *Hydrocephalus, chorioretinitis, and intracerebral calcification findings in congenital toxoplasmosis.*

of organ anomalies is 75% with the fetal infection in the first trimester and 5% if the infection happens during the third trimester. Overall, organ anomalies in congenital toxoplasmosis can be detected in 10–20% of infected fetuses. Preterm birth and intrauterine growth retardation are other complications of intrauterine toxoplasmosis [97]. Fetal infection during the first trimester of pregnancy may result in miscarriage or otherwise present as congenital infection with organ abnormalities specific to toxoplasmosis. Fetal infection occurring in the third trimester of pregnancy is often mild and asymptomatic depending upon the maturation of the fetal immune system and may at times only be serologically detected [98]. In addition, clinical symptoms may appear months or even years after birth. In a prospective study, it was reported that visual disturbances developed and detected during the regular well-child visit examinations of newborns asymptomatic at birth were diagnosed by serological to be due to toxoplasma by age as late as 20 years.

Other features of congenital toxoplasmosis are hydrocephalus, corpus callosum agenesis, cerebral calcification, microcephaly, intrauterine growth retardation, and nonimmune hydrops fetalis (**Figure 4**) [96, 99]. Pathologically, the placenta becomes first infected and appears to be pale, sludge-like, and edematous. Placental vasculitis along with granulomatous inflammatory lesions characterized by polymorphonuclear and lymphocyte infiltration in chorionic villi is specific for the disease. Following fetal transmission, fetal vasculitis develops [100], and the spreading trophozoites tend to settle in the brain and eyes. They form a granulomatous infectious lesion in the brain and its membranes. Eventually tissue necrosis happens around the parasite followed by fibrosis. These pathological processes cause congenital toxoplasmosis-specific microcephaly, cerebral calcifications, hydrocephalus, and chorioretinitis. It is reported that brain damage is more prominent in fetal infection before the 18th week of gestation. Eyes are the most commonly involved organ in congenital toxoplasmosis in which melanin pigment distribution disorder in the uvea and yellow-white edematous retinitis in the retina can be detected [101]. Microphthalmia and optic nerve atrophy may develop in infection encountered during early pregnancy. Deafness may develop in infants due to internal ear involvement. Skeletal muscles and myocardial infections are frequently involved. Moderate pneumonitis emulating viral pneumonia can be detected in the lungs. The liver usually enlarges and may present with pathological changes such as bile stasis, extramedullary hematopoiesis, dystrophic calcification, and portal fibrosis, while the pancreas, genital organs, urinary system, and gastrointestinal organs are generally not affected by the organism. The lymphoid tissue is affected and splenomegaly and adenopathy are commonly seen [102]. Clinically, fever, jaundice, espy direct, respiratory distress due to lung involvement, cardiovascular compromise due to myocarditis, hydrocephalus, and at times convulsions may be seen during neonatal period and in later life. In childhood, retardation is evident in mental and physical development. Vision and hearing disorders may occur in later life [103].
