**2. Other viral infections during pregnancy and their consequences on the fetus and offspring**

### **2.1 Influenza**

Pregnancy is a risk factor for infection by the influenza virus. During the 1918 (Spanish flu) and 1957 (Asian flu) pandemics, mortality in pregnant women was high. During the 1918 pandemic, a 27% mortality rate was recorded, and in 1957, it corresponded to 50% of deaths in women of reproductive age [14]. In seasonal influenza periods, an increased risk of hospitalization was observed in pregnant women at any stage of pregnancy, even without associated comorbidities [15].

There were higher rates of premature births, small for gestational age newborns, and stillbirths in hospitalized pregnant women than those in outpatient treatment [16]. Regarding the occurrence of malformations in the fetuses, the possibility of its teratogenic effect with the occurrence of neural tube defects, cleft lip and palate, and congenital heart disease was evaluated. A direct effect of the virus was unlikely to be the cause of these malformations, since control of fever with antipyretics, and the use of periconceptional folic acid in pregnant women with influenza reduced the risk of these malformations in their offspring (**Table 1**) [17].

Influenza infection in the first trimester of pregnancy increased the risk of schizophrenia by seven times. There was no increased risk in the other trimesters of pregnancy, according to a nested case–control study of 64 participants who were born from 1959 to 1966 and had psychiatric disorders 30 to 38 years later [12].

A cohort study of 196,929 children conducted in California did not find an increased risk of autism spectrum disorder (ASD) in offspring of pregnant women with influenza. In addition, there was no statistically significant relationship of ASD in children whose mothers received influenza vaccination in the first trimester [18].

*Perinatal COVID-19 Pandemic: Short- and Long-Term Impacts on the Health of Offspring DOI: http://dx.doi.org/10.5772/intechopen.99022*


**Table 1.**

*Clinical manifestations of conceptuses resulting from the infection of pregnant women by viral disease.*

## **2.2 Herpes simplex virus (HSV)**

There are two types of herpes viruses: HSV-1 and HSV-2. The latter is predominantly sexual and the etiologic agent of 70–85% of neonatal infections. Although transplacental or upward transmembrane transmission of HSV from the mother to the fetus during pregnancy is uncommon (about 5%), the rate of perinatal transmission during labor and delivery is 80–90%. The risk of neonatal infection is higher in HSV infections that start in late pregnancy (30–50%) than in early pregnancy (1%) [19, 20].

Intrauterine infection is clinically present in the fetus as a characteristic triad of cutaneous (vesicles, erosions, and scars), neurological (intracranial calcifications, microcephaly, and meningoencephalitis), and ophthalmic symptoms (microphthalmia and chorioretinitis). The clinical manifestations of neonatal peripartum and postpartum infection are found in the skin, eyes, and/or mouth (45%) and central nervous system (CNS; 30%) or as disseminated infection (25%). Regarding mortality and neurological prognosis, mortality is higher in disseminated infection cases (approximately 30%), and a worse neurological prognosis occurs in cases with CNS involvement (50%). In the treatment of neonatal HSV, high doses of intravenous acyclovir are indicated, which improves the prognosis and reduces the occurrence of neurological sequelae and delayed child development (**Table 1**) [19, 21].

### **2.3 Rubella**

It is an acute viral disease caused by the RNA Rubella virus of the Togaviridae family. Its clinical characteristics in healthy adults are often self-limited and include low fever, maculopapular rash, lymphadenomegaly, and oropharyngeal pain. The rates of asymptomatic cases range from 25–50% [22].

In pregnancy, maternal infections can determine a poor prognosis for the conceptus, especially when it occurs in the first trimester of pregnancy, which can result in congenital rubella syndrome (CRS), abortion, stillbirth, congenital malformations, and restricted uterine growth of the conceptus. The chances of malformation are 81% and 25% in the first and second trimesters, respectively. Rubella immunization is considered the best measure to combat this infection in the world. CRS has already been significantly eliminated in the USA; however, it cannot be said that it has been completely controlled, since outbreaks are still reported around the world [14].

Rubella virus infection findings can be found from prenatal life to later manifestations after the child's birth and development. Among them, it can cause ocular alterations (cataract, microphthalmia, glaucoma, pigmentary retinopathy, and chorioretinitis), cardiac malformations (peripheral pulmonary artery stenosis, patent duct artery, or ventricular septal defects), and CNS alterations (microcephaly). Children who survive the neonatal period may have severe developmental disabilities (e.g., visual and hearing impairments) and an increased risk of developmental delay, even autism. In the long term, congenital rubella infection may determine an increased risk of endocrinopathies, such as thyroiditis and insulin-dependent diabetes mellitus (**Table 1**) [23, 24].

## **2.4 Cytomegalovírus (CMV)**

CMV, like other viruses in the Herpesviridae family, causes a primary infection and remains latent in the body. Primary infection is generally harmless, but it can be fatal in immunocompromised patients and cause serious fetal damage due to vertical transmission, which can occur intrauterine during childbirth through cervical and blood secretions and postnatally through breastfeeding. Thus, identifying infection in pregnant women is important [25].

In 1–4% of pregnant women, seroconversion to CMV occurs, with most women being seropositive before pregnancy, which does not prevent the infection in about 60% of babies during pregnancy. In newborns, 0.2%–2.5% are infected in utero, and most are asymptomatic (90–80%). About 10–20% of neonates have symptoms at birth, such as intrauterine growth restriction (IUGR), hepatosplenomegaly, microcephaly, chorioretinitis, petechiae, jaundice, thrombocytopenia, and anemia. Of them, 20–30% progress to death, mainly from disseminated intravascular coagulation, liver dysfunction, or bacterial infection. Even asymptomatic children at birth can present sequelae of neurological development, such as mental retardation, motor impairment, sensorineural hearing loss, or visual impairment (**Table 1**) [26, 27].

### **2.5 Human immunodeficiency viruses (HIV)**

Vertical transmission by HIV can occur during pregnancy, childbirth, and during breastfeeding. Test implementation for HIV detection in prenatal care, antiretroviral therapy (ART) use during pregnancy and by the newborn after birth, elective cesarean delivery indication, and breastfeeding contraindication reduce the risk of HIV transmission to the baby from 40% to less than 1% in the USA [28].

Children exposed but not infected to HIV during pregnancy have a worse prognosis than those who are not since their mothers are more likely to have low CD4+ cell counts, detectable viremia, and higher morbidity. In addition, the effects on fetal development due to maternal immune dysfunction and the potential dysfunction of hereditary mitochondria in the fetus due to the exposure of women with HIV in early childhood to ART are unknown [29]. Adverse results in pregnancy associated with HIV infection can result in miscarriages, stillbirths, increased perinatal mortality, IUGR, low birth weight, and chorioamnionitis [30]. In symptomatic pregnant women, an increase in premature births has been observed (**Table 1**) [28].

*Perinatal COVID-19 Pandemic: Short- and Long-Term Impacts on the Health of Offspring DOI: http://dx.doi.org/10.5772/intechopen.99022*

### **2.6 Zika virus (ZIKV)**

ZIKV is a flavivirus transmitted by mosquitoes, mainly by *Aedes aegypti*, and became a major human pathogen during the 2015 pandemic. Although 80% of infected cases are asymptomatic, it can cause adverse results in pregnancy, such as congenital Zika syndrome [31], which presents as microcephaly associated with other brain malformations that can result in severe mental retardation, motor impairments, and eye and hearing abnormalities. In addition, other malformations were observed, such as hypospadias, cryptorchidism, and micropenis [13]. ZIKV infection in mothers during the first trimester is more likely to affect the CNS since this period is vital for neurological development [32].

One cohort study evaluated 244 pregnant women with confirmed ZIKV infection during pregnancy and reported that 223 (91.4%) babies were born alive. Of these, 216 babies had clinical follow-up after birth, of which 130 (60%) children had blood and/or urine samples obtained for ZIKV detection using the real-time polymerase chain reaction (RT-PCR) technique. Results revealed that 13% of the children who underwent brain imaging exams had structural brain abnormalities such as microcephaly, 5.5% who underwent ophthalmological evaluation had ocular changes, and 12.1% who underwent additive evaluation had an abnormal result. In addition, 7.7% were born small for gestational age, which may be associated with IUGR. Meanwhile, 19% who underwent neurological exams had an abnormality in the first 6 months of life. Neurodevelopment assessments carried out after 1 year of age showed that 13.2% had severe developmental delay (**Table 1**) [33].
