BACKGROUND

Congenital infections acquired in utero are a significant cause of neonatal mortality and childhood morbidity. The original concept of the TORCH acronym was to group five infections with similar presentations: toxoplasmosis, “other” (traditionally referring to syphilis), rubella, cytomegalovirus (CMV), and herpesvirus. However, recent additions have expanded the scope of this term to include infections such as human immunodeficiency virus (HIV), enteroviruses, parvovirus B19, and varicella. The incidence of TORCH infections in the United States is variable, ranging from 0.7% for CMV, the most common congenital viral infection, to ≤1 in 10,000 for rare infections such as rubella and toxoplasmosis. A high index of suspicion for congenital infection and awareness of the prominent features of the most common etiologies will help to facilitate early diagnosis and management.

Pathophysiology

Transplacental spread and invasion of the bloodstream after maternal infection is the primary route for intrauterine infection, though it is also possible for the fetus to be infected by extension from adjacent infections of the peritoneum and the genitalia during the birth process or during invasive procedures such as fetal monitoring and intrauterine transfusion.¹

In order for the maternal immune system to tolerate pregnancy, the placenta serves as a protective barrier that shields the fetus from maternal humoral and cell-mediated immune activity. Without immunologic mechanisms necessary to eradicate an infecting organism, the fetus is susceptible to infection, and a state of immunologic tolerance is often established. The fetus is particularly vulnerable during the first trimester of pregnancy, when the most complex events in embryogenesis occur, including development of sensory organs such as the eyes and ears.

The outcome of fetal infection depends on several factors, including gestational age at the time of infection, organism virulence, degree of associated placental damage, and maternal disease severity.¹ Primary infection is also likely to have more significant effects on the fetus than recurrent infection. Infection during the first few weeks of gestation may cause embryonal death and resorption, prior to recognition of pregnancy. Spontaneous abortion and stillbirth are among the earliest recognizable effects of fetal infection after 6 to 8 weeks of pregnancy. In infants who are live-born, effects of fetal infection may present as preterm birth, intrauterine growth restriction (IUGR), congenital anomalies, or local or systemic signs of infection. Alternatively, fetal infection may present in live-born infants as the complete absence of any clinical signs of disease, with abnormalities becoming obvious only as the child develops and fails to reach appropriate physiologic or developmental milestones.

CLINICAL PRESENTATION

Intrauterine infection with CMV, herpes simplex virus (HSV), syphilis, rubella, toxoplasmosis, and enterovirus may present in the neonatal period with signs of widely disseminated disease caused by microbial invasion and proliferation over weeks or months prior to delivery.¹ In such infants it can be difficult to determine whether infection was acquired in utero, intrapartum, or postpartum. However, if the onset of clinical symptoms after birth occurs within the minimal incubation period for the disease, it is likely that infection was acquired before delivery.

Cytomegalovirus

Congenital CMV infection may present at birth with generalized petechiae, direct hyperbilirubinemia, hepatosplenomegaly, purpuric rash, microcephaly, seizures, focal or general neurologic deficits, retinitis, and intracranial calcifications (usually periventricular) (Figure 128-1A). However, 90% of infants with congenital CMV infection are asymptomatic at birth, and most cases are undetected prior to discharge from the birth hospital. Infants who are symptomatic at birth are at highest risk of long-term neurological sequelae, including sensorineural hearing loss, mental retardation, cerebral palsy, and vision impairment. However, approximately 10% to 15% of asymptomatic, infected infants will also experience later, long-term adverse neurological outcomes.²

Herpes Simplex Virus

Intrauterine infection with HSV is rare (approximately 1 in 300,000 deliveries), compared with the vast majority of neonatal HSV infections which result from exposure during delivery. Intrauterine HSV transmission is highest during the first 20 weeks of pregnancy, resulting in abortion, stillbirth, and congenital anomalies in infants who survive.³ Perinatal mortality is high, and infected infants usually have clinical abnormalities identified at birth. Typical presentation is a triad of clinical findings: cutaneous manifestations (i.e. scarring, active lesions, hypo- and hyperpigmentation, aplasia cutis, and/or an erythematous macular exanthem), ophthalmologic findings (i.e. micro-opthalmia, retinal dysplasia, optic atrophy, and/or chorioretinitis), and neurologic involvement (i.e. microcephaly, encephalomalacia, hydranencephaly, and/or intracranial calcification).³

Clinical presentation for infants infected with HSV during delivery can be divided into three categories, each associated with different outcomes and manifestations. Neonates with infection confined to the skin, eyes, and mucosa (SEM) comprise about 45% of most case series, most often presenting with cutaneous or mucosal vesicular lesions.⁴ By definition, infants in this category have no central nervous system (CNS) or visceral organ involvement, although systemic therapy is required to prevent further disease progression. Infants with SEM HSV disease often have recurrent cutaneous outbreaks in early childhood. The second category is HSV infection with CNS involvement, comprising 30% of cases.⁴ CNS disease can present with lethargy, poor feeding, or seizures, with or without cutaneous lesions. Morbidity with CNS involvement is higher with HSV-2 than HSV-1 infection, with potential long-term sequelae including developmental delay, epilepsy, blindness, and cognitive disabilities. Relapses of CNS infection may also occur during childhood, further increasing morbidity. Disseminated HIV infection is the third category and occurs in 25% of cases. Mortality risk is highest for these infants (approximately 30%), as it is associated with multiorgan dysfunction. Clinical presentation can be indistinguishable from bacterial sepsis.⁴

Syphilis

Congenital syphilis results from fetal infection with the spirochete Treponema pallidum via transplacental transmission. In recent years, the rate of congenital syphilis in the United States has increased, now affecting 10 per 100,000 births.⁵ Untreated syphilis during pregnancy results in fetal or neonatal death in up to 40% of cases. Infected live-born infants are often asymptomatic, with only severe cases clinically apparent at birth. Untreated asymptomatic infants can subsequently develop severe sequelae in the first few weeks, months, or years of life.

Early presentation of congenital syphilis, manifesting within the first few months to first year of life, can include hepatosplenomegaly, jaundice, lymphadenopathy, meningoencephalitis, chorioretinitis, and mucocutaneous findings such as maculopapular erythema, bullae, and desquamation. Infants may fail to thrive and have a characteristic mucopurulent or blood-stained nasal discharge causing “snuffles.” Osteochondritis of the long bones and ribs may cause pseudoparalysis of the limbs with characteristic radiologic changes. Late presentation of congenital syphilis, manifesting after the first 1 to 2 years of life, can include gummatous ulcers of the nose, septum, or hard palate; periosteal lesions resulting in saber shins and frontal and parietal bossing; juvenile paresis and tabes secondary to neurosyphilis; optic atrophy and interstitial keratitis; and progressive sensorineural deafness. Dental abnormalities include Hutchinson incisors (small, widely spaced, peg-shaped, notched upper incisors with thin discolored enamel), hypoplastic enamel, and mulberry molars. “Hutchinson triad” is a pathognomonic constellation of findings that consist of interstitial keratitis, Hutchinson teeth, and sensorineural hearing loss.

Toxoplasmosis

Toxoplasma gondii is a protozoan parasite transmittable through contact with cat feces or consumption of contaminated foods, such as meat containing infective tissue cysts or unwashed produce from contaminated soil. The risk of transplacental infection is lower (10% to 25%) when maternal infection occurs in the first trimester compared with the third trimester (60% to 90%). However, severe sequelae, including stillbirth and neonatal death, are more likely when infection is acquired in the first trimester. Overall risk of congenital infection from acute prenatal infection ranges from approximately 20% to 50%. Most neonates with congenital toxoplasmosis are asymptomatic; however, clinical presentation can include hepatosplenomegaly, lymphadenopathy, maculopapular rash, jaundice, anemia, and thrombocytopenia. A classic triad of clinical findings associated with this disease is chorioretinitis with intracranial calcifications (typically generalized) (Figure 128-1B) and hydrocephalus.

Enteroviruses

Enteroviruses are small, single-stranded RNA viruses belonging to the Picornaviridae family. Congenital enterovirus infection often presents with a maternal history of viral illness including fever, respiratory concerns, or abdominal symptoms preceding or immediately following delivery. There may also be a history of viral symptoms in other family members. Signs of infection in neonates may include temperature instability, irritability, lethargy, jaundice, emesis, abdominal distension, diarrhea, respiratory distress, and macular or maculopapular rash. Most affected neonates have mild disease, however, a small percentage develop severe sequelae including meningoencephalitis, myocarditis, pneumonia, hepatitis, and coagulopathy. Myocarditis in particular confers high-mortality risk for affected infants and has special diagnostic significance for enterovirus infection.

Rubella

Since licensure of live attenuated rubella vaccines in the late 1960s, the number of reported US cases of congenital rubella infection has declined dramatically to <1 case per year. Risk of infection and associated defects is highest during the first 12 weeks of gestation. Severe sequelae including spontaneous abortion and stillbirth are possible outcomes of infection early in pregnancy. Infection in the first trimester is considered to be uniformly teratogenic, while birth defects are very rare among infants infected after 20 weeks of gestation.⁶ Common congenital manifestations include cataracts, congenital heart disease (most commonly patent ductus arteriosus or peripheral pulmonary artery stenosis), hearing impairment, and developmental delay. Affected infants usually present with more than one sign or symptom, however, they may present with a single defect. Eye findings including glaucoma, chorioretinitis, retinopathy, and cataracts have special diagnostic significance for this infection. In some cases, congenital rubella may only be identified years after birth due to isolated hearing defects.

Human Immunodeficiency Virus

Although the transmission rate of HIV from an untreated mother to the fetus is estimated to be about 25%, this risk can be reduced to <2% with use of antiretroviral regimens and obstetrical intervention (i.e. zidovudine or nevirapine and elective cesarean section at 38 weeks of pregnancy), and by avoiding breastfeeding. Infants with congenital HIV infection are usually asymptomatic at birth and through the first few months of life. The median age of onset for clinical signs is approximately 3 years, but many children remain asymptomatic for more than 5 years. Clinical presentation of congenital HIV infection can include failure to thrive, persistent diarrhea, recurrent suppurative infections, and opportunistic infections that occur weeks to months or years after birth.

Varicella

Varicella-zoster virus (VZV) is one of eight herpes viruses known to cause human infection; primary infection during pregnancy carries significant implications for both maternal and fetal health. Congenital varicella syndrome due to transplacental infection is rare and mostly occurs with infection between 8 and 20 weeks gestation. Characteristic findings in affected neonates may include: low birth weight; cutaneous scars in a dermatomal distribution; eye findings of cataracts, chorioretinitis, microphthalmos, or nystagmus; hypoplastic limbs; gastrointestinal abnormalities including bowel stenosis; and neurological findings of cortical atrophy or seizures. Varicella is not generally associated with spontaneous fetal loss, preterm birth, or stillbirth.

Parvovirus B19

Parvovirus B19 is a single-stranded, DNA virus that preferentially infects rapidly dividing cells and is cytotoxic for erythroid progenitor cells. The risk for transplacental transmission from an infected mother to the fetus is between 10% to 35%, and is highest in the first and second trimesters of pregnancy. Infection prior to 20 weeks gestation is associated with a higher fetal mortality rate (14.8%) compared with infection after 20 weeks (2.3%). Presentation is typically related to severe anemia, high-output cardiac failure, and extramedullary hematopoiesis, resulting in nonimmune hydrops fetalis, ascites, pleural effusion, and pericardial effusions. Persistent anemia due to hematopoietic suppression can also persist for months after birth.

DIFFERENTIAL DIAGNOSIS

As shown in Table 128-1, clinical presentations for infections acquired in utero share many features, including but not limited to IUGR, microcephaly, cataracts, hearing loss, hepatosplenomegaly, cutaneous findings, and thrombocytopenia. Consequently, in the absence of maternal history or prenatal laboratory results that suggest a specific infection (e.g. positive syphilis serology), the differential diagnosis for each TORCH infection includes all of the other TORCH or TORCH-like infections. It is also important to note that neonates with suspected or confirmed congenital HIV or syphilis infection should also be considered at risk for other sexually transmitted infections including gonorrhea and Chlamydia trachomatis.