Congenital Infections

Although the placenta provides some protection against infection, a wide variety of pathogens can cause congenital infections that are acquired in utero or during the birthing process. Some of the most common infections are referred to as TORCH infections. This section reviews classic TORCH infections in order of incidence and notable emerging congenital infections, including parvovirus B19, syphilis, varicella-zoster virus, and Zika virus.

TORCH infections include the following:

• Toxoplasmosis

• Other (parvovirus B19, syphilis, varicella-zoster, Zika)

• Rubella

• Cytomegalovirus (CMV)

• Herpes simplex virus (HSV)

Except for newborns with HSV infection, many newborns with other congenital infections are asymptomatic and develop clinical manifestations later in infancy or childhood. When neonates with congenital infections are symptomatic, the infection tends to be more severe.

Clinical findings in symptomatic neonates with congenital infection include:

• small for gestational age (SGA)

• hepatomegaly

• splenomegaly

• jaundice

• eye involvement

• hepatitis

• lethargy or irritability

• poor feeding

• seizures

• thrombocytopenia

• anemia

Infections that are associated with specific findings are described below:

• toxoplasmosis: diffuse intracerebral calcifications

• varicella: limb hypoplasia, cutaneous scarring

• rubella: cardiac defects

• HSV: hepatitis, vesicular rash

• CMV: sensorineural hearing loss, periventricular calcifications

• Zika: microcephaly

Cytomegalovirus

Cytomegalovirus (CMV) is by far the most common congenital infection, with an estimated 40,000 cases per year in the United States. CMV is more common than fetal alcohol syndrome and trisomy 21. It is the most common viral cause of mental retardation and the most common nonhereditary cause of congenital hearing loss. Maternal primary infection during pregnancy carries a 30% to 40% risk of transmission to the fetus, whereas risk with nonprimary infection is approximately 1%. Infection earlier in pregnancy is associated with more-severe disease.

Presentation

Most cases of CMV infection (90%-95%) are asymptomatic at birth. However, CMV continues replicating and causing damage in the central nervous system (CNS) after birth. In asymptomatic neonates, 7%-15% will be deaf at one year of age (most often unilateral hearing loss) but 2% can develop severe bilateral hearing loss.

Symptomatic congenital CMV infection is associated with the following:

• stigmata of congenital infection: growth restriction, hepatomegaly, periventricular intracranial calcifications, petechiae (sites of extramedullary hematopoiesis)

• microcephaly: a classic finding in congenital CMV that may not be noted until later in the first year of life

• hearing loss: 50%-75% of symptomatic neonates will be deaf at one year of age (often bilateral and severe)

(Source: Congenital Cytomegalovirus Infection. N Engl J Med 2018.)

(Source: Congenital Cytomegalovirus Infection. N Engl J Med 2010.)

Diagnosis

Congenital CMV disease can be diagnosed prenatally or during the first 3 weeks of life. After the first 3 weeks, the diagnosis is more challenging because positive tests may indicate postnatally acquired CMV.

• CMV polymerase chain reaction (PCR) in urine is the most sensitive diagnostic test in neonates, although PCR can be positive in other body fluids, including saliva.

• PCR positivity in blood is associated with poorer outcomes in neonates.

• Serologic diagnosis in the mother is possible, but IgM can be positive in reactivation of infection as well in new infections.

Management

The prognosis in patients with asymptomatic infection and no hearing loss is reported to be good and associated with the same IQ and academic performance as uninfected controls. In symptomatic infants, treatment with ganciclovir and oral valganciclovir has been shown to improve hearing. In one study, a 6-month course of treatment with valganciclovir improved developmental outcomes and total hearing.

Prevention

Given the ubiquitous nature of CMV infection in pregnancy, prevention is challenging. In one randomized study and several nonrandomized trials, hyperimmune globulin therapy during pregnancy was found to decrease transmission of CMV to the fetus. However, this treatment is not currently standard of care due to conflicting data, including a recent double-blind multicenter trial that did not demonstrate benefit. Although no recommendations exist for routine screening in asymptomatic neonates, several experts advocate for screening of infants failing their newborn screen, given the availability of treatment.

Toxoplasmosis

Toxoplasmosis is the second-most common congenital infection, with 400 to 4000 cases per year in the United States. Most congenital cases are due to maternal primary infection. Maternal infection occurs when the woman ingests oocysts from infected feces, most often from domestic cats (about 12% of cats in the United States are infected), cat litter, or contaminated garden vegetables, or from pseudocysts in undercooked meat. The estimated rate of congenital toxoplasmosis after primary infection during pregnancy is 40%. Infection is more likely later in pregnancy, likely due to a more permissive placental environment, but infection contracted early in pregnancy tends to be associated with more-severe complications. Infection during the first trimester most often results in severe disease or spontaneous abortion.

Presentation

As with many other congenital infections, 70%-90% of neonates with congenital toxoplasmosis are asymptomatic at birth. Up to 80% of infected infants will develop a learning disability, epilepsy, spasticity, or vision impairment later in life.

The classic triad in symptomatic neonates with toxoplasmosis is:

• chorioretinitis (86% of symptomatic cases)

• intracranial calcifications (37% of symptomatic cases)

• hydrocephalus (20% of symptomatic cases)

Diagnosis

Amniotic fluid PCR testing can be used for prenatal diagnosis, or infant serologies (toxoplasmosis infant panel) can be used for postnatal diagnosis. The Centers for Disease Control (CDC) recommends exclusively testing at a reference laboratory. Evaluation of every infant with suspected congenital toxoplasmosis should include:

• Toxoplasma gondii serologies from neonate and mother

• neuroimaging

• cerebrospinal fluid (CSF) analysis (including PCR)

• complete blood count (CBC)

• complete metabolic panel (CMP)

• placental exam for parasites

Management

In the United States, treatment consists of pyrimethamine-sulfadiazine and folinic acid for at least one year. Glucocorticoids should be considered in infants with CNS or eye disease, and a pediatric ophthalmologist should be involved in ongoing care. Patients receiving treatment require close clinical and laboratory monitoring. Recurrent disease can occur later in life because treatment does not eliminate the parasite. Screening of pregnant patients is not routinely recommended, although certain states (e.g., Massachusetts) and countries (e.g., France) include toxoplasmosis in the newborn screen, given the higher incidence. If infection is diagnosed during pregnancy, maternal treatment within 3 weeks of seroconversion reduces transmission risk. However, only 15% of mothers experience symptomatic infection.

Herpes Simplex Virus

When most pediatricians think about congenital herpes simplex virus (HSV) infection, they primarily think of neonatal HSV infection that is acquired intrapartum. In contrast, true congenital herpes is a result of intrauterine transmission due to maternal primary infection during pregnancy.

• Neonatal HSV infection that is untreated can be associated with high morbidity and mortality. Approximately 1500 cases of neonatal herpes occur annually in the United States. Most cases (60%-80%) are in neonates born to mothers with no history of symptomatic genital herpes disease and no symptoms at the time of delivery. HSV-1 and HSV-2 cause similar disease.

• Congenital HSV infection is a rare but devastating disease. Affected neonates have skin scarring, vesicles at birth, low birth weight, CNS involvement, and chorioretinitis.

Neonatal HSV Infection

All cases of neonatal HSV infection are symptomatic. The three classic clinical presentations are:

• Skin, eye, and mouth (SEM) disease accounts for 40% of neonatal HSV cases. Neonates present with vesicles or ulcerations on the skin, sometimes at sites of trauma, around the eyes, or in the mouth. Most SEM cases present in the first 2 weeks of life; presentation of neonatal HSV disease is rare after 6 weeks of life. Early symptoms can be subtle and include increased tearing, conjunctival erythema, or fever. Neonates are considered to have SEM disease if they do not have evidence of CNS or organ involvement. Of note, plasma or blood HSV PCR may be positive in roughly 75% of cases. Without treatment, the infection in 70% of neonates with SEM disease will progress to disseminated disease. Treatment is associated with a low risk of complications and low mortality.

• CNS disease or HSV meningoencephalitis accounts for 30% of cases. Neonates present with seizures, irritability, and poor feeding, with or without SEM signs. Up to 25% of neonates with CNS disease may initially be clinically well appearing. The most sensitive laboratory test for confirming the diagnosis of CNS disease is PCR-positive HSV DNA in CSF, although false negatives are possible and lumbar puncture should be repeated if clinical suspicion remains. CSF analysis usually shows a mononuclear pleocytosis; high erythrocyte count is not a hallmark of HSV CNS disease in neonates. Even with treatment, 50% to 70% of neonates will have neurologic complications.

• Disseminated disease accounts for 25% of cases. Neonates with disseminated disease are usually very ill at clinical presentation and may have pneumonitis, hepatitis, disseminated intravascular coagulation, and clinical sepsis. Less common manifestations include myocarditis and adrenal involvement. Most, but not all, infants have skin lesions, CNS involvement, or both. Disseminated disease is diagnosed in neonates who have positive HSV PCR in blood, CNS, or surface lesions and signs of end-organ involvement. Even with treatment, the mortality rate is roughly 30%.

(Source: Maternal and Neonatal Herpes Simplex Virus Infections. N Engl J Med 2009.)

Diagnosis: All neonates with symptoms of HSV infection should undergo thorough evaluation, including the following:

• lumbar puncture

• PCR surface swabs of conjunctiva, oropharynx, nasopharynx, rectum, skin lesions

• PCR from blood/plasma

• laboratory assessment of end-organ involvement

• neuroimaging

• ophthalmologic exam

Diagnosis usually relies on PCR testing, although viral cultures are also sensitive. The neonate should be placed on contact precautions until HSV infection is ruled out or lesions are crusted over. Treatment consists of intravenous (IV) acyclovir for 14 days for SEM disease and at least 21 days for CNS and disseminated disease, followed by at least 6 months of oral suppressive acyclovir. Serial lumbar punctures are performed in CNS disease to assess clearance by PCR testing; the course of IV acyclovir should be extended if clearance is not obtained. Some experts recommend a similar treatment strategy using blood clearance for disseminated disease. Prolonged therapy improves outcomes and decreases the rate of cutaneous recurrence in the first year of life. During treatment, infants should be monitored for side effects of neutropenia and renal dysfunction.

All children born to mothers with visible genital lesions or prodromal syndromes warrant evaluation and consideration of empiric treatment (see the Red Book Online for further information).

Prevention: Given the widespread nature of HSV infection in women of reproductive age, HSV prevention is important. The American College of Obstetricians and Gynecologists (ACOG) HSV guidelines recommends antiviral prophylaxis for all women with a history of recurrent symptomatic outbreaks in late pregnancy (>36 weeks’ gestation). Prophylaxis reduces the risk of clinical genital herpes by 75% and the need for cesarean section by 40%. According to ACOG, cesarean section is indicated for women with active genital lesions or prodromal symptoms at time of delivery. Cesarean section reduces the risk of intrapartum transmission from 3.7% to 1.7%. ACOG does not recommend screening pregnant women due to poor cost-effectiveness and poor correlation with viral shedding at time of delivery. If a mother with a history of HSV disease has no visible lesions and is asymptomatic, the risk of neonatal HSV infection is 2 per 10,000 births.

Congenital Syphilis

Coinciding with the increase in the rate of syphilis nationally, the incidence of congenital syphilis has continued to increase in the United States since 2012. In 2021, 2855 cases of congenital syphilis were reported, including 220 stillbirths and infant deaths. According to the CDC, the national congenital syphilis rate of 77.9 cases per 100,000 live births in 2021 represents a 30.5% increase relative to 2020 and 219% increase relative to 2017. Congenital syphilis most commonly results from maternal primary or secondary infection during pregnancy. Infection causes fetal death or stillbirth in 40% of cases, and 50% of surviving neonates will develop impairments.

Presentation: Most (75%) neonates are asymptomatic at birth. Clinical features of congenital syphilis are divided into early congenital syphilis (clinical manifestations in the first 2 years of life, and late congenital syphilis (clinical manifestations after age 2 years). All congenital syphilis cases are assumed to have neurosyphilis.

Early Congenital Syphilis

Manifestations of early congenital syphilis during the neonatal period include:

• low birth weight

• hepatosplenomegaly

• jaundice

• syphilitic maculopapular rash

• bullous or desquamating rash

• rhinitis (snuffles)

• pseudoparalysis of extremity (refusal to move an extremity due to bone pain)

• abnormal long bone on radiograph

Manifestations of early congenital syphilis in infants after the neonatal period but during the first 2 years of life include:

• nephrotic syndrome (peak incidence between 2 and 3 months of age)

• osteochondritis, classically of the tibial metaphysis (peak age, 8 months)

Late Congenital Syphilis

Late manifestations of congenital syphilis include:

• CNS and eye involvement

• saddle nose deformity

• Hutchinson teeth (notched, hypoplastic incisors)

• saber shins (anterior bowing of the tibia)

• Clutton joints (bilateral knee effusions)

(Source: Centers for Disease Control and Prevention, Office of the Associate Director for Communications, Division of Public Affairs. Image provided by CDC/Dr. Norman Cole.)

(Source: Congenital Syphilis. N Engl J Med 2019.)

Diagnosis: Congenital syphilis is diagnosed through comparison of maternal and neonate nontreponemal tests (rapid plasma reagin [RPR], Venereal Disease Research Laboratory [VDRL]); PCR; direct fluorescent antibody (DFA) staining; or darkfield microscopy on placenta or neonatal body fluids. All neonates undergoing evaluation for congenital syphilis require:

• CSF analysis including VDRL

• CBC

• long-bone radiograph

Additional evaluation is warranted if a neonate is symptomatic or is born to a mother who was untreated (see 2021 CDC STI treatment guidelines for additional information).

Management: Treatment of congenital syphilis consists of different formulations and durations of penicillin depending on the extent of the disease. A pediatric infectious diseases expert should be consulted and use CDC syphilis treatment guidelines for initial management. Treatment does not prevent eye pathology and saber shins. Prevention relies on maternal screening and treatment at any point during pregnancy.

Varicella-Zoster

True congenital varicella is rare; it accounts for less than 10% of all documented varicella cases and affects <2% of pregnancies. Neonatal varicella is more common, occurs during the first 28 days of life, and results from maternal chickenpox (93% of infections), or rarely, maternal zoster (7% of infections) during the last 2 weeks of pregnancy through the first days of life.

Congenital Varicella

Presentation: Manifestations of congenital varicella syndrome include:

• severe skin scarring

• limb abnormalities (i.e., clubfoot)

• developmental disability

Management: Acyclovir is used to treat congenital varicella. Prevention of congenital varicella is primarily through maternal immunization with varicella-zoster vaccine.

Neonatal Varicella

Presentation: Clinical manifestations of neonatal varicella include:

• diffuse pneumonia

• severe hepatitis

• meningoencephalitis

Management: Prophylaxis for term infants with varicella-zoster immune globulin (VariZIG) is indicated if the mother has chickenpox lesions at any time from 5 days prior to delivery through day 2 of the infant’s life. These infants should be cared for in airborne isolation when in the hospital and separated from their mother while the mother has active lesions and until all lesions are dry and crusted. VariZIG is not needed for maternal zoster exposure; covering localized lesions and hand hygiene is sufficient. Further information regarding administration of VariZIG in exposed infants can be found in the AAP’s Red Book Online.

Zika Virus

Zika virus is a flavivirus and an emerging congenital infection that gained widespread attention in 2015 after a large outbreak. Estimates for risk of vertical transmission vary, but longitudinal studies indicate that approximately 5%-10% of infected neonates have defects at birth (range, 7%-42%). Infection earlier in pregnancy is associated with more-severe defects and higher rates of fetal loss.

Presentation: The hallmark of congenital Zika syndrome (CZS) is microcephaly. Compared with other congenital infections, CZS is notable for the more severe degree of microcephaly; affected neonates frequently have head circumferences that are more than three standard deviations smaller than average.

(Source: Zika Virus. N Engl J Med 2016.)

Zika virus continues to cause damage in tissue after birth, which can result in decelerations in head growth and the development or progression of microcephaly during the first year of life. Neonates with CZS are at risk for numerous neurologic deficits. Many have severe developmental delay, irritability, abnormal sleep patterns, seizures, tremors, hypertonia, and contractures. Experts believe that neonates with microcephaly at birth will likely have severe cognitive and developmental disabilities. Currently, limited data exist on outcomes for infants with milder phenotypes.

Management: Any infant with birth defects and the possibility of maternal Zika exposure should undergo thorough evaluation, including Zika testing through local health departments and the CDC, head ultrasound, ophthalmologic evaluation, and audiologic evaluation within the first month of life. Infants without birth defects born to mothers who had Zika infection during pregnancy should undergo the same thorough evaluation. Currently, CDC recommends screening symptomatic pregnant women, asymptomatic women with ongoing exposure, and pregnant women with abnormal fetal ultrasounds. Practitioners may consider testing asymptomatic pregnant women. There is no treatment for Zika virus infection. Vaccines are currently in development.

Parvovirus B19

An estimated 3%-4% of pregnant women in the United States will be exposed to parvovirus during pregnancy. The risk of vertical transmission to the fetus is 10%-35%. Infection earlier in pregnancy is associated with more-severe fetal outcomes.

Parvovirus causes destruction of erythrocytes, resulting in severe anemia. Infected fetuses develop hydrops fetalis due to anemia. Hydrops develops in approximately 10% of infected fetuses and leads to fetal loss in approximately 34% of cases. In many cases, the hydrops can spontaneously resolve.

Diagnosis is usually made prenatally. Any pregnant woman with a rash and arthropathy should be evaluated for parvovirus with serologies; PCR testing can be performed on amniotic fluid. There is no treatment for parvovirus, although affected fetuses are monitored for anemia and may receive supportive blood transfusions. There are no recommended preventative measures for parvovirus. Exposures to toddlers and child care settings are known risk factors for infection in pregnant women.

Rubella

Rubella is mostly of global health interest given that fewer than 10 cases per year are reported in the United States and all of them are imported. Worldwide congenital rubella occurs where immunity in women of childbearing age is low; World Health Organization (WHO) estimates global vaccine coverage at around 52%.

Congenital rubella occurs due to maternal infection and subsequent viremia during pregnancy. The rates of infection and subsequent symptoms vary significantly with the gestational age at time of maternal infection. The fetus is more likely to be associated with birth defects if infection is earlier in the pregnancy.

• In the first 11 weeks of gestation, 90% of fetuses are infected and 100% will have defects.

• Between gestational weeks 11 and 20, the infection rate is 50% and defect rate is 30%.

• Between gestational weeks 20 and 35, 37% of fetuses are infected and 0% will have defects.

Presentation: One-half to two-thirds of cases are asymptomatic at birth, with children developing clinical manifestations within the first 5 years of life. The most common clinical manifestations are:

• cataracts

• deafness

• motor development deficits

Symptomatic newborns present with a classical triad of:

• cataracts

• cardiac murmur (due to patent ductus arteriosus and pulmonary artery stenosis)

• deafness

(Source: Congenital Rubella. N Engl J Med 2016.)

Management: Congenital rubella is diagnosed with serology and is a reportable disease in the United States. There is no specific treatment for congenital rubella. Prevention is primarily through immunization. Pregnant women found to be nonimmune should be vaccinated after delivery. Avoid rubella vaccination during pregnancy since it is a live-attenuated vaccine. However, more than 500 pregnancies in the United States have occurred in women who have received the vaccine without any increased risk of birth defects and no documented cases of associated congenital rubella.