Congenital infections: clinical approach

Congenital infections arise when a pathogen—bacterial, viral, or parasitic—traverses the placenta during pregnancy or is transmitted to the newborn during labor and delivery.

While some congenital infections show no symptoms, others can lead to severe outcomes, including intrauterine growth restriction, microcephaly, hearing loss, and eye abnormalities.

Traditionally, these infections have been categorized using the TORCH mnemonic, representing Toxoplasma, Other, Rubella, Cytomegalovirus, and Herpes simplex virus. The 'Other' category has expanded to include additional pathogens such as Zika virus, Varicella-zoster virus, syphilis, and human immunodeficiency virus.

In cases where a patient's primary concern may indicate a congenital infection, the initial step is to conduct a thorough history and physical examination.

This should involve measuring the newborn's weight, length, and head circumference, alongside performing a fundoscopic examination and a hearing test.

The mother's prenatal history might disclose signs of infection during pregnancy, immunosuppression, or possibly no prenatal care at all.

The history from the neonatal period might note that the infant was small for their gestational age; physical examination might reveal jaundice, hepatosplenomegaly or hsm, rash, or congenital anomalies, indicative of the type of infection. These findings should prompt consideration of a congenital infection.

Here's a clinical tip to remember! Jaundice, hepatosplenomegaly, and rash are common presentations of various congenital infections, so it's advisable to order a CBC and CMP during initial assessments. Typically, the CBC shows anemia and thrombocytopenia, while the CMP may show elevated serum bilirubin levels. These results are non-specific and should be correlated with clinical observations to guide further diagnostic efforts.

Upon suspecting a congenital infection, evaluate for a heart murmur as part of the initial investigation.

If a murmur is detected, congenital rubella should be considered. Reviewing the maternal history may reveal a mild febrile illness or rash in early pregnancy.

Examination of the newborn may display a bluish-purple maculopapular rash, known as a blueberry muffin rash, indicative of dermal hematopoiesis. A systolic or continuous machinery-like heart murmur might be observed, emanating from the left upper sternal border to the back. Eye examinations could uncover cataracts, glaucoma, or salt-and-pepper retinopathy, and a hearing test may show sensorineural hearing loss or SNHL.

To confirm the diagnosis, order a rubella IgM titer and viral cultures from blood, urine, cerebrospinal fluid, and oral or nasal secretions. It’s also useful to check IgG titers and schedule an echocardiogram.

A positive IgM titer or cultures, rising IgG titers, or an echocardiogram revealing patent ductus arteriosus or peripheral pulmonary stenosis confirm a diagnosis of congenital rubella.

Here's an important clinical insight to remember! Congenital rubella has become rare in developed countries due to widespread immunization. However, if an unvaccinated woman contracts the infection during pregnancy, the timing of infection relative to gestational age significantly influences the outcome. Infections occurring before 4 weeks of gestation can lead to pregnancy loss, while those occurring between 4 weeks and 4 months are often associated with congenital anomalies. Infections after 4 months typically do not result in adverse outcomes.

Now, shifting our focus to newborns and infants without a heart murmur, the next step is to measure the head circumference.

If microcephaly is detected, check for the presence of a skin rash. If a rash is present, inquire about maternal contact with cats or cat feces. In cases where microcephaly and a rash are observed but there is no exposure to cats, a cytomegalovirus (CMV) infection should be considered.

The mother might report having had a mild flu-like illness during pregnancy, and the neonatal history could indicate that the infant was born premature or small for gestational age. Typically, these newborns appear asymptomatic at birth but may later develop seizures and developmental delays.

During the physical examination of the newborn, you might see a blueberry muffin rash; fundoscopic examination may reveal chorioretinitis and retinal hemorrhages, and a hearing screen might indicate sensorineural hearing loss.

To confirm a diagnosis, perform a urine or salivary polymerase chain reaction (PCR) test, consider a viral culture of the blood or cerebrospinal fluid, and arrange for an MRI of the brain. Positive PCR results or cultures, along with MRI findings of periventricular cysts or calcifications and ventriculomegaly, confirm congenital CMV infection.

Here's a critical fact: Since most people of reproductive age are seropositive for CMV, routine prenatal screening is generally not performed. The greatest risk to the fetus arises from a primary infection during pregnancy, although reactivation of a latent maternal infection can also result in congenital CMV.

Now, let's turn to cases involving newborns with microcephaly, a rash, and known exposure to cats or cat feces.

In such situations, consider an infection with Toxoplasma gondii. The maternal history might also include exposure to raw meat or milk, or to contaminated soil or water. These newborns are often asymptomatic at birth but may develop seizures.

Physical examination might reveal a blueberry muffin rash, hypotonia, and microphthalmia; an eye examination typically shows chorioretinitis.

To confirm the diagnosis, order Toxoplasma IgA, IgG, and IgM titers, a PCR of the placenta, blood, or cerebrospinal fluid, and an MRI of the brain.

If the titers and PCR results are positive and the imaging shows cortical intracranial calcifications, hydrocephalus, and ventriculomegaly, diagnose congenital toxoplasmosis, caused by the parasite Toxoplasma gondii.

Lastly, for patients presenting with microcephaly but no skin rash, consider a Zika virus infection. Relevant maternal history might include travel or residence in a Zika-endemic area or symptoms of a mild viral illness during pregnancy.

The newborn examination may show severe microcephaly, hypertonia, and possible contractures like clubfoot; the fundoscopic examination may reveal macular scarring and chorioretinal atrophy.

For confirming the diagnosis, perform nucleic acid amplification tests (NAAT) for Zika virus, along with IgM titers and either an MRI of the brain or a head ultrasound. If the NAAT and IgM titers return positive and the imaging shows cerebellar hypoplasia, ventriculomegaly, or lissencephaly, diagnose the infant with congenital Zika infection.

Having covered microcephaly, let's shift our focus to infants with a normal head circumference.

Begin by examining the skin for abnormalities. Should you observe any abnormal skin findings, assess the appearance of the skin. If the patient presents with a vesicular rash or cutaneous scarring, delve into the maternal history for similar symptoms.

If the maternal history records a widespread vesicular rash occurring from 5 days before to 2 days after delivery, consider a diagnosis of varicella-zoster virus infection. This timing suggests that the newborn was infected transplacentally without sufficient time for maternal antibodies to be transferred, placing the newborn at a high risk of severe neonatal varicella, which is associated with significant morbidity and mortality.

These infants may exhibit symptoms of irritability or fever; the physical examination typically shows vesicular skin lesions.

In such cases, conduct a varicella PCR test from the vesicular fluid and possibly obtain an IgM titer, indicating a recent infection. A positive PCR and potentially positive IgM titer would confirm a diagnosis of neonatal varicella-zoster infection.

Here’s a critical fact: The timing of maternal varicella infection greatly affects the severity of sequelae in the newborn. If the maternal rash occurs more than a week before delivery, the newborn is likely to develop a vesicular rash but is at a low risk for severe disease due to adequate transfer of maternal antibodies. Such infants may also develop zoster within the first two years of life. Conversely, fetal infection during the first 20 weeks of gestation can lead to congenital varicella syndrome, which may result in spontaneous abortion, intrauterine fetal demise, or severe congenital anomalies including cerebral cortical atrophy, cerebellar aplasia, microcephaly, and developmental delays, as well as skin scars, aplasia cutis, limb hypoplasia, and ocular defects such as microphthalmia and cataracts.

Now, let’s consider infants born to mothers with active genital lesions at delivery.

In these situations, evaluate for herpes simplex virus (HSV) infection. Congenital HSV typically occurs when the virus is transmitted from the genital tract during labor and delivery. Though less common than other congenital infections, congenital HSV is linked with significant morbidity and mortality. Affected newborns may show signs of irritability and lethargy; seizures or tremors might also occur.

On physical examination, these infants might display fever or temperature instability, a bulging fontanelle, keratoconjunctivitis, or vesicular lesions affecting the skin, eyes, and mouth.

To proceed with the evaluation, order an HSV PCR of the blood and CSF, as well as a viral culture from the skin, eyes, mouth, rectum, or blood. Additionally, an MRI of the brain should be obtained.

If the laboratory tests return positive for PCR or culture, and the MRI shows edema and parenchymal changes indicative of encephalitis, establish a diagnosis of HSV infection.

Here's a vital fact to consider! Neonatal HSV may manifest in one of three forms: a localized infection of the skin, eyes, and mouth; disseminated disease that impacts multiple organs including the liver and lungs; or as encephalitis. These presentations can overlap and lead to significant morbidity and mortality if not addressed swiftly.

Now, turning our attention back to patients with a maculopapular rash, consider the maternal history, which might include limited prenatal care or a genital chancre.

Typically, the newborn examination is normal at birth, but around 1 to 2 months of age, infants may develop a desquamative maculopapular rash frequently observed on the palms, soles, or diaper area; and snuffles, characterized by rhinitis with mucopurulent nasal discharge. Other common signs include pseudoparalysis due to painful bone inflammation during movement; epitrochlear lymphadenopathy; and condyloma lata, wart-like lesions on moist skin areas.

With these clinical signs, evaluate for syphilis by obtaining a VDRL or RPR of the blood or CSF. A positive result confirms congenital syphilis, caused by the spirochete Treponema pallidum.

Here’s a clinical insight! Late congenital syphilis, appearing after two years of age, may present with dental anomalies like Hutchinson teeth and mulberry molars. Affected children might also suffer from deafness, interstitial keratitis, and skeletal changes such as saber shins.

Finally, for newborns with normal head circumference and no abnormal skin findings:

Consider the possibility of congenital human immunodeficiency virus (HIV) infection, typically transmitted during labor and delivery. The maternal history may show limited or no prenatal care or a confirmed diagnosis of HIV. Infected newborns usually appear asymptomatic initially but might later develop opportunistic infections, poor weight gain, and developmental delays.

In the newborn period, physical exam findings are often unremarkable. If HIV is suspected, order an HIV RNA or DNA NAAT. A positive result confirms the diagnosis of HIV infection.

One last clinical pearl! Remember, apart from the traditional TORCH pathogens, several other agents including enterovirus, hepatitis B, parvovirus B19, and Listeria monocytogenes can also cause congenital infections.

Here's a concise summary:

- **Congenital Rubella**: Suspected when there's a heart murmur, cataracts, and hearing loss.

- **Cytomegalovirus (CMV)**: Consider if the infant has microcephaly, a rash, and hearing loss, but no exposure to cats.

- **Toxoplasmosis**: Indicated by microcephaly, a rash, and chorioretinitis, particularly if there's been cat exposure.

- **Zika Virus**: Considered when there is severe microcephaly without a rash.

- **Varicella-Zoster Virus (VZV)**: Suggested by a normal head circumference and a vesicular rash during pregnancy.

- **Herpes Simplex Virus (HSV)**: Diagnose when active genital lesions are present at delivery.

- **Congenital Syphilis**: Suggested by a rash and snuffles appearing at 1 to 2 months of age.

- **Congenital HIV**: Consider if the infant has a normal newborn exam but later develops opportunistic infections and poor weight gain.

Each of these conditions has distinct clinical cues that can guide the initial diagnostic approach and subsequent management.

Ref:

" Concerning Newborn Rashes and Developmental Abnormalities: Part II: Congenital Infections, Ichthyosis, Neurocutaneous Disorders, Vascular Malformations, and Midline Lesions. " Pediatr Rev. (2023 Aug 1;44(8):447-465. )

"Focus on diagnosis: congenital infections (TORCH) [published correction appears in Pediatr Rev. 2012 Mar;33(3):109]." Pediatr Rev (2011;32(12):537-542. )

"Nelson Essentials of Pediatrics. 8th ed. " Elsevier (2023.)

"American Academy of Pediatrics Textbook of Pediatric Care. 2nd ed. " American Academy of Pediatrics (2017)

"The Term Newborn: Congenital Infections. " Clin Perinatol (2021;48(3):485-511. )

"Practice bulletin no. 151: Cytomegalovirus, parvovirus B19, varicella zoster, and toxoplasmosis in pregnancy." Obstet Gynecol (2015 Jun;125(6):1510-152)

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