Neonatal herpes simplex virus infection

Neonatal herpes simplex virus (HSV) infection is a potentially life-threatening infection caused by HSV-1 or HSV-2, most commonly transmitted from a birthing parent with active genital tract disease during delivery. Neonatal HSV infection can manifest as skin, eye, and mouth (SEM) disease; central nervous system (CNS) disease; and disseminated disease. SEM disease is characterized by vesicular lesions localized to the skin, eyes, and/or mouth; CNS disease manifests with meningoencephalitis; and disseminated disease is characterized by signs of neonatal sepsis and multiorgan involvement. Diagnosis is confirmed by detection of HSV via NAAT or viral culture from skin or mucosal surfaces, vesicles, cerebrospinal fluid, and/or blood. Immediate treatment with acyclovir is indicated for all forms of the disease. Asymptomatic neonates with exposure to HSV at delivery require additional monitoring, which includes assessment for signs of infection and diagnostic testing for HSV, regardless of the form of delivery (i.e., vaginal or cesarean). Prevention is critical and includes management of genital herpes in pregnancy and avoiding exposure of neonates to active lesions.

• US incidence: ∼ 1 case per 2,000 live births per year ^[1]
• Worldwide incidence: ∼ 1 case per 10,000 live births per year ^[2]

Epidemiological data refers to the US, unless otherwise specified.

• Pathogen: HSV-2 or HSV-1 ^[1]
• Transmission ^[1]
  • Occurs more commonly after primary infection in the birthing parent rather than recurrent infection ^[1]
  • Modes of transmission
    • Intrauterine (rare): contracted via ascending infection through intact or ruptured amniotic membranes ^[1]
    • Peripartum (most common): contracted during birth via contact with active genital tract disease ^[1]
    • Postnatal: contracted through close contact (e.g., oral secretions, skin lesions) with infected individuals such as caregivers and siblings ^[1]

In over 75% of cases, HSV infection occurs in neonates whose birthing parent has no history or clinical features of genital HSV. ^[1]

Clinical features depend on when the infection occurs. Symptoms may manifest at birth or develop up to 6 weeks later. ^[1][3]

Congenital HSV infection ^[4][5]

Congenital HSV is rare and caused by intrauterine infection. Features include:

• CNS abnormalities (e.g., microcephaly, hydranencephaly)
• Ocular abnormalities (e.g., microphthalmia, chorioretinitis) ^[6]
• Skin abnormalities (e.g., scarring, aplasia cutis congenita)

Peripartum or postpartum infection

• Localized skin, eye, and/or mouth (SEM) disease ^[1]
  • Vesicular oral and/or skin lesions
  • Ocular involvement (e.g., neonatal HSV conjunctivitis, keratitis) ^[7]
• CNS disease
  • Signs of meningoencephalitis (e.g., bulging fontanelle, seizures)
  • Skin involvement is common. ^[5][8]
• Disseminated disease ^[1]
  • Signs of sepsis (see "Clinical features of neonatal infection")
  • Symptoms of multiple organ involvement (e.g., viral pneumonia, clinical features of liver failure)
  • Most patients also have CNS and skin involvement. ^[1][4]

Vesicular skin lesions occur in up to two-thirds of infants with HSV with CNS and/or disseminated disease but may not manifest concurrently with other symptoms. ^[1]

Consider HSV in infants up to 6 weeks of age with vesicular skin lesions, persistent fever with negative cultures, and/or symptoms of meningitis, encephalitis, or sepsis. ^[1]

Indications for diagnostic testing include neonates with suggestive clinical features and asymptomatic HSV-exposed neonates. See also "Approach to suspected neonatal bacterial infection" and "Management of the well-appearing febrile infant ≤ 60 days of age."

Neonatal HSV testing ^[1]

• Diagnostic studies: Obtain all of the following in patients with suspected neonatal HSV infection.
  • Viral culture or HSV NAAT of samples from all of the following locations: ^[1];
    • Conjunctivae
    • Mouth
    • Nasopharynx
    • Anus
    • Skin vesicles (if present)
  • HSV NAAT from CSF and serum
  • Serum alanine aminotransferase (ALT)
• Findings
  • HSV isolation from any sample confirms diagnosis.
  • HSV may be detected in the blood in all three disease forms (i.e., SEM, CNS, and disseminated disease).
  • ↑ ALT: may suggest disseminated disease ^[1][8]

A positive serum NAAT cannot distinguish between disseminated disease, CNS disease, and SEM disease. Interpret findings in conjunction with clinical presentation. ^[1]

Additional diagnostic testing ^[1]

• All neonates with HSV infection
  • Ophthalmology evaluation: to assess for eye involvement
  • Neuroimaging: for a baseline evaluation of the brain
    • Preferred: MRI brain
    • Alternatives: CT or ultrasound brain
• Additional studies based on suspected sites of involvement
  • Disseminated disease
    • Diagnostics for neonatal sepsis: to exclude other neonatal infections
    • Coagulation studies: may show findings consistent with disseminated intravascular coagulation (DIC)
    • Chest x-ray: may show lung involvement
  • CNS disease ^[9]
    • CSF analysis: may show pleocytosis with negative Gram stain ^[1][10]
    • Electroencephalography: may show periodic lateralized epileptiform discharges ^[9]
    • See also "Diagnosis of HSV encephalitis."

• Neonates with confirmed or suspected neonatal HSV infection ^[1]
  • Admit to hospital and start IV acyclovir.
  • See "Management of neonates with confirmed or suspected HSV infection" for details.
• Asymptomatic neonates with a birthing parent with HSV ^[1]
  • Management depends on:
    • Presence of active genital herpes lesions at the time of delivery
    • Birthing parent's history of genital herpes before pregnancy
    • Timing of infection during pregnancy
  • See "Asymptomatic neonates exposed to HSV" for details.

SEM disease caused by HSV has a good prognosis if detected and treated early. ^[3]

Initial management ^[1][10]

• Admit and start contact precautions.
• Initiate cardiovascular (e.g., IV fluids) and respiratory support as needed.
• Urgently consult neonatology and infectious diseases.
• Start IV acyclovir. ^[1]
• Consult ophthalmology to assess for eye involvement; additional topical treatment may be indicated.

Ongoing management ^[1]

• SEM disease: Continue IV acyclovir for 14 days.
• CNS disease and/or disseminated disease
  • Continue IV acyclovir for at least 21 days. ^[1]
  • CNS involvement
    • Obtain CSF HCV NAAT before the end of treatment.
    • If CSF HSV is positive: Consult infectious diseases to determine treatment duration.
• All patients
  • Start oral suppressive therapy with acyclovir (off-label) after completion of IV therapy. ^[1]
    • Continue for 6 months, with monthly dosage adjustments to account for growth. ^[1]
    • Monitor absolute neutrophil count for neutropenia 2 and 4 weeks after starting, then monthly for the duration of treatment.
  • Obtain baseline neuroimaging (MRI preferred).
• Follow up with specialists (neurology, ophthalmology) as needed.

Recurrent skin lesions occur in up to 50% of infants, often within 1–2 weeks of stopping suppressive therapy. ^[1]

Birthing parent with active genital lesions ^[1]

• Perform additional evaluation of all neonates exposed to active genital herpes lesions at delivery, regardless of type of delivery (i.e., vaginal or cesarean section).
• Do not delay bathing of the neonate. ^[11]
• Perform HSV NAAT and culture (if available) on active lesions in the birthing parent and, if positive, determine HSV type to guide management.

Perform diagnostics for neonatal HSV and start IV acyclovir in any infant with clinical features of neonatal HSV regardless of the birthing parent's infection status.^[1]

Suspected initial genital infection in birthing parent

• Send HSV-1 and HSV-2 IgG antibodies for the birthing parent.
• When the neonate is 24 hours of age: ^[1]
  • Perform neonatal HSV testing.
  • Initiate IV acyclovir. ^[1]
• Further management depends on symptoms and laboratory studies.
  • Neonate becomes symptomatic and/or laboratory studies are abnormal: See "Management of neonates with confirmed or suspected HSV infection."
  • Neonate asymptomatic and all neonatal HSV studies normal at 48–72 hours: ^[1]
    • Birthing parent testing consistent with initial genital infection : Continue acyclovir for 10 days.
    • Birthing parent testing consistent with recurrent genital infection : Stop acyclovir; educate caregivers on monitoring for clinical features of neonatal HSV.

Recurrent genital infection in birthing parent ^[1]

• Obtain the following in the neonate at 24 hours of age:
  • HSV NAAT and culture (if available) of the conjunctivae, mouth, nasopharynx, and rectum ^[1]
  • Serum HSV NAAT
• Neonate asymptomatic and testing negative at 48 hours: Educate caregivers on clinical features of neonatal HSV.
• Neonate becomes symptomatic and/or laboratory studies are positive
  • Perform complete neonatal HSV testing, including CSF NAAT and serum ALT.
  • Initiate IV acyclovir. ^[1]
  • See "Management of neonates with confirmed or suspected HSV infection" for additional details.

Birthing parent with no active genital lesions ^[1]

• First episode of genital herpes in the third trimester: Management is the same as with birthing parent with active genital lesions from recurrent HSV.
• History of genital herpes before pregnancy and no active lesions at delivery: Educate caregivers on monitoring for clinical features of neonatal HSV.

Educate pregnant individuals and caregivers on how to reduce the risk of neonatal HSV infection. ^[1]

• Vertical transmission prevention: Provide management of genital herpes in pregnancy.
• Horizontal transmission prevention
  • Recommend hand hygiene before touching the neonate.
  • Avoid touching the neonate with any active HSV lesions (e.g., herpetic whitlow, oral lesions); lesions should be covered if possible.

A mother with HSV can safely breastfeed if there are no lesions on the breasts and all active lesions are covered. ^[1]