1. Epidemiology
2. Transmission
3. Clinical Syndromes
• Disseminated
• CNS
• Mucocutaneous/ocular
4. Approach to the exposed infant
5. Treatment

Incidence

• ~2/1000 mothers are HSV culture positive at delivery, asymptomatic. (1)
• 50-70% affected infants born to women asymptomatic at the time of delivery. (2,3,12)
• Antepartum cultures are not useful in assessing risk of neonatal infection. (11)
• Increased risk with primary maternal herpes vs. recurrent disease (see below). (4)
• Incidence: 1/2000 - 1/5000 live births and is increasing. (5)

Determining the risk of neonatal HSV infection

50% risk: Infants born to women with primary (defined by no detectable antibody to both type 1 or 2 HSV) infection near the time of delivery.

Risk factors associated with primary maternal HSV:

• Genital symptoms, UTI symptoms not responsive to therapy
• Positive HSV cultures from both cervix and labia
• New sexual partner immediately prior to or during pregnancy

30% risk: Infants born to mothers with a first episode, non-primary infection (antibody to type 1, new acquisition type 2 disease and vice versa).

1-3% of infants born to mothers with recurrent infection. (4,6)

Reasons for increased risk with primary maternal herpes infection.

• Prolonged shedding of virus ~3 wks. vs. 2-5 days.
• Increased number of viral particles excreted.
• Less passive immunity to HSV, i.e. less maternal-fetal transfer of HSV neutralizing antibodies.

Passive immunity probably protects against infection, but has little effect on the severity of disease once an infant is infected.

Neonatal risk factors:

• Rupture of membranes > 6 hours
• Scalp electrode or other internal monitoring
• Chorioamnionitis
• Cervicitis
• Vaginal delivery

• Requires intimate personal contact, like intercourse, kissing, or birth.(7)
• Very few cases of in utero transmission have been documented. In these cases you would expect: disease at birth, such as skin lesions, keratoconjunctivitis, or even hydranencephaly or microcephaly.
• Infection at the time of labor and delivery is the situation for the overwhelming majority of cases.
• Postnatal infection is very uncommon, although there have been cases of infection from a nipple lesion with breast feeding and infection from a father with a cold sore.(10)

Epidemiology

• Disseminated neonatal herpes is the most common and most lethal form of neonatal herpes.(7)
• 50% of infants with neonatal herpes.

Natural History

• Presents usually at 9-11 days of age, but as late as 4 weeks.
• Widespread disease, including: pneumonitis, hepatitis, disseminated intravascular coagulation, with or without encephalitis, exanthem, or kerato-conjunctivitis.

Chest X-ray of herpes pneumonitis

• Symptoms include: irritability, seizures, respiratory distress, jaundice, bleeding, shock, and a characteristic vesicular rash.
• 10-50% will not develop skin lesions during the course of their illness.(8)
• Encephalitis in 60 to 75%.

Prognosis

• Mortality without treatment is >80%, with treatment 57% (9), all but a few survivors impaired (abnormal neurologic status at one year 92% in untreated patients and 86% in treated patients with disseminated disease).

Definition

CNS involvement documented by abnormal LP results (increased cell count, positive CSF PCR) or head MRI or CT changes in conjunction with positive surface cultures.

Epidemiology

• 70% of infants with neonatal herpes (including those with disseminated/CNS disease).(7)

Natural History

• Symptoms include: irritability, seizures, poor feeding, bulging fontanel, thermal instability.
• CSF findings: HSV culture positive 25-40%, pleocytosis, and proteinosis.
• May not have mucocutaneous lesions.(8)

Prognosis

• 50% of untreated babies with localized CNS disease die, 10% of treated infants with localized CNS disease die. (9)
• 75% survivors have psychomotor retardation, often with: microcephaly, hydranencephaly, porencephalic cysts, spasticity, blindness, or learning disabilities.
• Abnormal neurologic status at one year decreased from 83% to 50% in patients with local CNS disease.

CT Scan of brain damaged by herpes encephalitis

Definition

Disease limited to skin or mucus membranes only. Normal LP, CXR, and LFT's. No evidence of CNS or visceral organ involvement. Diagnosis by positive culture or FA for HSV.

Epidemiology

• 30-40% of patients with neonatal herpes have localized disease.

Natural History

• Usually presents at 15-17 days of age (as late as 4 weeks).
• Sites include: skin, mouth, and eyes.

Prognosis

• Progression from local infection with skin lesions to CNS or disseminated disease decreased from ~70% to 5-20% with early treatment. (9)

Cutaneous Herpes

Typical cluster of early herpetic vesicles

Skin classically with clusters of discrete vesicles on an erythematous base, occur in 90% of infants with skin, eye, or mouth disease, invariably recur in first 6 months of life, many infants have lesions recurring after a year of age.

Oral Herpes

Mouth with mucosal ulcers

Labial mucoceles, don't confuse with herpetic vesicles (mucoceles have no associated erythema)

Ocular Herpes

Eyes with keratoconjunctivitis, or later, with chorioretinitis (dendritic keratitis is pathognomonic). May lead to corneal ulcers, cataracts, optic atrophy and/or blindness.

In mother with recurrent infection, who is HSV-2 seropositive

(Note these recommendations are likely to change, please consult a pediatric infectious disease specialist or neonatologist for the most recent recommendations).

• Culture nasopharynx, rectum, and conjunctivae after 24 to 48 hours of life, and repeat at 7-10 day intervals until 28 days old.
• If symptoms develop reculture all sites, including CSF, and begin treatment with acyclovir.

Mother with first episode infection of positive preparation prepartum cultures of both vulva and cervix

• Cultures of CSF, nasopharynx, rectum conjunctivae and blood
• Begin treatment with acyclovir, 5-7 days if cultures remain negative and no symptoms develop.

A. Treatment for mucocutaneous, ocular disease

• Contact pediatric infectious disease specialist, or Medcon, for latest recommendations.
• Treat with acyclovir 45 mg/kg/day I.V. divided q 8h for 14 days, (7). In cases of herpes keratitis treat with topical trifluorothymidine in addition to acyclovir.
• Monitor CBC and LFT's weekly; check creatinine QOD and send plasma for PCR on days 0,2-3,5-7,12-14
• At end of treatment repeat LP (CSF for cell count, HSV PCR), send blood for HSV serology, and buffy coat HSV PCR. Head CT or MRI scan at end of therapy.

B. Treatment protocol for CNS and/or Disseminated Disease

• Contact pediatric infectious disease specialist, or Medcon, for latest recommendations.
• Treat with acyclovir 60 mg/kg/day I.V. divided q8h for 21 days.
• Laboratory: CSF for cell count, viral and bacterial culture, and HSV PCR. Peripheral blood for HSV PCR on days 0, 2-3, 5-7, 12-14, and 19-21. Daily surface cultures until negative. Weekly CBC and LFTs. Creatinine QOD. Monitor coags if LFT's abnormal.
• CT scan with contrast or MRI at beginning and end of therapy.
• Dilated ophthalmologic examination to assess chorioretinitis during first week and at 6 mo.
• Brainstem auditory evoked potential during initial admission. Repeat at 6 mo. if abnormal.
• Developmental follow-up at 6 and 12 months of age.
• For any subsequent fever, neurologic symptoms, or skin lesions evaluate CSF and blood PCR and scrape any skin lesions for HSV culture and PCR until 6 mo. old.
• Consider oral acyclovir prophylaxis from day 21 to 6 mo. While on oral acyclovir monitor monthly CBC and at 3 and 6 months a serum creatinine.

C. Asymptomatic HSV-exposed infants born to mothers with known or suspected primary HSV 1 or 2 , or first episode non-primary HSV-2 (i.e. culture (+) and seronegative)

• Contact pediatric infectious disease specialist, or Medcon, for latest recommendations.
• Treat with acyclovir 45 mg/kg/day I.V. divided q8h for up to 14 days.
• Laboratory: CSF for viral and bacterial culture, cell count and PCR. Blood for HSV serology and PCR.
• Follow-up at 3, 6, and 9 mo. to assess clinical outcome and to determine whether patient was actually HSV infected (by development or persistence of HSV Ab).

All photographs courtesy of Lawrence Corey, M.D.

1. Prober, C.G., Hensleigh, P.A., Boucher, F.D., Yasukawa, L.L., Au, D.S., Arvin, A.M. Use of routine viral cultures at delivery to identify neonates exposed to herpes simplex virus. N.Engl.J.Med. 318:887-891,1988.
2. Whitley, R.J., Nahmias, A.J., Visintine, A.M., Fleming, C.L., Alford, C.A. The natural history of herpes simplex virus infection of mother and newborn. Pediatrics 66:489-490,1980.
3. Yeager, A.S., Arvin, A.M. Reasons for the absence of a history of recurrent genital infections in mothers of neonates infected with herpes simplex virus. Pediatrics 73:188-196,1984.
4. Brown, Z.A., Vontver, L.A., Benedetti, J., Critchlow, C.W., Sells, C.J., Berry, S., Corey, L. Effects on infants of a first episode of genital herpes during pregnancy. N.Engl.J.Med. 317:1246-1251,1987.
5. Sullivan-Bolyai, J., Hull, H.F., Wilson, C., Corey, L. Neonatal herpes simplex virus infection in King County, Washington. J.A.M.A. 250:3059-3062,1983.
6. Prober, C.G., Sullender, W.M., Yasukawa, L.L., Au, D.S., Yeager, A.S., Arvin, A.M. Low risk of herpes simplex virus infections in neonates exposed to the virus at the time of vaginal delivery to mothers with recurrent genital herpes simplex virus infections. N.Engl.J.Med. 316:240-244,1987.
7. Toltzis, P. Current issues in neonatal herpes simplex virus infection. Clin. Perinatol. 18:193-208,1991.
8. Arvin, A.M., Yeager, A.S., Bruhn, F.W., Grossman, M. Neonatal herpes simplex infection in the absence of mucocutaneous lesions. J.Pediatr. 100:715-721,1982.
9. Whitley, R.J., Nahmias, A.J., Soong, S., Galasso, G.G., Fleming, C.L., Alford, C.A. Vidarabine therapy of neonatal herpes simplex virus infection. Pediatrics 66: 495-501,1980.
10. Yeager, A.S., Ashley, R.L., Corey, L. Transmission of herpes simplex virus from father to neonate. J.Pediatr. 103:905-907,1983.
11. Arvin, A.M., Hensleigh, P.A., Prober, C.G., Au, D.S., Yasukawa, L.L., Wittek, A.E., Palumbo, P.E., Paryani, S.G. Failure of antepartum maternal cultures to predict the infant's risk of exposure ot herpes simplex virus at delivery. N.Engl.J.Med. 315:796-800,1986.
12. Brown, Z.A., Benedetti, J., Ashley, R., Burchett, S., Selke, S., Berry, S., Vontver, L.A., Corey, L. Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor. N.Engl.J.Med. 324:1247-1252,1991.
13. Kimberlin, D.W., et al. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes virus infections. Pediatrics 108:230-238,2001.

This document was created and prepared for this Web site by:

• Thomas P. Strandjord, M.D., Associate Professor
• EMAIL feedback to primary author