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The Canadian Paediatric Society gives permission to print single copies of this document from our website. AbstractHuman herpes simplex virus (HSV) infection in neonates can result in devastating outcomes, including mortality and significant morbidity.
Many factors influence the transmission of HSV infection to newborns, including the nature of maternal infection, the mode of delivery, the duration of rupture of membranes and the use of intrapartum instrumentation.
Recurrent (mother has pre-existing antibodies to the HSV type that is isolated from the genital tract). In most cases of NHSV infection, there is no known history of maternal genital HSV because mothers have never had or have never noticed external genital lesions. Delivery by elective Cesarean section markedly reduces but does not eliminate the risk for newborn infection.[15][16] Women with recurrent genital HSV are commonly prophylaxed with acyclovir (ACV) or valacyclovir from 36 weeks’ gestation until delivery. Obstetrical procedures that can cause scalp abrasions or a break in the infant’s skin during labour and delivery may increase risk of NHSV transmission to a newborn infant. In most cases, the initial symptoms of NHSV infection present within the first four weeks of life. Infants who present with disseminated disease are less likely to survive than infants with SEM or CNS disease.
It is important for the clinician to speak with a laboratory specialist or infectious disease consultant when NHSV is suspected, particularly in settings where testing for NHSV is performed less frequently. When skin lesions are present, rapid diagnostic techniques, such as direct immunofluorescence of virus-infected cells for the presence of HSV antigens, are of value.
The isolation of HSV by culture is still regarded as the definitive diagnostic method for establishing HSV disease outside of the CNS.[33] Some centres now only offer PCR because it is believed to be more sensitive.
For patients with CNS HSV, PCR is a critically important diagnostic test because it is more sensitive than culture.[34] As with any PCR test, false positive and false negative test results can occur. The evaluation of HSV viremia using DNA PCR is less well established than CSF DNA PCR testing.
Given the potential for significant neurological sequelae in survivors of NHSV infection, affected infants should have a structured follow-up program that allows for neurodevelopmental, ophthalmological and hearing assessments. There has been research into the role of suppressive antiviral therapy in infants with NHSV infections.
The standard tests for HSV include CSF PCR and swabs of vesicular lesions and mucous membranes (tested by the method recommended by the local laboratory). Serum hepatic transaminase levels should be measured to provide supporting evidence for disseminated HSV infection. When evaluating NHSV infection in exposed asymptomatic infants, mucous membrane swabs should be obtained from the mouth, nasopharynx and conjunctivae at least 24 h after delivery. For all the above tests, clinicians and laboratory staff should work together to minimize the turn-around time for test results.
Antibodies to HSV-1 or HSV-2 (type-specific HSV antibodies) take approximately three weeks to develop following infection.[41] Their identification is useful in managing NHSV and testing should be performed if available.
Note: Some experts recommend performing CSF cell count, chemistries and PCR when mucous membrane swabs are taken (ie, a complete work-up).
Where available, approved type-specific HSV antibody testing can be used to confirm whether the mother has primary, nonprimary or recurrent HSV.[42] Many women who are believed to be presenting with primary disease at delivery actually have recurrent disease. Figure 2) *Some experts consider swabs to be optional if a Cesarean section was performed with no rupture of membranes before delivery. An infant whose mother has a history of HSV but no active lesions at delivery should be observed for signs of NHSV but does not require ACV therapy. Disseminated HSV can mimic bacterial sepsis, and clinicians need to consider possible NHSV infection in unwell infants <6 weeks of age. Infants started on IV antibiotics for suspected sepsis (especially infants presenting with seizure or yielding abnormal CSF) who do not improve rapidly and have negative bacterial cultures at 24 h incubation. Infants admitted with pneumonia of uncertain etiology who do not improve after 24 h on antibiotics, especially if the radiographic picture is consistent with viral pneumonia.
Infants with unexplained bleeding from venipuncture sites or an unexplained, documented coagulopathy. Infants started on IV antibiotics for suspected sepsis who are found to have unexplained hepatitis. Early therapy with intravenous (IV) ACV improves the prognosis for all three presentations of NHSV.
For infants with CNS disease, CSF should be sampled near the end of a 21-day course of therapy.
In combination with parenteral ACV, neonates with ocular involvement should receive a topical ophthalmic agent such as trifluridine. Oral ACV is contraindicated for the acute treatment of NHSV because drugs levels are too low. Follow-up is necessary to detect and manage adverse effects related to suppressive ACV treatment as well as for the neurodevelomental sequelae of NHSV. Strategies to prevent NHSV, including the identification of high-risk pregnancies, Cesarean delivery, maternal antiviral therapy, and anticipatory guidance for prospective mothers and partners, are largely beyond the scope of this statement. Neonates with HSV infection should be managed using contact precautions when mucocutaneous lesions are present and until lesions have crusted.

Asymptomatic neonates whose mothers have active HSV lesions should be managed using contact precautions until the end of the incubation period (day 14) or until samples from the infant taken after the first 24 h of life are negative.
Mothers who are in hospital should be on contact precautions until their lesions have crusted. Mothers with herpes labialis should wear a disposable mask when caring for their infant <6 weeks of age, until lesions are crusted.
Some experts recommend wearing a surgical mask to cover orolabial lesions because these cannot be covered by dressings.
AcknowledgementsThis position statement has been reviewed by the Fetus and Newborn and Community Paediatrics Committees of the Canadian Paediatric Society. Kimberlin DW, Baley J; American Academy of Pediatrics, Committee on Infectious Diseases, Committee on Fetus and Newborn. Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Studies show that 75% to 90% of individuals who are seropositive for HSV-2 were unaware of their infection.[10] All infants, therefore, must be considered to be potentially at risk for NHSV infection. In this context, antiviral therapy near the end of pregnancy can lower recurrence of genital HSV and shedding at delivery;[17] however, it is not clear whether this prophylaxis translates to a reduced risk for NHSV infection.
Fetal scalp sampling and monitoring, use of forceps and vacuum-assisted deliveries[16][19]-[23] should be avoided if possible when maternal genital lesions are present.[16] Early or prolonged rupture of membranes may also increase risk. Occasionally, disease presents for the first time between four and six weeks after birth;[4] therefore, infants up to 42 days of age should be fully evaluated for NHSV when clinical features are consistent with NHSV. One study showed that 39% of infants with disseminated disease did not have skin lesions at any time during their illness, while 32% with CNS disease and 17% with SEM disease did not develop skin lesions.[25] NHSV infection should be considered in neonates with sepsis syndrome, particularly when this condition is accompanied by liver dysfunction and even when there is no known history of maternal HSV and the infant has no skin vesicles. Expert consultation is important because the utility of testing modalities varies according to sample type, and the laboratory must provide general as well as centre-specific advice on the types of specimens to send for testing. Caution should be exercised when using a negative CSF HSV PCR to rule out CNS HSV, particularly when the sample is obtained in the early stages of illness (the first 24 h to 48 h).Because CNS disease can be very subtle, any patient with suspected NHSV infection should have a lumbar puncture performed for CSF DNA PCR testing as soon as it is clinically feasible to do so, unless there is a contraindication to performing a lumbar puncture.
First, transplacental immunoglobulin (Ig) G antibodies cannot be differentiated from IgG produced by the infant. A recent randomized, double-blinded, placebo-controlled trial evaluated infants with CNS HSV or disseminated HSV with CNS involvement, while a second, parallel trial evaluated infants with SEM HSV disease. When a mother has active lesions at time of delivery but does not have type-specific antibodies, clinicians should presume it is a newly acquired first-episode primary infection.
Assuming that the infant is well, mother and child can be discharged pending results of the mucous membrane and nasopharyngeal swabs taken at 24 h of life. It remains controversial whether this testing should be performed at birth (with the risk being detection of surface contamination) or at 24 h of life.
In addition to mucous membrane swabs, some experts recommend blood for polymerase chain reaction (PCR), if this test is available.
Therefore, infants should be started on IV ACV before laboratory confirmation of NHSV, as soon as the infection is suspected clinically. Treatment duration should be 14 days if the disease is limited to the skin, eyes or mouth, and a minimum of 21 days if the infection involves the CNS or is disseminated. If the PCR remains positive, treatment should be extended with weekly CSF sampling and ACV stopped when a negative result is obtained.
Complete blood count, and urea and creatinine levels should be checked monthly for adverse effects, and the dose of ACV adjusted for growth. However, the following recommendations are especially pertinent to special care nurseries and neonatal intensive care units. Some experts do not recommend contact precautions if an infected infant is born by Cesarean section and membranes are ruptured <4 h to 6 h.
Neonatal herpes simplex virus infections in Canada: Results of a 3-year national prospective study. Effect of serologic status and Cesarean delivery on transmission rates of herpes simplex virus from mother to infant. Regional distribution of antibodies to herpes simplex virus type 1 (HSV-1) and HSV-2 in men and women in Ontario, Canada. Antenatal seroprevalence of herpes simplex virus type 2 (HSV-2) in Canadian women: HSV-2 prevalence increases throughout the reproductive years. Genital shedding of herpes simplex virus among symptomatic and asymptomatic persons with HSV-2 infection.
Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection. Neonatal herpes simplex meningoencephalitis associated with fetal monitor scalp electrodes.
Herpes simplex virus infection after vacuum-assisted vaginally delivered infants of asymptomatic mothers.
Herpes simplex virus infection in young infants during 2 decades of empiric acyclovir therapy. Human antibodies to herpes simplex virus type 1 glycoprotein C are neutralizing and target the heparan sulfate-binding domain.
Neonatal herpes simplex: Clinical findings and outcome in relation to type of maternal infection.

Safety and efficacy of high-dose acyclovir in the management of neonatal herpes simplex virus infections.
Predictors of morbidity and mortality in neonates with herpes simplex infections: The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group.
Detection of viral DNA in neonatal herpes simplex virus infections: Frequent and prolonged presence in serum and cerebrospinal fluid.
Multiplex real-time PCR for the simultaneous detection of herpes simplex virus, human herpesvirus 6, and human herpesvirus 7. Quantitation of viral load in neonatal herpes simplex virus infection and comparison between type 1 and type 2. Time course of seroconversion by HerpeSelect ELISA after acquisition of genital herpes simplex virus type 1 (HSV-1) or HSV-2.
Guidance on management of asymptomatic neonates born to women with active genital herpes lesions. Routine practices and additional precautions for preventing the transmission of infection in health care settings.
This position statement reviews epidemiology, transmission and risk factors, with a focus on intrapartum infection. Guidelines regarding the role of Cesarean delivery and the indications for acyclovir are published[16][18][19] but are not specifically addressed in the present statement. One study reviewed 32 infants with perinatal HSV, noting that 50% of cases came to medical attention with nonspecific complaints and 75% of these had fever alone.
Prospective studies regarding the utility of periodic surveillance cultures in the early diagnosis of NHSV infection are lacking for infants exposed to active genital lesions. CNS NHSV infection may occur despite ‘normal’ CSF cell counts and biochemical features, particularly in the early stages of infection. For SEM disease, the duration of therapy is 14 days, while for disseminated or CNS disease, the minimum duration of treatment is 21 days.
When she only has antibodies to the HSV type other than the type she is shedding, assume it is a first-episode nonprimary disease. ACV therapy would only be indicated when the swabs or blood PCR are positive or when the infant develops signs and symptoms of NHSV infection. Clinicians should speak with a laboratory specialist or infectious diseases consultant when neonatal HSV (NHSV) is suspected and laboratory tests are being requested. Clinicians should speak with a laboratory specialist or infectious diseases consultant when neonatal herpes simplex virus (NHSV) is suspected and laboratory tests are being requested. In scenarios in which the first clinical evidence of HSV was documented during the third trimester or near delivery, clinicians may consider mucous membrane swabs. Data are less convincing for SEM or disseminated disease, but suppressive therapy may still be offered. Infants should be followed in a program that enables their evaluation for the neurodevelopmental, ophthalmological and aural consequences of NHSV infection. There is no contraindication to breastfeeding unless there are herpetic lesions on the breast.
It considers diagnosis and prognosis according to infection category, along with testing modalities and limitations. Therefore, test results should be interpreted with careful consideration of the clinical context and results from nonspecific investigations including an electroencephalogram, computed tomography or magnetic resonance imaging, liver transaminase levels and platelet count.
Third, the commercially available assays for HSV IgM antibodies have only variable and limited reliability.
Oral ACV has limited bioavailability, resulting in inadequate drug levels for treatment;[38] consequently, parenteral therapy is required. When she has antibodies to both HSV-1 and HSV-2, this is likely to be a case of recurrent disease. If the infant’s swabs or blood PCR are positive, CSF PCR must be obtained to determine the duration of ACV therapy. Recommendations for managing newborns known to have been exposed intrapartum to HSV are based on expert opinion because a randomized trial to compare management options is not feasible.
If HSV is detected on a swab or in blood PCR, the infant should be managed as a case of NHSV.
If the infant’s swabs are negative, ACV can be stopped if type-specific serology testing shows that the mother has recurrent HSV. Guidance is provided for the empirical management of infants with suspected clinical sepsis, including those who do not respond to antibacterial therapy.
If type-specific serology testing is not available or shows the mother has first-episode HSV, the infant should receive ACV for 10 days despite negative swabs.
The present statement replaces a 2006 position statement by the Canadian Paediatric Society.

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