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Neonatal herpes simplex virus infection: Management and prevention

Neonatal herpes simplex virus infection: Management and prevention
Author:
Gail J Demmler-Harrison, MD
Section Editors:
Sheldon L Kaplan, MD
Leonard E Weisman, MD
Deputy Editor:
Carrie Armsby, MD, MPH
Literature review current through: Apr 2022. | This topic last updated: Apr 14, 2022.

INTRODUCTION — Genital herpes simplex virus (HSV) infection during pregnancy poses a significant risk to the developing fetus and newborn. Neonates can acquire HSV infection by intrauterine, perinatal, or postnatal transmission of the virus; most cases are acquired perinatally. Neonatal HSV infection causes serious morbidity and mortality and leaves many survivors with permanent sequelae.

The management and prevention of neonatal HSV infection will be reviewed here. The clinical features and diagnosis of neonatal HSV infection and genital HSV infection during pregnancy are discussed separately. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis" and "Genital herpes simplex virus infection and pregnancy".)

OVERVIEW — The treatment of neonatal HSV infection involves supportive measures and antiviral therapy.

Supportive measures — Supportive measures for the critically ill neonate with disseminated or central nervous system (CNS) disease include:

Fluid and electrolyte maintenance and avoidance of hypoglycemia (see "Fluid and electrolyte therapy in newborns" and "Management and outcome of neonatal hypoglycemia")

Management of shock, if present (see "Neonatal shock: Management")

Respiratory support (see "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn" and "Overview of mechanical ventilation in neonates")

Nutritional support (see "Overview of enteral nutrition in infants and children" and "Parenteral nutrition in infants and children")

Control of seizures (see "Treatment of neonatal seizures")

Management of disseminated intravascular coagulation (see "Disseminated intravascular coagulation in infants and children", section on 'Management')

Antimicrobial treatment for secondary bacterial infections (eg, gram-negative sepsis in neonates with ascites and liver necrosis) (see "Management and outcome of sepsis in term and late preterm infants", section on 'Antibiotic therapy')

ACYCLOVIR THERAPY — We recommend acyclovir as the antiviral agent of choice for the treatment of all categories of neonatal HSV disease, including skin, eye, and mouth (SEM); central nervous system (CNS); and disseminated disease (table 1) [1-4]. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Neonatal HSV'.)

Treatment of neonatal HSV disease with antiviral therapy improves survival and outcome, especially if treatment is begun early in the course of illness [2,3,5]. Before antiviral therapy was available, the one-year mortality rates for neonates with disseminated and CNS HSV disease were 85 and 50 percent, respectively [6]. With the advent of antiviral therapy, mortality rates declined to 29 and 4 percent, respectively [2,3,7].

Antiviral therapy also has increased the proportion of survivors of disseminated disease who have normal neurologic development (from 50 to approximately 80 percent) [2,6,7]. Antiviral therapy does not appear to have affected the proportion of survivors of CNS disease with normal neurologic development (approximately 30 percent both before and after antiviral therapy became available) [2,6,7].

Early antiviral treatment of infants with SEM disease prevents progression to CNS or disseminated disease [8]. Between 50 and 60 percent of infants with SEM who do not receive antiviral therapy progress to CNS or disseminated disease.

In a randomized controlled trial, the morbidity and mortality were similar among infants treated with acyclovir and vidarabine [3]. However, vidarabine has systemic toxicity and a dosing schedule that requires 12-hour infusions.

The mechanism of action, pharmacokinetics, and toxicity of acyclovir are discussed separately. (See "Acyclovir: An overview".)

Indications — Indications for acyclovir therapy include [1,9-11]:

Virologically proven HSV disease (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Detection of HSV')

Clinically suspected HSV disease (figure 1), pending viral studies (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical manifestations')

Asymptomatic but at risk due to exposure (maternal active genital lesions) (algorithm 1) (see 'Management of the asymptomatic exposed infant' below)

The indications for initiation of empiric acyclovir are not standardized. Most experts agree that empiric acyclovir is indicated for neonates with clinical features suggestive of HSV infection, which include mucocutaneous vesicles (picture 1A-C), seizures, lethargy, respiratory distress, thrombocytopenia, coagulopathy, blood oozing from intravascular catheter sites, hypothermia, sepsis-like illness, hepatomegaly, ascites, or markedly elevated transaminases (figure 1) [1,9-11]. Many experts recommend empiric treatment for ill-appearing neonates with fever or aseptic meningitis until results of HSV workup are known. However, expert opinions differ regarding the relative benefits, risks, and cost-effectiveness of empiric acyclovir before virologic confirmation in other clinical situations (eg, cerebrospinal fluid [CSF] pleocytosis with a predominance of mononuclear cells in an otherwise well-appearing infant, persistent or recurrent erythema or purulence/crusting at the site of a scalp electrode, fever without localizing signs in an infant ≤21 days of age, etc) [9-12]. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical manifestations'.)

The full course of acyclovir therapy should be administered for infants with positive HSV cultures or deoxyribonucleic acid (DNA) polymerase chain reaction (PCR), and infants with negative virologic studies in whom neonatal HSV is strongly suspected. (See 'Duration of therapy' below.)

Timing — Intravenous (IV) acyclovir should be administered at the time the diagnosis of neonatal HSV is suspected. Prompt administration improves outcome [2,3,5,13,14]. Acyclovir therapy should be continued while clinical observation and results of laboratory and imaging evaluations are completed.

Pretreatment evaluation — A comprehensive laboratory evaluation for HSV should be performed before initiation of acyclovir therapy. The evaluation should include (if the infant is clinically stable enough to undergo it) [1,7]:

Testing to detect HSV, including all of the following, which are discussed in greater detail separately (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Detection of HSV'):

Surface HSV cultures or HSV PCR from the conjunctivae, mouth, nasopharynx, and rectum

HSV culture or HSV PCR of swabs/scrapings of skin and mucous membrane lesions, if present; direct immunofluorescence assay may be used in addition to culture to permit rapid detection

CSF HSV PCR

Whole blood or plasma HSV PCR

Viral culture or HSV PCR of other specimens that are readily available (eg, tracheal aspirates in intubated patients)

Testing to determine the degree of organ involvement and studies to exclude other diseases that may cause similar symptoms (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Additional studies'):

Complete blood count, including differential and platelet count

Liver function tests, including transaminases and total and direct bilirubin; if these are abnormal, additional testing should include coagulation studies (prothrombin time, activated partial thromboplastin time) to evaluate hepatic synthetic function and ammonia to exclude fulminant liver failure and/or metabolic disease

Blood urea nitrogen (BUN), creatinine, and urinalysis (to assess renal function and hydration status)

CSF cell count and differential, glucose, protein

Ophthalmologic examination

Neuroimaging (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Brain imaging')

Electroencephalogram (EEG) in neonates suspected to have CNS disease (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Electroencephalogram')

Chest radiograph, for neonates with respiratory distress

Blood and CSF cultures to evaluate for bacterial sepsis

Initial treatment

Dose — The dose of acyclovir for all forms of neonatal HSV is 60 mg/kg per day IV divided every eight hours [2]. The dose of acyclovir must be adjusted for neonates with renal impairment. Once the infant is ≥3 months old, a lower dose (45 mg/kg per day) is used.

The efficacy of the 60 mg/kg dosing for neonates was established in an open-label study in which 72 neonates with CNS or disseminated HSV were treated with acyclovir 60 mg/kg per day for 21 days [2]. Their outcomes were compared with those of neonates in an earlier trial who were treated with acyclovir 30 mg/kg per day for 10 days [3]. The higher dose was associated with increased survival at 24 months (odds ratio 3.3, 95% CI 1.5-7.3).

Duration of therapy — The duration of acyclovir therapy for neonatal HSV infection depends upon the pattern of illness and response to therapy [1,2,4,13]:

SEM disease – Localized SEM disease should be treated for a minimum of 14 days if disseminated and CNS disease have been excluded (table 1).

Disseminated and CNS disease – Disseminated and CNS disease should be treated for a minimum of 21 days. Because the persistence of HSV DNA in the CSF is associated with poor outcome, lumbar puncture should be repeated near the end of therapy to ensure that CSF HSV PCR is negative [1,7,13,15-18].

For infants with persistently positive CSF HSV PCR despite 21 days of acyclovir therapy, antiviral treatment is continued and CSF HSV PCR testing is repeated weekly until negative [1,7]. Consultation with a pediatric infectious disease specialist is warranted in cases of persistently positive CSF or blood HSV PCR. The clinical significance of persistently positive blood PCR is uncertain. Data from a small cohort of infants (n = 6) with disseminated HSV disease who were monitored with serial plasma HSV PCR levels during treatment suggest that acyclovir therapy has a uniform and predictable effect on plasma HSV level regardless of the baseline viral level and that this monitoring can be used to help guide duration of therapy [19]. In our practice, we repeat the blood HSV PCR at the end of the 21-day treatment course to assess for viremia clearance. If the blood HSV PCR is persistently positive, additional IV acyclovir therapy and/or evaluation for primary immune disorder (eg, T cell or NK cell disorders) is undertaken. In addition, in our practice, we monitor quantitative plasma or whole blood PCR levels since high levels of HSV viremia are associated with severe disease and may help guide management [20].

Adverse effects — Systemic acyclovir therapy is well tolerated by most neonates and side effects are unusual. Potential adverse effects include:

Kidney injury caused by crystallization in the renal tubules, which is more likely to occur if the neonate is dehydrated

Dose-dependent reversible neutropenia [2,7,13]

Ulceration at the site of peripheral extravasation

Seizures, especially if the dose is not adjusted in patients with renal impairment

Monitoring — Routine monitoring for neonates receiving IV acyclovir includes the following:

Renal function – BUN and creatinine are monitored once or twice weekly, depending on the clinical status of the patient. For patients with acute kidney injury and/or severe disseminated HSV disease, BUN and creatinine should be monitored daily. In addition, the infant's hydration status should be monitored by assessing intake and output and measuring urine specific gravity. In our practice, we aim to keep urine specific gravity <1.010 during acyclovir therapy to reduce renal toxicity. The acyclovir dose should be adjusted if creatinine clearance is lower than expected for age of patient.

Absolute neutrophil count (ANC) – ANC should be followed approximately twice per week during the course of therapy [2,7]. The acyclovir dose should be reduced or granulocyte colony-stimulating factor should be administered if the ANC remains <500/microL for an extended period of time without an alternative explanation for the neutropenia.

Infusion site – Monitoring of the local infusion site is important because local infiltration can cause superficial or deep ulcerative lesions. If possible, administration through central access or a peripherally-inserted central catheter is preferred.

Intravenous acyclovir not available — If IV acyclovir is not available, in agreement with the American Academy of Pediatrics Committee on Infectious Diseases, we suggest IV ganciclovir as a first-line alternative [21-23]; the dose is 6 mg/kg every 12 hours IV for infants ≤90 days of age and 5 mg/kg every 12 hours IV for infants >90 days. We suggest IV foscarnet as a second-line alternative; the dose is 60 mg/kg every 12 hours IV.

Oral suppressive therapy — Following parenteral treatment for all forms of neonatal HSV disease (SEM, CNS, and disseminated disease) (table 1), we suggest suppressive therapy with oral acyclovir 300 mg/m2 per dose three times per day for six months; the dose should be adjusted each month to account for growth [1,18,24]. This recommendation is based on a randomized clinical trial in which suppressive therapy reduced cutaneous recurrences and was associated with improved neurologic outcomes in infants with CNS disease [24]. If HSV keratitis is present, many experts suggest oral suppression for up to one year with careful follow-up for recurrences [20]. (See 'Treatment of eye disease' below.)

Acyclovir is preferred to valacyclovir because the safety and efficacy of valacyclovir have not been established in infants younger than two years of age. Furthermore, since only tablet form is available, an extemporaneously compounded valacyclovir oral suspension (25 to 50 mg/mL) must be specially prepared for infants [25]. Based on limited data on the pharmacokinetics and safety of valacyclovir in pediatric patients, doses of 10 to 20 mg/kg of extemporaneously compounded valacyclovir oral suspension, administered twice daily, produce favorable acyclovir blood concentrations and appear well tolerated in most children [26,27].

The effectiveness of long-term suppression with oral acyclovir in reducing the risk of CNS recurrence after neonatal HSV disease is unknown. CNS recurrence in neonates receiving long-term oral suppression has been documented [28]. Nonetheless, oral acyclovir suppression appears to be associated with improved neurodevelopmental outcome. In a multicenter trial, 74 infants (45 with CNS HSV disease, 29 with SEM HSV disease) were randomly assigned to oral acyclovir 300 mg/m2 per dose three times per day or placebo immediately following parenteral acyclovir treatment [24]. In children with CNS involvement, acyclovir suppression was associated with higher mean infant development scores at 12 months of age (88 versus 68 on the Bayley Scales of Infant Development, 2nd edition in which scores range from 50 to 150). The incidence and degree of neutropenia were similar in the treatment and placebo groups.

Adverse effects of oral acyclovir suppression may include dose-dependent reversible neutropenia (in one-half to two-thirds of infants in previous studies) and emergence of HSV mutants that are acyclovir resistant [7,13,28,29]. We monitor the ANC monthly in neonates receiving oral suppressive therapy. (See 'Monitoring' above.)

Treatment of recurrences — The optimal management of cutaneous recurrence is not established. However, treatment doses of oral acyclovir (10 to 20 mg/kg per dose three times per day for young infants or 10 to 15 mg/kg per dose four to five times per day for older infants and children) may be administered early at the time of each cutaneous recurrence to reduce the discomfort and shedding associated with the lesions, or preemptively, for a brief period of one to two weeks, when a cutaneous recurrence is anticipated, such as times of high stress or exposure to sunlight.

In patients with frequent cutaneous recurrences that are painful or disruptive to daily life, long-term oral suppression may be of benefit. There is a broad range of acceptable doses. The author of this topic review generally prefers acyclovir 20 mg/kg per dose twice per day, but, in some patients, 10 mg/kg per dose twice per day is effective. Suppression may be discontinued, and the patient observed, if no cutaneous recurrences are documented after a 12-month period.

An increase of the dosing frequency to three or four times daily for a brief period of time may be of benefit if a recurrence "breaks through" twice-daily oral suppression. HSV lesions that occur while the patient is receiving acyclovir three to four times per day should be cultured and the HSV isolate tested for acyclovir resistance.

Treatment of eye disease — Neonates with ocular HSV involvement, such as keratitis, should receive a topical ophthalmic solution (eg, 1% trifluridine, 0.1% idoxuridine [iododeoxyuridine], or 0.15% ganciclovir) in addition to systemic acyclovir therapy [1,20]. They should also be referred to an ophthalmologist for consultation.

We suggest long-term suppressive therapy (up to one year) with oral acyclovir (300 mg/m2 per dose three times per day or 10 to 20 mg/kg per dose three times per day) for patients with HSV involvement of the eye, particularly keratitis, because of the risk of impaired vision with reactivation [7,13,18,20]. (See 'Oral suppressive therapy' above.)

OUTCOME — The outcome of neonatal HSV disease depends upon the clinical pattern. HSV infection is lifelong, even with appropriate therapy. Recurrence of mucocutaneous lesions, eye disease, and/or central nervous system (CNS) disease may occur.

Disseminated disease — The one-year mortality rate for disseminated disease is approximately 25 to 30 percent [2]. Factors that are associated with increased risk of mortality include [7,19,30,31]:

Severe hepatitis or acute liver failure

Severe lethargy or coma at the time of presentation

Disseminated intravascular coagulopathy

Prematurity

Pneumonitis

High levels of viremia at time of diagnosis (eg, quantitative polymerase chain reaction [PCR] >7 log10 copies/mL)

Approximately 80 percent of survivors of disseminated neonatal HSV disease may have normal neurologic development [2,6,7]. The risk of neurodevelopmental abnormalities (eg, developmental delay, hemiparesis, persistent seizures, microcephaly, blindness) is increased among infants with seizures at or before the initiation of antiviral therapy [7].

Severe hepatitis, caused by either HSV-1 or -2, may cause potentially fatal acute liver failure in neonates with disseminated disease. Liver transplantation has been carried out successfully in a few reported neonates with fulminant hepatic failure associated with disseminated neonatal HSV disease [32-34].

Central nervous system disease — The one-year mortality rate for CNS disease is 4 percent [2]. Prematurity, seizures, and coma or near-coma at the time of presentation are associated with increased risk of mortality in CNS disease [7,30,31].

Approximately 30 percent of survivors of neonatal CNS HSV have normal neurologic development [2,6,7]. The risk of neurodevelopmental abnormalities is increased among infants with seizures at or before the initiation of antiviral therapy [7].

Skin, eye, and mouth disease — Mortality is rare in neonatal HSV disease that is localized to the skin, eye, and mouth (SEM; in whom disseminated and CNS disease have been appropriately excluded). Less than 2 percent of acyclovir recipients have developmental delay after recovery from neonatal SEM HSV disease [2,3,7]. The risk of neurodevelopmental abnormalities is increased in infants with ≥3 recurrences of skin lesions before six months of age [31]. Patients with ocular involvement are at risk for long-term complications, including vision loss, and require close follow-up. If HSV eye disease is present, many experts suggest oral suppression for up to one year. (See 'Long-term follow-up' below and 'Treatment of eye disease' above.)

Cutaneous recurrence — Even after successful parenteral treatment, recurrence of HSV can occur and may be a lifelong problem for the patient and family/caregivers. Fortunately, recurrence of CNS disease is rare [28,29]. However, recurrent vesicles at sites in the SEM are common and occur in 50 to 80 percent of neonates, with 1 to 12 episodes in the first year of life [1]. Infants with ≥3 cutaneous recurrences during the first six months of life are at increased risk of neurodevelopmental abnormalities at follow-up [31]. Recurrence of skin lesions may affect child care arrangements and is disruptive to the lives of patients and their families [7].

Because the risk of recurrence in survivors of neonatal HSV disease is high, long-term suppressive therapy with oral acyclovir is recommended to reduce skin or eye recurrences during infancy [13]. (See 'Oral suppressive therapy' above.)

LONG-TERM FOLLOW-UP — Survivors of neonatal HSV infection, especially infants with involvement of the central nervous system (CNS), should be followed closely for achievement of developmental milestones [7]. They should undergo formal neurodevelopmental assessments as indicated. Referral to early intervention programs (eg, physical therapy, occupational therapy, speech therapy) should be made at the earliest sign of potential impairment. (See "Developmental-behavioral surveillance and screening in primary care", section on 'Follow-up'.)

Audiologic assessments are usually recommended as well. However, evidence suggests that the incidence of hearing loss after neonatal HSV disease is low [35]. (See "Hearing loss in children: Screening and evaluation".)

Patients with eye disease require careful follow-up with an ophthalmologist. To reduce the risk of recurrent eye disease, many experts suggest oral suppression with acyclovir for up to one year in this setting. Late onset recurrences have been reported [36,37]. The family/caregivers should be counseled to seek medical care promptly if symptoms of eye disease recur.

PREVENTION

General measures — Strategies for prevention of intrauterine and perinatally acquired HSV infection, including identification of high-risk pregnant women, cesarean delivery, maternal antiviral therapy, and anticipatory guidance for pregnant women and partners, are discussed separately. (See "Genital herpes simplex virus infection and pregnancy", section on 'Screening pregnant women with no HSV history'.)

Postnatal transmission of HSV can be prevented by counseling family members with active HSV lesions (cold sores, herpetic whitlow, herpetic gingivostomatitis) or a history of cold sores or HSV lesions in the recent past to avoid close contact with and avoid kissing the newborn infant. Women with herpetic breast lesions should not breastfeed from the affected breast until the lesions have resolved because direct contact with the lesions may transmit the HSV to the infant [38]. Mothers should use careful hand hygiene and cover any lesions with which the infant might come into contact.

The need for contact precautions during the birth hospitalization depends upon whether the mother had active lesions at the time of delivery and whether the infant has any mucocutaneous lesions (see "Infection prevention: Precautions for preventing transmission of infection", section on 'Contact precautions'):

Infants born to women with active HSV lesions should be managed with contact precautions during hospitalization, with a private room, or while rooming with the mother [1]. However, some experts suggest that contact precautions are not necessary for such infants who are born by cesarean delivery <4 hours after rupture of membranes.

Contact precautions also should be used for infants who are hospitalized with HSV infection if they have mucocutaneous lesions [1]. The median duration of viral shedding from skin vesicles and mucosal lesions in infants receiving acyclovir therapy is five to eight days [2]. However, contact precautions may be continued for a longer period of time if the patient is hospitalized.

Contact precautions are not necessary for infants born to women with a history of recurrent genital HSV who have no genital lesions at the time of delivery.

Infants and children with cutaneous recurrence of neonatal HSV should be counseled to cover the lesions to prevent potential transmission through direct contact [39].

Vaccine — There is no licensed, effective vaccine against HSV-1 or HSV-2 infection. However, both preventive and therapeutic HSV vaccines are being developed. A candidate HSV-2 vaccine containing two HSV-2 proteins, gD2 and ICP4, and Matrix-M2 adjuvant has shown promise in clinical trials [40,41].

MANAGEMENT OF THE ASYMPTOMATIC EXPOSED INFANT

Overview — The optimal management of asymptomatic infants who are exposed to maternal HSV at delivery (as documented by maternal virologic testing or active genital lesions [4]) has not been evaluated in controlled trials [18]. However, experts and professional societies provide some guidelines regarding the need for testing and prophylactic or anticipatory antiviral therapy based upon the risk of transmission under various circumstances (algorithm 1) [1,4,42-46]. (See 'Society guideline links' below.)

Our suggested approach is generally consistent with guidelines from the American Academy of Pediatrics, which provide guidance on the evaluation and management of asymptomatic neonates in settings where type-specific HSV polymerase chain reaction (PCR) testing with rapid turnaround time is available [1]. In addition, we provide guidance for settings where type-specific HSV serologic testing with rapid turnaround time is not available.

Consultation with a pediatric infectious diseases specialist is suggested for guidance in difficult clinical situations.

Risk of transmission — The risk of transmission to the infant depends upon a number of factors, including [1,18,46,47]:

Whether the maternal infection is primary or recurrent (the risk is highest with primary infection)

Delivery method (vaginal versus cesarean; the risk is higher with vaginal delivery)

Duration of rupture of membranes (the risk is higher if ≥4 hours)

Maternal HSV antibody status

Integrity of the infant's mucocutaneous barriers (eg, use of fetal scalp electrodes)

Availability of type-specific PCR or culture testing of maternal genital lesions and type-specific maternal HSV serology permits more accurate characterization of the type of maternal infection (table 2) and, therefore, estimation of the risk of transmission [46,47].

A more detailed discussion of the risk of transmission is provided separately. (See "Genital herpes simplex virus infection and pregnancy", section on 'Vertical transmission'.)

Monitoring — All neonates who are born to women with active genital HSV lesions or a history of genital HSV but no active lesions at the time of delivery should be monitored for clinical evidence of HSV infection (eg, skin or scalp rashes, conjunctival lesions, irritability, sepsis, etc) (figure 1) during the first six weeks of life [1]. The infant's parents and caregivers should be educated about the signs of neonatal HSV infection.

Infants who develop clinical evidence of HSV infection should undergo full clinical and laboratory evaluation and should receive treatment with acyclovir pending results of virologic evaluation. (See 'Pretreatment evaluation' above and 'Acyclovir therapy' above.)

Maternal history of HSV, no active lesions — The risk of transmission of HSV to infants born to women with a history of genital HSV but no active genital lesions at the time of delivery is low. Such infants who are asymptomatic should be monitored for neonatal HSV infection. However, they do not routinely require any additional evaluation of treatment for neonatal HSV if they remain asymptomatic [1]. (See 'Monitoring' above.)

Maternal history of HSV, active lesions — The risk of transmission of HSV to infants born to women with a history of genital HSV and active genital lesions at the time of delivery is relatively low (<2 percent) [1,18,46,47].

For asymptomatic newborns in this category, we suggest the following evaluation be performed at approximately 24 hours of age (whether they were delivered vaginally or by cesarean section) (algorithm 1) [1,18,46]:

Surface cultures (ie, swabs of the mouth, nasopharynx, conjunctivae, rectum, and scalp electrode site [if present] and, possibly, urine for viral culture)

HSV blood PCR

Surface cultures obtained before 12 to 24 hours may reflect contamination during delivery, rather than infection. The sensitivity of viral cultures for detecting neonatal HSV infection in infants whose mothers were treated with antiviral medication during pregnancy is not known [1].

If the surface cultures or blood HSV PCR are positive, the asymptomatic neonate should undergo full clinical and laboratory evaluation and should receive treatment with acyclovir. (See 'Pretreatment evaluation' above and 'Acyclovir therapy' above.)

We do not suggest routine prophylactic acyclovir for asymptomatic neonates who are born to women with a history of genital HSV and active genital lesions at the time of delivery [1,46]. However, prophylactic treatment may be warranted if there are additional risk factors for transmission (eg, rupture of membranes >4 to 6 hours, gestation <37 weeks, scalp electrode, skin lacerations) [46,47]. If acyclovir is initiated for such patients, a full clinical and laboratory evaluation should be performed before initiating therapy. Acyclovir should be discontinued after three to five days if the infant remains asymptomatic and HSV PCR and viral cultures are negative.

No maternal history of HSV, active lesions — The risk of transmission of HSV to infants born to women with no history of genital HSV and active genital lesions at the time of delivery is between 25 and 60 percent [1,13,18].

We suggest that the evaluation of asymptomatic infants born to women with no history of genital HSV and active genital lesions include the following studies obtained at approximately 24 hours of age (whether they were delivered vaginally or by cesarean section) (algorithm 1) [1,46]:

Surface cultures or HSV PCR (ie, swabs of the mouth, nasopharynx, conjunctivae, rectum, and scalp electrode site [if present] and, possibly, urine for viral culture)

HSV blood PCR

CSF HSV PCR, cell count, chemistries

Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

Complete blood count with differential and platelet count

We also suggest sending maternal blood for type-specific HSV serology as soon as possible after delivery (if available) to more accurately characterize maternal infection (table 2) [1,46].

Surface cultures or PCR tests obtained before 12 to 24 hours may reflect contamination during delivery, rather than active infection of the neonate. The sensitivity of viral cultures for detecting neonatal HSV infection in infants whose mothers were treated with antiviral medication during pregnancy is not known [1].

We suggest empiric treatment with acyclovir (60 mg/kg per day intravenously [IV] divided every eight hours) for these neonates while awaiting results of virologic testing [1,46].

The duration of acyclovir is determined by the neonate's clinical status, results of the neonate's evaluation for HSV disease, and maternal HSV infection classification (algorithm 1) [1,46]:

For neonates in whom type-specific HSV serologic testing is not available who remain asymptomatic and whose HSV evaluation is negative, we suggest continuing acyclovir for 10 days.

For neonates for whom maternal serologic testing indicates recurrent HSV infection (table 2), we suggest discontinuing acyclovir at 48 to 72 hours if the newborn remains asymptomatic and HSV PCR and viral studies are negative.

For neonates born to women with primary genital HSV infection or nonprimary first-episode genital HSV infection (based on serologic testing (table 2)) or assumed primary or nonprimary first-episode infection (based on strong clinical suspicion and discordant or unavailable genital and serologic test results) who remain asymptomatic and whose HSV evaluation is negative, we suggest continuing acyclovir for 10 days.

In all cases, if the infant becomes symptomatic or the HSV evaluation is abnormal (including positive PCR, culture, abnormal CSF, or serum ALT >2 times the upper limit of normal), we recommend continuing acyclovir for at least 14 days (for skin, eye, and mouth [SEM] infection) or at least 21 days (for central nervous system [CNS] or disseminated disease). In addition, the infant should undergo additional evaluation (including eye examination and neuroimaging). (See 'Pretreatment evaluation' above and 'Acyclovir therapy' above.)

INVESTIGATIVE THERAPIES — Investigative therapies for neonatal HSV disease include human and humanized monoclonal antibodies directed against HSV gB and gD glycoproteins. These therapies have been beneficial in animal models of HSV disease. Studies in humans have shown that high titers of neutralizing antibodies protect neonates following perinatal HSV exposure [13]. At present, antibody therapy for treatment or prevention of neonatal HSV is limited by the lack of an HSV hyperimmune globulin preparation and the variable amount of anti-HSV antibodies in intravenous immune globulin preparations.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: TORCH infections".)

SUMMARY AND RECOMMENDATIONS

Indications for antiviral therapy

We recommend antiviral therapy for neonates with virologically proven herpes simplex virus (HSV) disease (Grade 1A). (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Detection of HSV'.)

We also suggest empiric antiviral therapy pending viral studies for neonates with clinically suspected HSV disease (Grade 2C) since prompt treatment is necessary to prevent serious morbidity. While the indications for initiating empiric treatment are not standardized, most experts agree that empiric therapy is indicated for neonates with mucocutaneous vesicles (picture 1A-C), seizures, lethargy, febrile illness with ill appearance, sepsis-like illness, severe liver involvement, or cerebrospinal fluid (CSF) pleocytosis with negative Gram stain. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical manifestations'.)

In addition, we suggest empiric therapy pending viral studies in asymptomatic neonates with perinatal exposure if the mother had primary HSV infection with active genital lesions at the time of delivery (Grade 2C). The risk of transmission to the infant in this setting is estimated to be between 25 to 60 percent. (See 'No maternal history of HSV, active lesions' above.)

Pretreatment evaluation – A comprehensive laboratory evaluation for HSV should be performed before starting antiviral therapy. (See 'Pretreatment evaluation' above and "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Evaluation and diagnosis'.)

Preferred agent – For treatment of all categories of neonatal HSV infections, including skin, eye, and mouth (SEM); central nervous system (CNS); and disseminated disease (table 1), we recommend acyclovir rather than other agents (Grade 1B). The dose is 60 mg/kg per day intravenously (IV) divided every eight hours for all forms of neonatal HSV. (See 'Acyclovir therapy' above and 'Dose' above.)

Treatment duration – The duration of IV acyclovir therapy for neonatal HSV infection depends upon the pattern of illness and response to therapy. SEM disease is treated for a minimum of 14 days; CNS and disseminated disease are treated for a minimum of 21 days. (See 'Duration of therapy' above.)

Treatment of eye disease – For neonates with ocular HSV involvement (eg, keratitis), we suggest topical ophthalmic therapy (eg, 1% trifluridine, 0.1% idoxuridine [iododeoxyuridine], or 0.15% ganciclovir) in addition to systemic acyclovir therapy (Grade 2C). These patients should be managed in consultation with an ophthalmologist. (See 'Treatment of eye disease' above.)

Oral suppressive therapy – For all categories of neonatal HSV disease, including SEM, CNS, and disseminated disease (table 1), we suggest oral acyclovir suppressive therapy for six months immediately following parenteral acyclovir (Grade 2B). For infants with HSV eye disease (eg, keratitis), we suggest a longer duration of oral suppressive therapy (up to one year) (Grade 2C). This is because reactivated virus in this setting has potential to threaten vision. (See 'Oral suppressive therapy' above.)

Management of asymptomatic, exposed infants – The evaluation and management of asymptomatic neonates who are exposed to HSV during delivery depends upon the mother's history of genital HSV, maternal serologies for type-specific HSV (if available) (table 2), and presence or absence of HSV genital lesions at the time of delivery (algorithm 1). All such infants should be monitored for evidence of HSV infection (eg, skin or scalp rashes, conjunctival lesions, irritability, fever (figure 1)) during the first six weeks of life. (See 'Management of the asymptomatic exposed infant' above.)

Neonates who develop clinical evidence of HSV infection should undergo full diagnostic evaluation and should receive empiric therapy pending results. (See 'Pretreatment evaluation' above and 'Acyclovir therapy' above.)

Prevention – Strategies for prevention of intrauterine and perinatally acquired HSV infection are discussed separately. (See "Genital herpes simplex virus infection and pregnancy", section on 'Pregnancy management'.)

The risk of postnatal transmission of HSV can be minimized by counseling family members with active or recent history of HSV lesions (cold sores, herpetic whitlow, herpetic gingivostomatitis) to avoid close contact with and kissing the newborn infant. (See 'General measures' above.)

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