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PRACTICE PARAMETER

IDENTIFICATION and MANAGEMENT of NEONATAL HERPES SIMPLEX VIRUS INFECTION

Alastair A. Hutchison, M.B.Ch.B., F.R.A.C.P.

Revised August 2000

INTRODUCTION

Incidence, Mortality / Morbidity of Neonatal Herpes Simplex Infection

Neonatal herpes simplex virus (HSV) infections, types I and 2, (HSV-1 & HSV-2), occur in I/ 2000 to 1/20,000 births [1,2], with HSV-2 accounting for 70% of the infections [3]. Maternal genital HSV infection in pregnancy increases the risk of pregnancy loss and preterm labor [4). Infection with HSV can present at birth as a result of in utero infection (5%) or present later in the neonatal period as the result of perinatal (85%) or postnatal (10%) exposure. Herpes infections are categorized clinically into three types according to the site(s) of the infection: skin, eye and mouth (SEM); localized central nervous system disease (CNS) or disseminated disease. In untreated patients mortality is highest in the disseminated form (76%) followed by the localized CNS (37%) and the SEM form (7%) [4], Outcome is worse in those who present in coma or near-coma, have disseminated intravascular coagulation or are preterm [5]. Both mortality and morbidity have improved most likely as a consequence of recognizing and treating of the SEM form before it progresses to a disseminated form [6]. With therapy, all neonates with SEM disease survive but neonates with localized CNS disease or disseminated disease still have a mortality of approximately 14% and 50-60% respectively [7]. Morbidity in treated neonates is low in those with SEM involvement (2%) but remains high in those with disseminated (-40%) or localized CNS disease (60-70%) [7]. Neurological and developmental outcome is worse in survivors of encephalitis with HSV-2 than with HSV- 1 [8]. The possibility of recurrence [5] or progressive, insidious deterioration [9] during the first year of life is a major concern.

Methodology

The management proposed in this practice parameter was based, when possible, upon published data. The studies upon which reliance was placed were 1) randomized controlled clinical trials which provided strong evidence of a therapeutic effect or 2) observational studies performed in multiple centers which provided reasonable evidence of a therapeutic effect. Observational data from one center / author was viewed as weak evidence and identified as such if included in the development of the practice parameter. Where no studies exist to provide guidance to the clinician for therapy, a consensus was developed initially by a group of participants and finally by the larger body of clinicians involved in the process of developing the practice parameter. Published recommendations from national committees (e.g. American Academy of Pediatrics) are cited.

Definition of Neonatal Herpes Simplex Infection

Neonatal HSV infection is either strongly suspected on the basis of clinical findings compatible with neonatal HSV infection or proven by laboratory investigations.

Goals of identification and management of the neonate at-risk of HSV Infection

To prevent, if possible, neonatal HSV infection and /or minimize the effects of the

infection for the neonate.

To reduce the attendant effects of neonatal HSV infection for the family, namely emotional stress and separation from the baby.

To minimize the medical costs.

KNOWLEDGE, SKILLS AND RESOURCES REQUIRED TO IDENTIFY AND PROVIDE MANAGEMENT OF THE BABY AT-RISK OF EARLY NEONATAL SEPSIS

Knowledge

The health care team caring for newborn babies require a specific knowledge of the following appropriate to their training:

the pathophysiology of neonatal HSV infection.

the signs of neonatal HSV infection, including skin, mouth or eye lesions, localized central nervous system signs, e.g. apnea and seizures and other signs of disseminated disease, e.g. hypotension, severe pneumonitis, hepatitis, acidosis.

the perinatal risk factors associated with increased risk of neonatal HSV infection

the interpretation of white cell counts, cerebrospinal fluid and culture results

the pharmacology and dosages of antiviral therapy

the assessment of adequacy of perfusion

the assessment of adequacy of oxygenation

Skills

Education of the mother of signs in the baby requiring that medical attention is sought.

Ability to assess and monitor the sick neonate, including measurement of blood pressure, temperature, heart rate, respiratory rate and the use of a pulse oximeter.

Ability to draw venous blood and obtain specimens for laboratory investigations.

Ability to give intravenous fluids and medications.

Ability to resuscitate the sick neonate.

Resources

Availability of experienced medical staff to deal with shock.

Availability of experienced staff to provide frequent monitoring of well babies rooming-in with their mothers.

Availability of a transitional nursing area with an appropriately heated and lit area for investigation and treatment of a baby with or suspected of having HSV.

Availability of a consultant in pediatric infectious disease.

Capability to provide antibiotic therapy, oxygen and fluids as required.

Capability to assess oxygen saturation, blood pressure and monitor heart rate, respiration and temperature.

Management

This practice parameter addresses those management aspects dealing with identification of the neonate at risk and initial management mainly of the baby with neonatal HSV infection in the normal newborn nursery. Neonatal resuscitation, including adequacy of oxygenation and the treatment of volume depletion, are covered in the Neonatal Resuscitation Program (American Academy of Pediatrics / American Heart Association) and are not included. Intensive care of the baby with HSV infection, e.g. artificial ventilation, and administration of non-specific antiviral therapy for NSV disease, will not be covered in this practice parameter. Infection with other viruses of the herpes family is not covered in this practice parameter.

Maternal Herpes Infection During Pregnancy

Approximately 1% of mothers have a HSV genital infection at some time during pregnancy [10], with 0.01-0.39% shedding virus at delivery [2]. The seroprevalence of HSV-2 is approximately 32% in obstetric patients, of whom approximately 70% give no history of HSV genital infection [11]. The seroprevalence of the fathers is 25%. Of the seronegative pregnant women, 10% are at risk of contracting primary HSV-2 infection from their spouses [11].

Types of Maternal Herpes Simplex Virus Infection and Impact for Neonate

Maternal genital HSV infection is defined by 1) the presence or absence of maternal symptoms and signs and 2) the presence or absence of prior HSV infection. The latter is categorized as follows:

Primary maternal HSV infection is identified by a concurrent lack of neutralizing antibodies to HSV- I or HSV-2 and their subsequent development

Recurrent maternal HSV infection is identified by the presence of these antibodies.

The third category of HSV, termed non-primary, is that in which the mother has her first symptomatic genital infection, usually with HSV-2, in the presence of neutralizing antibodies usually to HSV-1.

The relative proportions of the types at the time of labor are: 91.3% recurrent; 2.1% primary and 6.6% non-primary [12]. Since 7O% of women with recurrent HSV infection have no history of HSV, the clinical differentiation between recurrent and primary HSV genital infections may not be possible.

For HSV infection acquired around the time of birth the risk of neonatal HSV depends upon: 1.) viral load (degree and duration of infection) that the neonate is exposed to. This is regardless of whether the mother has symptoms or genital lesions with active shedding of HSV or is shedding asymptomatically, and 2.) maternal HSV infection / immunity status [1,4,13] . The risks for the various types are:

primary >50% risk; accounts for 50% of the neonatal mortality / morbidity.

non-primary >30% risk (based upon small numbers, the risk could be larger)

recurrent <5% risk (estimate, risk is probably smaller).

Routes of Fetal / Neonatal Infection

Exposure and subsequent infection of the neonate can occur 1) via the transplacental route, 2) via delivery through an infected birth canal or secondary to ascending infection in babies whose mothers are delivered by cesarean section following rupture of the membranes, and 3) via postnatal exposure to HSV. Transplacental intrauterine infection of the fetus occurs in about 5% of neonatal HSV cases. These babies present at birth with congenital anomalies indicative of past infection or signs indicative of recent exposure or recurrence. This group includes neonates with an onset of HSV in the first few days after birth who were delivered by cesarean section of mothers with intact membranes. The majority of HSV infection is acquired perinatally (85%). In the absence of transplacental and ascending infection (including fetal instrumentation), this is the group whose exposure to genital HSV can be avoided by cesarean section. Postnatal acquisition accounts for the remaining 10% [4].

Identification of the Neonate At-Risk of RSV Infection

The neonate is at-risk if the mother has an infected birth canal around the time of delivery. Thus, identification of genital HSV lesions and considerations of maternal immunity are important. The neonatal HSV risk is approximately 33-50%, with a primary/non-primary maternal HSV genital infection around delivery [1,4,13]. Note, since antibodies to HSV are not detected for 3-4 weeks after the onset of a primary infection [14], recurrence of lesions / viral shedding after a primary infection within five weeks of delivery should be viewed as a "first symptomatic episode". A higher risk is also attributed to those neonates whose mothers had a primary genital HSV infection 6-10 weeks prior to term, i.e. at 30- 34 weeks of gestation [15]. However, in babies who develop neonatal HSV only 9% have mothers with genital lesions present at delivery and of those only about 10% are primary [12]. The neonatal HSV risk is less from exposure to maternal genital HSV lesions if there is a history of recurrent HSV, < 5% [2,4]. These lesions occur around the time of delivery in approximately 14.5% of women with a history of recurrent genital HSV. The shorter duration of these lesions and the presence of maternal antibodies are associated with a likely viral recovery from the lesions of 15-50% [12] and a lower risk of neonatal HSV infection (3-5%) [4]. However, identification of this at risk population is poor. Despite an approximately 32% prevalence of seropositivity for HSV-2 in the obstetric population, less than one third of those will give a history of a genital HSV infection. Thus, at delivery, a mother who presents with a "first" symptomatic episode around delivery may be uncertain whether this is truly primary or recurrent.

In 20% of babies who develop neonatal HSV, there is a history of recurrent genital HSV but the mother was asymptomatic around delivery. Active shedding of genital HSV at delivery in asymptomatic mothers with recurrence of genital HSV occurs in 10.6% of those with a primary infection during the pregnancy [13] and in 1.4% of those with a prior history of recurrent HSV [16]. In addition to the latter low risk of maternal shedding, if HSV exposure does occur the subsequent risk of neonatal HSV is low 1/33[1] or 0/34 of exposed neonates [17]. Overall the calculated risk for neonatal HSV in the asymptomatic mother around delivery with a history of recurrent genital HSV infection with no HSV culture available is <0. 1%, with an increase to a maximum of about 0.3% if the primary HSV genital infection occurred earlier during the pregnancy.

The remaining > 70% of babies with neonatal HSV are born to mothers who were asymptomatic at delivery and do not have a history of HSV genital infection. Screening

all mothers and infants at delivery for genital HSV gives a risk of shedding HSV at delivery of 0.2% [18] to 0.35%[I]. All 14 of 6904 screened mothers who were identified with genital HSV were asymptomatic at delivery and only 1/14 had a history of HSV genital infection [18]. Two of the 14 HSV maternal infections were primary with one baby developing HSV infection. The other 12/14 maternal infections were recurrent HSV

infections and there were no cases of neonatal HSV. Rarely (0.02%), neonatal HSV can occur when the maternal genital HSV culture is negative [1]. In a study of 15,923 mothers with 10 neonatal HSV infections, the usefulness of the HSV genital culture in identifying subsequent neonatal HSV was as follows: sensitivity 70%; specificity 99.7%; positive predictive value 12.5% and negative predictive value 99.9% [1].

Prevention / Reduction in Neonatal HSV Morbidity and Mortality

The current management strategies are:

prepartum identification and appropriate management of the mother with active primary, non-primary or recurrent genital HSV infection and postnatal evaluation of the baby;

postnatal identification of well neonates without signs of HSV infection who were born to asymptomatic mothers without HSV genital lesions but with a history of recurrent genital HSV infection or a first symptomatic episode earlier in the pregnancy;

postnatal identification of the neonate with signs compatible with HSV infection who requires immediate investigation, isolation, careful observation, specific antiviral and other supportive therapy.

The aims of the above strategies are:

1) preventing (antenatal management) or reducing the postnatal illness;

2) decreasing separation of baby and family and the family stresses of having a severely sick neonate and

3) reducing the medical and societal costs for the intensive care these babies can require.

Obstetric Management Considerations

There is debate about the optimal management in the case of the mother with active HSV genital infection whose membranes rupture before the onset of labor when the baby is still preterm. The options are: 1) to provide maternal treatment with acyclovir and watch for the onset of labor; 2) delay labor actively to provide the optimum opportunity for betamethasone to induce lung maturity or 3) to proceed to immediate cesarean section delivery with the attendant risks for the baby of immaturity of the lungs and other organs [2].

Cesarean section is recommended if first episode or recurrent genital HSV lesions are present at delivery and ideally before rupture of the membranes provided there are no contraindications[19,20]. The data to support this strategy is based up on the combined data of Nahmias and Amstey, who looked at the incidence of neonatal HSV in babies of mothers with lesions or proven genital HSV infection at delivery. Of those who delivered vaginally 9/20 (45%) had neonatal HSV. The incidence of neonatal HSV in babies delivered by c-section with >4 hours [21] or >6 hours [22] rupture of the membranes prior to delivery was 9/10 (90%). In those who delivered by c-section with <4 hours rupture of the membranes the incidence of neonatal HSV was 1/17(<6%). Specific antibody testing for prior HSV-2 infection was not available. Neonatal outcome following 18 c-section

deliveries for active lesions (rupture of the membrane interval not stated) in mothers with recurrent genital HSV has been reported as good - no cases of HSV infection [23]. However only 1/67 neonates developed neonatal HSV after vaginal delivery to asymptomatic mothers with HSV genital culture evidence of active intrapartum infection-- see above. Thus, some of the protective effect of c-section with a small duration of rupture of the membranes may be attributed to the nature of the maternal infection - primary versus secondary. The protective role of c-section delivery is also questioned by data from two large series of neonates with HSV infection [24] (n= 1 84) and [6] (n= 28 1) which indicate that 20-33% of neonatal HSV disease occurs following c-section. No benefit of a decreased duration of rupture of the membranes was seen with cases occurring without rupture of the membranes. In one study 38% of the c-section delivered cases had a rupture of the membrane duration < 6 hours and in the other the median rupture of the membrane interval was 4 hours. The above controversies have prompted a re-evaluation of the maternal risks and neonatal benefits of c-section delivery of the mother with active recurrent HSV around delivery, the need for safer sex practices and the potential role of other therapies such as prophylactic maternal acyclovir [14,20,251. The data look promising but no alterations have been made to the current recommendations [20]. It is clear that neonatal infection from a maternal genital HSV source requires exposure to that source. It is recommended that all neonates born to mothers with active lesions around delivery whether they be primary, potential primary or recurrent be evaluated [2].

If the mother has active lesions on the buttocks, thighs or abdomen, then, currently there are "Conflicting data regarding the likelihood of a concurrent genital shedding infection in patients who are in labor and….. there are no data regarding the likelihood of neonatal infection in such cases." [25].

The neonatal healthcare team should be informed that the mother has developed genital HSV lesions / prodrome in the immediate postnatal period or that a positive perinatal HSV genital culture result has provided evidence of a likely exposure of the neonate at birth.

Neonatal Management Guidelines

Evaluation of Neonate with Exposure to HSV Around Delivery

Neonatal management depends upon:

the clinical status of the baby - is the baby sick with signs compatible with HSV

the current maternal genital HSV infection status

the history of type of maternal HSV infection: primary, recurrent or unknown, and

the mode of delivery.

If the mother is immunocompromised, or has resistance to acyclovir a pediatric infectious disease consultation should be sought and management directed accordingly.

Clinical Presentations with Risk of Neonatal HSV Infection <0.5%

A. "Well" neonate with no signs judged to be compatible with HSV infection.

B. Asymptomatic mother with no signs of active infection of the birth canal, but with a history of:

a) recurrent genital HSV infection or

b) a first symptomatic episode occurred > 10 weeks before delivery

c) delivery was vaginal or by c-section.

C. Symptomatic mother with active infection of the birth canal and a history of:

a) a recurrent genital HSV infection or

b) a first symptomatic episode occurred >10 weeks before delivery.

c) delivery was vaginal or by c-section with no rupture of the membranes or < 4 hours of rupture of the membranes in a term baby with no fetal instrumentation

d) mother received acyclovir during labor

The neonate should be observed only and no special isolation precautions are required. Prior to discharge the physician should ensure that the parents have understood the information they have received regarding the recognition of any signs of HSV in their baby. In addition, it should be ensured that the family has access to emergency care and can contact medical care quickly. A follow-up visit is arranged.

Clinical Presentations with Risk of Neonatal HSV Infection ~<5%.

A. "Well" neonate with no signs judged to be compatible with RSV infection. But with symptomatic mother with active or recurrent HSV infection of the birth canal around delivery.

B. Symptomatic mother with HSV skin lesions on thigh, abdomen or buttock and a history of:

a) a recurrent HSV infection, or

b) a first symptomatic episode occurred between 6-10 weeks before delivery, and

c) delivery was vaginal or by c-section with > 4 hours of rupture of membranes or delivery occurred after rupture of the membranes < 4 hours and delivery was preterm or fetal instrumentation had occurred.

C, Symptomatic mother with a history of:

a) inability to determine if infection primary or recurrent,

b) the first symptomatic episode occurred between 6 to 10 weeks before delivery,

c) delivery was vaginal or by c-section, regardless of the time of rupture of the membranes.

D. Symptomatic mother with a history of:

a) current infection is the first symptomatic episode

b) infection occurred <6 weeks before delivery

c) delivery was by c-section with no rupture of the membranes or <4 hours rupture of the membranes.

Wound and skin isolation (gown and glove precautions) should be used for persons having contact with the baby, bed space and equipment. Double bagging of the articles should be performed. If possible the neonates should be room-in with their mothers and observed closely (4 hourly observations). If rooming-in is not possible, the infant should be placed in the regular nursery separated by two meters from other infants. Swab cultures of nasopharynx, eyes, and rectum should be sent at 12-24 hours. If a scalp electrode was used, those caring for the neonate should be alerted to the possibility of vesicles occurring at site of placement of the electrode whether on scalp or buttock. Delay of elective or ritual circumcision for about one month is advised [2]. This minimizes the chances of introducing HSV on the skin into the blood stream. In the event the baby remains clinically well he/she is discharged. Some physicians may wish to ensure that the HSV cultures are negative or that a sufficient period has passed so that the results are unlikely to be positive. The use of the shell culture technique has decreased the time for a positive HSV culture result such that 100% are available in 4 days [12]. Discharge considerations are the same as for infants with very low risk of infection.

Clinical Presentations with Risk of Neonatal HSV Infection - 33-50%

"Well" neonate with no signs judged to be compatible with HSV infection

Symptomatic mother with active HSV infection of the birth canal around delivery and a history of:

a) the current infection is the first symptomatic episode

b) a first infection < 6 weeks before delivery

c) delivery was vaginal or by c-section with > 4 hours rupture of the membranes.

All isolation precautions described above should be enforced. Swabs of nasopharynx, eyes and rectum and samples of blood and cerebrospinal fluid should be sent to the laboratory at 12-24 hours. Prophylactic acyclovir therapy should then commence and the baby should be closely observed [26]. Considerations should be given to ophthalmologic consultation. In the event the baby remains clinically well he/she is discharged. If the cultures are negative the prophylactic acyclovir can be stopped and the patient considered for discharge. The timing of discharge will be dependent upon the same discharge stipulations apply as in 1. Delay of circumcision at least until cultures are negative and for up to one month is advised [2]. Discharge considerations are the same as for infants with very low risk of infection.

Neonates with Signs of or Suggestive of HSV Infection.

Clinical Presentation

Neonatal HSV infection can present any time from soon after birth up to and beyond the neonatal period. There are three major types of presentation:

a) Skin, Eye, Mouth (SEM): patients with this form have HSV lesions (erythema, vesicles, ulcers and crusts) of the skin and mouth, and/or conjunctivitis; and/or keratitis & chorioretinitis. Without treatment 70% of cases progress to disseminated form.

b) Localized CNS: Meningoencephalitis.

c) Disseminated: The signs in babies with disseminated HSV infection without skin lesions (20%) can mimic those of a bacterial infection. Apnea, encephalitis, hepatitis, hepatomegaly, acidosis (especially if persistent), severe pneumonitis, thrombocytopenia, disseminated intravascular coagulation may suggest disseminated HSV. Consideration should be given to the coexistence of bacterial infection, hepatitis B, other sexually transmitted diseases and the possibility of maternal substance abuse.

Laboratory Specimens

The following should be sent for laboratory investigation:

cells from the base of skin vesicles for antigen assays

viral culture of swabs of the nasopharynx or mouth; eyes; rectum or stool

cerebrospinal fluid

consider urine and blood [2]

ALT

If the baby is being artificially ventilated for pneumonitis, a sample of endotracheal secretion may be sent for investigation.

The cerebrospinal glucose and protein may be normal but the presence of monocytosis and red blood cells should raise the suspicion of HSV infection [27].

The use of PCR amplified detection of I-ISV DNA is available in some laboratories.

Diagnosis

The diagnosis of neonatal herpes simplex virus infection is made by any or all of the following:

shell viral culture followed by antibody detection of HSV antigen (a very reliable test with 99% sensitivity and 100% specificity [4]

detection of HSV antigens in vesicle scrapings by direct fluorescent antibody staining or enzyme immunoassay [2]

the identification of HSV DNA amplified by use of the polymerase chain reaction (PCR) [28,29]

strongly suspected on the basis of cytopathic changes in a smear of vesicular cells

on the basis of clinical findings.

Therapy

a) The baby with HSV disease should be cared for in a regional Neonatal Intensive Care Unit. For these cases, the opinion and guidance of a consultant in pediatric infectious disease is advised.

b) Strict isolation should be practiced with the neonate with HSV infection being nursed in a private room or an isolette separated from other neonates by at least two meters. Caregivers wear gowns, gloves, and masks (if respiratory problem is present or if the baby is not in a closed isolette). Double bagging of articles (e.g. linens and diapers) is practiced.

c) Supportive care (e.g. intravenous fluids, cardiorespiratory support) is given as required. No elective surgery for one month.

d) Acyclovir 60mg/kg/day, in three divided doses is given for 14 days. Higher doses may be considered as well as longer periods of therapy [2].

e) An Ophthalmology consultation is obtained to assess any retinal and corneal lesions . f) 1-2% trifluridine or 1% iododeoxyuridine and 3% vidarabine may be used to treat superficial keratitis [26].

Outcome

With acyclovir and vidarabine therapy, mortality and morbidity from HSV have improved. Neonates with disseminated disease have a mortality of 50- 60% [7]. By contrast babies with only skin or eye or mouth infection all survive, while 14% of those with localized central nervous system disease die. Developmental outcome is good in 98% of those with only skin, eye or mouth involvement [7]. However in treated neonates with localized central nervous system disease or disseminated disease, the percentage of those who are normal at one-year falls to approximately 30 to 40% and 60% respectively [7]. Neurological and developmental outcome is worse in survivors of encephalitis with HSV-2 than with HSV- 1 [8]. All patients with HSV infections should have their hearing tested with the ABR prior to discharge. Follow-up care of survivors is very important in view of the possibilities of progressive insidious deterioration [9] or recurrence of the disease in the first year [5]. In addition there is a high incidence of other, especially neurological, sequelae. Currently the optimal long-term management of neonates who have had encephalitis or develop recurrent disease is unknown [5]. Prophylactic oral acyclovir at 300mg/m2/dose TID should be considered until the patient is six months old.

Prior to discharge the physician should discuss with the parents the current status of the neonate and potential problems which may arise. The physician should also arrange follow-up and ensure that a consultant in pediatric infectious disease is involved in their management.

Postnatally Acquired Neonatal HSV Infection

It is important to reduce the risk (10% of cases) of postnatally acquired HSV by avoiding contact of the baby with active HSV lesions [30]. Mothers or hospital personnel with labial HSV infection (cold sores) should: 1) cover and avoid touching their lesions; 2) adhere strongly to hand washing policies; and 3) avoid kissing or nuzzling the baby until the lesions have cleared [2,31]. If no maternal HSV breast lesions are noted and other active skin lesions are covered then breast milk feeding is acceptable [2].

SUMMARY

This practice parameter for neonatal HSV infection presents an approach to babies with HSV infection and those with different degrees of risk of acquiring HSV in the perinatal period. The general approach is summarized below.

The majority of neonates with HSV (70%) are born to mothers without symptoms or signs of perinatal genital HSV infection or a history or recurrent infection. Thus, emphasis is placed upon clinical evaluation.

ALGORITHM

The algorithm below is one approach to the identification and management of neonates at risk of perinatally acquired neonatal HSV or presenting with signs of HSV infection. It attempts to balance risk of neonatal HSV infection and the degree of laboratory investigation.

APPROACH to NEONATE with SIGNS of or at RISK of HSV INFECTIONS

e) includes early postnatal development of maternal symptoms or signs of HSV infection.