Guidance on Management of Asymptomatic Neonates Born to Women with Active Genital Herpes Lesions

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Guidance for the Clinician in Rendering Pediatric Care

CLINICAL REPORT Guidance on Management of Asymptomatic Neonates Born to Women With Active Genital Herpes Lesions

David W. Kimberlin, MD, Jill Baley, MD, COMMITTEE ON INFECTIOUS DISEASES, and COMMITTEE ON FETUS AND abstract NEWBORN Herpes simplex virus (HSV) infection of the neonate is uncommon, but KEY WORDS genital herpes infections in adults are very common. Thus, although newborn, herpes simplex virus, acyclovir, pregnancy treating an infant with neonatal herpes is a relatively rare occurrence, ABBREVIATIONS CNS—central nervous system managing infants potentially exposed to HSV at the time of delivery CSF—cerebrospinal fluid occurs more frequently. The risk of transmitting HSV to an infant dur- HSV—herpes simplex virus ing delivery is determined in part by the mother’s previous immunity HSV-1—herpes simplex virus type 1 HSV-2—herpes simplex virus type 2 to HSV. Women with primary genital HSV infections who are shedding IgG—immunoglobulin G HSV at delivery are 10 to 30 times more likely to transmit the virus to PCR—polymerase chain reaction their newborn infants than are women with recurrent HSV infection — SEM skin, eye, mouth who are shedding virus at delivery. With the availability of commer- This document is copyrighted and is property of the American cial serological tests that reliably can distinguish type-specificHSV Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American antibodies, it is now possible to determine the type of maternal Academy of Pediatrics. Any conflicts have been resolved through infection and, thus, further refine management of infants delivered a process approved by the Board of Directors. The American to women who have active genital HSV lesions. The management Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of algorithm presented herein uses both serological and virological this publication. studies to determine the risk of HSV transmission to the neonate The guidance in this report does not indicate an exclusive who is delivered to a mother with active herpetic genital lesions and course of treatment or serve as a standard of medical care. tailors management accordingly. The algorithm does not address the Variations, taking into account individual circumstances, may be approach to asymptomatic neonates delivered to women with a his- appropriate. tory of genital herpes but no active lesions at delivery. Pediatrics FUNDING: Funded in whole or in part with Federal funds from – the National Institute of Allergy and Infectious Diseases, National 2013;131:e635 e646 Institutes of Health, Department of Health and Human Services, under contract (N01-AI-30025, N01-AI-65306, N01-AI-15113, N01-AI- 62554), the General Clinical Research Unit (M01-RR00032), and the State of Alabama. Funded by the National Institutes of Health INTRODUCTION (NIH). Herpes simplex virus (HSV) infection of the neonate is an uncommon occurrence, with an estimated 1500 cases diagnosed annually in the United States from a birth cohort of more than 4 000 000. In contrast, genital herpes infections in adults are very common. Between 1 in 4 and 1 in 5 adults in the United States has genital herpes caused by HSV type 2 (HSV-2).1,2 In addition, HSV type 1 (HSV-1) now accounts for at least 20% and, in some locales, more than 50% of cases of genital herpes in the United States.3,4 Therefore, managing infants potentially www.pediatrics.org/cgi/doi/10.1542/peds.2012-3216 exposed to HSV at the time of delivery is not uncommon, and prevention of the devastating outcomes of neonatal HSV disease is par- doi:10.1542/peds.2012-3216 amount. All clinical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, Current recommendations for the management of infants after intra- revised, or retired at or before that time. partum exposure are based on expert opinion, because a randomized PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). controlled trial to determine whether an exposed neonate should be Copyright © 2013 by the American Academy of Pediatrics treated would be unethical. However, the existing recommendations do

PEDIATRICS Volume 131, Number 2, February 2013 e635 Downloaded from www.aappublications.org/news by guest on September 26, 2021 not take into account recent information RISK OF MATERNAL INFECTION 1. Type of maternal infection (primary correlating risk of transmission with DURING PREGNANCY versus recurrent)5,15–18; type of maternal infection (primary 5,14,19,20 Recurrent infections are the most com- 2. Maternal HSV antibody status ; versus recurrent) at the time of mon form of genital HSV during preg- 3. Duration of rupture of membranes18; delivery.5 The algorithm contained nancy.7 Approximately 10% of HSV-2– within this American Academy of 4. Integrity of mucocutaneous bar- seronegative pregnant women have an Pediatrics (AAP) clinical report for the riers (eg, use of fetal scalp electro- HSV-2–seropositive sexual partner and, 5,21,22 diagnostic and therapeutic approach des) ; and thus, are at risk for contracting a pri- to the neonate with known potential 5. Mode of delivery (cesarean versus mary HSV-2 infection during the preg- exposure to HSV during the perinatal vaginal delivery).5 nancy8 and transmitting the virus to period incorporates the most current their infants during delivery. Approxi- Infants born to mothers who have scientific understanding of the biology, mately one-fifth to one-third of women a first episode of genital HSV infection epidemiology, and pathology of HSV of childbearing age are seronegative near term and are shedding virus at infection and disease. for both HSV-1 and HSV-2,9,10 and, delivery are at much greater risk of among discordant couples, the chance developing neonatal herpes than are TERMINOLOGY OF HSV INFECTION that a woman will acquire either virus infants whose mothers have recurrent – AND DISEASE during pregnancy is estimated to be genital herpes (Fig 1).5,15 18 When an individual with no HSV-1 or 3.7%.11 For women who are already The largest assessment of the influence HSV-2 antibody acquires either virus in seropositive for HSV-1, the estimated of type of maternal infection on likelihood the genital tract, a first-episode primary chance of HSV-2 acquisition during the of neonatal transmission is a land- infection results. If a person with pre- pregnancy is 1.7%.11 Approximately two- mark study involving almost 60 000 existing HSV-1 antibody acquires HSV-2 thirds of women who acquire genital womeninlaborwhodidnothave genital infection (or vice versa), a first- herpes during pregnancy remain clinical evidence of genital HSV dis- episode nonprimary infection ensues. asymptomatic and have no symptoms ease, approximately 40 000 of whom Viral reactivation from latency and to suggest a genital HSV infection.11 had cultures performed within 48 hours subsequent antegrade translocation of This is consistent with the finding that of delivery (Fig 1).5 Of these, 121 women virus back to skin and mucosal surfaces 60% to 80% of women who deliver an were identified who were asymptomat- produces a recurrent infection. HSV-infected infant have a clinically ically shedding HSV and who had sera Genital HSV infection can be either unapparent genital HSV infection at the available for analysis. In this large trial, clinically apparent (eg, genital lesions) time of delivery and have neither a 57% of infants delivered to women with fi or inapparent (asymptomatic, or sub- past history of genital herpes nor a rst-episode primary HSV infection de- clinical). Transmission to the neonate at sexual partner reporting a history of veloped neonatal HSV disease, com- 12–14 the time of birth can occur with either genital HSV. pared with 25% of infants delivered fi presentation. to women with rst-episode nonprimary RISK OF NEONATAL HSV INFECTION infection and 2% of infants delivered The distinction between neonatal HSV to women with recurrent HSV disease HSV infection of the newborn infant is infection and neonatal HSV disease (Fig 1).5 warrants discussion. Infection occurs acquired during 1 of 3 distinct times: when viral replication has been estab- intrauterine (in utero), intrapartum lished, but the virus is not causing (perinatal), and postpartum (postnatal). CLINICAL MANIFESTATIONS OF illness. Disease occurs when viral rep- ThetimeoftransmissionofHSV-1or NEONATAL HSV DISEASE lication produces clinical signs of illness HSV-2 for the overwhelming majority of HSV infections acquired either intra- (eg, skin lesions, encephalitis, hepatitis). infected infants (∼85%) is in the intrapartum or postpartum can be classi- Once an infant is infected with HSV, partum period. An additional 10% of fied as: (1) disease involving multiple progression to neonatal HSV disease is infected neonates acquire HSV-1 post- visceral organs, including lung, liver, virtually certain. In an effort to prevent natally from either a maternal or non- adrenal glands, skin, eye, and/or brain this progression from neonatal infec- maternal source, and the final 5% are (disseminated disease); (2) central tion to neonatal disease, experts have infected with HSV-2 or HSV-1 in utero. nervous system (CNS) disease, with or recommended for many years that Five factors known to influence trans- without skin lesions (CNS disease); and parenteral acyclovir be administered mission of HSV from mother to neonate (3) disease limited to the skin, eyes, preemptively to HSV-infected neonates.6 are: and/or mouth (skin, eye, mouth [SEM]

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have been approved by the US Food and Drug Administration (Table 1). Many of these products are sold in kits that are used by clinical laboratories throughout the United States. Several additional tests that claim to distinguish between HSV-1 and HSV-2 antibody are available commercially, but high cross-reactivity rates attributable to their use of crude antigen preparations limit their utility,31 and their use is not recommended.

DIAGNOSIS OF NEONATAL HSV DISEASE Isolation of HSV by culture remains the FIGURE 1 definitive diagnostic method of estab- Type of maternal infection and risk of HSV transmission to the neonate.5 lishing neonatal HSV disease. If skin lesions are present, a scraping of the disease). This classification system is potential limitation of the PCR assay vesicles should be transferred in ap- predictive of both morbidity and mor- at the current time relates to its propriate viral transport media on tality.23–27 Neonates with disseminated availability in all clinical settings; some ice to a diagnostic virology laboratory.6 and SEM HSV disease typically present smaller or more remote medical fa- Other sites from which specimens for medical attention at 10 to 12 days cilities have limited or no access to should be obtained for culture of HSV of age, whereas infants with CNS dis- laboratories offering this technology. At include the conjunctivae, mouth, naso- ease typically present at 17 to 19 days many tertiary care centers, PCR assay pharynx, and rectum (“surface cul- of age.24 Overall, approximately half of results may be available within a day, tures”).6 Specimens for viral culture all infants with neonatal HSV disease whereas it takes 2 to 5 days for HSV to from mucosal body sites may be com- will have CNS involvement (CNS dis- grow in viral culture. Typing of an HSV bined before inoculating in cell culture ease or disseminated disease with CNS culture isolate or PCR assay product to to decrease costs, because the impor- involvement), and approximately 70% determine if it is HSV-1 or HSV-2 can be tant information gathered from such will have characteristic vesicular skin accomplished by one of several tech- cultures is the presence or absence of lesions (SEM disease, 83%; CNS disease, niques. The reliability of viral culture replicating virus rather than its pre- 63%; disseminated disease, 58%).24 depends on the stage of the episode, cise body site. The sensitivity of PCR with higher quantities of virus being assay on surface specimens has not DIAGNOSIS OF GENITAL HSV present during the prodromal and ve- been studied; if used, surface PCR as- DISEASE sicular stages than during crusting.30 say should be performed in addition to HSV can be detected from genital lesions Antigen detection methods are available (and not instead of) the gold-standard by polymerase chain reaction (PCR) commercially but may not distinguish surface culture. Rapid diagnostic tech- assay, viral culture, or antigen detection. HSV-1 from HSV-2 and are not recom- niques also are available, such as direct Of these, PCR assay or viral culture are mended by the Centers for Disease fluorescent antibody staining of vesicle the testing modalities recommended by Control and Prevention for the diagnosis scrapings or enzyme immunoassay de- the Centers for Disease Control and of genital herpes. tection of HSV antigens. These techniques Prevention for the diagnosis of genital Before the year 2000, commercially are as specific but slightly less sensitive HSV lesions.28 The sensitivity of viral available serological assays were unable than culture. culture from genital lesions is low, to distinguish between HSV-1 and HSV-2 The diagnosis of neonatal HSV CNS especially for recurrent infection, and antibodies, severely limiting their utility. disease has been greatly enhanced by declines rapidly as lesions begin to Over the past decade, a number of type- PCR testing of cerebrospinal fluid heal. PCR assays for HSV DNA are more specific serological assays that reliably (CSF) specimens,32–38 and PCR assay sensitive and are increasingly used distinguish between immunoglobulin G is now the method of choice for doc- for the diagnosis of genital HSV.28,29 A (IgG) directed against HSV-1 and HSV-2 umenting CNS involvement in an infant

PEDIATRICS Volume 131, Number 2, February 2013 e637 Downloaded from www.aappublications.org/news by guest on September 26, 2021 suspected of having HSV disease. How- ever, PCR assay of CSF should only be performed in conjunction with HSV surface cultures, given that up to 40% of infants with disseminated disease invernessmedicalpd. com laboratory) www. (moderate to high volume)

2h will not have CNS involvement, and, by ∼ Blood draw (sent to deﬁnition, no infants with SEM disease will have CNS involvement. The sensitivity of CSF PCR testing in neonatal HSV (sent to laboratory) com disease ranges from 75% to 100%.33,36,38 Liaison HSV-2 AtheNA MultiLyte Blood draw www.diasorin. PCR analysis of CSF also should play a role in determining the duration of antiviral therapy, because available data suggest that having HSV DNA Immunoblot Differentiation laboratory) com detected in CSF at or after completion 2 h 35 min HerpeSelect 1 and 2 ∼ Blood draw (sent to Low volume High volume Screening or testing of intravenous therapy is associated with poor outcomes.36,37 All infants with a positive CSF PCR assay result for HSV DNA at the beginning of antiviral therapy should have a repeat lumbar puncture near the end of treatment to determine laboratory) patients or pregnant women (moderate volume) that HSV DNA has been cleared from the HerpeSelect HSV-2 ELISA 2h HerpeSelect HSV-1 ELISA and Blood draw (sent to ∼ www.herpeselect.com www.herpeselect. CNS.24 Infants whose PCR assay result remains positive should continue to receive intravenous antiviral therapy until the CSF PCR assay result is negative.24,36 2 ELISA laboratory) euroimmunus. com

2h Application of PCR testing to blood HSV-1 and Anti-HSV- ∼ Moderate volume Screening or testing STD Blood draw (sent to specimens from infants with suspected HSV disease appears promising,37–42 and, in the 2012 Red Book,6 PCR assay c HSV Antibodies ﬁ of blood has been added to the laboratory evaluation for neonatal HSV disease. Data are insufﬁcientatthecurrent pregnant women or STD clinic patients (moderate volume) laboratory)

2h time to allow the use of serial PCR Trinity Biotech USA Euroimmun US LLC Focus Diagnostics Focus Diagnostics DiaSorin Inc.∼ Inverness Medical www.trinitybiotech.com www. Screening or testing Blood draw (sent to HSV-1 or HSV-2 or both HSV-1 or HSV-2 HSV-1 or HSV-2 or both HSV-1 and/or HSV-2 HSV-1 or HSV-2 HSV-1 and/or HSV-2 assays of blood to establish response to antiviral therapy or to guide decisions about the duration of therapy. Laboratories com testing (high volume) (sent to laboratory) 2 or both Serological testing is not helpful in the BioPlex HSV Captia ELISA Euroimmun Anti- Yes Yes Yes Yes Screening or Blood draw diagnosis of neonatal HSV infection, because transplacentally acquired maternal HSV IgG is present in most infants, 3mo

> given the substantial proportions of the adult American population who are HSV- 1 and/or HSV-2 seropositive. postexposure or serum in clinic individuals 800-926-3353 800-224-6723 800-325-3424 800-913-2022 800-328-5669 877-546-8633 HSV-2 only HSV-1 or HSV- Test by Fisher HealthCare) Biokit HSV-2 Rapid Test (also sold as SureVue HSV-2 Rapid PREVENTION OF NEONATAL HSV DISEASE

Quick Reference Guide for Blood Tests to Accurately Detect Type-Speci Cesarean delivery in a woman with active genital lesions can reduce the use during pregnancy information detected ’ 5,18 TABLE 1 FDA, US Food and Drug Administration; POC, point of care; STD, sexually transmitted disease. Adapted from http://www.ashastd.org/. Accessed August 5, 2010. Supplier Biokit USA Bio-Rad FDA approved for For more Test time 10 min 45 min FDA approvedAntibodies 1999 2009 2004 2007 2000/2002 2000 2008 2008 Test availabilityWeb site Limited www.biokitusa.com www.bio-rad. Limited Widely available Widely available Collection method Finger stick, whole blood, Best use of test POC test to screen or test infants risk of acquiring HSV. In

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1999, the American College of Obste- shedding HSV at delivery are 10 to 30 of these infants and may not be feasible tricians and Gynecologists updated its times more likely to transmit the virus in settings with limited access to PCR management guidelines for genital to their newborn infants than women assaysforHSVDNAortothenewer herpes in pregnancy.43 To reduce the with a recurrent infection.5 The in- type-specific serological tests. If, at any risk of neonatal HSV disease, cesarean creased risk is attributable both to point during the evaluation outlined delivery should be performed if genital lower concentrations of transplacental in the algorithm, an infant develops HSV lesions or prodromal symptoms HSV-specific antibodies (which also are symptoms that could possibly indicate are present at the time of delivery. less reactive to expressed polypeptides) neonatal HSV disease (fever, hypother- Neonatal HSV infection has occurred in women with primary infection19 and mia, lethargy, irritability, vesicular rash, despite cesarean delivery performed to the higher quantities of HSV that are seizures, etc), a full diagnostic evalua- before the rupture of membranes.12,44 shed for a longer period of time in the tion should be undertaken, and in- In women with a previous diagnosis of maternal genital tract in comparison travenous acyclovir therapy should be genital herpes, cesarean delivery to with women who have recurrent genital initiated. In applying this algorithm, ob- prevent neonatal HSV infection is not HSV infection.54 However, a substantial stetric providers and pediatricians indicated if there are no genital lesions percentage of women with first clinical likely will need to work closely with at the time of labor. In an effort to episodes of symptomatic genital herpes their diagnostic laboratories to ensure reduce cesarean deliveries performed actually are experiencing reactivation of that serological and virological testing for the indication of genital herpes, the a previously unrecognized genital her- is available and turnaround times are use of oral acyclovir or valacyclovir petic infection.55 Thus,totailor acceptable. In situations in which this near the end of pregnancy to suppress management of exposed neonates ac- is not possible, the approach detailed genital HSV recurrences has become cording to their degree of risk, one in the algorithm will have limited, and increasingly common in obstetric must distinguish primary versus re- perhaps no, applicability. practice. Several studies with small current maternal HSV infection in a sample sizes suggest that suppressive manner that relies on more than just TESTING OF WOMEN IN LABOR acyclovir therapy during the last weeks the history, or lack thereof, of genital Women in labor with visible genital of pregnancy decreases the occurrence herpes in the woman or her partner lesions that are characteristic of HSV of clinically apparent genital HSV dis- (s). Ideally, detection of HSV DNA from should have the lesions swabbed for ease at the time of delivery,45–48 with an genital swabs obtained from women in HSV PCR and culture (AI). Any positive associated decrease in cesarean de- labor would identify both symptomatic test result then requires further anal- livery rates for the indication of genital and asymptomatic HSV shedding, al- ysis to determine if the virus is HSV-1 HSV.45,46,49,50 However, because viral lowing for focused management of or HSV-2. Correlation of viral type with shedding still occurs (albeit with re- only those infants who are exposed; serological status allows for determi- duced frequency),47,51 the potential for however, the technology to accomplish nation of maternal infection classifica- neonatal infection is not avoided com- this on a broad scale is not readily tion (Table 2). pletely, and cases of neonatal HSV available commercially at this time. disease in newborn infants of women With the approval of commercially who were receiving antiviral suppres- Management of Asymptomatic available serological tests that can re- Neonates After Vaginal or Cesarean sion recently have been reported.52,53 liably distinguish type-specificHSVanti- Delivery to Women With Lesions at bodies (Table 1), the means to further Delivery and History of Genital HSV ALGORITHM FOR MANAGEMENT OF refine management of asymptomatic Preceding Pregnancy ASYMPTOMATIC NEONATES BORN neonates delivered to women with ac- For women with a history of genital VAGINALLY OR BY CESAREAN tive genital HSV lesions is now possible. herpes preceding the pregnancy, the DELIVERY TO WOMEN WITH ACTIVE ThealgorithmdetailedinFigs2and3 likelihood that the current outbreak GENITAL HSV LESIONS applies only to asymptomatic neonates represents reactivation of latent HSV is (FIGS 2 AND 3) after vaginal or cesarean (because ce- high, and, therefore, the likelihood of TheriskoftransmittingHSVtothe sarean delivery reduces but does not transmission to the infant is low (2%). newborn infant during delivery is influ- eliminate the risk of neonatal HSV Skin and mucosal specimens (con- enced directly by the mother’sprevious disease) delivery to women with active junctivae, mouth, nasopharynx, and immunity to HSV; women who have genital HSV lesions. It is intended to rectum, and scalp electrode site, if primary genital HSV infections who are outline 1 approach to the management present) should be obtained from the

PEDIATRICS Volume 131, Number 2, February 2013 e639 Downloaded from www.aappublications.org/news by guest on September 26, 2021 FIGURE 2 Algorithm for the evaluation of asymptomatic neonates after vaginal or cesarean delivery to women with active genital herpes lesions. ALT, alanine aminotransferase; D/C, discontinue. neonate for culture (and PCR assay, if The importance of waiting until ap- whereas a positive test result shortly desired) at approximately 24 hours proximately 24 hours after delivery to after birth could reﬂect only transient after delivery (BII), and blood should obtain virological studies is based on maternal contamination that may not be sent for HSV DNA PCR assay. Acy- the fact that a positive virological test lead to replication with resulting neo- clovir need not be started as long as result at that point represents actively natal HSV disease.56 It is permissible to the infant remains asymptomatic (BIII). replicating virus on the infant’s mucosa, discharge an asymptomatic infant after

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FIGURE 3 Algorithm for the treatment of asymptomatic neonates after vaginal or cesarean delivery to women with active genital herpes lesions. ALT, alanine aminotransferase; D/C, discontinue. 48 hours of negative HSV cultures (and If the surface and blood virological transaminase) to determine the extent negative PCR assay results) if other dis- study results are negative at 5 days, of disease, and intravenous acyclovir charge criteria have been met, there the infant should be evaluated if signs should be initiated as soon as possible. is ready access to medical care, and or symptoms of neonatal HSV disease If the evaluation findings are normal, a person who is able to comply fully with develop during the first 6 weeks of life indicating that the neonate has HSV instructions for home observation will be (AII). Conversely, if the surface and infection but that it has not yet pro- present (BIII). If any of these conditions is blood virological study results become gressed to HSV disease, the infant not met, the infant should be observed in positive, thus confirming neonatal HSV should be treated empirically with in- the hospital until HSV cultures are final- infection, the infant should undergo travenous acyclovir for 10 days to ized as negative or are negative for 96 a complete evaluation (lumbar puncture prevent progression from infection to hours after being set up in cell culture, with CSF sent for indices and HSV DNA disease (preemptive therapy) (BIII). If whichever is shorter. PCR assay, in addition to serum alanine the evaluation findings are abnormal,

TABLE 2 Maternal Infection Classification by Genital HSV Viral Type and Maternal Serologya Classification of Maternal Infection PCR/Culture From Genital Lesion Maternal HSV-1 and HSV-2 IgG Antibody Status Documented first-episode primary infection Positive, either virus Both negative Documented first-episode nonprimary infection Positive for HSV-1 Positive for HSV-2 AND negative for HSV-1 Positive for HSV-2 Positive for HSV-1 AND negative for HSV-2 Assume first-episode (primary or nonprimary) infection Positive for HSV-1 OR HSV-2 Not available Negative OR not availableb Negative for HSV-1 and/or HSV-2 OR not available Recurrent infection Positive for HSV-1 Positive for HSV-1 Positive for HSV-2 Positive for HSV-2 a To be used for women without a clinical history of genital herpes. b When a genital lesion is strongly suspicious for HSV, clinical judgment should supersede the virological test results for the conservative purposes of this neonatal management algorithm. Conversely, if in retrospect, the genital lesion was not likely to be caused by HSV and the PCR assay result or culture is negative, departure from the evaluation and management in this conservative algorithm may be warranted.

PEDIATRICS Volume 131, Number 2, February 2013 e641 Downloaded from www.aappublications.org/news by guest on September 26, 2021 indicating the neonate already has At approximately 24 hours after de- the infant’s evaluation results are ab- neonatal HSV disease, the infant should livery, neonatal skin and mucosal normal, indicating the neonate al- be treated for 14 to 21 days with in- specimens (conjunctivae, mouth, na- ready has neonatal HSV disease, the travenous acyclovir on the basis of the sopharynx, and rectum, and scalp infant should be treated for 14 to 21 extent of neonatal HSV disease (dis- electrode site, if present) should be days with intravenous acyclovir on the seminated, CNS, or SEM) (AII); if the obtained for culture (and PCR assay, if basis of the extent of neonatal HSV initial CSF PCR assay result is positive desired), and blood should be sent for disease (disseminated, CNS, or SEM) for HSV DNA, a repeat lumbar puncture HSV DNA PCR assay to evaluate for HSV (AII); if the initial CSF PCR assay should be obtained near the end of infection. In addition, the infant should results are positive for HSV DNA, a re- therapy (eg, on day 17 or 18 of an an- be evaluated for neonatal HSV disease peat lumbar puncture should be ticipated 21-day course of therapy), and (lumbar puncture with CSF sent for obtained near the anticipated end of intravenous acyclovir should be dis- indices and HSV DNA PCR assay, in therapy (eg, on day 17 or 18 of ther- continued at 21 days if the repeat HSV addition to serum alanine trans- apy), and intravenous acyclovir should PCR assay result is negative (AII). If the aminase) at the same time, and in- be discontinued at 21 days if the re- “end-of-therapy” CSF PCR assay result travenous acyclovir should be initiated peat HSV PCR assay result is negative is positive, intravenous acyclovir should pending the results of the evaluation, (AII). If the end-of-therapy CSF PCR be continued for another 7 days, with because the possibility is high that this assay result is positive, the intra- another repeat lumbar puncture near could be a primary maternal infection venous acyclovir should be continued the end of therapy, again with decisions (BIII). It is acceptable to wait to initiate for another 7 days, with another re- regarding cessation of therapy predi- therapy until approximately 24 hours peat lumbar puncture near the an- cated on the repeat HSV CSF PCR assay after delivery in an asymptomatic ne- ticipated new end of therapy, again result (BII). After completion of paren- onate, because the average age at onset with decisions regarding cessation of teral acyclovir for treatment of neonatal of neonatal HSV disease is between 1.5 therapy predicated on the HSV CSF HSV disease, infants should receive oral and 3 weeks of age. Some practitioners PCR assay result (BII). After comple- acyclovir suppressive therapy for 6 advocate evaluation and treatment tion of parenteral acyclovir for treat- months.57 immediately after delivery if the infant ment of neonatal HSV disease, infants is preterm or there has been prolonged should receive oral acyclovir sup- Management of Asymptomatic rupture of membranes (CIII). 57 Neonates After Vaginal or Cesarean pressive therapy for 6 months. Delivery to Women With Lesions at Laboratory correlations between vi- If the mother has recurrent genital HSV Delivery and No History of Genital rological (PCR/culture) and serological infection (that is, she has type-specific HSV Preceding Pregnancy results that define maternal disease antibody to the HSV serotype detected classification (first-episode primary, For women without a history of genital by her genital swab) and the neonatal first-episode nonprimary, and recurrent) herpes preceding pregnancy, the pres- surface and blood virology study are presented in Table 2. The table de- ence of genital lesions at delivery could results are negative, acyclovir should represent first-episode primary infec- liberately uses a conservative estimate be stopped, the parent(s) should re- fi tion (with a risk of transmission to the of rst-episode infection, because the ceive education regarding signs and newborn infant of 57%), first-episode likelihood of transmission in such a sit- symptoms of neonatal HSV, and the nonprimary infection (with a risk of uation is high. It is intended to be used infant may be discharged and reeval- fi transmission to the newborn infant of to determine maternal disease classi - uated with any signs or symptoms of 25%), or recurrent infection (with a risk cation in women without a clinical his- illness during the first 6 weeks of life of transmission to the newborn infant tory of genital herpes. (AII). Conversely, if virology study of 2%). Thus, with the availability of If the mother has a documented or results are positive, confirming neo- type-specific serological testing, the assumed first-episode primary or first- natal HSV infection, intravenous acy- practitioner can determine which type episode nonprimary infection (Table 2) clovir should be continued, with the of infection the outbreak represents, and the neonate’s evaluation results duration of treatment based on the given that the risks to the infant are so are normal, the infant should be evaluation for neonatal HSV disease. If disparate. Accordingly, serological test- treated empirically with intravenous the evaluation findings are normal, the ing should be performed to determine acyclovir for 10 days to prevent pro- infant should be treated empirically the type of HSV infection in the mother to gression from neonatal infection to with intravenous acyclovir for 10 days delineate between the 3 (Table 1). disease (preemptive therapy) (BIII). If to prevent progression from HSV

e642 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on September 26, 2021 FROM THE AMERICAN ACADEMY OF PEDIATRICS infection to HSV disease (preemptive Kathryn M. Edwards, MD David W. Kimberlin, MD – Red Book Editor therapy) (BIII). If the evaluation findings Mary P. Glode, MD Sarah S. Long, MD – Red Book Associate Editor Mary Anne Jackson, MD H. Cody Meissner, MD – Visual Red Book As- are abnormal, the infant should be Harry L. Keyserling, MD sociate Editor treated with intravenous acyclovir for Yvonne A. Maldonado, MD 14 to 21 days on the basis of the extent Dennis L. Murray, MD STAFF Walter A. Orenstein, MD of neonatal HSV disease (disseminated, Jennifer Frantz, MPH CNS, or SEM) (AII); if the initial CSF PCR Gordon E. Schutze, MD Rodney E. Willoughby, MD assay result is positive for HSV DNA, Theoklis E. Zaoutis, MD COMMITTEE ON FETUS AND a repeat lumbar puncture should be NEWBORN, 2012–2013 LIAISONS Lu-Ann Papile, MD, Chairperson obtained near the end of therapy (eg, – Marc A. Fischer, MD Centers for Disease Jill E. Baley, MD on day 17 or 18 of an anticipated 21-day Control and Prevention William Benitz, MD – course of therapy), and intravenous Bruce Gellin, MD National Vaccine Program Waldemar A. Carlo, MD fi acyclovir should be discontinued at Of ce James Cummings, MD Richard L. Gorman, MD – National Institutes of 21 days if the repeat HSV PCR assay Eric Eichenwald, MD Health Praveen Kumar, MD result is negative (AII). If the end-of- – Lucia Lee, MD Food and Drug Administration Richard A. Polin, MD – therapy CSF PCR assay result is pos- R. Douglas Pratt, MD Food and Drug Admin- Rosemarie C. Tan, MD, PhD itive, intravenous acyclovir should be istration Kasper S. Wang, MD Jennifer S. Read, MD – National Vaccine Pro- continued for another 7 days, with gram Office another repeat lumbar puncture near Joan Robinson, MD – Canadian Pediatric So- FORMER MEMBER the end of therapy, again with deci- ciety Kristi L. Watterberg, MD sions regarding cessation of therapy Marco Aurelio Palazzi Safadi, MD – Sociedad predicated on the basis of HSV CSF Latinoamericana de Infectologia Pediatrica LIAISONS (SLIPE) fi – PCR assay result (BII). After completion CAPT Wanda D. Bar eld, MD, MPH Centers for Jane Seward, MBBS, MPH – Centers for Disease Disease Control and Prevention of parenteral acyclovir for treatment Control and Prevention George Macones, MD – American College of of neonatal HSV disease, infants should Jeffrey R. Starke, MD – American Thoracic Obstetricians and Gynecologists receive oral acyclovir suppressive Society Ann L. Jefferies, MD – Canadian Pediatric So- Geoffrey Simon, MD – Committee on Practice ciety therapy for 6 months.57 Ambulatory Medicine Erin L. Keels, APRN, MS, NNP-BC – National As- Tina Q. Tan, MD – Pediatric Infectious Diseases sociation of Neonatal Nurses COMMITTEE ON INFECTIOUS Society Tonse N.K. Raju, MD, DCH – National Institutes of DISEASES, 2012–2013 Health Michael T. Brady, MD, Chairperson EX OFFICIO Carrie L. Byington, MD Henry H. Bernstein, DO – Red Book Online As- STAFF H. Dele Davies, MD sociate Editor Jim Couto, MA

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PEDIATRICS Volume 131, Number 2, February 2013 e645 Downloaded from www.aappublications.org/news by guest on September 26, 2021 APPENDIX Evidence-based Rating System Used To Determine Strength Of Recommendations Category Definition Recommendation Strength of recommendation A Strong evidence for efficacy and substantial clinical benefit Strongly recommended B Strong or moderate evidence for efficacy, but only limited Generally recommended clinical benefit C Insufficient evidence for efficacy, or efficacy does not Optional outweigh possible adverse consequences D Moderate evidence against efficacy or for adverse outcome Generally not recommended E Strong evidence against efficacy or for adverse outcome Never recommended Quality of evidence supporting recommendation I Evidence from at least 1 well-executed randomized controlled trial or 1 rigorously designed laboratory-based experimental study that has been replicated by an independent investigator II Evidence from at least 1 well-designed clinical trial without randomization; cohort or case-controlled analytic studies (preferably from >1 center); multiple time-series studies; dramatic results from uncontrolled studies; or some evidence from laboratory experiments III Evidence from opinions of respected authorities based on clinical or laboratory experience, descriptive studies, or reports of expert committees Adapted from Centers for Disease Control. 2009 guidelines for the prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected children. MMWR Recomm Rep. 2009;58(RR-11):5.

e646 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on September 26, 2021 Guidance on Management of Asymptomatic Neonates Born to Women With Active Genital Herpes Lesions David W. Kimberlin, Jill Baley, COMMITTEE ON INFECTIOUS DISEASES and COMMITTEE ON FETUS AND NEWBORN Pediatrics 2013;131;e635 DOI: 10.1542/peds.2012-3216 originally published online January 28, 2013;

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Downloaded from www.aappublications.org/news by guest on September 26, 2021 Guidance on Management of Asymptomatic Neonates Born to Women With Active Genital Herpes Lesions David W. Kimberlin, Jill Baley, COMMITTEE ON INFECTIOUS DISEASES and COMMITTEE ON FETUS AND NEWBORN Pediatrics 2013;131;e635 DOI: 10.1542/peds.2012-3216 originally published online January 28, 2013;

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