Herpes Simplex Virus Infections of the Newborn David W. Kimberlin, MD Herpes simplex virus (HSV) infections are fortunately quite rare in the neonatal population. Nevertheless, due to their life-threatening nature and the tremendous damage that surviving infants can incur, neonatal HSV is actually considered in a differential diagnosis relatively commonly. The availability of safe and effective antiviral therapy for the management of neonatal HSV also can accelerate a clinician’s decision to consider HSV as the cause of a neonate’s disease presentation, and then to obtain appropriate diagnostic studies and empirically institute antiviral treatment. Decisions on whether to continue antiviral therapy for a full course are predicated on the appropriate interpretation of these diagnostic studies as they subsequently are reported to the treating physician. For HSVinfected neonates, the duration of parenteral acyclovir therapy ranges from 14 to 21 days, depending on the extent of disease. Use of subsequent oral suppressive antiviral therapy is under investigation in randomized controlled trials, and at this time cannot be routinely recommended. This article will summarize the current state of neonatal HSV disease presentation, diagnosis, and management. Semin Perinatol 31:19-25 © 2007 Elsevier Inc. All rights reserved. KEYWORDS neonatal herpes, herpes simplex virus, HSV, acyclovir, antiviral therapy

N

eonatal infections with herpes simplex virus (HSV) were first reported in the mid-1930s, when Hass described the histopathologic findings of a fatal case1 and when Batignani reported a newborn with herpes simplex keratitis.2 In the 1960s and 1970s, the natural history of neonatal HSV infections was described in a series of elegant reports.3-5 Shortly thereafter, the early antiviral drugs which fortuitously were active against human herpesviruses were developed and systematically evaluated in the treatment of neonatal HSV. The road to safe and effective antiviral therapies for neonatal HSV was not a completely smooth one, however. The earliest antiviral agents with in vitro activity against HSV, including 5-iodo-2=-deoxyuridine (IDU) and 1-␤-D-arabinofuranosylcytosine (ara-C), proved too toxic in humans to be useful.6,7 Vidarabine (1-␤-D-arabinofuranosyladenine, ara-A) was the first systemically administered antiviral medication with activity against HSV for which therapeutic efficacy outweighed toxicity for the management of life-threatening HSV disease. Intravenous vidarabine was licensed in 1977, but due to toxicity when administered systemically was restricted by the Food and Drug Administration to life-threatening HSV and Department of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL. Address reprint requests to David W. Kimberlin, MD, Division of Pediatric Infectious Diseases, The University of Alabama at Birmingham, 1600 Seventh Avenue South, CHB 303, Birmingham, AL 35233. E-mail: [email protected]

0146-0005/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2007.01.003

VZV infections. Multicenter collaborative clinical trials conducted by The National Institute of Allergy and Infectious Diseases (NIAID) Collaborative Antiviral Study Group (CASG) established its efficacy in the treatment of neonatal HSV infections,8,9 providing the foundation for subsequent comparative trials with intravenous acyclovir in the 1980s. A relatively low dose of intravenous acyclovir (30 mg/kg/d administered intravenously in three divided doses for 10 days) was proven to be as effective in the treatment of neonatal HSV as vidarabine, to have fewer toxicities, and to be better tolerated.10 Subsequently, a higher dose of acyclovir (60 mg/kg/d administered intravenously in three divided doses for 21 days) has been shown to produce even better outcomes for neonatal HSV infections.11 Additional improvements in the outcomes of neonates with HSV disease have been achieved through advances in the diagnostics available to clinicians, the most powerful of which is the application of the polymerase chain reaction (PCR) to patients with neonatal HSV disease.12,13 Polymerase chain reaction analysis of cerebrospinal fluid has eliminated the need for brain biopsy to diagnose HSV infections in the central nervous system (CNS). For the diagnosis of HSV outside of the CNS, though, viral culture remains the gold standard. The scope of this review includes consideration of the natural history of neonatal HSV infections and their extent of involvement in neonates. The effect of parenteral antiviral 19

D.W. Kimberlin

20 treatment on outcomes will be discussed, and unanswered questions regarding long-term antiviral suppression following completion of treatment of acute disease will be explored. Finally, mention will be made of the increasingly common obstetrical practice of placing women with a history of genital HSV on suppressive therapy, with an emphasis on the impact that this may have on the subsequent development of neonatal HSV.

Epidemiology Timing of Acquisition of Neonatal Infection Neonatal HSV disease is acquired in one of three distinct times: intrauterine (in utero), peripartum (perinatal), and postpartum (postnatal). The vast majority (85%) of infected infants acquire their infection during birth, in the peripartum period. An additional 10% of infected neonates acquire the virus postnatally (eg, from someone shedding HSV from the mouth who then kisses the baby, from exposure to HSV from a breast lesion, or from a herpetic whitlow exposure in the nursery). The final 5% are infected with HSV in utero.

Incidence of Neonatal HSV Currently, neonatal HSV disease in the United States occurs in approximately 1 in 3200 deliveries,14 resulting in an estimated 1500 cases of neonatal HSV infection annually. As the baseline prevalence of HSV-2 genital infection increases in the overall population15,16 and the incidence of HSV-1 genital disease rises,17,18 it will become increasingly likely that a gravid woman may acquire HSV-2 for the first time during her pregnancy through sexual contact with a partner with a genital HSV-2 or an oral HSV-1 infection. As such, it is possible that the incidence of neonatal HSV disease may increase in the years to come. Fortunately, neonatal HSV disease occurs much less frequently in other countries of the world, although the reasons for these geographic disparities are not fully understood.19

to about 25% since the development and utilization of antiviral therapy, likely the consequence of recognizing and treating SEM infection before its progression to more severe disseminated disease.22 Central nervous system involvement is a common component of this category of infection, occurring in about 60% to 75% of infants with disseminated disease.23 Although the presence of a vesicular rash can greatly facilitate the diagnosis of HSV infection, over 20% of neonates with disseminated HSV disease will not develop cutaneous vesicles during the course of their illness.20,22,24,25 Patients commonly present with viral sepsis, including respiratory collapse, liver failure, and disseminated intravascular coagulopathy (DIC). Hepatitis and pneumonitis are common in disseminated neonatal HSV disease. Disease presentation is usually around day 10 to 12 of life. Death from disseminated neonatal HSV infection is usually the result of the severe coagulopathy, liver dysfunction, and pulmonary involvement.

CNS Disease Almost one-third of all neonates with HSV infection are categorized as having CNS disease (with or without SEM involvement).22 Clinical manifestations of CNS disease include seizures (both focal and generalized), lethargy, irritability, tremors, poor feeding, temperature instability, and bulging fontanelle. Disease presentation is usually around day 16 to 19 of life. Between 60% and 70% of babies classified as having CNS disease have associated skin vesicles at any point in the disease course.20,24 In the absence of skin lesions and frank CNS signs, the initial presentation can be indistinguishable from other viral and bacterial infections that lead clinicians to suspect possible sepsis in neonates. With CNS neonatal HSV disease, mortality is usually the product of devastating brain destruction, with resulting acute neurologic and autonomic dysfunction. Neonatal HSV can involve any and often multiple parts of the brain, in contrast with the typical temporal lobe predilection seen with herpes simplex encephalitis with onset beyond the neonatal period.

Clinical Presentations

Disease Limited to the Skin, Eyes, and/or Mouth (SEM Disease)

Herpes simplex virus infections acquired either peripartum or postpartum can be classified as: (1) disseminated disease involving multiple visceral organs, including lung, liver, adrenal glands, skin, eye, and/or the brain (disseminated disease); (2) central nervous system disease, with or without skin lesions (CNS disease); and (3) disease limited to the skin, eyes, and/or mouth (SEM disease). This classification system is predictive of both morbidity and mortality.8,10,11,20,21 Patients with disseminated or SEM disease generally present to medical attention at 10 to 12 days of life, whereas patients with CNS disease on average present somewhat later at 16 to 19 days of life.20

Infection localized to the skin, eye, and/or mouth (SEM disease) has historically accounted for approximately 20% of all cases of neonatal HSV disease. With the introduction of early antiviral therapy, this frequency has increased to approximately 45%.22 By definition, babies with SEM disease have limited infection, and 80% to 85% have associated vesicular lesions apparent on physical examination.20

Disseminated Disease Historically, disseminated HSV infections have accounted for approximately one-half to two-thirds of all children with neonatal HSV disease. However, this figure has been reduced

Differential Diagnosis A number of other conditions, both infectious and noninfectious, can mimic neonatal HSV infection. These include hyaline membrane disease, intraventricular hemorrhage, necrotizing enterocolitis, and various ocular or cutaneous disorders. Bacterial pathogens of newborns with systemic and/or cutaneous manifestations which can be confused with

HSV infection of the newborn

21

neonatal HSV disease include group B Streptococcus, Staphylococcus aureus, Listeria monocytogenes, and Gram-negative bacteria. Exanthemous viral agents which can be confused for neonatal HSV infection include varicella-zoster virus infection, enteroviral disease, and disseminated cytomegalovirus infection. Other infectious pathogens which are on the differential diagnosis list include toxoplasmosis, rubella, and syphilis. Noninfectious cutaneous disorders should also be considered, including erythema toxicum, neonatal melanosis, acrodermititis, and incontinentia pigmenti.

detected in their CSF by PCR.12,13 Overall sensitivities of CSF PCR in neonatal HSV disease have ranged from75% to 100%,12,28,31 with overall specificities ranging from 71% to 100%.12,28,31 In comparison, PCR of blood components has been evaluated to a much lesser extent, with only six relatively small studies reported to date in the literature.13,31-35 Further study of blood PCR in neonatal HSV infection is needed, as illustrated by one recent report questioning the sensitivity of serum PCR analysis from neonates with disseminated HSV disease.37

Evaluation of the Neonate with Suspected HSV Infection

Specimens to Obtain Before Starting Intravenous Acyclovir

Serologic Testing Serologic diagnosis of neonatal HSV infection is not of great clinical value due to the presence of transplacentally acquired maternal IgG which can confound the assessment of the neonatal antibody status during acute infection. This is especially true given the large proportions of the adult American population who are seropositive for HSV-1 and HSV-2.

Viral Culture Isolation of HSV by culture remains the definitive diagnostic method of documenting an HSV infection, including establishing neonatal HSV disease. Skin or mucous membrane lesions or surfaces are scraped and transferred in appropriate viral transport media on ice to a diagnostic virology laboratory.26 Such specimens are inoculated into cell culture systems, which are then monitored for cytopathic effects characteristic of HSV replication. Typing of an HSV isolate may then be done by one of several techniques. Other sites from which virus may be isolated in neonatal HSV disease include the CSF, urine, blood, stool or rectum, oropharynx, and conjunctivae.26 Specimens for viral culture from multiple body sites (with the exception of CSF) of babies suspected of having neonatal herpes may be combined before plating in cell culture to decrease costs since, with the exception of CNS involvement, the important information gathered from such cultures is the presence or absence of replicating virus, rather than its precise location.

Polymerase Chain Reaction The diagnosis of neonatal HSV infections has been revolutionized by the application of PCR to clinical specimens, including CSF12,13,27-31 and to a lesser extent blood.13,31-35 Due to the very power of the technology, however, performance of PCR is highly dependent on the manner in which the specimen was collected and maintained before reaching the laboratory for PCR analysis.36 Interpretation of PCR results, either positive or negative, must be correlated with the patient’s clinical presentation and disease course in determining their ultimate clinical or diagnostic significance. A negative PCR result does not in and of itself rule out neonatal HSV disease. In two relatively large reports of PCR in neonatal herpes, 76% to 78% of neonates with CNS HSV disease had HSV

Certain clinical circumstances warrant the empiric initiation of intravenous acyclovir pending additional diagnostic and clinical data. Before beginning antiviral therapy, however, sufficient diagnostic tests should be gathered to allow for informed decisions within several days as to whether acyclovir treatment should be continued for a full treatment course or discontinued when HSV is ruled out. The ability to gather these studies before initiating antiviral therapy is dependent on the clinical stability of the patient at the time. Ideally, the following studies should be collected before starting parenteral antiviral therapy: (1) CSF for indices, bacterial culture, and HSV PCR; (2) viral culture of any suspicious skin or mucous membrane lesions; and (3) surface cultures from the mouth, nasopharynx, conjunctivae, and rectum.26 Additionally, urine, stool, blood, and CSF can also be sent for viral culture. By gathering these specimens, the physician will have enough data over the ensuing 4 to 5 days to determine whether or not to continue acyclovir therapy.

Treatment of Neonatal HSV Neonates with HSV disease should be treated with intravenous acyclovir at 60 mg/kg/d divided every 8 hours (20 mg/ kg/dose).11,26 The dosing interval of intravenous acyclovir may need to be increased in premature infants, based on their creatinine clearance.38 Duration of therapy is 21 days for patients with disseminated or CNS neonatal HSV disease, and 14 days for patients with HSV infection limited to the SEM.26 All patients with CNS HSV involvement should have a repeat lumbar puncture at the end of intravenous acyclovir therapy to determine that the specimen is PCR-negative in a reliable laboratory, and to document the end-of-therapy CSF indices.20 Those persons who remain PCR-positive should continue to receive intravenous antiviral therapy until PCRnegativity is achieved.12,20 Absolute neutrophil counts should be followed about twice a week during the course of therapy.11

Prognosis/ Outcomes of Neonatal HSV Mortality In the preantiviral era, 85% of patients with disseminated neonatal HSV disease died by 1 year of age, as did 50% of patients with CNS neonatal HSV disease.8 With current an-

D.W. Kimberlin

Proportion Surviving

22

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

30mg/kg/d (n=18)* 45mg/kg/d (n=7) 60mg/kg/d (n=34)

0

1

2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Months Figure 1 Mortality in patients with disseminated neonatal HSV disease by daily dosage of acyclovir. Dosage was divided every 8 hours. Recipients of the 45 mg/kg/d and 60 mg/kg/d dosing were treated for 21 days, whereas recipients of the 30 mg/kg/d dosing (*) were from a historical cohort treated for 10 days.11

tiviral therapy, 12-month mortality has been reduced to 29% for disseminated neonatal HSV disease and to 4% for CNS HSV disease (Figs. 1 and 2, respectively).11 Lethargy and severe hepatitis are associated with mortality among patients with disseminated disease, and prematurity and seizures are associated with mortality in patients with CNS disease.20

Morbidity

Proportion Surviving

Improvements in morbidity rates with antiviral therapies have not been as dramatic as with mortality. The proportion of survivors of disseminated neonatal HSV disease who have

normal neurologic development has increased from 50% in the preantiviral era8 to 83% today.11 In the case of CNS neonatal HSV disease, there has been no change at all, with 33% of patients in the preantiviral era and 31% of patients today having normal neurologic development (Fig. 3).8,11 Seizures at or before the time of initiation of antiviral therapy are associated with increased risk of morbidity both in patients with CNS disease and in patients with disseminated infection.20 In contrast to disseminated or CNS neonatal HSV disease, morbidity following SEM disease has dramatically improved

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

30mg/kg/d (n=35)* 45mg/kg/d (n=5) 60mg/kg/d (n=23)

0

1

2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Months Figure 2 Mortality in patients with CNS neonatal HSV disease by daily dosage of acyclovir. Dosage was divided every 8 hours. Recipients of the 45 mg/kg/d and 60 mg/kg/d dosing were treated for 21 days, whereas recipients of the 30 mg/kg/d dosing (*) were from a historical cohort treated for 10 days.11

HSV infection of the newborn

23

Figure 3 Morbidity among patients with known outcomes after 12 months of life. The two groups represent those treated with acyclovir at 30 mg/kg/d for 10 days versus those treated with 60 mg/kg/d for 21 days. Mild impairment was defined as ocular sequelae without blindness, speech delay, or mild motor delay without hemiparesis. Moderate impairment was defined as hemiparesis, persistent seizure disorder, or ⬍3 month developmental delay. Severe impairment was defined as microcephaly, spastic quadriplegia, blindness or chorioretinitis, or ⬎3 month developmental delay.11

during the antiviral era. Before the development of vidarabine or acyclovir, 38% of SEM patients experienced developmental difficulties at 12 months of age.8 Today, fewer than 2% of acyclovir recipients have developmental delays following recovery from SEM disease (Fig. 3).10,11

Follow-Up of Neonatal HSV The most significant sequelae of neonatal HSV disease is neurologic impairment. Survivors of neonatal HSV infections should be followed closely for the achievement of developmental milestones, and should undergo developmental assessments as needed. Early intervention programs, including physical therapy, occupational therapy, and speech therapy, should be employed at the first sign of the potential for or risk of impairment. Cutaneous recurrences, although not of the same significance as neurologic sequelae, nevertheless are common10 and oftentimes are quite disruptive to the lives of the patients and their families, including impacting child care arrangements. The role of suppressive oral acyclovir currently is being evaluated in randomized controlled trials being conducted by the NIAID CASG. However, an earlier small Phase I/II study suggested that almost half of babies on suppressive oral acyclovir for 6 months can experience significant neutropenia,39 raising questions about the safety of such therapy. Pending the results of the placebo-controlled Phase III studies to define risk versus benefit, there are insufficient data to recommend routine utilization of suppression therapy following the acute management of neonatal HSV disease.40 Additionally, the development of CNS disease in a former premature infant on suppressive therapy raises questions about the efficacy of such an approach and, indeed, whether acyclovir suppression could have even contributed to the extent of the disease recurrence by masking early symptoms.41

Special Considerations A number of approaches are employed by obstetricians to try to prevent neonatal HSV disease. Cesarean delivery in a woman with active genital lesions can reduce the infant’s risk of acquiring HSV,5,14 and is recommended when genital HSV lesions or prodromal symptoms are present at the time of delivery.42 Physicians caring for neonates delivered by cesarean section should be aware that neonatal HSV infections have occurred despite cesarean delivery performed before the rupture of membranes.22,43 An increasingly common practice among obstetricians is the use of oral antiviral suppressive therapy near the end of pregnancy to prevent genital HSV recurrences at delivery. Several small studies suggest that suppressive acyclovir or valacyclovir therapy during the last weeks of pregnancy decreases the occurrence of clinically apparent genital HSV disease at the time of delivery,44-47 with an associated decrease in cesarean section rates for the indication of genital HSV.44,45,47 However, because viral shedding still occurs (albeit with reduced frequency),46-49 the potential for neonatal infection likely is not completely avoided. Cases of neonatal HSV disease have occurred among babies born to women who were on suppressive antiviral therapy at the end of pregnancy.50 Of the small studies evaluating suppressive antiviral therapy near the end of pregnancy, only 2 have investigated the babies for evidence of toxicity.47,49 Although these studies did not identify any neonatal side effects from maternal suppression, only 123 babies whose mothers received valaciclovir were evaluated.47,49 Given how widespread the use of antiviral suppression has become in pregnant women42 and the suggestion of toxicity in infants receiving suppressive therapy following neonatal HSV,39 additional studies are urgently needed to define the safety (and arguably the efficacy) of this approach.51 Pending these data, pediatricians should not assume that the risk of neonatal HSV is completely eliminated by a woman receiving suppressive oral antiviral therapy at the time of delivery.

24

Conclusions Neonatal HSV disease remains a significant cause of morbidity and mortality among affected babies. Following the acquisition of appropriate diagnostic tests, intravenous acyclovir should be started at 60 mg/kg/d. For babies with proven or highly suspected disease, the duration of therapy should be 14 to 21 days, depending on extent of disease involvement. All babies with CNS involvement should have a repeat lumbar puncture near the end of therapy to document virologic clearance from the CSF. The role of subsequent oral suppressive therapy with acyclovir remains under investigation at this time.

Acknowledgments This work was supported under contract with the Virology Branch, Division of Microbiology and Infectious Diseases of the National Institute of Allergy and Infectious Diseases (NIAID) (N01-AI-30025, N01-AI-65306, N01-AI-15113, N01-AI-62554), and by grants from the General Clinical Research Center Program (M01-RR00032) and the State of Alabama.

References 1. Hass M: Hepatoadrenal necrosis with intranuclear inclusion bodies: report of a case. Am J Pathol 11:127, 1935 2. Batignani A: Conjunctivite da virus erpetico in neonato. Boll Ocul 13: 1217, 1934 3. Nahmias AJ, Alford CA, Korones SB: Infection of the newborn with herpesvirus hominis. Adv Pediatr 17:185-226, 1970 4. Nahmias AJ, Josey WE, Naib ZM: Neonatal herpes simplex infection. Role of genital infection in mother as the source of virus in the newborn. JAMA 199:164-168, 1967 5. Nahmias AJ, Josey WE, Naib ZM, et al: Perinatal risk associated with maternal genital herpes simplex virus infection. Am J Obstet Gynecol 110:825-837, 1971 6. Boston Interhospital Virus Study Group: An NIAID-sponsored cooperative antiviral clinical study: failure of high dose 5-iodo-2=-deoxyuridine in the therapy of herpes simplex virus encephalitis. Evidence of unacceptable toxicity. N Engl J Med 292:599-603, 1975 7. Stevens DA, Jordan GW, Waddell TF, et al: Adverse effect of cytosine arabinoside on disseminated zoster in a controlled trial. N Engl J Med 289:873-878, 1973 8. Whitley RJ, Nahmias AJ, Soong SJ, et al: Vidarabine therapy of neonatal herpes simplex virus infection. Pediatrics 66:495-501, 1980 9. Whitley RJ, Yeager A, Kartus P, et al: Neonatal herpes simplex virus infection: follow-up evaluation of vidarabine therapy. Pediatrics 72: 778-785, 1983 10. Whitley R, Arvin A, Prober C, et al: A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection. N Engl J Med 324:444-449, 1991 11. Kimberlin DW, Lin CY, Jacobs RF, et al: Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics 108:230-238, 2001 12. Kimberlin DW, Lakeman FD, Arvin AM, et al: Application of the polymerase chain reaction to the diagnosis and management of neonatal herpes simplex virus disease. J Infect Dis 174:1162-1167, 1996 13. Malm G, Forsgren M: Neonatal herpes simplex virus infections: HSV DNA in cerebrospinal fluid and serum. Arch Dis Child Fetal Neonatal Ed 81:F24-F29, 1999 14. Brown ZA, Wald A, Morrow RA, et al: Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant. JAMA 289:203-209, 2003

D.W. Kimberlin 15. Fleming DT, McQuillan GM, Johnson RE, et al: Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med 337:1105-1111, 1997 16. Xu F, McQuillan GM, Kottiri BJ, et al: Trends in Herpes Simplex Virus Type 2 Infection in the United States, 42nd Annual Meeting of the Infectious Diseases Society of America. Boston, MA, 2004, Abstract 739 17. Lafferty WE, Downey L, Celum C, et al: Herpes simplex virus type 1 as a cause of genital herpes: impact on surveillance and prevention. J Infect Dis 181:1454-1457, 2000 18. Kimberlin DW, Rouse DJ: Genital herpes. N Engl J Med 350:19701977, 2004 19. Kimberlin DW: Neonatal HSV infections: the global picture. HERPES 11:31-32, 2004 20. Kimberlin DW, Lin CY, Jacobs RF, et al: Natural history of neonatal herpes simplex virus infections in the acyclovir era. Pediatrics 108:223229, 2001 21. Whitley R, Arvin A, Prober C, et al: Predictors of morbidity and mortality in neonates with herpes simplex virus infections. N Engl J Med 324:450-454, 1991 22. Whitley RJ, Corey L, Arvin A, et al: Changing presentation of herpes simplex virus infection in neonates. J Infect Dis 158:109-116, 1988 23. Whitley RJ: Herpes simplex virus infections, in Remington JS, Klein JO (eds): Infectious Diseases of the Fetus and Newborn Infants (ed 3). Philadelphia, PA, W.B. Saunders Company, 1990, pp 282-305 24. Sullivan-Bolyai JZ, Hull HF, Wilson C, et al: Presentation of neonatal herpes simplex virus infections: implications for a change in therapeutic strategy. Pediatr Infect Dis 5:309-314, 1986 25. Arvin AM, Yeager AS, Bruhn FW, et al: Neonatal herpes simplex infection in the absence of mucocutaneous lesions. J Pediatr 100:715-721, 1982 26. American Academy of Pediatrics: Herpes simplex, in Pickering LK (ed): 2006 Red Book: Report of the Committee on Infectious Diseases (ed 26). Elk Grove Village, IL, American Academy of Pediatrics, 2006, pp 361-371 27. Rowley AH, Whitley RJ, Lakeman FD, et al: Rapid detection of herpessimplex-virus DNA in cerebrospinal fluid of patients with herpes simplex encephalitis. Lancet 335:440-441, 1990 28. Troendle-Atkins J, Demmler GJ, Buffone GJ: Rapid diagnosis of herpes simplex virus encephalitis by using the polymerase chain reaction. J Pediatr 123:376-380, 1993 29. Anderson NE, Powell KF, Croxson MC: A polymerase chain reaction assay of cerebrospinal fluid in patients with suspected herpes simplex encephalitis. J Neurol Neurosurg Psychiatry 56:520-525, 1993 30. Schlesinger Y, Storch GA: Herpes simplex meningitis in infancy. Pediatr Infect Dis J 13:141-144, 1994 31. Kimura H, Futamura M, Kito H, et al: Detection of viral DNA in neonatal herpes simplex virus infections: frequent and prolonged presence in serum and cerebrospinal fluid. J Infect Dis 164:289-293, 1991 32. Barbi M, Binda S, Primache V, et al: Use of Guthrie cards for the early diagnosis of neonatal herpes simplex virus disease. Pediatr Infect Dis J 17:251-252, 1998 33. Diamond C, Mohan K, Hobson A, et al: Viremia in neonatal herpes simplex virus infections. Pediatr Infect Dis J 18:487-489, 1999 34. Lewensohn-Fuchs I, Osterwall P, Forsgren M, et al: Detection of herpes simplex virus DNA in dried blood spots making a retrospective diagnosis possible. J Clin Virol 26:39-48, 2003 35. Kimura H, Ito Y, Futamura M, et al: Quantitation of viral load in neonatal herpes simplex virus infection and comparison between type 1 and type 2. J Med Virol 67:349-353, 2002 36. Atkins JT: HSV PCR for CNS infections: pearls and pitfalls. Pediatr Infect Dis J 18:823-824, 1999 37. Kimberlin D, Cloud G, Lakeman F, et al: Serum polymerase chain reaction (PCR) may not diagnose neonatal herpes simplex virus (HSV) disease, 42nd Annual Meeting of the Infectious Diseases Society of America. Boston, MA, 2004, Abstract 992 38. Englund JA, Fletcher CV, Balfour HH Jr: Acyclovir therapy in neonates. J Pediatr 119:129-135, 1991 39. Kimberlin D, Powell D, Gruber W, et al: Administration of oral acyclovir suppressive therapy after neonatal herpes simplex virus disease

HSV infection of the newborn

40. 41.

42.

43.

44.

45.

limited to the skin, eyes and mouth: results of a phase I/II trial. Pediatr Infect Dis J 15:247-254, 1996 Gutierrez K, Arvin AM: Long term antiviral suppression after treatment for neonatal herpes infection. Pediatr Infect Dis J 22:371-372, 2003 Fonseca-Aten M, Messina AF, Jafri HS, et al: Herpes simplex virus encephalitis during suppressive therapy with acyclovir in a premature infant. Pediatrics 115:804-809, 2005 Anonymous: ACOG practice bulletin. Management of herpes in pregnancy. Number 8 October 1999. Clinical management guidelines for obstetrician-gynecologists. Int J Gynaecol Obstet 68:165-173, 2000 Peng J, Krause PJ, Kresch M: Neonatal herpes simplex virus infection after cesarean section with intact amniotic membranes. J Perinatol 16: 397-399, 1996 Braig S, Luton D, Sibony O, et al: Acyclovir prophylaxis in late pregnancy prevents recurrent genital herpes and viral shedding. Eur J Obstet Gynecol Reprod Biol 96:55-58, 2001 Scott LL, Sanchez PJ, Jackson GL, et al: Acyclovir suppression to prevent cesarean delivery after first-episode genital herpes. Obstet Gynecol 87:69-73, 1996

25 46. Scott LL, Hollier LM, McIntire D, et al: Acyclovir suppression to prevent recurrent genital herpes at delivery. Infect Dis Obstet Gynecol 10:71-77, 2002 47. Sheffield JS, Hill JB, Hollier LM, et al: Valacyclovir prophylaxis to prevent recurrent herpes at delivery: a randomized clinical trial. Obstet Gynecol 108:141-147, 2006 48. Brocklehurst P, Kinghorn G, Carney O, et al: A randomised placebo controlled trial of suppressive acyclovir in late pregnancy in women with recurrent genital herpes infection. Br J Obstet Gynaecol 105:275280, 1998 49. Andrews WW, Kimberlin DF, Whitley R, et al: Valacyclovir therapy to reduce recurrent genital herpes in pregnant women. Am J Obstet Gynecol 194:774-781, 2006 50. Haddad J, Langer B, Astruc D, et al: Oral acyclovir and recurrent genital herpes during late pregnancy. Obstet Gynecol 82:102-104, 1993 51. Kimberlin DW: Vertical transmission of HSV, 18th International Union Against Sexually Transmitted Diseases (IUSTI) Europe Congress on Sexually Transmitted Diseases. Vienna, Austria; #SAT12, Int J STD AIDS, 2002, pp 60; #SAT12