S EMINARS IN P ERINATOLOGY ] ( ]]]]) ]]]– ]]]

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Seminars in Perinatology

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Neonatal

⁎ Swetha G. Pinninti, MDa, and David W. Kimberlin, MDb, aDepartment of , University of Nebraska Medical Center, 982167 Nebraska Medical Center, Omaha, NE 68198 bDivision of Pediatric Infectious , The University of Alabama at Birmingham, 1600 Seventh Avenue South, CHB 303, Birmingham, AL 35233 article info abstract

Keywords: Neonatal (HSV) is an uncommon but devastating in the Neonatal newborn, associated with significant morbidity and mortality. The use of PCR for HSV identification of infected and acyclovir for treatment has significantly improved Acyclovir the prognosis for affected infants. The subsequent use of suppressive therapy with oral PCR acyclovir following completion of parenteral treatment of acute has further enhanced the long-term prognosis for these infants. This review article will discuss the epidemiology, risk factors and routes of acquisition, clinical presentation, and evaluation of an suspected to have the infection, and treatment of proven neonatal HSV disease. & 2018 Elsevier Inc. All rights reserved.

Viral structure majority of and possibly neonatal herpes in the United States and some European countries, primarily Herpes simplex (HSV-1 and HSV-2) are large, envel- due to changing sexual preferences including increasing 2–6 oped virions with a double-stranded DNA core. HSV-1 and practice of oral sex. HSV-2 reactivates more in the genital HSV-2 glycoproteins are responsible for attachment to and tract than HSV-1, thus increasing the chances of transmis- 7 penetration into cells besides evoking host immune sion to the neonate. responses. Despite considerable cross-reactivity between HSV-2 seroprevalence among pregnant women is esti- – HSV-1 and HSV-2, antibody responses to glycoprotein G allow mated to be 20 30%, and approximately 10% of HSV-2 sero- for serologic distinction between the two strains. negative women have a seropositive partner and hence are at risk for acquisition of genital HSV-2 infection during preg- nancy.8 Among discordant couples, women seronegative for Maternal genital herpes both HSV-1 and HSV-2 have an estimated 3.7% chance for seroconversion, while the risk for women already seropos- Seroprevalence rates of HSV-1 and -2 vary significantly itive for HSV-1 to seroconvert to HSV-2 is estimated to be depending on age, sex, race, and geographic distribution. 1.7%.9 HSV-2 prevalence has been reported to be highest in areas A majority of genital infections caused by HSV-1 or -2 are of Africa, followed by decreasing incidences in North Amer- asymptomatic (clinically inapparent), with two-thirds of ica, northern Europe and western and southern Europe, with women who acquire genital HSV infection during the least incidence reported from Asia.1,2 While HSV-2 histor- being either asymptomatic or having non-specific symptoms. ically has been the predominant serotype causing genital and Among women with prior history of genital herpes, 75% will neonatal herpes in the United States, HSV-1 now causes the have at least one recurrence during pregnancy and 14% will

⁎ Corresponding author. Tel.: þ1 205 934 5316; fax: þ1 205 975 9972. E-mail address: [email protected] (D.W. Kimberlin). https://doi.org/10.1053/j.semperi.2018.02.004 0146-0005/& 2018 Elsevier Inc. All rights reserved. 2 S EMINARS IN P ERINATOLOGY ] ( ]]]]) ]]]– ]]]

have prodromal symptoms or at the time of deliv- Table 1 – Risk factors for HSV transmission to neonate. ery.10,11 For peripartum neonatal transmission to occur, women must be shedding the virus in their genital tracts 1. Type of maternal infection (first-episode primary 4 first-episode symptomatically or asymptomatically around the time of non-primary 4 recurrent) delivery. Between 0.2% and 0.39%12 of all pregnant women 2. Maternal HSV serostatus 4 shed HSV in the genital tract around the time of delivery 3. Mode of delivery (vaginal C-section) 4. Duration of rupture of membranes irrespective of prior history of HSV, and shedding increases to 5. Disruption of cutaneous barrier (use of fetal scalp electrodes and 0.77–1.4% among women with prior history of recurrent other instrumentation) genital herpes.13,14 6. HSV serotype (HSV-1 4 HSV-2) The risk of transmission of HSV to the neonate remains significantly higher with primary maternal infections 21 acquired closer to the time of delivery compared with and 2% with recurrent genital HSV infections. Other statisti- recurrent infections (50–60% with primary infections vs cally significant risk factors for transmission of HSV to the o3% for recurrent infections), most likely due to lack of neonate were isolation of HSV-1 from genital lesions versus 21 transplacentally acquired antibodies in the neonate of HSV-2 and use of invasive monitoring techniques such as women with primary infection as well as exposure in the fetal scalp electrodes. birth canal of those women to larger quantities of virus for Even though cesarean delivery has been proven to be longer durations of time.15 Fortunately, most genital herpes effective in preventing the transmission of HSV to the neo- 26 infections during pregnancy are recurrent and therefore are nate, neonatal HSV cases have occurred despite cesarean 8 associated with lower risk of transmission to the neonate. delivery prior to rupture of membranes. The American College of Obstetricians and Gynecologists (ACOG) currently recommends cesarean section in the presence of lesions Neonatal HSV suggestive of herpes at the time of delivery, while the Royal College of Obstetricians and Gynecologists (RCOG) recom- Herpes simplex virus (HSV) infection of the neonate is mends cesarean delivery only with primary genital herpes uncommon with varying rates across the world due to differ- infections with lesions within 6 weeks of estimated 27 ing birth rates and HSV seroprevalence. Both HSV-1 and HSV- delivery. Evidence also exists for prolonged rupture of 28 2 have been recognized to cause neonatal herpes infection. membranes and disruption of mucocutaneous barrier by Studies have reported rates of 1.65 per 100,000, 1.6 per the use of fetal scalp electrodes and other instrumentation 100,000, 3.2 per 100,000 and 8.4 per 100,000 live births in the to increase the chances of acquisition of neonatal HSV 21,29 British Isles, Switzerland, the Netherlands, and Israel, respec- disease. – tively.16 19 In the United States, the incidence rates are While it has been shown that the chances of acquisition of reported to be higher with 5–33 per 100,000 live births, HSV-1 are decreased in women seropositive for HSV-2, trans- resulting in an estimated 1500 cases annually throughout mission of HSV-1 to the neonate has been documented to be 21 the country.20,21 Though neonatal HSV remains an uncom- high irrespective of primary or recurrent infection. mon infection and does not require mandatory reporting, the incidence is higher than currently reportable congenital infections like , , and ,22 and Clinical presentation may be increasing.23 The overall global rate of neonatal HSV, based on seroprevalence, birth rates and infections in Neonatal HSV can be acquired in-utero (5%), in the peripar- pregnancy is estimated to be 10 per 100,000 live births, with a tum period (85%), or in the postnatal period (10%). For the best estimate of 14,000 cases annually.24 This study marks latter two modes of acquisition, extent of disease can be the first attempt to quantify the global burden of neonatal classified into the following categories: HSV.25 1. SEM disease (skin, eye, and/or mouth) 2. CNS disease (central nervous system) Risk factors for transmission of HSV to neonate 3. Disseminated disease

When an individual with no HSV-1 or HSV-2 antibody This classification is predictive of morbidity and mortality 30–34 acquires either virus in the genital tract, a first-episode primary associated with this neonatal HSV. infection results (Table 1). If a person with preexisting HSV-1 antibody acquires HSV-2 genital infection (or vice versa), a first-episode non-primary infection ensues. Viral reactivation SEM disease from latency produces a recurrent infection. The risk of neonatal acquisition of HSV is significantly In infants with SEM disease, infection is confined to the skin, higher with first-episode primary and first-episode non-pri- eye, and/or mouth of newborns without any involvement of mary maternal infections compared with recurrent genital CNS or visceral organs. Infants with SEM disease historically infections. In a large study, the risk of neonatal transmission accounted for 20% of cases of neonatal herpes disease but was estimated as 57% with first-episode primary infection have increased to 45% with the introduction of antiviral compared with 25% with first-episode non-primary infection therapy, as fewer babies progress from an SEM to a S EMINARS IN P ERINATOLOGY ] ( ]]]]) ]]]– ]]] 3

disseminated extent of involvement.8 Infants with SEM dis- to 100%.37,38 A negative PCR result from the CSF does not in ease present at 10–12 days of life and 80% of these infants and of itself rule out neonatal HSV CNS disease, as the test have a vesicular rash on physical examination.34 may be negative in very early stages of the infection. In comparison, blood PCR in neonatal HSV has been evaluated to a lesser extent and in smaller cohorts, but appears to be a – CNS disease powerful tool in the diagnosis of neonatal HSV infections.38 40 A positive CSF PCR for HSV DNA defines that patient as Almost one-third of cases of neonatal herpes disease present having CNS involvement (categorized either as CNS Disease, as and are categorized as CNS disease, with or or as Disseminated Disease with CNS involvement). A pos- 8 without skin involvement. Neonates usually present at 16–19 itive blood PCR for HSV DNA confirms infection but does not days of life, although it is possible to have disease manifes- define disease classification, since all clinical disease catego- 34 tations start anytime within the first month of life. Infants ries (SEM, CNS, and disseminated) can have viremia and present with focal/generalized , lethargy, irritability, DNAemia.36,38 Blood PCR can be positive for weeks, with the poor feeding, temperature instability, and bulging fontanel. In clinical significance of this (if any) unknown.41 Currently, no all, 60–70% of these infants have skin lesions at some point data exist to support use of serial blood PCR assay to monitor 34 during the course of the illness. response to therapy.

Disseminated disease Specimens to obtain from newborn before initiating antiviral therapy In the era of effective antiviral therapy directed against HSV, disseminated disease accounts for ~25% of all neonatal Prior to initiation of empiric parenteral antiviral therapy, the herpes infections.8 Affected infants present around days 10– following specimens should be collected to aid in the diag- 12 of life. Newborns with disseminated disease present with nosis of neonatal HSV disease or to determine if antiviral respiratory and hepatic failure with disseminated intravas- therapy may be discontinued if HSV has been excluded: cular coagulation (DIC). Disease involves multiple organs, including CNS, lungs, liver, adrenal, skin, eye, and/or mouth. 1. Swab for viral culture from the base of vesicles, suspicious Two-thirds of infants have concurrent encephalitis and ~40% areas, and mucous membrane lesions for viral culture (if of infants never develop a vesicular rash during the entire available) or PCR 8,34 illness. Death from disseminated disease is usually due to 2. Swab from mouth, conjunctiva, nasopharynx, and rectum severe coagulopathy and extensive hepatic and pulmonary (surface cultures) for viral culture (if available) or PCR involvement. 3. CSF for indices, bacterial culture, and HSV DNA PCR 4. Whole blood for HSV DNA PCR 5. Blood to determine Alanine aminotransferase (ALT) level Evaluation of the neonate with suspected HSV infection Treatment of neonatal HSV The approach to an infant with suspected neonatal HSV infection is outlined in the Figure. The earliest antiviral agents effective against HSV included 5- iodo-2′-doexyuridine and 1-β-D-arabinofuranosylcytosine, Serologic testing but were found to be too toxic for human use. was licensed for use in cases of life-threatening HSV disease Serologic diagnosis of neonatal HSV is not helpful and is not in the United States in 1977. In the 1980s, lower dose acyclovir usually recommended for diagnostic purposes. (30 mg/kg/day administered three times a day for 10 days) was found to be efficacious for neonatal herpes disease31 and Viral culture was soon the treatment of choice due to its safety profile and ease of administration. Subsequently, a higher dose of acy- The definitive method of diagnosing neonatal HSV is by clovir (60 mg/kg/day divided in three doses for 14–21 days) isolation of HSV in tissue culture. Surface culture swabs was demonstrated to improve mortality and morbidity asso- (swabs from conjunctivae, nasopharynx, mouth, and anus), ciated with neonatal HSV disease.33 cerebrospinal fluid (CSF), or blood from affected newborns are The current recommendations are to treat all neonates inoculated into cell culture systems and monitored for with HSV disease parenterally with acyclovir given at 60 mg/ 35 cytopathic effect. kg/day divided every 8 hours.33,35 Duration of treatment is 14 days for infants with SEM disease and 21 days for CNS and Polymerase chain reaction disseminated disease presentations.35 All neonates with CNS involvement should have repeat CSF PCR near the end of 21 The application of PCR to CSF samples has revolutionized the days of treatment to document a negative CSF PCR result and – diagnosis of CNS neonatal herpes disease.36 39 The overall for CSF indices. HSV DNA detected in CSF at or after sensitivities of CSF PCR in neonatal HSV disease have ranged completion of acyclovir therapy has been associated with from 75% to 100%, with overall specificities ranging from 71% poorer outcomes.37 In those rare neonates with positive CSF 4 S EMINARS IN P ERINATOLOGY ] ( ]]]]) ]]]– ]]]

Fig. 1 – Evaluation and management of neonatal HSV disease.

PCR at the end of therapy, antiviral therapy should be of morbidity were associated with encephalitis, DIC, seizures, continued until PCR negativity is achieved.34,35,37 Since the and infection with HSV-2.32 Currently, with the utilization of significance of blood DNA PCR positivity on disease outcomes the higher dose of acyclovir (60 mg/kg/day divided in three remains largely unknown, serial measurement of blood DNA doses for 21 days), 1 year mortality has been reduced to 29% PCR for assessing response to therapy is not recommended at for disseminated disease and 4% for CNS disease,33 while 83% this time.35 of neonates with disseminated disease and 31% with CNS Adverse effects of high-dose acyclovir treatment include disease develop normally at 12 months of age.30,33 Seizures neutropenia, thrombocytopenia, and in elevated creatinine prior to or at the time of initiation of antiviral therapy has levels.33,42,43 There were no reported cases of renal failure and been associated with increased risk of morbidity in neonates most cases of neutropenia resolved without intervention or with disseminated and CNS disease.33 None of the infants dose reduction. Serial absolute neutrophil count (ANC) deter- with SEM disease in the high-dose acyclovir study developed mination should be made at least twice weekly while on developmental disabilities at 12 months age.33 high-dose acyclovir therapy. Decreasing the acyclovir dosage or administering granulocyte colony-stimulating factor should be considered for persistent neutropenia.33 Antiviral suppressive therapy after treatment

The outcome of neonatal herpes disease depends on the Prognosis extent of disease. Approximately 20% of survivors with disseminated disease have been shown to have neurologic In the pre-antiviral era, 85% of neonates with disseminated sequelae compared with 70% of neonates with CNS disease.33 disease and 50% of neonates with CNS disease died by 1 year A phase III, placebo-controlled trial performed by the of age, while 50% of survivors with disseminated disease and National Institute of Allergy and Infectious Diseases (NIAID) 33% of neonates with CNS disease developed normally at 12 Collaborative Antiviral Study Group (CASG) documented that months of age.30 Altered mental status, DIC, prematurity, and use of oral acyclovir suppressive therapy for 6 months after pneumonitis in infants with disseminated disease were completion of parenteral acyclovir therapy for neonatal associated with increased mortality, whereas increased rates HSV disease improves outcomes. Infants with CNS disease S EMINARS IN P ERINATOLOGY ] ( ]]]]) ]]]– ]]] 5

stratified to the treatment arm were found to have better • If the surface and blood virological studies are negative at 5 neurodevelopmental outcomes and to have fewer cutaneous days, further evaluation of the infant is recommended only recurrences compared to placebo group, and infants with with the development of any signs suggestive of neonatal SEM disease were found to have less frequent recurrence of HSV in the subsequent 6 weeks. skin lesions while receiving suppressive therapy.44 The cur- • If the surface and blood virological studies are positive, rent recommendation is to treat with oral acyclovir at suggesting HSV infection, a full evaluation (CSF for indices 300 mg/m2/dose, three times a day for 6 months. Absolute and HSV PCR, serum ALT level) is recommended to deter- neutrophil counts should be monitored at 2 and 4 weeks and mine presence and extent of HSV disease. Therapy with monthly thereafter following initiation of suppressive ther- intravenous acyclovir should be initiated in these infants as apy.35 Infection with acyclovir resistant strains or develop- soon as possible. ment of resistance after prolonged exposure to acyclovir has o If the results of this evaluation are negative (normal CSF – been reported,45 47 but is rare. Persistence of symptoms indices and negative CSF HSV PCR, normal ALT meas- despite strict adherence to therapy or clinical worsening urement), suggestive of neonatal HSV infection that has while on appropriate therapy should alert the clinician to not yet progressed to HSV disease, preemptive treat- consider infection with a resistant strain or development of ment for 10 days with parenteral acyclovir should be resistance during treatment. administered to prevent the progression of HSV infec- tion to HSV disease. o If this evaluation is suggestive of neonatal HSV disease Approach to infants exposed at delivery to active (abnormal CSF indices with HSV CSF PCR þ or elevated HSV lesions during maternal primary or recurrent serum ALT), treatment with acyclovir should be contin- genital HSV infection ued for 21 days for CNS or disseminated neonatal HSV disease or for 14 days for SEM disease, followed by oral The most recent guidance endorsed by the American Acad- suppressive therapy with acyclovir for 6 months. emy of Pediatrics (AAP) provides evidence-based recommen- dations on the management of neonates born to women with Management of newborns born to women with lesions at 48 active genital herpetic lesions. The recommendations take delivery and no history of genital herpes prior to pregnancy into consideration the maternal serological status, presence of genital lesions at the time of delivery, and the route of delivery. The recommendations are applicable only to insti- • In women without a history of genital herpes prior to tutions that have access to PCR facilities with a quick turn- pregnancy, the presence of genital lesions during labor around time, and only to infants exposed to HSV from could represent primary infection (450% risk of trans- maternal genital lesions present at the time of delivery. They mission to neonate), non-primary infection (25% risk of are not applicable to situations with asymptomatic maternal transmission to neonate), or recurrent infection (o3% risk shedding of HSV. of transmission). All women with genital lesions characteristic of HSV at the • At approximately 24 hours after birth, the following sam- time of delivery should have viral culture and PCR sent off ples should be collected: from the lesions. Further characterization of the virus as HSV-1 or HSV-2 is required for correlation with serology to (a) surface cultures (eye, mouth, nasopharynx, and rectum) determine status of maternal infection (primary vs recurrent). (b) blood for HSV DNA PCR (c) CSF for determination of indices and HSV PCR Management of newborns born to women with lesions at (d) serum for ALT level delivery and history of genital herpes prior to pregnancy • Due to higher risk, empiric treatment with intravenous acyclovir should be initiated. • • For women with history of genital herpes prior to preg- If the maternal serology and virological studies are sugges- nancy, the likelihood of lesions present at delivery being tive of a recurrent infection and the infant remains asymp- recurrent are high and therefore the risk of transmission to tomatic with no evidence of HSV infection/disease infant is low (o3%). (negative result on surface cultures, blood DNA PCR, and • Collect following samples from newborn approximately 24 CSF PCR; and normal ALT level), discontinuation of paren- hours after delivery: teral acyclovir with instructions for close monitoring and re-evaluation with the development of any new signs is (a) surface cultures (conjunctiva, mouth, nasopharynx, rec- recommended. tum, and scalp electrode site when present) • If the maternal studies are suggestive of a primary or non- (b) blood DNA PCR primary genital infection and the neonate remains asymp- tomatic and lacks evidence of HSV infection/disease, treat- • It is acceptable to discharge infants who continue to be ment with 10 days of parenteral acyclovir is recommended clinically well at 48 hours with instructions to caregivers for (preemptive therapy) because the neonate’s risk of devel- very close monitoring and immediate medical attention oping neonatal HSV disease is so high (25% to 450%). with development of any findings concerning for neonatal • In infants with evidence of HSV infection or HSV disease, HSV. the approach is similar to those outlined in the approach to 6 S EMINARS IN P ERINATOLOGY ] ( ]]]]) ]]]– ]]]

an infant born to a mother with history of genital herpes Prevention of postnatal acquisition prior to pregnancy: 10 days of parenteral acyclovir for HSV infection (preemptive therapy), 14 days of parenteral acy- Approximately, 10% of cases are acquired in the postpartum clovir for neonatal SEM disease, and 21 days of parenteral period by exposure to the virus from symptomatic lesions or acyclovir therapy for CNS or disseminated disease. asymptomatic shedding of care takers, including following Jewish ritual involving oro-genital contact.54 The recommendation for infected household contacts and Strategies for prevention of HSV in the newborn family members is to avoid contact with the newborn. The recommendation for infected healthcare personnel with Cesarean delivery active herpetic lesions is not to provide direct care for neonates.35 Delivery by cesarean section decreases but does not entirely prevent HSV transmission to the neonate. Transmission of HSV has been documented in circumstances where cesarean Conclusion section was performed prior to rupture of membranes.8,49 fi This mode of delivery in women with active genital lesions Neonatal HSV disease is associated with signi cant morbidity can reduce the infant’s risk of acquiring HSV21,28 and is and mortality. Physicians involved in the care of neonates recommended when genital lesions or prodromal symptoms should consider neonatal HSV in the differential for all sick are present at the time of delivery.26 Cesarean delivery is neonates, and initiate an evaluation for HSV as the cause of more likely to be effective if performed prior to rupture of illness. Appropriate diagnosis and initiation of antiviral membranes, but in situations where rupture of membranes therapy followed by long-term suppressive therapy has sig- fi has occurred and genital lesions are observed on physical ni cantly improved the outcome of these infants. examination, cesarean delivery is recommended to minimize exposure of HSV to the neonate.26 This intervention is not Conflict of interest recommended for women with a prior history of genital herpes but no active lesions/prodromal symptoms at the The authors report no proprietary or commercial interest in time of delivery.26,50 any product mentioned or concept discussed in this article.

Antiviral suppressive therapy during pregnancy Funding sources In women with recurrent genital herpes, initiation of antiviral suppressive therapy with acyclovir/valacyclovir at 36 weeks Dr. Pinninti: none. of gestation is associated with decreased likelihood of genital Dr. Kimberlin: NIH, Alios (for RSV study; all monies go lesions at the time of delivery and decreased viral detection directly to the University). by culture/PCR. This intervention is currently endorsed by ACOG.26 However, subclinical viral shedding is not entirely suppressed and the utility of such a practice in preventing Acknowledgments neonatal HSV disease is not well defined. A recent multi- center case series reported eight cases of infants with This work was supported under contract with the Division of neonatal HSV disease acquired from mothers despite Microbiology and Infectious Diseases of the National Institute receiving antiviral suppressive therapies beyond 36 weeks of Allergy and Infectious Diseases (NIAID) (N01-AI-30025, of gestation.51 N01-AI-65306, N01-AI-15113, and N01-AI-62554).

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