Perinatal/Neonatal Case Presentation &&&&&&&&&&&&&& Severe Intrauterine with Placentitis in a Newborn of a Mother with Recurrent Genital at Delivery

Archana Chatterjee, MD, PhD We present a case of fatal neonatal HSV-2 infection in a Stephen A. Chartrand, MD premature delivered by cesarean section to a mother who at Christopher J. Harrison, MD delivery had recurrent HSV-2 infection, based on history and Anna Felty-Duckworth, MD maternal antibody titers. It was clinically evident at birth, and Chhanda Bewtra, MD subsequently confirmed by laboratory studies, that the infant was infected before delivery, likely from the previous maternal episode during . This case illustrates an uncommonly documented, We present a case of fatal herpes simplex type 2 (HSV-2) in a premature but known complication in a mother with primary disease during infant born to a mother diagnosed with recurrent HSV-2, based on history pregnancy and recurrent at delivery — intrauterine and HSV serology results. It was clinically evident at delivery, and transmission to the fetus. subsequently confirmed by laboratory studies that the infant was infected before delivery. There was histopathologic evidence of placentitis and CASE REPORT upon examination of the placenta and fetal membranes. This case illustrates a relatively uncommon complication of recurrent A 27-weeks’ gestation male was delivered by due to genital herpes at delivery — intrauterine transmission to the fetus from a failed tocolysis and deteriorating biophysical profile. Twelve hours primary episode during pregnancy. before delivery, the mother developed active genital herpes simplex Journal of Perinatology 2001; 21:559 – 564. lesions over her labia. The obstetrician reported that her membranes were intact at the time of delivery. The mother had labial lesions 2 months prior (her first known clinical infection), which were culture positive for HSV-2. At that time, a diagnosis of primary INTRODUCTION genital herpes infection was made by the obstetrician, based on an HSV-2 IgM of 3.5 EIA units (normal <0.9) and HSV-2 IgG of 0.9 The most serious complication of maternal genital herpes simplex EIA units (normal 0.9, Specialty Laboratories, Los Angeles, CA). She virus (HSV) infection is neonatal HSV disease, which occurs due to did not receive antiviral therapy during her primary infection. She either ascending infection or, more commonly, by delivery through was also noted to have genital condylomata at about 15 weeks’ an infected birth canal.1,2 The estimated incidence of neonatal HSV gestation. infection is approximately one case in 2000 to 5000 deliveries per At the time of delivery the infant was noted to have multiple year.3 Thus, each year, 1500 to 2000 cases of neonatal herpes vesiculobullous lesions over the entire body (Figure 1A–C). His infection occur in the United States.4 The outcome of these Apgar scores were 7 and 7 at 1 and 5 minutes, respectively. He was can be devastating, including death or severe neurodevelopmental immediately intubated, given surfactant, and admitted to the disability.5 Four percent of these cases are acquired prenatally, 86% neonatal intensive care unit. Broad-spectrum antibiotics plus natally, and 10% postnatally.2 In the largest case series on acyclovir (10 mg/kg every 8 hours) were administered intra- intrauterine HSV infections (13 ), there was clinical evidence venously. A direct fluorescent antibody (DFA) examination of of primary genital HSV infection in 4 of the 13 mothers, and only 1 scrapings from the lesions was positive for HSV-2. An initial chest mother had a history compatible with recurrent genital HSV infection radiograph showed no infiltrates. Serologic tests for , HIV, and during pregnancy.6 were negative. Liver enzymes were elevated, with AST of 428 U/l (normal 17 to 59) and ALT of 81 U/l (normal 3 to 45), while total serum was 5.1 mg/dl (normal 1.3 to 11.3) on Combined Division of Pediatric Infectious Disease ( A.C., S. A.C. ) , Creighton University and the day 3 of life. Subsequently, cultures of the vesicular fluid and blood University of Nebraska Medical Center, Omaha, NE; Department of ( C.J.H. ) , obtained shortly after birth grew HSV-2. Culture of the amniotic fluid University of Louisville, Louisville, KY; and Department of Pathology ( A.F.-D., C.B. ) , Creighton University, Omaha, NE. taken at delivery was also positive for HSV-2. Polymerase chain reaction (PCR) on the blood was positive for HSV-2 using the Address correspondence and reprint requests to Archana Chatterjee, MD, PhD, Department of Pediatrics, Creighton University, 2500, California Plaza, Room 409, Criss II, Omaha, NE 68178. procedure of Kimura et al.7 A lumbar puncture was not performed

Journal of Perinatology 2001; 21:559 – 564 # 2001 Nature Publishing Group All rights reserved. 0743-8346/01 $17 www.nature.com/jp 559 Chatterjee et al. Fatal Neonatal HSV-2 Infection

Figure 1. A, B, C, Multiple vesiculobullous lesions seen all over the body of the infant. initially due to the infant’s instability, but on day 15 (day 14 of 28% monocytes. There were 10,000 red blood cells/cmm (normal 0 acyclovir), the CSF contained 189 white blood cells (WBCs) /cmm to 10/cmm), with 527 mg/dl protein (normal 15 to 45 mg/dl), (normal 0 to 5/cmm), with 55% neutrophils, 17% lymphocytes, and and 32 mg/dl glucose (normal 60 to 80 mg/dl). Cerebrospinal

560 Journal of Perinatology 2001; 21:559 – 564 Fatal Neonatal HSV-2 Infection Chatterjee et al.

Figure 1. (continued). fluid cultures were negative for bacteria and viruses, and PCR was The child’s hospital course was complicated by , bilateral negative for HSV-1 and HSV-2. intraventricular hemorrhage (IVH), and with Candida The placenta was discoid and small, measuring 16.3Â14.7Â1.2 parapsilosis on day 14 and Klebsiella pneumoniae on day 16. Blood cm, and weighing 229.8 g ( <25th percentile for estimated cultures remained positive for both organisms despite adequate gestational age). The inserted approximately 2.8 cm antibacterial and antifungal therapy. Due to his severe IVH and from the nearest margin. The fetal surface of the placenta was progressively deteriorating status, he was taken off life support on day smooth and had no vesicular lesions. The maternal surface was 21, following consultation with the family. An autopsy was requested, grossly unremarkable and all cotyledons appeared intact. The but refused by the family. umbilical cord was boggy, but no other gross abnormalities were identified. The membranes were somewhat discolored, but not friable or foul smelling. LITERATURE REVIEW AND DISCUSSION Microscopic examination of the placenta showed several necrotic Genital HSV infection can be acquired primarily or recur during abscesses in the intervillous spaces with an intense neutrophilic pregnancy. Several studies have suggested associations between HSV infiltrate, marked karyorrhexis and degeneration (Figure 2A). There infection acquired during pregnancy and preterm labor, intrauterine were varying degrees of neutrophilic infiltration in both intact and growth retardation, and spontaneous abortion.2,8 Specific maternal degenerating peripheral villi. No intranuclear inclusions were IgG against the relevant HSV serotype appears to provide relative identified in these areas on H&E stain and an immunoperoxidase protection against intrauterine infection, but this protection is not stain for HSV was negative. Gram stain for bacteria was also negative. absolute. Hutto et al.6 described 13 cases of intrauterine HSV-2 Microscopic examination of the membranes showed foci of acute infection, with only 1 of the mothers having recurrent disease. inflammation with frank necrosis in the decidua basalis and HSV-2 infects nearly 50% of infants whose mothers have primary chorionic plate (Figure 2B). Foci of increased chronic inflammation genital herpes at delivery, whereas <5% of infants exposed to were also present in these areas, containing a predominantly recurrent maternal infection at the time of delivery become infected. lymphocytic population. Gram stain was negative in these areas as Prober et al.9 reported no cases of neonatal herpes among 34 exposed well. The amnion was not directly involved in the acute or chronic babies in mothers with recurrent HSV infection who were shedding inflammatory process. Small nests of somewhat columnar, more virus at the time of delivery. Brown et al.10 documented infection in 1 reactive cells were observed, but no intranuclear inclusions or of 33 similarly exposed infants. Even with recurrent disease, multinucleated giant cells were identified on H&E sections. symptomatic HSV in the mother poses a greater risk than Immunoperoxidase staining of these reactive cell populations in the asymptomatic.11 Other risk factors for acquisition of neonatal HSV amnion was positive for HSV (Figure 2C). infection include: (1) cervical (as opposed to vulvar or buttock)

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Figure 2. A, Necrotic abscess in the intervillous space with an intense neutrophilic infiltrate, marked karyorrhexis and degeneration. B, Acute inflammation with frank necrosis in the decidua basalis and chorionic plate. C, Immunoperoxidase staining of reactive cell populations in the amnion positive for HSV. lesions, which result in more virus being shed into vaginal secretions; present in this dramatic fashion at birth. Herpes simplex needs to be (2) multiple lesions (greater viral load); (3) high virus inoculum included in the differential diagnosis of all vesiculobullous disease in in vaginal secretions, e.g., primary versus recurrent; (4) prolonged neonates, as well as in neonates who present with ‘‘culture-negative rupture of membranes — prolonged exposure to vaginal secretions; sepsis’’ or focal seizures. Other infectious agents that cause and (5) use of fetal scalp electrodes or other instrumentation during vesiculobullous rashes at birth include Staphylococcus aureus, delivery — providing a site for viral entry.11 Pseudomonas aeruginosa, Listeria monocytogenes, cytomegalo- While our patient’s clinical presentation consisted of character- virus, , coxsackieviruses, Candida sp. and istics of HSV infection, most infants with neonatal herpes do not Aspergillus sp.11

562 Journal of Perinatology 2001; 21:559 – 564 Fatal Neonatal HSV-2 Infection Chatterjee et al.

Figure 2. (continued).

Our patient’s mother apparently suffered a primary HSV-2 HSV-2 in utero with possible CNS involvement. The latter could infection 2 months before delivery. Her primary lesions had not be determined definitively because the virus was not detected in resolved during the interim, but she presented with recurrent new the CNS by culture or PCR. However, CSF cultures yield virus in vesicles at the time of delivery. Although it is possible that her only 25% to 40% of all neonatal cases.11 Also, he had already primary episode lasted until delivery, it is highly unlikely to have received 2 weeks of acyclovir therapy before the studies were persisted over 2 months and there are no clinical data to support obtained. Neuroimaging studies may have supported CNS this. At initial diagnosis (week 19 of gestation), her IgM for HSV- involvement, but could not be performed due to his unstable 2 was 3.6 EIA units (normal <0.9) and the IgG was negative. condition. The IVH, CSF leukocytosis, and elevated protein could be Eight weeks later at delivery, her IgM was 1.4 EIA units and IgG due to HSV infection.11 Alternatively, the IVH may have been related was 1.1 EIA units (normal 0.9, Specialty Laboratories). The to prematurity, and the CSF pleocytosis, proteinosis, and argument could be made that this low IgG with persistently positive hypoglycorrhachia secondary to IVH. IgM is indicative of prolonged primary infection with as yet Intrauterine HSV infection can occur as a consequence of either incomplete seroconversion. However, it should be noted that there transplacental (rare) or ascending infection. Pathologic examina- are no defined criteria to use serology as the basis for defining tion of the placenta and umbilical cord may provide important clues prolonged primary infection. to the route and/or timing of HSV infection.13 Although few cases of A recent, large, cohort study concluded that HSV infection with documented HSV placentitis have been reported, intact fetal seroconversion before labor did not appear to negatively affect the membranes at delivery and histopathologic evidence of placentitis outcome of pregnancy. However, infection acquired near the time of would suggest a transplacental route of infection. Conversely, labor was associated with an increased risk for neonatal HSV histopathologic evidence of chorioamnionitis indicates ascending infection and increased perinatal morbidity.12 In our case, infection. In our case, the membranes were intact by gross seroconversion occurred in the mother before delivery, but this did examination at delivery and there was evidence of placentitis, but not protect the fetus from infection. Our patient may have been at there also was histopathologic evidence of chorioamnionitis. The lack greater risk for acquisition of HSV due to his prematurity, because the of HSV-specific placental cytologic changes and immunostaining majority of maternal antibody is transferred after 32 weeks of suggest ascending infection. Microscopic breaks in the membranes gestation. Also, if HSV ascended into the amniotic fluid before may not have been clinically detected or the membranes may have maternal seroconversion, our patient’s risk for infection may have resealed before delivery. Although amniotic fluid cultures were increased. positive for HSV-2, neither the placenta itself nor the fetal From the clinical appearance of the neonate and the subsequent membranes were cultured for HSV. Other potentially useful studies laboratory studies, it was evident that he had acquired disseminated would include PCR on the placenta and amniotic membranes plus

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umbilical cord sections for histology. Unfortunately, none of these 2. Whitley R, Arvin A, Prober C, et al. Predictors of morbidity and mortality in were obtained in our patient. neonates with infections. N Engl J Med 1991;324:450–4. A question that arises from this case is whether treatment of the 3. Whitley R, Kimberlin D, Roizman B. Herpes simplex viruses. Clin Infect Dis primary episode during pregnancy would have helped to reduce the 1998;26:541–53. risk of fetal infection by decreasing cervical and vaginal virus titers 4. Overall J. Herpes simplex virus infection of the fetus and newborn. Pediatr and perhaps restricting potential access to the amniotic fluid and/or Ann 1994;23:131–6. 5. Corey L, Whitley R, Stone E, Mohan K. Difference between herpes simplex the fetus. Clinicians caring for pregnant women with primary genital virus type 1 and type 2 neonatal in neurological outcome. Lancet HSV infection should consider this option and perhaps offer acyclovir 1988;1:1–4. therapy to their patients, after discussing the risks/benefits of such 6. Hutto C, Arvin A, Jacobs R, et al. Intrauterine herpes simplex virus infections. therapy. J Pediatr 1987;110:97–101. 7. Kimura H, Futamura M, Kito H, et al. Detection of viral DNA in neonatal herpes simplex virus infections: frequent and prolonged presence in serum CONCLUSION and cerebrospinal fluid. J Infect Dis 1991;164:289–93. The clinical and histopathologic evidence in our patient points to a 8. Brown Z, Benedetti J, Selke S, Ashley R, Watts D, Corey L. Asymptomatic diagnosis of fatal intrauterine transmission of HSV-2 infection in a maternal shedding of herpes simplex virus at the onset of labor: Relationship premature infant born to a mother with primary HSV-2 infection 2 to preterm labor. Obstet Gynecol 1996;87:483–8. months before delivery and recurrent labial lesions at the time of 9. Prober C, Sullender W, Yasukawa L, Au D, Yeager A, Arvin A. Low risk of herpes simplex virus infections in neonates exposed to the virus at the time of cesarean delivery. Fetal acquisition clearly occurred before the onset vaginal delivery to mothers with recurrent genital herpes simplex viral of the mother’s recurrence. Amnion invasion probably occurred by infections. N Engl J Med 1987;316:240–4. the ascending route, although the membranes appeared to be 10. Brown Z, Benedetti J, Ashley R, et al. Neonatal herpes simplex virus infection clinically intact at delivery. Clinicians should be alert to the fact that in relation to asymptomatic maternal infection at the time of labor. N Engl J severe invasive HSV disease can occur in infants born to mothers with Med 1991;324:1247–52. clinically recurrent disease at delivery. 11. Overall J. Viral infections of the fetus and neonate. In: Feigin RD, Cherry JD, editors. Textbook of Pediatric Infectious , 4th ed. Philadelphia, PA: WB Saunders; 1998. p. 856–92. References 12. Brown Z, Selke S, Zeh J, et al. The acquisition of herpes simplex virus during 1. Whitley R. Herpes simplex virus infections of women and their offspring: pregnancy. N Engl J Med 1997;337(8):509–15. Implications for a developed society. Proc Natl Acad Sci USA 1994;91: 13. Schwartz D, Caldwell E. Herpes simplex virus infection of the placenta. Arch 2441–7. Pathol Lab Med 1991;115:1141–4.

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