Journal of Perinatology (2014) 34, 716–717 © 2014 Nature America, Inc. All rights reserved 0743-8346/14


Prolonged maternal postpartum fever and neonatal herpes infection M Anyebuno1, E Lopez-Medina2,3 and PJ Sánchez2,4 Maternal postpartum fever that is suggestive of endometritis often triggers evaluation of the mother and newborn infant for bacterial infection. Two neonates whose mothers had persistent postpartum fever despite broad-spectrum antimicrobial therapy developed disseminated herpes simplex virus (HSV) infection. Obstetric and pediatric healthcare providers should be mindful of possible HSV infection if there is postpartum fever unresponsive to antibiotics, and both mother and neonate should be evaluated appropriately and treated promptly. Journal of Perinatology (2014) 34, 716–717; doi:10.1038/jp.2014.82 INTRODUCTION Postpartum fever due to endometritis often results in evaluation of the mother and newborn infant for bacterial infection. A less frequent but possibly more important etiology that is often not considered in a timely manner and can have grave consequences for the infant is maternal herpes simplex virus (HSV) infection.1–5 This case report illustrates the need to consider HSV endometritis if maternal fever is persistent and refractory to antimicrobial therapy and promptly initiate antiviral treatment to the mother and the infant. CASE 1 A 25-year-old, gravida 3, para 2 African American mother presented to Parkland Memorial Hospital, Dallas, TX at 37 weeks’ gestation with a 2 day history of frontal headache. She lacked antibodies to HIV and rubella virus and had a nonreactive hepatitis-B surface antigen test. The rapid plasma reagin test during pregnancy was 1:2 and the treponemal test was reactive; she was diagnosed with syphilis of unknown duration and received three weekly injections of benzathine penicillin G at 17–20 weeks’ gestation. Neither she nor her partner had a history of genital HSV infection. Labor was induced because of severe preeclampsia and she delivered a 2260 g female infant vaginally after 6 h of rupture of membranes. The infant had Apgar scores of 9 and 9 at 1 min and 5 min, respectively, and she was admitted to the normal newborn nursery. Physical examination was normal, and the infant received a single intramuscular dose of benzathine penicillin G (50 000 U kg − 1). One day after delivery, the mother developed uterine fundal tenderness and fever that was persistent for several days despite broad-spectrum antibiotic therapy. Because of concern for pelvic abscess, a computed tomography scan was performed that showed bilateral multiple pelvic and inguinal lymphadenopathy that were likely to be inflammatory in nature. The infant did well for the first 3 days but remained in the newborn nursery because of jaundice requiring phototherapy and also because of the mother’s prolonged hospitalization. At 84 h of age, the infant developed tachypnea, poor feeding and abdominal distention. Oxygen saturation in room air was 86% and she was 1

admitted to the neonatal intensive care unit. A sepsis evaluation was performed; the white blood count was normal, platelets were 128 000 mm − 3, the chest radiograph was suggestive of pneumonia, and antibiotic therapy with ampicillin and gentamicin was initiated. Serum alanine transaminase was 18 IU l − 1 and bilirubin was 10.8 mg dl − 1. At 104 h of age, the infant had worsening respiratory status requiring increasing ventilatory support, bilateral pleural effusions and hypotension. Since blood cultures were sterile, evaluation for possible HSV infection was performed. Lumbar puncture yielded bloody cerebrospinal fluid (CSF; 316 500 red blood cells per mm3) with 100 white blood cells per mm3 (44%, polymorphonuclear leukocytes; 29%, lymphocytes). HSV CSF PCR test as well as conjunctival, throat and rectal mucosal cultures for HSV were obtained and acyclovir therapy (20 mg kg − 1per dose intravenous every 8 h) was initiated. On the following day, she developed hepatosplenomegaly, alanine transaminase was 1304 IU l − 1, and fulminant liver failure ensued. Platelet count decreased to 39 000 mm − 3 and she died at 120 h of age from a pulmonary hemorrhage. Subsequently, CSF HSV PCR test was positive for HSV (not typed; ARUP Laboratories, Salt Lake City, UT, USA); mucosal HSV cultures were negative. Autopsy was performed that showed disseminated HSV infection with tracheitis, pneumonitis with diffuse alveolar injury and submassive hepatic, splenic and adrenal gland necrosis. There was immunohistochemical evidence of HSVinfected cells in the trachea, lung, liver, spleen, lymph nodes, adrenal glands and umbilical cord. HSV was isolated from tissue cultures of trachea, pleural fluid, lung and spleen. The infant’s mother subsequently was treated with acyclovir for presumed HSV endometritis with prompt resolution of her symptoms. CASE 2 A 27-year-old, gravida 3, para 2 African American mother presented in labor to SwedishAmerican Hospital, Rockford, IL at 37 weeks’ gestation. She lacked antibodies to HIV, had nonreactive rapid plasma reagin and hepatitis-B surface antigen tests, and had immunoglobulin G antibodies to rubella. Tests for gonorrhea and Chlamydia trachomatis were negative during the

Department of Pediatrics, Pediatrix Medical Group, SwedishAmerican Hospital, Rockford, IL, USA; 2Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA; 3Department of Pediatrics, Universidad del Valle and Centro de Estudios en Infectología Pediátrica (CEIP), Cali, Colombia and 4Department of Pediatrics, Nationwide Children’s Hospital—The Ohio State University, Columbus, OH, USA. Correspondence: Dr M Anyebuno, Pediatrix Medical Group, SwedishAmerican Hospital, 1401 E State Street, Rockford, IL 61104, USA. E-mail: [email protected] Received 9 December 2013; revised 10 March 2014; accepted 27 March 2014

Prolonged postpartum fever and neonatal herpes M Anyebuno et al

717 pregnancy, and neither she nor her partner had a history of genital HSV infection. She had rectovaginal colonization with group B Streptococcus and received two intrapartum doses of intravenous aqueous crystalline penicillin G. Rupture of fetal membranes occurred 4 h before delivery and thick meconium was noted. She delivered vaginally a 3000 g, female infant who had Apgar scores of 9 and 9 at 1 min and 5 min, respectively. The infant was admitted to the neonatal intensive care unit owing to respiratory distress. Approximately 24 h after delivery, the mother had acute onset of diaphoresis and fever, with a maximum temperature of 103 °F, as well as headache and low back pain in the area of the epidural anesthesia. She received intravenous ampicillin–sulbactam and doxycycline after blood cultures were obtained. Since fever as high as 103.2 °F persisted, consultation with an infectious disease specialist was obtained on the third postpartum day. A computed tomography scan of the pelvis showed evidence of diffuse endometritis without any discrete abscess or retained products of conception. Blood and urine cultures were sterile. Daily fever spikes persisted despite a change in the antibiotic therapy to intravenous ceftriaxone and oral metronidazole with later addition of intravenous levofloxacin. The infant was diagnosed with meconium aspiration syndrome by chest radiograph and required 44% oxygen by oxyhood. She received ampicillin and gentamicin after blood culture was obtained and by 48 h of age, the respiratory status improved with less oxygen requirement. However, because of persistent tachypnea on the third day of age, temperature of 99.9 °F and maternal endometritis, a lumbar puncture was performed; results of CSF findings were normal with eight white blood cells per mm3 (50%, lymphocytes; 30%, polymorphonuclear leukocytes; 20%, macrophages), protein content of 87 mg dl − 1, and glucose of 59 mg dl − 1. Tachypnea and elevated temperatures (99.9–100.2 °F) persisted on the fourth and fifth days of age. On the fifth day, laboratory evaluation showed a white blood cell count of 11 300 mm − 3 (47%, neutrophils; 7%, band cells; 35%, lymphocytes; 9%, monocytes; 1%, eosinophils), alanine transaminase of 72 IU l − 1, serum interleukin-6 concentration of 82.3 pg ml − 1 (normal o3.7 pg ml − 1), and c-reactive protein of 2.25 mg dl − 1 (normal o0.8 mg dl − 1). A pediatric infectious disease specialist was consulted who recommended a higher dose of ampicillin for probable group B streptococcal infection but subsequent telephone consultation with another pediatric infectious disease specialist on the same day resulted in the infant being evaluated for possible HSV infection with initiation of empiric intravenous acyclovir therapy. The infant’s nasopharyngeal culture yielded HSV (not typed, ARUP Laboratories), and blood and CSF HSV DNA PCR tests (ARUP Laboratories) also were positive. The infant received intravenous acyclovir starting on day 5 of age and continued for 21 days. After knowledge of the infant’s disseminated HSV infection, the mother received acyclovir therapy with clinical improvement and was discharged home on oral acyclovir therapy. At 3 years of age, the infant’s development is normal. DISCUSSION Neonatal HSV infection can be a challenging diagnosis especially when the infant has no cutaneous lesions or seizures.6 Moreover, vertical transmission occurs more frequently with primary maternal HSV infection at delivery when the mother lacks any history of genital HSV infection that could aid in its earlier recognition. At the same time, prompt initiation of acyclovir therapy is crucial if neonatal outcome is to be improved.7 Because of these issues, knowledge of any possible factors that can lead to early antiviral therapy is paramount. We report two cases of neonatal HSV infection in which the mothers had persistent postpartum fever owing to presumed endometritis. Although the cause of the endometritis was not confirmed, a primary HSV infection was likely given the maternal symptoms and neonatal diagnosis. Importantly, the possibility that © 2014 Nature America, Inc.

the maternal symptomatology could be due to HSV was only considered after the infants’ HSV infection was confirmed. Neither of the mothers had genital HSV lesions noted at the time of delivery. Delayed recognition of perinatal HSV transmission had occurred and resulted in severe disease in both infants, one of whom died. In 1997, Hollier et al.2 first reported two neonates who died with disseminated HSV infection after being born to mothers with postpartum HSV endometritis manifested by persistent fever (duration of 6 and 7 days) despite antibiotic therapy. Robb et al.8 have proposed that the late secretory and gestational endometrium may be more susceptible to HSV infection and reactivation because of prostaglandin synthesis that causes local immune suppression. Baker and Thomas9 also have shown that the presence of prostaglandin E2 suppresses T-cell function following lymphocyte stimulation with herpes viruses, thus allowing for a clinical HSV recurrence. Previously published cases of fulminant or disseminated neonatal HSV infection associated with HSV endometritis have been reported only in obstetrical journals2,3,4,5 with no mention of such occurrence in pediatric textbooks. It is therefore possible that providers of neonatal care are not aware that HSV is an important albeit infrequent cause of postpartum endometritis that can result in neonatal infection. In conclusion, HSV infection should be suspected in any neonate with clinical signs of infection and whose mother has persistent postpartum fever that lasts for 48–72 h or more and is refractory to antibiotic therapy. These neonates should receive acyclovir therapy after having a complete evaluation consisting of complete blood cell count and platelets, serum alanine transaminase, mucosal HSV cultures or PCR, as well as blood and CSF HSV PCR tests.10 As seen in Case 1, the latter PCR tests may be positive even when mucosal cultures are negative. Consideration should also be given for performing mucosal HSV cultures or PCR and blood PCR testing on the newborns of such mothers even if they lack clinical signs of infection. Although neonatal HSV infection is infrequent, early antiviral therapy should improve its outcome. CONFLICT OF INTEREST The authors declare no conflict of interest.

ACKNOWLEDGEMENTS No honorarium, grant or other payment was given to anyone to produce this manuscript.

REFERENCES 1 Remadi S, Finci V, Ismail A, Zacharie S, Vassilakos P. Herpetic endometritis after pregnancy. Pathol Res Pract 1995; 191(1):31–34. 2 Hollier LM, Scott LL, Murphree SS, Wendel GD Jr. Postpartum endometritis caused by herpes simplex virus. Obstet Gynecol 1997; 89(5 Pt 2): 836–838. 3 Giraldo-Isaza MA, Jaspan D, Cohen AW. Postpartum endometritis caused by herpes and cytomegaloviruses. Obstet Gynecol 2011; 117(2 Pt 2): 466–467. 4 Hixson MJ, Collins JH. Postpartum herpes simplex endometritis. A case report. J Reprod Med 2001; 46(9): 849–852. 5 McGill AL, Bavaro MF, You WB. Postpartum herpes simplex virus endometritis and disseminated infection in both mother and neonate. Obstet Gynecol 2012; 120(2 Pt 2): 471–473. 6 Catlin EA, Warren HS, Shailam R, Lahoud-Rahme M, Lew M. Case records of the Massachusetts General Hospital. Case 19–2012. A premature newborn boy with respiratory distress. N Engl J Med 2012; 366(25): 2409–2419. 7 Shah SS, Aronson PL, Mohamad Z, Lorch SA. Delayed acyclovir therapy and death among neonates with herpes simplex virus infection. Pediatrics 2011; 128(6): 1153–1160. 8 Robb JA, Benirschke K, Barmeyer R. Intrauterine latent herpes simplex virus infection: I. Spontaneous abortion. Hum Pathol 1986; 17(12): 1196–1209. 9 Baker DA, Thomas J. The effect of prostaglandin E2 on the initial immune response to herpes simplex virus infection. Am J Obstet Gynecol 1985; 151(5): 586–590. 10 Cantey JB, Mejias A, Wallihan R, Doern C, Brock E, Salamon D et al. Use of blood polymerase chain reaction testing for diagnosis of herpes simplex virus infection. J Pediatr 2012; 161(2): 357–361.

Journal of Perinatology (2014), 716 – 717

Prolonged maternal postpartum fever and neonatal herpes infection.

Maternal postpartum fever that is suggestive of endometritis often triggers evaluation of the mother and newborn infant for bacterial infection. Two n...
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