Possible Neonatal Herpes Simplex Virus (HSV) Acquired Postpartum from Maternal Oral HSV Reactivation after Neuraxial Morphine M. Cecilia De Guzman, MD,* Rupesh Chawla, MD, MSc, FRCP,† and Kaylene Duttchen, MD, BSc (Pharm), FRCP* In this report, we describe a case of a neonatal oral herpes simplex virus (HSV) infection possibly acquired from a mother who had oral HSV reactivation in association with neuraxial morphine. Neuraxial morphine is commonly administered for postpartum analgesia after cesarean delivery. While there is evidence that neuraxial morphine increases the risks of oral HSV reactivation in parturients, there has been no report of neonatal HSV infection directly acquired from a mother who had HSV recurrence from neuraxial morphine. (A&A Case Reports. 2014;2:103–5.)
B
ased on numerous case reports and studies,1–5 the recurrence of oral herpes simplex virus (HSV) is associated with neuraxial morphine after cesarean delivery. While a possible complication of this reactivation is the risk of postpartum viral transmission to the neonate causing major morbidity and mortality, 1 review reported that there was no reported case of neonatal HSV acquired from the mother and concluded that the benefit of neuraxial morphine analgesia still outweighed the risk.6 This report describes a case of a 5-day-old neonate who possibly acquired a localized oral HSV from the mother who had oral HSV reactivation in association with neuraxial morphine. The mother of the patient gave verbal and written permission to publish this report.
CASE DESCRIPTION
The parturient was 37 years old gravida 2, para 1, healthy but with a history of oral HSV with recurrences approximately twice a year. Apart from that, the pregnancy was healthy. There was no reported bleeding, hypertension, diabetes, smoking, alcohol, or recreational drug use during pregnancy. Both the father and mother had no known immunodeficiency history. The medications used during pregnancy were doxylamine succinate and ondansetron. The maternal prenatal workup was negative for infection with chlamydia, HBsAg, varicella, human immunodeficiency virus, and syphillis. She was immune to rubella, and Group B streptococcal status was unknown. The mother reported a history of postpartum oral HSV after a previous otherwise normal pregnancy and cesarean delivery without evidence of postpartum neonatal HSV. From the *Department of Anesthesia, University of Calgary; and †Pediatric Infectious Disease, Alberta Children’s Hospital, Calgary, Alberta, Canada. Accepted for publication November 15, 2013. Funding: None. The authors declare no conflicts of interest. Address correspondence to M. Cecilia De Guzman, MD, Department of Anesthesia, University of Calgary, C229, 1403 29th St., NW, Calgary, Alberta T2N 2T9. Address e-mail to [email protected], and Kaylene Duttchen, MD, BSc (Pharm), FRCP, Department of Anesthesia, University of Calgary, C229, 1403 29th St., NW, Calgary, Alberta T2N 2T9. Address e-mail to [email protected]. Copyright © 2014 International Anesthesia Research Society DOI: 10.1213/XAA.0000000000000013
May 1, 2014 • Volume 2 • Number 9
Delivery for this pregnancy was through elective cesarean delivery under spinal anesthetic at 38 weeks of gestation after spontaneous rupture of membrane. The mother was given spinal hyperbaric bupivacaine 0.75%, 1.3 cc with 15-mcg fentanyl, and 150 mcg morphine. The neonate weighed 2822 g with Apgar scores of 9 and 9 at 1 and 5 minutes, respectively. There was no active oral HSV noted at birth. The mother and neonate were discharged home 30 hours after the procedure. On the third day after delivery, the mother noted HSV lesions around her mouth area for which she took oral valacyclovir. On the fifth day, the mother noted 4 lesions on the baby’s lower lip, with no fever. The baby was immediately brought to the Children’s Hospital where he was found to have 4 vesicular ulcers on the left inner lip. The rest of his examination was normal, and his neurologic examination was unremarkable. The possible differential diagnosis was an inclusion cyst, but given the significant history of maternal oral HSV, a full septic workup and IV acyclovir were initiated within 3 hours of the onset of lesions. All tests were normal including complete blood count and cerebrospinal fluid (CSF) cell count, glucose, and protein. Blood and CSF cultures were negative. CSF gram stain and CSF HSV by polymerase chain reaction were also negative. An HSV sample from an oral lesion was not culturable due to it being planted in inappropriate medium. The baby did well in the hospital, with no signs or symptoms of central nervous system (CNS) or disseminated infection. The infectious disease service advised a 14-day course of IV acyclovir, as CSF HSV polymerase chain reaction was negative. A 6-month prophylactic course of oral acyclovir was also recommended. The oral lesions improved after 1 dose acyclovir and were resolved after 1 week. The baby’s white blood cell count and renal function were monitored for potential side effects from acyclovir with monthly blood work for 6 months.
DISCUSSION
In the last 2 decades, several studies have confirmed an increasing rate of oral HSV reactivation among women receiving neuraxial morphine compared with systemic morphine.3–5,7 Although the benefits of postdelivery analgesia including better maternal comfort and mobility for improved cases-anesthesia-analgesia.org
103
Neonatal HSV from Maternal Recurrence After Spinal Morphine
infant care are clear,6 a theoretical risk of viral transmission from mother to infant is still possible. There was no CNS or multiorgan involvement in this case, but given a different scenario, such as a history of immunodeficiency, delay in treatment, or greater viral load exposure, catastrophic morbidity and mortality are possible. Bauchat,6 in her focused review of neuraxial morphine and oral HSV reactivation in parturients, commented that the maternal benefits of neuraxial analgesia outweigh the risk of neonatal herpes acquired postpartum from maternal recurrence because serious neonatal morbidity and mortality have not been described. There may be more cases that are not reported. This assumed neonatal oral HSV case, likely acquired from the mother who had oral HSV reactivation, was quickly recognized, because the mother is an anesthesiologist who was fully aware of the association between neuraxial opioids and HSV reactivation.
ANESTHETIC IMPLICATIONS
Assuming that maternal HSV reactivation from a neuraxial opioid is a potential risk for neonatal infection leading to major neonatal morbidity and mortality, should we modify our clinical practice? Oral HSV reactivation can be brought about by many factors including exposure to ultraviolet light, fever, stress, or immunosuppressed state such as pregnancy.8 However, there is strong evidence from previous clinical studies of an association between neuraxial opioid use and HSV recurrence. While morphine is the most studied and implicated spinally administered opioid to cause HSV reactivation, epidural fentanyl and spinal meperidine have also been reported in nonparturient patients.9,10 As for HSV reactivation based on route of opioid administration, 2 randomized controlled trials comparing epidural to systemic opioids showed increased HSV reactivation after epidural morphine. Crone et al.11 found the reactivation rate of 14.6% in patients receiving epidural opioids but 0% in patients receiving systemic opioids. Boyle7 reported a reactivation rate of 5.2% in patients receiving epidural opioids and 0.5% in patients receiving systemic opioids. A randomized controlled trial by Davies et al.5 showed that HSV reactivation follows both intrathecal opioids and systemic opioids but more frequently in patients receiving intrathecal opioids. One proposed theory for the mechanism of HSV reativation is that opioids in the CSF trigger the scratch center in the medulla, thereby indirectly reactivating the dormant HSV in the trigeminal nerve via mechanical scratching.5 The relationship between opioid dose and pruritus is also unclear as Palmer et al.12,13 found that there is no dose response in severity of pruritus with epidural morphine, but it is linear with increasing intrathecal doses of morphine. Another theory is through an altered immunologic response where morphine works at a molecular level, causing HSV replication in the trigeminal nerve and deficiency in cell-mediated immunity.14
IMPACT ON CLINICAL PRACTICE
Because of the potential neonatal complications from HSV infection, the following factors should be considered: •
Inclusion of HSV history as part of anesthesia assessment if the anesthetic plan includes neuraxial opioid.
104 cases-anesthesia-analgesia.org
• •
Strict adherence to proper hand hygiene for health care workers and family members in contact with postpartum patients with oral HSV and the newborn.15 Promote further research of hydromorphone, because it is unclear at this time if it has the same risk of oral HSV reactivation as neuraxial morphine.
Neonatal HSV infection is rare, with a national U.S. incidence of 9.6 in 100,000 births,16 but it is a significant cause of death and permanent neurodevelopmental disability in children. Transplacental maternal antibodies possibly reduce if not prevent transmission of HSV. Depending on demographic and social factors, exposure to HSV-1 occurs early in life (on or before 5 years) approximately 70% to 80% of adolescents are exposed, and there is another increase at age 20 to 40 years.17 HSV-1 (orofacial) and HSV-2 (genital) both cause genital and neonatal HSV infection, although genital HSV-1 infection seems to account for 30% to 50% of neonatal infections.16,17 Although most neonatal HSV occurs intrapartum (85%), it can also be acquired in utero (5%) and postnatally (10%) such as during handling of the baby by the mother or caretakers with a cold sore.17 Infection is symptomatic with high mortality (85%).18 Disease can be localized to the skin, eye, and mouth (SEM disease), can involve the CNS, or can manifest as disseminated infection involving multiple organs.18 In the absence of antiviral therapy, neurological impairment among these 3 disease categories is very high (38%–67%), and the mortality rate is as high as 85% for babies with disseminated infection.18 Even with active treatment, morbidity and mortality remain high. Only 40% and 60% of babies develop normally after encephalitis and disseminated disease, respectively.17 Thus, intervention to prevent neonatal HSV infection, early recognition, and treatment are essential in decreasing both mortality and neurological sequelae in surviving infants.
CONCLUSION
In summary, we describe a possible case of vertical transmission of oral HSV after the mother had presumed reactivation of oral HSV after receiving intrathecal morphine along with spinal anesthesia for cesarean delivery. We suggest inclusion of maternal HSV in the anesthetic assessment and counseling patients who have a history of oral HSV regarding possible antiviral prophylaxis treatment if an oral lesion occurs. E REFERENCES 1. Cardan E. Herpes simplex after spinal morphine. Anaesthesia 1984;39:938 2. Douglas MJ, McMorland GH. Possible association of herpes simplex type I reactivation with epidural morphine administration. Can J Anaesth 1987;34:426–7 3. Gieraerts R, Navalgund A, Vaes L, Soetens M, Chang JL, Jahr J. Increased incidence of itching and herpes simplex in patients given epidural morphine after cesarean section. Anesth Analg 1987;66:1321–4 4. Crone LA, Conly JM, Clark KM, Crichlow AC, Wardell GC, Zbitnew A, Rea LM, Cronk SL, Anderson CM, Tan LK. Recurrent herpes simplex virus labialis and the use of epidural morphine in obstetric patients. Anesth Analg 1988;67:318–23 5. Davies PW, Vallejo MC, Shannon KT, Amortegui AJ, Ramanathan S. Oral herpes simplex reactivation after intrathecal morphine: a prospective randomized trial in an obstetric population. Anesth Analg 2005;100:1472–6
A & A case reports
6. Bauchat JR. Focused review: neuraxial morphine and oral herpes reactivation in the obstetric population (focused review). Anesth Analg 2010;111:1238–41 7. Boyle RK. Herpes simplex labialis after epidural or parenteral morphine: a randomized prospective trial in an Australian obstetric population. Anaesth Intensive Care 1995;23:433–7 8. Riley ET, Ross BK XXI. Epidural and spinal analgesia/anesthesia. In: Chestnut DH, ed Chestnut’s Obstetric Anesthesia, Principles and Practice, 3rd ed. Philadelphia, PA: Elsevier Mosby, 2004:360 9. Valley MA, Bourke DL, McKenzie AM. Recurrence of thoracic and labial herpes simplex virus infection in a patient receiving epidural fentanyl. Anesthesiology 1992;76:1056–7 10. Acalovchi I. Herpes simplex after spinal pethidine (correspondence). Anaesthesia 1986;41:1271–2 11. Crone LA, Conly JM, Storgard C, Zbitnew A, Cronk SL, Rea LM, Greer K, Berenbaum E, Tan LK, To T. Herpes labialis in parturients receiving epidural morphine following cesarean section. Anesthesiology 1990;73:208–13
May 1, 2014 • Volume 2 • Number 9
12. Palmer CM, Emerson S, Volgoropolous D, Alves D. Dose-response relationship of intrathecal morphine for postcesarean analgesia. Anesthesiology 1999;90:437–44 13. Palmer CM, Nogami WM, Van Maren G, Alves DM. Postcesarean epidural morphine: a dose-response study. Anesth Analg 2000;90:887–91 14. Boyle RK. A review of anatomical and immunological links between epidural morphine and herpes simplex labialis in obstetric patients. Anaesth Intensive Care 1995;23:425–32 15. American College of Obstetricians and Gynecologists Practice Bulletin No. 82: management of herpes in pregnancy. Obstet Gynecol 2007;109:1489–98 16. Flagg EW, Weinstock H. Incidence of neonatal herpes sim plex virus infections in the United States, 2006. Pediatrics 2011;127:e1–8 17. Whitley RJ, Roizman B. Herpes simplex virus infections. Lancet 2001;357:1513–8 18. Kimberlin D. Herpes simplex virus, meningitis and encephalitis in neonates. Herpes 2004;11 Suppl 2:65A–76A
cases-anesthesia-analgesia.org
105
B
ased on numerous case reports and studies,1–5 the recurrence of oral herpes simplex virus (HSV) is associated with neuraxial morphine after cesarean delivery. While a possible complication of this reactivation is the risk of postpartum viral transmission to the neonate causing major morbidity and mortality, 1 review reported that there was no reported case of neonatal HSV acquired from the mother and concluded that the benefit of neuraxial morphine analgesia still outweighed the risk.6 This report describes a case of a 5-day-old neonate who possibly acquired a localized oral HSV from the mother who had oral HSV reactivation in association with neuraxial morphine. The mother of the patient gave verbal and written permission to publish this report.
CASE DESCRIPTION
The parturient was 37 years old gravida 2, para 1, healthy but with a history of oral HSV with recurrences approximately twice a year. Apart from that, the pregnancy was healthy. There was no reported bleeding, hypertension, diabetes, smoking, alcohol, or recreational drug use during pregnancy. Both the father and mother had no known immunodeficiency history. The medications used during pregnancy were doxylamine succinate and ondansetron. The maternal prenatal workup was negative for infection with chlamydia, HBsAg, varicella, human immunodeficiency virus, and syphillis. She was immune to rubella, and Group B streptococcal status was unknown. The mother reported a history of postpartum oral HSV after a previous otherwise normal pregnancy and cesarean delivery without evidence of postpartum neonatal HSV. From the *Department of Anesthesia, University of Calgary; and †Pediatric Infectious Disease, Alberta Children’s Hospital, Calgary, Alberta, Canada. Accepted for publication November 15, 2013. Funding: None. The authors declare no conflicts of interest. Address correspondence to M. Cecilia De Guzman, MD, Department of Anesthesia, University of Calgary, C229, 1403 29th St., NW, Calgary, Alberta T2N 2T9. Address e-mail to [email protected], and Kaylene Duttchen, MD, BSc (Pharm), FRCP, Department of Anesthesia, University of Calgary, C229, 1403 29th St., NW, Calgary, Alberta T2N 2T9. Address e-mail to [email protected]. Copyright © 2014 International Anesthesia Research Society DOI: 10.1213/XAA.0000000000000013
May 1, 2014 • Volume 2 • Number 9
Delivery for this pregnancy was through elective cesarean delivery under spinal anesthetic at 38 weeks of gestation after spontaneous rupture of membrane. The mother was given spinal hyperbaric bupivacaine 0.75%, 1.3 cc with 15-mcg fentanyl, and 150 mcg morphine. The neonate weighed 2822 g with Apgar scores of 9 and 9 at 1 and 5 minutes, respectively. There was no active oral HSV noted at birth. The mother and neonate were discharged home 30 hours after the procedure. On the third day after delivery, the mother noted HSV lesions around her mouth area for which she took oral valacyclovir. On the fifth day, the mother noted 4 lesions on the baby’s lower lip, with no fever. The baby was immediately brought to the Children’s Hospital where he was found to have 4 vesicular ulcers on the left inner lip. The rest of his examination was normal, and his neurologic examination was unremarkable. The possible differential diagnosis was an inclusion cyst, but given the significant history of maternal oral HSV, a full septic workup and IV acyclovir were initiated within 3 hours of the onset of lesions. All tests were normal including complete blood count and cerebrospinal fluid (CSF) cell count, glucose, and protein. Blood and CSF cultures were negative. CSF gram stain and CSF HSV by polymerase chain reaction were also negative. An HSV sample from an oral lesion was not culturable due to it being planted in inappropriate medium. The baby did well in the hospital, with no signs or symptoms of central nervous system (CNS) or disseminated infection. The infectious disease service advised a 14-day course of IV acyclovir, as CSF HSV polymerase chain reaction was negative. A 6-month prophylactic course of oral acyclovir was also recommended. The oral lesions improved after 1 dose acyclovir and were resolved after 1 week. The baby’s white blood cell count and renal function were monitored for potential side effects from acyclovir with monthly blood work for 6 months.
DISCUSSION
In the last 2 decades, several studies have confirmed an increasing rate of oral HSV reactivation among women receiving neuraxial morphine compared with systemic morphine.3–5,7 Although the benefits of postdelivery analgesia including better maternal comfort and mobility for improved cases-anesthesia-analgesia.org
103
Neonatal HSV from Maternal Recurrence After Spinal Morphine
infant care are clear,6 a theoretical risk of viral transmission from mother to infant is still possible. There was no CNS or multiorgan involvement in this case, but given a different scenario, such as a history of immunodeficiency, delay in treatment, or greater viral load exposure, catastrophic morbidity and mortality are possible. Bauchat,6 in her focused review of neuraxial morphine and oral HSV reactivation in parturients, commented that the maternal benefits of neuraxial analgesia outweigh the risk of neonatal herpes acquired postpartum from maternal recurrence because serious neonatal morbidity and mortality have not been described. There may be more cases that are not reported. This assumed neonatal oral HSV case, likely acquired from the mother who had oral HSV reactivation, was quickly recognized, because the mother is an anesthesiologist who was fully aware of the association between neuraxial opioids and HSV reactivation.
ANESTHETIC IMPLICATIONS
Assuming that maternal HSV reactivation from a neuraxial opioid is a potential risk for neonatal infection leading to major neonatal morbidity and mortality, should we modify our clinical practice? Oral HSV reactivation can be brought about by many factors including exposure to ultraviolet light, fever, stress, or immunosuppressed state such as pregnancy.8 However, there is strong evidence from previous clinical studies of an association between neuraxial opioid use and HSV recurrence. While morphine is the most studied and implicated spinally administered opioid to cause HSV reactivation, epidural fentanyl and spinal meperidine have also been reported in nonparturient patients.9,10 As for HSV reactivation based on route of opioid administration, 2 randomized controlled trials comparing epidural to systemic opioids showed increased HSV reactivation after epidural morphine. Crone et al.11 found the reactivation rate of 14.6% in patients receiving epidural opioids but 0% in patients receiving systemic opioids. Boyle7 reported a reactivation rate of 5.2% in patients receiving epidural opioids and 0.5% in patients receiving systemic opioids. A randomized controlled trial by Davies et al.5 showed that HSV reactivation follows both intrathecal opioids and systemic opioids but more frequently in patients receiving intrathecal opioids. One proposed theory for the mechanism of HSV reativation is that opioids in the CSF trigger the scratch center in the medulla, thereby indirectly reactivating the dormant HSV in the trigeminal nerve via mechanical scratching.5 The relationship between opioid dose and pruritus is also unclear as Palmer et al.12,13 found that there is no dose response in severity of pruritus with epidural morphine, but it is linear with increasing intrathecal doses of morphine. Another theory is through an altered immunologic response where morphine works at a molecular level, causing HSV replication in the trigeminal nerve and deficiency in cell-mediated immunity.14
IMPACT ON CLINICAL PRACTICE
Because of the potential neonatal complications from HSV infection, the following factors should be considered: •
Inclusion of HSV history as part of anesthesia assessment if the anesthetic plan includes neuraxial opioid.
104 cases-anesthesia-analgesia.org
• •
Strict adherence to proper hand hygiene for health care workers and family members in contact with postpartum patients with oral HSV and the newborn.15 Promote further research of hydromorphone, because it is unclear at this time if it has the same risk of oral HSV reactivation as neuraxial morphine.
Neonatal HSV infection is rare, with a national U.S. incidence of 9.6 in 100,000 births,16 but it is a significant cause of death and permanent neurodevelopmental disability in children. Transplacental maternal antibodies possibly reduce if not prevent transmission of HSV. Depending on demographic and social factors, exposure to HSV-1 occurs early in life (on or before 5 years) approximately 70% to 80% of adolescents are exposed, and there is another increase at age 20 to 40 years.17 HSV-1 (orofacial) and HSV-2 (genital) both cause genital and neonatal HSV infection, although genital HSV-1 infection seems to account for 30% to 50% of neonatal infections.16,17 Although most neonatal HSV occurs intrapartum (85%), it can also be acquired in utero (5%) and postnatally (10%) such as during handling of the baby by the mother or caretakers with a cold sore.17 Infection is symptomatic with high mortality (85%).18 Disease can be localized to the skin, eye, and mouth (SEM disease), can involve the CNS, or can manifest as disseminated infection involving multiple organs.18 In the absence of antiviral therapy, neurological impairment among these 3 disease categories is very high (38%–67%), and the mortality rate is as high as 85% for babies with disseminated infection.18 Even with active treatment, morbidity and mortality remain high. Only 40% and 60% of babies develop normally after encephalitis and disseminated disease, respectively.17 Thus, intervention to prevent neonatal HSV infection, early recognition, and treatment are essential in decreasing both mortality and neurological sequelae in surviving infants.
CONCLUSION
In summary, we describe a possible case of vertical transmission of oral HSV after the mother had presumed reactivation of oral HSV after receiving intrathecal morphine along with spinal anesthesia for cesarean delivery. We suggest inclusion of maternal HSV in the anesthetic assessment and counseling patients who have a history of oral HSV regarding possible antiviral prophylaxis treatment if an oral lesion occurs. E REFERENCES 1. Cardan E. Herpes simplex after spinal morphine. Anaesthesia 1984;39:938 2. Douglas MJ, McMorland GH. Possible association of herpes simplex type I reactivation with epidural morphine administration. Can J Anaesth 1987;34:426–7 3. Gieraerts R, Navalgund A, Vaes L, Soetens M, Chang JL, Jahr J. Increased incidence of itching and herpes simplex in patients given epidural morphine after cesarean section. Anesth Analg 1987;66:1321–4 4. Crone LA, Conly JM, Clark KM, Crichlow AC, Wardell GC, Zbitnew A, Rea LM, Cronk SL, Anderson CM, Tan LK. Recurrent herpes simplex virus labialis and the use of epidural morphine in obstetric patients. Anesth Analg 1988;67:318–23 5. Davies PW, Vallejo MC, Shannon KT, Amortegui AJ, Ramanathan S. Oral herpes simplex reactivation after intrathecal morphine: a prospective randomized trial in an obstetric population. Anesth Analg 2005;100:1472–6
A & A case reports
6. Bauchat JR. Focused review: neuraxial morphine and oral herpes reactivation in the obstetric population (focused review). Anesth Analg 2010;111:1238–41 7. Boyle RK. Herpes simplex labialis after epidural or parenteral morphine: a randomized prospective trial in an Australian obstetric population. Anaesth Intensive Care 1995;23:433–7 8. Riley ET, Ross BK XXI. Epidural and spinal analgesia/anesthesia. In: Chestnut DH, ed Chestnut’s Obstetric Anesthesia, Principles and Practice, 3rd ed. Philadelphia, PA: Elsevier Mosby, 2004:360 9. Valley MA, Bourke DL, McKenzie AM. Recurrence of thoracic and labial herpes simplex virus infection in a patient receiving epidural fentanyl. Anesthesiology 1992;76:1056–7 10. Acalovchi I. Herpes simplex after spinal pethidine (correspondence). Anaesthesia 1986;41:1271–2 11. Crone LA, Conly JM, Storgard C, Zbitnew A, Cronk SL, Rea LM, Greer K, Berenbaum E, Tan LK, To T. Herpes labialis in parturients receiving epidural morphine following cesarean section. Anesthesiology 1990;73:208–13
May 1, 2014 • Volume 2 • Number 9
12. Palmer CM, Emerson S, Volgoropolous D, Alves D. Dose-response relationship of intrathecal morphine for postcesarean analgesia. Anesthesiology 1999;90:437–44 13. Palmer CM, Nogami WM, Van Maren G, Alves DM. Postcesarean epidural morphine: a dose-response study. Anesth Analg 2000;90:887–91 14. Boyle RK. A review of anatomical and immunological links between epidural morphine and herpes simplex labialis in obstetric patients. Anaesth Intensive Care 1995;23:425–32 15. American College of Obstetricians and Gynecologists Practice Bulletin No. 82: management of herpes in pregnancy. Obstet Gynecol 2007;109:1489–98 16. Flagg EW, Weinstock H. Incidence of neonatal herpes sim plex virus infections in the United States, 2006. Pediatrics 2011;127:e1–8 17. Whitley RJ, Roizman B. Herpes simplex virus infections. Lancet 2001;357:1513–8 18. Kimberlin D. Herpes simplex virus, meningitis and encephalitis in neonates. Herpes 2004;11 Suppl 2:65A–76A
cases-anesthesia-analgesia.org
105
