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FOCUSED REVIEW Neuraxial Morphine and Oral Herpes Reactivation in the Obstetric Population Jeanette R. Bauchat, MD

FOCUSED REVIEW

Neuraxial Morphine and Oral Herpes Reactivation in the Obstetric Population

Jeanette R. Bauchat, MD

Neuraxial morphine administration is a common strategy for providing postcesarean delivery analgesia. Morphine delivered via this route increases the risk of herpes labialis (oral herpes) reactivation, a disease common in women of childbearing age. A primary concern is risk of transmission to the neonate from maternal reactivation. The benefits to the mother of this form of analgesia outweigh the risk of neonatal herpes acquired postpartum from maternal recurrence because serious neonatal morbidity from recurrent herpes has not been described. (Anesth Analg 2010;111:1238 –41)

A dministration of neuraxial morphine for postcesar- ean delivery analgesia increases the risk for herpes labialis reactivation (oral herpes). The prevalence

of herpes labialis in women of childbearing age ranges from 56% to 73%. 1 Thirty-three percent of women in the United States have a cesarean delivery. Neuraxial mor- phine, as part of a multimodal postoperative analgesic regimen, is one of the most widely used and effective methods of providing pain relief. 2 6 This focused review describes the pathophysiology and prevalence of herpes simplex virus (HSV), the evidence supporting the link between neuraxial opioids and increased HSV-1 reactiva- tion rates, and the risk to the fetus of maternal HSV reactivation in the postpartum period. Postulated mecha- nisms for this association are also briefly discussed.

HSV PATHOPHYSIOLOGY

The prevalence of HSV-1 is 68% in the United States (age 12 years) but varies with age, gender, socioeconomic status, sexual activity, and geographic location. 1,7 Primary infection with HSV-1 may present in infancy. The preva- lence reaches 27% by age 4 years, and continues to increase with age. 8,9 HSV causes lifelong infection in its host be- cause of its ability to travel retrograde via sensory nerves from infected tissues to the sensory nerve root ganglia, where it remains latent. 10 Primary HSV infection typically presents with malaise and myalgia, as well as pain, itching, and burning at the site of oral vesicular lesions. Young children are more likely to have asymptomatic primary infections. 7,11 Reactivation oc- curs with triggers such as fever, trauma, fatigue, emotional stress, common cold, ultraviolet light, and pregnancy. 7 Symptoms during reactivation tend to be milder with a prodrome of tingling, itching, paresthesia, and pain around the site of primary infection, but viral shedding can occur in the absence of symptoms. 12,13 Although HSV-1 typically affects the oral mucosa and HSV-2 typically affects the genital mucosa, the epidemiology of HSV infection is

From the Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Accepted for publication July 27, 2010. Disclosure: The author reports no conflicts of interest.

Address correspondence and reprint requests to Jeanette R. Bauchat, MD, Northwestern University Feinberg School of Medicine, 251 E. Huron St., F5-704, Chicago, IL 60611. Address e-mail to jbauchat@gmail.com.

Copyright © 2010 International Anesthesia Research Society

DOI: 10.1213/ANE.0b013e3181f57c30

changing. HSV-1 currently accounts for 78% of new cases of genital herpes in college-age women in the United States. 14 The true prevalence of oral lesions caused by HSV-2 is unknown. It is believed to be rare, acquired through sexual contact, and activated in the setting of a primary infection or recurrence of HSV-2 genital herpes. 15 HSV infection can be diagnosed by sending vesicular fluid for culture or viral polymerase chain reaction but accurate results are dependent on collection technique. 16 Serologic testing for HSV antibodies can distinguish HSV-1 from HSV-2, and helps to determine exposure history in the absence of active infection. However, serologic testing cannot identify site of infection. 16

HSV REACTIVATION AFTER NEURAXIAL MORPHINE FOR CESAREAN DELIVERY ANALGESIA

As the use of neuraxial morphine for postcesarean analgesia increased throughout the 1980s, case reports and letters to the editor suggesting a link between neuraxial morphine and reactivation of herpes labialis began appearing in the litera- ture. 1724 These reports were followed by retrospective and prospective trials that confirmed an increased rate of oral HSV reactivation among women receiving neuraxial morphine as compared with systemic morphine for postcesarean delivery analgesia. These studies are summarized in Table 1. The first prospective trial specifically addressing neuraxial morphine and HSV reactivation rates was con- ducted by Gieraerts et al. 25 Patients receiving epidural morphine for postcesarean delivery analgesia demon- strated a higher rate of reactivation than those receiving systemic morphine. The small number of patients in the trial and low baseline prevalence of HSV infection made it difficult to assess the true risk of HSV reactivation from epidural morphine. Fuller et al. 26 conducted a large, retrospective chart review of 4880 obstetric women who received epidural morphine after cesarean delivery. They reported that 3.5% of patients had a recurrence of herpes labialis. The low recurrence rate was likely in part attributable to the biases of retrospective studies such as lack of reporting or documentation. In 2 randomized controlled trials comparing epidural to systemic opioid analgesia, Crone et al. 27 and Boyle 28 con- firmed the previous findings of increased HSV reactivation after epidural morphine. Crone et al. found a reactivation rate of 14.6% in patients receiving epidural opioids, but 0% in patients receiving systemic opioids. Boyle reported a

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FOCUSED REVIEW Neuraxial Morphine and Oral Herpes Reactivation in the Obstetric Population Jeanette R. Bauchat, MD

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Neuraxial Morphine Herpes Reactivation

     
 

Table 1. Retrospective and Prospective Trials that Confirmed an Increased Rate of Oral Herpes Simplex Virus Reactivation Among Women Receiving Neuraxial Morphine as Compared with Systemic Morphine for Postcesarean Delivery Analgesia

 

HSV

 

HSV

reactivation

Study

Study design

No. of patients

prevalence (%)

Opioid dose

rate (%)

Gieraerts et al., 23 1987

Case-matched

Epidural morphine, n 26

39.1% a

Epidural morphine 3.5–5 mg q

35%

prospective trial

12 h prn

 

IM morphine, n 18

16.7%

IM morphine 10 mg to comfort then q 6 h prn

0%

Fuller et al., 26 1990

Retrospective

Epidural morphine, n 4880

Unknown

Epidural morphine 2–5 mg 1

3.5%

chart review

Crone et al., 27 1990

Randomized

Epidural morphine, n 96

64.6% b

Epidural morphine 4 or 5 mg,

14.6%*

controlled trial

1 dose

 

IM opioid, n 91

62.6%

IM meperidine 50–100 mg or IM morphine 7.5–10 mg

0%

Norris et al., 29 1994

Prospective cohort

Epidural morphine, n 48;

28.9% a

Epidural morphine 3–5 mg, 1

3.5%

trial

spinal morphine, n 153

dose; spinal morphine 0.15–0.25 mg, 1 dose

 

Systemic opioids, n 156

36.5%

Unspecified

2.6%

Boyle, 28 1995

Randomized

Epidural morphine, n 425

28% a

Unspecified

5.2%*

controlled trial

Parenteral morphine, n 386

30%

Unspecified

0.5%

Davies et al., 30 2005

Randomized

Spinal and PCIA morphine, n 50

66% b

Spinal morphine 0.25 mg and

38%*

controlled trial

IV morphine 1 mg q 6 min

 

PCIA morphine, n 48

77%

IV morphine 4 mg loading 1 mg q 6 min

16.6%

HSV herpes simplex virus; PCIA patient-controlled IV analgesia; q every; prn pro re nata (as needed). a HSV prevalence obtained by patient history. b HSV prevalence obtained by serologic testing. * P 0.05.

reaction rate of 5.2% in patients receiving epidural opioids, but only 0.5% in patients receiving systemic opioids. The different reactivation rates reported in these 2 studies was likely influenced by underlying prevalence of HSV in their patient populations. However, because they used different methods of assessing underlying prevalence, it is difficult to compare the reactivation rates directly. Patients in the Crone et al. 27 trial received 4 or 5 mg epidural morphine. The dose of epidural morphine used in the Boyle trial was not reported. 28 In contrast to previous findings, Norris et al. 29 found no increased incidence of herpes labialis in women receiving neuraxial morphine compared with systemic analgesia. How- ever, the majority of patients in the neuraxial morphine group received spinal morphine. It was unclear whether the low rate of reactivation and lack of difference between groups was a result of intrathecal morphine use, low baseline rate of HSV infection (9%), or inadequate study power. To clarify whether intrathecal morphine specifically increased the risk of reactivation versus systemic opioids, Davies et al. 30 designed a randomized controlled trial that included women with a reported history of HSV-1 sched- uled for elective cesarean delivery under spinal anesthesia. This trial confirmed an increased risk of reactivation with intrathecal morphine. Unlike the previous trials, in which the risk of postpartum herpes labialis in the control group was very low (0%–3%), these investigators demonstrated a 17% rate in women who received systemic analgesia, suggesting that other perioperative and peripartum factors may also influence reactivation in this “at-risk” population. Taken together, these trials show an increased risk of oral herpes reactivation in women receiving neuraxial morphine for postcesarean delivery analgesia compared

with systemic analgesia. There are no randomized con- trolled trials demonstrating whether HSV reactivation risk is increased after other neuraxial opioids. It is important to note that 72% to 86% of women with a history of herpes labialis who received neuraxial morphine did not have a recurrence. However, clinicians are understandably con- cerned about the risk of HSV transmission to the neonate whose mother has a recurrence. 27,28,30

NEONATAL HERPES

In pregnancy, primary maternal HSV infection presents pro- found risks to the fetus. HSV infection is among the congeni- tally acquired infections that lead to severe fetal anomalies and fetal loss in utero. Neonatal herpes infections acquired peripartum are rare, with an incidence estimated from 8 to 60 cases per 100,000 live births. They can cause skin, eye, and mouth disease, encephalitis, or disseminated infection. 31,32 Disseminated infection is exceedingly rare but can lead to cognitive impairment, severe neurological disease, and organ dysfunction. Mortality reaches 31% even with prompt admin- istration of antiviral treatment to the infant. 32 In the United States, 60% to 80% of acquired neonatal herpes infections result from mothers who have a primary HSV infection during the third trimester of pregnancy and shed HSV subclinically in the genital tract. 16,31,33 Neonatal herpes can be transmitted postpartum from the mother, family members, or hospital personnel with active herpes labialis. However, this route of transmission accounts for only 10% of cases of neonatal herpes. 34 Latent maternal HSV infection confers immunity to offspring via HSV immunoglobulin G antibodies transmitted transpla- centally. The higher the neonate’s neutralizing antibody

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Neuraxial Morphine Herpes Reactivation Table 1. Retrospective and Prospective Trials that Confirmed an Increased Rate of
FOCUSED REVIEW titer, the lower the incidence of neonatal herpes transmis- sion and severity of the

FOCUSED REVIEW

titer, the lower the incidence of neonatal herpes transmis- sion and severity of the disease. 3537 Maternal HSV immu- noglobulin G antibodies provide incomplete protection, however, and titers rapidly decrease in the first year of life. 9 It is reassuring that neonates of mothers with a known history of herpes labialis are unlikely to acquire neonatal herpes from maternal reactivation postpartum and if they did, they would have a mild form of the disease. 31,35 Currently, there are no reports in the literature of neonatal herpes contracted postpartum from maternal herpes labia- lis reactivation after neuraxial morphine administration. To minimize the risk of neonatal transmission, prompt treatment of maternal herpes labialis with topical antiviral creams or oral antiviral therapy should be considered to reduce the severity and length of infection. All caregivers and family members who have symptoms of herpes labialis should be educated on measures (i.e., refrain from kissing, frequent hand washing) to minimize transmission to the newborn. Given the low risk of HSV reactivation using neuraxial morphine and even smaller risk of postpartum transmission to the neonate, withholding neuraxial mor- phine, a highly effective analgesic technique for postcesar- ean delivery pain, is not supported by medical evidence.

POSTULATED MECHANISMS FOR HSV REACTIVATION WITH NEURAXIAL MORPHINE

The cellular and molecular mechanisms for HSV reactivation, independent of neuraxial morphine administration, are not clearly understood and are currently under investigation. The most frequently postulated, but unproven, mechanism for HSV reactivation is that irritation from facial scratching due to neuraxial opioid-induced pruritus (incidence ranging from 48% to 81%) leads to reactivation. 2527 The mechanism for opioid-induced pruritus is also not fully elucidated, but seems to be mediated primarily via direct or indirect activation of central nervous system -opioid receptors, a high density of which are expressed in the trigeminal nerve. 38,39 A dose- response study using epidural morphine (1.5–5 mg) demon- strated no dose response in severity of pruritus. Thus, if reactivation rates correlate with rates or severity of pruritus, reducing the epidural morphine doses would not be expected to be of benefit. 40 In contrast to epidural morphine, the severity of pruritus escalates with increasing doses of intra- thecal morphine (0.025– 0.5 mg) despite an analgesic ceiling effect at 0.1 mg morphine. 41,42 Therefore, the lowest effective analgesic dose of intrathecal morphine should be used to reduce pruritus if for no other reason than maternal comfort. 43 Although it may seem intuitive, there is no evidence that pruritus from neuraxial morphine actually has a role in HSV reactivation and this mechanism remains speculative. Boyle, after correcting for history of HSV and exposure to epidural morphine, did not demonstrate an association between pru- ritus and HSV reactivation. 28 Both trials using intrathecal morphine for postcesarean delivery analgesia demonstrated more frequent and severe pruritus in the intrathecal group, but there was no association between pruritus and HSV reactivation after correcting for a history of herpes labialis. 29,30 Given the lack of evidence that pruritus is the mechanism by which HSV is reactivated in women receiving neuraxial morphine for postcesarean analgesia, recommendations for

avoidance of facial scratching or aggressive treatment of pruritus cannot be advocated except for maternal comfort. There is more compelling evidence that HSV reactivation may be attributable to disruption of the molecular mecha- nisms promoting a balance between viral transcription and host immunity in the central nervous system that normally work to maintain HSV latency. 44 The HSV virus causes C fibers to release the neuropeptide calcitonin gene-related peptide, which prevents immune cells in the skin from maturing and destroying the virus. 10 Once inside the C fibers, the virus travels retrograde into the cell body where latency- associated transcript RNA and immediate early (IE) gene transcripts maintain latency. 10 Some IE gene transcripts in- hibit the display of human leukocyte antigen class I molecules on the cell surface, effectively evading the immune system. 10 CD8 T cells kill trigeminal neurons that are actively infected with virus. 45 These T cells may promote HSV latency by maintaining a noncytotoxic phase in response to low levels of IE viral proteins, thus preventing reactivation but not destroy- ing latently infected trigeminal neurons. 45 Trigger factors for HSV reactivation such as pregnancy, surgery, and acute morphine administration are well known, but the cellular and molecular mechanisms by which cellular immunity and viral latency are disrupted continue to be studied. 46 Catecholamines, glucocorticoids, and cytokines re- leased during stress-related states appear to activate intracel- lular pathways that promote HSV viral transcription. 46 Acute morphine administration can alter the immune response by suppressing interleukins and cytokines making cells more susceptible to HSV infection. 45 Activated T cells express -, -, and -opioid receptors and their populations are altered by exposure to morphine. 47 Altered opioid receptor expression may contribute to increased susceptibility to and reactivation of HSV-1 in mouse models after acute morphine administra- tion. 48 50 Knowledge of the molecular mechanisms control- ling the balance between HSV latency and active infection and its interconnection with CD8 T cell immunity is rapidly increasing, but a thorough discussion of this topic is outside the scope of this review.

CONCLUSIONS

Herpes labialis is common in women of childbearing age. Despite this, the majority of mothers receiving neuraxial morphine for postcesarean delivery analgesia will not have an HSV reactivation. The benefits of adequate analgesia for the mother include comfort, increased mobility, and im- proved infant care. Withholding this clinically beneficial, cost-effective analgesic technique to reduce maternal HSV reactivation or further minimize the remote possibility of transmitting HSV to the neonate is not supported by medical evidence.

FOCUSED REVIEW titer, the lower the incidence of neonatal herpes transmis- sion and severity of the

AUTHOR CONTRIBUTIONS

JRB helped write the manuscript and approved the final manuscript.

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Neuraxial Morphine Herpes Reactivation 3. Wu CL, Cohen SR, Richman JM, Rowlingson AJ, Courpas GE, Cheung