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The incidence of herpes simplex virus labialis after cesarean delivery
Q 1994 Longman
Group
Ltd
International Journal of Obstetric Anesthesia
The incidence of herpes simplex virus labialis after cesarean delivery M. C. Norris, J. Weiss, M. Carney, B. L. Leighton Department qf’ Anesthesiology, JefSerson Medical College, Thomas Jqferson University. Philadelphiu. PA SUMMA R Y. Epidural and subaracbnoid opioids have been associated with the development of oral herpes simplex lesions. Because of this risk, some anesthesiologists avoid neuraxial morphine in parturients with a history of herpes simplex virus labialis. When we began using neuraxial opioids for analgesia after cesarean delivery, we did not see any increased incidence of facial lesions. To confirm this impression, we studied 357 consecutive parturients presenting for elective or emergent cesarean delivery between 1 December 1989 and 27 June 1990. The women received spinal, epidural, or general anesthesia. Two hundred and one women received either spinal or epidural morphine, the remaining 156 parturients received only systemic opioids for postoperative analgesia. An investigator saw each patient daily until discharge. Only 11 patients (3%) developed oral lesions while hospitalized. None of these women had severe lesions. Neuraxial morphine did not increase the risk of labial lesions significantly (3.5% vs. 2.6%). Despite published data to the contrary, we found no correlation between neuraxial morphine and the risk of facial herpes virus lesions in women after cesarean delivery. We offer patients the option of neuraxial morphine for analgesia after cesarean delivery despite any history of oral herpes lesions.
Recently, three studies have reported an increased incidence of recurrent oral herpes simplex viral lesions in patients receiving epidural morphine for post cesarean section analgesia.‘-3 Some anesthesiologists recommend avoiding this modality in parturients with a history of ‘more sinister’ herpes virus infections.4 Others, however report their impression that intrathecal morphine does not increase the risk of oral herpes eruptions. ’ In our clinical experience, we saw no increased incidence of oral herpes lesions in parturients receiving neuraxial morphine. To shed more light on this issue, we completed this prospective study of the risk of oral herpes lesions in parturients after cesarean delivery.
receive spinal. epidural. or general anesthesia. Some patients also received spinal (0.15-0.25 mg) or epidural(3-5 mg) morphine for postoperative analgesia. The choice of anesthesia and the decision to use neuraxial opioids were made by the supervising anesthesiologist, independent of this study. All spinal anesthetics were done with 12-15 mg hyperbaric 0.75% bupivacaine. Labor epidural anesthetics were usually begun with lo-15 ml 0.25% bupivacaine, with or without 5 pg/ml fentanyl. We maintained analgesia with either intermittent 10 ml bolus injections of 0.25% bupivacaine or a continuous infusion of dilute bupivacaine (O.OS?G)mixed with I .45 pg/ml fentanyl and I:700 000 epinephrine. At cesarean delivery, we raised the level of block with either 0.5% bupivacaine, 2% lidocaine with epinephrine or 3% chloroprocaine. Additional epidural fentanyl (50-100 pg) was sometimes added to the lidocaine or bupivacaine. We induced general anesthesia with 3-5 mg/kg thiopental or 1 mg/kg ketamine and used l-l.5 mg/kg succinylchloline to facilitate intubation. Before delivery, we maintained anesthesia with 50% nitrous oxide in oxygen and 0.4-0.8X isoflurane. After delivery, we increased delivered concentration of nitrous oxide to 70% and added intravenous fentanyl or morphine. At surgery, we recorded demographic characteristics, the indication for operation, the type of anesthetic and all drugs given via the neuraxial route.
MATERIALS AND METHODS Between 1 December 1989 and 27 June 1990, 357 consecutive parturients presenting for elective or emergent cesarean delivery gave oral consent and participated in this institutional review board approved protocol. No eligible patient refused to participate in this study. As determined by patient preference and the clinical situation, the women Correspondence Anesthesiology. 19107, USA.
to Mark C. Norris MD, Department Thomas Jefferson University. Philadelphia.
of PA
137
128 International Journal of Obstetric Anesthesia
After surgery, we saw all patients daily until discharge (4-5 days). At the first postoperative visit, we asked about the occurrence of facial itching after delivery and any history of cold sores. On all days, we asked about developing cold sores. We used analysis of variance to examine the demographic characteristics of our patients. The Mann-Whitney U test and the x2 test compared the groups for itching, facial itching, indication for cesarean delivery, use of neuraxial epinephrine and recurrent oral lesions. PcO.05 was considered significant.
RESULTS We enrolled 357 parturients in this investigation. The demographic data are shown in Table 1. Two hundred and one women received neuraxial morphine while 156 did not. Figure 1 shows the distribution of anesthetics. Two hundred and twenty seven women received a single anesthetic, either general (n =27), Table 1. Demographics.
All values are mean + SD
Group
No neuraxial morphine (n=156)
Neuraxial morphine (n=201)
Age (years) Height (cm) Weight (kg) Race (black/white/other) Hx oral lesions (n = 115) Primary C/S (n = 248) Repeat C/S (n = 109) Elective C/S (n = 154) Non-elective C/S (n = 203)
28.6k6.7 162.3k7.3 82.3 + 18.2 6818018 57 127 29 40 116
30.2k5.8 162.7k7.3 81.5+ 17.5 72112019 58 121 80* 114* 87
*Patients having repeat or elective cesarean deliveries were more likely to receive neuraxial morphine than those having primary or non-elective operations (P
spinal (n = 196) or epidural (n = 104). The remaining 30 women received more than one anesthetic. Twentytwo had a functioning labor epidural that was converted to either spinal or general anesthesia at the time of surgery. Eight patients initially received a spinal anesthetic that proved inadequate for surgery. Eleven patients developed oral cold sores during their hospitalization (Table 2). Eight reported a history of facial lesions while 3 denied previous cold sores. None developed severe lesions. The patients receiving neuraxial morphine had a 3.5% (95% confidence interval (CI): 1.O%-6.0%) incidence of oral lesions (7/201). In those not receiving neuraxial morphine, the incidence was 2.6% (95% CI: 0.1%5.1%) (4/156) (P=O.85 vs. morphine). Of the women receiving general anesthesia, 2/27 (7.4%) (95% CI: 0%17.3%) developed facial lesions. Two of the 104 ( 1.9O/) (95% CI: 0%4.5%) women receiving epidural anesthesia developed lesions. One received epidural morphine, one did not. Six of the 196 (3.1%) (95% CI: 0.7%5.5%) women receiving spinal anesthesia developed cold sores. All 6 received spinal morphine (P=O.35 vs. no morphine). Table 3 shows the results of other pertinent comparisons. Among women who did not receive neuraxial morphine, only those with a history of cold sores developed cold sores after cesarean delivery (P= 0.017). The type of cesarean delivery (primary/repeat, elective/non-elective) did not correlate with the incidence of facial lesions. Demographics (age, height, weight, race, gravidity, parity) did not correlate with facial lesions. Women reporting a history of cold sores were more likely to develop lesions after cesarean delivery (P = 0.01). Patients who received neuraxial morphine had an increased incidence of both generalized and facial itching (P
n
148
T
Morphine (n=201) No Morphine (n=156)
0 General
Spinal
Epidural
EpidBpinal
Epid/GA
Spinal/GA
Epid/Sp/GA
Type of Anesthetic Fig. l-Distribution of anesthetic type. 227 women received a single anesthetic, while 30 received multiple anesthetics. The different bars show the distribution of the use of neuraxial morphine within the anesthetic groups.
The incidence
of herpes simplex virus labialis
after cesarean
delivery
129
Table 2. Characteristics of 11 women with oral lesions after cesarean delivery Pt
Hx cold sores
Neuraxial morphine
Anesthetic
Race
Type of delivery
Neuraxial drugs
Generalized itching
Epidural
Black Black
General
White
Bupivacaine. fentanyl Bupivacaine. morphine None
None
Spinal
Non-elective /primary Elective /repeat Non-electwe /primary Non-elective /primary Elective /primary Non-elective /primary Non-elective /primary
Bupivacaine. morphine Bupivacaine, morphine Bupivacaine. morphine Bupivacaine. fentanyl. lidocaine, morphine Bupivacaine. fentanyl Bupivacaine. morphine None
Severe
Bupivacaine. morphine
Mild
40
> I/years
80
$ l/years
104
5 I/years
116
None
0.15 mg
Spinal
Black
I19
None
0.15 mg
Spinal
White
120
None
0.15 mg
Spinal
White
181
> I/years
3.5 mg
Epidural
White
186
5 I!years
Other
192
2 I/years
0.15 mg
Epid/Spinal! GA Spinal
197
5 l/years
General
White
226
2 l/years
Spinal
White
0.15 mg
0.15 mg
Black
Table 3. Results Independent
variable
History cold sores Primary vs. repeat operation Elective vs. non-elective operation Type of anesthetic + Neuraxial morphine k Neuraxial morphine + Neuraxial morphine f Neuraxial epinephrine + Neuraxial epinephrine f Neuraxial epinephrine Generalized itching Facial itching
Dependent
variable
P Value
Cold sores Cold sores
0.01 0.57
Cold sores
0.88
Cold sores Generalized itching Facial itching Cold sores Generalized itching Facial itching Cold sores Cold sores Cold sores
0.41 c 0.000 I <0.0001 0.85 0.0081 0.002 0.27 0.52 0.07
itching (P= 0.52), nor facial itching (P=O.O7) correlated with oral lesions. Patients who received epidural epinephrine also had more itching than those who did not. Epinephrine use correlated strongly with morphine use (P= 0.0005). When the analysis was controlled for morphine, epinephrine had no effect on the incidence or severity of generalized or facial itching.
DISCUSSION
Oral herpes simplex infection is ubiquitous. Forty to 50% of adult patients will report a history of cold sores and up to 90% have antibodies to the infective agent, HSV-1.6 Reactivation of herpetic lesions may follow a variety of stresses. Some of these events include: sunburn, infection, trauma, immunosupression and emotional stress.’ Recently, three published
Non-elective /primary Elective /primary Non-elective/ primary Elective /repeat
Mild
Facial itching
+
None -t
None Mild
-t
Mild
+
None Severe None
studies also have suggested that epidural morphine after cesarean delivery could increase the incidence of recurrent oral iesions.1m3 These authors report a 9.7-34.6% incidence of cold sores in women receiving epidural morphine. In contrast, 0-l .5% of patients not receiving epidural morphine after cesarean delivery develop cold sores. In addition, isolated case reports claim a link between intrdthecal morphine,” or epidural fentanyl,’ and herpetic facial lesions. These data suggest that neuraxial morphine could either directly or indirectly promote reactivation of latent herpes simplex virus (HSV ). The most widely held theory suggests that morphine-induced facial pruritus begins a series of events that culminates in the appearance of recurrent cold sores.3,s In our study, 72% of women who received neuraxial morphine complained of generalized itching and 51% noted facial itching. Six of the 7 women in the morphine group who developed cold sores reported facial itching. None of the 4 women who did not receive morphine but developed cold sores had facial itching. Our data are consistent with the suggestion that facial itching related to neuraxial morphine may incite some recurrent oral lesions after cesarean delivery. Not all patients who developed lesions itched, however. Other mechanisms may be involved in inciting facial lesions in these women. In our study, epidural or intrathecal morphine did not significantly increase the risk of cold sores. Of our patients who received neuraxial morphine, only 3.5%~ developed cold sores compared to 2.6% of women who did not receive neuraxial morphine. These data do not prove that neuraxial opioids do not increase the risk of recurrent oral herpes simplex
130
International
Journal
of Obstetric
Anesthesia
lesions. In our population, power analysis suggests that such a study would require over 1100 patients in each group. lo These data do, however, show that, in our patient population, any increased risk of recurrent oral lesions conferred by neuraxial opioids is far smaller than previously reported and is not clinically significant. Several differences exist between our study and the ones mentioned above that may explain these discrepant findings. Firstly, the studies by Crone et a1,‘q3and Gieraerts et al,’ focused exclusively on epidural morphine. Most of our patients received spinal anesthesia for their cesarean delivery. A single case report has been published of a woman who suffered severe recurrent facial lesions after 1.5 mg of intrathecal morphine.8 Abouleish reports: ‘. . . we have used 0.2 mg ITM (intrathecal morphine) in thousands of cases with cesarean sections, (and) herpes simplex eruption has not occurred.‘5 Six women in our spinal anesthesia group (n= 148) developed facial lesions and all received intrathecal morphine. None of the women in the spinal group not receiving intrathecal morphine (n=48) developed cold sores. This trend, while suggestive, did not achieve statistical significance. If this difference were to persist in a larger study, it would attain statistical significance. However, a 4.1% (95% CI: 0.8-7.3%) incidence of facial lesions does not represent a clinically significant problem considering the 3.1% background incidence of facial lesions in our population. Secondly, in two of the studies reporting a strong correlation between epidural morphine and recurrent cold sores, all women received epinephrine-containing local anesthetics. In some reports, epinephrine appears to increase the severity of neuraxial morphineinduced pruritus. “J Crone et al also postulated that epinephrine may combine with morphine to induce reactivation and mobilization of latent virus in the spinal nucleus of the trigeminal nerve. Sixty-one of our patients received epidural epinephrine at some time during parturition. While the use of epinephrine correlated with the incidence and severity of itching, it also correlated with the use of neuraxial morphine. Epinephrine alone did not cause appreciable itching, nor did epinephrine increase the frequency or severity of itching associated with morphine. Note, however, that only 18 of the women in our study received both epidural morphine and epinephrine. Thus, any negative conclusion we might draw from these data is weak. Even in the subgroup of women receiving epidural anesthesia, our results differ from those reported earlier. Our series contains over 100 women receiving epidural anesthesia for cesarean delivery (40 with morphine, 64 without). Only 2 developed cold sores, one in each group. If we were to repeat this study, we would expect at most (upper 95% confidence limit) that 4.7% of women receiving epidural mor-
phine would develop cold sores. In contrast, Gieraerts et al,’ reported a 34.6% (95% CI: 15.9%52.3%) risk of cold sores after epidural morphine. Similarly Crone et al reported a 14.6% (95% CI: 7.5%21.7%) incidence of herpes labialis after epidural morphine.3 Thus, though only a portion of our patients received epidural morphine, the incidence of cold sores associated with epidural morphine in that subset is clearly lower than the incidence reported by others. Epidemiological factors may explain some differences between the reported studies and our data. Crone and colleagues studied the incidence of oral herpes lesions after uncomplicated vaginal or cesarean birth in women living in Saskatoon, Canada. Four percent of vaginal delivery patients and 9.6% of cesarean delivery patients developed oral lesions within 5 days of delivery. In contrast, only 3.1% of our patients developed cold sores after cesarean delivery. Differences in the prevalence of infection, virulence of viral strain or the presence and potency of factors that stimulate recurrence could account for the higher incidence of oral lesions in some populations. Survey data suggest that regional differences do exist in the frequency of herpes labialis recurrences. For example, the ‘lifetime prevalence’ (2 or more occurrences of lesions) of oral herpes labialis ranges from 14.4% in South America to 37.4% in North America.i3 In conclusion, while our study cannot prove that neuraxial opioids lack influence on the risk of recurrent oral herpes lesions, it does show that, in our patient population, neuraxial opioids are not associated with a clinically significant increase in the risk of facial lesions. In our practice, parturients with a history of cold sores can receive spinal or epidural morphine for post cesarean section analgesia without significantly increased risk of developing cold sores. However, because neuraxial morphine clearly increases the risk of HSV lesions in some populations, others should make this decision based on their clinical experience. References 1. Gieraerts R, Navalgund A, Vaes L, Soetens M, Chang J-L, Jahr J. Increased incidence of itching and herpes simplex in patients given epidural morphine after cesarean section. Anesth Analg 1987; 66: 1321-1324. 2. Crone L-A L, Conly J M, Clark K M et al. Recurrent herpes simplex virus labialis and the use of epidural morphine in obstetric patients. Anesth Analg 1988; 67: 3 18-323. 3. Crone L-A L, Conly J M, Storgard C et al. Hepers labialis in parturients receiving epidural morphine following cesarean section. Anesthesiology 1990; 73: 208-213. 4. Beriault M. Herpes virus infections and intraspinal opioids (letter). Anesthesiology 1991; 74: 199. 5. Abouleish E A. Intrathecal morphine as a cause for herpes simplex should be scratched out (letter). Anesthesiology 1991; 75: 919.
The incidence 6. Nahmias A J, Keyserling H, Lee F K. Herpes simplex viruses 1 and 2. In: Evans A S, ed. Viral infections of humans, 3rd Edn. New York: Plenum Medical Book Company. 1989; pp 3933417. Fiumara N J. Herpes simplex. Clinics in dermatology 1989; 7: 23336. Pennant J H, Wallace D. lntrathecal morphine and reactivation of oral herpes simplex. Anesthesiology 1991; 75: 167. Valley M A. Bourke D L. McKenzie A M. Recurrence of thoracic and labial herpes simplex virus infection in a patient receiving epidural fentanyl. Anesthesiology 1992; 76: 1056-1057. Schlesselman J J. Case-control studies: design,
of herpes simplex virus labialis
after cesarean
delivery
conduct, analysis. New York: Oxford University Press, 1982; p 145. II. Bromage P R, Camporesi E M, Duran P A, Nielsen C H. Influence of epinephrine as an adjuvant to epidural morphine. Anesthesiology 1983; 58: 2577262. 1’. Douglas M J. Ross P L E, McMorland G H. The etfect of epinephrine in local anaesthetic on epidural morphine-induced pruritus. Can Anaesth Sot J 1986: 33: 737-740. 13. Embil J A, Stephens R G, Manuel F R. Prevalence of recurrent herpes labiahs and apthous ulcers among young adults on six continents. CMA Journal 1975: 113: 627 630.
I3
Group
Ltd
International Journal of Obstetric Anesthesia
The incidence of herpes simplex virus labialis after cesarean delivery M. C. Norris, J. Weiss, M. Carney, B. L. Leighton Department qf’ Anesthesiology, JefSerson Medical College, Thomas Jqferson University. Philadelphiu. PA SUMMA R Y. Epidural and subaracbnoid opioids have been associated with the development of oral herpes simplex lesions. Because of this risk, some anesthesiologists avoid neuraxial morphine in parturients with a history of herpes simplex virus labialis. When we began using neuraxial opioids for analgesia after cesarean delivery, we did not see any increased incidence of facial lesions. To confirm this impression, we studied 357 consecutive parturients presenting for elective or emergent cesarean delivery between 1 December 1989 and 27 June 1990. The women received spinal, epidural, or general anesthesia. Two hundred and one women received either spinal or epidural morphine, the remaining 156 parturients received only systemic opioids for postoperative analgesia. An investigator saw each patient daily until discharge. Only 11 patients (3%) developed oral lesions while hospitalized. None of these women had severe lesions. Neuraxial morphine did not increase the risk of labial lesions significantly (3.5% vs. 2.6%). Despite published data to the contrary, we found no correlation between neuraxial morphine and the risk of facial herpes virus lesions in women after cesarean delivery. We offer patients the option of neuraxial morphine for analgesia after cesarean delivery despite any history of oral herpes lesions.
Recently, three studies have reported an increased incidence of recurrent oral herpes simplex viral lesions in patients receiving epidural morphine for post cesarean section analgesia.‘-3 Some anesthesiologists recommend avoiding this modality in parturients with a history of ‘more sinister’ herpes virus infections.4 Others, however report their impression that intrathecal morphine does not increase the risk of oral herpes eruptions. ’ In our clinical experience, we saw no increased incidence of oral herpes lesions in parturients receiving neuraxial morphine. To shed more light on this issue, we completed this prospective study of the risk of oral herpes lesions in parturients after cesarean delivery.
receive spinal. epidural. or general anesthesia. Some patients also received spinal (0.15-0.25 mg) or epidural(3-5 mg) morphine for postoperative analgesia. The choice of anesthesia and the decision to use neuraxial opioids were made by the supervising anesthesiologist, independent of this study. All spinal anesthetics were done with 12-15 mg hyperbaric 0.75% bupivacaine. Labor epidural anesthetics were usually begun with lo-15 ml 0.25% bupivacaine, with or without 5 pg/ml fentanyl. We maintained analgesia with either intermittent 10 ml bolus injections of 0.25% bupivacaine or a continuous infusion of dilute bupivacaine (O.OS?G)mixed with I .45 pg/ml fentanyl and I:700 000 epinephrine. At cesarean delivery, we raised the level of block with either 0.5% bupivacaine, 2% lidocaine with epinephrine or 3% chloroprocaine. Additional epidural fentanyl (50-100 pg) was sometimes added to the lidocaine or bupivacaine. We induced general anesthesia with 3-5 mg/kg thiopental or 1 mg/kg ketamine and used l-l.5 mg/kg succinylchloline to facilitate intubation. Before delivery, we maintained anesthesia with 50% nitrous oxide in oxygen and 0.4-0.8X isoflurane. After delivery, we increased delivered concentration of nitrous oxide to 70% and added intravenous fentanyl or morphine. At surgery, we recorded demographic characteristics, the indication for operation, the type of anesthetic and all drugs given via the neuraxial route.
MATERIALS AND METHODS Between 1 December 1989 and 27 June 1990, 357 consecutive parturients presenting for elective or emergent cesarean delivery gave oral consent and participated in this institutional review board approved protocol. No eligible patient refused to participate in this study. As determined by patient preference and the clinical situation, the women Correspondence Anesthesiology. 19107, USA.
to Mark C. Norris MD, Department Thomas Jefferson University. Philadelphia.
of PA
137
128 International Journal of Obstetric Anesthesia
After surgery, we saw all patients daily until discharge (4-5 days). At the first postoperative visit, we asked about the occurrence of facial itching after delivery and any history of cold sores. On all days, we asked about developing cold sores. We used analysis of variance to examine the demographic characteristics of our patients. The Mann-Whitney U test and the x2 test compared the groups for itching, facial itching, indication for cesarean delivery, use of neuraxial epinephrine and recurrent oral lesions. PcO.05 was considered significant.
RESULTS We enrolled 357 parturients in this investigation. The demographic data are shown in Table 1. Two hundred and one women received neuraxial morphine while 156 did not. Figure 1 shows the distribution of anesthetics. Two hundred and twenty seven women received a single anesthetic, either general (n =27), Table 1. Demographics.
All values are mean + SD
Group
No neuraxial morphine (n=156)
Neuraxial morphine (n=201)
Age (years) Height (cm) Weight (kg) Race (black/white/other) Hx oral lesions (n = 115) Primary C/S (n = 248) Repeat C/S (n = 109) Elective C/S (n = 154) Non-elective C/S (n = 203)
28.6k6.7 162.3k7.3 82.3 + 18.2 6818018 57 127 29 40 116
30.2k5.8 162.7k7.3 81.5+ 17.5 72112019 58 121 80* 114* 87
*Patients having repeat or elective cesarean deliveries were more likely to receive neuraxial morphine than those having primary or non-elective operations (P
spinal (n = 196) or epidural (n = 104). The remaining 30 women received more than one anesthetic. Twentytwo had a functioning labor epidural that was converted to either spinal or general anesthesia at the time of surgery. Eight patients initially received a spinal anesthetic that proved inadequate for surgery. Eleven patients developed oral cold sores during their hospitalization (Table 2). Eight reported a history of facial lesions while 3 denied previous cold sores. None developed severe lesions. The patients receiving neuraxial morphine had a 3.5% (95% confidence interval (CI): 1.O%-6.0%) incidence of oral lesions (7/201). In those not receiving neuraxial morphine, the incidence was 2.6% (95% CI: 0.1%5.1%) (4/156) (P=O.85 vs. morphine). Of the women receiving general anesthesia, 2/27 (7.4%) (95% CI: 0%17.3%) developed facial lesions. Two of the 104 ( 1.9O/) (95% CI: 0%4.5%) women receiving epidural anesthesia developed lesions. One received epidural morphine, one did not. Six of the 196 (3.1%) (95% CI: 0.7%5.5%) women receiving spinal anesthesia developed cold sores. All 6 received spinal morphine (P=O.35 vs. no morphine). Table 3 shows the results of other pertinent comparisons. Among women who did not receive neuraxial morphine, only those with a history of cold sores developed cold sores after cesarean delivery (P= 0.017). The type of cesarean delivery (primary/repeat, elective/non-elective) did not correlate with the incidence of facial lesions. Demographics (age, height, weight, race, gravidity, parity) did not correlate with facial lesions. Women reporting a history of cold sores were more likely to develop lesions after cesarean delivery (P = 0.01). Patients who received neuraxial morphine had an increased incidence of both generalized and facial itching (P
n
148
T
Morphine (n=201) No Morphine (n=156)
0 General
Spinal
Epidural
EpidBpinal
Epid/GA
Spinal/GA
Epid/Sp/GA
Type of Anesthetic Fig. l-Distribution of anesthetic type. 227 women received a single anesthetic, while 30 received multiple anesthetics. The different bars show the distribution of the use of neuraxial morphine within the anesthetic groups.
The incidence
of herpes simplex virus labialis
after cesarean
delivery
129
Table 2. Characteristics of 11 women with oral lesions after cesarean delivery Pt
Hx cold sores
Neuraxial morphine
Anesthetic
Race
Type of delivery
Neuraxial drugs
Generalized itching
Epidural
Black Black
General
White
Bupivacaine. fentanyl Bupivacaine. morphine None
None
Spinal
Non-elective /primary Elective /repeat Non-electwe /primary Non-elective /primary Elective /primary Non-elective /primary Non-elective /primary
Bupivacaine. morphine Bupivacaine, morphine Bupivacaine. morphine Bupivacaine. fentanyl. lidocaine, morphine Bupivacaine. fentanyl Bupivacaine. morphine None
Severe
Bupivacaine. morphine
Mild
40
> I/years
80
$ l/years
104
5 I/years
116
None
0.15 mg
Spinal
Black
I19
None
0.15 mg
Spinal
White
120
None
0.15 mg
Spinal
White
181
> I/years
3.5 mg
Epidural
White
186
5 I!years
Other
192
2 I/years
0.15 mg
Epid/Spinal! GA Spinal
197
5 l/years
General
White
226
2 l/years
Spinal
White
0.15 mg
0.15 mg
Black
Table 3. Results Independent
variable
History cold sores Primary vs. repeat operation Elective vs. non-elective operation Type of anesthetic + Neuraxial morphine k Neuraxial morphine + Neuraxial morphine f Neuraxial epinephrine + Neuraxial epinephrine f Neuraxial epinephrine Generalized itching Facial itching
Dependent
variable
P Value
Cold sores Cold sores
0.01 0.57
Cold sores
0.88
Cold sores Generalized itching Facial itching Cold sores Generalized itching Facial itching Cold sores Cold sores Cold sores
0.41 c 0.000 I <0.0001 0.85 0.0081 0.002 0.27 0.52 0.07
itching (P= 0.52), nor facial itching (P=O.O7) correlated with oral lesions. Patients who received epidural epinephrine also had more itching than those who did not. Epinephrine use correlated strongly with morphine use (P= 0.0005). When the analysis was controlled for morphine, epinephrine had no effect on the incidence or severity of generalized or facial itching.
DISCUSSION
Oral herpes simplex infection is ubiquitous. Forty to 50% of adult patients will report a history of cold sores and up to 90% have antibodies to the infective agent, HSV-1.6 Reactivation of herpetic lesions may follow a variety of stresses. Some of these events include: sunburn, infection, trauma, immunosupression and emotional stress.’ Recently, three published
Non-elective /primary Elective /primary Non-elective/ primary Elective /repeat
Mild
Facial itching
+
None -t
None Mild
-t
Mild
+
None Severe None
studies also have suggested that epidural morphine after cesarean delivery could increase the incidence of recurrent oral iesions.1m3 These authors report a 9.7-34.6% incidence of cold sores in women receiving epidural morphine. In contrast, 0-l .5% of patients not receiving epidural morphine after cesarean delivery develop cold sores. In addition, isolated case reports claim a link between intrdthecal morphine,” or epidural fentanyl,’ and herpetic facial lesions. These data suggest that neuraxial morphine could either directly or indirectly promote reactivation of latent herpes simplex virus (HSV ). The most widely held theory suggests that morphine-induced facial pruritus begins a series of events that culminates in the appearance of recurrent cold sores.3,s In our study, 72% of women who received neuraxial morphine complained of generalized itching and 51% noted facial itching. Six of the 7 women in the morphine group who developed cold sores reported facial itching. None of the 4 women who did not receive morphine but developed cold sores had facial itching. Our data are consistent with the suggestion that facial itching related to neuraxial morphine may incite some recurrent oral lesions after cesarean delivery. Not all patients who developed lesions itched, however. Other mechanisms may be involved in inciting facial lesions in these women. In our study, epidural or intrathecal morphine did not significantly increase the risk of cold sores. Of our patients who received neuraxial morphine, only 3.5%~ developed cold sores compared to 2.6% of women who did not receive neuraxial morphine. These data do not prove that neuraxial opioids do not increase the risk of recurrent oral herpes simplex
130
International
Journal
of Obstetric
Anesthesia
lesions. In our population, power analysis suggests that such a study would require over 1100 patients in each group. lo These data do, however, show that, in our patient population, any increased risk of recurrent oral lesions conferred by neuraxial opioids is far smaller than previously reported and is not clinically significant. Several differences exist between our study and the ones mentioned above that may explain these discrepant findings. Firstly, the studies by Crone et a1,‘q3and Gieraerts et al,’ focused exclusively on epidural morphine. Most of our patients received spinal anesthesia for their cesarean delivery. A single case report has been published of a woman who suffered severe recurrent facial lesions after 1.5 mg of intrathecal morphine.8 Abouleish reports: ‘. . . we have used 0.2 mg ITM (intrathecal morphine) in thousands of cases with cesarean sections, (and) herpes simplex eruption has not occurred.‘5 Six women in our spinal anesthesia group (n= 148) developed facial lesions and all received intrathecal morphine. None of the women in the spinal group not receiving intrathecal morphine (n=48) developed cold sores. This trend, while suggestive, did not achieve statistical significance. If this difference were to persist in a larger study, it would attain statistical significance. However, a 4.1% (95% CI: 0.8-7.3%) incidence of facial lesions does not represent a clinically significant problem considering the 3.1% background incidence of facial lesions in our population. Secondly, in two of the studies reporting a strong correlation between epidural morphine and recurrent cold sores, all women received epinephrine-containing local anesthetics. In some reports, epinephrine appears to increase the severity of neuraxial morphineinduced pruritus. “J Crone et al also postulated that epinephrine may combine with morphine to induce reactivation and mobilization of latent virus in the spinal nucleus of the trigeminal nerve. Sixty-one of our patients received epidural epinephrine at some time during parturition. While the use of epinephrine correlated with the incidence and severity of itching, it also correlated with the use of neuraxial morphine. Epinephrine alone did not cause appreciable itching, nor did epinephrine increase the frequency or severity of itching associated with morphine. Note, however, that only 18 of the women in our study received both epidural morphine and epinephrine. Thus, any negative conclusion we might draw from these data is weak. Even in the subgroup of women receiving epidural anesthesia, our results differ from those reported earlier. Our series contains over 100 women receiving epidural anesthesia for cesarean delivery (40 with morphine, 64 without). Only 2 developed cold sores, one in each group. If we were to repeat this study, we would expect at most (upper 95% confidence limit) that 4.7% of women receiving epidural mor-
phine would develop cold sores. In contrast, Gieraerts et al,’ reported a 34.6% (95% CI: 15.9%52.3%) risk of cold sores after epidural morphine. Similarly Crone et al reported a 14.6% (95% CI: 7.5%21.7%) incidence of herpes labialis after epidural morphine.3 Thus, though only a portion of our patients received epidural morphine, the incidence of cold sores associated with epidural morphine in that subset is clearly lower than the incidence reported by others. Epidemiological factors may explain some differences between the reported studies and our data. Crone and colleagues studied the incidence of oral herpes lesions after uncomplicated vaginal or cesarean birth in women living in Saskatoon, Canada. Four percent of vaginal delivery patients and 9.6% of cesarean delivery patients developed oral lesions within 5 days of delivery. In contrast, only 3.1% of our patients developed cold sores after cesarean delivery. Differences in the prevalence of infection, virulence of viral strain or the presence and potency of factors that stimulate recurrence could account for the higher incidence of oral lesions in some populations. Survey data suggest that regional differences do exist in the frequency of herpes labialis recurrences. For example, the ‘lifetime prevalence’ (2 or more occurrences of lesions) of oral herpes labialis ranges from 14.4% in South America to 37.4% in North America.i3 In conclusion, while our study cannot prove that neuraxial opioids lack influence on the risk of recurrent oral herpes lesions, it does show that, in our patient population, neuraxial opioids are not associated with a clinically significant increase in the risk of facial lesions. In our practice, parturients with a history of cold sores can receive spinal or epidural morphine for post cesarean section analgesia without significantly increased risk of developing cold sores. However, because neuraxial morphine clearly increases the risk of HSV lesions in some populations, others should make this decision based on their clinical experience. References 1. Gieraerts R, Navalgund A, Vaes L, Soetens M, Chang J-L, Jahr J. Increased incidence of itching and herpes simplex in patients given epidural morphine after cesarean section. Anesth Analg 1987; 66: 1321-1324. 2. Crone L-A L, Conly J M, Clark K M et al. Recurrent herpes simplex virus labialis and the use of epidural morphine in obstetric patients. Anesth Analg 1988; 67: 3 18-323. 3. Crone L-A L, Conly J M, Storgard C et al. Hepers labialis in parturients receiving epidural morphine following cesarean section. Anesthesiology 1990; 73: 208-213. 4. Beriault M. Herpes virus infections and intraspinal opioids (letter). Anesthesiology 1991; 74: 199. 5. Abouleish E A. Intrathecal morphine as a cause for herpes simplex should be scratched out (letter). Anesthesiology 1991; 75: 919.
The incidence 6. Nahmias A J, Keyserling H, Lee F K. Herpes simplex viruses 1 and 2. In: Evans A S, ed. Viral infections of humans, 3rd Edn. New York: Plenum Medical Book Company. 1989; pp 3933417. Fiumara N J. Herpes simplex. Clinics in dermatology 1989; 7: 23336. Pennant J H, Wallace D. lntrathecal morphine and reactivation of oral herpes simplex. Anesthesiology 1991; 75: 167. Valley M A. Bourke D L. McKenzie A M. Recurrence of thoracic and labial herpes simplex virus infection in a patient receiving epidural fentanyl. Anesthesiology 1992; 76: 1056-1057. Schlesselman J J. Case-control studies: design,
of herpes simplex virus labialis
after cesarean
delivery
conduct, analysis. New York: Oxford University Press, 1982; p 145. II. Bromage P R, Camporesi E M, Duran P A, Nielsen C H. Influence of epinephrine as an adjuvant to epidural morphine. Anesthesiology 1983; 58: 2577262. 1’. Douglas M J. Ross P L E, McMorland G H. The etfect of epinephrine in local anaesthetic on epidural morphine-induced pruritus. Can Anaesth Sot J 1986: 33: 737-740. 13. Embil J A, Stephens R G, Manuel F R. Prevalence of recurrent herpes labiahs and apthous ulcers among young adults on six continents. CMA Journal 1975: 113: 627 630.
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