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Poor Correlation Between Genital Lesions and Detection of Herpes Simplex Virus in Women in Labor

From the Departments of Obstetrics and Gynecology, Medicine, Epidemiology, and Laboratory Medicine, and Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Objective: To estimate the accuracy of clinical diagnosis of genital herpes for herpes simplex virus (HSV) detection among women in labor.

Methods: Viral detection by culture and HSV DNA polymerase chain reaction (PCR) among women who underwent cesarean delivery for genital herpes was compared with women without HSV symptoms in labor who had genital swabs collected for HSV culture and to a subset of these women who had genital specimens available for PCR analysis, regardless of culture results.

Results: From 1989 to 1999, 126 of 19,568 (0.6%) women underwent cesarean delivery for HSV. Twenty-six percent of 110 of these women had HSV detected by culture from at least 1 genital specimen and 46% of 70 of these women had HSV detected by PCR. During the same period, 61 of 12,623 (0.5%) asymptomatic women had HSV detected by culture. Between 1995 and 1996, 57 of 2,109 (2.7%) asymptomatic women had HSV detected by PCR. Thus, the presence of genital lesions had a sensitivity for HSV detection of 37% by culture and 41% by PCR. The amount of HSV present in asymptomatic women with HSV detected in genital secretions by PCR was often as high as those with genital lesions, although the median amount of HSV DNA detected was greater in women with lesions.

Conclusion: Clinical diagnosis of genital herpes at the time of labor correlates relatively poorly with HSV detection from genital sites or lesions by culture or PCR and fails to identify asymptomatic women who have HSV in their genital secretions at the time of labor.

Level of Evidence: II-2

Current guidelines for neonatal HSV prevention recommend cesarean delivery for women with genital lesions at the time of labor, because lesions are assumed to indicate the presence of infectious HSV.⁶ However, recent findings suggest imperfect correlation between genital lesions and HSV detection by culture or polymerase chain reaction (PCR). Further, this approach disregards the potential for HSV transmission from women with asymptomatic viral shedding from the genital tract, the clinical situation that is most commonly associated with neonatal herpes.⁴

This study evaluates the current standard of care, physical examination, to identify HSV in the genital tract of pregnant women at the time of labor. We investigated the correlation between the clinical diagnosis of genital lesions at the time of labor that led to cesarean delivery for herpes and HSV detection in genital secretions by culture or PCR. We also compared the amount of HSV DNA in the genital tract of women with genital lesions at the time of labor with that of asymptomatic women who had HSV detected in genital secretions at the time of labor.

	MATERIALS AND METHODS

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This study was nested in a larger University of Washington cohort study of risk factors for HSV transmission in pregnancy that has been detailed previously.⁴ For this report, cases were all women who underwent cesarean delivery for active genital herpes between January 1989 and December 1999. Genital swabs for HSV detection were obtained at the time of labor by swabbing the labia majora and minora, perineum, periclitoral and perianal areas with Dacron (E.I. du Pont de Nemours & Co., Inc., Wilmington, DE) swabs. Cervical specimens were obtained by swabbing the ectocervix and endocervix with Dacron swabs during speculum examination. An additional specimen was obtained by abrading the surface of the lesion with Dacron swabs. A separate Dacron swab pair was used to sample each anatomic site; the swabs were held together and used at the same time. One swab, for viral culture, was placed into a vial containing 1 mL of virus-transport medium; the other swab, for HSV DNA PCR, was placed into a vial containing 1 mL of PCR digestion buffer. All samples were refrigerated until transport to the laboratory. Clinical data regarding genital symptoms and physical examination findings at the time of labor were extracted from the medical records.

We defined 2 control groups to compare with the group that underwent cesarean delivery for genital herpes. The first consisted of all asymptomatic women who presented in labor to the University of Washington between January 1989 and December 1999 and had genital specimens collected for HSV detection in a manner identical to that described above. Viral cultures for HSV were performed on all available genital swabs from this group as part of the ongoing cohort study. The second control group consisted of a subset of these asymptomatic women who presented in labor between 1995 and 1996 and whose genital swabs were available for HSV DNA PCR analysis, regardless of HSV culture results.

All women had maternal sera for HSV serology obtained at the time of entry into prenatal care and at the time of labor as part of the cohort study. Routine antiviral prophylaxis for women at or beyond 36 weeks of gestation with a history of recurrent HSV was not prescribed during the study period. Consent was obtained according to the guidelines of the Human Subjects Review Board of the University of Washington.

Swabs for HSV culture were inoculated upon arrival in the laboratory, and isolates were subtyped as previously described.¹⁰ Genital specimens collected at the time of labor from asymptomatic women were retrieved from –20°C storage, and 200 µL of the sample extracted using Qiagen columns.¹¹ Quantification of HSV DNA was performed by PCR with the TaqMan (Roche Molecular Systems, Inc., Indianapolis, IN) system using the optimized gB forward primer CCG TCA GCA CCT TCA TCG A, reverse primer CGC TGG ACC TCC GTG TAG TC, and probe CCA CGA GAT CAA GGA CAG CGG CC as previously described.^11,12 Ten microliters of the extracted DNA was used in each assay. To control for pipetting variability, an internal control consisting of the passive fluorescent dye 6-carboxy-X-rhodamine was included in the master mixture for each reaction. The PCR machine (ABI Prism 7700 Sequence Detection System, Applied Biosystems, Foster City, CA) detected this dye and standardized each sample to the quantity of the reference dye in each reaction. The threshold of detection was set at the point that was more than 10 standard deviations above the background. Each PCR run contained several negative controls, including 2 reaction mixtures without DNA and several specimens that were known to contain no HSV DNA, a positive amplicon control, and a standard dilution curve for amplicon DNA. Sequence detector software determined the standard curve, which was then used to calculate the precise quantities of starting template molecules for the unknown sample. Each specimen was run in duplicate, and only those specimens in which the results of both replications were above the cutoff value were considered positive. We reported as positive only those samples in which more than 10 copies of HSV DNA/reaction (500 HSV DNA/mL of transport medium) were detected. For samples with HSV DNA above this cutoff, viral typing was performed with primers HSV-2 gB and HSV-1 gB.¹³ Antibodies to HSV-1 and HSV-2 were detected in serum samples by Western blot.¹⁴ Prenatal and delivery sera were run as paired samples to identify seroconversions.

Symptomatic shedding was defined as the detection of HSV when genital lesions or symptoms were present at the time of labor. Asymptomatic shedding was defined as detection of HSV from the genital specimens in the absence of genital symptoms or lesions.

Primary genital herpes was defined as isolation of HSV-1 or HSV-2 from the genital area in a woman without HSV antibodies at the time of labor. A nonprimary first episode was defined as HSV-2 isolated from genital secretions in a woman with HSV-1 antibodies present in sera obtained at the time of labor. Recurrent HSV-1 or HSV-2 was present when the virus isolated from genital secretions was the same type as the antibodies present in women’s sera obtained at the time of labor.

Groups were compared by Mann-Whitney nonparametric tests in the case of continuous measurements. Categorical outcomes were assessed with the ² or Fisher exact test as appropriate. Medians and ranges of HSV DNA by PCR were calculated among PCR-positive samples only. Box plots that identified the minimal, maximal, quartile, and median values were used to compare the distribution of HSV DNA between groups among PCR-positive samples. We calculated the sensitivity, specificity, and positive predictive value of a genital lesion for the presence of HSV by culture or PCR using standard definitions.¹⁵ Confidence intervals for these measures were constructed using exact binomial methods.

	RESULTS

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Between January 1989 and December 1999, 19,568 women delivered neonates at the University of Washington, of which 4,649 (24%) delivered by cesarean. Lesions or symptoms of genital herpes were noted at the time of labor in 148 women, of whom 126 (0.6% of all deliveries) had cesarean delivery for genital herpes; 107 (85%) were primary cesarean deliveries. Thus, 2.7% of all cesarean deliveries were performed specifically for genital herpes. In 22 of the 148 women, lesions were present, but cesarean delivery was not performed. In 6 of these women lesions were on the buttocks or other nongenital site, and in 16 of these women the lesion was noted too late to perform a cesarean delivery or the woman refused cesarean delivery.

Specimens for HSV cultures were obtained from 110 (87%) of the 126 women who underwent cesarean delivery for lesions or symptoms suggestive of genital herpes. Overall, 29 (26%) of the 110 women had HSV detected by culture from at least 1 genital site. Of the 104 women with culture specimens from both labia and cervix, 23 had a positive labial culture only, 2 had a positive cervical culture only and 3 had a positive culture from both the cervix and the labia.

Specimens for testing for HSV DNA by PCR were available for 70 (56%) of the 126 women. Overall, 32 (46%) of the 70 women had HSV DNA detected from at least 1 genital site. Among 63 women with specimens from both the vulva and the cervix, 16 (25%) had HSV DNA detected from both the cervix and vulva, 2 (3%) had HSV detected only from the cervix, 12 (19%) had HSV detected only from the vulva, and 33 (52%) were negative at both sites. The median amount of HSV DNA present was 10^5.2/mL (range 10^2.6–10^8.5/mL, Fig. 1).

View larger version (23K): [in this window] [in a new window]   Fig. 1. Amount of herpes simplex virus DNA by polymerase chain reaction among 32 women with cesarean delivery for herpes between 1989 and 1999 and 57 women with asymptomatic herpes simplex virus shedding at delivery between 1995 and 1996. HSV, herpes simplex virus. Gardella. Cesarean Delivery for Genital Herpes. Obstet Gynecol 2005.

Sixty-nine women who underwent cesarean delivery for genital herpes had both culture and PCR data. Comparing the rates of HSV detection by culture and PCR among these women, HSV was isolated in culture and detected by PCR in 18 women and only detected by PCR in 14 women. In 2 cases, HSV was detected by culture but PCR was negative. The median amount of HSV DNA was significantly greater in culture positive than culture negative specimens (10^6.1/mL compared with 10^4.4/mL respectively, P = .01, Fig. 2).

View larger version (24K): [in this window] [in a new window]   Fig. 2. Amount of herpes simplex virus DNA present in culture-positive (n = 18) compared with culture-negative (n = 14) samples from women who underwent cesarean delivery for genital herpes. HSV, herpes simplex virus. Gardella. Cesarean Delivery for Genital Herpes. Obstet Gynecol 2005.

Combining the results of prenatal and delivery sera HSV antibody testing and culture and PCR of genital swabs collected at the time of labor or postpartum, we determined that 3 of the 126 (2%) women with cesarean delivery for herpes had primary type 2 genital HSV, 1 of 126 (0.8%) had nonprimary first episode HSV-2 infection, and 28 (22%) had recurrent HSV infection (1 HSV-1, 27 HSV-2). Of the remaining women, 85 had serologic profiles consistent with recurrent HSV infection (5 HSV-1, 31 HSV 1&2, 49 HSV-2) and did not have HSV detected in the genital tract in labor, 8 could not be classified due to missing serology data, and 1 was likely misdiagnosed as having genital herpes because her serum was negative for HSV antibodies at delivery and her genital specimens were HSV culture–and PCR-negative (Table 1). One hundred eleven of these women had a history of prior genital herpes.

Medical records were available for review for 109 (87%) women who underwent cesarean delivery for genital herpes. Of these, the presence of a lesion suggestive of genital herpes at the time of labor was described in the medical records of 98 women. Symptoms consistent with an HSV prodrome in the absence of genital lesions at the time of labor were documented in the records of an additional 11 women. Among the 98 women for whom the lesion was described, an ulcer was the most common presentation. Lesions were most frequently noted on the labia and pain was the most common symptom reported. The median duration of lesions was 3 days (range 1–11 days) at the time of examination. There were no significant differences in lesion description or location between women with positive and negative HSV cultures for the subset of 89 women who also had culture results. Type of symptoms and duration of lesions also did not differ significantly between women with positive and negative HSV cultures for the subset of 52 women with symptom and culture data and the subset of 51 women with lesion duration and culture data (Table 2).

HSV was detected by viral culture from genital secretions of 61 (0.5%) of 12,623 women who presented in labor between 1989 and 1999 and who had no lesions or symptoms of genital HSV at the time of labor. The majority of these women were shedding HSV-2 (95%), with only 3 women shedding HSV-1. Sixty (98%) women had delivery sera available for typing. Combining the type-specific culture results with the antibody results, we determined that 2 (3%) women had primary HSV-1, 2 (3%) had primary HSV-2, 4 (7%) had nonprimary first episode disease, 51 (85%) had recurrent HSV-2, and 1 (2%) had recurrent genital HSV-1 at the time of labor (Table 1).

We recovered all available original genital specimens obtained from women admitted in labor between 1995 and 1996 who lacked lesions or symptoms suggestive of genital herpes. Of these 3,157 women, 2,109 (67%) had specimens available for PCR analysis. HSV was detected by PCR in 57 (2.7%) of these women. Fifty-five (96%) of these women had recurrent HSV-2, 1 (2%) had primary HSV-1, and 1 (2%) had HSV-2 detected but was missing antibody data (Table 1). The median amount of HSV DNA present was 10^4.1/mL (range 10^2.6/mL-10^6.9/mL), which was less than the amount found among women with lesions (P < .001, Fig. 1).

Combining the data from the women with lesions and those asymptomatically shedding at delivery, the presence of a genital lesion had a sensitivity of 37% and 41% and a specificity of 99.3% and 97.9%, respectively, for a positive HSV culture or PCR result (Tables 3 and 4). The positive predictive value of genital lesions for viral detection was 27.7% by culture and 47% by PCR. The negative predictive value of the absence of genital symptoms for the absence of viral detection was 99.5% by culture and 97.3% by PCR.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
We report several important findings that relate to the clinical care of women in labor to prevent neonatal herpes. First, we found a relatively poor correlation between the clinical diagnosis of active genital herpes and detection of HSV in genital specimens by culture or PCR. The positive predictive value of clinical examination for HSV detection was 28% by culture and 47% by PCR. Second, we found that the amount of HSV DNA in the genital secretions of women who shed virus at the time of labor but did not have symptoms or signs of genital herpes could be as high as women who underwent cesarean delivery for genital herpes, although the median amount of HSV DNA isolated from women with lesions was greater. Third, all 5 women who transmitted HSV to their infants and had specimens collected for PCR had HSV detected from genital secretions, but only one half of these women had HSV isolated by viral culture.

It is not surprising that the presence of genital lesions did not correlate well with HSV detection by culture among pregnant women. In previous studies of pregnant women, approximately one third of women with lesions at the time of labor had positive herpes cultures,^7,8 consistent with our findings. Further, studies of men and nonpregnant women found that clinical diagnosis of genital herpes had a sensitivity of 22–39% for HSV-2 infection documented by culture or antibody. False-positive diagnoses of genital herpes also are common, even among experienced clinicians.¹⁹ Thus, Centers for Disease Control and Prevention recommends laboratory confirmation of the clinical diagnosis of genital herpes in nonpregnant populations.²¹

The higher frequency of detection of HSV by PCR compared with culture is consistent with previous reports.^9,22 A review of 8 large studies demonstrated consistently higher HSV detection rates with PCR than culture.²³ The ability to isolate HSV in tissue culture is affected by collection method and ambient transport temperature. In contrast, viral DNA is stable, and PCR assay results are not affected even by prolonged storage.¹² The higher median number of copies of HSV DNA detected when lesions were present compared with asymptomatic shedding observed in our population is not surprising and may reflect both the biology of symptomatic compared with asymptomatic reactivation as well as a limitation of sampling in an asymptomatic woman. Detection of virus by PCR raises the clinical question of whether the detected virus particles are infectious or whether there is a quantitative threshold above which HSV DNA detected by PCR is transmissible. It has been previously demonstrated that the relationship between HSV copy number and isolation of HSV in culture is linear, and no clear threshold for culture positivity exists.⁹ In this report, PCR-positive samples that were also culture positive had greater median HSV DNA than PCR-positive samples that were culture negative, although there was some overlap indicating that even culture-negative samples could have high copy numbers. Further, transmission of HSV can occur even with low copy numbers, as demonstrated by sexual transmission among heterosexual couples using antiviral therapy. Despite a 95% decrease in HSV detection by culture and an 80% decrease in HSV detection by PCR, the risk of transmission decreased by only 50% among discordant couples using antiviral therapy.²⁴ As such, determination of the critical amount of HSV DNA in the maternal genital tract associated with transmission to the neonate will be difficult. In addition, host immune responses may influence this issue. It is clear that the herpes antibody status of the mother modifies the risk of neonatal transmission. This is demonstrated by infrequent transmission of HSV-2 to neonates in women with reactivation HSV-2, even in the presence of positive cultures from the cervix.⁴ Conversely, HSV culture-negative but PCR-positive genital secretions can result in neonatal HSV infection. Thus, other factors besides inoculum size modify the risk of infection.

The detection of HSV DNA in almost one half of the women who underwent cesarean delivery for genital herpes supports the use of this procedure for women with genital lesions. However, lack of HSV DNA detection in one half, and even occasional lack of HSV infection in this group, suggests the need for laboratory-based strategies to detect HSV in the genital tract at the time of labor. For example, a rapid HSV detection test that could determine which women with symptomatic recurrent disease at the time of labor were shedding virus theoretically could avert up to one half of the cesarean deliveries performed for symptomatic genital herpes, without an increase in neonatal herpes.

We believe that our findings are an important step toward recognizing that the currently recommended method of HSV detection at the time of labor, physical examination, is inadequate and that the amount of virus present among women who shed HSV asymptomatically at delivery can be as high as those with symptomatic disease. Further, our findings suggest the potential for development of a rapid PCR test to detect HSV at the time of labor that could inform clinical decision making regarding mode of delivery or postnatal infant care or both. Such a test could identify infants at risk for neonatal HSV for preventive measures at or after delivery such as cesarean delivery, prophylactic antiviral therapy for the infant, and careful infant monitoring for early signs of neonatal HSV. Further research to develop a rapid PCR to detect HSV and study its effect using clinical endpoints is needed.

	Footnotes

 
Supported by National Institute of Allergy and Infectious Diseases grant AI-30731.

Corresponding author: Carolyn Gardella, MD, MPH, Box 356460, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98195–6460; e-mail: cgardel{at}u.washington.edu.

doi:10.1097/01.AOG.0000171102.07831.74

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gardella, C. Articles by Corey, L. Search for Related Content PubMed PubMed Citation Articles by Gardella, C. Articles by Corey, L. Related Collections Infectious disease Labor and operative obstetrics