ACOG Practice Bulletin No. 82: Management of Herpes in Pregnancy

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in the sensory ganglia. Reactivation of viral replication occurs and may manifest clinically as recurrent ulcerative lesions or subclinically as asymptomatic viral shedding. Both the cellular and humoral immune systems play an important role in controlling this viral infection (2). Herpes virus has a characteristic protein coat, and each of the viral types has identifiable proteins. Typespecific antibodies to the viral proteins develop within the first several weeks of infection and persist. Antibodies to HSV can be detected by most assays within 2–3 weeks after infection with the virus (3). Genital infection with HSV is a primary infection when HSV-1 or HSV-2 is detected in individuals with no evidence of antibodies to either viral type in the serum. An outbreak is considered a nonprimary first episode when one viral type is detected in an individual with serologic evidence of past infection with the other viral type. Recurrent episodes are characterized by isolation of HSV-1 or HSV-2 in the presence of antibodies of the same serotype. Incidence Herpes simplex virus infection of the genital tract is one of the most common sexually transmitted infections. The true incidence of genital HSV infection is not known because it is not a reportable disease. It is estimated that approximately 45 million adolescent and adult Americans have been infected with HSV-2 (4). In a large, national serologic study, it was found that approximately 26% of women had serologic evidence of HSV-2 infection (4). It should be emphasized that serologic studies of HSV-2 underestimate the prevalence of genital herpes because HSV-1 also causes genital disease. Most individuals who are infected with HSV are unaware that they have contracted the virus. Only approximately 5–15% of infected individuals report recognition of their infection (4, 5). The increasing burden of infection has important implications for health care providers. The number of initial visits to physicians’ offices as a result of genital HSV infection increased from approximately 75,000 per year in 1978 to nearly 270,000 per year in 2004 (6). Risk factors for HSV infection include female gender, duration of sexual activity, minority ethnicity, previous genital infection, family income, and number of sex partners (4, 7). Whereas HSV-2 is virtually always a genital pathogen, HSV-1 is increasingly recognized as the etiologic agent of genital herpes infection. Up to 80% of new genital infections among all women may be caused by HSV-1 (8, 9). This increase in initial infections with HSV-1 is particularly pronounced in the adolescent and young adult populations. In these populations, genital infection with HSV-1 may have surpassed new genital infection with HSV-2 (1). Among women with serologic test results that indicate susceptibility to HSV infection, the incidence of new HSV-1 or HSV-2 infection during pregnancy is approximately 2% (10). Approximately 10% of women who are HSV-2 seronegative have partners who are seropositive and are at risk for transmission of HSV-2 during the pregnancy (11). Consistent with nonpregnant patients, most new infections in pregnant patients are asymptomatic (10). The timing of infection is relatively evenly distributed, with approximately one third of women becoming infected in each trimester (10). Among women with recurrent genital HSV, approximately 75% can expect at least one recurrence during pregnancy, and approximately 14% of patients will have prodromal symptoms or clinical recurrence at delivery (12, 13). Neonatal herpes usually is acquired during the intrapartum period through exposure to the virus in the genital tract, although in utero and postnatal infections are rare but can occur. Approximately 80% of infected infants are born to mothers with no reported history of HSV infection (14). Although the actual incidence is unknown because neonatal herpes infection is not a reportable disease, estimates suggest that approximately 1,200–1,500 cases occur each year in the United States (15). Approximately one third to one half of cases of neonatal herpes are caused by HSV-1 (15, 16). Neonatal HSV infections can be classified as disseminated disease (25%); central nervous system disease (30%); and disease limited to the skin, eyes, or mouth (45%) (14). Mortality has decreased substantially over the past two decades, decreasing to 30% for disseminated disease and 4% for central nervous system disease. Approximately 20% of survivors of neonatal herpes have long-term neurologic sequelae (17). Clinical Considerations and Recommendations How can the diagnosis of herpes simplex virus be established All suspected herpes virus infections should be confirmed through viral or serological testing. A diagnosis of genital herpes based on the clinical presentation alone has a sensitivity of 40% and specificity of 99% and a false-positive rate of 20% (18). The tests used to confirm the presence of HSV infection can be divided into two basic groups: 1) viral detection techniques and 2) antibody detection techniques. Primary viral DNA testing techniques are viral culture and HSV antigen detection by polymerase chain reaction (PCR). The antibody detection techniques include the use of both laboratory-based 1490 ACOG Practice Bulletin Management of Herpes in Pregnancy OBSTETRICS & GYNECOLOGY
and point-of-care serologic tests to detect the presence of antibodies to either HSV-1 or HSV-2. With viral detection techniques, negative results do not rule out the presence of infection. The diagnosis of HSV should be confirmed either serologically or with viral culture. Isolation of HSV in cell culture is the preferred virologic test for patients who seek medical treatment for genital ulcers or other mucocutaneous lesions and allows differentiation of the type of virus (HSV-1 versus HSV- 2) (18). The sensitivity of this test is limited because of several issues related to sampling and transportation of the specimen (19). Primary lesions are more likely than recurrent lesions to yield positive cultures (80% versus 40% of patients, respectively) (20, 21). Additionally, as the lesions heal, they are less likely to be culture positive (21). Thus, a positive genital culture provides conclusive evidence of genital HSV infection; however, a negative result does not exclude the presence of infection. When a genital specimen is collected for HSV culture, the vesicles should be unroofed, if present, and vesicular fluid should be collected. Polymerase chain reaction techniques involve the amplification of particular sequences of DNA or RNA before detection and can thus detect evidence of viral DNA at low concentrations. Because of the increased sensitivity of PCR, unroofing vesicles is unnecessary. In one very large study, PCR results were three to five times more likely to be positive than were cultures (19). Cultures were more likely to be positive at increasing concentrations of virus, as demonstrated by a linear relationship between the proportion of positive cultures and copy numbers of HSV DNA in samples. Polymerase chain reaction techniques are commercially available and can differentiate between HSV-1 and HSV-2. Polymerase chain reaction provides increased sensitivity over culture (19, 20, 22) and may ultimately replace culture as the standard of care for diagnosis. Presently, however, there are no interlaboratory standards that ensure that identical specimens processed in different laboratories will yield identical results. Additionally, the PCR tests are not U.S. Food and Drug Administration (FDA) approved for clinical testing of genital specimens (18). For patients who do not present with active lesions or whose lesions have negative culture or PCR test results, accurate type-specific serologic assays that accurately distinguish between HSV-1 and HSV-2 antibodies are now commercially available. Currently, there are several FDA-approved type-specific tests, and others are under development (see box). The sensitivity of these assays varies from 93–100% and specificity from 93–98% (23). The predictive value of a positive test result is influenced by the prevalence of the disease in U.S. Food and Drug Administration- Approved Type-Specific Tests Laboratory-based assays • HerpeSelect-1 and 2 ELISA IgG • HerpeSelect 1 and 2 Immunoblot IgG • Captia HSV-1 and 2 ELISA Rapid tests (formerly known as the POCkit test) • BiokitHSV-2 Rapid Test • Sure-Vue HSV-2 the population tested. In a high-risk population, the positive predictive value for the ELISA test results was 80–94% (24, 25). Repeat testing, using a different typespecific assay, has been shown to increase the positive predictive value of a single test result, and this may be especially important in populations with low HSV prevalence (24). Because HSV-2 is an uncommon cause of oral infection, detection of HSV-2 antibodies is virtually diagnostic of genital HSV infection (26). Conversely, detection of HSV-1 antibodies alone may represent orolabial infection or may be indicative of genital infection. Correlation with direct viral identification techniques and the patient’s symptoms is important. How can primary herpes simplex virus infection be distinguished from a nonprimary first episode during pregnancy It is not possible to distinguish primary from nonprimary herpes simplex virus infection on the basis of clinical findings alone (27). Diagnosis is based on the combination of positive viral detection and negative serologic test results or evidence of seroconversion. A primary outbreak in the first trimester of pregnancy has been associated with neonatal chorioretinitis, microcephaly, and skin lesions in rare cases (28). Although HSV has been associated with an increased risk for spontaneous abortion, recent studies do not support such a risk (29). How should a primary outbreak be managed in pregnancy At the time of the initial outbreak, antiviral treatment may be administered orally to pregnant women to reduce the duration and the severity of the symptoms as well as reduce the duration of viral shedding (Table 1) (30). In patients who have severe disease, oral treatment can be VOL. 109, NO. 6, JUNE 2007 ACOG Practice Bulletin Management of Herpes in Pregnancy 1491
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ACOG Practice Bulletin No. 82: Management of Herpes in Pregnancy

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