Serologic surveys conducted in the United States reveal that the prevalence of antibodies to HSV increases with age, and that it is higher in persons from lower socioeconomic strata and in groups with greater levels of sexual activity. Antibodies to HSV-1 may be present in 90% or more of adults from lower socioeconomic groups but in only about 30% of college students. Antibodies to HSV-2 are present in approximately 21.9% of the United States population 12 years of age or older, and in 27.2% of persons 30 to 49 years of age. African Americans are more likely to have antibodies against HSV-2 than Caucasians or Mexican-Americans (45.9%, 17.6%, and 22.3%, respectively). Among African Americans, women are more likely than men to be seropositive for this virus (55.1% vs. 34.7%, respectively). However, only 2.6% of adults report ever having genital herpes. The seroprevalence of HSV-2 has increased by about 30% during the period from 1988 to 1994 as compared with the years 1976 to 1980 (201). HSV-2 seropositivity is significantly correlated with being female, African American or Hispanic, having a low educational level, income below the poverty line, having ever used cocaine, and the number of lifetime sexual partners (201,202). A 2002 survey of 36 randomly chosen, relatively affluent primary care physician offices surrounding six major United States cities revealed an HSV-2 seroprevalence of 25%; only 12% of seropositive individuals reported a history of genital herpes (203).

Two percent or more of susceptible pregnant women become seropositive for HSV during pregnancy, but only one-third of them will have symptoms consistent with a herpes infection. The risk of transmission from an HSV-seropositive male to a seronegative female is approximately 20% annually. Seroconversion that was completed by the time of onset of labor was not associated with increased neonatal morbidity or cases of congenital herpes infection in one study; however, infants born to mothers who acquired HSV infection shortly before delivery had an almost 50% chance of developing neonatal herpes (195). A study of 35,940 pregnant women in Norway found no association between HSV-2 infection during pregnancy and fetal death (204).

By measuring type-specific antibodies against HSV-2 gG in a group of 190 pregnant women and their husbands, Kulhanjian and colleagues found that 73% of the couples were concordant with respect to their HSV-2 serologies (i.e., both partners were seronegative or seropositive). However, about 9.5% of the pregnant women were seronegative but had seropositive spouses, and therefore they were at risk of gestational primary HSV-2 infection; 56% of these husbands had no history of previous genital
HSV infection. Approximately 5% of pregnant women in this particular study were susceptible to HSV-2 infection but were unaware of their risk of acquiring the virus from their seropositive spouses, who gave no history of prior genital herpes (205).

Asymptomatic shedding of HSV occurs in 0.2% to 7.4% of pregnant women and in 0.2% to 4% of those at or near term. Most HSV infections during pregnancy represent recurrent disease. The frequency of asymptomatic shedding increases as pregnancy advances (10).

Many primary HSV infections are subclinical. Symptomatic primary HSV disease can include gingivostomatitis, genital herpes, herpetic whitlow, keratitis, chorioretinitis, encephalitis, esophagitis, pneumonia, and hepatitis (10,206).

The most common manifestations of primary HSV-1 infections are gingivostomatitis and pharyngitis, but these occur rarely during pregnancy (207,208,209). HSV-1 causes from 10% to over 50% of primary genital herpes infections in various populations (192,210). Recurrent episodes of herpes labialis are common, and HSV-1 may be recovered from the pharynx of 1% to 5% of asymptomatic healthy persons (191). One study suggested that the incidence of herpes labialis recurrences was lower during early pregnancy, but that women who did have clinical reactivation had them at higher frequencies than before they became pregnant (211).

The most common clinical illness caused by HSV-2 is genital herpes. Sixty-five percent to 90% of initial HSV-2 infections are subclinical or mild (192). Symptomatic patients can have extensive, painful, vesicular or ulcerative genital lesions with or without associated systemic manifestations (191). Over 75% of patients with symptomatic primary HSV-2 infection will have lesions of the skin and mucous membranes of the genital tract, but another 13% present with cystitis, meningitis, urethritis, or cervicitis (192). Serious complications of HSV infections include pneumonia, hepatitis, disseminated intravascular coagulation, shock, acute retinal necrosis, and encephalitis (191, 212-217). Recent data show that some individuals with no prior history of orolabial or genital herpes and who are seronegative for both HSV-1 and HSV-2 can have T cell responses to HSV suggesting that they may have either undetected infection or acquired immunity to the virus without actual infection (218).

Women with recurrent disease typically have mild or subclinical infections. The likelihood of reactivation of HSV infection is greater for genital than oral-labial disease and for HSV-2 than for HSV-1 (219,220). One-fifth of all patients with primary genital herpes subsequently will have nongenital recurrences; this is most likely to occur on the hands and face for HSV-1 and on the buttocks and legs for HSV-2. Buttock recurrences occur less frequently but last longer than genital lesions (221). Asymptomatic HSV-2 shedding occurs more often during the first 3 months after the primary genital HSV-2 infection than during subsequent periods (220). The overall rate for of cervical or external genital shedding during the first year after primary infection is 1.2% of days for HSV-1 and 4.3% of days for HSV-2 (210). For patients with a documented first episode of genital HSV-2 infection, 90% will have at least one recurrence within a year of diagnosis, 38% will have at least six recurrences, and 20% will have 10 or more recurrences (222). Among women with recurrent genital herpes, 55% of those with HSV-2 and 29% of those with HSV-1 had recurrences during a median follow-up of 105 days in one study (223). HSV-2 shedding (detected by culture) occurred on 2% of all days and usually lasted for 36 hours per recurrence; however, 5.5% of women shed HSV-2 for 4 days or longer. Subclinical shedding is more common in women with frequent symptomatic recurrences (223). When 42 women with no past history of genital herpes, but who were seropositive for HSV-2, were prospectively evaluated with daily swab specimens from their cervicovaginal, vulvar, and perianal areas for about three months, 69% were found to have subclinical shedding of the virus by culture methods at some point; the rate was 80% when a PCR assay was added. Viral shedding was documented on 3% of all days without lesions. For 46 women in the same study who did have a history of genital herpes, the frequency of viral shedding during the follow-up period (symptomatic and asymptomatic) was 91% and they shed the virus on 3.6% of all days with no apparent lesions (224).

Genital herpes infections are categorized according to HSV subtype, serologic evidence of past HSV-1 or HSV-2 infection, and the presence or absence of symptoms. This classification scheme is useful when examining the impact of gestational HSV infection on pregnancy outcome according to the type of maternal genital infection. First episode, primary HSV-1 or HSV-2 infection is considered present if the virus is isolated from the genital tract of a symptomatic or asymptomatic woman who has no serologic evidence of prior infection with HSV-1 or HSV-2 in the acute phase serum, but she subsequently has antibodies to the same HSV subtype when convalescent serum is tested. If the acute-phase serum contains antibodies to the other HSV subtype (e.g., HSV-1 antibodies in a woman with an HSV-2 genital isolate), first episode, nonprimary genital infection is considered present. Recurrent HSV-1 or HSV-2 infection is diagnosed if the patient has antibodies to the same HSV subtype isolated from the genital tract in the acute- and convalescent-phase sera (225). The value of this classification scheme is apparent from a study by Hensleigh and colleagues who evaluated 23 women whose clinical illnesses were consistent with the diagnosis of primary genital herpes. The diagnosis was verified serologically in only one woman with primary HSV-1 infection, whereas three others had nonprimary HSV-2 infection; the remaining 19 women proved to have recurrent disease (226). Wald and her co-investigators found that 62% of HSV-2 seropositive persons with no past history of genital herpes subsequently identified typical herpetic lesions once educated about the infection and its clinical manifestations (224).

The diagnosis can be made by isolating the virus from tissue cultures of ocular, mucocutaneous, or genital lesions. The best specimen is usually vesicle fluid obtained within 3 days of its appearance. Positive culture results may be obtained within 16 hours to 7 days, depending on the viral load in the clinical specimen. Shell vial cultures may become positive within 16 to 48 hours (227). The enzyme-linked virus-inducible systems (ELVIS tests) have sensitivities comparable to those of standard and shell vial cultures. They are done using genetically-altered cell lines that have a reporter gene β-galactosidase that is driven by the promoter from a specific HSV gene. Once infected by HSV, the cell lines express the reporter gene resulting in a color change (199).

Direct or indirect fluorescent antibody staining, with or without cytospinning, can detect HSV antigens in exfoliated cells within less than two hours. The sensitivity of the direct fluorescent antibody (DFA) stain is higher for specimens from vesicular lesions as compared to healing lesions (199). The Tzanck smear is a rapid and inexpensive method, but it is only 60% sensitive for HSV infections. It involves scraping the base of a fresh vesicle with a scalpel and spreading the cells and debris on a glass slide. The adherent cells are stained with Giemsa, Sedi, or Wright stain. The slide is examined for the presence of virus-induced cytopathic abnormalities, such as multinucleated giant cells, atypical keratinocytes with large nuclei, and ground-glass cytoplasm. A positive Tzanck smear cannot differentiate between VZV and HSV lesions (228).

Serologic methods can be used for the diagnosis of acute HSV infections. Earlier assays did not accurately distinguish HSV-1 from HSV-2 antibodies. Beginning in 1999, type-specific ELISA and immunoblot antibody assays based on gG became available in the United States. The ELISA assay has a sensitivity of 91% to 96% and a specificity of 92% to 95% for HSV-1. For HSV-2, the ELISA assay has a sensitivity of 80% to 98% and a specificity of 96% or higher. The immunoblot assays have higher sensitivities and specifities for HSV-1 and HSV-2 antibodies when compared to ELISA tests. False-negative results can be encountered if testing is done early in the course of an infection. Demonstrating seroconversion is diagnostic of an acute HSV infection. These tests are also useful in distinguishing primary from recurrent infection in pregnant women with their first clinical episodes of genital herpes (194, 199,200). IgM tests based on gG are not commercially available. Western blot assays for HSV antibodies are helpful in patients in which the antibody profiles are not clear for either HSV-1 or HSV-2, but these tests are time-consuming, expensive, and not readily available (199,200).

Molecular biological techniques have been applied for the diagnosis of HSV infection through the detection of viral DNA in clinical specimens (199,228-233). The PCR continues to detect HSV DNA in clinical specimens for several days after the culture becomes negative. The test is relatively rapid and can be completed within a few hours. The yield of PCR in detecting asymptomatic genital shedding is greater when specimens are collected using cervicovaginal lavage instead of a swab (234). The clinical relevance in obstetrical practice of culture-negative, PCR-positive results from genital specimens remains to be elucidated. PCR detection of HSV DNA in CSF specimens helps in the diagnosis of herpes encephalitis (235). Because the PCR technique is sensitive to even minuscule amounts of HSV, contamination from external sources, such as laboratory personnel, physicians, or nurses who may be shedding the virus, can yield false-positive results. The possibility of laboratory contamination is decreased with the use of real-time PCR detection systems (199). Extreme care should be taken while handling the CSF specimen to avoid making an erroneous diagnosis of herpes encephalitis and possibly missing the true culprit (236). False-negative PCR results can occur as a result of problems with the reaction, the presence of inhibitors in the clinical specimens, or because of timing issues such as obtaining the samples too early or too late during the course of the infection (199).

Three oral drugs are currently available for the treatment of primary and symptomatic recurrent genital HSV infection: acyclovir, valacyclovir, and famciclovir. The experience with acyclovir is the most extensive, particularly regarding its use in pregnant women.

Acyclovir inhibits the replication of HSV-1, HSV-2, and VZV. Acyclovir is converted in the body to its active triphosphate form, initially through the action of viral thymidine kinase to the monophosphate form and later by cellular enzymes to the diphosphate and triphosphate forms. Acyclovir triphosphate concentrations are 40 to 100 times higher in HSV-infected cells than in uninfected cells. The active form of the drug competes with deoxyguanosine triphosphate as a substrate for viral DNA polymerase and, once incorporated into viral DNA, leads to termination of HSV DNA synthesis (237).

The use of acyclovir during pregnancy is not approved by the Food and Drug Administration and generally is reserved for life-threatening or severe HSV infections such as pneumonia. However, it can be given orally to pregnant women with first episode genital herpes or severe recurrent herpes (194). Maternal antiviral therapy may fail to prevent fetal infection with HSV (238). Acyclovir is teratogenic in rats (239). It crosses the placenta, concentrates in amniotic fluid, and can accumulate in human breast milk (240,241).