Management of pregnancy complicated by maternal herpesvirus genital infection remains problematic. There are currently no available rapid diagnostic tests that reliably document contemporary infection. Moreover, there are few data to estimate risks for the neonate exposed to recurrent maternal infection.

VIROLOGY.
Two types of herpes simplex virus (HSV) have been distinguished based on immunological as well as clinical differences. Type 1 HSV is responsible for most nongenital herpetic infections, although genital HSV-1 occasionally recurs in adults (Engelberg and colleagues, 2003). In many adolescents and young adults, however, HSV-1 infection causes more than half of new cases of genital herpes (Mertz and associates, 2003). Type 2 HSV is recovered almost exclusively from the genital tract and is usually transmitted by sexual contact. It has been estimated that approximately 22 percent of adults in the United States have HSV-2 infection.

There have been projections that the seroprevalence in women may rise to nearly 50 percent by 2025 without intervention (Fisman and co-workers, 2002).

Antibodies. Several serological assay systems are available commercially and in research settings to detect antibody to HSV glycoproteins G-1 and G-2, which evoke type-specific antibody responses to HSV-1 and HSV-2 infection, respectively (Ashley, 2001). These tests have the potential to reliably differentiate HSV-1 from HSV-2 antibody and permit confirmation of clinical infection and identification of asymptomatic carriers.

Brown (2000) and Wald and Ashley-Morrow (2002) have proposed that serological screening of couples for HSV-2 antibodies during pregnancy would stimulate the need for safer sex practices and for antiviral suppression precautions if there is a discordancy (i.e., one seronegative and one seropositive partner). This is controversial, and there is no clinical evidence in pregnancy of its efficacy to prevent HSV transmission and neonatal infection (Scoular, 2002; Wilkinson and associates, 2000). The financial cost of prenatal type-specific antibody testing and of suppressive therapy for partners was judged excessive by Rouse and Stringer (2000) and Barnabas and co-workers (2002), but potentially cost-effective by Baker and associates (2004).

CLINICAL INFECTION.
Symptoms vary depending on whether there has been previous infection. Prior HSV-1 infection may modify a primary HSV-2 genital infection because of cross-reacting antibodies. According to the American College of Obstetricians and Gynecologists (1999a), HSV-2 infections clinically may be divided into three groups:

1. Primary infection is indicated by no prior antibodies to HSV-1 or HSV-2.

2. Nonprimary first episode defines newly acquired HSV-2 infection with preexisting HSV-1 cross-reacting antibodies.

3. Recurrent infection is reactivation of prior HSV-1 or HSV-2 infection in the presence of antibodies to the same type of HSV.

Primary Infection. Only a third of newly acquired HSV-2 genital infections are symptomatic (Langenberg and colleagues, 1999). The typical incubation period of 3 to 6 days is followed by a papular eruption with itching or tingling, which then becomes painful and vesicular, with multiple vulvar and perineal lesions that may coalesce (

Fig. 59-3). Inguinal adenopathy may be severe. Transient systemic influenza-like symptoms are common and are presumably caused by viremia. Occasionally, hepatitis, encephalitis, or pneumonia may develop. Cervical involvement is common, but it may be inapparent clinically. Some cases are severe enough to require hospitalization. In 2 to 4 weeks, all signs and symptoms of infection disappear.

Nonprimary First Episode. In general, these infections are characterized by fewer lesions, less systemic manifestations, less pain, and briefer duration of lesions and viral shedding. This is likely because of some immunity from cross-reacting antibodies from childhood-acquired type 1 infection. In some cases, it may be impossible to differentiate clinically between the two types of first infection (Hensleigh and associates, 1997). Serological diagnosis is beneficial in this setting.

Recurrent Infections. During the latency period in which viral particles reside in nerve ganglia, reactivation is common and mediated through variable but poorly understood stimuli. Reactivation is termed recurrent infection and results in herpesvirus shedding. Most recurrent genital herpes is caused by type 2 virus (Centers for Disease Control and Prevention, 2002d). These lesions generally are fewer in number, are less tender, and shed virus for shorter periods (2 to 5 days) than those of primary infection. Typically, they recur at the same sites. Finally, although commonly involved in primary disease, cervical involvement is less frequent with recurrent infections (Brown and co-workers, 1985).

In a study of 110 women with genital herpes infection, Wald and associates (1995) reported that 55 percent had subclinical shedding of HSV-2 at some time during a mean follow-up of 105 days. Shedding averaged 1.5 days and often followed symptomatic recurrence. Wald and colleagues (2000) reported that 3 percent of HSV-2 seropositive patients had subclinical shedding whether or not they had a history of genital infection.

Figure 59-3. First-episode primary genital herpes simplex virus infection. (From Wendel and Cunningham, 1991.)

DIAGNOSIS.
Recovery of virus by tissue culture is optimal for confirmation of clinically apparent infection and asymptomatic recurrences. The sensitivity of culture is nearly 95 percent before the lesions undergo crusting. There are virtually no false positives. About half of cultures are positive 48 hours following the onset of a symptomatic recurrence.

Cytological examination after alcohol fixation and Papanicolaou staining -  the Tzanck smear -  has a maximum sensitivity of 70 percent. False-positive cervical smears commonly may be due to cytomegalovirus infection. Use of PCR increases HSV detection by four- to eightfold (Cone and associates, 1994; Wald and co-workers, 2003).

TREATMENT.
Antiviral therapy with acyclovir, famciclovir, and valacyclovir has been used for treatment of first-episode genital herpes in nonpregnant women. Oral or parenteral preparations attenuate clinical infection as well as the duration of viral shedding. Suppressive therapy with these agents has also been given to limit recurrent infections and to reduce heterosexual transmissions (Corey and colleagues, 2004). For intense discomfort, analgesics and topical anesthetics may provide some relief, and severe urinary retention is treated with an indwelling bladder catheter.

Acyclovir appears to be safe for use in pregnant women (Ratanajamit and associates, 2003). The manufacturer of acyclovir and valacyclovir, in cooperation with the Centers for Disease Control and Prevention, maintained a registry for exposure to these drugs during pregnancy through 1999. More than 700 neonates have been exposed to acyclovir during the first trimester, and there do not appear to be increased adverse fetal or neonatal effects (Reiff-Eldridge and co-workers, 2000; Scott, 1999). There are theoretical concerns about potential neutropenia in the newborn, which is similar to that seen in infants given long-term suppressive acyclovir therapy (Kimberlin, 2004). Valacyclovir results in higher plasma drug levels than acyclovir when given in late pregnancy (Kimberlin and colleagues, 1998). There are insufficient data on valacyclovir and famciclovir exposure in pregnancy for analyses.

Many women with HIV infection also have genital herpes, and treatment failures with recommended doses of acyclovir have been reported. Higher doses of acyclovir may be beneficial for immunoincompetent women with HIV infection and severe recurrent genital herpes (Centers for Disease Control and Prevention, 2002d). In addition, reactivation of genital herpes in labor is common among HIV co-infected women; it was 8 percent in a cohort study from Washington (Hitti and associates, 1997).

Recurrent Infection. Other than suppression, acyclovir is of little benefit in recurrent genital herpes. It has been evaluated as suppressive therapy during pregnancy to prevent recurrences near term in several studies (Brocklehurst, 1998; Scott, 1996, 2001, 2002; Watts, 2004, and all their colleagues). In a meta-analysis of five randomized trials, Sheffield and associates (2003) reported that suppressive therapy after 36 weeks reduced the risk of a clinical or asymptomatic recurrence at delivery and of cesarean delivery for recurrent infection. The incidence of asymptomatic viral shedding was reduced but not eliminated. Scott and Alexander (1998) reported that acyclovir suppression in late pregnancy was cost effective.

Vaccine. In their recent review, Kimberlin and Rouse (2004) cite studies done with an HSV-2 glycoprotein-D subunit vaccine. In women seronegative for HSV-1 and -2, the vaccine prevented 75 percent of clinically apparent genital infection. The vaccine was not effective in women with anti-HSV-1 antibodies or in men.

CLINICAL COURSE DURING PREGNANCY.
Approximately 80 percent of women with recently acquired genital herpes infection have an average of 2 to 4 symptomatic recurrences during pregnancy (Brown and co-workers, 1985; Harger and associates, 1989). Concomitant cervical viral shedding is identified in about 15 percent of pregnant women with clinically evident vulvar recurrences. In addition, remote recurrences -  those on the buttocks, back, thigh, and anus -  have low rates of concomitant cervical virus shedding, and this allows consideration for vaginal delivery (Harger and colleagues, 1989; Wittek and co-workers, 1984).

Viral Shedding at Delivery. The reported prevalence rates for recovery of genital tract herpesvirus at delivery vary considerably depending on the population studied. Equally important is whether women were included or excluded because of prior symptomatic infection. Studies of viral shedding at delivery without regard to maternal history of genital herpes report positive culture results in 0.2 to 0.35 percent (Brown and associates, 1991; Prober and colleagues, 1988).

FETAL AND NEONATAL DISEASE.
Most primary and first-episode infections in early pregnancy are probably not associated with an increased rate of spontaneous abortion or stillbirth (Eskild and co-workers, 2002). In their review, Fagnant and Monif (1989) found only 15 cases of congenital herpetic infection that were acquired during early pregnancy. Brown and Baker (1989) reported that late-pregnancy primary infection results in an increased incidence of preterm labor. Fortunately, HSV acquisition in pregnancy is uncommon (0.34 percent) in most settings, and therefore neonatal herpes is rare (Mindel and associates, 2000).

According to Kimberlin (2004), neonatal infection is acquired in three ways: intrauterine (5 percent), peripartum (85 percent), or postnatal (10 percent). The fetus becomes infected by virus shed from the cervix or lower genital tract. The virus either invades the uterus following membrane rupture or contacts the fetus at delivery. Newborn infection has three forms:

1. Skin, eye, or mouth disease with localized involvement (45 percent of cases).

2. Central nervous system disease with encephalitis, with or without above involvement (30 percent of cases).

3. Disseminated disease with involvement of multiple major organs (25 percent of cases) (

Fig. 59-4).

The risk of neonatal infection correlates with whether there is primary or recurrent maternal infection. Nahmias and colleagues (1971) reported a 50-percent risk of neonatal infection with primary maternal infection but only 4 to 5 percent with recurrent infection. Prober and associates (1987) reported that none of 34 neonates exposed to recurrent viral shedding at delivery became infected, which is thought to be due to a smaller viral load in maternal secretions with recurrent infection. It also likely is related to transplacentally acquired antibody, which decreases the incidence and severity of neonatal disease. An additional risk is prematurity, and nearly half of infected neonates are born preterm.

Localized infection is usually associated with a good outcome. Conversely, even with treatment with acyclovir, disseminated neonatal infection is associated with a mortality rate of nearly 30 percent (Kimberlin and co-workers, 2001a,b). Importantly, serious developmental and central nervous system morbidity still occurs in 20 to 50 percent of survivors with disseminated or cerebral infection (

see Fig. 59-4).

Antepartum Management. Virological monitoring is not recommended. Because of the severity of neonatal infection, cesarean delivery has been used widely in instances when active genital herpetic recurrences are suspected. It seems reasonable to give acyclovir suppressive therapy beginning at 36 weeks for women with recurrent genital herpes who have had clinical recurrences during pregnancy (American College of Obstetricians and Gynecologists, 1999a; Centers for Disease Control and Prevention, 2002d; Sheffield and colleagues, 2003).

According to the American College of Obstetricians and Gynecologists (1999a), cesarean delivery is indicated in women with an active genital lesion or in those with a typical prodrome of an impending outbreak. Thus, cesarean delivery is performed only if primary or recurrent lesions are visualized near the time of labor or when the membranes are ruptured. Roberts and associates (1995) reported a decrease in the cesarean delivery rate in women with herpes during pregnancy from 59 percent to 37 percent after adoption of these guidelines, which succinctly stated are “no lesions, no cesarean.” Brown and colleagues (2003) confirmed this viewpoint by showing a reduced risk of neonatal HSV with cesarean delivery (85 percent) among women with symptomatic and asymptomatic HSV shedding at delivery.

Ruptured Membranes. There is no evidence that external lesions cause ascending fetal infection in the presence of preterm ruptured membranes. Major and associates (2003) described expectant management of preterm ruptured membranes in a cohort of 29 women at less than 31 weeks. There were no cases of neonatal HSV, and the maximum risk of infection was calculated to be 10 percent. The use of antivirals in this setting is reasonable, but of unproven efficacy.

For women with a clinical recurrence at delivery, there is not an absolute duration of membrane rupture beyond which the fetus would not benefit from cesarean delivery (American College of Obstetricians and Gynecologists, 1999a). Unless there are other contradictory factors (e.g., extreme immaturity), then cesarean delivery is performed.

Figure 59-4. Cross-section showing necrotic brain tissue in a newborn who died from disseminated herpesvirus infection.

CARE OF THE NEONATE.
An exposed infant born to a mother known to have or suspected of having genital herpes initially should be isolated from other neonates and cultures performed for herpes. It is not necessary to separate the pair. Instead, the woman should wash her hands thoroughly and avoid contact between her lesions, her hands, and the infant. Breast feeding is allowed, including if the woman is taking antiviral therapy. Acyclovir does not reach appreciable levels in breast milk (Sheffield and colleagues, 2002a). Family members with oral herpetic lesions should avoid kissing the newborn and should use careful hand-washing techniques.