INTRODUCTION

Infection with genital herpes simplex virus (HSV) is a major gynecological health problem.

  • Five percent of all women of childbearing age report a history of genital herpes, and 30% have antibodies to herpes simplex virus 2 (HSV-2).

  • Approximately 1500-2000 new cases of neonatal HSV infection are diagnosed each year. Neonatal HSV infection often leads to long-term neurologic impairment and even neonatal death.

Despite strategies designed to prevent perinatal transmission, the number of cases of neonatal HSV infection continues to rise, mirroring the rising prevalence of genital herpes infection in women of childbearing age.

GENITAL AND NEONATAL HSV INFECTIONS

HSV is a DNA virus. HSV has 2 subtypes: herpes simplex virus 1 (HSV-1) and HSV-2. Although each is a distinct virus, they share some antigenic components (eg, antibodies that react to one type may "neutralize" the other).

HSV-1 infections were traditionally associated with the oral area (fever blisters), whereas HSV-2 infections occurred in the genital region. However, because of increasing oral-genital contact, either HSV type may be found in either location. Currently, approximately 15% of genital HSV infections are caused by HSV-1.

The following 4 designations are given for genital HSV infections:

  • Primary

  • Nonprimary first episode

  • Recurrent

  • Asymptomatic viral shedding

Primary infections

In a primary infection, no type-specific antibodies to either HSV-1 or HSV-2 exist at the time of the outbreak. Before the current outbreak, the patient had no exposure to HSV.

Typically, lesions appear 2-14 days after exposure. Without antiviral therapy, the lesions usually last for 20 days. Viral shedding usually lasts 12 days, with the highest rates of shedding occurring during the prodrome and during the first half of the outbreak. Viral shedding usually ceases before complete resolution of the lesion.

Antibody response occurs 3-4 weeks after the infection and is lifelong. However, unlike protective antibodies to other viruses, antibodies to HSV do not prevent local recurrence(s). The symptoms associated with local recurrences tend to be milder than those occurring with primary disease.

The lesions of a primary infection begin as tender vesicles, which may rupture and become ulcers. The vaginal mucosa is commonly inflamed and edematous. The cervix is involved in 70-90% of patients.

Symptoms associated with primary infections are both local and constitutional. Local symptoms include intense pain, dysuria, occasional itching, vaginal discharge, and, commonly, lymphadenopathy. Constitutional symptoms are due to viremia and include fever, headache, nausea, malaise, and myalgia.

More than 75% of patients with primary genital HSV infection are asymptomatic. Asymptomatic primary HSV infections are responsible for many neonatal HSV infections.

Nonprimary first-episode infections

A nonprimary first-episode infection is a first genital HSV outbreak in a woman who has heterologous HSV antibodies. For example, if a woman develops a nonprimary first-episode HSV-2 infection on the labia, she would have antibodies against HSV-1 prior to and at the time of her genital outbreak. Because of the partial protection of the preexisting antibodies, these women tend to have fewer and shorter systemic symptoms.

The duration of lesions is shorter (averaging 15 d), and shedding lasts for approximately 7 days.

Distinguishing primary infections from nonprimary first-episode infections is difficult. The diagnosis is based on type-specific culture and type-specific serology. The absence of any HSV antibodies at the time of the outbreak confirms a primary infection, whereas antibody to the heterologous HSV type confirms a nonprimary first-episode infection.

Recurrent infections

Recurrent infections occur most frequently during the first 3 months after a primary infection, especially with HSV-2. Approximately 15% of all pregnant women with a history of genital HSV infection experience recurrent lesions at delivery. Recurrent HSV outbreaks may be symptomatic or asymptomatic. Most of the symptoms are localized (eg, pain, itching, vaginal discharge).

Lesions typically last for 9 days, and shedding lasts for approximately 4 days. The viral load tends to be lower in recurrent outbreaks than with primary lesions, and lesions usually arise during the prodrome and early stage of the clinical outbreak. Shedding is usually completed before the lesions resolve.

Asymptomatic viral shedding

Asymptomatic viral shedding is episodic and brief, usually lasting 24-48 hours. One to 2% of pregnant women with a history of recurrent HSV infection have asymptomatic shedding at the time of delivery.

Distinguishing the type of genital HSV infection

Recently, type-specific HSV serology was approved by the US Food and Drug Administration (FDA) for commercial use. This enables the clinician to accurately distinguish HSV-1 and HSV-2 antibodies. Using type-specific serology in conjunction with HSV culture, determining the type of genital infection is now possible.

Primary infections are often overdiagnosed.

PERINATAL TRANSMISSION OF HSV

HSV can be vertically transmitted to the infant during the antenatal, intranatal, or postnatal periods.

Antenatal

Five percent of all cases of neonatal HSV infection result from in utero transmission. With primary infection, transient viremia occurs. HSV has a potential risk for hematogenous spread to the placenta and to the fetus. Hematogenous spread can produce a spectrum of findings similar to other TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus infection, and herpes simplex) infections, eg, microcephaly, microphthalmia, intracranial calcifications, and chorioretinitis.

Intranatal

Intranatal infection accounts for the majority of infected infants and occurs from passage of the infant through an infected birth canal. Seventy-five to 90% of infants with neonatal HSV are born to asymptomatic mothers who have no history of HSV infection.

Postnatal

Postnatal transmission of HSV can occur through contact with infected parents or health care workers.

  • Primary HSV infection - Transmission rate of 50%

  • Nonprimary first-episode infection - Transmission rate of 33%

  • Recurrent infection or asymptomatic shedding - Transmission rate of 0-4%

The overall chance of neonatal infection from asymptomatic shedding in a woman with a history of genital HSV infection is estimated to be less than 4 in 10,000 (ie, 1% risk of asymptomatic shedding multiplied by the [up to] 4% risk of transmission).

Table 1. Types and Sequelae of Neonatal HSV Infection

Disease Type

Incidence, %

Mortality, %

Long-term Morbidity, %*

Localized disease of
skin, eye, mouth

45

0

5

CNS

35

15

65

Disseminated

20

60-80

40

*Morbidity includes mental retardation, chorioretinitis, seizures, and other CNS effects.


HSV DETECTION METHODS

HSV culture

HSV culture is the criterion standard for diagnosis of HSV infection, with a sensitivity of 70% and a specificity of nearly 100%. A final culture report may take up to 7 days. The decreased sensitivity of HSV culture is related to the HSV type and the location from which the culture is taken. The culture yield is highest during the prodrome and lowest during the second half of the outbreak. Sensitivity of HSV viral culture is lower for HSV-2 than for HSV-1. In asymptomatic women, the greatest yield is when cultures are taken from the cervix and/or the site of recurrence, even if no lesion is visualized.

Tzank smear

The Tzank smear is an older test that is no longer used because of the large number of both false-positive and false-negative results. The Tzank smear is taken in a manner similar to that of a Papanicolaou test (Pap smear), with unroofing and scraping of the base of a lesion. After spraying with a fixative and staining, light microscopy is used to look for the cytopathic effects of HSV on the cells, namely the presence of multinucleated giant cells.

Polymerase chain reaction

Polymerase chain reaction (PCR) is a molecular test that may ultimately replace HSV culture. The test takes approximately 1 day for results to be returned and has the potential for a higher detection rate than HSV culture. In one study, 9% of women in labor who had culture-negative results for HSV had PCR-positive results. Additionally, increased levels of HSV DNA may be associated with an increased risk of neonatal transmission. Unfortunately, PCR does not differentiate actively replicating HSV from latent HSV DNA.

PREVENTION OF VERTICAL HSV TRANSMISSION

Weekly cervical cultures of asymptomatic women with history of genital HSV infection

In 1988, the Infectious Disease Society for Obstetrics and Gynecology developed a position statement that recommended the following practices:

  • Abandon weekly cervical cultures.
  • In the absence of active lesions or prodromal symptoms, vaginal delivery should be allowed.
  • At the time of delivery, consider obtaining herpes culture from the mother or the neonate.
  • Herpes cultures should be obtained from the cervix and the site of recurrence.
  • If there is an active herpetic lesion, cesarean delivery should be performed, preferably within 4-6 hours of membrane rupture.
  • If there is a recent infection near term, check cervical cultures every 3-5 days until results are negative.
    ANTIVIRAL THERAPY

    Acyclovir

    Acyclovir, a nucleoside analogue, was the first antiviral therapy approved for treatment and prevention of HSV infection. Acyclovir selectively inhibits viral DNA replication of HSV, while having little effect on normal cells. Acyclovir is selective for HSV-infected cells because it requires phosphorylation by a viral enzyme (thymidine kinase) to acyclovir monophosphate. Phosphorylation does not occur in uninfected cells, where it remains virtually undetectable. After its conversion to acyclovir monophosphate in infected cells, other cellular enzymes convert it to acyclovir triphosphate, which acts to inhibit HSV-specific DNA polymerase, resulting in termination of the DNA transcript.

    With primary HSV infection in nonpregnant women, acyclovir reduces the duration of local pain, dysuria, and viral shedding, and it shortens the time to crusting and healing of lesions. With daily usage, acyclovir reduces symptomatic recurrences and subclinical viral shedding.

    During pregnancy, acyclovir crosses the placenta and concentrates in the amniotic fluid. Postpartum, acyclovir concentrates in breast milk. Fetal serum concentrations are equivalent to maternal serum concentrations. A potential drawback of acyclovir therapy is delayed and decreased antibody response to HSV infection. Whether this is due to a decreased viral load or to immune suppression is unknown. Acyclovir has not been approved by the FDA for use during pregnancy and is labeled a category C drug (to be used only if the potential benefit outweighs the risk).

    Valacyclovir and famciclovir

    Since the introduction of acyclovir, newer second-generation antivirals have been introduced (eg, valacyclovir, famciclovir). Valacyclovir is identical to acyclovir except for the addition of an ester side chain that increases bioavailability. Once absorbed, it is converted to acyclovir in vivo. This allows for higher serum levels with a less-frequent dosing schedule. Famciclovir is a nucleotide analogue that has a longer intracellular half-life.

    As with acyclovir, these second-generation agents have been used for treatment of symptomatic primary and recurrent lesions as well as for daily suppression. The recommended dosages of the 3 antiviral agents are as follows:

    Table 2. Recommended Dosages of the Antiviral Agents

    Indication
    Acyclovir
    Valacyclovir
    Famciclovir
    First episode
    (X 7-14 d)     		400 mg tid 1000 mg bid 250 mg tid
    Recurrent
    (X 5 d)     		400 mg tid 500 mg bid 125 mg bid
    Daily suppression 400 mg bid 500 mg qd
    or
    1000 mg qd
    (if >9 recurrences/y)

     

    		 250 mg bid

     

    CONCLUSIONS

    In 2000, the American College of Obstetricians and Gynecologists (ACOG) published a practice bulletin regarding HSV in pregnancy. Their conclusions are as follows:

    Level B recommendations (based on limited or inconsistent scientific evidence)

    • Women with primary HSV infection during pregnancy should be treated with antiviral therapy.

    • Cesarean delivery should be performed on women with first-episode HSV infection who have active genital lesions at delivery.

    • For women at or beyond 36 weeks of gestation with a first episode of HSV infection occurring during the current pregnancy, antiviral therapy should be considered.

    Level C recommendations (based on consensus or expert opinion)

    • Cesarean delivery should be performed on women with recurrent HSV infection who have active genital lesions or prodromal symptoms at delivery.

    • Expectant management of patients with preterm labor or premature rupture of membranes and active HSV infection may be warranted.

    • For women at or beyond 36 weeks of gestation who are at risk for recurrent HSV infection, antiviral therapy may be considered, although such therapy may not reduce the likelihood of cesarean delivery.

    • In women with no active lesions or prodromal symptoms during labor, cesarean delivery should not be performed on the basis of a history of recurrent disease.

    Despite the ACOG recommendations, recurrent HSV infections account for a small proportion of neonatal HSV infections. Whether cesarean delivery for recurrent genital lesions actually reduces vertical transmission has not been determined. Presently, however, HSV suppression with antiviral agents may suppress clinical recurrences in labor and may reduce the need for cesarean deliveries in these women.

    In order to truly reduce the incidence of neonatal HSV infection, physicians must focus on the prevention and recognition of asymptomatic primary genital HSV infections. In the future, this might require a combination of PCR analysis for faster diagnosis, as well as type-specific serology to identify pregnancies at risk for primary HSV infections.