Herpes Simplex Virus: Transmission, Diagnosis, and Pregnancy Management

Abstract and Introduction

Genital herpes simplex virus (HSV) infections are frequently asymptomatic or undiagnosed, but more than half the US population is seropositive for HSV, and about one-fifth are positive for HSV-2. These two factors contribute to the risk for sexual transmission and therefore to the risk of late-pregnancy acquisition of HSV. Most neonatal herpes infections are the result of undiagnosed, new-onset HSV infection in the mother. This article reviews the epidemiology of HSV, risks of transmission, and testing and management of HSV during pregnancy. Options for evaluation and management are presented.

Genital herpes simplex virus (HSV) is the most common sexually transmitted infection among the adult female population of the United States. The Centers for Disease Control and Prevention (CDC) estimates that about 45 million people in the United States have genital HSV, with up to a half-million new cases identified each year.^[1] Herpes is most commonly transmitted unintentionally. Unlike other incurable diseases, however, it is not generally associated with a long-term deterioration in health. Nonetheless, a new diagnosis is often associated with stress, embarrassment, and concerns about both the future of sexual relationships and the safety of childbearing. The greatest risk of disease in the newborn comes with late-pregnancy acquisition of genital infection in a previously unexposed woman; recurrent infections are rarely associated with disseminated neonatal disease in immune-competent women. Both detection of women at risk of infection and prevention of viral shedding near time of birth can contribute to improved outcomes. This paper reviews the epidemiology of genital HSV infection, risks of transmission, and testing and current prevention strategies, especially for the prevention of mother-to-child transmission.

The HSVs are part of a large family of DNA viruses, of which eight are known to be infectious in humans. Both HSV types 1 (HSV-1) and 2 (HSV-2) are transmitted across epithelial mucosal cells as well as through skin interruptions, and migrate to nerve tissues, where they persist in a latent stage. HSV-1 predominates in orofacial lesions and typically is found in the trigeminal ganglia, while HSV-2 is most commonly found in the lumbosacral ganglia. The apparent preference for a particular region of the body can be misleading, because either of these viruses can infect any region of the body.

The prevalence of HSV appears to be declining, according to the National Health and Nutrition Examination Surveys (NHANES), a series of stratified, random, cross-sectional surveys. The 1988 to 1994 (NHANES II) and 1999 to 2004 (NHANES III) surveys have been compared and showed an overall decrease in the seroprevalence of HSV-1 by 7% and of HSV-2 by 19%, as illustrated in Table 1 .^[2] Data from the NHANES reports indicate that the rates of HSV-2 are higher among women (23.1%) than men (11.2%) in the general population.^[2] Among those attending sexually transmitted disease clinics, much higher rates have been reported for both women (52.0%) and men (32.4%).^[3] Factors that affect a woman's risk of infection before pregnancy include ethnicity, poverty, cocaine abuse, earlier onset of sexual activity, number of lifetime sexual partners, sexual behavior, and the presence of bacterial vaginosis.^[2,3,4] Higher rates of HSV among both men and women with advancing age during adulthood have been reported; related factors include the persistence of virus over time and changing sexual relationships. Young adults are less likely to use condoms, but the risk from a single sexual event is low, so longer-term relationships increase the likelihood of heterosexual transmission.^[2]

While HSV-2 is associated in the lay literature with genital herpes, both HSV-1 and HSV-2 can cause genital lesions and shedding, and the rates of genital HSV-1 disease are increasing. Data from the two NHANES reports indicate that the incidence of persons who tested positive for HSV-1 only but reported genital herpes rose from 0.4% (NHANES II) to 1.8% (NHANES III); among those with both HSV-1 and HSV-2, the rates rose from 6.6% to 11.0%, respectively, and among those who tested positive only for HSV-2, rates increased from 17.2% to 19.3%, respectively. A person who is positive for HSV-2 only is significantly more likely to report genital outbreaks than someone having both HSV-1 and HSV-2.^[2] Infections caused by HSV-1 may represent as many as one-third of all new genital HSV diagnoses.^[2] In one study, new genital HSV-1 infections had increased to 78% in a young college population.^[5] In general, initial outbreaks of HSV-1 in the genital area will be severe, but recurrent outbreaks and shedding are less frequent than with HSV-2 and rarely occur more than 1 year after diagnosis.

Based on NHANES data from 1999 to 2002, Xu et al.^[6] found an overall seroprevalence of HSV among pregnant women of 72%. Keeping in mind that this represents any exposure to either HSV-1 or HSV-2 that resulted in infection and antibody formation, it remains an indicator of the likelihood of HSV spread among sexually active women. Among 7046 pregnant women without previous evidence of infection, Brown et al.^[7] found a conversion rate of approximately 2% during pregnancy, although only one-third of those who seroconverted became symptomatic. The timing of transmission during pregnancy had a direct bearing on risk to the fetus and neonate. Neonatal infection with HSV is almost exclusively limited to late exposure in mothers without previous antibody acquisition.^[7]

HSV is transmitted across broken skin and intact mucosa by direct exposure to the virus. Sexual activity is the most common route of exposure for genital infections, although autoinoculation also can occur. Studies of HSV-2 prevalence found that having antibody to HSV-1 may be partially protective against new infection with HSV-2, reducing the symptoms of an initial outbreak.^[8,9] At least one author also reports evidence that HSV-1 may be partially protective against HSV-2 acquisition.^[10]

Viral shedding occurs not only during the period of active outbreaks but also when no symptoms are present. Wald et al.^[11] reported that asymptomatic genital shedding episodes account for about one-third of all viral shedding in women with a history of genital herpes, and that one-half of that shedding occurs more than 7 days from a clinical outbreak. Recent infection and frequent symptomatic recurrences are associated with greater frequency of subclinical shedding.^[11,12] However, there is significant variation, and some persons will continue to have frequent viral reactivation for years after the initial outbreak, particularly with HSV-2.^[12] Among persons who are HSV-2 seropositive but have never had recognizable symptoms of HSV, asymptomatic shedding occurs as frequently as among those with an earlier diagnosis.^[13]

Up to 70% of heterosexual transmission of HSV occurs during these episodes of subclinical shedding.^[14,15] In addition, there is a strong likelihood that persons infected with HSV may not be aware of their diagnosis. Ashley and Wald^[8] summarized data indicating that only 20% of those infected with genital herpes have typical lesions, another 60% have atypical lesions, and 20% are completely asymptomatic.

Lautenschlager^[16] reviewed the records of 171 patients and found that more than half had either extragenital lesions (buttocks, thigh, anus, or fingers) or atypical genital lesions (single ulcers, erosion, crusting, fissure edema, or erythema). Clinicians dealing with genital complaints of unexplained etiology should strongly consider testing for HSV in order to identify those at risk for unintentional transmission of the virus.

The high rates of undiagnosed or asymptomatic HSV infections complicate the issue of prevention. Studies of condom use as a preventive measure have demonstrated that increased use of condoms is associated with decreased risk of heterosexual transmission of HSV-2.^[17] However, even regular condom use does not prevent all possibility of transmission, because condoms are not a complete barrier for the genital region. Further, in at least one study, the use of condoms has not been shown to decrease the risk of genital acquisition of HSV-1. The authors speculated that a relatively low number of HSV-1 seronegative individuals enrolled in the study and that a low incidence of transmission overall prevented a firm conclusion.^[18]

Another recommendation for the prevention of HSV transmission is the use of long-term viral suppression. Gupta et al.^[19] compared acyclovir and valacyclovir to each other and to placebo. They found that either drug was effective in decreasing both symptomatic and subclinical viral shedding (76%-82% reduction by polymerase chain reaction [PCR]). Valacyclovir once daily has been shown to reduce transmission to an at-risk partner by 48%.^[20] The American College of Obstetricians and Gynecologists (ACOG) currently recommends the use of suppressive therapy to decrease transmission in discordant couples.^[21]

One recent study has evaluated sexual partners of persons who have been newly diagnosed with HSV. When partners are aware that one of them has HSV-2, there is a documented reduction in sexual transmission.^[22] Wald's study did not identify specific protective factors, such as condom use, and younger partners appeared to have higher risks. These findings have caused some experts to recommend screening as a preventive measure.

Clinical diagnosis of genital herpes is limited in accuracy. First, HSV is only one of several diseases characterized by genital ulcers. More importantly, many persons are unaware that their symptoms are those of herpes. The lumbosacral sensory ganglia, where HSV is most likely to persist, innervate the lower half of the body as well as the genitalia. The typical lesions may not appear, and recurrences may be at different locations along a dermatome. Women may experience only prodromal symptoms, such as burning or tingling; have single ulcers, fissures, or erosion; or experience erythema or edema as the primary symptom. One author has argued that HSV-2 should be considered the cause of any such symptoms below the waist until that diagnosis is excluded.^[23]

Available tests for herpes include both culture and PCR-DNA testing for viral shedding, and the use of blood tests to screen for previous exposure. Which test to use and how to interpret the results is a key decision for clinicians. Confirmation of current infection requires direct detection of the virus with culture or PCR testing at the time of clinical diagnosis. Type-specific serology testing in the absence of symptoms establishes previous exposure and antibody response.

Cultures are most accurate early in the sequence of clinical outbreaks. Fluid collected from intact blisters will grow out in culture more than 90% of the time. By the time the lesions have crusted over, only about 25% of cultures will be positive.^[24] When PCR testing is available, its use should be considered in preference to cultures, because it is more sensitive. Wald et al.^[25] reported a four-fold increase in positive tests in a direct comparison of culture to PCR assay. PCR testing will also confirm viral shedding whether or not lesions are present. The 2006 CDC Sexually Transmitted Diseases Treatment Guidelines note that PCR testing is more sensitive, but has not yet been approved by the US Food and Drug Administration for the testing of genital specimens.^[26]

When using serology to confirm a clinical HSV diagnosis, the most common glycoprotein-G type specific tests are highly accurate. Various HSV-2 antibody tests have reported sensitivity between 90% and 100% and specificity between 91% and 100%.^[27] Women who are offered serology testing must understand the limitations of the tests. Serology cannot date the onset of infection or identify the locus of shedding. However, information regarding whether one is infected with HSV-1 or HSV-2 can prove useful in discussing risks for recurrence. In general, genital HSV-1 causes a severe initial outbreak but fewer recurrences than HSV-2.^[28] For the purposes of treatment, type-specific testing is useful but not essential, because treatment regimens do not vary by virus type.

Primary genital HSV infections require a more prolonged course of treatment, because antibodies that will help reduce the clinical symptoms have not developed. A 10-day course of oral antiviral medication is recommended. In the most severe cases, hospital admission for parenteral treatment may be required. Recurrent infections are treated with a shorter course. Table 2 lists the treatment regimens recommended by the CDC. When an individual has frequent recurrences of genital herpes (≥6 episodes/yr), long-term suppression can be considered both to reduce the individual's physical symptoms and to decrease the risk of transmission to a sexual partner.^[20]

During pregnancy, new HSV infections carry greater risks for both mother and child than does recurrent shedding, whether or not symptoms are present; counseling should reflect this fact. Women need to understand that even if they have rare or no clinical recurrences, there is a small risk of intrapartum transmission, which is decreased but not completely eradicated with third trimester suppression with antiviral medications and cesarean birth when symptoms are present. Knowledge of the viral type is useful in the setting of a woman with a reported history of HSV of unknown type. The woman who already has antibodies to both HSV-1 and HSV-2 at the onset of pregnancy has the least risk of perinatal transmission. HSV is common in the adult population; therefore, many women have been exposed before pregnancy.

Those most at risk for mother-to-child transmission are women who are previously uninfected and are in sero-discordant relationships. New-onset HSV infection late in pregnancy carries a 30% to 50% risk of neonatal infection, while early pregnancy infection carries a risk of less than 1%.^[26] When primary HSV infection occurs during late pregnancy, there is not adequate time for antibodies to develop and suppress viral replication before labor. Transmission of HSV from mother to fetus during pregnancy is uncommon; about 85% of perinatal transmission occurs during the intrapartum period.^[29] During pregnancy, a partner's history of oral herpes has been associated with the risk that a seronegative woman would acquire HSV-1, and having a new partner within 12 months was associated with HSV-2 acquisition during this study.^[30] HSV-1 is easily transmitted from mother to newborn, both at initial infection and with recurrences.^[31] Initial HSV-2 infection has been associated with preterm birth.^[32] It is, however, less easily transmitted to the newborn than HSV-1.^[33]

The consequences of a neonatal infection range from localized symptoms to encephalitis to disseminated disease, which carries a mortality rate in excess of 50%, even with treatment. Survivors are often left with significant neurologic deficits, blindness, seizures, and learning disabilities. Neonatal infection with HSV can also occur in the setting of recurrent herpes. Symptom recurrence producing viral shedding at labor onset is associated with up to a 3% risk of neonatal herpes; both young age and recent infection are associated with increased viral shedding.^[33,34] Asymptomatic viral shedding in recurrent disease at term has not been associated with neonatal disease.^[32]

Several interventions target pregnant women with a known history of HSV. These include both medications to suppress viral shedding at term and cesarean birth for identifiable outbreaks at the onset of labor or ruptured membranes. Cervical or vaginal cultures in late pregnancy have not been shown to improve outcomes, and can increase the number of unnecessary cesarean births. The CDC no longer recommends third trimester cultures in women known to have HSV.^[26]

Suppressive therapy during the last month of pregnancy reduces the likelihood of viral shedding at term.^[35] Studies have reported reductions in neonatal infection when acyclovir or valacyclovir are given beginning at 36 weeks' gestation.^[36,37] A randomized study of 1479 immunocompetent women led to the development of recommendations for suppressive therapy based on number of recurrences yearly, as shown in Table 3 .^[38] Acyclovir prophylaxis is beneficial even when the woman has had no clinical outbreaks during pregnancy.^[39] Persistence of viral shedding has been reported in the absence of clinical outbreaks, and inspection at the time of labor does not correlate well with culture or PCR results done at that time.^[30] However, this shedding is decreased with suppressive medication and is not associated with an increase in transmission, probably because the amount of virus is decreased.^[37,38] When lesions are present or prodromal symptoms occur at the onset of labor, both the CDC and ACOG continue to recommend cesarean birth to minimize the risk of viral exposure to the infant, even if suppressive therapy has been used.^[26,40] Cesarean birth before ruptured membranes virtually eliminates the risk of intrapartum transmission to the infant.^[31]

The CDC recommendations for prevention of neonatal herpes are shown in Table 4 . While they prevent transmission when the mother's status is known, they have no effect on the risk associated with infections acquired during late pregnancy. When a mother with HSV is in labor, invasive procedures such as amniotomy, the use of fetal scalp electrodes,^[41] and operative vaginal delivery, such as vacuum-assisted birth,^[42] should be avoided if possible. This decreases fetal exposure to vaginal secretions potentially containing the virus. Active management should be considered in these women when membranes rupture before the onset of labor. In addition to these recommendations, it is important to advise the nursery staff or pediatric provider of the possibility of HSV exposure.

When there is preterm premature rupture of the membranes (PPROM), the risks of prematurity outweigh the risks of HSV transmission, except in the situation of intraamniotic infection. A study by Major^[43] of HSV in PPROM before 31 weeks' gestation found that the risks of neonatal mortality were similar between preterm delivery and neonatal infection, and the risks of major morbidity from HSV were 75% lower than those associated with early delivery before 30 weeks. There is no consensus on the best timing of delivery for women with PPROM and a history of HSV.^[40]

HSV Seroprevalence is Declining in the United States
	1988-94	1999-2004
HSV-2	21.0%	17.0%
HSV-1	62.0%	57.7%

CDC Recommendations for Oral Treatment of Initial and Recurrent Genital Herpes Outbreaks
	Initial Episode	Recurrent Outbreaks	Suppression
Acyclovir	400 mg tid for 7-10 days OR 200 mg 5 times daily for 7-10 days	400 mg tid for 5 days OR 800 mg bid for 5 days OR 800 mg tid for 2 days	400 mg bid
Famciclovir	250 mg tid for 7-10 days	125 mg bid for 5 days OR 1 gram bid for 1 day	250 mg bid
Valacyclovir	1 gram bid for 7-10 days	500 mg bid for 3 days OR 1 gram daily for 5 days	500 mg daily OR 1 gram daily

Suppressive Therapy for Recurrent Genital Herpes ^[39]
	<10 Recurrences/yr	≥10 Recurrences/yr
Valacyclovir	500 mg daily	1 g daily
Acyclovir		400 mg twice daily

Recommendations for the Prevention of Neonatal Herpes
1. Inform both pregnant women and their partners of the risks associated with neonatal herpes during the prenatal history, and inquire about HSV status in either partner.
2. Offer screening to undiagnosed women whose partners have HSV.
3. Women diagnosed by serology without clinical history should receive the same information as women who have had symptomatic HSV.
4. Avoid sexual contact between an uninfected woman and her infected partner during the third trimester. This includes oral-genital activities when the partner has HSV-1.
5. Consider suppression at 36 weeks' gestation with an appropriate antiviral. Suppression is not recommended for women with positive serology and no history of clinical infection. There is no recommendation about partner suppression.
6. Inspect the perineum, vagina, and cervix at the onset of labor for any lesions, and inquire about symptoms the woman associates with prodromal HSV.
7. Offer cesarean birth at the onset of labor to women with visible lesions or prodromal symptoms.

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