How to manage genital herpes simplex virus infection in pregnancy

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Human herpes viruses are made of a linear double-stranded DNA, an icosahedral capsid, and an envelope with glycoproteins. Eight types have been identified (Table 1). Herpes simplex virus types 1 and 2 (HSV-1, HSV-2) produce orolabial and genital herpes infections following the sequence of primary infection, latency, and reactivation. Both HSV-1 and HSV-2 can be detected in oral and genital lesions.¹

Managing HSV in pregnancy is of high interest, and the main goal is to prevent neonatal HSV infection.

Table 1. The eight human herpesviruses.

Neonatal HSV infection

The frequency of neonatal herpes varies between 12 and 60 per 100,000 live births.² Congenital and postnatal herpes are uncommon, and most infections result from exposure to the virus in the genital tract during delivery, the risk of transmission being considerably higher in women who newly acquire genital HSV-1 or HSV-2 at the end of pregnancy.³ Although rarely reported, oral herpes has no serious morbidity in mother or infant during pregnancy.

Neonatal HSV infection has three types of presentation. The first is cutaneous, mucosal, and/or ocular infection (45% of cases). Grouped vesicles can be limited to a defined area or disseminated. If untreated, one-third of neonates will have progression to systemic involvement. Intravenous acyclovir (ACV) (20mg/kg/8h) during 14 days leads to a favorable outcome in almost all cases. Recurrent cutaneous outbreaks are also possible during early childhood.

Second is central nervous system infection (affecting 30% of cases). Encephalitis manifests as seizures and lethargy with or without skin lesions. Polymerase chain reaction (PCR) for HSV DNA detection in cerebrospinal fluid is the preferred diagnostic tool. Early intravenous ACV treatment (20mg/kg/8h) for 21 days reduces mortality from 50% to 6%. However, morbidity - which is higher with HSV-2 than with HSV-1 - remains important, and developmental delay, epilepsy, blindness, and frequent relapses are often seen.

Third is disseminated infection (affecting 25% of cases). Many organs can be involved, such as lungs, adrenals, liver, and brain. The presentation is that of bacterial sepsis, and intravenous ACV treatment (20mg/kg/8h) for 21 days reduces mortality from 85% to 31%.⁴

Maternal HSV infection

Diagnosis

Genital HSV infection is frequently asymptomatic. Viral shedding is a common risk factor for transmitting genital or neonatal herpes. Viral shedding on genital mucosa lasts between 8 and 20 days in primary infection and between 2 and 4 days in recurrent infection. It is also frequent during the first year following primary infection, the week preceding and following recurrent infection, and in women having more than 12 recurrent infections per year.⁵

Symptomatic, confusing diagnoses must be ruled out first, including syphilitic chancre, chancroid, lymphogranuloma venereum, genital aphthae, erosive lichen, and fungal infection. Genital herpes presents 3-7 days after exposure as multiple grouped and scattered painful vesicles involving the vulva and/or the vagina, and often spreads to the perineum.

Furthermore, primary infection produces a severe clinical picture with painful extensive erosions, tender inguinal lymphadenopathy, dysuria, and fever (Figure 1). Recurrent infection is limited in severity, with a few vesicles reappearing on the genitalia or the buttocks.

Figure 1. Primary genital herpes infection: multiple scattered vesicles and erosions of the vulva spreading to the perineum.

Multiple tests are available to confirm the diagnosis of genital herpes or to prove the presence of viral shedding. Scrapings of early lesions or suspicious mucosa can be studied as follows:

1. Direct fluorescent antibody assay (DFA) is a rapid and sensitive test able to detect viral antigens in keratinocytes and distinguish between HSV and varicella zoster virus.
2. DNA detection by PCR is helpful to detect viral shedding in pregnant women at the time of labor.
3. Viral culture is the reference technique, but it requires 2-5 days to complete.
4. Serology might help to identify primary infection in formerly seronegative women.

Treatment

Taking care of a pregnant woman with genital HSV might include the following options:

1. Treatment of primary infection.
2. Treatment of recurrent infection.
3. Prevention of primary infection.
4. Suppression of viral shedding during delivery.
5. Prevention of HSV transmission to the newborn.

Treatment of primary genital HSV infection in pregnancy^5,6

Newly acquired genital HSV should be treated with ACV, either orally or intravenously in cases of severe infection. ACV and valacyclovir (VCV) are not teratogenic and no fetal abnormalities are reported after drug exposure.⁷ However, because long-term outcomes are not available and no official approval for use in pregnancy is available, informed consent of the patient prior to treatment initiation is recommended. Many common regimens are valid, for example:

1. ACV 200mg po 5x/d x10days (iv: 5mg/kg/8h)
2. ACV 400mg po 3x/d x 10days
3. VCV 500mg po bid x 10days

Additionally, topical treatment has no proven efficacy. Pain may need further management with oral analgesics.

Treatment of recurrent genital HSV infection in pregnancy^5,6

The same treatment regimens for primary infection can be used to reduce viral shedding, although treatment duration can be limited to 5 days. Topical treatment is not effective.

Prevention of primary infection

The risk of neonatal HSV infection is highest for HSV infections that have a late onset in pregnancy (2-50%), whereas early pregnancy infection carries a risk of ~1%.⁸ When primary HSV infection occurs in late pregnancy, there is not sufficient time before labor to develop antibodies and suppress viral replication, which increases the risk of exposure of the newborn to HSV in the genital tract during delivery.

Various strategies are possible to reduce genital acquisition of HSV-1 or HSV-2 in late pregnancy, including the following examples:

1. Sexual behavior change: abstinence, condom use, and avoidance of unprotected oral-genital contact in late pregnancy are the main priorities.
2. Identification of serological profiles in partners: this may help in identifying discordant partners, and eventually treating the HSV-infected male partner. However, clinical trials are needed to define the impact of such measures.
3. Vaccines and microbicides would be an ideal tool of prevention; however, successful products are not yet available. Nevertheless, with further studies, vaccines and microbicides are viable options for future therapeutic and preventive strategies.⁹

Suppression of viral shedding during delivery

If primary or recurrent genital infection occurs in the month preceding delivery, the same treatment regimen is continued until delivery. If it occurs before this time, the treatment regimen is undertaken, and then, starting on the 36th week of amenorrhea, preventive treatment (ACV 400mg po tid or VCV 250mg po bid) is given until delivery.⁵

This suppressive treatment can reduce viral shedding at term, genital recurrences, and Cesarean deliveries, but there is no evidence of a subsequent decrease in neonatal HSV infection.¹⁰

Prevention of HSV transmission to the newborn

When the mother is assessed to be at a high risk of transmitting HSV to her newborn, Cesarean delivery and antiviral treatment of the asymptomatic newborn are to be discussed. Cesarean delivery is important to consider in the following situations:⁵

1. Presence of herpes lesions in the genital tract during delivery.
2. Detection of HSV (as assessed by PCR, DFA, culture) in the genital tract during delivery.
3. Occurrence of primary infection less than 6 weeks previously.
4. Recurrence of infection less than 7 days previously.

Cesarean section is protective only with intact membranes or within 4-6 hours of membrane rupture. With the increasing prevalence of genital HSV infection, along with the changing HSV-1 and HSV-2 trends, we need studies providing effective management guidelines to reduce neonatal herpes.

Conclusions

HSV infection is one of the most common viral sexually transmitted diseases worldwide. The primary infection of the mother may be very painful and lead to virus transmission from mother to fetus or newborn. With the increasing prevalence of genital HSV infection along with the changing HSV-1 and HSV-2 trends, we need studies providing effective management guidelines to reduce neonatal herpes.

References

1. Nahmias AJ, Lee FK, Bechman-Nahmias S. Sero-epidemiological and sociological patterns of herpes simplex virus infection in the world. Scand J Infect Dis 1990;69:19-36.
2. Whitley R, Davis EA, Suppapanya N. Incidence of neonatal herpes simplex virus infections in a managed-care population. Sex Transm Dis 2007;34:704-708.
3. Brown ZA, Selke SA, Zeh J, et al. Acquisition of herpes simplex virus during pregnancy. N Engl J Med 1997;337:509-515.
4. Kimberlin DW, Lin CY, Jacobs RF, et al. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics 2001;108:230-238.
5. Beylot-Barry M, Beylot C. Groupe des herpès-virus. In: Dermatologie et infections sexuellement transmissibles (Saurat JH, ed), 5th edn. Masson; 2008;109-115.
6. Madkan V, Sra K, Brantley J, et al. Human Herpes viruses. In: Dermatology (Bolognia JL, ed), 2nd edn, Vol. 1. Mosby Elsevier. 2008:1199-1204.
7. Pasternak B, Hviid A. Use of acyclovir, valacyclovir, and famciclovir in the first trimester of pregnancy and the risk of birth defects. JAMA 2010;304:859-866.
8. Whitley RJ. Herpes simplex virus infections. In: Infectious diseases of the fetus and newborn infant (Remington JS, Klein JO, eds). Philadelphia: WB Saunders;1990:282-305.
9. Wilson SS, Fakioglu E, Herold BC. Novel approaches in fighting herpes simplex virus infections. Expert Rev Anti Infect Ther 2009;7:559-568.
10. Corey L, Wald A. Maternal and Neonatal HSV Infections. N Engl J Med 2009;361:1376-1385.

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