Genital Herpes Simplex Virus Infection during Pregnancy
WHEC Practice Bulletin and Clinical Management Guidelines for the healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).
Herpes simplex virus (HSV) infection of the genital tract is one of the most common viral sexually transmitted diseases (STDs). Approximately 45 million adolescent and adult Americans have been infected with genital herpes based on positive serology test results for HSV-2 and estimates of genital HSV-1 infection. About 30% of the female population in the United States has antibodies to HSV-2.
Genital herpes simplex virus (HSV) infection during pregnancy poses a significant risk to the developing fetus and newborn. In the United States, the incidence of this sexually transmitted disease (STD) has increased significantly since 1970, because many women of childbearing age are infected or are becoming infected. The risk of maternal transmission of this virus to the fetus or newborn is a major health concern. Most newborns acquire the virus from asymptomatic mothers without identified lesions, and it occurs in the perinatal period from contact with infected maternal secretions (1).
The purpose of this document is to define the stages of herpetic infection, outline the spectrum of maternal and neonatal infection and provide the management guidelines.
Two types of HSV, herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2), can be identified on the basis of divergent biologic properties. Initial contact with HSV usually occurs early in childhood and involves HSV-1. Less than 10% of primary infections with HSV-1 are clinically overt. Herpes simplex virus type 1 causes most non-genital herpetic lesions: herpes labialis, gingivostomatitis, and keratoconjunctivitis. The female genital tract can be infected with HSV-1 or HSV-2. In the United States, most genital infection is from HSV-2.
Presentation of Infection:
There are three stages of HSV infection based on clinical presentation and serology (2).
- Primary Infection: Initial genital due to herpes may be either asymptomatic or associated with severe symptoms. Antibodies to both HSV-1 and HSV-2 are absent at the time the patient acquires genital HSV due to HSV-1 or HSV-2. With symptomatic primary infection, lesions may occur on the vulva, vagina, or cervix or on all three between 2 and 14 days following exposure to infectious virus. These lesions are larger in number and size than those observed in patients with recurrent disease and patients who have had prior infection with HSV-1. The initial vesicles rupture and subsequently appear as shallow and eroded ulcers. Inguinal lymphadenopathy as the consequence of virus replication in the site of lymph drainage is seen frequently. Symptoms of viremia - malaise, myalgias and fever, are most commonly seen in primary herpetic infections. Local symptoms of pain, dysuria, and soreness of the vulva and vagina are common in both primary and recurrent infections. The lesions of primary infection tend to resolve within 3 weeks without therapy. However, when secondary bacterial or mycotic infection is present and not treated, the lesions may persist up to 6 weeks.
Increased symptomatic and subclinical shedding from the lower genital of women occurs during the first 3 months after primary genital HSV-2 lesions have healed. Subclinical cervical and vulvar shedding occur at a rate of approximately 2.3% in women with HSV-2 infection and 0.65% in women with HSV-1 infection.
- Nonprimary First Episode: It is acquisition of genital HSV (due to HSV-1) with preexisting antibodies to HSV-2 or acquisition of genital HSV (due to HSV-2) with preexisting antibodies to HSV-1. It may be difficult for physicians to differentiate primary disease from nonprimary first-episode disease based only on clinical findings and patient symptoms; serologic confirmation would be required for definitive diagnosis. There are fewer systemic manifestations, less pain, a briefer duration of viral shedding, and a more rapid resolution of the clinical lesions. These episodes usually are thought to be the result of an initial HSV-2 infection in the presence of partially protective HSV-1 antibodies.
- Recurrent Infection: Reactivation of genital HSV where the HSV type recovered from the lesion is the same type as the antibody in the sera. Recurrences of genital HSV infection can be symptomatic or subclinical, and there is significant variation from patient in the frequency, severity, and duration of symptoms and amount of viral shedding. Confinement of the ulcers to the genital area is more common in recurrent forms of the disease. The ulcers tend to be limited in size, number, and duration. Local symptoms predominate over systemic symptoms. Shedding of the virus from the genital tract without symptoms or signs of clinical lesions is episodic and lasts an average of 1.5 days. During this time, the virus quantity is lower than when a lesion is present; however, a susceptible partner can acquire the infection. Subclinical shedding makes this viral STD difficult to control and prevent.
Neonatal Herpes Presentation:
Most neonatal HSV infection is the consequence of delivery of a neonate through an infected birth canal. There are three categories of neonatal disease:
- Localized disease of the skin, eye and mouth
- Central nervous system (CNS) disease with or without skin, eye and mouth disease
- Disseminated disease
Most infected neonates have localized skin, eye and mouth disease, which generally is a mild illness. Localized disease may progress to encephalitis or disseminated disease. Subtle signs, such as poor feeding, listlessness, and irritability, may indicate CNS disease. Studies show no mortality with skin, eye, and mouth disease, 15% mortality with CNS disease, and 57% mortality with disseminated disease (3).
Mode of Transmission:
1.Sexual and Direct Contact:
Herpes simplex virus is transmitted via direct contact with an individual who is infected. Genital-to-genital contact or contact of the genital tract with an area that is infected with HSV, such as oral-to-genital contact, can result in transmission. About 10% of pregnant women are at risk of contracting primary HSV-2 infection from their HSV-2 seropositive partners. Asymptomatic shedding is the source of more than half of all cases of transmission.
The vertical transmission of HSV appears to be related to gestational age and whether the disease is primary, non-primary first episode, or recurrent. The studies show that preexisting antibody to HSV-2 but not to HSV-1 reduced the vertical transmission reduced the vertical transmission of HSV-2. Vertical transmission rates at the time of vaginal delivery based on the type of maternal disease may be summarized as follows: primary HSV resulted in approximately 50% transmission; nonprimary first-episode HSV resulted in approximately 33% transmission; and recurrent HSV resulted in 0-3% transmission. HSV acquired at or near the time of delivery have about 50% chance of delivering neonate with infection, fetal death and developmental delays.
Complications during Pregnancy:
A threefold increase in the rate of spontaneous abortion following primary maternal genital infection with HSV early in pregnancy has been reported. Primary infection in the second or third trimesters increases the risk for preterm delivery as well as the risk of HSV transmission to the newborn. Asymptomatic genital shedding of herpes from a subclinical primary genital infection may be associated with preterm delivery. During pregnancy, primary maternal herpetic infection, in the absence of cross-protecting antibodies, theoretically may result in hematogenous dissemination of the virus to the fetus. Isolated case reports have associated in utero infection during the first 12-14 weeks of gestation with a variety of anomalies, such as microcephaly, microphthalmia, intracranial calcifications, and chorioretinitis.
Herpes simplex virus infection may be documented in several ways. The standard and most sensitive test for detecting HSV from clinical specimens continues to be isolation of the virus by cell culture. Because HSV is a DNA virus, it produces cytopathic effects in cells indicative of virus replication. However, the sensitivity of this technique is affected by numerous factors related to sampling and transporting the specimen. Cytologic tests have a maximum sensitivity of 60-70% when dealing with overt clinical disease; thus both the Papanicolaou and Tzanck tests are poor HSV screening procedures. Newer, more sensitive techniques are increasingly available, such as polymerase chain reaction and hybridization methods.
U.S. Food and Drug Administration-Approved Type-Specific Tests (8):
- HerpeSelect-1 and 2 Elisa IgG
- HerpeSelect 1 and 2 Immunoblot IgG
- Captia HSV-1 and 2 ELISA
- BiokitHSV-2 Rapid Test
- Sure-Vue HSV-2
Early primary and nonprimary first-episode ulcers yield the virus in 80% of patients, whereas ulcers from recurrent infections are less likely to be culture-positive; only 40% of crusted lesions contain recoverable virus. When testing for HSV, overt lesions that are not in the ulcerated state should be unroofed and the fluid sampled.
Commercially available serologic tests designed to detect genital herpes infection cannot reliably distinguish between HSV-1 and HSV-2. Serologic diagnosis of primary infection is possible by documenting seroconversion from a negative to a positive antibody titer. The usual time for obtaining a second specimen is 2-3 weeks after the onset of infection. The presence of an antibody titer in the initial specimen, obtained at the onset of disease, strongly suggests nonprimary first-episode or recurrent infection. Newer, tests to differentiate between HSV-1 and HSV-2 antibodies are currently in development.
Medical Management of Primary HSV Infection during Pregnancy:
Antiviral therapy for primary infection is recommended for women with primary HSV infection during pregnancy to reduce viral shedding and enhance lesion healing. It is important to recognize that primary HSV cannot be distinguished from nonprimary first-episode disease unless serology constitutes a higher risk for vertical transmission than does recurrent infection. The absence of episodes of symptomatic genital HSV infection throughout pregnancy does not eliminate the risk of asymptomatic shedding at delivery. Furthermore, suppressive therapy for the duration of the pregnancy needs to be considered to reduce the potential of continued viral shedding and the likelihood of recurrent episodes. Significant benefits of acyclovir antiviral therapy using acyclovir have been shown in cases of pregnant women with disseminated HSV, herpes pneumonitis, herpes hepatitis, and herpes encephalitis.
Medical Management of Recurrent HSV Infection during Pregnancy: Studies have shown acyclovir given after 36 weeks of gestation in women with recurrent genital herpes infection demonstrated a significant decrease in clinical recurrence. It also reduces the number of cesarean deliveries performed for active infection.
Medications and Dosage:
Numerous compounds are available for the treatment of genital herpes. Acyclovir, a class-C medication, has selective activity against HSV-1 and HSV-2, in the treatment of primary genital herpes infections. Oral acyclovir reduces viral shedding, reduces pain, and heals lesions faster. Acyclovir has been shown to be safe and has minimal side effects; however, only approximately 20% of each oral dose is absorbed. The newer antiherpetic drugs valacyclovir and famciclovir are class-B medications. The U.S. FDA has approved both valacyclovir and famciclovir for the treatment of episodes of recurrent disease, and the daily treatment for suppression of outbreaks of recurrent genital herpes.
Antiviral Treatments for Herpes Simplex Virus (4):
First clinical episode
1,000 mg twice a dayfor 7-14 days
200 mg five times a day or 400 mg three times a day for 7-14 days
250 mg three times a day for 7-14 days
500 mg twice a day for 5 days
200 mg five times a day or 400 mg three times a day for 5 days
125 mg twice a day for 5 days
Daily suppressive therapy
500 mg once a day (<9 recurrences per year) or 1,000 mg once a dayor 250 mg twice a day (>9 recurrences per year)
400 mg twice a day
250 mg twice a day
Numerous studies have demonstrated the safety of acyclovir use during pregnancy. Neither medically indicated nor inadvertent use in the first trimester of pregnancy demonstrated any increased risk to the developing fetus. When acyclovir is given orally or intravenously, it crosses the placenta, concentrates in amniotic fluid and breast milk, and reaches therapeutic levels in the fetus.
Mode of Delivery:
Cesarean delivery is indicated in women with active genital lesions or symptoms of vulvar pain or burning, which may indicate an impending outbreak. The incidence of infection in infants whose mothers have recurrent infections is low, but cesarean delivery is warranted because of the potentially serious nature of the disease. Cesarean delivery is not warranted in women with a history of HSV infection but with no active genital disease during labor. In patients with recurrent genital HSV and nongenital lesions at the time of labor, the only viral exposure faced by the infant during vaginal delivery is that of cervical shedding, which occurs in approximately 2% of such cases. Thus, the risk of neonatal HSV associated with vaginal delivery in a woman with recurrent HSV and nongenital lesions would appear to be very low. Cesarean delivery is not recommended for these women. Nongenital lesions should be covered with an occlusive dressing; the patient then can deliver vaginally.
In patients with active HSV infection and ruptured membranes at or near term, a cesarean delivery should be performed as soon as the necessary personnel and equipment can be made available. There is no evidence that there is duration of premature rupture of membranes beyond which the fetus does not benefit from cesarean delivery.
In the decision to deliver a patient with preterm premature rupture of membranes and active HSV, the risk of prematurity versus the potential risk of neonatal disease should be considered. In pregnancies remote from term, especially in women with recurrent disease, there is increasing support for continuing the pregnancy to gain benefit from time and glucocorticoids. If this expectant management plan is followed, treatment with an antiviral agent is indicated. The decision to perform a cesarean delivery depends on whether active lesions are present at the time of delivery. The utility of suppressive antiviral therapy to prevent ascending infection has not been proven.
In patients with recurrent HSV, invasive procedures, such as amniocentesis, percutaneous umbilical cord blood sampling, or transabdominal chorionic villus sampling may be performed; however, transcervical procedures should be delayed until lesions appear to have resolved. In a patient with primary HSV and systemic symptoms, it seems prudent to delay invasive procedures until symptoms appear to resolve. Local neonatal infection may result from the use of fetal scalp electrode monitoring in patients with a history of herpes, even when lesions are not present. However, it may be appropriate in a woman who has a history of recurrent HSV and no active lesions. If vesicular or vesiculopustular lesions develop at the site of the electrode, it is important to make a quick and accurate diagnosis and start systemic antiviral therapy.
Postnatally acquired disease can be as lethal as that acquired during delivery through an infected birth canal. Oropharyngeal or cutaneous lesions can be an effective source of virus. It is unlikely that breastfeeding will lead to neonatal infection; however, if the mother has an obvious lesion on the breast, breastfeeding is contraindicated. Because the herpes virus is transmitted through direct contact (eg, hand-to-mouth), neonatal infection may be acquired from family members other than the mother and from sites other than the genital tract (5). Most strains of HSV responsible for nosocomial neonatal disease are HSV-1 rather than HSV-2. Mothers with active lesions should use caution when handling their babies.
Role of Universal Screening:
Viral cultures are costly and imprecise. The correlation between asymptomatic viral shedding and ensuing neonatally acquired disease is poor. Negative cultures do not preclude the possibility of subsequent neonatal infection because the culture sensitivity is well below 100%, and infection may occur in the interim. Virology monitoring is not recommended for pregnant women whose onset of disease antedated pregnancy or for those whose sexual partners have had herpetic lesions. Similarly, there are no data to support the value of culturing asymptomatic patients with a history of recurrent disease (6).
Women with primary HSV during pregnancy should be treated with antiviral therapy. Cesarean delivery should be performed on women with first-episode HSV who have active genital lesions at delivery. For women at or beyond 36 weeks of gestation with a first-episode of HSV occurring during the current pregnancy, antiviral therapy should be considered (7).
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 preterm rupture of membranes and active HSV may be warranted. For women at or beyond 36 weeks of gestation who are at risk for recurrent HSV, antiviral therapy also 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.
Resources and Suggested Reading:
- World Health Organization
Herpes Simplex Virus Type 2: Programmatic and Research Priorities in Developing Countries (pdf)
- National Institutes of Health (NIH)
- Centers for Disease Control and Prevention
- Corey L, Spear PG. Infections with herpes simplex viruses. N Engl J Med 1986;314:686-69 (Level III)
- Hensleigh PA, Andrews WW, Brown Z, Greenspoon J, Yasukawa L, Prober CG. Genital herpes during pregnancy: inability to distinguish primary and recurrent infections clinically. Obstet Gynecol 1997;89:891-895 (Level III)
- Whitley RJ, Hutto C. Neonatal herpes simplex virus infections. Pediatr Rev 1985;7:119-126 (Level III)
- Baker DA. Antiviral therapy for genital herpes in nonpregnant and pregnant women. Int J Fertil 1998; 43:243-248
- Brown ZA, Benedetti J, Ashley R, Burchett S, Selke S, Berry S. Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor. N Eng J Med 1991;324:1247-1252 (Level II-3)
- Centers for Disease Control and Prevention. 1998 guidelines for treatment of sexually transmitted diseases. MMWR Morb Mortal Wkly Rep 1998;47(RR-I):20-24 (Level III)
- National Institute of Health. Consensus Development Conference Statement. Effect of corticoids for fetal maturation on perinatal outcomes, February 28-March 2, 1994. Am J Obstet Gynecol 1995;173:246-252 (Level III)
- ACOG Practice Bulletin. Management of Herpes in Pregnancy. Number 82, June 2007
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