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Diagnosis and Treatment of Herpes Simplex Infection During Pregnancy
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CLINICAL ISSUES
Diagnosis and Treatment of Herpes Simplex Infection During Pregnancy Deborah Blair Donahue, RNC, PhD
When pregnant women acquire primary herpes simplex genital infections or experience recurrent infections around the time of delivery, the risk of transmitting the disease to their newborns is significant. This perinatal transmission can result in a serious neonatal illness. Issues surrounding screening, treatment, and mode of delivery to prevent perinatal transmission often are confusing and controversial. Nurses delivering care to childbearing women and their newborns must be aware of the current information to give accurate and helpful information and support. Nurses also need to understand the effect this disease has both physiologically and psychosocially on women with primary infections, recurrent infections, and women at risk of acquiring the infection during pregnancy. JOGNN, 31, 99–106; 2002. Keywords: Antiviral treatment—Herpes— Neonate—Pregnancy Accepted: August 2001 The herpes simplex virus (HSV) Type 2 and HSV Type 1 genital infections are incurable sexually transmitted diseases. Type 2 (HSV-2) is associated most often with infections of the genital tract (herpes vulvovaginitis), and Type 1 (HSV-1) most often is an infection of the orofacial region (herpes labialis or cold sores). However, HSV-1 has been found in the genital tract in some cases (Centers for Disease Control and Prevention [CDC], 1998). HSV-1 or HSV-2, when first acquired during pregnancy, can result in severe systemic symptoms in the mother and significant morbidity and mortality in the newborn (Riley, 1998). Infants born to mothers with a primary herpes simplex infection have a 30–50% risk of acquiring the infection via perinatal transJanuary/February 2002
mission near or during the delivery. Recurrent maternal genital herpes simplex infections carry a 1–3% risk of neonatal infection if the recurrence occurs around the time of a vaginal delivery. Without a positive identification of the genital lesions or positive history for HSV in the mother, the infection in the newborn may not be immediately recognized. This may delay treatment and result in extreme neonatal complications or death. Therefore, key elements in controlling the disease in childbearing women and their infants are (a) understanding the disease process and risks of transmission, (b) emphasizing prevention, (c) early and accurate diagnosis in both the mother and newborn, and (d) appropriate and timely treatment.
Pathology HSV-1 can cause both orofacial lesions (cold sores) and genital tract lesions, whereas HSV-2 lesions are almost exclusively found in the genital tract. Also, HSV-1 infections in the genital tract have a lower recurrence rate than HSV-2 genital infections (Benedetti, Corey, & Ashley, 1994). Therefore, the genital HSV-2 infections are the most significant infections of concern during childbearing. HSVs are members of the Herpesviridae family of viruses, the same group of viruses as cytomegalovirus, varicella zoster, Epstein-Barr, and human herpes virus, Type 6. An infection caused by the HSV occurs when the virus enters the cells of the mucosa and replicates in the epithelial cells. The virus also will enter sensory nerve cell endings, travel through the nerve cells, and continue to replicate. The virus may then remain latent in these sensory ganglia. When reactivated, the virus travels back to
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the genital mucosa by way of the sensory nerve cells. These mature viruses are shed into the genital area, often causing symptoms associated with the infection. If contact is made during the reactivation, the infection may be transmitted to another person. The incubation period (time from infection to symptoms or expression of the disease) for HSV-2 infection is between 2 and 20 days. Primary lesions develop over a period of 8 to 10 days and last for approximately 10 to 12 days. The lesions often are associated with significant pain and on inspection appear as reddened areas on the mucus membrane with small clusters of fluid-filled blisters. Primary infections are new infections and often can be subclinical. It may not be until a nonprimary, first-episode infection (see Table 1 for definition of terms) that clinical symptoms are obvious to the patient, in this case the pregnant woman (Desselberger, 1998). Previous HSV-1 infection does help reduce the risk of acquiring a severe firstepisode HSV-2 infection. Ninety percent of the adult population has a positive antibody titer against HSV-1, indicating previous HSV-1 infection. However, this previous HSV-1 infection will not protect the pregnant woman or any individual from acquiring the HSV-2 infection. Reactivation or recurrence of an HSV-2 infection may either cause distinct clinical symptoms or may be symptomless or subclinical. In fact, only a minority of individuals with positive HSV-2 antibody titers, indicating previous infection, report having had symptoms related to an actual history of genital herpes infection (Hensleigh et al., 1997). Recurrent infections with subclinical shedding of HSV-2 infection are estimated to occur from 1–5% of the time, and shedding of the virus can last for several days (Desselberger, 1998). Reactivations of the infection may occur at any time, but certain stimuli are thought to be associated with outbreaks. These stimuli may be physical or emotional stress, exposure to ultraviolet light, tissue damage, or suppression of the immune system (Hensleigh et al., 1997). The natural immunosuppressive state of pregnancy contributes to the recurrent herpes infections, and the frequency, duration, and severity of symptoms often increase as pregnancy progresses (Brocklehurst, 1999).
Perinatal Transmission Perinatal transmission of HSV-2 is the almost exclusive cause of neonatal herpes HSV-2 infections. It has been estimated that 5% of cases of neonatal infections may occur from intrauterine transmission, and HSV-2 DNA has been isolated from amniotic fluid. However, in the cases in which HSV-2 DNA was found in the amniotic fluid, not one was shown to be associated with neonatal infection. Therefore, perinatal transmission to the newborn seems most likely to occur during delivery, particularly during vaginal delivery (Alanen & Hukkanen, 2000). 100 JOGNN
TABLE 1
Definitions of Genital Herpes (HSV-1 and HSV2) Infectious Status True primary, first episode
First clinical episode
Nonprimary, first clinical episode
Recurrent or reactivation of infection
Asymptomatic shedding
First presentation of clinical symptoms of either HSV-1 or HSV-2 infection in a woman seronegative (no previous exposure or infection) for both HSV-1 and HSV-2. Previous infection confirmed as seropositive for HSV-2 but experiencing clinical symptoms of disease for the first time. Initial genital infection in a woman seropositive to a viral strain of HSV different from the HSV strain on culture. For example, a woman seropositive for HSV-1 (previous HSV-1 infection) but HSV-2 seronegative with HSV-2 positive culture indicating HSV2 infection newly acquired. HSV infection in a woman seropositive for the same HSV viral strain on culture. For example, HSV-2 seropositive and lesions culture positive for HSV-2. Positive HSV culture from the genital tract of a woman not perceiving any symptoms of infection and no lesions observed by trained examiner.
Note. HSV-1 = herpes simplex virus type 1; HSV-2 = herpes simplex virus type 2.
Fetal complications have been reported as well as the neonatal complications. These complications are reported to occur more frequently with primary infections. Fetal complications include an increased risk of spontaneous abortion, preterm birth, and, when infection occurs during the 3rd trimester, an increased risk for fetal growth restriction (Hensleigh et al., 1997). The greatest herpes threat to the newborn occurs when the mother becomes infected and experiences a first episode of genital herpes during pregnancy, near term, without obvious lesions or signs and symptoms, and the infection is not recognized. The majority of neonatal infections are due to HSV-2 acquired through maternal transmission during the intrapartum or immediate postpartum period. Most of the infants infected by perinatal Volume 31, Number 1
transmission are born to mothers with no history of herpes infection or evidence of genital herpes lesions. This makes prevention of perinatal transmission a challenge. Women with true primary, first-episode genital herpes during pregnancy, and perinatal transmission, have the highest risk for fetal and neonatal morbidity (Prober et al., 1992). This may be in part because the lesions from primary, first-episode maternal HSV infections have higher rates of virus replication and a longer period of viral shedding than
T
he natural immunosuppressive state of pregnancy contributes to the recurrent herpes infections and the increases in frequency, duration, and severity of symptoms often seen as pregnancy progresses.
lesions from recurrent episodes. Primary infections also mean that there is a lack of maternal antibodies available for transport to the fetus via the placenta to help protect the infant from infection (Jones, 1996). Newborns of women who have had primary exposure to HSV-2 but have not yet seroconverted at the time of delivery seem to avoid neonatal disease. In these cases, even the very low levels of transplacentally acquired HSV antibodies seem to help protect these infants. This raises the possibility of the development of a vaccine. Such a vaccine could be given to mothers at risk for infection (no previous infection of HSV-2) to establish an antibody level to help prevent infection near delivery and reduce the risk of neonatal disease.
Neonatal Disease Congenital HSV-2 infection may occur in the newborn with the characteristic skin vesicles, chorioretinitis, hydroencephaly, or microencephaly (Riley, 1998). Neonatal HSV infection may develop after birth as a localized infection with lesions or vesicles occurring only on the skin, eyes, and/or in the mouth or as a diverse disseminating infection with systemic symptoms. Mortality rates are lower in infants with only localized infections (Jones, 1996). Systemic infections of the brain and central nervous system cause encephalitis and meningitis, and systemic infections of multiple organs may occur in the lungs, liver, and adrenals (Wyckoff, 2000). Systemic infections may occur with or without localized skin lesions. Diagnosis in the neonate is difficult without a history of or evidence of exposure to HSV. Neonatal herpes infection may resemble a more common bacterial sepsis. Some of the clinical symptoms of neonatal HSV infection are January/February 2002
irritability, seizures, respiratory distress, jaundice, disseminated intravascular coagulation, and shock (Wyckoff, 2000). Infants with immediate or early treatment have better outcomes than infants with late diagnosis and delayed treatment (Whitley et al., 1991). Mortality rates from disseminating infections have decreased from 90% to 60% because of early recognition and antiviral drug treatment (Wyckoff, 2000). The current CDC recommendation for treatment of neonates infected with HSV is the administration of 30 to 60 mg/kg/day of intravenous acyclovir for 10 to 21 days (CDC, 1998). If exposure to HSV is suspected, whether the newborn is delivered by cesarean or vaginally, some experts recommend that cultures of the newborn’s oral mucosa should be done. Isolating the virus before clinical symptoms become manifest allows treatment to begin earlier and may decrease the severity of the newborn’s infection.
Maternal Disease and Diagnosis The mean duration of first-episode clinical symptoms in nonprimary, recurrent infections is 12 days. Clinical symptoms of the first episode may include systemic symptoms, such as fever, headache, malaise, or myalgia, as well as active genital herpes lesions. Genital lesions often are associated with bilateral inguinal lymphadenopathy (Hensleigh et al., 1997). The severity of the symptoms, even when a severe first-episode genital herpes infection appears during the 2nd and 3rd trimesters of pregnancy, does not indicate whether the infection is a primary or recurrent infection (see Table 1). In a prospective research project designed to examine the prevalence rates and outcomes of HSV infections, cultures and viral serology testing were conducted on women with first-episode clinical signs and symptoms suggestive of primary infection. The results revealed that most of the cases were nonprimary infections (Hensleigh et al., 1997). The presence of HSV1 and/or HSV-2 antibodies confirmed previous infection, even though the women reported no previous symptoms or clinical signs of infection. Women with recurrent herpes can be reassured that their risk of transmitting the infection to their newborns is lower (CDC, 1998). Blood tests can be performed to detect HSV antibodies. However, with currently available serologic testing, it is difficult to distinguish between HSV-1 and HSV-2 infections. Western blot testing can be used to detect HSV-2 specifically, but these tests are expensive, laborious, and not routinely done for diagnostic purposes. HSV-1- and HSV-2-specific monoclonal antibodies can be identified and diagnosed by an immunoflourescence technique, also expensive and not available at all laboratories. HSV antigen assay is available and is cheaper, easier, and quicker. However, the currently available commercial enzyme immunoassays cannot distinguish between HSV-1 and HSV-2 (Desselberger, 1998).
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Viral cultures have been the gold standard (CDC, 1998) and can be obtained by scraping vesicles, ulcers, or crusted lesions. Viral DNA may be analyzed from the material obtained for cultures using polymerase chain reaction. With DNA analysis, the distinction between HSV-1 and HSV-2 can be easily made. Polymerase chain reaction is superior to viral culture alone and can be used to detect late infection and asymptomatic HSV infections during pregnancy (Alanen & Hukkanen, 2000; Boggess et al., 1997; Desselberger, 1998). However, this technique is available only in laboratories specializing in HSV detection and would prove difficult and expensive in testing a large population of women. The seroprevalence rate for HSV-2 infection in the United States has increased in the past few years as much as 30% for the age range of 12 to 39 years. This range coincides with the range of childbearing ages. Risk factors for acquiring an HSV-2 infection are related to sexual practices. A correlation exists between the number of sexual partners reported and the prevalence of HSV-2. Statistically, women are more likely than men to become infected (CDC, 1999; Riley, 1998). The reason for this may not be fully understood. Because of the known risk factors, a thorough sexual history may be helpful in identifying women most at risk for genital herpes infections.
Routine Screening for HSV-2 Status Debate exists regarding whether all pregnant women should be screened to identify their HSV status. The argument for screening is the potential to lower the risk of perinatal transmission by identifying women likely to be at risk of acquiring a primary infection during pregnancy or previously infected women at risk for recurrence at the time of delivery. The proposed method for screening would use HSV-2-specific serology on all pregnant women to identify those who are seronegative for HSV-1 and HSV-2 (Brown, 2000). Women with no previous exposure to HSV-1 or HSV-2 are the most vulnerable group should a genital herpes infection be acquired during pregnancy, particularly near the time of delivery. Women who are seronegative for HSV-2 and seropositive for HSV-1 are at risk, but to a lesser degree, of acquiring the disease, transmitting it to the fetus or newborn, and experiencing the morbidity and mortality risks seen in neonates. Both groups, if identified, could be counseled to practice safe sex by using condoms or abstinence during pregnancy, particularly during the 3rd trimester. Prevention strategies are of increased importance at that time because women are more susceptible to infection during the 3rd trimester because of the normal immunosuppression state then (Brown, 2000). Brown (2000) further suggested the efficacy of testing the male partner of the pregnant woman whose status is seronegative for HSV-2. If he is seropositive, indicating previous infection and risk for 102 JOGNN
recurrence and transmission, then he may be given viral suppression with antiviral medication to decrease the risk of transmission to the pregnant woman. However, this practice has many ethical and logistic problems. The other possibility, screening to identify women with seropositive status for HSV-2, would be beneficial as well. Seventy-five percent of this group reports being unaware of their status (Swanson, 1999). Further screening of these women for reactivation or performing viral cultures for subclinical asymptomatic shedding at the time of delivery will identify women at risk of transmitting the disease to the infant during a vaginal birth. Women with seropositive status and positive viral cultures for HSV-2 can be delivered via cesarean section. Wilkinson, Barton, and Cowan (2000) opposed routine screening for all pregnant women. They argued that because the incidence of neonatal HSV infection in the United States is 1 in 7,500 live births, the screening of all pregnant women would not be cost-effective. In addition, they point to a retrospective study conducted by Brown et al. (1997) of 94 seronegative women who converted to seropositive for HSV-2 during pregnancy. In the study population, 30% converted to seropositive during the 1st trimester, 30% converted during the 2nd trimester, and 40% during the 3rd trimester. In all subjects with seroconversion before labor (indicating the presence of maternal antibodies to the HSV-2), no neonatal disease was seen. Therefore, based on this information, Wilkinson et al. claimed that population testing would not be beneficial or cost-effective. Furthermore, these authors pointed out that reliable commercial testing for HSV-2-specific antibodies is not readily available. They argued that a bet-
T
he severity of the symptoms during an infection, even when a severe firstepisode genital herpes infection appears during pregnancy, does not indicate whether the infection is a primary infection or a recurrent one.
ter use of resources would be to develop a test to recognize the disease in the newborn such as rapid virus or antigen detection tests. Such tests would allow earlier treatment and thus prevent significant neonatal morbidity and mortality. It is possible that when such diagnostic strategies do become available, testing also could be used to better identify those women at risk for perinatal transmission. Volume 31, Number 1
Mode of Delivery Mode of delivery, vaginal versus cesarean, has been the main intervention strategy to prevent perinatal transmission of genital HSV to the newborn. The current recommendations are based on the American College of Obstetricians and Gynecologists (1999) guidelines for mode of delivery and management of labor for women with a history of HSV infection. Cesarean section is not recommended when a woman with a history of recurrent infections is in labor, no obvious lesions are apparent to the experienced examiner, and the woman reports no symptoms of infection (Roberts, Cox, Dax, Wendel, & Leveno, 1995). A cesarean section is recommended if active lesions are present and should be performed within 6 hours of rupture of membranes. However, even when lesions or symptoms of infection are not present at the
A
cyclovir given for treatment of first-episode infections of HSV-2 during the late 3rd trimester has been shown to be an effective alternative to routine cesarean delivery in preventing perinatal transmission.
time of delivery, because a very low risk of transmission exists, the use of fetal scalp electrodes or fetal blood sampling is not recommended during labor (Cline, BaileyDorton, & Cayelli, 2000). To restate the current policy for women with known HSV-2 infections, a vaginal birth is recommended for delivery if maternal genital herpes cultures are negative before labor. However, if herpes cultures are positive or unavailable at time of delivery, then a cesarean should be performed. This practice policy was examined by researchers at Parkland Hospital in Dallas, Texas (Roberts et al., 1995). In this study, the authors reported a significant decline in the cesarean birth rate at their hospital and no subsequent increase in the incidence of neonatal herpes simplex infection when this policy was applied. However, it must be emphasized that this policy is not guaranteed to prevent all perinatal transmission of infection to the newborn. Because there is a small chance that perinatal transmission can occur, even with negative HSV cultures at the time of vaginal delivery, other strategies are emerging. Randomized clinical trials, as well as retrospective data, support the administration of oral acyclovir to women with recurrent HSV-2 genital lesions as a method to reduce neonatal and maternal morbidity and mortality. January/February 2002
Acyclovir may reduce the recurrence rate by 80% and the asymptomatic shedding of virus by 80–95% (Randolph, Hartshorn, & Washington, 1996). However, acyclovir does not prevent all asymptomatic shedding of the virus (Haddad, Langer, Astruc, Messer, & Lokiec, 1993).
Maternal Treatment With Acyclovir The current advice and recommendations for treating and managing genital HSV infection during pregnancy often are confusing and conflicting. One such option is treatment with acyclovir during pregnancy. Oral acyclovir (pregnancy category C) may be administered for the first clinical episode of genital herpes infection during pregnancy. Acyclovir has few side effects and is usually well tolerated. In cases of disseminated infection, encephalitis, pneumonitis, or hepatitis, the acyclovir treatment should be administered intravenously (CDC, 1998). Acyclovir is more effective in treating primary infections for reducing symptoms, length of viral shedding, and time required to heal lesions than it is in recurrent infections (Baker, 1999). Unfortunately, once replication of the virus in the sensory ganglia is complete, antiviral medications are not effective in destroying the virus. The Acyclovir in Pregnancy Registry was established in 1984 to gather prospective and retrospective data on the effects of prenatal exposure to the antiviral agent, acyclovir (Andrews et al., 1992). The registry was disbanded recently, but the data have not shown an increase in the number of birth defects from 1st, 2nd, or 3rd trimester exposure when compared with defects expected in the general population. Acyclovir given for treatment of firstepisode infections of HSV-2 during the late 3rd trimester has been shown to be an effective alternative to routine cesarean in preventing perinatal transmission (Scott, Sanchez, Jackson, Zeray, & Wendel, 1996). The CDC recommendations for treatment of genital herpes with acyclovir are shown in Table 2. However, it must be made clear that although acyclovir is administered orally to treat a first clinical episode of genital HSV during pregnancy and intravenously to treat severe disease, the routine administration of acyclovir to pregnant women with a history of recurrent infection is not recommended by the Food and Drug Administration or the CDC (Cline et al., 2000). Acyclovir crosses the placenta and is concentrated in amniotic fluid and can actually reach therapeutic levels in the fetus through administration to the mother (Frenkel et al., 1991). Even with this information, no changes to practice recommendations have been made to support the routine use of acyclovir in pregnant women with a history of recurrent genital herpes to suppress viral shedding, prevent reactivation of lesions (CDC, 1998), or as a method to prevent neonatal infection. It also should be noted that newer agents such as valacyclovir and famciclovir, both listed as category B agents, have been approved by the
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TABLE 2
Centers for Disease Control and Prevention Recommended Dosages of Acyclovir for Treatment and Suppression of Genital Herpes Simplex Virus Primary Infection First episode 400 mg orally, 3 × daily for 7-10 days; or 200 mg orally, 5 × daily for 7-10 days
Recurrent Infection
Daily Suppression
Severe Disease
400 mg orally, 3 × daily for 5 days; or 200 mg orally, 5 × daily for 5 days; or 800 mg orally, 2 × daily for 5 days
Started: 36 weeks gestation 400 mg orally, 2 × daily until delivery
5-10 mg/kg body weight IV every 8 hours for 5-7 days
Note. Adapted from Centers for Disease Control and Prevention (1998).
Food and Drug Administration for the treatment of herpes. Despite the category B ratings and Food and Drug Administration approval, neither of these drugs has been recommended for use during pregnancy. This is mainly due to the lack of clinical trials or retrospective data on the safety and efficacy of these agents during pregnancy. Randolph et al. (1996) examined the cost-effectiveness of four strategies to prevent transmission to the newborn caused by a recurrent maternal herpes infection. Applying a decision analysis technique, they compared the outcomes of several randomized controlled trials. They reported the probability values for effectiveness and cost. The most effective method for reducing neonatal infection was found to be oral acyclovir prophylaxis in late pregnancy for women with recurrent genital herpes lesions and cesarean section for those women with active lesions at the time of delivery. This policy represents the current recommendations with the added treatment of antiviral suppression around the time of delivery. The highest rates of transmission were found in the group of women who received no intervention (no antiviral medications and vaginal delivery), followed by women with cesarean delivery without antiviral drug suppression. The group with acyclovir and cultures, delivered vaginally, with follow-up treatment of infants exposed to herpes (mothers with positive cultures), represent the lowest cost but resulted in a higher incidence of neonatal HSV infections than the cesarean groups with or without antiviral suppression.
Psychosocial Implications of the Disease The significance of the psychosocial impact that a diagnosis of genital herpes simplex has on women of childbearing age should not be underestimated. As stated earlier, there is anecdotal evidence that stress may play a role in triggering a reactivation of the disease (Swanson, Dibble, & Chenitz, 1995). Although this phenomenon is not totally understood and some of the data are inconsistent, the most commonly experienced psychologic or emotional response to the disease is depression (Swanson, 104 JOGNN
1999). The burden of living with the disease includes psychologic concerns, such as not knowing when a reactivation will occur, fear of transmission to a partner, and fear of transmission to the newborn during pregnancy or during delivery of the infant. Early studies suggest that the consequences of these psychologic aspects of the disease may lead to feelings of isolation and rejection, loss of confidence, altered sexual attitudes, and disrupted interpersonal relationships (Swanson et al., 1995). Nurses need to be aware of the psychologic effects of being diagnosed with herpes simplex genital infections and be sensitive to fears and concerns accompanying this diagnosis (Carney, Ross, Bunker, Ikkos, & Mindel, 1994). These psychologic effects may influence the behavior and decisions made by infected individuals related to safe sex practices, such as condom use and disclosure of the disease to sexual partners and health care providers. These behaviors will have an impact on transmission of the disease to others and may hinder the health care provider from providing the safest, most appropriate treatments and management interventions. Most interventions to control the spread of the disease focus on behaviors surrounding safe sex practices and disclosure issues. One approach, which combines psychologic support to increase coping skills and education on behaviors, has been shown to change risk behaviors. This approach has shown that individual education and counseling are more effective than group programs for individuals diagnosed with genital herpes (Swanson, 1999). Therefore, when offering support to women who either acquire HSV infection during pregnancy or have been previously infected and are at risk for reactivation during pregnancy, this approach may be the most helpful.
Nursing Implications In many medical centers, newborn nurseries, birthing centers, and ambulatory care facilities, nurses are the primary health care providers. Nurses need to know about the most current information on HSV infection and risks Volume 31, Number 1
of infection for the newborn. Nurses also must be clear on current recommendations or guidelines for care. Psychologic support for women who are anxious about the potential transmission of the disease to the newborn and education about the disease will help combat the spread of the disease and help the mother better care for her newborn. Primary prevention programs to reduce the spread of genital HSV infection should include information about the transmission of the disease, safe sex practices, and condom use. Nurses involved in these programs should use every opportunity to include information about the risk of an infected mother transmitting the disease to the newborn. Preconception counseling also should include this information. It is important for the nurse to obtain an accurate and thorough history concerning the signs and symptoms of genital herpes. Women who are infected may report no clinical symptoms, but they can and do shed the virus. Physical examinations should include inspection for signs of herpes lesions. The assessment of the pregnant woman should include an accurate history and physical examination. If the pregnant woman has a history of recurrent infections, options for treatment and delivery need to be discussed. The potential for a cesarean delivery if lesions are present at the time of spontaneous labor, rupture of membranes, or elective induction of labor should be included in the discussion. If medication, such as acyclovir, is used to suppress reactivation of lesions, then the nurse should reinforce the benefits and importance of this treatment. At the time of delivery, the newborn should be inspected for signs of lesions. Any symptoms of infection should be reported immediately. Herpes simplex always should be considered a potential source of infection in the sick neonate. Failure to consider HSV infection can lead to delayed treatment and increased likelihood of neonatal morbidity and mortality. Lesions caused by HSV (both orofacial and genital) present in the mother during the postpartum period require reinforcing good hand washing with the mother if she contacts these lesions with her hands. The mother should avoid kissing the infant, particularly on the mouth, if she has orofacial lesions. The mother also should be informed of the warning signs of infection and how to recognize lesions in the newborn on discharge. She should be encouraged to call the infant’s health care provider if she observes any of the signs of illness. Accurate information and clear explanations are important, along with sensitivity to the individual mother’s emotional state and her concerns about the diagnosis of genital herpes.
Conclusion Universal screening does not appear feasible at this time, and primary cases and asymptomatic cases often are missed. Cesarean section is recommended if lesions are January/February 2002
present around the time of delivery. Acyclovir can be used during pregnancy to treat infections. Although some evidence suggests that acyclovir may suppress viral shedding and may be of some benefit, the efficacy of this practice has not been proven. Early identification and neonatal diagnosis of the disease and early and rapid treatment remain critical in reducing newborn morbidity and mortality. The key to preventing the spreading of herpes infections and transmission to the neonate is recognition of risk factors and symptoms of the disease. Nurses can strengthen patient awareness through education and counseling. As the technology for screening and testing for the disease improves and becomes less expensive and more widely available, management issues and guidelines during pregnancy may become more precise. Treatment with antivirals, such as acyclovir, and vaccines may become part of the recommended guidelines. In the meantime, it is the obligation of health care providers who care for pregnant women and their infants to be knowledgeable about current practice and to provide accurate and sensitive information. REFERENCES Alanen, A., & Hukkanen, V. (2000). Herpes simplex virus DNA in amniotic fluid without neonatal infection. Clinical Infectious Diseases, 30, 363-367. American College of Obstetricians and Gynecologists. (1999). Management of herpes in pregnancy (ACOG Practice Bulletin No. 8). Washington, DC: Author. Andrews, E. B., Yankaskas, B. C., Cordero, J. F., Schoeffler, K., Hampp, S., & The Acyclovir in Pregnancy Registry Advisory Committee. (1992). Acyclovir in pregnancy registry: Six years’ experience. Obstetrics & Gynecology, 79, 7-13. Baker, D. A. (1999). The use of antiviral medications in the treatment of herpes simplex virus infections of women. International Journal of Fertility, 44, 227-233. Benedetti, J., Corey, L., & Ashley, R. L. (1994). Recurrence rate in genital herpes after symptomatic first-episode infection. Annals of Internal Medicine, 121, 847-854. Boggess, K., Watts, H., Hobson, A. C., Ashley, R. L., Brown, Z. A., & Corey, L. (1997). Herpes simplex virus type 2 detection by culture and polymerase chain reaction and relationship to genital symptoms and cervical antibody status during the third trimester of pregnancy. American Journal of Obstetrics and Gynecology, 176, 443-451. Brocklehurst, P. (1999). Update on the treatment of sexually transmitted infections in pregnancy-2. International Journal of STD & AIDS, 10, 636-643. Brown, Z. A. (2000). HSV-2 specific serology should be offered routinely to antenatal patients. Reviews in Medical Virology, 10, 141-144. Brown, Z. A., Selke, S., Zeh, J., Kopelman, J., Maslow, A., Ashley, R. L., et al. (1997). The acquisition of herpes simplex virus during pregnancy. New England Journal of Medicine, 337, 509-515.
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Carney, O., Ross, E., Bunker, C., Ikkos, G., & Mindel, A. (1994). A prospective study of the psychological impact on patients with a first episode of genital herpes. Genitourinary Medicine, 70, 40-45. Centers for Disease Control and Prevention. (1998). Guidelines for the treatment of sexually transmitted diseases. Morbidity and Mortality Weekly Report, 47, 19-27. Centers for Disease Control and Prevention. (1999). Sexually transmitted disease surveillance. Retrieved from CDC.gov/nchstp/dstd/stats. Cline, M. K., Bailey-Dorton, C., & Cayelli, M. (2000). Update in maternity care: Maternal infections diagnosis and management. Primary Care, 27, 13-33. Desselberger, U. (1998). Herpes simplex virus infection in pregnancy: Diagnosis and significance. Intervirology, 41, 185190. Frenkel, L. M., Brown, Z. A., Bryson, Y. J., Corey, L., Unadkat, J. D., Hensleigh, P. A., et al. (1991). Pharmacokinetics of acyclovir in the term human pregnancy and neonate. American Journal of Obstetrics and Gynecology, 164, 569-576. Haddad, J., Langer, B., Astruc, D., Messer, J., & Lokiec, F. (1993). Oral acyclovir and recurrent genital herpes during late pregnancy. Obstetrics and Gynecology, 82, 102-104. Hensleigh, P. A., Andrews, W. W., Brown, Z., Greenspoon, J., Yasukawa, L., & Prober, C. G. (1997). Genital herpes during pregnancy: Inability to distinguish primary and recurrent infections clinically. Obstetrics & Gynecology, 89, 891-895. Jones, C. L. (1996). Herpes simplex virus infection in the neonate: Clinical presentation and management. Neonatal Network, 15, 11-15. Prober, C. G., Corey, L., Brown, Z. A., Hensleigh, P. A., Frenkel, L. M., Bryson, Y. J., et al. (1992). The management of pregnancies complicated by genital infections with herpes simplex virus. Clinical Infectious Disease, 15, 1031-1038. Randolph, A. G., Hartshorn, R. M., & Washington, A. E. (1996). Acyclovir prophylaxis in late pregnancy to pre-
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vent neonatal herpes: A cost-effectiveness analysis. Obstetrics & Gynecology, 88, 603-610. Riley, L. E. (1998). Herpes simplex virus. Seminars in Perinatology, 22, 284-292. Roberts, S. W., Cox, S. M., Dax, J., Wendel, G. D., & Leveno, K. J. (1995). Genital herpes during pregnancy: No lesions, no cesarean. Obstetrics & Gynecology, 85, 261-264. Scott, L. L., Sanchez, P. J., Jackson, G. L., Zeray, F., & Wendel, G. D. (1996). Acyclovir suppression to prevent cesarean delivery after first-episode genital herpes. Obstetrics & Gynecology, 87, 69-73. Swanson, J. M. (1999). The biopsychosocial burden of genital herpes: Evidence-based and other approaches to care. Dermatology Nursing, 11, 257-268. Swanson, J. M., Dibble, S. L., & Chenitz, W. C. (1995). Clinical features and psychosocial factors in young adults with genital herpes. Image: Journal of Nursing Scholarship, 27, 16-22. Whitley, R. J., Arvin, A., Prober, C., Corey, L., Burchett, S., Plotkin, S., et al. (1991). Predictors of morbidity and mortality in neonates with herpes simplex virus infections. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. New England Journal of Medicine, 324, 450-454. Wilkinson, D., Barton, S., & Cowan, F. (2000). HSV-2 specific serology should not be offered routinely to antenatal patients. Reviews in Medical Virology, 10, 145-153. Wyckoff, M. M. (2000). Neonatal herpes simplex virus type II. Maternal Child Nursing, 25, 100-103.
Deborah Blair Donahue is a visiting scholar, Boston College School of Nursing, Chestnut Hill, MA. Address for correspondence: Deborah Blair Donahue, RNC, PhD, Boston College School of Nursing, Chestnut Hill, MA 02467. E-mail: [email protected].
Volume 31, Number 1
CLINICAL ISSUES
Diagnosis and Treatment of Herpes Simplex Infection During Pregnancy Deborah Blair Donahue, RNC, PhD
When pregnant women acquire primary herpes simplex genital infections or experience recurrent infections around the time of delivery, the risk of transmitting the disease to their newborns is significant. This perinatal transmission can result in a serious neonatal illness. Issues surrounding screening, treatment, and mode of delivery to prevent perinatal transmission often are confusing and controversial. Nurses delivering care to childbearing women and their newborns must be aware of the current information to give accurate and helpful information and support. Nurses also need to understand the effect this disease has both physiologically and psychosocially on women with primary infections, recurrent infections, and women at risk of acquiring the infection during pregnancy. JOGNN, 31, 99–106; 2002. Keywords: Antiviral treatment—Herpes— Neonate—Pregnancy Accepted: August 2001 The herpes simplex virus (HSV) Type 2 and HSV Type 1 genital infections are incurable sexually transmitted diseases. Type 2 (HSV-2) is associated most often with infections of the genital tract (herpes vulvovaginitis), and Type 1 (HSV-1) most often is an infection of the orofacial region (herpes labialis or cold sores). However, HSV-1 has been found in the genital tract in some cases (Centers for Disease Control and Prevention [CDC], 1998). HSV-1 or HSV-2, when first acquired during pregnancy, can result in severe systemic symptoms in the mother and significant morbidity and mortality in the newborn (Riley, 1998). Infants born to mothers with a primary herpes simplex infection have a 30–50% risk of acquiring the infection via perinatal transJanuary/February 2002
mission near or during the delivery. Recurrent maternal genital herpes simplex infections carry a 1–3% risk of neonatal infection if the recurrence occurs around the time of a vaginal delivery. Without a positive identification of the genital lesions or positive history for HSV in the mother, the infection in the newborn may not be immediately recognized. This may delay treatment and result in extreme neonatal complications or death. Therefore, key elements in controlling the disease in childbearing women and their infants are (a) understanding the disease process and risks of transmission, (b) emphasizing prevention, (c) early and accurate diagnosis in both the mother and newborn, and (d) appropriate and timely treatment.
Pathology HSV-1 can cause both orofacial lesions (cold sores) and genital tract lesions, whereas HSV-2 lesions are almost exclusively found in the genital tract. Also, HSV-1 infections in the genital tract have a lower recurrence rate than HSV-2 genital infections (Benedetti, Corey, & Ashley, 1994). Therefore, the genital HSV-2 infections are the most significant infections of concern during childbearing. HSVs are members of the Herpesviridae family of viruses, the same group of viruses as cytomegalovirus, varicella zoster, Epstein-Barr, and human herpes virus, Type 6. An infection caused by the HSV occurs when the virus enters the cells of the mucosa and replicates in the epithelial cells. The virus also will enter sensory nerve cell endings, travel through the nerve cells, and continue to replicate. The virus may then remain latent in these sensory ganglia. When reactivated, the virus travels back to
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the genital mucosa by way of the sensory nerve cells. These mature viruses are shed into the genital area, often causing symptoms associated with the infection. If contact is made during the reactivation, the infection may be transmitted to another person. The incubation period (time from infection to symptoms or expression of the disease) for HSV-2 infection is between 2 and 20 days. Primary lesions develop over a period of 8 to 10 days and last for approximately 10 to 12 days. The lesions often are associated with significant pain and on inspection appear as reddened areas on the mucus membrane with small clusters of fluid-filled blisters. Primary infections are new infections and often can be subclinical. It may not be until a nonprimary, first-episode infection (see Table 1 for definition of terms) that clinical symptoms are obvious to the patient, in this case the pregnant woman (Desselberger, 1998). Previous HSV-1 infection does help reduce the risk of acquiring a severe firstepisode HSV-2 infection. Ninety percent of the adult population has a positive antibody titer against HSV-1, indicating previous HSV-1 infection. However, this previous HSV-1 infection will not protect the pregnant woman or any individual from acquiring the HSV-2 infection. Reactivation or recurrence of an HSV-2 infection may either cause distinct clinical symptoms or may be symptomless or subclinical. In fact, only a minority of individuals with positive HSV-2 antibody titers, indicating previous infection, report having had symptoms related to an actual history of genital herpes infection (Hensleigh et al., 1997). Recurrent infections with subclinical shedding of HSV-2 infection are estimated to occur from 1–5% of the time, and shedding of the virus can last for several days (Desselberger, 1998). Reactivations of the infection may occur at any time, but certain stimuli are thought to be associated with outbreaks. These stimuli may be physical or emotional stress, exposure to ultraviolet light, tissue damage, or suppression of the immune system (Hensleigh et al., 1997). The natural immunosuppressive state of pregnancy contributes to the recurrent herpes infections, and the frequency, duration, and severity of symptoms often increase as pregnancy progresses (Brocklehurst, 1999).
Perinatal Transmission Perinatal transmission of HSV-2 is the almost exclusive cause of neonatal herpes HSV-2 infections. It has been estimated that 5% of cases of neonatal infections may occur from intrauterine transmission, and HSV-2 DNA has been isolated from amniotic fluid. However, in the cases in which HSV-2 DNA was found in the amniotic fluid, not one was shown to be associated with neonatal infection. Therefore, perinatal transmission to the newborn seems most likely to occur during delivery, particularly during vaginal delivery (Alanen & Hukkanen, 2000). 100 JOGNN
TABLE 1
Definitions of Genital Herpes (HSV-1 and HSV2) Infectious Status True primary, first episode
First clinical episode
Nonprimary, first clinical episode
Recurrent or reactivation of infection
Asymptomatic shedding
First presentation of clinical symptoms of either HSV-1 or HSV-2 infection in a woman seronegative (no previous exposure or infection) for both HSV-1 and HSV-2. Previous infection confirmed as seropositive for HSV-2 but experiencing clinical symptoms of disease for the first time. Initial genital infection in a woman seropositive to a viral strain of HSV different from the HSV strain on culture. For example, a woman seropositive for HSV-1 (previous HSV-1 infection) but HSV-2 seronegative with HSV-2 positive culture indicating HSV2 infection newly acquired. HSV infection in a woman seropositive for the same HSV viral strain on culture. For example, HSV-2 seropositive and lesions culture positive for HSV-2. Positive HSV culture from the genital tract of a woman not perceiving any symptoms of infection and no lesions observed by trained examiner.
Note. HSV-1 = herpes simplex virus type 1; HSV-2 = herpes simplex virus type 2.
Fetal complications have been reported as well as the neonatal complications. These complications are reported to occur more frequently with primary infections. Fetal complications include an increased risk of spontaneous abortion, preterm birth, and, when infection occurs during the 3rd trimester, an increased risk for fetal growth restriction (Hensleigh et al., 1997). The greatest herpes threat to the newborn occurs when the mother becomes infected and experiences a first episode of genital herpes during pregnancy, near term, without obvious lesions or signs and symptoms, and the infection is not recognized. The majority of neonatal infections are due to HSV-2 acquired through maternal transmission during the intrapartum or immediate postpartum period. Most of the infants infected by perinatal Volume 31, Number 1
transmission are born to mothers with no history of herpes infection or evidence of genital herpes lesions. This makes prevention of perinatal transmission a challenge. Women with true primary, first-episode genital herpes during pregnancy, and perinatal transmission, have the highest risk for fetal and neonatal morbidity (Prober et al., 1992). This may be in part because the lesions from primary, first-episode maternal HSV infections have higher rates of virus replication and a longer period of viral shedding than
T
he natural immunosuppressive state of pregnancy contributes to the recurrent herpes infections and the increases in frequency, duration, and severity of symptoms often seen as pregnancy progresses.
lesions from recurrent episodes. Primary infections also mean that there is a lack of maternal antibodies available for transport to the fetus via the placenta to help protect the infant from infection (Jones, 1996). Newborns of women who have had primary exposure to HSV-2 but have not yet seroconverted at the time of delivery seem to avoid neonatal disease. In these cases, even the very low levels of transplacentally acquired HSV antibodies seem to help protect these infants. This raises the possibility of the development of a vaccine. Such a vaccine could be given to mothers at risk for infection (no previous infection of HSV-2) to establish an antibody level to help prevent infection near delivery and reduce the risk of neonatal disease.
Neonatal Disease Congenital HSV-2 infection may occur in the newborn with the characteristic skin vesicles, chorioretinitis, hydroencephaly, or microencephaly (Riley, 1998). Neonatal HSV infection may develop after birth as a localized infection with lesions or vesicles occurring only on the skin, eyes, and/or in the mouth or as a diverse disseminating infection with systemic symptoms. Mortality rates are lower in infants with only localized infections (Jones, 1996). Systemic infections of the brain and central nervous system cause encephalitis and meningitis, and systemic infections of multiple organs may occur in the lungs, liver, and adrenals (Wyckoff, 2000). Systemic infections may occur with or without localized skin lesions. Diagnosis in the neonate is difficult without a history of or evidence of exposure to HSV. Neonatal herpes infection may resemble a more common bacterial sepsis. Some of the clinical symptoms of neonatal HSV infection are January/February 2002
irritability, seizures, respiratory distress, jaundice, disseminated intravascular coagulation, and shock (Wyckoff, 2000). Infants with immediate or early treatment have better outcomes than infants with late diagnosis and delayed treatment (Whitley et al., 1991). Mortality rates from disseminating infections have decreased from 90% to 60% because of early recognition and antiviral drug treatment (Wyckoff, 2000). The current CDC recommendation for treatment of neonates infected with HSV is the administration of 30 to 60 mg/kg/day of intravenous acyclovir for 10 to 21 days (CDC, 1998). If exposure to HSV is suspected, whether the newborn is delivered by cesarean or vaginally, some experts recommend that cultures of the newborn’s oral mucosa should be done. Isolating the virus before clinical symptoms become manifest allows treatment to begin earlier and may decrease the severity of the newborn’s infection.
Maternal Disease and Diagnosis The mean duration of first-episode clinical symptoms in nonprimary, recurrent infections is 12 days. Clinical symptoms of the first episode may include systemic symptoms, such as fever, headache, malaise, or myalgia, as well as active genital herpes lesions. Genital lesions often are associated with bilateral inguinal lymphadenopathy (Hensleigh et al., 1997). The severity of the symptoms, even when a severe first-episode genital herpes infection appears during the 2nd and 3rd trimesters of pregnancy, does not indicate whether the infection is a primary or recurrent infection (see Table 1). In a prospective research project designed to examine the prevalence rates and outcomes of HSV infections, cultures and viral serology testing were conducted on women with first-episode clinical signs and symptoms suggestive of primary infection. The results revealed that most of the cases were nonprimary infections (Hensleigh et al., 1997). The presence of HSV1 and/or HSV-2 antibodies confirmed previous infection, even though the women reported no previous symptoms or clinical signs of infection. Women with recurrent herpes can be reassured that their risk of transmitting the infection to their newborns is lower (CDC, 1998). Blood tests can be performed to detect HSV antibodies. However, with currently available serologic testing, it is difficult to distinguish between HSV-1 and HSV-2 infections. Western blot testing can be used to detect HSV-2 specifically, but these tests are expensive, laborious, and not routinely done for diagnostic purposes. HSV-1- and HSV-2-specific monoclonal antibodies can be identified and diagnosed by an immunoflourescence technique, also expensive and not available at all laboratories. HSV antigen assay is available and is cheaper, easier, and quicker. However, the currently available commercial enzyme immunoassays cannot distinguish between HSV-1 and HSV-2 (Desselberger, 1998).
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Viral cultures have been the gold standard (CDC, 1998) and can be obtained by scraping vesicles, ulcers, or crusted lesions. Viral DNA may be analyzed from the material obtained for cultures using polymerase chain reaction. With DNA analysis, the distinction between HSV-1 and HSV-2 can be easily made. Polymerase chain reaction is superior to viral culture alone and can be used to detect late infection and asymptomatic HSV infections during pregnancy (Alanen & Hukkanen, 2000; Boggess et al., 1997; Desselberger, 1998). However, this technique is available only in laboratories specializing in HSV detection and would prove difficult and expensive in testing a large population of women. The seroprevalence rate for HSV-2 infection in the United States has increased in the past few years as much as 30% for the age range of 12 to 39 years. This range coincides with the range of childbearing ages. Risk factors for acquiring an HSV-2 infection are related to sexual practices. A correlation exists between the number of sexual partners reported and the prevalence of HSV-2. Statistically, women are more likely than men to become infected (CDC, 1999; Riley, 1998). The reason for this may not be fully understood. Because of the known risk factors, a thorough sexual history may be helpful in identifying women most at risk for genital herpes infections.
Routine Screening for HSV-2 Status Debate exists regarding whether all pregnant women should be screened to identify their HSV status. The argument for screening is the potential to lower the risk of perinatal transmission by identifying women likely to be at risk of acquiring a primary infection during pregnancy or previously infected women at risk for recurrence at the time of delivery. The proposed method for screening would use HSV-2-specific serology on all pregnant women to identify those who are seronegative for HSV-1 and HSV-2 (Brown, 2000). Women with no previous exposure to HSV-1 or HSV-2 are the most vulnerable group should a genital herpes infection be acquired during pregnancy, particularly near the time of delivery. Women who are seronegative for HSV-2 and seropositive for HSV-1 are at risk, but to a lesser degree, of acquiring the disease, transmitting it to the fetus or newborn, and experiencing the morbidity and mortality risks seen in neonates. Both groups, if identified, could be counseled to practice safe sex by using condoms or abstinence during pregnancy, particularly during the 3rd trimester. Prevention strategies are of increased importance at that time because women are more susceptible to infection during the 3rd trimester because of the normal immunosuppression state then (Brown, 2000). Brown (2000) further suggested the efficacy of testing the male partner of the pregnant woman whose status is seronegative for HSV-2. If he is seropositive, indicating previous infection and risk for 102 JOGNN
recurrence and transmission, then he may be given viral suppression with antiviral medication to decrease the risk of transmission to the pregnant woman. However, this practice has many ethical and logistic problems. The other possibility, screening to identify women with seropositive status for HSV-2, would be beneficial as well. Seventy-five percent of this group reports being unaware of their status (Swanson, 1999). Further screening of these women for reactivation or performing viral cultures for subclinical asymptomatic shedding at the time of delivery will identify women at risk of transmitting the disease to the infant during a vaginal birth. Women with seropositive status and positive viral cultures for HSV-2 can be delivered via cesarean section. Wilkinson, Barton, and Cowan (2000) opposed routine screening for all pregnant women. They argued that because the incidence of neonatal HSV infection in the United States is 1 in 7,500 live births, the screening of all pregnant women would not be cost-effective. In addition, they point to a retrospective study conducted by Brown et al. (1997) of 94 seronegative women who converted to seropositive for HSV-2 during pregnancy. In the study population, 30% converted to seropositive during the 1st trimester, 30% converted during the 2nd trimester, and 40% during the 3rd trimester. In all subjects with seroconversion before labor (indicating the presence of maternal antibodies to the HSV-2), no neonatal disease was seen. Therefore, based on this information, Wilkinson et al. claimed that population testing would not be beneficial or cost-effective. Furthermore, these authors pointed out that reliable commercial testing for HSV-2-specific antibodies is not readily available. They argued that a bet-
T
he severity of the symptoms during an infection, even when a severe firstepisode genital herpes infection appears during pregnancy, does not indicate whether the infection is a primary infection or a recurrent one.
ter use of resources would be to develop a test to recognize the disease in the newborn such as rapid virus or antigen detection tests. Such tests would allow earlier treatment and thus prevent significant neonatal morbidity and mortality. It is possible that when such diagnostic strategies do become available, testing also could be used to better identify those women at risk for perinatal transmission. Volume 31, Number 1
Mode of Delivery Mode of delivery, vaginal versus cesarean, has been the main intervention strategy to prevent perinatal transmission of genital HSV to the newborn. The current recommendations are based on the American College of Obstetricians and Gynecologists (1999) guidelines for mode of delivery and management of labor for women with a history of HSV infection. Cesarean section is not recommended when a woman with a history of recurrent infections is in labor, no obvious lesions are apparent to the experienced examiner, and the woman reports no symptoms of infection (Roberts, Cox, Dax, Wendel, & Leveno, 1995). A cesarean section is recommended if active lesions are present and should be performed within 6 hours of rupture of membranes. However, even when lesions or symptoms of infection are not present at the
A
cyclovir given for treatment of first-episode infections of HSV-2 during the late 3rd trimester has been shown to be an effective alternative to routine cesarean delivery in preventing perinatal transmission.
time of delivery, because a very low risk of transmission exists, the use of fetal scalp electrodes or fetal blood sampling is not recommended during labor (Cline, BaileyDorton, & Cayelli, 2000). To restate the current policy for women with known HSV-2 infections, a vaginal birth is recommended for delivery if maternal genital herpes cultures are negative before labor. However, if herpes cultures are positive or unavailable at time of delivery, then a cesarean should be performed. This practice policy was examined by researchers at Parkland Hospital in Dallas, Texas (Roberts et al., 1995). In this study, the authors reported a significant decline in the cesarean birth rate at their hospital and no subsequent increase in the incidence of neonatal herpes simplex infection when this policy was applied. However, it must be emphasized that this policy is not guaranteed to prevent all perinatal transmission of infection to the newborn. Because there is a small chance that perinatal transmission can occur, even with negative HSV cultures at the time of vaginal delivery, other strategies are emerging. Randomized clinical trials, as well as retrospective data, support the administration of oral acyclovir to women with recurrent HSV-2 genital lesions as a method to reduce neonatal and maternal morbidity and mortality. January/February 2002
Acyclovir may reduce the recurrence rate by 80% and the asymptomatic shedding of virus by 80–95% (Randolph, Hartshorn, & Washington, 1996). However, acyclovir does not prevent all asymptomatic shedding of the virus (Haddad, Langer, Astruc, Messer, & Lokiec, 1993).
Maternal Treatment With Acyclovir The current advice and recommendations for treating and managing genital HSV infection during pregnancy often are confusing and conflicting. One such option is treatment with acyclovir during pregnancy. Oral acyclovir (pregnancy category C) may be administered for the first clinical episode of genital herpes infection during pregnancy. Acyclovir has few side effects and is usually well tolerated. In cases of disseminated infection, encephalitis, pneumonitis, or hepatitis, the acyclovir treatment should be administered intravenously (CDC, 1998). Acyclovir is more effective in treating primary infections for reducing symptoms, length of viral shedding, and time required to heal lesions than it is in recurrent infections (Baker, 1999). Unfortunately, once replication of the virus in the sensory ganglia is complete, antiviral medications are not effective in destroying the virus. The Acyclovir in Pregnancy Registry was established in 1984 to gather prospective and retrospective data on the effects of prenatal exposure to the antiviral agent, acyclovir (Andrews et al., 1992). The registry was disbanded recently, but the data have not shown an increase in the number of birth defects from 1st, 2nd, or 3rd trimester exposure when compared with defects expected in the general population. Acyclovir given for treatment of firstepisode infections of HSV-2 during the late 3rd trimester has been shown to be an effective alternative to routine cesarean in preventing perinatal transmission (Scott, Sanchez, Jackson, Zeray, & Wendel, 1996). The CDC recommendations for treatment of genital herpes with acyclovir are shown in Table 2. However, it must be made clear that although acyclovir is administered orally to treat a first clinical episode of genital HSV during pregnancy and intravenously to treat severe disease, the routine administration of acyclovir to pregnant women with a history of recurrent infection is not recommended by the Food and Drug Administration or the CDC (Cline et al., 2000). Acyclovir crosses the placenta and is concentrated in amniotic fluid and can actually reach therapeutic levels in the fetus through administration to the mother (Frenkel et al., 1991). Even with this information, no changes to practice recommendations have been made to support the routine use of acyclovir in pregnant women with a history of recurrent genital herpes to suppress viral shedding, prevent reactivation of lesions (CDC, 1998), or as a method to prevent neonatal infection. It also should be noted that newer agents such as valacyclovir and famciclovir, both listed as category B agents, have been approved by the
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TABLE 2
Centers for Disease Control and Prevention Recommended Dosages of Acyclovir for Treatment and Suppression of Genital Herpes Simplex Virus Primary Infection First episode 400 mg orally, 3 × daily for 7-10 days; or 200 mg orally, 5 × daily for 7-10 days
Recurrent Infection
Daily Suppression
Severe Disease
400 mg orally, 3 × daily for 5 days; or 200 mg orally, 5 × daily for 5 days; or 800 mg orally, 2 × daily for 5 days
Started: 36 weeks gestation 400 mg orally, 2 × daily until delivery
5-10 mg/kg body weight IV every 8 hours for 5-7 days
Note. Adapted from Centers for Disease Control and Prevention (1998).
Food and Drug Administration for the treatment of herpes. Despite the category B ratings and Food and Drug Administration approval, neither of these drugs has been recommended for use during pregnancy. This is mainly due to the lack of clinical trials or retrospective data on the safety and efficacy of these agents during pregnancy. Randolph et al. (1996) examined the cost-effectiveness of four strategies to prevent transmission to the newborn caused by a recurrent maternal herpes infection. Applying a decision analysis technique, they compared the outcomes of several randomized controlled trials. They reported the probability values for effectiveness and cost. The most effective method for reducing neonatal infection was found to be oral acyclovir prophylaxis in late pregnancy for women with recurrent genital herpes lesions and cesarean section for those women with active lesions at the time of delivery. This policy represents the current recommendations with the added treatment of antiviral suppression around the time of delivery. The highest rates of transmission were found in the group of women who received no intervention (no antiviral medications and vaginal delivery), followed by women with cesarean delivery without antiviral drug suppression. The group with acyclovir and cultures, delivered vaginally, with follow-up treatment of infants exposed to herpes (mothers with positive cultures), represent the lowest cost but resulted in a higher incidence of neonatal HSV infections than the cesarean groups with or without antiviral suppression.
Psychosocial Implications of the Disease The significance of the psychosocial impact that a diagnosis of genital herpes simplex has on women of childbearing age should not be underestimated. As stated earlier, there is anecdotal evidence that stress may play a role in triggering a reactivation of the disease (Swanson, Dibble, & Chenitz, 1995). Although this phenomenon is not totally understood and some of the data are inconsistent, the most commonly experienced psychologic or emotional response to the disease is depression (Swanson, 104 JOGNN
1999). The burden of living with the disease includes psychologic concerns, such as not knowing when a reactivation will occur, fear of transmission to a partner, and fear of transmission to the newborn during pregnancy or during delivery of the infant. Early studies suggest that the consequences of these psychologic aspects of the disease may lead to feelings of isolation and rejection, loss of confidence, altered sexual attitudes, and disrupted interpersonal relationships (Swanson et al., 1995). Nurses need to be aware of the psychologic effects of being diagnosed with herpes simplex genital infections and be sensitive to fears and concerns accompanying this diagnosis (Carney, Ross, Bunker, Ikkos, & Mindel, 1994). These psychologic effects may influence the behavior and decisions made by infected individuals related to safe sex practices, such as condom use and disclosure of the disease to sexual partners and health care providers. These behaviors will have an impact on transmission of the disease to others and may hinder the health care provider from providing the safest, most appropriate treatments and management interventions. Most interventions to control the spread of the disease focus on behaviors surrounding safe sex practices and disclosure issues. One approach, which combines psychologic support to increase coping skills and education on behaviors, has been shown to change risk behaviors. This approach has shown that individual education and counseling are more effective than group programs for individuals diagnosed with genital herpes (Swanson, 1999). Therefore, when offering support to women who either acquire HSV infection during pregnancy or have been previously infected and are at risk for reactivation during pregnancy, this approach may be the most helpful.
Nursing Implications In many medical centers, newborn nurseries, birthing centers, and ambulatory care facilities, nurses are the primary health care providers. Nurses need to know about the most current information on HSV infection and risks Volume 31, Number 1
of infection for the newborn. Nurses also must be clear on current recommendations or guidelines for care. Psychologic support for women who are anxious about the potential transmission of the disease to the newborn and education about the disease will help combat the spread of the disease and help the mother better care for her newborn. Primary prevention programs to reduce the spread of genital HSV infection should include information about the transmission of the disease, safe sex practices, and condom use. Nurses involved in these programs should use every opportunity to include information about the risk of an infected mother transmitting the disease to the newborn. Preconception counseling also should include this information. It is important for the nurse to obtain an accurate and thorough history concerning the signs and symptoms of genital herpes. Women who are infected may report no clinical symptoms, but they can and do shed the virus. Physical examinations should include inspection for signs of herpes lesions. The assessment of the pregnant woman should include an accurate history and physical examination. If the pregnant woman has a history of recurrent infections, options for treatment and delivery need to be discussed. The potential for a cesarean delivery if lesions are present at the time of spontaneous labor, rupture of membranes, or elective induction of labor should be included in the discussion. If medication, such as acyclovir, is used to suppress reactivation of lesions, then the nurse should reinforce the benefits and importance of this treatment. At the time of delivery, the newborn should be inspected for signs of lesions. Any symptoms of infection should be reported immediately. Herpes simplex always should be considered a potential source of infection in the sick neonate. Failure to consider HSV infection can lead to delayed treatment and increased likelihood of neonatal morbidity and mortality. Lesions caused by HSV (both orofacial and genital) present in the mother during the postpartum period require reinforcing good hand washing with the mother if she contacts these lesions with her hands. The mother should avoid kissing the infant, particularly on the mouth, if she has orofacial lesions. The mother also should be informed of the warning signs of infection and how to recognize lesions in the newborn on discharge. She should be encouraged to call the infant’s health care provider if she observes any of the signs of illness. Accurate information and clear explanations are important, along with sensitivity to the individual mother’s emotional state and her concerns about the diagnosis of genital herpes.
Conclusion Universal screening does not appear feasible at this time, and primary cases and asymptomatic cases often are missed. Cesarean section is recommended if lesions are January/February 2002
present around the time of delivery. Acyclovir can be used during pregnancy to treat infections. Although some evidence suggests that acyclovir may suppress viral shedding and may be of some benefit, the efficacy of this practice has not been proven. Early identification and neonatal diagnosis of the disease and early and rapid treatment remain critical in reducing newborn morbidity and mortality. The key to preventing the spreading of herpes infections and transmission to the neonate is recognition of risk factors and symptoms of the disease. Nurses can strengthen patient awareness through education and counseling. As the technology for screening and testing for the disease improves and becomes less expensive and more widely available, management issues and guidelines during pregnancy may become more precise. Treatment with antivirals, such as acyclovir, and vaccines may become part of the recommended guidelines. In the meantime, it is the obligation of health care providers who care for pregnant women and their infants to be knowledgeable about current practice and to provide accurate and sensitive information. REFERENCES Alanen, A., & Hukkanen, V. (2000). Herpes simplex virus DNA in amniotic fluid without neonatal infection. Clinical Infectious Diseases, 30, 363-367. American College of Obstetricians and Gynecologists. (1999). Management of herpes in pregnancy (ACOG Practice Bulletin No. 8). Washington, DC: Author. Andrews, E. B., Yankaskas, B. C., Cordero, J. F., Schoeffler, K., Hampp, S., & The Acyclovir in Pregnancy Registry Advisory Committee. (1992). Acyclovir in pregnancy registry: Six years’ experience. Obstetrics & Gynecology, 79, 7-13. Baker, D. A. (1999). The use of antiviral medications in the treatment of herpes simplex virus infections of women. International Journal of Fertility, 44, 227-233. Benedetti, J., Corey, L., & Ashley, R. L. (1994). Recurrence rate in genital herpes after symptomatic first-episode infection. Annals of Internal Medicine, 121, 847-854. Boggess, K., Watts, H., Hobson, A. C., Ashley, R. L., Brown, Z. A., & Corey, L. (1997). Herpes simplex virus type 2 detection by culture and polymerase chain reaction and relationship to genital symptoms and cervical antibody status during the third trimester of pregnancy. American Journal of Obstetrics and Gynecology, 176, 443-451. Brocklehurst, P. (1999). Update on the treatment of sexually transmitted infections in pregnancy-2. International Journal of STD & AIDS, 10, 636-643. Brown, Z. A. (2000). HSV-2 specific serology should be offered routinely to antenatal patients. Reviews in Medical Virology, 10, 141-144. Brown, Z. A., Selke, S., Zeh, J., Kopelman, J., Maslow, A., Ashley, R. L., et al. (1997). The acquisition of herpes simplex virus during pregnancy. New England Journal of Medicine, 337, 509-515.
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Carney, O., Ross, E., Bunker, C., Ikkos, G., & Mindel, A. (1994). A prospective study of the psychological impact on patients with a first episode of genital herpes. Genitourinary Medicine, 70, 40-45. Centers for Disease Control and Prevention. (1998). Guidelines for the treatment of sexually transmitted diseases. Morbidity and Mortality Weekly Report, 47, 19-27. Centers for Disease Control and Prevention. (1999). Sexually transmitted disease surveillance. Retrieved from CDC.gov/nchstp/dstd/stats. Cline, M. K., Bailey-Dorton, C., & Cayelli, M. (2000). Update in maternity care: Maternal infections diagnosis and management. Primary Care, 27, 13-33. Desselberger, U. (1998). Herpes simplex virus infection in pregnancy: Diagnosis and significance. Intervirology, 41, 185190. Frenkel, L. M., Brown, Z. A., Bryson, Y. J., Corey, L., Unadkat, J. D., Hensleigh, P. A., et al. (1991). Pharmacokinetics of acyclovir in the term human pregnancy and neonate. American Journal of Obstetrics and Gynecology, 164, 569-576. Haddad, J., Langer, B., Astruc, D., Messer, J., & Lokiec, F. (1993). Oral acyclovir and recurrent genital herpes during late pregnancy. Obstetrics and Gynecology, 82, 102-104. Hensleigh, P. A., Andrews, W. W., Brown, Z., Greenspoon, J., Yasukawa, L., & Prober, C. G. (1997). Genital herpes during pregnancy: Inability to distinguish primary and recurrent infections clinically. Obstetrics & Gynecology, 89, 891-895. Jones, C. L. (1996). Herpes simplex virus infection in the neonate: Clinical presentation and management. Neonatal Network, 15, 11-15. Prober, C. G., Corey, L., Brown, Z. A., Hensleigh, P. A., Frenkel, L. M., Bryson, Y. J., et al. (1992). The management of pregnancies complicated by genital infections with herpes simplex virus. Clinical Infectious Disease, 15, 1031-1038. Randolph, A. G., Hartshorn, R. M., & Washington, A. E. (1996). Acyclovir prophylaxis in late pregnancy to pre-
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vent neonatal herpes: A cost-effectiveness analysis. Obstetrics & Gynecology, 88, 603-610. Riley, L. E. (1998). Herpes simplex virus. Seminars in Perinatology, 22, 284-292. Roberts, S. W., Cox, S. M., Dax, J., Wendel, G. D., & Leveno, K. J. (1995). Genital herpes during pregnancy: No lesions, no cesarean. Obstetrics & Gynecology, 85, 261-264. Scott, L. L., Sanchez, P. J., Jackson, G. L., Zeray, F., & Wendel, G. D. (1996). Acyclovir suppression to prevent cesarean delivery after first-episode genital herpes. Obstetrics & Gynecology, 87, 69-73. Swanson, J. M. (1999). The biopsychosocial burden of genital herpes: Evidence-based and other approaches to care. Dermatology Nursing, 11, 257-268. Swanson, J. M., Dibble, S. L., & Chenitz, W. C. (1995). Clinical features and psychosocial factors in young adults with genital herpes. Image: Journal of Nursing Scholarship, 27, 16-22. Whitley, R. J., Arvin, A., Prober, C., Corey, L., Burchett, S., Plotkin, S., et al. (1991). Predictors of morbidity and mortality in neonates with herpes simplex virus infections. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. New England Journal of Medicine, 324, 450-454. Wilkinson, D., Barton, S., & Cowan, F. (2000). HSV-2 specific serology should not be offered routinely to antenatal patients. Reviews in Medical Virology, 10, 145-153. Wyckoff, M. M. (2000). Neonatal herpes simplex virus type II. Maternal Child Nursing, 25, 100-103.
Deborah Blair Donahue is a visiting scholar, Boston College School of Nursing, Chestnut Hill, MA. Address for correspondence: Deborah Blair Donahue, RNC, PhD, Boston College School of Nursing, Chestnut Hill, MA 02467. E-mail: [email protected].
Volume 31, Number 1