MOONDRAGON'S ARTICLES




PREVENTING HERPES IN THE PREGNANT WOMAN & THE NEONATE

From Medscape from WebMD




INTRODUCTION

At least 50 million people in the United States are infected with the pathogen that causes genital herpes, herpes simplex virus 2 (HSV-2), and more than a million new cases are diagnosed annually. Furthermore, the epidemiology of herpes is shifting, and there is also a significant number of people who have genital herpes caused by infection with HSV-1. Genital herpes is the most common sexually transmitted infection (STI) in the United States and, most likely, the world. A significant portion of those who are infected or vulnerable to infection are women of child-bearing age and their partners. In the United States, 25 to 70 percent of pregnant women are seropositive for HSV-2, depending on race, age, and sexual history, yet only 5 percent report a history of symptomatic infection. According to the most recent studies, 2 to 4 percent acquire the infection during pregnancy.

A complicating factor in managing genital herpes in pregnant women (and their partners) is the often invisible nature of the disease. In the National Health and Nutrition Examination Survey III (1988-1994), of the 22 percent who were seropositive for HSV-2, fewer than 10 percent reported a history of genital herpes. In another study of 5 STD clinics by Gottlieb and colleagues, over 40 percent of those tested were HSV-2 positive, but almost 90 percent of those had never been diagnosed with genital herpes. The most likely reasons for the under-diagnosis of genital herpes are atypical manifestation and asymptomatic infection. Although just 20 percent of HSV-seropositive people have a classic manifestation of the disease, these are still the only examples given in many textbooks. In recurrent episodes, there may be signs and symptoms that are different from or less severe than first-episode infection. This means that both pregnant women and their male partners may be infected without being aware of their HSV status.

Despite its often debilitating effects in adults, it is among neonates that HSV infection can be truly dangerous and can result in high morbidity and mortality. Although there is a low risk of infection for babies born to mothers with recurrent HSV-2 infection, there is a higher risk if the mother experiences primary infection during pregnancy. Up to 40 percent of babies born to mothers who are infected during the third trimester may acquire infection. In the United States, approximately 1600 to 2000 neonates contract HSV infection each year. Although HSV-2 is responsible for the majority of neonatal infections, up to 30 percent of infections are caused by HSV-1. Infections are classified as skin/eye/mouth (SEM), central nervous system (CNS), or disseminated disease, according to the extent of the disease at presentation. Neonatal infections are generally equally divided among the 3 categories. Mortality is highest for infants with disseminated disease, and morbidity is highest for survivors of CNS infection. Infections caused by HSV-1 tend to be less likely to result in severe disease, as HSV-2 seems to be responsible for most cases of neonatal herpes encephalitis.

As the prevalence of herpes rises, so will the risk of infection during pregnancy. Knowledge of the latest developments in managing pregnancy and delivery for infected women and treating infected neonates is essential. Current developments in type-specific serologic testing and antiviral therapy for HSV provide new options for managing and treating both infected pregnant women and neonates. One of the most important concerns is preventing transmission of the virus from mother to newborn. Most neonatal infections are acquired from contact with infected maternal genital tract secretions, and preventive strategies now in use include cesarean delivery, serologic screening of pregnant women, and prophylactic antiviral therapy. The 2 strategies currently accepted by most obstetricians are cesarean delivery for women with active lesions or prodromal symptoms and prophylactic antiviral therapy for women with gestational herpes. There has been and continues to be considerable controversy on the optimum management of infected pregnant women (see sections below on serologic testing, antiviral therapy, and delivery options for some examples), and recommendations are continually developing.

The recommendations for treatment of neonates and infants with HSV infection, the population most at risk for serious effects, are also constantly changing. As the use of antivirals in neonates and infants continues to be studied, guidelines for these treatments will become more sophisticated.





OUTCOMES FROM GENITAL HERPES INFECTION IN PREGNANT WOMEN & NEONATES

THE HEALTH OF THE PREGNANT WOMAN

Women who are already infected when they become pregnant may experience a slight increase in the frequency of outbreaks and asymptomatic shedding, especially in the third trimester. A study by Brown and colleagues from 1985 found that the frequency of outbreaks for women infected during pregnancy was slightly higher than that of women infected prior to pregnancy, but asymptomatic shedding was significantly higher. Young age was also associated with more frequent asymptomatic viral shedding. Virus excretion was more common from the vulvar area than the cervix, and women infected during pregnancy were more likely to shed virus from both sites simultaneously than women infected prior to pregnancy.

For most pregnant women who are not immunocompromised, acquiring genital herpes during pregnancy is not likely to significantly affect their overall health directly. However, there are documented cases of disseminated HSV disease in pregnant women; 21 cases have been reported where healthy women contracted life-threatening disseminated HSV infections in the third trimester of pregnancy. In a report on a case of maternal disseminated HSV with subsequent death at an estimated 31 weeks' gestation, the authors noted that most of these 21 patients had nonspecific symptoms, and many did not have mucocutaneous lesions. On physical examination, these women were usually febrile, although not jaundiced, and had notably high aminotransferase values without a corresponding rise in bilirubin. The authors also noted that prompt acyclovir therapy resulted in 100% survival, but that among patients receiving no treatment or late treatment, mortality was 63 percent. A recent Norwegian nested case-control study by Eskild and collaborators involving 35,940 women found no correlation between HSV-2 infection and fetal death.

For women infected with HIV as well as HSV, a study of the correlation between HIV infection and HSV endometritis by Wright and colleagues found a higher incidence of HSV endometritis in the HIV-positive patients. Coinfection with HSV-2 and HIV is common, and pregnant women who are HIV positive should be especially closely monitored if they are also infected with HSV or at risk for becoming infected. A study on the role of HSV infection and reactivation at delivery among pregnant women infected with HIV-1 found that HSV-2 reactivation complicated labor more often in this population than in other pregnant women.

THE HEALTH OF THE NEONATE

Neonatal herpes is a severe systemic viral infection with high morbidity and mortality, most commonly acquired after contact with maternal genital secretions during delivery. This can be through contact with active genital lesions in the mother, but many neonatal infections are the result of asymptomatic cervical shedding of the virus after a primary episode of genital HSV in the third trimester.


A diagnosis of neonatal HSV is made by culturing the blood, cerebrospinal fluid, and urine as well as fluid from eyes, nose, and mucous membranes. For neonates infected during delivery, the 3 categories of disease have distinctly different possible outcomes for morbidity and mortality. At presentation, SEM disease is characterized by lesions localized to the skin, eye, or mouth. With antiviral treatment, there is usually a complete recovery for infants born with SEM disease; without treatment up to 75 percent will progress to CNS or disseminated disease. CNS disease presents as encephalitis, with or without skin, eye, or mouth involvement. Infants with CNS disease exhibit fever and lethargy for 2 to 3 weeks after birth, generally followed by focal seizures that are difficult to control. The cerebrospinal fluid is usually bloody, with elevated white blood cell count, slightly reduced glucose, and a high protein concentration. In disseminated infection, multiple sites can be involved, including the CNS, lungs, liver, and adrenals, as well as skin, eye, or mouth. The symptoms during the first few days after birth often suggest severe bacterial sepsis, and the infants generally present with hepatomegaly, jaundice, an abnormal liver function test, coagulopathy, and pneumonia with progressive respiratory distress. Later in the course of the disease, approximately 66 percent will develop skin lesions.

TABLE 1. MANIFESTATIONS OF NEONATAL HERPES INFECTIONS


CATEGORY
SYMPTOMS
MORBIDITY / MORTALITY

SEM Involvement
(skin/eye/mouth)

  • Lesions on skin, eye or mouth.

  • 5% progression to morbid state.
  • For the most part, complete recovery for infants rapidly treated with antivirals.
  • Without treatment, </= 75% can advance to CNS or disseminated disease.

  • CNS Disease
    (central nervous system infection)

  • Encephalitis
  • Occasional SEM involvement
  • Fever and lethargy 2 to 3 weeks after birth.
  • Focal seizures.
  • Bloody cerebrospinal fluid.
  • Elevated WBC count.
  • Reduced glucose.
  • High protein concentration.

  • >/= 50% mortality.

  • Disseminated Disease

  • Symptoms immediately following birth may imply severe bacterial sepsis.
  • Involvement of multiple sites (eg, CNS, lungs, liver, and adrenals, skin, eye or mouth).
  • Hepatomegaly.
  • Jaundice.
  • Abnormal liver function test.
  • Coagulopathy.
  • Pneumonia with progressive respiratory distress.
  • Skin lesions approximately 66% during later stages of disease.

  • 70% mortality.


  • Over the past 2 decades there have been changes in the presentation of neonatal HSV infection, including an increase in the frequency of SEM disease, a relatively unchanged rate of CNS disease, and a relative decrease in disseminated infection. Antiviral therapy has helped to reduce mortality from neonatal HSV infections, but the mortality rates in CNS disease (15 percent) and disseminated disease (57 percent) remain high. Long-term morbidity has been seen most often in infants with CNS and disseminated disease, with possible symptoms including seizures, psychomotor retardation, spasticity, blindness, and learning disabilities. Seizures or infection with HSV-2 (as opposed to HSV-1) are risk factors for poor outcome in survivors.

    Neonatal HSV may be difficult to diagnose, partly because it is uncommon and partly because neonates with HSV infection often present with signs and symptoms similar to those of bacterial sepsis. The possibility of HSV infection should be considered for any neonate exhibiting any unusual vesicular lesions, or irritability, lethargy, fever or poor feeding at 1 week of age, especially those born to women with a known history of HSV infection. A high level of suspicion is required, but delay in diagnosis significantly affects outcome. With a delayed diagnosis, SEM disease will very likely progress to more serious manifestations, and mortality is high even with treatment.

    Keep in mind also that screening for HSV infection in newborns may bring up feelings of anxiety and distress among parents and physicians. A series of interviews with 15 physicians from one pediatric institution found that techniques useful for fostering good communication included being direct and honest and ensuring the time and place were appropriate for discussion. Strategies for managing the stigma of the disease included placing the diagnosis in an epidemiologic context and discussing the potential severity of the disease.





    MANAGEMENT STRATEGIES

    MANAGING THE PREGNANT WOMAN

    To ensure the proper management of a pregnant patient with genital herpes, and to ensure that the patient understands her medical management options during pregnancy and delivery, healthcare providers must be aware of the woman's HSV status by the beginning of the third trimester, preferably before week 28. Several evidence-based guidelines now recommend questioning all women about their HSV status and the HSV status of their male partner at their first prenatal visit.

    If the pregnant woman is HSV negative, it is important to counsel her on the necessity of remaining uninfected during pregnancy. If she is in an infection-discordant relationship, or has multiple sex partners, she should be counseled on several methods for avoiding infection, including condom use at all times, avoiding intercourse during the third trimester with partners known to have or suspected of having genital herpes infection, and avoiding cunnilingus during the third trimester with partners that may have orolabial herpes. For women in monogamous, HSV-discordant relationships, antiviral therapy for the infected partner may reduce the risk of transmission. Recent developments, reported at the 2002 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Diego, California, have shown that valacyclovir use in HSV-discordant couples significantly reduced HSV transmission between partners. The study was a randomized, double-blind, placebo-controlled trial of suppressive valacyclovir (500 mg once daily for 8 months) in 1494 monogamous, heterosexual couples with one partner that was seropositive for HSV-2 and one HSV-2 seronegative. During the treatment, symptomatic genital herpes occurred in 2.3 percent of placebo recipients, and asymptomatic HSV-2 seroconversion in 3.8 percent; of those receiving valacyclovir, however, 0.5% exhibited symptomatic infection and 1.9 percent showed asymptomatic infection. The authors concluded that both men and women were protected by their partners taking valacyclovir.

    Staying alert to the possibility of infection for pregnant patients is key, especially for those with a high risk of acquiring HSV. Atypical signs and symptoms of HSV infection should be kept in mind if unusual symptoms appear during the term.





    THE USE OF TYPE-SPECIFIC SEROLOGIC TESTING

    The advent of type-specific, commercially available serologic tests has shifted ideas about the utility of screening for HSV in pregnant women. In the past, viral culture was the only readily available, reliable test. However, only active lesions will give positive culture results, so with healing lesions, atypical manifestations of genital herpes without obvious lesions, or between outbreaks, culture results are unreliable. Type-specific serologic tests may be useful in identifying pregnant women at risk for HSV infection and as a guide for counseling on the risk of acquiring genital herpes during pregnancy. Such testing and counseling may be especially important when a woman's sex partner has HSV infection.

    Kulhanjian and colleagues, using a type-specific ELISA to test both pregnant women and their male partners, found that approximately 10 percent of the 227 pregnant women they tested were at risk of contracting a primary HSV-2 infection from their HSV-2-seropositive husbands, whereas roughly 33 percent of the women were seropositive for HSV-2 at baseline and therefore at risk for asymptomatic, reactivated infections. The investigators concluded that serologic testing of couples can be useful in identifying women who are at risk for primary or reactivated HSV-2 infections during pregnancy. A pilot test of the feasibility of screening pregnant teens for HSV-2 infection during their first prenatal visit was conducted by Crosby and associates with 127 African-American adolescent females recruited during their first attendance of a prenatal clinic in a large urban hospital. The investigators used the POCkit, a rapid, type-specific serologic test manufactured by Diagnology Inc., to assess HSV-2 infection. In this study, 21.3 percent of the adolescents tested positive for HSV-2, and only 1 adolescent was previously aware of her infection. Older teens and those reporting a history of other STDs were significantly more likely to test positive for HSV-2. In this population, HSV-2 testing in early pregnancy may be an efficient strategy for initiating patient education designed to promote protective behaviors and for teaching those who test positive how to recognize symptoms of herpes outbreaks. Given that young age is a risk factor for acquiring HSV infection during pregnancy, such assessment may be quite useful in the future.

    Universal type-specific serologic testing for HSV at the first prenatal visit, pending the commercial availability of relatively inexpensive tests, has been proposed. Pregnant women and their partners represent a broad cross-section of sexually active adults, and pregnancy is a time when many women are motivated, compliant, and interested in preventive care. Some investigators consider it a "golden opportunity" to identify patients already infected as well as those at risk for acquiring genital herpes. Other investigators have pointed out, however, that there is no evidence for a public or individual health benefit from prenatal HSV maternal screening. The possibility of increased patient anxiety weighed against a low probability of reducing the risk of neonatal herpes infection was questioned. These latter investigators also stated that identifying pregnant women who are at risk of acquiring genital herpes is dependent on access to the serostatus of the male sexual partner, curtailing the practical application of the test. They recommended devoting resources to improving currently established mechanisms for reducing morbidity in neonatal herpes rather than to routine testing of antenatal patients.

    REDUCING THE RISK OF NEONATAL HSV INFECTION


    Prevent Maternal Infection

    Ask all pregnant women and their partners about HSV status.

    Advise abstinence and antivirals for HSV-discordant couples, especially during outbreaks.

    Prenatal Monitoring

    Avoid fetal scalp monitors and other invasive monitoring techniques.

    Antiviral Medication

    Consider treating women with primary first-episode HSV infection during pregnancy with antiviral agent (acyclovir, famciclovir, valacyclovir).

    Labor & Delivery

    Question all women at the onset of labor about symptoms of genital herpes regardless of known HSV status.

    Examine all women for herpetic lesions at delivery.

    Perform vaginal delivery for infected women without signs or symptoms of genital herpes.

    Perform cesarean section for:

    Women with first-episode HSV and active genital lesions at delivery

    Women with recurrent infection with active genital lesions or prodromal symptoms at delivery.


    The first line of defense against HSV morbidity and mortality in infants is reducing the risk of acquisition of new infections during pregnancy, especially in late gestation. The present availability of type-specific serologic tests for HSV-2 and HSV-1 would be useful in augmenting existing strategies for preventing both maternal and neonatal herpes infection, diminishing the need for a cesarean section, and promoting individual and public health gains.

    Limitations of universal HSV screening in pregnancy include the variable risk of transmission to the neonate; that is, prenatal testing may not be a good predictor of subsequent neonatal infection. Detecting newly acquired infection in HSV-seronegative women would require repeat testing in late pregnancy, with the possibility of unnecessary medical intervention in pregnancies that may not have been complicated by perinatal HSV transmission in the first place. There is a need for risk- and cost-benefit analyses.

    An analysis by Qutub and coauthors of the cost-effectiveness of screening all pregnant women in Manchester, United Kingdom, for genital HSV infection found a cost of approximately $250,000/year. The authors noted that this did not include women with primary infection during pregnancy, the group at most risk for transmitting infection to the neonate. Further studies in the United States are warranted to truly determine cost-effectiveness in the US healthcare system.





    PREVENTING TRANSMISSION: ANTIVIRAL TREATMENT & OTHER MANAGEMENT OPTIONS

    Women presenting with a first episode of genital herpes during pregnancy should be managed in line with their clinical condition. It is important to differentiate first-episode genital herpes from a primary case of genital herpes during pregnancy and a first episode of visible lesions of other systemic symptoms from a non-primary infection acquired prior to pregnancy. In a primary infection, no type-specific antibodies to either HSV-1 or HSV-2 exist at the time of the first visible outbreak. A non-primary first-episode infection is a first genital HSV outbreak in a woman who has heterologous HSV antibodies. Because of the partial protection of the preexisting antibodies, these women tend to have fewer and shorter systemic symptoms, but milder symptoms should not automatically be treated as non-primary episodes.

    Any woman with suspected first-episode genital herpes should be advised about management, and screening for other STIs should be arranged. The main concern for treating pregnant women with recurrent or primary HSV infection is preventing transmission to the neonate. Most guidelines advise avoiding fetal scalp monitors and other invasive monitoring techniques; there are documented cases of fetal infection through scalp electrode and other invasive techniques that support this recommendation.

    Treatment with an antiviral agent should be considered for all women who develop a first episode of genital herpes in pregnancy. Although there are a variety of effective nucleoside analogues available for treating genital herpes, including acyclovir, famciclovir, and valacyclovir, at this time only acyclovir has been used extensively in pregnant women and neonates.

    The standard dosage of acyclovir in non-pregnant adults is 400 mg 3 times daily for 10 days for primary episodes, 400 mg 3 times daily for 5 days for acute treatment of recurrent episodes, and 400 mg twice daily for suppression of recurrent episodes. For pregnant women, there is no standard dosage - some clinical studies have used 400 mg 3 times daily, some have used 200 mg 4 times daily, with equivalent results for safety and efficacy. In non-pregnant adults, treatment of first-episode genital herpes reduces the duration and severity of symptoms and decreases the duration of viral shedding. Acyclovir has been used extensively during pregnancy, and is well tolerated in late pregnancy. There is no clinical or laboratory evidence of maternal or fetal toxicity from use of acyclovir either in late pregnancy or in the first trimester. In 1984, the Acyclovir Pregnancy Registry was established to collect data on prenatal exposure to the drug. Data from 1207 pregnancies reported prospectively to the Acyclovir Pregnancy Registry between 1984 and 1998 did not demonstrate any increase in the number of birth defects, or a discernible pattern of defects.

    Over the past several years, a variety of studies have examined the use of acyclovir treatment in late pregnancy to prevent recurrent genital herpes and viral shedding at delivery. Two studies (non-blinded) found that there was a significant reduction in rates of cesarean delivery for women treated prophylactically with acyclovir in late pregnancy. In a study by Braig and associates in Paris, France, pregnant women with at least 1 episode of genital herpes during pregnancy were randomly assigned to 2 groups; 1 group received oral acyclovir from 36 weeks of gestation to term, and the other group received no treatment. The control group, also given no treatment, was made up of women who had a history of genital herpes but no active episodes during pregnancy. The rate of cesarean section was lowest in the group given acyclovir (8.4 percent vs 16.5 percent and 9.9 percent), and, significantly, this group showed no evidence of viral shedding. In another study, an open-label trial by Scott and colleagues, suppressive acyclovir (400 mg orally 3 times daily) was prescribed from 36 weeks until delivery for 96 women with primary episodes of genital herpes in late pregnancy. Herpes cultures were obtained when the patients presented for delivery. The study found that the women were 85 percent compliant with suppressive therapy and that 1 percent of that compliant population had clinical outbreaks at delivery, compared with standard rates of 18 percent to 37 percent. A previous study by the same research team also found that suppressive acyclovir therapy reduced the need for cesarean delivery in women with a first clinical episode of genital HSV during pregnancy, did not increase asymptomatic viral shedding, and was not harmful to the term fetus.

    Scott and a colleague also conducted a study of the cost-effectiveness of using acyclovir during pregnancy to prevent recurrences, using literature reviews, prospective surveillance, and practices at their institution for estimates of the risk of HSV recurrence and cesarean delivery rates in acyclovir-treated and -untreated patients and the frequency of neonatal acyclovir treatment. Estimates of costs were derived from average hospital and outpatient clinic charges at their institution. In the authors' analysis, suppressive acyclovir treatment of all term pregnant women with a history of genital herpes resulted in an estimated savings of $183 per patient or $36,600,000 per year, with a savings of $455 and $391 per patient, respectively, for women with their first episode of herpes diagnosed during pregnancy or with frequent recurrences. If indirect costs associated with cesarean deliveries had been included in these calculations, the authors posited that the estimated savings would be even higher.

    Two blinded studies of acyclovir treatment in late pregnancy were conducted, both in women with recurrent herpes infection. The most recent, by Watts and her coworkers, studied the efficacy of acyclovir treatment in late pregnancy in reducing viral shedding and the need for cesarean delivery. The authors found that women with recurrent genital herpes who were treated with a standard dose of 400 mg acyclovir 3 times daily from 36 weeks until delivery were 10 percent less likely to have active lesions at delivery and 32 percent less likely to exhibit a positive result with polymerase chain reaction (PCR) near delivery, but there was no decrease in the rate of cesarean delivery.

    There have also been studies on the safety, efficacy, and pharmacokinetics of valacyclovir in pregnant women and postpartum nursing women. In 1998, Kimberlin and colleagues performed a phase 1 trial of valacyclovir in pregnant women. In this prospective, double-blind trial, the researchers gathered preliminary pharmacokinetic data on the presence of acyclovir in pregnant women receiving suppressive valacyclovir therapy. In the study, 20 women seropositive for HSV-2 with a history of recurrent genital herpes were randomly assigned at 36 weeks' gestation to receive oral valacyclovir (500 mg twice daily) or acyclovir (400 mg 3 times daily). Higher plasma acyclovir levels were reported for the women given valacyclovir therapy than for the women given acyclovir therapy. However, there was no difference in half-life or time to clearing and valacyclovir was well tolerated, with no significant laboratory or clinical evidence of toxicity. In another study, Sheffield and collaborators examined the pharmacokinetic profiles of valacyclovir and acyclovir in serum and breast milk for women who received valacyclovir therapy after delivery. The authors tested a valacyclovir dosage of 500 mg 3 times daily for 7 days in 5 women who were breast-feeding healthy term infants. They found that valacyclovir was rapidly converted to acyclovir, which then concentrated in breast milk. However, the investigators stipulated that the amount of acyclovir in breast milk after valacyclovir treatment was only 2 percent of that used for treating neonates with HSV infection.





    DELIVERY OPTIONS FOR WOMEN INFECTED WITH HSV

    The 2002 Sexually Transmitted Diseases Treatment Guidelines from the Centers for Disease Control and Prevention recommend that all women, regardless of known HSV status, be questioned at the onset of labor about symptoms of genital herpes, including the presence of lesions and prodromal symptoms. The guidelines also recommend examining all women for herpetic lesions at delivery. Evidence-based guidelines generally recommend vaginal delivery for women without symptoms or signs of genital herpes or its prodrome, regardless of the possibility of asymptomatic shedding.

    The most current clinical management guidelines from the American College of Obstetrics and Gynecology, from 1999, on managing herpes infections during pregnancy, recommend cesarean section for women with first-episode HSV who have active genital lesions at delivery (Level B), and for women with recurrent infection who have active genital lesions or prodromal symptoms at delivery (Level C).

    The CDC Treatment Guidelines take note of these recommendations but point out that abdominal delivery does not completely eliminate the risk for HSV transmission to the infant. A recent study by Brown and colleagues that quantified data on the effect of cesarean delivery on HSV transmission to the neonate did find a significant reduction of infection in babies born to HSV-positive women who opted for cesarean section. However, a study by Randolph and collaborators found that cesarean delivery was associated with high rates of morbidity and mortality in women exhibiting genital lesions at term, as well as substantial financial expense, and the authors stressed the importance of examining alternative management strategies.





    TREATMENT OPTIONS FOR HSV-INFECTED NEONATES

    All neonates suspected of or diagnosed with HSV infection should be treated with intravenous (IV) administration of high-dosage acyclovir, a total of 60 mg/kg/day, in divided doses every 8 hours, for 14 to 21 days, revising the previously standard dosage of 30 mg/kg/day. Oral acyclovir has also been suggested for use in infants, and a pharmacokinetic study by Tod and colleagues in 79 children younger than 2 years of age found that a dosage of 24 mg/kg 3 times daily for patients younger than 1 month of age, or 4 times a day otherwise, seemed to result in an adequate bioavailability for suppression. Dosage recommendations for use of the oral agents valacyclovir and famciclovir in children have not been established. An earlier study by the National Institutes of Allergy and Infectious Diseases Collaborative Antiviral Study Group (CASG), a phase 1/2 trial of oral acyclovir therapy for the suppression of cutaneous recurrences after SEM disease, administered a dosage of 300 mg/m twice daily or 3 times daily for 6 months in 26 neonates >/= 1 month of age. In the trial, 13 (81 percent) of the 16 infants who received drug 3 times daily had no recurrent skin lesions. By comparison, a previous CASG study found that without oral acyclovir suppressive therapy, 54 percent of infants have no cutaneous recurrences in the 6 months after resolution of neonatal HSV disease. Two complications in the trial were the isolation of acyclovir-resistant HSV from 1 patient during the course of the study, as well as the presence of neutropenia in 12 (46 percent) of the 26 infants. The authors concluded that oral acyclovir can prevent cutaneous recurrences of HSV after neonatal SEM disease, but that the effect of such therapy on neurologic outcome must be evaluated in a larger, phase 3 study before the routine use of suppressive oral acyclovir can be recommended.

    Further clinical trials on preventing recurrent SEM disease, therapy for preventing recurrences of CNS or disseminated disease, and the appropriate use of rapid diagnostic testing, as well as future therapies, such as adding passive antibody therapy to antiviral therapies or longer duration of higher doses of antiviral therapy, need to be evaluated. The use of PCR to evaluate clinical specimens from neonates suspected of HSV infection could eliminate the need for invasive brain biopsies, as well as providing a tool to shed new light on the natural history of neonatal HSV disease. Unfortunately, PCR is not yet standardized among different laboratories, which can impede a clinician's ability to interpret the PCR results. All test results, including those from PCR, must be evaluated in the context of the patient's medical condition. Disease outcome could also be improved by raising awareness of neonatal HSV disease, reducing the time between disease onset and the initiation of antiviral therapy, and evaluating monoclonal antibodies as adjunctive therapy to high-dose acyclovir.





    CONCLUSION

    Developing technologies in treatment and detection, as well as evolving counseling strategies, are likely to revolutionize the prevention and treatment of neonatal and maternal HSV over the next few years. The variation in presentation of HSV in adults and infants and the presence of asymptomatic viral shedding at delivery present some difficult hurdles, but current treatments and management procedures are already highly effective, if carefully applied.




    COUNSELING THE PREGNANT WOMAN WITH GENITAL HERPES

    In addition to medical treatment, many people with genital herpes often require a great deal of health information and emotional support from the clinician. The pregnant woman with genital herpes may have particular concerns about the health of her baby as her delivery date approaches. Patients may seek answers from many different sources, perhaps resulting in misinformation and misunderstanding. The clinician can provide comprehensive care by making patients feel accepted, providing information both verbally and in written form, and by offering recommendations for ongoing professional and personal support.

    THE PREGNANT WOMAN'S CONCERNS - IF I HAVE GENITAL HERPES, IS MY BABY AT RISK?

    The foremost concern on many women's minds is how genital herpes will affect their baby. The clinician can reassure the patient that new research suggests that the woman who has an established HSV-2 infection when a pregnancy begins has only about a 1 in 5000 chance of infecting her baby with herpes if she does not have symptomatic lesions at the time of delivery.

    Explain that a pregnant woman with established HSV-2 genital infection is able to pass antibody to her baby, through the placenta, during the pregnancy. That antibody seems to offer good, although not perfect, protection to the baby. Antiviral medications taken daily during the last month of pregnancy may further reduce the possibility of transmitting the virus to the baby. Patients with concerns about taking medications during pregnancy may be reassured to learn that taking antiviral medications for genital herpes has been approved by the American College of Obstetrics and Gynecology.

    Many women also ask about the chances of passing herpes to the baby during pregnancy. Reassure patients that we now believe that this is a very uncommon event and that they should take it off their list of worries.

    Some women ask, "Why can't I just have a cesarean section to be certain I do not pass herpes to my baby?" That's a very reasonable question that will likely require some detailed discussion. Although women need to understand that cesarean sections have risks of their own, and that the safety of the mother and the baby will need to be balanced, make it clear that a key component of this decision is the presence of symptoms or recurrence in the third trimester.

    IF MY PARTNER HAS HERPES, WHAT IS THE RISK OF SEXUAL ACTIVITY DURING PREGNANCY?

    Some women have concerns about genital herpes and pregnancy because they have a partner who may have herpes. You can advise that both she and her partner be tested. The pregnant woman can be best informed by reviewing the type-specific serologic test results obtained for both her and her partner and then explaining what is the safest sexual practice and treatment given the results. For example, if a pregnant woman and her partner both test positive for HSV-1 and negative for HSV-2, she should be advised to avoid receiving oral sex during the last trimester of pregnancy if her partner has a cold sore. She needs to understand that if she has had only an oral HSV-1 infection, she could be susceptible to infection in the genital area because her immune system is somewhat compromised during pregnancy and her partner's cold sore may contain a high viral load.

    In another scenario, the pregnant woman may test negative for both HSV-1 and -2 while her partner tests positive for HSV-1. Let's say the partner is aware that he gets cold sores or has had them in the past. In this situation, the pregnant woman should not receive oral sex from her partner during the last trimester of pregnancy. You may want to point out that HSV-1 infection can be transmitted to the baby as easily, if not more so, than HSV-2. If the partner does not have a history of cold sores, the couple should be advised to practice safe sex, using condoms, for the duration of the pregnancy. It is also recommended that the partner take suppressive antiviral therapy for the duration of the pregnancy. This is because the location of the HSV-1 infection is not known. The couple should abstain from intercourse and oral sex during the last trimester, but if this is unacceptable to the couple, the partner should be on suppressive therapy and condoms should be used.

    In a third scenario, the pregnant woman may test negative for HSV-1 and -2 while her partner tests positive for HSV-1 and -2. The advice is similar to that for the case above, in which the location of the HSV-1 infection is unknown. The clinician should recommend that the couple engage in safe sexual practice using condoms for the duration of the pregnancy, and the pregnant woman should not receive oral sex or have intercourse with her partner during the last trimester of the pregnancy. Again, it is appropriate to suggest that the partner take suppressive therapy as an extra caution.





    PATIENTS DIAGNOSED WITH GENITAL HERPES DURING PREGNANCY

    Patients may know that HSV-2 infection during pregnancy is a risk for neonatal herpes, but they may not know that a newborn is also at risk for infection when the mother has a type 1 HSV infection diagnosed during pregnancy. A frequent question is, "How does this happen?" A common scenario might be the couple that is in the last couple months of the pregnancy. Intercourse has become awkward and uncomfortable, and the couple decides that the pregnant patient receiving oral sex would be a good answer for sexual pleasuring. As a result, the partner passes HSV 1 infection to the genitals of the expectant mother through oral sex.

    The next question is often, "Why didn't this happen before? We've had oral sex lots of times before this." The patient should be told that, in pregnancy, the immune system is not working as well as it usually does, and that she is much more vulnerable to herpes infection at this time.

    PATIENT EDUCATION & COUNSELING: PRACTICAL GUIDELINES

    Counseling will best take place over a number of visits. In addition to providing information and advice, consider a referral to a community support group. The American Social Health Association sponsors support groups. Look for a program in your location by searching their Web site.

    In addition, consider developing a patient handout to use in your setting. Here are some teaching points you may wish to include:

    There are many things that happen during a pregnancy that can make a mother feel out of control - a changing body, nausea, or lack of energy. But with genital herpes, the mother's behavior is a very important part of keeping her baby healthy. Here are some things that you can do that can make a big difference.
    • At your first prenatal visit, your clinician will ask you about herpes. If you believe you have genital herpes or that your partner does, the first step is to find out the details about your own herpes infection and any infection your sexual partner may have.

    • Be open with the healthcare professionals who care for you. If you have genital herpes, tell them from the start. Although you may feel embarrassed, almost 1 in 4 adults (22 percent) in the United States has genital herpes, so you are not alone. This is not the time to let feelings of discomfort about being infected get in the way of a full and honest discussion. Your clinician will understand and will provide you with the best advice to prevent the possibility of your baby becoming infected with herpes.

    • You may think of a lot of questions to ask your clinician before you get to the office. For example, you may wish to ask whether your partner should be tested for herpes or whether you can have sex during pregnancy. Sometimes it helps to write down questions ahead of time so you can remember them.

    • If you believe that you have genital herpes, find out if you are infected with HSV-2. Get tested. If both you and your sex partner have HSV-2 genitally, then there is nothing that you need to do differently about sex when you are pregnant. You will not pass the virus back and forth or trigger outbreaks in each other. You can have sex in any way that you wish during your pregnancy without concern, unless you are advised otherwise for another reason. During the last trimester, you may be advised to take antiviral medication to reduce the chance of outbreak near the time of delivery.

    • If you do not know the type (1 or 2) of herpes you have, or if you know only that you have genital HSV-1, you and your sexual partner should be tested. If you have genital HSV-1, it is possible for you to acquire genital HSV-2 during the pregnancy. Unless your partner has tested negative for HSV-2, it is quite possible that your partner has HSV-2 and does not know it. The majority - 90 percent - of those infected with HSV-2 do not know that they are infected. It is very common for someone to say "I KNOW I do not have genital herpes", and then test positive by blood test anyway! If your partner has HSV-2 that is detected by one of the new type-specific blood tests and you do not, then you need to be very careful about transmission.

    • Once you and your partner have been tested, your healthcare provider will give you suggestions for safe sexual practice during your pregnancy, and especially during the last trimester.

    • If you have genital herpes, learn what your outbreaks look like. Near the time of delivery, keep track of anything that you think is an outbreak. If you notice something unusual, alert the clinician who is taking care of you at delivery. Be sure that you look everywhere in the "boxer shorts" area of your body for outbreaks. Remember that the virus can show up anywhere in that general area and that it might be shedding (released) from other locations within that area, including the cervix, at the same time. Look for outbreaks on the buttocks, the base of the spine, around the anus, the thighs or the lower abdomen, as well as the genital area.

    • Your clinician may prescribe an antiviral medication, such as acyclovir, valacyclovir, or famciclovir, to suppress herpes outbreaks during the last month of pregnancy. Taking one of these medications during pregnancy is increasingly common now because we have many years of experience showing that taking antiviral drugs during pregnancy is safe and effective for the prevention of neonatal herpes.

    • The latest research indicates that internal fetal monitors attached to the baby's head during labor may increase the chances of the baby getting herpes. You may want to talk to your clinician about these findings. The research suggests that these monitors should be used only when really necessary in the pregnant woman with genital herpes.

    • Remember that a cesarean section delivery is a possibility if you show symptoms or other signs or a recurrence near the time of delivery. Cesarean sections probably account for almost 1/4 of deliveries in the United States. If you have an outbreak, you will likely have a cesarean section to protect your baby from infection. Even though you might really want a vaginal delivery, a cesarean section offers very significant protection for the baby when the mother has a herpes outbreak. Keep your eye on the prize - not a vaginal delivery, but a healthy baby. Be ready to accept the kind of delivery needed.


    • You should also be aware that some infants get infected with herpes after they are born because someone with a cold sore has kissed them. Perhaps 5 to 10 percent of cases of neonatal herpes are transmitted in this way. Babies simply do not have an immune system that can handle getting herpes in any way. This particular kind of transmission is completely preventable. There is no need to let people kiss your baby on the mouth or the head (because inoculation could occur through a scalp electrode site). Kisses on the cheek or forehead are much less likely to transmit virus to the baby. But if someone with a cold sore wants to kiss the baby, simply say no. You do not have to point out why if it makes you uncomfortable, just say you would rather people not kiss the baby just yet.

    • Relax and enjoy your pregnancy. You have alerted the appropriate people, you have a good plan for the delivery in place, you are flexible and ready for anything, you are on the alert for kissers with cold sores, and you are ready to meet your new child. Do not take your eyes off the prize; it's going to be terrific!





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