AUTHOR INFORMATION

Section 1 of 12

Authored by Richard Fischer, MD, Co-Division Head, Maternal-Fetal Medicine, Professor, Department of Obstetrics and Gynecology, Section of Maternal-Fetal Medicine, Cooper University Hospital

Richard Fischer, MD, is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, Association of Professors of Gynecology and Obstetrics, and Society for Maternal-Fetal Medicine

Edited by Andrea Witlin, DO, PhD, Former Assistant Professor, Department of Obstetrics and Gynecology, University of Texas Medical Branch; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Richard S Legro, MD, Professor, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, Milton S Hershey Medical Center, Pennsylvania State University College of Medicine; Frederick B Gaupp, MD, Consulting Staff, Department of Family Practice, Assumption Community Hospital; and Lee P Shulman, MD, Professor of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University; Chief, Division of Reproductive Genetics, Department of Obstetrics and Gynecology, Prentice Women's Hospital, Northwestern Memorial Hospital

Author's Email:	Richard Fischer, MD
Editor's Email:	Andrea Witlin, DO, PhD

eMedicine Journal, April 11 2006, VOLUME 7, Number 4

INTRODUCTION

Section 2 of 12

Infection with genital herpes simplex virus (HSV) is a major gynecological health problem.

• As of this writing, in the United States, approximately 45 million individuals aged 12 years or older (1 in 5) have been infected with genital herpes. Each year, 1.5 million new cases are diagnosed.

• Five percent of all women of childbearing age report a history of genital herpes, and up to 30% have antibodies to herpes simplex virus 2 (HSV-2).

• Two percent of women acquire genital HSV during pregnancy.

• Approximately 1500-2000 new cases of neonatal HSV infection are diagnosed each year. Neonatal HSV infection may lead to long-term neurologic impairment and death.

Despite strategies designed to prevent perinatal transmission, the number of cases of neonatal HSV infection continues to rise, mirroring the rising prevalence of genital herpes infection in women of childbearing age.

This article reviews (1) the types of genital HSV infections, (2) the risks and sequelae of neonatal HSV infection, and (3) the strategies to reduce perinatal transmission of HSV.

GENITAL HSV INFECTIONS

Section 3 of 12

HSV is a DNA virus. HSV has 2 subtypes: herpes simplex virus 1 (HSV-1) and HSV-2. Although each is a distinct virus, they share some antigenic components, such that antibodies that react to one type may "neutralize" the other.

HSV-1 infections were traditionally associated with the oral area (fever blisters), whereas HSV-2 infections occurred in the genital region. However, because of increasing oral-genital contact, either HSV type may be found in either location. Currently, approximately 15% of genital HSV infections are caused by HSV-1. This rate is increasing, especially among college-aged women.

The following 4 designations are given for genital HSV infections:

• Primary

• Nonprimary first-episode

• Recurrent

• Asymptomatic viral shedding

Primary infections

In a primary infection, no type-specific immunoglobulin G (IgG) antibodies to either HSV-1 or HSV-2 exist at the time of the outbreak. This indicates that the patient had no prior exposure to HSV.

Typically, lesions appear 2-14 days after exposure. Without antiviral therapy, the lesions usually last for 20 days. Viral shedding usually lasts 12 days, with the highest rates of shedding occurring during the prodrome and during the first half of the outbreak. Viral shedding usually ceases before complete resolution of the lesion.

Antibody response occurs 3-4 weeks after the infection and is lifelong. However, unlike protective antibodies to other viruses, antibodies to HSV do not prevent local recurrence(s). The symptoms associated with local recurrences tend to be milder than those occurring with primary disease.

The lesions of a primary infection begin as tender vesicles, which may rupture and become ulcers. The vaginal mucosa is commonly inflamed and edematous. The cervix is involved in 70-90% of patients.

Symptoms associated with primary infections may be both local and constitutional. Local symptoms include intense pain, dysuria, itching, vaginal discharge, and lymphadenopathy. Constitutional symptoms are due to viremia and include fever, headache, nausea, malaise, and myalgia.

Importantly, more than 75% of patients with primary genital HSV infection are asymptomatic. Asymptomatic primary HSV infections in gravidas at term are responsible for most neonatal HSV infections.

Nonprimary first-episode infections

A nonprimary first-episode infection is a first genital HSV outbreak in a woman who has heterologous HSV antibodies. For example, if a woman develops a nonprimary first-episode HSV-2 infection on the labia, she would have antibodies against HSV-1 prior to and at the time of her genital outbreak. Because of the partial protection of the preexisting antibodies, these women tend to have fewer and shorter systemic symptoms.

The duration of lesions is shorter (averaging 15 d), and shedding lasts for approximately 7 days.

Distinguishing primary infections from nonprimary first-episode infections by clinical presentation is difficult. The diagnosis is based on type-specific culture and type-specific serology. The absence of any HSV antibodies at the time of the outbreak confirms a primary infection, whereas antibody to the heterologous HSV type confirms a nonprimary first-episode infection.

Recurrent infections

A recurrent infection is defined as a genital HSV outbreak in a woman with homologous IgG antibodies to the HSV type. Recurrent infections occur most frequently during the first 3 months after a primary infection, especially with HSV-2. Approximately 15% of all pregnant women with a history of genital HSV infection experience recurrent lesions at delivery. Recurrent HSV outbreaks may be symptomatic or asymptomatic. When present, most symptoms are localized (eg, pain, itching, vaginal discharge).

Lesions typically last for 9 days, and shedding lasts for approximately 4 days. The viral load tends to be lower in recurrent outbreaks than with primary lesions, and shedding tends to occur during the prodrome and early stage of the clinical outbreak. Shedding is usually completed before the lesions resolve.

Asymptomatic viral shedding

Asymptomatic viral shedding is episodic and brief, usually lasting 24-48 hours. One to 2% of pregnant women with a history of recurrent HSV infection have asymptomatic shedding at the time of delivery.

Distinguishing the type of genital HSV infection

Recently, type-specific HSV serology was approved by the US Food and Drug Administration (FDA) for commercial use. These assays can distinguish differences in the surface glycoprotein G between the two HSV subtypes, thereby enabling the clinician to accurately distinguish HSV-1 and HSV-2 antibodies. The Centers for Disease Control and Prevention (CDC) now recommends the use of glycoprotein G–based assays for all HSV type-specific serologic testing. Immunoglobulin M (IgM)-specific serology is generally not useful. Using type-specific serology in conjunction with HSV culture, determining the type of genital infection is now possible.

Hensleigh and colleagues (1997) evaluated 23 pregnant women with severe first-episode infections that were presumed to be primary by the clinician. All had HSV cultures and type-specific serology at the time of presentation. Of the 23 women, 1 (4%) had primary HSV-1, 3 (13%) had nonprimary first-episode infections (all HSV-2), and 19 (83%) had recurrent infection (14 with HSV-2).

This study demonstrated both the utility of HSV serology in determining the type of infection and the overdiagnosis of primary infections during pregnancy.

Unfortunately, in a recent proficiency test administered by the American College of Pathology to 172 participating laboratories, more than 50% reported the presence of HSV-2 antibodies from a sample that contained only HSV-1 antibodies. All of the labs using a glycoprotein G–based assay correctly identified only HSV-1 antibodies. These test results underscore the importance of knowing the type of assays used by individual laboratories when ordering type-specific serology to attempt to accurately distinguish the type of genital HSV infection. If the assay used is not a glycoprotein G–based test, the accuracy of the type-specific assay should be challenged.

PERINATAL TRANSMISSION OF HSV

Section 4 of 12

HSV can be vertically transmitted to the infant before, during, or after delivery, although intrapartum transmission accounts for most cases.

Antenatal

Five percent of all cases of neonatal HSV infection result from in utero transmission. With primary infection, transient viremia occurs. HSV has the potential for hematogenous spread to the placenta and to the fetus. Hematogenous spread can produce a spectrum of findings similar to other TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus, and herpes simplex) infections, such as microcephaly, microphthalmia, intracranial calcifications, and chorioretinitis.

Intrapartum

Intrapartum infection accounts for most infected infants and occurs from passage of the infant through an infected birth canal. Seventy-five to ninety percent of infants with neonatal HSV are born to infected asymptomatic mothers who have no known history of genital HSV.

Postnatal

Postnatal transmission of HSV can occur through contact with infected parents or health care workers.

Perinatal Transmission Rates

Intrapartum transmission rates depend on the type of clinical HSV infection. Lower rates are noted in the presence of protective maternal antibodies that cross the placenta.

• Primary HSV infection - Transmission rate of 50%

• Nonprimary first-episode infection - Transmission rate of 33%

• Recurrent infection or asymptomatic shedding - Transmission rate of 0-4%

The overall chance of neonatal infection from asymptomatic shedding in a woman with a history of genital HSV infection is estimated to be less than 4 in 10,000 (ie, 1% risk of asymptomatic shedding multiplied by the [up to] 4% risk of transmission).

To determine the frequency and sequelae of HSV shedding at the time of delivery, Brown and colleagues (2003) obtained HSV cultures (from both cervix and external genitalia) within 48 hours of delivery in 40,023 women. HSV was isolated in 202 women (0.5%), of which approximately one half had no prior history of genital HSV. Of the 202 cases, 177 also had serology available (see Image 2). Based on the serology of these 177 women, 26 (15%) had first-episode disease, and 151 (85%) had recurrent infection.

Of the 26 first-episode viral shedders, 3 had primary HSV-1, 6 had primary HSV-2, 1 had nonprimary HSV-1 and 16 had nonprimary HSV-2. Among those with recurrent infections, 11 had HSV-1 and 140 had HSV-2.

A total of 18 infants developed neonatal HSV during the study period, for a rate of 1 per 3200 of all deliveries and 5% (10 in 202) of all mothers shedding HSV at delivery.

The rates of perinatal transmission from women who had cultures positive for HSV at delivery were as follows:

• Primary HSV-1 - 100% (3 in 3)
• Primary HSV-2 - 17% (1 in 6)
  
• Nonprimary first-episode HSV-2 - 25% (4 in 16)
  
• Recurrent HSV-1 - 18% (2 of 11)
  
• Recurrent HSV-2 - 0% (0 in 140)

Although the presence of heterologous antibody did not appear protective, numerous factors significantly influenced perinatal transmission rates. These factors included the following:

• Cesarean delivery - Odds ratio (OR) 0.14; 95% confidence interval (CI) 0.02-1.08
• Lack of homologous antibodies - OR 33.1; 95% CI 6.5-168
  
• HSV-1 subtype - OR 16.5; 95% CI 4.1-65
  
• Use of scalp electrode during labor - OR 6.8; 95% CI 1.4-32

This important observational study demonstrated the following:

1. Neonatal transmission is highest in women who are seronegative, confirming the importance of maternal antibodies in preventing neonatal transmission.
2. The presence of HSV-2 antibodies appears to reduce not only neonatal HSV-2 infections (no neonatal HSV infections from 140 recurrent shedders) but also maternal HSV-1 infections (ie, no cases of nonprimary HSV-1 infections).
   
3. Rates of neonatal HSV infection, both primary and recurrent, are greater with HSV-1 than with HSV-2.
   
4. Cesarean delivery is protective against neonatal infection, confirming a long-standing practice that had never previously been scientifically validated.

NEONATAL HSV INFECTIONS

Section 5 of 12

The significance of neonatal HSV infection varies and depends on the extent of the infection (see Table 1). Localized infections are the most common and benign type. However, serious infections can occur and can lead to death or long-term CNS morbidity.

Table 1. Types and Sequelae of Neonatal HSV Infection

Disease Type	Incidence, %	Mortality, %	Long-term Morbidity, %*
Localized disease of skin, eye, mouth	45	0	5
CNS	35	15	65
Disseminated	20	60-80	40

*Morbidity includes mental retardation, chorioretinitis, seizures, and other CNS effects.

HSV DETECTION METHODS

Section 6 of 12

HSV culture

HSV culture has long been the criterion standard for diagnosis of HSV infection, with a sensitivity of 70% and a specificity of nearly 100%. A final culture report may take up to 7 days. The sensitivity of HSV culture is related to the HSV type and the location from which the culture is taken. The culture yield is highest during the prodrome and lowest during the second half of the outbreak, especially with recurrent lesions. Sensitivity of HSV viral culture is lower for HSV-2 than for HSV-1. In asymptomatic women, the greatest yield is when cultures are taken from the cervix and the site of recurrence, even if no lesion is visualized. When obtaining HSV cultures, request that the lab type the specimens for both HSV-1 and HSV-2 strains so that the results can be compared to type-specific serology to determine the type of clinical infection.

Tzank smear

The Tzank smear is an older test that is no longer used because of the large number of both false-positive and false-negative results. The Tzank smear was taken in a manner similar to that of a Papanicolaou test (Pap smear), with unroofing and scraping of the base of a lesion. After spraying with a fixative and staining, light microscopy was used to look for the presence of multinucleated giant cells. The Tzank smear is now of historical interest only.

Polymerase chain reaction

Polymerase chain reaction (PCR) is a molecular test that is being increasingly used and that may ultimately replace HSV culture as the criterion standard. Like the viral culture, PCR can distinguish HSV-1 from HSV-2. The test takes approximately 1 day for results to be returned and has the potential for a higher detection rate than HSV culture. In one study, 9% of women in labor who had culture-negative results for HSV had PCR-positive results. Additionally, increased levels of HSV DNA may be associated with an increased risk of neonatal transmission. Unfortunately, PCR does not differentiate actively replicating HSV from latent HSV DNA.

ANTIVIRAL THERAPY

Section 7 of 12

Acyclovir

Acyclovir, a nucleoside analogue, was the first antiviral therapy approved for the treatment and prevention of HSV infection. Acyclovir selectively inhibits viral DNA replication of HSV, while having little effect on normal cells. Acyclovir is selective for HSV-infected cells because it requires phosphorylation by a viral enzyme (thymidine kinase) to acyclovir monophosphate. Phosphorylation does not occur in uninfected cells, where it remains virtually undetectable. After its conversion to acyclovir monophosphate in infected cells, other cellular enzymes convert it to acyclovir triphosphate, which acts to inhibit HSV-specific DNA polymerase, resulting in termination of the DNA transcript.

With primary HSV infection in nonpregnant women, acyclovir reduces the duration of local pain, dysuria, and viral shedding, and it shortens the time to crusting and healing of lesions. With daily usage, acyclovir also reduces symptomatic recurrences and subclinical viral shedding.

During pregnancy, acyclovir crosses the placenta and concentrates in the amniotic fluid. Postpartum, acyclovir concentrates in breast milk. Fetal serum concentrations are equivalent to maternal serum concentrations. A potential drawback of acyclovir therapy is delayed and decreased antibody response to a primary HSV infection. Whether this is due to a decreased viral load or to immune suppression is unknown. Acyclovir has been labeled a category B drug (no teratogenic effects were found in animal studies, but no or limited human studies are available).

Valacyclovir and famciclovir

Since the introduction of acyclovir, newer second-generation antivirals have been introduced (eg, valacyclovir, famciclovir). Valacyclovir is identical to acyclovir except for the addition of an ester side chain that increases bioavailability. Once absorbed, it is converted to acyclovir in vivo. This allows for higher serum levels with a less-frequent dosing schedule. Famciclovir is a nucleotide analogue that has a longer intracellular half-life.

As with acyclovir, these second-generation agents have been used for treatment of symptomatic primary and recurrent lesions as well as for daily suppression. Both valacyclovir and famciclovir have been labeled category B drugs.

The recommended dosages of the 3 antiviral agents are as follows:

Table 2. Recommended Dosages of the Antiviral Agents

Indication	Acyclovir	Valacyclovir	Famciclovir
First episode	400 mg tid (for 7-14 d)	1000 mg bid (for 7-14 d)	250 mg tid (for 7-14 d)
Recurrent	400 mg tid (for 5 d)	500 mg bid (for 5 d)	125 mg bid (for 5 d)
Daily suppression	400 mg bid	500 mg qd or 1000 mg qd (if > 9 recurrences/y)	250 mg bid

Antiviral safety

In 1984, the manufacturer of acyclovir, in conjunction with the CDC, established a registry monitoring the safety of the drug. The registry was closed in 1999. In that time, 1129 acyclovir-exposed pregnancies were reported to the registry; 712 of these occurred in the first trimester. Additionally, 56 valacyclovir-exposed pregnancies were reported; 14 of these occurred in the first trimester.

No increase in the number of malformations occurred with acyclovir, and no pattern of birth defects emerged. Too few cases of valacyclovir-exposed pregnancies precluded the drawing of any meaningful conclusions. Thus, acyclovir appears to be relatively safe to use during pregnancy and should be prescribed as medically indicated. The acyclovir registry can be accessed at the GlaxoSmithKline Web site.

PREVENTION OF VERTICAL HSV TRANSMISSION

Section 8 of 12

Historical Approach: Weekly cervical cultures of asymptomatic women with history of genital HSV infection

In the early 1980s, weekly cervical cultures starting at 34 weeks were the standard in pregnant women with a history of genital HSV. If the last culture prior to labor was positive for HSV, a cesarean delivery was recommended. However, later studies demonstrated that most women with asymptomatic antepartum shedding were culture-negative during labor. Additionally, those women with positive intrapartum cultures were often negative during the antepartum period.

In 1988, the Infectious Disease Society for Obstetrics and Gynecology developed a position statement that recommended the following practices:

• Abandon weekly cervical cultures.

• In the absence of active lesions or prodromal symptoms, vaginal delivery should be allowed.

• At the time of delivery, consider obtaining a herpes culture from the mother or the neonate for the benefit of the pediatricians.

• Herpes cultures, when obtained, should be obtained from the cervix and the site of recurrence.

• If there is an active herpetic lesion, cesarean delivery should be performed, preferably within 4-6 hours of membrane rupture.

• If there is a recent infection near term, check cervical cultures every 3-5 days until results are negative.

CURRENT STRATEGIES TO PREVENT VERTICAL HSV TRANSMISSION

Current strategies to prevent vertical transmission with antiviral therapy have focused on 3 approaches.

1. Antiviral suppression for gravidas with first-episode infections during pregnancy
2. Routine antiviral suppression for gravidas with a history of genital HSV
   
3. Identification of seronegative gravidas at risk for primary and nonprimary first-episode genital HSV infections

Antiviral suppression for gravidas with first-episode infections during pregnancy

Recognizing that recurrent infections occur more frequently within the first year after a primary infection, Scott et al (1996) randomized 46 gravidas with first genital outbreak during pregnancy to either acyclovir (400 mg tid) or placebo beginning at 36 weeks' gestation. Patients receiving acyclovir experienced a significant reduction in the percentage of HSV recurrences at delivery (36% vs 0%) and cesarean deliveries for HSV (36% vs 0%). However, the reduction in the total number of cesarean deliveries in enrolled women was not statistically significant (40% vs 19%).

No patients in this study had asymptomatic shedding at the time of delivery, and no infant developed neonatal HSV infection or had complications from acyclovir. No attempt was made to distinguish between primary infections, nonprimary first-episode infections, or first-recognized recurrent infections. This study was, however, the first to demonstrate the utility of antiviral suppression in reducing the number of recurrences at the time of delivery.

Routine antiviral suppression for gravidas with a history of genital HSV

In 1998, Brocklehurst and colleagues performed a double-blind placebo-controlled trial that involved 63 women with a history of recurrent HSV infection. These women were randomized to either acyclovir (200 mg qid) or placebo, both beginning at 36 weeks' gestation. Nonsignificant reductions were found in recurrent HSV outbreaks at delivery, cesarean deliveries for HSV, and total cesareans in the acyclovir group. No infant in either group developed neonatal HSV, and no gravida experienced toxicity from acyclovir. The authors concluded that the sample size was too small to demonstrate a significant benefit from acyclovir and recommended that acyclovir be used only in clinical trials.

Since that time, additional randomized clinical studies have been performed, each demonstrating nonsignificant reductions in cesarean deliveries for recurrent HSV outbreaks and no differences in neonatal outcomes.

A recent meta-analysis pooled the results of five randomized clinical trials evaluating the use of antenatal suppressive acyclovir in 799 gravidas. The results of the meta-analysis are shown in Table 3.

Table 3. Antiviral Trial Results

Outcome	Acyclovir, %	Placebo, %	OR (95% CI)
Recurrent HSV infection at delivery	3.5	15.5	.25 (.15-.40)
Cesarean deliveries for HSV	4.0	14.7	.30 (.13-.67)
Total cesarean deliveries	16.7	25.9	.61 (.43-.86)
Asymptomatic HSV shedding at delivery	0	3.1	.09 (.02-.39)

All of the observed outcomes were significantly reduced with suppressive use of acyclovir (no 95% confidence interval included the value of 1). No cases of neonatal herpes were reported in any of the 799 infants in all 5 studies, whether in the acyclovir or placebo group. Due to the rarity of neonatal HSV infections, far larger numbers of subjects are required to demonstrate a significant difference in this important outcome.

In 1996, Randolph and colleagues performed a cost-effectiveness decision analysis of 4 strategies designed to reduce neonatal HSV infections in women with a history of genital HSV. The 4 strategies were as follows:

1. Cesarean delivery if an HSV lesion was present at the time of labor
2. Acyclovir prophylaxis beginning at 36 weeks’ gestation, with cesarean delivery if a lesion was present
   
3. Acyclovir prophylaxis beginning at 36 weeks’ gestation, with vaginal delivery if a lesion was present
   
4. No intervention (no acyclovir, no cesarean delivery for HSV lesions)

Table 4. Results of Randolph Cost-Effectiveness Decision Analysis

Strategy	Number of Cesarean Deliveries	Number of Neonatal HSV Infections Avoided	Cost
1	1082	2.8	$4 million
2	216	5.5	$3 million
3	0	5	$2.3 million
4	0	0	$360,000

The results suggested that acyclovir prophylaxis with vaginal delivery in the event of a recurrent HSV outbreak was the most cost-effective approach, with the greatest number of cesareans avoided and near-highest number of neonatal HSV infections averted. However, the authors cautioned that acyclovir may not have a large impact on neonatal outcome because most infants who developed neonatal HSV infection are born to asymptomatic women who have no history of HSV infection and, hence, would have no protective antibodies.

Identification of seronegative gravidas at risk for primary and nonprimary first-episode genital HSV infections

This approach is the most ambitious of all strategies to prevent vertical transmission. Its logic is based on the observation that most neonatal HSV transmission occurs not in gravidas with a history of genital HSV, but rather in women who have primary or nonprimary first-episode genital infections at the time of labor. If routine serologic screening revealed a woman at risk for primary HSV (no antibodies) or nonprimary first-episode infection (either HSV-1 or HSV-2 only), she could be counseled to avoid genital-genital or oral-genital contact in order to prevent new genital infections during the third trimester of pregnancy and, hence, reduce neonatal HSV infections.

An alternative strategy would be to check the serologic status of the sexual partner, as well, and to recommend sexual abstinence only if the woman was at risk and the couple was serologically discordant, which occurs in 15-25% of couples. For example, if a woman was seronegative for HSV-2, and her partner was seropositive for HSV-2, the woman’s risk of acquiring HSV-2 during pregnancy would be as high as 20%. Such a couple would, thus, be advised to abstain from sexual activity during pregnancy.

Despite the theoretical appeal of such an approach, no clinical trials have been published that show this approach resulting in a reduced rate of neonatal HSV infection. Three cost-benefit analyses have yielded conflicting results.

In 2000, Rouse and Stringer performed a decision analysis model to test the value of routine screening of couples for HSV serology during pregnancy. Of 1 million hypothetical women screened, the rate of neonatal HSV-1 transmission would be marginally reduced from 126 to 99, and the rate of neonatal HSV-2 infection would be reduced from 157 to 124. The cost per serious case of neonatal HSV averted would be $891,000. The authors concluded that HSV serology was not a cost-effective strategy to prevent neonatal HSV, predominantly through failure of counseling to prevent horizontal transmission.

Similarly, Thung and Grobman (2005) performed a decision analysis comparing 1) current routine care (no serology testing), 2) couple screening for susceptible gravidas with counseling for discordant couples, and 3) counseling for discordant couples plus acyclovir prophylaxis for seropositive women to prevent symptomatic and asymptomatic shedding in labor. Out of 100,000 hypothetical women, serology screening would prevent 2 and 3.8 neonatal deaths or neurologic sequelae for strategies 2 and 3, respectively, with respective costs of 5.8 and 4 million dollars for each adverse sequela prevented.

In contrast, Baker and colleagues (2004) conducted their own decision analysis of HSV-2 screening, comparing 1) no routine serology screening; 2) routine screening, counseling for HSV-negative gravidas about safe sex, and offering acyclovir prophylaxis to HSV-positive women at 36 weeks; and 3) testing the partners of HSV-negative women and offering suppressive therapy for HSV-positive men starting at 15 weeks. They found that the cost of each case of neonatal herpes prevented with strategy 2 was $194,000, while the additional cost of partner screening and suppressive therapy was nearly 5 million dollars for each case of neonatal herpes prevented. They concluded that routine maternal serology screening with acyclovir suppression of seropositive gravidas was cost-effective, while partner screening and suppression was not.

Currently, routine maternal serologic screening is not widespread. Reasons for this include cost considerations; the unproven value of abstinence counseling in susceptible women; and the psychosocial ramifications of discovering a positive serology, as HSV-2 is predominantly a sexually-transmitted disease. At this time, the American College of Obstetricians and Gynecologists has not endorsed routine maternal HSV serology screening.

CONCLUSIONS

Section 9 of 12

In 1999, the American College of Obstetricians and Gynecologists (ACOG) published a practice bulletin regarding HSV in pregnancy. Their conclusions were as follows:

Level B recommendations (based on limited or inconsistent scientific evidence)

• Women with primary HSV infection during pregnancy should be treated with antiviral therapy.

• Cesarean delivery should be performed on women with first-episode HSV infection who have active genital lesions at delivery.

• For women at or beyond 36 weeks of gestation with a first episode of HSV infection occurring during the current pregnancy, antiviral therapy should be considered.

Level C recommendations (based on consensus or expert opinion)

• Cesarean delivery should be performed on women with recurrent HSV infection who have active genital lesions or prodromal symptoms at delivery.

• Expectant management of patients with preterm labor or premature rupture of membranes and active HSV infection may be warranted.

• For women at or beyond 36 weeks of gestation who are at risk for recurrent HSV infection, antiviral therapy may be considered, although such therapy may not reduce the likelihood of cesarean delivery.

• In women with no active lesions or prodromal symptoms during labor, cesarean delivery should not be performed on the basis of a history of recurrent disease.

Currently, recurrent HSV infections account for only a small proportion of neonatal HSV infections. However, routine HSV suppression with antiviral agents, especially in pregnant women with a history of frequent recurrences, may suppress clinical recurrences during labor and may reduce the need for cesarean deliveries in these women.

In order to truly reduce the incidence of neonatal HSV infection, physicians and researchers must focus on the prevention and recognition of asymptomatic primary genital HSV infections. In the future, this might require a combination of PCR analysis for faster diagnosis, as well as type-specific serology to identify pregnancies at risk for primary HSV infections.

Patient education

For excellent patient education resources, visit eMedicine’s Sexually Transmitted Diseases Center and Teeth and Mouth Center. Also, see eMedicine’s patient education articles Genital Herpes and Oral Herpes.

TEST QUESTIONS

Section 10 of 12

CME Question 1: A pregnant woman presents at 28 weeks' gestation with her first clinical outbreak of genital herpes. She denies any history of oral or genital herpes infection. On physical examination, multiple painful herpetic lesions are found on her left labium minus. A herpes culture is obtained, which returns a positive finding for herpes simplex virus 2 (HSV-2). Type-specific immunoglobulin G (IgG) serology is concurrently drawn, which returns a positive finding for herpes simplex virus 1 (HSV-1) and HSV-2. Based on the complete evaluation, what is the most likely diagnosis?

A: Primary genital HSV infection
B: Nonprimary first-episode genital HSV infection
C: Recurrent HSV infection
D: Asymptomatic infection
E: None of the above

The correct answer is C: Despite the almost classic history of primary infection, the presence of both HSV-2 virus on culture and HSV-2 antibody indicates that this is a recurrent infection. In many cases, presumed primary HSV infection is in fact a first-recognized recurrent genital HSV infection. History and physical examination cannot distinguish among the various types of infection. Only through HSV culture and type-specific serology using surface glycoprotein G–based assays can the clinician determine the type of HSV infection with certainty.

CME Question 2: What is the greatest cause for neonatal herpes simplex virus (HSV) infection?

A: Antenatal HSV infection
B: Postnatal HSV infection
C: Recognized primary genital HSV infection at the time of delivery
D: Unrecognized primary genital HSV infection at the time of delivery
E: Asymptomatic shedding at the time of delivery

The correct answer is D: Although recurrent HSV infection has historically received the greatest attention, most infants born to women with recurrent genital HSV lesions do not develop HSV infection. This is thought to be related to protective HSV antibodies transmitted from the mother to the infant. In contrast, no such protective antibodies exist with primary HSV infections, which are usually asymptomatic. As a result, 75-90% of infants with neonatal HSV infection are born to presumably asymptomatic mothers with primary HSV infections.

Pearl Question 1 (T/F): Tzank smear is a rapid and reliable method of herpes simplex virus (HSV) detection.

The correct answer is False: While the Tzank smear is easy to perform (similar to a Papanicolaou test [Pap smear]), the high false-positive and false-negative rates make it unreliable in detecting acute HSV infection.

Pearl Question 2 (T/F): The rate of perinatal transmission of HSV-2 is greater than that of HSV-1.

The correct answer is False: Although recurrent maternal HSV infections are more frequent with HSV-2, rates of genital HSV-1 infections are increasing in college-aged women and have a greater risk of perinatal transmission when they occur.

Pearl Question 3 (T/F): Herpes simplex virus 2 (HSV-2) antibodies appear to protect the baby from neonatal HSV infections, as well as new maternal herpes simplex virus 1 (HSV-1) infections.

The correct answer is True: In one study of 89 gravidas with recurrent HSV-2 shedding, no infant developed neonatal HSV infection. In another study (939 gravidas with existing HSV-2 antibodies), no subject had an HSV-1 seroconversion during pregnancy. Previous HSV-2 infection therefore appears to protect infants from neonatal HSV infection and mothers from HSV-1 infections.

Pearl Question 4 (T/F): Acyclovir, valacyclovir, and famciclovir appear safe for use for symptomatic herpes simplex virus (HSV) infections and HSV suppression during pregnancy

The correct answer is True: None of the antiviral agents for HSV has been approved for use in pregnancy. However, the acyclovir registry containing 1129 exposed pregnancies (712 in the first trimester) showed no increase in the number of malformations compared with the general population. Although there were too few exposed fetuses in the registry from the second-generation agents (valacyclovir and famciclovir), these agents have a mode of action similar to acyclovir. Therefore, for symptomatic gravidas or those with frequent recurrent HSV outbreaks, antiviral agents may be used.

PICTURES

Section 11 of 12

Caption: Picture 1. Genital herpetic infection.
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Caption: Picture 2. Viral shedding in labor.
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BIBLIOGRAPHY

Section 12 of 12

• ACOG: ACOG practice bulletin. Management of herpes in pregnancy. Number 8 October 1999. Clinical management guidelines for obstetrician-gynecologists. Int J Gynaecol Obstet 2000 Feb; 68(2): 165-73[Medline].
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NOTE:

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eMedicine Journal, April 11 2006, VOLUME 7, Number 4
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eMedicine Journals > Medicine, Ob/Gyn, Psychiatry, and Surgery > Obstetrics/gynecology >Genital Herpes in Pregnancy

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Author Information | Introduction | Genital Hsv Infections | Perinatal Transmission Of Hsv | Neonatal Hsv Infections | Hsv Detection Methods | Antiviral Therapy | Prevention Of Vertical Hsv Transmission | Conclusions | Test Questions | Pictures | Bibliography