http://emedicine.medscape.com/article/274874-overview#a1

Overview

Infection with genital herpes simplex virus (HSV) (see the image below) remains a common viral sexually transmitted disease, often subclinical, and a major worldwide problem in women of reproductive age.

Genital herpetic infection.

Women newly diagnosed with genital herpes will often experience psychological distress and worry about future sexual relationships and childbearing.

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. The incidence of neonatal herpes varies considerably in international studies (about 1:3,200 births in the US and 1:60,000 in the UK). Untreated neonatal HSV infection is associated with a mortality rate of 60%, and even with early and appropriate treatment, survivors experience considerable disability.[1]

According to the National Health and Nutrition Examination Surveys (NHANES), the prevalence of HSV appears to be declining in the United States. The percentage of adults aged 20 – 29 years with genital herpes infection decreased from 17% during 1988 – 1994 to 10% during 2003 – 2006.[2] The 1988 – 1994 (NHANES II) and 1999 – 2004 (NHANES III) surveys showed an overall reduction in the seroprevalence of HSV-1 by 7% and of HSV-2 by 19%.

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

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 during the prodrome and 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, systemic symptoms during these outbreaks tend to be fewer and shorter in duration. The duration of lesions is also shorter (averaging 15 d), and shedding lasts for only approximately 7 days.

Distinguishing primary infections from nonprimary first-episode infections by clinical presentation is difficult. Instead, 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. Coinfection with HIV may increase asymptomatic shedding of HSV in women.[3]

Distinguishing the type of genital HSV infection

Type-specific HSV serologic assays have been approved by the US Food and Drug Administration (FDA) for commercial use. These assays distinguish HSV-1 from HSV-2 antibodies on the basis of differences in the surface glycoprotein G between the two HSV subtypes. 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. Use of type-specific serology in conjunction with HSV culture makes it possible to determine the type of genital infection.

Hensleigh and colleagues 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).[4] 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 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.[5] These test results underscore the importance for clinicians to know the type of assays used by their laboratory when ordering type-specific serology to distinguish the type of genital HSV infection. If the assay is not a glycoprotein G–based test, the accuracy of the typing should be challenged.

Perinatal Transmission of HSV

HSV can be vertically transmitted to the infant before, during, or after delivery, although intrapartum transmission accounts for most cases. Maternal age of less than 21 years is a risk factor for vertical transmission.[6]

Antenatal

Approximately 5% 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 transmission accounts for most neonatal infections and occurs with passage of the infant through an infected birth canal. The use of a fetal-scalp electrode increases the risk for intrapartum transmission.[6] From 75% to 90% 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. See the following:

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 obtained HSV cultures (from both cervix and external genitalia) within 48 hours of delivery in 40,023 women.[7] HSV was isolated in 202 women (0.5%), of whom approximately one half had no prior history of genital HSV. Serology was also available in 177 of the 202 cases (see image below). Based on the serology of these 177 women, 26 (15%) had first-episode disease, and 151 (85%) had recurrent infection.

Viral shedding in labor.

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:

Neonatal transmission is highest in women who are seronegative, confirming the importance of maternal antibodies in preventing neonatal transmission.

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).

Rates of neonatal HSV infection, both primary and recurrent, are greater with HSV-1 than with HSV-2.

Cesarean delivery is protective against neonatal infection, confirming a long-standing practice that had never previously been scientifically validated.

Neonatal HSV Infections

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.

A study by Kimberlin et al suggests that neonatal suppression therapy with acyclovir in infants with HSV may improve neurodevelopmental outcomes.[8]

Table 1. Types and Sequelae of Neonatal HSV Infection (Open Table in a new window)

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

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 yield is greatest 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 with 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.[9, 10, 11] 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.[10]

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

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.[12]

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 for Genital Herpes Infection (Open Table in a new window)

Indication Acyclovir Valacyclovir Famciclovir

First episode 400 mg tid OR 200 mg 5 times/d (for 7-10 d)

1000 mg bid (for 7-10 d)

250 mg tid (for 7-10 d)

Recurrent 400 mg tid (for 3-5 d) OR 800 mg PO tid (for 2 d)

500 mg bid (for 3 d) 1000 mg bid (for 1 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.

A recent Danish study that assessed more than 800,000 pregnancies suggests that exposure to acyclovir or valacyclovir in the first trimester is not associated with an increased risk of major birth defects.[13]

Prevention of Vertical HSV Transmission

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[14] :

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, as follows:

Antiviral suppression for gravidas with first-episode infections during pregnancy Routine antiviral suppression for gravidas with a history of genital HSV 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 randomized 46 gravidas with first genital outbreak during pregnancy to either acyclovir (400 mg tid) or placebo beginning at 36 weeks' gestation.[15]

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.[16] 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 2003 meta-analysis pooled the results of five randomized clinical trials evaluating the use of antenatal suppressive acyclovir in 799 gravidas.[17] The results of the meta-analysis are shown in Table 3.

Table 3. Antiviral Trial Results (Open Table in a new window)

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.[18] The 4 strategies were as follows:

Cesarean delivery if an HSV lesion was present at the time of labor Acyclovir prophylaxis beginning at 36 weeks' gestation, with cesarean delivery if a lesion was

present Acyclovir prophylaxis beginning at 36 weeks' gestation, with vaginal delivery if a lesion was

present No intervention (no acyclovir, no cesarean delivery for HSV lesions)

Table 4. Results of Randolph Cost-Effectiveness Decision Analysis (Open Table in a new window)

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 that a woman was 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.[19] 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 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.[20] 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, the decision analysis of HSV-2 screening by Baker and colleagues compared 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.[21] These researchers 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 in 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.[22]

1. Corey L, Wald A. Maternal and neonatal herpes simplex virus infections. N Engl J Med. Oct 1 2009;361(14):1376-85. [Medline]. [Full Text].

2. Centers for Disease Control and Prevention. QuickStats: Percentage of Adults Aged 20--29 Years with Genital Herpes* Infection, by Race/Ethnicity† --- National Health and Nutrition Examination Survey, United States, 1988--1994, 1999--2002, and 2003--2006. CDC. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5807a6.htm?s_cid=mm5807a6_e. Accessed December 14, 2009.

3. Nasoodi A, Quah S, Dinsmore WW. Neonatal herpes in herpes simplex virus type 2 and HIV-seropositive pregnant patients; the role of preventive measures in the

absence of clinical disease of herpes. Int J STD AIDS. Dec 2007;18(12):863-6. [Medline].

4. Hensleigh PA, Andrews WW, Brown Z, et al. Genital herpes during pregnancy: inability to distinguish primary and recurrent infections clinically. Obstet Gynecol. Jun 1997;89(6):891-5. [Medline].

5. Morrow RA, Brown ZA. Common use of inaccurate antibody assays to identify infection status with herpes simplex virus type 2. Am J Obstet Gynecol. Aug 2005;193(2):361-2. [Medline].

6. Baker DA. Consequences of herpes simplex virus in pregnancy and their prevention. Curr Opin Infect Dis. Feb 2007;20(1):73-6. [Medline].

7. Brown ZA, Wald A, Morrow RA, et al. Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant. JAMA. Jan 8 2003;289(2):203-9. [Medline].

8. Kimberlin DW, Whitley RJ, Wan W, et al. Oral acyclovir suppression and neurodevelopment after neonatal herpes. N Engl J Med. Oct 6 2011;365(14):1284-92. [Medline].

9. Boggess KA, Watts DH, Hobson AC, et al. 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. Am J Obstet Gynecol. Feb 1997;176(2):443-51. [Medline].

10. Cone RW, Hobson AC, Brown Z, et al. Frequent detection of genital herpes simplex virus DNA by polymerase chain reaction among pregnant women. JAMA. Sep 14 1994;272(10):792-6. [Medline].

11. Wald A, Huang ML, Carrell D, et al. Polymerase chain reaction for detection of herpes simplex virus (HSV) DNA on mucosal surfaces: comparison with HSV isolation in cell culture. J Infect Dis. Nov 1 2003;188(9):1345-51. [Medline].

12. Mertz GJ, Critchlow CW, Benedetti J, et al. Double-blind placebo-controlled trial of oral acyclovir in first- episode genital herpes simplex virus infection. JAMA. Sep 7 1984;252(9):1147-51. [Medline].

13. Pasternak B, Hviid A. Use of acyclovir, valacyclovir, and famciclovir in the first trimester of pregnancy and the risk of birth defects. JAMA. Aug 25 2010;304(8):859-66. [Medline].

14. Gibbs RS, Amstey MS, Sweet RL, et al. Management of genital herpes infection in pregnancy. Obstet Gynecol. May 1988;71(5):779-80. [Medline].

15. Scott LL, Sanchez PJ, Jackson GL, et al. Acyclovir suppression to prevent cesarean delivery after first-episode genital herpes. Obstet Gynecol. Jan 1996;87(1):69-73. [Medline].

16. Brocklehurst P, Kinghorn G, Carney O, et al. A randomised placebo controlled trial of suppressive acyclovir in late pregnancy in women with recurrent genital herpes infection. Br J Obstet Gynaecol. Mar 1998;105(3):275-80. [Medline].

17. Sheffield JS, Hollier LM, Hill JB. Acyclovir prophylaxis to prevent herpes simplex virus recurrence at delivery: a systematic review. Obstet Gynecol. Dec 2003;102(6):1396-403. [Medline].

18. Randolph AG, Hartshorn RM, Washington AE. Acyclovir prophylaxis in late pregnancy to prevent neonatal herpes: a cost-effectiveness analysis. Obstet Gynecol. Oct 1996;88(4 Pt 1):603-10. [Medline].

19. Rouse DJ, Stringer JS. An appraisal of screening for maternal type-specific herpes simplex virus antibodies to prevent neonatal herpes. Am J Obstet Gynecol. Aug 2000;183(2):400-6. [Medline].

20. Thung SF, Grobman WA. The cost-effectiveness of routine antenatal screening for maternal herpes simplex virus-1 and -2 antibodies. Am J Obstet Gynecol. Feb 2005;192(2):483-8. [Medline].

21. Baker D, Brown Z, Hollier LM, et al. Cost-effectiveness of herpes simplex virus type 2 serologic testing and antiviral therapy in pregnancy. Am J Obstet Gynecol. Dec 2004;191(6):2074-84. [Medline].

22. American College of Obstetricians and Gynecologists. ACOG practice bulletin. Management of herpes in pregnancy. 2007 Jun. 10 (ACOG practice bulletin; no. 82). Available at http://guideline.gov/content.aspx?id=11430. Accessed December 14, 2009.

Pregnancy and herpesHSV; Congenital herpes; Herpes - congenital; Birth-acquired herpes; Herpes during pregnancy

Last reviewed: August 23, 2012.

Birth-acquired herpes is a herpes virus infection that an infant gets (acquires) from the mother during pregnancy or birth.

Causes, incidence, and risk factors

Newborn infants can become infected with herpes virus:

In the uterus (congenital herpes -- this is unusual) Passing through the birth canal (birth-acquired herpes, the most common method of

infection) Right after birth (postpartum) from kissing or having other contact with someone who

has herpes mouth sores

If the mother has an active genital herpes infection at the time of delivery, the baby is more likely to become infected during birth. Some mothers may not be aware they have internal (inside the vagina) herpes sores.

Some people have had herpes infections in the past, but were not aware of it. These people, not knowing that they have herpes, may pass it to their baby.

Herpes type 2 (genital herpes) is the most common cause of herpes infection in newborn babies, but herpes type 1 (oral herpes) can also occur.

Symptoms

Herpes may only appear as a skin infection. Small, fluid-filled blisters (vesicles) may appear. These blisters rupture, crust over, and finally heal, often leaving a mild scar.

Herpes infection may also spread throughout the body (called disseminated herpes). In this type, the herpes virus can affect many different parts of the body.

Herpes infection in the brain is called herpes encephalitis

The liver, lungs, and kidneys may also be involved There may or may not be blisters on the skin

Newborn infants with herpes that has spread to the brain or other parts of the body are often very sick. Symptoms include:

Bleeding easily Breathing difficulties

o Blue appearance (cyanosis)o Flaring of the nostrilso Gruntingo Rapid breathing (tachypnea)o Short periods without breathing (apneic episodes)

Coma Jaundice Lethargy Low body temperature (hypothermia) Poor feeding Seizures Shock Skin lesions, fluid-filled blisters

Herpes that is caught in the period shortly after birth has symptoms similar to those of birth-acquired herpes.

Intrauterine herpes can cause:

Eye disease, such as inflammation of the retina (chorioretinitis) Severe brain damage Skin sores (lesions)

Signs and tests

Tests for birth-acquired herpes include:

DFA test for herpes (scraping from vesicle) EEG MRI of the head Spinal fluid culture Vesicle culture

Additional tests that may be done if the baby is very sick include:

Blood gas analysis Coagulation studies (PT, PTT) Complete blood count Electrolyte measurements Tests of liver function

Treatment

Herpes virus infections in infants are generally treated with medicine given through a vein (intravenous). Acyclovir is the most common antiviral medicine used for this purpose. The baby may need to take the medicine for several weeks.

Other therapy is often needed to treat the effects of herpes infection, such as shock or seizures. Often, because these babies are very ill, treatment is done in an intensive care unit.

Expectations (prognosis)

Infants with systemic herpes or encephalitis often do poorly, despite antiviral medications and early treatment.

In infants with skin disease, the vesicles may come back repeatedly even after treatment is finished. These recurrences put them at risk for learning disabilities, and may need to be treated.

Complications

Bacterial or fungal infection of skin lesions Coma Death Developmental delay Excessive bleeding, disseminated intravascular coagulation (DIC) Eye problems (chorioretinitis, keratitis) Gastrointestinal problems, including diarrhea Hepatitis Jaundice Liver failure Lung problems including pneumonia or pneumonitis Brain and nervous system (neurological) problems Respiratory distress Seizure Shock Skin lesions

Calling your health care provider

If your baby has any symptoms of birth-acquired herpes, including skin lesions alone, have the baby seen by your health care provider promptly.

Prevention

It is important for you to tell your doctor or nurse if you have a history of genital herpes. If you have frequent herpes outbreaks, you will be given a medicine called acyclovir to take during the last month of pregnancy. This helps prevent anoutbreak around the time of

delivery. C-section is recommended for pregnant women who have a new herpes sore and are in labor.  

Safer sexual practices can help prevent the mother from getting genital herpes. Mothers who are not infected with herpes cannot pass the herpes virus to the baby during delivery.

People with "cold sores" (herpes labialis) should avoid contact with newborn infants. Caregivers who have a cold sore should wear a surgical mask and wash their hands carefully before coming into contact with the infant to prevent transmitting the virus.

Mothers should speak to their health care providers about the best way to minimize the risk of transmitting herpes to their infant.

References

1. Red Book: 2009 Report on The Committee on Infectious Diseases, American Academy of Pediatrics.

2. Cernik C, Gallina K, Brodell RT. The treatment of herpes simplex infections: An evidence-based review. Arch Intern Med. 2008;168(11):1137-1144.

3. Hollier LM, Wendel GD. Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection. Cochrane Database Syst Rev. 2008;23(1):CD004946.

Review Date: 8/23/2012.

Reviewed by: Neil K. Kaneshiro, MD, MHA, Clinical Assistant Professor of Pediatrics, University of Washington School of Medicine. Susan Storck, MD, FACOG, Chief, Eastside Department of Obstetrics and Gynecology, Group Health Cooperative of Puget Sound, Bellevue, Washington; Clinical Teaching Faculty, Department of Obstetrics and Gynecology, University of Washington School of Medicine. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M. Health Solutions, Ebix, Inc.

http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002344/

Maternal and Neonatal HSV InfectionsLawrence Corey, MD1,2,3 and Anna Wald, MD, MPH1,2,3,4

Author information ► Copyright and License information ►

The publisher's final edited version of this article is available at N Engl J Med

This article has been corrected. See the correction in volume 361 on page 2681.

See other articles in PMC that cite the published article.

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Epidemiology

An estimated 30 to 65 percent of pregnant women in the U.S. have genital infection with herpes simplex virus (HSV)-1 or -2.1 Neonatal HSV, defined as infection in a newborn within 28 days of birth, is an especially devastating consequence of the genital herpes epidemic. Untreated neonatal HSV has only a 40 percent survival rate and even the early initiation of high-dose intravenous acyclovir therapy results in significant disability among survivors. The frequency of neonatal HSV infection varies by patient population; between 1 in 1,700 (60 per 100,000) and 1 in 8,200 (12 per 100,000) live births in the U.S. may be complicated by neonatal HSV infection (Table 1). A retrospective study in California reported rates of 12.2 per 100,000 births from 1995 to 2003.2 Data from 30 U.S. health plans including 17 million enrollees showed a rate of 60 per 100,000 births.3 Prospective, single center studies in the U.S. have shown neonatal HSV rates as high as 31.2 per 100,000 (1 in 3,200) births.4 These incidence data for neonatal HSV are similar to those of perinatal human immunodeficiency virus (HIV) infection before the advent of routine antiretroviral use in pregnancy and are higher than those of congenital syphilis, toxoplasmosis, and congenital rubella in endemic years (Table 1).2, 5–9

Table 1

Incidence of neonatal HSV and other congenital infections in North America

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Pathophysiology

Most neonatal infection results from exposure to HSV in the genital tract during delivery, although in utero and postnatal infections can occasionally occur.10 While most clinical management guidelines for HSV infections concentrate on women with long established disease, the risk of transmission is significantly greater among women who acquire genital infection with HSV-1 or HSV-2 during pregnancy (risk of 25 to 50 percent) than among those who have longstanding HSV-2 infection and subsequently reactivate virus in the genital tract at term (risk of <1 percent) (Figure 1, Table 2). Thus, while the number of infants born to women with newly acquired HSV at the end of pregnancy is much smaller than the number of infants born to women with established HSV-2, the much greater efficiency of HSV transmission during newly acquired genital HSV accounts for the fact that 50 to 80 percent of neonatal HSV cases result from women who acquire genital HSV-1 or HSV-2 infection near term.10, 11 Most genital HSV acquisition in women occurs without signs or symptoms of disease and is associated with cervical viral shedding.

Figure 1

Pathogenesis of Neonatal Herpes

Table 2

Common misperceptions about neonatal herpes

Approximately 2 percent of HSV-2 seropositive women by culture and 8 to 15 percent by polymerase chain reaction (PCR) have HSV-2 detected in genital secretions at term.12, 13 Almost none of this shedding is accompanied by clinically detectable genital lesions. Despite the frequent exposure to HSV during birth, <1 percent of infants delivered vaginally to women shedding HSV-2 at term develop neonatal herpes.10, 11, 14 The discrepancy between the high shedding rate among women with established HSV-2 infection and the low neonatal transmission rate suggests a role for transplacental antibody to abrogate the risk of infection. This difference in transmission risk to the neonate between the initial acquisition of HSV during pregnancy versus reactivation of prior infection contributes to the divergent patient management and public health strategies suggested to impact neonatal HSV.

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Diagnosis

Genital HSV infections are often subclinical and, even if symptomatic, lack specificity in their signs and symptoms. Case series have shown that most primary genital herpes infections in pregnant women are not diagnosed accurately by clinicians.15 Women who present in pregnancy with HSV infection should have both a type-specific serological assay as well as a test of the virus to identify and type their HSV infection.12 This approach allows the clinician to objectively categorize the infant at highest risk of infection. Laboratory tests include viral isolation in culture or direct fluorescent antibody (DFA) studies to detect viral protein from genital lesions,, or PCR to test for presence of viral DNA.12 PCR assessment is the most sensitive and usually most rapid measure.16 Accurate type-specific serological assays are based on the difference in epitope specific immune responses to the HSV glycoprotein G molecule of HSV-1 v. HSV-2; occasionally tests based on whole antigen response are

reported inaccurately as type-specific by diagnostic laboratories. Similarly, commercial IgM assays to HSV-1 and HSV-2 are not validated in pregnancy or in infants. Antibodies to gG1 or gG2 tend to develop reasonably late in the course of infection—2 to 12 weeks; hence, detection of virus in a seronegative woman or discordance between the type of viral isolate and antibody status, for example, HSV-2 isolate in a mother with only type specific HSV-1 antibodies, identifies women with recently acquired infection.

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Manifestations

Congenital HSV infection is rare, shares clinical features with other congenital infections, including microcephaly, hydrocephalus, and chorioretinitis, and usually presents with clinical abnormalities at birth. Post-natal acquisition is almost always due to HSV-1 and is associated with contact with hospital personnel or family members who are shedding HSV-117. Ritual circumcision that involves suctioning of the wound with the mouth also has been associated with neonatal HSV-1.18

Most neonatal infection results from exposure to HSV during delivery. The clinical presentation has been divided into three categories, each associated with different outcomes and clinical manifestations. Neonates with infection confined to skin, eyes and mucosa (SEM), which comprise about 45% of most case series, often present with vesicular lesions on the skin, eye or mouth and, by definition, have no central nervous system (CNS) or visceral organ involvement (normal CSF indices; normal neurological and CT findings; and no evidence of pneumonitis, hepatitis, coagulation problems, etc.). Systemic therapy is required; otherwise, further progression may occur. However, with high-dose intravenous acyclovir, the long-term developmental outcome of this form of neonatal herpes is good. Children with SEM herpes often have recurrent cutaneous herpes outbreaks during early childhood. Suppressive antiviral therapy reduces the frequency of these cutaneous recurrences, but breakthrough infections may still occur. CNS-associated infection, which comprises 30% of most large case series, is associated with lethargy, poor feeding, or seizures, with or without cutaneous lesions. CSF pleocytosis is usually present, HSV DNA in cerebral spinal fluid is the most sensitive laboratory test to confirm the diagnosis, and samples obtained early in the course of the disease may be falsely negative. Morbidity of CNS HSV in infants is higher with HSV-2 than HSV-1, and may include developmental delay, epilepsy, blindness and cognitive disabilities. Prompt initiation of therapy influences outcome; unfortunately, non-specific presentation may delay diagnosis. Acyclovir therapy has substantially improved survival (Table 3); however, neonates with CNS HSV-2 infection still have high rates of developmental problems at one year and over 50 percent have moderate to severe neurological abnormalities.19, 20 Moreover, relapses of CNS infection may occur, further increasing morbidity. The highest fatality rate for neonatal HSV is associated with disseminated infection (25% of case series) involving multiple organs (such as lung, liver and brain) and appearing clinically indistinguishable from bacterial sepsis.17, 19, 20 The risk of death from disseminated neonatal HSV is still high (30 percent), even with antiviral therapy. 19, 20. Any vesicular rash in a neonate should be evaluated for HSV. As up to 50 percent of neonatal HSV infection presents without skin rash, all infants younger than 4 weeks with CNS infection or sepsis syndromes should have a laboratory evaluation, preferably with PCR, performed for HSV infection, including plasma/blood sample for HSV

DNA.21, 22 CSF HSV PCR assay is considered cost-effective in febrile newborns with pleocytosis.23

Table 3

Outcome of neonatal herpes by category of disease

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Treatment of Neonatal Herpes

Antiviral therapy with intravenous acyclovir reduces mortality to 30 percent in infants with disseminated disease and to 6 percent for those with CNS disease (Table 3). Recommended doses are acyclovir 20 mg/kg body weight intravenous every eight hours for 21 days for disseminated and CNS disease21 and for 14 days for disease limited to the skin and mucous membranes. Many experts also recommend the 14 day regimen for asymptomatic infants born to women who acquired HSV near term. Acyclovir is superior to vidarabine, the only other antiviral that has been systematically evaluated for neonatal HSV. Transient neutropenia has been noted in about 20% of infants treated with these high doses of acyclovir, but has not been reported to result in clinically significant adverse outcomes.20 Rare cases of acyclovir-resistant neonatal HSV have been reported.

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Prevention

Neonatal HSV is as severe a disease as other neonatal infections for which prevention strategies have been implemented and remains one of the most serious neonatal infections (Table 3). Recent reports in the medical and popular press document an ongoing controversy about best management for the prevention of neonatal HSV infection, with diverse and sometimes opposite conclusions.24–28 As this is an area of common misunderstanding, we will review these issues.

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Preventing Neonatal HSV by Reducing Acquisition of HSV-1 or -2 in Late Pregnancy

Development of a vaccine that prevents acquisition of HSV-1 and HSV-2 infection would be the most effective strategy to reduce neonatal herpes. However, at present such a vaccine is

not available. Protective immunity against HSV is incompletely understood, and the commonly used animal models – mice and guinea pigs – reflect only certain aspects of human HSV infections accurately. This has limited development of candidate HSV vaccines. Prior investigational vaccines have lacked efficacy against HSV-2 infection in clinical trials; a single-antigen recombinant vaccine showed partial efficacy against HSV-2 disease but demonstrated only marginal efficiency in reducing HSV-2 acquisition among seronegative women. An additional Phase 3 trial with this product is underway. An effective HSV-2 vaccine for pregnant women would need to prevent subclinical reactivation of HSV at the time of delivery to impact neonatal herpes.

Non vaccine proposed strategies to reduce acquiring HSV during pregnancy include (1) counseling all women to avoid unprotected sexual intercourse and unprotected oral-genital contact in late pregnancy, (2) HSV serological testing of women to identify those at risk of acquisition and (3) HSV serological testing of women and partners to identify those with discordant serological status. These strategies rely on sexual behavior change by pregnant women at risk. Advocates of abstinence in late pregnancy emphasize its universal applicability and low cost. However, this does not address women with prior HSV-2 infection which constitute from 30 to 60 percent of most obstetrical practices. Moreover, abstinence is an approach that alone is untested, and studies of abstinence in other situations shed doubt on its effectiveness.29, 30

Identification of women as high-risk for transmission of HSV to the neonate on the basis of demographic or clinical characteristics is a potentially cost-effective strategy; this approach is initially adopted for hepatitis B, HIV and Group B Strep testing in pregnancy. A recent population-based case control study using Washington State data on neonatal HSV infection indicated that demographic or clinical characteristics could not differentiate women at high risk of transmitting HSV to their infants, suggesting such an approach is not likely to be effective.31 Similarly, universal testing is now recommended for hepatitis B, HIV and Group B strep in pregnancy.

Type-specific HSV serological testing to identify women at risk of acquiring genital herpes near term also has been advocated as a potential prevention strategy. Knowledge of HSV status in women at special risk of acquiring infection near term may allow more effective counseling of risk reduction behavior, such as abstinence or protected coitus in the last trimester in combination with no oral-genital contact (cunnilingus). Surveys show that women are interested in testing for HSV during pregnancy, and psychosocial distress resulting from unexpectedly testing HSV-2 seropositive is small and transient.32, 33 Serologic identification of infection status is widely advocated and has been successful for HIV prevention in the U.S. and Africa.34, 35 Critical to the knowledge of serologic status is the effectiveness of strategies that target pregnant women identified as HSV-2 seronegative. Condoms appear to be 50 percent effective in reducing the risk of HSV transmission from men to women, and from women to men.36 Valacyclovir therapy of those with HSV-2 also has reduced the risk of sexual transmission to the susceptible partner by 48 percent.37 However, pregnancy may increase susceptibility to acquisition of HSV infection; it is unknown whether the use of condoms or antiviral therapy of the sexual partner with HSV-2 will have similar effects in HSV-2 seronegative pregnant women.38

Serological testing of both the pregnant woman and her partner has also been suggested. This strategy allows identification of 12 to 20 percent of situations in which the partner is HSV seropositive and the pregnant woman is seronegative (and at risk for infection).39, 40 This

approach may be expensive and not applicable when there is considerable partner change during pregnancy. However, the advantage of such an approach is that it targets the high-risk couples for intensive behavioral strategies, including consistent condom use. It also is the approach most amenable to the use of antiviral therapy in the HSV-2 infected male partner. There are no clinical trials to define if identification of discordant couples by serologic testing will reduce incident maternal HSV infection, and such trials are needed.

The aforementioned approaches address reducing incident HSV-2 infection. As neonatal HSV-1 infection comprises 30 to 50 percent of neonatal herpes,41 attention to the role genital HSV-1 plays in neonatal infection seems prudent, especially as commercial assays for defining antibody status are available for both HSV-1 and HSV-2. We are unaware of any studies that have examined prevention strategies for genital HSV-1.

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Reducing Neonatal Herpes in the HSV-2 Seropositive Woman

Type-specific HSV-2 serological testing during pregnancy can identify women who are HSV-2 seropositive but who have unrecognized genital herpes. Knowledge of HSV-2 may impact obstetrical management to reduce the risk of transmission of infection, such as decreasing the use of invasive monitoring devices (Figure 2); a public health advantage of such an approach is less clear. Diagnosis of newly recognized genital herpes and explanation of attendant risks during pregnancy (as well as the risk of transmission to sexual partners) require considerable effort. Approximately 20 to 25 percent of patients would require counseling about a new disease. For a practitioner who sees neonatal HSV rarely (1 in 5,000 to 10,000 deliveries), this approach may be viewed as impractical. Moreover, the optimal strategy to manage women with newly identified, established genital HSV-2 in pregnancy is unclear.

Figure 2

Risk of Neonatal HSV Among 40,023 Women with Genital Cultures for HSV at Delivery

Current guidelines recommend cesarean deliveries for women with clinical recurrent genital herpes at term (Figure 2).12 Several small studies have shown that daily antivirals at the end of pregnancy can reduce genital HSV recurrences and shedding at term, as well as the need for subsequent cesarean deliveries,42 but have not provided insight on the potential to reduce neonatal herpes. Transmission to the neonate from women who are HSV-2 seropositive is rare; as such, one would expose a large number of mothers and neonates to antiviral therapy to prevent each case of neonatal HSV. The levels of acyclovir reached in amniotic fluid can be similar to those seen in infants treated with systemic acyclovir, of which up to 20 percent develop neutropenia.20 While a pharmacologic approach may offer potential benefit for reducing morbidity from HSV-related cesarean deliveries, widespread exposure of neonates

to acyclovir has not been tested and could result in unnecessary toxicity. As such, routine use of antivirals in late pregnancy in HSV-2 seropositive women, especially the majority of those without a history of genital herpes, should require evidence of efficacy in reducing neonatal herpes and minimal toxicity to the infant.

Because of the morbidity to the mother, many authorities recommend that recently acquired genital HSV infections in pregnant women should be treated with antiviral medications.12 Acyclovir is not teratogenic and may be administered either orally to pregnant women with first episode genital herpes or intravenously to pregnant women with severe HSV infection. A common regimen for pregnant women with first episode genital herpes is acyclovir 400 mg orally three times a day or valacyclovir 500 mg BID for seven to 10 days. No data are available whether such therapy reduces the infection rate in the infant.

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Identifying the Infant at Risk

The isolation of HSV from the maternal genital tract at delivery is associated with >300-fold risk of neonatal herpes.4 Other risk factors associated with acquisition include fetal scalp monitors and cervical HSV infection (Figure 2). Identifying HSV-exposed infants allows resources to be focused on those at highest risk and defines a strategy that could be applied to infants born to mothers with first or recurrent HSV episodes. Once exposure is identified, one could initiate antiviral prophylaxis (or early expectant therapy). This approach requires (1) a rapid, accurate assay to define HSV shedding at delivery, (2) initiation of early antiviral therapy for those at risk, and (3) determination of the effectiveness of the intervention to reduce acquisition of HSV or to improve the outcome of infected infants (Table 3).

Rapid PCR assays have been developed for many diseases, implemented in field hospitals and used for testing samples from women in labor.43, 44 In addition, point-of care tests to identify HSV-2 specific antibodies have been developed and are commercially available, allowing clinicians to define the risk of neonatal infections as high (seronegative mother) or low (seropositive mother)—a factor that many authorities use in determining if systemic acyclovir prophylaxis should be administered.45 At present, little data exist to guide optimal intervention for managing infants exposed to HSV at birth. Use of antiviral prophylaxis has been quite effective in preventing HSV-1 or HSV-2 infection in neonatal animal models.46 One recommendation for infants born to mothers shedding HSV-2 at term is to follow them with sequential sampling for virus in urine and on the mucosa in conjunction with close clinical follow-up for sign of illness and to initiate systemic therapy if HSV infection is present.21 This approach could result in early initiation of therapy for those with neonatal HSV, which is a major determinant of favorable outcome.19, 20, 47 Thus, the identification and observation of exposed infants would at least provide “best practices” monitoring. Alternatively, antiviral therapy could be initiated at birth in infants whose mothers lacked HSV antibody, as their risk of invasive disease is high. Infants born to women with antibodies to the viral type detected could be closely followed. These approaches, while potentially attractive, need to be empirically evaluated.

In summary, whether caused by HSV-1 or HSV-2, neonatal HSV infection is severe and persistent in the U.S., exceeding in incidence other infectious diseases for which nationwide prevention strategies exist. The tools to devise better prevention strategies have been

developed, and several strategies to conceptually reduce infection have been outlined. Current guidelines by the American College of Obstetrics and Gynecology provide useful patient management tools but are not directed at neonatal HSV prevention and appear not to have altered the epidemiology of neonatal HSV in the U.S. in the last decade.12 A concentrated effort to conduct studies that may provide guidance to effectively reduce neonatal herpes is needed and will require an alliance between practitioners and academicians.

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Acknowledgments

Grant Acknowledgement and Contributions

Supported by grants PO1 AI-30731, R37 AI-42528, and CA-15704. LC and AW discussed the content of the Tables, Figures and text. LC wrote the first draft of the paper, which was then critically revised by both authors.

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Footnotes

Conflict of Interest

Dr. Corey is director of the University of Washington Virology Division, which has received grant support from GlaxoSmithKline, a company that make antiviral drugs for the treatment of HSV-2. Dr. Corey receives no salary support from these studies. He is a consultant for Aicuris, which is developing a drug for treating HSV infection. Dr. Corey is a co-inventor on several patents describing antigens/epitopes to which T cell responses to HSV-2 are directed. These proteins have the potential to be utilized in candidate HSV vaccines.

Dr. Wald has received grant support from the National Institutes of Health, GlaxoSmithKline, Antigenics and Astellas. She has been a consultant for Aicuris and Medigene, as well as a speaker for Merck Vaccines. No other potential conflict of interest relevant to this article is reported.

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