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Genital Herpes in Pregnancy

  • Author: Serdar H Ural, MD; Chief Editor: Thomas Chih Cheng Peng, MD  more...
 
Updated: Apr 16, 2015
 

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. Genital herpetic infection.

See Herpes Simplex Viruses: Test Your Knowledge, a Critical Images slideshow, for more information on clinical, histologic, and radiographic imaging findings in HSV-1 and HSV-2.

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]

Pregnant women with untreated genital herpes during the first or second trimester appear to have a greater than two-fold risk of preterm delivery compared with women not exposed to herpes, particularly in relation to premature rupture of membrane and early preterm delivery (≤ 35 wk of gestation).[23] Pregnant women who receive antiherpes treatment have a lower risk of preterm delivery than untreated women, and their preterm delivery risk is similar to that seen in unexposed women.

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.

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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.

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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. 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.
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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.
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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.

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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]

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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.
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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]

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Conclusions

In 2007, the American College of Obstetricians and Gynecologists (ACOG) published a practice bulletin regarding HSV in pregnancy.[22] Their conclusions were as follows:

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

See the list below:

  • Women with active recurrent genital herpes should be offered suppressive viral therapy at or beyond 36 weeks of gestation.
  • Cesarean delivery is indicated in women with active genital lesions or prodromal symptoms (eg, vulvar pain or burning) at the time of delivery, because these symptoms may indicate an impending outbreak.

level C recommendations (based on consensus or expert opinion)

See the list below:

  • In women with premature rupture of membranes, there is no consensus on the gestational age at which the risks of prematurity outweigh the risks of HSV infection.
  • Cesarean delivery is not recommended for women with a history of HSV infection but no active genital disease during labor.
  • Routine antepartum genital HSV cultures in asymptomatic patients with recurrent disease are not recommended.
  • Routine HSV screening of pregnant women is not recommended.

In 2013, the American Academy of Pediatrics (AAP) Committees on Infectious Diseases and on Fetus and Newborn developed an algorithm for the management of asymptomatic neonates born vaginally or by cesarean delivery to women with active genital HSV lesions.[24] Clinicians should determine primary versus recurrent infection and obtain HSV DNA results from genital swabs taken from women in labor to identify symptomatic or asymptomatic shedding.

If the mother has a history of prepregnancy genital HSV infection, the following are included in the AAP algorithm[24] :

  • At about 24 hours post delivery, if the neonate is asymptomatic, obtain neonatal skin and mucosal cultures as well as neonatal blood for HSV DNA PCR assay. If the neonate is asymptomatic, do not administer acyclovir.
  • If the neonatal surface cultures as well as the blood and surface PCRs are negative for 48 hours and there are no clinical conditions indicating otherwise, the infant may be discharged, with close monitoring for signs/symptoms of neonatal HSV. A full diagnostic evaluation and initiation of intravenous (IV) acyclovir are necessary if signs/symptoms of neonatal HSV develop.
  • If the neonatal surface cultures or the blood or surface PCRs are positive, perform a full diagnostic evaluation (eg, obtain cerebrospinal fluid [CSF] analyses and HSV DNA PCR assay, serum chemistries, including alanine transaminase [ALT] levels) and initiate IV acyclovir.

If the mother does not have a history of prepregnancy genital HSV infection, the AAP algorithm includes the following[24] :

  • If available, obtain maternal type specific serology for HSV-1 and HSV-2 antibodies.
  • At about 24 hours post delivery, if the neonate is asymptomatic, obtain neonatal skin and mucosal cultures and neonatal blood for HSV DNA PCR assay. In addition, obtain CSF analyses and HSV DNA PCR assay, serum chemistries, including ALT levels, and initiate IV acyclovir.
  • Once the maternal disease classification is determined (eg, first episode primary/nonprimary, recurrent), further management options include further diagnostic workup and/or neonatal empiric IV acyclovir or IV acyclovir for treatment of surface, CNS, or disseminated disease.

For full details of the 2013 AAP algorithm, see Kimberlin DW, Baley J, for the Committee on Infectious Diseases and Committee on Fetus and Newborn. Guidance on management of asymptomatic neonates born to women with active genital herpes lesions. Pediatrics. 2013 Feb;131(2):383-6. PMID: 23378604.[24]

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.

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Contributor Information and Disclosures
Author

Serdar H Ural, MD Associate Professor of Obstetrics and Gynecology and Radiology, Director, Division of Maternal-Fetal Medicine, Medical Director, Labor and Delivery Suite, Pennsylvania State University College of Medicine

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

Disclosure: Received honoraria from GSK for speaking and teaching; Received honoraria from J&J for speaking and teaching.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Richard S Legro, MD Professor, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, Pennsylvania State University College of Medicine; Consulting Staff, Milton S Hershey Medical Center

Richard S Legro, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, Society of Reproductive Surgeons, American Society for Reproductive Medicine, Endocrine Society, Phi Beta Kappa

Disclosure: Received honoraria from Korea National Institute of Health and National Institute of Health (Bethesda, MD) for speaking and teaching; Received honoraria from Greater Toronto Area Reproductive Medicine Society (Toronto, ON, CA) for speaking and teaching; Received honoraria from American College of Obstetrics and Gynecologists (Washington, DC) for speaking and teaching; Received honoraria from National Institute of Child Health and Human Development Pediatric and Adolescent Gynecology Research Thi.

Chief Editor

Thomas Chih Cheng Peng, MD Professor (Collateral), Department Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine, VCU Health System

Thomas Chih Cheng Peng, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, Society for Maternal-Fetal Medicine

Disclosure: Nothing to disclose.

References
  1. Corey L, Wald A. Maternal and neonatal herpes simplex virus infections. N Engl J Med. 2009 Oct 1. 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. 2007 Dec. 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. 1997 Jun. 89(6):891-5. [Medline].

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  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. 1998 Mar. 105(3):275-80. [Medline].

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Genital herpetic infection.
Viral shedding in labor.
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.
Table 2. Recommended Dosages of the Antiviral Agents for Genital Herpes Infection
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
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)
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
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