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Abstract

Genital herpes is the leading cause of genital ulcer disease worldwide and it is one of the most common sexually transmitted infections. Genital herpes simplex virus infection during pregnancy poses significant risks, predominantly vertical transmission of infection with resulting neonatal disease. While uncommon, neonatal infection has a high mortality rate and significant long-term morbidity. This article will examine the current recommendations for diagnosis using serologic and viral detection techniques. Treatment options for initial and recurrent genital herpes infection in pregnancy are reviewed. The use of prophylactic antivirals and cesarean delivery are discussed. The article concludes with a look to the future, including potential changes in the management of herpes simplex virus-infected pregnant women.

Keywords

genital herpes herpes simplex virus management neonatal herpes pregnancy

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Learning objectives

Upon completion of this activity, participants should be able to:

Identify the epidemiology of infection with herpes simplex virus (HSV)

Describe the prevalence of HSV infection during pregnancy and the risk for vertical transmission

Specify clinical scenarios in which HSV serologic assays may be helpful

Describe the management of HSV infection during pregnancy

Etiology

Herpes simplex virus (HSV) type 1 and 2 are large, double-stranded DNA viruses of the Herpesviridae family. HSV-1 and −2 share 83% sequence homology of their protein-coding regions and the structure of their genomes is alike. They can be differentiated into type 1 and 2 based on the glycoproteins in the lipid bilayer envelope [1]. Although the virus types are distinct, antibodies to one cross-react and modify infections with the other type [2].

Herpes simplex virus is transmitted from person to person through direct contact. At initial infection, HSV enters the body through skin or mucosal surfaces where it initiates cytolytic replication in the epithelial cells. The incubation period after acquisition of HSV-1 or −2 ranges from 2 to 12 days. Histologically, virions are seen within epithelial cells as intranuclear inclusions. HSV induces cells to fuse and form multi-nucleated giant cells. Clinically, cellular destruction and inflammation in the skin or mucosa causes the formation of fluid-filled vesicles.

Concomitant with the primary infection, HSV ascends in a retrograde manner up the sensory nerve axons to the sensory nerve root ganglia. There the virus enters a latent state where it persists for the life of the infected person. Recurrent episodes are the result of periodic viral reactivation [3]. During these episodes of reactivation, the virus is transported back down the neuron. The result can be clinically apparent lesions, symptoms without lesions or asymptomatic viral shedding.

Prevalence

Herpes simplex virus infections are among the most common sexually transmitted infections. The most recent age-adjusted seroprevalence of HSV-2 among women in the USA was 23%, and longitudinal serologic studies in this country suggest a recent decline in the prevalence of genital HSV-2 [4]. The seroprevalence of HSV-2 is much lower in other developed nations, for example, 15% among women in Germany and 16% among women in Australia [5,6]. The seroprevalence is higher among women than among men across various populations [7]. In a recent US study, the seroprevalence among men was only 11% compared with 23% among women [4]. The seroprevalence of HSV-1 in adults is approximately 70% in developed countries and 100% in developing countries [4,8].

Herpes simplex virus type 1 is the primary etiologic agent of herpes labialis, gingivostomatitis and keratoconjunctivitis. While HSV-2 is almost exclusively a genital pathogen, HSV-1 is increasingly recognized as the etiologic agent of genital HSV infection. In many teens and young adults, HSV-1 infection causes more than half of new cases of genital HSV [9 –11].

Both HSV-1 and −2 can be transmitted to other sites by direct contact with infected secretions or autoinoculation. In addition, both can be transmitted vertically and cause symptomatic neonatal disease. Asymptomatic shedding is very common – longitudinal studies of persons with HSV-2 antibodies suggest that more than 90% of individuals reactivate HSV intermittently in the genital tract [12]. In the first year after acquisition of the infection, HSV can be detected on a mean of 25–30% of days. Asymptomatic shedding probably represents the major source of sexual transmission.

Risk factors for HSV-2 include duration of sexual activity, Black race, previous genital infections, low socioeconomic status or level of education and number of sexual partners. Women are more susceptible to HSV-2 infection than men [13,14].

Herpes infection in pregnancy

Overall, the incidence of new HSV-1 or −2 infection during pregnancy is approximately 2% [15]. Approximately 10% of HSV-2 seronegative women have seropositive partners and are at risk for transmission of HSV-2 during the pregnancy. In one couples study of women at risk, approximately 20% of women acquired HSV-2 in pregnancy [16]. Consistent with non-pregnant patients, the majority of new infections are asymptomatic [17]. The timing of infection is relatively evenly distributed, with approximately a third of the women becoming infected in each trimester [15]. Among women with recurrent genital HSV, nearly 75% can expect at least one recurrence during pregnancy, and approximately 14% of patients will have prodromal symptoms or clinical recurrence at delivery [18,19]. HSV infection does not appear to be associated with an increased risk for spontaneous abortion [15].

The risk of neonatal transmission is influenced by the maternal antibody status and the timing of maternal infection. The risk of vertical transmission when a primary infection occurs at the time of delivery is approximately 30–60% [15,20]. Among women with recurrent lesions at the time of delivery, the rate of transmission is approximately 3% and for women with recurrent disease and no visible lesions at delivery, the transmission risk has been estimated to be less than 1% and possibly as low as 2/10,000 [21,22].

Neonatal herpes is usually acquired during the intrapartum period through exposure to the virus in the genital tract, although in utero and postnatal infection can occur. Approximately 80% of infected infants are born to mothers with no reported history of HSV infection [23]. The incidence of neonatal HSV in the USA is unknown because it is not mandatory to report diagnosed cases. Estimates suggest that nearly 1200–1500 cases occur each year in the USA (incidence of neonatal HSV of 1 in 3000 to 1 in 20,000 live births) [24 –26]. Reflecting the lower prevalence of HSV in women in The Netherlands compared with the USA, the incidence of neonatal HSV is estimated to be approximately 3.2 per 100,000 live births in The Netherlands [27]. This incidence rate has been low and stable for the last two decades. Approximately a third to a half of cases of neonatal HSV are caused by HSV-1 [20,28]. Mortality from neonatal HSV has decreased significantly over the last two decades; however, approximately 20% of survivors have long-term neurologic sequelae [29].

Diagnosis

The classic presentation of a painful cluster of vesicles and ulcers occurs in a small proportion of women, and many women will have atypical lesions, such as abrasions, fissures or itching without obvious lesions. Conversely, even in at-risk women with a presentation compatible with genital herpes, up to 20% of women will not have genital herpes [2]. The tests used to confirm the presence of HSV infection can be divided into two basic groups: viral detection techniques and antibody detection techniques. Viral detection techniques for diagnosis include viral culture, HSV antigen detection by enzyme immunoassay or direct fluorescent antibody and PCR tests for viral DNA. Antibody detection techniques include both laboratory-based and point-of-care type-specific serologic tests to detect the presence of antibodies to either HSV-1 (no point-of-care test exists for HSV-1) or HSV-2.

Demonstration of HSV in lesions is the preferred virologic test for patients who seek medical treatment for genital ulcers or other mucocutaneous lesions and allows differentiation of the type of HSV (HSV-1 vs −2) [30]. However, the sensitivity of culture is limited [31,32]. Primary lesions are more likely to yield positive cultures than recurrent lesions, and lesions are less likely to be positive as they heal [33,34]. Thus, a positive genital culture provides conclusive evidence of genital HSV infection; however, a negative culture does not exclude the presence of infection.

PCR techniques are commercially available and appear to be much more sensitive for the detection of HSV than culture [32,35]. These tests can differentiate between HSV-1 and −2 and may ultimately replace culture as the standard of care for diagnosis. Several large reference laboratories have developed their own type-specific PCR assays. These assays must be validated appropriately before clinical use. At present, there are no interlaboratory standards that assure that identical specimens processed in different laboratories will yield identical results.

For patients who do not present with active lesions or whose lesions are culture- or PCR-negative, type-specific serologic assays that accurately distinguish between HSV-1 and −2 antibodies are commercially available. In a high-risk population, the positive predictive value for the ELISA tests was 80–94% [36,37]. Repeat testing using a different type-specific assay has been shown to increase the positive predictive value of a single test, and this may be especially important in populations with low HSV prevalence [36]. Since HSV-2 is an uncommon cause of oral infection, the detection of HSV-2 antibodies is virtually diagnostic of genital HSV infection [38]. Conversely, detection of HSV-1 antibodies may represent orolabial infection or may be indicative of genital infection. The correlation with direct viral identification techniques and the patient's symptoms will be important.

Type-specific HSV serologic assays might be useful in the following scenarios:

Recurrent genital symptoms or atypical symptoms with negative HSV cultures;

Clinical diagnosis of genital HSV without laboratory confirmation;

Patient whose partner has genital HSV;

Patient who presents with their first genital HSV infection during the third trimester of pregnancy.

Some specialists believe that HSV serologic testing should be included in a comprehensive evaluation for sexually transmitted diseases among persons with multiple sex partners or with HIV infection [30].

Serologic screening of women or couples during pregnancy for HSV-2 antibodies has been proposed. Women who are HSV seronegative are at risk for acquiring HSV infection during pregnancy and, in fact, are the group of women at highest risk for neonatal HSV. Several analyses have evaluated the cost–effectiveness of various screening protocols for pregnant patients to reduce the incidence of neonatal HSV infection [39 –43]. The results from these analyses are highly variable – estimates of the cost to prevent one case of neonatal HSV range from US$200,000 to $4 million. One study addressed the costs and calculated the benefit in terms of quality-adjusted life years (QALY) saved and identified a cost of $48,946 per QALY for the testing of pregnant women and their partners, which is within a commonly accepted margin of $50,000 per QALY. A number of factors influence the cost estimates, including the costs of testing and counseling, effectiveness of antiviral therapy, the probability of lesions or shedding at delivery in asymptomatic women diagnosed with HSV only by the screening test and the likelihood of neonatal HSV with vaginal delivery [40,41]. At this time, there is no clinical evidence to support the efficacy of universal serologic screening of pregnant women to prevent HSV transmission and neonatal infection. While screening may be beneficial in particular populations or couples, universal screening of pregnant women is not currently recommended [21,101].

Treatment

There is no cure for HSV infection, but the use of antiviral medications in nonpregnant women has been demonstrated to reduce the frequency and duration of outbreaks, reduce the frequency of asymptomatic shedding and reduce transmission to sexual partners [30,44]. In one study, more than 700 infants were reported to be exposed to acyclovir during the first trimester, and there does not appear to be an increase in adverse fetal or neonatal effects [45]. There are insufficient data on valacyclovir and famciclovir exposure in the pregnancy registry for analyses. Table 1 summarizes suggestions for antiviral treatment in pregnant women. At the time of the initial outbreak, antiviral treatment may be administered orally to pregnant women in order to reduce the duration and the severity of the symptoms as well as to reduce the duration of viral shedding [46]. In patients who have severe disease, oral treatment can be extended for more than 10 days if lesions are incompletely healed at that time [30]. Acyclovir should be administered intravenously to pregnant women with severe HSV infection or in disseminated herpetic infections.

Table 1.

Recommended doses of antiviral medications for herpes simplex virus infections in pregnancy.

Indication	Acyclovir	Valacyclovir
Initial infection	400 mg p.o. t.i.d. for 7–10 days*	1 g p.o. b.i.d. for 7–10 days*
Symptomatic recurrent episode	400 mg p.o. t.i.d. for 5 days or 800 mg p.o. b.i.d. for 5 days	500 mg p.o. b.i.d. for 3 days or 1 g p.o. daily for 5 days
Daily suppression	400 mg p.o. t.i.d. from 36 weeks estimated gestational age until delivery	500 mg p.o. b.i.d. from 36 weeks estimated gestational age until delivery
Disseminated infection	5–10 mg/kg intravenously every 8 h for 2–7 days followed by oral therapy with acyclovir or valacyclovir as above for initial infection to complete at least 10 days of total therapy

Published data regarding the use of famciclovir in pregnancy is not available.

Treatment duration may be extended if healing is incomplete after 10 days.

b.i.d.: Twice daily; p.o.: Per orem; t.i.d.: Three-time daily.

Data taken from [30].

Numerous clinical trials have evaluated the effectiveness of antiviral suppression to reduce cesarean delivery. Findings of several trials were limited owing to the small sample size. The efficacy of suppressive therapy with acyclovir and valacyclovir during pregnancy in order to prevent recurrences near term is supported by meta-analyses of randomized trials [47,48]. The rate of recurrence at delivery and the rate of cesarean delivery for recurrent genital HSV are reduced by approximately 70% for women who received antiviral suppression from 36 weeks of gestation until delivery. Viral detection at delivery using culture or PCR was reduced by 90% among women who were treated, however, shedding was not completely eliminated [19,48]. The effect of antepartum antiviral prophylaxis on neonatal herpes could not be estimated because there were no cases of symptomatic neonatal HSV in the studies included in either the treatment or placebo groups. The doses of antiviral medication used for suppression in the randomized trials are higher than the corresponding doses in nonpregnant women, including acyclovir 400 mg orally three-times daily and valacyclovir 500 mg orally twice daily. No clinical trials have been conducted using famciclovir. The pharmacokinetics and metabolism of acyclovir in the human fetus are not known. In the absence of such data, areas of potential complications associated with any infant receiving parenteral antiviral therapy include bone marrow, renal and hepatic toxicity [49]. Hepatotoxicity, nephrotoxicity and neutropenia were not observed in neonates born to women receiving valacyclovir 500 mg orally twice daily in a recent randomized trial [18]. The risks and benefits of suppression after 36 weeks gestation should be discussed with patients who have primary HSV in pregnancy and those with a history of HSV prior to pregnancy.

All women should be questioned about symptoms of genital HSV, including the patient's typical prodromal symptoms, and should be examined for herpetic lesions when they present for evaluation in labor and delivery [30]. Invasive monitors, such as fetal scalp electrodes, are a significant risk factor for transmission of HSV, increasing the risk of neonatal infection by approximately six-times compared with externally monitored patients [20]. However, if there are indications for fetal scalp monitoring, it may be reasonable in a woman who has a history of recurrent HSV and no active lesions.

While the incidence of neonatal disease is low, cesarean delivery is indicated in women with active genital lesions or prodromal symptoms, which may indicate an impending outbreak [21]. Evidence supporting cesarean delivery comes from a large cohort study, in which women who had been delivered by cesarean were much less likely to transmit HSV infection to their infants [20]. Among women with HSV detected at delivery, neonatal HSV occurred in 1.2% of infants delivered by cesarean compared with 7.7% of infants delivered vaginally [20].

Primary infection with HSV during the third trimester confers the highest risk of neonatal transmission (∼30–60%) [15,20]. There are several potential contributing factors, for example, during the primary infection, the woman is viremic and transplacental passage of the virus can occur. Most importantly, viral shedding with primary infection is prolonged and the concentration of virus in the genital tract is higher. The mean duration of viral shedding associated with primary infection is approximately 15 days, although shedding can persist for longer periods. Type-specific antibodies to the virus develop within 2–3 weeks of infection. The presence of glycoprotein (Gp) G2 antibodies may play a role in preventing neonatal infection after exposure to HSV-2 [50]. At this time, there is little evidence to guide obstetric management. Two national organizations address this topic in practice guidelines [51,101]. The Society of Obstetricians and Gynaecologists of Canada recommends that women with primary genital HSV in the third trimester of pregnancy be counseled regarding their high risk of transmitting HSV to their neonates and should be offered a cesarean delivery to decrease the risk [51]. According to the 2007 guideline published by The Royal College of Obstetricians and Gynaecologists, cesarean delivery should be recommended to all women presenting with primary episode genital HSV lesions at the time of delivery, or within 6 weeks of the expected date of delivery [101].

Cesarean delivery does not completely prevent vertical transmission to the neonate [24,52]. Importantly, cesarean delivery is not warranted in women with a history of HSV infection but with no active genital disease during labor [21]. In patients with active HSV infection and ruptured membranes at or near term, a cesarean delivery should be performed as soon as the necessary personnel and equipment can be readied. There is no evidence suggesting that there is a duration of rupture of membranes beyond which the fetus does not benefit from cesarean delivery [53].

In a patient with preterm premature rupture of membranes and active HSV, the risks of prematurity versus the potential risk of neonatal disease should be weighed. In such situations, it may be appropriate to consult personnel who are well versed in the management of such complicated cases.

Postnatally acquired disease can be as lethal as that acquired during delivery. Oropharyngeal or cutaneous lesions can be an effective source of virus for transmission to the newborn. It is unlikely that breastfeeding will lead to neonatal infection; however, if the mother has an obvious lesion on the breast, breastfeeding is contra-indicated. Since HSV is transmitted through direct contact (e.g., hand–mouth), neonatal infection may be acquired from any caregiver (e.g., mother, father, other family member or healthcare provider) with oral or cutaneous HSV [54,55]. Most strains of HSV responsible for nosocomial neonatal disease are HSV-1 rather than HSV-2. Mothers and other caregivers with active lesions should use proper handwashing and contact precautions when handling babies.

Both acyclovir and valacyclovir appear to be safe for use in breastfeeding mothers. In a group of women breastfeeding while taking valacyclovir, acyclovir was found in the breast milk in concentrations that were higher than the maternal serum; however, the amount of acyclovir in the breast milk was only 2% of that used for the therapeutic dosing of neonates [56].

Future perspective

In 10 years, the overall number of genital infections due to HSV-1 may exceed the number of genital infections due to HSV-2. HSV-1 may also become the leading cause of neonatal HSV. Accurate statistics for the incidence of neonatal HSV are necessary to evaluate the impact of interventions aimed at reducing the burden of neonatal disease [57]. National reporting systems for neonatal HSV should be adopted and international cooperation would be beneficial. These epidemiologic data would improve the design of clinical trials upon which practice guidelines are based and, in turn, strengthen public health policies.

Given the improved sensitivity of PCR compared with HSV culture, PCR is likely to become the preferred tool for direct viral detection in the future. This will require standardization of testing methods and development of widely available commercial products. Populations of women who would benefit from serologic screening during pregnancy may be better defined.

New interventions to reduce neonatal herpes will be needed as current interventions are limited. Prevention of new HSV infection in pregnancy would be an important step in reducing the incidence of neonatal disease. Research regarding the impact of behavioral interventions may be forthcoming. If reliable rapid PCR testing becomes widely available, we may see universal screening for detection of genital HSV at the time of delivery.

Finally, the development of an effective vaccine against HSV is very important for primary prevention. In previous trials, a candidate vaccine demonstrated efficacy in women who were seronegative for both HSV-1 and −2 prior to vaccination [58]. A large, Phase III trial of a candidate vaccine is underway, which evaluates the effectiveness of a GpD-based vaccine among women who are seronegative for HSV-1 and −2. The trial recently closed enrollment and is anticipated to be completed in November 2009 [102].

Executive summary

Prevalence

Herpes simplex virus (HSV) infections are among the most common sexually transmitted infections.

HSV-2 affects approximately 23% of women in the USA; the seroprevalence of HSV-1 is approximately 70%.

HSV-1 is increasingly recognized as the etiologic agent of genital HSV infection, accounting for more than half of the new cases of genital HSV among teens and young adults.

Etiology

HSV-1 and −2 are large, double-stranded DNA viruses.

At initial infection, HSV initiates cytolytic replication in the epithelial cells.

HSV ascends up sensory nerve axons to the nerve root ganglia where it persists in a latent phase.

During recurrent episodes, the virus is transported back down the neuron, resulting in either recurrent lesions or asymptomatic viral shedding.

Clinical course

The overall incidence of new HSV-1 or −2 infection during pregnancy is approximately 2%.

Among women with recurrent genital HSV, nearly 75% can expect at least one recurrence during pregnancy and 14% of patients will have prodromal symptoms or clinical recurrence at delivery.

The risk of vertical transmission is highest when a primary outbreak occurs at the time of delivery (∼30–60%).

Diagnosis

For patients with genital ulcers, isolation of HSV in cell culture is the preferred virologic test; however, the sensitivity of culture is limited.

PCR techniques appear to be more sensitive for the detection of HSV in a patient with active lesions.

Type-specific serologic assays are helpful for diagnosis in select patients.

Treatment

Antiviral treatment may be administered orally to pregnant women at the time of HSV outbreak.

Suppressive therapy during pregnancy from 36 weeks to delivery decreased the rate of recurrence at delivery and the rate of cesarean delivery for recurrent genital HSV by 70%.

Cesarean delivery is indicated in women with active genital lesions or prodromal symptoms at the time of delivery.

Future perspective

Serologic screening of women or couples during pregnancy for HSV-2 antibodies has been proposed.

HSV vaccine is currently an area of development.

Footnotes

CME Author

Charles P Vega, MD, FAAFP , Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine, USA. Disclosure: Charles P Vega, MD, FAAFP, has disclosed that he has served as an advisor or consultant to Novartis, Inc.

Editor

Elisa Manzotti, Editorial Director, Future Science Group. Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

Authors and Disclosures

Irene E Aga, Department of Obstetrics, Gynecology & Reproductive Sciences, UT Houston LBJ General Hospital, 5656 Kelley Street, Houston, TX 77026, USA.

Disclosure: Irene E Aga has disclosed no relevant financial relationships.

Lisa M Hollier, Department of Obstetrics, Gynecology & Reproductive Sciences, UT Houston LBJ General Hospital, 5656 Kelley Street, Houston, TX 77026, USA.

Disclosure: Lisa M Hollier has disclosed no relevant financial relationships.

References

Papers of special note have been highlighted as:

of interest

of considerable interest

Dolan

Jamieson

Cunningham

Barnett

McGeoch

: The genome sequence of herpes simplex virus type 2. J. Virol. 72, 2010–2021 (1998).

Langenberg

AGM

Corey

Ashley

Leong

Straus

: A prospective study of new infections with herpes simplex virus type 1 and type 2. N. Engl. J. Med. 341, 1432–1438 (1999).

Gupta

Warren

Wald

: Genital herpes. Lancet 370(9605), 2127–2137 (2007).

Sternberg

Kottiri

: Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA 296(8), 964–973 (2006).

Most recent US seroprevalence data.

Wutzler

Doerr

Farber

: Seroprevalence of herpes simplex virus type 1 and type 2 in selected German populations: relevance for the incidence of genital herpes. J. Med. Virol. 61(2), 201–207 (2000).

10.

Cunningham

Taylor

Marks

Shaw

Mindel

: Prevalence of infection with herpes simplex virus types 1 and 2 in Australia: a nationwide population based survey. Sex Trans. Infect. 82(2), 164–168 (2006).

11.

Cowan

French

Mayaud

: Seroepidemiological study of herpes simplex virus types 1 and 2 in Brazil, Estonia, India, Morocco, and Sri Lanka. Sex Trans. Infect. 79(4), 286–290 (2004).

12.

Nahmias

Lee

Beckman-Nahmias

: Sero-epidemiological and sociological patterns of herpes simplex virus infection in the world. Scand. J. Infect. Dis. 69, 19–36 (1990).

13.

Mertz

Rosenthal

Stanberry

: Is herpes simplex virus type 1 (HSV-1) now more common than HSV-2 in first episodes of genital herpes? Sex Trans. Dis. 30, 801–802 (2003).

14.

Roberts

Pfister

Spear

: Increasing proportion of herpes simplex virus type 1 as a cause of genital herpes infection in college students. Sex Trans. Dis. 30, 797–800 (2003).

15.

Scoular

Norrie

Gillespie

Mir

Carman

: Longitudinal study of genital infection by herpes simplex virus type 1 in Western Scotland over 15 years. Br. Med. J. 324, 1366–1367 (2002).

16.

Wald

Zeh

Selke

: Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N. Engl. J. Med. 342(12), 844–850 (2000).

17.

Mertz

Benedetti

Ashley

Selke

Corey

: Risk factors for the sexual transmission of genital herpes. Ann. Intern. Med. 116, 197–202 (1992).

18.

Wald

: Herpes simplex virus type 2 transmission: risk factors and virus shedding. Herpes 11(Suppl. 3), 130A–137A (2004).

19.

Brown

Selke

Zeh

: The acquisition of herpes simplex virus during pregnancy. N. Engl. J. Med. 337, 509–515 (1997).

20.

Gardella

Brown

Wald

: Risk factors for herpes simplex virus transmission to pregnant women: a couples study. Am. J. Obstet. Gynecol. 193, 1891–1899 (2005).

21.

Langenberg

Corey

Ashley

Leong

Straus

: A prospective study of new infections with herpes simplex virus type 1 and type 2. N. Engl. J. Med. 341, 1432–1438 (1999).

22.

Sheffield

Hill

Hollier

: Valacyclovir prophylaxis to prevent recurrent herpes at delivery: a randomized clinical trial. Obstet. Gynecol. 108, 141–147 (2006).

23.

Watts

Brown

Money

: A double-blind, randomized, placebo-controlled trial of acyclovir in late pregnancy for the reduction of herpes simplex virus shedding and cesarean delivery. Am. J. Obstet. Gynecol. 188, 836–843 (2003).

24.

Brown

Wald

Morrow

Selke

Zeh

Corey

: Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant. JAMA 289, 203–209 (2003).

25.

Landmark article regarding the transmission risks for neonatal herpes.

26.

ACOG Committee on Practice Bulletins: ACOG Practice Bulletin. Clinical management guidelines for obstetrician–gynecologists. No. 82, June 2007. Management of herpes in pregnancy. Obstet. Gynecol. 109(6), 1489–1498 (2007).

27.

Brown

Benedetti

Ashley

: Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor. N. Engl. J. Med. 324, 1247 (1991).

28.

Hutto

Arvin

Jacobs

: Intrauterine herpes simplex virus infections. J. Pediatr. 110, 97–101 (1987).

29.

Whitley

Corey

Arvin

: Changing presentation of herpes simplex virus infection in neonates. J. Infect. Dis. 158, 109–116 (1988).

30.

Dinh

Dunne

Markowitz

Weinstock

Berman

: Assessing neonatal herpes reporting in the United States, 2000–2005. Sex Trans. Dis. 35(1), 19–21 (2008).

31.

Mahnert

Roberts

Laibl

Sheffield

Wendel

: The incidence of neonatal herpes infection. Am. J. Obstet. Gynecol. 196(5), E55–E556 (2007).

32.

Poeran

Wildschut

Gaytant

Galama

Steegers

van der Meijden

: The incidence of neonatal herpes in The Netherlands. J. Clin. Virol. 42(4), 321–325 (2008).

33.

Whitley

Arvin

Prober

: A controlled trial comparing vidarabine with acyclovir in neonates with herpes simplex virus infection. N. Engl. J. Med. 324, 444–449 (1991).

34.

Kimberlin

Lin

Jacobs

: Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics 108, 230–238 (2001).

35.

Centers for Disease Control and Prevention, Workowski

Berman

: Sexually transmitted diseases treatment guidelines 2006. MMWR Recomm. Rep. 55(RR-11), 16–20 (2006).

36.

Slomka

Emery

Munday

Moulsdale

Brown

: A comparison of PCR with virus isolation and direct antigen detection for diagnosis of typing of genital herpes. J. Med. Virol. 55, 177–183 (1998).

37.

Wald

Huang

Carrell

Selke

Corey

: Polymerase chain reaction for detection of herpes simplex virus (HSV) DNA on mucosal surfaces: comparison with HSV isolation in cell culture. J. Infect. Dis. 188, 1345–1351 (2003).

38.

Moseley

Corey

Benjamin

Winter

Remington

: Comparison of viral isolation, direct immunofluorescence, and indirect immunoperoxidase techniques for detection of genital herpes simplex virus infection. J. Clin. Microbiol. 13, 913–918 (1981).

39.

Cone

Hobson

Palmer

Remington

Corey

: Extended duration of herpes simplex virus DNA in genital lesions detected by the polymerase chain reaction. J. Infect. Dis. 164, 757–760 (1991).

40.

Cone

Hobson

Brown

: Frequent detection of genital herpes simplex virus DNA by polymerase chain reaction among pregnant women. JAMA 272, 792–796 (1994).

41.

Morrow

Friedrich

Meier

Corey

: Use of “biokit HSV-2 Rapid Assay” to improve the positive predictive value of Focus HerpeSelect HSV-2 ELISA. BMC Infect. Dis. 5, 84–90 (2005).

42.

Turner

Wong

Kent

Klausner

: Serologic herpes testing the in the real world. Validation of new type-specific serologic herpes simplex virus tests in a public health laboratory. Sex Trans. Dis. 29, 422–425 (2002).

43.

Wald

Ericsson

Krantz

Selke

Corey

: Oral shedding of herpes simplex virus type 2. Sex Trans. Infect. 80, 272–276 (2004).

44.

Cleary

Pare

Stamilio

Macones

: Type-specific screening for asymptomatic herpes infection in pregnancy: a decision analysis. BJOG 112(6), 731–736 (2005).

45.

Thung

Grobman

: The cost–effectiveness of routine antenatal screening for maternal herpes simplex virus-1 and −2 antibodies. Am. J. Obstet. Gynecol. 192(2), 483–488 (2005).

46.

Baker

Brown

Hollier

: Cost–effectiveness of herpes simplex virus type 2 serologic testing and antiviral therapy in pregnancy. Am. J. Obstet. Gynecol. 191(6), 2074–2084 (2004).

47.

Barnabas

Carabin

Garnett

: The potential role of suppressive therapy for sex partners in the prevention of neonatal herpes: a health economic analysis. Sex Trans. Infect. 78(6), 425–429 (2002).

48.

Rouse

Stringer

: An appraisal of screening for maternal type-specific herpes simplex virus antibodies to prevent neonatal herpes. Am. J. Obstet. Gynecol. 183(2), 400–406 (2000).

49.

Corey

Wald

Patel

: Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N. Engl. J. Med. 350, 11–20 (2004).

50.

Ratanajamit

Skriver

Vinther M

Jepsen

Chongsuvivatwong

Olsen

Sorensen

: Adverse pregnancy outcomes in women exposed to acyclovir during pregnancy: a population-based observational study. Scand. J. Infect. Dis. 35, 255–259 (2003).

51.

Bryson

Dillon

Lovett

: Treatment of first episodes of genital herpes simplex virus infection with oral acyclovir. A randomized double-blind controlled trial in normal subjects. N. Engl. J. Med. 308, 916–921 (1983).

52.

Sheffield

Hollier

Hill

Stuart

Wendel

: Acyclovir prophylaxis to prevent herpes simplex virus recurrence at delivery: a systematic review. Obstet. Gynecol. 102, 1396–1403 (2003).

53.

Hollier

Wendel

: Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection. Cochrane Database Syst. Rev. (1), CD004946 (2008). • Informative meta-analysis of randomized trials.

54.

Arvin

Whitley

: Herpes simplex virus infections. In: Infectious Diseases of the Fetus and Newborn Infant (5th Edition). Remington

Klein

(Eds). WB Saunders, Philadelphia, PA, USA (2001).

55.

Ashley

Dalessio

Burchett

: Herpes simplex virus-2 (HSV-2) type-specific antibody correlates of protection in infants exposed to HSV-2 at birth. J. Clin. Invest. 90(2), 511–514 (1992).

56.

Society of Obstetricians and Gynaecologists of Canada: Guidelines for the management of herpes simplex virus in pregnancy. J. Obstet. Gynaecol. Can. 30(6), 514–519 (2008).

57.

Peng

Krause

Kresch

: Neonatal herpes simplex virus infection after cesarean section with intact amniotic membranes. J. Perinatol. 16, 397–399 (1996).

58.

Nahmias

Josey

Naib

Freeman

Fernandez

Wheeler

: Perinatal risk associated with maternal genital herpes simplex virus infection. Am. J. Obstet. Gynecol. 110, 825–837 (1971).

59.

Douglas

Schmidt

Corey

: Acquisition of neonatal HSV-1 infection from a paternal source contact. J. Pediatr. 103, 908–910 (1983).

60.

Hammerberg

Watts

Chernesky

Luchsinger

Rawls

: An outbreak of herpes simplex virus type 1 in an intensive care nursery. Pediatr. Infect. Dis. J. 2, 290–294 (1983).

61.

Sheffield

Fish

Hollier

Cadematori

Nobles

Wendel

: Acyclovir concentrations in human breast milk after valacyclovir administration. Am. J. Obstet. Gynecol. 186, 100–102 (2002).

62.

Handsfield

Waldo

Brown

: Neonatal herpes should be a reportable disease. Sex Trans. Dis. 32(9), 521–525 (2005).

63.

Stanberry

Spruance

Cunningham

: Glycoprotein-d-adjuvant vaccine to prevent genital herpes. N. Engl. J. Med. 347, 1652–1661 (2002).

64.

Royal College of Obstetricians and Gynecologists: management of genital herpes in pregnancy. No. 30, September 2007. www.rcog.org.uk/resources/Public/pdf/greentop30_genital_herpes0907.pdf (Accessed 1 September 2008).

65.

GlaxoSmithKline and National Institute of Allergy and Infectious Diseases. HerpeVac trial for young women. http://clinicaltrials.gov/ct2/show/NCT00057330 (Accessed 10 December 2008).

Managing Genital Herpes Infections in Pregnancy

Abstract

Keywords

Etiology

Prevalence

Herpes infection in pregnancy

Diagnosis

Treatment

Future perspective

Footnotes

References