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DOI: 10.1111/j.1471-0528.2010.02785.

x
Review article
www.bjog.org

Prevention of neonatal herpes


C Gardella, Z Brown
Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA
Correspondence: Dr C Gardella, Department of Obstetrics and Gynecology, University of Washington, Box 356460, Seattle, WA 98195-6460,
USA. Email cgardel@u.washington.edu

Accepted 8 October 2010.

Neonatal herpes can occur when the neonate is exposed to herpes neonatal herpes simplex virus exposure or early recognition of
simplex virus in the maternal genital tract during labour. Attack exposure is important. The incidence of neonatal herpes has not
rates are highest when the mother has a newly acquired infection declined despite national guidelines for prevention. This suggests
and, therefore, does not have antibodies to protect the neonate. that the prevention guidelines need to be re-addressed.
Even with early therapy, there is significant morbidity and mortality
Keywords Herpes, neonate, prevention.
associated with neonatal herpes, suggesting that preventing

Please cite this paper as: Gardella C, Brown Z. Prevention of neonatal herpes. BJOG 2011;118:187–192.

tion may occur much more frequently than previously


Epidemiology of genital herpes
understood, and may be characterised by frequent short
Based on serological data from a large National Health and bursts of viral shedding that do not correlate with symp-
Nutrition Examination Survey (NHANES), 22% of preg- toms.13
nant women in the USA are infected with herpes simplex As HSV-2 seroprevalence decreased, HSV-1 seropreva-
virus 2 (HSV-2), 63% are HSV-1 seropositive, 13% have lence in the USA increased to 62% in 1988–94 from 57.7%
both HSV-1 and HSV-2, and 28% are seronegative.1 In the in 1999–2004.2 Among persons infected with HSV-1
general population, for the first time since the 1976 incep- but not HSV-2, a higher percentage reported a diagnosis
tion of NHANES, the seroprevalence of HSV-2 has of genital herpes in 1999–2004 compared with 1988–94
decreased; overall, the age-adjusted HSV-2 seroprevalence (1.8% versus 0.4%).2 HSV-1 has emerged as a major cause
was 17% in 1999–2004, compared with 21% in 1988–94, a of genital herpes among college-age populations, in which
relative decrease of 19% between the two study periods. up to 80% of new cases of genital HSV were caused
Among those infected with HSV-2, the percentage who by HSV-1.14–16 Epidemiological studies suggest that oral
reported being diagnosed was 14.3% in 1999–2004 and genital contact is the major risk factor for the acquisition
9.9% in 1988–94, suggesting that more providers are aware of genital HSV-1.17
of genital herpes, and able to make appropriate diagnoses.2 Similar findings have been reported worldwide. In Scan-
However, the vast majority of people infected with HSV-2 dinavia, the seroprevalance of HSV-2 among pregnant
remain undiagnosed and, therefore, untreated and able to women was 33%,18 and in Canada this rate was 17%.19
spread the infection. Between 75% and 90% of HSV-2- Among people attending a sexually transmitted disease
infected people are not aware of having the infection.3–6 clinic in the UK, 25% were seropositive for HSV-2.
This is important because most sexual transmission of HSV In developing countries, seroprevalence rates are even
occurs during episodes of subclinical reactivation among higher, reaching 60–90% among commercial sex workers
persons with unrecognized infection.4,7–10 Virtually all and HIV-positive factory workers in Africa.20 Data from
HSV-2 seropositive people have intermittent shedding from Australia and Wales similarly suggest that HSV-1 genital
the genital mucosa, and most have mild (and hence unrec- infection is becoming more common.21,22
ognized and undiagnosed) disease.5 In the absence of
symptoms, HSV-2 can be detected in the genital tract, by
Neonatal herpes
viral culture, on 3% of days for the first year after initial
infection, then on 1% of days for the next 2 years. HSV-2 The incidence of neonatal HSV in the USA varies in rela-
DNA can be detected by polymerase chain reaction testing tion to the source of data, and is probably underestimated.
15–20% of days.11,12 Recent data suggest that HSV reactiva- Neonatal HSV is not reportable nationally in the USA,

ª 2010 RCOG No claim to original US government works Journal compilation ª RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology 187
Gardella, Brown

although in ten states reporting is mandatory. Under- For all infants, prompt diagnosis and initiation of therapy
reporting and imprecise International Classification of Dis- are critical to neonatal outcome.32,33
eases 9th revision coding result in wide variations in the
published rates. Retrospective studies based on hospital dis-
Pathogenesis of neonatal HSV
charge data suggest a rate of approximately 12 per 100 000
in California and as high as 60 per 100 000 based on a new Rarely, congenital neonatal herpes occurs from viral infec-
review of managed care data from 30 plans between 1997 tion before the onset of labour. These infants manifest with
and 2002.23–25 In our prospective study based on more microcephaly, hydrocephalis and chorioretinitis at birth.
than 50 000 women, we observed neonatal HSV at a rate Postnatal acquisition is almost exclusively from HSV-1
of 30.8 per 100 000.26 This rate is consistent with a pro- contracted from hospital personnel or family members.
jected rate of 33 per 100 000 live births calculated using Neonatal herpes refers to the acquisition of infection at
the recent NHANES data.1 The incidence of neonatal her- the time of delivery by exposure to the virus in the mater-
pes has remained stable over the past 20 years,25 suggesting nal genital tract and is diagnosed within the first 28 days of
that current prevention recommendations are not ade- life.34 Neonatal HSV can occur in women regardless of
quate. HSV antibody status in pregnancy.26 However, as shown in
Reported neonatal herpes rates are lower in the UK, Table 1, the risk of neonatal HSV varies by maternal HSV
where active surveillance by the British Paediatric Surveil- status and is highest among women who are HSV seroneg-
lance Unit demonstrated an incidence of one in 60 000 live ative. This apparent contradiction is the result of the extre-
births annually (95% CI 1.3–2.0). This rate was estimated mely high efficiency of HSV transmission in women with
to be 50% that of Europe and Japan.27 The reported inci- newly acquired genital HSV-1 or HSV-2 in late pregnancy
dence rate of neonatal herpes in Canada from a prospective (30–50% transmission rate among women who have HSV
study was 0.59 per 10 000 live births.28 detected in the genital tract at delivery) compared with
Little is known regarding the risk of neonatal herpes in relatively low efficiency of HSV-2 transmission among
immunocompromised populations. There are emerging women who have established HSV-2 (<1% of women with
data that HSV-2 may increase the risk of mother to child established HSV-2 who shed at delivery transmit neonatal
transmission of HIV although the converse has not been HSV). Maternal HSV antibody crosses the placenta and
studied.29 HIV-positive women have a high rate of HSV-2 provides neonatal protection from infection. Overall, most
infection (80–90%), and may be at increased risk for HSV neonatal HSV results from women who acquire genital
shedding from the genital tract, and genital lesions at the HSV in late pregnancy because these women lack antibody
time of delivery.30,31 to protect the neonate and are at high risk of viral shed-
ding at the time of delivery.
Risk factors for neonatal herpes are shown in Table 2.
Disease manifestations of neonatal
Notably, the main risk factor for neonatal herpes is detec-
herpes
tion of HSV in the genital tract at the time of labour,
Neonatal herpes is categorized as skin, eye, mouth infec- followed by maternal antibody status, and HSV type. Intra-
tion, central nervous system (CNS) disease, or disseminated partum interventions that break the neonatal skin, such as
disease depending on clinical manifestations. Skin, eye, application of a fetal scalp electrode or forceps delivery,
mouth infection accounts for 45% of infants and is charac- increase the risk of neonatal infection.
terized by vesicular lesions on the skin, eye or mouth with-
out CNS or organ-system involvement. Skin, eye, mouth
Increasing importance of neonatal
infection may progress to CNS or disseminated disease
HSV-1
without intravenous acyclovir treatment. With treatment,
outcome is good although these children may have recur- The incidence of genital HSV-1 has continued to increase
rent outbreaks of cutaneous herpes during childhood.32,33 in the last decade. The increase in genital HSV-1 initially
Infection of the CNS accounts for 30% of infected was observed in Europe, and more recently in the USA and
infants and presents as lethargy, feeding difficulty and sei- Australia.15,21,22 The increase is thought to be the result of
zures with or without skin lesions. With intravenous acy- both less frequent acquisition of HSV-1 in childhood and
clovir therapy, there is a 6% mortality rate, and 50% of more frequent oral–genital contact at the initiation of
survivors have moderate-to-severe neurological abnormali- sexual activity.35,36
ties.32,33 Not surprisingly, the increase in genital HSV-1 infection
The remaining 25% have disseminated infections that has resulted in an increase in neonatal HSV-1 in propor-
involve multiple organs and present with clinical sepsis. tions that meet or exceed that caused by HSV-2. HSV-1
With intravenous acyclovir treatment, mortality is 30%. caused 63% of neonatal HSV in Canada28 and 50% in

188 ª 2010 RCOG No claim to original US government works Journal compilation ª RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology
Neonatal herpes prevention

Table 1. Transmission rates of neonatal HSV by maternal status in


tests but the practitioner should be sure that the assay tests
a cohort of 48 390 pregnant women26 for glycoprotein G (gG), the protein that differs between
HSV-1 and HSV-2 on the capsule of the HSV virion.39
Maternal Rate/100 000 If the serology type-specific result is discrepant from the
HSV status live births (95% CI)
culture or PCR result, a new infection is diagnosed. If the
serology type-specific result is the same as the culture or
HSV seronegative 54 (19.8–118)
PCR result then a recurrent infection is diagnosed.
HSV-1 seropositive only 26 (9.3–56)
Relying on symptoms to diagnose genital herpes in preg-
HSV-2 seropositive (±HSV-1) 22 (4.4–64)
nancy misses the 70–90% of persons with genital HSV
infection who are asymptomatic. The majority of persons
with genital HSV infection will shed virus sporadically and
Table 2. Risk factors for neonatal herpes26 unpredictably regardless of whether they have symptoms
and most sexual transmission of HSV occurs during epi-
Risk factor Odds ratio sodes of asymptomatic shedding in persons previously
undiagnosed with genital herpes.12 Serological testing of
HSV in the genital tract at the 346 (125–956) asymptomatic women is an option to detect asymptomatic
time of labour herpes. If a woman is seropositive for HSV-2, she is diag-
Stage of maternal infection 59 (6.7–525)
nosed with genital herpes. However, if she is seropositive
(primary versus recurrent)
Type of HSV isolated from the genital 35 (3.6–335)
for HSV-1 and is without oral or genital symptoms then
tract HSV1 versus HSV2 she may have either oral or genital HSV-1. If she develops
Invasive obstetric procedures 3.5 (0.6–19) oral or genital lesions in the future, virological testing
of the lesion is indicated to confirm the site of HSV-1
infection.
Routine serological testing for herpes in pregnancy is
Seattle.26 Although HSV-1 does not reactivate in the genital controversial and is not recommended by the American
tract as often as HSV-2,12,37 when HSV-1 reactivation does College of Obstetricians and Gynecologists (ACOG) or the
occur, the neonate appears more likely to become infected Royal College of Obstetricians and Gynaecologists
than when HSV-2 reactivation occurs. This was initially (RCOG).40,41 Guidelines do not include serologic testing
observed in our prospective study in which HSV-1 isola- because it is unclear that it would be cost effective, or
tion at birth was associated with an adjusted 15-fold higher effective in reducing the neonatal herpes incidence. Future
risk of neonatal HSV than genital HSV-2 isolation,26 and studies are needed to address these important issues. Stud-
was confirmed by data from California that showed an ies find that women are amenable to HSV testing as part of
adjusted relative risk for HSV-1 versus HSV-2 of 35.25 routine prenatal care.42,43 New diagnosis of genital HSV in
A larger proportion of infants with neonatal HSV-1 are an asymptomatic person causes mild, transient distress that
developmentally normal (70% with HSV-1 versus 43% should not preclude testing44,45 if it is indicated.
with HSV-2); however, disseminated HSV-1 can be fatal Women with new genital HSV infection or with recur-
in infancy with mortality comparable to disseminated rent, symptomatic infection during pregnancy should be
HSV-2.38 Hence, HSV-1 cannot be ignored as a cause of offered anti-viral therapy and suppression, consistent with
neonatal HSV, and strategies for prevention need to ACOG and RCOG guidelines.40
encompass both HSV-1 and HSV-2 infection.
Current recommendations for
Diagnosis and treatment of maternal neonatal herpes prevention
genital herpes
Published US and Canadian prevention guidelines focus on
Most infections of maternal genital herpes are unrecognized pregnant women with symptomatic genital herpes and rec-
and undiagnosed. For women with genital lesions, viral cul- ommend thorough examination for genital lesions at the
ture or polymerase chain reaction (PCR) should be per- time of labour with caesarean delivery to avoid contact
formed to detect and type the virus. PCR is now preferred with infected genital secretions if lesions are identified.40,46
because of the relative ease of specimen handling, its Additionally, women with frequent recurrent lesions during
improved sensitivity and faster turn around time. In addi- pregnancy may be offered antiviral suppressive therapy to
tion, if serological testing is indicated, type-specific testing prevent genital lesions at the time of labour.40 This is
should be performed to accurately classify the infection as generally given from 36 weeks of gestation until delivery.
new or recurrent. There are many commercially available Suppressive therapy has been shown to decrease the risk of

ª 2010 RCOG No claim to original US government works Journal compilation ª RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology 189
Gardella, Brown

genital lesions that would lead to caesarean delivery at the would also identify women with asymptomatic genital HSV
time of labour, and to decrease, but not eliminate, the inci- for education. Whether women with asymptomatic genital
dence of viral shedding at the time of delivery.47,48 Studies herpes should be prescribed antiviral suppression therapy is
were underpowered to determine if suppression therapy in debatable and ACOG does not recommend it at this time.
these women decreased the risk of neonatal herpes. UK Although acyclovir is thought to be safe in pregnancy, wid-
prevention guidelines regarding caesarean delivery for geni- ening exposure to a larger proportion of pregnant women
tal lesions focus on the maternal stage of infection. If the without data to indicate that it will decrease the risk of
mother has a primary infection or had a primary infection neonatal herpes seems imprudent without further study.
within 6 weeks of delivery then caesarean section is recom- 3. Serotest both the pregnant woman and her partner to
mended. However, in the case of genital lesions caused by identify women at risk for HSV acquisition. This would iden-
an established infection caesarean delivery is not recom- tify a smaller group of high-risk women for more intensive
mended because the risk to the neonate is small.41 counselling to prevent infection during pregnancy. About
Although it makes empiric sense to focus on women 12–20% of women are at risk of acquiring HSV from their
with symptomatic disease, it does not fit with the complex partners during pregnancy.49 Further, antiviral suppressive
pathophysiology of neonatal herpes. The main risk factor therapy could be offered to the infected partner to decrease
for transmission is detection of HSV in the genital tract at his risk of viral reactivation and shedding. This approach
the time of vaginal birth. Relying solely on physical exami- has worked in non-pregnant couples to reduce the risk of
nation is inadequate to detect the presence of virus because infection by 50%50 during the 8 months of observation.
most viral shedding episodes are asymptomatic and most Partner testing appears to be feasible, at least in a predomi-
cases of neonatal herpes occur among women who were nately monogamous population, but is unlikely to work
asymptomatic at the time of labour. Further, it focuses on among women with multiple partners in pregnancy.51
women with established infection, who are least likely to The previous prevention possibilities are relatively com-
transmit to their neonates (1% risk of transmission), while plicated, requiring serological testing, time and effort to
disregarding women with new infection in pregnancy, who counsel regarding results and safer sex practices, and deci-
are at highest risk of transmitting. These factors contribute sion-making regarding antiviral use in pregnancy and are
to the lack of progress to decrease the incidence of neonatal unlikely to be applicable to the broad obstetric population.
herpes over the past 20 years. A more direct prevention strategy would be to identify
neonates at risk for exposure to HSV at the time of labour
by sampling the genital secretions for HSV of all women in
Proposed strategies for prevention
labour. For those with HSV detected in the genital tract,
Despite the obvious problems with our current prevention determination of serostatus could be performed using a
strategies, there are no obvious solutions. It appears that point of care serological test to identify women with recur-
reduction in neonatal herpes will happen only if we widen rent genital herpes, 99% of whom will not transmit to the
our focus to include women with newly acquired genital neonate, and those with newly acquired infection, 50% of
herpes during pregnancy and a primary prevention strategy whom will transmit the infection to the neonate. For those
would be to prevent new infections during pregnancy. with recurrent infection, options could include vaginal
In our opinion, there are several possible approaches. 1. Tell delivery with acyclovir prophylaxis, enhanced observation
all pregnant women to abstain from any sexual contact of the neonate, and antiviral prophylaxis for the neonate.
during pregnancy. This approach has been advocated by There is a risk that unnecessary caesarean deliveries would
some as a simple, inexpensive prevention message. be performed in this relatively low-risk population. If cae-
Although this may be easy to implement, data suggest that sarean delivery was performed reflexively in this popula-
women will not adhere to abstinence in pregnancy. Even tion, the number of caesarean deliveries needed to prevent
among pregnant women known to be HSV-2 seronegative, one case of neonatal herpes is 99. However, for women
the frequency of abstinence and unprotected sex was the with new infection, every two caesarean deliveries would
same as for women with known seroconcordant partners, prevent one case of neonatal herpes.
suggesting that this method is unlikely to work. 2. Add We recently developed a rapid HSV PCR test that can
serological testing to routine prenatal care to identify provide results within 2 hours to inform clinical decision-
women who are HSV-2 seropositive, and those who are making for mode of delivery and postpartum care of the
HSV-2 seronegative, and therefore at risk of acquiring the neonate with excellent sensitivity and specificity.52 Eighty-
infection during pregnancy. Among serologically ‘at-risk’ five percent of women surveyed said that they would be
women, safer-sex counselling could advocate for abstinence willing to use such a test in labour, suggesting that testing
or condom use, but, as noted above, this did not improve will be feasible.42 Although the technical development of
compliance with risk reduction strategies. This approach this test needs to be followed by clinical studies among

190 ª 2010 RCOG No claim to original US government works Journal compilation ª RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology
Neonatal herpes prevention

pregnant women, and appropriate management strategies 10 Langenberg A, Corey L, Ashley R, Leong W, Straus S. A prospective
for women who are HSV positive in labour need to be study of new infections with herpes simplex virus type 1 and type 2.
N Engl J Med 1999;341:1432–8.
evaluated, we are hopeful that this tool will allow clinical 11 Wald A, Corey L, Cone R, Hobson A, Davis G, Zeh J. Frequent geni-
studies to be conducted toward defining effective strategies tal HSV-2 shedding in immunocompetent women. J Clin Invest
for reducing the burden of neonatal HSV. 1997;99:1092–7.
12 Wald A, Zeh J, Selke S, Ashley RL, Corey L. Virologic characteristics
Disclosure of interests of subclinical and symptomatic genital herpes infections. N Engl J
Med 1995;333:770–5.
CG has no potential conflicts of interest. ZB has received 13 Mark KE, Wald A, Magaret AS, Selke S, Olin L, Huang ML, et al.
grants for educational activities from and has served as a Rapidly cleared episodes of herpes simplex virus reactivation in
paid advisor or consultant to GlaxoSmithKline. immunocompetent adults. J Infect Dis 2008;198:1141–9.
14 Roberts CM, Pfister JR, Spear SJ. Increasing proportion of herpes
Contribution to authorship simplex virus type 1 as a cause of genital herpes infection in college
students. Sex Transm Dis 2003;30:797–800.
CG and ZB wrote this review article. CG was the primary 15 Ribes JA, Steele AD, Seabolt JP, Baker DJ. Six-year study of the
author and ZB edited the paper and provided substantive incidence of herpes in genital and nongenital cultures in a central
feedback. Kentucky medical center patient population. J Clin Microbiol 2001;
39:3321–5.
Details of ethics approval 16 Mertz GJ, Rosenthal SL, Stanberry LR. Is herpes simplex virus type 1
(HSV-1) now more common than HSV-2 in first episodes of genital
Not applicable for this review article. herpes? Sex Transm Dis 2003;30:801–2.
17 Lafferty WE, Downey L, Celum C, Wald A. Herpes simplex virus type
Funding 1 as a cause of genital herpes: impact on surveillance and preven-
None. tion. J Infect Dis 2000;181: 1454–7.
18 Forsgren M. Genital herpes simplex virus infection and incidence of
neonatal disease in Sweden. Scand J Infect Dis Suppl 1990;69:
Acknowledgement 37–41.
None. j 19 Patrick DM, Dawar M, Cook DA, Krajden M, Ng HC, Rekart ML.
Antenatal seroprevalence of herpes simplex virus type 2 (HSV-2) in
Canadian women: HSV-2 prevalence increases throughout the
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