DOI: 10.1111/j.1471-0528.2010.02785.
x
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
simplex virus in the maternal genital tract during labour. Attack
rates are highest when the mother has a newly acquired infection
and, therefore, does not have antibodies to protect the neonate.
Even with early therapy, there is significant morbidity and mortality
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.
Epidemiology of genital herpes
Based on serological data from a large National Health and
Nutrition Examination Survey (NHANES), 22% of preg-
nant women in the USA are infected with herpes simplex
virus 2 (HSV-2), 63% are HSV-1 seropositive, 13% have
both HSV-1 and HSV-2, and 28% are seronegative.1 In the
general population, for the first time since the 1976 incep-
tion of NHANES, the seroprevalence of HSV-2 has
decreased; overall, the age-adjusted HSV-2 seroprevalence
was 17% in 1999–2004, compared with 21% in 1988–94, a
relative decrease of 19% between the two study periods.
Among those infected with HSV-2, the percentage who
reported being diagnosed was 14.3% in 1999–2004 and
9.9% in 1988–94, suggesting that more providers are aware
of genital herpes, and able to make appropriate diagnoses.2
However, the vast majority of people infected with HSV-2
remain undiagnosed and, therefore, untreated and able to
spread the infection. Between 75% and 90% of HSV-2-
infected people are not aware of having the infection.3–6
This is important because most sexual transmission of HSV
occurs during episodes of subclinical reactivation among
persons with unrecognized infection.4,7–10 Virtually all
HSV-2 seropositive people have intermittent shedding from
the genital mucosa, and most have mild (and hence unrec-
ognized and undiagnosed) disease.5 In the absence of
symptoms, HSV-2 can be detected in the genital tract, by
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
DNA can be detected by polymerase chain reaction testing
15–20% of days.11,12 Recent data suggest that HSV reactiva-
ª 2010 RCOG No claim to original US government works Journal compilation ª RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology
Review article
neonatal herpes simplex virus exposure or early recognition of
exposure is important. The incidence of neonatal herpes has not
declined despite national guidelines for prevention. This suggests
that the prevention guidelines need to be re-addressed.
Keywords Herpes, neonate, prevention.
tion may occur much more frequently than previously
understood, and may be characterised by frequent short
bursts of viral shedding that do not correlate with symp-
toms.13
As HSV-2 seroprevalence decreased, HSV-1 seropreva-
lence in the USA increased to 62% in 1988–94 from 57.7%
in 1999–2004.2 Among persons infected with HSV-1
but not HSV-2, a higher percentage reported a diagnosis
of genital herpes in 1999–2004 compared with 1988–94
(1.8% versus 0.4%).2 HSV-1 has emerged as a major cause
of genital herpes among college-age populations, in which
up to 80% of new cases of genital HSV were caused
by HSV-1.14–16 Epidemiological studies suggest that oral
genital contact is the major risk factor for the acquisition
of genital HSV-1.17
Similar findings have been reported worldwide. In Scan-
dinavia, the seroprevalance of HSV-2 among pregnant
women was 33%,18 and in Canada this rate was 17%.19
Among people attending a sexually transmitted disease
clinic in the UK, 25% were seropositive for HSV-2.
In developing countries, seroprevalence rates are even
higher, reaching 60–90% among commercial sex workers
and HIV-positive factory workers in Africa.20 Data from
Australia and Wales similarly suggest that HSV-1 genital
infection is becoming more common.21,22
Neonatal herpes
The incidence of neonatal HSV in the USA varies in rela-
tion to the source of data, and is probably underestimated.
Neonatal HSV is not reportable nationally in the USA,
187
 Gardella, Brown
although in ten states reporting is mandatory. Under-
reporting and imprecise International Classification of Dis-
eases 9th revision coding result in wide variations in the
published rates. Retrospective studies based on hospital dis-
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
review of managed care data from 30 plans between 1997
and 2002.23–25 In our prospective study based on more
than 50 000 women, we observed neonatal HSV at a rate
of 30.8 per 100 000.26 This rate is consistent with a pro-
jected rate of 33 per 100 000 live births calculated using
the recent NHANES data.1 The incidence of neonatal her-
pes has remained stable over the past 20 years,25 suggesting
that current prevention recommendations are not ade-
quate.
Reported neonatal herpes rates are lower in the UK,
where active surveillance by the British Paediatric Surveil-
lance Unit demonstrated an incidence of one in 60 000 live
births annually (95% CI 1.3–2.0). This rate was estimated
to be 50% that of Europe and Japan.27 The reported inci-
dence rate of neonatal herpes in Canada from a prospective
study was 0.59 per 10 000 live births.28
Little is known regarding the risk of neonatal herpes in
immunocompromised populations. There are emerging
data that HSV-2 may increase the risk of mother to child
transmission of HIV although the converse has not been
studied.29 HIV-positive women have a high rate of HSV-2
infection (80–90%), and may be at increased risk for HSV
shedding from the genital tract, and genital lesions at the
time of delivery.30,31
Disease manifestations of neonatal
herpes
Neonatal herpes is categorized as skin, eye, mouth infec-
tion, central nervous system (CNS) disease, or disseminated
disease depending on clinical manifestations. Skin, eye,
mouth infection accounts for 45% of infants and is charac-
terized by vesicular lesions on the skin, eye or mouth with-
out CNS or organ-system involvement. Skin, eye, mouth
infection may progress to CNS or disseminated disease
without intravenous acyclovir treatment. With treatment,
outcome is good although these children may have recur-
rent outbreaks of cutaneous herpes during childhood.32,33
Infection of the CNS accounts for 30% of infected
infants and presents as lethargy, feeding difficulty and sei-
zures with or without skin lesions. With intravenous acy-
clovir therapy, there is a 6% mortality rate, and 50% of
survivors have moderate-to-severe neurological abnormali-
ties.32,33
The remaining 25% have disseminated infections that
involve multiple organs and present with clinical sepsis.
With intravenous acyclovir treatment, mortality is 30%.
188 ª 2010 RCOG No claim to original US government works Journal compilation ª RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology
For all infants, prompt diagnosis and initiation of therapy
are critical to neonatal outcome.32,33
Pathogenesis of neonatal HSV
Rarely, congenital neonatal herpes occurs from viral infec-
tion before the onset of labour. These infants manifest with
microcephaly, hydrocephalis and chorioretinitis at birth.
Postnatal acquisition is almost exclusively from HSV-1
contracted from hospital personnel or family members.
Neonatal herpes refers to the acquisition of infection at
the time of delivery by exposure to the virus in the mater-
nal genital tract and is diagnosed within the first 28 days of
life.34 Neonatal HSV can occur in women regardless of
HSV antibody status in pregnancy.26 However, as shown in
Table 1, the risk of neonatal HSV varies by maternal HSV
status and is highest among women who are HSV seroneg-
ative. This apparent contradiction is the result of the extre-
mely high efficiency of HSV transmission in women with
newly acquired genital HSV-1 or HSV-2 in late pregnancy
(30–50% transmission rate among women who have HSV
detected in the genital tract at delivery) compared with
relatively low efficiency of HSV-2 transmission among
women who have established HSV-2 (<1% of women with
established HSV-2 who shed at delivery transmit neonatal
HSV). Maternal HSV antibody crosses the placenta and
provides neonatal protection from infection. Overall, most
neonatal HSV results from women who acquire genital
HSV in late pregnancy because these women lack antibody
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.
Notably, the main risk factor for neonatal herpes is detec-
tion of HSV in the genital tract at the time of labour,
followed by maternal antibody status, and HSV type. Intra-
partum interventions that break the neonatal skin, such as
application of a fetal scalp electrode or forceps delivery,
increase the risk of neonatal infection.
Increasing importance of neonatal
HSV-1
The incidence of genital HSV-1 has continued to increase
in the last decade. The increase in genital HSV-1 initially
was observed in Europe, and more recently in the USA and
Australia.15,21,22 The increase is thought to be the result of
both less frequent acquisition of HSV-1 in childhood and
more frequent oral–genital contact at the initiation of
sexual activity.35,36
Not surprisingly, the increase in genital HSV-1 infection
has resulted in an increase in neonatal HSV-1 in propor-
tions that meet or exceed that caused by HSV-2. HSV-1
caused 63% of neonatal HSV in Canada28 and 50% in

Table 1. Transmission rates of neonatal HSV by maternal status in
a cohort of 48 390 pregnant women26
Maternal Rate/100 000
HSV status live births (95% CI)
HSV seronegative 54 (19.8–118)
HSV-1 seropositive only 26 (9.3–56)
HSV-2 seropositive (±HSV-1) 22 (4.4–64)
Table 2. Risk factors for neonatal herpes26
Risk factor Odds ratio
HSV in the genital tract at the 346 (125–956)
time of labour
Stage of maternal infection 59 (6.7–525)
(primary versus recurrent)
Type of HSV isolated from the genital 35 (3.6–335)
tract HSV1 versus HSV2
Invasive obstetric procedures 3.5 (0.6–19)
Seattle.26 Although HSV-1 does not reactivate in the genital
tract as often as HSV-2,12,37 when HSV-1 reactivation does
occur, the neonate appears more likely to become infected
than when HSV-2 reactivation occurs. This was initially
observed in our prospective study in which HSV-1 isola-
tion at birth was associated with an adjusted 15-fold higher
risk of neonatal HSV than genital HSV-2 isolation,26 and
was confirmed by data from California that showed an
adjusted relative risk for HSV-1 versus HSV-2 of 35.25
A larger proportion of infants with neonatal HSV-1 are
developmentally normal (70% with HSV-1 versus 43%
with HSV-2); however, disseminated HSV-1 can be fatal
in infancy with mortality comparable to disseminated
HSV-2.38 Hence, HSV-1 cannot be ignored as a cause of
neonatal HSV, and strategies for prevention need to
encompass both HSV-1 and HSV-2 infection.
Diagnosis and treatment of maternal
genital herpes
Most infections of maternal genital herpes are unrecognized
and undiagnosed. For women with genital lesions, viral cul-
ture or polymerase chain reaction (PCR) should be per-
formed to detect and type the virus. PCR is now preferred
because of the relative ease of specimen handling, its
improved sensitivity and faster turn around time. In addi-
tion, if serological testing is indicated, type-specific testing
should be performed to accurately classify the infection as
new or recurrent. There are many commercially available
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
tests but the practitioner should be sure that the assay tests
for glycoprotein G (gG), the protein that differs between
HSV-1 and HSV-2 on the capsule of the HSV virion.39
If the serology type-specific result is discrepant from the
culture or PCR result, a new infection is diagnosed. If the
serology type-specific result is the same as the culture or
PCR result then a recurrent infection is diagnosed.
Relying on symptoms to diagnose genital herpes in preg-
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
unpredictably regardless of whether they have symptoms
and most sexual transmission of HSV occurs during epi-
sodes of asymptomatic shedding in persons previously
undiagnosed with genital herpes.12 Serological testing of
asymptomatic women is an option to detect asymptomatic
herpes. If a woman is seropositive for HSV-2, she is diag-
nosed with genital herpes. However, if she is seropositive
for HSV-1 and is without oral or genital symptoms then
she may have either oral or genital HSV-1. If she develops
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
controversial and is not recommended by the American
College of Obstetricians and Gynecologists (ACOG) or the
Royal College of Obstetricians and Gynaecologists
(RCOG).40,41 Guidelines do not include serologic testing
because it is unclear that it would be cost effective, or
effective in reducing the neonatal herpes incidence. Future
studies are needed to address these important issues. Stud-
ies find that women are amenable to HSV testing as part of
routine prenatal care.42,43 New diagnosis of genital HSV in
an asymptomatic person causes mild, transient distress that
should not preclude testing44,45 if it is indicated.
Women with new genital HSV infection or with recur-
rent, symptomatic infection during pregnancy should be
offered anti-viral therapy and suppression, consistent with
ACOG and RCOG guidelines.40
Current recommendations for
neonatal herpes prevention
Published US and Canadian prevention guidelines focus on
pregnant women with symptomatic genital herpes and rec-
ommend thorough examination for genital lesions at the
time of labour with caesarean delivery to avoid contact
with infected genital secretions if lesions are identified.40,46
Additionally, women with frequent recurrent lesions during
pregnancy may be offered antiviral suppressive therapy to
prevent genital lesions at the time of labour.40 This is
generally given from 36 weeks of gestation until delivery.
Suppressive therapy has been shown to decrease the risk of
189
 Gardella, Brown
genital lesions that would lead to caesarean delivery at the
time of labour, and to decrease, but not eliminate, the inci-
dence of viral shedding at the time of delivery.47,48 Studies
were underpowered to determine if suppression therapy in
these women decreased the risk of neonatal herpes. UK
prevention guidelines regarding caesarean delivery for geni-
tal lesions focus on the maternal stage of infection. If the
mother has a primary infection or had a primary infection
within 6 weeks of delivery then caesarean section is recom-
mended. However, in the case of genital lesions caused by
an established infection caesarean delivery is not recom-
mended because the risk to the neonate is small.41
Although it makes empiric sense to focus on women
with symptomatic disease, it does not fit with the complex
pathophysiology of neonatal herpes. The main risk factor
for transmission is detection of HSV in the genital tract at
the time of vaginal birth. Relying solely on physical exami-
nation is inadequate to detect the presence of virus because
most viral shedding episodes are asymptomatic and most
cases of neonatal herpes occur among women who were
asymptomatic at the time of labour. Further, it focuses on
women with established infection, who are least likely to
transmit to their neonates (1% risk of transmission), while
disregarding women with new infection in pregnancy, who
are at highest risk of transmitting. These factors contribute
to the lack of progress to decrease the incidence of neonatal
herpes over the past 20 years.
Proposed strategies for prevention
Despite the obvious problems with our current prevention
strategies, there are no obvious solutions. It appears that
reduction in neonatal herpes will happen only if we widen
our focus to include women with newly acquired genital
herpes during pregnancy and a primary prevention strategy
would be to prevent new infections during pregnancy.
In our opinion, there are several possible approaches. 1. Tell
all pregnant women to abstain from any sexual contact
during pregnancy. This approach has been advocated by
some as a simple, inexpensive prevention message.
Although this may be easy to implement, data suggest that
women will not adhere to abstinence in pregnancy. Even
among pregnant women known to be HSV-2 seronegative,
the frequency of abstinence and unprotected sex was the
same as for women with known seroconcordant partners,
suggesting that this method is unlikely to work. 2. Add
serological testing to routine prenatal care to identify
women who are HSV-2 seropositive, and those who are
HSV-2 seronegative, and therefore at risk of acquiring the
infection during pregnancy. Among serologically ‘at-risk’
women, safer-sex counselling could advocate for abstinence
or condom use, but, as noted above, this did not improve
compliance with risk reduction strategies. This approach
190 ª 2010 RCOG No claim to original US government works Journal compilation ª RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology
would also identify women with asymptomatic genital HSV
for education. Whether women with asymptomatic genital
herpes should be prescribed antiviral suppression therapy is
debatable and ACOG does not recommend it at this time.
Although acyclovir is thought to be safe in pregnancy, wid-
ening exposure to a larger proportion of pregnant women
without data to indicate that it will decrease the risk of
neonatal herpes seems imprudent without further study.
3. Serotest both the pregnant woman and her partner to
identify women at risk for HSV acquisition. This would iden-
tify a smaller group of high-risk women for more intensive
counselling to prevent infection during pregnancy. About
12–20% of women are at risk of acquiring HSV from their
partners during pregnancy.49 Further, antiviral suppressive
therapy could be offered to the infected partner to decrease
his risk of viral reactivation and shedding. This approach
has worked in non-pregnant couples to reduce the risk of
infection by 50%50 during the 8 months of observation.
Partner testing appears to be feasible, at least in a predomi-
nately monogamous population, but is unlikely to work
among women with multiple partners in pregnancy.51
The previous prevention possibilities are relatively com-
plicated, requiring serological testing, time and effort to
counsel regarding results and safer sex practices, and deci-
sion-making regarding antiviral use in pregnancy and are
unlikely to be applicable to the broad obstetric population.
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
labour. For those with HSV detected in the genital tract,
determination of serostatus could be performed using a
point of care serological test to identify women with recur-
rent genital herpes, 99% of whom will not transmit to the
neonate, and those with newly acquired infection, 50% of
whom will transmit the infection to the neonate. For those
with recurrent infection, options could include vaginal
delivery with acyclovir prophylaxis, enhanced observation
of the neonate, and antiviral prophylaxis for the neonate.
There is a risk that unnecessary caesarean deliveries would
be performed in this relatively low-risk population. If cae-
sarean delivery was performed reflexively in this popula-
tion, the number of caesarean deliveries needed to prevent
one case of neonatal herpes is 99. However, for women
with new infection, every two caesarean deliveries would
prevent one case of neonatal herpes.
We recently developed a rapid HSV PCR test that can
provide results within 2 hours to inform clinical decision-
making for mode of delivery and postpartum care of the
neonate with excellent sensitivity and specificity.52 Eighty-
five percent of women surveyed said that they would be
willing to use such a test in labour, suggesting that testing
will be feasible.42 Although the technical development of
this test needs to be followed by clinical studies among

pregnant women, and appropriate management strategies
for women who are HSV positive in labour need to be
evaluated, we are hopeful that this tool will allow clinical
studies to be conducted toward defining effective strategies
for reducing the burden of neonatal HSV.
Disclosure of interests
CG has no potential conflicts of interest. ZB has received
grants for educational activities from and has served as a
paid advisor or consultant to GlaxoSmithKline.
Contribution to authorship
CG and ZB wrote this review article. CG was the primary
author and ZB edited the paper and provided substantive
feedback.
Details of ethics approval
Not applicable for this review article.
Funding
None.
Acknowledgement
None. j
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