Prevention of Neonatal Herpes
Prevention of Neonatal Herpes
Prevention of Neonatal Herpes
x
Review article
www.bjog.org
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.
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
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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