Download Herpes simplex and varicella-zoster virus infections during pregnancy

Med Microbiol Immunol (2007) 196:89–94
DOI 10.1007/s00430-006-0031-0
O RI G I NAL IN VE S T I GA TI O N
Herpes simplex and varicella-zoster virus infections during
pregnancy: current concepts of prevention, diagnosis
and therapy. Part 1: Herpes simplex virus infections
A. Sauerbrei · P. Wutzler
Received: 24 August 2006 / Published online: 13 December 2006
© Springer-Verlag 2006
Abstract Primary herpes simplex virus (HSV) infection may lead to severe illness in pregnancy and may be
associated with transplacental virus transmission and
fetal infection. The consequences may be abortion, stillbirth and congenital malformations. In neonates, the
clinical Wndings after intrauterine HSV infection are
characterized by skin lesions, diseases of the eye and
neurologic damage. Herpes genitalis of pregnant women
at the time of labor may result in life-threatening neonatal herpes. Currently, neither active nor passive immunization is available to prevent HSV infections during
pregnancy and in the newborn infant. Therefore, antiviral treatment using aciclovir and/or valaciclovir must be
considered in all primary episodes of genital herpes as
well as in neonates who show signs of either infection.
Clinical herpes lesions of the genitalia and/or positive
test for virus detection at the time of delivery are an
indication for cesarean section. However, this surgical
intervention may be reduced by suppressive treatment
of recurrent genital herpes with aciclovir or valaciclovir.
Keywords Herpes simplex virus infection ·
Pregnancy · Neonate · Prevention · Diagnosis · Therapy
Introduction
Herpes simplex virus (HSV) and varicella-zoster virus
(VZV) induce a wide variety of diseases, which are nor-
A. Sauerbrei (&) · P. Wutzler
Institute of Virology and Antiviral Therapy,
Friedrich-Schiller University of Jena,
Hans-Knoell-Strasse 2, 07745 Jena, Germany
e-mail: [email protected]
mally mild and can be treated satisfactorily. During
pregnancy, both pathogens are able to infect the
mother as well as the fetus leading occasionally to disastrous maternal, fetal and neonatal diseases. Most infections are a great challenge to medical doctors since the
potential beneWts of therapeutic and prophylactic measures to the mother and the potential risks to the fetus
or the nursing infant have to be weighed up. Whilst varicella can be generally prevented by vaccination, special
diagnostic and therapeutic measures are needed in case
of HSV infections. As a Wrst part, the present paper
reviews the clinical consequences of HSV infections
during pregnancy and summarizes the currently available concepts of prevention, diagnosis and therapy.
VZV infections during pregnancy and in newborn
infants will follow as the second part of the manuscript.
Herpes simplex virus infections during pregnancy
The HSV has been considered as one of the most common viral infectious agents in humans. There are two
closely related viral types, the HSV type 1 (HSV-1)
and the HSV type 2 (HSV-2), which are genetically
diVerent. In Germany, the prevalence of HSV-1 antibodies reaches high levels of more than 90% in adults
whereas nearly 15% of the adult population possess
antibodies to HSV-2 [44]. The number of women, who
acquire HSV-1 or HSV-2 infection during pregnancy,
has been calculated as 0.5–2% [8, 10].
Primary infections
Primary HSV infections in pregnant women can result
in more severe diseases than in nonpregnant ones. In
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Med Microbiol Immunol (2007) 196:89–94
particular, gingivostomatitis and vulvovaginitis herpetica tend towards dissemination. As a result, women
can develop disseminated skin lesions associated with
visceral involvement such as hepatitis, encephalitis,
thrombocytopenia, leucopenia and coagulopathy [45].
Although disseminated HSV infection is uncommon in
pregnancy, the mortality is about 50%. In particular,
pregnant women with primary mucous membrane
infection during the third trimester have an increased
risk for dissemination [32].
The most important HSV infection during pregnancy is the primary genital HSV infection (Fig. 1),
since it can cause the most severe neonatal diseases.
However, a Wrst manifestation of genital herpes during
pregnancy is in most cases not a primary infection [17].
In principle, genital herpes can be caused by either
HSV-2 or by HSV-1, which is the usual agent of orolabial herpes. While genital infection with HSV-1 is
clinically indistinguishable from that caused by HSV-2,
it is less likely to cause recurrent diseases [5].
Primary symptomatic genital herpes presents with
blistering and ulceration of the external genitalia and
cervix leading to vulval pain, dysuria, vaginal discharge
and local lymphadenopathy. Infection may be complicated by systemic symptoms such as fever and myalgia
and occasionally by autonomic neuropathy resulting in
urinary retention and meningitis. In some cases, systemic clinical Wndings may be the only presenting
symptoms of infection [37]. In more than half of the
patients, primary infection goes unnoticed [38].
Women, who acquire genital herpes during the third
trimester, are at risk of transmitting HSV to their
babies during vaginal delivery. Studies suggest that
viral shedding from vulva and cervix persists for a variable time after healing of the primary lesion, and these
Pregnant women
0.5-2%
Genital HSV infection
Primary HSV-2 (HSV-1)
Viremic
Recurrent HSV-2 (HSV-1)
Ascending
Intrauterine infection
1st - 20th weeks
Intrauterine
death of fetus
Congenital
anomalies
of newborn
Infection under birth
genital herpes in last trimester
Postnatal
infection
Neonatal HSV infection
70-85% HSV-2 and 15-30% HSV-1
Incidence: 7/100,000 life births
women may be at increased risk of preterm delivery
[9]. Neonates are exposed to virus during the process
of birth or shortly thereafter by direct contact with herpetic lesions in the birth canal or genitalia [30]. Infection intrapartum can lead to neonatal herpes, also
referred to as herpes neonatorum, which is considered
a life-threatening illness of the neonate. Prolonged
rupture of membranes could increase the risk of virus
transmission to the fetus, probably as the consequence
of ascending infection. Transplacental infection has
also been reported, especially after primary HSV infection, independent of the localization of herpes lesions
[20].
Recurrent infections
HSV can reactivate in the genital tract either asymptomatically or symptomatically. Classical signs are
grouped vesicles with progression to ulceration and
crusting, localized to a small area of external genitalia.
Lesions are typically fewer and smaller than in primary
disease and constitutional symptoms are rare [38]. The
great majority of recurrent genital herpes is due to
HSV-2 [33]. Although no clinical signs can be recognized in many HSV-2 infections, there is an asymptomatic viral shedding in most patients. Sexual contacts
with such subjects infected subclinically during periods
of asymptomatic viral shedding carry a substantial risk
of transmitting HSV-2 to sexual partners [29]. Viral
shedding is of shorter duration than in primary infection. Although there is a smaller risk of vertical viral
transmission than in primary infection, recurrent genital herpes must be regarded as the most common cause
of neonatal infections and the passage through an
infected birth canal is the most probable route of transmission [14, 26]. In recurrent infections associated with
clinical symptoms, the risk of neonatal disease is
reduced dramatically by cesarean section [41]. Transmission of HSV by women with asymptomatic viral
shedding is of greater signiWcance, since neonates
mostly acquire infection without being recognized.
Individuals with recurrent HSV lesions outside the
genitalia must be regarded as infective for neonates,
too. Thus, viral transmission from a mother with
lesions of the breast as well as transmission to infants
of seronegative mothers from fathers or relatives have
been reported.
Abortion
Clinical findings
• Localized infections including skin, eye, and mouth
• Involvement of the central nervous system
• Generalized infections
Fig. 1 Herpes simplex virus infections and their consequences
during pregnancy
123
Intrauterine herpes simplex virus infection
Intrauterine HSV infection is a rare disorder and
accounts for 5% of HSV infections in neonates. The
Med Microbiol Immunol (2007) 196:89–94
highest risk of intrauterine infection with about 50%
has been observed in pregnant women who develop
disseminated HSV infections. Among HSV infections
acquired in utero, 90% of those with an identiWed type
are due to HSV-2 [30]. Both primary and recurrent
maternal infection can result in congenital disease [19],
even so the risk after recurrent infection must be
regarded as smaller. The danger to intrauterine viral
transmission is highest during the Wrst 20 weeks of gestation leading to abortion, stillbirth and congenital
anomalies. The diagnostic criteria of intrauterine HSV
infection consist of identiWcation of infected infants in
the Wrst 48 h of life, virologic conWrmation of infection
and exclusion of other pathologic conditions. The classic triad of Wndings is listed in Table 1. In the diVerential diagnosis, other congenital infections such as by the
varicella-zoster virus (VZV) have to be considered.
Neonatal herpes simplex virus infections
In 85–90% of neonatal HSV infections, HSV is
acquired at the time of delivery and 5–10% are caused
by early postnatal acquisition of the virus. The disease
is referred to as neonatal herpes. Neonatal HSV infections of 70–85% are caused by HSV-2 and the remainder cases are due to HSV–1 [34]. Infection with HSV-2
is associated with a poorer prognosis [43], but severe
cases have also been found to be caused by HSV-1 [28].
A review of literature suggests that the incidence is
around 7/100,000 life births [11] and up to 40% of the
suVered infants are premature [43].
Neonatal herpes is a rare disorder in newborn
infants, but it belongs due to its high morbidity and
mortality to the most severe infections acquired during
the perinatal period [12, 39]. Therefore, neonatal HSV
infection should be considered in the diVerential diagnosis of each acutely unwell neonate. At the onset, the
disease is often diYcult to distinguish from bacterial
Table 1 Clinical manifestations of intrauterine [15, 18, 20, 31]
and neonatal herpes simplex virus (HSV) infections [25]
Intrauterine HSV infections
• Skin vesicles or scarring
• Eye lesions (chorioretinitis, microphthalmia,
cataract)
• Neurologic damage (microcephaly,
intracranial calciWcations,
seizures, encephalomalacia)
Neonatal HSV infections
• Localized infections of skin, eye and
mucous membranes
• Infections of the central nervous system
• Disseminated systemic infections
91
sepsis and the maternal infection may be completely
asymptomatic [21]. Clinical manifestations are divided
into three major categories summarized in Table 1.
Localized infections have been found in 50% of the
aVected neonates, involvement of the central nervous
system (CNS) in 33%, and generalized infections in
17% of the cases [25]. Several studies have demonstrated that generalized HSV infections can present
with the major symptom of liver failure associated with
shock symptoms and disseminated intravascular coagulopathy [16, 28]. Despite the availability of antiviral
drugs for treatment of neonatal HSV infections, the
outcome remains poor, particularly for babies with disseminated multi-organ infections or manifestations of
CNS [42]. The course predominantly involving the CNS
is the neonatal hemorrhagic-necrotizing encephalitis
that manifests as lethargy and seizures. Although the
mortality rate is only 5% for neonates with encephalitis,
over 50% of survivors are left with signiWcant neurological impairment [42]. After a neonatal herpes infection,
cutaneous recurrences may occur for some time [24].
Prevention, diagnosis and therapy for herpes simplex
virus infections during pregnancy
Preventive measures
The most eVective measure to prevent perinatal herpes
infections is to avoid exposure to virus since there is
highest risk to the neonate after primary genital herpes
during late pregnancy. In case of recurrent genital herpes, the risk of severe neonatal infection can be
regarded as small. However, all women should be asked
at their booking visit if they or their partners have ever
had genital herpes. Female partners of men with genital
herpes, but who do not themselves have a history of
genital herpes, should be strongly advised not to have
sexual intercourse at the time of recurrence. Conscientious use of condoms throughout pregnancy should be
advised to minimize the risk of viral acquisition.
Diagnostic procedures
The diagnosis of genital herpes is conWrmed by detection of HSV DNA using polymerase chain reaction
(PCR) or by isolating the virus by culture from the genital tract [18]. Viral antigen can also be detected using
commercially available antigen test kits. Serological
procedures are only useful in the diagnosis of primary
genital infection when the virus-speciWc immunoglobulin (Ig) M is expected to be positive and when a reliable
diVerentiation between primary and latent infection
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Med Microbiol Immunol (2007) 196:89–94
with HSV-1 and HSV-2 is desirable. The viral envelope
glycoprotein G of HSV-1 and HSV-2, used as aYnity
puriWed or recombinant antigens in several commercially distributed enzyme immunoassays, have been
recognized as type-speciWc antigens [6, 35]. In molecular biological studies, a unique region was identiWed in
the glycoprotein G-2–encoding gene, which could not
be found in the glycoprotein G-1 [27].
Type-speciWc enzyme immunoassays can be recommended to identify mothers at high risk of infecting
their infants as well as silent HSV-2 carriers, who may
be an important reservoir for viral transmission. When
HSV-2 has been detected in pregnant women several
weeks before delivery, type-speciWc HSV serology can
be useful to distinguish primary from recurrent episodes of genital herpes [7]. This is possible by detection
of seroconversion after testing samples are taken
sequentially. Women who acquire genital HSV infection during pregnancy, but who do not complete their
seroconversion prior to the time of labor, will most
likely infect their neonates and, therefore, cesarean
section should be considered [8]. On the other hand, a
cesarean section is not necessary if the seroconversion
is completed at the time of delivery. In this case, the
neonate is likely to be protected by maternal antibodies.
Therapeutic measures
All primary episodes of genital herpes in pregnant
women should be treated with aciclovir or valaciclovir
at the recommended dosage [3, 38] (Table 2). Results
from the aciclovir-in-pregnancy registry do not show
teratogenic eVects of the drug [2]. Comparable data
have been reported for the oral administration of
valaciclovir [13], whereas no data about other nucleoside analogous compounds such as famciclovir during
Table 2 Antiviral treatment
of genital herpes in pregnancy
and of neonatal herpes simplex virus infection
pregnancy are available. As aciclovir and valaciclovir
are not oYcially approved for the treatment of pregnant women, patients should be informed about the
limited information and give consent before the drug is
used. Randomized studies have shown that suppressive
treatment with aciclovir (Table 2) from the 36th week
of pregnancy until delivery reduces the frequency of
clinical manifestation and virus shedding at the time of
delivery. Thus, the cesarean section rate can be
decreased signiWcantly [36].
Prevention, diagnosis and therapy for herpes simplex
virus infections in neonates
Preventive measures
If clinical herpes lesions, positive tests for virus detection, or both are present at the time of delivery, then
a cesarean section is indicated as an eVective measure
for prevention of neonatal herpes infection [10]. In
case of acute recurrent genital herpes, a vaginal delivery can be considered when the oral administration of
2 £ (200-) 400 (-800) mg aciclovir was started
two days before delivery [40]. At membrane rupture,
if it may be assumed that the fetal lungs are mature, a
cesarean section should be performed as quickly as
possible and no more than 4–6 h later [1]. In case of
immature lungs, there is no established basis for the
decision [38].
Neonates with a conWrmed or suspected HSV infection should be isolated. Direct contact with skin and
mucosal lesions as well as excretions and body Xuids
should be avoided. Since neonatal herpes can also be
acquired postnatally, women or relatives with active
herpes lesions should be advised about the risk of viral
transmission. Medical staV and visitors with recur-
Primary genital herpes
Aciclovir
Orally: 5 £ 200 mg
Valaciclovir
Orally: 2 £ 500 mg
Recurrent genital herpes
Aciclovir
Orally: 5 £ 200 mg
Valaciclovir
Orally: 2 £ 500 mg
Suppressive treatment of genital
herpes
Aciclovir
Orally: 3 £ 400 mg
Valaciclovir
Orally: 2 £ 250 mg
Neonatal herpes
Aciclovir
Length of therapy: 10 days
Length of therapy: 10 days
Length of therapy: 5 days
Length of therapy: 5 days
Maintenance therapy
Length of therapy: from week
36 until delivery
Intravenously:
Length of therapy: 14–21 days
3 £ 10–15 (¡20) mg/kg
Suppressive treatment of cutaneous recurrences after neonatal herpes
Aciclovir
Orally: 2–3 £ 300 mg/m2
Length of therapy: for weeks
to months
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Med Microbiol Immunol (2007) 196:89–94
rences of herpes should take necessary precautionary
measures to prevent direct contact with the skin or
mucosa of the neonate or should be excluded from the
neonatal unit until the lesions are fully healed.
Diagnostic procedures
Because HSV infection in neonates can mimic other
neonatal diseases including VZV infection, laboratory
diagnosis is indispensable. In case of manifest genital
herpes or known maternal virus shedding at the time of
delivery, it is advisable to cultivate swabs from the neonate’s conjunctiva, oropharynx and rectum [38]. If the
neonate exhibits suspicious symptoms, diagnosis must
be rapid and reliable. PCR technology has to be
regarded as the “gold standard” for detecting HSV
[22]. Vesicular, conjunctival, oropharyngeal, stool/rectal swabs, urine and cerebrospinal Xuid serve as specimens. The detection of HSV in the blood can allow an
early diagnosis and can speed up decision to initiate
antiviral treatment.
Although serological methods have traditionally
been widely used for the diagnosis of HSV infections,
studies have shown that the determination of antibodies including virus-speciWc IgM does not allow an early
diagnosis of neonatal HSV infections [18]. In most
cases, serological studies are only convenient for retrospective diagnosis. However, detection of type-speciWc
antibodies can be of great signiWcance to conWrm a clinical diagnosis of HSV-2 infection without using relatively expensive and labor-intensive methods for virus
detection.
Therapeutic measures
There is clear evidence that intravenous administration
of high-dose aciclovir signiWcantly reduces the mortality of babies with either encephalitis or disseminated
disease [42] (Table 2). Nevertheless, neonatal herpes
infection is still associated with high residual mortality
and morbidity. The point in time, at which treatment is
started, is crucial for prognosis especially in case of disseminated infection. Thus, antiviral treatment must be
introduced before an irreversible damage in particular
of CNS and liver tissue is present [4]. An empiric treatment with aciclovir (Table 2) has been recommended
in neonates with (1) typical HSV lesions of the skin,
eyes or mouth, (2) encephalitis or sepsis with negative
bacterial cultures and (3) the combination of hepatitis
and pneumonitis [30]. Suppressive antiviral treatment
using aciclovir is indicated when cutaneous recurrences
are observed after neonatal HSV infection [23]
(Table 2).
93
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