Seminars in Fetal & Neonatal Medicine 14 (2009) 209–217

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Seminars in Fetal & Neonatal Medicine

journal homepage: www.elsevier.com/locate/siny

Varicella in the fetus and newborn

Candice K. Smith*, Ann M. Arvin
Stanford University School of Medicine, 300 Pasteur Drive, G322, Stanford, CA 94305, USA

s u m m a r y

Keywords: Varicella (chickenpox) in pregnancy is unusual because most women of childbearing age are immune. It
Congenital varicella syndrome can, however, cause significant morbidity for the pregnant woman and in rare cases cause congenital
Diagnosis varicella syndrome. The incidence of congenital varicella syndrome after maternal varicella during the
Fetal infection
first two trimesters is <1% across multiple cohort studies. Maternal infection in the third trimester is not
Herpes zoster
associated with congenital varicella syndrome, but the infant may develop herpes zoster during the first
Pregnancy
Vaccination one or two years. Maternal infection just before or after delivery presents a high risk for disseminated
Varicella varicella in the infant. Serious infection can be prevented with passive antibody prophylaxis and antiviral
therapy. Maternal herpes zoster does not result in adverse fetal or neonatal outcomes.
Ó 2008 Elsevier Ltd. All rights reserved.

1. Introduction the widespread annual varicella epidemics, w90% of adults born in

Varicella zoster virus (VZV) is a human alphaherpesvirus found
throughout the world. As is characteristic of the alphaherpesvi-
ruses, VZV establishes latency in the cells of the sensory nerve
ganglia after primary infection. It causes varicella (chickenpox) as
the primary infection and herpes zoster when it reactivates. The
clinical disease, which is usually self-limited, is a febrile illness with
a pruritic vesicular rash. However, primary VZV infection can have
severe consequences when it is acquired in pregnancy or the
neonatal period.
VZV is highly infectious.1 Most adults in the USA are immune to
varicella secondary to the high prevalence of transmission during
childhood years.2 In addition, the varicella vaccine was licensed in
1995 and has significantly reduced the incidence of primary VZV
infection in the population as a whole.3 For these reasons, varicella
affecting women during pregnancy or neonates is rare. Pregnant
women who contract varicella, particularly in the third trimester, are
at higher risk for more severe disease, including pneumonia. The fetal
outcomes include normal healthy infants in almost all cases, possible
zoster in infancy, and, rarely, fetal death or congenital varicella
syndrome (CVS). Perinatally acquired VZV can also cause significant
morbidity and mortality in the newborn. Maternal herpes zoster is
benign for both the pregnant woman and the fetus or newborn.
2. VZV epidemiology
VZV is a readily transmissible virus, with w90% of susceptible
household contacts becoming infected after exposure. Because of
* Corresponding author. Tel.: þ1 650 723 5682; fax: þ1 650 725 8040.
E-mail address: candices@stanford.edu (C.K. Smith).
the USA and Europe are immune to VZV. The introduction of
universal varicella vaccination in the USA has modified the pattern
of VZV transmission since 1995, but before then, the annual inci-
dence of varicella was roughly equal to the birth cohort. Morbidity
and mortality rates are higher in adults than in children, and
pregnant women in particular are at risk, specifically for varicella
pneumonia.4
Although VZV infections occur in a worldwide distribution,
there are notable variations in the incidence by latitude and
climate. In the absence of varicella vaccination programs, varicella
outbreaks follow a seasonal pattern of increasing numbers of cases
in winter and spring in temperate climates. Through these
epidemics, >90% of children become infected by age 15 years. By
contrast, in tropical climates, VZV is acquired at less frequency and
at older ages. These geographical differences in epidemic patterns
are not understood, but may be secondary to viral strain
differences, environmental conditions that limit survival of this
heat-labile virus in the tropics, or host genetic factors.
Just before introduction of varicella vaccine in the USA, varicella
had shifted from a peak incidence in children aged 5–9 years to 1–4
years. This shift was attributed primarily to earlier exposure
through daycare attendance.5 VZV vaccine was licensed in 1995 and
decreased the incidence of disease by 85–90% in the decade
following licensure. In the USA, the national varicella vaccination
program follows VZV with active surveillance, documenting
a vaccine coverage rate of 80% within surveillance areas.6 Varicella
incidence decreased most significantly in children aged 1–4 years,
but decreases were shown in all age groups, including adults.
Among adults, incidence of varicella declined 74% during
1995–2005, despite vaccination rates of only 3%. Herd immunity is
the likely explanation for this decrease among adults. 7

1744-165X/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.siny.2008.11.008
210 C.K. Smith, A.M. Arvin / Seminars in Fetal & Neonatal Medicine 14 (2009) 209–217
Thus, the majority of adults who have lived since childhood in
temperate climates are immune, as evidenced by the detection of
VZV IgG antibodies in nearly 95% of adults in the USA.8,9 Therefore,
only w5% of women of childbearing age remain susceptible to
VZV.10 The incidence of primary VZV infection during pregnancy is
correspondingly low. The rate was seven per 1000 in an early study
of 30 000 pregnancies followed prospectively during the period
1958–1964.11 Introduction of universal childhood immunization
against varicella has the potential to reduce the occurrence of
varicella in pregnant women through herd immunity. Conversely,
varicella vaccination programs must be comprehensive because of
the risk that women will reach childbearing age without having
either natural or vaccine-induced immunity.
3. Pathogenesis and clinical manifestations of primary VZV
infection
Primary infection with VZV begins with mucosal inoculation of
the virus through respiratory exposure or direct contact with fluid
from varicella or herpes zoster skin lesions. The incubation period
usually is 14–16 days but can vary from as few as 10 or as many as
21 days after contact. Based upon a poxvirus model, VZV had been
presumed to replicate first in the regional lymphoid tissues, fol-
lowed by primary viremia and viral replication in the liver and
spleen; a secondary viremia was proposed to occur just before the
appearance of skin or mucosal lesions in which infected mono-
nuclear cells transported the virus to these sites.12 Recently,
however, studies in the SCID-hu mouse model of VZV pathogenesis
have shown that infected T-lymphocytes transport the virus to the
skin xenografts within 24 h. A robust epidermal innate antiviral
response with interferon-a contributes to the delay in eruption of
varicella skin lesions.13 From these studies, one may postulate that
the 10–21 day incubation period is the interval required for VZV to
overcome this innate immune response and create visible lesions at
skin or mucosal surfaces. During the incubation period, the virus
may spread as uninfected T-lymphocytes traffic into early stage
lesions and transport progeny virus to new mucocutaneous sites;
replication in reticuloendothelial tissue may also amplify the cell-
associated viremia. By late incubation (24–48 h before the
appearance of the rash), infectious VZV may be present in respi-
ratory secretions, since respiratory transmission to susceptible
contacts has been observed after exposures during this period.
Approximately half of individuals with primary VZV infection,
more commonly older children and adults, experience a prodrome
of fever, malaise, headache, and abdominal pain. The rash is initially
manifested on the scalp, face, or trunk and consists of pruritic
erythematous macules that evolve to small fluid-filled vesicles. The
vesicular fluid of skin lesions contains high concentrations of
infectious virions, and the virus may be present in respiratory
droplets or secretions. The period of contagiousness is one to two
days before the onset of rash until all the lesions are crusted, usually
five to seven days after the first lesions appear. Subclinical disease is
rare – a difference between VZV and other herpes viruses that are
typically asymptomatic during primary infection. Varicella is
generally short in duration and mild in healthy hosts. The initial
phase of illness may follow this apparently uncomplicated course
in pregnant women and neonates. However, instead of resolving, it
sometimes progresses rapidly to life-threatening disseminated
infection involving the lungs, liver and central nervous system.
The clinical course of varicella in adults is more likely to be
complicated, and this higher incidence of serious varicella in adults
is magnified in pregnant women. Varicella pneumonia, which may
progress to respiratory failure, constitutes the source of most
morbidity and mortality in pregnant women, as it does in non-
pregnant adults.14,15 The onset of varicella pneumonia is usually
three to five days after the appearance of the rash. In a recent case
series of 347 pregnant women with varicella, 18 (5.2%) had pneu-
monia, all were treated with acyclovir, and none died.4 The
reduction in mortality compared with historical rates of 20–45%
reflects both the availability of antiviral therapy and better respi-
ratory management.16
When primary VZV infection occurs in pregnancy, the virus can
be transferred across the placenta to the developing fetus as
a consequence of viremia. While transplacental transmission is
assumed to be the most likely route, infection of the genital tract
mucosa leading to an ascending infection with transfer across the
amniotic membranes cannot be excluded. While viral transfer
occurs and is evidenced by detection of VZV DNA in amniotic fluid,
the rates of transplacental transmission do not correlate directly
with fetal infection. The amniotic fluid may be positive for VZV by
polymerase chain reaction (PCR) testing for viral DNA without
causing fetal disease.17 Spontaneous abortion, fetal demise, and
premature delivery have been reported after varicella in pregnancy,
but the risk of these complications is low.18
4. Intrauterine VZV infection
Primary VZV infection in the pregnant woman most often
results in the birth of a normal newborn either because the virus
was not transmitted to the fetus or fetal infection was controlled
without consequences. Some of these infants may develop herpes
zoster in infancy. However, the majority of infants with intrauterine
infection evidenced by persistence of IgG at one to two years of age
escape without signs or symptoms.14 Rarely, the outcome is
congenital varicella syndrome (CVS) and/or fetal death. VZV may be
transmitted across the placenta and cause intrauterine infection at
any time during gestation. However, the spectrum of clinical
disease that occurs correlates with the gestational age of the fetus.
The highest risk for spontaneous abortion or CVS is in the first 20
weeks of gestation, but the overall risk of CVS in the first 20 weeks
is <1%. There are a few case reports of infants with CVS whose
mothers had varicella at 21–28 weeks’ gestation.16,19 If VZV trans-
mission occurs as a consequence of maternal infection during the
perinatal period, from approximately two days before delivery to
five days after, the infant is at risk of severe life-threatening vari-
cella disease.
4.1. Congenital varicella syndrome
CVS was first described in 1947, and >100 cases have been
reported subsequently.16,20 A large prospective study of 1373
pregnancies complicated by maternal varicella performed in
Germany and the UK confirmed several earlier studies with fewer
such pregnancies that had suggested a low incidence of CVS. Nine
cases of CVS were documented. All cases occurred during the first
20 weeks of gestation. The highest risk (2.0%) was observed
between 13 and 20 weeks of gestation, with seven affected infants
identified among 351 pregnancies. Only two cases of CVS were
identified among 472 pregnancies in which maternal varicella
occurred before 13 weeks (0.4%).21 Overall the incidence of CVS in
nine reported cohort studies was 0.55% in the first trimester, 1.4% in
the second trimester, and 0% in the third trimester.16
The defects of CVS involve the skin, the limbs, the eyes, and the
central and autonomic nervous systems (Table 1).22,23 The charac-
teristic cicatricial skin lesions may be depressed and pigmented in
a dermatomal distribution or hypopigmented (Fig. 1). Ocular
defects include cataracts, chorioretinitis, Horner syndrome, ptosis,
microphthalmia and nystagmus. The typical limb and joint abnor-
malities are hypoplasia of the bones and muscle and/or absent or
malformed digits (Figs. 2 and 3). Central nervous system abnor-
malities in CVS patients include cortical atrophy, seizures, and
mental retardation. Many affected infants have microcephaly.
 C.K. Smith, A.M. Arvin / Seminars in Fetal & Neonatal Medicine 14 (2009) 209–217 211

Table 1 supports the hypothesis of early viremia and with dissemination

Clinical manifestations of congenital varicella syndrome. caused by a poor host immune response.24,25 Microcephaly can be
Skin attributed to VZV encephalitis and irreversible damage to growth of
Cicatricial lesions the developing brain. Of interest, the virus does not appear to cause
Cutaneous defects intrauterine damage to the lungs or liver in infants with CVS, as it
Hypopigmentation
Nervous system
can in perinatal varicella or in other immunocompromised hosts.
Intrauterine encephalitis Fulminant infection involving these organs may result in fetal
Cortical atrophy/porencephaly demise, rather than birth of an infant with CVS. VZV is also
Seizures a neurotropic virus and many of the defects have been postulated to
Mental retardation
be a direct result of spinal cord and ganglia infection, causing
Autonomic instability
Eye destruction of the plexi during embryogenesis and leading to
Chorioretinitis denervation of the limb bud and subsequent hypoplasia. Failure of
Cataracts muscle development has consequences for limb bone formation.
Micropthalmia The cutaneous defects are also likely to reflect VZV infection of
Anisocoria
Musculoskeletal
sensory nerves. VZV infection of cells in developing optic tracts also
Limb hypoplasia explains the optic atrophy and chorioretinitis.26 In addition, VZV
Muscle hypoplasia appears to destroy neural cells that comprise the autonomic
Systemic nervous system in the affected fetus. Some skin lesions, which have
Intrauterine growth retardation
the dermatomal distribution associated with herpes zoster, may be
Developmental delay
Cardiovascular defects caused by VZV reactivation in utero. The short latency phase, if
Gastrointestinal tract latency is established at all, can be explained by an inadequate cell-
Gastrointestinal reflux mediated immune response in the fetus.27
Urinary tract Overall, the prognosis of infants born with CVS is poor, with
Hydroureter
Hydronephrosis
death in infancy resulting from intractable gastroesophageal reflux,
severe recurrent aspiration pneumonia and respiratory failure.
However, there are some reports of more favorable outcomes.28–30
Cohort studies show a higher rate of females with CVS, 66–85%.16
Dysfunction of the autonomic nervous system is evidenced by The cause for these higher rates is unknown, but one study
neurogenic bladder, hydroureter, esophageal dilation and reflux hypothesized that it is secondary to higher rates of male fetal
leading to aspiration pneumonia.24 death.31
The pathogenesis of CVS may reflect disseminated infection in
utero or consequences of failure of virus–host interaction to result
in establishment of latency, as normally occurs in postnatal VZV 4.2. Herpes zoster in infancy
infection. Since VZV is a lymphotropic virus, it has the potential to
spread to all fetal organs by the hematogenous route. A few reports Maternal varicella during pregnancy can manifest as infant zoster
that have examined fetuses infected after maternal varicella have in the first or second year.32–34 (Fig. 4). In one report, out of ten children
shown that VZV is distributed throughout fetal tissue which who were asymptomatic at birth, but later presented with zoster, eight

Fig. 1. Classic cicatricial scarring is visualized in an infant with congenital varicella syndrome.
212 C.K. Smith, A.M. Arvin / Seminars in Fetal & Neonatal Medicine 14 (2009) 209–217
Fig. 2. Infant with congenital varicella syndrome. The right lower leg has significant bone and muscle hypoplasia. The classic cicatricial scarring is also visualized.
did so in the first year of life. The gestational age at the time of maternal
varicella ranged from 14 to 33 weeks, with a median age of 25 weeks.
The observed risk of zoster when maternal infection occurs before 24
weeks was 0.8%, compared to a 1.7% observed risk if maternal varicella
was after 25 weeks.21 In another report, the risk of postnatal herpes
Fig. 3. X-ray images of the lower extremities of the above infant, noting the bone
hypoplasia.
zoster infection in infancy was 3.8% in cases when maternal amniotic
fluid had been positive for VZV DNA by PCR.17
5. Diagnosis of varicella and fetal complications in pregnancy
The diagnosis of varicella in pregnant women can often be made
from the classic clinical presentation of a vesicular pruritic rash. In
addition, there are often preceding or other secondary cases of
varicella within the household. A case series of pregnant women
with varicella identified 90% of index cases as one of the woman’s
children.17 However, as the incidence of varicella decreases in
countries with high vaccination rates, younger physicians will have
less opportunity to see the characteristic skin lesions and may feel
less confident with the clinical diagnosis. If the diagnosis is in
question, laboratory testing can be performed. The base of a vesic-
ular skin lesion can be scraped for culture, immunohistochemical
staining, and/or PCR. VZV culture is highly specific, but takes seven
to 10 days and is insensitive. Direct fluorescent antigen staining
using monoclonal antibodies to detect VZV glycoproteins in cells
from a skin lesion scraping can be performed within hours and has
high sensitivity and specificity. If a qualified laboratory is available,
rapid testing can also be done by VZV PCR. Serologic tests are of
little or no value for the diagnosis of varicella as VZV IgG antibodies
often only become detectable a few days after the onset of the
illness, VZV IgG enzyme-linked immunosorbent assay (ELISA)
methods have substantial false negative rates (15–20%), and
seroconversion is a retrospective approach to diagnosis. Further, no
validated serologic tests for VZV IgM are available to clinicians and
VZV IgM antibodies can be detected in individuals who have had
varicella at some time in the past.35,36 When standard ELISA
methods are used to detect VZV IgM antibodies, the rate of false
positives is high.
Evaluating the fetus for intrauterine infection after maternal
varicella presents several challenges and developing validated
 C.K. Smith, A.M. Arvin / Seminars in Fetal & Neonatal Medicine 14 (2009) 209–217
Fig. 4. Infant aged 14 months with herpes zoster in the classic dermatomal pattern. There was a maternal history of varicella at 28 weeks of pregnancy.
approaches is difficult because the incidence of both varicella in
pregnancy and any associated fetal damage is fortunately quite low.
Several studies have sought correlations between the detection of
VZV IgM in fetal blood or the PCR detection of VZV DNA in fetal
blood or amniotic fluid postnatal evidence of fetal infection. VZV
IgM was positive in only 25% of infants born with clinical mani-
festations of disease.21 A study of 107 women who had varicella
before the 24th week of pregnancy showed that negative PCR
results in amniotic fluid correlated with favorable fetal outcome –
good health, with normal psychomotor development.17 However, it
is necessary to note that this sample size was not powered to
evaluate for risk of fetal pathology when the risk of such sequelae is
<1%. Additionally, VZV PCR has a poor positive predictive value for
fetal disease or disease severity. One limitation of testing amniotic
fluid for VZV by PCR is timing; an amniocentesis can only be per-
formed after 16–18 weeks of gestation, so in some clinical situa-
tions the PCR could be obtained well after initial presentation of
varicella in the mother. The risk of fetal demise from amniocentesis,
which is low, must also be weighed against the low risk of VZV-
related fetal damage. Importantly, VZV DNA in amniotic fluid does
not indicate whether the fetus has been infected or, if infected,
whether fetal damage will occur. In the study of 107 pregnant
women with varicella, nine amniotic fluid specimens were VZV PCR
positive (8.4%); of these, the pregnancy outcomes were five full-
term normal infants, one infant with bilateral microphthalmia, two
therapeutic abortions, of which one fetus showed limb hypoplasia,
and one spontaneous abortion. Thus only two pregnancies were
associated with signs of intrauterine varicella. Since varicella is
a systemic infection, it should be assumed that the pregnant
woman with varicella may have viral genomic DNA in many bodily
fluids, including amniotic fluid, and the duration of persistence of
VZV genomes, and whether it represents the presence of infectious
virus is not known. The rate of detection of VZV DNA by PCR might
be higher when the mother’s infection is more recent, but would
not imply a higher risk of fetal sequelae. At this point, no conclu-
sions can be drawn about the significance of a positive VZV PCR of
213
amniotic fluid with regard to risk of VZV transmission to fetus or
risk for fetal defects.
Serial evaluations of fetal development by prenatal ultrasound
may be useful to identify severe manifestations of intrauterine VZV
infection.37 Ultrasound is most definitive when the fetus has
defects such as limb atrophy or evidence of microcephaly, but
subtle findings such as liver calcifications on prenatal ultrasound
were the only sign of damage in an infant who was severely
affected.38 The role of prenatal magnetic resonance imaging for
assessment of the fetus after maternal varicella is only beginning to
be delineated, but it may provide improved specificity, particularly
for central nervous system damage.39
6. Antiviral treatment of varicella in pregnancy and
intrauterine infection
Acyclovir is an analogue of guanosine that inhibits viral repli-
cation and is highly specific for cells infected with herpes simplex
virus and VZV. Acyclovir is activated by the virus-encoded thymi-
dine kinase. Acyclovir crosses the placenta and is excreted by the
fetal kidney. Although it is concentrated in amniotic fluid, it does
not appear to accumulate in the fetus.40 Valacyclovir is an orally
administered prodrug of acyclovir that has improved oral
bioavailability and improved pharmacokinetic properties. Acyclovir
and valacyclovir are pregnancy category B and are not approved for
any indication in pregnant women. However, a registry of neonates
exposed to acyclovir during the first trimester showed that no
teratogenic effects could be attributed to acyclovir.41 Therefore, in
instances of serious disease or complication such as pneumonia in
the mother, the Committee on Infectious Diseases of the American
Academy of Pediatrics concluded that the benefit of treating with
acyclovir in these cases outweighs risk.42 Valacylovir achieves
higher serum levels than oral acyclovir; there are no data regarding
the risk to the fetus, but the risk can be considered low, based on
outcomes when pregnant women have been given intravenous
acyclovir.
214 C.K. Smith, A.M. Arvin / Seminars in Fetal & Neonatal Medicine 14 (2009) 209–217
Uncomplicated maternal varicella can be treated orally with
acyclovir or valacyclovir and treatment should be considered,
particularly later in gestation when risks of maternal complication
from disease are increased and risks to the developing fetus can be
considered minimal. This approach addresses the problem that VZV
dissemination can occur very rapidly in a patient whose clinical
course seems benign. The decision to treat must be based on clinical
judgment despite the lack of an approved indication because the
low frequency of maternal varicella means that sufficient data to
establish risks and benefits cannot be obtained. Intravenous anti-
viral therapy is indicated for the pregnant woman who develops
any signs of pneumonia including cough, dyspnea, hypoxia, or an
abnormal chest X-ray.43 There is no information about whether
giving acyclovir or valacyclovir to pregnant women with varicella
reduces the already low risk for CVS.4
Because the manifestations of CVS result from intrauterine
damage to the developing fetus, antiviral therapy in the newborn
period cannot be expected to have substantial impact on the
sequelae. However, a case-by-case evaluation of infants with CVS is
necessary in making decisions about when or whether to treat with
acyclovir. There is a paucity of evidence regarding the role of
antiviral therapy in controlling any potential damage that might
arise from continued VZV replication postnatally. Nevertheless, if
the infant has or develops clinical signs of active infection, it is
prudent to treat. The acyclovir dose should be that established as
safe for treating neonatal herpes simplex infections, which is
15 mg/kg per dose given intravenously every 8 h. The duration of
therapy must be determined from evidence of control of active VZV
replication, either by cessation of lesion formation or by using
laboratory tests, e.g. VZV PCR or viral culture.
Herpes zoster in infants who acquired VZV in utero has been
self-limited or responsive to treatment with acyclovir. If the zoster
is extensive and painful, it is usually prudent to treat with intra-
venous acyclovir at least initially, followed by oral acyclovir. No
antiviral regimen has been evaluated but treatment for seven to 10
days can be expected to be sufficient because these infants are not
otherwise immunocompromised. Serious complications have been
reported in only one case of a four-month-old infant of a mother
who had had varicella at 17 weeks’ gestation. The infant was born
full term without complications, developed herpes zoster at three
months, then had generalized seizures, with VZV DNA in cerebro-
spinal fluid by PCR and findings consistent with central nervous
system infection.44 This infant received intravenous acyclovir for 10
days, followed by oral acyclovir for three weeks; VZV PCR of the CSF
became negative but whether resolution of the infection was
accelerated or the outcome was improved cannot be judged from
a single case report.
7. Management of pregnant women exposed to VZV
Passive antibody prophylaxis with immune globulin prepara-
tions that contain VZV IgG antibodies is indicated if a pregnant
woman is susceptible to VZV, the exposure was a close contact and
prophylaxis can be administered within 72–96 h after the expo-
sure. Pregnant women who have a history of varicella are not
considered at risk. Symptomatic re-infection with VZV is quite rare
and pre-existing maternal immunity would be expected to protect
the fetus. A clinical history of varicella is considered sufficient
evidence of immunity. A recent study assessing the validity of
a self-reported history of varicella showed that it is a strong
predictor that the pregnant woman will have VZV IgG antibodies
(>98%).45 However, since 95% of adult women have VZV IgG
antibodies, this correlation is not unexpected. Only a minority of
women who had a negative or uncertain varicella disease history
were actually seronegative, which is also consistent with the
epidemiology of VZV infection in women of childbearing age from
temperate climates. Because of the difference in epidemiology,
concern about VZV susceptibility should be highest if the pregnant
woman who has no varicella history is from a geographical area
where epidemic varicella is less common. Cost-benefit analysis
supports testing for serum VZV IgG titers if the mother with no
history is from a high prevalence area because prophylaxis is likely
to be necessary in <5% of cases. In practice, this approach requires
access to a laboratory that can report the results on an urgent basis
so that prophylaxis can be given within the 72–96 h, if required.
Since VZV IgG assays have a significant false-negative rate, some
women who are identified as susceptible will be immune to VZV.
However, adverse reactions to prophylaxis are unusual in immune
or susceptible individuals.
High titer varicella zoster immune globulin (VZIG) prepared
from individuals with recent zoster or from donors screened for
high VZV IgG titers (VariZIG) is preferred because of the intra-
muscular route of administration; intravenous immune globulin
(IVIG) can be substituted if necessary at a dose of 400 mg/kg. The
VariZIG can be obtained 24 h a day from the sole authorized US
distributor (FFF Enterprises, Temecula, CA, USA; tel. 1-800-843-
7477 or online at http://www.fffenterprises.com), and the recom-
mended dose is 125 units/10 kg of body weight, up to a maximum
of 625 units. The minimum dose is 125 units. VZIG prevents vari-
cella or reduces the severity of infection in most cases; however,
patients should be monitored for breakthrough infection.46
Passive antibody prophylaxis is intended to protect the
susceptible pregnant woman from severe varicella. Whether the
fetus is protected from transplacental VZV transmission is not
known, but it is reasonable to assume that preventing maternal
viremia will reduce risk. In one prospective study, maternal
breakthrough infection occurred despite VZIG prophylaxis in 97
cases. None of the infants had CVS, but this sample size is not
sufficient to conclude that the fetus was protected, as the incidence
of CVS is <1%.21 Acyclovir prophylaxis is not recommended because
of the lack of information about its safety or efficacy compared to
VZV immune globulin. Varicella vaccine can be given for post-
exposure prophylaxis in non-pregnant individuals but the live
attenuated vaccine is contraindicated in pregnancy.
As more women of childbearing age have vaccine-induced
immunity to VZV, the assessment of immune status will shift to
documenting that the exposed pregnant woman has received two
doses of live attenuated varicella vaccine. If this history is docu-
mented, serologic testing is not recommended. Commercially
available serologic assays for VZV IgG antibodies have even higher
false negative rates in vaccine recipients than in naturally immune
individuals. The correlation with protection against exposure is
with the number of vaccine doses received. As the vaccine era
progresses, it will be important to confirm immune status because
some women may have not been vaccinated and are less likely to
have natural infection as varicella epidemics are controlled.
8. Perinatal varicella
Varicella of the newborn is a life-threatening illness that may
occur when maternal disease occurs within an approximate seven-
day window that spans from five days before delivery until two
days after delivery. These infants should be given VZIG if available
or IVIG at birth or as soon as the maternal symptoms appear in the
two days after delivery.47 IVIG contains high titers of VZV-specific
IgG, and VZV antibody titers have been shown to be equivalent after
treatment with either VZIG or IVIG.48 Before the use of VZIG, an
estimated 17–30% of the newborns contracted severe varicella
because of the lack of maternal VZV IgG antibody transfer to protect
the neonate and the relative immaturity of the neonatal immune
system.49 Before VZV immunoglobulin was available, the risk of
death among neonates born to mothers with the onset of rash up to
 C.K. Smith, A.M. Arvin / Seminars in Fetal & Neonatal Medicine 14 (2009) 209–217
four days before delivery was 31%.50 The rate decreased to 7% when
the use of VZIG was introduced and neonatal intensive care
improved.51
Infants born to mothers with varicella within this high risk
period are usually initially well-appearing. VZV presents with the
classical skin lesions, but can disseminate with pneumonia, hepa-
titis, encephalitis and severe coagulopathy resulting from liver
failure and thrombocytopenia (Fig. 5).52 Despite the administration
of VZIG, infants exposed to maternal varicella in this high risk
period should be monitored very closely and intravenous acyclovir
should be given if there are any signs of illness. Acyclovir prophy-
laxis is not recommended because IVIG is readily available even if
VZIG is not. A small uncontrolled trial of acyclovir and immuno-
globulin in combination compared to immunoglobulin alone
showed no clinical varicella in any of 10 infants given treatment
with the combination versus two of four infants given immuno-
globulin alone.53 The dosing of acyclovir in this trial was 5 mg/kg
intravenously every 8 h for five days. The sample size is too small to
determine whether the combination improved outcomes, and
a standard prophylaxis dosage or duration has not been deter-
mined. Careful monitoring and early treatment of breakthrough
varicella can be expected to be highly effective. Treatment of infants
who develop breakthrough varicella with intravenous acyclovir
should be continued for 48 h after the last new lesions have
appeared; a duration of seven days is usually sufficient. There is no
indication for additional therapy with oral acyclovir, but the infant
should be monitored for new lesions and re-treated with intrave-
nous acyclovir if necessary.
Fig. 5. Newborn with varicella acquired from the mother in the perinatal period.
215
Infants who are born more than a week after the first appear-
ance of the maternal rash are not at high risk of severe disease. They
will likely have lesions at birth or within the first several days of life,
but they are protected from severe disease secondary to maternal
VZV antibodies having time to traverse the placenta. Again, despite
the lower risk, if there are signs and symptoms of active VZV
disease, treating with an antiviral is recommended. When the
history of maternal varicella is in the few weeks preceding delivery,
the infants may be asymptomatic or may have cutaneous lesions at
birth or developing shortly thereafter, but are at low risk of
dissemination of varicella disease or complications; nevertheless
treatment is prudent.
9. Varicella vaccination
The early childhood varicella immunization program in the USA
was recommended based on an analysis of the annual morbidity
and mortality associated with varicella epidemics, most of which
was associated with secondary Streptococcus pyogenes and Staph-
ylococcal aureus infections or neurologic complications, including
encephalitis and cerebellar ataxia in otherwise healthy individuals.
Universal vaccination was implemented because of the almost
universal prevalence of varicella disease, causing an estimated four
million cases each year, and because those at risk for complications
could not be predicted. The program of universal vaccination
against varicella has decreased the varicella death rate in the USA
across all age groups because of the impact on the annual
epidemics.54
216 C.K. Smith, A.M. Arvin / Seminars in Fetal & Neonatal Medicine 14 (2009) 209–217
When possible, maternal VZV immune status should be deter-
mined before pregnancy by reviewing the varicella history or
documenting vaccination with two doses of varicella vaccine. If
both are negative, then VZV IgG antibody testing should be done
because the vaccine can be offered if the woman is not immune.
Women of childbearing age without a history of chickenpox or
vaccination and who are confirmed seronegative should be coun-
seled about the risks of varicella during pregnancy and receive two
doses of vaccine, given four to eight weeks apart. If more than eight
weeks elapse after the first dose, the second dose can still be given
without restarting the schedule.55 Vaccination can be given in the
immediate postpartum period, and breastfeeding is not a contra-
indication for immunization.56 The US Advisory Committee on
Immunization Practices recommends that postpartum women
without evidence of immunity be given the first dose of vaccine
before discharge from the hospital, and the second dose of vaccine
at the follow-up postpartum visit (six to eight weeks after
delivery).55 As the varicella vaccine was licensed in 1995, the cohort
of infants immunized at 12–15 months is approaching childbearing
age. It should be emphasized that each of these women should be
screened for a history of two doses of vaccine to reduce the risk of
varicella during pregnancy. While waning immunity following
vaccine has been suggested from some epidemiological data,
infection in vaccinated children may be due to failure to induce
immunity associated with a single-dose vaccine regimen; a two-
dose regimen has been introduced in response to these epidemi-
ologic observations.57 The active surveillance sites for varicella are
designed to identify changes in epidemiology that could indicate
the need for booster doses of the vaccine. Changes in varicella
epidemiology may occur because the continued circulation of VZV
in the community may have provided a natural boosting of vaccine-
induced immunity. As vaccine coverage rates improve and varicella
outbreaks become increasingly rare, it may be necessary to give an
adolescent/young adult dose of the vaccine as follow-up to the
universal childhood vaccination program.
Because the effect on fetal development is not known, the
varicella vaccine is contraindicated in pregnancy. The Advisory
Committee on Immunization Practices recommends that preg-
nancy be avoided for one month after vaccination. However, there
are cases of inadvertent vaccination of pregnant women, or vacci-
nation within the few months prior to pregnancy. This is a low risk
exposure as the vaccine strain of virus is attenuated and would be
less virulent than wild type varicella. A registry has followed
a cohort of 944 women and their infants since 1995 who received
vaccine anytime during the pregnancy or three months before
conception, and there were no infants with signs consistent with
congenital varicella syndrome or birth defects suggesting varicella
infection.58
9.1. Herpes zoster in pregnancy
Herpes zoster is not unusual in pregnancy, especially in later
gestation, probably because of some suppression of maternal
immune responses associated with pregnancy. However, among
366 cases of herpes zoster in pregnancy in which outcomes were
followed prospectively, no defects consistent with CVS and no cases
of herpes zoster were reported in the infants.21 There are a few case
reports of infants with abnormalities after maternal herpes zoster
but the findings were non-specific and none had signs of CVS.
Infants whose mothers develop herpes zoster in the peripartum
period are not at risk for serious illness from perinatal varicella.
However, a dermatomal vesicular rash in the lumbosacral area
raises the possibility of herpes simplex virus (HSV) infection, as this
(usually HSV-2) causes as many as 15% of the ‘zoster’ cases in this
distribution.52 The diagnosis should be established by laboratory
testing of the lesions for VZV and HSV.
10. Future research directions
Research to evaluate the persistence of VZV immunity in vaccine
recipients and to document the changing epidemiology of varicella
will be important now that the universal varicella immunization
program has been implemented. Such research has already led to
the revision of the early childhood vaccine schedule to provide two
doses. Further modification of the current varicella vaccine sched-
ules could occur depending on observations about the rates of
breakthrough varicella. Basic research about VZV remains a high
priority in order to better understand the molecular mechanisms of
pathogenesis and host control of this ubiquitous human pathogen.
It is now possible to manipulate the VZV genome to reduce its
capacity to infect human T-cells and sensory ganglia.13 This
research is likely to reveal strategies for creating second generation
genetically engineered live attenuated varicella vaccines that would
be safe in immunocompromised patients and for making higher
potency vaccines that could reduce the number of doses required,
without increasing adverse events and risk of spread of the vaccine
virus from the site of inoculation. A better understanding of the
VZV proteins and the host response to these components of the
virus may also lead to the design of protein/adjuvant vaccines that
would be valuable for high risk patients.
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