DOI: 10.1002/pd.

3843

REVIEW

Fetal varicella diagnosis, management, and outcome

Laurent Mandelbrot*
Hopital Louis Mourier, Service de Gyncologie-Obsttrique, Hpitaux Universitaires Paris Nord Val de Seine, Assistance Publique-Hpitaux de Paris, Universit Paris-Diderot, 178 rue des Renouillers, 92701, Colombes cedex, France *Correspondence to: Laurent Mandelbrot. E-mail: laurent.mandelbrot@lmr.aphp.fr

ABSTRACT
Fetal varicella syndrome (FVS) is due to transplacental infection by the Varicella zoster virus following maternal infection. The risks for the fetus and neonate depend on the timing. When varicella occurs around delivery, it often leads to disseminated neonatal varicella. When varicella occurs during pregnancy, transmission can occur, but is usually asymptomatic; some infants develop zoster postnatally and a few have FVS. Before 20 weeks gestation, FVS can occur, with an incidence of about 1%. The lesions can affect the skin, limbs, central and autonomous nervous systems, eyes, cause calcications, and growth retardation; mortality is high. Lesions typically follow one or several nerve territories, suggesting that damage results from in utero zoster following primary fetal infection. There has been little study of prenatal diagnosis of FVS. Serial ultrasound examination can detect various anomalies, magnetic resonance imaging can be of use to investigate for microphthamia and cerebral lesions, and amniocentesis can diagnose viral transmission. Prevention strategies include vaccination and post-exposure prophylaxis with immune globulin and/or antivirals. Perspectives for treating infected fetuses in utero require further research. 2012 John Wiley & Sons, Ltd.

Funding sources: None Conicts of interest: None declared

INTRODUCTION
Chickenpox in a pregnant woman is an uncommon occurrence, but causes concern for patients and their families, and clinicians, because of the risks for both the mother and child. In temperate countries, over 90 to 95% of adult women are immunized to Varicella zoster virus (VZV), having had chickenpox or vaccination in childhood, but the proportion is lower in tropical latitudes. The incidence of chickenpox is variably estimated, between 1 and 10 per 10 000 pregnancies.1,2 There is a risk of complications for the women herself, on the order of 10%,3 the main concern being respiratory distress, for which risk factors are third trimester infection, numerous skin lesions, and smoking.4 Otherwise, varicella has little impact on pregnancy outcomes such as fetal loss,5,6 but is a risk factor for preterm delivery.6 The fetus can be infected transplacentally, the consequences differing greatly according to the period of gestation. Infants who are infected in utero are usually asymptomatic at birth, although some will develop herpes zoster later in infancy. In some cases, a characteristic pattern of fetal anomalies can occur, including limb hypoplasia and cutaneous scars, which may also involve the central nervous system. Because of the rst description in 1947 by Laforet and Lynch, 7 over 100 cases have been reported. 8 This disease spectrum is often called congenital varicella syndrome (CVS), but preferably should be referred
Prenatal Diagnosis 2012, 32, 511518

to as fetal varicella syndrome (FVS) to avoid confusion with neonatal varicella.

VERTICAL TRANSMISSION OF VZV

The virus can cross the placenta during primary VZV infection, as a consequence of maternal viremia during incubation and rash. In a large prospective study in Germany and the UK between 1980 and 1993,9 IgM was detected in 5%, 10%, and 25% of infants at birth, following maternal varicella in the rst, second, and third trimester, respectively. These results suggest that the mother-to-child transmission rate increases with advancing gestation, although some infected infants do not produce specic IgM, and the immune response increases with advancing fetal maturity. In a prenatal study using amniocentesis with PCR diagnosis,10 the transmission rate was 9/107 (8.4%) following maternal varicella in the rst 24 weeks of pregnancy. This incidence is consistent with the data of Enders et al.9 Most cases of in utero transmission are asymptomatic, although FVS or postnatal shingles can occur, as developed below. In contrast, following maternal varicella near the time of delivery, there is a high incidence of neonatal varicella,11,12 because of the lack of protective maternal antibodies and the immaturity of the neonatal immune system. Two thirds of infants born 7 days before to 7 days after the maternal
2012 John Wiley & Sons, Ltd.

512

l. Mandelbrot

rash are infected and one half have symptoms, including skin lesions, ulcerated necrotic or hemorrhagic lesions, and/or systemic disease (pneumonia, liver failure, encephalitis, and coagulopathy), leading to a high mortality. The risk is increased in preterm infants.1 In case of herpes zoster (shingles) during the pregnancy, the risk of transmission is negligible. In a total of 380 prospectively followed cases of herpes zoster in pregnancy, there occurred no FVS and no herpes zoster in the infants.9,13 It has been suggested that asymptomatic maternal infection or reinfection may be transmitted14; however, neither maternal nor neonatal varicella were convincingly documented in this article. Similarly, the occurrence of varicella in an immunized woman carries little risk for the fetus.15

FETAL VARICELLA SYNDROME

Signs and symptoms
The characteristic defects of FVS involve the skin, the limbs, the eyes, and the central and autonomic nervous systems (Table 1).2,1618 Affected fetuses may have a spectrum of anomalies or a single sign. Skin lesions follow a dermatomal distribution; they are usually retracted scars but in some cases remain active. They can be the only sign of fetal varicella,19 while some typical cases of FVS have no skin lesions.20 The musculoskeletal deformities are hypoplasia of the bones and muscle (Figure 1) and/or absent or malformed digits. Ocular manifestations include microphthalmia, chorioretinitis, cataract, opaque cornea, optic nerve atrophy or hypoplasia and Horner syndrome.2125 Brain lesions include cerebral dysgenesis or atrophy,26,27 porenchephaly,28 and microcephaly.29 Diffuse spinal cord scarring has been described.30 Autonomic nervous system denervation can result in laryngeal paralysis,31 RamsayHunt syndrome32 diaphragmatic paralysis, intestinal

Figure 1 Clubfoot with amyotrophic leg at 29 weeks in a case of fetal varicella syndrome following maternal varicella at 9 and 1/2 weeks gestation. At birth, the child had bilateral scarring from the buttocks to the legs, associated with colon atresia, and died from neurological complications (photos courtesy of Dr Catherine Noel)

atresia,33,34 neurogenic bladder,35 hydroureter, esophageal dilation, and reux.36 Intractable gastroesophageal reux or diaphragmatic paralysis can result in respiratory failure, which may be fatal. Other anomalies are intrauterine growth retardation, thrombocytopenia, erythroblastosis and elevated liver enzymes5 and calcications mostly in the liver and abdomen, which are due to focal necrosis. Multiple organ microcalcications are associated with poor outcome.3740 The perinatal mortality of FVS is high. In a review of 96 cases,2 nearly 30% of infants with clinically apparent lesions died during the rst month of life. Developmental delay occurs in about 12% of survivors.2

Pathogenesis
Birth defects in FVS can be attributed to a disturbance of the developing nervous system, involving disseminated VZV infection and/or in utero herpes zoster. In a few cases, VZV was found in numerous fetal organs,36,4145 indicating disseminated infection, as in neonatal varicella, and active fetopathy has also been described39,46 (Figure 2). However, in the majority of fetuses or

Table 1 Principal signs and symptoms of fetal varicella syndrome (n = 96 children) literature review.2 Each child could have one or more symptom
Symptoms
Skin lesions (scars, skin loss) Neurologic damage (cortical atrophy, spinal atrophy, limb paresis, seizures, microcephaly, Horners syndrome, encephalitis, dysphagia) Eye diseases (microphthalmia, chorioretinitis, cataract, nystagmus, anisocoria, optic atrophy) Limb hypoplasia and other skeletal anomalies IUGR Muscle hypoplasia Gastrointestinal abnormalities Affections of internal organs Developmental delay Genitourinary abnormalities Cardiovascular anomalies Defects of other organs IUGR, intrauterine growth restriction.

Proportion of children (%)

76 60

51 49 22 21 15 13 12 12 8 7

Figure 2 Vesicular lesions in a case of intrauterine demise following

fetal varicella at 17 weeks (photo courtesy of Alain Berrebi, MD)

Prenatal Diagnosis 2012, 32, 511518

2012 John Wiley & Sons, Ltd.

Fetal varicella diagnosis, management and outcome

513

neonates with typical FVS, VZV cannot be isolated.2,47,48 This supports the hypothesis that the lesions are due to herpes zoster in utero,49 based on the observation that skin lesions follow the dermatomal pattern distribution associated with herpes zoster, and that musculoskeletal and nervous system lesions are also segmental. Conversely, infection of the placenta and fetal tissues can occur without any lesions.42 The consequences for the fetus depend on the timing of infection and the sites that are affected. The latent period between primary fetal varicella-like infection and reactivation of herpes zoster can be short or even absent because of the poor fetal immune response.18,49,50 Even postnatally, the child can be unable to clear infection for prolonged periods.33,51 Varicella zoster virus is neurotropic, and can therefore arrest development of the central, peripheral or autonomic nervous systems. Infection of the spinal cord and ganglia can lead to denervation of the limb bud resulting in hypoplasia. Infection of the optic tract can result in optic atrophy and chorioretinitis, and infection of the fetal brain may lead to microcephaly. It is thought that brain lesions are due to intrauterine encephalitis during VZV reactivation,49 through destructive and inammatory lesions.52,53

hepatitis C virus (HCV),61 and a higher incidence of symptomatic infection in females has been reported for CMV infection.62

PRENATAL DIAGNOSIS OF FETAL VARICELLA

The diagnosis of maternal varicella is usually straightforward, presenting as a characteristic pruritic vesicular rash involving the scalp and face and often the trunk (Table 2). Asymptomatic forms are very unusual, in contrast with most other herpes virus infections. If the physician is not condent with the diagnosis, uid or scrapings from lesions can be tested for presence of VZV by culture, uorescent antigen staining, or PCR. Serologic tests are not of use for diagnosis, because specic antibodies only become detectable after the rash. Their use for retrospective diagnosis is also limited, because enzyme-linked immunosorbent assays have substantial false negatives for IgG, and false positives for IgM. Prenatal diagnosis is based mainly on ultrasound and amniocentesis. The work-up requires time to avoid false negative results, and women should not even be seen in the prenatal clinic until two weeks after all active lesions have disappeared to avoid contact with other pregnant women.

Incidence
Following maternal varicella before 20 weeks, the incidence of FVS is on the order of 1%, based on two large prospective studies,9,10 and a review including seven other smaller studies, with a total of 1423 exposed pregnancies.18 In this review, the incidence of FVS was 0.55% in the rst trimester, 1.4% in the midtrimester, and 0 in the third trimester. In another cohort study54 only 1 case of FVS was documented in 276 exposed pregnancies (0.4%), but details were lacking concerning gestational age and follow-up. The period at highest risk of FVS is between 8 and 20 weeks. Few cases have been reported before 8 weeks, but several cases have been observed after 20 weeks, as late as 25 weeks.55 There is no documented case of typical FVS following third trimester infection, but cases have been published of in utero skin ulcers56 and low birthweight,57 and there is potential for cerebral lesions to occur even after late in utero infection.58

Ultrasound ndings
Many of the severe manifestations of FVS are accessible to prenatal ultrasound diagnosis. However, only a few case reports and small series have been published, as summarized (Table 2),1,6,10,37,3941,46,47,5355,57,6371 such as limb atrophy, microcephaly, cataract, microphthalmia, cerebellar dysplasia. Nonspecic ndings, such as intrauterine growth retardation, polyhydramnios, oligohydramnios, hydrops and/or calcications in the abdominal cavity may be due to VZV fetopathy, and various other TORCH infections. They are usually, but not always, associated with limb deformities. However, many anomalies because of VZV infection are not accessible to ultrasound. In one case of fetal infection conrmed by amniocentesis, the only ultrasound sign was transient hyperechogenic bowel,72 but severe inguinal lesions of the skin with muscle and nerve destruction were observed at birth

Risk factors for FVS

The clearest factor is the timing of infection. Most of the reported cases of FVS followed infection between 12 and 20 weeks.9,53 In later pregnancy, the risk is low, presumably because of maturation of the fetal immune system. The dynamics of perinatal varicella indicate that passively transferred maternal IgG are also of importance to control the infection. Manifestations in the fetus and neonate may also depend on other pathogen and host-related factors, as described for other viruses. No data are available relating higher risks of transmission to higher maternal viremia, and no correlation has been shown between severe maternal symptoms and the risks for the fetus. Genetic factors in the fetus may play a role in the fetal immune response, but there has been no study to date. Interestingly, in a case of monochorionic twins,59 one had typical FVS while the other twin was healthy at 3 years follow-up. In cohorts of FVS, there is a predominance of females, 66% to 85%.18 Higher transmission to females has been described for other viruses, i.e. human immunodeciency virus (HIV)60 and
Prenatal Diagnosis 2012, 32, 511518

Table 2 Principal ultrasound signs in prenatal diagnosis of fetal varicella syndrome (n = 32 fetuses).1,6,10,37,3941,46,47,5355,57,6371 Each case could have one or more sign
Symptoms
CNS or eye anomalies (ventriculomegaly, cerbral hypoplasia, microcephaly, calcications, porencephaly, microphthalmia) Limb hypoplasia and other skeletal anomalies Calcications (liver, adominal, thoracic) IUGR Polyhydramnios and/or hydrops Placental anomalies Defects of other organs CNS, central nervous system; IUGR, intrauterine growth restriction.

Proportion of fetuses (%)

48%

37% 37% 22% 11% 7% 22%

2012 John Wiley & Sons, Ltd.

514

l. Mandelbrot

varicella, to establish the diagnosis. The anomalies that can be seen are nonspecic, and even a pattern of birth defects highly suggestive of FVS can be due to other causes, including herpes simplex75 or genetic causes such as MIDAS (microphthalmia, dermal aplasia, sclerocornea) or MLS (microphthalmia with linear skin defects) syndrome, while the presence of malformations in a fetus following maternal varicella can be coincidental.54,65

Fetal blood sampling

Fetal blood sampling is more invasive than amniocentesis, but less reliable. Testing for VZV IgM in fetal blood was used before the PCR era,63,76 but its sensitivity and specicity are poor.10 The poor sensitivity is known from postnatal experience, because VZV IgM was detected in only 4 of 16 infants born with clinical manifestations of disease.9

Chorionic villi sampling

The data on CVS for prenatal diagnosis of fetal varicella is scarce and disappointing. In one study, 4/13 chorionic villi samples tested positive with PCR following maternal varicella,65 but some of these fetuses proved to be uninfected. In another study where two chorionic villi samples were found positive, neither of the infants had VZV.77 These false positives may be due to maternal contamination or signify that the placenta was infected without vertical transmission occurring.

Figure 3 Ulcerative inguinal lesion in a term neonate following

maternal varicella at 15 weeks, with favorable outcome following plastic surgery (previously published in black and white,96 photo courtesy of Vronique Mirlesse, MD)

(Figure 3). Of note, alpha-fetoprotein was elevated in maternal blood and amniotic uid and acetylcholinesterase in amniotic uid, which may be related to fetal skin and nerve lesions. Prenatal magnetic resonance imaging (MRI) may be useful to diagnose central nervous system damage. In one case of FVS,70 central nervous system (CNS) lesions including cerebellar hypoplasia were missed by ultrasound, but were clearly demonstrated by MRI at 32 weeks. MRI would also be of use to detect microphthalmia.

Management issues following prenatal diagnosis of varicella

The diagnosis of fetal infection during pregnancy raises several difcult issues, considering that FVS is rare and has a highly variable prognosis. As in other infections for which no validated in utero therapy is available, two approaches should be discussed with patients. One is to perform invasive prenatal diagnosis with amniocentesis in case of maternal varicella before 20 weeks. The other is to perform serial ultrasound follow-up, with amniocentesis only in case anomalies are detected. A major advantage of the invasive approach is to reassure over 90% of parents that their child has no risk of FVS, or of any long-term impairment.78 One disadvantage is the risk of fetal loss because of amniocentesis, although low. Most importantly, in the event that PCR is positive, the prognostic evaluation will be based on ultrasound. Conversely, in the noninvasive approach, ultrasound lacks sensitivity and specicity as a diagnostic tool. A key issue, which has been raised in the context of congenital CMV infection,79 is the possibility that the predictive value of prenatal ultrasound may be better if there is a denitive diagnosis of fetal infection. On the other hand, a positive diagnosis may lead some parents to request termination of pregnancy even without ultrasound anomalies. Whether amniocentesis precedes or follows ultrasound follow-up, it is difcult in most cases to establish prognosis. In cases with limb atrophy, in the absence of any other ultrasound or MRI abnormality, the child is most likely to have a normal neurodevelopmental outcome. However, he may have cerebral lesions that are undetected prenatally.38 Poor neurological outcome is possible even in the absence of prenatal
2012 John Wiley & Sons, Ltd.

Amniocentesis
Fetal infection can be diagnosed using specic VZV PCR on amniotic uid.10 An amniocentesis should not be performed until 1 month after maternal infection to avoid false negative results.58 Furthermore, VZV genoma can persist for weeks in peripheral blood of infected women. A false positive resulting from maternal blood contamination of amniotic uid has been reported,72 and the authors suggest that the mother should be tested for negative viremia before the amniocentesis. Some authors3 were concerned that viral DNA could be detected in the amniotic uid in the absence of infectious virus. In the largest prenatal diagnosis cohort,10 of nine amniotic uid samples testing positive for specic VZV DNA with PCR, only two were culture positive, but VZV infection was conrmed postnatally or postmortem in six infants. These and other cases66 conrm the poor sensitivity of virus culture, described below. Because IgM in cord/neonatal blood lacks both sensitivity and specicity, there is no gold standard to conrm prenatal diagnosis. Nonetheless, current PCR techniques are widely considered to be highly sensitive and specic.73,74 Amniocentesis is clearly indicated in case of structural, growth or amniotic uid anomalies following maternal
Prenatal Diagnosis 2012, 32, 511518

Fetal varicella diagnosis, management and outcome

515

morphological anomalies. Microphthalmia can be missed during prenatal ultrasound diagnosis. Any lesions may be of delayed onset. Intrauterine growth restriction (IUGR), transient effusions, or calcications are compatible with disseminated congenital infection and normal postnatal development. In one infant with severe neurologic damage,37 the only sign detected at serial specialized prenatal ultrasound was liver calcications. When several different signs are visible at ultrasound, the likelihood of central nervous system lesions is probably increased, whether or not cerebral lesions are seen prenatally.39,40 In infants without prenatal signs, the parents can be reassured that their child is likely to have a normal postnatal outcome. They must be informed however that postnatal herpes zoster can occur in infants infected with VZV in utero who are asymptomatic at birth,55 usually within the rst 2 years of life. Among infants with documented in utero infection before 24 weeks,10 the incidence of shingles was 3.8%. When considering all infants exposed to maternal varicella during the pregnancy,9 the incidence of zoster increased with advancing gestational age at the time of the maternal rash, from 0.8% at 13 to 24 weeks to 1.7% at 25 to 36 weeks. In infants who are completely normal at birth, there is no evidence for any long-term consequences on intellectual performance and neurodevelopment. A case was reported of an infant without symptoms at birth80 who had seizures and focal post-ischemic lesions at 4 months, after an ophthalmic zoster rash. However, in the large prospective cohort,57 in-depth pediatric, ophthalmological, and audiology examinations were unremarkable at 18 to 30 months. Studies in the psychiatric literature have raised the hypothesis that viral infections during pregnancy may be a risk factor for disorders such as schizophrenia for the offspring.81 However, in a large study82 that tested for neurobehavioral outcome at 3 to 15 years, there was no pattern of impaired development or autistic spectrum disorders, and no difference with controls. Further research is required to determine whether in utero therapy can be benecial by reducing VZV replication in the active phase of infection. High-dose acyclovir is used to treat neonatal varicella.12 In cases of ongoing systemic infection, which can be quite severe,44,80 therapy could be useful. Even if FVS results from in utero herpes zoster, rather than the primary infection, antiviral therapy may decrease the risk of sequelae. Although these drugs have not yet been formally approved for use in pregnancy, there is mounting evidence of safety for (val)acyclovir use in pregnancy. It is widely used off-label, mostly to treat herpes simplex virus. In the Acyclovir Pregnancy Registry, 749 pregnancies in women exposed to systemic acyclovir during the rst trimester of pregnancy were followed prospectively.83 Although the sample size was not sufcient to rule out all risks for specic birth defects, the incidence of birth defects approximates that found in the general population. Importantly, the action of (val)acyclovir is highly specic for cells infected with herpes viruses, and thus does not interfere with human DNA. The doses used orally are acyclovir 800 mg ve times daily or valacyclovir 1000 mg three times daily. Both forms cross the placenta.
Prenatal Diagnosis 2012, 32, 511518

PREVENTION ISSUES
Post-exposure prophylaxis in pregnancy
Exposure is dened as close contact with a person with varicella, from 2 days before to 5 days after the rash. The key issue is whether or not the pregnant woman is susceptible. A history of varicella or two-dose vaccination are sufcient to reassure her.84 If the history is negative, serologic testing should be conducted without delay. Even among adults who do not recall having varicella, 70% to 80% are actually immune.84 However, the proportion is lower in immigrants from tropical countries. If the serology is negative, prophylaxis must be considered. Theoretically, there are three approaches to secondary prevention, post-exposure vaccination, immune globulin or antivirals. Post-exposure vaccination is not an option because the vaccine is contraindicated during pregnancy. Varicella zoster immune globulin (VZVIG) is recommended for pregnant women who are both exposed and susceptible, because it reduces maternal disease and complications by 75%.85 There is also evidence that VZVIG reduces the risk of fetal infection.86 For efcacy, it should be administered within 72 to 96 h after the exposure.85 The dose is 125 or 250 units/10 kg of body weight. The cost is considerable and the availability of specic immune globulin is a recurrent problem worldwide. As mentioned above, the indications to use antiviral drugs in pregnancy are not clearly dened. When varicella occurs in pregnancy, there are indications to treat the mother with (val)acyclovir for her own health.18,87 The indication is undisputed in case of respiratory symptoms.8 There is a large consensus to treat pregnant women with varicella in late pregnancy, because this is the period at highest risk for maternal complications and neonatal varicella.87 Use of acyclovir in early pregnancy is more controversial with regards to the theoretical benet for the prevention of FVS. Acyclovir has also been considered for post-exposure prophylaxis.18,87 This strategy has the potential to prevent or attenuate VZV infection, and would thus be an alternative to immune globulin for susceptible women exposed to varicella who did not receive immune globulin, because of delay or lack of availability, especially in late pregnancy.

Primary prevention immunization

Varicella vaccine is an attenuated live virus, which is safe and highly efcacious, preventing 90% of cases.88,89 In the United States and some other countries (including Germany and Australia), a two-dose varicella vaccination is recommended for all infants,85,88 resulting in a sharp reduction in the incidence of congenital and neonatal varicella.90 France and several countries in Europe have selective varicella vaccination programs, which include adolescents with no recollection of having had the disease.91 Women who present before becoming pregnant should be counseled on varicella among infections that can be transmitted to the fetus,92 and vaccination should be offered when there is no history of chickenpox or two-dose vaccination. Postpartum vaccination is of clear benet for susceptible women, because they can get infected via their rst child. The rst shot of vaccine can be given immediately postpartum, and breastfeeding is not a contraindication.93
2012 John Wiley & Sons, Ltd.

516

l. Mandelbrot

Because varicella vaccine is a live attenuated virus, it is contraindicated in pregnancy.94 The US Advisory Committee on Immunization Practices recommends avoiding pregnancy for one month after vaccination.85 However, pregnant women who are inadvertently vaccinated can be reassured. The Varicella Vaccine Pregnancy Registry followed 944 infants after vaccination during the pregnancy or three months before conception, and none had any sign or symptom of varicella.95

ACKNOWLEDGEMENTS
We warmly thank Dr Vronique Mirlesse for her support and thoughtful comments and Dr Alain Berrebi and Dr Catherine Noel for contributing gures. WHATS ALREADY KNOWN ABOUT THIS TOPIC? Fetal varicella syndrome (FVS) is a rare, but potentially devastating,
complication due to transplacental infection. Most cases of FVS occur following infection between 8 and 20 weeks gestational age.

CONCLUSIONS
Fetal varicella syndrome is rare, but can have devastating consequences. Prenatal diagnosis is possible using ultrasound; without MRI and amniocentesis, however, prognostic evaluation is a challenge. FVS is a preventable disease. The best primary prevention is vaccination before pregnancy. In seronegative exposed pregnant women, VZV immune globulin can be used. Antiviral drugs are used to treat women for severe varicella during pregnancy, and are also under consideration as a secondary prevention after contact. The possibility of treating fetuses in utero for congenital VZV is a topic for future research.

WHAT DOES THIS STUDY ADD? Prenatal diagnosis of FVS can be performed with ultrasound, MRI
and amniocentesis. Most serious FVS lesions can be detected by ultrasound if expert, serial examination is performed. The perspectives for prenatal antiviral therapy warrant further research.

REFERENCES
1. Mirlesse V, Lebon P. Chickenpox during pregnancy. Arch Pediatr 2003;10(12):11138. 2. Sauerbrei A, Wutzler P. The congenital varicella syndrome. J Perinatol 2000;20(8 Pt 1):54854. 3. Smith CK, Arvin AM. Varicella in the fetus and newborn. Semin Fetal Neonatal Med 2009;14(4):20917. 4. Harger JH, Ernest JM, Thurnau GR, Moawad A, Momirova V, Landon MB, et al. Risk factors and outcome of varicella-zoster virus pneumonia in pregnant women. J Infect Dis 2002a;185(4):4227. 5. Connan L, Ayoubi J, Icart J, Halasz A, Thene M, Berrebi A. Intra-uterine fetal death following maternal varicella infection. Eur J Obstet Gynecol Reprod Biol 1996;68(12):2057. 6. Pastuszak AL, Levy M, Schick B, Zuber C, Feldkamp M, Gladstone J, et al. Outcome after maternal varicella infection in the rst 20 weeks of pregnancy. N Engl J Med 1994;330(13):9015. 7. Laforet EG, Lynch CL, Jr. Multiple congenital defects following maternal varicella; report of a case. N Engl J Med 1947;236(15):5347. 8. Lamont RF, Sobel JD, Carrington D, Mazaki-Tovi S, Kusanovic JP, Vaisbuch E, et al. Varicella-zoster virus (chickenpox) infection in pregnancy. BJOG 2011;118(10):115562. 9. Enders G, Miller E, Cradock-Watson J, Bolley I, Ridehalgh M. Consequences of varicella and herpes zoster in pregnancy: prospective study of 1739 cases. Lancet 1994;343(8912):154851. 10. Mouly F, Mirlesse V, Meritet JF, Rozenberg F, Poissonier MH, Lebon P, et al. Prenatal diagnosis of fetal varicella-zoster virus infection with polymerase chain reaction of amniotic uid in 107 cases. Am J Obstet Gynecol 1997;177(4):8948. 11. Miller E, Cradock-Watson JE, Ridehalgh MK. Outcome in newborn babies given anti-varicella-zoster immunoglobulin after perinatal maternal infection with varicella-zoster virus. Lancet 1989;2(8659): 3713. 12. Sauerbrei A, Wutzler P. Neonatal varicella. J Perinatol 2001;21(8): 545 9. 13. Paryani SG, Arvin AM. Intrauterine infection with varicella-zoster virus after maternal varicella. N Engl J Med 1986;314(24):15426. 14. Mustonen K, Mustakangas P, Valanne L, Professor MH, Koskiniemi M. Congenital varicella-zoster virus infection after maternal subclinical infection: clinical and neuropathological ndings. J Perinatol 2001;21(2): 1416. 15. Picone O, Vauloup-Fellous C, Senat MV, Frydman R, Grangeot-Keros L. Maternal varicella infection during pregnancy in a vaccinated patient. Prenat Diagn 2008;28(10):9712. Prenatal Diagnosis 2012, 32, 511518 16. Alkalay AL, Pomerance JJ, Yamamura JM, Sittler S, Baladi KS. Visual diagnosis casebook: congenital anomalies associated with maternal varicella infection during early pregnancy. J Perinatol 1987;7(1):6971. 17. Birthistle K, Carrington D. Fetal varicella syndrome--a reappraisal of the literature. A review prepared for the UK Advisory Group on Chickenpox on behalf of the British Society for the Study of Infection. J Infect 1998;36(Suppl 1):259. 18. Tan MP, Koren G. Chickenpox in pregnancy: revisited. Reprod Toxicol 2006;21(4):41020. 19. Lloyd KM. Skin lesions as the sole manifestation of the fetal varicella syndrome. Arch Dermatol 1990;126(4):5467. 20. Hammad E, Helin I, Pacsa A. Early pregnancy varicella and associated congenital anomalies. Acta Paediatr Scand 1989;78(6):9634. 21. Al-Katawee YA, Al-Hasoun YA, Taha MN, Al-Moslem K. Congenital varicella-zoster virus infection. A rare case of severe brain and ocular malformations without limb or cutaneous involvement in a newborn after maternal subclinical infection. Saudi Med J 2005;26(5):86971. 22. Andreou A, Basiakos H, Hatzikoumi I, Lazarides A. Fetal varicella syndrome with manifestations limited to the eye. Am J Perinatol 1995;12(5):3478. 23. Brice JE. Congenital varicella resulting from infection during second trimester of pregnancy. Arch Dis Child 1976;51(6):4746. 24. Garrido Martin J, Aviles Puigvert M, Espejo Gonzalez A, Sanchez Luque JR. Congenital Horners syndrome associated to varicella. Arch Soc Esp Oftalmol 2002;77(4):2235. 25. Lambert SR, Taylor D, Kriss A, Holzel H, Heard S. Ocular manifestations of the congenital varicella syndrome. Arch Ophthalmol 1989;107(1):526. 26. Dimova PS, Karparov AA. Congenital varicella syndrome: case with isolated brain damage. J Child Neurol 2001;16(8):5957. 27. Wheatley R, Morton RE, Nicholson J. Chickenpox in mid-trimester pregnancy: always innocent? Dev Med Child Neurol 1996;38(5):4626. 28. Deasy NP, Jarosz JM, Cox TC, Hughes E. Congenital varicella syndrome: cranial MRI in a long-term survivor. Neuroradiology 1999; 41(3):2057. 29. Scheffer IE, Baraitser M, Brett EM. Severe microcephaly associated with congenital varicella infection. Dev Med Child Neurol 1991;33(10): 91620. 30. Cooper C, Wojtulewicz J, Ratnamohan VM, Arbuckle S. Congenital varicella syndrome diagnosed by polymerase chain reaction--scarring of the spinal cord, not the skin. J Paediatr Child Health 2000;36(2):1868. 31. Rizzardi E, Tagliaferro T, Snijders D, Bertuola F, Spolaore F, Monciotti CM, et al. Unilateral laryngeal paralysis in a newborn with congenital varicella syndrome. Int J Pediatr Otorhinolaryngol 2009;73(1):1158.

2012 John Wiley & Sons, Ltd.

Fetal varicella diagnosis, management and outcome

517

32. Balatsouras DG, Rallis E, Homsioglou E, Fiska A, Korres SG. Ramsay Hunt syndrome in a 3-month-old infant. Pediatr Dermatol 2007;24(1): 347. 33. Bruder E, Ersch J, Hebisch G, Ehrbar T, Klimkait T, Stallmach T. Fetal varicella syndrome: disruption of neural development and persistent inammation of non-neural tissues. Virchows Arch 2000; 437(4):4404. 34. Sauve RS, Leung AK. Congenital varicella syndrome with colonic atresias. Clin Pediatr (Phila) 2003;42(5):4513. 35. Fujita H, Yoshii A, Maeda J, Maeda J, Kosaki K, Shishido S, Nakai H, et al. Genitourinary anomaly in congenital varicella syndrome: case report and review. Pediatr Nephrol 2004;19(5):5547. 36. Ussery XT, Annunziato P, Gershon AA, Reid BS, Lungu O, Langston C, et al. Congenital varicella-zoster virus infection and Barretts esophagus. J Infect Dis 1998;178(2):53943. 37. Boumahni B, Kauffmann E, Laftte A, Randrianaivo H, Fourmaintraux A. Congenital varicella: limits of prenatal diagnosis. Arch Pediatr 2005;12(9):13613. 38. Bruel H, Chabrolle JP, El Khoury E, Poinsot J, Amusini P, Beurrier J. Two cases of congenital varicella syndrome: plea for the varicella vaccine. Arch Pediatr 2004;11(3):2168. 39. Meyberg-Solomayer GC, Fehm T, Muller-Hansen I, Enders G, Poets C, Wallwiener D, et al. Prenatal ultrasound diagnosis, follow-up, and outcome of congenital varicella syndrome. Fetal Diagn Ther 2006; 21(3):296 301. 40. Petignat P, Vial Y, Laurini R, Hohlfeld P. Fetal varicella-herpes zoster syndrome in early pregnancy: ultrasonographic and morphological correlation. Prenat Diagn 2001;21(2):1214. 41. Hartung J, Enders G, Chaoui R, Arents A, Tennstedt C, Bollmann R. Prenatal diagnosis of congenital varicella syndrome and detection of varicella-zoster virus in the fetus: a case report. Prenat Diagn 1999;19(2): 1636. 42. Nikkels AF, Delbecque K, Pierard GE, Wienkotter B, Schalasta G, Enders M. Distribution of varicella-zoster virus DNA and gene products in tissues of a rst-trimester varicella-infected fetus. J Infect Dis 2005;191(4): 5405. 43. Puchhammer-Stockl E, Kunz C, Wagner G, Enders G. Detection of varicella zoster virus (VZV) DNA in fetal tissue by polymerase chain reaction. J Perinat Med 1994;22(1):659. 44. Sauerbrei A, Muller D, Eichhorn U, Wutzler P. Detection of varicella-zoster virus in congenital varicella syndrome: a case report. Obstet Gynecol 1996;88(4 Pt 2):6879. 45. Scharf A, Scherr O, Enders G, Helftenbein E. Virus detection in the fetal tissue of a premature delivery with a congenital varicella syndrome. A case report. J Perinat Med 1990;18(4):31722. 46. Hofmeyr GJ, Moolla S, Lawrie T. Prenatal sonographic diagnosis of congenital varicella infection--a case report. Prenat Diagn 1996;16 (12):1148 51. 47. Auriti C, Piersigilli F, De Gasperis MR, Seganti G. Congenital varicella syndrome: still a problem? Fetal Diagn Ther 2009;25(2):2249. 48. Demetrick DJ, Magliocco AM, Hwang WS. Absence of varicella zoster DNA in varicella embryopathy tissue utilizing the polymerase chain reaction. Pediatr Pathol 1993;13(3):34555. 49. Higa K, Dan K, Manabe H. Varicella-zoster virus infections during pregnancy: hypothesis concerning the mechanisms of congenital malformations. Obstet Gynecol 1987;69(2):21422. 50. Williamson AP. The varicella-zoster virus in the etiology of severe congenital defects. A survey of eleven reported instances. Clin Pediatr (Phila) 1975;14(6):5535, 5589. 51. Boussault P, Boralevi F, Labbe L, Sarlangue J, Taieb A, Leaute-Labreze C. Chronic varicella-zoster skin infection complicating the congenital varicella syndrome. Pediatr Dermatol 2007;24(4):42932. 52. Harding B, Baumer JA. Congenital varicella-zoster. A serologically proven case with necrotizing encephalitis and malformation. Acta Neuropathol 1988;76(3):3115. 53. Mazzella M, Arioni C, Bellini C, Allegri AE, Savioli C, Serra G. Severe hydrocephalus associated with congenital varicella syndrome. CMAJ 2003;168(5):5613. 54. Sanchez MA, Bello-Munoz JC, Cebrecos I, Sanz TH, Martinez JS, Moratonas EC, et al. The prevalence of congenital varicella syndrome after a maternal infection, but before 20 weeks of pregnancy: a prospective cohort study. J Matern Fetal Neonatal Med 2011;24(2):3417.

55. Katz G, Pfau A. Congenital varicella causing neurogenic bladder and anal dysfunction. Urology 1986;28(5):4245. 56. Bai PV, John TJ. Congenital skin ulcers following varicella in late pregnancy. J Pediatr 1979;94(1):657. 57. Harger JH, Ernest JM, Thurnau GR, Moawad A, Thom E, Landon MB, et al. Frequency of congenital varicella syndrome in a prospective cohort of 347 pregnant women. Obstet Gynecol 2002b;100(2):2605. 58. Koren G. Congenital varicella syndrome in the third trimester. Lancet 2005;366(9497):15912. 59. Borzyskowski M, Harris RF, Jones RW. The congenital varicella syndrome. Eur J Pediatr 1981;137(3):3358. 60. Warszawski J, Tubiana R, Le Chenadec J, Blanche S, Teglas JP, Dollfus C, et al . Mother-to-child HIV transmission despite antiretroviral therapy in the ANRS French Perinatal Cohort. AIDS 2008;22(2):28999. 61. European PHCVN. A signicant sex--but not elective cesarean section-effect on mother-to-child transmission of hepatitis C virus infection. J Infect Dis 2005;192(11):18729. 62. Picone O, Costa JM, Dejean A, Ville Y. Is fetal gender a risk factor for severe congenital cytomegalovirus infection? Prenat Diagn 2005;25(1):348. 63. Cuthbertson G, Weiner CP, Giller RH, Grose C. Prenatal diagnosis of second-trimester congenital varicella syndrome by virus-speci c immunoglobulin M. J Pediatr 1987;111(4):592 5. 64. Huang CS, Lin SP, Chiu NC, Hung HY. Congenital varicella syndrome as an unusual cause of congenital malformation: report of one case. Acta Paediatr Taiwan 2001;42(4):23942. 65. Kustermann A, Zoppini C, Tassis B, Della Morte M, Colucci G, Nicolini U. Prenatal diagnosis of congenital varicella infection. Prenat Diagn 1996;16(1):714. 66. Lecuru F, Taurelle R, Bernard JP, Parrat S, Lafay-pillet MC, Rozenberg F, et al. Varicella zoster virus infection during pregnancy: the limits of prenatal diagnosis. Eur J Obstet Gynecol Reprod Biol 1994;56(1):678. 67. Ong CL, Daniel ML. Antenatal diagnosis of a porencephalic cyst in congenital varicella-zoster virus infection. Pediatr Radiol 1998;28(2):94. 68. Pons JC, Rozenberg F, Imbert MC, Lebon P, Olivennes F, Lelaidier C, et al. Prenatal diagnosis of second-trimester congenital varicella syndrome. Prenat Diagn 1992;12(11):9756. 69. Pretorius DH, Hayward I, Jones KL, Stamm E. Sonographic evaluation of pregnancies with maternal varicella infection. J Ultrasound Med 1992;11(9):45963. 70. Verstraelen H, Vanzieleghem B, Defoort P, Vanhaesebrouck P, Temmerman M. Prenatal ultrasound and magnetic resonance imaging in fetal varicella syndrome: correlation with pathology ndings. Prenat Diagn 2003;23(9):7059. 71. World AC. Children hit by AIDS. Manushi 1997; (103):301. 72. Mirlesse V, Sole Y, Jacquemard F, Delhommeau F, Daffos F. Persistent maternal viremia after varicella infection during pregnancy as a possible cause of false positive prenatal diagnosis of fetal infection on amniotic uid. BJOG 2004;111(8):8857. 73. Leung J, Harpaz R, Baughman AL, Heath K, Loparev V, Vazquez M, et al. Evaluation of laboratory methods for diagnosis of varicella. Clin Infect Dis 2010;51(1):2332. 74. Mendelson E, Aboudy Y, Smetana Z, Tepperberg M, Grossman Z. Laboratory assessment and diagnosis of congenital viral infections: Rubella, cytomegalovirus (CMV), varicella-zoster virus (VZV), herpes simplex virus (HSV), parvovirus B19 and human immunodeciency virus (HIV). Reprod Toxicol 2006;21(4):35082. 75. Johansson AB, Rassart A, Blum D, Van Beers D, Liesnard C. Lower-limb hypoplasia due to intrauterine infection with herpes simplex virus type 2: possible confusion with intrauterine varicella-zoster syndrome. Clin Infect Dis 2004;38(7):e5762. 76. Liesnard C, Donner C, Brancart F, Rodesch F. Varicella in pregnancy. Lancet 1994;344(8927):9501. 77. Isada NB, Paar DP, Johnson MP, Evans MI, Holzgreve W, Qureshi F, et al. In utero diagnosis of congenital varicella zoster virus infection by chorionic villus sampling and polymerase chain reaction. Am J Obstet Gynecol 1991;165(6 Pt 1):172730. 78. Weisz B, Book M, Lipitz S, Katorza E, Achiron R, Grossman Z, et al. Fetal outcome and amniocentesis results in pregnancies complicated by varicella infection. J Obstet Gynaecol Can 2011;33(7):7204. 79. Guerra B, Simonazzi G, Puccetti C, Lanari M, Farina A, Lazzarotto T, et al . Ultrasound prediction of symptomatic congenital cytomegalovirus infection. Am J Obstet Gynecol 2008;198(4):380 e3817.

Prenatal Diagnosis 2012, 32, 511518

2012 John Wiley & Sons, Ltd.

518

l. Mandelbrot

80. Sauerbrei A, Pawlak J, Luger C, Wutzler P. Hints of intracerebral varicella-zoster virus reactivation in congenital varicella syndrome. Eur J Pediatr 2003;162(5):3545. 81. Brown AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry 2010;167(3): 26180. 82. Mattson SN, Jones KL, Gramling LJ, Schonfeld AM, Riley EP, Harris JA, et al. Neurodevelopmental follow-up of children of women infected with varicella during pregnancy: a prospective study. Pediatr Infect Dis J 2003;22(9):81923. 83. Stone KM, Reiff-Eldridge R, White AD, Cordero JF, Brown Z, Alexander ER, et al. Pregnancy outcomes following systemic prenatal acyclovir exposure: Conclusions from the international acyclovir pregnancy registry, 19841999. Birth Defects Res A Clin Mol Teratol 2004;70(4):2017. 84. Watson B, Civen R, Reynolds M, Heath K, Perella D, Carbajal T, et al. Validity of self-reported varicella disease history in pregnant women attending prenatal clinics. Public Health Rep 2007;122(4):499506. 85. Marin M, Guris D, Chaves SS, Schmid S, Seward JF. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007;56(RR-4):140. 86. Cohen A, Moschopoulos P, Stiehm RE, Koren G. Congenital varicella syndrome: the evidence for secondary prevention with varicellazoster immune globulin. CMAJ 2011;183(2):2048. 87. Heuchan AM, Isaacs D. The management of varicella-zoster virus exposure and infection in pregnancy and the newborn period. Australasian Subgroup in Paediatric Infectious Diseases of the

88. 89. 90.

91. 92.

93.

94.

95.

96.

Australasian Society for Infectious Diseases. Med J Aust 2001;174(6): 28892. American Academy of Pediatrics. CoID. Varicella vaccine update. Pediatrics 2000;105(1 Pt 1):13641. Sauerbrei A. Preventing congenital varicella syndrome with immunization. CMAJ 2011;183(3):E169-170. Khandaker G, Marshall H, Peadon E, Zurynski Y, Burgner D, Buttery J, et al. Congenital and neonatal varicella: impact of the national varicella vaccination programme in Australia. Arch Dis Child 2011;96(5):4536. Martin RM. Prevention of congenital rubella and congenital varicella in Europe. Euro Surveill 2009;14(14):10; author reply 11. Coonrod DV, Jack BW, Boggess KA, Long R, Conry JA, Cox SN, et al. The clinical content of preconception care: immunizations as part of preconception care. Am J Obstet Gynecol 2008;199(6 Suppl 2):S2905. Bohlke K, Galil K, Jackson LA, Schmid DS, Starkovich P, Loparev VN, et al. Postpartum varicella vaccination: is the vaccine virus excreted in breast milk? Obstet Gynecol 2003;102(5 Pt 1):9707. Apuzzio J, Ganesh V, Iffy L, Al-Khan A. Varicella vaccination during early pregnancy: a cause of in utero miliary fetal tissue calci cations and hydrops? Infect Dis Obstet Gynecol 2002;10(3):159 60. Wilson E, Goss MA, Marin M, Shields KE, Seward JF, Rasmussen SA, et al. Varicella vaccine exposure during pregnancy: data from 10 Years of the pregnancy registry. J Infect Dis 2008;197 Suppl 2:S7884. Mirlesse V, Duguy N, Cynober E, Franois Magny J, Daffos F. Alphafoetoprotein and acetylcholinesterase in amniotic uid as a factor suggesting fetal skin and nerve lesions in a case of congenital varicella syndrome. Prenat Diagn 2004;24(7):498500.

Prenatal Diagnosis 2012, 32, 511518

2012 John Wiley & Sons, Ltd.