Congenital Varicella syndrome: Difference between revisions

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{{SK}} Fetal varicella syndrome, Congenital varicella-zoster syndrome, Varicella embryo-fetopathy, Varicella embryopathy, Varicella fetopathy, Fetal varicella-zoster syndrome
{{SK}} Fetal varicella syndrome, Congenital varicella-zoster syndrome, Varicella embryo-fetopathy, Varicella embryopathy, Varicella fetopathy, Fetal varicella-zoster syndrome
==Overview==
==Overview==
Congenital varicella syndrome is a rare disease resulting from [[Varicella Zoster Virus|Varicella Zoster virus]](VZV) infection during the period of [[gestation]]. [[Viremia]] during the primary infection can result in [[transplacental]] transmission of the infection to the developing [[fetus]]. An estimated 25% of fetuses get infected with [[varicella]] infection when mother has a [[varicella[[ infection during the[[ pregnancy]] but the risk of developing congenital varicella syndrome is around 2%, therefore majority of the outcomes are normal [[newborns]]. Patients with primary infection before 20 weeks of [[gestation]] are at a higher risk of developing the severe form of infection, affecting the [[eyes]], [[limbs]], [[skin]] and the [[central nervous system]]. Diagnosis requires a documented history of primary infection in the mother and serial [[ultrasound]] demonstrating features suggestive of congenital [[varicella]] syndrome. There is no definitive treatment, termination of [[pregnancy]] in fetuses with severe features is recommended. [[Vaccination]] to prevent maternal [[varicella]] infection and proper counseling to avoid contact with infected people are important for the management options to reduce the incidence of congenital varicella syndrome.
Congenital varicella syndrome is a rare disease resulting from [[Varicella Zoster Virus|Varicella Zoster virus]](VZV) infection during the period of [[gestation]]. [[Viremia]] during the primary infection can result in [[transplacental]] transmission of the infection to the developing [[fetus]]. An estimated 25% of fetuses get infected with [[varicella]] infection when mother has a [[varicella]] infection during the[[ pregnancy]] but the risk of developing congenital varicella syndrome is around 2%, therefore majority of the outcomes are normal [[newborns]]. Patients with primary infection before 20 weeks of [[gestation]] are at a higher risk of developing the severe form of infection, affecting the [[eyes]], [[limbs]], [[skin]] and the [[central nervous system]]. Diagnosis requires a documented history of primary infection in the mother and serial [[ultrasound]] demonstrating features suggestive of congenital [[varicella]] syndrome. There is no definitive treatment, termination of [[pregnancy]] in fetuses with severe features is recommended. [[Vaccination]] to prevent maternal [[varicella]] infection and proper counseling to avoid contact with infected people are important for the management options to reduce the incidence of congenital varicella syndrome.


==Historical Perspective==
==Historical Perspective==
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==Causes==
==Causes==
Congenital varicella syndrome is caused by [[Varicella zoster virus]] ([[VZV]]), a human alpha herpes virus.
Congenital varicella syndrome is caused by [[Varicella zoster virus]] ([[VZV]]), a human alpha herpes [[virus]].


==Differentiating Congenital Varicella Syndrome From Other Diseases==
==Differentiating Congenital Varicella Syndrome From Other Diseases==
The most important congenital infections, which can be transmitted vertically from mother to fetus are the [[TORCH infections]]. These infections have overlapping features and hence, must be differentiated from Congenital varicella syndrome:<ref name="pmid25677998">{{cite journal |vauthors=Neu N, Duchon J, Zachariah P |title=TORCH infections |journal=Clin Perinatol |volume=42 |issue=1 |pages=77–103, viii |year=2015 |pmid=25677998 |doi=10.1016/j.clp.2014.11.001 |url=}}</ref><ref name="pmid25654000">{{cite journal |vauthors=Ajij M, Nangia S, Dubey BS |title=Congenital rubella syndrome with blueberry muffin lesions and extensive metaphysitis |journal=J Clin Diagn Res |volume=8 |issue=12 |pages=PD03–4 |year=2014 |pmid=25654000 |pmc=4316306 |doi=10.7860/JCDR/2014/10271.5293 |url=}}</ref>
The most important congenital infections, which can be transmitted vertically from mother to fetus are the [[TORCH infections]]. These infections have overlapping features and hence, must be differentiated from congenital varicella syndrome:<ref name="pmid25677998">{{cite journal |vauthors=Neu N, Duchon J, Zachariah P |title=TORCH infections |journal=Clin Perinatol |volume=42 |issue=1 |pages=77–103, viii |year=2015 |pmid=25677998 |doi=10.1016/j.clp.2014.11.001 |url=}}</ref><ref name="pmid25654000">{{cite journal |vauthors=Ajij M, Nangia S, Dubey BS |title=Congenital rubella syndrome with blueberry muffin lesions and extensive metaphysitis |journal=J Clin Diagn Res |volume=8 |issue=12 |pages=PD03–4 |year=2014 |pmid=25654000 |pmc=4316306 |doi=10.7860/JCDR/2014/10271.5293 |url=}}</ref>
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!Congenital Varicella syndrome
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![[Congenital]] [[Syphillis]]
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![[Cytomegalovirus]] ([[CMV]])
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==Natural History, Prognosis and Complications==
==Natural History, Prognosis and Complications==
===Natural History===
===Natural History===
[[VZV]] infection during [[pregnancy]] results in a normal newborn birth in majority of the patients, however, in a few patients it can result in congenital varicella syndrome or [[neonatal varicella]] or [[clinical zoster]] during [[infancy]], the outcomes are dependent on the [[gestational]] age of [[fetus]] at the time of infection. Early gestational period infection via the [[transplacental]] route can result in congenital varicella syndrome resulting in a [[misscarriage]], [[abortion]] or a [[newborn]] with features affecting the [[limbs]], [[eyes]], [[central nervous system]], [[autonomic nervous system]] and present with features such as [[low birthweight]], cutaneous scarring, limb hypoplasia, [[microcephaly]], cortical atrophy, [[chorioretinitis]] and [[cataracts]].<ref name="pmid7802767">{{cite journal| author=Enders G, Miller E, Cradock-Watson J, Bolley I, Ridehalgh M| title=Consequences of varicella and herpes zoster in pregnancy: prospective study of 1739 cases. | journal=Lancet | year= 1994 | volume= 343 | issue= 8912 | pages= 1548-51 | pmid=7802767 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7802767  }} </ref><ref name="pmid402633">{{cite journal| author=Frey HM, Bialkin G, Gerson AA| title=Congenital varicella: case report of a serologically proved long-term survivor. | journal=Pediatrics | year= 1977 | volume= 59 | issue= 1 | pages= 110-2 | pmid=402633 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=402633  }} </ref>
[[VZV]] infection during [[pregnancy]] results in a normal newborn birth in majority of the patients, however, in a few patients it can result in congenital varicella syndrome or neonatal varicella or [[clinical zoster]] during [[infancy]], the outcomes are dependent on the gestational age of [[fetus]] at the time of infection. Early gestational period infection via the [[transplacental]] route can result in congenital varicella syndrome resulting in a [[misscarriage]], [[abortion]] or a [[newborn]] with features affecting the [[limbs]], [[eyes]], [[central nervous system]], [[autonomic nervous system]] and present with features such as [[low birth weight]], cutaneous scarring, limb hypoplasia, [[microcephaly]], cortical atrophy, [[chorioretinitis]] and [[cataracts]].<ref name="pmid7802767">{{cite journal| author=Enders G, Miller E, Cradock-Watson J, Bolley I, Ridehalgh M| title=Consequences of varicella and herpes zoster in pregnancy: prospective study of 1739 cases. | journal=Lancet | year= 1994 | volume= 343 | issue= 8912 | pages= 1548-51 | pmid=7802767 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7802767  }} </ref><ref name="pmid402633">{{cite journal| author=Frey HM, Bialkin G, Gerson AA| title=Congenital varicella: case report of a serologically proved long-term survivor. | journal=Pediatrics | year= 1977 | volume= 59 | issue= 1 | pages= 110-2 | pmid=402633 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=402633  }} </ref>


===Prognosis===
===Prognosis===
Severe infection of the fetus  can result in an [[abortion]]. [[Infants]] born with signs of congenital varicella syndrome the [[prognosis]] is poor and die during the first few months of life.<ref name="pmid11190597">{{cite journal| author=Sauerbrei A, Wutzler P| title=The congenital varicella syndrome. | journal=J Perinatol | year= 2000 | volume= 20 | issue= 8 Pt 1 | pages= 548-54 | pmid=11190597 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11190597  }} </ref><ref name="pmid7802767">{{cite journal| author=Enders G, Miller E, Cradock-Watson J, Bolley I, Ridehalgh M| title=Consequences of varicella and herpes zoster in pregnancy: prospective study of 1739 cases. | journal=Lancet | year= 1994 | volume= 343 | issue= 8912 | pages= 1548-51 | pmid=7802767 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7802767  }} </ref> Infants with milder symptoms can have a normal development and good [[prognosis]].<ref name="pmid6328456">{{cite journal| author=Kotchmar GS, Grose C, Brunell PA| title=Complete spectrum of the varicella congenital defects syndrome in 5-year-old child. | journal=Pediatr Infect Dis | year= 1984 | volume= 3 | issue= 2 | pages= 142-5 | pmid=6328456 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6328456  }} </ref><ref name="pmid11113846">{{cite journal| author=Schulze A, Dietzsch HJ| title=The natural history of varicella embryopathy: a 25-year follow-up. | journal=J Pediatr | year= 2000 | volume= 137 | issue= 6 | pages= 871-4 | pmid=11113846 | doi=10.1067/mpd.2000.109005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11113846  }} </ref>
Severe infection of the fetus  can result in an [[abortion]]. [[Infants]] born with signs of congenital varicella syndrome have poor [[prognosis]] and die during the first few months of life.<ref name="pmid11190597">{{cite journal| author=Sauerbrei A, Wutzler P| title=The congenital varicella syndrome. | journal=J Perinatol | year= 2000 | volume= 20 | issue= 8 Pt 1 | pages= 548-54 | pmid=11190597 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11190597  }} </ref><ref name="pmid7802767">{{cite journal| author=Enders G, Miller E, Cradock-Watson J, Bolley I, Ridehalgh M| title=Consequences of varicella and herpes zoster in pregnancy: prospective study of 1739 cases. | journal=Lancet | year= 1994 | volume= 343 | issue= 8912 | pages= 1548-51 | pmid=7802767 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7802767  }} </ref> Infants with milder symptoms can have a normal development and good [[prognosis]].<ref name="pmid6328456">{{cite journal| author=Kotchmar GS, Grose C, Brunell PA| title=Complete spectrum of the varicella congenital defects syndrome in 5-year-old child. | journal=Pediatr Infect Dis | year= 1984 | volume= 3 | issue= 2 | pages= 142-5 | pmid=6328456 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6328456  }} </ref><ref name="pmid11113846">{{cite journal| author=Schulze A, Dietzsch HJ| title=The natural history of varicella embryopathy: a 25-year follow-up. | journal=J Pediatr | year= 2000 | volume= 137 | issue= 6 | pages= 871-4 | pmid=11113846 | doi=10.1067/mpd.2000.109005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11113846  }} </ref>


===Complications===
===Complications===
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*Primary infection in the mother presents with [[fever]], [[malaise]] and a [[maculopapular]] skin rash in the beginning which becomes [[vesicular]] and crust over with healing.<ref name="pmid8533407">{{cite journal| author=Katz VL, Kuller JA, McMahon MJ, Warren MA, Wells SR| title=Varicella during pregnancy. Maternal and fetal effects. | journal=West J Med | year= 1995 | volume= 163 | issue= 5 | pages= 446-50 | pmid=8533407 | doi= | pmc=1303168 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8533407  }} </ref>
*Primary infection in the mother presents with [[fever]], [[malaise]] and a [[maculopapular]] skin rash in the beginning which becomes [[vesicular]] and crust over with healing.<ref name="pmid8533407">{{cite journal| author=Katz VL, Kuller JA, McMahon MJ, Warren MA, Wells SR| title=Varicella during pregnancy. Maternal and fetal effects. | journal=West J Med | year= 1995 | volume= 163 | issue= 5 | pages= 446-50 | pmid=8533407 | doi= | pmc=1303168 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8533407  }} </ref>
'''Symptoms in the Neonate'''
'''Symptoms in the Neonate'''
*[[Skin Rash]]<ref name="pmid17180380">{{cite journal| author=Sauerbrei A, Wutzler P| title=Herpes simplex and varicella-zoster virus infections during pregnancy: current concepts of prevention, diagnosis and therapy. Part 2: Varicella-zoster virus infections. | journal=Med Microbiol Immunol | year= 2007 | volume= 196 | issue= 2 | pages= 95-102 | pmid=17180380 | doi=10.1007/s00430-006-0032-z | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17180380  }} </ref>
*[[Skin rash]]<ref name="pmid17180380">{{cite journal| author=Sauerbrei A, Wutzler P| title=Herpes simplex and varicella-zoster virus infections during pregnancy: current concepts of prevention, diagnosis and therapy. Part 2: Varicella-zoster virus infections. | journal=Med Microbiol Immunol | year= 2007 | volume= 196 | issue= 2 | pages= 95-102 | pmid=17180380 | doi=10.1007/s00430-006-0032-z | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17180380  }} </ref>
*Shortened hands and legs with malformed fingers
*Shortened hands and legs with malformed fingers
*Cloudiness of the [[cornea]]<ref name="pmid8540940">{{cite journal| author=Andreou A, Basiakos H, Hatzikoumi I, Lazarides A| title=Fetal varicella syndrome with manifestations limited to the eye. | journal=Am J Perinatol | year= 1995 | volume= 12 | issue= 5 | pages= 347-8 | pmid=8540940 | doi=10.1055/s-2007-994493 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8540940  }} </ref>
*Cloudiness of the [[cornea]]<ref name="pmid8540940">{{cite journal| author=Andreou A, Basiakos H, Hatzikoumi I, Lazarides A| title=Fetal varicella syndrome with manifestations limited to the eye. | journal=Am J Perinatol | year= 1995 | volume= 12 | issue= 5 | pages= 347-8 | pmid=8540940 | doi=10.1055/s-2007-994493 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8540940  }} </ref>
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!'''History'''
!'''History'''
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*Positive history for [[varicella]] infection during the [[period of gestation]]                                                                                                               
*Positive history for [[varicella]] infection during the period of [[gestation]]                                                                                                               
|-
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!'''Fetus / Neonatal Findings'''
!'''Fetus / Neonatal Findings'''
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*Direct fluroscent [[antigen]] staining with [[monoclonal]] [[antibodies]] detects the [[VZV]] glycoproteins in the cells.
*Direct fluroscent [[antigen]] staining with [[monoclonal]] [[antibodies]] detects the [[VZV]] glycoproteins in the cells.
*[[PCR]] for [[VZV]] [[DNA]]  
*[[PCR]] for [[VZV]] [[DNA]]  
*[[Serological]] tests are not useful for the dectection of primary infection in the [[mother]] as it takes time for the [[IgG]] antibodies to be produced aganist [[VZV]].
*[[Serological]] tests are not useful for the dectection of primary infection in the mother as it takes time for the [[IgG]] antibodies to be produced aganist [[VZV]].
'''Prenatal Diagnosis'''
'''Prenatal Diagnosis'''
*Sequential [[ultrasound]] of the [[fetus]] is helpful to establish the presence of [[varicella]] infection and assess the severity of intrauterine infection.<ref name="pmid10215075">{{cite journal| author=Hartung J, Enders G, Chaoui R, Arents A, Tennstedt C, Bollmann R| title=Prenatal diagnosis of congenital varicella syndrome and detection of varicella-zoster virus in the fetus: a case report. | journal=Prenat Diagn | year= 1999 | volume= 19 | issue= 2 | pages= 163-6 | pmid=10215075 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10215075  }} </ref><ref name="pmid16601342">{{cite journal| author=Meyberg-Solomayer GC, Fehm T, Muller-Hansen I, Enders G, Poets C, Wallwiener D et al.| title=Prenatal ultrasound diagnosis, follow-up, and outcome of congenital varicella syndrome. | journal=Fetal Diagn Ther | year= 2006 | volume= 21 | issue= 3 | pages= 296-301 | pmid=16601342 | doi=10.1159/000091360 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16601342  }} </ref>
*Sequential [[ultrasound]] of the [[fetus]] is helpful to establish the presence of [[varicella]] infection and assess the severity of intrauterine infection.<ref name="pmid10215075">{{cite journal| author=Hartung J, Enders G, Chaoui R, Arents A, Tennstedt C, Bollmann R| title=Prenatal diagnosis of congenital varicella syndrome and detection of varicella-zoster virus in the fetus: a case report. | journal=Prenat Diagn | year= 1999 | volume= 19 | issue= 2 | pages= 163-6 | pmid=10215075 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10215075  }} </ref><ref name="pmid16601342">{{cite journal| author=Meyberg-Solomayer GC, Fehm T, Muller-Hansen I, Enders G, Poets C, Wallwiener D et al.| title=Prenatal ultrasound diagnosis, follow-up, and outcome of congenital varicella syndrome. | journal=Fetal Diagn Ther | year= 2006 | volume= 21 | issue= 3 | pages= 296-301 | pmid=16601342 | doi=10.1159/000091360 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16601342  }} </ref>
*[[Amniocentesis]] should be performed 4 weeks after the primary infection in the mother, positive [[amniotic fluid]] [[PCR]] for [[VZV]] can establish the presence of infection in the amniotic fluid but does not provide evidence regarding the presence of infection or the severity of infection in the [[fetus]]. There is no established evidence to recommend [[amniocentesis]] for the diagnosis and is not performed on regular basis.<ref name="pmid9369842">{{cite journal| author=Mouly F, Mirlesse V, Méritet JF, Rozenberg F, Poissonier MH, Lebon P et al.| title=Prenatal diagnosis of fetal varicella-zoster virus infection with polymerase chain reaction of amniotic fluid in 107 cases. | journal=Am J Obstet Gynecol | year= 1997 | volume= 177 | issue= 4 | pages= 894-8 | pmid=9369842 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9369842  }} </ref>
*[[Amniocentesis]] should be performed 4 weeks after the primary infection in the mother, positive [[amniotic fluid]] [[PCR]] for [[VZV]] can establish the presence of infection in the [[amniotic fluid]] but does not provide evidence regarding the presence of infection or the severity of infection in the [[fetus]]. There is no established evidence to recommend [[amniocentesis]] for the diagnosis and is not performed on regular basis.<ref name="pmid9369842">{{cite journal| author=Mouly F, Mirlesse V, Méritet JF, Rozenberg F, Poissonier MH, Lebon P et al.| title=Prenatal diagnosis of fetal varicella-zoster virus infection with polymerase chain reaction of amniotic fluid in 107 cases. | journal=Am J Obstet Gynecol | year= 1997 | volume= 177 | issue= 4 | pages= 894-8 | pmid=9369842 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9369842  }} </ref>
*Presence of [[VZV]] [[IgM]] [[antibodies]] in [[fetal blood]].
*Presence of [[VZV]] [[IgM]] [[antibodies]] in [[fetal blood]].


===Imaging Studies===
===Imaging Studies===
====Ultrasound====
====Ultrasound====
*Sequential [[ultrasound]] in women with [[varicella]] infection during the [[period of gestation]] is the preffered diagnostic investigation to identify anomalies in the [[fetus]]. [[Ultrasound]] is usally done 4 weeks after the primary infection as earlier [[ultrasound]] might fail to detect anomalies. The findings suggestive of congenital varicella syndrome include limb deformities, [[microcephaly]] and [[hydrops]].  
*Sequential [[ultrasound]] in women with [[varicella]] infection during the period of gestation is the preffered diagnostic investigation to identify anomalies in the [[fetus]]. [[Ultrasound]] is usally done 4 weeks after the primary infection as early [[ultrasound]] might fail to detect anomalies. The findings suggestive of congenital varicella syndrome include limb deformities, [[microcephaly]] and [[hydrops]].  
*The following is a list of features that can be present in the fetus<ref name="pmid1337112">{{cite journal| author=Pretorius DH, Hayward I, Jones KL, Stamm E| title=Sonographic evaluation of pregnancies with maternal varicella infection. | journal=J Ultrasound Med | year= 1992 | volume= 11 | issue= 9 | pages= 459-63 | pmid=1337112 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1337112  }} </ref><ref name="pmid8994252">{{cite journal| author=Hofmeyr GJ, Moolla S, Lawrie T| title=Prenatal sonographic diagnosis of congenital varicella infection--a case report. | journal=Prenat Diagn | year= 1996 | volume= 16 | issue= 12 | pages= 1148-51 | pmid=8994252 | doi=10.1002/(SICI)1097-0223(199612)16:12<1148::AID-PD7>3.0.CO;2-J | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8994252  }} </ref>
*The following is a list of features that can be present in the fetus<ref name="pmid1337112">{{cite journal| author=Pretorius DH, Hayward I, Jones KL, Stamm E| title=Sonographic evaluation of pregnancies with maternal varicella infection. | journal=J Ultrasound Med | year= 1992 | volume= 11 | issue= 9 | pages= 459-63 | pmid=1337112 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1337112  }} </ref><ref name="pmid8994252">{{cite journal| author=Hofmeyr GJ, Moolla S, Lawrie T| title=Prenatal sonographic diagnosis of congenital varicella infection--a case report. | journal=Prenat Diagn | year= 1996 | volume= 16 | issue= 12 | pages= 1148-51 | pmid=8994252 | doi=10.1002/(SICI)1097-0223(199612)16:12<1148::AID-PD7>3.0.CO;2-J | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8994252  }} </ref>
**Cutaneous scars
**Cutaneous scars
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**[[Micropthalmia]] and congenital [[cataracts]]
**[[Micropthalmia]] and congenital [[cataracts]]
**Calcification in the [[brain]], [[spleen]] and [[liver]]<ref name="pmid9285750">{{cite journal| author=Rigsby CK, Donnelly LF| title=Fetal varicella syndrome: association with multiple hepatic calcifications and intestinal atresia. | journal=Pediatr Radiol | year= 1997 | volume= 27 | issue= 9 | pages= 779 | pmid=9285750 | doi=10.1007/s002470050229 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9285750  }} </ref>
**Calcification in the [[brain]], [[spleen]] and [[liver]]<ref name="pmid9285750">{{cite journal| author=Rigsby CK, Donnelly LF| title=Fetal varicella syndrome: association with multiple hepatic calcifications and intestinal atresia. | journal=Pediatr Radiol | year= 1997 | volume= 27 | issue= 9 | pages= 779 | pmid=9285750 | doi=10.1007/s002470050229 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9285750  }} </ref>
**Features of [[Hydrops fetalis]] such as [[skin edema]], [[hepatosplenomegaly]]
**Features of [[Hydrops fetalis]] such as skin edema, [[hepatosplenomegaly]]
**[[Colonic Atresia]]<ref name="pmid8523241">{{cite journal| author=Hitchcock R, Birthistle K, Carrington D, Calvert SA, Holmes K| title=Colonic atresia and spinal cord atrophy associated with a case of fetal varicella syndrome. | journal=J Pediatr Surg | year= 1995 | volume= 30 | issue= 9 | pages= 1344-7 | pmid=8523241 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8523241  }} </ref>
**Colonic atresia<ref name="pmid8523241">{{cite journal| author=Hitchcock R, Birthistle K, Carrington D, Calvert SA, Holmes K| title=Colonic atresia and spinal cord atrophy associated with a case of fetal varicella syndrome. | journal=J Pediatr Surg | year= 1995 | volume= 30 | issue= 9 | pages= 1344-7 | pmid=8523241 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8523241  }} </ref>
**[[Polyhydramnios]]
**[[Polyhydramnios]]
**[[Hydroureter]] and [[hydronephrosis]]
**Hydroureter and [[hydronephrosis]]


====MRI====
====MRI====
Line 274: Line 274:


===Medical Therapy===
===Medical Therapy===
*In patients with established infection early in the [[period of gestation]], regular follow up and [[ultrasound]] examination is recommended.<ref name="SauerbreiWutzler2006">{{cite journal|last1=Sauerbrei|first1=A.|last2=Wutzler|first2=P.|title=Herpes simplex and varicella-zoster virus infections during pregnancy: current concepts of prevention, diagnosis and therapy. Part 2: Varicella-zoster virus infections|journal=Medical Microbiology and Immunology|volume=196|issue=2|year=2006|pages=95–102|issn=0300-8584|doi=10.1007/s00430-006-0032-z}}</ref>
*In patients with established infection early in the period of [[gestation]], regular follow up and [[ultrasound]] examination is recommended.<ref name="SauerbreiWutzler2006">{{cite journal|last1=Sauerbrei|first1=A.|last2=Wutzler|first2=P.|title=Herpes simplex and varicella-zoster virus infections during pregnancy: current concepts of prevention, diagnosis and therapy. Part 2: Varicella-zoster virus infections|journal=Medical Microbiology and Immunology|volume=196|issue=2|year=2006|pages=95–102|issn=0300-8584|doi=10.1007/s00430-006-0032-z}}</ref>
*[[Termination]] of [[pregnancy]] is indicated in cases with the presence of definitive signs of congenital varicella infection.
*[[Termination]] of [[pregnancy]] is indicated in cases with the presence of definitive signs of congenital varicella infection.
*There is insufficient evidence regarding the prevention of transmission and treatment of congenital varicella syndrome with [[IgG]] [[immunoglobulins]] and [[acyclovir]].<ref name="pmid15979274">{{cite journal| author=Tan MP, Koren G| title=Chickenpox in pregnancy: revisited. | journal=Reprod Toxicol | year= 2006 | volume= 21 | issue= 4 | pages= 410-20 | pmid=15979274 | doi=10.1016/j.reprotox.2005.04.011 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15979274  }} </ref>
*There is insufficient evidence regarding the prevention of transmission and treatment of congenital varicella syndrome with [[IgG]] [[immunoglobulins]] and [[acyclovir]].<ref name="pmid15979274">{{cite journal| author=Tan MP, Koren G| title=Chickenpox in pregnancy: revisited. | journal=Reprod Toxicol | year= 2006 | volume= 21 | issue= 4 | pages= 410-20 | pmid=15979274 | doi=10.1016/j.reprotox.2005.04.011 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15979274  }} </ref>
*Varicella infection doesnot progress [[postnatally]], so treatment with [[acyclovir]] is not indicated.<ref name="HarishJamwal2009">{{cite journal|last1=Harish|first1=Rekha|last2=Jamwal|first2=Ashu|last3=Dang|first3=Ketan|title=Congenital varicella syndrome/ vericella zoster virus VZV fetopathy|journal=The Indian Journal of Pediatrics|volume=77|issue=1|year=2009|pages=92–93|issn=0019-5456|doi=10.1007/s12098-009-0259-y}}</ref>
*Varicella infection doesnot progress postnatally, so treatment with [[acyclovir]] is not indicated.<ref name="HarishJamwal2009">{{cite journal|last1=Harish|first1=Rekha|last2=Jamwal|first2=Ashu|last3=Dang|first3=Ketan|title=Congenital varicella syndrome/ vericella zoster virus VZV fetopathy|journal=The Indian Journal of Pediatrics|volume=77|issue=1|year=2009|pages=92–93|issn=0019-5456|doi=10.1007/s12098-009-0259-y}}</ref>
*[[Isolation]] is recommended in patients with active skin lesions.
*Isolation is recommended in patients with active skin lesions.


===Surgical Therapy===
===Surgical Therapy===
Line 291: Line 291:
*In [[pregnant]] [[women]] with [[negative]] [[IgG]], counseling regarding the risks of [[varicella]] infection and education regarding the measures to avoid contact with [[varicella]] are recommended as [[vaccination]] aganist [[VZV]] is contraindicated during the [[pregnancy]].
*In [[pregnant]] [[women]] with [[negative]] [[IgG]], counseling regarding the risks of [[varicella]] infection and education regarding the measures to avoid contact with [[varicella]] are recommended as [[vaccination]] aganist [[VZV]] is contraindicated during the [[pregnancy]].
*Women who are [[seronegative]] should recieve two doses of the [[vaccine]] during the [[postpartum]] period 4 to 8 weeks apart with no effect on [[breast feeding]].
*Women who are [[seronegative]] should recieve two doses of the [[vaccine]] during the [[postpartum]] period 4 to 8 weeks apart with no effect on [[breast feeding]].
*Women can be [[vaccinated]] during the [[preconception]] period, but are adviced to avoid conceiving for a month after the last dose of the [[vaccine]].
*Women can be [[vaccinated]] during the preconception period, but are adviced to avoid conceiving for a month after the last dose of the [[vaccine]].


===Secondary Prevention===
===Secondary Prevention===

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

Synonyms and keywords: Fetal varicella syndrome, Congenital varicella-zoster syndrome, Varicella embryo-fetopathy, Varicella embryopathy, Varicella fetopathy, Fetal varicella-zoster syndrome

Overview

Congenital varicella syndrome is a rare disease resulting from Varicella Zoster virus(VZV) infection during the period of gestation. Viremia during the primary infection can result in transplacental transmission of the infection to the developing fetus. An estimated 25% of fetuses get infected with varicella infection when mother has a varicella infection during thepregnancy but the risk of developing congenital varicella syndrome is around 2%, therefore majority of the outcomes are normal newborns. Patients with primary infection before 20 weeks of gestation are at a higher risk of developing the severe form of infection, affecting the eyes, limbs, skin and the central nervous system. Diagnosis requires a documented history of primary infection in the mother and serial ultrasound demonstrating features suggestive of congenital varicella syndrome. There is no definitive treatment, termination of pregnancy in fetuses with severe features is recommended. Vaccination to prevent maternal varicella infection and proper counseling to avoid contact with infected people are important for the management options to reduce the incidence of congenital varicella syndrome.

Historical Perspective

Classification

There is no classification for congenital varicella syndrome.

Pathophysiology

Pathogenesis

Epidemiology and Demographics

Congenital varicella syndrome is a rare disease with over a 100 cases reported in literature.[11]

Causes

Congenital varicella syndrome is caused by Varicella zoster virus (VZV), a human alpha herpes virus.

Differentiating Congenital Varicella Syndrome From Other Diseases

The most important congenital infections, which can be transmitted vertically from mother to fetus are the TORCH infections. These infections have overlapping features and hence, must be differentiated from congenital varicella syndrome:[12][13]

Congenital Infection Cardiac Findings Skin Findings Ocular Findings Hepatosplenomegaly Hydrocephalus Microcephaly Intracranial calcifications Hearing deficits
Congenital Varicella syndrome -
  • Cicatrical Skin Lesions
  • Skin edema
Toxoplasmosis Diffuse intracranial calcifications
Congenital Syphillis
Rubella
Cytomegalovirus (CMV) Periventricular calcifications
Herpes simplex virus (HSV)
Parvovirus B19

Natural History, Prognosis and Complications

Natural History

VZV infection during pregnancy results in a normal newborn birth in majority of the patients, however, in a few patients it can result in congenital varicella syndrome or neonatal varicella or clinical zoster during infancy, the outcomes are dependent on the gestational age of fetus at the time of infection. Early gestational period infection via the transplacental route can result in congenital varicella syndrome resulting in a misscarriage, abortion or a newborn with features affecting the limbs, eyes, central nervous system, autonomic nervous system and present with features such as low birth weight, cutaneous scarring, limb hypoplasia, microcephaly, cortical atrophy, chorioretinitis and cataracts.[14][15]

Prognosis

Severe infection of the fetus can result in an abortion. Infants born with signs of congenital varicella syndrome have poor prognosis and die during the first few months of life.[16][14] Infants with milder symptoms can have a normal development and good prognosis.[17][18]

Complications

Congenital varicella infection can result in the following complications:[19]

Diagnosis

History and Symptoms

Symptoms of primary infection in Mother :

Symptoms in the Neonate

Physical Examination

Physical examination findings suggestive of congenital varicella syndrome include:[24][25]

Physical examination findings in congenital varicella syndrome
Skin
  • Cicatricial lesions( Zig-Zag scarring in dermatomal distribution)[26]
  • Hypopigmentation
Eye
Central Nervous System
Musculoskeletal system
  • Limb hypoplasia
  • Muscle hypoplasia
Systemic Manifestations

Table adopted from varicella in fetus and newborn[30]

Laboratory Findings

The diagnosis of congenital varicella syndrome is based on a documented history of varicella infection during the pregnancy and the presence of fetal manifestations on ultrasound.[31]

Key findings for diagnosis of congenital varicella syndrome
History
Fetus / Neonatal Findings
  • Presence of characteristic cicatrical skin lesions, eye lesions, neurological deficits, limb abnormalities
Proof of Intrauterine Varicella infection

Table adopted from Herpes simplex and varicella-zoster virus infections during pregnancy: current concepts of prevention, diagnosis and therapy. Part 2: Varicella-zoster virus infections[32]

Diagnosis of primary infection in the mother : In pregnant women diagnosis of a primary infection requires a combination of clinical manifestations and series of diagnostic tests. The tests are performed on the samples from the vesicular skin lesions and include the following:

  • Culture for VZV, but takes 10 to 12 days to obtain the results.
  • Direct fluroscent antigen staining with monoclonal antibodies detects the VZV glycoproteins in the cells.
  • PCR for VZV DNA
  • Serological tests are not useful for the dectection of primary infection in the mother as it takes time for the IgG antibodies to be produced aganist VZV.

Prenatal Diagnosis

Imaging Studies

Ultrasound

MRI

Prenatal MRI is a useful investigation to assess the extent of CNS involvement and to confirm the findings of ultrasound.[39]

Postnatal Diagnosis

Treatment

Medical Therapy

  • In patients with established infection early in the period of gestation, regular follow up and ultrasound examination is recommended.[32]
  • Termination of pregnancy is indicated in cases with the presence of definitive signs of congenital varicella infection.
  • There is insufficient evidence regarding the prevention of transmission and treatment of congenital varicella syndrome with IgG immunoglobulins and acyclovir.[6]
  • Varicella infection doesnot progress postnatally, so treatment with acyclovir is not indicated.[41]
  • Isolation is recommended in patients with active skin lesions.

Surgical Therapy

There are no surgical therapies for treatment of congenital varicella syndrome.

Prevention

Primary Prevention

Secondary Prevention

References

  1. Laforet, Eugene G.; Lynch, Charles L. (1947). "Multiple Congenital Defects Following Maternal Varicella". New England Journal of Medicine. 236 (15): 534–537. doi:10.1056/NEJM194704102361504. ISSN 0028-4793.
  2. McKendry JB, Bailey JD (1973). "Congenital varicella associated with multiple defects". Can Med Assoc J. 108 (1): 66–8. PMC 1941110. PMID 4682642.
  3. Paryani, Sharon G.; Arvin, Ann M. (1986). "Intrauterine Infection with Varicella-Zoster Virus after Maternal Varicella". New England Journal of Medicine. 314 (24): 1542–1546. doi:10.1056/NEJM198606123142403. ISSN 0028-4793.
  4. Brice JE (1976). "Congenital varicella resulting from infection during second trimester of pregnancy". Arch Dis Child. 51 (6): 474–6. PMC 1546018. PMID 942245.
  5. Pastuszak, Anne L.; Levy, Maurice; Schick, Betsy; Zuber, Carol; Feldkamp, Marcia; Gladstone, Johnathan; Bar-Levy, Fanny; Jackson, Elaine; Donnenfeld, Alan; Meschino, Wendy; Koren, Gideon (1994). "Outcome after Maternal Varicella Infection in the First 20 Weeks of Pregnancy". New England Journal of Medicine. 330 (13): 901–905. doi:10.1056/NEJM199403313301305. ISSN 0028-4793.
  6. 6.0 6.1 Tan MP, Koren G (2006). "Chickenpox in pregnancy: revisited". Reprod Toxicol. 21 (4): 410–20. doi:10.1016/j.reprotox.2005.04.011. PMID 15979274.
  7. Higa K, Dan K, Manabe H (1987). "Varicella-zoster virus infections during pregnancy: hypothesis concerning the mechanisms of congenital malformations". Obstet Gynecol. 69 (2): 214–22. PMID 3027637.
  8. Grose C (1989). "Congenital varicella-zoster virus infection and the failure to establish virus-specific cell-mediated immunity". Mol Biol Med. 6 (5): 453–62. PMID 2560525.
  9. Nikkels AF, Delbecque K, Pierard GE, Wienkotter B, Schalasta G, Enders M (2005). "Distribution of varicella-zoster virus DNA and gene products in tissues of a first-trimester varicella-infected fetus". J Infect Dis. 191 (4): 540–5. doi:10.1086/426942. PMID 15655777.
  10. 10.0 10.1 Rigsby CK, Donnelly LF (1997). "Fetal varicella syndrome: association with multiple hepatic calcifications and intestinal atresia". Pediatr Radiol. 27 (9): 779. doi:10.1007/s002470050229. PMID 9285750.
  11. Satti, Komal Fayyaz; Ali, Syed Asad; Weitkamp, Jörn-Hendrik (2010). "Congenital Infections, Part 2: Parvovirus, Listeria, Tuberculosis, Syphilis, and Varicella". NeoReviews. 11 (12): e681–e695. doi:10.1542/neo.11-12-e681. ISSN 1526-9906.
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  13. Ajij M, Nangia S, Dubey BS (2014). "Congenital rubella syndrome with blueberry muffin lesions and extensive metaphysitis". J Clin Diagn Res. 8 (12): PD03–4. doi:10.7860/JCDR/2014/10271.5293. PMC 4316306. PMID 25654000.
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  17. Kotchmar GS, Grose C, Brunell PA (1984). "Complete spectrum of the varicella congenital defects syndrome in 5-year-old child". Pediatr Infect Dis. 3 (2): 142–5. PMID 6328456.
  18. Schulze A, Dietzsch HJ (2000). "The natural history of varicella embryopathy: a 25-year follow-up". J Pediatr. 137 (6): 871–4. doi:10.1067/mpd.2000.109005. PMID 11113846.
  19. Savage MO, Moosa A, Gordon RR (1973). "Maternal varicella infection as a cause of fetal malformations". Lancet. 1 (7799): 352–4. PMID 4121940.
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  21. Sauerbrei A, Wutzler P (2007). "Herpes simplex and varicella-zoster virus infections during pregnancy: current concepts of prevention, diagnosis and therapy. Part 2: Varicella-zoster virus infections". Med Microbiol Immunol. 196 (2): 95–102. doi:10.1007/s00430-006-0032-z. PMID 17180380.
  22. Andreou A, Basiakos H, Hatzikoumi I, Lazarides A (1995). "Fetal varicella syndrome with manifestations limited to the eye". Am J Perinatol. 12 (5): 347–8. doi:10.1055/s-2007-994493. PMID 8540940.
  23. Alexander I (1979). "Congenital varicella". Br Med J. 2 (6197): 1074. PMC 1596860. PMID 519294.
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  25. Mendívil A, Mendívil MP, Cuartero V (1992). "Ocular manifestations of the congenital varicella-zoster syndrome". Ophthalmologica. 205 (4): 191–3. PMID 1336591.
  26. Lloyd KM (1990). "Skin lesions as the sole manifestation of the fetal varicella syndrome". Arch Dermatol. 126 (4): 546–7. PMID 2322006.
  27. Charles NC, Bennett TW, Margolis S (1977). "Ocular pathology of the congenital varicella syndrome". Arch Ophthalmol. 95 (11): 2034–7. PMID 411463.
  28. Cotlier E (1978). "Congenital varicella cataract". Am J Ophthalmol. 86 (5): 627–9. PMID 717518.
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  30. Smith, Candice K.; Arvin, Ann M. (2009). "Varicella in the fetus and newborn". Seminars in Fetal and Neonatal Medicine. 14 (4): 209–217. doi:10.1016/j.siny.2008.11.008. ISSN 1744-165X.
  31. Scharf A, Scherr O, Enders G, Helftenbein E (1990). "Virus detection in the fetal tissue of a premature delivery with a congenital varicella syndrome. A case report". J Perinat Med. 18 (4): 317–22. PMID 2175786.
  32. 32.0 32.1 Sauerbrei, A.; Wutzler, P. (2006). "Herpes simplex and varicella-zoster virus infections during pregnancy: current concepts of prevention, diagnosis and therapy. Part 2: Varicella-zoster virus infections". Medical Microbiology and Immunology. 196 (2): 95–102. doi:10.1007/s00430-006-0032-z. ISSN 0300-8584.
  33. Hartung J, Enders G, Chaoui R, Arents A, Tennstedt C, Bollmann R (1999). "Prenatal diagnosis of congenital varicella syndrome and detection of varicella-zoster virus in the fetus: a case report". Prenat Diagn. 19 (2): 163–6. PMID 10215075.
  34. Meyberg-Solomayer GC, Fehm T, Muller-Hansen I, Enders G, Poets C, Wallwiener D; et al. (2006). "Prenatal ultrasound diagnosis, follow-up, and outcome of congenital varicella syndrome". Fetal Diagn Ther. 21 (3): 296–301. doi:10.1159/000091360. PMID 16601342.
  35. Mouly F, Mirlesse V, Méritet JF, Rozenberg F, Poissonier MH, Lebon P; et al. (1997). "Prenatal diagnosis of fetal varicella-zoster virus infection with polymerase chain reaction of amniotic fluid in 107 cases". Am J Obstet Gynecol. 177 (4): 894–8. PMID 9369842.
  36. Pretorius DH, Hayward I, Jones KL, Stamm E (1992). "Sonographic evaluation of pregnancies with maternal varicella infection". J Ultrasound Med. 11 (9): 459–63. PMID 1337112.
  37. Hofmeyr GJ, Moolla S, Lawrie T (1996). "Prenatal sonographic diagnosis of congenital varicella infection--a case report". Prenat Diagn. 16 (12): 1148–51. doi:10.1002/(SICI)1097-0223(199612)16:12<1148::AID-PD7>3.0.CO;2-J. PMID 8994252.
  38. Hitchcock R, Birthistle K, Carrington D, Calvert SA, Holmes K (1995). "Colonic atresia and spinal cord atrophy associated with a case of fetal varicella syndrome". J Pediatr Surg. 30 (9): 1344–7. PMID 8523241.
  39. Verstraelen H, Vanzieleghem B, Defoort P, Vanhaesebrouck P, Temmerman M (2003). "Prenatal ultrasound and magnetic resonance imaging in fetal varicella syndrome: correlation with pathology findings". Prenat Diagn. 23 (9): 705–9. doi:10.1002/pd.669. PMID 12975778.
  40. Gershon AA, Raker R, Steinberg S, Topf-Olstein B, Drusin LM (1976). "Antibody to Varicella-Zoster virus in parturient women and their offspring during the first year of life". Pediatrics. 58 (5): 692–6. PMID 185578.
  41. Harish, Rekha; Jamwal, Ashu; Dang, Ketan (2009). "Congenital varicella syndrome/ vericella zoster virus VZV fetopathy". The Indian Journal of Pediatrics. 77 (1): 92–93. doi:10.1007/s12098-009-0259-y. ISSN 0019-5456.
  42. "Prevention of Varicella: Recommendations of the Advisory Committee on Immunization Practices (ACIP)".
  43. Shrim A, Koren G, Yudin MH, Farine D, Maternal Fetal Medicine Committee (2012). "Management of varicella infection (chickenpox) in pregnancy". J Obstet Gynaecol Can. 34 (3): 287–92. PMID 22385673.
  44. Cohen A, Moschopoulos P, Maschopoulos P, Stiehm RE, Koren G (2011). "Congenital varicella syndrome: the evidence for secondary prevention with varicella-zoster immune globulin". CMAJ. 183 (2): 204–8. doi:10.1503/cmaj.100615. PMC 3033924. PMID 21262937.