Abnormal Development - Cytomegalovirus

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P35.1 Congenital cytomegalovirus infection

International Classification of Diseases: P35 Congenital viral diseases | XVI Perinatal Period
Viral Links: TORCH Infections | Cytomegalovirus | Hepatitis Virus | HIV | Parvovirus | Polio Virus | Rubella Virus | Chickenpox | Lymphocytic Choriomeningitis Virus | Zika Virus | Vaccination | Environmental

Introduction

Cytomegalovirus infected spermatozoon[1]

Human cytomegalovirus (HCMV, Greek, cyto = "cell", megalo = "large") or Human Herpesvirus 5 (HHV-5) is a member of the herpes virus family. A viral infection that causes systemic infection and extensive brain damage and cell death by necrosis. Cytomegalovirus is the leading cause of congenital viral infection, with a range of incidence between 0·5–3% of live births worldwide. Approximately 30% of maternal infections during pregnancy can result in congenital infection. Neonates with congenital or perinatal cytomegalovirus infection can be asymptomatic and infection can also be transmitted postnatally from mother to infant by breastfeeding.


HCMV infection is ranked as one of the most common infections in adults, with the seropositive rates ranging from 60–99% globally. In Western countries, adults with advanced AIDS prior to the introduction of highly active antiretroviral therapy (HAART) this virus also a cause of blindness (CMV retinitis) and death in patients.


Congenital cytomegalovirus infection is also a cause of non-hereditary congenital sensorineural hearing loss.[2]


CDC Congenital abnormality graph.jpg

Some Recent Findings

Human cytomegalovirus beta-catenin juxtanuclear region[3]
  • Congenital Cytomegalovirus Infection in the Absence of Maternal Cytomegalovirus-IgM Antibodies[4]

"Congenital cytomegalovirus (cCMV) infections are the most prevalent intrauterine infections worldwide and are the result of maternal primary or non-primary infections. Early maternal primary infections are thought to carry the highest risk of fetal developmental abnormalities as seen by ultrasound; however, non-primary infections may prove equally detrimental. METHODS/RESULTS: This case series presents 5 cases with fetal abnormalities detected in the second and third trimester, in which cCMV infection was ruled out due to negative maternal CMV-IgM. DISCUSSION: This series highlights the possible pitfalls in serology interpretation and fetal diagnosis necessary for appropriate parental counseling. Once fetal abnormalities have been confirmed and cCMV is suspected, maternal CMV serostatus and fetal infection should be determined. Maternal CMV serology may be ambiguous; therefore, caution should be exercised when interpreting the results."

  • Prenatal diagnosis of congenital cytomegalovirus infection in 115 cases: a 5 years' single center experience[5] "The objective of this study is to investigate the diagnostic value of invasive prenatal diagnosis (PD) of congenital cytomegalovirus (CMV) infection from amniotic fluid (AF) and fetal blood (FB). A retrospective study was conducted on 115 pregnancies with CMV primary infection. A total of 111 AF and 106 FB samples were investigated for various virological and non-virological markers. Detailed ultrasound examinations were performed at time of PD. Overall sensitivity of CMV PCR in FB (75.6%; 95%CI 60-87) and AF (72.7%; 95%CI 57-85) was comparable. In women with amniocentesis >8  weeks between seroconversion and PD, we did not observe significant differences between amniocentesis performed ≥17 + 0 (sensitivity 90.9%; 95%CI 71-99) and ≥20 + 0 gestational weeks (sensitivity 90.0%; 95%CI 68-99). Virological markers in FB were higher in symptomatic compared with asymptomatic fetuses (p < 0.05). ...Optimal timing of amniocentesis in women with primary infection in early gestation should be reevaluated in a prospective study. Analysis of FB markers may be beneficial in the individual management of pregnant women with confirmed congenital CMV infection."
  • Clinical Implications for Children Born With Congenital Cytomegalovirus Infection Following a Negative Amniocentesis[6] "Recently, congenital cytomegalovirus (cCMV) infection was reported irrespective of a negative amniotic fluid prenatal analysis for cytomegalovirus (CMV). The question of whether this phenomenon represents low sensitivity of the test or late development of fetal infection (after amniocentesis) was discussed, but not answered. However, if late transmission is the rule, then infants born with cCMV after negative amniocentesis would be expected to carry better prognosis than those who tested positive. Data of all infants with cCMV infection, followed in 2 pediatric centers from 2006 to 2015, were reviewed. Infant outcome after birth of symptomatic vs asymptomatic disease was compared with infants born after a negative amniocentesis (study group) and those with a positive amniocentesis (control group).Amniocentesis was performed in 301 pregnancies of our cohort of infants with cCMV and was negative for CMV in 47 (15.6%). There were fewer symptomatic cCMV neonates in the study group than in the control group (4.3% vs 25%; P < .001). Hearing impairment at birth was also less frequent in the study group (2.2% vs 17.4%; P = .012). None of the children in the study group had neurologic sequelae at long-term follow up, compared with 13 (14.1%) in the control group (P < .001). Although negative amniocentesis does not exclude cCMV, infants with cCMV born after a negative amniocentesis seldom present with mild clinical symptoms or cerebral ultrasound features at birth. These children also have a very good long-term outcome. Our findings support the theory of a late development of fetal infection, after the time of the amniocentesis."
  • Neuro-Imaging Findings in Infants with Congenital Cytomegalovirus Infection: Relation to Trimester of Infection[7] "Demographic and clinical data were collected in infants with cCMV infection (1992-2013). Trimester of infection, neuro-imaging results and outcome were reviewed. Cerebral abnormalities were categorized into none, mild (lenticulostriate vasculopathy, germinolytic cysts, high signal intensity on T2-weighted images) and severe (migrational disorder, ventriculomegaly, cerebellar hypoplasia). Results were statistically analysed. RESULTS: Thirty-six infants were eligible for analysis. cUS was performed in all and cranial MRI in 20 infants. Migrational disorders were only diagnosed using MRI (p < 0.01). In 17 infants trimester of infection was ascertained. Seven out of 10 infants infected during the first trimester had severe abnormalities on cUS (5 confirmed on MRI) and adverse sequelae; 3 had no/mild abnormalities on cUS/MRI and normal outcome. Two out of 3 infants infected during the second trimester with no/mild abnormalities on cUS/MRI had normal outcome; 1 with mild cUS and MRI abnormalities developed sensorineural hearing loss. Four infants infected during the third trimester with no/mild abnormalities on cUS/MRI had normal outcome. CONCLUSION: Infants with a first trimester cCMV infection are most at risk of severe cerebral abnormalities and neurological sequelae. MRI, and not cUS, enables an early diagnosis of migrational disorders, which can improve prediction of outcome."
More recent papers  
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This table shows an automated computer PubMed search using the listed sub-heading term.

  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in this list based upon the date of the actual page viewing.

References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

Links: References | Discussion Page | Pubmed Most Recent | Journal Searches


Search term: Abnormal Development Cytomegalovirus

Mathilde Letouzey, Alexandra Chadie, Marie Brasseur-Daudruy, François Proust, Eric Verspyck, Pascal Boileau, Stéphane Marret Severe Apparently Isolated Fetal Ventriculomegaly And Neurodevelopmental Outcome. Prenat. Diagn.: 2017; PubMed 28622418

Dasol Han, Sung-Hyun Byun, Juwan Kim, Mookwang Kwon, Samuel J Pleasure, Jin-Hyun Ahn, Keejung Yoon Human cytomegalovirus IE2 protein disturbs brain development by dysregulating neural stem cell maintenance and the polarization of migrating neurons. J. Virol.: 2017; PubMed 28615204

Haruo Yoshida, Haruo Takahashi, Yukihiko Kanda, Kyoko Kitaoka, Minoru Hara Long-term Outcomes of Cochlear Implantation in Children With Congenital Cytomegalovirus Infection. Otol. Neurotol.: 2017; PubMed 28604578

Przemyslaw Zdziarski, Andrzej Gamian, Grzegorz Dworacki A case report of lymphoid intestitial pneumonia in common variable immunodeficiency: Oligoclonal expansion of effector lymphocytes with preferential cytomegalovirus-specific immune response and lymphoproliferative disease promotion. Medicine (Baltimore): 2017, 96(23);e7031 PubMed 28591035

Older papers  
  • Human fetal inner ear involvement in congenital cytomegalovirus infection[8] "Congenital cytomegalovirus (CMV) infection is a leading cause of sensorineural hearing loss (SNHL). ...CMV-infection of the marginal cell layer of the stria vascularis may alter potassium and ion circulation, dissipating the endocochlear potential with consequent SNHL. Although abnormal cerebral ultrasound is highly predictive of brain and inner ear damage, normal ultrasound findings cannot exclude them either." Hearing Abnormalities
  • Human Cytomegalovirus Infection Dysregulates the Canonical Wnt/β-catenin Signaling Pathway[3] "In this study, we demonstrate that HCMV dysregulates Wnt/β-catenin signaling in dermal fibroblasts and human placental extravillous trophoblasts. Infection inhibits Wnt-induced transcriptional activity of β-catenin and expression of β-catenin target genes in these cells. HCMV infection leads to β-catenin protein accumulation in a discrete juxtanuclear region. Levels of β-catenin in membrane-associated and cytosolic pools, as well as nuclear β-catenin, are reduced after infection; while transcription of the β-catenin gene is unchanged, suggesting enhanced degradation. Given the critical role of Wnt/β-catenin signaling in cellular processes, these findings represent a novel and important mechanism whereby HCMV disrupts normal cellular function."
  • A preliminary evaluation of safety and efficacy of standard intravenous immunoglobulins in pregnant women with primary Cytomegalovirus infection[9] "Hyperimmune globulins were reported to prevent and treat fetal CMV infection during pregnancy. Here we report that infusions of standard human intravenous immunoglobulin significantly increase CMV IgG titres and avidity indexes in pregnant women, paving the way to their use for passive transfer of maternal CMV humoral immunity to foetuses. Preliminary data on perinatal outcomes of the first 67 newborns are encouraging." ClinicalTrials.gov NCT01659684
  • Update on the prevention, diagnosis and management of cytomegalovirus infection during pregnancy[10] "Given the high risk of mother-fetus transmission and fetal damage, prenatal diagnosis is recommended to women with primary CMV infection contracted in the first half of pregnancy and in case of fetal abnormalities suggestive of infection. The correct interpretation of serological and virological tests followed by appropriate counselling by an expert physician is an effective tool to reduce the number of unnecessary pregnancy terminations by over 70% (Am J Obstet Gynecol 2007; 196: 221.e1)."

Cytomegalovirus Structure

  • double-stranded linear DNA virus
  • 235 Kb in size

Cytomegalovirus infected spermatozoa nucleus[1]

Cytomegalovirus infected spermatozoa EM01.jpg Cytomegalovirus virions EM.jpg
Full and empty viral capsids HCMV virions


Links: Genome | Sequence

Cytomegalovirus Detection

Cytomegalovirus Detection

Image shows human embryonic lung infected by cytomegalovirus demonstrated by an immunofluorescent technique. Viral infection causes systemic infection and extensive brain damage and cell death by necrosis.

A combination of tests has been used for prenatal diagnosis and there are some less reliable sonographic features to the infection.

  • maternal serum - specific immunoglobulin (IgM) antibodies
  • amniotic fluid - viral culture and PCR amplification of CMV DNA.

Cytomegalovirus History

  • 1921 - first to suggest that the "cytomegalia" could be due to a viral agent.
  • 1950 - demonstrated that infection may occur in utero.
  • 1956-57 - several groups independently isolate human CMV strains.
  • 1960 - the term "cytomegalovirus" introduced.


Cytomegalovirus Musculoskeletal

A mouse model of effects of cytomegalovirus infection on development has shown induction of micrognathia and other musculoskeletal abnormalities by impacting on signalling pathways, involving FN, NF-kappaB2, RelA, RelB, and Shh and Smad7 proteins. Cytomegalovirus induced micrognathia and abnormal skeletogenesis.jpg

Cytomegalovirus induced micrognathia and abnormal skeletogenesis in mouse model.[11]

Cytomegalovirus Placentitis

Clinical term for the cytomegalovirus infection of the placenta.

A earlier histological study[12] identified fixed connective tissue cells predominantly infected cell type in placental tissue. In addition, endothelial cells, macrophages and in some cases trophoblast infection. While a more recent in vitro study[13] suggests that all villi cell types are likely to be infected.

References

  1. 1.0 1.1 Victor A Naumenko, Yurii A Tyulenev, Sergei A Yakovenko, Lubov' F Kurilo, Ludmila V Shileyko, Aleksander S Segal, Larisa E Zavalishina, Regina R Klimova, Anton S Tsibizov, Sergei V Alkhovskii, Alla A Kushch Detection of human cytomegalovirus in motile spermatozoa and spermatogenic cells in testis organotypic culture. Herpesviridae: 2011, 2(1);7 PubMed 21711549 | Herpesviridae.
  2. Natacha Teissier, Anne-Lise Delezoide, Anne-Elisabeth Mas, Suonavy Khung-Savatovsky, Bettina Bessières, Jeannette Nardelli, Christelle Vauloup-Fellous, Olivier Picone, Nadira Houhou, Jean-François Oury, Thierry Van Den Abbeele, Pierre Gressens, Homa Adle-Biassette Inner ear lesions in congenital cytomegalovirus infection of human fetuses. Acta Neuropathol.: 2011, 122(6);763-74 PubMed 22033878
  3. 3.0 3.1 Magdalena Angelova, Kevin Zwezdaryk, MaryBeth Ferris, Bin Shan, Cindy A Morris, Deborah E Sullivan Human cytomegalovirus infection dysregulates the canonical Wnt/β-catenin signaling pathway. PLoS Pathog.: 2012, 8(10);e1002959 PubMed 23071438 | PLoS Pathog.
  4. Julia Gunkel, Bloeme J van der Knoop, Joppe Nijman, Linda S de Vries, Gwendolyn T R Manten, Peter G J Nikkels, Jean-Luc Murk, Johanna I P de Vries, Tom F W Wolfs Congenital Cytomegalovirus Infection in the Absence of Maternal Cytomegalovirus-IgM Antibodies. Fetal. Diagn. Ther.: 2017; PubMed 28259882
  5. M Enders, A Daiminger, S Exler, K Ertan, G Enders, R Bald Prenatal diagnosis of congenital cytomegalovirus infection in 115 cases: a 5 years' single centre experience. Prenat. Diagn.: 2017; PubMed 28207161
  6. Efraim Bilavsky, Joseph Pardo, Joseph Attias, Itzhak Levy, Jean-François Magny, Yves Ville, Marianne Leruez-Ville, Jacob Amir Clinical Implications for Children Born with Congenital Cytomegalovirus Infection Following a Negative Amniocentesis. Clin. Infect. Dis.: 2016; PubMed 27114380
  7. Natanja Oosterom, Joppe Nijman, Julia Gunkel, Tom F W Wolfs, Floris Groenendaal, Malgosia A Verboon-Maciolek, Linda S de Vries Neuro-Imaging Findings in Infants with Congenital Cytomegalovirus Infection: Relation to Trimester of Infection. Neonatology: 2015, 107(4);289-296 PubMed 25790782
  8. Liliana Gabrielli, Maria Paola Bonasoni, Donatella Santini, Giulia Piccirilli, Angela Chiereghin, Brunella Guerra, Maria Paola Landini, Maria Grazia Capretti, Marcello Lanari, Tiziana Lazzarotto Human fetal inner ear involvement in congenital cytomegalovirus infection. Acta Neuropathol Commun: 2013, 1(1);63 PubMed 24252374
  9. Ennio Polilli, Giustino Parruti, Francesca D'Arcangelo, Elisa Tracanna, Luigi Clerico, Vincenzo Savini, Francesco D'Antonio, Maurizio Rosati, Lamberto Manzoli, Domenico D'Antonio, Giovanni Nigro Preliminary evaluation of the safety and efficacy of standard intravenous immunoglobulins in pregnant women with primary cytomegalovirus infection. Clin. Vaccine Immunol.: 2012, 19(12);1991-3 PubMed 23100477
  10. T Lazzarotto, B Guerra, L Gabrielli, M Lanari, M P Landini Update on the prevention, diagnosis and management of cytomegalovirus infection during pregnancy. Clin. Microbiol. Infect.: 2011, 17(9);1285-93 PubMed 21631642
  11. Tina Jaskoll, George Abichaker, Parish P Sedghizadeh, Pablo Bringas, Michael Melnick Cytomegalovirus induces abnormal chondrogenesis and osteogenesis during embryonic mandibular development. BMC Dev. Biol.: 2008, 8;33 PubMed 18371224 | BMC Dev Biol.
  12. C Sinzger, H Müntefering, T Löning, H Stöss, B Plachter, G Jahn Cell types infected in human cytomegalovirus placentitis identified by immunohistochemical double staining. Virchows Arch A Pathol Anat Histopathol: 1993, 423(4);249-56 PubMed 8236822
  13. Liu Tao, Chen Suhua, Chen Juanjuan, Yin Zongzhi, Xiao Juan, Zhang Dandan In vitro study on human cytomegalovirus affecting early pregnancy villous EVT's invasion function. Virol. J.: 2011, 8;114 PubMed 21392403

Textbooks

Reviews

Amanda Carlson, Errol R Norwitz, Robert J Stiller Cytomegalovirus infection in pregnancy: should all women be screened? Rev Obstet Gynecol: 2010, 3(4);172-9 PubMed 21364849

Yoav Yinon, Dan Farine, Mark H Yudin Screening, diagnosis, and management of cytomegalovirus infection in pregnancy. Obstet Gynecol Surv: 2010, 65(11);736-43 PubMed 21375790

F Mosca, L Pugni Cytomegalovirus infection: the state of the art. J Chemother: 2007, 19 Suppl 2;46-8 PubMed 18073181

J Hassan, J Connell Translational mini-review series on infectious disease: congenital cytomegalovirus infection: 50 years on. Clin. Exp. Immunol.: 2007, 149(2);205-10 PubMed 17635529

Shimon Degani Sonographic findings in fetal viral infections: a systematic review. Obstet Gynecol Surv: 2006, 61(5);329-36 PubMed 16635273

Maria Grazia Revello, Giuseppe Gerna Diagnosis and management of human cytomegalovirus infection in the mother, fetus, and newborn infant. Clin. Microbiol. Rev.: 2002, 15(4);680-715 PubMed 12364375


Articles

Jessica L Nyholm, Mark R Schleiss Prevention of maternal cytomegalovirus infection: current status and future prospects. Int J Womens Health: 2010, 2;23-35 PubMed 21072294

Suresh B Boppana, Shannon A Ross, Zdenek Novak, Masako Shimamura, Robert W Tolan, April L Palmer, Amina Ahmed, Marian G Michaels, Pablo J Sánchez, David I Bernstein, William J Britt, Karen B Fowler, National Institute on Deafness and Other Communication Disorders CMV and Hearing Multicenter Screening (CHIMES) Study Dried blood spot real-time polymerase chain reaction assays to screen newborns for congenital cytomegalovirus infection. JAMA: 2010, 303(14);1375-82 PubMed 20388893

H D Riley History of the cytomegalovirus. South. Med. J.: 1997, 90(2);184-90 PubMed 9042169


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Cite this page: Hill, M.A. 2017 Embryology Abnormal Development - Cytomegalovirus. Retrieved June 26, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Cytomegalovirus

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