Abnormal Development - Cytomegalovirus

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KA62.3 Congenital cytomegalovirus infection

ICD-11: "A condition affecting neonates, caused by an infection with cytomegalovirus in utero. This condition is characterized by jaundice, low birth weight, splenomegaly, hepatomegaly, or pneumonia if symptoms develop shortly after birth, or may be asymptomatic. This condition commonly present later in life with loss of hearing, loss of vision, or developmental disabilities. Transmission is by vertical transmission. Confirmation is by detection of cytomegalovirus in neonatal urine, saliva, blood, or other body tissues within 2-3 weeks of birth."

ICD-10 P35.1 Congenital cytomegalovirus infection | International Classification of Diseases: P35 Congenital viral diseases | XVI Perinatal Period
Viral Links: viral infection | TORCH | cytomegalovirus | hepatitis | HIV | parvovirus | polio | rubella virus | chickenpox | Lymphocytic Choriomeningitis Virus | Zika virus | human papillomavirus | rotavirus | West Nile virus | varicella virus | vaccination | zoonotic infection | environment
Historic Embryology - Viral 
1941 Rubella Cataracts | 1944 Rubella Defects

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]
  • Maternal and fetal cytomegalovirus infection: diagnosis, management, and prevention[4] "Congenital cytomegalovirus infection is a major cause of central nervous system and sensory impairments that affect cognition, motor function, hearing, language development, vestibular function, and vision. Although the importance of congenital cytomegalovirus infection is readily evident, the vast majority of maternal and fetal infections are not identified, even in developed countries. Multiple studies of prenatal cytomegalovirus infections have produced a body of knowledge that can inform the clinical approach to suspected or proven maternal and fetal infection. Reliable diagnosis of cytomegalovirus infection during pregnancy and accurate diagnosis of fetal infection are a reality. Approaches to preventing the transmission of cytomegalovirus from mother to fetus and to the treatment of fetal infection are being studied. There is evidence that public health approaches based on hygiene can dramatically reduce the rate of primary maternal cytomegalovirus infections during pregnancy. This review will consider the epidemiology of congenital cytomegalovirus infection, the diagnosis and management of primary infection during pregnancy, and approaches to preventing maternal infection." vaccination
  • Congenital Cytomegalovirus Infection in the Absence of Maternal Cytomegalovirus-IgM Antibodies[5] "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."
  • Natural killer cells attenuate cytomegalovirus-induced hearing loss in mice[6] }Congenital cytomegalovirus (CMV) infection is the most common non-hereditary cause of sensorineural hearing loss (SNHL) yet the mechanisms of hearing loss remain obscure. Natural Killer (NK) cells play a critical role in regulating murine CMV infection via NK cell recognition of the Ly49H cell surface receptor of the viral-encoded m157 ligand expressed at the infected cell surface.... These results demonstrate participation of NK cells in protection from CMV-induced labyrinthitis and SNHL in mice." mouse
  • Prenatal diagnosis of congenital cytomegalovirus infection in 115 cases: a 5 years' single center experience[7] "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."
More recent papers  
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Older papers  
  • Clinical Implications for Children Born With Congenital Cytomegalovirus Infection Following a Negative Amniocentesis[8] "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[9] "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."
  • Human fetal inner ear involvement in congenital cytomegalovirus infection[10] "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[11] "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[12] "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.[13]

Cytomegalovirus Placentitis

Clinical term for the cytomegalovirus infection of the placenta.

A earlier histological study[14] 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[15] suggests that all villi cell types are likely to be infected.

References

  1. 1.0 1.1 Naumenko VA, Tyulenev YA, Yakovenko SA, Kurilo LF, Shileyko LV, Segal AS, Zavalishina LE, Klimova RR, Tsibizov AS, Alkhovskii SV & Kushch AA. (2011). Detection of human cytomegalovirus in motile spermatozoa and spermatogenic cells in testis organotypic culture. Herpesviridae , 2, 7. PMID: 21711549 DOI.
  2. Teissier N, Delezoide AL, Mas AE, Khung-Savatovsky S, Bessières B, Nardelli J, Vauloup-Fellous C, Picone O, Houhou N, Oury JF, Van Den Abbeele T, Gressens P & Adle-Biassette H. (2011). Inner ear lesions in congenital cytomegalovirus infection of human fetuses. Acta Neuropathol. , 122, 763-74. PMID: 22033878 DOI.
  3. 3.0 3.1 Angelova M, Zwezdaryk K, Ferris M, Shan B, Morris CA & Sullivan DE. (2012). Human cytomegalovirus infection dysregulates the canonical Wnt/β-catenin signaling pathway. PLoS Pathog. , 8, e1002959. PMID: 23071438 DOI.
  4. Pass RF & Arav-Boger R. (2018). Maternal and fetal cytomegalovirus infection: diagnosis, management, and prevention. F1000Res , 7, 255. PMID: 29560263 DOI.
  5. Gunkel J, van der Knoop BJ, Nijman J, de Vries LS, Manten GTR, Nikkels PGJ, Murk JL, de Vries JIP & Wolfs TFW. (2017). Congenital Cytomegalovirus Infection in the Absence of Maternal Cytomegalovirus-IgM Antibodies. Fetal. Diagn. Ther. , 42, 144-149. PMID: 28259882 DOI.
  6. Almishaal AA, Mathur PD, Hillas E, Chen L, Zhang A, Yang J, Wang Y, Yokoyama WM, Firpo MA & Park AH. (2017). Natural killer cells attenuate cytomegalovirus-induced hearing loss in mice. PLoS Pathog. , 13, e1006599. PMID: 28859161 DOI.
  7. Enders M, Daiminger A, Exler S, Ertan K, Enders G & Bald R. (2017). Prenatal diagnosis of congenital cytomegalovirus infection in 115 cases: a 5 years' single center experience. Prenat. Diagn. , 37, 389-398. PMID: 28207161 DOI.
  8. Bilavsky E, Pardo J, Attias J, Levy I, Magny JF, Ville Y, Leruez-Ville M & Amir J. (2016). Clinical Implications for Children Born With Congenital Cytomegalovirus Infection Following a Negative Amniocentesis. Clin. Infect. Dis. , 63, 33-8. PMID: 27114380 DOI.
  9. Oosterom N, Nijman J, Gunkel J, Wolfs TF, Groenendaal F, Verboon-Maciolek MA & de Vries LS. (2015). Neuro-imaging findings in infants with congenital cytomegalovirus infection: relation to trimester of infection. Neonatology , 107, 289-96. PMID: 25790782 DOI.
  10. Gabrielli L, Bonasoni MP, Santini D, Piccirilli G, Chiereghin A, Guerra B, Landini MP, Capretti MG, Lanari M & Lazzarotto T. (2013). Human fetal inner ear involvement in congenital cytomegalovirus infection. Acta Neuropathol Commun , 1, 63. PMID: 24252374 DOI.
  11. Polilli E, Parruti G, D'Arcangelo F, Tracanna E, Clerico L, Savini V, D'Antonio F, Rosati M, Manzoli L, D'Antonio D & Nigro G. (2012). Preliminary evaluation of the safety and efficacy of standard intravenous immunoglobulins in pregnant women with primary cytomegalovirus infection. Clin. Vaccine Immunol. , 19, 1991-3. PMID: 23100477 DOI.
  12. Lazzarotto T, Guerra B, Gabrielli L, Lanari M & Landini MP. (2011). Update on the prevention, diagnosis and management of cytomegalovirus infection during pregnancy. Clin. Microbiol. Infect. , 17, 1285-93. PMID: 21631642 DOI.
  13. Jaskoll T, Abichaker G, Sedghizadeh PP, Bringas P & Melnick M. (2008). Cytomegalovirus induces abnormal chondrogenesis and osteogenesis during embryonic mandibular development. BMC Dev. Biol. , 8, 33. PMID: 18371224 DOI.
  14. Sinzger C, Müntefering H, Löning T, Stöss H, Plachter B & Jahn G. (1993). Cell types infected in human cytomegalovirus placentitis identified by immunohistochemical double staining. Virchows Arch A Pathol Anat Histopathol , 423, 249-56. PMID: 8236822
  15. Tao L, Suhua C, Juanjuan C, Zongzhi Y, Juan X & Dandan Z. (2011). In vitro study on human cytomegalovirus affecting early pregnancy villous EVT's invasion function. Virol. J. , 8, 114. PMID: 21392403 DOI.

Textbooks

Baron S, editor. Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996. Available from: https://www.ncbi.nlm.nih.gov/books/NBK7627/

Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Available from: https://www.ncbi.nlm.nih.gov/books/NBK21054/

Disease Control Priorities in Developing Countries. 2nd edition. Jamison DT, Breman JG, Measham AR, et al., editors. Washington (DC): World Bank; 2006.

Reviews

Wood AM & Hughes BL. (2018). Detection and Prevention of Perinatal Infection: Cytomegalovirus and Zika Virus. Clin Perinatol , 45, 307-323. PMID: 29747890 DOI.

Leruez-Ville M & Ville Y. (2017). Fetal cytomegalovirus infection. Best Pract Res Clin Obstet Gynaecol , 38, 97-107. PMID: 27923540 DOI.

Carlson A, Norwitz ER & Stiller RJ. (2010). Cytomegalovirus infection in pregnancy: should all women be screened?. Rev Obstet Gynecol , 3, 172-9. PMID: 21364849

Yinon Y, Farine D & Yudin MH. (2010). Screening, diagnosis, and management of cytomegalovirus infection in pregnancy. Obstet Gynecol Surv , 65, 736-43. PMID: 21375790 DOI.

Mosca F & Pugni L. (2007). Cytomegalovirus infection: the state of the art. J Chemother , 19 Suppl 2, 46-8. PMID: 18073181

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

Degani S. (2006). Sonographic findings in fetal viral infections: a systematic review. Obstet Gynecol Surv , 61, 329-36. PMID: 16635273 DOI.

Revello MG & Gerna G. (2002). Diagnosis and management of human cytomegalovirus infection in the mother, fetus, and newborn infant. Clin. Microbiol. Rev. , 15, 680-715. PMID: 12364375

Articles

Nyholm JL & Schleiss MR. (2010). Prevention of maternal cytomegalovirus infection: current status and future prospects. Int J Womens Health , 2, 23-35. PMID: 21072294

Boppana SB, Ross SA, Novak Z, Shimamura M, Tolan RW, Palmer AL, Ahmed A, Michaels MG, Sánchez PJ, Bernstein DI, Britt WJ & Fowler KB. (2010). Dried blood spot real-time polymerase chain reaction assays to screen newborns for congenital cytomegalovirus infection. JAMA , 303, 1375-82. PMID: 20388893 DOI.

Riley HD. (1997). History of the cytomegalovirus. South. Med. J. , 90, 184-90. PMID: 9042169

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Cite this page: Hill, M.A. (2024, March 28) Embryology Abnormal Development - Cytomegalovirus. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Cytomegalovirus

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