|A personal message from Dr Mark Hill (May 2020)
| I have decided to take early retirement in September 2020. During the many years online I have received wonderful feedback from many readers, researchers and students interested in human embryology. I especially thank my research collaborators and contributors to the site. The good news is Embryology will remain online and I will continue my association with UNSW Australia. I look forward to updating and including the many exciting new discoveries in Embryology!
KA62.3 Congenital cytomegalovirus infection
ICD-11: KA62.3 Congenital cytomegalovirus infection "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
Cytomegalovirus infected spermatozoon
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.
Some Recent Findings
Human cytomegalovirus beta-catenin juxtanuclear region
- Survey of cellular immune responses to human cytomegalovirus infection in the microenvironment of the uterine-placental interface "Congenital human cytomegalovirus (HCMV) infection is a leading cause of birth defects, yet there are no established treatments for preventing maternal-fetal transmission. During first trimester, HCMV replicates in basal decidua that functions as a reservoir for virus and source of transmission to the attached placenta and fetal hemiallograft but also contains immune cells, including natural killer cells, macrophages, and T cell subsets, that respond to pathogens, protecting the placenta and fetus. However, the specific cellular and cytokine responses to infection are unknown, nor are the immune correlates of protection that guide development of therapeutic strategies. Here we survey immune cell phenotypes in intact explants of basal decidua infected with a clinical pathogenic HCMV strain ex vivo and identify specific changes occurring in response to infection in the tissue environment. Using 4-color immunofluorescence microscopy, we found that at 3 days postinfection, virus replicates in decidual stromal cells and epithelial cells of endometrial glands. Infected cells and effector memory CD8+ T cells (TEM) in contact with them make IFN-γ. CD8+ TEM cells produce granulysin and cluster at sites of infection in decidua and the epithelium of endometrial glands. Quantification indicated expansion of two immune cell subtypes-CD8+ TEM cells and, to a lesser extent, iNKT cells. Approximately 20% of immune cells were found in pairs in both control and infected decidua, suggesting frequent cross-talk in the microenvironment of decidua. Our findings indicate a complex immune microenvironment in basal decidua and suggest CD8+ TEM cells play a role in early responses to decidual infection in seropositive women."
- Sequelae of congenital cytomegalovirus (cCMV) following maternal primary infection are limited to those acquired in the first trimester of pregnancy "Relationship between gestational age at maternal primary infection and outcome in cCMV was based on small retrospective studies between 1980 and 2011. They reported sequelae in 32% and 15% following maternal primary infection in first and second or third trimester respectively. ...These results suggest that CMV infection can be severe only when the virus hits the fetus in the embryonic or early fetal period. Recent guidelines recommend auditory follow-up for at least 5 years of all infected children. This raises parental anxiety and generates significant cost. We suggest that auditory and specialized neurologic follow-up may be recommended only to children infected from maternal infection in the first trimester."
- Neuroimaging Profiles and Neurodevelopmental Outcome in Infants With Congenital Cytomegalovirus Infection "The accurate stratification of infants with congenital cytomegalovirus (CMV) infection at risk for more severe outcome may help in the management of patients. All consecutive neonates born from 2002 to 2015 with congenital CMV infection were considered eligible for the study. Neuroimaging findings were scored according to both scores. ...Although HUS is the safest neuroimaging technique, it performs less well in detecting some brain abnormalities that can be associated with a poor neurodevelopmental outcome. A comprehensive neuroimaging evaluation is mandatory in infants with congenital CMV infection to decide for treatment and make a prognostic evaluation.
- Maternal Immunity and the Natural History of Congenital Human Cytomegalovirus Infection "Congenital HCMV infections account for an estimated 25% of all cases of hearing loss in the US. It has long been argued that maternal adaptive immune responses to HCMV can modify both the likelihood of intrauterine transmission of HCMV, and the severity of fetal infection and risk of long term sequelae in infected infants. Over the last two decades, multiple studies have challenged this paradigm, including findings that have demonstrated that the vast majority of infants with congenital HCMV infections in most populations are born to women with established immunity prior to conception. Furthermore, the incidence of clinically apparent congenital HCMV infection in infants born to immune and non-immune pregnant women appears to be similar."
|More recent papers
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Search term: Abnormal Development Cytomegalovirus | Congenital Cytomegalovirus
|These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.
See also the Discussion Page for other references listed by year and References on this current page.
- Maternal and fetal cytomegalovirus infection: diagnosis, management, and prevention "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
- Pathogenesis of developmental anomalies of the central nervous system induced by congenital cytomegalovirus infection "In humans, the herpes virus family member cytomegalovirus (CMV) is the most prevalent mediator of intrauterine infection-induced congenital defect. Central nervous system (CNS) dysfunction is a distinguishing symptom of CMV infection, and characterized by ventriculoencephalitis and microglial nodular encephalitis. Reports on the initial distribution of CMV particles and its receptors on the blood brain barrier (BBB) are rare. Nevertheless, several factors are suggested to affect CMV etiology. Viral particle size is the primary factor in determining the pattern of CNS infections, followed by the expression of integrin β1 in endothelial cells, pericytes, meninges, choroid plexus, and neural stem progenitor cells (NSPCs), which are the primary targets of CMV infection. After initial infection, CMV disrupts BBB structural integrity to facilitate the spread of viral particles into parenchyma. Then, the initial meningitis and vasculitis eventually reaches NSPC-dense areas such as ventricular zone and subventricular zone, where viral infection inhibits NSPC proliferation and differentiation and results in neuronal cell loss. These cellular events clinically manifest as brain malformations such as a microcephaly."
- Congenital Cytomegalovirus Infection in the Absence of Maternal Cytomegalovirus-IgM Antibodies "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 }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 "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 "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 "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 "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 "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 "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 "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)."
- double-stranded linear DNA virus
- 235 Kb in size
Cytomegalovirus infected spermatozoa nucleus
|Full and empty viral capsids
- Links: Genome | Sequence
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.
- 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.
|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 in mouse model.
Clinical term for the cytomegalovirus infection of the placenta.
A earlier histological study 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 suggests that all villi cell types are likely to be infected.
- ↑ 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.
- ↑ 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.
- ↑ 3.0 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.
- ↑ Tabata T, Petitt M, Fang-Hoover J & Pereira L. (2019). Survey of cellular immune responses to human cytomegalovirus infection in the microenvironment of the uterine-placental interface. Med. Microbiol. Immunol. , 208, 475-485. PMID: 31065796 DOI.
- ↑ Faure-Bardon V, Magny JF, Parodi M, Couderc S, Garcia P, Maillotte AM, Benard M, Pinquier D, Astruc D, Patural H, Pladys P, Parat S, Guillois B, Garenne A, Bussières L, Guilleminot T, Stirnemann J, Ghout I, Ville Y & Leruez-Ville M. (2018). Sequelae of congenital cytomegalovirus (cCMV) following maternal primary infection are limited to those acquired in the first trimester of pregnancy. Clin. Infect. Dis. , , . PMID: 30596974 DOI.
- ↑ Giannattasio A, Bruzzese D, Di Costanzo P, Capone E, Romano A, D'Amico A, Bravaccio C, Grande C, Capasso L & Raimondi F. (2018). Neuroimaging Profiles and Neurodevelopmental Outcome in Infants With Congenital Cytomegalovirus Infection. Pediatr. Infect. Dis. J. , 37, 1028-1033. PMID: 30222696 DOI.
- ↑ Britt WJ. (2018). Maternal Immunity and the Natural History of Congenital Human Cytomegalovirus Infection. Viruses , 10, . PMID: 30081449 DOI.
- ↑ Pass RF & Arav-Boger R. (2018). Maternal and fetal cytomegalovirus infection: diagnosis, management, and prevention. F1000Res , 7, 255. PMID: 29560263 DOI.
- ↑ Kawasaki H, Kosugi I, Meguro S & Iwashita T. (2017). Pathogenesis of developmental anomalies of the central nervous system induced by congenital cytomegalovirus infection. Pathol. Int. , 67, 72-82. PMID: 28074532 DOI.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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
- ↑ 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.
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