Characteristics and serology of pregnant women with cytomegalovirus immunoglobulin G seroconversion during pregnancy in Japan.

OBJECTIVE: Investigate the characteristics and serology of pregnant women with cytomegalovirus (CMV) immunoglobulin (Ig)G seroconversion during pregnancy to understand the risk factors associated with primary CMV infection and the occurrence of fetal congenital CMV infection. MATERIALS AND METHODS: We retrospectively studied 3202 pregnant women who were CMV IgG-negative in early pregnancy and were retested for IgG in late pregnancy. Characteristics were compared between participants with and without IgG seroconversion, and serological parameters were compared between participants with and without fetal congenital CMV infection. RESULTS: Twenty-six participants showed CMV IgG seroconversion and fifteen showed fetal congenital CMV infection. Seroconversion rates were significantly higher in teens (5.0%) than in older women (20s: 0.8%; 30s and over: 0.6%) (p < 0.001). Titers of CMV IgM at IgG seroconversion were higher in women without (median 8.66) than with (median 6.54) congenital infection (p = 0.045). The congenital infection rate was high when IgM titers at IgG seroconversion were low (47.1% with 4.00-12.00 titers and 100% with 1.21-3.99 IgM titers) (p = 0.048). CONCLUSIONS: Nulliparous pregnant teenagers have a high risk of CMV IgG seroconversion and the CMV IgM titer at IgG seroconversion may help predict the occurrence of fetal congenital CMV infection.

First-trimester diagnosis of congenital cytomegalovirus infection after maternal primary infection in early pregnancy: feasibility study of viral genome amplification by PCR on chorionic villi obtained by CVS.

OBJECTIVE: To evaluate the feasibility of amplification of the viral genome by polymerase chain reaction (PCR) analysis of trophoblast samples obtained by chorionic villus sampling (CVS) in cases of maternal primary infection (MPI) with cytomegalovirus (CMV) in early pregnancy. METHODS: This was a prospective study carried out at the Department of Obstetrics and Fetal Medicine, Hopital Necker-E.M., between October 2019 and October 2020. Following CMV serology screening in early pregnancy, CVS was offered to women at 11-14 weeks' gestation after CMV-MPI ≤ 10 weeks. Array-comparative genomic hybridization and amplification of the viral genome by PCR were performed on the trophoblasts obtained by CVS. All cases also underwent amniocentesis from 17 weeks onwards and PCR was performed on the amniotic fluid. Secondary prevention with valacyclovir was initiated as soon as MPI was diagnosed, to decrease the risk of vertical transmission. We evaluated the diagnostic performance of CMV-PCR of trophoblast obtained by CVS, using as the reference standard PCR of amniotic fluid obtained by amniocentesis. RESULTS: CVS was performed in 37 pregnancies, at a median (range) gestational age of 12.7 (11.3-14.4) weeks. CMV-PCR in chorionic villi was positive in three and negative in 34 cases. CMV-PCR following amniocentesis, performed at a median (range) gestational age of 17.6 (16.7-29.9) weeks, was positive for the three cases which were positive following CVS and, of the 34 patients with a negative finding following CVS, amniocentesis was negative in 31 and positive in three. The sensitivity of CMV-PCR analysis of trophoblast obtained by CVS for the diagnosis of CMV, using as the reference standard PCR analysis of amniotic fluid obtained by amniocentesis, was 50% (95% CI, 19-81%), specificity was 100% (95% CI, 89-100%), positive predictive value was 100% (95% CI, 44-100%) and negative predictive value was 91% (95% CI, 77-97%). CONCLUSIONS: Diagnosis of placental infection following MPI in early pregnancy can be achieved by PCR amplification of the CMV genome in chorionic villi. We propose that negative CMV-PCR in the trophoblast after 12 weeks could be used to exclude CMV-related embryopathy leading to sequelae. However, this needs to be confirmed through long-term follow-up evaluation. These findings could help to establish CVS as the diagnostic test of choice following maternal serology screening in early pregnancy. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Outcome of fetuses with congenital cytomegalovirus infection and normal ultrasound at diagnosis: systematic review and meta-analysis.

OBJECTIVE: To report the outcome of fetuses with congenital cytomegalovirus (CMV) infection and normal ultrasound at the time of diagnosis, and to evaluate the rate of an additional anomaly detected only on magnetic resonance imaging (MRI). METHODS: Medline, EMBASE, CINAHL and Cochrane databases were searched for studies reporting on the outcome of fetuses with congenital CMV infection. Inclusion criteria were fetuses with confirmed CMV infection and normal ultrasound assessment at the time of the initial evaluation. The outcomes observed were an anomaly detected on a follow-up ultrasound scan, an anomaly detected on prenatal MRI but missed on ultrasound, an anomaly detected on postnatal assessment but missed prenatally, perinatal mortality, symptomatic infection at birth, neurodevelopmental outcome and hearing and visual deficits. Neurodevelopmental outcome was assessed only in cases of isolated CMV infection confirmed at birth. Subgroup analysis was performed according to the trimester in which maternal infection occurred. Random-effects meta-analysis of proportions was used to analyze the data. RESULTS: Twenty-six studies were included, comprising 2603 fetuses with congenital CMV infection, of which 1178 (45.3%) had normal ultrasound at the time of diagnosis and were included in the analysis. The overall rate of an associated central nervous system (CNS) anomaly detected on a follow-up ultrasound scan was 4.4% (95% CI, 1.4-8.8%) (32/523; 15 studies), while the rates of those detected exclusively on prenatal MRI or on postnatal imaging were 5.8% (95% CI, 1.9-11.5%) (19/357; 11 studies) and 3.2% (95% CI, 0.3-9.0%) (50/660; 17 studies), respectively. The rate of an associated extra-CNS anomaly detected on a follow-up ultrasound scan was 2.9% (95% CI, 0.8-6.3%) (19/523; 15 studies), while the rates of those detected exclusively on MRI or on postnatal imaging were 0% (95% CI, 0.0-1.7%) (0/357; 11 studies) and 0.9% (95% CI, 0.3-1.8%) (4/660; 17 studies), respectively. Intrauterine death and perinatal death each occurred in 0.7% (95% CI, 0.3-1.4%) (2/824; 23 studies) of cases. In cases without an associated anomaly detected pre- or postnatally, symptomatic infection was found in 1.5% (95% CI, 0.7-2.7%) (6/548; 19 studies) of infants, the overall rate of a neurodevelopmental anomaly was 3.1% (95% CI, 1.6-5.1%) (16/550; 19 studies), and hearing problems affected 6.5% (95% CI, 3.8-10.0%) (36/550; 19 studies) of children. Subanalyses according to the trimester in which maternal infection occurred were affected by the very small number of included cases and lack of comparison of the observed outcomes in the original studies. Compared with fetuses infected in the second or third trimester, those infected in the first trimester had a relatively higher risk of having an additional anomaly detected on follow-up ultrasound or MRI, abnormal neurodevelopmental outcome and hearing problems. CONCLUSIONS: In fetuses with congenital CMV infection in which no anomalies are detected on prenatal ultrasound or MRI, the risk of adverse postnatal outcome is lower than that reported previously in the published literature when not considering the role of antenatal imaging assessment. The results from this review also highlight the potential role of MRI, even in fetuses with no anomalies detected on ultrasound, as an anomaly can be detected exclusively on MRI in about 6% of cases. The findings from this study could enhance prenatal counseling of pregnancies with congenital CMV infection with normal prenatal imaging. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Revisiting short- and long-term outcome after fetal first-trimester primary cytomegalovirus infection in relation to prenatal imaging findings.

OBJECTIVE: To determine the short- and long-term outcome of pregnancies with proven first-trimester fetal cytomegalovirus (CMV) infection in a large prospective cohort. METHODS: This was a prospective cohort study of pregnancies with documented primary maternal CMV infection in the first trimester and evidence of fetal infection, referred for further evaluation between January 2011 and January 2018. Maternal serological diagnosis of primary CMV infection was documented by seroconversion. Vertical CMV transmission was identified by amniocentesis with polymerase chain reaction (PCR) for the CMV genome. After birth, fetal infection was re-tested by PCR in neonatal urine or saliva samples. All patients underwent serial prenatal ultrasound scans and fetal magnetic resonance imaging (MRI) at 32-33 weeks' gestation. All neonates underwent ocular fundus examination, an ultrasound brain scan and hearing evaluation, and were followed periodically for a median of 2 years (range, 6 months to 10 years). Follow-up information was obtained from hospital charts and by telephone interviews with parents. The CMV-associated outcomes assessed were sensorineural hearing loss (SNHL), neurodevelopmental abnormality, composite clinical outcome (including SNHL and neurodevelopmental abnormality) and composite outcome (additionally including termination of pregnancy (TOP)). The association between prenatal ultrasound or MRI findings and abnormal outcome was assessed. RESULTS: Primary CMV infection in the first trimester occurred in 123 patients. The rate of an abnormal ultrasound finding was 30.9%, and the rate of an abnormal MRI finding was 30.1% overall and 14.1% in the subgroup of patients with normal ultrasound. Of the 85 patients with normal ultrasound, 12 had an abnormal MRI finding, of whom five (5.9%) had true anatomical findings. Fifteen patients decided to terminate the pregnancy owing to abnormal prenatal findings on either ultrasound or MRI. Overall, the rate of CMV-associated postnatal and childhood sequelae was 27.8%, with a rate of 16.7% for SNHL and 11.1% for neurodevelopmental abnormalities, mostly slight motor or verbal delay. Approximately half of the cases with CMV-associated sequelae did not have any abnormal prenatal imaging findings. Abnormal prenatal findings on ultrasound were not associated significantly with SNHL, neurodevelopmental delay or composite clinical outcome (P = 0.084, 0.109 and 0.176, respectively), but they were associated with the composite outcome including TOP (P < 0.001). We identified a non-significant trend for a higher rate of SNHL in the group with abnormal ultrasound than in those with normal ultrasound. For abnormal MRI findings, we found a correlation only with neurodevelopmental abnormality and composite outcome (P = 0.014 and P < 0.001, respectively). CONCLUSIONS: The risk of childhood sequelae after first-trimester fetal CMV infection is most often associated with abnormal prenatal imaging findings. However, normal imaging does not rule out the development of SNHL and minor neurodevelopmental abnormalities. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Middle cerebral artery peak systolic velocity in perinatal cytomegalovirus infection.

A middle cerebral artery peak systolic velocity value (MCA-PSV) persistently greater than 1.5 times the median of the normal population is utilized to detect moderate and severe anemia in fetuses at risk. Cytomegalovirus (CMV) is the most common perinatal infection and can cause fetal anemia. We present four cases with CMV perinatal infection. Although their MCA-PSV values were the highest recorded in normal as well as in anemic fetuses, only two of them developed moderate or severe anemia. These findings suggest that high MCA-PSV values in cases with perinatal CMV infection may have a different pathophysiologic mechanism than anemia.

Antenatal treatment options for primary cytomegalovirus infections.

PURPOSE OF REVIEW: Cytomegalovirus (CMV) infection is by far the most common fetal viral infection. It carries a risk of long-term sequelae for the neonate; though the severity depends on the gestational age at the time of infection. Improvement in primary prevention of a CMV infection during pregnancy can be achieved by providing information regarding hygiene to the mother. Once a maternal infection occurs, treatment options include prevention of maternal-fetal transmission and, once transmission occurs, attempts to reduce the severity of its effect on the fetus. RECENT FINDINGS: Several recent studies have shown that providing detailed information regarding the effects of CMV on the fetus and providing common sense hygiene advice reduced new primary infections by more than 75%. In cases with a documented maternal primary CMV infection, treatment with intravenous immunoglobulins have been tried to reduce maternal fetal transmission with a variable degree of success. In the randomized controlled study of Revello et al., immunoglobulins did not reduce the transmission rate. In a recent study, immunoglobulins were given only to women with very recent first trimester infections. In this study, the transmission rate was 2.5%, which is significantly less than expected. Leruez-Ville et al. treated mothers with known transmission of CMV to the fetus with 8 g of valaciclovir daily. They observed a significant reduction in the number of neonatal symptoms in the treated cases. SUMMARY: Protocols are available to prevent primary CMV infections during pregnancy and, in cases where an infection does occur, steps can be taken to reduce its effect on the fetus thereby reducing the chance of long-term sequelae.

[Fetal cytomegalovirus infection diagnosed on autopsy: a case report]. / Infection fœtale à cytomégalovirus de diagnostic autopsique: à propos d'un cas.

The cytomegalovirus (CMV) is the most common maternal-fetal transmission infectious disease. The diagnosis of this infection is rarely made on antenatal sonographic signs. Pathological examination could, in this case, make etiologic diagnosis. We report the case of a terminated pregnancy, at the term of 19 weeks of gestation, occurring in a 31-year-old woman. The sonography found a terminated pregnancy with anamnios. Histological examination of samples of fetal internal organs showed intranuclear inclusions, compatible with CMV infection. The main objective of our work is to emphasize the value of histological examination in the diagnosis of fetal death etiology. Moreover, we will discuss the benefit of antenatal screening of CMV maternal infection.

[Arguments for an infectious cause of IUGR]. / Quels arguments pour déterminer l'origine infectieuse d'un retard de croissance intra-utérin?

Intra-uterine growth retardation (IUGR) is a frequent cause of consultation in antenatal care unit. The prognosis relies on the etiology: vascular, chromosomic, genetic, or infectious. Because of chronic fetal distress, hypotrophy increase morbidity, mortality and neurosensorial long term effect. Usually, infection is involved in 5 to 15% of the IUGR, mainly by Cytomegalovirus (CMV), Varicella Zoster virus, rubella, toxoplasmosis, herpes and syphilis. Maternal sera and amniotic liquid analysis make the diagnosis possible but fetal ultrasound scan is used to find other features. Most of the abnormalities are unspecific but their combination can worsen fetal prognosis. Infection should always be ruled out in the assessment of IUGR.

[The importance of prenatal neuroimaging in prediction of developmental outcome of fetuses infected with cytomegalovirus].

Cytomegalovirus (CMV) infection is the most common viral cause of congenital infection and one of the most common contributors to neurodevelopmental disabilities in children. The physiological condition of the infants at birth is a good predictor of long-term cognitive functioning, while children who manifest clinical symptoms at birth (symptomatic) are more likely to develop future cognitive impairments. Brain imaging studies from prenatal diagnosed children are scant, focusing mainly on fetuses with brain signs of CMV infection. While several studies demonstrate a poor outcome for children with neurosonographic findings during pregnancy, a systematic investigation regarding long-term neurodevelopmental outcome of fetuses infected with CMV, but without fetal ultrasonographic brain findings, has not been reported.

Kissing as an evolutionary adaptation to protect against Human Cytomegalovirus-like teratogenesis.

Mouth to mouth sexual kissing is seen in more than 90% of human cultures. Various theories have been put forward to account for this but none offer a full explanation within an evolutionary framework. As mouth to mouth sexual kissing exposes each participant to the diseases of the other, it must confer significant benefit. Human Cytomegalovirus (HCMV) is a ubiquitous infection that carries a severe teratogenic risk if primary infection is acquired during certain critical periods. As HCMV is present in salivary gland epithelial cells and sheds from periodontitis induced lesions, female inoculation with a specific male's HCMV is most efficiently achieved through mouth to mouth contact and saliva exchange, particularly where the flow of saliva is from the male to the typically shorter female. The current hypothesis proposes that mouth to mouth sexual kissing enables females to control when they become infected with a particular male's HCMV and so protect their offspring from the threat of teratogenesis from primary infection during vulnerable times in their development. Females only gain this benefit if they also avoid becoming infected by other males. Hence HCMV induced teratogenesis is a strong viral pressure towards the development of monogamy as well as kissing as a behavioural strategy to protect against it.

Prenatal diagnosis of cerebral lesions acquired in utero and with a late appearance.

Although no precise figures are available, many congenital brain lesions arise from intrauterine disruption, frequently due to obstetric complications. The most common entities include intracranial hemorrhage, ischemic lesions, thrombosis of venous vessels and infections. Accurate prenatal diagnosis is possible in many of these cases. However, the findings may be subtle, particularly in the early stage of the disruptive process. Identification of these conditions requires therefore specific expertise, the combination of fetal neurosonography and magnetic resonance, and frequently there is a need for serial examinations. Targeted diagnostic imaging should be offered to obstetric patients with conditions predisposing to prenatal cerebral insults.

Magnetic resonance spectroscopy of the fetal brain.

Fetal magnetic resonance spectroscopy (MRS) is technically feasible in utero and demonstrates similar findings to those observed in neonatal populations. MRS can provide additional information to conventional T1- and T2-weighted imaging of the fetal brain. It is of particular use when subtle changes are present on conventional fetal MRI sequences, and when imaging fetuses at risk of brain injury and metabolic abnormalities.

Comparison between ultrasound and magnetic resonance imaging in assessment of fetal cytomegalovirus infection.

OBJECTIVE: To evaluate whether fetal brain magnetic resonance imaging (MRI) adds useful information to the one obtained by ultrasound in fetuses with cytomegalovirus (CMV) infection. METHODS: MRI and ultrasonographic findings were analyzed retrospectively in 38 fetuses with proven congenital CMV infection. Both techniques were performed on the same week at a mean gestational age of 33 weeks (24-37). The referral indications were maternal seroconversion (n = 19), and ultrasound findings (n = 19). The results were compared with the fetopathologic examination in cases with fetal death or termination of pregnancy (TOP) or the infant's neurological examination. RESULTS: The 38 cases were classified into three groups, depending on ultrasound findings at referral. Group 1: no ultrasound features (n = 11); group 2: extracerebral features without cerebral abnormalities at ultrasound (n = 13); group 3: presence of cerebral features at ultrasound (n = 14). In group 1, MRI was always normal. In group 2, MRI revealed cerebral features in six cases (46%). In group 3, MRI always confirmed the lesions seen at ultrasound and highlighted other cerebral features. CONCLUSIONS: MRI can provide important additional information with regard to abnormal gyration, cerebellar hypoplasia, or abnormal signal in white matter. It is certainly useful in the assessment of fetuses with extracerebral features without brain abnormalities detected with ultrasounds. If the fetal ultrasound is strictly normal in an infected fetus, MRI may not detect brain anomalies; however, it seems difficult to not perform this noninvasive procedure.

Secondary cytomegalovirus infection can cause severe fetal sequelae despite maternal preconceptional immunity.

OBJECTIVES: To describe our experience in cases with sonographic signs of fetal infection and with maternal serological 'immunity' to cytomegalovirus (CMV) infection. METHODS: This was a bicenter study of six pregnant women referred for evaluation of suspected fetal infection. All cases had confirmed maternal serology for past exposure to CMV but no evidence of recent secondary CMV infection. All underwent sonographic evaluation as well as complete investigation for CMV infection. RESULTS: The mean age of the women was 29 (range, 23-35) years and the mean gestational age at diagnosis was 23.5 weeks (range, 20-31) weeks. Sonographic findings included microcephaly, ventriculomegaly, periventricular calcifications and cystic lesions, echogenic bowel, hydrops and hepatosplenomegaly. Amniocentesis was performed in all cases for fetal karyotyping and viral assessment, and all were found by polymerase chain reaction to be positive for CMV infection. Four pregnancies were terminated following the parents' request. One pregnancy continued until intrauterine fetal death occurred 2 weeks after diagnosis. Postmortem was denied in all cases but one. One infant was delivered with evidence of severe cerebral palsy. CONCLUSION: In the presence of sonographic findings suggestive of fetal CMV infection, prompt investigation of amniotic fluid should follow even if maternal serology does not support recent maternal seroconversion.

Cytomegalovirus induces abnormal chondrogenesis and osteogenesis during embryonic mandibular development.

BACKGROUND: Human clinical studies and mouse models clearly demonstrate that cytomegalovirus (CMV) disrupts normal organ and tissue development. Although CMV is one of the most common causes of major birth defects in humans, little is presently known about the mechanism(s) underlying CMV-induced congenital malformations. Our prior studies have demonstrated that CMV infection of first branchial arch derivatives (salivary glands and teeth) induced severely abnormal phenotypes and that CMV has a particular tropism for neural crest-derived mesenchyme (NCM). Since early embryos are barely susceptible to CMV infection, and the extant evidence suggests that the differentiation program needs to be well underway for embryonic tissues to be susceptible to viral infection and viral-induced pathology, the aim of this study was to determine if first branchial arch NCM cells are susceptible to mCMV infection prior to differentiation of NCM derivatives. RESULTS: E11 mouse mandibular processes (MANs) were infected with mouse CMV (mCMV) for up to 16 days in vitro. mCMV infection of undifferentiated embryonic mouse MANs induced micrognathia consequent to decreased Meckel's cartilage chondrogenesis and mandibular osteogenesis. Specifically, mCMV infection resulted in aberrant stromal cellularity, a smaller, misshapen Meckel's cartilage, and mandibular bone and condylar dysmorphogenesis. Analysis of viral distribution indicates that mCMV primarily infects NCM cells and derivatives. Initial localization studies indicate that mCMV infection changed the cell-specific expression of FN, NF-kappaB2, RelA, RelB, and Shh and Smad7 proteins. CONCLUSION: Our results indicate that mCMV dysregulation of key signaling pathways in primarily NCM cells and their derivatives severely disrupts mandibular morphogenesis and skeletogenesis. The pathogenesis appears to be centered around the canonical and noncanonical NF-kappaB pathways, and there is unusual juxtaposition of abnormal stromal cells and surrounding matrix. Moreover, since it is critically important that signaling molecules are expressed in appropriate cell populations during development, the aberrant localization of components of relevant signaling pathways may reveal the pathogenic mechanism underlying mandibular malformations.

Human cytomegalovirus immediate-early-gene expression disrupts embryogenesis in transgenic Drosophila.

Intrauterine infection with human cytomegalovirus (HCMV) is the leading viral cause of birth defects involving the central nervous system. Due to the highly species specific nature of the virus, its course of natural infection cannot be studied in animal models. Here we introduce a novel transgenic Drosophila model system for studying the effects of the major viral regulatory genes, the immediate-early genes, on normal embryonic development. We show that ectopic expression of the immediate-early genes in Drosophila led to increased embryonic lethality manifested in disintegration of the embryos. Further analysis suggested that immediate-early gene expression interfered with adherens junction maintenance, leading to the disruption of embryonic epithelial integrity. Owing to the evolutionary conservation of developmental mechanisms from invertebrates to mammals, we anticipate that the studies in Drosophila will be relevant also to humans and will ultimately provide a versatile system for studying different aspects of viral-host interactions.

Late human cytomegalovirus (HCMV) proteins inhibit differentiation of human neural precursor cells into astrocytes.

Human cytomegalovirus (HCMV) is the most common cause of congenital infections in developed countries, with an incidence varying between 0.5-2.2%. Such infection may be the consequence of either a primary infection or reactivation of a latent infection in the mother and the outcome may vary from asymptomatic to severe brain disorders. Moreover, infants that are asymptomatic at the time of birth may still develop neurologic sequelae at a later age. Our hypothesis is that infection of stem cells of the central nervous system by HCMV alters the proliferation, differentiation or migration of these cells, and thereby gives rise to the brain abnormalities observed. We show that infection of human neural precursor cells (NPCs) with the laboratory strain Towne or the clinical isolate TB40 of HCMV suppresses the differentiation of these cells into astrocytes even at an multiplicity of infection (MOI) as low as 0.1 (by 33% and 67%, respectively). This inhibition required active viral replication and the expression of late HCMV proteins. Infection as late as 24 hr after the onset of differentiation, but not after 72 hr, also prevented the maturation of infected cultures. Furthermore, in cultures infected with TB40 (at an MOI of 1), approximately 54% of the cells were apoptotic and cell proliferation was significantly attenuated. Clearly, HCMV can reduce the capacity of NPCs to differentiate into astrocytes and this effect may provide part of the explanation for the abnormalities in brain development associated with congenital HCMV infection.

No CMV DNA in Guthrie cards from children who later developed ALL.

An association of a viral infection in utero and development of acute lymphoblastic leukemia (ALL) has been suggested. Cytomegalovirus (CMV) has been reported as a leading agent of intrauterine infections resulting in some cases of congenital infections. The authors investigated the presence of prenatal CMV infection in children who later developed ALL. Guthrie cards were obtained from 48 children with ALL and 46 healthy children and were analyzed for the presence of CMV DNA by a real-time TaqMan PCR. CMV DNA was not detected in Guthrie cards from the children with ALL, from the control healthy children. The results show that prenatal CMV infection does not seem to be associated with later development of childhood ALL.