Establishing correlates of maternal-fetal cytomegalovirus transmission-one step closer through predictive modeling.

BACKGROUND: Determinants of maternal-fetal cytomegalovirus (CMV) transmission and factors influencing the severity of congenital CMV (cCMV) infection are not well understood. METHODS: We conducted a descriptive, multi-center study in pregnant women ≥18 years old with primary CMV infection and their newborns (NCT01251744) to explore maternal immune responses to CMV and determine potential immunologic/virologic correlates of cCMV following primary infection during pregnancy. We developed alternative approaches looking into univariate/multivariate factors associated with cCMV, including a participant clustering/stratification approach and an interpretable predictive model-based approach using trained decision trees for risk prediction (post-hoc analyses). RESULTS: Pregnant women were grouped in three distinct clusters with similar baseline characteristics, particularly gestational age at diagnosis. We observed a trend for higher viral loads in urine and saliva samples from mothers of infants with cCMV versus without cCMV. When using a trained predictive-model approach that accounts for interaction effects between variables, anti-pentamer IgG antibody concentration and viral load in saliva were identified as biomarkers jointly associated with the risk of maternal-fetal CMV transmission. CONCLUSION: We identified biomarkers of CMV maternal-fetal transmission. After validation in larger studies, our findings will guide the management of primary infection during pregnancy and the development of vaccines against cCMV.

The human cytomegalovirus (CMV) is common and usually causes no symptoms in healthy individuals. However, CMV infections can be life-threatening in individuals with improperly functioning or immature immune systems, such as fetuses. Women can become infected with CMV for the first time (primary infection) during pregnancy. If CMV is transmitted from mother to fetus before the second trimester, the infant can suffer from severe disorders such as hearing loss and delayed development. We aimed to identify characteristics of pregnant women with a primary CMV infection that may increase the likelihood of transmitting CMV to the fetus. We considered demographical, clinical, and behavioral characteristics, as well as immune responses and the quantity of virus detected in the women's blood, urine, saliva, and vaginal mucus. Because we could not identify one single characteristic that could predict a high risk of CMV transmission, we developed new data analysis models to study how they can be combined. We found that antibodies targeting a pentameric antigen of the virus envelope and the presence of virus in saliva can together predict the risk of CMV transmission from mother to fetus. Our results can help improve the care of CMV-infected pregnant women and the design of CMV vaccines.

Consensus recommendation for prenatal, neonatal and postnatal management of congenital cytomegalovirus infection from the European congenital infection initiative (ECCI).

Congenital cytomegalovirus (cCMV) infection carries a significant burden with a 0.64% global prevalence and a 17-20% chance of serious long-term effects in children. Since the last guidelines, our understanding, particularly regarding primary maternal infections, has improved. A cCMV guidelines group was convened under the patronage of the European Society of Clinical Virology in April 2023 to refine these insights. The quality and validity of selected studies were assessed for potential biases and the GRADE framework was employed to evaluate quality of evidence across key domains. The resulting recommendations address managing cCMV, spanning prevention to postnatal care. Emphasizing early and accurate maternal diagnosis through serological tests enhances risk management and prevention strategies, including using valaciclovir to prevent vertical transmission. The guidelines also strive to refine personalized postnatal care based on risk assessments, ensuring targeted interventions for affected families.

Congenital cytomegalovirus infection in a preterm infant with 22q11.2 deletion syndrome and immunological abnormalities.

The 22q11.2 deletion syndrome has many complications; one of them is immunodeficiency. However, the time of onset and the degree of immunodeficiency can vary. We report a case of a preterm infant with congenital cytomegalovirus infection complicated with 22q11.2 deletion syndrome and immunological abnormalities. Ultrasonography revealed pulmonary atresia, ventricular septal defect, major aortopulmonary collateral artery, and thymic hypoplasia. His serum chemistry tests on admission revealed immunoglobulin G, A, and M levels of 1,547 mg/dL, 70 mg/dL, and 274 mg/dL, respectively. A surface antigen analysis of the peripheral lymphocytes using flow cytometry revealed the following: relatively low CD4-positive T-cell levels (18.1%; 1,767/µL), very high CD8-positive T-cell levels (58.9%; 5,751/µL), and CD4/CD8 ratio of 0.31. The level of T-cell receptor excision circles was relatively low at 17.5 copies/µL. After birth, the CD8-positive T-cell level began to gradually decrease, whereas the CD4/CD8 ratio began to increase. Thrombocytopenia, neutropenia, and skin petechiae were observed on admission. However, the condition improved. Treatment for congenital cytomegalovirus infection was not provided due to the absence of viremia. Unfortunately, the patient died suddenly on the 158th day of life, and the cause of death was unknown. To the best of our knowledge, no association between 22q11 deletion syndrome and cCMV has been described in the recent medical literature. According to the calculation, around one newborn infant who have both 22q11 deletion syndrome and cCMV infection will be born each year in Japan. Healthcare providers should pay more attention to this medical situation in the future.

Late-onset, progressive sensorineural hearing loss in the paediatric population: a systematic review.

PURPOSE: To review possible risk factors for permanent delayed-onset, progressive sensorineural hearing loss (SNHL) in the paediatric population to recommend follow-up protocols for early detection. METHODS: PRISMA-compliant systematic review was performed, including observational studies on the paediatric population up to 16 years old who have passed the newborn hearing screening programme (NHSP), investigating the development of late-onset, progressive SNHL. Electronic searches were performed through Medline, Embase, Cochrane, and Emcare. RESULTS: 37 studies were included. 21 showed an association between late-onset SNHL and congenital cytomegalovirus (cCMV) infection (age at hearing loss diagnosis 0.75 to 204 months, mean 45.6 ± 43.9), while 16 between late-onset SNHL and other congenital or perinatal factors, namely Neonatal Intensive Care Unit (NICU) stay, prematurity, neonatal respiratory failure, mechanical ventilation, extracorporeal membrane oxygenation (ECMO) support, hypocapnia, hypoxia, alkalosis, seizure activity, congenital diaphragmatic hernia (CDH), inner ear malformation, and gene mutations (age at hearing loss diagnosis 2.5 to 156 months, mean 38.7 ± 40.7). CONCLUSIONS: cCMV infection may cause late-onset SNHL, which can be missed on standard NHSP. There is, therefore, evidence to support universal screening programmes to enable detection in even asymptomatic neonates. Ongoing audiological follow-up for all children with cCMV is advisable, to enable timely treatment. In the paediatric population presenting conditions such as NICU stay > 5 days, prematurity ≤ 34 weeks gestation, severe neonatal respiratory failure, mechanical ventilation, ECMO support, and CDH surgery, an audiological follow-up from 3 months of age up to at least 3-4 years of age, and at least annually, should be recommended.

The effect of valacyclovir on secondary prevention of congenital cytomegalovirus infection, following primary maternal infection acquired periconceptionally or in the first trimester of pregnancy. An individual patient data meta-analysis.

OBJECTIVE: Recent studies have shown that a dosage of 8 g/d of oral valacyclovir reduces substantially the vertical transmission rate of cytomegalovirus in women with primary cytomegalovirus infection acquired periconceptionally or during the first trimester of pregnancy. This individual patient data meta-analysis aimed to assess the effectiveness and safety of valacyclovir treatment in the secondary prevention of congenital cytomegalovirus infection. DATA SOURCES: MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, the US registry of clinical trials (www. CLINICALTRIALS: gov), and gray literature sources were searched from inception to March 2023. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials and quasi-randomized studies administering 8 g/d of oral valacyclovir in pregnant women with primary cytomegalovirus infection acquired periconceptionally or during the first trimester of pregnancy were included. METHODS: All corresponding authors of the eligible studies were contacted. Cochrane's Risk of Bias 2 and Risk Of Bias In Non-randomised Studies - of Interventions tools were used for the risk of bias assessment. The result of amniocentesis was the primary outcome of interest. A 1-stage individual patient data meta-analysis was performed, using a generalized linear mixed model, clustered by the different trials. A subgroup analysis was performed, assessing separately the effect of valacyclovir in the periconceptional period and first trimester of pregnancy. RESULTS: Overall, 3 studies were included in the analysis (n=527 women). Valacyclovir reduced the vertical transmission rate of cytomegalovirus (adjusted odds ratio, 0.34; 95% confidence interval, 0.18-0.61). This reduction was apparent for both periconceptional period (adjusted odds ratio, 0.34; 95% confidence interval, 0.12-0.96) and first-trimester (adjusted odds ratio, 0.35; 95% confidence interval, 0.16-0.76) infections. Moreover, valacyclovir reduced the rate of neonatal infection (adjusted odds ratio, 0.30; 95% confidence interval, 0.19-0.47), in both periconceptional period (adjusted odds ratio, 0.30; 95% confidence interval, 0.14-0.61) and first-trimester (adjusted odds ratio, 0.30; 95% confidence interval, 0.17-0.54) infections. Furthermore, valacyclovir reduced the rate of termination of pregnancy because of cytomegalovirus-associated severe fetal findings (adjusted odds ratio, 0.23; 95% confidence interval, 0.22-0.24). The gestational age at the initiation of treatment has a positive correlation with all outcomes. The overall prevalence of severe side effects was 2.1%. CONCLUSION: A dosage of 8 g/d of oral valacyclovir reduced the vertical transmission rates of cytomegalovirus following primary maternal infection acquired periconceptionally or in the first trimester of pregnancy, with a low incidence of side effects.

Long-term linguistic outcome in adults with congenital cytomegalovirus infection.

BACKGROUND: Congenital cytomegalovirus (cCMV) is the most common prenatal infection and the main infectious cause of neurodevelopmental abnormalities in developed countries. Long-term neuropsychological outcome of cCMV infection is still not well understood. This is the first study that presents linguistic follow-up data performed on adults who were infected in utero. METHOD: All individuals from a universal newborn CMV screening study in Sweden sampled from 1977 to 1985 were invited to participate in a follow-up study. 34/71 persons (48%) with cCMV and 22/46 controls (48%) were enrolled. Participants were between 34 and 43 years. Linguistic ability was evaluated with two-word fluency tasks (FAS letter fluency and verb fluency), and a qualitative analysis of the participants' word retrieval strategies was conducted. RESULTS: No statistically significant group differences were found in the total number of retrieved words. When related to Swedish norm data, 43% of participants with cCMV infection, all asymptomatic at birth, had adequate results on both FAS and verb fluency tasks, compared to 86% of the controls. Education level was the most important factor for word fluency ability in both groups. Adults with cCMV infection and higher education levels used less effective retrieval strategies on FAS letter fluency than controls. CONCLUSION: This study suggests that adults with cCMV infection may have deficits in the word retrieval process, even in the absence of known neurodevelopmental disorders. Long-term effects of cCMV infection may exist even in those with asymptomatic infection at birth.

Comparison of two serological screening strategies for cytomegalovirus primary infection in the first trimester of pregnancy.

INTRODUCTION: CMV serology screening in the first trimester pregnancy is based on IgG and IgM testing followed by IgG avidity in cases with positive IgM. However, the sensitivity of this strategy to diagnose maternal primary infection has been questioned. The objective of the study was to compare this strategy 1 with a strategy 2 consisting of running avidity test on all samples with positive IgG (ignoring IgM results) using fully automated current generation CMV IgG, IgM and IgG avidity assays. POPULATION AND METHODS: 1516 consecutive pregnant women between 12 and 14 weeks were screened in one maternity. Strategy 1 was done prospectively with LIAISON® CMV IgG II and LIAISON® CMV IgM II, followed by LIAISON® CMV IgG Avidity II and VIDAS® CMV IgG avidity II testing in cases with positive or equivocal IgM. Strategy 2 was done retrospectively on the same population and consisted of running avidity with the LIAISON® CMV IgG Avidity II in all samples with positive IgG. RESULTS: The sensitivity to diagnose a confirmed or a possible maternal primary infection in the first trimester was 91.6 % and 83 % for strategy 1 and 2 respectively (p > 0.99). Strategy 1 missed one possible primary infection and strategy 2 missed 2 confirmed primary infection. Inconclusive results happened in 0 and 0.7 % of samples with strategy 1 and 2 respectively. CONCLUSION: This study suggests that strategy 1 has better sensitivity and practicability than strategy 2. However, to achieve a good performance with strategy 1, using highly sensitive IgM assay is mandatory.

Loop-mediated isothermal amplification assay for screening congenital cytomegalovirus infection in newborns.

Congenital cytomegalovirus (CMV) infection is a common cause of sensorineural hearing loss and neurodevelopmental impairment in newborns. However, congenital CMV infection cannot be diagnosed using samples collected more than 3 weeks after birth because testing after this time cannot distinguish between congenital infection and postnatal infection. Herein, we developed a robust loop-mediated isothermal amplification (LAMP) assay for the large-scale screening of newborns for congenital CMV infection. In contrast to conventional quantitative polymerase chain reaction (qPCR), which detects CMV within a dynamic range of 1.0 × 106 to 1.0 × 102 copies/µL, our quantitative LAMP assay (qLAMP) detects CMV within a dynamic range of 1.1 × 108 to 1.1 × 103 copies/µL. Moreover, the turnaround time for obtaining results following DNA extraction is 90 min in qPCR but only 15 min in qLamp. The colorimetric LAMP assay can also detect CMV down to 1.1 × 103 copies/µL within 30 min, irrespective of the type of heat source. Our LAMP assay can be utilized in central laboratories as an alternative to conventional qPCR for quantitative CMV detection, or for point-of-care testing in low-resource environments, such as developing countries, via colorimetric naked-eye detection. KEY POINTS: • LAMP assay enables large-scale screening of newborns for congenital CMV infection. • LAMP allows colorimetric or quantitative detection of congenital CMV infection. • LAMP assay can be used as a point-of-care testing tool in low-resource environments.

Proteomic Analysis Reveals Novel Plasma Biomarkers for Neurological Complications in Patients With Congenital Cytomegalovirus Infection.

BACKGROUND: Congenital cytomegalovirus (cCMV) infection is a leading cause of nonhereditary neurological complications. When considering antiviral treatment, it is important to differentiate between symptomatic and asymptomatic patients. This study aimed to identify candidate plasma biomarkers for neurological complications of cCMV infection using proteomic analysis. METHODS: This study retrospectively enrolled five patients with symptomatic cCMV infection, four with asymptomatic cCMV infection with isolated sensorineural hearing loss (SNHL), and five with asymptomatic cCMV infection. The plasma samples were collected during neonatal period. The peptides were analyzed using liquid chromatography-mass spectrometry. The concentrations of differentially expressed proteins were validated using an enzyme-linked immunosorbent assay. RESULTS: A total of 456 proteins were identified and quantified. The levels of 80 proteins were significantly different between patients with and without cCMV-related symptoms including isolated SNHL. The levels of 31 proteins were significantly different between patients with and without neuroimaging abnormalities. The plasma concentrations of Fms-related receptor tyrosine kinase 4 in patients with cCMV-related symptoms were significantly higher than those in patients with asymptomatic cCMV infection. Moreover, plasma peptidylprolyl isomerase A levels were significantly higher in patients with neuroimaging abnormalities than in those without. CONCLUSIONS: Proteomic analysis of patients with cCMV infection showed that Fms-related receptor tyrosine kinase 4 and peptidylprolyl isomerase A could be novel diagnostic biomarkers for neurological complications of cCMV infection.

The Audiological Follow-Up of Children with Symptomatic Congenital Cytomegalovirus Infection: An Experience in Two Italian Centers.

BACKGROUND: Congenital cytomegalovirus (cCMV) infection is the leading cause of non-hereditary sensorineural hearing loss in children. While about 10% of children reportedly display symptoms at birth, 85-90% of cCMV infection cases are asymptomatic. However, 10-15% of these asymptomatic infants may later develop hearing, visual, or neurodevelopmental impairments. This study aimed to evaluate the impact of cCMV infection on newborns' hearing function with a particular emphasis on progressive and late-onset cases. METHODS: This study is a retrospective chart analysis with longitudinal character and was conducted in two Italian centers: Center 1 (from 1 November 2007 to 31 December 2021) and Center 2 (from 1 January 2012 to 31 December 2021). Data collected included newborn hearing screening results, characterization of hearing loss (unilateral/bilateral, degree of impairment), and audiological follow-up. RESULTS: The cohort consisted of 103 children (42% males, 58% females). In total, 28 children presented with hearing impairment; 71.4% (20 out of 28) of the cases of hearing loss were severe/profound, with 35.7% of the cases due to unilateral hearing loss. Out of twenty-eight, six experienced progression of hearing loss and four had late-onset hearing loss. CONCLUSIONS: In the absence of universal cCMV screening, hearing screening at birth for cCMV remains a critical factor for early diagnosis. A significant percentage of children affected by cCMV with normal audiological evaluations at birth is easily lost to follow-up. Close collaboration between neonatologists, pediatricians, and audiological services is fundamental to ensure timely diagnosis and treatment of cCMV-related hearing loss.

Transient Decrease in Incidence Rate of Maternal Primary Cytomegalovirus Infection during the COVID-19 Pandemic in Japan.

This study evaluated the impact of the coronavirus disease 2019 (COVID-19) pandemic on the occurrence of maternal primary cytomegalovirus (CMV) infection in Japan. We performed a nested case-control study using data from maternal CMV antibody screening under the Cytomegalovirus in Mother and infant-engaged Virus serology (CMieV) program in Mie, Japan. Pregnant women with negative IgG antibodies at ≤20 weeks of gestation who were retested at ≥28 weeks were enrolled. The study period was divided into 2015-2019 as the pre-pandemic and 2020-2022 as the pandemic period, and the study site included 26 institutions conducting the CMieV program. The incidence rate of maternal IgG seroconversion was compared between the pre-pandemic (7008 women enrolled) and pandemic (2020, 1283 women enrolled; 2021, 1100 women; and 2022, 398 women) periods. Sixty-one women in the pre-pandemic period and five, four, and five women during 2020, 2021, and 2022, respectively, showed IgG seroconversion. The incidence rates in 2020 and 2021 were lower (p < 0.05) than that in the pre-pandemic period. Our data suggest a transient decrease in the incidence of maternal primary CMV infection in Japan during the COVID-19 pandemic, which could be due to prevention and hygiene measures taken at the population level.

Neurodevelopmental outcome in children with congenital cytomegalovirus infection: A prospective multicenter cohort study.

BACKGROUND: Congenital cytomegalovirus infection (cCMV) is the most common congenital infection worldwide and is a major cause of neurodevelopmental impairment in children. At this point there are insufficient data on neurodevelopmental outcome of children with cCMV, both symptomatic and asymptomatic. AIM: This study aimed to describe the neurodevelopmental outcome in a large prospective cohort of children with cCMV. METHODS: All children with cCMV, included in the Flemish cCMV register, were eligible for this study. Data on neurodevelopmental outcome was available in 753 children. Data on neuromotor, cognitive, behavioral, audiological and ophthalmological outcome were analyzed. RESULTS: Neurodevelopmental outcome was normal in 530/753 (70,4 %) at any age of last follow-up. Mild, moderate and severe neurodevelopmental impairment was found in 128/753 (16,9 %), 56/753 (7,4 %) and 39/753 (5,2 %), respectively. Adverse outcome is found both in the symptomatic and asymptomatic children (53,5 % versus 17,8 %). Autism spectrum disorder (ASD) was diagnosed more often than in the general population in Flanders (2,5 % versus 0,7 %). Speech and language impairment was found in 2 %, even in absence of hearing loss. CONCLUSION: Both symptomatic and asymptomatic cCMV children are at risk of sequelae, with higher risk in case of first trimester infection. During follow-up of this population, special attention should be given to the audiological follow-up, the presence of hypotonia at young age, the possible higher risk of ASD and the risk of speech and language impairment even in absence of hearing loss. Our results emphasize the need for multidisciplinary neurodevelopmental follow-up of all cCMV infected children.

Cytomegalovirus (CMV) seroprevalence among women at childbearing age, maternal and congenital CMV infection: policy implications of a descriptive, retrospective, community-based study.

BACKGROUND: Maternal CMV infection during pregnancy, either primary or non-primary, may be associated with fetal infection and long-term sequelae. While guidelines recommend against it, screening for CMV in pregnant women is a prevalent clinical practice in Israel. Our aim is to provide updated, local, clinically relevant, epidemiological information about CMV seroprevalence among women at childbearing age, the incidence of maternal CMV infection during pregnancy and the prevalence of congenital CMV (cCMV), as well as to provide information about the yield of CMV serology testing. METHODS: We performed a descriptive, retrospective study of women at childbearing age who were members of Clalit Health Services in the district of Jerusalem and had at least one gestation during the study period (2013-2019). We utilized serial serology tests to determine CMV serostatus at baseline and at pre/periconception and identified temporal changes in CMV serostatus. We then conducted a sub-sample analysis integrating inpatient data on newborns of women who gave birth in a single large medical center. cCMV was defined as either positive urine CMV-PCR test in a sample collected during the first 3 weeks of life, neonatal diagnosis of cCMV in the medical records, or prescription of valganciclovir during the neonatal period. RESULTS: The study population Included 45,634 women with 84,110 associated gestational events. Initial CMV serostatus was positive in 89% women, with variation across different ethno-socioeconomic subgroups. Based on consecutive serology tests, the detected incidence rate of CMV infection was 2/1000 women follow-up years, among initially seropositive women, and 80/1000 women follow-up years, among initially seronegative women. CMV infection in pregnancy was identified among 0.2% of women who were seropositive at pre/periconception and among 10% of women who were seronegative. In a subsample, which included 31,191 associated gestational events, we identified 54 newborns with cCMV (1.9/1000 live births). The prevalence of cCMV among newborns of women who were seropositive at pre/periconception was lower than among newborns of women who were seronegative (2.1 vs. 7.1/1000). Frequent serology tests among women who were seronegative at pre/periconception detected most primary CMV infections in pregnancy that resulted in cCMV (21/24). However, among women who were seropositive, serology tests prior to birth detected none of the non-primary infections that resulted in cCMV (0/30). CONCLUSIONS: In this retrospective community-based study among women of childbearing age characterized by multiparity and high seroprevalence of CMV, we find that consecutive CMV serology testing enabled to detect most primary CMV infections in pregnancy that led to cCMV in newborns but failed to detect non-primary CMV infections in pregnancy. Conducting CMV serology tests among seropositive women, despite guidelines' recommendations, has no clinical value, while it is costly and introduces further uncertainties and distress. We thus recommend against routine CMV serology testing among women who were seropositive in a prior serology test. We recommend CMV serology testing prior to pregnancy only among women known to be seronegative or women whose serology status is unknown.

Cytomegalovirus reactivation in a SARS-CoV-2 infected woman experiencing fetal demise in the first trimester with fetal trisomy 21: A case report.

Cytomegalovirus (CMV) is the most common cause of congenital viral infections. Women seropositive for CMV prior to pregnancy can develop a non-primary CMV infection. Here, we present a case of first trimester pregnancy loss during active SARS-CoV-2 infection. There was no evidence of SARS-CoV-2 RNA in placenta and fetal tissue, but there was presence of congenital cytomegalovirus infection by nested PCR. To the best of our knowledge, this is the first report demonstrating association of early congenital CMV infection due to reactivation and fetal demise in a SARS-CoV-2 positive woman with fetal trisomy 21.

Expanded targeted screening for congenital cytomegalovirus infection.

An early diagnosis and intervention for congenital cytomegalovirus infection can reduce long-term disability; however, the introduction of universal neonatal screening has been controversial worldwide. The present study clarified the outcome of a targeted screening protocol for detecting congenital cytomegalovirus infection based on suggestive perinatal conditions. In addition, the positive rate was compared to those from the reported studies and the validity of the targeted screening criteria was discussed. A total of 2121 newborn infants were admitted to our hospital between October 2018 and October 2021. Cytomegalovirus DNA was examined by the isothermal nucleic acid amplification method for urine samples from newborns with any of the following: microcephaly, abnormal ultrasound findings in the brain and visceral organs, repeated failure in neonatal hearing screening, suspicious maternal cytomegalovirus infection during pregnancy, and other abnormal findings suggestive of congenital cytomegalovirus infection. Among 2121 newborns, 102 (4.8%) were subject to the urine cytomegalovirus DNA test based on the abovementioned criteria. Of them, three were cytomegalovirus DNA-positive. According to the protocol, the cytomegalovirus DNA-positive rates were 0.14% among the total enrollment of 2121 newborns and 2.9% (3/102) among the targeted newborns. This protocol may overlook congenital cytomegalovirus infection that is asymptomatic or exhibits inapparent clinical manifestations only at birth; however, it is feasible and helps lead to the diagnosis of congenital cytomegalovirus infection that may otherwise be overlooked.

Long-term outcome of vestibular function and hearing in children with congenital cytomegalovirus infection: a prospective cohort study.

PURPOSE: Congenital cytomegalovirus infection (cCMV) is the most frequent nonhereditary cause for sensorineural hearing loss (SNHL) in children. Data on vestibular function in children with cCMV are, however, scarce, although some evidence for cCMV-associated vestibular dysfunction exists. In this prospective cohort study, we evaluated long-term vestibular function and hearing outcomes in a cohort of children with cCMV. METHODS: Participants were 6-7-year-old children with cCMV from a large population-based screening study. Controls were age and gender matched healthy children, who were CMV-negative at birth. Hearing was examined with pure tone audiometry. Definition of hearing loss was pure-tone average > 20 dB. Vestibular function was assessed using the video head impulse test that provides a measure of semicircular canal function. Definition of vestibular dysfunction was lateral semicircular canal gain < 0.75. RESULTS: Vestibular dysfunction occurred in 7/36 (19.4%) of children with cCMV and in 1/31 (3.2%) of controls (p = 0.060). SNHL was recorded in 4/38 (10.5%) of children with cCMV and in 0/33 of controls (p = 0.118). Hearing loss was unilateral in all cases. In cCMV group, the two children with bilateral vestibular dysfunction also had SNHL, whereas those with unilateral vestibular dysfunction (n = 5) had normal hearing. CONCLUSIONS: In this cohort of children with cCMV identified using newborn screening, vestibular dysfunction was more common than SNHL at 6 years of age. Vestibular dysfunction occurred both in children with and without SNHL. Based on these data, inclusion of vestibular tests in follow-up protocol of cCMV should be considered.

Prognostic Value of Amniotic Fluid Viral Load to Predict Adverse Outcome in Pregnancies Complicated by Congenital Cytomegalovirus Infection: A Multicenter Study.

INTRODUCTION: The aim of the study was to report the prognostic value of cytomegalovirus (CMV) viral load in the amniotic fluid (AF) in predicting the outcome of infected pregnancies. METHODS: Multicenter retrospective study involving 11 Italian referral centers from 2012 to 2021 was conducted. Inclusion criteria were fetuses with confirmed congenital CMV infection. The primary outcome was the prognostic value accuracy of CMV quantitative polymerase chain reaction (qPCR) in AF in predicting the risk of additional anomalies detected either at follow-up ultrasound or fetal magnetic resonance imaging (MRI). The secondary outcome was prediction of postnatal clinical symptoms related to CMV infection. Multivariate logistic regression and area under the curve (AUC) analyses were used to analyze the data. RESULTS: 104 fetuses were included. Associated anomalies detected at follow-up ultrasound or fetal MRI were detected in 14.4% of cases (15/104). Mean AF CMV viral load was significantly higher in fetuses with additional anomalies compared to those without additional anomalies at follow-up ultrasound or fetal MRI (3,346,634.27 ± 402,582.95 vs. 761,934 ± 222513,2 p < 0.001). At multivariate logistic regression analysis, CMV AF viral load was independently associated with the presence of additional anomalies at follow-up ultrasound or MRI, with an OR of 1.07 (p = 0.010), while maternal age (p = 0.24), trimester at maternal infection (p = 0.97), and type of infection (primary vs. non-primary) (p = 0.12) were not. CMV AF viral load had AUC of 0.755 for the occurrence of anomalies due to CMV infection, with an optimal cut-off point of >1,310,520 copies/mL, a sensitivity of 66.7%, a specificity of 84.3%, and a positive likelihood ratio of 4.24. Once excluding fetuses with anomalies at ultrasound or MRI, the diagnostic performance of qPCR in identifying fetuses with symptomatic infection after birth was low, with an AUC of 0.586. CONCLUSION: CMV viral load at second trimester amniocentesis has a moderate accuracy for the occurrence of CMV-related anomalies in fetuses with congenital infection and normal ultrasound at the initial diagnosis. Conversely, prediction of symptomatic infection is low.

Fetal Ultrasound and Magnetic Resonance Imaging Abnormalities in Congenital Cytomegalovirus Infection Associated with and without Fetal Growth Restriction.

Congenital cytomegalovirus infection (cCMV) can cause fetal growth restriction (FGR) and severe sequelae in affected infants. Clinicians generally suspect cCMV based on multiple ultrasound (US) findings associated with cCMV. However, no studies have assessed the diagnostic accuracy of fetal US for cCMV-associated abnormalities in FGR. Eight FGR and 10 non-FGR fetuses prenatally diagnosed with cCMV were examined by undergoing periodic detailed US examinations, as well as postnatal physical and imaging examinations. The diagnostic accuracy of prenatal US for cCMV-associated abnormalities was compared between FGR and non-FGR fetuses with cCMV. The diagnostic sensitivity rates of fetal US for cCMV-related abnormalities in FGR vs. non-FGR fetuses were as follows: ventriculomegaly, 66.7% vs. 88.9%; intracranial calcification, 20.0% vs. 20.0%; cysts and pseudocysts in the brain, 0% vs. 0%; ascites, 100.0% vs. 100.0%; hepatomegaly, 40.0% vs. 100.0%; splenomegaly, 0% vs. 0%. The diagnostic sensitivity of fetal US for hepatomegaly and ventriculomegaly in FGR fetuses with cCMV was lower than that in non-FGR fetuses with cCMV. The prevalence of severe long-term sequelae (e.g., bilateral hearing impairment, epilepsy, cerebral palsy, and severe developmental delay) in the CMV-infected fetuses with FGR was higher, albeit non-significantly. Clinicians should keep in mind the possibility of overlooking the symptoms of cCMV in assessing fetuses with FGR.

Neonatal and long-term outcomes of infants with congenital cytomegalovirus infection and negative amniocentesis: systematic review and meta-analysis.

OBJECTIVE: Cytomegalovirus (CMV) DNA is detectable in the amniotic fluid collected by amniocentesis in cases in which the fetus has been infected. However, cases of congenital neonatal CMV infection with a negative amniocentesis result have also been reported in the literature. The aim of the present study was to compare pregnancies with a negative amniocentesis result to those with a positive amniocentesis result in terms of incidence of fetal insult and long-term sequelae. METHODS: Observational studies that included pregnant women with CMV infection who underwent amniocentesis and that reported their results together with neonatal and/or long-term outcomes of the offspring were included. The risk of bias in included studies was assessed using the Newcastle-Ottawa Scale. The rate of severe symptoms at birth, defined as neurological symptoms or multiorgan involvement at birth, and the rate of severe sensorineural hearing loss (SNHL) and/or neurodevelopmental impairment at follow-up were the main outcomes of the study. The secondary outcome was the rate of pregnancy termination due to the presence of CMV-associated central nervous system (CNS) findings or multiorgan involvement on ultrasound/magnetic resonance imaging (MRI). RESULTS: Seven studies were included in the systematic review and meta-analysis. The pooled false-negative rate of amniocentesis was 8.0% (95% CI, 5.0-13.0%). The pooled rate of severe symptoms at birth was 0.0% (95% CI, 0.0-1.0%; I2 = 0%) in fetuses with a negative amniocentesis result and 22.0% (95% CI, 11.0-38.0%; I2 = 75%) in those with a positive amniocentesis result. The pooled odds ratio (OR) was 0.03 (95% CI, 0.01-0.10; I2 = 0%). The pooled rate of severe SNHL and/or neurodevelopmental impairment at follow-up in fetuses with a negative amniocentesis result was 0.0% (95% CI, 0.0-1.0%; I2 = 0%) and, in those with a positive amniocentesis result, it was 14.0% (95% CI, 7.0-26.0%; I2 = 64%). The pooled OR was 0.04 (95% CI, 0.01-0.14; I2 = 0%). The pooled rate of pregnancy termination due to the presence of CMV-associated CNS findings or multiorgan involvement on ultrasound/MRI was 0.0% (95% CI, 0.0-2.0%; I2 = 0%) in fetuses with a negative amniocentesis result and 20.0% (95% CI, 10.0-36.0%; I2 = 82%) in those with a positive amniocentesis result. The pooled OR was 0.03 (95% CI, 0.01-0.08; I2 = 0%). A subgroup analysis including only pregnancies with primary CMV infection and a sensitivity analysis including only prospective studies were carried out, showing very similar results to those of the main analysis. CONCLUSION: A negative amniocentesis result in pregnant women with CMV infection ensures lack of fetal insult and long-term sequelae to the child, even if transmission has occurred. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Late-onset and congenital hearing loss detected using AABR due to congenital cytomegalovirus infection that improved with valganciclovir.

Congenital cytomegalovirus (cCMV) infection is the most common congenital viral infection and is the leading non-genetic cause of sensorineural hearing loss and an important cause of neurodevelopmental disabilities. Auto auditory brainstem response (AABR) is a simple hearing test and used for the purpose of neonatal hearing screening, but can use it for early detection hard of hearing within the study age of the model. We experienced two case of asymptomatic CMV infection in which congenital and late-onset hearing loss were diagnosed early with AABR, and hearing loss improved with valganciclovir.