Neopterin as a marker of congenital cytomegalovirus infection.

Predicting mid-term hearing and developmental outcome in clinically inapparent congenital cytomegalovirus infection with hearing loss at birth.

Congenital cytomegalovirus (cCMV) is the leading infectious cause of birth defects worldwide, yet immune determinants of protection to inform maternal vaccine design remain elusive due to the lack of a translational animal model. Here, we characterized the outcome of primary rhesus CMV (RhCMV) infection in pregnant, immunocompetent, RhCMV-naïve rhesus macaques. RhCMV DNA was detected in amniotic fluid and/or fetal tissues in six of 12 (50% placental transmission) dams following early second trimester gestation RhCMV inoculation. Widespread tissue dissemination dominated by one of two inoculated RhCMV strains was present in one fetus (8.3% cCMV disease). RhCMV DNA detection in the amniotic fluid was associated with elevated fetal and maternal plasma TNF-alpha and reduced maternal brain-derived neurotrophic factor and IL-10 levels. Maternal RhCMV exposure during pregnancy had a broad impact on the placenta and fetus even in the absence of congenital infection, as evidenced by ubiquitous maternal-fetal interface infection, and reduced placental efficiency and small-for-gestation age fetuses compared to control pregnancies. This model provides new insights into the complexity of CMV vertical transmission and can be used to evaluate immune and viral determinants of protection against cCMV.

In utero acquisition of cytomegalovirus (CMV) represents the most common infectious cause of paediatric developmental disability. With a global prevalence of approximately 0.7%, congenital CMV (cCMV) infection can produce wide-ranging injury to the developing fetal and neonatal central nervous system, leading to microcephaly, intracranial calcifications, neuronal migration defects and damage to the developing cochlea and retina. Clinical sequelae include cerebral palsy, seizure disorder, intellectual disabilities, developmental delay, autism spectrum disorders, sensorineural hearing loss (SNHL) and visual impairment. It has been generally believed that most cCMV infections are asymptomatic in nature, and are not associated with long-term neurodevelopmental impairment. This dogma, however, has been called into question in the context of several state and provincial universal cCMV screening programmes that have been implemented in recent years in the United States and Canada. Moreover, the full spectrum of neurodevelopmental sequelae amongst asymptomatic cCMV cases is just starting to be recognized. Host and/or viral factors that predict which asymptomatic infants will have sequelae, including SNHL, are unknown. This review summarizes the current state of the art with respect to the search for predictive biomarkers that can inform the prognosis of asymptomatic cCMV, and aid in decision-making about therapeutic intervention.This article is part of the discussion meeting issue 'The indirect effects of cytomegalovirus infection: mechanisms and consequences'.

Introduction: Testing for congenital Cytomegalovirus (cCMV) infection is not part of routine care in resource-limited settings. Consequently, the diagnosis is often missed because most infections are asymptomatic and when present, symptoms are non specific. Diagnosis is required to prevent long-term sequelae. Aim: To introduce a clinical screening strategy for detecting possible CMV infections, including both congenital and postnatal infections among symptomatic neonates/infants presenting after 21 days. Materials and Methods: In this cross-sectional study, 387 subjects with clinical signs or symptoms compatible with congenital or postnatal CMV infection from birth to 365 days of life were included from three metropolitan hospitals in Kolkata, West Bengal, India, from January 2018 to March 2020. CMV infection was determined by Polymerase Chain Reaction (PCR) analysis of the urine. The Constellation of Symptoms (COS) was employed as a clinical screening tool for subjects older than 21 days. The Chi-square test was used to compare categorical variables, while the Mann-Whitney U test assessed differences in numerical data. Results: Of the 387 subjects with compatible signs or symptoms, 126 (32.6%) tested positive for CMV. Among the CMV-infected group, 8 (6.3%) presented within 21 days, while 118 (93.7%) presented after 21 days. CMV-infected infants had slightly lower birth weight and younger age at presentation compared with CMV-negative infants, though the differences were not statistically significant. The presence of individual symptoms of CMV infection did not differ significantly between CMV-positive and CMV-negative groups (p-value>0.05). However, the COS was significantly associated with CMV positivity (p-value<0.001). The sensitivity and specificity of COS were in the ranges of 77%-81% and 40%-44%, respectively. The Positive Predictive Value (PPV) and Negative Predictive Value (NPV) were in the ranges of 38%-44% and 75%-82%, respectively. Conclusion: The COS-based strategy will be a valuable tool for screening symptomatic CMV infections in individuals up to one year of age in resource-limited settings where routine CMV screening is unavailable.

Congenital cytomegalovirus awareness and screening practices among healthcare providers in Poland: The CASP-D web-based cross-sectional study.

Clinically Recognized Congenital Cytomegalovirus Infection and the Risk of Neurodevelopmental Disorders

Hearing Trajectories in Congenital Cytomegalovirus Infection: A 4-Year Follow-Up Study.

BackgroundCytomegalovirus is a leading cause of congenital disease, and multiple strains enable congenital CMV (cCMV) from both primary and non-primary infections. Therefore, a cross-strain protective cCMV vaccine is a high priority. Guinea pigs are the only small animal model for cCMV and guinea pig cytomegalovirus (GPCMV) encodes functional homolog proteins, including cell entry gB glycoprotein and non-structural immediate early 1 protein (IE1), which are essential for lytic infection. A gB vaccine antibody response fails to provide horizontal protection against highly cell-associated clinical GPCMV strain TAMYC compared to prototype strain 22122. Previously, a recombinant defective adenovirus (Ad) vaccine encoding IE1, a T cell antigen, provided high-level cCMV protection. In this study, we hypothesized that a combined Ad-based strategy encoding trimeric gB complex and IE1 (AdgB + AdIE1) could improve cross-strain protection against cCMV compared to a gB vaccine (AdgB).MethodsA preconception vaccine study was conducted to evaluate the immune response and ability of vaccines to provide cross-strain protection against cCMV. Seronegative female animals were assigned to three vaccine groups: Group 1 (AdgB), Group 2 (AdgB + AdIE1), and Group 3 (no vaccine). Animals were vaccinated following a previously defined protocol, and antibody ELISAs were used to evaluate the gB immune response (AD1, prefusion gB, and wild-type gB). Additionally, an IFNγ-ELISPOT assay was used to evaluate the IE1 T-cell response. During the second trimester, dams were challenged with GPCMV (22122 and TAMYC co-infection), and pregnancy proceeded to term. Viral loads in pup target organs (liver, lung, spleen, brain), blood, and placenta were evaluated.ResultsVaccinated dams elicited a higher gB neutralizing antibody response than that of experimentally infected convalescent animals. Antibodies recognized homolog AD1 gB domain as well as prefusion gB with a response surpassing that in GPCMV-infected convalescent animals. Group 2 dams also elicited a T cell response to IE1. Evaluation of viral load in pups demonstrated that the AdgB + AdIE1 vaccine reduced GPCMV transmission to below detectable limits compared to 91.7% in the unvaccinated group. In contrast, AdgB reduced cCMV transmission to 12% in the pups.ConclusionComplete cross-strain cCMV protection is a significant milestone in this model and is achieved by the inclusion of an antibody response to trimeric gB and T-cell response to IE1. Importantly, gB and IE1 responses can synergize and increase protection against cCMV, unlike prior approaches with gB and pp65 tegument proteins.

Background/Objectives: Cytomegalovirus (CMV)-associated hearing loss is common in non-genetic congenital hearing loss. Despite this high prevalence, a wide range of clinical characteristics exists, and the pattern of hearing loss remains unknown. This study aims to describe the clinical manifestations in children with CMV-associated hearing loss and to clarify the timing of hearing level change and the degree of hearing level fluctuation. Methods: A total of 54 patients with hearing loss due to congenital CMV infection were included. Hearing loss type (congenital or later onset), hearing loss laterality (unilateral or bilateral), severity at first and last visit, hearing progression and timing, and the difference between patients with intellectual disability and without intellectual disability were assessed. Results: The number of patients with congenital hearing loss and later onset hearing loss were 19 patients and 13 patients, respectively. Seventy-four percent (14/19) of the congenital hearing loss patients and 62% (8/13) of the later onset hearing loss patients eventually progressed to severe to profound hearing loss bilaterally. Progression occurred in less than 1 year (9 cases), between 1 and 3 years (7 cases), between 3 and 7 years (4 cases), or more than 8 years (1 case). Multiple progression events occurred in 11 cases. Conclusions: Sixty-one percent of patients had progression of hearing loss. Several cases experienced progression over more than one year and showed multiple progression events. CMV patients without intellectual disability tended to suffer later onset hearing loss. Sixty-nine percent of the patients eventually progressed to bilateral severe to profound hearing loss, which means that continuous long-term follow-up is required.

Introduction: Congenital cytomegalovirus (cCMV) infection is the foremost non-genetic etiology of sensorineural hearing loss (SNHL) in the pediatric population, representing a significant global public health challenge (Pignataro et al., 2024). The clinical presentation of cCMV is markedly heterogeneous, ranging from asymptomatic infection to severe, multi-system disease. The early identification of newborns at the highest risk for congenital SNHL represents a significant clinical challenge, as hearing loss can be present at birth or have a delayed onset (Goderis et al., 2014). This systematic review aims to comprehensively identify, appraise, and synthesize the existing evidence on maternal, neonatal, and diagnostic risk factors that are predictive of SNHL present at birth in newborns with confirmed cCMV. Methods: A systematic literature search was conducted across the PubMed, Google Scholar, Semanthic Scholar, Springer, Wiley Online Library databases for cohort, case-control, and cross-sectional studies published through 2024. Studies were deemed eligible for inclusion if they investigated specific risk factors for congenital SNHL in newborns with virologically confirmed cCMV infection within the first 21 days of life (Rawlinson et al., 2017). The methodological quality and risk of bias of included non-randomized studies were rigorously assessed using the Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) tool. Data were extracted and narratively synthesized, categorized by the specific domain of the risk factor. Results: A total of 17 studies, encompassing over 3,000 newborns with cCMV, met the inclusion criteria. The synthesis of evidence revealed several consistent and significant predictors of congenital SNHL. Key risk factors included maternal primary infection occurring within the first trimester of pregnancy (De Cuyper et al., 2022; Foulon et al., 2019), the presence of symptomatic disease at birth, particularly with evidence of central nervous system (CNS) involvement (Pignataro et al., 2024; Rivera et al., 2002), and specific abnormalities on neonatal neuroimaging, such as periventricular cysts on magnetic resonance imaging (MRI) (De Cuyper et al., 2022) and temporal-pole white matter abnormalities (Fink et al., 2024). The clinical finding of petechiae at birth also emerged as a strong independent predictor of congenital SNHL (De Cuyper et al., 2022). In contrast, the predictive utility of neonatal viral load measurements was found to be inconsistent across the analyzed studies (Boppana et al., 2005; Walter et al., 2008). Discussion: The synthesized evidence strongly indicates that the risk of congenital SNHL is not uniformly distributed among all newborns with cCMV. A distinct risk gradient exists, which is powerfully linked to the timing of maternal infection and the degree of viral impact on the neonatal central nervous system (Rivera et al., 2002). Neuroimaging, particularly brain MRI, emerges from this review as a paramount prognostic instrument for early risk stratification, capable of identifying specific lesions that confer a high risk of adverse outcomes (Fink et al., 2024; Manara et al., 2021). Conclusion: Maternal primary infection in the first trimester, clinical signs of CNS involvement at birth, specific neuroimaging findings, and the presence of petechiae are significant and clinically relevant risk factors for congenital SNHL in newborns with cCMV. These identified factors can be effectively utilized for early risk stratification, guiding targeted audiological surveillance, and facilitating informed parental counseling (De Cuyper et al., 2022).

Ganciclovir remains the primary therapeutic for cytomegalovirus (CMV) infections in early infancy, but its pharmacokinetics and dosing in very preterm infants with end-organ CMV disease have not been fully evaluated. Premature infants with confirmed CMV infection and receiving ganciclovir as standard of care were enrolled into a pharmacokinetic sampling study. All were <32 weeks gestational age and >500 grams at enrollment. Plasma for ganciclovir quantitation was collected at steady-state at 0, 1, and between 2-3, 5-7, and 10-12 hours post-dose. Specimens were shipped, analyzed, and pharmacokinetic parameters calculated in real-time. Noncompartmental and modeling approaches were used for analysis. Eighteen infants were enrolled; mean gestational age at delivery was 26.7 weeks, and mean age and weight at enrollment were 42 days and 1519.0 grams, respectively. Seventeen completed pharmacokinetic assessments. Geometric mean dose and resulting 12 hour area-under-the-curve (AUC12) were 5.19 mg/kg and 52.7 mgxh/L, respectively. A total of 85 ganciclovir concentration-time data points were available for modeling. A one-compartment power covariate model with weight and serum creatinine on clearance and weight on distribution volume was used. Noncompartmental and modeled pharmacokinetic parameters were similar. These are the first intravenous ganciclovir population pharmacokinetic data with covariate assessments in premature infants being treated for CMV disease. Results suggest an intravenous dose of 5 mg/kg/dose every 12 hours may be an appropriate starting regimen for treatment of premature infants with congenital CMV. Additional data are needed in this and other populations to better define optimal ganciclovir exposure targets.

ObjectivesTo describe the impact associated with congenital cytomegalovirus (cCMV) infection and experiences and perceptions of people with experience of CMV in pregnancy and families / caregivers of children diagnosed with cCMV, who responded to a UK National Screening Committee (UK NSC) public consultation on cCMV screening.MethodsThe public consultation was conducted in 2021-22 on a draft evidence review and was aimed at informing the UK NSC's decision on newborn screening for cCMV. Data were analysed using framework analysis: a subgroup of responses was inductively coded, codes were refined and initial themes identified, before targeted coding of the remainder of the data and identification of final themes and sub-themes.ResultsOf a total 155 responses, 125 (describing 128 pregnancy/child outcomes) contained information relevant to the coding framework and were included. Most (n = 109) described a live birth of a surviving child, of whom 90% (98/109) were living with symptoms or long-term sequelae of cCMV at the time of the response. Two main themes were identified: missed opportunities and emotional impacts attributed by respondents to not screening for cCMV. Many families described delays in their child's cCMV diagnosis, including due to healthcare professionals' lack of awareness of cCMV, and viewed newborn screening as a solution to avoid delays in diagnostic pathways. Diagnostic delays resulted in a lasting sense of injustice and unfairness due to possible missed opportunities to improve outcomes (e.g., through antiviral treatment or early therapies), as well as uncertainty and anxiety.ConclusionsResponses were predominantly from parents and caregivers of children with cCMV who experienced long term disability. They highlight significant gaps in awareness, support and health care for affected children that need addressing, regardless of national screening policy decisions. These responses contribute to the literature on lived experiences of individuals and families affected by cCMV.

Evaluate screening practices for congenital cytomegalovirus (cCMV), the most common infectious cause of childhood deafness, in American birthing hospitals. A survey was developed and distributed to hospitals across the US including the Northeast, Midwest, West, and Southwest between November-December 2023 to understand cCMV screening practices. Summary data were calculated. Hospital characteristics associated with screening were analyzed using a logistic regression model. Hospital practice was reported as a function of legislative mandate. 134 responses were received (28.5% response rate). 78 respondents (58.2%) indicated their hospital screens for cCMV. Common screening indications were newborn hearing screen referral (67.5%) and symptoms that could be attributed to cCMV (57.1%). Odds ratio of cCMV screening for states with screening legislation versus without was 18.0 (p < 0.001). Odds ratio of cCMV screening for urban, level 3 facilities versus rural, level 1 facilities was 6.7 (p < 0.02). Wide variability exists in cCMV screening practices. Legislative screening mandates are associated with higher screening rates. Opportunity exists for development of screening guidelines for newborns at risk for cCMV infection.

Congenital cytomegalovirus (CMV) infection, a leading cause of sensorineural hearing loss and neurological impairment, is typically diagnosed by second-trimester amniocentesis, delaying clinical decision-making. This study aimed to assess the predictive value of maximum trophoblast thickness (MTT) measured by first-trimester three-dimensional (3D) ultrasound, in combination with maternal biomarkers, for the early prediction of CMV vertical transmission. This was a retrospective cohort study of pregnant women, not previously seropositive for CMV, who were referred to Necker-Enfants malades Hospital between October 2019 and May 2024 for maternal primary infection (MPI) with CMV in early pregnancy. Multiple pregnancies and fetuses with genetic anomaly were excluded. MTT measurement was performed using 3D multiplanar ultrasound between 11 + 0 and 14 + 6 weeks' gestation by two independent observers. Interobserver agreement for MTT measurement was assessed using the intraclass correlation coefficient (ICC). We recorded maternal characteristics, including first-trimester maternal biomarkers (pregnancy-associated plasma protein-A, free β-human chorionic gonadotropin and placental growth factor) and CMV polymerase chain reaction (PCR) status in the maternal blood and urine. Vertical transmission was confirmed by CMV-PCR in chorionic villi (CV) and/or amniotic fluid (AF). Thepredictive value of MTT, alone and in combination with relevant covariables, was assessed using logistic regression models and receiver-operating-characteristics (ROC)-curve analysis. A total of 127 pregnant women with a median gestational age (GA) at CMV-MPI of 2.0 (interquartile range, -2.5 to 7.0) weeks were included, of whom 120 (94.5%) received valacyclovir for secondary prevention. CMV-PCR was positive in 7.1% of CV samples (median GA at sampling, 13.7 weeks) and 9.4% of AF samples (median GA at sampling, 17.4 weeks). MTT was significantly higher in cases with a positive CMV-PCR result in AF compared to those with a negative result (median, 21.3 mm vs 17.1 mm; P = 0.017). The ICC for MTT measurement was 0.827 (95% CI, 0.763-0.875), indicating good interobserver reproducibility. ROC-curve analysis identified 19.0 mm as the optimal MTT threshold, yielding a sensitivity of 83.33% (95% CI, 62.25-100%) for predicting vertical transmission. When combined with CMV-PCR positivity in the maternal blood in the first trimester and delayed valacyclovir initiation beyond 10 weeks, the predictive model achieved an area under the ROC curve of 0.94 (95% CI, 0.87-0.99) for CMV-PCR positivity in AF, with a sensitivity of 80.00% (95% CI, 44.39-97.48%), specificity of 93.26% (95% CI, 85.90-97.49%), positive predictive value of 57.14% (95% CI, 36.71-75.40%) and negative predictive value of 97.65% (95% CI, 92.31-99.31%). Increased MTT measured by 3D ultrasound in the first trimester is associated with CMV vertical transmission and may serve as an early non-invasive marker. Combining MTT with CMV-PCR status in the maternal blood and timing at initiation of treatment improves predictive accuracy and could guide early counseling and targeted invasive testing. © 2025 International Society of Ultrasound in Obstetrics and Gynecology.

Immunological profile of pregnant women with preconception immunity with or without vertical transmission of human cytomegalovirus to the fetus: a retrospective observational study.

Cytomegalovirus (CMV) is a leading cause of congenital infection and long-term clinical complications, such as sensorineural hearing loss and neurological impairment. This study determines the distribution of CMV glycoprotein N (gN) variants and their potential effect on the occurrence of cytomegaly symptoms in infants. A total of 95 neonates with congenital CMV (cCMV) infection and 126 symptomatic infants with postnatal CMV (pCMV) or unproven cCMV infection were recruited for the study. The UL73 genotyping was performed by nested PCR-RFLP and sequencing, while the CMV DNA load was evaluated by quantitative RT-PCR. The gN3a variant was detected more frequently in neonates with cCMV infection than in infants with pCMV or unproven cCMV infection (p < 0.005), while the gN4b genotype was more common in infants than in newborns (p = 0.010). cCMV infection with the gN4c variant increased the risk of neurological dysfunction and sensorineural hearing loss (p = 0.018 and p = 0.010, respectively). At the same time, the gN1 genotype was associated with a decreased risk of anemia (p = 0.007), while gN3b reduced the risk of thrombocytopenia in examined neonates (p = 0.014). No correlation was found between the gN variants and viral load. Our results suggest that the gN4c variant may be associated with the development of neurological dysfunction in newborns with cCMV infection.

Cytomegalovirus infection prevention counseling during pregnancy in France: A national population-based study.

The effect of valacyclovir on secondary prevention of congenital cytomegalovirus infection.

Advancements and potential in the prevention of congenital CMV infection.