Newborn congenital cytomegalovirus screening and hearing outcomes: a systematic review of current literature.

PURPOSE OF REVIEW: The purpose of this review is to summarize the very recent literature surrounding hearing outcomes of children with congenital cytomegalovirus (cCMV) detected through systematic screening programs. RECENT FINDINGS: There are several different approaches to cCMV screening including forms of targeted vs. universal screening of newborns as well as maternally-derived prenatal testing. However, many studies fail to document hearing-related outcomes both in the newborn period and further into childhood when late-onset sensorineural hearing loss (SNHL) can occur. This systematic review included studies of neonates screened for cCMV reporting hearing outcomes for at least one point in time. Hearing targeted screening appeared the most widely reported for detection of unilateral and bilateral SNHL in those with cCMV. A few studies examined these clinical findings in relation to antiviral treatment. SUMMARY: Congenital CMV is an important and common cause of childhood hearing loss. Newborn screening programs may expand opportunities for early diagnosis and treatment of the infection and its sequelae.

Autism Spectrum Disorder Diagnoses and Congenital Cytomegalovirus.

OBJECTIVE: To examine the association between congenital cytomegalovirus (cCMV) and autism spectrum disorder (ASD) administrative diagnoses in US children. METHODS: Cohort study using 2014 to 2020 Medicaid claims data. We used diagnosis codes to identify cCMV (exposure), ASD (outcome), and covariates among children enrolled from birth through ≥4 to <7 years. Covariates include central nervous system (CNS) anomaly or injury diagnosis codes, including brain anomaly, microcephaly within 45 days of birth, cerebral palsy, epilepsy, or chorioretinitis. We used Cox proportional hazards regression models to estimate hazard ratios and 95% confidence intervals, overall and stratified by sex, birth weight and gestational age outcome (low birth weight or preterm birth), and presence of CNS anomaly or injury. RESULTS: Among 2 989 659 children, we identified 1044 (3.5 per 10 000) children with cCMV and 74 872 (25.0 per 1000) children with ASD. Of those with cCMV, 49% also had CNS anomaly or injury diagnosis codes. Children with cCMV were more likely to have ASD diagnoses (hazard ratio: 2.5; 95% confidence interval: 2.0-3.2, adjusting for birth year, sex, and region). This association differed by sex and absence of CNS anomaly or injury but not birth outcome. CONCLUSIONS: Children with (versus without) cCMV diagnoses in Medicaid claims data, most of whom likely had symptomatic cCMV, were more likely to have ASD diagnoses. Future research investigating ASD risk among cohorts identified through universal cCMV screening may help elucidate these observed associations.

Estimates of congenital cytomegalovirus-attributable infant mortality in high-income countries: A review.

As many as 5%-10% of infants with symptomatic congenital cytomegalovirus (cCMV) disease, or 0.4%-0.8% of all liveborn infants with cCMV infection, die in early infancy in high-income countries. However, estimates are uncertain due to several potential biases that can result from data limitations and study designs. First, infants with cCMV infections who die prior to diagnosis, which usually occurs at 1-4 weeks after birth, may be excluded from both the count of deaths and the denominator of cCMV births, resulting in left truncation and immortal time biases. These 'biases' are features of the data and do not reflect bias on the part of researchers, but understanding the potential existence of threats to validity can help with interpretation of findings. Left truncation of infant deaths occurring prior to diagnosis of cCMV can result in understatement of the burden of infant deaths due to cCMV. Conversely, overestimation of infant deaths associated with symptomatic cCMV may occur in clinical case series owing to greater representation of relatively severely affected infants owing to ascertainment and referral biases. In this review, we summarise the characteristics of 26 studies that reported estimates of cCMV-associated infant deaths, including potential biases or limitations to which those estimates may have been subject. We discuss study designs whose implementation might generate improved estimates of infant deaths attributable to cCMV. More complete estimates of the overall public health impact of cCMV could inform current and future screening, prevention, and vaccine research.

Neurodevelopmental outcomes of children with congenital cytomegalovirus: a systematic scoping review.

BACKGROUND: With the emergence of newborn congenital cytomegalovirus (cCMV) screening programs, more infants are being diagnosed and require long-term follow-up. The objective of the study was to summarize the literature to date on neurodevelopmental outcomes in children with cCMV with attention to study-specific definitions of disease severity (symptomatic vs. asymptomatic). METHODS: This systematic scoping review included studies of children with cCMV (≤18 years-old) measuring neurodevelopment in ≥1 domain: global, gross motor, fine motor, speech/language, and intellectual/cognitive. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. PubMed, PsychInfo, and Embase databases were searched. RESULTS: 33 studies met inclusion criteria. Global development most frequently measured (n = 21), followed by cognitive/intellectual (n = 16) and speech/language (n = 8). Most (31/33) studies differentiated children by cCMV severity (symptomatic vs. asymptomatic), definitions of which ranged broadly. 15/21 studies described global development categorically (e.g., normal vs. abnormal). Across studies and domains, children with cCMV generally had equivalent or lower scores (vs. controls or normed measures). CONCLUSIONS: Variation in definitions of cCMV severity and blunt categorical outcomes may limit the generalizability of findings. Future studies should utilize standardized definitions of disease severity and in-depth measurement and reporting of neurodevelopmental outcomes in children with cCMV. IMPACT: Neurodevelopmental delays are common among children with cCMV, although gaps in the literature to have made quantification of such delays challenging. Variation in definitions of asymptomatic and symptomatic cCMV as well as the use of categorical outcomes of neurodevelopment (e.g., normal vs. abnormal) limits the generalizability and clinical utility of findings.

Developmental trajectories of eating behaviors and cross-lagged associations with weight across infancy.

Examining typical developmental trajectories of infant eating behaviors, correlates of those trajectories, and cross-lagged associations between eating behaviors and anthropometry, is important to understand the etiology of these behaviors and their relevance to growth early in the lifespan. Mothers (N = 276) completed the Baby Eating Behavior Questionnaire (BEBQ) and infant anthropometrics were measured at ages 1, 2, 4, 6, and 10 months. Infant and maternal characteristics were collected by maternal report. Trajectories of eating behaviors were identified using latent class growth modeling and bivariate analyses examined associations of infant eating behavior trajectory membership with infant and maternal characteristics. Cross-lagged analyses examined associations between BEBQ subscales and infant weight-for-length z-score. Infant eating behavior trajectories included: Consistently High (62%) and Consistently Moderate (38%) Enjoyment of Food; Consistently High (9%), Moderate & Decreasing (43%), and Low & Decreasing (48%) Food Responsiveness; and Consistently High (62%) and Moderate & Decreasing (38%) General Appetite. Trajectory group membership was not associated with infant sex, gestational age, birthweight, or having been exclusively fed breastmilk at 2 months. Consistently High trajectories for Enjoyment of Food, Food Responsiveness, and General Appetite were associated with maternal demographic markers of psychosocial risk (e.g., lower maternal age and educational attainment). Food Responsiveness and General Appetite tracked strongly across infancy within individuals. Cross-lagged associations of Enjoyment of Food, Food Responsiveness, and General Appetite with weight-for-length z-score across infancy were generally null. Much additional work is needed to understand eating behaviors in infancy, their development, and their etiology. Further understanding of infant eating behaviors will provide the basis for future interventions to improve life course nutrition, growth, and health.

The Psychosocial Impact of Congenital Cytomegalovirus on Caregivers and Families: Lived Experiences and Review of the Literature.

Caring for a child with congenital cytomegalovirus (cCMV) can be costly for families, not only in terms of out-of-pocket expenses, but also in terms of caregiver time, relationships, career trajectories, and mental health. These additional burdens are sometimes referred to as "spillover effects". As parents of children with cCMV, we, the authors of this article, discuss the impact that cCMV has had on our families. While multiple studies have reported on the epidemiology, prevention, screening, diagnosis, and management of cCMV, there has been minimal research regarding the possible impact on the family unit. In this narrative review, we discuss the various areas of the lives of families and caregivers that may be impacted by raising a child with cCMV. Whether children are minimally or severely affected by the sequelae of cCMV, they and their families merit the progression of awareness of the virus and governmental policies to help end cCMV. As the existing cCMV-specific literature is limited, we correlate studies of other childhood disabilities and find the mutuality experienced by families affected by cCMV.

Early childhood outcomes of NICU graduates with cytomegalovirus infection in California.

BACKGROUND: To assess demographics and outcomes up to 3 years of age among children with cytomegalovirus (CMV) infection in California neonatal intensive care units (NICUs) during 2010-2021. METHODS: The California Perinatal Quality Care Collaborative (CPQCC) collects data on all very low birth weight (VLBW, birth weight ≤ 1500 g) and acutely ill infants with birth weight > 1500 g across 92% of NICUs in California. VLBW infants and those with neurological conditions are referred to a statewide high-risk infant follow-up (HRIF) program. CMV infection was defined as a positive culture or PCR identified during the NICU hospitalization. RESULTS: During 2010-2021, CMV reporting rates averaged 3.5/1000 VLBW infants (n = 205) and 1.1/1000 infants >1500 g (n = 128). Among all 333 infants with CMV, 314 (94%) were discharged home alive, 271 (86%) were referred for HRIF and 205 (65%) had ≥1 visit. Whereas infants born to mothers <20 years of age had highest CMV reporting rates and those born to Hispanic mothers comprised 49% of all infected infants, they had the highest loss of follow-up. At the 12-month visit (n = 152), 19 (13%) infants with CMV had bilateral blindness and 18 (12%) had hearing loss. At the 24-month visit, 5 (5%) of 103 had severe cerebral palsy. CONCLUSIONS: Among infants admitted to the NICU, those with CMV diagnoses may over represent infants with more severe CMV disease and outcomes. The CPQCC and HRIF program findings may help inform implementation of surveillance for congenital CMV infection in other U.S. states and guide strategies to reduce disparities in access to services.

A Cross-Sectional Survey of Pediatric Infectious Disease Physicians' Approach to Congenital Cytomegalovirus Infection.

Congenital cytomegalovirus (cCMV) continues to be a major public health care issue due to its high prevalence throughout the world. However, there is a paucity of studies evaluating how providers manage this infection. This study surveyed North American Pediatric Infectious Disease (PID) physicians to elicit their approach towards the evaluation and treatment of this condition. Thirty-two PID physicians responded to this survey. Institutional testing and screening for cCMV were infrequently reported. The respondents in general agreed upon most laboratory and diagnostic testing except for neuroimaging. For those tests, there was a disparity in indications for head ultrasound versus brain MRI imaging. Most (68.8%) agreed with the clinical practice of starting valganciclovir in an infant less than 1 month of age with one sign or symptom of disease, and 62.5% would do so for an infant with isolated sensorineural hearing loss. However, only 28.1% would treat cCMV-infected infants older than 1 month of age. In conclusion, few healthcare institutions represented by PID physicians in this cohort had a cCMV screening or testing initiative, yet most respondents would test at a much higher level based on their clinical practice. While there is general consensus in evaluation and treatment of these children, there are disparities in practices regarding neuroimaging and indications for antiviral treatment with respect to age and severity of disease. There is a great need for an evidence based policy statement to standardize cCMV workup and treatment.

Inconsistent Provider Testing Practices for Congenital Cytomegalovirus: Missed Diagnoses and Missed Opportunities.

Newborn congenital cytomegalovirus (cCMV) screening programs have been found to increase the rates of early diagnosis and treatment. In North America, newborn cCMV screening programs have not been widely implemented, leaving healthcare providers to rely on clinical suspicion alone to prompt testing. This study sought to examine healthcare providers' cCMV testing practices at a quaternary children's hospital. A retrospective review of the electronic health record was completed for eligible infants over a six-year period. Bivariate calculations and analyses were performed. Between 2014 and 2019, a total of 40,091 infants were cared for at the study institution, of which 178 were tested for cCMV and 10 infants were diagnosed with cCMV. Isolated small-for-gestational age was the most common indication (53/178) to prompt testing. Overall, the cCMV testing rate was 4.5 tests per 1000 infants, with a resulting diagnostic prevalence of 0.2 cases per 1000 infants, which is 15-fold lower than the expected prevalence. Providers relying on clinical suspicion alone are infrequently testing infants for cCMV, resulting in missed diagnoses and missed opportunities for treatment. Systematic cCMV screening practices may improve diagnosis, treatment, and childhood outcomes.