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.

Congenital Cytomegalovirus Testing Outcomes From the ValEAR Trial.

OBJECTIVE: To determine the positivity rate of congenital cytomegalovirus (cCMV) testing among universal, hearing-targeted CMV testing (HT-cCMV) and delayed targeted dried blood spot (DBS) testing newborn screening programs, and to examine the characteristics of successful HT-cCMV testing programs. STUDY DESIGN: Prospective survey of birth hospitals performing early CMV testing. SETTING: Multiple institutions. METHODS: Birth hospitals participating in the National Institutes of Health ValEAR clinical trial were surveyed to determine the rates of cCMV positivity associated with 3 different testing approaches: universal testing, HT-cCMV, and DBS testing. A mixed methods model was created to determine associations between successful HT-cCMV screening and specific screening protocols. RESULTS: Eighty-two birth hospitals were surveyed from February 2019 to December 2021. Seven thousand six hundred seventy infants underwent universal screening, 9017 infants HT-cCMV and 535 infants delayed DBS testing. The rates of cCMV positivity were 0.5%, 1.5%, and 7.3%, respectively. The positivity rate for universal CMV screening was less during the COVID-19 pandemic than that reported prior to the pandemic. There were no statistically significant drops in positivity for any approach during the pandemic. For HT-cCMV testing, unique order sets and rigorous posttesting protocols were associated with successful screening programs. CONCLUSION: Rates of cCMV positivity differed among the 3 approaches. The rates are comparable to cohort studies reported in the literature. Universal CMV prevalence decreased during the pandemic but not significantly. Institutions with specific order set for CMV testing where the primary care physician orders the test and the nurse facilitates the testing process exhibited higher rates of HT-cCMV testing.

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.

Emerging Concepts in Congenital Cytomegalovirus.

Over a century of research has focused on improving our understanding of congenital cytomegalovirus (cCMV), yet it remains the most common congenital infection in the United States, affecting 3 to 6 per 1000 live born infants each year. Pregnancies affected by cCMV are at a heightened risk of spontaneous abortion and intrauterine fetal demise. Neonates born with cCMV are also at substantial risk for long-term neurodevelopmental sequelae and disability, including sensorineural hearing loss, even those born without clinically apparent disease. Considerable progress has been made in recent years in study of the epidemiology and transmission of cCMV, developing better diagnostic strategies, implementing newborn screening programs, improving therapeutics, and launching vaccine trials. In this article, we review recent developments in the understanding of the virology and immunobiology of cytomegalovirus. We further discuss how this knowledge informs our understanding of the pathophysiology of cCMV and directs strategies aimed at improving outcomes and quality of life for congenitally infected children. We also provide an update on the epidemiology of cCMV in the United States, evolving scientific understanding of maternal-fetal transmission, enhanced screening approaches, and recognition of neonatal and long-term sequelae. Finally, we review the current landscape of pediatric cCMV research and provide recommendations for novel and high-priority areas for future investigation.

Congenital Cytomegalovirus Knowledge, Practices, and Beliefs Among Primary Care Physicians and Newborn Hospitalists.

BACKGROUND: Congenital cytomegalovirus (cCMV) affects 1 in every 200 United States infants, at present there are 9 states which mandate newborn cCMV screening. With more infants being diagnosed, more children will need continuing care from providers who are knowledgeable about cCMV. OBJECTIVES: To examine pediatric provider knowledge, practices, and beliefs around cCMV. METHODS: Primary care and newborn hospitalist pediatricians (N = 103) from Michigan, who "regularly care for infants" were invited to participate in a survey about their cCMV-related knowledge, clinical practices, and beliefs. RESULTS: Respondents had low knowledge of typical cCMV presentation and sequelae, with mixed knowledge of screening and testing standards. Most (68%) reported rarely/never screening for cCMV, though 71% strongly agreed/agreed that primary care providers should test for cCMV. Most (90%) strongly agreed/agreed that infants who fail/refer on their newborn hearing screen should be tested for cCMV, yet 81% expressed not being comfortable diagnosing and managing cCMV. Most (72%) felt that cCMV was not sufficiently covered in their medical training; almost all respondents endorsed interest in learning more. CONCLUSIONS: Primary care and newborn hospitalists in this study expressed mixed knowledge about, infrequent practice of and low comfort with screening and caring for children with cCMV. This may present a prime opportunity for education and clinician support by professional organizations.

An Ethical Analysis of Newborn Congenital Cytomegalovirus Screening.

Congenital cytomegalovirus (cCMV) affects approximately 1 in every 200 US infants and can be associated with long-term neurodevelopmental sequelae, including sensorineural hearing loss, cerebral palsy, and intellectual disability. As cCMV is infrequently diagnosed based on clinical suspicion alone, newborn cCMV screening programs have been gaining traction, especially hearing-targeted programs which only test infants who fail their newborn hearing screen. cCMV screening programs raise unique ethical dilemmas of both under- and over-diagnosis of cCMV. In this Ethics Rounds, we present a case in which the parents of a child with symptomatic cCMV that was not recognized until 4 years of age urge the birth hospital to implement a cCMV screening program. We then ask a parent-clinician, a medical ethicist and pediatrician, and a primary care pediatrician to comment on how they would advise the hospital administration and consider the ethical and clinical implications of a cCMV screening program. The commentaries herein arrive at differing conclusions about cCMV screening. The first highlights the developmental advantages of early cCMV detection, supporting a broad approach to treatment beyond antiviral medication alone. The second explores cCMV screening from the perspective of newborn screening as a public health program, noting shortcomings in available testing platforms, and raising concerns about overdiagnosis and overtreatment. The final commentary challenges the risks of undue parental anxiety and vulnerable child syndrome as a barrier to screening, instead considering cCMV screening as a controlled opportunity to understand and support the experiences of affected children and their families.

Changes in Valganciclovir Use Among Infants with Congenital Cytomegalovirus Diagnosis in the United States, 2009-2015 and 2016-2019.

From 2009-2015 to 2016-2019, the proportion of infants in the US with congenital cytomegalovirus treated with valganciclovir roughly doubled for infants enrolled with employer-sponsored insurance (from 16% to 29%) and Medicaid (from 16% to 36%). The proportion treated with valganciclovir increased for all congenital cytomegalovirus disease severity groups.

Emerging Ideas Brief Report. How Do Low-Income Mothers Talk to Children About Weight and Body Shape?

OBJECTIVE: Identify mothers' perceptions of how they talk about weight and body shape with their children and examine how approaches vary by mother and child characteristics. BACKGROUND: Youth who report that their parents talk with them about their weight experience poor health. However, very little is known about the content of these conversations. METHOD: Mothers and their 6- to 11-year-old children (N = 188 dyads) participated in a mixed-methods study. Themes in mothers' responses to the interview question "How do you talk to your child about weight or body shape?" were identified, and latent class analysis was used to characterize patterns of weight and shape talk. RESULTS: Seven themes of weight and shape talk were identified, including talking about "Healthy Habits" (39.9%), "Avoids Weight and Body Talk" (21.8%), and tells "Cautionary Tales" (18.6%). Three patterns emerged from themes: talk to promote health, avoid talking about weight and shape, and talk to build children's self-esteem. Mothers of children with obesity were more likely to talk to promote health versus other patterns. CONCLUSION: The content of family conversations about weight and shape is diverse. IMPLICATIONS FOR EMERGING IDEAS: Future research is needed to understand the impacts of specific ways parents talk about weight and shape.

Cytomegalovirus Infection in Pregnancy: Prevention, Presentation, Management and Neonatal Outcomes.

Congenital cytomegalovirus (cCMV) is the most common congenital infection in the United States, with 1 of 200 live births affected. It is the leading viral cause of intrauterine fetal demise and miscarriage. It is a common cause of neonatal hearing loss, second only to genetic factors. Yet, health care provider awareness remains low. The purpose of this article is to provide a brief overview of the epidemiology, presentation, diagnosis, and treatment of antenatal cytomegalovirus (CMV) infection and cCMV in the neonate. Maternal CMV infection in pregnancy often presents with mild cold-like symptoms or is asymptomatic. The virus can be vertically transmitted to a growing fetus, the risk of transmission and severity of fetal impact varying by timing of exposure during pregnancy. Most neonates born with cCMV show no signs at birth, yet 15% to 25% will have long-term adverse neurodevelopmental conditions. Misconceptions that cCMV cannot be prevented or that neonates born without signs of the disease will be unaffected are common. Evidence supporting antenatal education around behavioral change to lower a woman's risk of acquiring CMV during pregnancy is mounting. CMV infection during pregnancy should be co-managed with a maternal-fetal medicine specialist. There is early evidence for the use of antiviral medication in reducing risk of vertical transmission. Identification of cCMV during pregnancy may help ensure the neonate receives timely treatment after birth. Midwives can play an important role in providing antenatal education about cCMV risk reduction and in initiating a diagnostic evaluation when there is clinical suspicion.

Pediatrician's Beliefs and Practices Around Rapid Infant Weight Gain: A Qualitative Study.

Rapid infant weight gain is a risk factor for later obesity. The objective of this study was to examine primary care pediatricians' beliefs and practices around rapid infant weight gain. Primary care pediatricians (N = 16) participated in a semi-structured interview about infant growth. Interviews were transcribed, analyzed for themes using the grounded theory and the constant comparative method then reliably coded for the presence of each theme. Three themes were identified, pediatricians (1) are uncertain about the concept, definition, and implications of excessive or rapid infant weight gain (N = 16, 100%), (2) are more comfortable with management of inadequate versus excessive or rapid weight gain (N = 10, 62.5%), and (3) perceive the primary cause of excessive or rapid infant weight gain to be overfeeding (N = 10, 62.5%). In conclusion, pediatricians are uncertain about the concept, definition, management, and long-term risks of rapid infant weight gain. Interventions to increase awareness and pediatrician sense of competence in management of rapid infant weight gain are needed.

Improving Obstetric Provider Congenital Cytomegalovirus Knowledge and Practices.

Background: Congenital cytomegalovirus infection (cCMV) is the most common congenital infection. Antenatal education is proven to reduce cCMV risk. Little is known about obstetric provider knowledge and practice patterns around cCMV. Objectives: To evaluate obstetric provider knowledge and practice patterns regarding cCMV at baseline and again after a brief educational intervention. Methods: Obstetric providers (N = 53) at a US academic community hospital were invited to complete a survey regarding their knowledge and practice patterns around cCMV. Providers attended a brief presentation about cCMV and later were invited to repeat the same survey. Univariate statistics were calculated for baseline data, and prepost intervention comparison analyses were conducted. Results: Baseline cCMV knowledge was low at 49% (M = 17.54 out of a possible 36, SD 6.4), with most providers (51%) reporting never counseling pregnant patients about cCMV. Post intervention, overall cCMV knowledge increased to 80% (M = 29.33, SD 4.1, p < .001); provider intention to counsel about cCMV prevention increased to 100%. Conclusions: Obstetric provider knowledge about cCMV is low, which likely impacts their antenatal counseling. Educational initiatives to increase awareness about cCMV may increase antenatal education and thereby decrease the risk of cCMV.