Cranial Ultrasound Findings in Infants with Congenital Cytomegalovirus Infection in a Universal Newborn Screening Study in Minnesota.

BACKGROUND: Congenital cytomegalovirus (cCMV) is the most common infectious cause of neurodevelopmental deficits in US children. To inform patient management, it is important to define whether central nervous system (CNS) manifestations are present at birth. This study characterized neuroimaging findings in infants with cCMV identified by a universal screening study in Minnesota during February 2016 - December 2022. METHODS: Newborns with cCMV infection (confirmed by urine CMV PCR following a positive screening saliva and/or dried blood spot result) underwent diagnostic evaluation, including cranial ultrasound (cUS), laboratory studies, ophthalmological, and audiological evaluation. Neuroimaging findings and cCMV disease classification were interpreted based on international consensus guidelines. RESULTS: Among 87 newborns with confirmed cCMV, 76 underwent cUS. Of these, 53/76 (70%) had normal examinations, while 23/76 (30%) exhibited cUS findings: for 5 infants, these were clearly cCMV disease-defining, while for 18 infants, there were findings of uncertain significance. Magnetic resonance imaging (MRI) results (n=10 infants) aligned with cUS cCMV-disease defining findings in 2 infants, while cCMV-specific abnormalities were noted by MRI in 2 of 6 infants with nondiagnostic/incidental cUS findings. Of 9 infants who had both cUS and MRI examination, the average time interval between studies was 220 days (range, 2 to 1061). Excluding infants with cCMV CNS disease-defining cUS abnormalities, incidental findings were observed more commonly in infants with clinical/laboratory features described in cCMV disease classification guidelines (9/13) than in newborns with completely asymptomatic infections (9/58; p<0.0001). CONCLUSIONS: Among infants with cCMV identified in a universal screening study, the majority had a normal cUS. CNS disease-defining abnormalities were present in 7%, while 24% had findings of uncertain significance. We propose that many cUS findings are incidental, and not diagnostic of symptomatic cCMV infection. Although insufficient to define symptomatic disease, incidental findings were more common in infants with other manifestations of cCMV infection.

Neurobehavioral outcomes of neonatal asymptomatic congenital cytomegalovirus infection at 12-months.

BACKGROUND: Congenital cytomegalovirus (cCMV) is the most common congenital viral infection in the United States. Symptomatic infections can cause severe hearing loss and neurological disability, although ~ 90% of cCMV infections are asymptomatic at birth. Despite its prevalence, the long-term neurobehavioral risks of asymptomatic cCMV infections are not fully understood. The objective of this work was to evaluate for potential long-term neurobehavioral sequelae in infants with asymptomatic cCMV. METHODS: Infants with cCMV were identified from a universal newborn cCMV screening study in a metropolitan area in the midwestern United States. Asymptomatic infants with cCMV were enrolled in a longitudinal neurodevelopmental study (N = 29). Age- and sex-matched healthy control infants (N = 193) were identified from the Baby Connectome Project (BCP), a longitudinal study of brain and behavioral development. The BCP sample supplemented an additional group of healthy control infants (N = 30), recruited from the same participant registry as the BCP specifically for comparison with infants with asymptomatic cCMV. Neurobehavioral assessments and parent questionnaires, including the Mullen Scales of Early Learning, the Repetitive Behavior Scales for Early Childhood (RBS-EC), and the Infant Toddler Social Emotional Assessment (ITSEA) were administered at 12 months of age. Neurobehavioral scores were compared between infants with asymptomatic cCMV and all identified healthy control infants. RESULTS: Infants with asymptomatic cCMV performed equivalently compared to healthy control infants on the neurobehavioral measures tested at 12 months of age. CONCLUSIONS: These results indicate that at 12 months of age, infants with asymptomatic cCMV are not statistically different from controls in a number of neurobehavioral domains. Although follow-up is ongoing, these observations provide reassurance about neurobehavioral outcomes for infants with asymptomatic cCMV and inform the ongoing discussion around universal screening. Additional follow-up will be necessary to understand the longer-term outcomes of these children.

Clinical, Virologic and Immunologic Correlates of Breast Milk Acquired Cytomegalovirus (CMV) Infections in Very Low Birth Weight (VLBW) Infants in a Newborn Intensive Care Unit (NICU) Setting.

Cytomegalovirus (CMV) infections acquired by very-low-birthweight (VLBW) infants are incompletely characterized. To examine CMV transmission in VLBW infants, we evaluated maternal DNAlactia, infant DNAemia, and presence of clinical disease in a blinded study in VLBW infants in our newborn intensive care unit (NICU). To examine these issues, 200 VLBW infants were enrolled in a surveillance study, with weekly breast milk and infant whole blood samples collected, as available. Virologic (breast milk and infant whole blood real time PCR) and immunologic (IgG, IgM, and IgG avidity) correlates were evaluated. A chart review examined whether infants had symptoms compatible with CMV disease. DNAlactia was identified in 65/150 (43%) of lactating mothers. Nine CMV infections were identified in 9/75 CMV-exposed infants (12% of exposed infants). A higher median breast milk viral load (DNAlactia) correlated with an increased likelihood of DNAemia (p = 0.05). Despite potential symptoms compatible with CMV infection, clinicians had not considered the diagnosis of CMV in 6/9 cases (66%). All of these infants had chronic lung disease at discharge. There was no correlation between IgG antibody titer or IgG avidity index and the likelihood of transmission or CMV disease. In conclusion, in VLBW infants receiving milk from seropositive mothers, CMV infections are commonly acquired, and are frequently unrecognized. Future studies are needed to determine whether routine surveillance for CMV of either breast milk or infant plasma is beneficial in preventing or recognizing infection.

Sensitivity of Dried Blood Spot Testing for Detection of Congenital Cytomegalovirus Infection.

Importance: The sensitivity of dried blood spots (DBS) to identify newborns with congenital cytomegalovirus (cCMV) infection has not been evaluated in screening studies using the current, higher-sensitivity methods for DBS processing. Objective: To assess the sensitivity of DBS polymerase chain reaction (PCR) for newborn screening for cCMV infection using saliva as the reference standard for screening, followed by collection of a urine sample for confirmation of congenital infection. Design, Setting, and Participants: This population-based cohort study took place at 5 newborn nurseries and 3 neonatal intensive care units in the Minneapolis/Saint Paul area in Minnesota from April 2016 to June 2019. Newborns enrolled with parental consent were screened for cCMV using DBS obtained for routine newborn screening and saliva collected 1 to 2 days after birth. Dried blood spots were tested for CMV DNA by PCR at both the University of Minnesota (UMN) and the US Centers for Disease Control and Prevention (CDC). Saliva swabs were tested by CMV DNA PCR at the UMN laboratory only. Newborns who screened positive by saliva or DBS had a diagnostic urine sample obtained by primary care professionals, tested by PCR within 3 weeks of birth. Analysis began July 2019. Exposures: Detection of CMV from a saliva swab using a PCR assay. Main Outcomes and Measures: Number of children with urine-confirmed cCMV and the proportion of them who were CMV positive through DBS screening. Results: Of 12 554 individuals enrolled through June 2019 (of 25 000 projected enrollment), 56 newborns were confirmed to have cCMV (4.5 per 1000 [95% CI, 3.3-5.7]). Combined DBS results from either UMN or CDC had a sensitivity of 85.7% (48 of 56; 95% CI, 74.3%-92.6%), specificity of 100.0% (95% CI, 100.0%-100.0%), positive predictive value (PPV) of 98.0% (95% CI, 89.3%-99.6%), and negative predictive value (NPV) of 99.9% (95% CI, 99.9%-100.0%). Dried blood spot results from UMN had a sensitivity of 73.2% (95% CI, 60.4%-83.0%), specificity of 100.0% (100.0%-100.0%), PPV of 100.0% (95% CI, 91.4%-100.0%), and NPV of 99.9% (95% CI, 99.8%-99.9%). Dried blood spot results from CDC had a sensitivity of 76.8% (95% CI, 64.2%-85.9%), specificity of 100.0% (95% CI, 100.0%-100.0%), PPV of 97.7% (95% CI, 88.2%-99.6%), and NPV of 99.9% (95% CI, 99.8%-99.9%). Saliva swab results had a sensitivity of 92.9% (52 of 56; 95% CI, 83.0%-97.2%), specificity of 99.9% (95% CI, 99.9%-100.0%), PPV of 86.7% (95% CI, 75.8%-93.1%), and NPV of 100.0% (95% CI, 99.9%-100.0%). Conclusions and Relevance: This study demonstrates relatively high analytical sensitivity for DBS compared with previous studies that performed population-based screening. As more sensitive DNA extraction and PCR methods continue to emerge, DBS-based testing should remain under investigation as a potential low-cost, high-throughput option for cCMV screening.

Impact of breast milk-acquired cytomegalovirus infection in premature infants: Pathogenesis, prevention, and clinical consequences?

Maternal-fetal transmission of cytomegalovirus (CMV) represents the most common infectious cause of long-term neurodevelopmental disability in children. Congenital CMV (cCMV) infection is associated with microcephaly, seizure disorders, cognitive disability, developmental delay, and sensorineural hearing loss (SNHL). Of these disabilities, SNHL is the most common, affecting approximately 10% of infants with cCMV. Although the sequelae of cCMV are well recognized, it is much less clear what long-term morbidities may occur in neonates that acquire post-natal CMV infection. Post-natal CMV (pCMV) infection is most commonly transmitted by breast-feeding, and in full-term infants is of little consequence. However, in preterm, very-low birthweight (VLBW) infants (<1500 g), pCMV can result in a severe sepsis-like syndrome, with wide-ranging end-organ disease manifestations. Although such short-term complications are well recognized among clinicians caring for premature infants, the long-term risks with respect to adverse neurodevelopmental outcomes remain controversial. In this review, we provide an overview of the clinical manifestations of breast milk-acquired pCMV infection. In particular, we summarize studies that have examined-sometimes with conflicting conclusions-the risks of long-term adverse neurodevelopmental outcome in VLBW infants that acquire pCMV from breast milk. We highlight proposed preventive strategies and antiviral interventions, and offer recommendations for high-priority areas for future basic science and clinical research.

Institutional Factors Associated With Burnout Among Assistant Professors.

Phenomenon: Factors related to individual circumstance and organizational climate are contributing to a worsening burnout problem among providers in healthcare settings. In the academic health center, junior faculty may be at particular risk for burnout given intersecting responsibilities of clinical expertise, research rigor, teaching commitments, and service expectations. To date, much of the focus on preventing and mitigating burnout has been located at the individual level, addressing lifestyle modification and self-regulation skills. We sought to examine relationships between institutional context and burnout qualities as a means to identify opportunities for organizational leadership to address faculty burnout. Approach: Data are from a baseline survey of assistant professors (faculty with diverse ratios for clinical, research, and teaching responsibilities) located within a pediatrics department in an academic medical center. Pearson correlation coefficients and logistic regression models were used to examine relationships between institutional factors (mentorship, collaboration opportunities, feelings of empowerment, value, and support of well-being) and experiences of burnout as measured by the original 22-item Maslach Burnout Inventory (subscales: Emotional Exhaustion, Depersonalization, and Low Personal Accomplishment). Findings: Three perceived institutional characteristics were significantly associated with all three dimensions of burnout, particularly emotional exhaustion, which decreased with increasing perception of (a) empowerment to communicate professional needs, (b) feeling valued for contributions to the department, and (c) department commitment to support faculty well-being. In multivariate logistic regression models, adjusted for gender identity and years since training, increased positive perceptions of these three institutional characteristics were associated with significantly lower odds of burnout. For example, for each unit increase along a 5-point rating scale in feeling empowered to communicate needs and feeling valued for contributions to the department, the odds of meeting cutoff scores for burnout were reduced by 78% (p = .002) to 84% (p = .002), respectively. Insights: Although much of the focus on addressing burnout in healthcare settings has been on promoting coping skills and building resilience at the individual level, our findings add to a growing literature documenting a significant role for institutional leadership in identifying and facilitating strategies to promote faculty well-being. Findings also support leadership's role for improving institutional climate via creating opportunities to increase faculty perceptions of empowerment and value in the department.

Lasting Legacy: Maternal Perspectives of Perinatal Palliative Care.

BACKGROUND: Many of the leading causes of infant mortality are diagnosed prenatally, presenting providers with the ability to present perinatal palliative care planning as an option. OBJECTIVE: Our study adds to the literature both by describing infant interaction with the health care system and by gaining deeper understanding of the maternal experience after being offered perinatal palliative care. METHODS: The study was conducted at a public university-based medical center in the Midwest. Phase 1 consisted of a retrospective review of electronic medical records of 27 mother-infant pairs offered perinatal palliative care, 18 of whom elected to develop a perinatal palliative care. Phase 2 consisted of a focus group and interviews of seven of the mothers. RESULTS: In the initial phase of this study, results revealed differences regarding the infant's end-of-life trajectory, including location of death, number of invasive procedures, and death in the setting of withholding versus withdrawing life-sustaining treatment. Highlighting that without a perinatal palliative care plan in place, the default treatment for infants with prenatally diagnosed life-limiting conditions is likely to be invasive and painful with often times minimal likelihood of long-term survival. Analysis of interview and focus group data revealed three themes: care, choice, and legacy. CONCLUSION: The authors used their experience with the health care system to draw implications for practice from the focus group and interview data, which care can serve to promote women feeling cared for and cared about, as well as promote opportunities for hope during a fragile pregnancy.

Management of giant omphaloceles: A systematic review of methods of staged surgical vs. nonoperative delayed closure.

PURPOSE: Despite the numerous methods of closure for giant omphaloceles, uncertainty persists regarding the most effective option. Our purpose was to review the literature to clarify the current methods being used and to determine superiority of either staged surgical procedures or nonoperative delayed closure in order to recommend a standard of care for the management of the giant omphalocele. METHODS: Our initial database search resulted in 378 articles. After de-duplification and review, we requested 32 articles relevant to our topic that partially met our inclusion criteria. We found that 14 articles met our criteria; these 14 studies were included in our analysis. 10 studies met the inclusion criteria for nonoperative delayed closure, and 4 studies met the inclusion criteria for staged surgical management. RESULTS: Numerous methods for managing giant omphaloceles have been described. Many studies use topical therapy secondarily to failed surgical management. Primary nonoperative delayed management had a cumulative mortality of 21.8% vs. 23.4% in the staged surgical group. Time to initiation of full enteric feedings was lower in the nonoperative delayed group at 14.6days vs 23.5days. CONCLUSION: Despite advances in medical and surgical therapies, giant omphaloceles are still associated with a high mortality rate and numerous morbidities. In our analysis, we found that nonoperative delayed management with silver therapy was associated with lower mortality and shorter duration to full enteric feeding. We recommend that nonoperative delayed management be utilized as the primary therapy for the newborn with a giant omphalocele.

Research review: maternal prenatal distress and poor nutrition - mutually influencing risk factors affecting infant neurocognitive development.

BACKGROUND: Accumulating data from animal and human studies indicate that the prenatal environment plays a significant role in shaping children's neurocognitive development. Clinical, epidemiologic, and basic science research suggests that two experiences relatively common in pregnancy - an unhealthy maternal diet and psychosocial distress - significantly affect children's future neurodevelopment. These prenatal experiences exert their influence in the context of one another and yet, almost uniformly, are studied independently. SCOPE AND METHOD OF REVIEW: In this review, we suggest that studying neurocognitive development in children in relation to both prenatal exposures is ecologically most relevant, and methodologically most sound. To support this approach, we selectively review two research topics that demonstrate the need for dual exposure studies, including exemplar findings on (a) the associations between pregnant women's inadequate maternal intake of key nutrients - protein, fat, iron, zinc, and choline - as well as distress in relation to overlapping effects on children's neurocognitive development; and (b) cross-talk between the biology of stress and nutrition that can amplify each experience for the mother and fetus,. We also consider obstacles to this kind of study design, such as questions of statistical methods for 'disentangling' the exposure effects, and aim to provide some answers. CONCLUSION: Studies that specifically include both exposures in their design can begin to determine the relative and/or synergistic impact of these prenatal experiences on developmental trajectories - and thereby contribute most fully to the understanding of the early origins of health and disease.

Alterations in stress responses of the hypothalamic-pituitary-adrenal axis in small for gestational age infants.

Mounting epidemiologic evidence and animal models suggest that stressful conditions during the intrauterine period may increase susceptibility to several adult conditions, including metabolic syndrome, cardiovascular disease, and psychiatric disorders. Increased cortisol levels due to alterations in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis are believed to be one mediating mechanism. Infants born after significant exposure to stressful conditions are often small for gestational age (SGA) based on standardized growth norms. Lifelong programming of the HPA axis has been proposed as a mechanism to explain the association between SGA infants and adult disease. However, few studies have measured HPA axis function proximal to birth as done in this study of SGA infants during the first week of life. Participants included 37 infants in two groups based on birth size (gestational age range: 34-41weeks). SGA infants were <10th percentile for age (n=21) and appropriate for gestational age (AGA) infants (n=16) were from 20 to 90th percentile for age. Cortisol response to a heel lance for blood collection was measured for all infants. Hierarchical Linear Modeling was used to test the effect of AGA/SGA group status on cortisol trajectories in response to the stressor. Group was a significant predictor of quadratic slopes (t=2.84, χ(2)=8.19, p=.004) after controlling for the effect of group on intercepts and linear slopes. Predicted growth curves for ln-cortisol were plotted for each group based on regression coefficients. The predicted curves capture the significant group difference in trajectories, as well as the blunted response for the SGA group and the robust peak in cortisol production in response to the stressor for the AGA group. This evidence suggests SGA neonates have blunted HPA axis responses to stressors in comparison to AGA infants. These findings are consistent with animal models showing that adverse intrauterine conditions can result in blunted cortisol responses to acute stressors and may provide a mechanism for adult susceptibility to disease for individuals that are SGA at birth.